Heart rate variability impairment during sleep in Veterans with REM sleep behavior disorder, traumatic brain injury, and posttraumatic stress disorder: An early potential window into autonomic dysfunction?

Individuals with comorbid REM sleep behavior disorder (RBD) and neurotrauma (defined by traumatic brain injury and post-traumatic stress disorder) have an earlier age of RBD symptom onset, increased RBD-related symptom severity and more neurological features indicative of prodromal synucleinopathy compared to RBD only. An early sign of neurodegenerative condition is autonomic dysfunction, which we sought to evaluate by examining heart rate variability during sleep. Participants with overnight polysomnography were recruited from the VA Portland Health Care System. Veterans without neurotrauma or RBD (controls; n=19), with RBD only (RBD, n=14), and with RBD and neurotrauma (RBD+NT, n=19) were evaluated. Eligible 5-minute NREM and REM epochs without apneas/hypopneas, microarousals, and ectopic beats were analyzed for frequency and time domain (e.g. low frequency power, LF; high frequency power, HF; root mean square of successive RR intervals, RMSSD; % of RR intervals that vary ≥50 ms, pNN50) heart rate variability outcomes. Heart rate did not significantly differ between groups in any sleep stage. Time domain and frequency domain variables (e.g., LF power, HF power, RMSSD, and pNN50) were significantly reduced in the RBD and RBD+NT groups compared to controls and RBD only during NREM sleep. There were no group differences detected during REM sleep. These data suggest significant reductions in heart rate variability during NREM sleep in RBD+NT participants, suggesting greater autonomic dysfunction compared to controls or RBD alone. Heart rate variability during sleep may be an early, promising biomarker, yielding mechanistic insight for diagnosis and prognosis of early neurodegeneration in this vulnerable population. STATEMENT OF SIGNIFICANCE: Comorbid REM sleep behavior disorder (RBD) and neurotrauma (NT, traumatic brain injury + post-traumatic stress disorder; RBD+NT) is associated with increased neurodegenerative symptom burden and worsened health. Sleep and autonomic function are integrally and bidirectionally related to neurodegenerative processes. In the current study, we sought to determine if early signs of autonomic dysfunction, measured via heart rate variability (HRV), were present during sleep in comorbid RBD+NT compared to RBD only and controls. Our data show reduced time and frequency domain HRV during NREM sleep in RBD+NT Veterans compared to RBD only and controls. These data contribute evidence that participants with RBD and comorbid NT demonstrate significantly worse autonomic dysfunction compared to age/sex matched participants with RBD alone.

Injuries and deaths due to tree failure in The Netherlands: analysis of observational data from 1998-2021.

Urban and roadside trees contribute to health and resilience. However, when trees or branches fall, it can cause injuries or deaths. This study examined trends and variations of injuries and deaths due to tree failure in The Netherlands from 1998 to 2021, considering urban-rural location, sex, age and traffic mode. This study is the first to describe long-term trends in injuries and deaths due to tree failure from 1998-2021. The standardised rate of injuries per 1,000,000 population increased from 0.14 (SE 0.10) in 1998 to 0.91 (SE 0.21) in 2021, with an annual percentage increase of 5.3% (p = 0.002). The data shows a strong increase for rural areas, contrary to urban ones. The annual percentage increase in rural areas was 13.2% (p < 0.001) while injuries in urban areas increased with 3.0% (p = 0.026), which revealed large urban-rural disparities. A trend was absent in the frequency of deaths. More attention needs to be given to investigating causes, drivers and stressors associated with tree failure-related injuries. In particular, efforts should be made to reduce the prevalence in rural areas. The increase in injuries over time makes it necessary to create awareness and share knowledge among residents and local governments about tree failure risks.

IGLON5 Frequency in Idiopathic REM Sleep Behavior Disorder: A Multicenter Study.

BACKGROUND AND OBJECTIVES: Idiopathic/isolated REM sleep behavior disorder (iRBD) has been strongly linked to neurodegenerative synucleinopathies such as Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. However, there have been increasing reports of RBD as a presenting feature of serious and treatable autoimmune syndromes, particularly IGLON5. This study's objective was to investigate the frequency of autoantibodies in a large cohort of participants with iRBD. METHODS: Participants were enrolled in the North American Prodromal Synucleinopathy cohort with polysomnography-confirmed iRBD, free of parkinsonism and dementia. Plasma samples were systematically screened for the autoantibodies IGLON5, DPPX, LGI1, and CASPR2 using plasma IgG cell-based assay. Positive or equivocal results were confirmed by repeat testing, plus tissue-based indirect immunofluorescence assay for IGLON5. RESULTS: Of 339 samples analyzed, 3 participants (0.9%) had confirmed positive IGLON5 autoantibodies in the cell-based assay, which were confirmed by the tissue-based assay. An additional participant was positive for CASPR2 with low titer by cell-based assay only (of lower clinical certainty). These cases exhibited a variety of symptoms including dream enactment, cognitive decline, autonomic dysfunction, and motor symptoms. In 1 IGLON5 case and the CASPR2 case, evolution was suggestive of typical synucleinopathy, suggesting the possibility that findings were incidental. However, 2 participants with IGLON5 died before diagnosis was clinically suspected, with a final clinical picture highly suggestive of autoimmune disease. DISCUSSION: Our finding that nearly 1% of a large iRBD cohort may have a serious but potentially treatable autoantibody syndrome has important clinical implications. In particular, it raises the question of whether autoantibody testing for IGLON-5-IgG should be widely implemented for participants with iRBD, considering the difficulty in diagnosis of autoimmune diseases, their response to treatment, and the potential for rapid disease progression. However, any routine testing protocol will also have to consider costs and potential adverse effects of false-positive findings. TRIAL REGISTRATION INFORMATION: NCT03623672.

"No such thing as good cancer": a qualitative exploration of the experience of early-onset thyroid cancer in survivors.

BACKGROUND: The incidence of thyroid cancer has increased exponentially in recent decades. At the same time, there is a growing concern surrounding the overdiagnosis of indolent thyroid cancer, leading to invasive and potentially unnecessary interventions that can significantly impact young patients' lives. Yet, the experiences of survivors of thyroid cancer have been largely understudied. The purpose of this study was to explore the experiences of survivors of early-onset thyroid cancer. METHODS: The qualitative research design of hermeneutic phenomenology guided this study. Participants completed a demographic survey and semi-structured interview that was subsequently transcribed verbatim and analyzed using reflexive thematic analysis. RESULTS: Thirty-six survivors of thyroid cancer (83% female, median age at diagnosis: 37.1 years, median age at interview: 43.5 years) participated. Participants' experiences were characterized by two themes: (1) reconciling the meaning of the "c" word (cancer) as a dangerous and life-threatening diagnosis with lived experience of thyroid cancer and (2) thyroid cancer leaves patients with lifelong physical and emotional scars. CONCLUSIONS: Survivors of early-onset thyroid cancer experience significant short and late effects on their physical and psychosocial well-being. Survivors shared some of the difficulties of having to reconcile what they were told was a "good cancer" and their previously held beliefs of cancer, including feeling lost in the healthcare system and like they could not access services or be impacted because they had been told they had "good cancer." Increased communication of risks and acknowledgement of the perceptions surrounding cancer is needed to help patients make better informed decisions and feel supported throughout their thyroid cancer journey. Gaps in care pathways, especially adjustments post-treatment, should be filled to help support these survivors.

Aquaporin-4 mis-localization slows glymphatic clearance of α-synuclein and promotes α-synuclein pathology and aggregate propagation.

The appearance of misfolded and aggregated proteins is a pathological hallmark of numerous neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. Sleep disruption is proposed to contribute to these pathological processes and is a common early feature among neurodegenerative disorders. Synucleinopathies are a subclass of neurodegenerative conditions defined by the presence of α-synuclein aggregates, which may not only enhance cell death, but also contribute to disease progression by seeding the formation of additional aggregates in neighboring cells. The mechanisms driving intercellular transmission of aggregates remains unclear. We propose that disruption of sleep-active glymphatic function, caused by loss of precise perivascular AQP4 localization, inhibits α-synuclein clearance and facilitates α-synuclein propagation and seeding. We examined human post-mortem frontal cortex and found that neocortical α-synuclein pathology was associated with AQP4 mis-localization throughout the gray matter. Using a transgenic mouse model lacking the adapter protein α-syntrophin, we observed that loss of perivascular AQP4 localization impairs the glymphatic clearance of α-synuclein from intersititial to cerebrospinal fluid. Using a mouse model of α-synuclein propogation, using pre-formed fibril injection, we observed that loss of perivascular AQP4 localization increased α-synuclein aggregates. Our results indicate α-synuclein clearance and propagation are mediated by glymphatic function and that AQP4 mis-localization observed in the presence of human synucleinopathy may contribute to the development and propagation of Lewy body pathology in conditions such as Lewy Body Dementia and Parkinson's disease.

Biological sex and BMI influence the longitudinal evolution of adolescent and young adult MRI-visible perivascular spaces.

Background and Purpose: An association recently emerged between magnetic resonance imaging (MRI)-visible perivascular spaces (MV-PVS) with intracerebral solute clearance and neuroinflammation, in adults. However, it is unknown how MV-PVS change throughout adolescence and what factors influence MV-PVS volume and morphology. This study assesses the temporal evolution of MV-PVS volume in adolescents and young adults, and secondarily evaluates the relationship between MV-PVS, age, sex, and body mass index (BMI). Materials and Methods: This analysis included a 783 participant cohort from the longitudinal multicenter National Consortium on Alcohol and Neurodevelopment in Adolescence study that involved up to 6 imaging visits spanning 5 years. Healthy adolescents aged 12-21 years at study entry with at least two MRI scans were included. The primary outcome was mean MV-PVS volume (mm 3 /white matter cm 3 ). Results: On average, males had greater MV-PVS volume at all ages compared to females. A linear mixed-effect model for MV-PVS volume was performed. Mean BMI and increases in a person's BMI were associated with increases in MV-PVS volume over time. In females only, changes in BMI correlated with MV-PVS volume. One unit increase in BMI above a person's average BMI was associated with a 0.021 mm 3 /cm 3 increase in MV-PVS volume (p<0.001). Conclusion: This longitudinal study showed sex differences in MV-PVS features during adolescence and young adulthood. Importantly, we report that increases in BMI from a person's mean BMI are associated with increases in MV-PVS volume in females only. These findings suggest a potential link between MV-PVS, sex, and BMI that warrants future study.

Safety of biologic immunosuppressants in pregnant women with immune-mediated inflammatory diseases.

BACKGROUND: Immune-mediated inflammatory diseases (IMIDs) typically affect women of childbearing age. One of the challenges in treating these women during pregnancy is to manage the disease while minimizing or avoiding the use of disease-modifying antirheumatic drugs (DMARDs) that may increase the risk to the mother or fetus. Biologic therapy has transformed the management of these patients. This study aimed to evaluate the maternal-fetal safety and perinatal outcomes in pregnant women with IMID exposed to biologic DMARDs either preconceptionally or during pregnancy and compare them with women using conventional DMARDs and a group of healthy pregnant women. METHODS: We conducted a retrospective study with prospective follow-up of pregnant women with IMID at a single center. We analyzed baseline maternal demographic characteristics, diseases, DMARDs, and maternal-fetal outcomes. RESULTS: A cohort of 244 pregnancies was studied. One hundred twenty-eight patients met classificatory criteria for rheumatic and musculoskeletal diseases (RMD) or inflammatory bowel disease (IBD), and 116 pregnancies of healthy women were evaluated from the same study period. One hundred and one pregnancies in IMID patients (89.84 %) occurred under immunosuppressive treatment, 78.91 % of IMID pregnancies were under cDMARD (33.59 % exclusive cDMARD), 56.25 % under bDMARD, and 27.34 % under oral glucocorticoids. Anti-TNF was the most frequent (88.88 %) bDMARD and was used in 50.78 % of the IMIDs. There was at least one flare in 37.10 % of the IMID pregnancies, and 9.38 % experienced more than one. Among flares, 43.48 % happened in the first trimester, 34.78 % in the second trimester, and 19.57 % in the third. Flares were more frequent in the RMD patients compared with IBD (p = 0.041; OR 2.15, 95%CI: 1.03-4.52). Flare was associated with discontinuation of bDMARD before the eighth week of gestation (p = 0.016), but especially in the second (p = 0.042) and third trimester (p = 0.012). Maternal infections were an infrequent complication overall (7.66 %), although more frequent in patients with IMIDs (p = 0.004) but were not associated with cDMARD or bDMARD. IMID patients needed assisted reproductive techniques (ART) more often (p = 0.001, OR 2.83, 95%CI: 1.02-7.90). More cesarean sections were performed in gestations under treatment with bDMARD (p = 0.020) and especially in those under treatment with anti-TNF. Aneuploidies calculation risk and fetal malformations were not correlated with DMARDs (cDMARDs, bDMARDs, or its combination) nor with any of the DMARDs individually preconcepcionally or during gestation. Small for gestational age (SGA) newborns were higher in patients with IMIDs however, it was not associated with DMARD use. DISCUSSION: In general, patients with IMIDs who require treatment with bDMARDs have a more severe or refractory disease prior to gestation. In our cohort, we found a higher risk of flare among patients with bDMARDs, especially when those were suspended early. Among maternal outcomes, we found that IMID patients needed ART more often. This is probably, first of all, because of maternal age. Among fetal outcomes, there are no differences in congenital malformations in the IMIDs and healthy patients and were not correlated with DMARDs. CONCLUSION: The use of bDMARDs was effective in disease control and safe from a maternal-fetal point of view, with no increase in prematurity, SGA, malformations, or infections.

Neurologists' Attitudes and Perceptions on Palliative Care: A Qualitative Study.

Background and Objectives: Despite significant advances in the treatment of neurologic disorders, many conditions require complex care planning and advanced care planning. Neurologists are in a unique position because they are integral in providing patient centered care, understanding neurologic disease and illness trajectory, and how disease can affect patients' sense of self and values. Currently, little is known about neurologists' perceptions and challenges in care planning and palliative care for their patients. Methods: Neurologists from one Canadian academic institution participated in a 30-minute semistructured interview from November 2022 to April 2023. Interviews were conducted until saturation was reached and confirmed. Interviews occurred online through a secure platform or in-person and were recorded. Data were analyzed using a constant comparative method using constructivist grounded theory. Member checking was conducted post interview. Results: Ten neurologists participated across a broad spectrum of neurology experience and subspecialties. We developed a detailed theory of understanding neurologists' attitudes and perceptions of palliative care. When neurologists delay or fail to initiate care planning discussions or palliative care, it results from a complex interplay between patient, physician, and resource accessibility factors. Certain contextual factors, such as a first visit or follow-up, inpatient vs outpatient setting, clinic culture, and the type of clinic practice, are factors that can influence these conversations. As a result, physicians may fail to use available resources, or they may involve other care providers or refer to subspecialty neurologic clinics. However, this delay can still lead to patient and provider harm. Opportunities to improve care exist with continuing education opportunities for trainees and staff, collaboration with palliative care specialists, and health systems support, such as increasing public awareness to address misconceptions about palliative care and resource availability. Discussion: Our findings identify that failure or delay to initiate care planning and palliative care by neurologists results from a complex interplay between local culture, experience, context, practice type, and patient factors. Opportunities to improve care include increasing educational opportunities, building integrated and collaborative practices, and dedicated health systems support.

Sex-Specific Impacts of Early Life Sleep Disruption: Ethanol Seeking, Social Interaction, and Anxiety Are Differentially Altered in Adolescent Prairie Voles.

Early life sleep is important for neuronal development. Using the highly social prairie vole rodent model, we have previously reported that early life sleep disruption (ELSD) during the preweaning period results in interference with social bonding and increases ethanol consumption following a stressor in adulthood. Furthermore, ELSD increases parvalbumin expression and reduces glutamatergic neurotransmission in cortical regions in adult prairie voles. To understand the impact of ELSD on the lifespan, an examination of an earlier time in life is necessary. The aim of the present study was to examine behavioral outcomes of ELSD on adolescent prairie voles. Given the known effects of ELSD on development of neuronal systems involved in mood and social motivation, we hypothesized that anxiety, risk, and reward-related behaviors would be impacted by ELSD in adolescent prairie voles. We report that both male and female adolescent prairie voles that experienced ELSD showed heightened anxiety-like behavior compared to age-matched controls (CONs) as measured by a light-dark box. Additionally, both male and female ELSD voles showed reductions in both ethanol preference and consumption, and affiliative behavior compared to CONs. These results suggest that adolescent prairie voles of both sexes experience heightened anxiety-like behavior and reduced reward-seeking behaviors after ELSD. These results further suggest that early life sleep is critically important for neurotypical behaviors in adolescence.

Quantifying social roles in multi-animal videos using subject-aware deep-learning.

Analyzing social behaviors is critical for many fields, including neuroscience, psychology, and ecology. While computational tools have been developed to analyze videos containing animals engaging in limited social interactions under specific experimental conditions, automated identification of the social roles of freely moving individuals in a multi-animal group remains unresolved. Here we describe a deep-learning-based system - named LabGym2 - for identifying and quantifying social roles in multi-animal groups. This system uses a subject-aware approach: it evaluates the behavioral state of every individual in a group of two or more animals while factoring in its social and environmental surroundings. We demonstrate the performance of subject-aware deep-learning in different species and assays, from partner preference in freely-moving insects to primate social interactions in the field. Our subject-aware deep learning approach provides a controllable, interpretable, and efficient framework to enable new experimental paradigms and systematic evaluation of interactive behavior in individuals identified within a group.

Bifunctional Ligands: Evaluating the Role of Acidic Protons in the Secondary Coordination Sphere.

To evaluate bifunctional ligand reactivity involving NH acidic sites in the secondary coordination sphere, complexes where the proton has been substituted with a methyl group (NMe) are often investigated. An alternative strategy involves substitution of the NH group for an O. This contribution considers and compares the merits of these approaches; the synthesis and characterization of cationic square-planar Rh carbonyl complexes bearing diprotic bispyrazole pyridine ligand L1, and the bis-methylated pyrazole pyridine ligand L1Me are described. The syntheses and characterization of the novel monoprotic pyrazole isoxazole pyridine ligand L2 and aprotic bisisoxazole pyridine ligand L3, and their corresponding Rh carbonyl complexes are also described. Comparison of the CO stretching frequencies of the four Rh complexes suggest that substitutions of NH with NMe, as well as with O, lead to significant electronic differences. These electronic differences result in different reactivities with respect to ligand addition/substitution of the Rh carbonyl complexes. Overall, the data suggest that electronic differences arising due to the NH substitutions can be significant and should be considered when the NH group is substituted in investigations of the participation of the NH proton in a reaction.

Feasibility and acceptability for LION, a fully remote, randomized clinical trial within the VA for light therapy to improve sleep in Veterans with and without TBI: An MTBI2 sponsored protocol.

Sleep-wake disturbances frequently present in Veterans with mild traumatic brain injury (mTBI). These TBI-related sleep impairments confer significant burden and commonly exacerbate other functional impairments. Therapies to improve sleep following mTBI are limited and studies in Veterans are even more scarce. In our previous pilot work, morning bright light therapy (MBLT) was found to be a feasible behavioral sleep intervention in Veterans with a history of mTBI; however, this was single-arm, open-label, and non-randomized, and therefore was not intended to establish efficacy. The present study, LION (light vs ion therapy) extends this preliminary work as a fully powered, sham-controlled, participant-masked randomized controlled trial (NCT03968874), implemented as fully remote within the VA (target n=120 complete). Randomization at 2:1 allocation ratio to: 1) active: MBLT (n=80), and 2) sham: deactivated negative ion generator (n=40); each with identical engagement parameters (60-min duration; within 2-hrs of waking; daily over 28-day duration). Participant masking via deception balanced expectancy assumptions across arms. Outcome measures were assessed following a 14-day baseline (pre-intervention), following 28-days of device engagement (post-intervention), and 28-days after the post-intervention assessment (follow-up). Primary outcomes were sleep measures, including continuous wrist-based actigraphy, self-report, and daily sleep dairy entries. Secondary/exploratory outcomes included cognition, mood, quality of life, circadian rhythm via dim light melatonin onset, and biofluid-based biomarkers. Participant drop out occurred in <10% of those enrolled, incomplete/missing data was present in <15% of key outcome variables, and overall fidelity adherence to the intervention was >85%, collectively establishing feasibility and acceptability for MBLT in Veterans with mTBI.

Preimplantation development of in vitro-produced bovine embryos treated with hydroxychloroquine.

Hydroxychloroquine (HCQ) is a safe antimalarial drug but its overdosage or inappropriate use, such as during the pandemic, may cause adverse effects once this drug is considered a potent inhibitor of autophagy. Information about HCQ's effects on the reproductive field, including gametes and initial embryos, is limited. In this study, we evaluated the effect of HCQ (1, 6, 12, and 24 µM) on pre-implantation embryo development, autophagy, and apoptosis of bovine embryos produced in vitro. A dose-response experiment showed a reduction (p < 0.05) in cleavage only at the highest concentration. Blastocyst rate was gradually reduced (p < 0.05) with the increase of HCQ dosage starting at 6 µM, with no embryo formation occurring at 24 µM. Further analysis showed that embryos treated with 12 µM of HCQ had a higher (p < 0.05) accumulation of acidic autophagic vesicles on Days 5 and 7 of development and a higher (p < 0.01) apoptotic index on Day 7. To our knowledge, this is the first study to evaluate the effects of HCQ on embryo pre-implantation development in mammals. The results contribute with more information related to the study of autophagy in embryology as well as add some discussion on HCQ toxicology and its effects on reproductive cells.

The potential role of chronic pain and the polytrauma clinical triad in predicting prodromal PD: A cross-sectional study of U.S. Veterans.

Introduction: The research criteria for prodromal Parkinson disease (pPD) depends on prospectively validated clinical inputs with large effect sizes and/or high prevalence. Neither traumatic brain injury (TBI), post-traumatic stress disorder (PTSD), nor chronic pain are currently included in the calculator, despite recent evidence of association with pPD. These conditions are widely prevalent, co-occurring, and already known to confer risk of REM behavior disorder (RBD) and PD. Few studies have examined PD risk in the context of TBI and PTSD; none have examined chronic pain. This study aimed to measure the risk of pPD caused by TBI, PTSD, and chronic pain. Methods: 216 US Veterans were enrolled who had self-reported recurrent or persistent pain for at least three months. Of these, 44 met criteria for PTSD, 39 for TBI, and 41 for all three conditions. Several pain, sleep, affective, and trauma questionnaires were administered. Participants' history of RBD was determined via self-report, with a subset undergoing confirmatory video polysomnography. Results: A greater proportion of Veterans with chronic pain met criteria for RBD (36 % vs. 10 %) and pPD (18.0 % vs. 8.3 %) compared to controls. Proportions were increased in RBD (70 %) and pPD (27 %) when chronic pain co-occurred with TBI and PTSD. Partial effects were seen with just TBI or PTSD alone. When analyzed as continuous variables, polytrauma symptom severity correlated with pPD probability (r = 0.28, P = 0.03). Conclusion: These data demonstrate the potential utility of chronic pain, TBI, and PTSD in the prediction of pPD, and the importance of trauma-related factors in the pathogenesis of PD.

Smoking, nicotine and pregnancy 2 (SNAP2) trial: protocol for a randomised controlled trial of an intervention to improve adherence to nicotine replacement therapy during pregnancy.

INTRODUCTION: Smoking during pregnancy is harmful to unborn babies, infants and women. Nicotine replacement therapy (NRT) is offered as the usual stop-smoking support in the UK. However, this is often used in insufficient doses, intermittently or for too short a time to be effective. This randomised controlled trial (RCT) explores whether a bespoke intervention, delivered in pregnancy, improves adherence to NRT and is effective and cost-effective for promoting smoking cessation. METHODS AND ANALYSIS: A two-arm parallel-group RCT was conducted for pregnant women aged ≥16 years and who smoke ≥1 daily cigarette (pre-pregnancy smoked ≥5) and who agree to use NRT in an attempt to quit. Recruitment is from antenatal care settings and via social media adverts. Participants are randomised using blocked randomisation with varying block sizes, stratified by gestational age (<14 or ≥14 weeks) to receive: (1) usual care (UC) for stop smoking support or (2) UC plus an intervention to increase adherence to NRT, called 'Baby, Me and NRT' (BMN), comprising adherence counselling, automated tailored text messages, a leaflet and website. The primary outcome is biochemically validated smoking abstinence at or around childbirth, measured from 36 weeks gestation. Secondary outcomes include NRT adherence, other smoking measures and birth outcomes. Questionnaires collect follow-up data augmented by medical record information. We anticipate quit rates of 10% and 16% in the control and intervention groups, respectively (risk ratio=1.6). By recruiting 1320 participants, the trial should have 90% power (alpha=5%) to detect this intervention effect. An economic analysis will use the Economics of Smoking in Pregnancy model to determine cost-effectiveness. ETHICS AND DISSEMINATION: Ethics approval was granted by Bloomsbury National Health Service's Research Ethics Committee (21/LO/0123). Written informed consent will be obtained from all participants. Findings will be disseminated to the public, funders, relevant practice/policy representatives, researchers and participants. TRIAL REGISTRATION NUMBER: ISRCTN16830506. PROTOCOL VERSION: 5.0, 10 Oct 2023.

Head Injury Treatment With Healthy and Advanced Dietary Supplements: A Pilot Randomized Controlled Trial of the Tolerability, Safety, and Efficacy of Branched Chain Amino Acids in the Treatment of Concussion in Adolescents and Young Adults.

Concussion is a common injury in the adolescent and young adult populations. Although branched chain amino acid (BCAA) supplementation has shown improvements in neurocognitive and sleep function in pre-clinical animal models of mild-to-moderate traumatic brain injury (TBI), to date, no studies have been performed evaluating the efficacy of BCAAs in concussed adolescents and young adults. The goal of this pilot trial was to determine the efficacy, tolerability, and safety of varied doses of oral BCAA supplementation in a group of concussed adolescents and young adults. The study was conducted as a pilot, double-blind, randomized controlled trial of participants ages 11-34 presenting with concussion to outpatient clinics (sports medicine and primary care), urgent care, and emergency departments of a tertiary care pediatric children's hospital and an urban tertiary care adult hospital, between June 24, 2014 and December 5, 2020. Participants were randomized to one of five study arms (placebo and 15 g, 30 g, 45 g, and 54 g BCAA treatment daily) and followed for 21 days after enrollment. Outcome measures included daily computerized neurocognitive tests (processing speed, the a priori primary outcome; and attention, visual learning, and working memory), symptom score, physical and cognitive activity, sleep/wake alterations, treatment compliance, and adverse events. In total, 42 participants were randomized, 38 of whom provided analyzable data. We found no difference in our primary outcome of processing speed between the arms; however, there was a significant reduction in total symptom score (decrease of 4.4 points on a 0-54 scale for every 500 g of study drug consumed, p value for trend = 0.0036, [uncorrected]) and return to physical activity (increase of 0.503 points on a 0-5 scale for every 500 g of study drug consumed, p value for trend = 0.005 [uncorrected]). There were no serious adverse events. Eight of 38 participants reported a mild (not interfering with daily activity) or moderate (limitation of daily activity) adverse event; there were no differences in adverse events by arm, with only two reported mild adverse events (both gastrointestinal) in the highest (45 g and 54 g) BCAA arms. Although limited by slow enrollment, small sample size, and missing data, this study provides the first demonstration of efficacy, as well as safety and tolerability, of BCAAs in concussed adolescents and young adults; specifically, a dose-response effect in reducing concussion symptoms and a return to baseline physical activity in those treated with higher total doses of BCAAs. These findings provide important preliminary data to inform a larger trial of BCAA therapy to expedite concussion recovery.

How resilient are farmers in Africa to climate shocks? A case study of Nigerian farmers.

Agriculture in sub-Saharan Africa remains highly vulnerable to climate related shocks, since most production relies on rainfall. It is important to accurately measure the resilience of farmers and farming communities to weather variabilities, for both government policy and farmer management responses. This paper develops a Resilience Index Framework, which is further used to assess the resilience of farmers to climate shocks in Nigeria. We conceptualized our Resilience Index (RI) in this study to be a composite function of 60 indicators encompassing four resilience domains namely, Economic & Financial Resilience (ER); Technical-know-how Resilience (TR); Social Resilience (SR); and Physical Resilience (PR). A three-stage standardization approach to construct the resilience index is taken in this study. In the first stage, each indicator is standardized. In the second stage, the resilience domain is computed by averaging the corresponding standardized indicators. In the final stage, the composite RI is computed by estimating the weighted average of all the resilience domains. The study uses the baseline survey data collected between 2021 and 2022 from a total of 5954 farmers in the rainforest, derived and guinea savannah agroecological zones of Nigeria. The result of the study shows that the majority (96.5%) of the farmers are less resilient to climate shocks, with only 0.9% economically & financially resilient, 1.4% socially resilient, 31.4% technically resilient, and 18.5% physically resilient. Finally, some recommend steps to be taken by the government and relevant stakeholders to improve the resilience of farmers through provision of good infrastructural facilities and subsidized improved resistant seed varieties are proposed.

Social Risk Determinants for Successful Same Calendar Day Discharge in Total Joint Arthroplasty.

Background: While many studies have examined the impact of comorbidities on the success of same calendar day discharge (SCDD) in total joint arthroplasty (TJA), literature surrounding the impact of social determinants is lacking. Purpose: We sought to investigate the relationship between various social determinants and success of SCDD after primary total hip arthroplasty (THA) and total knee arthroplasty (TKA). Methods: We conducted a retrospective review of 1160 THA and 1813 TKA performed at a single academic institution between November 2020 and August 2022. Social factors including substance use, occupation, marital status, income, and participation in physical exercise were included. In addition, aspects of discharge planning were reviewed such as living situation and transportation details. Results: Overall, 952 (32%) patients had successful SCDD, whereas 2021 (68%) patients were discharged on postoperative day 1 (POD1) or greater. Successful SCDD patients were more likely to have health care (4.8% vs 2.5%) and active (5.4% vs 4.6%) rather than sedentary occupations, be married (79.6% vs 67.4%), have access to transportation (95.6% vs 92.9%), live in a higher median income area ($64,044 [16,183] vs $61,572 [14,594]), and exercise weekly (62.6% vs 23.9%). Interestingly, the successful patients had more stories in their homes (1.62 [0.56] vs 1.43 [0.53]), more stairs to enter their homes (5.19 [5.22] vs 4.60 [5.24]), lived farther from the hospital (43.3 [138.0] vs 32.0 [75.9] miles), and a higher prevalence of alcohol use (60.7% vs 44.7%) and tobacco use (19.3% vs 17.3%). Conclusion: These findings may help arthroplasty surgeons to better understand the social factors that contribute to successful SCDD in TJA patients, ultimately aiding in patient selection and preoperative counseling.

Perivascular Space Burden and Cerebrospinal Fluid Biomarkers in US Veterans With Blast-Related Mild Traumatic Brain Injury.

Blast-related mild traumatic brain injury (mTBI) is recognized as the "signature injury" of the Iraq and Afghanistan wars. Sleep disruption, mTBI, and neuroinflammation have been individually linked to cerebral perivascular space (PVS) dilatation. Dilated PVSs are putative markers of impaired cerebrospinal fluid (CSF) and interstitial fluid exchange, which plays an important role in removing cerebral waste. The aim of this cross-sectional, retrospective study was to define associations between biomarkers of inflammation and MRI-visible PVS (MV-PVS) burden in Veterans after blast-related mTBI (blast-mTBI) and controls. The CSF and plasma inflammatory biomarker concentrations were compared between blast-mTBI and control groups and correlated with MV-PVS volume and number per white matter cm3. Multiple regression analyses were performed with inflammatory biomarkers as predictors and MV-PVS burden as the outcome. Correction for multiple comparisons was performed using the Banjamini-Hochberg method with a false discovery rate of 0.05. There were no group-wise differences in MV-PVS burden between Veterans with blast-mTBI and controls. Greater MV-PVS burden was significantly associated with higher concentrations of several proinflammatory biomarkers from CSF (i.e., eotaxin, MCP-1, IL-6, IL-8) and plasma (i.e., MCP-4, IL-13) in the blast-mTBI group only. After controlling for sleep time and symptoms of post-traumatic stress disorder, temporal MV-PVS burden remained significantly associated with higher CSF markers of inflammation in the blast-mTBI group only. These data support an association between central, rather than peripheral, neuroinflammation and MV-PVS burden in Veterans with blast-mTBI independent of sleep. Future studies should continue to explore the role of blast-mTBI related central inflammation in MV-PVS development, as well as investigate the impact of subclinical exposures on MV-PVS burden.