Identification of a novel GNAS mutation in a family with pseudohypoparathyroidism type 1A.

BACKGROUND: Pseudohypoparathyroidism (PHP) is caused by loss-of-function mutations at the GNAS gene (as in the PHP type 1A; PHP1A), de novo or inherited at heterozygous state, or by epigenetic alterations at the GNAS locus (as in the PHP1B). The condition of PHP refers to a heterogeneous group of disorders that share common clinical and biological features of PTH resistance. Manifestations related to resistance to other hormones are also reported in many patients with PHP, in association with the phenotypic picture of Albright hereditary osteodystrophy characterized by short stature, round facies, subcutaneous ossifications, brachydactyly, mental retardation and, in some subtypes, obesity. The purpose of our study is to report a new mutation in the GNAS gene and to describe the significant phenotypic variability of three sisters with PHP1A bearing the same mutation. CASE PRESENTATION: We describe the cases of three sisters with PHP1A bearing the same mutation but characterized by a significantly different phenotypic picture at onset and during follow-up in terms of clinical features, auxological pattern and biochemical changes. Clinical exome sequencing revealed a never before described heterozygote mutation in the GNAS gene (NM_000516.5 c.118_139 + 51del) of autosomal dominant maternal transmission in the three siblings, confirming the diagnosis of PHP1A. CONCLUSIONS: This study reported on a novel mutation of GNAS gene and highlighted the clinical heterogeneity of PHP1A characterized by wide genotype-phenotype variability. The appropriate diagnosis has crucial implications for patient care and long-term multidisciplinary follow-up.

Genes of Inflammation and Placental Function GWAS Associated with Idiopathic Recurrent Miscarriage in the Kazakh Population.

Background: The loss of two or more pregnancies is considered recurrent miscarriage (RM). One of the causes of this pathology is the occurrence of mutations both in pleiotropic and pathway-specific regulators and in structural genes. The simplest type of such mutations is single nucleotide polymorphisms. Aims: The aim of the study is to study the relationship between gene polymorphisms of anti- and pro-inflammatory cytokines - interferon-gamma (T874A), interleukin (IL1B) (C3954T), IL6 (G572C) and IL10 (G1082A); placental function, apoptosis and angiogenesis - apolipoprotein C-III (APOC3) (G5163C), kinase insert domain receptor (A1719T, G1192A), P53 (Arg72Pro) and signal transducer and activator of transcription 3 (STAT3) (C1697G) with the development of idiopathic RM (iRM) in the Kazakh population. Settings and Design: This was a case-control study. Materials and Methods: Molecular genetic studies were performed by TaqMan using a single site-specific amplification and real-time genotyping method in 302 women with iRM and 300 with normal reproduction. DNA isolation from the biomaterial was carried out using kits containing binding magnetic particles. Both samples were analysed for alleles and genotypes for the studied polymorphisms. Statistical Analysis Used: For statistical data processing, Pearson's criterion, confidence interval (CI) and probability value were taken into account. Results: It was found that the carriage of unfavourable genotypes (G/C, C/C) for the G5163C polymorphism of the APOC3 gene increases the risk of developing iRM by three times (odds ratio = 3.0; 95% CI = 2.24-4.07). Other studied polymorphisms in the genes of ILs, interferon, P53 proapoptotic protein, kinase domain receptor and STAT3 transcription activator were not associated with RM. Conclusion: Significant associations of APOC3 gene genotypes with the development of iRM in the Kazakh population indicate the involvement of the placental system, which is realised by vascularisation defects and defective embryo implantation and leads to early pregnancy termination.

Evaluation of the Newcastle disease virus genotype VII-mismatched vaccines in SPF chickens: A challenge efficacy study.

Newcastle disease virus (NDV) strains, while falling under a single serotype, are classified into distinct genotypes. Genotype VII virulent NDVs pose a significant threat to poultry due to their association with high mortality rates and economic losses. This study aimed to evaluate the efficacy of three commercial live vaccines based on genotype II against genotype VII virulent NDV (vNDV) in specific pathogen-free (SPF) chickens. Forty one-day-old chickens were randomly divided into four groups (n = 10) and inoculated with one dose of each ND pneumotropic vaccine-B1, Clone.12IR, and La Sota-or received phosphate-buffered saline (PBS) as a control at eight days of age via eye drop. At 28 days of age (20th post-vaccination days), chickens were intramuscularly challenged with genotype VII virulent NDV (≥ 105 LD50). Serum samples were collected at 28 days of age (challenge day), 7 and 14 post-challenge days to measure NDV antibodies via the hemagglutination inhibition (HI) test. Cloacal and oropharyngeal swabs were taken on the 3rd, 5th, 7th, and 10th post-challenge days to evaluate virus shedding. Vaccinated groups exhibited significantly higher antibody titers and greater protection levels compared to the control group (P≤ 0.001). While HI antibody titer was not different at 28 and 35 days of age between vaccinated chickens, the Clone.12IR groups showed higher HI antibody titer compared to B1 at day 42 of age (9.43 vs. 7.42; P≤ 0.002). La Sota and Clone.12IR vaccines demonstrated superior protection against mortality compared to the B1 vaccine (90 %, 80% vs. 60 %, respectively) with 6.0 and 2.67 odds ratio of survivability. All three mismatched vaccines effectively curbed the shedding of virulent genotype VII NDV, with 0 % to 11 % positive cloacal samples up to the 3rd post-challenge day. These findings demonstrate that in the experimental setting, the administration of mismatched ND vaccines, particularly La Sota and Clone.12IR, confer protection against genotype VII virulent NDV and control viral shedding, which can help to develop effective vaccination strategies to mitigate the impact of vNDV outbreaks in the poultry farms.

A novel variant in NSUN2 causes intellectual disability in a Chinese family.

NSUN2-intellectual disability syndrome, also known as intellectual disability type 5 (MRT5), is an autosomal recessive disorder that is characterized by intellectual disability (ID), postnatal growth retardation, dysmorphic facies, microcephaly, short stature, developmental delay, language impairment and other congenital abnormalities. The disease is caused by mutations in the NSUN2 gene, which encodes a tRNA cytosine methyltransferase that has an important role in spindle assembly during mitosis and chromosome segregation. In this study, we recruited a family that had two individuals with ID. Whole exome sequencing was performed to identify a homozygous frameshift variant (c.1171_1175delACCAT(p.Thr391fs*18*)) in NSUN2 (NM_017755.5) in the proband. The varint was confirmed as segregating in his affected brother and his parents by Sanger sequencing. The individuals that we described showed a similar dysmorphology profile to that associated with MRT5. To analyze the correlations between genotypes of NSUN2 and phenotypes of individuals with ID, we examined 17 variants and the associated phenotypes from 32 ID individuals in current and previous studies. We concluded that mutations in NSUN2 cause a wide range of phenotypic defects. Although some clinical manifestations were highly variable, the core phenotypes associated with NSUN2 mutations were dysmorphic facies, microcephaly, short stature, ID, growth restriction, language impairment, hypotonia and delayed puberty. Our study expands the genetic spectrum of NSUN2 mutations and helps to further define the genotype-phenotype correlations in MRT5.

Molecular Characterization of Giardia intestinalis and Cryptosporidium spp. Detected in Humans in Agri, Türkiye.

Background: We aimed to determine the prevalence of Giardia intestinalis and Cryptosporidium spp. in patients who admitted hospital with diarrhea and to gain information about the transmission of these parasites in Agri, Türkiye. Methods: This study included 184 patients who applied to Agri-Diyadin State Hospital, Türkiye in 2022. The immunochromatographic card test was used for detection of the G. intestinalis and Cryptosporidium spp. Nested PCR-RFLP analysis of the COWP gene and sequence analysis of the gp60 gene were used to genotype and subtype Cryptosporidium spp., whereas Nested PCR and sequence analyses of ß-giardin gene were used genotype G. intestinalis. Results: Of the 184 stool specimens examined, 12 (14.29%) and 7 (3.80%) were positive for G. intestinalis and Cryptosporidium spp., respectively. The Cryptosporidium species were identified as C. parvum belonging to the IId sub-type family. The G. intestinalis were identified assemblages A. Conclusion: Assemblage A, which is associated with diarrhea, is responsible for giardiasis and C. parvum IId subtype, often found in sheep, goats and cattle, is responsible for cryptosporidiosis in Agri, Türkiye.

Sex-specific differences in the association between APOE genotype and metabolic syndrome among middle-aged and older rural Indians.

Background: Metabolic syndrome (MetS), characterized by elevated blood pressure, high blood glucose, excess abdominal fat, and abnormal cholesterol or triglyceride levels, significantly increases the risk of various non-communicable diseases. This study focuses on understanding the sex-specific association between Apolipoprotein E (APOE) polymorphism and MetS among middle-aged and older adults in rural southern India. Methods: This cross-sectional study utilized data from the Centre for Brain Research-Srinivaspura Aging, Neuro Senescence, and COGnition (CBR-SANSCOG) study. Participants (n = 3741) underwent comprehensive clinical assessments and blood investigations, including APOE genotyping. MetS was defined using the National Cholesterol Education Program - Adult Treatment Panel III (NCEP ATP III) and the Consensus criteria. Statistical analyses, including chi-square tests, ANCOVA, and logistic regression, were conducted to explore the association of APOE genotype with MetS and its components, stratified by sex. Results: Females carrying the APOE E4 allele had 1.31-fold increased odds of MetS (95 % CI: 1.02,1.69, p = 0.035) according to the NCEP ATP III criteria but not when the Consensus criteria were applied. The study also noted sex-specific differences in the association of APOE with various MetS components, including lipid levels and waist circumference. Discussion: Our findings reveal a sex-specific association between the APOE E4 allele and MetS, with only females having an increased risk. This study contributes to the understanding of the genetic underpinnings of MetS and highlights the importance of considering sex-specific differences in MetS research and its prevention strategies. This study underscores the complexity of MetS etiology and emphasizes the need for further research to elucidate the role of genetic, environmental, and lifestyle factors in its progression, particularly in sex-specific contexts.

Whole-genome resequencing and transcriptional profiling association analysis revealed the intraspecies difference response to oligosaccharides utilization in Bifidobacterium animalis subsp. lactis.

Introduction: As prebiotics, oligosaccharides are frequently combined with Bifidobacterium to develop synbiotic products. However, a highly diverse gene repertoire of Bifidobacterium is involved in sugar catabolism, and even phylogenetically close species may differ in their sugar utilization capabilities. To further explore the mechanism underlying the differences in Bifidobacterium animalis subsp. lactis oligosaccharide metabolism. Methods: This study screened strains with differential oligosaccharide metabolism. Subsequently, these strains were subjected to genome-wide resequencing and RT-qPCR. Results: The resequencing results indicated that the subspecies of B. animalis subsp. lactis had a high genome similarity. The RT-qPCR results revealed that glycosidase genes exhibited consistency in the phenotype of metabolism at the transcriptional level; the better the growth of the strains on the oligosaccharides, the higher was the expression of glycosidase genes related to the oligosaccharides. Our results suggested that the differences in the gene transcription levels led to intraspecies differences in the ability of the strains to metabolize oligosaccharides even when they belonged to the same subspecies. Discussion: Future studies with more sample size could generalizable the conclusion to all B. animalis subsp. lactis strains, thus would lay the theoretical foundation for the utilization of the B. animalis subsp. lactis strain as probiotics and the development of synbiotic products.

Risk factors for hepatocellular carcinoma associated with hepatitis C genotype 3 infection: A systematic review.

BACKGROUND: Hepatitis C virus (HCV) is a blood-borne virus which globally affects around 79 million people and is associated with high morbidity and mortality. Chronic infection leads to cirrhosis in a large proportion of patients and often causes hepatocellular carcinoma (HCC) in people with cirrhosis. Of the 6 HCV genotypes (G1-G6), genotype-3 accounts for 17.9% of infections. HCV genotype-3 responds least well to directly-acting antivirals and patients with genotype-3 infection are at increased risk of HCC even if they do not have cirrhosis. AIM: To systematically review and critically appraise all risk factors for HCC secondary to HCV-G3 in all settings. Consequently, we studied possible risk factors for HCC due to HCV-G3 in the literature from 1946 to 2023. METHODS: This systematic review aimed to synthesise existing and published studies of risk factors for HCC secondary to HCV genotype-3 and evaluate their strengths and limitations. We searched Web of Science, Medline, EMBASE, and CENTRAL for publications reporting risk factors for HCC due to HCV genotype-3 in all settings, 1946-2023. RESULTS: Four thousand one hundred and forty-four records were identified from the four databases with 260 records removed as duplicates. Three thousand eight hundred and eighty-four records were screened with 3514 excluded. Three hundred and seventy-one full-texts were assessed for eligibility with seven studies included for analysis. Of the seven studies, three studies were retrospective case-control trials, two retrospective cohort studies, one a prospective cohort study and one a cross-sectional study design. All were based in hospital settings with four in Pakistan, two in South Korea and one in the United States. The total number of participants were 9621 of which 167 developed HCC (1.7%). All seven studies found cirrhosis to be a risk factor for HCC secondary to HCV genotype-3 followed by higher age (five-studies), with two studies each showing male sex, high alpha feto-protein, directly-acting antivirals treatment and achievement of sustained virologic response as risk factors for developing HCC. CONCLUSION: Although, studies have shown that HCV genotype-3 infection is an independent risk factor for end-stage liver disease, HCC, and liver-related death, there is a lack of evidence for specific risk factors for HCC secondary to HCV genotype-3. Only cirrhosis and age have demonstrated an association; however, the number of studies is very small, and more research is required to investigate risk factors for HCC secondary to HCV genotype-3.

Clinical prediction of GBA carrier status in Parkinson's disease.

Introduction: Given the unique natural history of GBA-related Parkinson's disease (GBA-PD) and the potential for novel treatments in this population, genetic testing prioritization for the identification of GBA-PD patients is crucial for prognostication, individualizing treatment, and stratification for clinical trials. Assessing the predictive value of certain clinical traits for the GBA-variant carrier status will help target genetic testing in clinical settings where cost and access limit its availability. Methods: In-depth clinical characterization through standardized rating scales for motor and non-motor symptoms and self-reported binomial information of a cohort of subjects with PD (n = 100) from our center and from the larger cohort of the Parkinson's Progression Marker Initiative (PPMI) was utilized to evaluate the predictive values of clinical traits for GBA variant carrier status. The model was cross-validated across the two cohorts. Results: Leveraging non-motor symptoms of PD, we established successful discrimination of GBA variants in the PPMI cohort and study cohort (AUC 0.897 and 0.738, respectively). The PPMI cohort model successfully generalized to the study cohort data using both MDS-UPDRS scores and binomial data (AUC 0.740 and 0.734, respectively) while the study cohort model did not. Conclusions: We assessed the predictive value of non-motor symptoms of PD for identifying GBA carrier status in the general PD population. These data can be used to determine a simple, clinically oriented model using either the MDS-UPDRS or subjective symptom reporting from patients. Our results can inform patient counseling about the expected carrier risk and test prioritization for the expected identification of GBA variants.

Severe Vincristine-Induced Peripheral Neuropathic Weakness in Both Lower Limbs in an Asian Adolescent with CYP3A4 rs2740574 TT Genotype.

Background: Vincristine (VCR)-induced peripheral neuropathy (VIPN) is a common adverse reaction during cancer treatment, typically characterized by numbness and paresthesias. This study aimed to report a rare case of VIPN with an atypical genotype, manifesting as grade 3 weakness of the lower limbs. Case Presentation: A 19-year-old man, diagnosed with alveolar rhabdomyosarcoma for 8 months, was transferred to our hospital for further treatment after the failure of first-line treatment. He developed severe long-standing weakness in both lower limbs and could not walk after four sessions of second-line chemotherapy. The diagnosis of VIPN was confirmed based on the patient's physical examination, imaging studies, electromyogram results, and treatment history. Furthermore, the pharmacogenetic analysis indicated that the patient harbored CYP3A4 rs2740574 TT genotypes. Conclusion: We have reported for the first time a VIPN patient whose main clinical manifestation is severe weakness in both lower limbs, accompanied by the CYP3A4 rs2740574 TT phenotype. This case may provide new information on the phenotypic features of VIPN, and may help to better understand the disease pathogenesis and contributing factors.

A novel framework for human leukocyte antigen (HLA) genotyping using probe capture-based targeted next-generation sequencing and computational analysis.

Human leukocyte antigen (HLA) genes play pivotal roles in numerous immunological applications. Given the immense number of polymorphisms, achieving accurate high-throughput HLA typing remains challenging. This study aimed to harness the human pan-genome reference consortium (HPRC) resources as a potential benchmark for HLA reference materials. We meticulously annotated specific four field-resolution alleles for 11 HLA genes (HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, -DQB1, -DRB1, -DRB3, -DRB4 and -DRB5) from 44 high-quality HPRC personal genome assemblies. For sequencing, we crafted HLA-specific probes and conducted capture-based targeted sequencing of the genomic DNA of the HPRC cohort, ensuring focused and comprehensive coverage of the HLA region of interest. We used publicly available short-read whole-genome sequencing (WGS) data from identical samples to offer a comparative perspective. To decipher the vast amount of sequencing data, we employed seven distinct software tools: OptiType, HLA-VBseq, HISAT genotype, SpecHLA, T1K, QzType, and DRAGEN. Each tool offers unique capabilities and algorithms for HLA genotyping, allowing comprehensive analysis and validation of the results. We then compared these results with benchmarks derived from personal genome assemblies. Our findings present a comprehensive four-field-resolution HLA allele annotation for 44 HPRC samples. Significantly, our innovative targeted next-generation sequencing (NGS) approach for HLA genes showed superior accuracy compared with conventional short-read WGS. An integrated analysis involving QzType, T1K, and DRAGEN was developed, achieving 100% accuracy for all 11 HLA genes. In conclusion, our study highlighted the combination of targeted short-read sequencing and astute computational analysis as a robust approach for HLA genotyping. Furthermore, the HPRC cohort has emerged as a valuable assembly-based reference in this realm.

Pharmacogenetic variability of tuberculosis biomarkers in native and mestizo Peruvian populations.

In Peru, 29 292 people were diagnosed with tuberculosis in 2022. Although tuberculosis treatments are effective, 3.4%-13% are associated with significant adverse drug reactions, with drug-induced liver injury (DILI) considered the most predominant. Among the first-line antituberculosis drugs, isoniazid is the main drug responsible for the appearance of DILI. In liver, isoniazid (INH) is metabolized by N-acetyltransferase-2 (NAT2) and cytochrome P450 2E1 (CYP2E1). Limited information exists on genetic risk factors associated with the presence of DILI to antituberculosis drugs in Latin America, and even less is known about these factors in the native and mestizo Peruvian population. The aim of this study was to determine the prevalence of NAT2 and CYP2E1 genotypes in native and mestizo population. An analytical cross-sectional analysis was performed using genetic data from mestizo population in Lima and native participants from south of Peru. NAT2 metabolizer was determined as fast, intermediate and slow, and CYP2E1 genotypes were classified as c1/c1, c1/c2 and c2/c2, from molecular tests and bioinformatic analyses. Of the 472 participants, 36 and 6 NAT2 haplotypes were identified in the mestizo and native population, respectively. In mestizo population, the most frequent NAT2*5B and NAT2*7B haplotypes were associated with DILI risk; while in natives, NAT2*5G and NAT2*13A haplotypes were associated with decreased risk of DILI. For CYP2E1, c1/c1 and c1/c2 genotypes are the most frequent in natives and mestizos, respectively. The linkage disequilibrium of NAT2 single nucleotide polymorphisms (SNPs) was estimated, detecting a block between all SNPs natives. In addition, a block between rs1801280 and rs1799929 for NAT2 was detected in mestizos. Despite the limitations of a secondary study, it was possible to report associations between NAT2 and CYP2E alleles with Peruvian native and mestizo by prevalence ratios. The results of this study will help the development of new therapeutic strategies for a Tuberculosis efficient control between populations.

Biomarkers and Proteomics in Sarcomeric Hypertrophic Cardiomyopathy in the Young-FGF-21 Highly Associated with Overt Disease.

Background: Any difference in biomarkers between genotype-positive individuals with overt hypertrophic cardiomyopathy (HCM), and genotype-positive but phenotype-negative individuals (G+P-) in HCM-associated pathways might shed light on pathophysiological mechanisms. We studied this in young HCM patients. Methods: 29 HCM patients, 17 G+P--individuals, and age- and sex-matched controls were prospectively included. We analyzed 184 cardiovascular disease-associated proteins by two proximity extension assays, categorized into biological pathways, and analyzed with multivariate logistic regression analysis. Significant proteins were dichotomized into groups above/below median concentration in control group. Results: Dichotomized values of significant proteins showed high odds ratio (OR) in overt HCMphenotype for Fibroblast growth factor-21 (FGF-21) 10 (p = 0.001), P-selectin glycoprotein ligand-1 (PSGL-1) OR 8.6 (p = 0.005), and Galectin-9 (Gal-9) OR 5.91 (p = 0.004). For G+P-, however, angiopoietin-1 receptor (TIE2) was notably raised, OR 65.5 (p = 0.004), whereas metalloproteinase inhibitor 4 (TIMP4) involved in proteolysis, in contrast, had reduced OR 0.06 (p = 0.013). Conclusions: This study is one of the first in young HCM patients and G+P- individuals. We found significantly increased OR for HCM in FGF-21 involved in RAS-MAPK pathway, associated with cardiomyocyte hypertrophy. Upregulation of FGF-21 indicates involvement of the RAS-MAPK pathway in HCM regardless of genetic background, which is a novel finding.

Population Genetic Analyses and Trichothecene Genotype Profiling of Fusarium pseudograminearum Causing Wheat Crown Rot in Henan, China.

In China, Fusarium pseudograminearum has emerged as a major pathogen causing Fusarium crown rot (FCR) and caused significant losses. Studies on the pathogen's properties, especially its mating type and trichothecene chemotypes, are critical with respect to disease epidemiology and food/feed safety. There are currently few available reports on these issues. This study investigated the species composition, mating type idiomorphs, and trichothecene genotypes of Fusarium spp. causing FCR in Henan, China. A significant shift in F. pseudograminearum-induced FCR was found in the present study. Of the 144 purified strains, 143 were F. pseudograminearum, whereas only 1 Fusarium graminearum was identified. Moreover, a significant trichothecene-producing capability of F. pseudograminearum strains from Henan was observed in this work. Among the 143 F. pseudograminearum strains identified, F. pseudograminearum with a 15ADON genotype was found to be predominant (133 isolates), accounting for 92.36% of all strains, followed by F. pseudograminearum with a 3ADON genotype, whereas only one NIV genotype strain was detected. Overall, a relatively well-balanced 1:1 ratio of the F. pseudograminearum population was found in Henan. To the best of our knowledge, this is the first study that has examined the Fusarium populations responsible for FCR across the Henan wheat-growing region.

The Frequency of Porcine Cysticercosis and Factors Associated with Taenia solium Infection in the Municipality of Tuchín-Córdoba, Colombia.

Taeniasis and cysticercosis are parasitic infections that affect humans and pigs. Their global distribution constitutes a serious public health issue with significant implications for pork production. The purpose of this study was to evaluate the presence of porcine cysticercosis in backyard swine from 42 indigenous communities throughout Tuchín-Córdoba, Colombia. Between December 2020 and March 2021, free-range pigs (n = 442) were assessed using the ELISA cysticercosis Ag test; 85 pigs were examined through sublingual visual evaluation, and 4 slaughtered pig carcasses were subjected to standard operation inspection. The collected cysticercus underwent histological and PCR analysis. Furthermore, 192 surveys of knowledge, attitudes, and practices (KAP) were used to identify the factors that facilitate infection transmission. Serological investigation revealed that 9.7% (46/472) of the animals were positive for cysticerci Ag. Sublingual inspection identified cysticercus in 28.7% (25/87) of the animals, while PCR analysis indicated that cysticercus corresponded to the T. solium American/African genotype. The factors associated with T. solium infection in the pigs in the surveyed areas numbered 14. The majority are associated with factors that promote the active persistence of Taenia solium's life cycle in an area, such as lack of environmental sanitation, a lack of coverage or care for drinking water and wastewater treatment services, and no solid waste disposal.

Effect of CYP2D6, 2C19, and 3A4 Phenoconversion in Drug-Related Deaths.

Molecular autopsy is a very important tool in forensic toxicology. However, many determinants, such as co-medication and physiological parameters, should be considered for optimal results. These determinants could cause phenoconversion (PC), a discrepancy between the real metabolic profile after phenoconversion and the phenotype determined by the genotype. This study's objective was to assess the PC of drug-metabolizing enzymes, namely CYP2D6, 2C19, and 3A4, in 45 post-mortem cases where medications that are substrates, inducers, or inhibitors of these enzymes were detected. It also intended to evaluate how PC affected the drug's metabolic ratio (MR) in four cases. Blood samples from 45 cases of drug-related deaths were analyzed to detect and determine drug and metabolite concentrations. Moreover, all the samples underwent genotyping utilizing the HaloPlex Target Enrichment System for CYP2D6, 2C19, and 3A4. The results of the present study revealed a statistically significant rate of PC for the three investigated enzymes, with a higher frequency of poor metabolizers after PC. A compatibility was seen between the results of the genomic evaluation after PC and the observed MRs of venlafaxine, citalopram, and fentanyl. This leads us to focus on the determinants causing PC that may be mainly induced by drug interactions. This complex phenomenon can have a significant impact on the analysis, interpretation of genotypes, and accurate conclusions in forensic toxicology. Nevertheless, more research with more cases in the future is needed to confirm these results.

Newborn Screening for ß-Thalassemia Identifies a Complex Genotype Involving a Novel ß-Globin Gene Mutation (HBB:c.336dup).

Newborn screening identified a Chinese-Canadian infant who was positive for possible ß-thalassemia (ß-thal). Detailed family studies demonstrated that the proband was a compound heterozygote for the Chinese Gγ(Aγδß)0-thal deletion and a novel frameshift mutation within exon 3 (HBB:c.336dup), and heterozygous for the Southeast Asian α-thal deletion (--SEA/αα). This case illustrates the importance of follow-up molecular testing of positive newborn screening results to confirm the diagnosis and define risks for future pregnancies.

Satellite-enabled Enviromics to Enhance Crop Improvement.

Enviromics refers to the characterization of micro- and macroenvironments based on large-scale environmental datasets. By providing genotypic recommendations with predictive extrapolation at a site-specific level, enviromics could inform plant breeding decisions across varying conditions and anticipate productivity in a changing climate. Enviromics-based integration of statistics, envirotyping (i.e., classifying environmental factors), and remote sensing could help unravel the complex interplay of genetics, environment, and management (G × E × M). To support this goal, exhaustive envirotyping to generate precise environmental profiles would significantly improve predictions of genotype performance and genetic gain in crops. Already, informatics management platforms aggregate diverse environmental datasets obtained using optical, radar, and LiDAR sensors that capture detailed information about vegetation, surface structure, and terrain. This wealth of information, coupled with freely available climate data, fuels innovative enviromics research. While enviromics holds immense potential for sustainable breeding, a few obstacles remain, such as the need for 1) integrative methodologies to systematically collect field data to scale and expand observations across the landscape with satellite data; 2) state-of-the-art artificial intelligence (AI) models for data integration, simulation, and prediction; 3) cyberinfrastructure for processing big data across scales and providing seamless interfaces to deliver forecasts to stakeholders; and 4) collaboration and data sharing among farmers, breeders, physiologists, geoinformatics experts, and programmers across research institutions. Overcoming these challenges is essential for leveraging the full potential of big data captured by satellites to transform 21st century agriculture and crop improvement through enviromics.

Establishment and clinical application of the HLA genotype database of platelet-apheresis donors in Suzhou.

The establishment of a platelet-apheresis donor database may provide a feasible solution to improve the efficacy of platelet transfusion in patients with immune platelet transfusion refractoriness (PTR). This study aimed to establish HLA genotype database in Suzhou, to provide HLA-I compatible platelets for PTR patients to ensure the safety and effectiveness of platelet transfusions. We used a polymerase chain reaction sequence-based typing (PCR-SBT) method to establish the database by performing high-resolution HLA-A, -B, and -C genotyping on 900 platelet-apheresis donors. HLA-I antibody was detected in patients using a Luminex device, and HLA-I gene matching was performed by an HLA-Matchmaker. We found that the highest frequency of the HLA-A allele was A*11:01 (17.06 %), followed by A*24:02 (14.67 %) and A*02:01 (13.61 %). The highest frequency of the HLA-B allele was B*46:01 (9.78 %), followed by B*40:01 (8.39 %) and B*13:02 (33 %). After the detection of platelet antibodies in 74 patients with immune PTR, we found 30 HLA-A antibodies and 48 HLA-B antibodies, and there were a variety of high frequency antibodies whose alleles were low in the donor database, such as HLA-A*68:02, and B*57:01. After avoiding donor-specific antibodies (DSA) matching, 102 of 209 platelet-compatible transfusions were effective, resulting in an effective rate of 48.8 %, which significantly improved the efficacy of platelet transfusion. The establishment of a platelet donor database is of great significance to improve the therapeutic effect of platelet transfusion in patients with hematologic disorder, and save blood resources, and it is also the premise and guarantee of precise platelet transfusion.

The FGFR2 Variant rs13387042 is Associated With Breast Cancer Risk: A Meta-Analysis and Systematic Review.

OBJECTIVE: The association of FGFR2-rs13387042 polymorphism with breast cancer (BC) susceptibility in women remains inconclusive due to varying reports. In this study, we conducted a meta-analysis to explore the relationship between FGFR2-rs13387042 polymorphism and susceptibility to BC. METHODS: Relevant literature were acquired through searches across multiple databases. Odds ratio (OR) values were pooled to assess the risk of BC for different alleles and genotypes. The heterogeneity among the included literature was evaluated. Sensitivity analysis was used to verify the stability of the results. Egger's linear regression test was used to assess the significance of publication bias of the included literature. RESULTS: A total of 17 publications were included, encompassing 122,607 cases and 175,966 controls. There was significantly increased risk of BC for allele A compared with G (OR = 1.15, 95% CI = 1.14-1.67, P < .001), genotype AA compared with GG (OR = 1.34, 95% CI = 1.29-1.38, P < .001), and genotype GA compared with GG (OR = 1.19, 95% CI = 1.12-1.26, P < .001). Both Egger's test and funnel plot indicated the presence of publication bias. After adjusting potential publication bias by the trim-and-fill method, the comparison of allele A versus G (OR = 1.15, 95% CI = 1.13-1.17, P < .001), genotype AA versus GG (OR = 1.32, 95% CI = 1.28-1.37, P < .001), and genotype GA versus GG (OR = 1.15, 95% CI = 1.09-1.22, P < .001) remained statistically significant. In various subgroups, the allele A showed significantly higher risk of BC upon allele G in estrogen receptor (ER) positive BC, ER negative BC, progesterone receptor (PR) positive BC, PR negative BC, triple-negative BC, pathological grade I BC, grade II BC, and grade III breast cancer. The subsequent sensitivity analysis suggested the above findings stable and reliable. CONCLUSION: In this study, we found that the allele A of the FGFR2-rs13387042 polymorphism is associated with increased risk of developing breast cancer. This study underscores its potential as a genetic marker for personalized risk assessment and targeted interventions.