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The article presents the discussion on identifying biologic causes required for further reducing unexplained infant deaths. Topics include focusing on prevention based on associations between infant-sleep practices and SIDS rates in multiple countries; and public health campaigns relying on simple, clear messages, emphasizing on addressing sleep position and the sleep environment for preventing SIDS.

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. 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. 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. 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. This 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. [ABSTRACT FROM AUTHOR]

Background: Sudden Unexpected Death in Pediatrics (SUDP) is a tragic event, likely caused by the complex interaction of multiple factors. The presence of hippocampal abnormalities in many children with SUDP suggests that epilepsy‐related mechanisms may contribute to death, similar to Sudden Unexplained Death in Epilepsy. Because of known associations between the genes SCN1A and SCN5A and sudden death, and shared mechanisms and patterns of expression in genes encoding many voltage‐gated sodium channels (VGSCs), we hypothesized that individuals dying from SUDP have pathogenic variants across the entire family of cardiac arrhythmia‐ and epilepsy‐associated VGSC genes. Methods: To address this hypothesis, we evaluated whole‐exome sequencing data from infants and children with SUDP for variants in VGSC genes, reviewed the literature for all SUDP‐associated variants in VGSCs, applied a novel paralog analysis to all variants, and evaluated all variants according to American College of Medical Genetics and Genomics (ACMG) guidelines. Results: In our cohort of 73 cases of SUDP, we assessed 11 variants as pathogenic in SCN1A, SCN1B, and SCN10A, genes with long‐standing disease associations, and in SCN3A, SCN4A, and SCN9A, VGSC gene paralogs with more recent disease associations. From the literature, we identified 82 VGSC variants in SUDP cases. Pathogenic variants clustered at conserved amino acid sites intolerant to variation across the VGSC genes, which is unlikely to occur in the general population (p <.0001). For 54% of variants previously reported in literature, we identified conflicting evidence regarding pathogenicity when applying ACMG criteria and modern population data. Conclusion: We report variants in several VGSC genes in cases with SUDP, involving both arrhythmia‐ and epilepsy‐associated genes. Accurate variant assessment as well as future studies are essential for an improved understanding of the contribution of sodium channel‐related variants to SUDP. [ABSTRACT FROM AUTHOR]

Introduction: Despite many advances in burn care, the development of extremity contracture remains a common and vexing problem. Extremity contractures have been documented in up to one third of severely burned patients at discharge. However, little is known about the long-term impact of these contractures. The purpose of this study was to examine the association of extremity contractures with employment after burn injury.Methods: We obtained data from the Burn Model System database from 1994 to 2003. We included in the study cohort all adult patients who were working prior to injury and identified those discharged with and without a contracture in one of the major extremity joints (shoulder, elbow, wrist, hip, knee and ankle). We classified contracture severity according to mild, moderate and severe categories. We performed descriptive analyses and predictive modeling to identify injury and patient factors associated with return to work (RTW) at 6, 12, and 24 months.Results: A total of 1,203 participant records met criteria for study inclusion. Of these, 415 (35%) had developed a contracture at discharge; 9% mild, 12% moderate, and 14% severe. Among 801 (67%) participants who had complete data at 6 months after discharge, 70% of patients without contracture had returned to work compared to 45% of patients with contractures (p < 0.001). RTW increased at each subsequent follow-up time point for the contracture group, however, it remained significantly lower than in no-contracture group (both p < 0.01). In multivariable analyses, female sex, non-Caucasian ethnicity, larger burn size, alcohol abuse, number of in-hospital operations, amputation, and in-hospital complications were associated with a lower likelihood of employment. In adjusted analyses, discharge contracture was associated with a lower probability of RTW at all 3 time points, although its impact significantly diminished at 24 months.Conclusions: This study indicates an association between discharge contracture and reduced employment 6, 12 and 24 months after burn injury. Among many other identified patient, injury, and hospitalization related factors that are barriers to RTW, the presence of a contracture at discharge adds a significant reintegration burden for working-age burn patients. [ABSTRACT FROM AUTHOR]

The current era of drug discovery has been marked by a significant increase in the development of immune modulating agents to address a range of diseases such as cancer, chronic inflammation, and other conditions of dysregulated immunity. Non-clinical evaluation of these agents in animal models can be challenging, as the presence of an active immune state is often required in order to detect the effects of the test agent. Modulation of interleukin (IL)-10 signaling represents this type of situation in that altering IL-10 action in vivo can be difficult to appreciate in the absence of an ongoing immune response. The study presented here reports on the use of lipopolysaccharide (LPS) challenge in cynomolgus macaques to induce predictable inflammatory cytokine responses. The results showed that IL-10 receptor (IL-10R) blockade with an antagonist monoclonal antibody (mAb) dramatically enhanced the LPS-induced cytokine response, thus demonstrating in vivo pharmacologic activity of this immunomodulatory antibody. We submit that this approach could be applied to other cases where the intent of a candidate therapeutic is to modulate components of inflammatory cytokine responses. [ABSTRACT FROM AUTHOR]

This report details the proceedings and conclusions from the 3rd International Congress on Unexplained Deaths in Infants and Children, held November 26–27, 2018 at the Radcliffe Institute at Harvard University. The Congress was motivated by the increasing rejection of the diagnosis Sudden Infant Death Syndrome (SIDS) in the medical examiner community, leading to falsely depressed reported SIDS rates and undermining the validity and reliability of the diagnosis, which remains a leading cause of infant and child mortality. We describe the diagnostic shift away from SIDS and the practical issues contributing to it. The Congress was attended by major figures and opinion leaders in this area from countries significantly engaged in this problem. Four categories (International Classification of Diseases (ICD)-11 categories of MH11, MH12, MH14, PB00-PB0Z) were recommended for classification, and explicit definitions and guidance were provided for death certifiers. SIDS was reframed as unexplained sudden death in infancy or SIDS/MH11 to emphasize that either term signifies the lack of explanation following a rigorous investigation. A distinct category for children over the age of 1 was recommended (MH12). Definitions and exclusions were provided for the alternative categories of accidental asphyxia and undetermined. As recommended, unexplained sudden death in infancy or SIDS on a death certificate will code a unique, trackable entity, accurately reflecting the inability to determine a definitive explanation, while satisfying surveillance needs and reliable identification for research efforts. The conclusions will be submitted to the World Health Organization for inclusion in the upcoming ICD-11. [ABSTRACT FROM AUTHOR]

Background: Identifying characteristics of individuals at greatest risk for prolonged grief disorder (PGD) can improve its detection and elucidate the etiology of the disorder. The Safe Passage Study, a study of women at high risk for sudden infant death syndrome (SIDS), prospectively examined the psychosocial functioning of women while monitoring their healthy pregnancies. Mothers whose infants died of SIDS were followed in bereavement. Methods: Pre-loss data were collected from 12 000 pregnant mothers and analyzed for their associations with grief symptoms and PGD in 50 mothers whose infants died from SIDS, from 2 to 48 months after their infant's death, focusing on pre-loss risk factors of anxiety, depression, alcohol use, maternal age, the presence of other living children in the home, and previous child loss. Results: The presence of any four risk factors significantly predicted PGD for 24 months post-loss (p < 0.003); 2–3 risk factors predicted PGD for 12 months (p = 0.02). PGD rates increased in the second post-loss year, converging in all groups to approximately 40% by 3 years. Pre-loss depressive symptoms were significantly associated with PGD. Higher alcohol intake and older maternal age were consistently positively associated with PGD. Predicted risk scores showed good discrimination between PGD and no PGD 6–24 months after loss (C -statistic = 0.83). Conclusions: A combination of personal risk factors predicted PGD in 2 years of bereavement. There is a convergence of risk groups to high rates at 2–3 years, marked by increased PGD rates in mothers at low risk. The risk factors showed different effects on PGD. [ABSTRACT FROM AUTHOR]

Initial studies examining patient demographics and outcomes in traumatic brain injury (TBI) suggest a trend toward increasing patient age and decreasing rehabilitation length of stay, but such studies have not been repeated since the passage of healthcare reform legislation, most notably the Affordable Care Act. This study utilized the Uniform Data System for Medical Rehabilitation® (UDSMR) for patients admitted to medical rehabilitation facilities after sustaining a TBI from January 1, 2002 through December 31, 2016. Trends for demographic and medical data were evaluated. In total, 233,843 patients from 1290 facilities were included; mean patient age increased from 54.1 to 64.8 years, rehabilitation length of stay decreased from 19 to 14.5 days, and mean admission Functional Independence Measure® (FIM) decreased from 56.9 to 54.5. Sex and racial distribution remained relatively stable across all years, as did discharge FIM. There was an increase in Medicare patients from 40.7% to 62.1%, a concomitant decrease in commercially insured patients from 29.2% to 15.4%, and a decrease in unreimbursed patients from 7.2% to 2.6% over the course of the study. Based on these data, medical rehabilitation facilities appear to be admitting an older TBI patient population that is less functional on admission and discharging them after shorter rehabilitation lengths of stay. Similar discharge functional status, despite shorter rehabilitation lengths of stay and an older population may suggest a change in the typical mechanism of injury. Many current TBI patients would fail to meet inclusion criteria for post-acute clinical trials in TBI because of their age, and treatments based on such trials may not be generalizable, which has significant implications on both research and clinical care realms within brain injury rehabilitation. [ABSTRACT FROM AUTHOR]

Developmental system drift is a likely mechanism for the origin of hybrid incompatibilities between closely related species. We examine here the detailed mechanistic basis of hybrid incompatibilities between two allopatric lineages, for a genotype-phenotype map of developmental system drift under stabilising selection, where an organismal phenotype is conserved, but the underlying molecular phenotypes and genotype can drift. This leads to number of emergent phenomenon not obtainable by modelling genotype or phenotype alone. Our results show that: 1) speciation is more rapid at smaller population sizes with a characteristic, Orr-like, power law, but at large population sizes slow, characterised by a sub-diffusive growth law; 2) the molecular phenotypes under weakest selection contribute to the earliest incompatibilities; and 3) pair-wise incompatibilities dominate over higher order, contrary to previous predictions that the latter should dominate. The population size effect we find is consistent with previous results on allopatric divergence of transcription factor-DNA binding, where smaller populations have common ancestors with a larger drift load because genetic drift favours phenotypes which have a larger number of genotypes (higher sequence entropy) over more fit phenotypes which have far fewer genotypes; this means less substitutions are required in either lineage before incompatibilities arise. Overall, our results indicate that biophysics and population size provide a much stronger constraint to speciation than suggested by previous models, and point to a general mechanistic principle of how incompatibilities arise the under stabilising selection for an organismal phenotype. [ABSTRACT FROM AUTHOR]

Describes the folding and compaction features in model proteins. Use of diffusion equation to study the impact of energetic parameters on the protein folding dynamics; Free-energy landscape characterized by two different order parameters.

The author comments on a study published within the issue which employed unbiased computational modeling without predetermined age boundaries to know distinct age-related subgroups in sudden unexplained infant death (SUID). Topics covered include the limitations of the study caused by its focus on birth and death statistics in early life, the inconsistencies as to which deceased infants receive or do not receive birth certificates, and the clinical implications of the study.

Objective: The aim of the study was to examine whether the chair stand component of the Short Physical Performance Battery predicts fall-related injury among older adult primary care patients. Design: A 2-yr longitudinal cohort study of 430 Boston-area primary care patients aged ≥65 yrs screened to be at risk for mobility decline was conducted. The three components of the Short Physical Performance Battery (balance time, gait speed, and chair stand time) were measured at baseline. Participants reported incidence of fall-related injuries quarterly for 2 yrs. Complementary log-log discrete time hazard models were constructed to examine the hazard of fall-related injury across Short Physical Performance Battery scores, adjusting for age, sex, race, Digit Symbol Substitution Test score, and fall history. Results: Participants were 68% female and 83% white, with a mean (SD) age of 76.6 (7.0). A total of 137 (32%) reported a fall-related injury during the follow-up period. Overall, inability to perform the chair stand task was a significant predictor of fall-related injury (hazard ratio = 2.11, 95% confidence interval = 1.23-3.62, P = 0.01). Total Short Physical Performance Battery score, gait component score, and balance component score were not predictive of fall-related injury. Conclusions: Inability to perform the repeated chair stand task was associated with increased hazard of an injurious fall for 2 yrs among a cohort of older adult primary care patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: The loss of a child is associated with elevated grief severity, and sudden infant death syndrome (SIDS) is the leading cause of postneonatal mortality in the United States. The diagnosis of prolonged grief disorder (PGD) has gained broader acceptance and use. Little is known about PGD in mothers after SIDS. METHODS: Between May 2013 and July 2016, we assessed 49 SIDS-bereaved mothers living in informal settlements near Cape Town, South Africa, and on the Pine Ridge Indian Reservation and 359 SIDS-bereaved mothers affiliated with SIDS parent-support organizations in the United States, United Kingdom, Australia, New Zealand, and the Netherlands. We examined PGD symptom severity and diagnostic prevalence rates between the samples and other significant grief indicators during the period 2 to 48 months after the deaths of their infants. RESULTS: Extremely high, persistent, and similar rates of PGD were found in both samples at every time interval. The prevalence of PGD was 50.0% in either sample (mean months from loss: 20.5 vs 24.9). Daily, intrusive emotional pain or yearning was found in 68.1% of subjects; yearning was significantly associated with emotional pain (P < .0001). Role confusion and anger were the most prevalent symptoms, reported by the majority at every time interval. Rates of role confusion, anger, and diminished trust in others remained constant. Acceptance was less prevalent than other grief indicators at every interval. CONCLUSIONS: Severe symptoms and heightened risk for PGD was seen in mothers after their infants died of SIDS, with discernible symptom profiles. Given their involvement with families after SIDS, pediatricians may have a unique role in identifying this problem and helping address its consequences. [ABSTRACT FROM AUTHOR]

Summary: We identified SCN1A variants in 2 infants who died of sudden infant death syndrome (SIDS) with hippocampal abnormalities from an exome sequencing study of 10 cases of SIDS but no history of seizures. One harbored SCN1A G682V, and the other had 2 SCN1A variants in cis: L1296M and E1308D, a variant previously associated with epilepsy. Functional evaluation in a heterologous expression system demonstrated partial loss of function for both G682V and the compound variant L1296M/E1308D. Our cases represent a novel association between SCN1A and SIDS, extending the SCN1A spectrum from epilepsy to SIDS. Our findings provide insights into SIDS and support genetic evaluation focused on epilepsy genes in SIDS. [ABSTRACT FROM AUTHOR]

Skeletal muscle (SKM) injury or myopathy results in structural or functional defects in SKMs that can be caused by variety of factors such as (1) genetic, (2) drug-induced, (3) disease progression (cachexia), or (4) aging (sarcopenia). Creatine kinase (CK) and aspartate transaminase (AST) activity assays have been routinely used as SKM injury biomarkers, but they lack sensitivity and tissue specificity. In collaboration with the Predictive Safety Testing Consortium, we evaluated the diagnostic performance of a muscle injury biomarker panel (MIP) compared to CK and AST and their correlation with the histology scores across 34 different rat studies. The MIP panel included the analytes skeletal troponin I, myosin light chain 3, fatty acid binding protein 3, and a CK mass (versus activity) assay. The area under the receiver operator characteristic curve for MIP panel ranged from 0.82 to 0.91 as compared to 0.71 and 0.82 for CK and AST activity assays, respectively. Because the MIP biomarkers outperformed the routine biomarkers, the European Medicines Agency and U.S. Food and Drug Administration posted Letters of Support encouraging further study of these analytes and acknowledged the utility of the MIP panel. Ongoing efforts are directed toward the application of the MIP panel biomarkers in clinical studies and regulatory qualification. [ABSTRACT FROM AUTHOR]

The article discusses the different aspects of sudden unexplained death in pediatrics (SUDP). Topics covered include the highlights of various studies conducted to search for biological evidence for SUDP, the development of the Robert's Program on SUDP, and the assessment approach used to investigate SUDP. It also discusses the noted benefits of using the Robert's Program.

Objective Few studies have focused on 30-day readmission rates in inpatient rehabilitation facilities (IRFs) and factors that contribute to this. The purpose of this study was to examine the variation in 30-day readmission rates among medically complex patients at IRFs nationally and explore how patient and facility characteristics are associated with this variation. Design Retrospective review of an administrative database. Setting IRFs throughout the United States. Participants Patients from the medically complex impairment group treated at IRFs nationwide represented in the Uniform Data System for Medical Rehabilitation (UDS MR ) from 2002 to 2011. Measurements Using multilevel logistic regression analysis, 16 patient and facility characteristics were examined to identify and adjust for variables with a significant effect on readmission rates. Unadjusted and adjusted readmission rates were plotted by facility rank. Facilities were grouped by decile, based on readmission rates, and the mean unadjusted and adjusted rates for the lowest and highest deciles were compared to quantify the variation due to adjustment. Patient and facility characteristics for the highest and lowest deciles were compared. Results A total of 117,156 medically complex patients from 682 IRFs nationwide were included. Patients were 46% male and 84% white with an average age of 71.5 years. Nine of 16 characteristics were identified that significantly increased the odds of readmission, including older age, male gender, poorer admission motor function, longer duration of impairment, higher Elixhauser comorbidity index, unemployed or retired status, larger facility size, lower mean facility admission motor function, and eastern or western geographic area. The average unadjusted and adjusted readmission rates for all facilities were 15.63% and 15.86%, respectively. The unadjusted readmission rates for the lowest and highest deciles were 6.71% and 26.48%, respectively. After adjustment, this narrowed to 10.33% and 21.91%, respectively. Patient and facility characteristics accounted for 41% of the variation seen in the readmission rates for these groups. Facilities with the highest readmission rates (highest decile) more commonly cared for patients at highest risk for readmission: unemployed, male patients with higher comorbidity index and poorer motor function on admission. Conclusion This study shows significant variation in readmission rates for medically complex patients across IRFs. However, nearly half (41.4%) of this variation was attributed to 9 patient and facility characteristics, suggesting the need for risk adjustment if readmission rates are to be used as a quality indicator for IRFs. [ABSTRACT FROM AUTHOR]