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Major Depressive Disorder (MDD) is a heterogeneous disorder that affects twice as many women than men. Precluding advances in more tailored and efficacious treatments for depression is the lack of reliable biomarkers. While depression is linked to elevations in inflammatory immune system functioning, this relationship is not evident among all individuals with depression and may vary based on symptom subtypes and/or sex. This systematic review and meta-analysis examined whether inflammatory immune peripheral markers of depression are sex-specific. PRISMA guidelines were followed for the systematic review, and a comprehensive search strategy that identified studies from PubMed and PsycInfo was applied. Studies were included if they reported C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor (TNF)-α and/or IL-1ß for males and/or females among depressed and healthy adults. We identified 23 studies that satisfied these inclusion criteria. Random-effects meta-analysis models were fit, and measures of association were summarized between levels of circulating markers of inflammation in depressed and healthy males and females. Sex-based analyses revealed elevated levels of CRP among females with depression (Cohen's d = 0.19) relative to their healthy counterparts (p = 0.02), an effect not apparent among males (Cohen's d = -0.01). Similarly, levels of IL-6 were increased among females with depression compared to healthy controls (Cohen's d = 0.51; p = 0.04), but once again this was not found among males (Cohen's d = 0.16). While TNF-α levels were elevated among individuals with depression compared to controls (p = 0.01), no statistically significant sex differences were found. The meta-analysis for IL-1ß resulted in only three articles, and thus, results are presented in the supplemental section. This meta-analysis advances our understanding of the unique involvement of inflammatory biomarkers in depression among men and women, which may help inform more tailored sex-specific treatment approaches in the future.

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The transmembrane protein known as the mitochondrial calcium uniporter (MCU) mediates the influx of calcium ions (Ca2+) into the mitochondrial matrix. An overload of mitochondrial Ca2+ ( m Ca2+) is directly linked to damaging effects in pathological conditions. Therefore, inhibitors of the MCU are important chemical biology tools and therapeutic agents. Here, two new analogues of previously reported Ru- and Os-based MCU inhibitors Ru265 and Os245, of the general formula [(C10H15CO2)M(NH3)4(µ-N)M(NH3)4(O2CC10H15)](CF3SO3)3, where M = Ru (1) or Os (2), are reported. These analogues bear adamantane functional groups, which were installed to act as guests for the host molecule cucurbit-[7]-uril (CB[7]). These complexes were characterized and analyzed for their efficiency as guests for CB[7]. As shown through a variety of spectroscopic techniques, each adamantane ligand is encapsulated into one CB[7], affording a supramolecular complex of 1 : 2 stoichiometry. The biological effects of these compounds in the presence and absence of two equiv. CB[7] were assessed. Both complexes 1 and 2 exhibit enhanced cellular uptake compared to the parent compounds Ru265 and Os245, and their uptake is increased further in the presence of CB[7]. Compared to Ru265 and Os245, 1 and 2 are less potent as m Ca2+ uptake inhibitors in permeabilized cell models. However, in intact cell systems, 1 and 2 inhibit the MCU at concentrations as low as 1 µM, marking an advantage over Ru265 and Os245 which require an order of magnitude higher doses for similar biological effects. The presence of CB[7] did not affect the inhibitory properties of 1 and 2. Experiments in primary cortical neurons showed that 1 and 2 can elicit protective effects against oxygen-glucose deprivation at lower doses than those required for Ru265 or Os245. At low concentrations, the protective effects of 1 were modulated by CB[7], suggesting that supramolecular complex formation can play a role in these biological conditions. The in vivo biocompatibility of 1 was investigated in mice. The intraperitoneal administration of these compounds and their CB[7] complexes led to time-dependent induction of seizures with no protective effects elicited by CB[7]. This work demonstrates the potential for supramolecular interactions in the development of MCU inhibitors.

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Anthropogenic (man-made) noise constitutes a novel and widespread pollutant which is increasing in prevalence in terrestrial and aquatic ecosystems, resulting in alterations of natural soundscapes. There is proliferating evidence that noise leads to maladaptive behaviour in wildlife, yet few studies have addressed the effect on mammalian parent-offspring interactions. We investigated the impact of road noise on dwarf mongoose (Helogale parvula) offspring nearest-neighbour decision-making while foraging, using a field-based playback experiment. We predicted that offspring would forage closer to groupmates, especially adult and dominant individuals, when experiencing road noise compared with ambient sound to reduce communication masking and alleviate stress. We also predicted that noise would have a reduced effect with increasing offspring age owing to reduced reliance on adult groupmates for provisioning and predator defence. However, we found that mean nearest-neighbour distance and nearest-neighbour intrinsic characteristics (age, sex and dominance status) did not differ significantly between sound treatments, and these responses did not vary significantly with focal individual age. Noise may not impact nearest-neighbour decision-making owing to habituation from chronic natural exposure; alternatively, noise could induce stress and distraction, resulting in maladaptive decision-making. Future work should aim to detangle the underlying mechanisms mediating parent-offspring interactions in conditions of anthropogenic noise.

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BACKGROUND AND AIMS: Pathogenic desmoplakin (DSP) gene variants are associated with the development of a distinct form of arrhythmogenic cardiomyopathy known as DSP cardiomyopathy. Patients harbouring these variants are at high risk for sustained ventricular arrhythmia (VA), but existing tools for individualized arrhythmic risk assessment have proven unreliable in this population. METHODS: Patients from the multi-national DSP-ERADOS (Desmoplakin SPecific Effort for a RAre Disease Outcome Study) Network patient registry who had pathogenic or likely pathogenic DSP variants and no sustained VA prior to enrolment were followed longitudinally for the development of first sustained VA event. Clinically guided, step-wise Cox regression analysis was used to develop a novel clinical tool predicting the development of incident VA. Model performance was assessed by c-statistic in both the model development cohort (n = 385) and in an external validation cohort (n = 86). RESULTS: In total, 471 DSP patients [mean age 37.8 years, 65.6% women, 38.6% probands, 26% with left ventricular ejection fraction (LVEF) < 50%] were followed for a median of 4.0 (interquartile range: 1.6-7.3) years; 71 experienced first sustained VA events {2.6% [95% confidence interval (CI): 2.0, 3.5] events/year}. Within the development cohort, five readily available clinical parameters were identified as independent predictors of VA and included in a novel DSP risk score: female sex [hazard ratio (HR) 1.9 (95% CI: 1.1-3.4)], history of non-sustained ventricular tachycardia [HR 1.7 (95% CI: 1.1-2.8)], natural logarithm of 24-h premature ventricular contraction burden [HR 1.3 (95% CI: 1.1-1.4)], LVEF < 50% [HR 1.5 (95% CI: .95-2.5)], and presence of moderate to severe right ventricular systolic dysfunction [HR 6.0 (95% CI: 2.9-12.5)]. The model demonstrated good risk discrimination within both the development [c-statistic .782 (95% CI: .77-.80)] and external validation [c-statistic .791 (95% CI: .75-.83)] cohorts. The negative predictive value for DSP patients in the external validation cohort deemed to be at low risk for VA (<5% at 5 years; n = 26) was 100%. CONCLUSIONS: The DSP risk score is a novel model that leverages readily available clinical parameters to provide individualized VA risk assessment for DSP patients. This tool may help guide decision-making for primary prevention implantable cardioverter-defibrillator placement in this high-risk population and supports a gene-first risk stratification approach.

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The B cell receptor (BCR) signals together with a multi-component co-receptor complex to initiate B cell activation in response to antigen binding. Here, we take advantage of peroxidase-catalyzed proximity labeling combined with quantitative mass spectrometry to track co-receptor signaling dynamics in Raji cells from 10 s to 2 h after BCR stimulation. This approach enables tracking of 2,814 proximity-labeled proteins and 1,394 phosphosites and provides an unbiased and quantitative molecular map of proteins recruited to the vicinity of CD19, the signaling subunit of the co-receptor complex. We detail the recruitment kinetics of signaling effectors to CD19 and identify previously uncharacterized mediators of B cell activation. We show that the glutamate transporter SLC1A1 is responsible for mediating rapid metabolic reprogramming and for maintaining redox homeostasis during B cell activation. This study provides a comprehensive map of BCR signaling and a rich resource for uncovering the complex signaling networks that regulate activation.

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Neuroinflammation is a pathological feature of many neurodegenerative diseases, including Alzheimer's disease (AD)1,2 and amyotrophic lateral sclerosis (ALS)3, raising the possibility of common therapeutic targets. We previously established that cytoplasmic double-stranded RNA (cdsRNA) is spatially coincident with cytoplasmic pTDP-43 inclusions in neurons of patients with C9ORF72-mediated ALS4. CdsRNA triggers a type-I interferon (IFN-I)-based innate immune response in human neural cells, resulting in their death4. Here, we report that cdsRNA is also spatially coincident with pTDP-43 cytoplasmic inclusions in brain cells of patients with AD pathology and that type-I interferon response genes are significantly upregulated in brain regions affected by AD. We updated our machine-learning pipeline DRIAD-SP (Drug Repurposing In Alzheimer's Disease with Systems Pharmacology) to incorporate cryptic exon (CE) detection as a proxy of pTDP-43 inclusions and demonstrated that the FDA-approved JAK inhibitors baricitinib and ruxolitinib that block interferon signaling show a protective signal only in cortical brain regions expressing multiple CEs. Furthermore, the JAK family member TYK2 was a top hit in a CRISPR screen of cdsRNA-mediated death in differentiated human neural cells. The selective TYK2 inhibitor deucravacitinib, an FDA-approved drug for psoriasis, rescued toxicity elicited by cdsRNA. Finally, we identified CCL2, CXCL10, and IL-6 as candidate predictive biomarkers for cdsRNA-related neurodegenerative diseases. Together, we find parallel neuroinflammatory mechanisms between TDP-43 associated-AD and ALS and nominate TYK2 as a possible disease-modifying target of these incurable neurodegenerative diseases.

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BACKGROUND AND PURPOSE: Excitotoxicity due to mitochondrial calcium (Ca2+) overloading can trigger neuronal cell death in a variety of pathologies. Inhibiting the mitochondrial calcium uniporter (MCU) has been proposed as a therapeutic avenue to prevent calcium overloading. Ru265 (ClRu(NH3)4(µ-N)Ru(NH3)4Cl]Cl3) is a cell-permeable inhibitor of the mitochondrial calcium uniporter (MCU) with nanomolar affinity. Ru265 reduces sensorimotor deficits and neuronal death in models of ischemic stroke. However, the therapeutic use of Ru265 is limited by the induction of seizure-like behaviours. EXPERIMENTAL APPROACH: We examined the effect of Ru265 on synaptic and neuronal function in acute brain slices and hippocampal neuron cultures derived from mice, in control and where MCU expression was genetically abrogated. KEY RESULTS: Ru265 decreased evoked responses from calyx terminals and induced spontaneous action potential firing of both the terminal and postsynaptic principal cell. Recordings of presynaptic Ca2+ currents suggested that Ru265 blocks the P/Q type channel, confirmed by the inhibition of currents in cells exogenously expressing the P/Q type channel. Measurements of presynaptic K+ currents further revealed that Ru265 blocked a KCNQ current, leading to increased membrane excitability, underlying spontaneous spiking. Ca2+ imaging of hippocampal neurons showed that Ru265 increased synchronized, high-amplitude events, recapitulating seizure-like activity seen in vivo. Importantly, MCU ablation did not suppress Ru265-induced increases in neuronal activity and seizures. CONCLUSIONS AND IMPLICATIONS: Our findings provide a mechanistic explanation for the pro-convulsant effects of Ru265 and suggest counter screening assays based on the measurement of P/Q and KCNQ channel currents to identify safe MCU inhibitors.

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BACKGROUND: As more pediatric patients become candidates for heart transplantation (HT), understanding pathological predictors of outcome and the accuracy of the pretransplantation evaluation are important to optimize utilization of scarce donor organs and improve outcomes. The authors aimed to investigate explanted heart specimens to identify pathologic predictors that may affect cardiac allograft survival after HT. METHODS: Explanted pediatric hearts obtained over an 11-year period were analyzed to understand the patient demographics, indications for transplant, and the clinical-pathological factors. RESULTS: In this study, 149 explanted hearts, 46% congenital heart defects (CHD), were studied. CHD patients were younger and mean pulmonary artery pressure and resistance were significantly lower than in cardiomyopathy patients. Twenty-one died or underwent retransplantation (14.1%). Survival was significantly higher in the cardiomyopathy group at all follow-up intervals. There were more deaths and the 1-, 5- and 7-year survival was lower in patients ≤10 years of age at HT. Early rejection was significantly higher in CHD patients exposed to homograft tissue, but not late rejection. Mortality/retransplantation rate was significantly higher and allograft survival lower in CHD hearts with excessive fibrosis of one or both ventricles. Anatomic diagnosis at pathologic examination differed from the clinical diagnosis in eight cases. CONCLUSIONS: Survival was better for the cardiomyopathy group and patients >10 years at HT. Prior homograft use was associated with a higher prevalence of early rejection. Ventricular fibrosis (of explant) was a strong predictor of outcome in the CHD group. We presented several pathologic findings in explanted pediatric hearts.

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The monthly search volumes for drought were extracted from Google® for South Africa using the Keywordsevery-where.com plugin from January 2004 until June 2022. To identify the potential qualitative drivers for such public interest the following data extracted by the plugin were investigated and analysed: the drought-related keywords, the long-tail keywords similar to drought, and the "people also searched for category" from the South African users. The Google Trends monthly score was extracted for South Africa and the Eastern Cape Province, and specific local municipalities/towns/cities in the province. The aim was to assess the relative significance of the drought interest in comparison to public interest in other search terms. The results of the Kruskal-Wallis analyses of variance by ranks showed that there was a statistically significant difference between individual values of the monthly search volumes for drought in South Africa, as a function of time of data extraction (5 percent level of significance; p-value ≤ 4.7 × 10-14). The monthly search volumes increased with time, which is based on the results of the Mann-Kendall test at a 5 percent level of significance (p-value ≤ 0.0092). Analyses of the Google Trends scores indicate that the relative interest in drought in South Africa and the Eastern Cape Province increased with time between January 2004 and June 2022 (the Mann-Kendall test at a 5 percent level of significance; p-value = 0.0011). The population's searches for drought were relatively low when compared to other search terms on Google. Drought adaptation of the South African community could be considered a driver of the Google searches for drought, but it is a marginal topic compared to other topics in Google searches. It might be necessary to increase this significance by investigating the "Google-search patterns for droughts" in the areas of Tshikaro, Mafusini, Cofimvaba, and Nxotsheni in the Eastern Cape Province of South Africa.

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This study aimed to assess the association between the oral microbiome, age, and frailty. Data and saliva samples were obtained from male and female participants aged 35-70 years (n = 1357). Saliva samples were analysed by 16S rRNA gene sequencing and differences in microbial diversity and community compositions were examined in relation to chronological age and the frailty index (FI). Most alpha diversity measures (Richness, Shannon Diversity, Faith's Phylogenetic Diversity) showed an inverse association with frailty, whereas a positive association was observed with age and Shannon Diversity and Evenness. A further sex-stratified analysis revealed differences in measures of microbial diversity and composition. Multiple genera were detected as significantly differentially abundant with increasing frailty and age by at least two methods. With age, the relative abundance of Veillonella was reduced in both males and females, whereas increases in Corynebacterium appeared specific to males and Aggregatibacter, Fusobacterium, Neisseria, Stomatobaculum, and Porphyromonas specific to females. Beta diversity was significantly associated with multiple mental health components of the FI. This study shows age and frailty are differentially associated with measures of microbial diversity and composition, suggesting the oral microbiome may be a useful indicator of increased risk of frailty or a potential target for improving health in ageing adults.

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BACKGROUND: National estimates of the prevalence of vision impairment and blindness in people with diabetes are required to inform resource allocation. People with diabetes are more susceptible to conditions such as diabetic retinopathy that can impair vision; however, these are often missed in national studies. This study aims to determine the prevalence and risk factors of vision impairment and blindness in people with diabetes in India. METHODS: Data from the SMART-India study, a cross-sectional survey with national coverage of 42 147 Indian adults aged 40 years and older, collected using a complex sampling design, were used to obtain nationally representative estimates for the prevalence of vision impairment and blindness in people with diabetes in India. Vulnerable adults (primarily those who did not have capacity to provide consent); pregnant and breastfeeding women; anyone deemed too ill to be screened; those who did not provide consent; and people with type 1 diabetes, gestational diabetes, or secondary diabetes were excluded from the study. Vision impairment was defined as presenting visual acuity of 0·4 logMAR or higher and blindness as presenting a visual acuity of 1·0 logMAR or higher in the better-seeing eye. Demographic, anthropometric, and laboratory data along with geographic distribution were analysed in all participants with available data. Non-mydriatic retinal images were used to grade diabetic retinopathy, and risk factors were also assessed. FINDINGS: A total of 7910 people with diabetes were included in the analysis, of whom 5689 had known diabetes and 2221 were undiagnosed. 4387 (55·5%) of 7909 participants with available sex data were female and 3522 (44·5%) participants were male. The estimated national prevalence of vision impairment was 21·1% (95% CI 15·7-27·7) and blindness 2·4% (1·7-3·4). A higher prevalence of any vision impairment (29·2% vs 19·6%; p=0·016) and blindness (6·7% vs 1·6%; p<0·0001) was observed in those with ungradable images. In known diabetes, diabetic retinopathy (adjusted odds ratio [aOR] 3·06 [95% CI 1·25-7·51]), vision-threatening diabetic retinopathy (aOR 7·21 [3·52-14·75]), and diabetic macular oedema (aOR 5·41 [2·20-13·33]) were associated with blindness in adjusted analysis. Common sociodemographic risk factors for vision impairment and blindness include older age, lower educational attainment, and unemployment. INTERPRETATION: Based on the estimated 101 million people with diabetes in 2021 and the interpretation of the data from this study, approximately 21 million people with diabetes have vision impairment in India, of whom 2·4 million are blind. Higher prevalence is observed in those from lower socio-economic strata and policy makers should focus on these groups to reduce inequalities in health care. FUNDING: Global Challenge Research Fund of United Kingdom Research and Innovation through the Medical Research Council.

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Hydroxyproline-rich glycoproteins (HRGPs) are a ubiquitous class of protein in the extracellular matrices and cell walls of plants and algae, yet little is known of their native structures or interactions. Here, we used electron cryomicroscopy (cryo-EM) to determine the structure of the hydroxyproline-rich mastigoneme, an extracellular filament isolated from the cilia of the alga Chlamydomonas reinhardtii. The structure demonstrates that mastigonemes are formed from two HRGPs (a filament of MST1 wrapped around a single copy of MST3) that both have hyperglycosylated poly(hydroxyproline) helices. Within the helices, O-linked glycosylation of the hydroxyproline residues and O-galactosylation of interspersed serine residues create a carbohydrate casing. Analysis of the associated glycans reveals how the pattern of hydroxyproline repetition determines the type and extent of glycosylation. MST3 possesses a PKD2-like transmembrane domain that forms a heteromeric polycystin-like cation channel with PKD2 and SIP, explaining how mastigonemes are tethered to ciliary membranes.

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PURPOSE: This review synthesised the evidence for the effect of prehabilitation interventions on biopsychosocial and service outcomes. MATERIALS AND METHODS: A systematic review was conducted. 10 databases were searched to December 2023. Prospective experimental studies exploring prehabilitation interventions in adults undergoing upper gastrointestinal surgery were included. Prehabilitation was any preoperative intervention to improve physical or psychological outcomes. Included studies required a comparator group or alternative preoperative intervention as well as baseline, presurgical and postoperative assessment points. Study quality was assessed using the Cochrane risk of bias tool (v.2). Data synthesis was narrative (SWiM guidance). RESULTS: 6028 studies were screened, with 25 studies included. Prehabilitation interventions were: inspiratory muscle training (five studies n = 450); exercise (nine studies n = 683); psychological (one study n = 400); and nutritional (ten studies n = 487). High quality studies showed preoperative improvements in impairments directly targeted by the interventions. Generally, these did not translate into functional or postoperative improvements, but multimodal interventions were more promising. CONCLUSION: Current evidence supports prehabilitation as safe to preserve or improve preoperative function. Heterogeneity in outcomes and variable study quality means definitive conclusions regarding interventions are not yet possible, limiting implementation. Agreement of clinical outcomes and cost effectiveness evaluation is required.

Prehabilitation interventions are safe and when combined optimally may preserve or improve preoperative function in patients undergoing upper gastrointestinal surgery.Multimodal interventions (including exercise, nutritional, and psychological components) showed promise which supports the delivery of prehabilitation by multidisciplinary teams.Development of a core outcome set and agreed time points for both preoperative and postoperative outcomes is needed for effective evidence synthesis.Focus on long term outcomes is necessary to determine cost effectiveness and commissioning of resources.

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Introduction: Undergraduate university students experienced many academic and non-academic stressors during the first year of the coronavirus (COVID-19) pandemic, putting them at a greater risk of negative mental health outcomes. Reports worldwide have shown high incidences of depressive, anxiety, and stress scores among university students at the beginning of the pandemic. Emerging evidence also suggests that to cope with the stress and loneliness of the pandemic, many youth and young adults increased the amount of time they spent on social media platforms. Methods: Undergraduate students participated in an online study aimed to understand the link between time spent on social media, coping through the use of social media and problematic social media use (PSMU) with mental health symptoms, such as stress, depression, anxiety, and loneliness, during the COVID-19 pandemic. Results: While time spent on social media was only weakly associated with stress, depression, anxiety and loneliness scores, PSMU more strongly mapped onto these outcomes. Additionally, students who were coping highly using social media displayed elevated stress, depression, anxiety and loneliness levels in comparison to those reporting low levels of coping with social media. Finally, students who reported high levels of coping using social media displayed higher PSMU scores, with this relationship appearing more pronounced in students who had higher levels of loneliness. Conclusion: These data support evidence that it is not necessarily time spent on social media but rather PSMU that is relevant for mental health symptoms, and that PSMU is exacerbated by loneliness. Moreover, the current results highlight the effects of maladaptive coping on mental health symptoms and PSMU among university students during the COVID-19 pandemic.

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The use of reduced-intensity conditioning (RIC) regimens has increased in an effort to minimize hematopoietic stem cell transplantation (HCT) end-organ toxicity, including gonadal toxicity. We aimed to describe the incidence of fertility potential and gonadal function impairment in adolescent and young adult survivors of HCT and to identify risk factors (including conditioning intensity) for impairment. We performed a multi-institutional, international retrospective cohort study of patients age 10 to 40 years who underwent first allogeneic HCT before December 1, 2019, and who were alive, in remission, and available for follow-up at 1 to 2 years post-HCT. For females, an AMH level of ≥.5 ng/mL defined preserved fertility potential; an AMH level of ≥.03 ng/mL was considered detectable. Gonadal failure was defined for females as an elevated follicle-stimulating hormone (FSH) level >30 mIU/mL with an estradiol (E2) level <17 pg/mL or current use of hormone replacement therapy (regardless of specific indication or intent). For males, gonadal failure was defined as an FSH level >10.4 mIU/mL or current use of hormone replacement therapy. A total of 326 patients (147 females) were available for analysis from 17 programs (13 pediatric, 4 adult). At 1 to 2 years post-HCT, 114 females (77.6%) had available FSH and E2 levels and 71 (48.3%) had available AMH levels. FSH levels were reported for 125 males (69.8%). Nearly all female HCT recipients had very low levels of AMH. One of 45 (2.2%) recipients of myeloablative conditioning (MAC) and four of 26 (15.4%) recipients of reduced-intensity conditioning (RIC) (P = .06) had an AMH ≥.5 ng/m, and 8 of 45 MAC recipients (17.8%) and 12 of 26 RIC recipients (46.2%) (P = .015) had a detectable AMH level. Total body irradiation (TBI) dose and cyclophosphamide equivalent dose (CED) were not associated with detectable AMH. The incidence of female gonadal hormone failure was 55.3%. In univariate analysis, older age at HCT was associated with greater likelihood of gonadal failure (median age, 17.6 versus 13.9; P < .0001), whereas conditioning intensity (RIC versus MAC), TBI, chronic graft-versus-host disease requiring systemic therapy, and CED were not significantly associated with gonadal function. In multivariable analysis, age remained statistically significant (odds ratio [OR]. 1.11; 95% confidence interval [CI], 1.03 to 1.22) for each year increase; P = .012), Forty-four percent of the males had gonadal failure. In univariate analysis, older age (median, 16.2 years versus 14.4 years; P = .0005) and TBI dose (P = .002) were both associated with gonadal failure, whereas conditioning intensity (RIC versus MAC; P = .06) and CED (P = .07) were not statistically significant. In multivariable analysis, age (OR, 1.16; 95% CI, 1.06-1.27 for each year increase; P = .0016) and TBI ≥600 cGy (OR, 6.23; 95% CI, 2.21 to 19.15; P = .0008) remained significantly associated with gonadal failure. Our data indicate that RIC does not significantly mitigate the risk for gonadal failure in females or males. Age at HCT and (specifically in males) TBI use seem to be independent predictors of post-transplantation gonadal function and fertility status. All patients should receive pre-HCT infertility counseling and be offered appropriate fertility preservation options and be screened post-HCT for gonadal failure.

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BACKGROUND: The complex neurobiology of posttraumatic stress disorder (PTSD) calls for the characterization of specific disruptions in brain functions that require targeted treatment. One such alteration could be an overactive locus coeruleus (LC)-norepinephrine system, which may be linked to hyperarousal symptoms, a characteristic and burdensome aspect of the disorder. METHODS: Study participants were Canadian Armed Forces veterans with PTSD related to deployment to combat zones (n = 34) and age- and sex-matched healthy control participants (n = 32). Clinical measures included the Clinician-Administered PTSD Scale for DSM-5, and neuroimaging measures included a neuromelanin-sensitive magnetic resonance imaging scan to measure the LC signal. Robust linear regression analyses related the LC signal to clinical measures. RESULTS: Compared with control participants, the LC signal was significantly elevated in the PTSD group (t62 = 2.64, p = .010), and this group difference was most pronounced in the caudal LC (t56 = 2.70, Cohen's d = 0.72). The caudal LC signal was also positively correlated with the severity of Clinician-Administered PTSD Scale for DSM-5 hyperarousal symptoms in the PTSD group (t26 = 2.16, p = .040). CONCLUSIONS: These findings are consistent with a growing body of evidence indicative of elevated LC-norepinephrine system function in PTSD. Furthermore, they indicate the promise of neuromelanin-sensitive magnetic resonance imaging as a noninvasive method to probe the LC-norepinephrine system that has the potential to support subtyping and treatment of PTSD or other neuropsychiatric conditions.

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BACKGROUND: Focal hyperintense lesions within the navicular bursa emanating from the dorsal border of the deep digital flexor tendon (DDFT) can be recognised on T1-weighted magnetic resonance images (MRI) and have been attributed to lameness in horses. Removal of these lesions, also referred to as synovial masses, by navicular bursoscopy is currently recommended. OBJECTIVES: To investigate the correlation between MRI and navicular bursoscopic findings. It is hypothesised that the prognosis following surgery is proportional to the size of the DDFT lesion. STUDY DESIGN: Retrospective analysis of clinical records. METHODS: Horses undergoing standing low-field MRI and navicular bursoscopy with >1 year follow-up were included. A grading system was developed to classify the size of synovial mass(es) and lesion(s) of the DDFT on MRI and at surgery. Generalised estimating equations were used to evaluate the association between MRI findings and surgery and between outcome and severity of the tendon injury. RESULTS: Fifty-nine horses presenting over a 15-year period (2006-2021) fulfilled inclusion criteria. Ninety navicular bursae were examined both on MRI and endoscopically. There was strong correlation between the size of synovial masses and tendon lesions on MRI and bursoscopy (p < 0.001, OR: 25.61, 95% CI 8.71-75.29 and p < 0.001, OR: 7.34, 95% CI 2.70-19.92, respectively). Size of tendon lesion and synovial mass had no impact on prognosis (p = 0.3, OR: 1, 95% CI 1-1 and p = 0.1, OR: 1, 95% CI 1-1, respectively), which was guarded (30.5% return to previous level of exercise). MAIN LIMITATIONS: Performance data for conservatively treated horses with MRI-detected synovial masses was not considered, nor was the effect of navicular bursal effusion. Horses were not randomly assigned to treatment protocols. CONCLUSION: There is good correlation between MRI and bursoscopic findings of DDFT lesions and synovial masses within the navicular bursa, with no false positives. Size of the synovial masses and DDFT lesions does not influence prognosis following navicular bursoscopy.

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