Distribution and diagnostic value of single and multiple high-risk HPV infections in detection of cervical intraepithelial neoplasia: A retrospective multicenter study in China.

The risk associated with single and multiple human papillomavirus (HPV) infections in cervical intraepithelial neoplasia (CIN) remains uncertain. This study aims to explore the distribution and diagnostic significance of the number of high-risk HPV (hr-HPV) infections in detecting CIN, addressing a crucial gap in our understanding. This comprehensive multicenter, retrospective study meticulously analyzed the distribution of single and multiple hr-HPV, the risk of CIN2+, the relationship with CIN, and the impact on the diagnostic performance of colposcopy using demographic information, clinical histories, and tissue samples. The composition of a single infection was predominantly HPV16, 52, 58, 18, and 51, while HPV16 and 33 were identified as the primary causes of CIN2+. The primary instances of dual infection were mainly observed in combinations such as HPV16/18, HPV16/52, and HPV16/58, while HPV16/33 was identified as the primary cause of CIN2+. The incidence of hr-HPV infections shows a dose-response relationship with the risk of CIN (p for trend <0.001). Compared to single hr-HPV, multiple hr-HPV infections were associated with increased risks of CIN1 (1.44, 95% confidence interval [CI]: 1.20-1.72), CIN2 (1.70, 95% CI: 1.38-2.09), and CIN3 (1.08, 95% CI: 0.86-1.37). The colposcopy-based specificity of single hr-HPV (93.4, 95% CI: 92.4-94.4) and multiple hr-HPV (92.9, 95% CI: 90.8-94.6) was significantly lower than negative (97.9, 95% CI: 97.0-98.5) in detecting high-grade squamous intraepithelial lesion or worse (HSIL+). However, the sensitivity of single hr-HPV (73.5, 95% CI: 70.8-76.0) and multiple hr-HPV (71.8, 95% CI: 67.0-76.2) was higher than negative (62.0, 95% CI: 51.0-71.9) in detecting HSIL+. We found that multiple hr-HPV infections increase the risk of developing CIN lesions compared to a single infection. Colposcopy for HSIL+ detection showed high sensitivity and low specificity for hr-HPV infection. Apart from HPV16, this study also found that HPV33 is a major pathogenic genotype.

Does one size really fit all? The case for personalized antiplatelet therapy in interventional cardiology.

Cardiovascular disease is the leading cause of death worldwide. Dual antiplatelet therapy (DAPT), with aspirin plus a P2Y12 inhibitor, is currently recommended as a default for patients after acute coronary syndrome (ACS) and following percutaneous coronary intervention (PCI). However, controversies arise over the role of aspirin, the optimal duration of DAPT after drug-eluting stent (DES) implantation, the choice of P2Y12 inhibitor and the variability in individual responses to antiplatelet agents. Recent data indicate that monotherapy with a P2Y12 inhibitor may have adequate anti-ischemic effects with lower bleeding risk. Additionally, discrepancies in DAPT duration recommendations and the optimal P2Y12 inhibitor, provides more uncertainty. We ask the question "does one size really fits all?" or should a more personalized strategy should be implemented.

Diseases affecting the heart and blood circulation are the leading cause of death worldwide. Treatment with drugs that prevents platelets from clumping (called antiplatelets) like aspirin plus another drug group (called P2Y12 inhibitors) like clopidogrel, ticagrelor and prasugrel, is currently recommended as a default for patients after heart attack and/or in whom coronary stents are inserted. However, it is very well documented that the response of any individual to these drugs is highly variable, and that the patients who don't respond as well to them are at increased risk of having clot events in their coronary arteries. On the other hand, people who respond to the drugs very sensitively have a higher bleeding risk. Despite these observations, there is no attempt to test the response of individuals patients to their antiplatelet drugs in routine practice. This review article looks in detail and whether the currently used strategy of "One size fits all" should be changed, given that there may well now be the chance to perform routine testing on everyone, and personalize their treatment accordingly.

Efficacy, safety, and quality of life profile of Genotype-3 Chronic Hepatitis-C Pakistani patients receiving ledipasvir plus sofosbuvir treatment.

Objective: This study aimed to assess the overall treatment response of Genotype-3 Chronic HCV Pakistani Patients with or without cirrhosis to Ledipasvir plus Sofosbuvir combination. Method: In this observational study, HCV Genotype-3 patients were enrolled from Liver Center, DHQ Hospital, Faisalabad and divided into two groups, i.e., non-cirrhotic and compensated cirrhotic patients. The study spanned for a period of 24 months (November 2019 - November 2021) from the first enrollment to the last follow up. Non-cirrhotic patients received Ledipasvir/Sofosbuvir (LDV/SOF) 90/400mg for 12 weeks and cirrhotic patients received LDV/SOF with Ribavirin (RBV) for 12 weeks and without RBV for 24 weeks. The treatment efficacy in terms of sustained virological response (SVR12) was monitored 12 weeks post-treatment. The safety profile, and health-related quality of life (HRQoL) were monitored from baseline to follow-up visits. Results: Two hundred and ninety out of 309 (93.85%) non-cirrhotic and 31 out of 33 (93.94%) compensated cirrhotic patients achieved SVR-12. The safety profile of the non-cirrhotic and compensated cirrhotic patients was comparable throughout the study duration. Fatigue was the most commonly reported adverse event (AE) in non-cirrhotic and compensated cirrhotic patients, followed by headache, nausea, and fever. The HRQoL improved from baseline to follow-up visits among patients of both groups. Conclusion: It is concluded that LDV and SOF combination regimen is safe and effective for treating Genotype-3 HCV patients without cirrhosis/compensated cirrhosis, and also improves the patient's HRQoL.

Inopinatus corneliae sp. nov. gen. nov. isolated from human skin: A newly discovered keratinophilic hyphomycete, order Onygenales.

BACKGROUND: Fungi clinically relevant to human skin comprise prevalent commensals and well-known pathogens. Only rarely human skin harbours fungi that evade identification. OBJECTIVE: To characterise an enigmatic specimen isolated from a skin lesion. METHODS: A comprehensive clinical and mycological workup including conventional methods for phenotypic characterisation and sequencing based on internal transcribed spacer (ITS) and large subunit (LSU) regions to infer a phylogenetic tree. RESULTS: Cultures on common solid media were macroscopically inconspicuous initially until mycelial tufts developed on the surface, notably on potato dextrose agar. Polymorphous chlamydospores were detected but no aleurospores and ascomata. At 26°C, the isolate grew on standard agars, plant materials and garden soil and utilised peptone, keratins, lipids, inulin, erythrocytes and cellulose. It also grew at 5°C and at 37°C. Nucleotide sequences of its ITS region showed 93% similarity to sequences of different Malbranchea species. The closest matches among LSU rRNA sequences were obtained with the genera Amauroascus, Arthroderma, Auxarthronopsis and Malbranchea (93%-95%). A combined phylogenetic analysis placed the fungus in a sister clade to Neogymnomycetaceae, classified as incertae sedis in Onygenales, on a large distance to either Diploospora rosea or 'Amauroascus' aureus. CONCLUSIONS: The genus Inopinatus gen. nov. (MB854685) with the species Inopinatus corneliae sp. nov. (MB854687) is introduced to accommodate our isolate (holotype: DSM 116806; isotypes: CBS 151104, IHEM 29063). Probably Inopinatus corneliae is a geophilic species that, although potentially harmful, was no relevant pathogen in our case. Its ecology, epidemiology and pathogenicity need to be further clarified.

Pathogenicity of genotype 2.1 classical swine fever virus isolated from Japan in 2019 in pigs.

Classical swine fever (CSF) re-emerged in Japan in 2018 for the first time in 26 years. The disease has been known to be caused by a moderately pathogenic virus, rather than the highly pathogenic virus that had occurred in the past. However, the underlying pathophysiology remains unknown. This study conducted an experimental challenge on specific pathogen-free (SPF) pigs in a naïve state for 2, 4, and 6 weeks and confirmed the disease state during each period by clinical observation, virus detection, and pathological necropsy. We revealed the pathological changes and distribution of pathogens and virus-specific antibodies at each period after virus challenge. These results were comprehensively analyzed and approximately 70% of the pigs recovered, especially at 4- and 6-week post-virus challenge. This study provides useful information for future countermeasures against CSF by clarifying the pathogenicity outcomes in unvaccinated pigs with moderately pathogenic genotype 2.1 virus.

Testing the evolutionary potential of an alpine plant: Phenotypic plasticity in response to growth temperature far outweighs parental environmental effects and other genetic causes of variation.

Phenotypic plasticity and rapid evolution are fundamental processes by which organisms can maintain their function and fitness in the face of environmental changes. Here we quantified the plasticity and evolutionary potential of an alpine herb Wahlenbergia ceracea. Utilising its mixed-mating system, we generated outcrossed and self-pollinated families that were grown in either cool or warm environments, and that had parents that had also been grown in either cool or warm environments. We then analysed the contribution of environmental and genetic factors to variation in a range of phenotypic traits including phenology, leaf mass per area, photosynthetic function, thermal tolerance, and reproductive fitness. The strongest effect was that of current growth temperature, indicating strong phenotypic plasticity. All traits except thermal tolerance were plastic, whereby warm-grown plants flowered earlier, grew larger, produced more reproductive stems compared to cool-grown plants. Flowering onset and biomass were heritable and under selection, with early flowering and larger plants having higher relative fitness. There was little evidence for transgenerational plasticity, maternal effects, or genotype-by-environment interactions. Inbreeding delayed flowering and reduced reproductive fitness and biomass. Overall, we found that W. ceracea has the capacity to respond rapidly to climate warming via plasticity, and the potential for evolutionary change.

Genotype-Phenotype Correlation in Neurofibromatosis Type 1: Evidence for a Mild Phenotype Associated with Splicing Variants Leading to In-Frame Skipping of NF1 Exon 24 [19a].

Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder caused by loss-of-function variants in the NF1 gene. As of 20 November 2023, over 5000 distinct pathogenic or likely pathogenic variants have been reported in public databases. However, only a few NF1 genotype-phenotype correlations have been established so far. In this study, we present findings on 40 individuals with NF1, comprising 26 unrelated probands and 14 affected relatives, who carry one of nine NF1 heterozygous pathogenic splicing variants, all of which result in the in-frame skipping of exon 24 [19a] (NM_000267.3:r.3114_3197del, p.Asn1039_Arg1066del). These variants include c.3114-2A>G, c.3114-1G>A, c.3196A>G, c.3197G>A, c.3197G>T, c.3197+1G>A, c.3197+1G>T, c.3197+2T>C, and c.3197+3A>T. Among individuals with these variants, none exhibit externally visible plexiform neurofibromas, histopathologically confirmed cutaneous or subcutaneous neurofibromas, symptomatic spinal neurofibromas, or symptomatic optic pathway gliomas. The most prevalent, and sometimes sole, clinical feature observed in this cohort is multiple café-au-lait macules, with or without skinfold freckles: 85% and 60.5% of the individuals display six or more café-au-lait macules and freckles, respectively. In comparison to established NF1 genotype-phenotype correlations, these patients demonstrate highly similar clinical presentations to those associated with the NF1 pathogenic variant c.2970_2972del (p.Met992del), known for resulting in the mildest clinical features. Despite the generally mild phenotype, cognitive impairment, developmental delay, and/or learning difficulties are still observed in 33.3% of these patients, suggesting that learning challenges remain a prominent aspect of the phenotypic presentation in these individuals and necessitate specialized care. This newly established genotype-phenotype correlation will assist clinicians in improving the management of patients harboring NF1 exon 24 [19a] skipping variants and provide a new therapeutic target for NF1 treatment.

Global prevalence of norovirus gastroenteritis after emergence of the GII.4 Sydney 2012 variant: a systematic review and meta-analysis.

Introduction: Norovirus is widely recognized as a leading cause of both sporadic cases and outbreaks of acute gastroenteritis (AGE) across all age groups. The GII.4 Sydney 2012 variant has consistently prevailed since 2012, distinguishing itself from other variants that typically circulate for a period of 2-4 years. Objective: This review aims to systematically summarize the prevalence of norovirus gastroenteritis following emergence of the GII.4 Sydney 2012 variant. Methods: Data were collected from PubMed, Embase, Web of Science, and Cochrane databases spanning the period between January 2012 and August 2022. A meta-analysis was conducted to investigate the global prevalence and distribution patterns of norovirus gastroenteritis from 2012 to 2022. Results: The global pooled prevalence of norovirus gastroenteritis was determined to be 19.04% (16.66-21.42%) based on a comprehensive analysis of 70 studies, which included a total of 85,798 sporadic cases with acute gastroenteritis and identified 15,089 positive cases for norovirus. The prevalence rate is higher in winter than other seasons, and there are great differences among countries and age groups. The pooled attack rate of norovirus infection is estimated to be 36.89% (95% CI, 36.24-37.55%), based on a sample of 6,992 individuals who tested positive for norovirus out of a total population of 17,958 individuals exposed during outbreak events. Conclusion: The global prevalence of norovirus gastroenteritis is always high, necessitating an increased emphasis on prevention and control strategies with vaccine development for this infectious disease, particularly among the children under 5 years old and the geriatric population (individuals over 60 years old).

Epidemiological and phylogenetic assessment of human respiratory syncytial virus among pediatric patients presenting acute respiratory infections in Shiraz, Iran during 2015-2016.

Background and Objectives: The pediatric population worldwide bears a significant morbidity and death burden due to acute respiratory infections (ARIs). Human Orthopneumovirus, sometimes referred to as the Human Respiratory Syncytial Virus (HRSV), is one of the main causes of ARIs in infants. The main goal of this study was to identify the genetic diversity of HRSV strains that were circulating in the Iranian population at a certain time of year. Materials and Methods: Two hundred youngsters less than 12 years old with acute respiratory infections had samples taken from their throat and pharynx secretions. Then, external and hemi-nested PCR were employed, using specific primers targeting the G gene region to detect HRSV. Subsequently, nine randomly selected positive samples were subjected to sequencing. The results were then compared with reference strains cataloged in GeneBank, and phylogenetic tree was constructed using Chromes and MEGA7. Results: Out of 200 samples, 34 were identified as containing HRSV. Subgroup A was predominant, accounting for 61.76% of cases, followed by subgroup BA (35.29%) and subgroup B (2.94%). Phylogenetic analysis revealed five samples associated with subtype B and four with genotype A. Genomic analysis showed three samples under the GA2 subgroup and one under GA1 for subtype A, and four samples in subgroup BA and one in GB2 for subtype B. Conclusion: In this study, subgroup A strains, particularly genotype GA2, exhibited a higher prevalence compared to subgroup B strains during the specific period under investigation, shedding light on the genetic landscape of HRSV in this region.

Prenatal diagnosis of a 15q24.1 microdeletion in a fetus with cerebral and urogenital abnormalities.

15q24.1 microdeletion syndrome is a recently described condition often resulting from non-allelic homologous recombination (NAHR). Typical clinical features include pre and post-natal growth retardation, facial dysmorphism, developmental delay and intellectual disability. Nonspecific urogenital, skeletal, and digit abnormalities may be present, although other congenital malformations are less frequent. Consequently, only one case was reported prenatally, complicating the genotype-phenotype correlation and the genetic counseling. We identified prenatally a second case, presenting with cerebral abnormalities including hydrocephaly, macrocephaly, cerebellum hypoplasia, vermis hypoplasia, rhombencephalosynapsis, right kidney agenesis with left kidney duplication and micropenis. Genome-wide aCGH assay allowed a diagnosis at 26 weeks of amenorrhea revealing a 1.6 Mb interstitial deletion on the long arm of chromosome 15 at 15q24.1-q24.2 (arr[GRCh37] 15q24.1q24.2(74,399,112_76,019,966)x1). A deep review of the literature was undertaken to further delineate the prenatal clinical features and the candidate genes involved in the phenotype. Cerebral malformations are typically nonspecific, but microcephaly appears to be the most frequent in postnatal cases. Our case is the first reported with a frank cerebellar involvement.

Variable expressivity of the autosomal dominant vitreoretinochoroidopathy (ADVIRC) phenotype associated with a novel variant in BEST1.

BACKGROUND: This case report explores the relationship between genetics and phenotypic variability in autosomal dominant vitreoretinochoroidopathy (ADVIRC). The study focuses on a case presenting a novel mutation in the BEST1 gene and its phenotype in the case's relatives, shedding light on the structural and functional intricacies underlying this rare ophthalmologic disorder. CASE PRESENTATION: A 33-year-old female presented for consultation with a history of bilateral retinal damage accompanied by a complaint of decreased visual acuity, progressive visual field deficit, and night blindness over the past year. Ophthalmic examination revealed a distinctive phenotype, including fibrillar vitreous, pigmented cells, and atrophic hyperpigmented retina in the periphery which was suggestive of a diagnosis of ADVIRC. Genetic testing revealed a heterozygous c.1101-1 G>T variant in BEST1, a novel splice site mutation. Functional analysis confirmed its impact on pre-mRNA splicing, resulting in an in-frame deletion (p(Ser367_Asn579del)). Family investigation revealed varying degrees of ophthalmologic impairment in the patient's mother and half-sister, both carrying the same mutation. CONCLUSIONS: This case report provides the first clinical description of the c.1101-1 G>T mutation in the BEST1 gene associated with ADVIRC. The presence of intrafamilial variability, as evidenced by the differing clinical features observed in the index case and her half-sister, suggests the potential involvement of mechanisms influencing phenotype expression.Abbreviation: ADVIRC : autosomal dominant vitreoretinochoroidopathy; RNA : ribonucleic acid; RPE : retinal pigment epithelium.

Ideotype based genotype selection in a multivariate dataset of sweet potato (Ipomoea batatas L.).

The dataset extensively examines the factors considered when choosing sweet potato genotypes, considering various characteristics. Notably, Moz1.15 demonstrated the highest marketable root yield at 46.46 t/ha, H5.ej.10 exhibited the highest beta-carotene level at 48.94 mg/100 g, and Moz1.9 recorded the highest vitamin C content at 23.89 mg/100 g. Moreover, there were significant correlations (ranging from 0.21 to 0.84) among the yield and quality traits studied in sweet potatoes. Principal component analysis (PCA) confirmed the connections among these traits, identifying four distinct clusters of genotypes, each characterized by specific significant combinations of traits. Factor analysis using the multi-trait genotype-ideotype index (MGIDI) highlighted the considerable impact of sweet potato traits across two growing seasons (2020-21 and 2021-22), facilitating the selection of genotypes with potential genetic gains ranging from 1.86 % to 75.4 %. Broad-sense heritability (h2) varied from 64.9 % to 99.8 %. The use of the MGIDI index pinpointed several promising genotypes, with BARI Mistialu-12 and H9.7.12 consistently performing well over both years. These genotypes exhibited both strengths and weaknesses.

Landscape genomics reveals genetic signals of environmental adaptation of African wild eggplants.

Crop wild relatives (CWR) provide a valuable resource for improving crops. They possess desirable traits that confer resilience to various environmental stresses. To fully utilize crop wild relatives in breeding and conservation programs, it is important to understand the genetic basis of their adaptation. Landscape genomics associates environments with genomic variation and allows for examining the genetic basis of adaptation. Our study examined the differences in allele frequency of 15,416 single nucleotide polymorphisms (SNPs) generated through genotyping by sequencing approach among 153 accessions of 15 wild eggplant relatives and two cultivated species from Africa, the principal hotspot of these wild relatives. We also explored the correlation between these variations and the bioclimatic and soil conditions at their collection sites, providing a comprehensive understanding of the genetic signals of environmental adaptation in African wild eggplant. Redundancy analysis (RDA) results showed that the environmental variation explained 6% while the geographical distances among the collection sites explained 15% of the genomic variation in the eggplant wild relative populations when controlling for population structure. Our findings indicate that even though environmental factors are not the main driver of selection in eggplant wild relatives, it is influential in shaping the genomic variation over time. The selected environmental variables and candidate SNPs effectively revealed grouping patterns according to the environmental characteristics of sampling sites. Using four genotype-environment association methods, we detected 396 candidate SNPs (2.5% of the initial SNPs) associated with eight environmental factors. Some of these SNPs signal genes involved in pathways that help adapt to environmental stresses such as drought, heat, cold, salinity, pests, and diseases. These candidate SNPs will be useful for marker-assisted improvement and characterizing the germplasm of this crop for developing climate-resilient eggplant varieties. The study provides a model for applying landscape genomics to other crops' wild relatives.

Real-world Effectiveness and Tolerability of Interferon-free Direct-acting Antiviral for 15,849 Patients with Chronic Hepatitis C: A Multinational Cohort Study.

Background and Aims: As practice patterns and hepatitis C virus (HCV) genotypes (GT) vary geographically, a global real-world study from both East and West covering all GTs can help inform practice policy toward the 2030 HCV elimination goal. This study aimed to assess the effectiveness and tolerability of DAA treatment in routine clinical practice in a multinational cohort for patients infected with all HCV GTs, focusing on GT3 and GT6. Methods: We analyzed the sustained virological response (SVR12) of 15,849 chronic hepatitis C patients from 39 Real-World Evidence from the Asia Liver Consortium for HCV clinical sites in Asia Pacific, North America, and Europe between 07/01/2014-07/01/2021. Results: The mean age was 62±13 years, with 49.6% male. The demographic breakdown was 91.1% Asian (52.9% Japanese, 25.7% Chinese/Taiwanese, 5.4% Korean, 3.3% Malaysian, and 2.9% Vietnamese), 6.4% White, 1.3% Hispanic/Latino, and 1% Black/African-American. Additionally, 34.8% had cirrhosis, 8.6% had hepatocellular carcinoma (HCC), and 24.9% were treatment-experienced (20.7% with interferon, 4.3% with direct-acting antivirals). The largest group was GT1 (10,246 [64.6%]), followed by GT2 (3,686 [23.2%]), GT3 (1,151 [7.2%]), GT6 (457 [2.8%]), GT4 (47 [0.3%]), GT5 (1 [0.006%]), and untyped GTs (261 [1.6%]). The overall SVR12 was 96.9%, with rates over 95% for GT1/2/3/6 but 91.5% for GT4. SVR12 for GT3 was 95.1% overall, 98.2% for GT3a, and 94.0% for GT3b. SVR12 was 98.3% overall for GT6, lower for patients with cirrhosis and treatment-experienced (TE) (93.8%) but ≥97.5% for treatment-naive patients regardless of cirrhosis status. On multivariable analysis, advanced age, prior treatment failure, cirrhosis, active HCC, and GT3/4 were independent predictors of lower SVR12, while being Asian was a significant predictor of achieving SVR12. Conclusions: In this diverse multinational real-world cohort of patients with various GTs, the overall cure rate was 96.9%, despite large numbers of patients with cirrhosis, HCC, TE, and GT3/6. SVR12 for GT3/6 with cirrhosis and TE was lower but still excellent (>91%).

Type 2N von Willebrand disease: Genotype drives different bleeding phenotypes and treatment needs.

BACKGROUND: Von Willebrand disease type 2N (VWD2N) is usually perceived as a mild bleeding disorder that can be treated by desmopressin (DDAVP). However, VWD2N-patients can be compound heterozygous or homozygous for different variants, p.Arg854Gln (R854Q) being the most frequent causative one. There is limited data about the impact of 2N-variants on VWD2N phenotype and DDAVP-response. OBJECTIVES: To describe the phenotype of VWD2N, including DDAVP-response, according to genotype. PATIENTS/METHODS: VWD2N-patients with a complete genotype/phenotype characterization by the French reference center for VWD, including MCMDM-1VWD bleeding score (BS) were eligible to the study. Results of DDAVP-trial were also collected. RESULTS: A total of 123 VWD2N-patients from the French registry were included in this study. Results were stratified according to the presence (R854QPos, n=114) or absence (R854QNeg, n=9) of at least one R854Q-allele. Three R854QPos-subgroups were further individualized: patients homozygous (R854QHmz, n=55), compound heterozygous for R854Q and a null allele (R854Q/3, n=48) or compound heterozygous for R854Q and another 2N variant (R854Q/2N, n=11). FVIII: C levels were significantly lower in R854QNeg- and R854Q/3-patients compared to R854QHmz-ones (p<0.001 and p<0.0001 respectively). R854QNeg-patients were diagnosed earlier due to bleeding symptoms and had a higher BS than R854QPos-patients (p<0.001). In DDAVP-trial, FVIII:C survival was lower in VWD type 2N than in type 1. R854QPos-patients had a heterogeneous DDAVP-response, which was best predicted by baseline FVIII:C level. CONCLUSION: The heterogeneous genetic background of VWD2N drives different bleeding phenotypes and response patterns to DDAVP, underlining the clinical relevance of DDAVP-trial to identify patients potentially eligible to alternative therapeutic options.

CYP2B6 and ABCB1 genotypes predict methadone plasma exposure among patients on maintenance therapy against opioid addictions in Tanzania.

AIMS: Methadone maintenance therapy (MMT) exhibits significant variability in pharmacokinetics and clinical response, partly due to genetic variations. However, data from sub-Saharan African populations are lacking. We examined plasma methadone variability and pharmacogenetic influences among opioid-addicted Tanzanian patients. METHODS: Patients attending MMT clinics (n = 119) in Tanzania were genotyped for common functional variants of the CYP3A4, CYP3A5, CYP2A6, CYP2B6, CYP2C19, CYP2D6, ABCB1, UGT2B7 and SLCO1B1 genotypes. Trough plasma concentrations of total methadone, S-methadone (S-MTD) and R-methadone (R-MTD), with their respective metabolites, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The methadone-to-EDDP metabolic ratio (MMR) was used to categorize the phenotype. RESULTS: The proportions of MMR-predicted ultrarapid, extensive, intermediate and slow methadone metabolizer phenotypes were 2.5%, 58.2%, 23.7% and 15.6%, respectively. CYP2B6 genotype significantly correlated with S-methadone (P = .006), total methadone (P = .03), and dose-normalized methadone plasma concentrations (P = .001). Metabolic ratios of R-methadone (R-MTD/R-EDDP), S-methadone (S-MTD/S-EDDP), and total methadone (MMR) were significantly higher among patients homozygous for defective variants (*6 or *18) than heterozygous or CYP2B6*1/*1 genotypes (P < .001). The metabolic ratio for S-MTD and total methadone was significantly higher among ABCB1c.3435T/T than in the C/C genotype. No significant effect of CYP2D6, CYP2C19, CYP3A4, CYP3A5, CYP2A6, UGT2B7 and SLCO1B1 genotypes on S-methadone, R-methadone, or total methadone was observed. CONCLUSIONS: Approximately one in six opioid-addicted Tanzanian patients are methadone slow metabolizers, influenced by genetic factors. Both the CYP2B6 and ABCB1 genotypes are strong predictors of methadone metabolic capacity and plasma exposure. Further investigation is needed to determine their predictive value for methadone treatment outcomes and to develop genotype-based dosing algorithms for safe and effective therapy.

Genotype-by-environment interaction and stability analysis of grain yield of bread wheat (Triticum aestivum L.) genotypes using AMMI and GGE biplot analyses.

Bread wheat is a vital staple crop worldwide; including in Ethiopia, but its production is prone to various environmental constraints and yield reduction associated with adaptation. To identify adaptable genotypes, a total of 12 bread wheat genotypes (G1 to G12) were evaluated for their genotype-environment interaction (GEI) and stability across three different environments for two years using Additive Main Effect and Multiplicative Interaction (AMMI) and genotype main effect plus genotype-by-environment interaction (GGE) biplots analysis. GEI is a common phenomenon in crop improvement and is of significant importance in genotype assessment and recommendation. According to combined analysis of variance, grain yield was considerably impacted by environments, genotypes, and GEI. AMMI and GGE biplots analysis also provided insights into the performance and stability of the genotypes across diverse environmental conditions. Among the 12 genotypes, G6 was selected by AMMI biplot analysis as adaptive and high-yielding genotype; G5 and G7 demonstrated high stability and minimal interaction with the environment, as evidenced by their IPCA1 values. G7 was identified as the most stable and high-yielding genotype. The GGE biplot's polygon view revealed that the highest grain yield was obtained from G6 in environment three (E3). E3 was selected as the ideal environment by the GGE biplot. The top three stable genotypes identified by AMMI stability value (ASV) were G5, G7, and G10, while the most stable genotype determined by Genotype Selection Index (GSI) was G7. Even though G6 was a high yielder, it was found to be unstable according to ASV and ranked third in stability according to GSI. Based on the study's findings, the GGE biplot genotype view for grain yield identified Tay genotype (G6) to be the most ideal genotype due to its high grain yield and stability in diverse environments. G7 showed similar characteristics and was also stable. These findings provide valuable insights to breeders and researchers for selecting high-yielding and stable, as well as high-yielding specifically adapted genotypes.

Genotypic and morphological identification of opportunistic microorganisms in triple-syringe tubing from dental units.

BACKGROUND: In Mexico and around the world, water in dental units, including triple syringes, comes from municipal chlorinated water mains. The microbial contamination of dental unit water systems constitutes a risk factor for opportunistic infections. OBJECTIVES: The present work aimed to identify the bacteria present in the triple-syringe water lines of dental units at a dental school of a public university in Mexico, with a hypothesis that opportunistic bacteria of importance to human health would be found. MATERIAL AND METHODS: A cross-sectional study was carried-out. A total of 100 samples of triple-syringe tubing from dental units operated by a dental school of a public university in Mexico were analyzed before and after their use in dental practice. Bacterial biofilm was cultured and isolated from the tubing, using standard microbiological methods, and then the species present were identified through 16S rRNA gene sequencing. The characterization of the biofilm was performed by means of scanning electron microscopy (SEM). RESULTS: Bacterial growth was observed in 20% of the non-disinfected and 10% of the disinfected samples, with 11 strains isolated. Six genera and 11 bacterial species were genetically identified. Coagulasenegative staphylococci (CoNS), considered opportunistic human pathogens, were among the most critical microorganisms. Scanning electron microscopy revealed a thick polymeric matrix with multiple bacterial aggregates. CONCLUSIONS: Opportunistic bacteria from human skin and mucous membranes were detected. Under normal conditions, these bacteria are incapable of causing disease, but are potentially harmful to immunosuppressed patients.

Phenotype-Genotype Correlation of a Cohort of Patients with Congenital Myopathy: A Single Centre Experience from India.

Background: Congenital myopathies (CMs) are a diverse group of inherited muscle disorders with broad genotypic and phenotypic heterogeneity. While the literature on CM is available from European countries, comprehensive data from the Indian subcontinent is lacking. Objectives: This study aims to describe the clinical and histopathological characteristics of a cohort of genetically confirmed CMs from India and attempts to do phenotype-genotype correlation. Methods: A retrospective chart review of genetically confirmed CMs was evaluated between January 2016 and December 2020 at the neuromuscular clinic. The clinical, genetic, and follow-up data were recorded in a pre-structured proforma as per the medical records, and the data was analyzed. Results: A total of 31(M: F = 14 : 17) unrelated patients were included. The median age at onset and duration of illness are 2.0(IQR:1-8) years and 6.0(IQR:3-10) years respectively. Clinical features observed were proximodistal weakness (54.8%), facial weakness (64.5%), and myopathic facies (54.8%), followed by ptosis (33.3%), and ophthalmoplegia (19.4%). Muscle histopathology was available in 38.7% of patients, and centronuclear myopathy was the most common histopathology finding. The pathogenic genetic variants were identified in RYR1 (29.0%), DNM2 (19.4%), SELENON (12.9%), KBTBD13 (9.7%), NEB (6.5%), and MYPN (6.5%) genes. Novel mutations were observed in 30.3% of the cohort. Follow-up details were available in 77.4% of children, and the median duration of follow-up and age at last follow-up was 4.5 (Range 0.5-11) years and 13 (Range 3-35) years, respectively. The majority were ambulant with minimal assistance at the last follow-up. Mortality was noted in 8.3% due to respiratory failure in Centronuclear myopathy 1 and congenital myopathy 3 with rigid spines (SELENON). Conclusion: This study highlights the various phenotypes and patterns of genetic mutations in a cohort of pediatric patients with congenital myopathy from India. Centronuclear myopathy was the most common histological classification and the mutations in RYR1 followed by DNM2 gene were the common pathogenic variants identified. The majority were independent in their activities of daily living during the last follow-up, highlighting the fact that the disease has slow progression irrespective of the genotype.

Immune phenotype-genotype associations in primary clear cell renal cell carcinoma and matched metastatic tissue.

Adjuvant immunotherapy has been recently recommended for patients with metastatic ccRCC, but there are no tissue biomarkers to predict treatment response in ccRCC. Potential predictive biomarkers are mainly assessed in primary tumor tissue, whereas metastases remain understudied. To explore potential differences between genomic alterations and immune phenotypes in primary tumors and their matched metastases, we analyzed primary tumors (PTs) of 47 ccRCC patients and their matched distant metastases (METs) by comprehensive targeted parallel sequencing, whole-genome copy number variation (CNV) analysis, determination of microsatellite instability (MSI) and tumor mutational burden (TMB). We quantified the spatial distribution of tumor-infiltrating CD8+ T cells, and co-expression of the T-cell-exhaustion marker TOX by digital immunoprofiling and quantified tertiary lymphoid structures (TLS). Most METs were pathologically "cold". Inflamed, pathologically "hot" PTs were associated with a decreased disease-free survival (DFS), worst for patients with high levels of CD8+TOX+ T cells. Interestingly, inflamed METs showed a relative increase of exhausted CD8+TOX+ T cells and increased accumulative size of TLS compared to PTs. Integrative analysis of molecular and immune phenotypes revealed BAP1 and CDKN2A/B deficiency to be associated with an inflamed immune phenotype. Our results highlight the distinct spatial distribution and differentiation of CD8+ T cells at metastatic sites, and the association of an inflamed microenvironment with specific genomic alterations.