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To evaluate the association between the use of low-dose aspirin for preeclampsia prophylaxis and risks of gestational diabetes (primary outcome), neonatal hypoglycemia, macrosomia, large for gestational age, birth trauma, and shoulder dystocia (secondary outcomes).We searched Ovid MEDLINE, Embase, CINAHL, and Cochrane/CENTRAL for studies published between January 1, 1989, and April 24, 2021.Randomized controlled trials (RCTs) or cohort studies of any size conducted in any setting were included.We assessed risk of bias using the Cochrane Risk of Bias tool 2.0 (for RCTs) and the Newcastle-Ottawa Scale (for cohort studies). We meta-analyzed relative risks (RRs) using random-effects models.Our search retrieved 4441 records, of which 9 studies (6 RCTs with 1932 patients and 3 cohort studies with 313 837 patients) met inclusion criteria. We rated only 4 of the 6 RCTs and 1 of the 3 cohort studies at low risk of bias. Low-dose aspirin in pregnancy for preeclampsia prophylaxis was not associated with a greater risk of gestational diabetes (RR 1.18; 95% confidence interval 0.80-1.74). No studies reported data for the secondary outcomes. In summary, the use of low-dose aspirin does not appear associated with risk of gestational diabetes. The poor quality and small number of studies limit the interpretation of these results.

A personal or family medical history is inherently part of a genetic counselor's life story. Yet, the degree to which this history influences counselors' clinical specialty choice and professional psychosocial practice is unexplored. A medical diagnosis may foster capacity for greater empathy, understanding, and rapport-building self-disclosure. Conversely, it could lead to disruptive countertransference, compassion fatigue, and eventually burnout. Research, however, has not specifically investigated this intersection. The aim of this study was to explore the impact of genetic counselors' personal and/or family medical history on choice of practice area and self-perceived impact on their psychosocial work within sessions. Members of the National Society of Genetic Counselors were recruited to complete an online screening survey. Of the 69 survey respondents that met inclusion criteria, 23 volunteered for and completed a telephone interview. Interview questions explored counselors' medical narratives and their consequent influence on specialty choice and clinical interaction with patients. Inductive analysis yielded nine domains within three major themes: Medical Story, Specialty Impact, and Psychosocial Influence. Participants were more likely to be attracted to a specialty possessing overlap with their medical history and attributed many of their psychosocial strengths to personal and/or family medical experiences, such as increased empathy or a more expansive scope in how they cared for patients. Many counselors, however, noted their medical history did not frequently influence their clinical practice, with most initially denying or downplaying use of self-disclosure about their history. Contradictory to their statements, the majority gave at least one example of self-disclosure, whether indirect, prompted, or direct. Importantly, almost all participants named or demonstrated countertransference. This study highlights that while medical history can be a valuable asset in providing care for patients, it requires a genetic counselor's diligent attentiveness and commitment to honest self-reflection.

The bioelectrical signals that produce uterine contractions during parturition are not completely understood. The objectives are as follows: (1) to review the literature and information concerning uterine biopotential waveforms generated by the uterus, known to produce contractions, and evaluate mechanotransduction in pregnant patients using electromyographic (EMG) recording methods and (2) to study a new approach, uterine vector analysis, commonly used for the heart: vectorcardiography analysis. The patients used in this study were as follows: (1) patients at term not in labor (n = 3); (2) patients during the 1st stage of labor at cervical dilations from 2 to 10 cm (n = 30); and (3) patients in the 2nd stage of labor and during delivery (n = 3). We used DC-coupled electrodes and PowerLab hardware (model no. PL2604, ADInstruments, Castle Hill, Australia), with software (LabChart, ADInstruments) for storage and analysis of biopotentials. Uterine and abdominal EMG recordings were made from the surface of each patient using 3 electrode pairs with 1 pair (+ and −, with a 31-cm spacing distance) placed in the right/left position (X position) and with 1 pair placed in an up/down position (Y position, also 31 cm apart) and with the third pair at the front/back (Z position). Using signals from the three X, Y, and Z electrodes, slow (0.03 to 0.1 Hz, high amplitude) and fast wave (0.3 to 1 Hz, low amplitude) biopotentials were recorded. The amplitudes of the slow waves and fast waves were significantly higher during the 2nd stage of labor compared to the 1st stage (respectively, p = 9.54 × e−3 and p = 3.94 × e−7). When 2 channels were used, for example, the X vs. Y, for 2-D vector analysis or 3 channels, X vs. Y vs. Z, for 3-D analysis, are plotted against each other on their axes, this produces a vector electromyometriogram (EMMG) that shows no directionality for fast waves and a downward direction for slow waves. Similarly, during the 2nd stage of labor during abdominal contractions (“pushing”), the slow and fast waves were enlarged. Manual applied pressure was used to evoke bioelectrical activity to examine the mechanosensitivity of the uterus. Conclusions: (1) Phasic contractility of the uterus is a product of slow waves and groups of fast waves (bursts of spikes) to produce myometrial contractile responses. (2) 2-D and 3-D uterine vector analyses (uterine vector electromyometriogram) demonstrate no directionality of small fast waves while the larger slow waves represent the downward direction of biopotentials towards the cervical opening. (3) Myometrial cell action event excitability and subsequent contractility likely amplify slow wave activity input and uterine muscle contractility via mechanotransduction systems. (4) Models illustrate the possible relationships of slow to fast waves and the association of a mechanotransduction system and pacemaker activity as observed for slow waves and pacemakers in gastrointestinal muscle. (5) The interaction of these systems is thought to regulate uterine contractility. (6) This study suggests a potential indicator of delivery time. Such vector approaches might help us predict the progress of gestation and better estimate the timing of delivery, gestational pathologies reflected in bioelectric events, and perhaps the potential for premature delivery drug and mechanical interventions.

In any given year, approximately 130 million babies are born worldwide. Previous research has shown that pregnant women may be more severely affected and vulnerable to contracting emerging infections, making them a particularly high-risk population. Therefore, special considerations should be given to treatment methods for pregnant women with COVID-19. In this narrative review, the authors evaluate scholarly journal articles and electronic databases to determine what is known about the pathophysiology of COVID-19 in pregnancy and the associated mortality rate. Osteopathic manipulative treatment techniques to mitigate the underlying pathology were identified, and modifications for use in pregnancy and the critical care setting are described.

A lack of models that recapitulate the complexity of human bone marrow has hampered mechanistic studies of normal and malignant hematopoiesis and the validation of novel therapies. Here, we describe a step-wise, directed-differentiation protocol in which organoids are generated from iPSCs committed to mesenchymal, endothelial and hematopoietic lineages. These 3-dimensional structures capture key features of human bone marrow - stroma, lumen-forming sinusoidal vessels and myeloid cells including pro-platelet forming megakaryocytes. The organoids supported the engraftment and survival of cells from patients with blood malignancies, including cancer types notoriously difficult to maintain ex vivo. Fibrosis of the organoid occurred following TGFβ stimulation and engraftment with myelofibrosis but not healthy donor-derived cells, validating this platform as a powerful tool for studies of malignant cells and their interactions within a human bone marrow-like milieu. This enabling technology is likely to accelerate discovery and prioritization of novel targets for bone marrow disorders and blood cancers.Significance StatementWe present a 3D, vascularised human bone marrow organoid that supports growth of primary cells from patients with myeloid and lymphoid blood cancers. This model allows for mechanistic studies of blood cancers in the context of their microenvironment, and provides a much-needed, ex vivo tool for prioritization of new therapeutics.

Evidence about specific carbohydrate diet (SCD) for inflammatory bowel disease (IBD) is limited. We conducted 54 single-subject, double-crossover N-of-1 trials comparing SCD with a modified SCD (MSCD) and comparing each with the participant's baseline, usual diet (UD).Across 19 sites, we recruited patients aged 7-18 years with IBD and active inflammation. Following a 2-week baseline (UD), patients were randomized to 1 of 2 sequences of 4 alternating 8-week SCD and MSCD periods. Outcomes included fecal calprotectin and patient-reported symptoms. We report posterior probabilities from Bayesian models comparing diets.Twenty-one (39%) participants completed the trial, 9 (17%) completed a single crossover, and 24 (44%) withdrew. Withdrawal or early completion occurred commonly (lack of response [n = 11], adverse events [n = 11], and not desiring to continue [n = 6]). SCD and MSCD performed similarly for most individuals. On average, there was1% probability of a clinically meaningful difference in IBD symptoms between SCD and MSCD. The average treatment difference was -0.3 (95% credible interval -1.2, 0.75). There was no significant difference in the ratio of fecal calprotectin geometric means comparing SCD and MSCD (0.77, 95% credible interval 0.51, 1.10). Some individuals had improvement in symptoms and fecal calprotectin compared with their UD, whereas others did not.SCD and MSCD did not consistently improve symptoms or inflammation, although some individuals may have benefited. However, there are inherent difficulties in examining dietary changes that complicate study design and ultimately conclusions regarding effectiveness.

Summary Predicting disease progression remains a particularly challenging endeavor in chronic degenerative disorders and cancer, thus limiting early detection, risk stratification, and preventive interventions. Here, profiling the three chronic subtypes of myeloproliferative neoplasms (MPNs), we identify the blood platelet transcriptome as a proxy strategy for highly sensitive progression biomarkers that also enables prediction of advanced disease via machine-learning algorithms. The MPN platelet transcriptome reveals an incremental molecular reprogramming that is independent of patient driver mutation status or therapy. Subtype-specific markers offer mechanistic and therapeutic insights, and highlight impaired proteostasis and a persistent integrated stress response. Using a LASSO model with validation in two independent cohorts, we identify the advanced subtype MF at high accuracy and offer a robust progression signature toward clinical translation. Our platelet transcriptome snapshot of chronic MPNs demonstrates a proof-of-principle for disease risk stratification and progression beyond genetic data alone, with potential utility in other progressive disorders., Graphical abstract, Highlights Platelet transcriptome yields progressive markers across MPN subtypes Lasso-penalized multinomial regression model predicts advanced MPNs Impaired protein homeostasis and an integrated stress response feature in MPN progression, Shen et al. leverage two independent MPN patient cohorts to identify progressive platelet transcriptomic markers, which also enable an externally validated prediction for advanced MPNs. The platelet RNA-seq data identify impaired protein homeostasis in MPN progression and offer potential targets of therapy.

OBJECTIVE Explore the utility of expanded carrier screening in evaluating heritable causes of congenital anomalies detected by prenatal ultrasound. METHOD A retrospective chart review was conducted to collect structural abnormality and genetic testing data on infants who were evaluated postnatally by a medical geneticist. These were used to determine if expanded carrier screening could have determined the etiology prior to delivery. Additionally, recessive and X-linked conditions on clinically available carrier screening panels were evaluated to determine the number of conditions associated with abnormal ultrasound findings. RESULTS Our retrospective chart review found 222 patients with genetic etiologies, including eight unique autosomal recessive conditions and six X-linked conditions in the 23% who underwent exome sequencing. Of these 14 unique conditions detected, three were included on a list of 271 conditions for which screening was available in 2019 and five were included on a 500 condition panel available in 2020. A literature review was performed on the list of 271 conditions and 88 were reported to be associated with one or more ultrasound abnormalities. CONCLUSION This study demonstrates limited but potential utility for expanded carrier screening to determine the underlying etiology of congenital anomalies.

OBJECTIVE To describe uptake of carrier screening by male reproductive partners of prenatal and preconception patients. METHODS A retrospective database review of all prenatal and preconception patients seen for genetic counseling in Maternal Fetal Medicine clinics was performed. Descriptive statistics and chi-square analysis were used on the data set. RESULTS Within the study period, 6087 patients were seen for genetic counseling, of whom 661 were identified as a carrier of an autosomal recessive disorder by their referring provider or genetic counselor. Despite guidelines recommending partner testing for risk clarification when a woman is known to be a carrier of an autosomal recessive condition, only 41.5% male partners elected carrier screening to clarify the couple's reproductive risk, with a majority of males (75%) having screening consecutively. Of all assessed variables, the only significant predictors of male carrier screening uptake were female parity and earlier gestational age (p < .0001, and p = .001, respectively). CONCLUSION With less than half of male partners pursuing carrier screening when indicated, its utility becomes severely diminished. More research is needed to explore reasons why males elect or decline carrier screening.

Wahlster et al. describe a multigenerational family with inherited thrombocytopenia. Long-read sequencing and RNA sequencing revealed a complex structural variant, causing overexpression of a pathogenic gain-of-function WAC-ANKRD26 fusion transcript., In this issue, Wahlster, Verboon, and colleagues (2021. J. Exp. Med. https://doi.org/10.1084/jem.20210444) describe a multigenerational family with inherited thrombocytopenia where the causal variant was not identified using conventional genome sequencing approaches. Long-read sequencing and RNA sequencing revealed a complex structural variant, causing overexpression of a pathogenic gain-of-function WAC-ANKRD26 fusion transcript.

Objective : To determine if the incidence of pressure injuries (PIs) upon admission to an inpatient rehabilitation hospital (IRH) system of care was increased during the early COVID-19 pandemic period. Design : Retrospective survey chart review of consecutive cohorts. Admissions to four acute IRHs within one system of care over the first consecutive 6-week period of admitting COVID-19 positive patients during the initial peak of the COVID-19 pandemic, April 1 to May 9, 2020. A comparison was made with the pre-COVID-19 period of 2020, January 1 to February 19, 2020. Setting : Four acute IRHs with admissions on a referral basis from acute care hospitals. Participants : A consecutive sample of pre-COVID-19 admissions (n = 768) and COVID-19 period admissions (n = 357); including persons who were COVID positive (n = 161) and COVID negative (n = 196). Main Outcome Measure(s) : Incidence of PIs on admission to IRH. Results : Prevalence of PIs on admission during the COVID-19 pandemic was increased when compared to the pre-COVID-19 period by 14.9% (p < 0.001). There was no difference in the prevalence of PIs in the COVID-19 period between patients who were COVID-19 positive and COVID-19 negative (35.4% to 35.7%). The severity of PIs, measured by the wound stage of the most severe PI the patient present with, worsened during the COVID-19 period in comparison to pre-COVID-19 (chi-squared 32.04%, p < 0.001). The length of stay in the acute care hospital prior to transfer to the IRH during COVID-19 was greater than in pre-COVID-19 by 10.9 % (p < 0.001). Conclusions : During the early part of the COVID-19 pandemic timeframe, there was an increase in the prevalence and severity of PIs noted on admission to our IRHs. This may represent the significant burden placed on the health care system by the pandemic, affecting all patients regardless of COVID-19 status. This information is important to help all facilities remain vigilant to prevent PIs as the pandemic continues, and potential future pandemics that place strain on medical resources.

The institution of medicine was built on a foundation of racism and segregation, the consequences of which still permeate the experiences of Black physicians and patients. To predict the future direction of medical inclusivity, we must first understand the history of medicine as it pertains to race, diversity, and equity. In this Commentary, we review material from publicly available books, articles, and media outlets in a variety of areas, including undergraduate medical education and professional medical societies, where we found an abundance of policies and practices that created a foundation of systemic racism in medical training that carried through the career paths of Black physicians. The objective of this Commentary is to present the history of race in the medical education system and medical society membership, acknowledge the present state of both, and offer concrete solutions to increase diversity in our medical community.

Screening for perinatal depression and anxiety in community-based maternal and child health settings may help close the detection and treatment gap among women at higher risk for these conditions. We aim to review perinatal depression and anxiety screening tools, timing, and follow-up processes for positive screens in community-based settings. We conducted a systematic review of the literature to identify papers describing screening and interventions for perinatal depression and anxiety in community-based settings. We identified 49 papers describing 47 studies of perinatal depression or anxiety screening in community-based settings. The Edinburgh Postnatal Depression Scale (EPDS) was the most frequently used screening tool. Referral and referral tracking for those who screened positive for symptoms were inadequately described. Types of training and technical assistance provided for screening varied widely. It is feasible and acceptable to screen for perinatal depression in community settings, but there is a need for systematic research examining which screening tools to use, the ideal frequency of screening, and referral completion rates. There is a lack of information regarding perinatal anxiety screening and a lack of uniformity in training regarding screening in community-based settings. Future studies should compare the efficacy of screening in community-based settings to screening in healthcare settings.

Objective To investigate residential mobility among community-living adults with spinal cord injury (SCI) and the individual, health, and neighborhood factors associated with the propensity to relocate. Design Retrospective analysis of data from the National SCI Model Systems (SCIMS) Database collected between 2006 and 2018 and linked with the American Community Survey 5-year estimates. Setting Community. Interventions Not applicable. Participants People with traumatic SCI (N=4599) who participated in 2 waves of follow-up and had residential geographic identifiers at the census tract level. Main Outcome Measures Moving was a binary measure reflecting change in residential locations over a 5-year interval. Move distance distinguished nonmovers from local movers (different tracts within the same county) and long-distance movers (to different county or state). Move quality included 4 categories: stayed/low poverty tract, stayed/high poverty tract, moved/low poverty tract, and moved/high poverty tract. Results One in 4 people moved within a 5-year interval (n=1175). Of the movers, 55% relocated to a different census tract within the same county and 45% relocated to a different county or state. Thirty-five percent of all movers relocated to a high poverty census tract. Racial and ethnic minorities, people from low-income households, and younger adults were more likely to move, move locally, and relocate to a high poverty neighborhood. High poverty and racial/ethnic segregation in the origin neighborhood predicted an increased risk for remaining in or moving to a high poverty neighborhood. Conclusions Although people with SCI relocated at a lower rate than has been reported in the general population, moving was a frequent occurrence postinjury. People from vulnerable groups were more likely to remain in or relocate to socioeconomically disadvantaged neighborhoods, thus increasing the risk for health disparities and poorer long-term outcomes among minorities and people from low-income households. These findings inform policy makers’ considerations of housing, health care, and employment initiatives for individuals with SCI and other chronic disabilities.

The bioelectrical signals that produce uterine contractions during parturition are not completely understood. The objectives are as follows: (1) to review the literature and information concerning uterine biopotential waveforms generated by the uterus, known to produce contractions, and evaluate mechanotransduction in pregnant patients using electromyographic (EMG) recording methods and (2) to study a new approach, uterine vector analysis, commonly used for the heart: vectorcardiography analysis. The patients used in this study were as follows: (1) patients at term not in labor (n = 3); (2) patients during the 1st stage of labor at cervical dilations from 2 to 10 cm (n = 30); and (3) patients in the 2nd stage of labor and during delivery (n = 3). We used DC-coupled electrodes and PowerLab hardware (model no. PL2604, ADInstruments, Castle Hill, Australia), with software (LabChart, ADInstruments) for storage and analysis of biopotentials. Uterine and abdominal EMG recordings were made from the surface of each patient using 3 electrode pairs with 1 pair (+ and -, with a 31-cm spacing distance) placed in the right/left position (X position) and with 1 pair placed in an up/down position (Y position, also 31 cm apart) and with the third pair at the front/back (Z position). Using signals from the three X, Y, and Z electrodes, slow (0.03 to 0.1 Hz, high amplitude) and fast wave (0.3 to 1 Hz, low amplitude) biopotentials were recorded. The amplitudes of the slow waves and fast waves were significantly higher during the 2nd stage of labor compared to the 1st stage (respectively, p = 9.54 × e

The aim of this narrative review is to describe the toxicologic confounders of brain death currently reported in the literature to offer guidance for physicians assessing brain death after a toxic exposure. We established an a priori definition of a "brain death mimic" as an unresponsive, intubated patient missing some, but not all brainstem reflexes. We completed a review of the literature utilizing MEDLINE and EMBASE to find case reports of patients of all ages in English, French, and Spanish meeting the criteria and hand searched the references of the results. We recorded xenobiotic dose, duration of physical exam suggesting brain death, and how the cases failed to meet full brain death criteria, when available. Fifty-six cases representing 19 different substances met the a priori definition of brain death mimic. Xenobiotic toxicities included: snake envenomation (13), baclofen (11), tricyclic antidepressants (8), bupropion (7), alcohols (4), antiepileptic agents (3), barbiturates (2), antidysrhythmics (2), organophosphates (2), and one case each of magnesium, succinylcholine, tetrodotoxin, and zolpidem. All patients except one survived to discharge and the majority at their baseline physical health. The most common means by which the cases failed brain death examination prerequisites was via normal neuroimaging. The xenobiotics in this review should be considered in cases of poisoning resulting in loss of brainstem reflexes and addressed before brain death determination. Brain death diagnosis should not be pursued in the setting of normal cerebral imaging or incomplete evaluation of brain death prerequisites.

Clonazolam is a designer triazolobenzodiazepine first synthesized in the 1970s that has never been licensed for therapeutic use. Clonazolam first surfaced on the internet in 2014 as a drug of abuse...

Summary Myelofibrosis is a severe myeloproliferative neoplasm characterized by increased numbers of abnormal bone marrow megakaryocytes that induce fibrosis, destroying the hematopoietic microenvironment. To determine the cellular and molecular basis for aberrant megakaryopoiesis in myelofibrosis, we performed single-cell transcriptome profiling of 135,929 CD34+ lineage− hematopoietic stem and progenitor cells (HSPCs), single-cell proteomics, genomics, and functional assays. We identified a bias toward megakaryocyte differentiation apparent from early multipotent stem cells in myelofibrosis and associated aberrant molecular signatures. A sub-fraction of myelofibrosis megakaryocyte progenitors (MkPs) are transcriptionally similar to healthy-donor MkPs, but the majority are disease specific, with distinct populations expressing fibrosis- and proliferation-associated genes. Mutant-clone HSPCs have increased expression of megakaryocyte-associated genes compared to wild-type HSPCs, and we provide early validation of G6B as a potential immunotherapy target. Our study paves the way for selective targeting of the myelofibrosis clone and illustrates the power of single-cell multi-omics to discover tumor-specific therapeutic targets and mediators of tissue fibrosis., Graphical Abstract, Highlights • Single-cell-omics demonstrate megakaryocyte-biased hematopoiesis in myelofibrosis (MF) • Megakaryocyte progenitors (MkPs) show high expression of a fibrosis signature in MF • MkPs are heterogeneous in MF with aberrant metabolic and inflammatory signatures • Targeting aberrant surface G6B expression may selectively ablate the MF clone, Myelofibrosis (MF) is characterized by increased numbers of morphologically abnormal megakaryocytes (Mks). Single-cell RNA sequencing of >120,000 hematopoietic stem and progenitor cells demonstrated Mk-biased hematopoiesis across clinical and molecular MF subgroups. Mk progenitors were heterogeneous, with distinct expression of inflammatory mediators. Aberrant surface G6B expression on MF stem and progenitors could allow selective immunotherapeutic targeting of the MF clone.

OBJECTIVE To examine the effect of age of first exposure to tackle football on chronic traumatic encephalopathy (CTE) pathological severity and age of neurobehavioral symptom onset in tackle football players with neuropathologically confirmed CTE. METHODS The sample included 246 tackle football players who donated their brains for neuropathological examination. Two hundred eleven were diagnosed with CTE (126 of 211 were without comorbid neurodegenerative diseases), and 35 were without CTE. Informant interviews ascertained age of first exposure and age of cognitive and behavioral/mood symptom onset. RESULTS Analyses accounted for decade and duration of play. Age of exposure was not associated with CTE pathological severity, or Alzheimer's disease or Lewy body pathology. In the 211 participants with CTE, every 1 year younger participants began to play tackle football predicted earlier reported cognitive symptom onset by 2.44 years (p

Research Objectives To investigate 1) rates of post-injury moves among people with spinal cord injury (SCI), 2) reasons for moving and move distance, and 3) associations of moving with sociodemographic and injury-related characteristics. Design Cross-sectional study consisting of one telephone interview. Data were linked to existing data from the National Spinal Cord Injury Model Systems (SCIMS) database. Setting Six SCI Model Systems centers. Participants Individuals 18 years and older with chronic, traumatic SCI who have lived in the community for at least one year after completing inpatient rehabilitation (N= 696). Interventions Not applicable. Main Outcome Measures "Moving" is a binary measure indicating whether participants ever moved after SCI. "Reasons for moving" assesses participants’ most recent move with 5 categories: family, employment, housing quality, accessibility, or other reasons. "Move distance" compares geographic identifiers for participants’ most recent move using 4 categories: within the same Census tract; different tract, same county; different county, same state; and different state. Results 64% reported at least one post-injury move. The most frequently reported reasons for moving were housing quality and accessibility concerns. Higher move rates were reported among racial/ethnic minorities, unmarried individuals, wheelchair users, and those with severe injuries, and these groups were also more likely to move for housing quality and accessibility reasons. Female participants were more likely than males to move for family reasons, although males were more likely to make intra-county moves. Inter-state moves were more likely to occur for employment and less likely to occur for housing quality or accessibility reasons. Conclusions Residential moves are common after SCI. Housing and accessibility issues among socially disadvantaged groups and those with severe injuries are key drivers of this trend. We discuss the implications for community reintegration after SCI. Author(s) Disclosures Nothing to disclose.

Background Bupropion is associated with a dose-dependent increased risk of seizures. Use of concomitant bupropion and electroconvulsive therapy (ECT) remains controversial because of an increased risk of prolonged seizures. This is the first systematic evaluation of the effect of bupropion on ECT. Methods A case group (n = 119), patients treated with concomitant ECT and bupropion, was compared with an age and gender frequency-matched control group (n = 261), treated with only ECT. Electroconvulsive therapy treatment data including seizure length, number of treatments, and concurrent medications were extracted. Longitudinal mixed models examined ECT versus ECT + bupropion group differences over the course of treatments measured by seizure duration (electroencephalogram [EEG] and motor). Multivariable models examined the total number of treatments and first and last seizure duration. All models considered group differences with ECT treatment measures adjusted for age, gender, benzodiazepine treatment, lead placement, and setting. Results Electroconvulsive therapy treatment with bupropion led to shorter motor seizure duration (0.047) and EEG seizure duration (P = 0.001). The number of ECT treatments (7.3 vs 7.0 treatments; P = 0.23), respectively, or the probability of a prolonged seizure (P = 0.15) was not significantly different. Benzodiazepine use was significantly more common in control subjects (P = 0.01). Limitations This is a retrospective analysis limited in part by unavailable variables (seizure threshold, nature of EEG and motor seizure monitoring, type of ECT device, dosing and formulation of bupropion, and duration of the current depressive illness). Conclusions This study revealed a significantly shorter duration in seizure length with ECT + concomitant bupropion, but not in the number of required treatments in those treated compared with ECT without bupropion. There remains a critical need to reevaluate the efficacy of concomitant use of psychotropic medications + ECT.

Advanced phase myeloproliferative neoplasms (AP-MPN) are associated with a very poor prognosis. The Phase Ib PHAZAR study set out to assess the safety & tolerability of oral ruxolitinib (RUX) in combination with 5-azaciditine (AZA) in patients (pts) with advanced-phase-MPN, defined as blast count >10%. The study included an observational arm for pts not suitable for the trial intervention. The clinical results of this study are presented in a separate abstract. Here we evaluate the molecular characteristics of PHAZAR pts and correlate with clinical features, outcome and therapy response. Driver mutation (JAK2/CALR/MPL) allele burdens were quantified using targeted next-generation sequencing (NGS) and non-driver mutation analysis was performed using an ISO accredited Illumina TruSeq Custom Amplicon Panel, including 32 gene mutation hotspots & exons (~36,000 bp, 287 amplicons). SNP karyotyping was performed using the Illumina InfiniumOmniExpress-24v1-3 BeadChip assay. Data analysis was performed using R v4.0. Clinical data were censored in February 2020, and NGS sequencing data were available for 24 interventional trial and 13 observational cohort participants. 11/13 observational pts received best supportive care, while 2/13 were treated with high-dose chemotherapy. All pts had a mutation in ≥1 targeted gene. 16% of pts were 'triple-negative' for MPN driver mutations, while 59%, 16% & 8% carried canonical mutations in JAK2, CALR & MPL respectively. 89% carried additional non-driver mutations, with a median of 2 (range 0-4) detected per pt (Fig 1A). Mutations in epigenetic regulators were detected in 21/37 pts (57%) (TET2, 38%; EZH2, 19%; ASXL1, 14%; PHF6, 5%; SETBP1, 3%) while 8/37 (22%) carried mutually exclusive spliceosomal mutations (SRSF2, 8%; U2AF1, 8%; SF3B1, 5%). 10/37 (27%) were TP53 mutant. High molecular risk (HMR) mutations (ASXL1, EZH2, IDH1/2, SRSF2, TP53, U2AF1 Q157) were detected in 24/37 (65%), and >1 HMR mutation in 7/37 (19%). SNP karyotyping data were available for 42 pts (n=29 interventional, n=13 observational). 4/42 (10%) were wild-type, while 90% harboured >=1 chromosomal aberrations (median 4, range 0-16). Of these, 21 were recurrent in 3+ samples. 9 frequently recurrent events in >=5 samples included gains at 1q, 3q26, 17q21and losses of 5q, 6q12, 17p13, 19q13, 20q, and multiple losses and gains on chromosome 21q. 5 pts demonstrated evidence of chromothripsis. The presence of TP53 mutation was associated with a higher number of chromosomal aberrations (median of 3 vs 6.5, p=0.02). Concerning clinical correlation, baseline driver mutation status did not impact on OS nor likelihood of achieving a durable response (DR, defined as having achieved a minimum of 6 months of complete or partial remission or stable disease as per published criteria (Cheson Blood 2006, Mascarenhas Leuk Res 2012)). The presence of >=3 additional mutations significantly impaired OS regardless of trial arm (1 yr OS 12% vs 55%, p=0.02), as did the presence of HMR mutations (1 yr OS 22% vs 73%, p=0.008) and TP53 mutations in isolation (1 yr OS 13% vs 55%, p=0.05). The presence of HMR mutations reduced the likelihood of achieving a DR (p=0.02). Pts with losses of >=1 chromosomal arms (other than 5q-) had a poor prognosis (1yr OS 27% vs 58%, p=0.05), while no pt with chromothripsis (n=5) survived to a year (1yr OS 0% vs 53%, p=0.002). Mutational profiling of serial samples on therapy were available for 5 pts who achieved a remission during AZA and RUX therapy. One pt achieved a CMR but developed clonal evolution and emergence of a new ETV6 mutant clone at relapse. The other 4 cases demonstrated no change in clonal abundance during remission. This supports the hypothesis that response to AZA is mediated by alteration of subclonal contributions or prevention of further clonal evolution, rather than elimination of founder clones. AP-MPN continues to confer a very poor prognosis and more effective therapies are urgently required. Genetic and molecular profiling of this prospective trial cohort demonstrates the high mutational burden and structural variants seen in this disease. Initial serial sample profiling demonstrates that molecular responses to AZA and RUX are rare and, where they occur, are not sustained. Incorporation of molecular profiling into trial design may help inform which patients are more likely to benefit from the intervention - e.g. those without evidence of chromothripsis at trial entry. Disclosures Harrison: Gilead Sciences: Honoraria, Speakers Bureau; CTI Biopharma Corp: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Incyte Corporation: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Shire: Honoraria, Speakers Bureau; AOP Orphan Pharmaceuticals: Honoraria; Promedior: Honoraria; Roche: Honoraria; Sierra Oncology: Honoraria. Drummond:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Jazz: 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, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint Medicine Corporation: Research Funding. Knapper:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mead:Gilead: Consultancy; CTI: Consultancy; Abbvie: Consultancy; Celgene/BMS: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau.

BACKGROUND: Attentional bias is linked to a range of mood disorders, including posttraumatic stress disorder (PTSD). The present study examined attention bias patterns in African American children exposed to trauma, in order to better understand potential risk factors for PTSD. METHODS: 31 children (ages 8-14) completed an eye-tracking task to assess gaze bias patterns while viewing pairs of emotional and neutral faces. Trauma exposure and PTSD symptoms were assessed in a subsample of children (n = 24). RESULTS: Repeated measures analysis of variance (ANOVA) results examining attention bias indices and gender showed greater attention bias toward angry faces than happy faces (p < .01) and toward emotional faces in males than females (p < .05). Correlational analyses showed attention bias toward angry faces was associated with greater levels of child trauma exposure (p < .05). Based on linear regression analysis, child trauma exposure accounted for 17% of variance in attention bias toward angry versus neutral faces independent of gender or posttraumatic stress symptoms (p < .05). CONCLUSIONS: Trauma exposure in children is related to altered attention bias, via enhanced attention towards threatening cues. Results contribute to evidence that males and females may exhibit different attentional patterns. This study highlights the importance of additional research on attention bias patterns and prospective mental health outcomes across gender and through development.