Journal articles: 'Persisting primary reflexes' – Grafiati (2024)

Abstract:

Purpose Developmental language disorder (DLD) is a developmental disorder where children fail to acquire language in the absence of a clear cause. Many studies have reported general motor deficits in children with DLD, but no studies have uncovered a cure. The purpose of our study is to better understand the underlying motor deficits in DLD, starting from uninhibited primary reflexes—which are the most basic stage of motor development. Knowledge of this motor–language relationship should lead to earlier and more targeted interventions in young children with DLD. Method Children with DLD ( n = 75, age range: 4–10 years) and 99 age-matched typically developing (TD) children completed a nonword repetition test to assess DLD and six other tests to assess primitive reflexes. Results Children with DLD demonstrated higher levels of persistent primitive reflexes compared to TD children. As the scores for neuromotor immaturity increased, nonword repetition test scores decreased ( r = −.44, p < .01). Results indicated that TD children exhibited lower neuromotor immaturity ( M = 7.63, SD = 3.75) compared to children with DLD ( M = 13.51, SD = 4.47). All primitive reflexes (the Moro reflex, the symmetrical tonic neck reflex in flexion and in extension, the asymmetrical tonic neck reflex, the tonic labyrinthine reflex, and the Galant reflex) turned out to be statistically significantly different for the TD and DLD groups ( p < .001). We also observed some differences between sexes. Conclusions Children with impaired language development underwent slower neuromotor development. However, further research is needed to determine whether motor intervention programs that inhibit primitive reflexes are helpful for children with DLD.

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ABSTRACT The lengthy chemotherapy of tuberculosis reflects the ability of a small subpopulation of Mycobacterium tuberculosis bacteria to persist in infected individuals. To date, the exact location of these persisting bacteria is not known. Lung lesions in guinea pigs infected with M. tuberculosis have striking similarities, such as necrosis, mineralization, and hypoxia, to natural infections in humans. Guinea pigs develop necrotic primary lesions after aerosol infection that differ in their morphology compared to secondary lesions resulting from hematogenous dissemination. In infected guinea pigs conventional therapy for tuberculosis during 6 weeks reduced the bacterial load by 1.7 logs in the lungs and, although this completely reversed lung inflammation associated with secondary lesions, the primary granulomas remained largely unaffected. Treatment of animals with the experimental drug R207910 (TMC207) for 6 weeks was highly effective with almost complete eradication of the bacteria throughout both the primary and the secondary lesions. Most importantly, the few remnants of acid-fast bacilli remaining after R207910 treatment were to be found extracellular, in a microenvironment of residual primary lesion necrosis with incomplete dystrophic calcification. This zone of the primary granuloma is hypoxic and is morphologically similar to what has been described for human lung lesions. These results show that this acellular rim may, therefore, be a primary location of persisting bacilli withstanding drug treatment.

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The study of primate memory substrates, the CNS alterations which preserve conditioned responses, requires an experimental model that fulfills two criteria. First, the essential alterations must be in a technically accessible location. Second, they must persist without input from other CNS regions. The spinal cord is the most technically accessible and readily isolated portion of the primate CNS. Recent work has demonstrated that the spinal stretch reflex (SSR), the initial, wholly segmental response to muscle stretch, can be operantly conditioned and suggests that this conditioning may produce persistent spinal alteration. The present study attempted similar operant conditioning of the H-reflex, the electrical analog of the SSR. The primary goals were to demonstrate that spinal reflex conditioning can occur even if the muscle spindle is removed from the reflex arc and to demonstrate conditioning in the lumbosacral cord, which is far preferable to the cervical cord for future studies of neuronal and synaptic mechanisms. Nine monkeys prepared with chronic fine-wire triceps surae (gastrocnemius and soleus) electromyographic (EMG) electrodes were taught by computer to maintain a given level of background EMG activity. At random times, a voltage pulse just above M response (direct muscle response) threshold was delivered to the posterior tibial nerve via a chronically implanted silicon nerve cuff and elicited the triceps surae H-reflex. Under the control mode, reward always followed. Under the HR increases or HR decreases mode, reward followed only if the absolute value of triceps surae EMG from 12 to 22 ms after the pulse (the H-reflex interval) was above (HR increases) or below (HR decreases) a set value. Monkeys completed 3,000-6,000 trials/day over study periods of 2-3 mo. Background EMG and M response amplitude remained stable throughout data collection. H-reflex amplitude remained stable under the control mode. Under the HR increases mode (5 animals) or HR decreases mode (4 animals), H-reflex amplitude (EMG amplitude in the H-reflex interval minus background EMG amplitude) changed appropriately over at least 6 wk. Change appeared to occur in two phases: an abrupt change within the first day, followed by slower change, which continued indefinitely. Change occurred in all three triceps surae muscles (medial and lateral gastrocnemii and soleus). Under the HR increases mode, H-reflex amplitude rose to an average of 213% of control, whereas under the HR decreases mode it fell to an average of 68% of control. The results demonstrate that the H-reflex can be operantly conditioned.(ABSTRACT TRUNCATED AT 400 WORDS)

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Background The roles of descending facilitatory pathway from the rostral medial medulla (RMM) in development of persistent spontaneous nociception and hyperalgesia were evaluated in the bee venom (BV) test and the formalin test. Methods Bilateral lesions of the RMM with ibotenic acid, a soma-selective neurotoxin, were performed to study their effects on the spontaneous pain-related behaviors and hyperalgesia, which were determined by counting the number of flinching reflex per 5 min (1 h) and by measuring paw withdrawal thermal latency (PWTL) and mechanical threshold (PWMT) to radiant heat and von-Frey filaments to both hind paws in conscious rats, respectively. Results 1) Bilateral lesions of the RMM produced a similarly significant inhibition of persistent spontaneous flinching reflexes in the BV test and the formalin test; however, the inhibitory effect occurred in the late 50 min (11-60 min), but not the first 10 min (0-10 min) following intraplantar injection of either BV or formalin. 2) Bilateral lesions of the RMM prevented the development of the BV-induced referred mirror heat hyperalgesia occurred in the noninjected paw, but had no effect on the primary heat and mechanical hyperalgesia occurred in the injected paw. Conclusions The present results provide a new line of behavioral evidence that tonic activation of descending facilitatory pathway contributes to the establishment of 1) the BV and formalin-induced persistent spontaneous nociception; and 2) the BV-induced referred mirror heat hyperalgesia and the central sensitization, but not the primary heat and mechanical hyperalgesia.

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Anal cancer is an uncommon malignancy, with the majority of cases comprised of squamous cell carcinomas. The increasing incidence of this disease reflects a rise in the transmission of the human papillomavirus, the causative organism of most tumours. Abdominoperineal resection (APR), once the primary mode of treatment, has been supplanted by sphincter-saving combination chemoradiation as the first-line therapy. However, surgeons continue to play a role in the multidisciplinary management of patients with anal cancer for diagnosis and post-treatment surveillance. Sentinel node biopsy may identify patients with clinically and radiographically negative inguinal lymph nodes who will benefit from groin irradiation. In very select cases, the controversial means of local excision has been employed as primary treatment, often in conjunction with radiation and chemotherapy. The management of persistent or recurrent anal cancers following primary chemoradiation remains a concern, for which only salvage APR currently offers the possibility of a cure. The introduction of human papillomavirus vaccines presents the exciting potential for the eradication of the disease.

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Anal cancer is an uncommon malignancy, with the majority of cases comprised of squamous cell carcinomas. The increasing incidence of this disease reflects a rise in the transmission of the human papillomavirus, the causative organism of most tumours. Abdominoperineal resection (APR), once the primary mode of treatment, has been supplanted by sphincter-saving combination chemoradiation as the first-line therapy. However, surgeons continue to play a role in the multidisciplinary management of patients with anal cancer for diagnosis and post-treatment surveillance. Sentinel node biopsy may identify patients with clinically and radiographically negative inguinal lymph nodes who will benefit from groin irradiation. In very select cases, the controversial means of local excision has been employed as primary treatment, often in conjunction with radiation and chemotherapy. The management of persistent or recurrent anal cancers following primary chemoradiation remains a concern, for which only salvage APR currently offers the possibility of a cure. The introduction of human papillomavirus vaccines presents the exciting potential for the eradication of the disease.

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Purpose: To assess the incidence and predictors of severe, persistent postprocedural hypotension (PPH) after carotid artery stenting (CAS). Materials and Methods: A total of 146 patients (mean age 72.8 years; 104 men) who underwent 160 CAS procedures using a standardized protocol at 3 vascular centers were retrospectively analyzed. The primary endpoint was postprocedural hypotension, defined as a reduction in systolic blood pressure (SBP) >40 mm Hg from baseline or an SBP of <90 mm Hg sustained for >1 hour after CAS. Potential prognostic factors for postprocedural hypotension were identified and subjected to logistic regression analyses; outcomes are presented as the odds ratios (ORs) with 95% confidence intervals (CIs). Results: PPH developed in 36 (24.7%) patients after 37 (23.1%) CAS procedures. These patients had significantly longer intensive care unit and hospital stays than those who did not develop hypotension (p<0.001). PPH was associated with severe lesion calcification (OR 6.28, 95% CI 1.81 to 21.98, p=0.004) and contrast volume (OR 1.02, 95% CI 1.01 to 1.02, p<0.001). A 4-fold increase in the risk of PPH (OR 4.22, 95% CI 1.38 to 13.33, p=0.012) was found between the embolic protection device most associated with PPH (Angioguard) and the device least associated with PPH (Emboshield NAV6). A similar trend was also observed for the Precise vs Xact stents (OR 6, 95% CI 2.08 to 17.6, p=0.001). Bootstrapped multivariable modeling identified the Precise stent and contrast volume as significant predictors of persistent postprocedural hypotension. Further investigation of the contrast volume revealed associations with sex, severe calcification, arch type, previous coronary artery bypass surgery, and primary stenting, suggesting that the contrast volume reflects the complexity of the procedure. Conclusion: The complexity of the procedure and type of stent may play a role in the development of postprocedural hypotension after CAS.

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Objective. Acute thyrotoxic bulbar palsy is rare, severe, and rapidly progressive. We describe a case of thyrotoxicosis with bulbar palsy, encephalopathy, and pyramidal tract dysfunction.Case Report. 64-year-old white male with toxic multinodular goiter presented with rapid atrial fibrillation. He had mild tremor, normal cranial nerve examination, 4/5 strength in all extremities, normal reflexes, and down going plantars. TSH was low at 0.09 (normal: 0.34–5.6 uIU/mL), and free T4 was high at 5.22 (normal: 0.47–1.41 ng/dL). Despite optimal AV nodal blockade, he had persistent rapid atrial fibrillation. He later developed cervical dystonia, rigidity, clonus, dysarthria, dysphagia, vocal cord palsy, and absent gag reflex. Thyroid storm was suspected. Neuroimaging and cerebrospinal fluid cultures were nondiagnostic. Acetylcholine receptor antibodies were negative. Swallow ability was impaired with heavy secretions. Remarkable improvement in symptoms was noted after initiation of treatment for thyroid storm.Conclusion. Pyramidal tract symptoms and bulbar palsy may occur with thyrotoxicosis. Cranial nerve involvement and encephalopathy raise a question of primary brain mechanism causing bulbar palsy. This is reversible with prompt treatment of thyroid storm.

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Abstract. The effect of treatment with estradiol valerate (6 days, 2-6 mg/day) on basal levels of LH and FSH and on response of LH and FSH levels to GnRH challenge (2 × 25 μg GnRH, iv) were investigated in women with "hypothalamic amenorrhea", but without other endocrine disorders. Three groups were studied: 11 women with primary amenorrhea, 10 women exhibiting secondary amenorrhea related with weight loss, and 7 women with normal weight and with amenorrhea persisting after a period of severe weight loss. Before treatment with estradiol valerate the estradiol concentrations in all women were at the lower limit of the follicular phase of a normal ovulatory cycle. In addition, there were no differences between the groups in basal LH and FSH levels and in responses to GnRH challenges. Treatment with estradiol valerate suppressed the basal levels of FSH but not of LH in all women. Estradiol did not affect the response to GnRH challenge in women with primary amenorrhea, weakly augmented the response in women with secondary amenorrhea associated with weight loss, and strongly increased the response in secondary amenorrheic women who had regained normal weight. The results are interpreted in the light of the well-established fact that estrogen augments the gonadotropin response only if the pituitary gland is not exposed to high concentrations of GnRH. It is hypothesized that the differential response to GnRH of the present patients after estrogen treatment reflects differences in GnRH exposure of the pituitary gland, with patients with primary amenorrhea having the highest level of GnRH exposure.

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In animals, the recovery of motoneuron excitability in the months following a complete spinal cord injury is mediated, in part, by increases in constitutive serotonin (5-HT2) and norepinephrine (α1) receptor activity, which facilitates the reactivation of calcium-mediated persistent inward currents (CaPICs) without the ligands serotonin and norepinephrine below the injury. In this study we sought evidence for a similar role of constitutive monoamine receptor activity in the development of spasticity in human spinal cord injury. In chronically injured participants with partially preserved sensory and motor function, the serotonin reuptake inhibitor citalopram facilitated long-lasting reflex responses (spasms) previously shown to be mediated by CaPICs, suggesting that in incomplete spinal cord injury, functional descending sources of monoamines are present to activate monoamine receptors below the lesion. However, in participants with motor or motor/sensory complete injuries, the inverse agonist cyproheptadine, which blocks both ligand and constitutive 5-HT2/α1 receptor activity, decreased long-lasting reflexes, whereas the neutral antagonist chlorpromazine, which only blocks ligand activation of these receptors, had no effect. When tested in noninjured control participants having functional descending sources of monoamines, chlorpromazine was effective in reducing CaPIC-mediated motor unit activity. On the basis of these combined results, it appears that in severe spinal cord injury, facilitation of persistent inward currents and muscle spasms is mainly mediated by the activation of constitutive 5-HT2 and α1 receptor activity. Drugs that more selectively block these constitutively active monoamine receptors may provide better oral control of spasticity, especially in motor complete spinal cord injury where reducing motoneuron excitability is the primary goal.

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Activation of receptors by serotonin (5-HT1) and norepinephrine (α2) on primary afferent terminals and excitatory interneurons reduces transmission in spinal sensory pathways. Loss or reduction of descending sources of serotonin and norepinephrine after spinal cord injury (SCI) and the subsequent reduction of 5-HT1/α2 receptor activity contributes, in part, to the emergence of excessive motoneuron activation from sensory afferent pathways and the uncontrolled triggering of persistent inward currents that depolarize motoneurons during muscle spasms. We tested in a double-blind, placebo-controlled study whether facilitating 5-HT1B/D receptors with the agonist zolmitriptan reduces the sensory activation of motoneurons during an H-reflex in both noninjured control and spinal cord-injured participants. In both groups zolmitriptan, but not placebo, reduced the size of the maximum soleus H-reflex with a peak decrease to 59% (noninjured) and 62% (SCI) of predrug values. In SCI participants we also examined the effects of zolmitriptan on the cutaneomuscular reflex evoked in tibialis anterior from stimulation to the medial arch of the foot. Zolmitriptan, but not placebo, reduced the long-latency, polysynaptic component of the cutaneomuscular reflex (first 200 ms of reflex) by ∼50%. This ultimately reduced the triggering of the long-lasting component of the reflex (500 ms poststimulation to end of reflex) known to be mediated by persistent inward currents in the motoneuron. These results demonstrate that facilitation of 5-HT1B/D receptors reduces sensory transmission in both monosynaptic and polysynaptic reflex pathways to ultimately reduce long-lasting reflexes (spasms) after SCI.

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Abstract. PCBs are ubiquitous environmental pollutants expected to decline in abiotic environmental media in response to decreasing primary emissions since the 1970s. A coupled atmosphere-ocean general circulation model with embedded dynamic sub-models for atmospheric aerosols and the marine biogeochemistry and air-surface exchange processes with soils, vegetation and the cryosphere is used to study the transport and fate of four PCB congeners covering a range of 3–7 chlorine atoms. The change of the geographic distribution of the PCB mixture reflects the sources and sinks' evolvement over time. Globally, secondary emissions (re-volatilisation from surfaces) are on the long term increasingly gaining importance over primary emissions. They are most important for congeners of medium hydrophobicity (5–6 chlorine atoms). Their levels are predicted to decrease slowest. Congeners' fractionation is characterized both geographically and temporally. It causes enrichment of the lighter, less persistent congeners and more delayed decreasing levels in high latitudes in response to decreasing emissions. Delivery of contaminants to high latitudes is predicted to be more efficient than previously suggested. The results suggest furthermore that the effectiveness of emission control measures may significantly vary among substances: trends of decline in abiotic environmental media do not only vary with latitude (slow in high latitudes), but do also show longitudinal gradients

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ABSTRACTUrogenitalChlamydiaserovars replicating in reproductive epithelium pose a unique challenge to host immunity and vaccine development. Previous studies have shown that CD4 T cells are necessary and sufficient to clear primaryChlamydia muridarumgenital tract infections in the mouse model, making a protective CD4 T cell response a logical endpoint for vaccine development. Our previous proteomics studies identified 13 candidateChlamydiaproteins for subunit vaccines. Of those, PmpG-1 is the most promising vaccine candidate. To further that work, we derived a PmpG303-311-specific multifunctional Th1 T cell clone, designated PmpG1.1, from an immune C57BL/6 mouse and used it to investigate the presentation of the PmpG303-311epitope by infected epithelial cells. Epithelial presentation of the PmpG303-311epitope required bacterial replication, occurred 15 to 18 h postinfection, and was unaffected by gamma interferon (IFN-γ) pretreatment. Unlike epitopes recognized by otherChlamydia-specific CD4 T cell clones, the PmpG303-311epitope persisted on splenic antigen-presenting cells (APC) of mice that cleared primary genital tract infections. PmpG1.1 was activated by unmanipulated irradiated splenocytes from immune mice without addition of exogenousChlamydiaantigen, and remarkably, activation of PmpG1.1 by unmanipulated immune splenocytes was stronger 6 months postinfection than it was 3 weeks postinfection. Enhanced presentation of PmpG303-311epitope on splenic APC 6 months postinfection reflects some type of “consolidation” of a protective immune response. Understanding the antigen-presenting cell populations responsible for presenting PmpG303-311early (3 weeks) and late (6 months) postinfection will likely provide important insights into stable protective immunity againstChlamydiainfections of the genital tract.

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At present there is no consensus on defining “Recovery” in schizophrenia,while there is an accepted definition of “Remission”. Remission model considers “stability” the treatment primary goal and, once achieved, focus is on mainteining stability and preventing relapse. This model reflects a condition where are absent prominent symptoms but may be present some mild symptoms of schizophrenia, retaining not realistic absence of any symptoms. It would require treating an acute psychotic episode,then there still may be a range of no detectable or persistent and disabling symptoms:remission and level of functioning are related but not the same. Some patients could have good level of functioning despite persistent symptoms and others could meet remission criteria despite considerable impairments. Remission is an obteinable outcome for many psychotic outpatients:the point of departure between manteinance and recovery-oriented model happens only after “stability” is achieved;no one could recover in face of repeated crisis,hospitalisation or unrelenting psychotic symptoms. Unfortunately two causes have resulted in a relative neglect of the concept of recovery from psychotic illness:the divide between mainstream biologically oriented psychiatry and the psychiatric rehabilitation movement;the misunderstanding fact that term “recovery movement” is sometimes construed as anti-medication or anti-psychiatry orientation. Irrefuteble point is that recovery model not rejects the importance of remission:stability and relapse prevention. The recovery model besides asserts that achieving remission is the beginning and not the end of treatment plan:then there will be continued efforts to work with patient,family,caregiver,to continue to achieve further improvements in life goals. The “Recovery” patient-centred model have to be embraced as prymary goal by mainstream organizations and services in Mental Health.

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Nociceptive pain alerts the body to potential or actual tissue damage. By contrast, neuropathic or "noninflammatory" pain, which results from injury to the nervous system, serves no useful purpose. It typically continues for years after the original injury has healed. Sciatic nerve lesions can invoke chronic neuropathic pain that is accompanied by persistent, spontaneous activity in primary afferent fibers. This activity, which reflects changes in the properties and functional expression of Na+, K+, and Ca2+ channels, initiates a further increase in the excitability of second-order sensory neurons in the dorsal horn. This change persists for many weeks. The source of origin of the pain thus moves from the peripheral to the central nervous system. We hypothesize that this centralization of pain involves the inappropriate release of peptidergic neuromodulators from primary afferent fibers. Peptides such as substance P, neuropeptide Y (NPY), calcitonin-gene-related peptide (CGRP), and brain-derived neurotrophic factor (BDNF) may promote enduring changes in excitability as a consequence of neurotrophic actions on ion channel expression in the dorsal horn. Findings that form the basis of this hypothesis are reviewed. Study of the neurotrophic control of ion channel expression by spinal peptides may thus provide new insights into the etiology of neuropathic pain.Key words: neuropathic pain, spinal cord injury, allodynia, dorsal root ganglion, axotomy.

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Abstract. PCBs are ubiquitous environmental pollutants expected to decline in abiotic environmental media in response to decreasing primary emissions since the 1970s. A coupled atmosphere-ocean general circulation model with embedded dynamic sub-models for atmospheric aerosols and the marine biogeochemistry and air-surface exchange processes with soils, vegetation and the cryosphere is used to study the transport and fate of four PCB congeners covering a range of 3–7 chlorine atoms. The change of the geographic distribution of the PCB mixture reflects the sources and sinks' evolvement over time. Globally, secondary emissions (re-volatilisation from surfaces) are on the long term increasingly gaining importance over primary emissions. Secondary emissions are most important for the congeners with 5–6 chlorine atoms. Correspondingly, the levels of these congeners are predicted to decrease slowest. Changes in congener mixture composition (fractionation) are characterized both geographically and temporally. In high latitudes enrichment of the lighter, less persistent congeners and more delayed decreasing levels in response to decreasing emissions are found. The delivery of the contaminants to high latitudes is predicted to be more efficient than previously suggested. The results suggest furthermore that the effectiveness of emission control measures may significantly vary among substances. The trends of decline of organic contaminant levels in the abiotic environmental media do not only vary with latitude (slow in high latitudes), but do also show longitudinal gradients.

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On August 25 2017, an unprecedented influx of Rohingya refugees began from Rakhine State in Myanmar into Bangladesh’s district of Cox’s Bazar. The scale and acuteness of this humanitarian crisis was unprecedented and unique globally, requiring strong coordination of a multitude of actors. This paper reflects on the health sector coordination from August 2017 to October 2019, focusing on selected achievements and persisting challenges of the health sector strategic advisory group (HSSAG), and the health sector working groups including epidemiology and case management, sexual and reproductive health, community health, mental health and psychosocial support, and emergency preparedness. In the early days of the response, minimum service standards for primary health care were established, a fundamental initial step which enabled the standardization of services based on critical needs. Similarly, establishing standards for community health outreach was the backbone for capitalizing on this important health workforce. Novel approaches were adopted for infectious disease responses for acute watery diarrhoea and varicella, drawing on inter-sectoral collaborations. Sexual and reproductive health services were prioritized from the initial onset of the crisis and improvements in skilled delivery attendance, gender-based violence services, abortion care and family planning were recorded. Mental health service provision was strengthened through community-based approaches although integration of mental health programmes into primary health care has been limited by availability of specialist psychiatrists. Strong, collaborative and legitimate leadership by the health sector strategic advisory group, drawing on inter-sectoral collaborations and the technical expertise of the different technical working groups, were critical in the response and proved effective, despite the remaining challenges to be addressed. Anticipated reductions in funding as the crisis moves into protracted status threatens the achievements of the health sector in provision of health services to the Rohingya refugees.

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Abstract Objectives Chronic stress activates danger-associated molecular patterns (DAMPs), stimulating the NLRP3 inflammasome. NLRP3 activation triggers the release of pro-inflammatory cytokine IL-1β. The activity of the NLRP3 inflammasome propagates pro-inflammatory signaling cascades implicated in the onset of depression. Our previous studies show that polyphenolic compounds were found to ameliorate stress induced depression in mouse models. However, the relevant mechanism has not been identified. This study examined the effect of administering polyphenols on DAMP signaling in enriched mice microglia. Methods This study examined the effect of administering polyphenols on DAMP signaling in mice microglia. To recapitulate stress-induced depression, mice underwent chronic unpredictable stress (CUS). Microglia were isolated at various time points throughout the CUS protocol. We also assessed long-term persistent changes after CUS and susceptibility to subthreshold unpredictable stress (US) re-exposure. Results Interestingly, the development of US – induced depression and anxiety depended upon a previous exposure to CUS. We found that CUS caused robust upregulation of IL-1β mRNA in enriched microglia, an effect that persists for up to 4 weeks following CUS exposure. Following the subthreshold US re-exposure, we observed the upregulation of pro- IL-1β as well as pro-receptor for advanced glycation end products (RAGE). Toll-like receptor 4 (TLR-4) was not. We also observed an increase in RAGE mRNA expression when mice were exposed to US prior to the start of the CUS paradigm. Importantly, a primary exposure to US, was sufficient to increase RAGE mRNA expression. We found that polyphenol administration significantly improved CUS-induced depressive-like phenotypes and also reversed neuroinflammation in mice. Treatment with dietary flavonoids prevented upregulation of IL-1β, RAGE mRNA, which reflects the ability of polyphenols that may have begun following the primary exposure to US. Conclusions Taken all together, the results provide evidence of the role of dietary polyphenols in preventing persistent microglial activation, which has been shown to result in reduced long term vulnerability to depressive-like behaviors following expose to chronic stress. Funding Sources This study was supported by a P50 CARBON Center grant from the NCCIH/ODS.

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The most widely reported surgical procedure for obstructive sleep apnea syndrome is uvulopalatopharyngoplasty. The success rate for this procedure is variable, and the reason for failure is incompletely understood. Failure in some patients is postulated to result from tongue-base obstruction. To investigate this, we identified the level of collapse and obstruction in 11 cases of uvulopalatopharyngoplasty failure, using upper airway manometry and videoendoscopy, while patients slept. Airway manometry measured the initial level of complete obstruction. Videoendoscopy identified significant resting airway narrowing (> 75%) at the tongue base on obstructed compared with nonobstructed breaths. Results of manometry indicated that the palate was the primary level of obstruction in eight (73%) compared with the tongue base in three (27%). However, collapse on videoendoscopy at the tongue base was observed in an additional three patients. A total of six patients (54%) demonstrated significant tongue-base abnormalities. In six patients with uvulopalatopharyngoplasty as the only pharyngeal surgery, one (17%) had an obstruction at the tongue base, as measured with manometry. Three of the six also had collapses at the tongue base, as measured endoscopically. Tongue-base abnormalities were identified in four of six (67%). Two additional patients who had failed uvulopalatopharyngoplasty and franspalatal advancement pharyngoplasty had obstructions on manometry at the level of tongue base. Six of eight (75%) palatopharyngoplasty failures demonstrated tongue-base collapse. In the three patients with tongue-base surgery, all had obstructions on manometry at the palate and none had endoscopic tongue-base collapse. These results indicate that in most uvulopalatopharyngoplasty failures the initial level of obstruction occurs at the palate. However, tongue-base collapse is frequent, and the associated increases in upper airway resistance, changes in ventilation, airflow limitatioins, and changes in airway reflexes may contribute to persistent apnea through complex mechanisms. Both obstructed and nonobstructed upper airway segments must be included in a model for surgical failures.

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Cystic fibrosis (CF) reflects the loss of adenosine 3',5'-cyclic monophosphate (cAMP)-regulated Cl- secretion consequent to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In humans, but not mice, with CF, the disease is associated with male infertility. The present study investigated the relative magnitudes of the cAMP pathways and an alternative Ca(2+)-regulated Cl- secretory pathway in primary cultures of the epididymides and the seminal vesicles of normal and CF mice. The basal equivalent short-circuit currents (Ieq) of cultures derived from the epididymides and the seminal vesicles from the CF mice were lower (6.0 +/- 0.6 and 4.0 +/- 1.0 muA/cm2, respectively) than those from normal mice (11.1 +/- 1.0 and 6.6 +/- 0.6 muA/cm2, respectively). Forskolin induced significant Ieq responses in both the epididymis (8.0 +/- 0.7 muA/cm2) and seminal vesicles (4.0 +/- 0.5 muA/cm2) from normal mice, whereas forskolin-induced changes in Ieq in CF mouse epididymis and seminal vesicles were absent, consistent with defective cAMP-CFTR-mediated Cl- secretion in CF mice. Ieq responses to agonists (ionomycin, ATP) that raise intracellular Ca2+ (Ca2+i) were larger than forskolin responses in normal animals (6.6 +/- 0.9 and 13.4 +/- 1.8 muA/cm2, respectively) and were preserved in CF (6.5 +/- 0.9 and 17.1 +/- 1.0 muA/cm2, respectively). We speculate that the fertility of male CF mice is maintained by persistent expression of the predominant alternative Ca(2+)-mediated Cl- transport system in the epididymides and seminal vesicles.

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Almost all of patients treated for cancers, experience episodes of persistent depression. Which moment is the most terrible? The moment patients hear their diagnosis,or time suffer while getting chemotherapy?The time on controls tumor markers or when their relatives give up on them? When mirror reflects damaged body and face. Or felt useless in the presence of their children?•diagnosis of cancers C00,E05 are difficult to accept, and go hand in hand with major depression F33/ according to ICD-10.•why excitaloprim as choice?Patients age 27 to 37 need antidepressant with pharmaco*kinetic superiority. Excitaloprim works faster than any other antidepressant, and it is strong, thanks to its dual serotonergic bonding on primar part as well as alosteric part bonding. It is weak inhibitor of the well defined liver cytochrome P450 isoenzym, CYP2D6., EEg .EKG is ok, so its safe drug/.In this study, I followed the results of excitaloprim treatment on 30 patients (20 females, 10 males).During 2 months, 20 patients were diagnosed with cancer (mostly colon and breast). All this patients have already been operated. Some have anus praeternaturalis.Other patients have AIDSinitial phase, and autoimmune dg/On Hamilton scale, 45, points, MADRS on 10 items, 40, on Becks scale 65.Zung self rating index o,6. In this project, patients without children were much more suicidal.Cancer patients got 20 mg excitaloprim pro die, other 10 mg pro die. After 2 mothsscales showed statistically important improvements despite severity.

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Background: Persistent healthcare emphasis on universal moral philosophy has not advantaged indigenous and marginalised groups. Centralising cultural components of care is vital to provide ethical healthcare services to indigenous people and cultural minorities internationally. Woods’ theoretical explication of how nurses can integrate cultural safety into a socioethical approach signposts ethical practice that reflects culturally congruent relational care and systemic critique. Aim: To demonstrate the empirical utility of Woods’ ethical elements of cultural safety within a socioethical model, through analysis of indigenous nurses’ practice realities in Aotearoa New Zealand. Research design: The study used a qualitative indigenous narrative inquiry. Participants and research context: Participants were recruited nationally. Twelve Māori registered nurses and nurse practitioners were interviewed. All participants provided direct care in either primary or secondary health services. Ethical considerations: Research approval was gained from the Human Ethics Committee of the lead author’s tertiary institution. Participation was voluntary, and written informed consent was obtained. Findings: Analysis highlighted the following: (1) cultural needs, which for Māori were integral to care, were easily subsumed by clinical care being prioritised; (2) ethical care by non-indigenous nurses requires critical reflection about broader equity issues that impact Māori disengagement from healthcare; (3) retention of indigenous nurses was seen as essential because their advocacy and the cultural ‘fit’ for Māori contributed to positive healthcare outcomes; and (4) committed leadership ensured culturally safe care was not eroded through workplace efficiencies. Discussion: The data provide rich representation of Woods’ model. The data indicate that nurses must engage reflexively with a relational ethic of care and social justice dimensions in order to deliver culturally safe care. Conclusion: Woods’ model provides a critical lens for nurses to examine their relational practice and systemic factors that enhance or detract from culturally safe care when caring for members of any indigenous group.

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Abstract PURPOSE: The AHOD0831 study tested a response-based treatment approach for pediatric patients with very high risk Hodgkin lymphoma (HL). Central response review following 2 cycles of dose intensive chemotherapy by FDG-PET was utilized to assign consolidation chemotherapy and risk-adapted radiotherapy. The primary outcome was second event-free survival (2nd EFS), defined as freedom from second relapse or malignancy. Because many patients with relapsed HL can be successfully cured with retrieval therapy, 2nd EFS more accurately reflects long-term overall survival (OS). AHOD0831 was designed to test whether this treatment protocol will maintain 4-year 2nd EFS ≥95%. PATIENTS AND METHODS : Patients aged ≤ 21 with stage IIIB or IVB HL were nonrandomly assigned to receive two 21-day courses of ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide). Rapid Early Response (RER) was defined by FDG-PET negativity (i.e. no activity above background), irrespective of size of residual masses. Patients with RER were consolidated with 2 additional cycles of ABVE-PC. Slow early responders (SER) received 2 cycles of ifosfamide/vinorelbine (IFOS/VINO) followed by 2 more cycles of ABVE-PC. Radiotherapy (RT), 21 Gy in 14 fractions, was administered to sites of initial bulky involvement (large mediastinal mass, nodal aggregate >6cm, splenic macronodular involvement) and regions of SER. For the primary aim of 2nd EFS, second events were defined as any relapse/progression of HL or SMN, new SMN or death after a first event which can be relapse/progression, SMN, persistent bone marrow involvement at completion of chemotherapy, or biopsy proven HL for SER at completion of chemotherapy. RESULTS: Among 165 eligible patients, median age was 15.8 yrs (5.2-21.4), 61% were male, 71 (43%) were stage IIIB, and 94 (57%) IVB. 50% were RER (stage IIIB: 58%; IVB: 45%). At time of current analysis the median follow-up was 42 months. 2nd EFS at 4 years is 89.8% (95% CI:80.8%-94.8%), below the projected baseline with 4-yr rate of 95% (P=0.01). Subgroup analyses showed that 4 yr 2nd EFS for RER (n=77) is 91.9% (76.3%-97.4%), SER (n=68) is 87.8% (75.8%-94.1%) and stage IVB 89.6% (76.3%-95.7%). 20 patients were excluded from 2nd EFS analysis secondary to premature termination or deviation of protocol therapy. 31 patients had reported at least one event for EFS (first event: 29 relapse/progressions, 1 SMN, and 1 death secondary to disseminated fungal infection during RT). Standard 1st EFS rates at 4 yrs are: 80.2% (73%-85.6%). 4 yr OS 95.9% (90%-98.4%). 12 SER patients had persistent PET positive lesions at end of chemotherapy. Eight of these 12 had clinical evidence of active disease (3 biopsy-proven HL, 2 with progressive disease by clinical or radiographic criteria, and 3 later relapses). In retrospective analysis, no specific Deauville score could be identified to predict which patients were at highest risk for progression. CONCLUSIONS: Among pediatric patients with very high risk HL (IIIB, IVB), a response directed approach utilizing limited chemotherapy (4 cycles for RER; 6 cycles for SER) and risk directed RT did not reach the ambitiously high pre-specified target for 2nd EFS. However, 4 year EFS and OS rates are comparable with results of recent trials for this population (POG 9425: IIIB/IVB, n=88: 4 yr EFS 81.7% (71.8%-88.3%); 4 yr OS 92.9% (84.9%-96.8%)). Our study achieved these similar outcomes, despite the reduction in RT volumes from historical involved fields (which did not account for relapse risk). Persistent PET at end of chemotherapy identifies a cohort at an especially high risk for relapse/early progression. Novel approaches incorporating enhanced risk stratification beyond stage and B symptoms, identification of better predictive factors beyond PET response, and incorporation of novel agents are still needed for this highest risk group of patients with newly diagnosed pediatric HL. Disclosures No relevant conflicts of interest to declare.

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Abstract. Continuous multiyear records of sediment-trap-gained microorganism fluxes are scarce. Such studies are important to identify and to understand the main forcings behind seasonal and multiannual evolution of microorganism flux dynamics. Here, we assess the long-term flux variations and population dynamics of diatoms, coccolithophores, calcareous and organic dinoflagellate cysts, foraminifera and pteropods in the eastern boundary upwelling ecosystem of the Canary Current. A multiannual, continuous sediment trap experiment was conducted at the mooring site CBeu (Cap Blanc eutrophic; ∼20∘ N, 18∘ W; trap depth is ca. 1300 m) off Mauritania (northwest Africa), between June 2003 and March 2008. Throughout the study, the reasonably consistent good match of fluxes of microorganisms and bulk mass reflects the seasonal occurrence of the main upwelling season and relaxation and the contribution of microorganisms to mass flux off Mauritania. A clear successional pattern of microorganisms, i.e., primary producers followed by secondary producers, is not observed. High fluxes of diatoms, coccolithophores, organic dinoflagellate cysts, and planktonic foraminifera occur simultaneously. Peaks of calcareous dinoflagellate cysts and pteropods mostly occurred during intervals of upwelling relaxation. A striking feature of the temporal variability of population occurrences is the persistent pattern of seasonal groups contributions. Species of planktonic foraminifera, diatoms, and organic dinoflagellate cysts typical of coastal upwelling, as well as cooler-water planktonic foraminifera and the coccolithophore Gephyrocapsa oceanica, are abundant at times of intense upwelling (late winter through early summer). Planktonic foraminifera and calcareous dinoflagellate cysts are dominant in warm pelagic surface waters, and all pteropod taxa are more abundant in fall and winter when the water column stratifies. Similarly, coccolithophores of the upper and lower photic zones, together with Emiliania huxleyi, and organic dinoflagellate cysts dominate the assemblage during phases of upwelling relaxation and deeper layer mixing. A significant shift in the “regular” seasonal pattern of taxa relative contribution is observed between 2004 and 2006. Benthic diatoms strongly increased after fall 2005 and dominated the diatom assemblage during the main upwelling season. Additional evidence for a change in population dynamics is the short dominance of the coccolithophore Umbilicosphaera annulus, the occurrence of the pteropod Limacina bulimoides and the strong increase in the flux of calcareous dinoflagellate cysts, abundant in warm tropical oligotrophic waters south of the study area after fall 2005. Altogether, this suggests that pulses of southern waters were transported to the sampling site via the northward Mauritania Current. Our multiannual trap experiment provides a unique opportunity to characterize temporal patterns of variability that can be extrapolated to other eastern boundary upwelling ecosystems (EBUEs), which are experiencing or might experience similar future changes in their plankton community.

Abstract:

Abstract A therapeutically crucial sub-set of leukemia cells are those that self-renew (leukemia stem-cells or LSC). An open question is whether LSC self-renewal is mediated by the same pathways or factors that self-renew normal hematopoietic stem-cells (HSC). A difference in self-renewal mechanisms could form the basis for LSC-specific therapy. Hematopoietic differentiation is dependent on lineage-determining factors such as Pu.1. Pu.1 can repress or activate genes, depending on its interaction partners. We show that Pu.1 mediated terminal differentiation involves sequential repression of genes associated with self-renewal (pro-SR) (HoxB4, Bmi-1, c-Kit) followed-by activation of genes associated with differentiation (pro-DIFF)(Mcsfr, Gmcsfr, F4/80). DNA methyl-transferase 1 (DNMT1) is an arbiter of transcription repression. DNMT1 depletion concurrent with Pu.1 introduction prevents the first step of pro-SR repression and maintains self-renewal. However, DNMT1 depletion 6 hours after Pu.1 introduction (at which point pro-SR repression by Pu.1 is complete), increases differentiation. Therefore, the phenotypic consequences of DNMT1 depletion critically depend on the differentiation chronology of the cell. We then examined the effects of a leukemia first-hit event, Runx1 disruption, on Pu.1 mediated differentiation. Runx1 knock-down allowed Pu.1 mediated pro-SR repression but prevented pro-DIFF up-regulation and terminal differentiation, resulting in persistent dysregulated proliferation (self-renewal) despite pro-SR repression. DNMT1 depletion in these abnormally self-renewing cells, with an epigenetic and transcript profile distinct from parental self-renewing cells, relieved pro-DIFF repression and restored the terminal differentiation response. Therefore, DNMT1 depletion had opposite effects in the cells containing the leukemia-associated abnormality versus parental cells. Suggesting that these findings were relevant to clinical disease, leukemic bone marrow (n=130), although consisting largely of myeloblasts, demonstrated a DNA methylome (1505 CpGs, Illumina) profile that resembled differentiated cells and not precursors, with aberrant methylation concentrated at precursor signature (pro-SR) promoters and hypomethylation at differentiation signature (pro-DIFF) promoters. To therapeutically exploit these observations, we demonstrate that the nucleoside analogue Decitabine, given at doses that deplete DNMT1 without causing DNA damage, and given frequently but intermittently to allow for cell-division, produces an ideal therapeutic profile with terminal differentiation of leukemia cells but increased self-renewal of human CD34+ HSC. This effect was seen in different models of human LSC (primary human CD34+ cells transduced with either the MLL-AF9 or RUNX1-ETO leukemia fusion genes) and in primary leukemia cell samples (n=15) containing a variety of chromosome abnormalities. This therapeutic approach increased survival in a murine xeno-graft model of aggressive human MLL-AF9 leukemia. In conclusion, leukemia and LSC self-renewal, in a number of examples covering a variety of transformation-initiating abnormalities, is programmatically distinct from HSC selfrenewal. Leukemia self-renewal is associated with an epigenetic and transcript profile that reflects part-way commitment into differentiation with aberrant gene repression preventing completion of the process. This difference could explain the opposite effects of DNMT1 depletion on HSC and leukemia self-renewal, and provides the scientific foundation for differentiation (frequent metronomic low-dose) instead of cytotoxic (infrequent high-dose) regimens of epigenetically active and clinically available agents such as Decitabine.

Abstract:

Background Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by reactivation of the polyomavirus John Cunningham (JCV) in the setting of immunosuppression. It has been described in patients with hematologic malignancies including multiple myeloma (MM), solid organ malignancies, granulomatous and inflammatory diseases, transplant recipients, lymphopenic patients (including patients with HIV) and with the use of certain drugs (rituximab, natalizumab). We present the first report to our knowledge of a patient with MM developing PML in association with daratumumab and pomalidomide therapy. Case Report A 63yo woman with relapsed/refractory IgA-Lambda MM on daratumumab and pomalidomide, presented to the emergency department after noticing difficulty putting her hair up in a ponytail. Her MM was diagnosed in 2003 and treated with steroids, high-dose melphalan and autologous stem cell transplant, maintenance therapy with thalidomide, switched to lenalidomide; upon relapse in 2010, she was treated with bortezomib, doxorubicin and dexamethasone, followed by bortezomib maintenance. Ten months prior to presentation, she relapsed and was started on daratumumab and pomalidomide, achieving an unconfirmed complete response (uCR), complicated by acquired hypogammaglobulinemia for the prior 8 months without infections. She developed progressive left arm weakness and gait instability; she denied any fevers, dysarthria, vision changes, headaches or seizures. On exam, she was alert and oriented; no cranial nerve abnormality; calculation, concentration and recall were intact; 4/5 strength in left upper extremity and 5/5 strength in all other extremities with preserved sensation and reflexes; coordination intact but a hemiparetic gait; rest of the exam was unremarkable. A brain MRI showed patchy and confluent areas of T2 hyperintense signal in the right greater than left cerebral hemispheres. She underwent a lumbar puncture which was positive for JCV by PCR (98 copies/mL) in her CSF and negative for neoplastic involvement by flow cytometry. The rest of her work-up was unremarkable. A diagnosis of PML was made and daratumumab and pomalidomide were discontinued. On follow-up brain MRIs four and eight weeks later, she had persistent extensive asymmetric patchy T2 hyperintense signal. Repeat LP revealed stable JCV in the CSF (95 copies/mL). Despite the lack of radiologic improvement, she had a remarkable clinical response with near resolution of neurologic symptoms and remains in an uCR. Discussion PML has been reported in association with multiple drugs used in the management of MM including corticosteroids, alkylating agents (cyclophosphamide, melphalan), immunomodulatory drugs (thalidomide, lenalidomide) and proteasome inhibitors (bortezomib, ixazomib), however, an association with pomalidomide or daratumumab has not yet been reported. In a clinical trial of daratumumab and pomalidomide for MM, a case of PML was reported, however, it was not considered to be related to these agents given that the patient received only one dose of daratumumab (Chari A. Blood 2017). PML has been reported in patients with primary hypogammaglobulinemia, however, it is not known whether acquired hypogammaglobulinemia - either due to MM or its therapy - is a risk factor for PML. Furthermore, the role for IVIG in the primary prevention or treatment of PML has not been clearly defined and warrants further study. The current treatment approach of PML remains the restoration of the host's adaptive immune response, including the discontinuation of immunosuppressive agents, unfortunately, evidence is lacking for any specific pharmacologic treatment. Recently, immune checkpoint inhibitors have shown clinical improvement or stabilization in small cohorts of patients with PML (NEJM 2019;380), however, given the safety concerns regarding their use in MM (KEYNOTE-183,-185) and the rapid clinical response seen in this case, no further therapy was instituted. This is the first report of pomalidomide and daratumumab as potential drugs associated with PML. Although it is not possible to ascertain their direct role in the reactivation of JCV, it should help clinicians recognize this potentially fatal complication in patients receiving either immunomodulatory drugs or anti-CD38 monoclonal antibodies, since prompt discontinuation may be life-saving. Disclosures Perry: Celgene: Speakers Bureau. Coleman:Gilead, Bayer, Celgene: Consultancy, Research Funding, Speakers Bureau; Kite Pharmaceuticals: Equity Ownership; Merck: Research Funding; Pharmacyclics: Speakers Bureau. Rossi:Janssen, Celgene, Amgen: Consultancy; BMS: Research Funding. Niesvizky:Takeda, Amgen, BMS, Janssen, Celgene: Consultancy, Research Funding.

Abstract:

Abstract Introduction: Empiric antifungal therapy (EAT) is recommended for persistent or recurrent febrile neutropenia based on an old randomized controlled trial, but such treatment is apparently overtreatment for the majority of patients. On the other hand, preemptive therapy triggered by positive blood tests for fungal antigens and/or imaging study findings was shown to increase the incidence of invasive fungal infection, and thus, a risk-based approach is important. The D-index, which is defined as the area over the neutrophil curve during neutropenia and hence reflects both the duration and depth of neutropenia (Figure 1A), enables real-time monitoring of the risk of invasive fungal infection. Previous studies showed that the cumulative D-index (c-D-index), which was calculated as cumulative D-index from the onset of neutropenia (Figure 1B), had high negative predictive values for invasive mold infection or pulmonary infection with cutoff values of 5,800 or 5,500 in high-risk neutropenic patients [J Clin Oncol 2009; 27: 3849-54. Biol Blood Marrow Transplant 2010; 16: 1355-61]. Methods: We investigated a novel approach, called D-index-guided early antifungal therapy (DET) and compared it to EAT in high-risk neutropenic patients. In the EAT group, empiric antifungal therapy was started for persistent (>=4 days) or recurrent febrile neutropenia. For patients with persistent or recurrent febrile neutropenia in the DET group, preemptive antifungal therapy was applied until c-D-index reached 5,500, but antifungal agent was initiated after c-D-index exceeded 5,500, even if there was no significant finding in serum fungal makers or imaging studies, to prevent excessive invasive fungal infection. Micafungin at 150 mg/day was administered as EAT or DET in this study. We randomized 423 patients who underwent chemotherapy or hematopoietic stem cell transplantation for hematological malignancies, in which predicted period of neutropenia exceeded 7 days, into the EAT group or the DET group, and 413 were eligible for intent-to-treat analyses (201 patients in the EAT group, 212 patients in the DET group). The prophylactic use of fluconazole or itraconazole was allowed. Primary endpoint was the development of proven/probable invasive fungal infection. Results: Backgrounds of the patients were similar between the 2 groups (Table 1). Invasive fungal infection (proven/probable/possible) was observed in 12 patients (6.0%) of the EAT group and 5 patients (2.4%) of DET group, respectively. Proven/probable invasive fungal infection was identified in 5 patients (2.5%) of the EAT group and 1 patient (0.5%) of DET group, which fulfilled the predetermined criteria of non-inferiority of the DET group. Regarding the pathogens, the EAT group included 1 case of candidemia and 4 cases of invasive pulmonary aspergillosis, and the DET group included one fusariosis. The survival rate of the EAT and DET group was 98.0% vs. 98.6% at day 42 and 96.4% vs. 96.2% at day 84, respectively. During the observation period, 31 patients died due to disease progression (n=19), infection (n=5) or other causes (n=7). Causes of infection related mortality included Pseudomonas aerginosa infection (n=2), fusariosis (n=1), toxoplasmosis (n=1) and septic shock by unknown pathogen (n=1). The frequency of micafungin use was significantly lower in the DET group than the EAT group (32.5% vs. 60.2%, P<0.001). Similar results were obtained in per-protocol set analyses. Conclusions: DET successfully reduced the use of antifungal agents without increasing invasive fungal infection or mortality compared to EAT. This randomized controlled study revealed the feasibility of DET in high-risk neutropenic patients. Disclosures Kimura: Astellas: Honoraria; Pfizer: Honoraria; Sumitomo Dainippon Pharma: Honoraria; MSD: Other: Investigator in the institute; Nippon Kayaku: Honoraria; Celgene: Honoraria; Kyowa Hakko Kirin: Honoraria; Takeda: Honoraria. Kanda:Chugai: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Nippon-Shinyaku: Research Funding; Ono: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; CSL Behring: Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; Tanabe-Mitsubishi: Research Funding; Novartis: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Dainippon-Sumitomo: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Taisho-Toyama: Research Funding; Taiho: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria. Fujiwara:Shire: Consultancy; Pfizer: Consultancy; Chugai: Consultancy; Kirin: Consultancy; Kyowa-Hakko: Consultancy; Astellas: Consultancy. Suzumiya:Celltrion: Research Funding; Taiho: Research Funding, Speakers Bureau; SymBio: Research Funding; Toyama Chemical: Research Funding; Takeda: Research Funding, Speakers Bureau; Eisai: Research Funding, Speakers Bureau; Chugai-Roche: Research Funding, Speakers Bureau; Kyowa Hakko Kirin: Research Funding, Speakers Bureau; Zenyaku Kogyo: Consultancy; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Pfizer: Research Funding; Sumitomo Dainioppon: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Nippon Shinyaku: Speakers Bureau; Ono: Speakers Bureau; Ohtsuka: Speakers Bureau; Shire Japan: Speakers Bureau. Takamatsu:Taisho Toyama Pharmaceutical: Research Funding; TAIHO Pharmaceutical: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Ono Pharmaceutical: Research Funding; Astellas Pharma: Research Funding; Kyowa Hakko Kirin: Research Funding; Chugai Pharma: Research Funding; Takeda Pharmaceutical: Research Funding; Celgene: Honoraria. Tamura:Astellas Phrma: Research Funding; Eisai: Speakers Bureau; Kyowa Hakko Kirin: Speakers Bureau; Ono Pharmaceutical: Speakers Bureau.

Abstract:

Background: Thrombopoietin receptor agonists (TPO-RAs) (e.g., romiplostim, eltrombopag, avatrombopag) are used to stimulate platelet production in patients with primary immune thrombocytopenia (ITP). While it was previously thought that patients would need to remain on a TPO-RA indefinitely, case reports and cohort studies have shown that some patients have discontinued TPO-RAs while maintaining a hemostatic platelet count. We convened a panel of experts to develop clinical recommendations on when it is appropriate to consider tapering and how to taper TPO-RAs in children and adults with persistent or chronic primary ITP. Methods: Using a RAND/UCLA modified Delphi panel, we convened 9 hematologists with an average of 25 years of experience and 1 patient representative. Experts were provided with a summary of evidence from 12 case reports, 11 cohort studies, and 2 clinical trial analyses on sustained remission in patients with ITP treated with TPO-RAs. Experts collaboratively developed and then rated (on a 1 to 9 scale) how appropriate it would be to recommend tapering (with the aim of discontinuing) TPO-RA monotherapy in 432 patient scenarios. Each scenario was a simplified patient history which varied by current platelet count, history of bleeding, intensification of treatment, trauma risk, use of anticoagulants or platelet inhibitors, duration of ITP, months on TPO-RA monotherapy, and early platelet response to TPO-RA (Table 1). In addition, the rating form included different ways to taper patients off therapy, how to monitor patients after discontinuation, and how to restart therapy. Ratings were completed independently by each expert before a full-day meeting. Median ratings were grouped into 3 categories (1-3, 4-6, 7-9) and disagreement was defined as ≥2 ratings of 1-3 and ≥2 ratings of 7-9 for a given scenario. During the meeting, discordant ratings were discussed. At the conclusion, experts completed ratings again (final round). Chi-square tests were conducted to determine if each patient characteristic significantly impacted ratings. Final ratings were used to describe the circ*mstances when it is inappropriate or appropriate to consider tapering TPO-RA monotherapy, how to taper TPO-RAs, how to monitor patients after discontinuation, and how to restart therapy. The panel was double-blinded while work was ongoing: the sponsor did not know the identity of the experts and the experts did not know the identity of the sponsor. The sponsor did not provide input on study design, methods, results, or interpretation of findings. Results: The proportion of items with disagreement decreased from 20% to 10% following the meeting. In the final round, 5 patient characteristics were found to significantly impact ratings and thus the appropriateness of tapering TPO-RA treatment: platelet count (p&lt;0.001), history of bleeding (p=0.001), intensification of treatment (p&lt;0.001), trauma risk (p&lt;0.001), use of anticoagulants or platelet inhibitors (p&lt;0.001). These characteristics were used to describe when it is inappropriate or appropriate to consider tapering TPO-RA monotherapy (Table 1). Experts agreed that it is inappropriate to consider tapering TPO-RA monotherapy in responding patients with low platelet counts, in patients with less than normal but still adequate platelet counts who have a history of major bleeding, or in patients who have a high risk of trauma and are using anticoagulants or platelet inhibitors (regardless of platelet count). It is appropriate to consider tapering TPO-RA monotherapy in patients with normal/above normal platelet counts, no history of major bleeding, and who have not required an intensification of treatment in the past 6 months. Recommendations on how to taper patients off therapy, how to monitor patients after discontinuation, and how to restart therapy were also developed. Conclusion: A validated methodology was used to assist an expert panel in developing clinical recommendations on when it is inappropriate or appropriate to consider tapering TPO-RA monotherapy and how to safely taper patients off therapy. The guidance reflects areas of greatest agreement based on clinical experience and currently available limited evidence. These recommendations could serve as a guide to clinical care and inform the development and design of clinical trials that prospectively test the safety of tapering TPO-RA monotherapy in patients with ITP. Disclosures Cuker: Pfizer: Research Funding; Novartis: Research Funding; Novo Nordisk: Research Funding; Sanofi: Research Funding; Spark: Research Funding; Takeda: Research Funding; Alexion: Research Funding; Bayer: Research Funding; Synergy CRO: Consultancy. Despotovic:Dova: Consultancy; Amgen: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Grace:Novartis: Research Funding; Dova: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding; Pfizer: Research Funding. Kruse:UCB: Other: Grant and consultancy fee, all paid to PDSA; Rigel: Other: Grant paid to PDSA; Principia: Other: Grant paid to PDSA; Pfizer: Other: Grant and consultancy fee, all paid to PDSA; Argenx: Other: Grant paid to PDSA; Amgen: Other: Grant and honorarium, all paid to PDSA; Novartis: Other: PDSA received payment for recruiting patients to I-WISh and for promoting I-WISh on the globalitp.org website. Grant and consultancy fee, all paid to PDSA outside the submitted work; CSL Behring: Other: Grant paid to PDSA. Lambert:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Platelet Disorder Support Association (PDSA): Consultancy; ClinGen: Honoraria; Principia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenix: Consultancy; Bayer: Consultancy; ITP Australia: Consultancy; AstraZeneca: Research Funding; Sysmex: Research Funding; Dova: Consultancy, Membership on an entity's Board of Directors or advisory committees; CdLS Foundation: Consultancy; RDMD ITP study: Consultancy; 22qSociety: Consultancy; Octapharma: Consultancy, Research Funding; Educational Concepts in Medicine: Consultancy; Shionogi: Consultancy. Liebman:Janssen: Consultancy; Amgen: Research Funding; Novartis: Honoraria, Research Funding; Kezar: Research Funding; Argenix: Research Funding; Alexion: Other; Genzyme: Consultancy; BMS: Consultancy; Rigel: Consultancy, Research Funding; Portola: Consultancy; Principia Biopharma: Consultancy. Lyons:Novartis: Honoraria; Texas Oncology/US Oncology: Current Employment. McCrae:Dova: Consultancy; Rigel: Consultancy; Momenta Pharmaceuticals: Consultancy; Novartis: Honoraria. Pullarkat:Dova: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genetech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Wasser:Amgen: Consultancy; Biogen: Current equity holder in publicly-traded company, Other: He and his wife have equity ownership; Eli Lilly: Current equity holder in publicly-traded company, Other: He and his wife have equity ownership; Novartis: Honoraria, Speakers Bureau; Pfizer: Current equity holder in publicly-traded company, Other: He and his wife have equity ownership, Research Funding; Incyte: Research Funding; Merck: Current equity holder in publicly-traded company, Other: He and his wife have equity ownership, Research Funding. Beenhouwer:Dr. Beenhouwer reports other from Novartis during the conduct of the study; other from AbbVie, other from Akcea, other from ASPC, other from Amgen, other from AstraZeneca, other from BMS, other from Boston Scientific Corporation, other from Celgene, other: Other: Dr. Beenhouwer reports other from Novartis during the conduct of the study; other from AbbVie, other from Akcea, other from ASPC, other from Amgen, other from AstraZeneca, other from BMS, other from Boston Scientific Corporation, other from Celgene, other. Gibbs:Ms. Gibbs reports other from Novartis during the conduct of the study; other from AbbVie, other from Akcea, other from ASPC, other from Amgen, other from AstraZeneca, other from BMS, other from Boston Scientific Corporation, other from Celgene, other from: Other: SN Gibbs is an employee of the Partnership for Health Analytic Research (PHAR), LLC, which was paid by Novartis to conduct this research.. Yermilov:Dr. Yermilov reports other from Novartis during the conduct of the study; other from AbbVie, other from Akcea, other from ASPC, other from Amgen, other from AstraZeneca, other from BMS, other from Boston Scientific Corporation, other from Celgene, other f: Other: Dr. Yermilov reports other from Novartis during the conduct of the study; other from AbbVie, other from Akcea, other from ASPC, other from Amgen, other from AstraZeneca, other from BMS, other from Boston Scientific Corporation, other from Celgene, other f. Broder:Dr. Broder reports other from Novartis during the conduct of the study; other from AbbVie, other from Akcea, other from ASPC, other from Amgen, other from AstraZeneca, other from BMS, other from Boston Scientific Corporation, other from Celgene, other fro: Other: MS Broder is an employee of the Partnership for Health Analytic Research (PHAR), LLC, which was paid by Novartis to conduct this research..

Abstract:

Background Unsafe worker behavior is often identified as a major cause of dangerous incidents in the petrochemical industry. Behavioral safety models provide frameworks that may help to prevent such incidents by identifying factors promoting safe or unsafe behavior. We recently conducted a qualitative study to identify factors affecting workers' unsafe behaviors in an Iranian petrochemical company. Objective The aims of this study were to (1) conduct a review of the relevant research literature between the years 2000 and 2019 to identify theoretical models proposed to explain and predict safe behavior in the workplace and (2) to select the model that best reflects our qualitative findings and other evidence about the factors influencing safe behaviors among petrochemical workers. Methods This research used mixed methods. Initially, we conducted a qualitative study of factors that Iranian petrochemical workers believed affected their safety behavior. Four themes emerged from the semistructured interviews: (1) poor direct safety management and supervision; (2) unsafe workplace conditions; (3) workers’ perceptions, skills, and training; and (4) broader organizational factors. Electronic databases, including PubMed, Embase, Scopus, Google Scholar, EBSCOhost, and Science Direct, were then searched for eligible studies on models to explain and predict safe behaviors, which were published between the years 2000 and 2019. Medical subject headings were used as the primary analytical element. Medical subject headings and subheadings were then extracted from the literature. One researcher conducted the search and 3 researchers performed screening and data extraction. Then, constructs described in each study were assessed to determine which were the most consistent with themes derived from our qualitative analysis. Results A total of 2032 publications were found using the search strategy. Of these, 142 studies were assessed and 28 studies met the inclusion criteria and were included in the review. The themes identified in the qualitative study most closely matched 3 scales included in Wu et al's model that measured safety behavior and performance, safety leadership, and safety climate in petrochemical industries. Poor direct safety management and supervision matched with safety leadership and its subscales; unsafe workplace conditions matched with safety climate and its subscales; workers' perceptions, skills, and training matched with safety performance and its subscales; and broader organizational factors matched with some subscales of the model. Conclusions This is the first literature review to identify models intended to explain and predict safe behavior and select the model most consistent with themes elicited from a qualitative study. Our results showed that effective safety leadership and management and safety climate and culture systems are the most frequently identified factors affecting safe behaviors in the petrochemical industry. These results can further help safety researchers and professionals design effective behavior-based safety interventions, which can have a more sustainable and persistent impact on workers’ safety behaviors. Trial Registration Iranian Registry of Clinical Trials IRCT20170515033981N2; https://www.irct.ir/trial/26107 International Registered Report Identifier (IRRID) RR2-10.1186/s12889-019-7126-1

Abstract:

Abstract Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood with often fatal outcome. Despite many attempts to develop alternative treatment options allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative modality. In the past our group has linked the prognosis of JMML to differential DNA methylation patterns (Olk-Batz, Blood 2011;117:4871-80 and Poetsch, Epigenetics 2014;9:1252-60), suggesting a key role of epigenetic modifications in JMML pathophysiology. To overcome the lack of suitable preclinical JMML research models we have developed an ex vivo JMML xenotransplantation system using neonatal Rag2-/- gamma-c-/- mice. Transplantation of 1x106 primary JMML cells resulted in stable xenologous engraftment and reproduced a characteristic JMML phenotype including myelomonocytic expansion; infiltration of spleen, liver and, notably, lung; splenomegaly; and reduced survival (median 26 weeks). Persistent human engraftment and leukemic organ infiltration was confirmed by both flow cytometry and immunohistology. Ras pathway mutations present in xenotransplanted patient samples were invariably confirmed in engrafted tissues. In addition, the model sustained serial transplantations and can therefore be used to amplify scarce patient material. We first tested if DNA methylation patterns in JMML cells were stable even after xenologous engraftment because such stability would be a prerequisite if the model were to be used for preclinical investigation of DNA methyltransferase inhibitors. JMML cells before xenotransplantation and those retrieved from the bone marrow of engrafted mice were profiled for global CpG methylation using Illumina 450K arrays. DNA methylation patterns in JMML were patient-specific and surprisingly robust in functional regions over several months of engraftment time (on average, 0.29% of 30877 promoters and 0.25 % of 30725 intragenic regions were called as "differentially methylated" between source and xenograft; 0.2 β-value change cutoff). These findings confirm the suitability of the xenograft model to investigate JMML epigenetics and, more importantly, indicate that patient-specific epigenetic profiles originate in leukemia-initiating stem cells, reinforcing a fundamental role of these alterations in JMML biology. Our group recently published a retrospective case series demonstrating unprecedented clinical efficacy of the DNA methyltransferase inhibitor 5-azacytidine (5AC) to induce partial or complete remissions in JMML before allogeneic HSCT (Cseh, Blood 2015;125:2311-3). To further investigate the drug on the preclinical level we administered 5AC to Rag2-/- gamma-c-/- mice xenografted with primary JMML cells. After a leukemia establishment phase the mice were divided into treatment or mock groups and treated with 5AC (3mg/kg body weight i.p., N=6) or saline (N=6) for 2 cycles (1 dose daily for 5 days; 9 days of recovery). This regimen was tolerated well by the animals. We found that 5AC reduced JMML infiltration in all organs analyzed, with most pronounced effects in spleen (human CD45+ fraction of all CD45+ cells, 0.24% +/- 0.04% vs 39.78% +/- 10.72%; p<0.01) and lung (0.41% +/-0.18% vs 42.88% +/-8.42%; p<0.01). The proportion of early progenitor cells (CD34+) within the human leukemia population in murine bone marrow was dramatically reduced after 5AC treatment (7.89% +/-0.74% vs 32.65% +/-3.76%; p<0.01) while the amount of granulocytes increased simultaneously (44.90% +/-1.74% vs 9.35% +/-1.95%; p<0.01). These findings suggest a loss of JMML cells induced by forced differentiation of more immature cells into mature myelomonocytic cells with reduced proliferation potential. Bisulfite pyrosequencing of the human BMP4 promoter CpG island, a locus frequently hypermethylated in JMML, showed significantly reduced DNA methylation in JMML cells retrieved from 5AC-treated mice (31.32% +/-2.66% vs 52.46% +/-1.39%; p<0.001). In summary we created an ex vivo JMML xenograft model in immunodeficient mice that reflects many important aspects of this disorder and proved its usefulness for preclinical research of DNA methyltransferase inhibition because of extraordinary stability of leukemic DNA methylation patterns. 5AC showed clear preclinical efficacy in this model, supporting its further development in clinical treatment strategies for JMML. Disclosures No relevant conflicts of interest to declare.

Abstract:

Abstract This study retrospectively evaluated 144 consecutive patients with unusual site thrombosis who referred to our Thrombosis Center between 2000 and 2016. All patients were classified as having either splanchnic venous thrombosis (SVT; n=127) or cerebral venous thrombosis (CVT; n=17). On the presence and type of provoking risk factors, then patients were categorized into three groups: unprovoked, those with possibly resolved provoking factors (PR), and those with persistent provoking factors (PP). Among the identified risk factors regarded as PP, we focused on Myeloproliferative Neoplasms (MPN) and performed a clinical comparison between MPN patients with SVT (MPN-SVT) and those with CVT (MPN-SVT). The characteristics of our cohort well reflects the clinical heterogeneity of clinical features commonly found in the routine clinical practice of diagnosing unusual site thrombosis. One hundred and twenty seven SVT patients were included: 7 unprovoked SVT, 10 SVT with PR, 110 SVT with PP; seventeen patients showed CVT, 5 unprovoked, 6 CVT with PR and 6 CVT with PP. Major risk factor for SVT with PP was liver cirrhosis (71.6%), whereas for CVT were MPN (5 patients, 29.4%). MPN was present in 8 patients (6.2%) of SVT (MPN-SVT vs MPN-CVT, p=0.009). For MPN-SVT, 3 patients showed the morphological features of polycytemia vera (PV), 2 of essential thrombocytemia (ET), 1 of primary myelofibrosis (PMF) and 2 fell into the MPN unclassified category (U-MPN); distribution of MPN subtypes for CVT was as follows: 1 PV, 2 ET and 2 U-MPN. Molecular analysis identified the JAK2V617F mutation respectively in 75% patients with MPN-SVT and in 60% patients with MPN-CVT; bone marrow histological features supported the diagnosis of MPN in all cases. Median age at MPN-SVT diagnosis was 46 years (range 17-78) vs 43 years (range 31-84) for MPN-CVT. Coexisting PR and thrombophilic abnormalities were identified in 75% and 20% of MPN-SVT and MPN-CVT respectively, so MPN are per se a strong risk for thrombosis and the leading systemic cause of CVT. In four of five cases (80%), CVT antedate the clinical phenotype of an overt MPN, whereas SVT occurred at MPN diagnosis in five patients and during MPN follow-up in three patients (median 164 months, range 88-215). At diagnosis MPN-SVT tended to have significantly lower platelet and white blood cell counts and haemoglobin concentration than MPN-CVT (respectively p<0.001, p<0.001 and p=0.002). Similar proportion of MPN patients in the two groups received cytoreductive treatment (hydroxyurea and alpha interferon) and appropriate anticoagulant therapy that consisted of low molecular weight heparin (LMWH) followed by oral vitamin K antagonists (VKA). MPN-SVT and MPN-CVT experienced similar median duration of anticoagulation (26 months for MPN-SVT, range 1-62, and 26 months for MPN-CVT, range 4-168) and a good quality anticoagulation control (median time within therapeutic range of 71 vs 87% respectively for MPN-SVT and MPN-CVT). Seventy-five percent MPN-SVT and 80% of MPN-CVT remain on indefinite anticoagulation. All patients were alive at last follow-up and the results of imaging techniques showed resolution of thrombosis in 87.5% and 80% of MPN-SVT and MPN-CVT respectively; the probability of recanalization of the occluded vessels was 18 months and 4 months for MPN-SVT and MPN-CVT, respectively. Only in one patient with MPN-SVT, a major bleed occurred on-treatment while the incidence of recurrent thrombosis was the same for both MPN-SVT and MPN-CVT (0.02 per 100 patients-year). In conclusion, our study evaluated unselected populations with unusual site thrombosis that were followed in our Thrombosis Center, an anticoagulation clinic well experienced on pathogenic mechanisms and anticoagulant treatment. Our findings have practical implications and point out the role of MPN as a major contributory factor for the pathogenesis of CVT with PP, even in absence of overt myeloproliferative features and additional prothombotic factors. Regarding management of vascular complications, patients with MPN-SVT and MPN-CVT responded equally well and efficacy of anticoagulation was not affected by the site of thrombosis. Disclosures Offidani: Celgene: Honoraria, Research Funding; Janssen: Honoraria.

Abstract:

Background Unrelated cord blood transplantation (UCBT) after reduced intensity conditioning regimen (RIC) has extended the use of cord blood in elderly patients and those with co-morbidities without an HLA identical donor, although relapse post transplant remains a concern in high risk AML patients. HLA incompatibilities between donor and recipient might enhance Natural Killer (NK) cell alloreactivity after allogeneic hematopoietic stem cell transplantation (HSCT). We previously observed that the quality of NK cell reconstitution was impaired after haploidentical HSCT, impacting on graft versus leukemia (GvL) effect, but was preserved after UCBT in a small cohort of patients. Methods To evaluate RIC-UCBT in patients with acute myeloid leukemia (AML), a prospective phase II multicentric trial was conducted in France, whose primary objective was to show a reduction in non-relapse mortality (NRM) from 40% (based on registry data) to 20%. Seventy-nine patients were enrolled for a de novo or secondary AML in complete remission (CR). The conditioning regimen consisted of cyclophosphamide (50mg/kg) + fludarabine (200mg/m2) + total body irradiation (2Gy), CsA +MMF as GVHD prophylaxis and GCSF from day +1. Patients were enrolled in 23 centers from October 2007 to September 2009. Engraftment rate was 87 % at day+60. At 2 years, overall survival, incidence of relapse and LFS were respectively 44%, 46% and 35%. Peripheral blood samples were collected following UCBT in order to realize an extensive phenotypic and functional study of NK cells. Studies were started at 1 month (M1) post UCBT with available samples for 62 out of the 69 included patients, and were compared to 20 healthy donors and 15 cord blood (CB). Results Total CD3+ T-cells were 117 /mm3 at M1 (range 0-934), and 465 /mm3 at M3 (range 0-2917). CD19+ B-cells were 36/mm3, (range 0-524) and 342/mm3 (range 0-2990) at M1 and M3 respectively. NK cell recovery was prompt, representing 47% of the total lymphocyte population at M1 (186 CD3-CD56+ NK cells/mm3), 30% at M3 (239/mm3; range 2-767) and decreasing to normal rate at M6 (20% of lymphocytes). At M1 post-UCBT, NK cells exhibited high rate of CD56bright, NKG2A, and KIR2DL4 associated with a decreased expression of CD8 and CD161, compared to CB and healthy donors. These immature characteristics were transient and return to normal value from M3 or M6 post-UCBT. Interestingly, we also observed a significant increased expression of the activation markers CD69, and HLA-DR during the whole period of the study, compared to CB and healthy donors, which probably reflects a persistent proliferation state of the NK cells. On the other hand, NK cells post-UCBT were indistinguishable from CB and healthy donors control samples for other receptor tested such as NKp30, NKp46, NKp80, and NKG2D. Notably, Expression of KIR2DL1 was decreased at M1 and M3 but reached similar values to controls at M6, whereas, KIR3DL1 was increased during the whole study. To determine the significance of these phenotypic features, we assessed polyfunctional ability of NK cells following UCBT by a combined analysis of the degranulation (CD107a), and the production of IFN-γ and TNF-α. This study reveals that NK at M1 post-graft exhibited a transient higher ability to produce IFN-γ than healthy donors (p<0.0001), which reaches normal values by 6 months after UCBT, in correlation with the evolution of the immunoregulatory NKG2A+/CD56brightNK cells subset post transplant. Production of TNF-α was reduced in CB and at M1 as compared to healthy donors (p<0.0001) but quickly restored starting from M3. Degranulation’s ability was slightly impaired at M1 and M3, as compared to CB and healthy donors (p=0.002), but restored at M6. Conclusion This study shows that after RIC-UCBT, NK cells display some phenotypic features of activation associated with a prompt and complete restoration of their ability for polyfunctional activities. Further analyzes are needed to assess the impact of such observation on NK cell mediated GvL effect in this prospective trial of RIC-UCBT for AML patients in CR. Disclosures: No relevant conflicts of interest to declare.

Abstract:

Abstract Abstract 2994 The suboptimal numbers of hematopoietic stem cells (HSC) present in human umbilical cord blood (CB) grafts results in a significant delay in blood cell reconstitution or graft failure, particularly in adult patients following transplantation. Using chromatin modifying agents (CMAs), including 5aza-2-deoxycytidine (5azaD) and trichostatin A (TSA), we developed an ex-vivo expansion strategy that permits 7-fold expansion of transplantable HSC (Araki et al. Blood 2007, Exp Hematol 2009). Here we performed validation studies in non-human primate (NHP) baboons to examine the potential genotoxicity of CMA-expanded bone marrow (BM) graft. To our knowledge, there have been no reports suggesting 5azaD exacerbate chromosomal instability in human. We have demonstrated that the sequential addition of low-dose 5azaD (5 micromolar) and TSA (5 ng/ml) to human CB CD34+ cells does not result in a persistent depletion of Dnmt1 transcripts and protein levels. In this global methylation analysis using a LINE-1 assay indicates that DNA demethylation, which occurs with CMA treatment in culture, is transient: LINE-1 methylation of CD34+ cells in the absence or presence of CMA was 78.5% ± 2.2% and 55.4 % ± 2.2% respectively at day 3 while methylation levels of treated CD34+ cells returns to 69.7% ± 2.1% by day 9. In an attempt to evaluate the genotoxic potential of low-dose 5azaD/TSA, we transplanted baboons with CMA-expanded autologous BM grafts following a myeloablative dose of IV busulfan (4 mg/kg/day × 4 days). Although the initial pre-expansion CD34+ cell dose of CMA-expanded BM grafts was low (0.68, 2.64 and 5.18 × 106 CD34+ cells/kg respectively), all three baboons engrafted following transplantation. Following peripheral blood (PB) cell count recovery we examined BM CD34 and colony-forming cell (CFC) counts. Of note, the absolute number of CD34+ cells in the BM following hematopoietic reconstitution (926.0 ± 142.8 /microliter) was 3.5 fold higher than pre-transplant levels (257.9 ± 56.2 /microliter). However, the absolute number of CFC in the BM was 2.2 fold lower than pre-transplant levels. BM biopsies performed on the 3 baboons serially prior to, and 56, 120 and 400 days post-transplant respectively to examine hematopoietic recovery, myeloid-to-erythroid ratio and cellularity did not demonstrate myelodysplasia or malignancy. There was tri-lineage hematopoiesis evident in the BM in all 3 baboons with 50 to 70% cellularity. Further evaluation of the safety of 5azaD/TSA-expanded grafts was performed using three independent methods. Firstly, 150 NOD/SCID mice who received 5azaD/TSA expanded human CB grafts have not displayed any signs of tumor formation after primary or secondary transplantation. Secondly, karyotyping of CMA-expanded human CB graft or baboon CD34+ cells prior to and following transplant (day 266) reveals no detectable chromosomal anomalies. Thirdly, we used Flow-FISH, an in situ flow cytometry-based assay to measure relative telomere lengths (RTL) of purified CD11a+ (97.59% ± 0.38%) leukocytes from baboon BM prior to and following transplantation. The majority of CD11a+ leukocytes are short-lived which indirectly reflects the telomere lengths of the respective HSC from which they are derived. Our results show that the RTL of Jurkat cells were 10.6% ± 0.37%, while human CB cell RTLs were 19.7% ± 1.2%. The pre- and post-transplant (day 56) BM cells of one baboon (PA7619) displayed (average) RTL values of 13.48% ± 0.76 % and 13.96% ± 0.68% respectively. In another animal (PA7963), average RTL values were determined serially using Flow-FISH on BM CD11a+ enriched cells at multiple time-points post-transplant up to day 417 which displayed mean RTL of 17.66 % ± 0.52% while pre-transplant RTL was 15.39% ± 0.62%. In summary, the mean RTL values of baboon leukocytes were stable and post-transplant values were comparable to pre-transplant levels. Importantly, year-long monitoring shows no evidence of hematologic malignancies as determined by PB counts, BM examination (including cytogenetics) and measurements of leukocyte RTL values in a clinically relevant NHP model. These studies offer preliminary evidence that CMA-mediated expansion of CD34+ cells transferred into primates (and human CB CD34+ cells transferred into mice) is not genotoxic and does not induce hematopoietic malignancies, of relevance to use of human CMA-expanded CB grafts in clinical trials. Disclosures: No relevant conflicts of interest to declare.

Abstract:

Abstract Chronic myeloid leukemia (CML) reflects the biology of a stem cell driven neoplasm. The cytogenetic marker t(9;22) gives rise to Bcr-Abl protein that activates various signaling pathways resulting in increased proliferation and differentiation, protection from apoptosis and altered adhesion properties of CML cells. The implementation of Bcr-Abl tyrosine kinase inhibitors (TKI) has greatly improved therapy outcome of CML patients. However, more than one third of newly diagnosed CML patients develops primary or secondary resistance mostly due to Bcr-Abl mutations or intolerance to TKIs. Moreover, even in patients without mutations, mechanisms such as low persisting Bcr-Abl levels in patients on TKI and/or a lack of oncogene addiction have been described to induce CML stem cell persistence. We have previously demonstrated Bcr-Abl independent stem cell persistence using inducible SCLtTA/Bcr-Abl mice (BLOOD 2010, 115:3185; BLOOD 2012, 119:1501), and recent data suggest an important role for TNF-alpha in MPN stem cell persistence (BLOOD 2011, 118:6392), including CML (BLOOD 2013, 112:3335). Therefore, we have now interrogated our mouse model for a novel stem cell directed therapeutic approach, using pharmacologic inhibition of TNF-alpha. Analysis of TNF-alpha expression by qRT-PCR in Bcr-Abl infected 32Dcl3 and Ba/F3 cells revealed elevated cytokine expression upon Bcr-Abl transduction. Imatinib treatment of 32Dcl3:Bcr-Abl cells reverted elevated TNF-alpha levels suggesting that TNF-alpha upregulation is kinase mediated in this cell line. ChIP-Seq of TKI treated vs non-treated 32Dcl3:Bcr-Abl cells showed H3K9 acetylation of the TNF-alpha promoter in untreated cells, which decreased upon Bcr-Abl inhibition. Subsequently, we analyzed TNF-alpha expression in lin-;Sca-1+;c-kit+ (LSK) cells isolated from SCLtTA/Bcr-Abl mice that had been induced to express Bcr-Abl for 3 weeks. Leukemic LSK cells showed again significantly increased TNF-alpha expression. Interestingly, TNF-alpha RNA levels were not altered in total bone marrow (BM) cells isolated from transplanted leukemic Bcr-Abl mice compared to controls, suggesting a stem cell specific mechanism regulating TNF-alpha expression in vivo. Next, we tested the therapeutic effect of TNF-alpha inhibition combined with TKI therapy. We applied the chimeric antibody infliximab that blocks soluble as well as membrane-bound TNF-alpha. We transplanted 1.5x105 wildtype (wt) or Bcr-Abl BM cells expressing CD45.1 into 10 Gy irradiated CD45.2+ wt recipients (wt n=4; Bcr-Abl n=24) and allowed these cells to engraft and expand for 2 weeks. We then either treated Bcr-Abl transplanted mice with nilotinib alone (50mg/kg, daily) or combined the TKI therapy with infliximab (10mg/kg, weekly i.v.). As controls, we either treated Bcr-Abl transplanted mice with vehicle alone (daily) or together with IgG (10mg/kg, i.v., weekly). Wt recipients remained untreated. After 2.5 weeks of therapy, we sacrificed all mice for analyses. Spleen weight of vehicle and vehicle+IgG treated mice were increased compared to nilotinib and nilotinib+infliximab treated recipients (Table 1). Table 1. Analyses of mice that were subjected to TNF-alpha and Bcr-Abl inhibition wt Bcr-Abl vehicle vehicle + IgG nilotinib nilotinib + infliximab spleen weight (mg) 73 ± 5 274 ± 63 280 ± 55 125 ± 5 185 ± 31 % of lin- cells 4.8 ± 1.1 31.1 ± 11.0 25.0 ± 14.1 3.4 ± 1.0 3.1 ± 1.4 % of LSK/CD45.1+ cells 5.7 ± 0.7 41.2 ± 5.9 31.6 ± 11.7 20.3 ± 10.8 7.2 ± 3.4 FACS analyses s that lin- cells were significantly elevated in vehicle and vehicle+IgG treated Bcr-Abl recipients compared to wt mice. Nilotinib and nilotinib+infliximab therapy decreased lin- cells to 3.4% and 3.1% respectively. As expected, leukemic CD45.1+ LSK cells were significantly increased in vehicle (7-fold) and vehicle+IgG (5.5-fold) treated mice compared to CD45.1+ wt LSK cells. Nilotinib treatment decreased the elevated levels of CD45.1+ LSK cells compared to wt controls to 3.6-fold but combining TKI+infliximab decreased the leukemic stem cell population further to 1.3-fold difference compared to wt mice. In conclusion, we show that TNF-alpha expression is elevated in Bcr-Abl positive leukemic stem cells and this cell population is significantly reduced by combining TKI therapy with an anti TNF-alpha approach. Our data reveal that this combinational therapy is a powerful tool to target the TKI resistant stem cell population in CML. Disclosures Koschmieder: Janssen Cilag: Other: Travel reimbursem*nt for scientific conferences; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursem*nt for scientific conferences; Sanofi: Membership on an entity's Board of Directors or advisory committees; Baxalta/CTI: Membership on an entity's Board of Directors or advisory committees; Novartis Foundation: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursem*nt for scientific conferences, Research Funding. Brümmendorf:Ariad: Consultancy, Honoraria; Bristol-Meyers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria. Schemionek:Novartis Foundation for Therapeutic Research: Research Funding. Off Label Use: Infliximab used in CML mouse model.

Abstract:

Education in Oceania continues to reflect the embedded implicit and explicit colonial practices and processes from the past. This paper conceptualises a cultural approach to education and leadership appropriate and relevant to the Republic of the Marshall Islands. As elementary school leaders, we highlight Kanne Lobal, a traditional Marshallese navigation practice based on indigenous language, values and practices. We conceptualise and develop Kanne Lobal in this paper as a framework for understanding the usefulness of our indigenous knowledge in leadership and educational practices within formal education. Through bwebwenato, a method of talk story, our key learnings and reflexivities were captured. We argue that realising the value of Marshallese indigenous knowledge and practices for school leaders requires purposeful training of the ways in which our knowledge can be made useful in our professional educational responsibilities. Drawing from our Marshallese knowledge is an intentional effort to inspire, empower and express what education and leadership partnership means for Marshallese people, as articulated by Marshallese themselves. Introduction As noted in the call for papers within the Waikato Journal of Education (WJE) for this special issue, bodies of knowledge and histories in Oceania have long sustained generations across geographic boundaries to ensure cultural survival. For Marshallese people, we cannot really know ourselves “until we know how we came to be where we are today” (Walsh, Heine, Bigler & Stege, 2012). Jitdam Kapeel is a popular Marshallese concept and ideal associated with inquiring into relationships within the family and community. In a similar way, the practice of relating is about connecting the present and future to the past. Education and leadership partnerships are linked and we look back to the past, our history, to make sense and feel inspired to transform practices that will benefit our people. In this paper and in light of our next generation, we reconnect with our navigation stories to inspire and empower education and leadership. Kanne lobal is part of our navigation stories, a conceptual framework centred on cultural practices, values, and concepts that embrace collective partnerships. Our link to this talanoa vā with others in the special issue is to attempt to make sense of connections given the global COVID-19 context by providing a Marshallese approach to address the physical and relational “distance” between education and leadership partnerships in Oceania. Like the majority of developing small island nations in Oceania, the Republic of the Marshall Islands (RMI) has had its share of educational challenges through colonial legacies of the past which continues to drive education systems in the region (Heine, 2002). The historical administration and education in the RMI is one of colonisation. Successive administrations by the Spanish, German, Japanese, and now the US, has resulted in education and learning that privileges western knowledge and forms of learning. This paper foregrounds understandings of education and learning as told by the voices of elementary school leaders from the RMI. The move to re-think education and leadership from Marshallese perspectives is an act of shifting the focus of bwebwenato or conversations that centres on Marshallese language and worldviews. The concept of jelalokjen was conceptualised as traditional education framed mainly within the community context. In the past, jelalokjen was practiced and transmitted to the younger generation for cultural continuity. During the arrival of colonial administrations into the RMI, jelalokjen was likened to the western notions of education and schooling (Kupferman, 2004). Today, the primary function of jelalokjen, as traditional and formal education, it is for “survival in a hostile [and challenging] environment” (Kupferman, 2004, p. 43). Because western approaches to learning in the RMI have not always resulted in positive outcomes for those engaged within the education system, as school leaders who value our cultural knowledge and practices, and aspire to maintain our language with the next generation, we turn to Kanne Lobal, a practice embedded in our navigation stories, collective aspirations, and leadership. The significance in the development of Kanne Lobal, as an appropriate framework for education and leadership, resulted in us coming together and working together. Not only were we able to share our leadership concerns, however, the engagement strengthened our connections with each other as school leaders, our communities, and the Public Schooling System (PSS). Prior to that, many of us were in competition for resources. Educational Leadership: IQBE and GCSL Leadership is a valued practice in the RMI. Before the IQBE programme started in 2018, the majority of the school leaders on the main island of Majuro had not engaged in collaborative partnerships with each other before. Our main educational purpose was to achieve accreditation from the Western Association of Schools and Colleges (WASC), an accreditation commission for schools in the United States. The WASC accreditation dictated our work and relationships and many school leaders on Majuro felt the pressure of competition against each other. We, the authors in this paper, share our collective bwebwenato, highlighting our school leadership experiences and how we gained strength from our own ancestral knowledge to empower “us”, to collaborate with each other, our teachers, communities, as well as with PSS; a collaborative partnership we had not realised in the past. The paucity of literature that captures Kajin Majol (Marshallese language) and education in general in the RMI is what we intend to fill by sharing our reflections and experiences. To move our educational practices forward we highlight Kanne Lobal, a cultural approach that focuses on our strengths, collective social responsibilities and wellbeing. For a long time, there was no formal training in place for elementary school leaders. School principals and vice principals were appointed primarily on their academic merit through having an undergraduate qualification. As part of the first cohort of fifteen school leaders, we engaged in the professional training programme, the Graduate Certificate in School Leadership (GCSL), refitted to our context after its initial development in the Solomon Islands. GCSL was coordinated by the Institute of Education (IOE) at the University of the South Pacific (USP). GCSL was seen as a relevant and appropriate training programme for school leaders in the RMI as part of an Asia Development Bank (ADB) funded programme which aimed at “Improving Quality Basic Education” (IQBE) in parts of the northern Pacific. GCSL was managed on Majuro, RMI’s main island, by the director at the time Dr Irene Taafaki, coordinator Yolanda McKay, and administrators at the University of the South Pacific’s (USP) RMI campus. Through the provision of GCSL, as school leaders we were encouraged to re-think and draw-from our own cultural repository and connect to our ancestral knowledge that have always provided strength for us. This kind of thinking and practice was encouraged by our educational leaders (Heine, 2002). We argue that a culturally-affirming and culturally-contextual framework that reflects the lived experiences of Marshallese people is much needed and enables the disruption of inherent colonial processes left behind by Western and Eastern administrations which have influenced our education system in the RMI (Heine, 2002). Kanne Lobal, an approach utilising a traditional navigation has warranted its need to provide solutions for today’s educational challenges for us in the RMI. Education in the Pacific Education in the Pacific cannot be understood without contextualising it in its history and culture. It is the same for us in the RMI (Heine, 2002; Walsh et al., 2012). The RMI is located in the Pacific Ocean and is part of Micronesia. It was named after a British captain, John Marshall in the 1700s. The atolls in the RMI were explored by the Spanish in the 16th century. Germany unsuccessfully attempted to colonize the islands in 1885. Japan took control in 1914, but after several battles during World War II, the US seized the RMI from them. In 1947, the United Nations made the island group, along with the Mariana and Caroline archipelagos, a U.S. trust territory (Walsh et al, 2012). Education in the RMI reflects the colonial administrations of Germany, Japan, and now the US. Before the turn of the century, formal education in the Pacific reflected western values, practices, and standards. Prior to that, education was informal and not binded to formal learning institutions (Thaman, 1997) and oral traditions was used as the medium for transmitting learning about customs and practices living with parents, grandparents, great grandparents. As alluded to by Jiba B. Kabua (2004), any “discussion about education is necessarily a discussion of culture, and any policy on education is also a policy of culture” (p. 181). It is impossible to promote one without the other, and it is not logical to understand one without the other. Re-thinking how education should look like, the pedagogical strategies that are relevant in our classrooms, the ways to engage with our parents and communities - such re-thinking sits within our cultural approaches and frameworks. Our collective attempts to provide a cultural framework that is relevant and appropriate for education in our context, sits within the political endeavour to decolonize. This means that what we are providing will not only be useful, but it can be used as a tool to question and identify whether things in place restrict and prevent our culture or whether they promote and foreground cultural ideas and concepts, a significant discussion of culture linked to education (Kabua, 2004). Donor funded development aid programmes were provided to support the challenges within education systems. Concerned with the persistent low educational outcomes of Pacific students, despite the prevalence of aid programmes in the region, in 2000 Pacific educators and leaders with support from New Zealand Aid (NZ Aid) decided to intervene (Heine, 2002; Taufe’ulungaki, 2014). In April 2001, a group of Pacific educators and leaders across the region were invited to a colloquium funded by the New Zealand Overseas Development Agency held in Suva Fiji at the University of the South Pacific. The main purpose of the colloquium was to enable “Pacific educators to re-think the values, assumptions and beliefs underlying [formal] schooling in Oceania” (Benson, 2002). Leadership, in general, is a valued practice in the RMI (Heine, 2002). Despite education leadership being identified as a significant factor in school improvement (Sanga & Chu, 2009), the limited formal training opportunities of school principals in the region was a persistent concern. As part of an Asia Development Bank (ADB) funded project, the Improve Quality Basic Education (IQBE) intervention was developed and implemented in the RMI in 2017. Mentoring is a process associated with the continuity and sustainability of leadership knowledge and practices (Sanga & Chu, 2009). It is a key aspect of building capacity and capabilities within human resources in education (ibid). Indigenous knowledges and education research According to Hilda Heine, the relationship between education and leadership is about understanding Marshallese history and culture (cited in Walsh et al., 2012). It is about sharing indigenous knowledge and histories that “details for future generations a story of survival and resilience and the pride we possess as a people” (Heine, cited in Walsh et al., 2012, p. v). This paper is fuelled by postcolonial aspirations yet is grounded in Pacific indigenous research. This means that our intentions are driven by postcolonial pursuits and discourses linked to challenging the colonial systems and schooling in the Pacific region that privileges western knowledge and learning and marginalises the education practices and processes of local people (Thiong’o, 1986). A point of difference and orientation from postcolonialism is a desire to foreground indigenous Pacific language, specifically Majin Majol, through Marshallese concepts. Our collective bwebwenato and conversation honours and values kautiej (respect), jouj eo mour eo (reciprocity), and jouj (kindness) (Taafaki & Fowler, 2019). Pacific leaders developed the Rethinking Pacific Education Initiative for and by Pacific People (RPEIPP) in 2002 to take control of the ways in which education research was conducted by donor funded organisations (Taufe’ulungaki, 2014). Our former president, Dr Hilda Heine was part of the group of leaders who sought to counter the ways in which our educational and leadership stories were controlled and told by non-Marshallese (Heine, 2002). As a former minister of education in the RMI, Hilda Heine continues to inspire and encourage the next generation of educators, school leaders, and researchers to re-think and de-construct the way learning and education is conceptualised for Marshallese people. The conceptualisation of Kanne Lobal acknowledges its origin, grounded in Marshallese navigation knowledge and practice. Our decision to unpack and deconstruct Kanne Lobal within the context of formal education and leadership responds to the need to not only draw from indigenous Marshallese ideas and practice but to consider that the next generation will continue to be educated using western processes and initiatives particularly from the US where we get a lot of our funding from. According to indigenous researchers Dawn Bessarab and Bridget Ng’andu (2010), doing research that considers “culturally appropriate processes to engage with indigenous groups and individuals is particularly pertinent in today’s research environment” (p. 37). Pacific indigenous educators and researchers have turned to their own ancestral knowledge and practices for inspiration and empowerment. Within western research contexts, the often stringent ideals and processes are not always encouraging of indigenous methods and practices. However, many were able to ground and articulate their use of indigenous methods as being relevant and appropriate to capturing the realities of their communities (Nabobo-Baba, 2008; Sualii-Sauni & Fulu-Aiolupotea, 2014; Thaman, 1997). At the same time, utilising Pacific indigenous methods and approaches enabled research engagement with their communities that honoured and respected them and their communities. For example, Tongan, Samoan, and Fijian researchers used the talanoa method as a way to capture the stories, lived realities, and worldviews of their communities within education in the diaspora (Fa’avae, Jones, & Manu’atu, 2016; Nabobo-Baba, 2008; Sualii-Sauni & Aiolupotea, 2014; Vaioleti, 2005). Tok stori was used by Solomon Islander educators and school leaders to highlight the unique circles of conversational practice and storytelling that leads to more positive engagement with their community members, capturing rich and meaningful narratives as a result (Sanga & Houma, 2004). The Indigenous Aborigine in Australia utilise yarning as a “relaxed discussion through which both the researcher and participant journey together visiting places and topics of interest relevant” (Bessarab & Ng’andu, 2010, p. 38). Despite the diverse forms of discussions and storytelling by indigenous peoples, of significance are the cultural protocols, ethics, and language for conducting and guiding the engagement (Bessarab & Ng’andu, 2010; Nabobo-Baba, 2008; Sualii-Sauni & Aiolupotea, 2014). Through the ethics, values, protocols, and language, these are what makes indigenous methods or frameworks unique compared to western methods like in-depth interviews or semi-structured interviews. This is why it is important for us as Marshallese educators to frame, ground, and articulate how our own methods and frameworks of learning could be realised in western education (Heine, 2002; Jetnil-Kijiner, 2014). In this paper, we utilise bwebwenato as an appropriate method linked to “talk story”, capturing our collective stories and experiences during GCSL and how we sought to build partnerships and collaboration with each other, our communities, and the PSS. Bwebwenato and drawing from Kajin Majel Legends and stories that reflect Marshallese society and its cultural values have survived through our oral traditions. The practice of weaving also holds knowledge about our “valuable and earliest sources of knowledge” (Taafaki & Fowler, 2019, p. 2). The skilful navigation of Marshallese wayfarers on the walap (large canoes) in the ocean is testament of their leadership and the value they place on ensuring the survival and continuity of Marshallese people (Taafaki & Fowler, 2019; Walsh et al., 2012). During her graduate study in 2014, Kathy Jetnil-Kijiner conceptualised bwebwenato as being the most “well-known form of Marshallese orality” (p. 38). The Marshallese-English dictionary defined bwebwenato as talk, conversation, story, history, article, episode, lore, myth, or tale (cited in Jetnil Kijiner, 2014). Three years later in 2017, bwebwenato was utilised in a doctoral project by Natalie Nimmer as a research method to gather “talk stories” about the experiences of 10 Marshallese experts in knowledge and skills ranging from sewing to linguistics, canoe-making and business. Our collective bwebwenato in this paper centres on Marshallese ideas and language. The philosophy of Marshallese knowledge is rooted in our “Kajin Majel”, or Marshallese language and is shared and transmitted through our oral traditions. For instance, through our historical stories and myths. Marshallese philosophy, that is, the knowledge systems inherent in our beliefs, values, customs, and practices are shared. They are inherently relational, meaning that knowledge systems and philosophies within our world are connected, in mind, body, and spirit (Jetnil-Kijiner, 2014; Nimmer, 2017). Although some Marshallese believe that our knowledge is disappearing as more and more elders pass away, it is therefore important work together, and learn from each other about the knowledges shared not only by the living but through their lamentations and stories of those who are no longer with us (Jetnil-Kijiner, 2014). As a Marshallese practice, weaving has been passed-down from generation to generation. Although the art of weaving is no longer as common as it used to be, the artefacts such as the “jaki-ed” (clothing mats) continue to embody significant Marshallese values and traditions. For our weavers, the jouj (check spelling) is the centre of the mat and it is where the weaving starts. When the jouj is correct and weaved well, the remainder and every other part of the mat will be right. The jouj is symbolic of the “heart” and if the heart is prepared well, trained well, then life or all other parts of the body will be well (Taafaki & Fowler, 2019). In that light, we have applied the same to this paper. Conceptualising and drawing from cultural practices that are close and dear to our hearts embodies a significant ontological attempt to prioritize our own knowledge and language, a sense of endearment to who we are and what we believe education to be like for us and the next generation. The application of the phrase “Majolizing '' was used by the Ministry of Education when Hilda Heine was minister, to weave cultural ideas and language into the way that teachers understand the curriculum, develop lesson plans and execute them in the classroom. Despite this, there were still concerns with the embedded colonized practices where teachers defaulted to eurocentric methods of doing things, like the strategies provided in the textbooks given to us. In some ways, our education was slow to adjust to the “Majolizing '' intention by our former minister. In this paper, we provide Kanne Lobal as a way to contribute to the “Majolizing intention” and perhaps speed up yet still be collectively responsible to all involved in education. Kajin Wa and Kanne Lobal “Wa” is the Marshallese concept for canoe. Kajin wa, as in canoe language, has a lot of symbolic meaning linked to deeply-held Marshallese values and practices. The canoe was the foundational practice that supported the livelihood of harsh atoll island living which reflects the Marshallese social world. The experts of Kajin wa often refer to “wa” as being the vessel of life, a means and source of sustaining life (Kelen, 2009, cited in Miller, 2010). “Jouj” means kindness and is the lower part of the main hull of the canoe. It is often referred to by some canoe builders in the RMI as the heart of the canoe and is linked to love. The jouj is one of the first parts of the canoe that is built and is “used to do all other measurements, and then the rest of the canoe is built on top of it” (Miller, 2010, p. 67). The significance of the jouj is that when the canoe is in the water, the jouj is the part of the hull that is underwater and ensures that all the cargo and passengers are safe. For Marshallese, jouj or kindness is what living is about and is associated with selflessly carrying the responsibility of keeping the family and community safe. The parts of the canoe reflect Marshallese culture, legend, family, lineage, and kinship. They embody social responsibilities that guide, direct, and sustain Marshallese families’ wellbeing, from atoll to atoll. For example, the rojak (boom), rojak maan (upper boom), rojak kōrā (lower boom), and they support the edges of the ujelā/ujele (sail) (see figure 1). The literal meaning of rojak maan is male boom and rojak kōrā means female boom which together strengthens the sail and ensures the canoe propels forward in a strong yet safe way. Figuratively, the rojak maan and rojak kōrā symbolise the mother and father relationship which when strong, through the jouj (kindness and love), it can strengthen families and sustain them into the future. Figure 1. Parts of the canoe Source: https://www.canoesmarshallislands.com/2014/09/names-of-canoe-parts/ From a socio-cultural, communal, and leadership view, the canoe (wa) provides understanding of the relationships required to inspire and sustain Marshallese peoples’ education and learning. We draw from Kajin wa because they provide cultural ideas and practices that enable understanding of education and leadership necessary for sustaining Marshallese people and realities in Oceania. When building a canoe, the women are tasked with the weaving of the ujelā/ujele (sail) and to ensure that it is strong enough to withstand long journeys and the fierce winds and waters of the ocean. The Kanne Lobal relates to the front part of the ujelā/ujele (sail) where the rojak maan and rojak kōrā meet and connect (see the red lines in figure 1). Kanne Lobal is linked to the strategic use of the ujelā/ujele by navigators, when there is no wind north wind to propel them forward, to find ways to capture the winds so that their journey can continue. As a proverbial saying, Kanne Lobal is used to ignite thinking and inspire and transform practice particularly when the journey is rough and tough. In this paper we draw from Kanne Lobal to ignite, inspire, and transform our educational and leadership practices, a move to explore what has always been meaningful to Marshallese people when we are faced with challenges. The Kanne Lobal utilises our language, and cultural practices and values by sourcing from the concepts of jouj (kindness, love), kautiej (respect), and jouj eo mour eo (reciprocity). A key Marshallese proverb, “Enra bwe jen lale rara”, is the cultural practice where families enact compassion through the sharing of food in all occurrences. The term “enra” is a small basket weaved from the coconut leaves, and often used by Marshallese as a plate to share and distribute food amongst each other. Bwe-jen-lale-rara is about noticing and providing for the needs of others, and “enra” the basket will help support and provide for all that are in need. “Enra-bwe-jen-lale-rara” is symbolic of cultural exchange and reciprocity and the cultural values associated with building and maintaining relationships, and constantly honouring each other. As a Marshallese practice, in this article we share our understanding and knowledge about the challenges as well as possible solutions for education concerns in our nation. In addition, we highlight another proverb, “wa kuk wa jimor”, which relates to having one canoe, and despite its capacity to feed and provide for the individual, but within the canoe all people can benefit from what it can provide. In the same way, we provide in this paper a cultural framework that will enable all educators to benefit from. It is a framework that is far-reaching and relevant to the lived realities of Marshallese people today. Kumit relates to people united to build strength, all co-operating and working together, living in peace, harmony, and good health. Kanne Lobal: conceptual framework for education and leadership An education framework is a conceptual structure that can be used to capture ideas and thinking related to aspects of learning. Kanne Lobal is conceptualised and framed in this paper as an educational framework. Kanne Lobal highlights the significance of education as a collective partnership whereby leadership is an important aspect. Kanne Lobal draws-from indigenous Marshallese concepts like kautiej (respect), jouj eo mour eo (reciprocity), and jouj (kindness, heart). The role of a leader, including an education leader, is to prioritise collective learning and partnerships that benefits Marshallese people and the continuity and survival of the next generation (Heine, 2002; Thaman, 1995). As described by Ejnar Aerōk, an expert canoe builder in the RMI, he stated: “jerbal ippān doon bwe en maron maan wa e” (cited in Miller, 2010, p. 69). His description emphasises the significance of partnerships and working together when navigating and journeying together in order to move the canoe forward. The kubaak, the outrigger of the wa (canoe) is about “partnerships”. For us as elementary school leaders on Majuro, kubaak encourages us to value collaborative partnerships with each other as well as our communities, PSS, and other stakeholders. Partnerships is an important part of the Kanne Lobal education and leadership framework. It requires ongoing bwebwenato – the inspiring as well as confronting and challenging conversations that should be mediated and negotiated if we and our education stakeholders are to journey together to ensure that the educational services we provide benefits our next generation of young people in the RMI. Navigating ahead the partnerships, mediation, and negotiation are the core values of jouj (kindness, love), kautiej (respect), and jouj eo mour eo (reciprocity). As an organic conceptual framework grounded in indigenous values, inspired through our lived experiences, Kanne Lobal provides ideas and concepts for re-thinking education and leadership practices that are conducive to learning and teaching in the schooling context in the RMI. By no means does it provide the solution to the education ills in our nation. However, we argue that Kanne Lobal is a more relevant approach which is much needed for the negatively stigmatised system as a consequence of the various colonial administrations that have and continue to shape and reframe our ideas about what education should be like for us in the RMI. Moreover, Kannel Lobal is our attempt to decolonize the framing of education and leadership, moving our bwebwenato to re-framing conversations of teaching and learning so that our cultural knowledge and values are foregrounded, appreciated, and realised within our education system. Bwebwenato: sharing our stories In this section, we use bwebwenato as a method of gathering and capturing our stories as data. Below we capture our stories and ongoing conversations about the richness in Marshallese cultural knowledge in the outer islands and on Majuro and the potentialities in Kanne Lobal. Danny Jim When I was in third grade (9-10 years of age), during my grandfather’s speech in Arno, an atoll near Majuro, during a time when a wa (canoe) was being blessed and ready to put the canoe into the ocean. My grandfather told me the canoe was a blessing for the family. “Without a canoe, a family cannot provide for them”, he said. The canoe allows for travelling between places to gather food and other sources to provide for the family. My grandfather’s stories about people’s roles within the canoe reminded me that everyone within the family has a responsibility to each other. Our women, mothers and daughters too have a significant responsibility in the journey, in fact, they hold us, care for us, and given strength to their husbands, brothers, and sons. The wise man or elder sits in the middle of the canoe, directing the young man who help to steer. The young man, he does all the work, directed by the older man. They take advice and seek the wisdom of the elder. In front of the canoe, a young boy is placed there and because of his strong and youthful vision, he is able to help the elder as well as the young man on the canoe. The story can be linked to the roles that school leaders, teachers, and students have in schooling. Without each person knowing intricately their role and responsibility, the sight and vision ahead for the collective aspirations of the school and the community is difficult to comprehend. For me, the canoe is symbolic of our educational journey within our education system. As the school leader, a central, trusted, and respected figure in the school, they provide support for teachers who are at the helm, pedagogically striving to provide for their students. For without strong direction from the school leaders and teachers at the helm, the students, like the young boy, cannot foresee their futures, or envisage how education can benefit them. This is why Kanne Lobal is a significant framework for us in the Marshall Islands because within the practice we are able to take heed and empower each other so that all benefit from the process. Kanne Lobal is linked to our culture, an essential part of who we are. We must rely on our own local approaches, rather than relying on others that are not relevant to what we know and how we live in today’s society. One of the things I can tell is that in Majuro, compared to the outer islands, it’s different. In the outer islands, parents bring children together and tell them legends and stories. The elders tell them about the legends and stories – the bwebwenato. Children from outer islands know a lot more about Marshallese legends compared to children from the Majuro atoll. They usually stay close to their parents, observe how to prepare food and all types of Marshallese skills. Loretta Joseph Case There is little Western influence in the outer islands. They grow up learning their own culture with their parents, not having tv. They are closely knit, making their own food, learning to weave. They use fire for cooking food. They are more connected because there are few of them, doing their own culture. For example, if they’re building a house, the ladies will come together and make food to take to the males that are building the house, encouraging them to keep on working - “jemjem maal” (sharpening tools i.e. axe, like encouraging workers to empower them). It’s when they bring food and entertainment. Rubon Rubon Togetherness, work together, sharing of food, these are important practices as a school leader. Jemjem maal – the whole village works together, men working and the women encourage them with food and entertainment. All the young children are involved in all of the cultural practices, cultural transmission is consistently part of their everyday life. These are stronger in the outer islands. Kanne Lobal has the potential to provide solutions using our own knowledge and practices. Connie Joel When new teachers become a teacher, they learn more about their culture in teaching. Teaching raises the question, who are we? A popular saying amongst our people, “Aelon kein ad ej aelon in manit”, means that “Our islands are cultural islands”. Therefore, when we are teaching, and managing the school, we must do this culturally. When we live and breathe, we must do this culturally. There is more socialising with family and extended family. Respect the elderly. When they’re doing things the ladies all get together, in groups and do it. Cut the breadfruit, and preserve the breadfruit and pandanus. They come together and do it. Same as fishing, building houses, building canoes. They use and speak the language often spoken by the older people. There are words that people in the outer islands use and understand language regularly applied by the elderly. Respect elderly and leaders more i.e., chiefs (iroj), commoners (alap), and the workers on the land (ri-jerbal) (social layer under the commoners). All the kids, they gather with their families, and go and visit the chiefs and alap, and take gifts from their land, first produce/food from the plantation (eojōk). Tommy Almet The people are more connected to the culture in the outer islands because they help one another. They don’t have to always buy things by themselves, everyone contributes to the occasion. For instance, for birthdays, boys go fishing, others contribute and all share with everyone. Kanne Lobal is a practice that can bring people together – leaders, teachers, stakeholders. We want our colleagues to keep strong and work together to fix problems like students and teachers’ absenteeism which is a big problem for us in schools. Demetria Malachi The culture in the outer islands are more accessible and exposed to children. In Majuro, there is a mixedness of cultures and knowledges, influenced by Western thinking and practices. Kanne Lobal is an idea that can enhance quality educational purposes for the RMI. We, the school leaders who did GCSL, we want to merge and use this idea because it will help benefit students’ learning and teachers’ teaching. Kanne Lobal will help students to learn and teachers to teach though traditional skills and knowledge. We want to revitalize our ways of life through teaching because it is slowly fading away. Also, we want to have our own Marshallese learning process because it is in our own language making it easier to use and understand. Essentially, we want to proudly use our own ways of teaching from our ancestors showing the appreciation and blessings given to us. Way Forward To think of ways forward is about reflecting on the past and current learnings. Instead of a traditional discussion within a research publication, we have opted to continue our bwebwenato by sharing what we have learnt through the Graduate Certificate in School Leadership (GCSL) programme. Our bwebwenato does not end in this article and this opportunity to collaborate and partner together in this piece of writing has been a meaningful experience to conceptualise and unpack the Kanne Lobal framework. Our collaborative bwebwenato has enabled us to dig deep into our own wise knowledges for guidance through mediating and negotiating the challenges in education and leadership (Sanga & Houma, 2004). For example, bwe-jen-lale-rara reminds us to inquire, pay attention, and focus on supporting the needs of others. Through enra-bwe-jen-lale-rara, it reminds us to value cultural exchange and reciprocity which will strengthen the development and maintaining of relationships based on ways we continue to honour each other (Nimmer, 2017). We not only continue to support each other, but also help mentor the next generation of school leaders within our education system (Heine, 2002). Education and leadership are all about collaborative partnerships (Sanga & Chu, 2009; Thaman, 1997). Developing partnerships through the GCSL was useful learning for us. It encouraged us to work together, share knowledge, respect each other, and be kind. The values of jouj (kindness, love), kautiej (respect), and jouj eo mour eo (reciprocity) are meaningful in being and becoming and educational leader in the RMI (Jetnil-Kijiner, 2014; Miller, 2010; Nimmer, 2017). These values are meaningful for us practice particularly given the drive by PSS for schools to become accredited. The workshops and meetings delivered during the GCSL in the RMI from 2018 to 2019 about Kanne Lobal has given us strength to share our stories and experiences from the meeting with the stakeholders. But before we met with the stakeholders, we were encouraged to share and speak in our language within our courses: EDP05 (Professional Development and Learning), EDP06 (School Leadership), EDP07 (School Management), EDP08 (Teaching and Learning), and EDP09 (Community Partnerships). In groups, we shared our presentations with our peers, the 15 school leaders in the GCSL programme. We also invited USP RMI staff. They liked the way we presented Kannel Lobal. They provided us with feedback, for example: how the use of the sail on the canoe, the parts and their functions can be conceptualised in education and how they are related to the way that we teach our own young people. Engaging stakeholders in the conceptualisation and design stages of Kanne Lobal strengthened our understanding of leadership and collaborative partnerships. Based on various meetings with the RMI Pacific Resources for Education and Learning (PREL) team, PSS general assembly, teachers from the outer islands, and the PSS executive committee, we were able to share and receive feedback on the Kanne Lobal framework. The coordinators of the PREL programme in the RMI were excited by the possibilities around using Kanne Lobal, as a way to teach culture in an inspirational way to Marshallese students. Our Marshallese knowledge, particularly through the proverbial meaning of Kanne Lobal provided so much inspiration and insight for the groups during the presentation which gave us hope and confidence to develop the framework. Kanne Lobal is an organic and indigenous approach, grounded in Marshallese ways of doing things (Heine, 2002; Taafaki & Fowler, 2019). Given the persistent presence of colonial processes within the education system and the constant reference to practices and initiatives from the US, Kanne Lobal for us provides a refreshing yet fulfilling experience and makes us feel warm inside because it is something that belongs to all Marshallese people. Conclusion Marshallese indigenous knowledge and practices provide meaningful educational and leadership understanding and learnings. They ignite, inspire, and transform thinking and practice. The Kanne Lobal conceptual framework emphasises key concepts and values necessary for collaborative partnerships within education and leadership practices in the RMI. The bwebwenato or talk stories have been insightful and have highlighted the strengths and benefits that our Marshallese ideas and practices possess when looking for appropriate and relevant ways to understand education and leadership. Acknowledgements We want to acknowledge our GCSL cohort of school leaders who have supported us in the development of Kanne Lobal as a conceptual framework. A huge kommol tata to our friends: Joana, Rosana, Loretta, Jellan, Alvin, Ellice, Rolando, Stephen, and Alan. References Benson, C. (2002). Preface. In F. Pene, A. M. Taufe’ulungaki, & C. Benson (Eds.), Tree of Opportunity: re-thinking Pacific Education (p. iv). Suva, Fiji: University of the South Pacific, Institute of Education. Bessarab, D., Ng’andu, B. (2010). Yarning about yarning as a legitimate method in indigenous research. International Journal of Critical Indigenous Studies, 3(1), 37-50. Fa’avae, D., Jones, A., & Manu’atu, L. (2016). Talanoa’i ‘a e talanoa - talking about talanoa: Some dilemmas of a novice researcher. AlterNative: An Indigenous Journal of Indigenous Peoples,12(2),138-150. Heine, H. C. (2002). A Marshall Islands perspective. In F. Pene, A. M. Taufe’ulungaki, & C. Benson (Eds.), Tree of Opportunity: re-thinking Pacific Education (pp. 84 – 90). Suva, Fiji: University of the South Pacific, Institute of Education. Infoplease Staff (2017, February 28). Marshall Islands, retrieved from https://www.infoplease.com/world/countries/marshall-islands Jetnil-Kijiner, K. (2014). Iep Jaltok: A history of Marshallese literature. (Unpublished masters’ thesis). Honolulu, HW: University of Hawaii. Kabua, J. B. (2004). We are the land, the land is us: The moral responsibility of our education and sustainability. In A.L. Loeak, V.C. Kiluwe and L. Crowl (Eds.), Life in the Republic of the Marshall Islands, pp. 180 – 191. Suva, Fiji: University of the South Pacific. Kupferman, D. (2004). Jelalokjen in flux: Pitfalls and prospects of contextualising teacher training programmes in the Marshall Islands. Directions: Journal of Educational Studies, 26(1), 42 – 54. http://directions.usp.ac.fj/collect/direct/index/assoc/D1175062.dir/doc.pdf Miller, R. L. (2010). Wa kuk wa jimor: Outrigger canoes, social change, and modern life in the Marshall Islands (Unpublished masters’ thesis). Honolulu, HW: University of Hawaii. Nabobo-Baba, U. (2008). Decolonising framings in Pacific research: Indigenous Fijian vanua research framework as an organic response. AlterNative: An Indigenous Journal of Indigenous Peoples, 4(2), 141-154. Nimmer, N. E. (2017). Documenting a Marshallese indigenous learning framework (Unpublished doctoral thesis). Honolulu, HW: University of Hawaii. Sanga, K., & Houma, S. (2004). Solomon Islands principalship: Roles perceived, performed, preferred, and expected. Directions: Journal of Educational Studies, 26(1), 55-69. Sanga, K., & Chu, C. (2009). Introduction. In K. Sanga & C. Chu (Eds.), Living and Leaving a Legacy of Hope: Stories by New Generation Pacific Leaders (pp. 10-12). NZ: He Parekereke & Victoria University of Wellington. Suaalii-Sauni, T., & Fulu-Aiolupotea, S. M. (2014). Decolonising Pacific research, building Pacific research communities, and developing Pacific research tools: The case of the talanoa and the faafaletui in Samoa. Asia Pacific Viewpoint, 55(3), 331-344. Taafaki, I., & Fowler, M. K. (2019). Clothing mats of the Marshall Islands: The history, the culture, and the weavers. US: Kindle Direct. Taufe’ulungaki, A. M. (2014). Look back to look forward: A reflective Pacific journey. In M. ‘Otunuku, U. Nabobo-Baba, S. Johansson Fua (Eds.), Of Waves, Winds, and Wonderful Things: A Decade of Rethinking Pacific Education (pp. 1-15). Fiji: USP Press. Thaman, K. H. (1995). Concepts of learning, knowledge and wisdom in Tonga, and their relevance to modern education. Prospects, 25(4), 723-733. Thaman, K. H. (1997). Reclaiming a place: Towards a Pacific concept of education for cultural development. The Journal of the Polynesian Society, 106(2), 119-130. Thiong’o, N. W. (1986). Decolonising the mind: The politics of language in African literature. Kenya: East African Educational Publishers. Vaioleti, T. (2006). Talanoa research methodology: A developing position on Pacific research. Waikato Journal of Education, 12, 21-34. Walsh, J. M., Heine, H. C., Bigler, C. M., & Stege, M. (2012). Etto nan raan kein: A Marshall Islands history (First Edition). China: Bess Press.

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AbstractAnolis lizards originated in continental America but have colonized the Greater Antillean islands and recolonized the mainland, resulting in three major groups (Primary and Secondary Mainland and Greater Antillean). The adaptive radiation in the Greater Antilles has famously resulted in the repeated evolution of ecomorphs. Yet, it remains poorly understood to what extent this island radiation differs from diversification on the mainland. Here, we demonstrate that the evolutionary modularity between girdles and limbs is fundamentally different in the Greater Antillean and Primary Mainland Anolis. This is consistent with ecological opportunities on islands driving the adaptive radiation along distinct evolutionary trajectories. However, Greater Antillean Anolis share evolutionary modularity with the group that recolonized the mainland, demonstrating a persistent phylogenetic inertia. A comparison of these two groups support an increased morphological diversity and faster and more variable evolutionary rates on islands. These macroevolutionary trends of the locomotor skeleton in Anolis illustrate that ecological opportunities on islands can have lasting effects on morphological diversification.

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AbstractWhile prolactinoma patients have high bone turnover, current data are inconclusive when it comes to determining whether correction of hyperprolactinemia and associated hypogandism improves osteodensitometric data in men and women over the long term. In a large cohort of including 40 men and 60 women, we studied the long-term impact of prolactinoma treatment on bone mineral density (BMD) in men versus women, assessed adverse effects of a primary surgical or medical approach, and evaluated data for risk factors for impaired BMD at last follow-up using multivariate regression analyses. Median duration of follow-up was 79 months (range 13–408 months). Our data indicate that the prevalence of impaired BMD remained significantly higher in men (37%) than in women (7%, p < 0.001), despite the fact that hyperprolactinemia and hypogonadism are under control in the majority of men. We found that persistent hyperprolactinemia and male sex were independent risk factors for long-term bone impairment. Currently, osteoporosis prevention and treatment focus primarily on women, yet special attention to bone loss in men with prolactinomas is advised. Bone impairment as “end organ” reflects the full range of the disease and could become a surrogate marker for the severity of long-lasting hyperprolactinemia and associated hypogonadism.

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AbstractThe fitness consequences of cooperation can vary across an organism’s lifespan. For non-kin groups, especially, social advantages must balance intrinsic costs of cooperating with non-relatives. In this study, we asked how challenging life history stages can promote stable, long-term alliances among unrelated ant queens. We reared single- and multi-queen colonies of the primary polygynous harvester ant, Pogonomyrmex californicus, from founding through the first ten months of colony growth, when groups face high mortality risks. We found that colonies founded by multiple, unrelated queens experienced significant survival and growth advantages that outlasted the colony founding period. Multi-queen colonies experienced lower mortality than single-queen colonies, and queens in groups experienced lower mortality than solitary queens. Further, multi-queen colonies produced workers at a faster rate than did single-queen colonies, even while experiencing lower per-queen worker production costs. Additionally, we characterized ontogenetic changes in the organization of labor, and observed increasing and decreasing task performance diversity by workers and queens, respectively, as colonies grew. This dynamic task allocation likely reflects a response to the changing role of queens as they are increasingly able to delegate risky and costly tasks to an expanding workforce. Faster worker production in multi-queen colonies may beneficially accelerate this behavioral transition from a vulnerable parent–offspring group to a stable, growing colony. These combined benefits of cooperation may facilitate the retention of multiple unrelated queens in mature colonies despite direct fitness costs, providing insight into the evolutionary drivers of stable associations between unrelated individuals.

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Abstract Introduction Universal provision of effective antiretroviral medication has been essential to reduce mortality, increase longevity, and reduce onward transmission of HIV. This study aims to illuminate persistent threats to the health and longevity of under-served PLWH in British Columbia (BC), Canada. Methods Between 2007 and 2010, 1000 PLWH across BC were enrolled in the Longitudinal Investigation into Supportive and Ancillary health services (LISA) study and completed a cross-sectional survey on their HIV-care experiences and healthcare engagement. The sample generally reflects an under-served population of PLWH. A linkage to the provincial Vital Statistics registry is used in this analysis in order to examine overall mortality and cause-specific mortality trends; probability of death was modeled using logistic regression for participants with ongoing clinical monitoring (n = 910). Results By June 2017, 208 (20.8%) participants had died. The majority of deaths 57 (27.4%) were attributed to drug-related complications or overdoses, 39 (18.8%) were attributed to HIV-related complications, and 36 (17.3%) to non-AIDS-defining malignancies. We observed elevated odds of death among PLWH who smoked tobacco (aOR: 2.11, 95% CI: 1.38, 3.23), were older (aOR: 1.06 per one-year increase, 95% CI: 1.04, 1.08), indicated heavy alcohol consumption (aOR: 1.57, 95% CI: 1.11, 2.22), and reported unstable housing (aOR: 1.96, 95% CI: 1.37, 2.80); while higher CD4 cell count was protective (aOR: 0.87 per 100-unit increase, 95% CI: 0.79, 0.94) as was male gender), though non-significant (aOR: 0.73, 95% CI: 0.49, 1.07). Conclusions Overdose is - the leading cause of mortality among a cohort of under-served PLWH in BC, Canada. Public health efforts to end the HIV epidemic and support the health and well-being of PLWH are being thwarted by persistent health inequities and the enormous and persistent risks facing people who use drugs. Integrated low-barrier primary care is essential for supporting under-served PLWH, and safe drug supply is needed to support PLWH who use drugs.

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Abstract Objectives Chronic stress activates danger-associated molecular patterns (DAMPs), which then stimulate the NLRP3 inflammasome. NLRP3 activation triggers the released of the pro-inflammatory cytokine IL‐1β.The activity of the NLRP3 inflammasome propagates pro-inflammatory signaling cascades implicated in the onset of depression. In previous studies conducted in our lab, polyphenolic compounds were found to ameliorate stress induced depression in mouse models. However, the mechanism by which they do so has not been identified. This study examined the effect of administering polyphenols on DAMP signaling in enriched mice microglia. Methods This study examined the effect of administering polyphenols on DAMP signaling in mice microglia. To recapitulate stress-induced depression, mice underwent chronic unpredictable stress (CUS). Microglia were isolated at various time points throughout the CUS protocol. We also assessed long-term persistent changes after CUS and susceptibility to subthreshold unpredictable stress (US) re-exposure. Results Interestingly, the development of US - induced depression and anxiety depended upon a previous exposure to CUS. We found that CUS caused robust upregulation of IL-1β mRNA in enriched microglia, an effect that persists for up to 4 weeks following CUS exposure. Following the subthreshold US re-exposure, we observed the upregulation of pro- IL-1β as well as pro-receptor for advanced glycation end products (RAGE). Toll-like receptor 4 (TLR-4) was not. We also observed an increase in RAGE mRNA expression when mice were exposed to US prior to the start of the CUS paradigm. Importantly, a primary exposure to US, was sufficient to increase RAGE mRNA expression. We found that polyphenol administration improved CUS-induced depressive-like phenotypes and also reversed neuroinflammation in mice. Treatment with dietary polyphenols prevented upregulation of IL-1β, RAGE mRNA, which reflects the ability of polyphenols that may have begun following the primary exposure to US. Conclusions Taken all together, the results provide evidence of the role of polyphenols in preventing persistent microglial activation, which has been shown to result in reduced long term vulnerability to depressive-like behaviors following expose to chronic stress. Funding Sources This study was supported by a P50 CARBON Center grant from the NCCIH and ODS.

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The purpose of this article is to discuss poverty as a multidimensional factor influencing health. We will also explicate how racism contributes to and perpetuates the economic and financial inequality that diminishes prospects for population health improvement among marginalized racial and ethnic groups. Poverty is one of the most significant challenges for our society in this millennium. Over 40% of the world lives in poverty. The U.S. has one of the highest rates of poverty in the developed world, despite its collective wealth, and the burden falls disproportionately on communities of color. A common narrative for the relatively high prevalence of poverty among marginalized minority communities is predicated on racist notions of racial inferiority and frequent denial of the structural forms of racism and classism that have contributed to public health crises in the United States and across the globe. Importantly, poverty is much more than just a low-income household. It reflects economic well-being, the ability to negotiate society relative to education of an individual, socioeconomic or health status, as well as social exclusion based on institutional policies, practices, and behaviors. Until structural racism and economic injustice can be resolved, the use of evidence-based prevention and early intervention initiatives to mitigate untoward effects of socioeconomic deprivation in communities of color such as the use of social media/culturally concordant health education, social support, such as social networks, primary intervention strategies, and more will be critical to address the persistent racial/ethnic disparities in chronic diseases.

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Abstract Background Timely primary percutaneous coronary intervention (PCI) is currently the treatment of choice for ST-elevation myocardial infarction (STEMI). Although cardiac units were established in all central hospitals in late 1990s for sparsely populated Finland, studies have shown that regional variation has increased. Additionally, the dense Finnish hospital network includes non-cardiac facilities where patients may be inappropriately admitted and then transferred for PCI. We aim to investigate the current regional differences in receiving timely PCI, determinants of these variations and the effect of hospital transfers. Methods Finnish Hospital Discharge Register data on PCIs for STEMI patients in 2015-17 were linked to register data on socio-demographics. In these preliminary analyses we used logistic regression modelling. Results Our results suggest that there were significant regional differences both for timely PCI in STEMI patients and in the probability of hospital transfers during an episode of care. The regional odds ratios (OR) for receiving PCI on time varied from 0.41 (95% confidence interval 0.33-0.52) to 2.73 (2.09-3.57) compared with the capital region when controlling for age, gender and hospital transfers. The ORs for being transferred during an episode of care varied from 0.26 (0.15-0.44) to 16.6 (11.6-23.6). Patients not transferred were more likely to receive PCI (OR 1.89 (1.67-2.15)). Men received PCI on time more often (OR 1.31 (1.18-1.46)) and women were more likely to be transferred (OR 1.29 (1.15-1.45)). Conclusions The probability for receiving PCI on time was related to the size of the hospital's population base and academic affiliation and inversely to transfers between hospitals. Hospital transfers during care episode and atypical symptoms often seen in women may cause critical delays for PCI. Other determinants for variation of timely PCI and its effects on equity will be analysed using multilevel modelling. Key messages Appropriate care for STEMI varies across regions and reflects inept practices in provider network. These findings are more pronounced in women showing persisting gender-related inequity.

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Secondary injury in the thalamus has been observed following cortical stroke in rodents and humans and is associated with worsened recovery. Interruption of this progressive injury reflects an important therapeutic goal. However, the mechanisms whereby primary cortical infarction leads to remote injury in distant regions of brain are not well defined. We used a mouse model of cortical stroke (which demonstrates delayed thalamic injury) to define the time course of thalamic gliosis and neuronal injury and then test the potential of delayed memantine treatment (an NMDA receptor antagonist) to attenuate this secondary injury. Methods: Cortical infarction was induced by permanent occlusion of the distal middle cerebral artery (pdMCAO) in male C57BL/6J mice (young and aged) and CCR2-RFP mice. Brain infarct, cell-specific injury, and gliosis were measured by cresyl violet, Fluoro-jade C (FJC), TTC, FACS, and immunofluorescence. In young mice, memantine was injected at 4 and 24 hours post-stroke (100 and 50 mg/kg, ip). Brains were evaluated at post-stroke day 3 and 14 (PSD3 and PSD14). Results: At PSD3, the primary infarct was restricted to the cortex of the MCA territory, with no infarct detected in the thalamus of young mice. However, by PSD 14, neurons in the ipsilateral thalamus exhibited significant injury (FJC positive, condensed pyknotic nuclei). Gliosis was first detectable in the ipsilateral thalamus at PSD3 and progressively increased to PSD14 (anti-GFAP and Iba1). Infiltration of peripheral-derived monocytes was determined to be one source of the activated microglia in the thalamus (CCR2-RFP reporter mice, n=3). Interestingly, pdMCAO mice allowed to recover for two years demonstrated persistent astrogliosis (cortex and thalamus), though microgliosis was no longer evident (n=2). Aged mice subjected to pdMCAO also demonstrated gliosis in thalamus at PSD14, albeit to a lesser extent than young mice (n=5 each age). Finally, delayed treatment with memantine resulted in significantly attenuated gliosis and neuronal loss in the thalamus at PSD14 (young mice, n=9 each). Conclusions: These results further define gliosis in the mechanism of secondary injury and importantly demonstrate attenuation of secondary injury by delayed NMDA receptor antagonism.

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ABSTRACT Decay of the HIV reservoir is slowed over time in part by expansion of the pool of HIV-infected cells. This expansion reflects homeostatic proliferation of infected cells by interleukin-7 (IL-7) or antigenic stimulation, as well as new rounds of infection of susceptible target cells. As novel therapies are being developed to accelerate the decay of the latent HIV reservoir, it will be important to identify interventions that prevent expansion and/or repopulation of the latent HIV reservoir. Our previous studies showed that HIV protease cleaves the host protein procaspase 8 to generate Casp8p41, which can bind and activate Bak to induce apoptosis of infected cells. In circ*mstances where expression of the anti-apoptotic protein BCL2 is high, Casp8p41 instead binds BCL2, and cell death does not occur. This effect can be overcome by treating cells with the clinically approved BCL2 antagonist venetoclax, which prevents Casp8p41 from binding BCL2, thereby allowing Casp8p41 to bind Bak and kill the infected cell. Here we assess whether the events that maintain the HIV reservoir are also antagonized by venetoclax. Using the J-Lat 10.6 model of persistent infection, we demonstrate that proliferation and HIV expression are countered by the use of venetoclax, which causes preferential killing of the HIV-expressing cells. Similarly, during new rounds of infection of primary CD4 T cells, venetoclax causes selective killing of HIV-infected cells, resulting in decreased numbers of HIV DNA-containing cells. IMPORTANCE Cure of HIV infection requires an intervention that reduces the HIV reservoir size. A variety of approaches are being tested for their ability to impact HIV reservoir size. Even if successful, however, these approaches will need to be combined with additional complementary approaches that prevent replenishment or repopulation of the HIV reservoir. Our previous studies have shown that the FDA-approved BCL2 antagonist venetoclax has a beneficial effect on the HIV reservoir size following HIV reactivation. Here we demonstrate that venetoclax also has a beneficial effect on HIV reservoir size in a model of homeostatic proliferation of HIV as well as in acute spreading infection of HIV in primary CD4 T cells. These results suggest that venetoclax, either alone or in combination with other approaches to reducing HIV reservoir size, is a compound worthy of further study for its effects on HIV reservoir size.

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Abstract OBJECTIVES Among patients undergoing transcatheter mitral valve repair with the MitraClip device, a relevant proportion (2–6%) requires open mitral valve surgery within 1 year after unsuccessful clip implantation. The goal of this review is to pool data from different reports to provide a comprehensive overview of mitral valve surgery outcomes after the MitraClip procedure and estimate in-hospital and follow-up mortality. METHODS All published clinical studies reporting on surgical intervention for a failed MitraClip procedure were evaluated for inclusion in this meta-analysis. The primary study outcome was in-hospital mortality. Secondary outcomes were in-hospital adverse events and follow-up mortality. Pooled estimate rates and 95% confidence intervals (CIs) of study outcomes were calculated using a DerSimionian–Laird binary random-effects model. To assess heterogeneity across studies, we used the Cochrane Q statistic to compute I2 values. RESULTS Overall, 20 reports were included, comprising 172 patients. Mean age was 70.5 years (95% CI 67.2–73.7 years). The underlying mitral valve disease was functional mitral regurgitation in 50% and degenerative mitral regurgitation in 49% of cases. The indication for surgery was persistent or recurrent mitral regurgitation (grade &gt;2) in 93% of patients, whereas 6% of patients presented with mitral stenosis. At the time of the operation, 80% of patients presented in New York Heart Association functional class III–IV. Despite favourable intraoperative results, in-hospital mortality was 15%. The rate of periprocedural cerebrovascular accidents was 6%. At a mean follow-up of 12 months, all-cause death was 26.5%. Mitral valve replacement was most commonly required because the possibility of valve repair was jeopardized, likely due to severe valve injury after clip implantation. CONCLUSIONS Surgical intervention after failed transcatheter mitral valve intervention is burdened by high in-hospital and 1-year mortality, which reflects reflecting the high-risk baseline profile of the patients. Mitral valve replacement is usually required due to leaflet injury.

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Abstract Background Persistent income inequality, the increase in precarious employment, the inadequacy of many welfare systems, and economic impact of the COVID-19 pandemic have increased interest in Basic Income (BI) interventions. Ensuring that social interventions, such as BI, are evaluated appropriately is key to ensuring their overall effectiveness. This systematic review therefore aims to report on available methods and domains of assessment, which have been used to evaluate BI interventions. These findings will assist in informing future program and research development and implementation. Methods Studies were identified through systematic searches of the indexed and grey literature (Databases included: Scopus, Embase, Medline, CINAHL, Web of Science, ProQuest databases, EBSCOhost Research Databases, and PsycINFO), hand-searching reference lists of included studies, and recommendations from experts. Citations were independently reviewed by two study team members. We included studies that reported on methods used to evaluate the impact of BI, incorporated primary data from an observational or experimental study, or were a protocol for a future BI study. We extracted information on the BI intervention, context and evaluation method. Results 86 eligible articles reported on 10 distinct BI interventions from the last six decades. Workforce participation was the most common outcome of interest among BI evaluations in the 1960–1980 era. During the 2000s, studies of BI expanded to include outcomes related to health, educational attainment, housing and other key facets of life impacted by individuals’ income. Many BI interventions were tested in randomized controlled trials with data collected through surveys at multiple time points. Conclusions Over the last two decades, the assessment of the impact of BI interventions has evolved to include a wide array of outcomes. This shift in evaluation outcomes reflects the current hypothesis that investing in BI can result in lower spending on health and social care. Methods of evaluation ranged but emphasized the use of randomization, surveys, and existing data sources (i.e., administrative data). Our findings can inform future BI intervention studies and interventions by providing an overview of how previous BI interventions have been evaluated and commenting on the effectiveness of these methods. Registration This systematic review was registered with PROSPERO (CRD 42016051218).

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PurposeThis paper is designed to provide primary research which illuminates both the motivations for Cambodian migration as well as the risks entailed in undertaking migration.Design/methodology/approachThis paper gathered its information through a structured interview with 49 respondents aged between 17–29 years of mixed gender. The questionnaire comprised 18 questions in addition to a demographics section. Findings were subsequently analysed in order to extract commonalities amongst the experiences and perceptions of migrants.FindingsThe present research study found that the migration of Cambodians to Thailand is largely forced in the sense that there is a lack of economic opportunities within Cambodia. Of the respondents, 88% indicated that their preference would be to remain in Cambodia. What is more, the authors found that the migration is fraught with insecurity and risk, with a range of security issues faced by respondents including not being paid, being abused and being overworked.Research limitations/implicationsThis response group is not a representative sample of Cambodians who work in Thailand. The study’s respondents in Cambodia were at a deportation centre, where migrants caught by Thai authorities worked without documentation, which had a clear impact upon migration experience. Additionally, the study’s respondents in Pattaya, Thailand, were accessed via an associate of a colleague, so this too is not a representative sample of Cambodians working in Thailand.Practical implicationsThis can have practical use for a variety of stakeholders by providing quantitative information as well as analysis into the migration of Cambodians to Thailand. Within the Recommendations section, it is illustrated how a temporary migrant worker programme can be beneficial to the host and receiving countries and individual migrants. Individual migrants can benefit from being employed by legitimate, accountable employers and hence result in higher provision of human rights for this demographic.Social implicationsThere is a highly entrenched culture of migration within Cambodia's bordering provinces. Through changes to the personal health, well-being and prosperity of migrants in Thailand because of reduced exploitation and increased pay. Host communities in Cambodia are also likely to receive higher levels of remittances, which can stimulate development in Cambodian communities.Originality/valueDeepened understanding of the motivations for migration and highlighted lack of desire amongst Cambodians to migrate continue to demonstrate the persistent need for effective and substantial development policies within Cambodia. The proposal of a temporary migrant worker scheme is in its short-term nature and reflects the necessity of this demographic to migrate irrespective of whether they can receive official working papers.