Whole-genome sequencing analysis of suicide deaths integrating brain-regulatory eQTLs data to identify risk loci and genes.

Recent large-scale genome-wide association studies (GWAS) have started to identify potential genetic risk loci associated with risk of suicide; however, a large portion of suicide-associated genetic factors affecting gene expression remain elusive. Dysregulated gene expression, not assessed by GWAS, may play a significant role in increasing the risk of suicide death. We performed the first comprehensive genomic association analysis prioritizing brain expression quantitative trait loci (eQTLs) within regulatory regions in suicide deaths from the Utah Suicide Genetic Risk Study (USGRS). 440,324 brain-regulatory eQTLs were obtained by integrating brain eQTLs, histone modification ChIP-seq, ATAC-seq, DNase-seq, and Hi-C results from publicly available data. Subsequent genomic analyses were conducted in whole-genome sequencing (WGS) data from 986 suicide deaths of non-Finnish European (NFE) ancestry and 415 ancestrally matched controls. Additional independent USGRS suicide deaths with genotyping array data (n = 4657) and controls from the Genome Aggregation Database were explored for WGS result replication. One significant eQTL locus, rs926308 (p = 3.24e-06), was identified. The rs926308-T is associated with lower expression of RFPL3S, a gene important for neocortex development and implicated in arousal. Gene-based analyses performed using Sherlock Bayesian statistical integrative analysis also detected 20 genes with expression changes that may contribute to suicide risk. From analyzing publicly available transcriptomic data, ten of these genes have previous evidence of differential expression in suicide death or in psychiatric disorders that may be associated with suicide, including schizophrenia and autism (ZNF501, ZNF502, CNN3, IGF1R, KLHL36, NBL1, PDCD6IP, SNX19, BCAP29, and ARSA). Electronic health records (EHR) data was further merged to evaluate if there were clinically relevant subsets of suicide deaths associated with genetic variants. In summary, our study identified one risk locus and ten genes associated with suicide risk via gene expression, providing new insight into possible genetic and molecular mechanisms leading to suicide.

A population-wide analysis of the familial risk of suicide in Utah, USA.

BACKGROUND: The 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. METHODS: A 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 (<25 v. ⩾25 years) was examined. RESULTS: Significantly 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). CONCLUSIONS: Elevated 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.

Protective effect of SIRT6 on cholesterol crystal-induced endothelial dysfunction via regulating ACE2 expression.

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.

Extended familial risk of suicide death is associated with younger age at death and elevated polygenic risk of suicide.

Suicide accounts for >800,000 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 with >90% 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.

Genome-wide significant regions in 43 Utah high-risk families implicate multiple genes involved in risk for completed suicide.

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.

Rare protein-coding variants implicate genes involved in risk of suicide death.

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 <1%) putatively functional single-nucleotide polymorphisms (SNPs) present on the Illumina PsychArray genotyping array in 2,672 USGRS suicide deaths of non-Finnish European (NFE) ancestry and 51,583 NFE controls from the Genome Aggregation Database. Secondary analyses used an independent control sample of 21,324 NFE controls from the Psychiatric Genomics Consortium. Five novel, high-impact, rare SNPs were identified with significant associations with suicide death (SNAPC1, rs75418419; TNKS1BP1, rs143883793; ADGRF5, rs149197213; PER1, rs145053802; and ESS2, rs62223875). 119 suicide decedents carried these high-impact SNPs. Both PER1 and SNAPC1 have other supporting gene-level evidence of suicide risk, and psychiatric associations exist for PER1 (bipolar disorder, schizophrenia), and for TNKS1BP1 and ESS2 (schizophrenia). Three of the genes (PER1, TNKS1BP1, and ADGRF5), together with additional genes implicated by genome-wide association studies on suicidal behavior, showed significant enrichment in immune system, homeostatic and signal transduction processes. No specific diagnostic phenotypes were associated with the subset of suicide deaths with the identified rare variants. These findings suggest an important role for rare variants in suicide risk and implicate genes and gene pathways for targeted replication.

Correlation between essential and toxic elements in maternal blood during early pregnancy and atrial septal defects/ventricular septal defects/patent ductus arteriosus in offspring.

BACKGROUND: Congenital heart defects (CHDs) are the most common congenital malformation in the world. Recent studies have found that essential and toxic trace element levels may play a crucial role in the risk of neonatal malformation. However, the relationships between element levels in early pregnancy and CHD risk among humans remain unclear. This study investigates the association between maternal essential element (copper [Cu], zinc [Zn], calcium [Ca], manganese [Mg] and iron [Fe]) and toxic element (lead [Pb] and cadmium [Cd]) levels during early pregnancy and CHDs. METHODS: A hospital-based case-control study was conducted, including 181 cases and 218 controls. Eligible participants underwent antenatal examination during gestational weeks 11-14 and trace element levels were detected by the atomic absorption method. Multi-variable logistic regression was used to examine the associations between the level of maternal trace elements and CHD risks. RESULTS: Higher levels of Ca in early pregnancy were associated with lower risk of ASD/VSD risks. Moreover, higher Fe, Pb, and Cd levels in the first trimester were associated with higher risks of all CHD and the subtypes risks, and the tests for trend were significant (all p < .05). The restricted cubic spline analysis showed that there was a nonlinear inverted u-shaped dose-response relationship between levels of Zn, Pb, and Cd in the first trimester and risk of CHDs (non-linearity test p < .05). CONCLUSIONS: A moderate increase in Zn and Ca levels and a decrease in Pb and Cd levels during early pregnancy are needed to reduce the incidence of CHDs in the Chinese population.

Absence of nonfatal suicidal behavior preceding suicide death reveals differences in clinical risks.

Nonfatal suicidality is the most robust predictor of suicide death. However, only ~10% of those who survive an attempt go on to die by suicide. Moreover, ~50% of suicide deaths occur in the absence of prior known attempts, suggesting risks other than nonfatal suicide attempt need to be identified. We studied data from 4,000 population-ascertained suicide deaths and 26,191 population controls to improve understanding of risks leading to suicide death. This study included 2,253 suicide deaths and 3,375 controls with evidence of nonfatal suicidality (SUI_SI/SB and CTL_SI/SB) from diagnostic codes and natural language processing of electronic health records notes. Characteristics of these groups were compared to 1,669 suicides with no prior nonfatal SI/SB (SUI_None) and 22,816 controls with no lifetime suicidality (CTL_None). The SUI_None and CTL_None groups had fewer diagnoses and were older than SUI_SI/SB and CTL_SI/SB. Mental health diagnoses were far less common in both the SUI_None and CTL_None groups; mental health problems were less associated with suicide death than with presence of SI/SB. Physical health diagnoses were conversely more often associated with risk of suicide death than with presence of SI/SB. Pending replication, results indicate highly significant clinical differences among suicide deaths with versus without prior nonfatal SI/SB.

The Utah psychotropic oversight program: collaboratively addressing antipsychotic use within youth in foster care without prior authorization.

Objectives: Fostered youth have increased risk of exposure to trauma. Antipsychotic medications are often utilized within the foster care system, potentially to address problematic behaviors that may be associated with trauma. The Utah Psychotropic Oversight Program (UPOP) was formed to support prescribers and encourage evidence-based treatment approaches for fostered youth. However, it is unclear what impact an oversight program can have on a high turnover population and without tools such as prior authorization. This study evaluates 4 years of collected data from the UPOP program for efficacy and to identify future intervention targets. Methods: Deidentified data were collected as a routine function of the oversight program over 4 years (01/2019-12/2022), from individuals aged 0-18 years old (total N = 8,523, 48.3% female). UPOP oversight criteria: ≤6yo + any psychotropic medication, ≥7yo + 2 or more psychotropic medications. For this analysis, youth were divided by UPOP individuals ever receiving an antipsychotic (AP) prescription (UPOP_AP; N = 755, 42.3% female) or not (UPOP_NAP, N = 1,006, 48.3% female) and non-UPOP fostered (N = 6,762, 48.9% female). Comparisons were made across demographic and clinical variables via ANOVA, Chi-square, unpaired t-test, and logistic regression. Results: UPOP_AP more likely to be older males with behavioral diagnoses, increased polypharmacy, longer duration of fostering, and higher care level. AP prescription rates dropped from 52.8 to 39.1% for males and 43.3 to 38.2% in females with unchanged number of psychotropic prescriptions and care level across 2019-2022. UPOP_AP that discontinued AP treatment had fewer average psychotropic medications, but increased antidepressant and sleep prescriptions, as compared with individuals that remained on AP. Conclusion: Youth within the foster care system receive antipsychotics at high rates and in an uneven distribution. Prescribing practices can change in the context of supportive oversight programs without components such as prior authorization, and without increasing the need for higher levels of care. Specific emphasis on the treatment of mood, anxiety, and sleep issues may also lead to greater success in discontinuing AP treatment. Oversight may support treatment providers while reducing exposure to medications with considerable side effect burden that could cause future comorbidity.

Isoliquiritigenin from licorice flavonoids attenuates NLRP3-mediated pyroptosis by SIRT6 in vascular endothelial cells.

ETHNOPHARMACOLOGIC RELEVANCE: 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. AIM OF THE STUDY: The aim of this paper is to investigate the active components of licorice flavonoids that exert anti-atherosclerotic effects and the underlying mechanisms. MATERIALS AND METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

A gold nanoparticle-based visual aptasensor for rapid detection of acetamiprid residues in agricultural products using a smartphone.

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.

Synergistically Detachable Microneedle Dressing for Programmed Treatment of Chronic Wounds.

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.

Rhaponticum carthamoides improved energy metabolism and oxidative stress through the SIRT6/Nrf2 pathway to ameliorate myocardial injury.

BACKGROUND: 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 NAD+-dependent class III histone deacetylase, plays a considerable role in the administration of CVDs. However, the specific effects and mechanism of Rha on myocardial injury remain unknown. PURPOSE: This study aimed to explore the therapeutic potential of Rha against myocardial injury as well as its underlying mechanisms in vivo and in vitro. METHODS: 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, H&E staining, and myocardial enzyme detection. Biochemical indicators of energy metabolism and oxidative stress, such as NAD+/NADH, ATP, and MDA, were analysed by assay kits to assess the effects of Rha. The protein and mRNA expression levels of SIRT6 and Nrf2 in the myocardium were determined by western blotting and real-time PCR. RESULTS: Our results showed that Rha ameliorated myocardial ischaemia and inhibited energy metabolism disorders (NAD+/NADH ratio, ATP, and LD) and oxidative stress (SOD, ROS, etc.) in rat myocardial tissue and H9c2 cells. In addition, Rha upregulated SIRT6 and Nrf2 expression in myocardial injury. Mechanistic studies then found that SIRT6 knockdown reduced the expression of Nrf2 as well as the effects of Rha on the levels of ATP, LD, and ROS, whereas activation of Nrf2 improved the effects of Rha in cells. In summary, Rha might exert its cardioprotective effects via the SIRT6-mediated Nrf2 signaling pathway. CONCLUSION: The results suggest that Rha regulates energy metabolism and oxidative stress through the SIRT6/Nrf2 signaling pathway to play a protective role in myocardial injury.

HDAC11 promotes both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways causing pyroptosis via ERG in vascular endothelial cells.

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)-1ß, 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.

Suicide and Psychosis: Results From a Population-Based Cohort of Suicide Death (N = 4380).

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.

Sirt6 inhibits vascular endothelial cell pyroptosis by regulation of the Lin28b/let-7 pathway in atherosclerosis.

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-/-) mice fed with a high-fat diet (HFD) for 8 or 12 weeks. Then, in vitro study found Lin28b was involved in tumor necrosis factor-α (TNF-α)-induced vascular endothelial cell pyroptosis, as indicated by the increased number of PI-positive cells and gasdermin D (GSDMD) cleavage, as well as the increased release of lactate dehydrogenase (LDH) and interleukin (IL)-1ß. Further studies demonstrated that TNF-α significantly decreased the expression of let-7, while Lin28b knockdown significantly increased the expression of let-7a, let-7d and let-7g. In addition, Sirt6 overexpression decreased Lin28b expression. Moreover, Sirt6 overexpression suppressed pyroptosis by decreasing the number of PI-positive cells and GSDMD cleavage, as well as by decreasing the release of LDH and IL-1ß in TNF-α-induced vascular endothelial cells. Further mechanistic studies revealed that Sirt6 directly interacted with and deacetylated Lin28b. Taken together, these findings indicate that Sirt6 inhibits vascular endothelial cell pyroptosis by negatively regulating the Lin28b/let-7 pathway in AS.

Inter-specialty variation of the Press Ganey Outpatient Medical Practice Survey.

ABSTRACT: 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 < .001), 0.63 (P = .005), 0.57 (P < .001), and 0.51 (P = .006), respectively. Compared to pediatric specialties, adult specialties were more likely to achieve satisfaction (OR 1.73; P < .001). There were no significant differences between surgical versus non-surgical specialties.Press Ganey scores systematically differ between specialties within the studied institution. These differences should be considered by healthcare systems that use patient satisfaction data to modify provider reimbursement.

SIRT6 inhibits endothelial-to-mesenchymal transition through attenuating the vascular endothelial inflammatory response.

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-1ß 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.

Invasive Pulmonary Aspergillosis in Acute-on-Chronic Liver Failure Patients: Short-Term Outcomes and Antifungal Options.

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 < 0.001) than those without (n = 383). The respiratory failure-associated 28-day mortality was greater in ACLF patients with IPA than in those without before (17.1% vs. 0.3%, p < 0.001) and after (16.0% vs. 0.0%, p < 0.001) propensity score matching in 116 pairs. IPA patients with lung injury had greater 28-day all-cause mortality (66.5% vs. 24.2%, p < 0.001) and IPA-associated mortality (45.8% vs. 8.1%, p < 0.001) than patients without lung injury (PaO2/FiO2 ≥ 400 mmHg). Antifungal therapy was prescribed to 139 of 145 patients, and 102 patients were treated with voriconazole alone (n = 59) or sequential/combined therapy (n = 43) with varying loading doses (100-800 mg) and daily maintenance doses (0-800 mg). A proposed optimal voriconazole regimen (loading dose, 200 mg twice daily; daily maintenance dose, 100 mg) achieved comparable short-term survival and optimal trough drug concentrations (1-5 µg/mL) on therapeutic drug monitoring in 26 patients. CONCLUSION: Presence of IPA increases the short-term mortality of ACLF patients mainly due to respiratory failure. An optimal voriconazole regimen is needed for such critical patients.

Survey of Postoperative Pain in Photorefractive Keratectomy Using Topical versus Oral Nonsteroidal Anti-Inflammatory Drugs.

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<0.0001) after PRK. When comparing each postoperative day after PRK, the pain scores from 24 to 48 hours (day 2) were significantly higher in the oral NSAID group (mean 5.17, SD 2.25) as compared to the topical NSAID group (mean 3.21, SD 2.09) (p<0.0001). Pain scores 24-72 hours after surgery (days 2 and 3) were higher than pain scores on days 1, 4, and 5 for both groups. CONCLUSION: Twice daily oral naproxen sodium 220 mg is inferior to twice daily topical ketorolac 0.4% in the treatment of early postoperative pain after PRK. This study also identified a consistent trend in which pain scores were highest 24-72 hours after the procedure. This additional observation may be useful in understanding, preventing, and treating post-PRK pain.