A rare case of bilateral subclavian artery agenesis.

Arterial agenesis is a rare condition and has been reported to affect the internal carotid artery, common carotid artery, and pulmonary artery. However, to the best of our knowledge, it has not yet been reported to affect the subclavian arteries. We present a case of asymptomatic bilateral subclavian artery agenesis and left subclavian artery aneurysm. This patient's abnormal vasculature was found incidentally. Despite being asymptomatic, repair of the aneurysm via vertebral transposition and ligation of the subclavian artery was performed to prevent eventual thrombosis, emboli, and stroke.

Single nucleotide polymorphisms rs148582811 regulates its host gene ARVCF expression to affect nicotine-associated hippocampus-dependent memory.

Although numerous susceptibility loci are nominated for nicotine dependence (ND), no report showed any association of ARVCF with ND. Through genome-wide sequencing analysis, we first identified genetic variants associated nominally with ND and then replicated them in an independent sample. Of the six replicated variants, rs148582811 in ARVCF located in the enhancer-associated marker peak is attractive. The effective-median-based Mendelian randomization analysis indicated that ARVCF is a causal gene for ND. RNA-seq analysis detected decreased ARVCF expression in smokers compared to nonsmokers. Luciferase reporter assays indicated that rs148582811 and its located DNA fragment allele-specifically regulated ARVCF expression. Immunoprecipitation analysis revealed that transcription factor X-ray repair cross-complementing protein 5 (XRCC5) bound to the DNA fragment containing rs148582811 and allele-specifically regulated ARVCF expression at the mRNA and protein levels. With the Arvcf knockout mouse model, we showed that Arvcf deletion not only impairs hippocampus-dependent learning and memory, but also alleviated nicotine-induced memory deficits.

Prevalence and determinants of contraception utilization over time in Migori County, Kenya: Repeated cross-sectional household surveys.

Contraception use and family planning have been shown to save lives and benefit women, their families, and their communities. We conducted a cross-sectional study analyzing data from a 2021 survey that was conducted across eight different regions in Migori County, Kenya to examine the potential role that different factors play in meeting family planning targets. Comparisons are made to data collected in 2018/2019 in order to estimate the change over time of contraception uptake. Descriptive statistics were calculated, the Cochran-Mantel-Haenszel test was used to compare contraception use over time, and multivariable logistic regression was used to model determinants of contraceptive use. Sixty-four percent of respondents in 2021 reported that they currently use some form of contraception, and implants are the most popular contraceptive method. Factors associated with higher contraception usage were region, ages 25-34 years, and marital status. Contraception uptake increased significantly in East Kamagambo following a community-driven sexual and reproductive health intervention by the Lwala Community Alliance, suggesting that increased investment in family planning may be influential. We recommend targeted outreach to population groups with low uptake of contraception and investment in both demand- and supply-side interventions to increase contraceptive uptake. Additional research, especially for populations under 18, is needed to further inform effective investment and policy.

An HBV susceptibility variant of KNG1 modulates the therapeutic effects of interferons α and λ1 in HBV infection by promoting MAVS lysosomal degradation.

BACKGROUND: Hepatitis B virus (HBV) infection is one of the main causes of hepatocellular carcinoma (HCC). The relationship between HBV infection and the host genome as well as their underlying mechanisms remain largely unknown. METHODS: In this study, we performed a whole-genome exon sequencing analysis of 300 sib-pairs of Chinese HBV-infected families with the goal of identifying variants and genes involved in HBV infection. A site-direct mutant plasmid was used to investigate the function of SNP rs76438938 in KNG1. The functional and mechanical studies of KNG1 were conducted with in vitro liver cell lines and a hydrodynamic injection model in vivo. The impact of KNG1 on HBV infection therapy was determined in hepatocytes treated with IFN-α/λ1. FINDINGS: Our whole-exon association study of 300 families with hepatitis B infection found that SNP rs76438938 in KNG1 significantly increased the risk for HBV infection, and the rs76438938-T allele was found to promote HBV replication by increasing the stability of KNG1 mRNA. By competitively binding HSP90A with MAVS, KNG1 can inhibit the expression of types I and III IFNs by promoting MAVS lysosomal degradation. Such suppression of IFN expression and promotion of HBV replication by Kng1 were further demonstrated with an animal model in vivo. Lastly, we showed that the rs76438938-C allele can improve the therapeutic effect of IFN-α and -λ1 in HBV infection. INTERPRETATION: This study identified a SNP, rs76438938, in a newly discovered host gene, KNG1, for its involvement in HBV infection and treatment effect through modulating the cellular antiviral process. FUNDING: This study was supported in part by the Independent Task of State Key Laboratory for Diagnosis and Treatment of Infectious Diseases of the First Affiliated Hospital of Zhejiang University, the China Precision Medicine Initiative (2016YFC0906300), and the Research Center for Air Pollution and Health of Zhejiang University.

A Disease-Specific Antibiogram to Evaluate Empiric Coverage Patterns in Fournier's Gangrene.

OBJECTIVE: To analyze our local antibiogram and antibiotic resistance patterns given concern for multidrug-resistant and fungal organisms in contemporary series detailing causative organisms in Fournier's Gangrene (FG). METHODS: All patients from 2018 to 2022 were identified from the institutional FG registry. Microorganisms and sensitivities were collected from operative tissue cultures. The primary outcome of this study was the adequacy of our empiric. Secondary outcomes included the rate of bacteremia, the concordance of blood cultures and tissue cultures, and the rate of fungal tissue infections. RESULTS: Escherichia coli and Streptococcus anginosus were most common, identified in 12 patients each (20.0%). Enterococcus faecalis (9, 15.0%), S agalactiae (8, 13.3%) and mixed cultures without a predominant organism (9, 15.0%) were also common. A fungal organism was identified in 9 (15.0%) patients. Patients who were started on Infectious Diseases Society of America guideline adherent antibiotic regimen were not significantly different in terms of bacteremia rate (P = .86), mortality (P = .25), length of stay (P = .27), or final antibiotic duration (P = .43) when compared to those on alternative regimens. Patients with a tissue culture positive for a fungal organism were not significantly different in terms of Fournier's Gangrene Severity Index (P = .25) or length of stay (P = .19). CONCLUSION: Local disease-specific antibiograms can be a powerful tool to guide empiric antibiotic therapy in FG. Although fungal infections are responsible for a majority of the gaps in empiric antimicrobial coverage at our institution they were present in only 15% of patients and their effect on outcomes does not justify addition of empiric antifungal agents.

Class switching is differentially regulated in RBC alloimmunization and vaccination.

BACKGROUND: Studies of human patients have shown that most anti-RBC alloantibodies are IgG1 or IgG3 subclasses, although it is unclear why transfused RBCs preferentially drive these subclasses over others. Though mouse models allow for the mechanistic exploration of class-switching, previous studies of RBC alloimmunization in mice have focused more on the total IgG response than the relative distribution, abundance, or mechanism of IgG subclass generation. Given this major gap, we compared the IgG subclass distribution generated in response to transfused RBCs relative to protein in alum vaccination, and determined the role of STAT6 in their generation. STUDY DESIGN AND METHODS: WT mice were either immunized with Alum/HEL-OVA or transfused with HOD RBCs and levels of anti-HEL IgG subtypes were measured using end-point dilution ELISAs. To study the role of STAT6 in IgG class-switching, we first generated and validated novel STAT6 KO mice using CRISPR/cas9 gene editing. STAT6 KO mice were then transfused with HOD RBCs or immunized with Alum/HEL-OVA, and IgG subclasses were quantified by ELISA. RESULTS: When compared with antibody responses to Alum/HEL-OVA, transfusion of HOD RBCs induced lower levels of IgG1, IgG2b, and IgG2c but similar levels of IgG3. Class switching to most IgG subtypes remained largely unaffected in STAT6 deficient mice in response to HOD RBC transfusion, with the one exception being IgG2b. In contrast, STAT6 deficient mice showed altered levels of all IgG subtypes following Alum vaccination. DISCUSSION: Our results show that anti-RBC class-switching occurs via alternate mechanisms when compared with the well-studied immunogen alum vaccination.

Class switching is differentially regulated in RBC alloimmunization and vaccination.

Background: Studies of human patients have shown that most anti-RBC alloantibodies are IgG1 or IgG3 subclasses, though it is unclear why transfused RBCs preferentially drive these subclasses over others. Though mouse models allow for the mechanistic exploration of class-switching, previous studies of RBC alloimmunization in mice have focused more on the total IgG response than the relative distribution, abundance, or mechanism of IgG subclass generation. Given this major gap, we compared the IgG subclass distribution generated in response to transfused RBCs relative to protein in alum vaccination, and determined the role of STAT6 in their generation. Study Design and Methods: WT mice were either immunized with Alum/HEL-OVA or transfused with HOD RBCs and levels of anti-HEL IgG subtypes were measured using end-point dilution ELISAs. To study the role of STAT6 in IgG class-switching, we first generated and validated novel STAT6 KO mice using CRISPR/cas9 gene editing. STAT6 KO mice were then transfused with HOD RBCs or immunized with Alum/HEL-OVA, and IgG subclasses were quantified by ELISA. Results: When compared to antibody responses to Alum/HEL-OVA, transfusion of HOD RBCs induced lower levels of IgG1, IgG2b and IgG2c but similar levels of IgG3. Class switching to most IgG subtypes remained largely unaffected in STAT6 deficient mice in response to HOD RBC transfusion, with the one exception being IgG2b. In contrast, STAT6 deficient mice showed altered levels of all IgG subtypes following Alum vaccination. Discussion: Our results show that anti-RBC class-switching occurs via alternate mechanisms when compared to the well-studied immunogen alum vaccination.

The lysophospholipid-binding molecule CD1D is not required for the alloimmunization response to fresh or stored RBCs in mice despite RBC storage driving alterations in lysophospholipids.

BACKGROUND: Despite the significant adverse clinical consequences of RBC alloimmunization, our understanding of the signals that induce immune responses to transfused RBCs remains incomplete. Though RBC storage has been shown to enhance alloimmunization in the hen egg lysozyme, ovalbumin, and human Duffy (HOD) RBC alloantigen mouse model, the molecular signals leading to immune activation in this system remain unclear. Given that the nonclassical major histocompatibility complex (MHC) Class I molecule CD1D can bind to multiple different lysophospholipids and direct immune activation, we hypothesized that storage of RBCs increases lysophospholipids known to bind CD1D, and further that recipient CD1D recognition of these altered lipids mediates storage-induced alloimmunization responses. STUDY DESIGN AND METHODS: We used a mass spectrometry-based approach to analyze the changes in lysophospholipids that are induced during storage of mouse RBCs. CD1D knockout (CD1D-KO) and wild-type (WT) control mice were transfused with stored HOD RBCs to measure the impact of CD1D deficiency on RBC alloimmunization. RESULTS: RBC storage results in alterations in multiple lysophospholipid species known to bind to CD1D and activate the immune system. Prior to transfusion, CD1D-deficient mice had lower baseline levels of polyclonal immunoglobulin (IgG) relative to WT mice. In response to stored RBC transfusion, CD1D-deficient mice generated similar levels of anti-HOD IgM and anti-HOD IgG. CONCLUSION: Although storage of RBCs leads to alteration of several lysophospholipids known to be capable of binding CD1D, storage-induced RBC alloimmunization responses are not impacted by recipient CD1D deficiency.

Determination of shared genetic etiology and possible causal relations between tobacco smoking and depression.

BACKGROUNDS: Cigarette smoking is strongly associated with major depressive disorder (MDD). However, any genetic etiology of such comorbidity and causal relations is poorly understood, especially at the genome-wide level. METHODS: In the present in silico research, we analyzed summary data from the genome-wide association study of the Psychiatric Genetic Consortium for MDD (n = 191 005) and UK Biobank for smoking (n = 337 030) by using various biostatistical methods including Bayesian colocalization analysis, LD score regression, variant effect size correlation analysis, and Mendelian randomization (MR). RESULTS: By adopting a gene prioritization approach, we identified 43 genes shared by MDD and smoking, which were significantly enriched in membrane potential, gamma-aminobutyric acid receptor activity, and retrograde endocannabinoid signaling pathways, indicating that the comorbid mechanisms are involved in the neurotransmitter system. According to linkage disequilibrium score regression, we found a strong positive correlation between MDD and current smoking (rg = 0.365; p = 7.23 × 10-25) and a negative correlation between MDD and former smoking (rg = -0.298; p = 1.59 × 10-24). MR analysis suggested that genetic liability for depression increased smoking. CONCLUSIONS: These findings inform the concomitant conditions of MDD and smoking and support the use of self-medication with smoking to counteract depression.

Clostridiales are predominant microbes that mediate psychiatric disorders.

BACKGROUND: An increasing number of studies have documented associations between psychiatric diseases and the gut microbiome. By taking genetic correlation and comorbidity of different psychiatric diseases into consideration, we hypothesized that different psychiatric diseases might share some similar microbial shift patterns. However, a deep understanding of whether and how those psychiatric disease-associated microbial dysbiosis spectrums are correlated is currently lacking. METHODS: In this study, we analyzed six case-control 16S amplicon sequencing datasets for psychiatric disorders, which included a total of 430 subjects, and compared microbial dysbiosis patterns across these studies. RESULTS: Different psychiatric diseases exhibited similar overall shift patterns. Significant correlations of overall shift patterns existed between schizophrenia and anorexia (p = 0.0008), as well as between schizophrenia and autism (p = 0.028). We identified 6 genera within order Clostridiales (genus Gemmiger, Faecalibacterium, Roseburia, Lachnospira, Anaerostipes, and two unclassified genera from family Lachnopsiraceae and Christensenellaceae) that were significantly depleted in multiple psychiatric diseases. Our further functional analysis revealed that depletion of these Clostridiales was associated with dysfunction in amino acid metabolism and carbohydrate metabolism. Short chain fatty acid (SCFA) producing bacteria Roseburia was the most important contributor for major KEGG (Kyoto Encyclopedia of Genes and Genomes) orthology entries involved in amino acid metabolism. CONCLUSIONS: Our study revealed common microbial shift patterns across psychiatric disorders and found predominant psychiatry-associated intestinal microbes and functions. Depletion of Clostridiales (e.g., Roseburia) probably mediated different psychiatric diseases by dysfunction of intestinal amino acid metabolism and SCFA production. Furthermore, our study indicated that correlations of microbial shift patterns between psychiatric diseases may derived from their genetic associations. Such shared microbial dysbiosis patterns are intriguing for discovering biomarkers and investigating therapeutic targets for treating psychiatric diseases.