RESUMO

One of the main challenges in food microbiology is to prevent the risk of outbreaks by avoiding the distribution of food contaminated by bacteria. This requires constant monitoring of the circulating strains throughout the food production chain. Bacterial genomes contain signatures of natural evolution and adaptive markers that can be exploited to better understand the behavior of pathogen in the food industry. The monitoring of foodborne strains can therefore be facilitated by the use of these genomic markers capable of rapidly providing essential information on isolated strains, such as the source of contamination, risk of illness, potential for biofilm formation, and tolerance or resistance to biocides. The increasing availability of large genome datasets is enhancing the understanding of the genetic basis of complex traits such as host adaptation, virulence, and persistence. Genome-wide association studies have shown very promising results in the discovery of genomic markers that can be integrated into rapid detection tools. In addition, machine learning has successfully predicted phenotypes and classified important traits. Genome-wide association and machine learning tools have therefore the potential to support decision-making circuits intending at reducing the burden of foodborne diseases. The aim of this chapter review is to provide knowledge on the use of these two methods in food microbiology and to recommend their use in the field.

Assuntos

RESUMO

BACKGROUND: Medical records are essential documents that outline a patient's medical history and current health status. It involves maintaining records that include assessments of patient outcomes, care plans, and interventions necessary to meet patient needs. A patient's medical record encompasses details about their condition, as documented by healthcare professionals, including clinical assessments, evaluations, and professional opinions related to the delivery of care. METHODS:  This retrospective study aimed to evaluate the adequacy of our documentation for acute ankle fractures in accordance with the British Orthopaedic Association Standards for Trauma and Orthopaedics (BOAST) guidelines, encompassing a total of 41 cases. The research was conducted at the Gezira Center for Orthopedic Surgery and Traumatology (GCOST) in Wad Madani, Sudan, from May 12 to July 12, 2022. RESULTS: Of the 41 recorded notes for acute ankle fractures, 26 (63.4%) were documented by medical officers and 15 (36.6%) by orthopaedic trainees. Most fractures (25 cases, 61%) occurred in individuals aged 18-40 years, and the gender distribution showed that males accounted for most fractures, with 29 cases (70.7%). Additionally, all patients (100%) had a documented cause of injury. Skin integrity was noted in 38 patients (92.7%). Vascular examination was documented in 18 patients (43.9%), while neurological examination was recorded in 16 patients (39%). CONCLUSION: Although the cause of ankle fractures was reported in all patients, the neurovascular examination was insufficiently documented, compromising patient care and failing to meet national standards, as highlighted in our study. We recommend implementing the BOAST guidelines to ensure proper documentation and essential assessments.

RESUMO

Introduction: The degree of perceived smoking stigma can differ, based on various factors such as gender; this may influence the effect of smoking cessation interventions, including denormalization. This study investigates the gender differences in smoking stigma recognized by Korean smokers and explores the effect of these differences on the success of smoking cessation messages that aim to initiate an identity crisis among smokers. It aims to contribute to effective smoking cessation intervention strategies for female smokers. Methods: The smoker-gender Implicit Association Test (IAT) was used to measure gender-based smoking stigma; the test comprised photos of people smoking, with positive and negative descriptors. Participants were 120 smokers aged 19-35 years (60 males and 60 females). Participants' cognitive attitudes toward smoking and cessation intentions were assessed at baseline. To investigate the effect of social stigmatization on smokers, participants were asked to watch anti-smoking campaigns that stigmatized either smoking behavior or smokers' self-identity. Cognitive attitudes and cessations intention were used to show differences in gender and message conditions. Results: The IAT D-score showed that female smokers perceived other female smokers significantly more negatively than they did male smokers, suggesting a higher level of smoking stigma. Female smokers in the socially stigmatizing condition reduced their negativity toward smoking less than those who were not stigmatized. Moreover, cessation intentions did not improve when female smokers received identity-threatening messages, indicating that female smokers tended to resist stigmatizing messages. Discussions: These findings provide empirical evidence that the gender of Korean smokers is significantly related to differences in smoking stigma. The negative perception and resistance responses of female smokers shown in this study are consistent with the findings of previous studies on the stigma of substance use disorders and addiction. High smoking stigma can also be a risk factor in anti-smoking interventions, including health communication; therefore, these findings should be interpreted with caution.

RESUMO

To counteract the growing population and climate changes, resilient varieties adapted to regional environmental changes are required. Landraces are valuable genetic resources for achieving this goal. Recent advances in sequencing technology have enabled national seed/gene banks to share genomic and genetic information from their collections including landraces, promoting the more efficient utilization of germplasms. In this study, we developed genomic and genetic resources for Myanmar rice germplasms. First, we assembled a diversity panel consisting of 250 accessions representing the genetic diversity of Myanmar indica varieties, including an elite lowland variety, Inn Ma Yebaw (IMY). Our population genetic analyses illustrated that the diversity panel represented Myanmar indica varieties well without any apparent population structure. Second, de novo genome assembly of IMY was conducted. The IMY assembly was constructed by anchoring 2888 contigs, which were assembled from 30× coverage of long reads, into 12 chromosomes. Although many gaps existed in the IMY genome assembly, our quality assessments indicated high completeness in the gene-coding regions, identical to other near-gap-free assemblies. Together with dense variant information, the diversity panel and IMY genome assembly will facilitate deeper genetic research and breeding projects that utilize the untapped Myanmar rice germplasms.

RESUMO

Background: Prior research suggests a potential link between ABO blood types and susceptibility to various malignancies. The correlation between ABO blood types and hematological myeloid neoplasms, however, remains inadequately explored. Objective: This study investigates the association between ABO blood groups and the incidence of hematological myeloid neoplasms in adolescents and adults. Methods: In this retrospective clinical study, 1,022 adolescent and adult cases of myeloid neoplasms diagnosed at our institution were initially considered. After excluding conditions potentially linked to ABO blood types from prior studies, 792 eligible cases were analyzed. These cases were categorized based on disease subtypes and compared with a control group for blood type distribution. Results: Our findings reveal a significantly higher prevalence of blood type A in patients with myeloid neoplasms compared to the control group, except for chronic myelocytic leukemia and myeloproliferative neoplasms. Conversely, the prevalence of blood type AB in myeloid neoplasms was notably lower than in the control group. Conclusion: The study suggests a potential association between ABO blood types and the risk of developing hematological myeloid neoplasms in adolescents and adults. Further research is warranted to elucidate the underlying mechanisms of this relationship.

RESUMO

Wampee (Clausena lansium) is an economically significant subtropical fruit tree widely cultivated in Southern China. To provide high-quality genomic resources for C. lansium, we report a chromosome-level genome sequence for the "JinFeng" cultivar. The 297.1 Mb C. lansium genome contained nine chromosomes with a scaffold N50 of 29.2 Mb and encoded 23,468 protein-coding genes. Selective sweep analysis between sweet and sour C. lansium varieties and genome-wide association analysis identified 14 candidate genes putatively involved in sugar and acid accumulation. ClERF061, encoding an ethylene response factor, and ClSWEET7, encoding a Sugars Will Eventually be Exported Transporters (SWEET) family protein, were proposed as key regulators of the sweet and sour tastes of the wampee fruit. ClERF061 and ClSWEET7 overexpression in tomatoes increased the total sugar and acid content in fruits. ClSWEET7 promoter activation by ClERF061 was confirmed via Nicotiana benthamiana transient expression. Our study provides valuable genomic resources for C. lansium genetics and breeding.

RESUMO

The neural mechanisms supporting semantic association and categorization are examined in this study. Semantic association involves linking concepts through shared themes, events, or scenes, while semantic categorization organizes meanings hierarchically based on defining features. Twenty-three adults participated in an fMRI study performing categorization and association judgment tasks. Results showed stronger activation in the inferior frontal gyrus during association and marginally weaker activation in the posterior middle temporal gyrus (pMTG) during categorization. Granger causality analysis revealed bottom-up connectivity from the visual cortex to the hippocampus during semantic association, whereas semantic categorization exhibited strong reciprocal connections between the pMTG and frontal semantic control regions, together with information flow from the visual association area and hippocampus to the pars triangularis. We propose that demands on semantic retrieval, precision of semantic representation, perceptual experiences and world knowledge result in observable differences between these two semantic relations.

RESUMO

Tailwater from wastewater treatment plants (WWTP) usually reduces the nitrogen (N) removal efficiency while simultaneously elevates nitrous oxide (N2O) emissions due to the low carbon-nitrogen (C/N) ratio. Conflicts between N removal and N2O emissions require mitigation by selecting appropriate aquatic plants for tailwater treatment. In this study, a simulated tailwater mesocosm was established using three aquatic plants including Eichhornia crassipes, Myriophyllum aquaticum and Pistia stratiotes. Results of the 15N isotope mass balance analysis revealed the considerable contributions from plant uptake and benthic retention to overall N removal. It was demonstrated that the N assimilation efficiency of aquatic plants depended more on the root-shoot ratio rather than on growth rate. Furthermore, aquatic plants indirectly influence microbial N removal and N2O emissions by altering the water quality parameters. Additionally, aquatic plants could regulate the N transformation through affecting the structure of bacterial community, including microbial abundance, diversity and association networks. Overall, the study underlined the enormous capacities of E. crassipes and P. stratiotes for N uptake and N2O mitigation in tailwater treatment. Utilizing these two aquatic plants for phytoremediation may help mitigate the conflict between tailwater purification and N2O production.

RESUMO

The Sol-gel precursor solution reaction mechanism has a significant impact on the Cu2ZnSn(S, Se)4 (CZTSSe) solar cells. It is discovered that in the Cu2ZnSnS4 (CZTS) precursor solution (CZTS-PS) in the preparation, there is an association reaction among Cu2+, thiourea (Tu), and carboxyl (-COOH), which is an important reason for the undesirable CZTSSe solar cells. The strong association reaction generates excessive Cu2+ ions, forming the CuxSe secondary phase on the surface of the CZTSSe absorber. The secondary phase causes a short circuit and deterioration of gadget performance. Following a 6-h aging period for the CZTS-PS, the average photoelectric conversion efficiency (PCE) of the device is enhanced to 8.02%, and there is also an improvement in device uniformity, as evidenced by a decrease in the standard deviation to less than 1. To inhibit the association reaction and eliminate the aging time phenomenon, a strategy is developed using hydrochloric acid to regulate the CZTS-PS environment. This strategy shifts the REDOX reaction in Cu2++Sn2+ toward the formation of Cu1++Sn4+, leading to a decrease in the defect concentrations of VSn(-/0) and CuSn(-/0), which increases the carrier concentration and reduces the impact of band tailing. The average power conversion efficiency (PCE) of the devices improved from 7.45% to 9.26%, the PCE of the best-performing CZTSSe solar cells increased from 9.25% to 9.83%, and the consistency among the devices is further enhanced, as indicated by a reduction in the standard deviation from 0.98 to 0.44. Ultimately, the device performance of the Cu2++Sn2+-DMF system improved by 11.01% (without the MgF2 layer) after optimization. This study serves as a reference for regulating the environment of the CZTS-PS to further enhance the CZTSSe devices' performance, and the photoelectric conversion efficiency is improved by ≈30%.

RESUMO

Background: Cathepsins, key regulators of the pathology of gastrointestinal disorders such as inflammatory bowel disease (IBD), are a target protease that has attracted much attention in recent years. IBD is a chronic and relapsing inflammatory disorder of the gut. Traditional studies have shown a correlation between cathepsin and the risk of IBD, while the causal relationship remains unclear. Methods: This study utilized Mendelian randomization techniques to evaluate the causal relationships between eleven cathepsins and the subtypes of IBD, such as ulcerative colitis (UC) and Crohn's disease (CD). We also performed a series of sensitivity analyses to validate the primary Mendelian randomization (MR) results, including Cochran's Q test, the MR-PRESSO global test, and the MR pleiotropy test. Results: The forward MR analyses showed no significant association between cathepsins and IBD. Reverse Mendelian randomization analyses suggested that UC might lead to elevated cathepsin G levels [inverse-variance weighted (IVW): p = 0.038, b = 9.966], and CD might cause a decrease in cathepsin B levels [IVW: p = 0.002, b = -10.525] and cathepsin L1 levels [IVW: p = 0.045, b = -4.742]. Conclusions: Our findings offer novel and comprehensive evidence on the impact of UC or CD on cathepsins, potentially providing valuable insights into the treatment and prognosis of IBD.

RESUMO

On the basis of comparisons between bovine and ovine genome mapping information, the aim of the study was to analyze the genetic diversity of selected DNA microsatellites from the bovine genome and to investigate their correlation with the average daily milk yield in Awassi sheep. 18 informative microsatellite markers were selected from the significant QTL regions affecting milk yield identified in the bovine genome in previous studies. The selected microsatellite markers were then amplified by PCR as reciprocal amplifications on the genomic DNA of Awassi sheep, with standard daily milk yield records. Thus, in this study, 18 microsatellite markers associated with milk yield in the bovine genome were examined for both determination of genetic polymorphism within the flock and the effects of marker loci on average daily milk yield in Awassi sheep. Allele frequencies of markers were determined based on the results of fragment analysis. The analysis of variance showed that the 123 bp allele at the marker locus BMS1341 on BTA2 significantly influenced the average daily milk yield of Ivesi sheep (P < 0.01). On the other hand, the BMS381 locus with a 115 bp allele on BTA2, the MCM140 locus with a 185 bp allele on BTA6, the BMS2721 locus with a 155 bp allele, the BM1237 locus with 174 and 180 bp alleles on BTA7, and finally, the BMS1967 locus with a 117 bp allele, the BM4208 locus with 176 and 182 bp alleles, and the INRA locus with a185 bp allele on BTA8 showed moderately significant effects on the average daily milk yield of Ivesi ewes (P < 0.05).

Assuntos

RESUMO

BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by 22q13 deletions that include the SHANK3 gene or pathogenic sequence variants in SHANK3. It is characterized by global developmental delay, intellectual disability, speech impairment, autism spectrum disorder, and hypotonia; other variable features include epilepsy, brain and renal malformations, and mild dysmorphic features. Here, we conducted genotype-phenotype correlation analyses using the PMS International Registry, a family-driven registry that compiles clinical data in the form of family-reported outcomes and family-sourced genetic test results. METHODS: Data from the registry were harmonized and integrated into the i2b2/tranSMART clinical and genomics data warehouse. We gathered information from 401 individuals with 22q13 deletions including SHANK3 (n = 350, ranging in size from 10 kb to 9.1 Mb) or pathogenic or likely pathogenic SHANK3 sequence variants (n = 51), and used regression models with deletion size as a potential predictor of clinical outcomes for 328 phenotypes. RESULTS: Our results showed that increased deletion size was significantly associated with delay in gross and fine motor acquisitions, a spectrum of conditions related to poor muscle tone, renal malformations, mild dysmorphic features (e.g., large fleshy hands, sacral dimple, dysplastic toenails, supernumerary teeth), lymphedema, congenital heart defects, and more frequent neuroimaging abnormalities and infections. These findings indicate that genes upstream of SHANK3 also contribute to some of the manifestations of PMS in individuals with larger deletions. We also showed that self-help skills, verbal ability and a range of psychiatric diagnoses (e.g., autism, ADHD, anxiety disorder) were more common among individuals with smaller deletions and SHANK3 variants. LIMITATIONS: Some participants were tested with targeted 22q microarrays rather than genome-wide arrays, and karyotypes were unavailable in many cases, thus precluding the analysis of the effect of other copy number variants or chromosomal rearrangements on the phenotype. CONCLUSIONS: This is the largest reported case series of individuals with PMS. Overall, we demonstrate the feasibility of using data from a family-sourced registry to conduct genotype-phenotype analyses in rare genetic disorders. We replicate and strengthen previous findings, and reveal novel associations between larger 22q13 deletions and congenital heart defects, neuroimaging abnormalities and recurrent infections.

Assuntos

RESUMO

Introduction: Male pattern baldness (MPB), also known as androgenetic alopecia, represents the most prevalent form of progressive hair loss in humans. It is characterized by a distinctive pattern of hair loss progression from the scalp; however, its underlying mechanism remains elusive and is influenced by hereditary, immune, and environmental factors. Genome-wide association studies (GWASs) have uncovered numerous risk genes/loci among European individuals with MPB. However, the validation of these susceptibility genes/loci within Han Chinese men remains largely unexplored. The aim of this study was to investigate whether the 71 susceptibility loci identified in a recent GWAS among European men also confer risk for MPB in Chinese men. Methods: Forty-seven single nucleotide polymorphisms (SNPs) previously reported in GWASs of MPB were selected and genotyped in independent individuals comprising 499 Han Chinese cases and 1,489 controls using the Sequenom MassArray system. After stringent quality control measures, 25 SNPs were subjected to statistical analyses. Cochran-Armitage trend test was used to evaluate the association between SNPs and disease susceptibility. To address multiple tests, Bonferroni correction was conducted, setting the threshold for statistical significance at a p-value <2 × 10-3 (0.05/25). Results: The rs13405699 SNP located at 2q31.1 exhibited a significant association with MPB in Han Chinese men (p = 4.84 × 10-5, OR = 1.37, 95% CI: 1.18-1.59). Moreover, the difference in rs13405699 genotype distribution between MPB cases and controls was statistically significant (p = 7.00 × 10-5). Genotype-based association analysis suggested that the recessive model provided the best fit for the rs13405699 polymorphism. Conclusion: This study represents the first confirmation of the association between the rs13405699 SNP at 2q31.1 and MPB within the Han Chinese population, thereby enhancing our understanding of the genetic underpinnings of MPB.

RESUMO

PURPOSE: To investigate the causal association between gut microbiota and allergic conjunctivitis. METHODS: A two-sample Mendelian randomization (MR) analysis was performed using the summary statistics of gut microbiota (18,340) from MiBio-Gen consortium and allergic conjunctivitis data (n = 218,792) obtained from the IEU Open GWAS project. F-statistics and sensitivity analyses were used to address potential biases and ensure the reliability of our findings. Reverse MR analysis was conducted to assess the possible of reverse causal relationships. RESULTS: The inverse variance weighted estimates revealed the protective potential of the phylum Euryarchaeota against allergic conjunctivitis (OR = 0.87, p = 6.17 × 10-4). On the other hand, the genus Christensenellaceae R.7 group (OR = 0.75, p = 2.89 × 10-3), family Peptostreptococcaceae (OR = 0.83, p = 6.22 × 10-3), genus Lachnospiraceae FCS020 group (OR = 0.82, p = 0.02) all showed a suggestive protective association with allergic conjunctivitis. Additionally, sensitivity analysis confirmed the robustness of the above associations. In the reverse MR analysis, no significant causal association was found between gut microbiota and allergic conjunctivitis. CONCLUSION: This study has revealed a potential causal correlation between the phylum Euryarchaeota and allergic conjunctivitis, offering new insights to improve prevention and treatment of this condition.

RESUMO

Epigenome-wide association studies (EWAS) are susceptible to widespread confounding caused by population structure and genetic relatedness. Nevertheless, kinship estimation is challenging in EWAS without genotyping data. Here, we proposed MethylGenotyper, a method that for the first time enables accurate genotyping at thousands of single nucleotide polymorphisms (SNPs) directly from commercial DNA methylation microarrays. We modeled the intensities of methylation probes near SNPs with a mixture of three beta distributions corresponding to different genotypes and estimated parameters with an expectation-maximization algorithm. We conducted extensive simulations to demonstrate the performance of the method. When applying MethylGenotyper to the Infinium EPIC array data of 4662 Chinese samples, we obtained genotypes at 4319 SNPs with a concordance rate of 98.26%, enabling the identification of 255 pairs of close relatedness. Furthermore, we showed that MethylGenotyper allows for the estimation of both population structure and cryptic relatedness among 702 Australians of diverse ancestry. We also implemented MethylGenotyper in a publicly available R package (https://github.com/Yi-Jiang/MethylGenotyper) to facilitate future large-scale EWAS.

Assuntos

RESUMO

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease caused by a combination of aging, environmental, and genetic factors. Previous research has implicated both causative and susceptibility genes in PD development. Nogo-A, a neurite outgrowth inhibitor, has been shown to impact axon growth through ligand-receptor interactions negatively, thereby involved in the deterioration of dopaminergic neurons. However, rare genetic studies have identified the relationship between neurite outgrowth inhibitor (Nogo)-associated genes and PD from a signaling pathway perspective. METHODS: We enrolled 3959 PD patients and 2931 healthy controls, categorized into two cohorts based on their family history and age at onset: sporadic early Parkinson's disease & familial Parkinson's disease (sEOPD & FPD) cohort and sporadic late Parkinson's disease (sLOPD) cohort. We selected 17 Nogo-associated genes and stratified them into three groups via their function, respectively, ligand, receptors, and signaling pathway groups. Additionally, we conducted the burden analysis in rare variants, the logistic regression analysis in common variants, and the genotype-phenotype association analysis. Last, bioinformatics analysis and functional experiments were conducted to identify the role of the MTOR gene in PD. RESULTS: Our findings demonstrated that the missense variants in the MTOR gene might increase PD risk, while the deleterious variants in the receptor subtype of Nogo-associated genes might mitigate PD risk. However, common variants of Nogo-associated genes showed no association with PD development in two cohorts. Furthermore, genotype-phenotype association analysis suggested that PD patients with MTOR gene variants exhibited relatively milder motor symptoms but were more susceptible developing dyskinesia. Additionally, bioinformatics analysis results showed MTOR gene was significantly decreased in PD, indicating a potential negative role of the mTOR in PD pathogenesis. Experimental data further demonstrated that MHY1485, a mTOR agonist, could rescue MPP+-induced axon inhibition, further implicating the involvement of mTOR protein in PD by regulating cell growth and axon growth. CONCLUSIONS: Our preliminary investigation highlights the association of Nogo-associated genes with PD onset in the Chinese mainland population and hints at the potential role of the MTOR gene in PD. Further research is warranted to elucidate the mechanistic pathways underlying these associations and their therapeutic implications.

Assuntos

RESUMO

AIM: Various anthropometric measures capture distinct as well as overlapping characteristics of an individual's body composition. To characterize independent body composition measures, we aimed to reduce easily-obtainable individual measures reflecting adiposity, anthropometrics and energy expenditure into fewer independent constructs, and to assess their potential sex- and age-specific relation with cardiometabolic diseases. METHODS: Analyses were performed within European ancestry participants from UK Biobank (N = 418,963, mean age 58.0 years, 56% women). Principal components (PC) analyses were used for the dimension reduction of 11 measures of adiposity, anthropometrics and energy expenditure. PCs were studied in relation to incident type 2 diabetes mellitus (T2D) and coronary artery disease (CAD). Multivariable-adjusted Cox regression analyses, adjusted for confounding factors, were performed in all and stratified by age. Genome-wide association studies were performed in half of the cohort (N = 156,295) to identify genetic variants as instrumental variables. Genetic risk score analyses were performed in the other half of the cohort stratified by age of disease onset (N = 156,295). RESULTS: We identified two PCs, of which PC1 reflected lower overall adiposity (negatively correlated with all adiposity aspects) and PC2 reflected more central adiposity (mainly correlated with higher waist-hip ratio, but with lower total body fat) and increased height, collectively capturing 87.8% of the total variance. Similar to that observed in the multivariable-adjusted regression analyses, we found associations between the PC1 genetic risk score and lower risks of CAD and T2D [CAD cases <50 years, odds ratio: 0.91 (95% confidence interval 0.87, 0.94) per SD; T2D cases <50 years, odds ratio: 0.76 (0.72, 0.81)], which attenuated with higher age (p-values 8.13E-4 and 2.41E-6, respectively). No associations were found for PC2. CONCLUSIONS: The consistently observed weaker associations of the composite traits with cardiometabolic disease suggests the need for age-specific cardiometabolic disease prevention strategies.

RESUMO

Cholecystitis, characterized by inflammation of the gallbladder, is intricately linked to immune cells and the cytokines they produce. Despite this association, the specific contributions of immune cells to the onset and progression of cholecystitis remain to be fully understood. To delineate this relationship, we utilized the Mendelian randomization (MR) method to scrutinize the causal connections between 731 immune cell phenotypes and cholecystitis. By conducting MR analysis on 731 immune cell markers from public datasets, this study seeks to understand their potential impact on the risk of cholecystitis. It aims to elucidate the interactions between immune phenotypes and the disease, aiming to lay the groundwork for advancing precision medicine and developing effective treatment strategies for cholecystitis. Taking immune cell phenotypes as the exposure factor and cholecystitis as the outcome event, this study used single nucleotide polymorphisms (SNPs) closely associated with both immune cell phenotypes and cholecystitis as genetic instrumental variables. We conducted a two-sample MR analysis on genome-wide association studies (GWAS) data. Our research thoroughly examined 731 immune cell markers, to determine potential causal relationships with susceptibility to cholecystitis. Sensitivity analyses were performed to ensure the robustness of our findings, excluding the potential impacts of heterogeneity and pleiotropy. To avoid reverse causality, we conducted reverse MR analyses with cholecystitis as the exposure factor and immune cell phenotypes as the outcome event. Among the 731 immune phenotypes, our study identified 21 phenotypes with a causal relationship to cholecystitis (P < 0.05). Of these, eight immune phenotypes exhibited a protective effect against cholecystitis (odds ratio (OR) < 1), while the other 13 immune phenotypes were associated with an increased risk of developing cholecystitis (OR > 1). Additionally, employing the false discovery rate (FDR) method at a significance level of 0.2, no significant causal relationship was found between cholecystitis and immune phenotypes. Our research has uncovered a significant causal relationship between immune cell phenotypes and cholecystitis. This discovery not only enhances our understanding of the role of immune cells in the onset and progression of cholecystitis but also establishes a foundation for developing more precise biomarkers and targeted therapeutic strategies. It provides a scientific basis for more effective and personalized treatments in the future. These findings are expected to substantially improve the quality of life for patients with cholecystitis and mitigate the impact of the disease on patients and their families.

RESUMO

Opioid prescription records in existing electronic health record (EHR) databases are a potentially useful, high-fidelity data source for opioid use-related risk phenotyping in genetic analyses. Prescriptions for codeine derived from EHR records were used as targeting traits by screening 16 million patient-level medication records. Genome-wide association analyses were then conducted to identify genomic loci and candidate genes associated with different count patterns of codeine prescriptions. Both low- and high-prescription counts were captured by developing 8 types of phenotypes with selected ranges of prescription numbers to reflect potentially different levels of opioid risk severity. We identified one significant locus associated with low-count codeine prescriptions (1, 2 or 3 prescriptions), while up to 7 loci were identified for higher counts (≥ 4, ≥ 5, ≥6, or ≥ 7 prescriptions), with a strong overlap across different thresholds. We identified 9 significant genomic loci with all-count phenotype. Further, using the polygenic risk approach, we identified a significant correlation (Tau = 0.67, p = 0.01) between an externally derived polygenic risk score for opioid use disorder and numbers of codeine prescriptions. As a proof-of-concept study, our research provides a novel and generalizable phenotyping pipeline for the genomic study of opioid-related risk traits.

Assuntos

RESUMO

Major depressive disorder (MDD), a leading cause of years of life lived with disability, presents challenges in diagnosis and treatment due to its complex and heterogeneous nature. Emerging evidence indicates that reward processing abnormalities may serve as a behavioral marker for MDD. To measure reward processing, patients perform computer-based behavioral tasks that involve making choices or responding to stimulants that are associated with different outcomes, such as gains or losses in the laboratory. Reinforcement learning (RL) models are fitted to extract parameters that measure various aspects of reward processing (e.g. reward sensitivity) to characterize how patients make decisions in behavioral tasks. Recent findings suggest the inadequacy of characterizing reward learning solely based on a single RL model; instead, there may be a switching of decision-making processes between multiple strategies. An important scientific question is how the dynamics of strategies in decision-making affect the reward learning ability of individuals with MDD. Motivated by the probabilistic reward task within the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study, we propose a novel RL-HMM (hidden Markov model) framework for analyzing reward-based decision-making. Our model accommodates decision-making strategy switching between two distinct approaches under an HMM: subjects making decisions based on the RL model or opting for random choices. We account for continuous RL state space and allow time-varying transition probabilities in the HMM. We introduce a computationally efficient Expectation-maximization (EM) algorithm for parameter estimation and use a nonparametric bootstrap for inference. Extensive simulation studies validate the finite-sample performance of our method. We apply our approach to the EMBARC study to show that MDD patients are less engaged in RL compared to the healthy controls, and engagement is associated with brain activities in the negative affect circuitry during an emotional conflict task.