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Introduction: Women veterans are at elevated risk for suicide and experience a high prevalence of suicidal ideation (SI) and suicide attempt (SA) history. Knowledge regarding SI/SA correlates among women veterans who use reproductive health care services is limited, inhibiting development of evidence-based, gender-sensitive suicide prevention programming tailored to meet women veterans' needs and preferences. This study aimed to 1) describe the prevalence and characteristics of SI and SA among women veterans using Veterans Health Administration (VHA) reproductive health care services and 2) provide an initial exploration of associations between fertility-, pregnancy-, and parenting-related factors with SI and SA to guide future research., Methods: Post-9/11 women veterans (n = 352) who used VHA reproductive health care in fiscal year 2018 completed a cross-sectional survey on reproductive health, mental health, and parenting., Results: Approximately 30% and 12% experienced SI and SA(s), respectively, after military service; 10% reported past-month SI. Infertility, pregnancy loss, age at first pregnancy, and parental status were not significantly associated with SI or SA history, although notable effect sizes were observed for infertility and age at first pregnancy; further research is warranted. Among parents, parental functioning was not associated with SI/SA, but lower parental satisfaction was significantly associated with past-month SI (prevalence ratio, 3.36; 95% confidence interval, 1.19-9.46; adjusting for demographics, military characteristics, mental health symptoms)., Conclusions: Postmilitary SI and SA(s) are common among women veterans accessing VHA reproductive health care services. Those with low parental satisfaction may be at particularly high risk. Findings can guide future research and inform clinical care to facilitate suicide prevention., (Published by Elsevier Inc.)

Sequence-based genetic testing identifies causative variants in ~ 50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are implicated in various neurodevelopmental disorders but remain unstudied in DEEs. We interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 582 individuals with genetically unsolved DEEs. We identify rare differentially methylated regions (DMRs) and explanatory episignatures to uncover causative and candidate genetic etiologies in 12 individuals. Using long-read sequencing, we identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and four copy number variants. We also identify pathogenic variants associated with episignatures. Finally, we refine the CHD2 episignature using an 850 K methylation array and bisulfite sequencing to investigate potential insights into CHD2 pathophysiology. Our study demonstrates the diagnostic yield of genome-wide DNA methylation analysis to identify causal and candidate variants as 2% (12/582) for unsolved DEE cases., (© 2024. The Author(s).)

Objective: To understand the etiological landscape and phenotypic differences between 2 developmental and epileptic encephalopathy (DEE) syndromes: DEE with spike-wave activation in sleep (DEE-SWAS) and epileptic encephalopathy with spike-wave activation in sleep (EE-SWAS)., Methods: All patients fulfilled International League Against Epilepsy (ILAE) DEE-SWAS or EE-SWAS criteria with a Core cohort (n = 91) drawn from our Epilepsy Genetics research program, together with 10 etiologically solved patients referred by collaborators in the Expanded cohort (n = 101). Detailed phenotyping and analysis of molecular genetic results were performed. We compared the phenotypic features of individuals with DEE-SWAS and EE-SWAS. Brain-specific gene co-expression analysis was performed for D/EE-SWAS genes., Results: We identified the etiology in 42/91 (46%) patients in our Core cohort, including 29/44 (66%) with DEE-SWAS and 13/47 (28%) with EE-SWAS. A genetic etiology was identified in 31/91 (34%). D/EE-SWAS genes were highly co-expressed in brain, highlighting the importance of channelopathies and transcriptional regulators. Structural etiologies were found in 12/91 (13%) individuals. We identified 10 novel D/EE-SWAS genes with a range of functions: ATP1A2, CACNA1A, FOXP1, GRIN1, KCNMA1, KCNQ3, PPFIA3, PUF60, SETD1B, and ZBTB18, and 2 novel copy number variants, 17p11.2 duplication and 5q22 deletion. Although developmental regression patterns were similar in both syndromes, DEE-SWAS was associated with a longer duration of epilepsy and poorer intellectual outcome than EE-SWAS., Interpretation: DEE-SWAS and EE-SWAS have highly heterogeneous genetic and structural etiologies. Phenotypic analysis highlights valuable clinical differences between DEE-SWAS and EE-SWAS which inform clinical care and prognostic counseling. Our etiological findings pave the way for the development of precision therapies. ANN NEUROL 2024., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: To identify distinct subgroups of veterans with mild traumatic brain injury (mTBI) based on configurations of postconcussive symptom (PCS) endorsement, and to examine predictors of subgroup membership., Setting: Outpatient Veterans Health Administration (VHA)., Participants: Veterans with clinician-confirmed mTBI who completed the Neurobehavioral Symptom Inventory (NSI), determined using the Comprehensive Traumatic Brain Injury Evaluation database. Individuals who tended to overreport symptoms were excluded via an embedded symptom validity scale., Design: Retrospective cohort study leveraging national VHA clinical data from 2012 to 2020. Latent class analysis (LCA) with a split-sample cross-validation procedure was used to identify subgroups of veterans. Multinomial logistic regression was used to examine predictors of subgroup membership., Main Measures: Latent classes identified using NSI items., Results: The study included 72 252 eligible veterans, who were primarily White (73%) and male (94%). The LCA supported 7 distinct subgroups of veterans with mTBI, characterized by diverging patterns of risk for specific PCS across vestibular (eg, dizziness), somatosensory (eg, headache), cognitive (eg, forgetfulness), and mood domains (eg, anxiety). The most prevalent subgroup was Global (20.7%), followed by Cognitive-Mood (16.3%), Headache-Cognitive-Mood (H-C-M; 16.3%), Headache-Mood (14.2%), Anxiety (13.8%), Headache-Sleep (10.3%), and Minimal (8.5%). The Global class was used as the reference class for multinomial logistic regression because it was distinguished from others based on elevated risk for PCS across all domains. Female (vs male), Black (vs White), and Hispanic veterans (vs non-Hispanic) were less likely to be members of most subgroups characterized by lesser PCS endorsement relative to the Global class (excluding Headache-Mood)., Conclusion: The 7 distinct groups identified in this study distill heterogenous patterns of PCS endorsement into clinically actionable phenotypes that can be used to tailor clinical management of veterans with mTBI. Findings reveal empirical support for potential racial, ethnic, and sex-based disparities in PCS among veterans, informing efforts aimed at promoting equitable recovery from mTBI in this population., Competing Interests: The authors declare no conflicts of interest.

Background: Traumatic brain injury (TBI) is an acute injury that is understudied in civilian cohorts, especially among women, as TBI has historically been considered to be largely a condition of athletes and military service people. Both the Centres for Disease Control and Prevention (CDC) and Department of Defense (DOD)/Veterans Affairs (VA) have developed case definitions to identify patients with TBI from medical records; however, their definitions differ. We sought to re-examine these definitions to construct an expansive and more inclusive definition among a cohort of women with TBI., Methods: In this study, we use electronic health records (EHR) from a single healthcare system to study the impact of using different case definitions to identify patients with TBI. Specifically, we identified adult female patients with TBI using the CDC definition, DOD/VA definition and a combined and expanded definition herein called the Penn definition., Results: We identified 4446 adult-female TBI patients meeting the CDC definition, 3619 meeting the DOD/VA definition, and together, 6432 meeting our expanded Penn definition that includes the CDC ad DOD/VA definitions., Conclusions: Using the expanded definition identified almost two times as many patients, enabling investigations to more fully characterise these patients and related outcomes. Our expanded TBI case definition is available to other researchers interested in employing EHRs to investigate TBI., Competing Interests: Competing interests: ALCS is an Associate Editor at Neurology. DJW provides consulting services on the topic of concussion/TBI epidemiology to the NCAA., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Type 2 (T2) inflammation plays a pathogenic role in chronic rhinosinusitis (CRS). The effects of endoscopic sinus surgery (ESS) on T2 inflammation are unknown., Objective: The aim of this study was to compare T2 inflammatory biomarkers from middle meatal (MM) mucus for distinguishing patients with CRS from CRS-free patients, identifying major phenotypes (CRS without nasal polyps [CRSsNP] and CRS with nasal polyps [CRSwNP]), assessing endotypic change, and establishing cross-sectional and longitudinal outcomes in patients undergoing ESS., Methods: MM mucus samples were collected from patients with CRSsNP and patients with CRSwNP before and 6 to 12 months after ESS and compared with samples from CRS-free control patients. T2 biomarkers were evaluated both continuously and using threshold-based definitions of T2 endotype to identify relationships with patient-reported (based on the 22-Item Sinonasal Outcomes Test and Chronic Rhinosinusitis Patient-Reported Outcomes Measure) and clinician-reported (radiographic and endoscopic) severity. Linear mixed models were developed to analyze clinical variables associated with T2 biomarker levels., Results: A total of 154 patients with CRS (89 with CRSsNP and 65 with CRSwNP) were enrolled, with a mean interval of 9 months between ESS and follow-up. An analysis of pre-ESS MM mucus samples revealed elevated levels of T2 mediators in patients with CRSwNP versus in patients with CRSsNP and CRS-free controls. Temporally stable correlations between levels of IL-13 and IL-5, levels of periostin and complement 5a, and levels of eosinophil cationic protein (ECP) and eotaxin-3 were observed. On this basis and on the basis of pathologic significance, levels of IL-13, periostin and ECP were further analyzed. After ESS, levels of IL-13 and periostin decreased significantly, whereas ECP levels remained unchanged. Across pre- and post-ESS evaluation, the T2 endotype was associated with radiographic severity but did not predict outcomes. CRSwNP status and African American race were associated with higher levels of IL-13 and periostin, whereas ECP level was higher in patients undergoing extensive surgery., Conclusion: ESS decreased levels of IL-13 and periostin in the middle meatus. T2 inflammation after ESS was correlated with patient- and clinician-reported severity across phenotypes. Pre-ESS T2 inflammation did not predict post-ESS outcomes., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objective: SCN1A variants are associated with epilepsy syndromes ranging from mild genetic epilepsy with febrile seizures plus (GEFS+) to severe Dravet syndrome (DS). Many variants are de novo, making early phenotype prediction difficult, and genotype-phenotype associations remain poorly understood., Methods: We assessed data from a retrospective cohort of 1018 individuals with SCN1A-related epilepsies. We explored relationships between variant characteristics (position, in silico prediction scores: Combined Annotation Dependent Depletion (CADD), Rare Exome Variant Ensemble Learner (REVEL), SCN1A genetic score), seizure characteristics, and epilepsy phenotype., Results: DS had earlier seizure onset than other GEFS+ phenotypes (5.3 vs. 12.0 months, p < .001). In silico variant scores were higher in DS versus GEFS+ (p < .001). Patients with missense variants in functionally important regions (conserved N-terminus, S4-S6) exhibited earlier seizure onset (6.0 vs. 7.0 months, p = .003) and were more likely to have DS (280/340); those with missense variants in nonconserved regions had later onset (10.0 vs. 7.0 months, p = .036) and were more likely to have GEFS+ (15/29, χ 2  = 19.16, p < .001). A minority of protein-truncating variants were associated with GEFS+ (10/393) and more likely to be located in the proximal first and last exon coding regions than elsewhere in the gene (9.7% vs. 1.0%, p < .001). Carriers of the same missense variant exhibited less variability in age at seizure onset compared with carriers of different missense variants for both DS (1.9 vs. 2.9 months, p = .001) and GEFS+ (8.0 vs. 11.0 months, p = .043). Status epilepticus as presenting seizure type is a highly specific (95.2%) but nonsensitive (32.7%) feature of DS., Significance: Understanding genotype-phenotype associations in SCN1A-related epilepsies is critical for early diagnosis and management. We demonstrate an earlier disease onset in patients with missense variants in important functional regions, the occurrence of GEFS+ truncating variants, and the value of in silico prediction scores. Status epilepticus as initial seizure type is a highly specific, but not sensitive, early feature of DS., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

We herein introduce voyAGEr, an online graphical interface to explore age-related gene expression alterations in 49 human tissues. voyAGEr offers a visualisation and statistical toolkit for the finding and functional exploration of sex- and tissue-specific transcriptomic changes with age. In its conception, we developed a novel bioinformatics pipeline leveraging RNA sequencing data, from the GTEx project, encompassing more than 900 individuals. voyAGEr reveals transcriptomic signatures of the known asynchronous ageing between tissues, allowing the observation of tissue-specific age periods of major transcriptional changes, associated with alterations in different biological pathways, cellular composition, and disease conditions. Notably, voyAGEr was created to assist researchers with no expertise in bioinformatics, providing a supportive framework for elaborating, testing and refining their hypotheses on the molecular nature of human ageing and its association with pathologies, thereby also aiding in the discovery of novel therapeutic targets. voyAGEr is freely available at https://compbio.imm.medicina.ulisboa.pt/app/voyAGEr., Competing Interests: AS, RM, AK, NS, NB No competing interests declared, (© 2023, Schneider, Martins-Silva, Kaizeler et al.)

Animal and human bites are a common reason for emergency consultation, especially in children. The most common complication of bite wounds is local infection. Systemic infections are much rarer. The key in reducing the risk of infection after a mammalian bite is local wound management with either primary or delayed closure. The benefit of administering prophylactic antibiotics is controversial.In this review, we provide a summary of the current evidence for the management of mammalian bites in children, including recommendations for appropriate investigations, wound management, administration of prophylactic and therapeutic antibiotics and the prevention of systemic infections., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Bright light therapy (BLT) is efficacious for seasonal and non-seasonal depression. However, the current state of BLT use in practice is unknown, impeding efforts to identify and address utilization gaps. This study's objective was to investigate BLT delivery in a nationwide U.S. healthcare system., Methods: This was a retrospective observational study of electronic medical records from all veterans who received outpatient mood disorder-related care in the Veterans Health Administration (VHA) from October 2008 through September 2020. BLT delivery was measured through the placement of light box consults., Results: Of the 3,442,826 veterans who received outpatient mood disorder care, only 57,908 (1.68 %) received a light box consult. Consults increased by 548.44 % (99.9 % credible interval: 467.36 %, 638.74 %) over the timeframe and displayed a robust yearly cycle that peaked on either December 21st or December 22nd. Past mental health treatment for a mood disorder was associated with a higher probability of a consult (relative risk = 4.79, 99.9 % CI: 4.21, 5.60). There was low representation related to veteran age, gender, race, and ethnicity., Limitations: No information on patients who declined light boxes or actual light box use following consult placement., Conclusions: Outpatient BLT delivery for mood disorders in the VHA remains low, despite significant growth over the past decade. It also displays a strong seasonal rhythm that peaks on the winter solstice, suggesting a limited focus on seasonal depression and a suboptimal reactive approach to changing sunlight. Overall, there exists ample opportunity for novel implementation efforts aimed at increasing utilization of BLT., Competing Interests: Declaration of competing interest The authors have no known conflicts of interest to disclose., (Published by Elsevier B.V.)

Introduction: Knowledge of suicide rates and methods among Asian American, Native Hawaiian, and Pacific Islander (AANHPI) Veterans remains sparse. Age- and sex-specific suicide rates, methods, and trends were examined among AANHPI Veterans and were compared with findings reported for all Veterans., Methods: For this population-based retrospective cohort study, average annual suicide rates (2005-2019) were computed in 2023 using population (U.S. Veterans Eligibility Trends and Statistics) and mortality (National Death Index [NDI]) data. The cohort included 416,454 AANHPI Veterans (356,146 males, 60,229 females) separated from military service and alive as of 1/1/2005. Suicide was determined from NDI underlying cause-of-death ICD-10 codes., Results: The age-adjusted average annual suicide rate among AANHPI Veterans increased 36.85% from 2005-2009 to 2015-2019 (2015-2019: 30.97/100,000). Relative to other ages, 2015-2019 suicide rates were highest among AANHPI Veterans 18-34 (overall: 53.52/100,000; males: 58.82/100,000; females: 32.24/100,000) and exceeded those of similarly aged Veterans in the overall Veteran population (overall: 44.71/100,000; males: 50.59/100,000; females: 19.24/100,000). The sex difference in suicide rates was lower among AANHPI Veterans than in Veterans overall (relative risk [males to females]=1.65 and 2.33, among those 18-54). Firearms were used less and suffocation more among AANHPI Veterans, relative to Veterans overall., Conclusions: Suicide among AANHPI Veterans is an increasing public health concern, with younger males and females at particularly elevated risk. Lethal means safety strategies for AANHPI Veterans should consider distinctions in suicide methods compared to the overall Veteran population. Research is warranted to understand the lower magnitude sex difference in suicide rates among AANHPI Veterans., (Published by Elsevier Inc.)

Objective: To investigate whether participation restrictions, an indicator of need for occupational therapy (OT), was associated with outpatient OT utilization in the Veterans Health Administration (VHA) among Veterans with mild traumatic brain injury (mTBI), and whether this relation differs by facility characteristics., Design: In a secondary analysis of national VHA data, we used modified Poisson regression to model OT utilization (yes/no) as a function of participation restrictions (Mayo-Portland Adaptability Inventory Participation Index [M2PI]), facility characteristics, and covariates. Facility characteristics included complexity, geographic region, and self-reported access to specialty care. Covariates included prior OT utilization, sociodemographic factors, injury characteristics, and spatial access (eg, drive time). Interactions estimated whether the relation between participation restrictions and OT utilization differed across facility characteristics., Setting: Outpatient setting in the VHA., Participants: 8684 Veterans with a clinician-confirmed mTBI who received outpatient VHA care between 2012 and 2020 (N=8684)., Interventions: None., Main Outcome Measure(s): OT utilization was measured within a year of M2PI administration using VHA administrative data., Results: Many Veterans who did not receive OT reported participation limitations, indicating unmet need for OT (eg, 67% with leisure restrictions). Participation restrictions were associated with increased likelihood of receiving OT (risk ratio [RR]=1.01; 95% confidence interval [CI]=1.006-1.019), suggesting a tendency for Veterans' OT-related needs to be satisfied. However, interactions indicated that this was not the case among Veterans receiving care in lower complexity facilities, and those in the South. Veterans with longer drive times were less likely to receive OT (RR=0.82; 95% CI=0.744-0.904)., Conclusions: Participation restrictions were associated with OT utilization, yet many Veterans with mTBI who may have benefited did not receive such care. Specific barriers to accessing OT (eg, OT practitioner supply) should be investigated. Novel care models can ensure access to OT services among Veterans seeking care at less-resourced and/or geographically distant VHA facilities., (Published by Elsevier Inc.)

The suicide rate among Asian American, Native Hawaiian, and Pacific Islander (AANHPI) Veterans increased from 2001 to 2020. Identifying regions where suicide rates are elevated and increasing among AANHPI Veterans would inform targeted prevention efforts for members of this cohort. We conducted a population-based retrospective cohort study of 377,833 AANHPI Veterans to examine suicide rates and methods (2005-2019) by United States (US) region and over time (2005-2009, 2010-2014, 2015-2019), using US Veteran Eligibility Trends and Statistics and Joint DoD/VA Mortality Data Repository data. AANHPI Veterans across most regions experienced increases in suicide rates from the earliest to latest period; however, patterns differed by region. Age-adjusted suicide rates increased across all three periods among those in the Northeast and West, but increased, then declined in the Midwest and South. In 2015-2019, the age-adjusted suicide rate among AANHPI Veterans was highest in the Northeast (42.0 per 100,000) and lowest in the West (27.5). However, the highest percentages of AANHPI Veteran suicide deaths in 2005-2019 occurred in the West (39.5%) and South (34.7%), with lower percentages in the Midwest (15.0%) and Northeast (10.8%). Across regions, those ages 18-34 had the highest suicide rates. Firearms were the most frequently used suicide method across regions (44.4%-60.2%), except the Northeast (35.2%), where suffocation was more common (38.3%). Results suggest particular needs for suicide prevention efforts among AANHPI Veterans in the Northeast and to ensure that lethal means safety initiatives for AANHPI Veterans encompass both firearms and suffocation, with some variations in emphasis across regions., Competing Interests: Declaration of Competing Interest Authors were employed by the Department of Veterans Affairs (VA) during the initial analysis and writing of this manuscript. Authors have received funding from the VA Office of Mental Health and Suicide Prevention (Monteith, Schneider, Miller, Gaeddert, Holliday, Spark, Brenner, Hoffmire), VA Health Services Research and Development (Monteith, Schneider, Miller, Gaeddert, Holliday, Spark, Brenner, Hoffmire), VA Rehabilitation Research and Development (Brenner), VA Office of Rural Health (Schneider, Brenner, Spark), VA National Center on Homelessness among Veterans (Holliday, Monteith, Brenner), VA National Center for Patient Safety (Monteith, Hoffmire), VA Office of Women’s Health (Monteith), VA Office of Health Equity (Holliday, Monteith), the National Institutes of Health (Brenner, Holliday, Hoffmire), the Department of Defense (Monteith, Holliday, Brenner, Hoffmire), the American Psychological Association (Monteith), and the State of Colorado (Brenner, Hoffmire). In her current employment with Westat, Dr. Spark has also received funding from the CDC and SAMHSA. Dr. Brenner also reports editorial remuneration from Wolters Kluwer, royalties from the American Psychological Association and Oxford University Press, and consults with sports leagues via her university affiliation., (Published by Elsevier B.V.)

The COVID-19 pandemic has had significant impacts, including increases in mental health problems, distress, interpersonal conflict, unemployment, loss of income, housing instability, and food insecurity. Veterans may be particularly vulnerable to such impacts given their burden of mental and physical health problems. Few existing measures assess pandemic impact, and none have been validated for use with Veterans. We developed such a measure (the Perceived Impact of the Pandemic Scale; PIPS) and examined its psychometric performance in a national sample of US Veterans. Survey data from 567 Veterans were collected between 12/2020 and 2/2021. To examine PIPS factor structure, split sample exploratory/confirmatory factor analyses (EFA/CFA) were conducted to identify and test the most plausible model among an initial set of 18 items. Based on tests of factor extraction and factor loadings, 15 items clearly loaded onto three distinct factors. Internal reliability of all factors was ω > 0.8 and CFA model fit was good (χ 2 (87) = 167.39, p < .001; SRMR = 0.068; RMSEA = 0.060 [95% CI: 0.05, 0.07], CFI = 0.92). Mean factor scores were significantly positively correlated with measures of depression and loneliness, and negatively correlated with perceived social support. Results suggest the PIPS assesses three internally reliable factors comprised of perceived impact of the pandemic on interpersonal relationships, financial impact, and personal health and well-being. Construct validity with US Veterans was supported. The PIPS may be useful for examining the potentially disparate impact of pandemics on different populations. Research is needed to validate the PIPS in non-Veteran populations., Competing Interests: Declaration of competing interest All authors were employed by the VA while writing this manuscript. Authors have received grant funding from the VA Office of Mental Health and Suicide Prevention (Monteith, Hoffmire, Holliday, Schneider, Barnes), VA Health Services Research and Development (Monteith, Hoffmire, Holliday, Schneider), VA Rehabilitation Research and Development (Barnes), VA Office of Clinical Science Research and Development (Barnes), VA Office of Rural Health (Monteith, Schneider), VA National Center on Homelessness among Veterans (Holliday, Monteith), VA National Center for Patient Safety (Monteith, Hoffmire), VA Office of Women’s Health (Monteith), the National Institutes of Health (Brenner, Hoffmire, Holliday), the Department of Defense (Monteith, Hoffmire, Holliday), the American Psychological Association (Monteith, Holliday), and the State of Colorado (Hoffmire). The other authors (Kittel, Tock) report no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The master transcriptional regulator PU.1/Spi-1 engages DNA sites with affinities spanning multiple orders of magnitude. To elucidate this remarkable plasticity, we have characterized 22 high-resolution co-crystallographic PU.1/DNA complexes across the addressable affinity range in myeloid gene transactivation. Over a purine-rich core (such as 5'-GGAA-3') flanked by variable sequences, affinity is negotiated by direct readout on the 5' flank via a critical glutamine (Q226) sidechain and by indirect readout on the 3' flank by sequence-dependent helical flexibility. Direct readout by Q226 dynamically specifies PU.1's characteristic preference for purines and explains the pathogenic mutation Q226E in Waldenström macroglobulinemia. The structures also reveal how disruption of Q226 mediates strand-specific inhibition by DNA methylation and the recognition of non-canonical sites, including the authentic binding sequence at the CD11b promoter. A re-synthesis of phylogenetic and structural data on the ETS family, considering the centrality of Q226 in PU.1, unifies the model of DNA selection by ETS proteins., Competing Interests: Declaration of interests U.S. has received research funding from GlaxoSmithKline, Bayer Healthcare, Aileron Therapeutics, and Novartis; has received compensation for consultancy services and for serving on scientific advisory boards from GlaxoSmithKline, Bayer Healthcare, Celgene, Aileron Therapeutics, Stelexis Therapeutics, and Pieris Pharmaceuticals; and has equity ownership in and is serving on the board of directors of Stelexis Therapeutics., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Military sexual trauma (MST) is highly prevalent among women veterans. Research among MST survivors has focused on individuals receiving care in specific settings, such as mental health services. There is a dearth of knowledge regarding MST prevalence and associations in other settings commonly accessed by women veterans, including reproductive healthcare settings. We examined MST prevalence (overall, by MST type and extent of underreporting) and associations with suicidal ideation and suicide attempts, among women veterans accessing Veterans Health Administration (VHA) reproductive health care. Our sample included 352 post-9/11 women veterans who used VHA reproductive health care in Fiscal Year (FY) 2018 and participated in a cross-sectional survey. Approximately 68.7% screened positive for MST, including 44.9% who reported experiencing military sexual assault. Notably, 30.8% reported MST on the survey, but had a negative MST screen for their most recent MST screen in their VHA medical record. Both military sexual harassment and assault were associated with increased prevalence of experiencing suicidal ideation following military service; however, a significant association among military sexual harassment, past-month suicidal ideation, and post-military suicide attempts was not detected. Military sexual assault was uniquely associated with past-month suicidal ideation and post-military suicide attempts. As MST and underreporting are highly prevalent among women veterans using VHA reproductive health care, rescreening for MST within this population is essential. A trauma-informed approach is recommended irrespective of prior MST screening results and may facilitate suicide prevention in this population. Addressing barriers to MST disclosure and preventing MST and its sequelae remain critical.

Background and Objectives: The genetic developmental and epileptic encephalopathies (DEEs) comprise a large group of severe epilepsy syndromes, with a wide phenotypic spectrum. Currently, the rates of convulsive status epilepticus (CSE), nonconvulsive status epilepticus (NCSE), and sudden unexplained death in epilepsy (SUDEP) in these diseases are not well understood. We aimed to describe the proportions of patients with frequently observed genetic DEEs who developed CSE, NCSE, mortality, and SUDEP. Understanding the risks of these serious presentations in each genetic DEE will enable earlier diagnosis and appropriate management., Methods: In this retrospective analysis of patients with a genetic DEE, we estimated the proportions with CSE, NCSE, and SUDEP and the overall and SUDEP-specific mortality rates for each genetic diagnosis. We included patients with a pathogenic variant in the genes SCN1A , SCN2A , SCN8A , SYNGAP1 , NEXMIF , CHD2 , PCDH19 , STXBP1 , GRIN2A , KCNT1 , and KCNQ2 and with Angelman syndrome (AS)., Results: The cohort comprised 510 individuals with a genetic DEE, in whom we observed CSE in 47% and NCSE in 19%. The highest proportion of CSE occurred in patients with SCN1A -associated DEEs, including 181/203 (89%; 95% CI 84-93) patients with Dravet syndrome and 8/15 (53%; 95% CI 27-79) non-Dravet SCN1A -DEEs. CSE was also notable in patients with pathogenic variants in KCNT1 (6/10; 60%; 95% CI 26-88) and SCN2A (8/15; 53%; 95% CI 27-79). NCSE was common in patients with non-Dravet SCN1A -DEEs (8/15; 53%; 95% CI 27-79) and was notable in patients with CHD2 -DEEs (6/14; 43%; 95% CI 18-71) and AS (6/19; 32%; 95% CI 13-57). There were 42/510 (8%) deaths among the cohort, producing a mortality rate of 6.1 per 1,000 person-years (95% CI 4.4-8.3). Cases of SUDEP accounted for 19/42 (48%) deaths. Four genes were associated with SUDEP: SCN1A , SCN2A , SCN8A , and STXBP1. The estimated SUDEP rate was 2.8 per 1,000 person-years (95% CI 1.6-4.3)., Discussion: We showed that proportions of patients with CSE, NCSE, and SUDEP differ for commonly encountered genetic DEEs. The estimates for each genetic DEE studied will inform early diagnosis and management of status epilepticus and SUDEP and inform disease-specific counseling for patients and families in this high-risk group of conditions., (© 2023 American Academy of Neurology.)

Background: In the USA, deaths due to suicide, alcohol, or drug-related causes (e.g., alcohol-related liver disease, overdose) have doubled since 2002. Veterans appear disproportionately impacted by growing trends. Limited research has been conducted regarding the relationship between community-level factors (e.g., rurality, community distress resulting from economic conditions) and the presence of spatial clustering of suicide, alcohol-related, or drug-related deaths. We explored community-level relationships in Colorado Veterans and compared suicide, alcohol-, and drug-related death rates between the Colorado adult population and Veterans., Methods: 2009-2020 suicide, alcohol-related, and/or drug-related deaths were identified using qualifying multiple cause-of-death International Classification of Disease (ICD)-10 codes in CDC WONDER for the general adult population and Colorado death data for Veteran populations. Age and race adjusted rates were calculated to compare risk overall and by mortality type (i.e., suicide, alcohol-related, drug-related). In Veteran decedents, age-adjusted rates were stratified by rurality and community distress, measured by the Distressed Communities Index. Standardized mortality ratios were calculated to measure spatial autocorrelation and identify clusters using global and local Moran's I, respectively., Results: 6.4% of Colorado Veteran deaths (n = 6948) were identified as being related to suicide, alcohol, or drugs. Compared to rates in the general population of Colorado adults, Veterans had 1.8 times higher rates of such deaths overall (2.1 times higher for suicide, 1.8 times higher for alcohol-related, 1.3 times higher for drug-related). Among Veterans, community distress was associated with an increased risk of alcohol-related [age-adjusted rate per 100,000 (95% CI) = 129.6 (89.9-193.1)] and drug-related deaths [95.0 (48.6-172.0)]. This same significant association was not identified among those that died by suicide. Rurality was not associated with risk for any of the deaths of interest. There was significant spatial clustering for alcohol-related deaths in southeast Colorado., Conclusions: Colorado Veterans have higher rates of deaths due to suicide, alcohol-related, and drug-related causes compared to members of the general adult population. Upstream prevention efforts, such as community-based interventions targeting alcohol-use and community economic distress, are warranted. More research is also needed to understand how community distress and other social determinants of health impact the community burden of suicide, alcohol-related, and drug-related mortality., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Aims: Firearm purchasing increased within the U.S. during the coronavirus disease 2019 pandemic. While rates of firearm ownership and suicide are elevated among women Veterans compared to women non-Veterans, no studies have examined if and how firearm beliefs and behaviors changed among women Veterans during the pandemic. We examined women Veterans' changes in firearm beliefs and engagement in firearm behaviors during the early pandemic era., Method: 3,000 post-9/11 era women Veterans were invited to participate in a survey. 501 respondents (May-December 2020) comprised the sample for this concurrent nested mixed-method analysis. Thematic analysis and log-binomial regression were used., Results: 13.88% (n = 69) of women Veterans in our sample reported changes in their firearm beliefs; 22.15% (n = 109) reported engaging in firearm behaviors. The most prevalent reported behaviors were making household firearms more accessible (16.13%) and purchasing ammunition (11.97%). Smaller percentages reported carrying a firearm more frequently (6.71%), loading previously unloaded firearms (5.69%), or purchasing a firearm (4.24%). Thematic analysis suggested firearm behaviors were likely driven by a perceived increased need to protect oneself, family, and property due to: (1) uncertainties brought on by the pandemic; (2) pandemic-related threats necessitating self-defense, preparedness, and self-sufficiency; (3) political, social, and racial unrest and protests. PTSD symptom severity and military sexual assault history were associated with higher prevalence of changes in firearm beliefs and engagement in firearm behaviors during the pandemic., Discussion: Consideration of women Veterans' prior experiences and pandemic-related factors may be necessary to contextualize firearm discussions and inform future research. Given associations of military sexual assault and PTSD symptoms with firearm beliefs and behaviors, it may be crucial to ensure that such discussion are trauma-informed., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: All authors report grant funding from the VA. Drs. Monteith, Holliday, Hoffmire and Brenner also report grant funding from the Department of Defense. Drs. Hoffmire and Brenner additionally report funding from the National Institutes of Health. Dr. Brenner also reports grants from the State of Colorado, editorial renumeration from Wolters Kluwer, and royalties from the American Psychological Association and Oxford University Press. In addition, she consults with sports leagues via her university affiliation. While this funding does not alter our adherence to PLOS ONE policies on sharing data and materials, we do not have approval by our regulatory authority to share de-identified data publicly for this study, but rather are able to consider such requests through a Data Use Agreement and verification of IRB approval from the requestor., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background and Objectives: To determine the frequency and spectrum of complications of influenza infection in individuals with SCN1A -positive Dravet syndrome ( SCN1A -DS)., Methods: Individuals with SCN1A -DS were identified in neurologists' care at 2 hospitals in Melbourne, Australia, with additional searches of EEG databases, the Victorian PAEDS FluCan influenza database, and the University of Melbourne Epilepsy Genetics Research Program database. Medical records were searched and families questioned to identify individuals who had an influenza infection; reported infections were confirmed by pathology report. For these individuals, we obtained baseline clinical characteristics and clinical details of the influenza infection., Results: Twenty-one of 82 individuals (26%) had 24 documented influenza infections (17 influenza A and 7 influenza B) at age 0.5-25 years (median 4 years). All presented to hospital, 18/24 (75%) for status epilepticus or seizure exacerbations. Recovery was prompt in 18/24 (75%) infections, delayed but complete in 1/24 (4%) and incomplete in 5/24 (21%). One child died from influenza pneumonia, and long-term neurologic sequelae were seen with 4 infections. These individuals were poorly responsive after termination of status epilepticus. Brain imaging in 2 showed cerebral edema and 1 also having imaging features of laminar necrosis. All have ongoing neurologic deficits compared with their baseline, 1 having profound global impairment., Discussion: Our data show that patients with SCN1A -DS are highly susceptible to neurologic complications during and severe sequelae after influenza infection, including moderate to severe persistent neurologic impairments and death. Safe administration of the seasonal influenza vaccine should be prioritized for this population., (© 2022 American Academy of Neurology.)

Introduction: Among women Veterans, firearms are the leading suicide means. This has prompted efforts to elucidate factors associated with women Veterans' firearm ownership. This cross-sectional study examined if deployment experiences were associated with firearm ownership among women Veterans and if safety-related beliefs mediated these associations., Methods: 492 previously deployed post-9/11 women Veterans participated in a national survey that included the Deployment Risk and Resilience Inventory-2, subscales of the Posttraumatic Cognitions Inventory and Posttraumatic Maladaptive Beliefs Scale, and firearm ownership questions. Path analysis was used., Results: Perceived threat during deployment was associated with firearm ownership, irrespective of safety-related beliefs. Indirect effects did not support that safety-related beliefs mediated relations between deployment experiences and firearm ownership. The other deployment experiences (sexual harassment, sexual assault, general harassment, combat experiences) were not indirectly associated with firearm ownership, nor were safety-related beliefs (negative cognitions about the world, threat of harm, beliefs about others' reliability and trustworthiness) directly associated with firearm ownership. In an exploratory serial mediation analysis, perceived threat during deployment mediated the association between combat experiences and firearm ownership. In a sensitivity analysis examining firearm acquisition following military service, results were similar, except the indirect effect of combat experiences upon firearm acquisition through perceived threat was not significant., Conclusion: Post-9/11 women Veterans' firearm acquisition and ownership may relate to specific deployment experiences, such as perceived threat; however, longitudinal studies are needed to fully ascertain this. Efforts to address firearm access among post-9/11 women Veterans may benefit from assessing heightened sense of danger during deployment., Competing Interests: Declaration of competing interest The authors report grant funding from the Department of Veterans Affairs (Monteith, Kinney, Holliday, Miller, Schneider, Hoffmire, Simonetti, Brenner, Forster), Department of Defense (Monteith, Hoffmire, Brenner, Holliday, Forster), National Institutes of Health (Brenner, Hoffmire, Forster), American Psychological Association (Monteith), and State of Colorado (Brenner). Dr. Brenner also reports editorial renumeration from Wolters Kluwer, and royalties from the American Psychological Association and Oxford University Press. In addition, she consults with sports leagues via her university affiliation., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Patients with chronic rhinosinusitis (CRS) may have persistence of polyps, discharge, or edema after endoscopic sinus surgery (ESS). Inflammation in CRS can be classified into three endotypes, with the presence of polyps associated with the type 2 endotype. Here, we evaluate the endotypic underpinnings of discharge or edema without polyps after ESS., Methods: At a visit 6-12 months post ESS, patients underwent endoscopy and completed the CRS-PRO and SNOT-22. Luminex analysis of middle meatal mucus obtained at that visit was performed for IFN-γ, ECP, and IL-17a. Type 1, 2, and 3 endotypes were defined as greater than the 90th percentile expression of each marker, respectively, in controls. Wilcoxon rank-sum and chi-squared tests were used to compare cytokine levels and endotype prevalence between those with and without endoscopic findings., Results: A total of 122 CRS patients completed a clinical exam (median: 8.2 months post ESS). Of the 122 patients, 107 did not have polyps on endoscopy. Of these 107 patients, 48 had discharge, 44 had edema, and 46 had neither discharge nor edema. Compared with those patients without any findings, patients with discharge or edema reported significantly worse severity as measured by CRS-PRO (10.5 vs. 7.0, p = 0.009; 12.0 vs. 7.0, p < 0.001; respectively), and had higher post-ESS IFN-γ, ECP, and IL-17a. Patients with discharge had higher prevalence of only T1 and T3 endotypes, while patients with edema had higher prevalence of only the T3 endotype., Conclusions: Post-ESS discharge or edema in the absence of polyps was associated with higher patient-reported outcome severity and was more strongly associated with type 1 or 3 inflammation., (© 2022 The Authors. International Forum of Allergy & Rhinology published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngic Allergy and American Rhinologic Society.)

Objectives: The rise and fall of the health technology startup Theranos is emblematic of the promise and peril of point-of-care testing (POCT). Instruments that deliver immediate results from minimally invasive samples at the location of collection can provide powerful tools to deliver health data in clinical and public health contexts. Yet, POCT availability is driven largely by market interests, which limits the development of inexpensive tests for diverse health conditions that can be used in resource-limited settings. These constraints, combined with complex regulatory hurdles and substantial ethical challenges, have contributed to the underutilization of POCT in human biology research., Methods: We evaluate current POCT capabilities and limitations, discuss promising applications for POCT devices in resource-limited settings, and discuss the future of POCT., Results: As evidenced by publication trends, POCT platforms have rapidly advanced in recent years, gaining traction among clinicians and health researchers. We highlight POCT devices of potential interest to population-based researchers and present specific examples of POCT applications in human biology research., Conclusions: Several barriers can limit POCT applications, including cost, lack of regulatory approval for non-clinical use, requirements for expensive equipment, and the dearth of validation in remote field conditions. Despite these issues, we see immense potential for emerging POCT technology capable of analyzing new sample types and used in conjunction with increasingly common technology (e.g., smart phones). We argue that the fallout from Theranos may ultimately provide an opportunity to advance POCT, leading to more ethical data collection and novel opportunities in human biology research., (© 2021 Wiley Periodicals LLC.)

The 22-item Sino-Nasal Outcome Test (SNOT-22) and 12-item Patient Reported Outcomes in Chronic Rhinosinusitis (CRS-PRO) instrument are validated patient-reported outcomes measures in CRS. In this study we assess the correlation of these with type 2 (T2) biomarkers before and after endoscopic sinus surgery (ESS)., Methods: Middle meatal mucus data were collected and the SNOT-22 and CRS-PRO were administered to 123 patients (71 CRS without nasal polyps [CRSsNP], 52 CRS with nasal polyps [CRSwNP]) with CRS before and 6 to 12 months after undergoing ESS. Interleukin (IL)-4, IL-5, IL-13, and eosinophilic cationic protein (ECP) were measured using a multiplexed bead assay and enzyme-linked immunoassay. Pre- and post-ESS SNOT-22 and CRS-PRO were compared with T2 biomarkers., Results: Before ESS neither PROM correlated with any biomarker. After ESS, CRS-PRO showed a correlation with 2 mediators (IL-5 and IL-13: p = 0.012 and 0.003, respectively) compared with none for the SNOT-22. For CRSwNP patients, pre-ESS CRS-PRO and SNOT-22 correlated with IL-4 (p = 0.04 for both). However, after ESS, CRS-PRO correlated with 3 biomarkers (IL-5, IL-13, and ECP: p = 0.02, 0.024, and 0.04, respectively) and SNOT-22 with 2 biomarkers (IL-5 and IL-13: p = 0.038 and 0.02, respectively). There were no significant relationships between any of the T2 biomarkers pre- or post-ESS among patients with CRSsNP. Exploratory analyses of the subdomains showed the SNOT-22 rhinologic and CRS-PRO rhinopsychologic subdomains correlated better with the T2 biomarkers. On individual item analysis, IL-13 correlated significantly post-ESS with 8 of 12 items on the CRS-PRO vs 6 of 22 items on the SNOT-22., Conclusion: The CRS-PRO total score showed a significant correlation with T2 biomarkers especially when assessed post-ESS and among CRSwNP patients., (© 2022 ARS-AAOA, LLC.)

Background: Mometasone-eluting stents (MES) have demonstrated improvement in short-term endoscopic outcomes and reduce short- to medium-term rescue interventions. Their effect on the local inflammatory environment, longer-term patient-reported outcomes, and radiographic severity have not been studied., Methods: Middle meatal mucus and validated measures of disease severity were collected before and 6 to 12 months after endoscopic surgery in 52 patients with chronic rhinosinusitis with nasal polyps (CRSwNPs). Operative findings, type 2 mediator concentrations, intraoperative variables, and disease severity measures were compared between those who did and those who did not receive intraoperative frontal MES., Results: A total of 52 patients with CRSwNPs were studied; 33 received frontal MES and were compared with 19 who did not. Pre-endoscopic sinus surgery (ESS) middle meatus (MM) interleukin (IL) 13 and eosinophil cationic protein (ECP) were higher in the stented group (p < 0.05), but pre-ESS clinical measures of disease severity were similar as were surgical extent and post-ESS medical management. Intraoperative eosinophilic mucin was more frequent in the stented group (58% vs 11%, p = 0.001). IL-5 (p < 0.05) and IL-13 (p < 0.001) decreased post-ESS in the stented group, but this was not observed in the nonstented group. Post-ESS IL-4 and IL-13 were higher in the nonstented vs stented group (p < 0.05 for both)., Conclusion: Although patients who received intraoperative frontal MES had significantly higher pre-ESS MM IL-13 and ECP, patients who received frontal MES had lower concentrations of IL-4 and IL-13 than those who did not at a median of 8 months post-ESS. However, these changes did not correspond to significantly different measures of symptomatic or radiographic disease severity., (© 2022 The Authors. International Forum of Allergy & Rhinology published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngic Allergy and American Rhinologic Society.)

Background: Sleep problems are common among Veterans with mild traumatic brain injury (mTBI) and may contribute to participation restrictions. However, explanatory mechanisms underlying this relationship are poorly understood. Sleep problems are associated with post-concussive symptoms (e.g., headaches). In turn, post-concussive symptoms contribute to participation restrictions. We hypothesized that post-concussive symptom severity mediates the purported relationship between sleep problems and participation restrictions among Veterans with mTBI., Materials and Methods: This study was a retrospective analysis of clinical data among 8,733 Veterans with mTBI receiving Veterans Health Administration outpatient care. Sleep problems (yes/no) were identified using the sleep-related item from the Neurobehavioral Symptom Inventory (NSI). Post-concussive symptoms were measured using remaining NSI items. Participation restrictions were measured using the Mayo-Portland Adaptability Inventory Participation Index. We specified a latent variable path model to estimate relationships between: (1) sleep problems and three latent indicators of post-concussive symptoms [vestibular-sensory (e.g., headache)]; mood-behavioral [e.g., anxiety]; cognitive [e.g., forgetfulness]); and, (2) the three latent indicators of post-concussive symptoms and two latent indicators of participation restrictions (social and community participation [e.g., leisure activities]; productivity [e.g., financial management]). We examined the indirect effects of sleep problems upon participation restrictions, as mediated by post-concussive symptoms. Estimates were adjusted for sociodemographic factors (e.g., age), injury characteristics (e.g., blast), and co-morbid conditions (e.g., depression)., Results: 87% of Veterans reported sleep problems. Sleep problems were associated with greater social and community participation restrictions, as mediated by mood-behavioral ( β  = 0.41, p  < 0.001) and cognitive symptoms ( β  = 0.13, p  < 0.001). There was no evidence that vestibular-sensory symptoms mediated this relationship ( β  = -0.01, p  = 0.48). Sleep problems were associated with greater productivity restrictions, as mediated by vestibular-sensory ( β  = 0.16, p  < 0.001) and cognitive symptoms ( β  = 0.14, p  < 0.001). There was no evidence that mood-behavioral symptoms mediated this relationship ( β  = 0.02, p  = 0.37)., Discussion: Findings suggest that evidence-based sleep treatment should occupy a prominent role in the rehabilitation of Veterans with mTBI. Indirect effects of sleep problems differed when considering impact on social and community participation vs. productivity, informing individualized rehabilitative care for Veterans with mTBI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (This work is authored by Adam R. Kinney, Xiang-Dong Yan, Alexandra Lindsay Schneider, Samuel King, Jeri E. Forster, Nazanin Bahraini and Lisa Anne Brenner on behalf of the U.S. Government and as regards Dr. Kinney, Dr. Yan, Dr. Schneider, Dr. King, Dr. Forster, Dr. Bahraini and Dr. Brenner, and the U.S. Government, is not subject to copyright protection in the United States. Foreign and other copyrights may apply.)

Objectives: To explore the degree to which patients undergoing unilateral endoscopic sinus surgery (ESS) experience post-operative contralateral sinonasal symptoms and determine risk factors for contralateral symptomatology following unilateral ESS., Methods: Patients who underwent unilateral surgery for chronic rhinosinusitis (CRS) were contacted and asked if they felt symptomatic on the contralateral side at that point in time. Nasal Obstruction Symptom Evaluation (NOSE) scores were obtained based on contralateral symptomatology they recalled at the following time points: pre-ESS, 1 month post-ESS, and 3 months post-ESS. Demographics, contralateral symptomatology, and NOSE scores were compared between those with 2 or fewer sinusotomies versus 3 or more sinusotomies., Results: Of the 97 patients included in this study, 24% of patients reported contralateral congestion, a median of 24 months post-ESS, and more than 10% of patients reported other contralateral symptoms including swelling, rhinorrhea, difficulty breathing, and hyposmia post-ESS. Those with 2 or fewer sinusotomies were more likely to feel that they had developed worsened sensation of contralateral sinus swelling ( P = .008). The median amount of time from the participants' index surgery until the time they were interviewed was 24 months. There were no differences in long-term contralateral symptomatology between those who did and did not have septoplasty (27%)., Conclusion: Patients who have unilateral ESS for CRS may experience long-term contralateral symptoms. Having a septoplasty did not affect contralateral symptoms., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Suicide rates have increased among women Veterans, with increased use of firearms as the method. Addressing suicide risk in this population requires understanding the prevalence and correlates of firearm access in healthcare settings frequented by women Veterans., Objectives: Characterize the prevalence and correlates of firearm ownership and storage practices among women Veterans using Department of Veterans Affairs (VA) reproductive healthcare (RHC) services., Design: Cross-sectional national survey conducted in 2018-2019 (17.9% response rate)., Participants: Post-9/11 women Veterans using RHC (n=350)., Main Measures: VA Military Sexual Trauma Screen, PTSD Checklist for DSM-5, Hurt/Insult/Threaten/Scream, Columbia-Suicide Severity Rating Scale screener, self-reported firearm access., Key Results: 38.0% (95% confidence interval [95% CI]: 32.9, 43.3) of participants reported personally owning firearms, and 38.9% (95% CI: 33.7, 44.2) reported other household members owned firearms. Among those with firearms in or around their homes, 17.8% (95% CI: 12.3, 24.4) and 21.9% (95% CI: 15.9, 28.9) reported all were unsafely stored (loaded or unlocked, respectively). Women who experienced recent intimate partner violence were less likely to report personally owning firearms (adjusted prevalence ratio [APR]=0.75; 95% CI: 0.57, 0.996). Those who experienced military sexual harassment (APR=1.46; 95% CI=1.09, 1.96), were married (APR=1.74; 95% CI: 1.33, 2.27), or lived with other adult(s) (APR=6.26; 95% CI: 2.87, 13.63) were more likely to report having household firearms owned by someone else. Storing firearms loaded was more prevalent among women with lifetime (APR=1.47; 95% CI=1.03, 2.08) or past-month (APR=1.69; 95% CI=1.15, 2.48) suicidal ideation and less likely among those with other adult(s) in the home (unadjusted PR=0.62; 95% CI=0.43, 0.91). Those with parenting responsibilities (APR=0.61; 95% CI=0.38, 0.97) were less likely to store firearms unlocked., Conclusions: Firearm access is prevalent among post-9/11 women Veterans using VA RHC. Interpersonal factors may be important determinants of firearm access in this population. Safe firearm storage initiatives are needed among women Veterans using RHC, particularly for those with suicidal ideation., (© 2022. The Author(s).)

Background: Women veterans of reproductive age experience a suicide rate more than double their civilian peers. Developing effective suicide prevention strategies for women veterans requires identifying settings frequented by women veterans where acceptable prevention initiatives can be implemented. Reproductive health care (RHC) settings may provide such an opportunity., Methods: We conducted semi-structured interviews with 21 cisgender women veterans of reproductive age using RHC services provided or paid for by the Department of Veterans Affairs (VA) to understand their beliefs, attitudes, and preferences regarding suicide risk assessment and prevention within these settings. Interview analysis was inductive and used a thematic analysis framework., Results: Four major themes emerged from the interviews: 1) positive patient-provider relationships in RHC settings are important; 2) some women veterans prefer women providers for RHC and suicide risk screening; 3) women veterans' experiences with VA suicide risk screening and assessment vary; and 4) suicide risk screening and prevention in RHC settings is a desired and acceptable, yet unmet opportunity., Conclusions: Findings from this novel study suggest that VA RHC settings may present a viable milieu for implementing upstream, gender-sensitive, veteran-centric suicide prevention strategies. Future research is needed with VA RHC providers to determine their needs for successfully implementing such strategies., (Published by Elsevier Inc.)

Objective: The Suicide Cognitions Scale (SCS) may be beneficial for suicide risk assessment. However, research has identified diverging factor structures and focused primarily on samples composed of males. Given limited prior research with female veterans, who have experienced increased rates of suicide, we examined the factor structure of the SCS among a national sample of female veterans., Method: Four-hundred thirty-one female veterans using and not using Veterans Health Administration care participated in an anonymous survey., Results: Exploratory factor analysis identified a three-factor solution, consistent with some prior research. This factor structure was not replicated in a confirmatory factor analysis., Conclusions: Findings did not identify a consistent factor structure for the SCS among a sample of female veterans. Research is warranted to determine if suicide-specific cognitions differ among female veterans and to identify SCS items that should be added or removed to produce a more consistent factor structure among female veterans.HighlightsA consistent factor structure of the SCS among female Veterans was not identifiedSuicide-specific cognitions may differ among female VeteransAddition or removal of SCS items may be warranted in this population.

Fixed-charge (non-polarizable) forcefields are accurate and computationally efficient tools for modeling the molecular dynamics of nucleic acid polymers, particularly DNA, well into the µs timescale. The continued utility of these forcefields depends in part on expanding the residue set in step with advancing nucleic acid chemistry and biology. A key step in parameterizing new residues is charge derivation which is self-consistent with the existing residues. As atomic charges are derived by fitting against molecular electrostatic potentials, appropriate structural models are critical. Benchmarking against the existing charge set used in current AMBER nucleic acid forcefields, we report that quantum mechanical models of deoxynucleosides, even at a high level of theory, are not optimal structures for charge derivation. Instead, structures from molecular mechanics minimization yield charges with up to 6-fold lower RMS deviation from the published values, due to the choice of such an approach in the derivation of the original charge set. We present a contemporary protocol for rendering self-consistent charges as well as optimized charges for a panel of nine non-canonical residues that will permit comparison with literature as well as studying the dynamics of novel DNA polymers.

Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. The FBXW7 neurodevelopmental syndrome is distinguished by global developmental delay, borderline to severe intellectual disability, hypotonia, and gastrointestinal issues. Brain imaging detailed variable underlying structural abnormalities affecting the cerebellum, corpus collosum, and white matter. A crystal-structure model of FBXW7 predicted that missense variants were clustered at the substrate-binding surface of the WD40 domain and that these might reduce FBXW7 substrate binding affinity. Expression of recombinant FBXW7 missense variants in cultured cells demonstrated impaired CYCLIN E1 and CYCLIN E2 turnover. Pan-neuronal knockdown of the Drosophila ortholog, archipelago, impaired learning and neuronal function. Collectively, the data presented herein provide compelling evidence of an F-Box protein-related, phenotypically variable neurodevelopmental disorder associated with monoallelic variants in FBXW7., Competing Interests: Declaration of interests I.E.S. has served on scientific advisory boards for UCB, Eisai, GlaxoSmithKline, BioMarin, Nutricia, Rogcon, Chiesi, Encoded Therapeutics, Xenon Pharmaceuticals, and Knopp Biosciences; has received speaker honoraria from GlaxoSmithKline, UCB, BioMarin, Biocodex, and Eisai; has received funding for travel from UCB, Biocodex, GlaxoSmithKline, Biomarin and Eisai; has served as an investigator for Zogenix, Zynerba, Ultragenyx, GW Pharma, UCB, Eisai, Anavex Life Sciences, Ovid Therapeutics, Epygenyx, Encoded Therapeutics and Marinus; and has consulted for Zynerba Pharmaceuticals, Atheneum Partners, Ovid Therapeutics, Care Beyond Diagnosis, Epilepsy Consortium and UCB. She may accrue future revenue on pending patent WO2009/086591; her patent for SCN1A testing is held by Bionomics and is licensed to various diagnostic companies; and she has a patent for a molecular diagnostic/therapeutic target for benign familial infantile epilepsy (BFIE) (PRRT2), WO/2013/059884. She receives and/or has received research support from the National Health and Medical Research Council of Australia, Medical Research Future Fund, Health Research Council of New Zealand, CURE, Australian Epilepsy Research Fund, and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health. J.P. is co-chief scientific officer for Global Gene Corp. All other authors declare no competing interests., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: American Indian and Alaska Natives (AI/ANs) veterans may be at elevated risk for suicide, but little is known about suicide among this population., Methods: We conducted a retrospective cohort analysis of AI/AN veterans who received health care services provided or paid for by the Veterans Health Administration (VHA) between October 1, 2002, and September 30, 2014, and who were alive as of September 30, 2003. Age-specific and age-adjusted suicide rates through 2018, per 100,000 person-years (PY) at risk and 95% confidence intervals were computed., Results: Age-adjusted suicide rates among AI/AN veterans in this cohort more than doubled (19.1-47.0/100,000 PY) over the 15-year observation period. In the most recent observation period (2014-2018), the age-adjusted suicide rate was 47.0 per 100,000 PY, with the youngest age group (18-39) exhibiting the highest suicide rate (66.0/100,000 PY). The most frequently used lethal means was firearms (58.8%), followed by suffocation (19.3%), poisoning (17.2%), and other (4.7%)., Conclusions: Results suggest that: (1) suicide is an increasing problem among AI/AN VHA veterans; and (2) younger AI/AN VHA veterans are at particularly high risk and warrant focused prevention efforts. Findings are similar to those observed in general AI/AN population. There is a compelling need to review and strengthen VHA suicide prevention efforts directed towards AI/AN veterans., Competing Interests: The authors declare no conflict of interest.

Background and Objectives: Pathogenic variants in the neuronal sodium channel α1 subunit gene ( SCN1A ) are the most frequent monogenic cause of epilepsy. Phenotypes comprise a wide clinical spectrum, including severe childhood epilepsy; Dravet syndrome, characterized by drug-resistant seizures, intellectual disability, and high mortality; and the milder genetic epilepsy with febrile seizures plus (GEFS+), characterized by normal cognition. Early recognition of a child's risk for developing Dravet syndrome vs GEFS+ is key for implementing disease-modifying therapies when available before cognitive impairment emerges. Our objective was to develop and validate a prediction model using clinical and genetic biomarkers for early diagnosis of SCN1A -related epilepsies., Methods: We performed a retrospective multicenter cohort study comprising data from patients with SCN1A -positive Dravet syndrome and patients with GEFS+ consecutively referred for genetic testing (March 2001-June 2020) including age at seizure onset and a newly developed SCN1A genetic score. A training cohort was used to develop multiple prediction models that were validated using 2 independent blinded cohorts. Primary outcome was the discriminative accuracy of the model predicting Dravet syndrome vs other GEFS+ phenotypes., Results: A total of 1,018 participants were included. The frequency of Dravet syndrome was 616/743 (83%) in the training cohort, 147/203 (72%) in validation cohort 1, and 60/72 (83%) in validation cohort 2. A high SCN1A genetic score (133.4 [SD 78.5] vs 52.0 [SD 57.5]; p < 0.001) and young age at onset (6.0 [SD 3.0] vs 14.8 [SD 11.8] months; p < 0.001) were each associated with Dravet syndrome vs GEFS+. A combined SCN1A genetic score and seizure onset model separated Dravet syndrome from GEFS+ more effectively (area under the curve [AUC] 0.89 [95% CI 0.86-0.92]) and outperformed all other models (AUC 0.79-0.85; p < 0.001). Model performance was replicated in both validation cohorts 1 (AUC 0.94 [95% CI 0.91-0.97]) and 2 (AUC 0.92 [95% CI 0.82-1.00])., Discussion: The prediction model allows objective estimation at disease onset whether a child will develop Dravet syndrome vs GEFS+, assisting clinicians with prognostic counseling and decisions on early institution of precision therapies (http://scn1a-prediction-model.broadinstitute.org/)., Classification of Evidence: This study provides Class II evidence that a combined SCN1A genetic score and seizure onset model distinguishes Dravet syndrome from other GEFS+ phenotypes., (© 2022 American Academy of Neurology.)

Military sexual trauma (MST; i.e., sexual harassment and/or sexual assault during one's military service) is highly prevalent among female veterans and is associated with numerous adverse health and psychosocial sequelae. When institutions fail to prevent sexual trauma from happening or respond in an unsupportive manner (i.e., institutional betrayal [IB]), MST survivors typically report more severe health-related outcomes. Although the Institutional Betrayal Questionnaire.2 (IBQ.2) was developed to assess IB, no studies have examined the factor structure or dimensionality of the IBQ.2 among MST survivors. In addition, initial research has reported differing factor structures for this measure. The present study examined the dimensionality and factor structure of the IBQ.2, and tested for differential item functioning (DIF) based on whether military sexual assault was experienced. The sample comprised 235 female veterans who reported a history of MST in an anonymous national survey. Rasch analysis suggested multidimensionality and DIF based on history of military sexual assault. Exploratory factor analysis and parallel analysis suggested the IBQ.2 comprises three factors: (1) Environment Leading to MST, (2) Institutional Response to MST, and (3) Institutional Belongingness following MST. Although these results suggest that the IBQ.2 is multidimensional, the three-factor model had significant issues with respect to dimensionality, item fit, and person separation and reliability. Thus, using the full IBQ.2 may be more advantageous. Further examination of the IBQ.2 is warranted to ensure optimal assessment of IB in relation to MST, irrespective of whether the MST comprised sexual harassment or sexual assault, as well as to ensure that the IBQ.2 is culturally meaningful for MST survivors.

Natural Attenuation (NA) processes have been demonstrated to reduce pollutant loads at different contaminated groundwater sites world-wide and are increasingly considered in contaminated site management concepts. However, data are mainly available for steady state groundwater flow and stable redox conditions as well as pollutants listed in standard regulatory schemes. In this study, the influence of transient groundwater flow and redox conditions on NA was examined at a former gas works site near the river Rhine in Germany. The investigated 78 pollutants included 40 mono- and polyaromatic hydrocarbons (MAHs, PAHs) and 38 NSO-heterocyclic aromatic hydrocarbons (NSO-HET). In the highly polluted areas, the MAHs benzene, indene and indane, the PAHs naphthalene, acenaphthene, 1- and 2-methylnaphthalene and the NSO-HET 2-methylquinoline, carbazole, benzothiophene, dibenzofuran and benzofuran were predominant. Pollutant concentrations decreased with increasing distance from the sources of contamination. At the plume fringes, the MAHs benzene and indane, the PAH acenaphthene, the NSO-HET carbazole, 5-methylbenzothiophene, 2- and 3-methylbenzofuran and 2-methyldibenzofuran were predominant, indicating low retention and slow intrinsic biodegradation of these compounds. The influence of surface water on groundwater level, pollutant concentrations, and redox conditions in the monitoring wells was observed with a permanently installed groundwater sensor. The temporary availability of oxygen was observed at the plume fringes, resulting in aerobic and ferric iron reducing biodegradation processes. Field and laboratory data were used to set-up a groundwater flow and reactive transport model used for quantification of the field mass transfer rates. In conclusion, the study demonstrates that NA is effective under transient flow and redox conditions. A conceptual model and reactive transport simulation can facilitate the interpretation of pronounced fluctuations of pollutant concentration in monitoring wells. Based on the analysis of 78 pollutants, indane, indene and several NSO-HET like carbazole, benzothiophene and 2-methyldibenzofuran are recommended for monitoring at tar oil polluted sites, besides EPA-PAHs and BTEX., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Women veterans experience disproportionately high rates of military sexual trauma (MST). Nonetheless, many MST survivors delay or forgo health care, particularly within Veterans Health Administration (VHA) settings. Institutional betrayal (IB) has been posited as a potential explanation for this., Objective: The current study examined if IB was associated with women veterans' willingness to seek VHA and non-VHA mental health and medical care, prior use of VHA care, past year use of VHA care, and use of VHA and non-VHA MST-related care., Method: Participants were 242 women veterans who screened positive for MST and completed self-report measures of IB and willingness to seek VHA and non-VHA mental health and medical care. Use of VHA care was assessed through VA Corporate Data Warehouse data., Results: IB was associated with lower willingness to use VHA medical care and higher willingness to use non-VHA mental health care. Although IB was not significantly associated with prior use of VHA care, participants who reported more IB were more likely to have used VHA care in the past year and to have used both VHA and non-VHA MST-related care., Conclusion: These findings illuminate the relationship between the institutional response to MST with women's help-seeking willingness and use. Addressing IB may be important for increasing women MST survivors' willingness to use VHA medical care. Additionally, as IB was associated with greater willingness to use non-VHA mental health care, non-VHA institutions and providers should be prepared to serve women veterans who have experienced MST-related IB. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

To extend the value of biosensor-SPR in the characterization of DNA recognition by nucleoproteins, we report a comparative analysis of DNA-facilitated target search by two ETS-family transcription factors: Elk1 and ETV6. ETS domains represent an attractive system for developing biosensor-based techniques due to a broad range of physicochemical properties encoded within a highly conserved DNA-binding motif. Building on a biosensor approach in which the protein is quantitatively sequestered and presented to immobilized cognate DNA as nonspecific complexes, we assessed the impact of intrinsic cognate and nonspecific affinities on long-range (intersegmental) target search. The equilibrium constants of DNA-facilitated binding were sensitive to the intrinsic binding properties of the proteins such that their relative specificity for cognate DNA were reinforced when binding occurred by transfer vs. without nonspecific DNA. Direct measurement of association and dissociation kinetics revealed ionic features of the activated complex that evidenced DNA-facilitated dissociation, even though Elk1 and ETV6 harbor only a single DNA-binding surface. At salt concentrations that masked the effects of nonspecific pre-binding at equilibrium, the dissociation kinetics of cognate binding were nevertheless distinct from conditions under which nonspecific DNA was absent. These results further strengthen the significance of long-range DNA-facilitated translocation in the physiologic environment., (Copyright © 2021. Published by Elsevier Inc.)

Objective: The classical description of Dravet syndrome, the prototypic developmental and epileptic encephalopathy, is of a normal 6-month-old infant presenting with a prolonged, febrile, hemiclonic seizure and showing developmental slowing after age 1 year. SCN1A pathogenic variants are found in >80% of patients. Many patients have atypical features resulting in diagnostic delay and inappropriate therapy. We aimed to provide an evidence-based definition of SCN1A-Dravet syndrome in readiness for precision medicine trials., Methods: Epilepsy patients were recruited to the University of Melbourne Epilepsy Genetics Research Program between 1995 and 2020 by neurologists from around the world. Patients with SCN1A pathogenic variants were reviewed and only those with Dravet syndrome were included. Clinical data, including seizure and developmental course, were analyzed in all patients with SCN1A-Dravet syndrome., Results: Two hundred and five patients were studied at a median age of 8.5 years (range 10 months to 60 years); 25 were deceased. The median seizure-onset age was 5.7 months (range 1.5-20.6 months). Initial seizures were tonic-clonic (52%) and hemiclonic (35%), with only 55% being associated with fever. Only 34% of patients presented with status epilepticus (seizure lasting ≥30 minutes). Median time between first and second seizure was 30 days (range 4 hours to 8 months), and seven patients (5%) had at least 6 months between initial seizures. Median ages at onset of second and third seizure types were 9.1 months (range 3 months-25.4 years) and 15.5 months (range 4 months-8.2 years), respectively. Developmental slowing occurred prior to 12 months in 27%., Significance: An evidence-based definition of SCN1A-Dravet syndrome is essential for early diagnosis. We refine the spectrum of Dravet syndrome, based on patterns of seizure onset, type, and progression. Understanding of the full spectrum of SCN1A-Dravet syndrome presentation is essential for early diagnosis and optimization of treatment, especially as precision medicine trials become available., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: To evaluate risk for suicide among veterans with a history of stroke, seeking care within the Veterans Health Administration (VHA), we analyzed existing clinical data., Design: This retrospective cohort study was approved and performed in accordance with the local Institutional Review Board. Veterans were identified via the VHA's Corporate Data Warehouse. Initial eligibility criteria included confirmed veteran status and at least 90 days of VHA utilization between fiscal years 2001-2015. Cox proportional hazards models were used to assess the association between history of stroke and suicide. Among those veterans who died by suicide, the association between history of stroke and method of suicide was also investigated., Setting: VHA., Participants: Veterans with at least 90 days of VHA utilization between fiscal years 2001-2015 (N=1,647,671). Data from these 1,647,671 veterans were analyzed (1,405,762 without stroke and 241,909 with stroke)., Interventions: Not applicable., Main Outcome Measures: Suicide and method of suicide., Results: The fully adjusted model, which controlled for age, sex, mental health diagnoses, mild traumatic brain injury, and modified Charlson/Deyo Index (stroke-related diagnoses excluded), demonstrated a hazard ratio of 1.13 (95% confidence interval, 1.02-1.25; P=.02). The majority of suicides in both cohorts was by firearm, and a significantly larger proportion of suicides occurred by firearm in the group with stroke than the cohort without (81.2% vs 76.6%)., Conclusions: Findings suggest that veterans with a history of stroke are at increased risk for suicide, specifically by firearm, compared with veterans without a history of stroke. Increased efforts are needed to address the mental health needs and lethal means safety of veterans with a history of stroke, with the goal of improving function and decreasing negative psychiatric outcomes, such as suicide., (Copyright © 2021 The American Congress of Rehabilitation Medicine. All rights reserved.)

Chronic rhinosinusitis with nasal polyps (CRSwNP) represents a challenging disease entity with significant rates of recurrence following appropriate medical and surgical therapy. Recent approval of targeted biologics in CRSwNP compels deeper understanding of underlying disease pathophysiology. Both of the approved biologics for CRSwNP modulate the type 2 inflammatory pathway, and the majority of drugs in the clinical trials pathway are similarly targeted. However, there remain multiple other pathogenic mechanisms relevant to CRSwNP for which targeted therapeutics already exist in other inflammatory diseases that have not been studied directly. In this article we summarize pathogenic mechanisms of interest in CRSwNP and discuss the results of ongoing clinical studies of targeted therapeutics in CRSwNP and other related human inflammatory diseases., (© 2021 ARS-AAOA, LLC.)

Electrostatic protein/DNA interactions arise from the neutralization of the DNA phosphodiester backbone as well as coupled exchanges by charged protein residues as salt bridges or with mobile ions. Much focus has been and continues to be paid to interfacial ion pairs with DNA. The role of extra-interfacial ionic interactions, particularly as dynamic drivers of DNA sequence selectivity, remain poorly known. The ETS family of transcription factors represents an attractive model for addressing this knowledge gap given their diverse ionic composition in primary structures that fold to a tightly conserved DNA-binding motif. To probe the importance of extra-interfacial salt bridges in DNA recognition, we compared the salt-dependent binding by Elk1 with ETV6, two ETS homologs differing markedly in ionic composition. While both proteins exhibit salt-dependent binding with cognate DNA that corresponds to interfacial phosphate contacts, their nonspecific binding diverges from cognate binding as well as each other. Molecular dynamics simulations in explicit solvent, which generated ionic interactions in agreement with the experimental binding data, revealed distinct salt-bridge dynamics in the nonspecific complexes formed by the two proteins. Impaired DNA contact by ETV6 resulted in fewer backbone contacts in the nonspecific complex, while Elk1 exhibited a redistribution of extra-interfacial salt bridges via residues that are non-conserved between the two ETS relatives. Thus, primary structure variation in ionic residues can encode highly differentiated specificity mechanisms in a highly conserved DNA-binding motif.

Background: Advanced breast cancer (BC) impact immune cells in the blood but whether such effects may reflect the presence of early BC and its therapeutic management remains elusive., Methods: To address this question, we used multiparametric flow cytometry to analyze circulating leukocytes in patients with early BC (n = 13) at the time of diagnosis, after surgery, and after adjuvant radiotherapy, compared to healthy individuals. Data were analyzed using a minimally supervised approach based on FlowSOM algorithm and validated manually., Results: At the time of diagnosis, BC patients have an increased frequency of CD117 + CD11b + granulocytes, which was significantly reduced after tumor removal. Adjuvant radiotherapy increased the frequency of CD45RO + memory CD4 + T cells and CD4 + regulatory T cells. FlowSOM algorithm analysis revealed several unanticipated populations, including cells negative for all markers tested, CD11b + CD15 low , CD3 + CD4 - CD8 - , CD3 + CD4 + CD8 + , and CD3 + CD8 + CD127 + CD45RO + cells, associated with BC or radiotherapy., Conclusions: This study revealed changes in blood leukocytes associated with primary BC, surgical removal, and adjuvant radiotherapy. Specifically, it identified increased levels of CD117 + granulocytes, memory, and regulatory CD4 + T cells as potential biomarkers of BC and radiotherapy, respectively. Importantly, the study demonstrates the value of unsupervised analysis of complex flow cytometry data to unravel new cell populations of potential clinical relevance.

Objectives: Corticosteroids represent one of the mainstays of medical management of chronic rhinosinusitis (CRS) in both locally acting topical and systemic derivations. The application of topical corticosteroids is limited by a variety of factors including patient compliance, positioning, and nasal anatomy. Systemic corticosteroids confer a risk of medical complication that restricts their ability to be used repeatedly. The objective of this publication is to review the evolution of the in-office intranasal placement of corticosteroids in the management of CRS. The efficacy, outcomes, and safety of a variety of corticosteroid-containing devices meant to be placed in an office setting are reviewed., Methods: Pertinent literature was reviewed and summarized beginning with the earliest reports of direct intralesional injection of corticosteroids up through manufactured modern-day bioresorbable implants that contain corticosteroids., Results: The utilization of in-office placement of corticosteroid-containing material and implants has rapidly evolved since the concept was introduced, particularly in the last decade. Modern-day corticosteroid-eluting implants are reliably placed in the office, yield results across a range of objective and subjective outcomes, may decrease the need for revision endoscopic sinus surgery, and have a favorable safety profile., Conclusions: In-office placement of corticosteroid-containing stents are a viable treatment option for select patients, particularly those wishing to avoid revision surgery, and should be considered an important adjunct for treatment of refractory CRS in an otolaryngologist's armamentarium.