Dysregulation of platelet serotonin, 14-3-3, and GPIX in sudden infant death syndrome.

Sudden infant death syndrome (SIDS) is the leading cause of post-neonatal infant mortality, but the underlying cause(s) are unclear. A subset of SIDS infants has abnormalities in the neurotransmitter, serotonin (5-hydroxytryptamine [5-HT]) and the adaptor molecule, 14-3-3 pathways in regions of the brain involved in gasping, response to hypoxia, and arousal. To evaluate our hypothesis that SIDS is, at least in part, a multi-organ dysregulation of 5-HT, we examined whether blood platelets, which have 5-HT and 14-3-3 signaling pathways similar to brain neurons, are abnormal in SIDS. We also studied platelet surface glycoprotein IX (GPIX), a cell adhesion receptor which is physically linked to 14-3-3. In infants dying of SIDS compared to infants dying of known causes, we found significantly higher intra-platelet 5-HT and 14-3-3 and lower platelet surface GPIX. Serum and plasma 5-HT were also elevated in SIDS compared to controls. The presence in SIDS of both platelet and brainstem 5-HT and 14-3-3 abnormalities suggests a global dysregulation of these pathways and the potential for platelets to be used as a model system to study 5-HT and 14-3-3 interactions in SIDS. Platelet and serum biomarkers may aid in the forensic determination of SIDS and have the potential to be predictive of SIDS risk in living infants.

Examination of pain comorbid diagnoses in the inpatient rehabilitation population across all impairment groups.

OBJECTIVE: Pain is common in inpatient rehabilitation patients; however, the prevalence of pain diagnoses in this population is not well-defined. This study examines comorbid pain diagnoses in inpatient rehabilitation patients across impairment groups. DESIGN: Adult inpatient rehabilitation patients discharged from January 2016 through December 2019 were identified in the Uniform Data System for Medical Rehabilitation® database using a literature-established framework containing ICD-10-CM pain diagnoses. Demographic data, clinical data, and pain diagnoses were compared across the 17 rehabilitation impairment groups. RESULTS: Of 1,925,002 patients identified, 1,347,239 (70.0%) had at least one ICD-10 pain diagnosis. Over half of all patients in each impairment group had at least one pain diagnosis. The most common pain diagnoses were limb/extremity and joint pain, with variation between impairment groups. Female sex and being in the arthritis, major multiple trauma, and pain syndrome impairment groups were associated with a greater odds of a pain diagnosis. CONCLUSION: Over half of all patients in each rehabilitation impairment group have a pain diagnosis, which varies between impairment groups. Due to the high prevalence of pain diagnoses, a new focus on pain management in inpatient rehabilitation patients is needed. Rehabilitation outcomes may also be affected by pain.

Sudden Death in a Child With Ocular Lesions.

This case report describes a patient treated for ocular lesions who died suddenly at age 8 years and was diagnosed postmortem with Carney complex.

Comparative evaluation of Borrelia burgdorferi antibody detection between the VetScan Flex4 and SNAP 4Dx Plus.

Two studies were developed to compare Borrelia burgdorferi antibody detection between the VetScan Flex4 and SNAP 4Dx Plus tests. The objective of the first study was to evaluate the diagnostic sensitivity (Se) and specificity (Sp) of VetScan Flex4 and SNAP 4Dx Plus B. burgdorferi results using field sourced samples compared to a Western Blot reference method. The sensitivity and specificity of VetScan Flex4 were 81.9 % (95 % CI: 71.9 %-89.5 %) and 89.3 % (95 % CI: 85.2 %-92.9 %) respectively, and SNAP 4Dx Plus's sensitivity and specificity were 80.7 % (95 % CI: 70.6 %-88.6 %) and 92.8 % (95 % CI: 89.1 %-95.5 %) respectively. When comparing VetScan Flex4 and Snap 4Dx Plus, the Simple Kappa Coefficient estimate was 0.76 (95 % CI: 0.69-0.84) indicating substantial agreement between the two methods. McNemar's Test revealed concordance between the two methods was not statistically significant (P = 0.05). The objective of the second study was to evaluate whether VetScan Flex4 differentiates between B. burgdorferi antibodies derived from infection versus vaccination with commonly used canine Lyme vaccines. The sensitivity and specificity of the VetScan Flex4 in differentiating canine Lyme vaccination from infection with Borrelia burgdorferi were 100 % (Se 95 % CI: 78.2 %-100 %; Sp 95 % CI: 91.2 %-100 %). In conclusion, the VetScan Flex4 is a reliably sensitive and specific point-of-care test that is similar to Snap 4Dx Plus, can differentiate between infection and Lyme vaccination, and can be utilized by veterinarians for Lyme disease diagnosis and surveillance of B. burgdorferi exposure.

Favipiravir induces HuNoV viral mutagenesis and infectivity loss with clinical improvement in immunocompromised patients.

Chronic human norovirus (HuNoV) infections in immunocompromised patients result in severe disease, yet approved antivirals are lacking. RNA-dependent RNA polymerase (RdRp) inhibitors inducing viral mutagenesis display broad-spectrum in vitro antiviral activity, but clinical efficacy in HuNoV infections is anecdotal and the potential emergence of drug-resistant variants is concerning. Upon favipiravir (and nitazoxanide) treatment of four immunocompromised patients with life-threatening HuNoV infections, viral whole-genome sequencing showed accumulation of favipiravir-induced mutations which coincided with clinical improvement although treatment failed to clear HuNoV. Infection of zebrafish larvae demonstrated drug-associated loss of viral infectivity and favipiravir treatment showed efficacy despite occurrence of RdRp variants potentially causing favipiravir resistance. This indicates that within-host resistance evolution did not reverse loss of viral fitness caused by genome-wide accumulation of sequence changes. This off-label approach supports the use of mutagenic antivirals for treating prolonged RNA viral infections and further informs the debate surrounding their impact on virus evolution.

Seizures and Sudden Death Beyond SUDEP.

Many physicians and researchers are familiar with the tragic phenomenon known as sudden infant death syndrome (SIDS), the leading cause of postneonatal mortality in high-resource countries. A less familiar category of unexplained deaths is the problem of sudden unexplained death in childhood (SUDC), a more rare and unusual presentation of sudden death in children who are no longer infants and whose reasons for death defy explanation. A substantial body of research in SUDC now supports the possibility of an overlap with epilepsy and associated sudden death in that context (SUDEP). Stemming from the first contemporary reports of SUDC, we have learned that a disproportionate number of these children have personal and/or family histories of febrile seizures,1 in many cases, inherited in an autosomal dominant manner.2 Their febrile seizures can be associated with abnormalities in their temporal lobes,3,4 including bilamination of the dentate gyrus and other findings conventionally associated with temporal lobe epilepsy, implicating potential epilepsy-related mechanisms.5 Further evaluation of this emerging epilepsy-related phenotype has led to the identification of genetic variants in SCN1A and other epilepsy-associated genes,6,7 moving SUDC away from being considered an unexplained phenomenon to one where the working hypothesis includes a role for genetic predisposition and epilepsy-like mechanisms in the deaths, even without an established history of epilepsy. Nonetheless, because the terminal events of these seemingly healthy children are unexpected and unobserved, the clinical manifestations of whatever underlying vulnerabilities exist-generally discovered posthumously-remain a matter of speculation.

Multiomic Analysis of Neuroinflammation and Occult Infection in Sudden Infant Death Syndrome.

Importance: Antemortem infection is a risk factor for sudden infant death syndrome (SIDS)-the leading postneonatal cause of infant mortality in the developed world. Manifestations of infection and inflammation are not always apparent in clinical settings or by standard autopsy; thus, enhanced resolution approaches are needed. Objective: To ascertain whether a subset of SIDS cases is associated with neuroinflammation and occult infection. Design, Setting, and Participants: In this case-control study, postmortem fluids from SIDS cases and controls collected between July 2011 and November 2018 were screened for elevated inflammatory markers, specifically cerebrospinal fluid (CSF) neopterin and CSF and serum cytokines. CSF, liver, and brain tissue from SIDS cases with elevated CSF neopterin were subjected to metagenomic next-generation sequencing (mNGS) to probe for infectious pathogens. Brainstem tissue from a subset of these cases was analyzed by single-nucleus RNA sequencing (snRNAseq) to measure cell type-specific gene expression associated with neuroinflammation and infection. All tissue and fluid analyses were performed from April 2019 to January 2023 in a pathology research laboratory. Included was autopsy material from infants dying of SIDS and age-matched controls dying of known causes. Exposures: There were no interventions or exposures. Main Outcomes and Measures: CSF neopterin levels were measured by high-performance liquid chromatography. Cytokines were measured by multiplex fluorometric assay. mNGS was performed on liver, CSF, brain, and brainstem tissue. snRNAseq was performed on brainstem tissue. Results: A cohort of 71 SIDS cases (mean [SD] age, 55.2 [11.4] postconceptional weeks; 42 male [59.2%]) and 20 controls (mean [SD] age, 63.2 [16.9] postconceptional weeks; 11 male [55.0%]) had CSF and/or serum available. CSF neopterin was screened in 64 SIDS cases and 15 controls, with no exclusions. Tissues from 6 SIDS cases were further analyzed. For CSF neopterin measures, SIDS samples were from infants with mean (SD) age of 54.5 (11.3) postconceptional weeks (38 male [59.4%]) and control samples were from infants with mean (SD) age of 61.5 (17.4) postconceptional weeks (7 male [46.7%]). A total of 6 SIDS cases (9.3%) with high CSF neopterin were identified, suggestive of neuroinflammation. mNGS detected human parechovirus 3 (HPeV3) in tissue and CSF from 1 of these 6 cases. snRNAseq of HPeV3-positive brainstem tissue (medulla) revealed dramatic enrichment of transcripts for genes with predominately inflammatory functions compared with 3 age-matched SIDS cases with normal CSF neopterin levels. Conclusions and Relevance: Next-generation molecular tools in autopsy tissue provide novel insight into pathogens that go unrecognized by normal autopsy methodology, including in infants dying suddenly and unexpectedly.

Multicenter evaluation of the Vetscan Imagyst system using Ocus 40 and EasyScan One scanners to detect gastrointestinal parasites in feces of dogs and cats.

The Vetscan Imagyst system (Zoetis) is a novel, artificial intelligence-driven detection tool that can assist veterinarians in the identification of enteric parasites in dogs and cats. This system consists of a sample preparation device, an automated digital microscope scanner, and a deep-learning algorithm. The EasyScan One scanner (Motic) has had good diagnostic performance compared with manual examinations by experts; however, there are drawbacks when used in veterinary practices in which space for equipment is often limited. To improve the usability of this system, we evaluated an additional scanner, the Ocus 40 (Grundium). Our objectives were to 1) qualitatively evaluate the performance of the Vetscan Imagyst system with the Ocus 40 scanner for identifying Ancylostoma, Toxocara, and Trichuris eggs, Cystoisospora oocysts, and Giardia cysts in canine and feline fecal samples, and 2) expand the assessment of the performance of the Vetscan Imagyst system paired with either the Ocus 40 or EasyScan One scanner to include a larger dataset of 2,191 fecal samples obtained from 4 geographic regions of the United States. When tested with 852 canine and feline fecal samples collected from different geographic regions, the performance of the Vetscan Imagyst system combined with the Ocus 40 scanner was correlated closely with manual evaluations by experts. Sensitivities were 80.0‒97.0% and specificities were 93.7‒100.0% across the targeted parasites. When tested with 1,339 fecal samples, the Vetscan Imagyst system paired with the EasyScan One scanner successfully identified the targeted parasite stages; sensitivities were 73.6‒96.4% and specificities were 79.7‒100.0%.

Quantifying EHR and Policy Factors Associated with the Gender Productivity Gap in Ambulatory, General Internal Medicine.

BACKGROUND: The gender gap in physician compensation has persisted for decades. Little is known about how differences in use of the electronic health record (EHR) may contribute. OBJECTIVE: To characterize how time on clinical activities, time on the EHR, and clinical productivity vary by physician gender and to identify factors associated with physician productivity. DESIGN, SETTING, AND PARTICIPANTS: This longitudinal study included general internal medicine physicians employed by a large ambulatory practice network in the Northeastern United States from August 2018 to June 2021. MAIN MEASURES: Monthly data on physician work relative value units (wRVUs), physician and practice characteristics, metrics of EHR use and note content, and temporal trend variables. KEY RESULTS: The analysis included 3227 physician-months of data for 108 physicians (44% women). Compared with men physicians, women physicians generated 23.8% fewer wRVUs per month, completed 22.1% fewer visits per month, spent 4.0 more minutes/visit and 8.72 more minutes on the EHR per hour worked (all p < 0.001), and typed or dictated 36.4% more note characters per note (p = 0.006). With multivariable adjustment for physician age, practice characteristics, EHR use, and temporal trends, physician gender was no longer associated with productivity (men 4.20 vs. women 3.88 wRVUs/hour, p = 0.31). Typing/dictating fewer characters per note, relying on greater teamwork to manage orders, and spending less time on documentation were associated with higher wRVUs/hour. The 2021 E/M code change was associated with higher wRVUs/hour for all physicians: 10% higher for men physicians and 18% higher for women physicians (p < 0.001 and p = 0.009, respectively). CONCLUSIONS: Increased team support, briefer documentation, and the 2021 E/M code change were associated with higher physician productivity. The E/M code change may have preferentially benefited women physicians by incentivizing time-intensive activities such as medical decision-making, preventive care discussion, and patient counseling that women physicians have historically spent more time performing.

Workplace Belonging of Women Healthcare Professionals Relates to Likelihood of Leaving.

Purpose: There is a high rate of attrition of professionals from healthcare institutions, which threatens the economic viability of these institutions and the quality of care they provide to patients. Women professionals face particular challenges that may lower their sense of belonging in the healthcare workplace. We sought to test the hypothesis that workplace belonging of women healthcare professionals relates to the likelihood that they expect to leave their institution. Methods: Participants of a continuing education course on women's leadership skills in health care completed a survey about their experiences of belonging in workplace and their likelihood of leaving that institution within the next 2 years. An association between workplace belonging (measured by the cumulative number of belonging factors experienced, scale 0-10) and likelihood of leaving (measured on a 5-point Likert scale) was evaluated using ordinal logistic regression. The relative importance of workplace belonging factors in predicting the likelihood of leaving was assessed using dominance analysis. Results: Ninety-nine percent of survey participants were women, and 63% were clinicians. Sixty-one percent of participants reported at least a slight likelihood of leaving their healthcare institution within the next 2 years. Greater workplace belonging was found to be associated with a significant reduction in the reported likelihood of leaving their institution after accounting for the number of years having worked in their current institution, underrepresented minority status, and the interaction between the latter two covariates. The workplace belonging factor found to be most important in predicting the likelihood of leaving was the belief that there was an opportunity to thrive professionally in the institution. Belonging factors involving feeling able to freely share thoughts and opinions were also found to be of relatively high importance in predicting the likelihood of leaving. Conclusion: Greater workplace belonging was found to relate significantly to a reduced likelihood of leaving their institution within the next 2 years. Our findings suggest that leaders of healthcare organizations might reduce attrition of women by fostering workplace belonging with particular attention to empowering professional thriving and creating a culture that values open communication.

Sudden Unexplained Death in Childhood: Current Understanding.

ABSTRACT: Sudden unexplained death in childhood is a term that encompasses apparently natural deaths in children aged older than 1 year with no discernible cause despite a thorough assessment. Definitive underlying causes vary but most cases remain largely unexplained. Research has furthered the view that sudden unexplained death in childhood is not an accident, but rather a sentinel medical event for which a thorough postmortem investigation is indicated. Emerging evidence in genetics, neurology, and neuropathology point to heterogeneous causes that in some cases share features of recognized diseases.

Within-host diversity improves phylogenetic and transmission reconstruction of SARS-CoV-2 outbreaks.

Accurate inference of who infected whom in an infectious disease outbreak is critical for the delivery of effective infection prevention and control. The increased resolution of pathogen whole-genome sequencing has significantly improved our ability to infer transmission events. Despite this, transmission inference often remains limited by the lack of genomic variation between the source case and infected contacts. Although within-host genetic diversity is common among a wide variety of pathogens, conventional whole-genome sequencing phylogenetic approaches exclusively use consensus sequences, which consider only the most prevalent nucleotide at each position and therefore fail to capture low-frequency variation within samples. We hypothesized that including within-sample variation in a phylogenetic model would help to identify who infected whom in instances in which this was previously impossible. Using whole-genome sequences from SARS-CoV-2 multi-institutional outbreaks as an example, we show how within-sample diversity is partially maintained among repeated serial samples from the same host, it can transmitted between those cases with known epidemiological links, and how this improves phylogenetic inference and our understanding of who infected whom. Our technique is applicable to other infectious diseases and has immediate clinical utility in infection prevention and control.

During an infectious disease outbreak, tracing who infected whom allows public health scientists to see how a pathogen is spreading and to establish effective control measures. Traditionally, this involves identifying the individuals an infected person comes into contact with and monitoring whether they also become unwell. However, this information is not always available and can be inaccurate. One alternative is to track the genetic data of pathogens as they spread. Over time, pathogens accumulate mutations in their genes that can be used to distinguish them from one another. Genetically similar pathogens are more likely to have spread during the same outbreak, while genetically dissimilar pathogens may have come from different outbreaks. However, there are limitations to this approach. For example, some pathogens accumulate genetic mutations very slowly and may not change enough during an outbreak to be distinguishable from one another. Additionally, some pathogens can spread rapidly, leaving less time for mutations to occur between transmission events. To overcome these challenges, Torres Ortiz et al. developed a more sensitive approach to pathogen genetic testing that took advantage of the multiple pathogen populations that often coexist in an infected patient. Rather than tracking only the most dominant genetic version of the pathogen, this method also looked at the less dominant ones. Torres Ortiz et al. performed genome sequencing of SARS-CoV-2 (the virus that causes COVID-19) samples from 451 healthcare workers, patients, and patient contacts at participating London hospitals. Analysis showed that it was possible to detect multiple genetic populations of the virus within individual patients. These subpopulations were often more similar in patients that had been in contact with one another than in those that had not. Tracking the genetic data of all viral populations enabled Torres Ortiz et al. to trace transmission more accurately than if only the dominant population was used. More accurate genetic tracing could help public health scientists better track pathogen transmission and control outbreaks. This may be especially beneficial in hospital settings where outbreaks can be smaller, and it is important to understand if transmission is occurring within the hospital or if the pathogen is imported from the community. Further research will help scientists understand how pathogen population genetics evolve during outbreaks and may improve the detection of subpopulations present at very low frequencies.

Rehabilitation clinical trials in global registries: reporting of participant inclusion by sex, age, race and ethnicity.

PURPOSE: Registries of clinical trials exist in part to standardize data for the scientific community. Studies in the United States demonstrated gaps in reporting on ClinicalTrials.gov. The purpose of this cross-sectional study was to evaluate clinical trial participation among global registries. METHODS: This study identified registries with results reported and assessed available results for physical and rehabilitation medicine (PRM) diagnosis, intervention, primary outcome, and the International Classification of Functioning, Disability and Health (ICF) categories. Participant characteristics including sex, age, and race/ethnicity were assessed. RESULTS: A total of 93 rehabilitation trials from eight registries met inclusion criteria. Most trials included persons with musculoskeletal disorders (50.5%), technology such as robotics (25.8%) and outcomes in ICF category of body functions and structures (54.7%). Sex was reported in 61.3% of trials and varied among registries (0 to 100%). Participation of women in trials showed variability from 0 to 75%. Reporting of age of the participants was not uniform and six registries did not include age in all trials. Information about race/ethnicity was absent in most trials and registries. CONCLUSIONS: Based on trials registered with accessible results, these findings may reveal either a gap in reporting results or a lack of trials investigating important PRM diagnoses, interventions, and outcomes.Implications for RehabilitationThis study contributes to the growing body of evidence that there are gaps in standardization of rehabilitation results reported on clinical trials registries.The uniform reporting of results is an important component of advancing rehabilitation science and may be a factor in high-quality study design and improved transparency.

Genomic and geographical structure of human cytomegalovirus.

Human cytomegalovirus (CMV) has infected humans since the origin of our species and currently infects most of the world's population. Variability between CMV genomes is the highest of any human herpesvirus, yet large portions of the genome are conserved. Here, we show that the genome encodes 74 regions of relatively high variability each with 2 to 8 alleles. We then identified two patterns in the CMV genome. Conserved parts of the genome and a minority (32) of variable regions show geographic population structure with evidence for African or European clustering, although hybrid strains are present. We find no evidence that geographic segregation has been driven by host immune pressure affecting known antigenic sites. Forty-two variable regions show no geographical structure, with similar allele distributions across different continental populations. These "nongeographical" regions are significantly enriched for genes encoding immunomodulatory functions suggesting a core functional importance. We hypothesize that at least two CMV founder populations account for the geographical differences that are largely seen in the conserved portions of the genome, although the timing of separation and direction of spread between the two are not clear. In contrast, the similar allele frequencies among 42 variable regions of the genome, irrespective of geographical origin, are indicative of a second evolutionary process, namely balancing selection that may preserve properties critical to CMV biological function. Given that genetic differences between CMVs are postulated to alter immunogenicity and potentially function, understanding these two evolutionary processes could contribute important information for the development of globally effective vaccines and the identification of novel drug targets.

The fundamental need for unifying phenotypes in sudden unexpected pediatric deaths.

A definitive, authoritative approach to evaluate the causes of unexpected, and ultimately unexplained, pediatric deaths remains elusive, relegating final conclusions to diagnoses of exclusion in the vast majority of cases. Research into unexplained pediatric deaths has focused primarily on sudden infant deaths (under 1 year of age) and led to the identification of several potential, albeit incompletely understood, contributory factors: nonspecific pathology findings, associations with sleep position and environment that may not be uniformly relevant, and the elucidation of a role for serotonin that is practically difficult to estimate in any individual case. Any assessment of progress in this field must also acknowledge the failure of current approaches to substantially decrease mortality rates in decades. Furthermore, potential commonalities with pediatric deaths across a broader age spectrum have not been widely considered. Recent epilepsy-related observations and genetic findings, identified post-mortem in both infants and children who died suddenly and unexpectedly, suggest a role for more intense and specific phenotyping efforts as well as an expanded role for genetic and genomic evaluation. We therefore present a new approach to reframe the phenotype in sudden unexplained deaths in the pediatric age range, collapsing many distinctions based on arbitrary factors (such as age) that have previously guided research in this area, and discuss its implications for the future of postmortem investigation.

Altered 5-HT2A/C receptor binding in the medulla oblongata in the sudden infant death syndrome (SIDS): Part I. Tissue-based evidence for serotonin receptor signaling abnormalities in cardiorespiratory- and arousal-related circuits.

The sudden infant death syndrome (SIDS), the leading cause of postneonatal infant mortality in the United States, is typically associated with a sleep period. Previously, we showed evidence of serotonergic abnormalities in the medulla (e.g. altered serotonin (5-HT)1A receptor binding), in SIDS cases. In rodents, 5-HT2A/C receptor signaling contributes to arousal and autoresuscitation, protecting brain oxygen status during sleep. Nonetheless, the role of 5-HT2A/C receptors in the pathophysiology of SIDS is unclear. We hypothesize that in SIDS, 5-HT2A/C receptor binding is altered in medullary nuclei that are key for arousal and autoresuscitation. Here, we report altered 5-HT2A/C binding in several key medullary nuclei in SIDS cases (n = 58) compared to controls (n = 12). In some nuclei the reduced 5-HT2A/C and 5-HT1A binding overlapped, suggesting abnormal 5-HT receptor interactions. The data presented here (Part 1) suggest that a subset of SIDS is due in part to abnormal 5-HT2A/C and 5-HT1A signaling across multiple medullary nuclei vital for arousal and autoresuscitation. In Part II to follow, we highlight 8 medullary subnetworks with altered 5-HT receptor binding in SIDS. We propose the existence of an integrative brainstem network that fails to facilitate arousal and/or autoresuscitation in SIDS cases.

Copy Number Variation and Structural Genomic Findings in 116 Cases of Sudden Unexplained Death between 1 and 28 Months of Age.

In sudden unexplained death in pediatrics (SUDP) the cause of death is unknown despite an autopsy and investigation. The role of copy number variations (CNVs) in SUDP has not been well-studied. Chromosomal microarray (CMA) data are generated for 116 SUDP cases with age at death between 1 and 28 months. CNVs are classified using the American College of Medical Genetics and Genomics guidelines and CNVs in our cohort are compared to an autism spectrum disorder (ASD) cohort, and to a control cohort. Pathogenic CNVs are identified in 5 of 116 cases (4.3%). Variants of uncertain significance (VUS) favoring pathogenic CNVs are identified in 9 cases (7.8%). Several CNVs are associated with neurodevelopmental phenotypes including seizures, ASD, developmental delay, and schizophrenia. The structural variant 47,XXY is identified in two cases (2/69 boys, 2.9%) not previously diagnosed with Klinefelter syndrome. Pathogenicity scores for deletions are significantly elevated in the SUDP cohort versus controls (p = 0.007) and are not significantly different from the ASD cohort. The finding of pathogenic or VUS favoring pathogenic CNVs, or structural variants, in 12.1% of cases, combined with the observation of higher pathogenicity scores for deletions in SUDP versus controls, suggests that CMA should be included in the genetic evaluation of SUDP.

Longitudinal Trends in Severe Traumatic Brain Injury Inpatient Rehabilitation.

OBJECTIVE: The goal of this study is to describe national trends in inpatient rehabilitation facility (IRF) discharges for the most severely disabled cohort of patients with traumatic brain injury (TBI). METHODS: Data from the Uniform Data System for Medical Rehabilitation for patients discharged from an IRF between January 1, 2002, and December 31, 2017, with a diagnosis of TBI and an admission Functional Independence Measure of 18, the lowest possible score, were obtained and analyzed. RESULTS: Of the 252 112 patients with TBI discharged during the study period, 10 098 met the study criteria. From 2002 to 2017, the number of patients with an IRF admission Functional Independence Measure of 18 following TBI discharged from IRFs annually decreased from 649 to 488, modeled by a negative regression (coefficient = -2.97; P = .001), and the mean age (SD) increased from 43.0 (21.0) to 53.7 (21.3) years (coefficient = 0.70; P < .001). During the study period, the number of patients with the most severe disability on admission to IRF who were discharged annually as a proportion of total patients with TBI decreased from 5.5% to 2.5% (odds ratio = 0.95; P < .001) and their mean length of stay decreased from 41.5 (36.2) to 29.3 (24.9) days (coefficient = -0.83; P < .001]. CONCLUSION: The number and proportion of patients with the most severe disability on IRF admission following TBI who are discharged from IRFs is decreasing over time. This may represent a combination of primary prevention, early mortality due to withdrawal of life-sustaining treatment, alternative discharge dispositions, or changes in admitting and reimbursement practices. Furthermore, there has been a decrease in the duration of IRF level care for these individuals, which could ultimately lead to poorer functional outcomes, particularly given the importance of specialized rehabilitative care in this population.

Comparison of DXA-based versus CT-based indices to predict prevalent fracture history in men with spinal cord injury.

Fracture risk prediction remains challenging in adults with spinal cord injury. Here, we compare the ability of CT- and DXA-derived indices to discriminate between those with and without prevalent osteoporotic fracture. Novel CT-derived indices may offer improved assessment of fragility fracture risk as well as improved monitoring of response to therapies. INTRODUCTION: Individuals with spinal cord injury are particularly susceptible to osteoporosis. As advanced imaging techniques become more readily available clinically, there is limited information on the relative strength of various outcomes for fracture risk prediction. The purpose of this study was to compare the ability of DXA-based versus CT-based indices to predict prevalent fracture history in adults with spinal cord injury. METHODS: Thirty-six men with known SCI underwent dual energy X-ray absorptiometry and computed tomography assessments of the lower extremities. We used age-adjusted area under the curve models to compare the predictive value for each bone parameter to identify prevalent fracture history. RESULTS: CT-based indices outperformed DXA-based indices at all sites. The site with the highest AUC was the trabecular BMD at the proximal tibial epiphysis. CONCLUSIONS: CT imaging may have clinical utility to improve fracture risk prediction in adults with SCI. More work is needed to confirm these findings and to assess the value of CT-based indices to predict incident fracture, monitor longitudinal bone loss, and monitor response to various therapies, both pharmacological and rehabilitation.

Haplotype assignment of longitudinal viral deep sequencing data using covariation of variant frequencies.

Longitudinal deep sequencing of viruses can provide detailed information about intra-host evolutionary dynamics including how viruses interact with and transmit between hosts. Many analyses require haplotype reconstruction, identifying which variants are co-located on the same genomic element. Most current methods to perform this reconstruction are based on a high density of variants and cannot perform this reconstruction for slowly evolving viruses. We present a new approach, HaROLD (HAplotype Reconstruction Of Longitudinal Deep sequencing data), which performs this reconstruction based on identifying co-varying variant frequencies using a probabilistic framework. We illustrate HaROLD on both RNA and DNA viruses with synthetic Illumina paired read data created from mixed human cytomegalovirus (HCMV) and norovirus genomes, and clinical datasets of HCMV and norovirus samples, demonstrating high accuracy, especially when longitudinal samples are available.