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Traumatic brain injury (TBI) is closely and bi-directionally linked with alcohol use, as by some estimates intoxication is the direct or indirect cause of one-third to one-half of all TBI cases. Alcohol use following injury can reduce the efficacy of rehabilitation and increase the chances for additional injury. Finally, TBI itself may be a risk factor for the development of alcohol use disorders. Children who suffer TBIs have poorer life outcomes and more risk of substance abuse. We used a standardized closed-head injury to model mild traumatic brain injuries. We found that mice injured as juveniles but not during adulthood exhibited much greater alcohol self-administration in adulthood. Further, this phenomenon was limited to female mice. Using behavioral testing, including conditioned place preference assays, we showed that early injuries increase the rewarding properties of alcohol. Environmental enrichment administered after injury reduced axonal degeneration and prevented the increase in drinking behavior. Additionally, brain-derived neurotrophic factor gene expression, which was reduced by TBI, was normalized by environmental enrichment. Together, these results suggest a novel model of alterations in reward circuitry following trauma during development.

Background Traumatic brain injury (TBI) is a complex condition common among individuals treated in behavioral healthcare, but TBI screening has not been adopted in these settings which can affect optimal clinical decision-making. Integrating evidence-based practices that address complex health comorbidities into behavioral healthcare settings remains understudied in implementation science, limited by few studies using theory-driven hypotheses to disentangle relationships between proximal and medial indicators on distal implementation outcomes. Grounded in the Theory of Planned Behavior, we examined providers’ attitudes, perceived behavioral control (PBC), subjective norms, and intentions to adopt The Ohio State University TBI Identification Method (OSU TBI-ID) in behavioral healthcare settings. Methods We used an explanatory sequential mixed-methods design. In Phase I, 215 providers from 25 organizations in the USA completed training introducing the OSU TBI-ID, followed by a survey assessing attitudes, PBC, norms, and intentions to screen for TBI. After 1 month, providers completed another survey assessing the number of TBI screens conducted. Data were analyzed using structural equation modeling (SEM) with logistic regressions. In Phase II, 20 providers were purposively selected for semi-structured interviews to expand on SEM results. Qualitative data were analyzed using thematic analysis, integrated with quantitative results, and combined into joint displays. Results Only 25% (55/215) of providers adopted TBI screening, which was driven by motivations to trial the intervention. Providers who reported more favorable attitudes ( OR : 0.67, p  < .001) and greater subjective norms ( OR : 0.12, p  < .001) toward TBI screening demonstrated increased odds of intention to screen, which resulted in greater TBI screening adoption ( OR : 0.30; p  < .01). PBC did not affect intentions or adoption. Providers explained that although TBI screening can improve diagnostic and clinical decision-making, they discussed that additional training, leadership engagement, and state-level mandates are needed to increase the widespread, systematic uptake of TBI screening. Conclusions This study advances implementation science by using theory-driven hypothesis testing to disentangle proximal and medial indicators at the provider level on TBI screening adoption. Our mixed-methods approach added in-depth contextualization and illuminated additional multilevel determinants affecting intervention adoption, which guides a more precise selection of implementation strategies.

To evaluate the impact of COVID-19 pandemic exposure on changes in alcohol use and mood from years 1 to 2 after traumatic brain injury (TBI). We used a difference-in-difference (DiD) study design to analyze data from 1,059 individuals with moderate-to-severe TBI enrolled in the TBI Model Systems (TBIMS) National Database. We defined COVID-19 pandemic exposure as participants who received their year 1 post-injury interviews prior to January 1, 2020, and their year 2 interview between April 1, 2020 and January 15, 2021. Pandemic-unexposed participants had both year 1 and 2 follow-up interviews before January 1, 2020. We measured current alcohol use as any past month alcohol use, average number of drinks per drinking occasion, and past month binge drinking. We measured depression symptoms using Patient Health Questionnaire-9, and anxiety symptoms using the Generalized Anxiety Disorder-7. We found persons with TBI exposed to the pandemic had greater increases in the average number of drinks per occasion from year 1 to 2 post-injury compared to pandemic-unexposed individuals (β = 0.36, 95% CI: 0.16, 0.57, p = 0.001), with males, adults <65 years old, and Black and Hispanic subgroups showing the greatest increases in consumption. Though average consumption was elevated, changes in rates of any alcohol use or binge drinking by pandemic exposure were not observed. Overall, there were no significant changes in depressive and anxiety symptoms over time between pandemic exposed and unexposed groups; however, pandemic-exposed Hispanics with TBI reported significant increases in anxiety symptoms from year-1 to year-2 post-injury compared to pandemic-unexposed Hispanics (β = 2.35, 95% CI: 0.25, 4.47, p = 0.028). Among persons living with TBI, those exposed to the pandemic had significant increases in average alcohol consumption. Pandemic-exposed Hispanics with TBI had large elevations in anxiety symptoms, perhaps reflecting health inequities exacerbated by the pandemic, and suggesting a need for targeted monitoring of psychosocial distress.

Serum response factor (SRF) transcriptionally regulates expression of contractile genes in smooth muscle cells (SMC). Lack or decrease of SRF is directly linked to a phenotypic change of SMC, leading to hypomotility of smooth muscle in the gastrointestinal (GI) tract. However, the molecular mechanism behind SRF-induced hypomotility in GI smooth muscle is largely unknown. We describe here how SRF plays a functional role in the regulation of the SMC contractility via myotonic dystrophy protein kinase (DMPK) and L-type calcium channel CACNA1C. GI SMC expressed Dmpk and Cacna1c genes into multiple alternative transcriptional isoforms. Deficiency of SRF in SMC of Srf knockout (KO) mice led to reduction of SRF-dependent DMPK, which down-regulated the expression of CACNA1C. Reduction of CACNA1C in KO SMC not only decreased intracellular Ca2+ spikes but also disrupted their coupling between cells resulting in decreased contractility. The role of SRF in the regulation of SMC phenotype and function provides new insight into how SMC lose their contractility leading to hypomotility in pathophysiological conditions within the GI tract.

Zircon textures and composition have been used to infer magmatic processes including closed-system fractional crystallization, magma mixing or replenishment, and country-rock assimilation. Here, we propose that zircon textures and composition may also be refractory recorders of magmatic volatile evolution. We present field, whole-rock chemical, textural, mineral chemical, and U–Pb age data from evolved, fine-to-coarse-grained granite intrusions on Melville Peninsula, Nunavut, Canada. Zircon forms two main populations in these granites, Type-1 and Type-2 zircon. Type-1 zircon is present in all samples, but predominant in fine-grained granite. Crystals are euhedral and inclusion-rich and show periodic, fine-scale oscillatory zoning, comparatively low concentrations of U (<2,200 ppm) and Hf (<1.6 wt%), high Zr/Hf (~40–62), and pervasive alteration. Type-2 zircon is predominant in coarse-grained granite. Crystals form overgrowths on Type-1 zircon and individual crystals. They are subhedral and inclusion-poor and show weak, irregular, large-scale oscillatory zoning, high U (up to ~7,250 ppm) and Hf (1.5–2.0 wt%), low Zr/Hf (~37–44), and only local alteration. Compatible trace-element concentrations and Zr/Hf change sharply across the boundary of Type-1 to Type-2 zircon; 207 Pb/ 206 Pb ages preclude a significant hiatus between crystallization of the two types. We argue against magmatic versus hydrothermal crystallization, country-rock assimilation, or magma mixing as causes for the crystallization of Type-1 and Type-2 zircon. We propose instead that Type-1 zircon formed from volatile-undersaturated magmas and that Type-2 zircon formed from volatile-saturated magmas. Magmas fractionated by volatile-driven filter pressing into crystal-rich mush and crystal-poor magma. Crystal-rich mush with abundant Type-1 zircon crystallized to fine-grained granite. Volatile-rich magma crystallized to Type-2 zircon and coarse-grained granite. While Type-1 zircon was pervasively altered by exsolving magmatic volatiles, Type-2 zircon was only locally affected by subsolidus hydrothermal alteration.

Volume accommodation occurs via a novel mechanism involving interstitial cells in detrusor muscles. The interstitial cells in the bladder are PDGFRα + , and they restrain the excitability of smooth muscle at low levels and prevents the development of transient contractions (TCs). A common clinical manifestation of spinal cord injury (SCI)-induced bladder dysfunction is detrusor overactivity (DO). Although a myogenic origin of DO after SCI has been suggested, a mechanism for development of SCI-induced DO has not been determined. In this study we hypothesized that SCI-induced DO is related to loss of function in the regulatory mechanism provided by PDGFRα + cells. Our results showed that transcriptional expression of Pdgfra and Kcnn3 was decreased after SCI. Proteins encoded by these genes also decreased after SCI, and a reduction in PDGFRα + cell density was also documented. Loss of PDGFRα + cells was due to apoptosis. TCs in ex vivo bladders during filling increased dramatically after SCI, and this was related to the loss of regulation provided by SK channels, as we observed decreased sensitivity to apamin. These findings show that damage to the mechanism restraining muscle contraction during bladder filling that is provided by PDGFRα + cells is causative in the development of DO after SCI.

Traumatic brain injury (TBI) is a global health priority, associated with substantial burden. Historically conceptualised as an injury event with finite recovery, TBI is now recognised as a chronic condition that can affect multiple domains of health and function, some of which might deteriorate over time. Many people who have had a TBI remain moderately to severely disabled at 5 years, are rehospitalised up to 10 years post-injury, and have a reduced lifespan relative to the general population. Understanding TBI as a chronic disease process can be highly informative for optimising care, which has traditionally focused on acute care. Chronic brain injury care models must be informed by a holistic understanding of long-term outcomes and the factors that can affect how care needs evolve over time. The United States Traumatic Brain Injury Model Systems of Care follows up individuals with moderate-to-severe TBI for over 30 years, allowing characterisation of the chronic (2–30 years or more post injury) functional, cognitive, behavioural, and social sequelae experienced by individuals who have had a moderate-to-severe TBI and the implications for their health and quality of life. Older age, social determinants of health, and lower acute functional status are associated with post-recovery deterioration, while younger age and greater functional independence are associated with risky health behaviours, including substance misuse and re-injury. Systematically collected data on long-term outcomes across multiple domains of health and function are needed worldwide to inform the development of models for chronic disease management, including the proactive surveillance of commonly experienced health and functional challenges.

Abstract A long-held precept is that vitamin D supplementation primarily, if not exclusively, benefits individuals with low circulating 25-hydroxyvitamin D (25[OH]D) concentrations at baseline. However, the most appropriate 25(OH)D threshold to distinguish unacceptably low vs reliably adequate concentrations remains controversial. Such threshold proposals have largely been based on observational studies, which provide less robust evidence compared to randomized clinical trials (RCTs). Since the Endocrine Society's first vitamin D–related guideline was published in 2011, several large vitamin D–related RCTs have been published, and a newly commissioned guideline development panel (GDP) prioritized 4 clinical questions related to the benefits and harms of vitamin D supplementation in generally healthy individuals with 25(OH)D levels below a threshold. The GDP determined that available clinical trial evidence does not permit the establishment of 25(OH)D thresholds that specifically predict meaningful benefit with vitamin D supplementation. The panel noted important limitations in the available evidence, and the panel's overall certainty in the available evidence was very low. Nonetheless, based on the GDP's analyses and judgments, the Endocrine Society no longer endorses its previously proposed definition of vitamin D “sufficiency” (ie, at least 30 ng/mL [75 nmol/L]) or its previously proposed definition of vitamin D “insufficiency” (ie, greater than 20 ng/mL [50 nmol/L] but lower than 30 ng/mL [75 nmol/L]). The Endocrine Society's rationale for such is the subject of this Guideline Communication.

Genetically encoded Ca(2+) indicators (GECIs) have been used extensively in many body systems to detect Ca(2+) transients associated with neuronal activity. Their adoption in enteric neurobiology has been slower, although they offer many advantages in terms of selectivity, signal-to-noise and non-invasiveness. Our aims were to utilize a number of cell-specific promoters to express the Ca(2+) indicator GCaMP3 in different classes of neurons and glia to determine their effectiveness in measuring activity in enteric neural networks during colonic motor behaviors. We bred several GCaMP3 mice: (1) Wnt1-GCaMP3, all enteric neurons and glia; (2) GFAP-GCaMP3, enteric glia; (3) nNOS-GaMP3, enteric nitrergic neurons; and (4) ChAT-GCaMP3, enteric cholinergic neurons. These mice allowed us to study the behavior of the enteric neurons in the intact colon maintained at a physiological temperature, especially during the colonic migrating motor complex (CMMC), using low power Ca(2+) imaging. In this preliminary study, we observed neuronal and glial cell Ca(2+) transients in specific cells in both the myenteric and submucous plexus in all of the transgenic mice variants. The number of cells that could be simultaneously imaged at low power (100-1000 active cells) through the undissected gut required advanced motion tracking and analysis routines. The pattern of Ca(2+) transients in myenteric neurons showed significant differences in response to spontaneous, oral or anal stimulation. Brief anal elongation or mucosal stimulation, which evokes a CMMC, were the most effective stimuli and elicited a powerful synchronized and prolonged burst of Ca(2+) transients in many myenteric neurons, especially when compared with the same neurons during a spontaneous CMMC. In contrast, oral elongation, which normally inhibits CMMCs, appeared to suppress Ca(2+) transients in some of the neurons active during a spontaneous or an anally evoked CMMC. The activity in glial networks appeared to follow neural activity but continued long after neural activity had waned. With these new tools an unprecedented level of detail can be recorded from the enteric nervous system (ENS) with minimal manipulation of tissue. These techniques can be extended in order to better understand the roles of particular enteric neurons and glia during normal and disordered motility.