Genetic Status Research Articles

P16-CD8-Ki67 Triple Algorithm for Prediction of CDKN2A Mutations in Patients with Multiple Primary and Familial Melanoma.

Melanoma, a malignant neuroectodermic tumor originating from the neural crest, presents a growing global public health challenge and is anticipated to become the second most prevalent malignancy in the USA by 2040. The CDKN2A gene, particularly p16INK4a, plays a pivotal role in inhibiting the cell cycle via the cyclin D/CDK2-pRb pathway in certain tumors. In familial melanomas (FM), 40% exhibit CDKN2A mutations affecting p16INK4a, impacting checkpoint G1, and stabilizing p53 expression. This study aims to establish a scoring system using immunohistochemical antibodies, providing a cost-saving approach to classify multiple primary melanomas (MPM) and FM patients based on their mutational status, thus mitigating genetic testing expenses. This retrospective study included 23 patients with MPM and FM, assessing the p16, CD8, and Ki67 immunohistochemical status. Analyses of each parameter and associations between their value intervals and genetic CDKN2A status were conducted. A total score of at least 9 out of 10 points per tumor defined melanomas with homozygous CDKN2A deletions, exhibiting a sensitivity of 100% and specificity of 94.11%. In conclusion, p16, CD8, and Ki67 individually serve as valuable indicators for predicting melanoma evolution. The algorithm, comprising these three immunohistochemical parameters based on their prognostic and evolutionary significance, proves to be a valuable auxiliary diagnostic tool for cost-effective prediction of mutational status in detecting multiple and familial primary melanomas with CDKN2A homozygous deletion.

A Descriptive Analysis of Nasal Polyposis in HIV Positive Versus HIV Negative Patients

Nasal polyposis (NP) represents a benign proliferation of soft tissue tumors within the nasal cavity and paranasal sinuses, characterized by chronic inflammation of the sinonasal mucosa. This phenomenon, attributed to various environmental and physiological factors, presents clinically as semi-transparent masses with variable morphology, often obstructing nasal passages and causing respiratory compromise, olfactory dysfunction, and recurrent infections. Predominantly associated with chronic rhinosinusitis (CRS), NP poses significant challenges in diagnosis and management, particularly in the context of comorbid conditions such as human immunodeficiency virus (HIV) infection. HIV infection, known for its debilitating effects on the immune system, is theorized to exacerbate NP development and manifestation through mechanisms involving CD4 cell depletion and dysregulation of immune responses. Despite extensive research, elucidating potential pathways linking HIV infection to NP, comprehensive understanding remains elusive. This study aims to address this knowledge gap by conducting a retrospective chart review of patients presenting with NP at Charlotte Maxeke Johannesburg Academic Hospital between January 2016 and December 2020. The primary objective is to investigate the influence of HIV status on the clinical, radiological, and histological features of NP. Data collection, encompassing patient demographics, HIV status, clinical presentations, radiological findings, and histopathological characteristics, will be conducted between March 2021 and August 2022. Preliminary analysis of collected data reveals a cohort of 41 patients meeting inclusion criteria, with notable exclusions based on undisclosed HIV status and incomplete documentation. Initial findings suggest a nuanced interplay between genetic predisposition, environmental factors, and HIV status in NP pathogenesis, underscoring the need for further research to validate these observations. In conclusion, this study underscores the importance of elucidating the complex relationship between HIV infection and NP to optimize diagnostic and therapeutic approaches, particularly in regions with a high HIV prevalence such as South Africa. By comprehensively assessing the clinical, radiological, and histological features of NP in HIV-positive and HIV-negative populations, this research endeavours to enhance our understanding of NP pathophysiology and improve patient outcomes.

Microsatellite instability and mismatch repair protein deficiency: equal predictive markers?

Current clinical guidelines recommend mismatch repair (MMR) protein immunohistochemistry (IHC) or molecular microsatellite instability (MSI) tests as predictive markers of immunotherapies. Most of the pathological guidelines consider MMR protein IHC as the gold standard test to identify cancers with MMR deficiency and recommend molecular MSI tests only in special circumstances or to screen for Lynch syndrome. However, there are data in the literature which suggest that the two test types may not be equal. For example, molecular epidemiology studies reported different rates of deficient MMR (dMMR) and MSI in various cancer types. Additionally, direct comparisons of the two tests revealed relatively frequent discrepancies between MMR IHC and MSI tests, especially in non-colorectal and non-endometrial cancers and in cases with unusual dMMR phenotypes. There are also scattered clinical data showing that the efficacy of immune checkpoint inhibitors is different if the patient selection was based on dMMR versus MSI status of the cancers. All these observations question the current dogma that dMMR phenotype and genetic MSI status are equal predictive markers of the immunotherapies.

The genetic status and rescue measure for a geographically isolated population of Amur tigers

The Amur tiger is currently confronted with challenges of anthropogenic development, leading to its population becoming fragmented into two geographically isolated groups: smaller and larger ones. Small and isolated populations frequently face a greater extinction risk, yet the small tiger population’s genetic status and survival potential have not been assessed. Here, a total of 210 samples of suspected Amur tiger feces were collected from this small population, and the genetic background and population survival potentials were assessed by using 14 microsatellite loci. Our results demonstrated that the mean number of alleles in all loci was 3.7 and expected heterozygosity was 0.6, indicating a comparatively lower level of population genetic diversity compared to previously reported studies on other subspecies. The genetic estimates of effective population size (Ne) and the Ne/N ratio were merely 7.6 and 0.152, respectively, representing lower values in comparison to the Amur tiger population in Sikhote-Alin (the larger group). However, multiple methods have indicated the possibility of genetic divergence within our isolated population under study. Meanwhile, the maximum kinship recorded was 0.441, and the mean inbreeding coefficient stood at 0.0868, both of which are higher than those observed in other endangered species, such as the African lion and the grey wolf. Additionally, we have identified a significant risk of future extinction if the lethal equivalents were to reach 6.26, which is higher than that of other large carnivores. Further, our simulation results indicated that an increase in the number of breeding females would enhance the prospects of this population. In summary, our findings provide a critical theoretical basis for further bailout strategies concerning Amur tigers.

Genetics, geography, and subspecies status of American mink in Florida, with an emphasis on Neogale vison evergladensis

Historical records of American mink (Neogale vison) in Florida suggest they occur in four populations, each currently recognized as a separate subspecies. The Everglades mink (N. v. evergladensis) is a state-listed threatened subspecies, and the Atlantic salt marsh mink (N. v. lutensis) and Gulf salt marsh mink (N. v. halilimnetes) are both Species of Greatest Conservation Need, but support for their taxonomic status is limited. We acquired 62 samples of mink for genetic analysis using mtDNA and microsatellite data with the objective of assessing the subspecies status of mink in Florida with an emphasis on evergladensis. We also compared historical and current range estimates of mink subspecies in Florida using museum specimens, public sightings, and detection records from scientific studies. All estimates of FST were significant when evergladensis was paired with other subspecies and both assignment tests and the Principal Coordinate Analysis separated evergladensis from other subspecies. The single mtDNA haplotype from evergladensis was not found elsewhere in Florida but was present in a subspecies outside of Florida (vulgivaga). Genetic diversity was lowest in evergladensis and highest for vulgivaga from Louisiana. We found support for lutensis as a separate taxonomic unit and assignment tests found some support for the genetic distinctiveness of halilimnetes. Sample sizes limited analyses in halilimnetes and prevented any conclusions about the subspecies status of mink in the Panhandle. Based on current range estimates, mink from evergladensis, lutensis, and halilimnetes are geographically isolated from one another and supports the genetic analysis. Using a more modern definition of subspecies that includes genetics, distribution, and ecology, we conclude that the data supports multiple subspecies of mink in Florida.

Excessive Exogenous Gonadotropins and Genetic and Pregnancy Outcomes After Euploidy Embryo Transfer

The safety of exogenous gonadotropin treatment, based on its effect on embryos and pregnancy outcomes, remains inconclusive. To evaluate the associations of different doses and durations of gonadotropins with embryonic genetic status and pregnancy outcomes after euploid embryo transfer in couples with infertility. This study was a post hoc analysis of a multicenter randomized clinical trial (RCT) conducted at 14 reproductive centers throughout China from July 2017 to June 2018 that evaluated the cumulative live birth rate with or without preimplantation genetic testing for aneuploidy (PGT-A) among couples with infertility and good prognosis. The PGT-A group from the original RCT was selected for secondary analysis. Patients were divided into 4 groups according to the total dosage of exogenous gonadotropins and treatment duration: group 1 (≤1500 IU and <10 days), group 2 (≤1500 IU and ≥10 days), group 3 (>1500 IU and <10 days), and group 4 (>1 500 IU and ≥10 days). Group 1 served as the control group. Data were analyzed from June through August 2023. Blastocyst biopsy and PGT-A. The primary outcomes were embryonic aneuploidy, embryonic mosaicism, and cumulative live birth rates after euploid embryo transfer. A total of 603 couples (mean [SD] age of prospective mothers, 29.13 [3.61] years) who underwent PGT-A were included, and 1809 embryos were screened using next-generation sequencing. The embryo mosaicism rate was significantly higher in groups 2 (44 of 339 embryos [13.0%]; adjusted odds ratio [aOR], 1.69 [95% CI, 1.09-2.64]), 3 (27 of 186 embryos [14.5%]; aOR, 1.98 [95% CI, 1.15-3.40]), and 4 (82 of 651 embryos [12.6%]; aOR, 1.60 [95% CI, 1.07-2.38]) than in group 1 (56 of 633 embryos [8.8%]). There were no associations between gonadotropin dosage or duration and the embryo aneuploidy rate. The cumulative live birth rate was significantly lower in groups 2 (83 of 113 couples [73.5%]; aOR, 0.49 [95% CI, 0.27-0.88]), 3 (42 of 62 couples [67.7%]; aOR, 0.41 [95% CI, 0.21-0.82]), and 4 (161 of 217 couples [74.2%]; aOR, 0.53 [95% CI, 0.31-0.89]) than in group 1 (180 of 211 couples [85.3%]). In this study, excessive exogenous gonadotropin administration was associated with increased embryonic mosaicism and decreased cumulative live birth rate after euploid embryo transfer in couples with a good prognosis. These findings suggest that consideration should be given to minimizing exogenous gonadotropin dosage and limiting treatment duration to improve embryo outcomes and increase the live birth rate. ClinicalTrials.gov Identifier: NCT03118141.

Unraveling goitered gazelle (Gazella subgutturosa) diversification: insights from phylogeography and species distribution modeling

Abstract The impact of climate fluctuations on the genetic diversity and distribution of species is of particular concern for large mammals that are already at risk of extinction. In this study, we investigated the genetic status of populations, the evolutionary relationships, and the current and future state of population dispersion of the goitered gazelle, Gazella subgutturosa, using 109 mtDNA sequences (cytb) and species distribution modeling. We assessed the impact of past (Last Glacial Maximum [lgm: 21 Kya] and Mid-Holocene [6 Kya]), current, and future (2070) climate on the phylogeography and spatial distribution of the species. Our results indicate evidence of divergence of two main clades (G. subgutturosa subgutturosa, and G. subgutturosa yarkandensis) (1.052 Mya) and a further split between two clades of G. s. subgutturosa (Middle Eastern and Central Iranian) in the middle Pleistocene. Historical species distribution models suggest the species’ range has not changed much across all periods examined, but there has been a decreasing trend from 21k to the current. Future climate projections (bcc-csm1 and ccsm4, rcp s 4.5 and 6 scenarios) predict a contraction of suitable habitat at the northern and southern edges of the species’ current distribution, shifting the range to the center of the study area. Biogeographic analyses suggest that vicariance and dispersal events have shaped the genetic structure of G. subgutturosa. Our findings suggest that the current genetic structure of the species is potentially related to Pleistocene climatic fluctuations and refuges (Alborz, Zagros, and Kope Dagh Mountains) during cold periods. The study highlights the importance of understanding the genetic status of populations and their evolutionary relationships to effectively prevent further declines of species at risk of extinction.

Population status and genetic assessment of mugger (Crocodylus palustris) in a tropical regulated river system in North India

For rewilding the depleted crocodylian populations in India, a targeted ‘one-species one area’ based conservation approach was adopted in the early-1970s. Suitable habitats were identified and designated as protected areas, specifically targeted to recover a particular crocodylian species. A ~ 610 km stretch of Chambal River in the Ganga River Basin was declared as National Chambal Sanctuary to restore the ‘Critically Endangered’ gharial (Gavialis gangeticus), where active management of mugger (Crocodylus palustris) was discouraged. In the present study, we examined the population trends, occupancy, and genetic status of mugger by conducting population monitoring and genetic assessment to understand the status of potentially competitive mugger in the Sanctuary. Our finding suggests that the mugger population has notably increased and colonised the Sanctuary. We observed a moderate level of genetic diversity in the mugger, which was relatively higher compared to the gharial in the Sanctuary. The rapid colonization of ecological generalist mugger raises concerns about potential competition with ecological specialist gharial threatening its long-term sustainability. Considering the coexistence dynamics between the species, it is essential to extend adaptive management strategies for mugger to ensure successful recovery of gharial population in the Sanctuary.

Quantitative ultrasonography reveals skeletal muscle abnormalities in carriers of DMD pathogenic variants.

Carriers of DMD pathogenic variants may become symptomatic and develop muscle-related manifestations. Despite that, few studies have attempted to characterize changes in the muscles of these carriers using imaging tools, particularly muscle ultrasound (MUS). The aim of this study was to compare lower limb MUS findings in carriers of DMD pathogenic variants (cDMD) vs healthy controls. Twenty-eight women (15 cDMD and 13 controls) underwent clinical evaluation and MUS. We collected information about muscle-related symptoms and assessed muscle strength. MUS was performed by a single physician (blind to the genetic status of subjects). The following muscles were assessed: rectus femoris, sartorius, tibialis anterior, and medial gastrocnemius. For each site, we computed data on muscle thickness, cross-sectional area, sound attenuation index, and elastography. Between-group comparisons were assessed using nonparametric tests and p-values <.05 were deemed significant. None of the subjects had objective muscle weakness, but exercise intolerance/fatigue was reported by four cDMDs and only one control. Regarding MUS, sound attenuation indices were significantly higher among carriers for all muscles tested. Longitudinal and axial deep echo intensities for the rectus femoris and tibialis anterior were also higher in the cDMD group compared with controls. No significant between-group differences were noted for elastography values, muscle area, or mean echo intensities. cDMD have skeletal muscle abnormalities that can be detected using quantitative MUS. Further studies are needed to determine whether such abnormalities are related to muscle symptoms in these patients.

Adrenal-Permissive Germline HSD3B1 Allele and Prostate Cancer Outcomes

The adrenal androgen-metabolizing 3β-hydroxysteroid dehydrogenase-1 enzyme, encoded by the HSD3B1 gene, catalyzes the rate-limiting step necessary for synthesizing nontesticular testosterone and dihydrotestosterone production. The common adrenal-permissive HSD3B1(1245C) allele is responsible for encoding the 3β-HSD1 protein with decreased susceptibility to degradation resulting in higher extragonadal androgen synthesis. Retrospective studies have suggested an association of the HSD3B1 adrenal-permissive homozygous genotype with androgen deprivation therapy resistance in prostate cancer. To evaluate differences in mortality outcomes by HSD3B1 genetic status among men with prostate cancer. This cohort study of patients with prostate cancer who were enrolled in the Million Veteran Program within the Veterans Health Administration (VHA) system between 2011 and 2023 collected genotyping and phenotyping information. HSD3B1 genotype status was categorized as AA (homozygous adrenal-restrictive), AC (heterozygous adrenal-restrictive), or CC (homozygous adrenal-permissive). The primary outcome of this study was prostate cancer-specific mortality (PCSM), defined as the time from diagnosis to death from prostate cancer, censored at the date of last VHA follow-up. Secondary outcomes included incidence of metastases and PCSM in predefined subgroups. Of the 5287 participants (median [IQR] age, 69 [64-74] years), 402 (7.6%) had the CC genotype, 1970 (37.3%) had the AC genotype, and 2915 (55.1%) had the AA genotype. Overall, the primary cause of death for 91 patients (1.7%) was prostate cancer. Cumulative incidence of PCSM at 5 years after prostate cancer diagnosis was higher among men with the CC genotype (4.0%; 95% CI, 1.7%-6.2%) compared with the AC genotype (2.1%; 95% CI, 1.3%-2.8%) and AA genotype (1.9%; 95% CI, 1.3%-2.4%) (P = .02). In the 619 patients who developed metastatic disease at any time, the cumulative incidence of PCSM at 5 years was higher among patients with the CC genotype (36.0%; 95% CI, 16.7%-50.8%) compared with the AC genotype (17.9%; 95% CI, 10.5%-24.7%) and AA genotype (18.5%; 95% CI, 12.0%-24.6%) (P = .01). In this cohort study of US veterans undergoing treatment for prostate cancer at the VHA, the HSD3B1 CC genotype was associated with inferior outcomes. The HSD3B1 biomarker may help identify patients who may benefit from therapeutic targeting of 3β-hydroxysteroid dehydrogenase-1 and the androgen-signaling axis.

Abstract MP56: Screening for Familial Hypercholesterolemia: School Based Programs May Be Best Alternative

Introduction: Familial Hypercholesterolemia (FH) is an autosomal dominant condition characterized by elevated cholesterol and premature development of cardiovascular (CV) disease affecting 1/200 - 1/500 individuals. Only 10% of the affected population in the United States have been identified and treated compared to 50-70% in Scandinavian countries identified through school-based or universal screening programs. Hypothesis Statement: School based programs are the best mechanism for FH screening. Methods: The Healthy Hearts and Minds Program (HHM) through UCHealth performs biometric screenings on 5th, 7th, and 10th grade students in Northern Colorado. HHM tested 10,991 5th grade students (9/2017 - 5/2022) and identified 424 students with total cholesterol levels ≥200 mg/dL (range 200-302). A buccal smear test (APOB, LDLR, PCSK9) was performed on 99 individuals with the highest total cholesterol levels to identify genetic status. A binomial logistic regression model was used for analysis. Results: Of the 99 students, six tested positive (50% male, 10.3 years, 22.8 BMI) for FH with five (40% male, 11.3 years, 17.3 BMI.) reporting a variant of indeterminate significance. A sigmoidal association between total cholesterol and predicted chance of FH was identified with the inflection point at ~270 mg/dL. Conclusions: Comprehensive school based programs are the most effective and equitable means of identifying this genetic based disease and should be supported in a collaborative manner with health care systems, industry and the community. With availability to all students, diversity, equity, and inclusion concerns are addressed and provide at risk populations with personalized health information. The results from this study suggest a school-based screening program can be effective at identifying students most at risk for FH. These results further define the relation between total cholesterol and predicted chance of FH for a school-aged population where 245 mg/dL indicates a 10.3% of testing positive for FH whereas 275 mg/dL has a 54.8% chance. Additionally, the multiplier effect documented through cascade FH testing enhances the benefit of the information to other family members, as the autosomal dominant pattern insures that 50% of members will be at risk. The individual benefit of identifying FH early is the treatability of this condition. Early use of lipid lowering agents can make the CV disease risk equal to the general population. If left untreated, CV disease occurs approximately 10 years earlier which results in increased mortality and disability, along with increased health care costs. Therefore, if elevated cholesterol is present in school children, genetic testing is warranted and treatment considered by age 8-10 years, especially if signs of abnormal vascular plaquing is identified.

Developmental outcomes of preschool children requiring craniosynostosis surgery in Manitoba: a cohort study.

Craniosynostosis is a congenital abnormality resulting in the premature fusion of one or more cranial sutures and usually requires surgical correction in the first year of life. While the majority of craniosynostosis cases represent isolated, nonsyndromic defects, approximately 25% are linked to a genetic diagnosis. Craniosynostosis has been associated with developmental delay. Therefore, historically in Manitoba, all children with surgically managed craniosynostosis were referred to the Child Development Clinic (CDC) for developmental assessment. There are currently prolonged wait times for neurodevelopmental assessments at CDC, leading to the need to better prioritize children who require neurodevelopmental assessment. The aim of the study was then to determine the developmental outcomes of preschool children requiring craniosynostosis surgery in Manitoba from July 1, 2016 through December 1, 2021. In this retrospective cohort study, clinical records were reviewed to evaluate the developmental outcomes of patients who were assessed at CDC for surgically managed craniosynostosis. Out of 67 children included in this study, 18% demonstrated global developmental delay, 24% demonstrated mild developmental delay, and 58% were developmentally appropriate across all levels. The presence of a genetic syndrome, multisutural craniosynostosis, and parental socioeconomic status were associated with risk of global developmental delay. The findings of this study suggest that while not all children with craniosynostosis present with developmental delay, those with suspected or confirmed syndromic involvement, multisutural cranyosinostosis, and/or low SES, should be referred for neurodevelopmental evaluation.

Immune and genetic profile of workers with metabolic syndrome contaminated with benzene (based on the example of the petrochemical industry)

Exposure to harmful chemical factors of production can contribute to the development of metabolic disorders in workers in the petrochemical industry. Oil production conditions are associated with exposure to endocrine disruptors, such as aromatic hydrocarbons, whose effects are associated, among other things, with disorders of immuno-endocrine regulation.&#x0D; The aim of the study was to analyze the features of the immune and genetic status of workers in the oil-producing segment of the petrochemical industry with metabolic syndrome contaminated with benzene.&#x0D; 142 operators of the oil production enterprise with pathology with metabolic syndrome were examined. The observation group included workers (n=94) characterized by contamination of the biological medium with benzene. The comparison group consisted of 48 people who were not contaminated with benzene. The state of cellular immunity was assessed by flow cytometry (CD3+CD8+, CD3+CD95+, CD3+), cytokine profile by enzyme immunoassay (IL‑6). Gene polymorphism was studied by real-time PCR.&#x0D; In workers with metabolic syndrome contaminated with benzene, the features of the clinical course of the metabolic syndrome, accompanied by functional and laboratory signs of atherosclerotic vascular changes, as well as an imbalance of the immune profile, whose phenotypes were: an increase in the absolute and relative content of CD3+CD8+ lymphocytes (1.3–1.6 times, respectively) (p&lt;0.05), CD3+ lymphocytes (1.2–1.3 times) (p&lt;0.05) relative to the comparison group, CD95+ cluster deficiency in relation to the reference interval and the indicators of the comparison group (1.4–1.9 times; p&lt;0.05), IL-6 hyperproduction (1.6 times; p&lt;0.05) relative to the values of the corresponding indicators of the group of workers where benzene contamination was absent. The genetic profile of workers (SNP) contaminated with benzene allowed us to establish a 1.4-fold increased prevalence of the C-allele of the FADS2 gene (OR=2.13; 95% CI: 1.05–4.29, p&lt;0.05); 2.3 times the G-allele (OR=3.30; 95% CI: 1.46–7.33, p&lt;0.05) of the TP53 gene.&#x0D; Established in operators of the oil-producing segment of the petrochemical industry with metabolic syndrome contaminated with benzene, features of the immune status: an increase in the expression of CD3+ and CD8+ lymphocyte clusters, IL-6 cytokine, and a decrease in CD95+ lymphocyte reception (p&lt;0.05) were accompanied by polymorphisms of candidate genes FADS2 (rs174583) and TP53 (rs 1042522) associated with obesity and apoptosis.&#x0D; Ethics. The study was approved by the ethics committee of the Federal Scientific Center for Medical and Preventive Health Risk Management Technologies. All patients were informed about the purpose of the study, and voluntary informed consent was obtained.

Frequency and Distribution of Ophthalmic Surgical Procedures among Patients with Inherited Retinal Diseases

Objective or PurposeIn this study, we aimed to characterize the frequency and distribution of ocular surgeries in patients with inherited retinal diseases (IRDs) and evaluate associated patient and disease factors. DesignRetrospective cohort. ParticipantsSubjects 18 years and older who were followed at the Johns Hopkins Genetic Eye Disease (GEDi) Center. MethodsWe studied a retrospective cohort of patients with an IRD diagnosis to analyze the occurrence of laser and incisional surgeries. Subjects were categorized into two groups: central dysfunction (macular/cone/cone-rod dystrophy, "MCCRD group") and panretinal or peripheral dysfunction (retinitis pigmentosa-like, "RP group"). Genetic testing status was recorded. The association of patient and disease factors on the frequency, distribution, and timing of surgeries was analyzed. Main outcome MeasurePrevalence, prevalence odds ratio (POR), hazard ratio (HR) of ophthalmic procedures by phenotype. ResultsA total of 1472 eyes of 736 subjects were evaluated. Among them, 31.3% (n = 230) had undergone ocular surgery, and 78.3% of those (n=180/230) had a history of more than one surgery. A total of 602 surgical procedures were analyzed. Cataract extraction with intraocular lens implantation (CEIOL) was the most common (51.2%), followed by YAG capsulotomy, refractive surgery, retinal surgery, and others. CEIOL occurred more frequently in RP than in MCCRD subjects (POR 2.59, p = 0.002). RP subjects underwent CEIOL at a younger age than MCCRD patients (HR = 2.11, p < 0.001). ConclusionApproximately one-third of IRD patients had a history of laser or incisional surgery. CEIOL was the most common surgery; its frequency and timing may be associated with IRD phenotype. This data may inform the design of prospective research. Such efforts may illuminate routine clinical decision-making and contribute to surgical strategy development for cell and gene therapy delivery.

Population genetics of the critically endangered three-striped turtle, Batagur dhongoka, from the Ganga river system using mitochondrial DNA and microsatellite analysis

The three-striped roofed (Batagur dhongoka) is a semi-aquatic turtle that belongs to family Geoemydidae. Due to anthropogenic pressure, it has been facing an intense decline of over 80% in its distribution range in the past 50 years. It is considered as 'Critically Endangered' so effective conservation strategies are needed to protect the species by determining their genetic diversity and population genetic structure. This study investigates the genetic diversity, population structure and demographic pattern of B. dhongoka from two Turtle Rescue and Rehabilitation Centre established near Ganga river using mitochondrial cytochrome b (Cyt b: 1140 bp) ; control region (CR: 451 bp) and ten nuclear microsatellite loci. mtDNA results show low levels of nucleotide diversity (π = 0.0022) in B. dhongoka haplotypes and provide evidence for a low substitution rate. The demographic pattern estimated by the Bayesian skyline plot (BSP) analysis indicates historical stability followed by growth in the effective population size, with a recent reduction in population size from ~ 2 thousand years ago. The microsatellite findings show a moderate level of observed heterozygosity (Ho: 0.49). Bayesian-based clustering analysis revealed weak genetic structures in B. dhongoka and presence of admixed assignations suggesting close genetic relationships. These findings shed light on B. dhongoka's genetic status and underline the necessity of comprehensive rehabilitation and relocation programs and conservation and management techniques to ensure the species' long-term survival. In order to ensure the effective protection and conservation of B. dhongoka, the Government of India has taken a proactive measure by incorporating it into Schedule I of the Wildlife (Protection) Act, 1972, as amended in 2022.

Too simple, too complex, or just right? Advantages, challenges, and guidance for indicators of genetic diversity

Abstract Measuring genetic diversity of wild species using DNA-based data remains resource intensive and time consuming for nearly all species. However, genetic assessments are needed for global conservation commitments, including the Convention on Biological Diversity, and for governments and managers to evaluate conservation progress, as well as prioritizing species and populations to preserve and recover genetic diversity (e.g., via genetic rescue). Recently, indicators were developed for tracking and reporting genetic diversity status and trends for hundreds of species. The indicators quantify two simple proxies of within-population and among-population genetic diversity and adaptive potential: small effective population size (Ne &amp;lt; 500) and the loss of genetically distinct populations. The indicators must balance scientific credibility, practicality, and simplicity. In the present article, we summarize the advantages of these pragmatic indicators, address critiques by scientists for simplifying assumptions and by policymakers for complexity, and propose potential solutions and next steps. We aim to support practitioners putting indicators into policy, action, legislation, and reporting.

Overview of the population genetics and connectivity of sea turtles in the East Asia Region and their conservation implications

Understanding the current status and recent development of the population genetics and connectivity of sea turtles is crucial for effective conservation management of the species. Five sea turtle species, green turtle (Chelonia mydas), loggerhead turtle (Caretta caretta), hawksbill turtle (Eretmochelys imbricata), olive ridley turtle (Lepidochelys olivacea) and leatherback turtle (Dermochelys coriacea), are recorded in the East Asia Region situated in the western side of the North Pacific Ocean. We compiled information from 35 published genetic studies on the five sea turtle species, with a focus on green turtle and loggerhead turtle, which are the most studied species (in 30 studies) in view of their commonness and occurrence of nesting populations. We provided an overview of the key methods and findings of these previous studies, addressing two main objectives on genetic structure of the rookeries and their differences compared to other populations, and connectivity of the rookeries and foraging aggregations. By identifying information gaps and conservation needs, we discussed future developments for sea turtle genetic studies and conservation implications in the region.

Rim enhancement of pancreatic ductal adenocarcinoma: investigating the relationship with DCE-MRI-based radiomics and next-generation sequencing.

To identify the clinical and genetic variables associated with rim enhancement of pancreatic ductal adenocarcinoma (PDAC) and to develop a dynamic contrast-enhanced (DCE) MRI-based radiomics model for predicting the genetic status from next-generation sequencing (NGS). Patients with PDAC, who underwent pretreatment pancreatic DCE-MRI between November 2019 and July 2021, were eligible in this prospective study. Two radiologists evaluated presence of rim enhancement in PDAC, a known radiological prognostic indicator, on DCE MRI. NGS was conducted for the tissue from the lesion. The Mann-Whitney U and Chi-square tests were employed to identify clinical and genetic variables associated with rim enhancement in PDAC. For continuous variables predicting rim enhancement, the cutoff value was set based on the Youden's index from the receiver operating characteristic (ROC) curve. Radiomics features were extracted from a volume-of-interest of PDAC on four DCE maps (Ktrans, Kep, Ve, and iAUC). A random forest (RF) model was constructed using 10 selected radiomics features from a pool of 392 original features. This model aimed to predict the status of significant NGS variables associated with rim enhancement. The performance of the model was validated using test set. A total of 55 patients (32 men; median age 71 years) were randomly assigned to the training (n = 41) and test (n = 14) sets. In the training set, KRAS, TP53, CDKN2A, and SMAD4 mutation rates were 92.3%, 61.8%, 14.5%, and 9.1%, respectively. Tumor size and KRAS variant allele frequency (VAF) differed between rim-enhancing (n = 12) and nonrim-enhancing (n = 29) PDACs with a cutoff of 17.22%. The RF model's average AUC from 10-fold cross-validation for predicting KRAS VAF status was 0.698. In the test set comprising 6 tumors with low KRAS VAF and 8 with high KRAS VAF, the RF model's AUC reached 1.000, achieving a sensitivity of 75.0%, specificity of 100% and accuracy of 87.5%. Rim enhancement of PDAC is associated with KRAS VAF derived from NGS-based genetic information. For predicting the KRAS VAF status in PDAC, a radiomics model based on DCE maps showed promising results.

Body odours as putative chemosignals in the father-child relationship: New insights on paternal olfactory kin recognition and preference from infancy to adolescence

Children's body odours are effective chemical cues in the parent-child relationship. Mothers can recognize the odour of their child and prefer this odour over that of unfamiliar children. This effect is mediated by genetic similarity and developmental stage and is therefore suited to promote parental care at pre-pubertal stage, while facilitating incest avoidance at (post-)pubertal stage. The present study tested whether similar mechanisms apply to fathers. Therefore n = 56 fathers evaluated body odour samples of their own and of unfamiliar children in varying genetic and developmental stages. Genetic status was determined by human leucocyte antigen (HLA) profiling, developmental status by standardized assessment of pubertal status and steroid hormone concentration (estradiol, testosterone). Similar to mothers, fathers identified their own child's body odour above chance and preferred that odour. The paternal preference did not relate to HLA similarity but decreased with increasing age of the child. The decline was associated with higher pubertal stages in daughters only, which supports the hypothesis of odour-mediated incest prevention in opposite-sex parent-child dyads.

Electrophysiological Characterization of Subclinical and Overt Hypertrophic Cardiomyopathy by Magnetic Resonance Imaging-Guided Electrocardiography

BackgroundVentricular arrhythmia in hypertrophic cardiomyopathy (HCM) relates to adverse structural change and genetic status. Cardiovascular magnetic resonance (CMR)–guided electrocardiographic imaging (ECGI) noninvasively maps cardiac structural and electrophysiological (EP) properties. ObjectivesThe purpose of this study was to establish whether in subclinical HCM (genotype [G]+ left ventricular hypertrophy [LVH]−), ECGI detects early EP abnormality, and in overt HCM, whether the EP substrate relates to genetic status (G+/G−LVH+) and structural phenotype. MethodsThis was a prospective 211-participant CMR-ECGI multicenter study of 70 G+LVH−, 104 LVH+ (51 G+/53 G−), and 37 healthy volunteers (HVs). Local activation time (AT), corrected repolarization time, corrected activation-recovery interval, spatial gradients (GAT/GRTc), and signal fractionation were derived from 1,000 epicardial sites per participant. Maximal wall thickness and scar burden were derived from CMR. A support vector machine was built to discriminate G+LVH− from HV and low-risk HCM from those with intermediate/high-risk score or nonsustained ventricular tachycardia. ResultsCompared with HV, subclinical HCM showed mean AT prolongation (P = 0.008) even with normal 12-lead electrocardiograms (ECGs) (P = 0.009), and repolarization was more spatially heterogenous (GRTc: P = 0.005) (23% had normal ECGs). Corrected activation-recovery interval was prolonged in overt vs subclinical HCM (P < 0.001). Mean AT was associated with maximal wall thickness; spatial conduction heterogeneity (GAT) and fractionation were associated with scar (all P < 0.05), and G+LVH+ had more fractionation than G−LVH+ (P = 0.002). The support vector machine discriminated subclinical HCM from HV (10-fold cross-validation accuracy 80% [95% CI: 73%-85%]) and identified patients at higher risk of sudden cardiac death (accuracy 82% [95% CI: 78%-86%]). ConclusionsIn the absence of LVH or 12-lead ECG abnormalities, HCM sarcomere gene mutation carriers express an aberrant EP phenotype detected by ECGI. In overt HCM, abnormalities occur more severely with adverse structural change and positive genetic status.