Abstract Context Although an inverse association between vitamin D status and mortality has been reported in observational studies, the precise association shape and optimal vitamin D status remain undetermined. Objective To investigate the association between vitamin D status and risk of all-cause and cause-specific mortality, and estimate optimal serum 25-hydroxyvitamin D [25(OH)D] concentrations. Design Prospective cohort study. Setting UK Biobank. Participants 365,530 participants who had serum 25(OH)D measurements and no history of cardiovascular disease (CVD), cancer, or diabetes at baseline (2006-2010). Main outcome measures All-cause and cause-specific mortality. Results During a median follow-up of 8.9 (interquartile range: 8.3-9.5) years, 10,175 deaths occurred, including 1841 (18.1%) due to CVD and 5737 (56.4%) due to cancer. The multivariate analyses revealed non-linear inverse associations, with a decrease in mortality risk appearing to level off at 60 nmol/L of 25(OH)D for all-cause and CVD deaths, and at 45 nmol/L for cancer deaths. Compared to participants with 25(OH)D concentrations below the cutoffs, those with higher concentrations had a 17% lower risk for all-cause mortality (HR: 0.83, 95% CI: 0.79-0.86), 23% lower risk for CVD mortality (HR: 0.77, 95% CI: 0.68-0.86), and 11% lower risk for cancer mortality (HR: 0.89, 95% CI: 0.84-0.95). Conclusions Higher 25(OH)D concentrations are non-linearly associated with lower risk of all-cause, CVD, and cancer mortality. The thresholds of 45-60 nmol/L might represent an intervention target to reduce the overall risk of premature death, which needs further confirmation in large clinical trials.

Synapse impairment is associated with post‐traumatic stress disorder (PTSD), which is characterized by enhanced apoptosis in the hippocampus, amygdala, and other brain regions. However, there are no detailed studies on the relationship between apoptosis and synaptic connectivity in PTSD. In this review, we discuss results from various studies describing the synaptic changes observed in the PTSD brain. A decreased number of dendrites/spines or increased number of immature spines in the hippocampus, medial prefrontal cortex, and other brain regions has been reported. Studies on axon guidance, myelination, and the cytoskeleton suggest that PTSD may involve axon overgrowth and overbranching. Apoptosis affects synapse formation; low levels of caspase maintain the balance between growth cone attraction and repulsion and inhibit axon elongation. PTSD enhances neuronal apoptosis through caspase activation, which disrupts the balance between growth cone attraction and repulsion and alters growth cone trajectory, leading to axon mistargeting. Meanwhile, caspase activation induces dendritic pruning and dendrite degeneration. These events contribute to the formation of fewer and aberrant synapses, which is associated with enhanced apoptosis in PTSD.

Postoperative delirium (POD) is a common post‐operative complication in elderly patients that is associated with increased morbidity and mortality. However, the neuropathogenesis of this complication remains unknown. The blood–cerebrospinal fluid barrier (BCB) and brain–blood barrier (BBB) are composed of tight junctions between cells that form physical barriers, and BBB damage plays an important role in the neuropathogenesis of POD. Nevertheless, the role of BCB in POD remains to be elucidated. Herein, we investigated the effect of adenosine A2A receptor (A2AR), a key regulator of the permeability of barriers, on surgery‐induced increased permeability of BCB and POD‐like behaviors. Open field, buried food, and Y maze tests were used to evaluate behavioral changes in rats after surgery. Levels of tight junction proteins, adherens junction proteins, A2AR, GTP‐RhoA, and ROCK2 in the choroid plexus were assessed by western blotting. The concentrations of NaFI and FITC‐dextran in the cerebrospinal fluid (CSF) were detected by fluorescence spectrophotometry. Transmission electron microscopy was applied to observe the ultrastructure of the choroid plexus. Surgery/anesthesia decreased the levels of tight junction (e.g., ZO‐1, occludin, and claudin1) proteins, increased concentrations of NaFI and FITC‐dextran in CSF, damaged the ultrastructure of choroid plexus, and induced POD‐like behaviors in rats. An A2AR antagonist alleviated POD‐like behaviors in rats. Furthermore, the A2AR antagonist increased the levels of tight junction proteins and restored the permeability of BCB in rats with POD. Fasudil, a selective Rho‐associated protein kinase 2 (ROCK2) inhibitor, ameliorated POD‐like behaviors induced by A2AR activation. Moreover, fasudil also abolished the increased levels of GTP‐RhoA/ROCK2, decreased levels of tight junction proteins, and increased permeability of BCB caused by A2AR activation. Our findings demonstrate that A2AR might participate in regulating BCB permeability in rats with POD via the RhoA/ROCK2 signaling pathway, which suggests the potential of A2AR as a therapeutic target for POD.

Background: Insulin-like growth factor 1 (IGF-1) is an important growth factor modulating development, homeostasis, and aging. However, whether and how circulating IGF-1 concentrations influence early death risk in the general population remains largely unknown. Methods: We included 380,997 participants who had serum IGF-1 measurement and no history of cancer, cardiovascular disease (CVD) or diabetes at baseline from UK Biobank, a prospective cohort study initiated in 2006-2010. Restricted cubic splines and Cox proportional hazards regression models were used to assess the association between baseline IGF-1 concentrations and all-cause and cause-specific mortality. Results: Over a median follow-up of 8.8 years, 10,753 of the participants died, including 6110 from cancer and 1949 from CVD. Dose-response analysis showed a U-shaped relationship between IGF-1 levels and mortality. Compared to the fifth decile of IGF-1, the lowest decile was associated with 39% (95% CI: 29%-50%), 20% (95% CI: 8%-34%), and 39% (95% CI: 14%-68%) higher risk of all-cause, cancer, and CVD mortality, respectively, while the highest decile was associated with 17% (95% CI: 7%-28%) and 38% (95% CI: 11%-71%) higher risk of all-cause and CVD mortality, respectively. The results remained stable in detailed stratified and sensitivity analyses. Conclusions: Our findings indicate that both low and high concentrations of serum IGF-1 are associated with increased risk of mortality in the general population. Our study provides a basis for future interrogation of underlying mechanisms of IGF-1 in early death occurrence and possible implications for mitigating the risk.

A promising option as the treatment of choice for premenopausal patients with locally advanced or metastatic breast cancer (MBC) could be the combination of a luteinizing hormone-releasing hormone analog and an aromatase inhibitor. However, no prospective studies on the efficacy of goserelin with exemestane in locally advanced or MBC premenopausal breast cancer patients have been reported.We present the phase II trial of goserelin plus exemestane in a total of 44 premenopausal women with locally advanced or MBC. All patients received a subcutaneous injection of 3.6 mg goserelin every 4 weeks along with 25 mg exemestane daily. The primary end point was progression-free survival (PFS). The second end point included overall survival (OS), objective response rate (ORR), duration of response (DOR), and clinical benefit rate (CBR) based on complete response (CR), partial response (PR), or stable disease (SD) for ≥6 months.The median PFS was 13 months (range: 2–42 months). The median DOR was 8 months (range: 2–40 months). Two patients achieved CR (4.5%), and 15 patients experienced PR (34.1%). Fifteen patients (34.1%) had SD ≥6 months. The ORR was 38.6%, and the CBR was 65.9%. Primary progressive disease occurred in 15 patients (34.1%). Five patients (11.4%) died during the study period. Because a few patients have died, the median OS has not been reached. Drug therapy was well tolerated. The most frequent grade-3 adverse events were arthralgia (18.2%), skin rash (6.8%), and myalgia (4.5%). No participants withdrew from the study due to drug toxicity.This study suggested that goserelin and exemestane might be highly effective and well-tolerated regimens in premenopausal women with hormone-responsive, locally advanced or MBC.