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Suicide accounts for800,000 deaths annually worldwide; prevention is an urgent public health issue. Identification of risk factors remains challenging due to complexity and heterogeneity. The study of suicide deaths with increased extended familial risk provides an avenue to reduce etiological heterogeneity and explore traits associated with increased genetic liability. Using extensive genealogical records, we identified high-risk families where distant relatedness of suicides implicates genetic risk. We compared phenotypic and polygenic risk score (PRS) data between suicides in high-risk extended families (high familial risk (HFR), n = 1,634), suicides linked to genealogical data not in any high-risk families (low familial risk (LFR), n = 147), and suicides not linked to genealogical data with unknown familial risk (UFR, n = 1,865). HFR suicides were associated with lower age at death (mean = 39.34 years), more suicide attempts, and more PTSD and trauma diagnoses. For PRS tests, we included only suicides with90% European ancestry and adjusted for residual ancestry effects. HFR suicides showed markedly higher PRS of suicide death (calculated using cross-validation), supporting specific elevation of genetic risk of suicide in this subgroup, and also showed increased PRS of PTSD, suicide attempt, and risk taking. LFR suicides were substantially older at death (mean = 49.10 years), had fewer psychiatric diagnoses of depression and pain, and significantly lower PRS of depression. Results suggest extended familiality and trauma/PTSD may provide specificity in identifying individuals at genetic risk for suicide death, especially among younger ages, and that LFR of suicide warrants further study regarding the contribution of demographic and medical risks.

Approximately 5% of individuals with schizophrenia die from suicide. However, suicide in psychosis is still poorly characterized, partly due to a lack of adequate population-based clinical or genetic data on suicide death. The Utah Suicide Genetics Research Study (USGRS) provides a large population-based cohort of suicide deaths with medical record and genome-wide data (N = 4380). Examination of this cohort identified medical and genetic risks associated with type of suicide death and investigated the relative contributions of psychotic and affective symptoms to method of suicide. Key differences in method of suicide (common vs. atypical methods) were tested in relation to lifetime psychosis and genome-wide genetic risk for schizophrenia, major depressive disorder, and neuroticism. Consistent with previous studies, psychosis-spectrum disorders were observed to be common in suicide (15% of the cohort). Individuals with psychosis more frequently died from atypical methods, with rates of atypical suicide increasing across the schizophrenia spectrum. Genetic risk for schizophrenia was also associated with atypical suicide, regardless of clinical diagnosis, though this association weakened when filtering individuals with schizophrenia from the analysis. Follow-up examination indicated that high rates of atypical suicide observed in schizophrenia are not likely accounted for by restricted access to firearms. Overall, better accounting for the increased risk of atypical suicide methods in psychosis could lead to improved prevention strategies in a large portion of the suicide risk population.

Introduction Acute-on-chronic liver failure (ACLF) patients are susceptible to invasive fungal infections. We evaluated the prognosis and antifungal options in ACLF patients with invasive pulmonary aspergillosis (IPA). Methods ACLF patients with IPA from 15 hospitals were retrospectively screened from 2011 to 2018, and 383 ACLF patients without lung infections were included from a prospective cohort (NCT02457637). Demographic, laboratory, clinical data, and 28-day outcomes were documented in the two cohorts. Results ACLF patients with probable IPA (n = 145) had greater 28-day mortality (33.6% vs. 15.7%, p

BackgroundThe degree to which suicide risk aggregates in US families is unknown. The authors aimed to determine the familial risk of suicide in Utah, and tested whether familial risk varies based on the characteristics of the suicides and their relatives.MethodsA population-based sample of 12 160 suicides from 1904 to 2014 were identified from the Utah Population Database and matched 1:5 to controls based on sex and age using at-risk sampling. All first through third- and fifth-degree relatives of suicide probands and controls were identified (N = 13 480 122). The familial risk of suicide was estimated based on hazard ratios (HR) from an unsupervised Cox regression model in a unified framework. Moderation by sex of the proband or relative and age of the proband at time of suicide (v. ⩾25 years) was examined.ResultsSignificantly elevated HRs were observed in first- (HR 3.45; 95% CI 3.12–3.82) through fifth-degree relatives (HR 1.07; 95% CI 1.02–1.12) of suicide probands. Among first-degree relatives of female suicide probands, the HR of suicide was 6.99 (95% CI 3.99–12.25) in mothers, 6.39 in sisters (95% CI 3.78–10.82), and 5.65 (95% CI 3.38–9.44) in daughters. The HR in first-degree relatives of suicide probands under 25 years at death was 4.29 (95% CI 3.49–5.26).ConclusionsElevated familial suicide risk in relatives of female and younger suicide probands suggests that there are unique risk groups to which prevention efforts should be directed – namely suicidal young adults and women with a strong family history of suicide.

Identification of genetic factors leading to increased risk of suicide death is critical to combat rising suicide rates, however, only a fraction of the genetic variation influencing risk has been accounted for. To address this limitation, we conducted the first comprehensive analysis of rare genetic variation in suicide death leveraging the largest suicide death biobank, the Utah Suicide Genetic Risk Study (USGRS). We conducted a single-variant association analysis of rare (minor allele frequency

Background Hospital-acquired pressure injuries disproportionately affect critical care patients. Although risk factors such as moisture, illness severity, and inadequate perfusion have been recognized, nursing skin assessment data remain unexamined in relation to the risk for hospital-acquired pressure injuries. Objective To identify factors associated with hospital-acquired pressure injuries among surgical critical care patients. The specific aim was to analyze data obtained from routine nursing skin assessments alongside other potential risk factors identified in the literature. Methods This retrospective cohort study included 5101 surgical critical care patients at a level I trauma center and academic medical center. Multivariate logistic regression using the least absolute shrinkage and selection operator method identified important predictors with parsimonious representation. Use of specialty pressure redistribution beds was included in the model as a known predictive factor because specialty beds are a common preventive intervention. Results Independent risk factors identified by logistic regression were skin irritation (rash or diffuse, nonlocalized redness) (odds ratio, 1.788; 95% CI, 1.404-2.274; P < .001), minimum Braden Scale score (odds ratio, 0.858; 95% CI, 0.818-0.899; P < .001), and duration of intensive care unit stay before the hospital-acquired pressure injury developed (odds ratio, 1.003; 95% CI, 1.003-1.004; P < .001). Conclusions The strongest predictor was irritated skin, a potentially modifiable risk factor. Irritated skin should be treated and closely monitored, and the cause should be eliminated to allow the skin to heal.

Purpose To evaluate and compare postoperative pain following photorefractive keratectomy (PRK) in patients using a preventive regimen of oral versus topical nonsteroidal anti-inflammatory drugs (NSAIDs). Patients and Methods A prospective, randomized, longitudinal survey of postoperative PRK pain was performed on 157 subjects in a tertiary academic medical center setting. Patients were randomized to either topical ketorolac 0.4% every 12 hours or oral naproxen sodium 220 mg every 12 hours for 72 hours following PRK, beginning at the time of surgery. The primary outcome measure was the daily peak pain score from the validated numerical rating scale (NRS) for five days after surgery. Results The peak pain scores were significantly higher in the oral NSAID group (mean 5.82, SD 1.94) compared to the topical NSAID group (mean 4.2, SD 2.19) (p

Background: Trace elements status plays an important role in the health of pregnant women and in the healthy development of their offspring. Recent evidence showed that associate between trace element levels in mid-and late-pregnancy and congenital heart defects (CHDs) in offspring. The primary purpose of this study is to evaluate the associations between concentrations of copper (Cu), zinc (Zn), calcium (Ca), manganese (Mg), iron (Fe), lead (Pb) and cadmium (Cd) in maternal blood during early pregnancy and CHDs in offspring. Methods: This hospital-based, case–control study included 181 cases and 218 controls from Shaanxi, China. Eligible pregnant women underwent routine prenatal examinations in the hospital. Maternal elbow venous blood draws were performed during gestational weeks 11-14 and were used to detect the levels of Cu, Zn, Ca, Mg, Fe, Pb, and Cd by the atomic absorption method. Multivariable logistic regression was used to evaluate the associations of each of the seven elements with risk for overall CHDs and patent ductus arteriosus (PDA)/atrial septal defect (ASD)/ventricular septal defect (VSD) subtypes, adjusted for maternal age, parity, pregnancy complications, gestational age at birth weeks. We also conducted non-linear associations using restricted cubic spline models.Results: The median maternal blood levels of Zn, Fe, Pb and Cd of during early pregnancy in foetuses with the PDA/ASD/VSD subtypes were significantly different from those in the control group (all p < 0.001). The levels of Fe [OR, 3.684 (1.437); OR, 4.917 (1.786)] and Pb [OR, 1.026 (0.009); OR, 1.027 (0.008)] and Cd [OR, 1.643 (0.468); OR, 1.855 (0.503)], were associated with an increased risk for PDA/ASD/VSD subtypes, and that of Zn [OR, 0.944 (0.017); OR, 0.947(0.015)] was associated with a decreased risk. We observed non-linear dose–response associations between the levels of Fe, Pb, and Zn and the risk of PDA/ASD/VSD subtypes. Conclusions: This exploratory study determined that the levels of Pb during early pregnancy are associated with overall CHDs as well as ASD/VSD/PDA subtypes, however high Pb and Cd was associate with high risk of ASD/VSD/PDA subtypes, further confirming that there was is a nonlinear correlation.

Rhaponticum carthamoides (Willd.) Iljin (Rha) is a member of the family Compositae that is widely used in folk medicine as a dietary supplement to treat cardiovascular diseases (CVDs), such as senile cardiac insufficiency, and to restore myocardial function after surgery. Sirtuin 6 (SIRT6), an NADThis study aimed to explore the therapeutic potential of Rha against myocardial injury as well as its underlying mechanisms in vivo and in vitro.A myocardial ischaemia model was established in male SD rats by subcutaneously injecting ISO. The rats were gavaged with Rha (40, 80, 160 mg/kg) or Rho (6 ml/kg) for 14 successive days and then injected subcutaneously with ISO or saline solution on the 13th and 14th days. The positive effects of Rha against myocardial injury in rats were evaluated by ECG assessment, BP measurements, HE staining, and myocardial enzyme detection. Biochemical indicators of energy metabolism and oxidative stress, such as NADOur results showed that Rha ameliorated myocardial ischaemia and inhibited energy metabolism disorders (NADThe results suggest that Rha regulates energy metabolism and oxidative stress through the SIRT6/Nrf2 signaling pathway to play a protective role in myocardial injury.

Licorice is a traditional Chinese medicine that has been used for cardiovascular diseases. Recent studies found that supplementation with licorice extracts attenuated the development of atherosclerosis (AS) in hypercholesterolemic patients. Many studies have shown that licorice flavonoids, the main active components of licorice, have a variety of pharmacological effects, including anti-inflammation, regulation of lipid metabolism, and antioxidation. However, the key active components against AS in licorice flavonoids are still unclear.The aim of this paper is to investigate the active components of licorice flavonoids that exert anti-atherosclerotic effects and the underlying mechanisms.Network pharmacology was used to screen the active components of licorice flavonoids that have anti-atherosclerotic effects. Combining bioinformatics analysis and in vitro studies, the effects and underlying mechanisms of the active component isoliquiritigenin (ISL) on cell pyroptosis were further investigated in tumor necrosis factor (TNF)-α-treated human umbilical vein endothelial cells (HUVECs).We constructed a compound-target network and screened 3 active components, namely, ISL, glabridin, and naringenin in licorice flavonoids. The half maximal effective concentration values of these 3 components suggested that ISL was the key active component against TNF-α-induced endothelial cell injury. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that ISL could potentially treat AS via the nucleotide-binding and oligomerization domain (NOD)-like receptor signaling pathway. An in vitro study verified that ISL suppressed TNF-α-induced NLRP3 activation and pyroptosis in HUVECs. The molecular docking and cellular thermal shift assay showed good compatibility between ISL and class III histone deacetylase sirtuin 6 (SIRT6). Moreover, we found that ISL upregulated the expression of SIRT6 in TNF-α-treated HUVECs. Further study found that SIRT6 knockdown reduced the inhibitory effect of ISL on pyroptosis, whereas the NLRP3 inhibitor reversed this process in TNF-α-treated HUVECs.Our results demonstrate that ISL is a key active component of licorice flavonoids. ISL attenuates NLRP3-mediated vascular endothelial cell pyroptosis via SIRT6, and SIRT6 may be a potential target of ISL for the treatment of AS.

Chronic wounds such as diabetic feet undergo a lifetime risk of developing into incurable ulcers. Current treatments for chronic wounds remain unsatisfactory due to the lack of ideal wound dressings that integrate facile dressing change, long-acting treatment, and high therapeutic efficacy into one system. Herein, a synergistically detachable microneedle (MN) dressing with a dual-layer structure is presented to enable programmed treatment via one-time dressing application. Such a dual-layer dressing MN system (DDMNS) is composed of chitosan (CS) hydrogel dressing (CSHD) on top of a detachable MN patch with a CS tip and a polyvinyl pyrrolidone (PVP) backing substrate incorporated with magnesium (Mg). The synergistic detachment is achieved with the backing Mg/PVP substrate dissolving within minutes due to the local moist environment of the CSHD enhancing the reaction between Mg and inflammation microenvironment. The combined treatment of Mg and panax notoginseng saponins (PNS) loaded in DDMNS achieves antibacterial, neovascularization, and activating a benign immune response so that the three overlapping periods of the inflammation, tissue proliferation, and tissue remodeling of wound healing reach a dynamic balance. This advanced DDMNS provides a facile approach for the programmed treatment of chronic wound management indicating potential value in wound healing and other related biomedical fields.

Based on the colorimetric analysis of gold nanoparticles and a smartphone readable strategy, a stable, sensitive, and visual method was established for rapid detection of acetamiprid residues in agricultural products. By optimizing the key parameters, the detection process only took 40 minutes with good specificity. The acetamiprid aptamer can help AuNPs to resist salt-induced aggregation. Conversely, in the presence of acetamiprid, the anti-protection is weakened and the AuNPs aggregated with the color change of the solution. The photographs of the solution are recorded by the smartphone and analyzed through image processing. In the range from 25 to 300 μM the method can realize a quantitative analysis of acetamiprid, and the detection limit is about 3.81 μM. Excellent recoveries are taken in samples of cucumber, cabbage, and river water, ranging from 96.78% to 129.95%. These results show no significant difference from the results obtained by the microplate reader. What's more, the method employs a smartphone to read without the assistance of professional equipment, which greatly reduces the cost of detection, and shows a promising application prospect for on-site rapid detection of acetamiprid.

Histone deacetylase 11 (HDAC11), a sole member of the class IV HDAC subfamily, participates in various cardiovascular diseases. Recent evidence showed that pyroptosis was a form of inflammatory programmed cell death and is critical for atherosclerosis (AS). However, little is known about the effect of HDAC11 on endothelial cell pyroptosis in AS. Thus, this study aims to investigate the role of HDAC11 in vascular endothelial cell pyroptosis and its molecular mechanism. Firstly, we found that HDAC11 expression was up-regulated and pyroptosis occurred in the aorta of ApoE−/− mice fed with a high-fat diet (HFD) for 8 or 12 weeks. Then, in vitro study found the treatment of human umbilical vein endothelial cells (HUVECs) with tumor necrosis factor-α (TNF-α) resulted in pyroptosis, as evidenced by activation of caspase-1 and caspase-3 activation, cleavage of downstream gasdermin D (GSDMD) and gasdermin E (GSDME/DFNA5), the release of pro-inflammatory cytokines interleukin (IL)-1β, IL-6 and IL-18, as well as elevation of LDH activity and increase of propidium iodide (PI)-positive cells. Besides, TNF-α increased HDAC11 expression and induced pyroptosis via TNFR1 in HUVECs. HDAC11 knockdown mitigated pyroptosis by suppressing both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways in TNF-α-induced HUVECs. Moreover, GSDME knockdown by siRNA significantly decreased pyroptosis and inflammatory response, while treatment with disulfiram or necrosulfonamide (NSA) further augmented the inhibitory effects of GSDME siRNA on pyroptosis and inflammatory response. Further studies found HDAC11 formed a complex with ERG and decreased the acetylation levels of ERG. More importantly, ERG knockdown augmented vascular endothelial cell pyroptosis in TNF-α-induced HUVECs. Taken together, our study suggests that HDAC11 might promote both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways leading to pyroptosis via regulation of ERG acetylation in HUVECs. Modulation of HDAC11 may serve as a potential target for therapeutic strategies of AS.

Background The optimal treatment sequence for patients with advanced BRAF V600 mutant melanoma is unknown. BRAF/MEK inhibition (BRAF/MEKi), single agent anti‐PD‐1 (aPD‐1) antibodies and combination immune checkpoint inhibition with nivolumab and ipilimumab (niv/ipi) are all approved; however, they have not been prospectively compared. Therefore, we sought to compare overall survival of patients with advanced BRAF mutant melanoma treated with either front‐line BRAF/MEKi, aPD‐1, or niv/ipi. Methods Patients with advanced BRAF mutant melanoma who had received BRAF/MEKi, niv/ipi, or aPD‐1 in the front‐line setting were identified from a nationwide database comprising de‐identified patient‐level structured and unstructured data derived from electronic health records. Survival was compared using Kaplan‐Meier curves and log‐rank analysis. Univariate and multivariate Cox regression models were used to measure the effect of front‐line treatment, age (>64 or not), LDH (elevated or not), and Eastern Cooperative Oncology Group (ECOG) performance status (>1 or not) on survival. Results Five hundred and sixty seven patients with advanced disease and treated with front‐line aPD‐1 (n = 162), BRAF/MEKi (n = 297) or niv/ipi (n = 108) were identified. With a median follow‐up of 22.4 months, median overall survival (OS) for patients treated with front‐line niv/ipi was not reached (NR) while median OS for patients treated with aPD‐1 or BRAF/MEKi was 39.5 months and 13.2 months, respectively. Front‐line treatment with PD‐1 and niv/ipi were associated with statistically longer survival than BRAF/MEKi in multivariate analyses. Conclusions In our real‐world retrospective analysis, patients with advanced BRAF mutant melanoma treated with front‐line niv/ipi or aPD‐1 had longer survival compared to those treated with front‐line BRAF/MEKi., Real‐world overall survival of patients with advanced BRAF mutant melanoma treated with front‐line BRAF/MEK inhibitors, anti‐PD‐1 antibodies, or nivolumab/ipilimumab.

Most cognitive and psychiatric disorders are thought to be disorders of the synapse, yet the precise synapse defects remain unknown. Because synapses are highly specialized anatomical structures, defects in synapse formation and function can often be observed as changes in microscale neuroanatomy. Unfortunately, few methods are available for accurate analysis of synaptic structures in human postmortem tissues. Here, we present a methodological pipeline for assessing presynaptic and postsynaptic structures in human postmortem tissue that is accurate, rapid, and relatively inexpensive. Our method uses small tissue blocks from postmortem human brains, immersion fixation, lipophilic dye (DiI) labeling, and confocal microscopy. As proof of principle, we analyzed presynaptic and postsynaptic structures from hippocampi of 13 individuals aged 4 months to 71 years. Our results indicate that postsynaptic CA1 dendritic spine shape and density do not change in adults, while presynaptic DG mossy fiber boutons undergo significant structural rearrangements with normal aging. This suggests that mossy fiber synapses, which play a major role in learning and memory, may remain dynamic throughout life. Importantly, we find that human CA1 spine densities observed using this method on tissue that is up to 28 h postmortem is comparable to prior studies using tissue with much shorter postmortem intervals. Thus, the ease of our protocol and suitability on tissue with longer postmortem intervals should facilitate higher-powered studies of human presynaptic and postsynaptic structures in healthy and diseased states.

Our previous study showed that Sirtuin 6 (Sirt6) plays an important role in the regulation of vascular endothelial cell inflammation. Recently, studies have reported that the RNA binding protein Lin28b directly regulates the let-7 microRNA (miRNA), which participates in the process of atherosclerosis (AS) by regulating inflammation. Pyroptosis is a form of programmed cell death that is accompanied by inflammation and is critical for AS. Thus, this study aimed to investigate the role of Sirt6 and Lin28b in vascular endothelial cell pyroptosis and the related mechanism. The present study showed that Lin28b expression was upregulated in the aortic intima and aorta of apolipoprotein E knockout (ApoE

Endothelial-to-mesenchymal transition (EndMT) is a process of transdifferentiation in which endothelial cells gradually adopt the phenotypic characteristics of mesenchymal cells. Emerging studies demonstrate the importance of EndMT in endothelial dysfunction during inflammation. Sirtuin 6 (SIRT6), a member of the mammalian NAD+-dependent deacetylase sirtuin family, plays a critical role in cardiovascular diseases by regulating the inflammatory response. However, little is known about the effect of SIRT6 on EndMT during vascular inflammation. Therefore, we aimed to investigate the effect of SIRT6 on EndMT in endothelium-specific SIRT6 knockout (ecSIRT6-/-) mice and human umbilical vein endothelial cells (HUVECs) stimulated with inflammatory cytokines. First, we found that TNF-α and IL-1β co-treatment induced EndMT and down-regulated SIRT6 expression in HUVECs. Adenovirus-mediated SIRT6 overexpression suppressed inflammation-induced EndMT in HUVECs. In contrast, SIRT6 knockdown further promoted EndMT. Our findings also revealed that SIRT6 attenuated the inflammatory response of HUVECs. Additionally, vascular inflammation was induced by carotid artery ligation in ecSIRT6-/- mice. Results showed that the intima of ligated carotid arteries in ecSIRT6-/- mice was significantly thickened compared to that in ecSIRT6+/+ ligated mice. Moreover, endothelium-specific SIRT6 knockout promoted EndMT and increased the expression of proinflammatory cytokines in the carotid arteries of mice. These results suggest that SIRT6 inhibits EndMT through attenuating the vascular endothelial inflammatory response. These findings may have significance for reducing the occurrence of EndMT and ameliorating certain aspects of vascular inflammation.

Sirtuins are a family of highly conserved nicotinamide adenine dinucleotide (NAD+)-dependent enzymes. Among the sirtuins, SIRT1 and SIRT6 participate in the regulation of endothelial functions and play significant roles in the physiological and pathological processes of cardiovascular diseases (CVD). Recently, our study found that minute cholesterol crystals (CC) can be endocytosed by endothelial cells and further impair endothelial functions. Since previous studies have reported that angiotensin-converting enzyme (ACE2) involves Angiotensin (Ang) II-induced inflammation in endothelial cells, this study was designed to investigate the role of SIRT1 and SIRT6 in CC-induced variation of ACE2 expression and the related mechanism between SIRT6 and ACE2. We found that ACE2 is involved in CC-induced endothelial dysfunction, which inhibits decreases in nitric oxide (NO) level and endothelial nitric oxide synthase (eNOS) activity and increases in inflammatory factors and adhesion molecules. Besides, SIRT1 and SIRT6 regulated the protein expression of ACE2 in CC-stimulated human umbilical vein endothelial cells (HUVECs). Moreover, bioinformatics analysis from the Enrichr database indicated that activating transcription factor 2 (ATF2), is highly correlated with genes that significantly upregulated after infection with the SIRT6 adenovirus vector. In CC-induced HUVECs, ACE2 expression was up-regulated in cells transfected with ATF2 siRNA. However, further mechanism studies revealed that overexpression of SIRT6 decreases the accumulation of p-ATF2 in the nucleus, but did not affect p-ATF2 expression in the cytoplasm. Taken together, these data indicated that SIRT6 regulates ACE2 might via inhibiting the accumulation of nucleus p-ATF2 in CC-induced endothelial dysfunction.

Purpose To evaluate and compare postoperative pain following photorefractive keratectomy (PRK) in patients using a preventive regimen of oral versus topical nonsteroidal anti-inflammatory drugs (NSAIDs). Patients and Methods A prospective, randomized, longitudinal survey of postoperative PRK pain was performed on 157 subjects in a tertiary academic medical center setting. Patients were randomized to either topical ketorolac 0.4% every 12 hours or oral naproxen sodium 220 mg every 12 hours for 72 hours following PRK, beginning at the time of surgery. The primary outcome measure was the daily peak pain score from the validated numerical rating scale (NRS) for five days after surgery. Results The peak pain scores were significantly higher in the oral NSAID group (mean 5.82, SD 1.94) compared to the topical NSAID group (mean 4.2, SD 2.19) (p

Suicide death is a worldwide health crisis, claiming close to 800,000 lives per year. Recent evidence suggests that prediction and prevention challenges may be aided by discoveries of genetic risk factors. Here we focus on the role of rare (MAF SNAPC1, rs75418419; TNKS1BP1, rs143883793; ADGRF5, rs149197213; PER1, rs145053802; and ESS2, rs62223875). Both PER1 and SNAPC1 have other supporting gene-level evidence of suicide risk, and an association with bipolar disorder has been reported for PER1 and with schizophrenia for PER1, TNKS1BP1, and ESS2. Three genes (PER1, TNKS1BP1, and ADGRF5), with additional genes implicated by GWAS studies on suicidal behavior, showed significant enrichment in immune system, homeostatic and signal transduction processes. Pain, depression, and accidental trauma were the most prevalent phenotypes in electronic medical record data for the categories assessed. These findings suggest an important role for rare variants in suicide risk and provide new insights into the genetic architecture of suicide death. Furthermore, we demonstrate the added utility of careful assessment of genotyping arrays in rare variant discovery.

Measuring patient satisfaction scores and interpreting factors that impact their variation is of importance as scores influence various aspects of health care administration. Our objective was to evaluate if Press Ganey scores differ between medical specialties.New patient visits between January 2014 and December 2016 at a single tertiary academic center were included in this study. Press Ganey scores were compared between specialties using a multivariable logistic mixed effects model. Secondary outcomes included a comparison between surgical versus non-surgical specialties, and pediatric versus adult specialties. Due to the survey's high ceiling effect, satisfaction was defined as a perfect total score.Forty four thousand four hundred ninety six patients met inclusion criteria. Compared to internal medicine, plastic surgery, general surgery, dermatology, and family medicine were more likely to achieve a perfect overall score, as, with odds ratios of 1.46 (P = .02), 1.29 (P = .002), 1.22 (P = .004), and 1.16 (P = .02) respectively. Orthopaedics, pediatric medicine, pediatric neurology, neurology, and pain management were less likely to achieve satisfaction with odds ratios of 0.85 (P = .047), 0.71 (P

Most cognitive and psychiatric disorders are thought to be disorders of the synapse, yet the precise synapse defects remain unknown. Because synapses are highly specialized anatomical structures, defects in synapse formation and function can often be observed as changes in micro-scale neuroanatomy. Unfortunately, few methods are available for accurate analysis of synaptic structures in human postmortem tissues. Here, we present a methodological pipeline for assessing pre- and postsynaptic structures in human postmortem tissue that is accurate, rapid, and relatively inexpensive. Our method uses small tissue blocks from postmortem human brains, immersion fixation, DiI labeling, and confocal microscopy. As proof of principle, we analyzed pre- and postsynaptic structures from hippocampi of 13 individuals aged 4 months to 71 years. Our results indicate that postsynaptic CA1 dendritic spine shape and density do not change in adults, while presynaptic DG mossy fiber boutons undergo significant structural rearrangements with normal aging. This suggests that mossy fiber synapses, which play a major role in learning and memory, may remain dynamic throughout life. Importantly, we find that human CA1 spine densities observed using this method on tissue that is up to 28 hours postmortem is comparable to prior studies using tissue with much shorter postmortem intervals. Thus, the ease of our protocol and suitability on tissue with longer postmortem intervals should facilitate higher-powered studies of human pre and postsynaptic structures in healthy and diseased states.

Suicide is the 10th leading cause of death in the United States. Although environment has undeniable impact, evidence suggests that genetic factors play a significant role in completed suicide. We linked a resource of ~ 4500 DNA samples from completed suicides obtained from the Utah Medical Examiner to genealogical records and medical records data available on over eight million individuals. This linking has resulted in the identification of high-risk extended families (7–9 generations) with significant familial risk of completed suicide. Familial aggregation across distant relatives minimizes effects of shared environment, provides more genetically homogeneous risk groups, and magnifies genetic risks through familial repetition. We analyzed Illumina PsychArray genotypes from suicide cases in 43 high-risk families, identifying 30 distinct shared genomic segments with genome-wide evidence (p = 2.02E-07–1.30E-18) of segregation with completed suicide. The 207 genes implicated by the shared regions provide a focused set of genes for further study; 18 have been previously associated with suicide risk. Although PsychArray variants do not represent exhaustive variation within the 207 genes, we investigated these for specific segregation within the high-risk families, and for association of variants with predicted functional impact in ~ 1300 additional Utah suicides unrelated to the discovery families. None of the limited PsychArray variants explained the high-risk family segregation; sequencing of these regions will be needed to discover segregating risk variants, which may be rarer or regulatory. However, additional association tests yielded four significant PsychArray variants (SP110, rs181058279; AGBL2, rs76215382; SUCLA2, rs121908538; APH1B, rs745918508), raising the likelihood that these genes confer risk of completed suicide.