Visual dysfunction in dementia with Lewy bodies.

PURPOSE OF REVIEW: To review the literature on visual dysfunction in dementia with Lewy bodies (DLB), including its mechanisms and clinical implications. RECENT FINDINGS: Recent studies have explored novel aspects of visual dysfunction in DLB, including visual texture agnosia, mental rotation of 3-dimensional drawn objects, and reading fragmented letters. Recent studies have shown parietal and occipital hypoperfusion correlating with impaired visuoconstruction performance. While visual dysfunction in clinically manifest DLB is well recognized, recent work has focused on prodromal or mild cognitive impairment (MCI) due to Lewy body pathology with mixed results. Advances in retinal imaging have recently led to the identification of abnormalities such as parafoveal thinning in DLB. Patients with DLB experience impairment in color perception, form and object identification, space and motion perception, visuoconstruction tasks, and illusions in association with visual cortex and network dysfunction. These symptoms are associated with visual hallucinations, driving impairment, falls, and other negative outcomes.

Trends and Disparities in the Utilization of Thymectomy for Myasthenia Gravis in the United States.

Background and Objectives: In 2016, a randomized controlled trial demonstrated the clinical efficacy of trans-sternal thymectomy for patients with non-thymomatous myasthenia gravis (MG). Whether large-scale changes occurred in clinical practice after this trial is unknown. Methods: We performed a retrospective longitudinal cross-sectional analysis using National Inpatient Sample (NIS) data from 2012 to 2019. Our study included hospitalized adults at least 18 years of age diagnosed with MG without an associated thymoma. We used joinpoint regression to analyze annual trends in thymectomy volume and surgical approach (minimally invasive vs trans-sternal) from 2012 to 2019. Using logistic regression models, we examined patient and hospital-level factors that may have influenced whether thymectomy was performed, such as age, sex, race, insurance payor, hospital size and teaching status, and Elixhauser Comorbidity Index. Sampling weights were applied to account for the complex survey design of NIS. Results: The total number of thymectomy procedures increased by 69.8% per year (95% CI 40.1-105.8) between 2012 and 2019. Trans-sternal thymectomies increased by 62.8% per year (95% CI 35.8-95.2) and minimally invasive thymectomies by 83.7% per year (95% CI 38.1-144.3). Thymectomies were significantly more likely to occur in 2017-2019 compared with 2012-2016 (OR 1.93, 95% CI 1.62-2.31). In a multivariable regression model, several factors decreased the odds of patients with MG having a thymectomy: older age, Black race (OR 0.62, 95% CI 0.49-0.77), female (OR 0.73, 95% CI 0.63-0.86), and higher Elixhauser Comorbidity Index. Patients in medium (OR 1.82, 95% CI 1.30-2.55) or large (OR 2.81, 95% CI 2.07-3.82) size and urban teaching hospitals (OR 6.09, 95% CI 2.65-13.97) were more likely to undergo thymectomy. Discussion: Thymectomy is being performed more frequently for non-thymomatous MG, especially after 2016 after publication of a positive phase III clinical trial. There are several disparities in thymectomy utilization that warrant further attention.

Diagnostic Accuracy of Fine-Needle Aspiration Cytology (FNAC) in Thyroid Nodule Excision Cases.

INTRODUCTION: Fine needle aspiration cytology (FNAC) for thyroid nodules has a high diagnostic accuracy, according to several studies worldwide. Patients who experienced preoperative FNAC had more optimal surgical treatment than others who did not perform FNAC. Therefore, achieving an accurate FNAC procedure appears to be an important tool for the proper management of thyroid nodules. We aimed to study the accuracy and challenges of the thyroid FNAC diagnostic tool in the Al-Baha region, Kingdom of Saudi Arabia. METHODS: The study involves 52 patients with thyroid nodules who underwent preoperative FNAC and postoperative histopathology with the same surgery and pathology team at Al-Baha region in 2022-2023. RESULTS AND CONCLUSION: The mean age of the included patients was 47.7 years, with a female predominance. The diagnostic accuracy was 90%, and the main cause of inaccurate diagnosis was processing challenges, where the majority of cases were taken on the palpation-only technique, a few cases were ultrasound-guided, and the only technique used in the laboratory was conventional smears. The applied interrater reliability Cohen kappa coefficient (κ) for the clinical-histopathological agreement was "moderate agreement". We recommend using and evaluating more cytological techniques in addition to the currently used conventional smears in pathology laboratories to enhance the efficacy of the FNAC diagnosis of thyroid lesions.

Assessing Medical Student Perceptions of Open-Book Exams for Self-Directed Learning.

Introduction  The landscape of medical education is constantly evolving, with innovative assessment methods being integrated to better align with the requirements of modern healthcare education. Among these, open-book exams (OBEs) represent a significant shift from traditional closed-book exams (CBEs), promising to enhance learning outcomes and better evaluate students' understanding of medical concepts. This study aims to explore the multifaceted impact of OBEs on medical students, including their perceptions, study behaviors, stress levels, and the cultivation of critical thinking and self-directed learning skills. Methodology  This is a cross-sectional study, which utilized a mixed-methods approach, conducted at Al Baha University's College of Medicine, to explore the impact of OBEs on self-directed learning among 129 medical students over a 15-day period in October 2023. The research combined quantitative data from online questionnaires, assessing students' experiences, stress, understanding, and study strategies, with qualitative insights from in-depth interviews and open-ended survey questions. Participants were final-year medical students with prior experience in OBEs, selected to minimize bias. Data analysis was performed using Statistical Product and Service Solutions (SPSS, version 25; IBM SPSS Statistics for Windows, Armonk), focusing on descriptive and inferential statistics, while qualitative data underwent thematic analysis to identify patterns in students' perceptions of self-directed learning opportunities. The study was ethically approved, ensuring participant confidentiality and informed consent. Result  Regarding the medical student perspectives on OBEs, the study revealed that the majority of medical students strongly perceive OBEs as less stressful (77, 59.69%) and easier to prepare for (79, 61.24%) compared to traditional exams. A significant proportion also believe OBEs accurately assess their comprehension (106, 82.17%) and prefer them as a mode of assessment (106, 82.17%). Furthermore, most students (87, 67.44%) reported performing better on OBEs compared to CBEs. Regarding the assessment of self-directed learning using the OBE method, students predominantly utilized highlighting important points (70, 54.26%) as a preparation method for OBEs. A large majority (85, 65.89%) considered OBEs as a fair assessment of self-directed learning and believed that they encourage self-directed learning (114, 88.37%). Conclusion  OBEs represent a promising direction for medical education, offering a way to better prepare students for the complexities of real-world medical practice. Future strategies should include not only the refinement of OBE methodologies but also the integration of practice opportunities that enable students to hone their skills in applying knowledge effectively.

Self-reported Visual Difficulty, Age-related Eye Disease, and Neuropsychiatric Outcomes in Older Adults.

PURPOSE: Self-reported visual difficulty is consistently associated with dementia and other neuropsychiatric outcomes, but studies of specific age-related eye diseases have yielded conflicting results. METHODS: We conducted a retrospective cohort study using data from The National Health and Aging Trends Study, an ongoing nationally representative survey of older U.S. adults (n = 10,089). All subjects are screened for self-reported visual difficulty annually. Using linked Medicare claims data, we identified subjects with age-related macular degeneration (AMD), primary open-angle glaucoma (POAG), diabetic retinopathy, and cataract. For each condition, controls with complete Medicare eligibility and at least one eye care encounter were selected. We used semiparametric discrete time proportional hazards models to measure associations with incident dementia, and generalized estimating equations to examine longitudinal associations with depression, anxiety, and hallucinations, adjusting for baseline demographics and time-varying comorbidities. RESULTS: Self-reported visual difficulty was associated with dementia (HR 1.16, 95% CI: 1.00-1.34), depression (OR 1.14, 95% CI: 1.04-1.26), anxiety (OR 1.17, 95% CI: 1.06-1.29), and hallucinations (OR 1.54, 95% CI: 1.29-1.84). Diabetic retinopathy was associated with depression (OR 1.31, 95% CI: 1.05-1.64), and cataracts were associated with a lower risk of depression (OR 0.84, 95% CI: 0.74-0.95) and anxiety (OR 0.86, 95% CI: 0.75-0.99). There were no other associations between age-related eye disease and neuropsychiatric outcomes. CONCLUSION: Self-reported visual difficulty is associated with dementia and other neuropsychiatric outcomes to a greater degree than age-related eye disease. These findings highlight the distinction between self-reported vision and clinically diagnosed eye disease with regard to health outcomes in older adults.

Consensus practice recommendations for management of gastrointestinal dysfunction in Parkinson disease.

BACKGROUND: Gastrointestinal (GI) dysfunction is a common non-motor feature of Parkinson disease (PD). GI symptoms may start years before the onset of motor symptoms and impair quality of life. Robust clinical trial data is lacking to guide screening, diagnosis and treatment of GI dysfunction in PD. OBJECTIVE: To develop consensus statements on screening, diagnosis, and treatment of GI dysfunction in PD. METHODS: The application of a modified Delphi panel allowed for the synthesis of expert opinions into clinical statements. Consensus was predefined as a level of agreement of 100 % for each item. Five virtual Delphi rounds were held. Two movement disorders neurologists reviewed the literature on GI dysfunction in PD and developed draft statements based on the literature review. Draft statements were distributed among the panel that included five movement disorder neurologists and two gastroenterologists, both experts in GI dysmotility and its impact on PD symptoms. All members reviewed the statements and references in advance of the virtual meetings. In the virtual meetings, each statement was discussed, edited, and a vote was conducted. If there was not 100 % consensus, further discussions and modifications ensued until there was consensus. RESULTS: Statements were developed for screening, diagnosis, and treatment of common GI symptoms in PD and were organized by anatomic segments: oral cavity and esophagus, stomach, small intestine, and colon and anorectum. CONCLUSIONS: These consensus recommendations offer a practical framework for the diagnosis and treatment of GI dysfunction in PD.

Assisting the analysis of insertions and deletions using regional allele frequencies.

Accurate estimation of population allele frequency (AF) is crucial for gene discovery and genetic diagnostics. However, determining AF for frameshift-inducing small insertions and deletions (indels) faces challenges due to discrepancies in mapping and variant calling methods. Here, we propose an innovative approach to assess indel AF. We developed CRAFTS-indels (Calculating Regional Allele Frequency Targeting Small indels), an algorithm that combines AF of distinct indels within a given region and provides "regional AF" (rAF). We tested and validated CRAFTS-indels using three independent datasets: gnomAD v2 (n=125,748 samples), an internal dataset (IGM; n=39,367), and the UK BioBank (UKBB; n=469,835). By comparing rAF against standard AF, we identified rare indels with rAF exceeding standard AF (sAF≤10-4 and rAF>10-4) as "rAF-hi" indels. Notably, a high percentage of rare indels were "rAF-hi", with a higher proportion in gnomAD v2 (11-20%) and IGM (11-22%) compared to the UKBB (5-9% depending on the CRAFTS-indels' parameters). Analysis of the overlap of regions based on their rAF with low complexity regions and with ClinVar classification supported the pertinence of rAF. Using the internal dataset, we illustrated the utility of CRAFTS-indel in the analysis of de novo variants and the potential negative impact of rAF-hi indels in gene discovery. In summary, annotation of indels with cohort specific rAF can be used to handle some of the limitations of current annotation pipelines and facilitate detection of novel gene disease associations. CRAFTS-indels offers a user-friendly approach to providing rAF annotation. It can be integrated into public databases such as gnomAD, UKBB and used by ClinVar to revise indel classifications.

Risk of Intracranial Hemorrhage in Persons with Hemophilia A in the United States: Real-World Retrospective Cohort Study Using the ATHNdataset.

Introduction: Intracranial hemorrhage (ICH), a serious complication in persons with hemophilia A (PWHA), causes high rates of mortality and morbidity. Identified ICH risk factors from patient data spanning 1998-2008 require reassessment in light of changes in the current treatment landscape. Aim and methods: PWHA identified in the ATHNdataset were evaluated retrospectively to assess incidence of ICH and determine the association between ICH risk and key characteristics using time-to-event analyses (Cox proportional-hazards models, survival curves, and sensitivity analyses). Results: Over a median follow-up time of 10.7 patient-years, 135 of 7837 PWHA over 2 years of age in the ATHNdataset (1.7%) experienced an ICH. Stratification by prophylaxis status and inhibitor status resulted in an incidence rate (IR) ratio (IRR) (IR+/IR-) of 0.63 (95% confidence interval [CI], 0.43-0.94; P=0.020) and 1.76 (95% CI, 0.97-3.20; P=0.059), respectively. Characteristics associated with greater risk of developing ICH include being aged 2-12 years; being covered by Medicaid; having had HIV, hepatitis C, or hypertension; and never having received factor VIII or prophylactic treatment. In multivariable analysis with interaction, the estimated hazard ratio for PWHA never receiving prophylaxis was 7.67 (95% CI, 2.24-26.30), which shrunk to 2.03 (95% CI, 1.30-9.12) in bootstrapping analysis and 3.09 in the highest-penalty ridge-regression analysis but was still significant. Inhibitor status was found not to be statistically associated with ICH in all analyses. Conclusion: These results align with previous studies demonstrating that prophylaxis confers a protective effect against ICH. Previously, inhibitor positivity had been shown to increase risk for ICH; however, this study did not corroborate those findings.

Validity of Administrative Coding for Nonarteritic Ischemic Optic Neuropathy.

BACKGROUND: Administrative claims have been used to study the incidence and outcomes of nonarteritic ischemic optic neuropathy (NAION), but the validity of International Classification of Diseases (ICD)-10 codes for identifying NAION has not been examined. METHODS: We identified patients at 3 academic centers who received ≥1 ICD-10 code for NAION in 2018. We abstracted the final diagnosis from clinical documentation and recorded the number of visits with an NAION diagnosis code. We calculated positive predictive value (PPV) for the overall sample and stratified by subspecialty and the number of diagnosis codes. For patients with ophthalmology or neuro-ophthalmology visit data, we recorded presenting symptoms, examination findings, and laboratory data and calculated PPV relative to case definitions of NAION that incorporated sudden onset of symptoms, optic disc edema, afferent pupillary defect, and other characteristics. RESULTS: Among 161 patients, PPV for ≥1 ICD-10 code was 74.5% (95% CI: 67.2%-80.7%). PPV was similar when restricted to patients who had visited an ophthalmologist (75.8%, 95% CI: 68.4%-82.0%) but increased to 86.8% when restricted to those who had visited neuro-ophthalmologists (95% CI: 79.2%-91.9%). Of 113 patients with >1 ICD-10 code and complete examination data, 37 (32.7%) had documented sudden onset, optic disc swelling, and an afferent pupillary defect (95% CI: 24.7%-42.0%). Of the 76 patients who did not meet these criteria, 54 (71.0%) still received a final clinical diagnosis of NAION; for most (41/54, 75.9%), this discrepancy was due to lack of documented optic disc edema. CONCLUSIONS: The validity of ICD-10 codes for NAION in administrative claims data is high, particularly when combined with provider specialty.

Electrochemical DNA-nano biosensor for the detection of Goserelin as anticancer drug using modified pencil graphite electrode.

Goserelin is an effective anticancer drug, but naturally causes several side effects. Hence the determination of this drug in biological samples, plays a key role in evaluating its effects and side effects. The current studies have concentrated on monitoring Goserelin using an easy and quick DNA biosensor for the first time. In this study, copper(II) oxide nanoparticles were created upon the surface of multiwalled carbon nanotubes (CuO/MWCNTs) as a conducting mediator. The modified pencil graphite electrode (ds-DNA/PA/CuO/MWCNTs/PGE) has been modified with the help of polyaniline (PA), ds-DNA, and CuO/MWCNTs nanocomposite. Additionally, the issue with the bio-electroanalytical guanine oxidation signal in relation to ds-DNA at the surface of PA/CuO/MWCNTs/PGE has been examined to determination Goserelin for the first time. It also, established a strong conductive condition to determination Goserelin in nanomolar concentration. Thus, Goserelin's determining, however, has a 0.21 nM detection limit and a 1.0 nM-110.0 µM linear dynamic range according to differential pulse voltammograms (DPV) of ds-DNA/PA/CuO/MWCNTs/PGE. Furthermore, the molecular docking investigation highlighted that Goserelin is able to bind ds-DNA preferentially and supported the findings of the experiments. The determining of Goserelin in real samples has been effectively accomplished in the last phase using ds-DNA/PA/CuO/MWCNTs/PGE.

Developing a genetic testing panel for evaluation of morbidities in kidney transplant recipients.

Cardiovascular disease, infection, malignancy, and thromboembolism are major causes of morbidity and mortality in kidney transplant recipients (KTR). Prospectively identifying monogenic conditions associated with post-transplant complications may enable personalized management. Therefore, we developed a transplant morbidity panel (355 genes) associated with major post-transplant complications including cardiometabolic disorders, immunodeficiency, malignancy, and thrombophilia. This gene panel was then evaluated using exome sequencing data from 1590 KTR. Additionally, genes associated with monogenic kidney and genitourinary disorders along with American College of Medical Genetics (ACMG) secondary findings v3.2 were annotated. Altogether, diagnostic variants in 37 genes associated with Mendelian kidney and genitourinary disorders were detected in 9.9% (158/1590) of KTR; 25.9% (41/158) had not been clinically diagnosed. Moreover, the transplant morbidity gene panel detected diagnostic variants for 56 monogenic disorders in 9.1% KTRs (144/1590). Cardiovascular disease, malignancy, immunodeficiency, and thrombophilia variants were detected in 5.1% (81), 2.1% (34), 1.8% (29) and 0.2% (3) among 1590 KTRs, respectively. Concordant phenotypes were present in half of these cases. Reviewing implications for transplant care, these genetic findings would have allowed physicians to set specific risk factor targets in 6.3% (9/144), arrange intensive surveillance in 97.2% (140/144), utilize preventive measures in 13.2% (19/144), guide disease-specific therapy in 63.9% (92/144), initiate specialty referral in 90.3% (130/144) and alter immunosuppression in 56.9% (82/144). Thus, beyond diagnostic testing for kidney disorders, sequence annotation identified monogenic disorders associated with common post-transplant complications in 9.1% of KTR, with important clinical implications. Incorporating genetic diagnostics for transplant morbidities would enable personalized management in pre- and post-transplant care.

Knowledge about Breast Cancer and Barriers to Screening among Saudi Women in Al-Baha Region.

OBJECTIVE: The aim of this study was to measure the knowledge about breast cancer and to identify the barriers in screening among Saudi women in the Al-Baha region. To achieve this, a cross-sectional study was conducted, involving 468 women, to assess their understanding of breast cancer and to explore the obstacles they face in accessing breast cancer screening services. METHODS: The cross-sectional study included 468 women from Al Baha, Saudi Arabia, starting from May 17, 2022, to May 17, 2023. Participants were interviewed by well-trained team members of the research, and their responses were subsequently entered into a Google Form. This process aimed to evaluate their awareness, knowledge, and barriers to breast cancer screening. RESULTS: The majority of participants (48.9%) were in the 18-28 age group. The findings reveal a high level of awareness (96.4%) among participants regarding the significance of early breast cancer detection. For the effectiveness of breast cancer treatment, 59% believed there is an effective treatment, while 32.9% were uncertain or did not know. Knowledge about various risk factors for breast cancer varied. Smoking (73.5%), genetic factors (65.6%), and a family history of breast cancer (70.7%) were well-recognized as risk factors. Education and occupation significantly influenced knowledge about breast cancer (p-value of 0.000, and 0.035 respectively). CONCLUSION: this research highlights strong awareness of breast cancer's importance but gaps in knowledge regarding lesser-known factors. Education is crucial, requiring tailored campaigns and healthcare professional engagement.

Disparities in Genetic Testing for Neurologic Disorders.

BACKGROUND AND OBJECTIVES: Genetic testing is now the standard of care for many neurologic conditions. Health care disparities are unfortunately widespread in the US health care system, but disparities in the utilization of genetic testing for neurologic conditions have not been studied. We tested the hypothesis that access to and results of genetic testing vary according to race, ethnicity, sex, socioeconomic status, and insurance status for adults with neurologic conditions. METHODS: We analyzed retrospective data from patients who underwent genetic evaluation and testing through our institution's neurogenetics program. We tested for differences between demographic groups in 3 steps of a genetic evaluation pathway: (1) attending a neurogenetic evaluation, (2) completing genetic testing, and (3) receiving a diagnostic result. We compared patients on this genetic evaluation pathway with the population of all neurology outpatients at our institution, using univariate and multivariable logistic regression analyses. RESULTS: Between 2015 and 2022, a total of 128,440 patients were seen in our outpatient neurology clinics and 2,540 patients underwent genetic evaluation. Black patients were less than half as likely as White patients to be evaluated (odds ratio [OR] 0.49, p < 0.001), and this disparity was similar after controlling for other demographic factors in multivariable analysis. Patients from the least wealthy quartile of zip codes were also less likely to be evaluated (OR 0.67, p < 0.001). Among patients who underwent evaluation, there were no disparities in the likelihood of completing genetic testing, nor in the likelihood of a diagnostic result after adjusting for age. Analyses restricted to specific indications for genetic testing supported these findings. DISCUSSION: We observed unequal utilization of our clinical neurogenetics program for patients from marginalized and minoritized demographic groups, especially Black patients. Among patients who do undergo evaluation, all groups benefit similarly from genetic testing when it is indicated. Understanding and removing barriers to accessing genetic testing will be essential to health care equity and optimal care for all patients with neurologic disorders.

Fatigue Impacts Quality of Life in People with Spinocerebellar Ataxias.

BACKGROUND: Fatigue is a prevalent and debilitating symptom in neurological disorders, including spinocerebellar ataxias (SCAs). However, the risk factors of fatigue in the SCAs as well as its impact have not been well investigated. OBJECTIVES: To study the prevalence of fatigue in SCAs, the factors contributing to fatigue, and the influence of fatigue on quality of life. METHODS: Fatigue was assessed in 418 participants with SCA1, SCA2, SCA3, and SCA6 from the Clinical Research Consortium for the Study of Cerebellar Ataxia using the Fatigue Severity Scale. We conducted multi-variable linear regression models to examine the factors contributing to fatigue as well as the association between fatigue and quality of life. RESULTS: Fatigue was most prevalent in SCA3 (52.6%), followed by SCA1 (36.7%), SCA6 (35.7%), and SCA2 (35.6%). SCA cases with fatigue had more severe ataxia and worse depressive symptoms. In SCA3, those with fatigue had a longer disease duration and longer pathological CAG repeat numbers. In multi-variable models, depressive symptoms, but not ataxia severity, were associated with more severe fatigue. Fatigue, independent of ataxia and depression, contributed to worse quality of life in SCA3 and SCA6 at baseline, and fatigue continued affecting quality of life throughout the disease course in all types of SCA. CONCLUSIONS: Fatigue is a common symptom in SCAs and is closely related to depression. Fatigue significantly impacts patients' quality of life. Therefore, screening for fatigue should be considered a part of standard clinical care for SCAs.

Genetic versus self-reported African ancestry of the recipient and neighborhood predictors of kidney transplantation outcomes in 2 multiethnic urban cohorts.

African American (AA) kidney recipients have a higher risk of allograft rejection and failure compared to non-AAs, but to what extent these outcomes are due to genetic versus environmental effects is currently unknown. Herein, we tested the effects of recipient self-reported race versus genetic proportion of African ancestry (pAFR), and neighborhood socioeconomic status (SES) on kidney allograft outcomes in multiethnic kidney transplant recipients from Columbia University (N = 1083) and the University of Pennsylvania (N = 738). All participants were genotyped with SNP arrays to estimate genetic admixture proportions. US census tract variables were used to analyze the effect of neighborhood factors. In both cohorts, self-reported recipient AA race and pAFR were individually associated with increased risk of rejection and failure after adjustment for known clinical risk factors and neighborhood SES factors. Joint analysis confirmed that self-reported recipient AA race and pAFR were both associated with a higher risk of allograft rejection (AA: HR 1.61 (1.31-1.96), P = 4.05E-06; pAFR: HR 1.90 (1.46-2.48), P = 2.40E-06) and allograft failure (AA: HR 1.52 (1.18-1.97), P = .001; pAFR: HR 1.70 (1.22-2.35), P = .002). Further research is needed to disentangle the role of genetics versus environmental, social, and structural factors contributing to poor transplantation outcomes in kidney recipients of African ancestry.

Light curve analysis and evolutionary status of four newly identified short-period eclipsing binaries.

We present the physical and orbital parameters of four short-period eclipsing W UMa systems: [Formula: see text] (referred to as S1), [Formula: see text] (referred to as S2), [Formula: see text] (referred to as S3), and [Formula: see text] (referred to as S4). The absolute parameters and evolutionary status of these systems are determined, and new times of minima are calculated. Additionally, we present the 3D fill-out configuration for each system. The four Systems exhibit moderate contact W UMa binary with a fill-out factor of 49%, 38%, 28%, and 51%, respectively. Comparing the systems' periods, we observed a proportional relationship, where shorter periods correspond to lower fill-out factors, and longer periods were associated with higher fill-out factors. Based on the derived surface temperatures and mass ratios of the components, all systems are classified as A-type W UMa binaries. The obtained parameters in addition to a list of previously published data are then utilized to derive an updated Mass-Luminosity relation (M-L) for both A and W-type eclipsing W UMa systems. A comparison with previously published relations reveals that the majority of the EW systems lie between 0.2 and 2 Msun on the M-L diagram. Moreover, we discuss the dynamical evolutionary aspects and evolutionary status of the four components, along with their positions on the Zero Age Main Sequence (ZAMS) and Terminal Age Main Sequence (TAMS).

Targeting WIP1 phosphatase promotes partial remission in experimental collapsing glomerulopathy.

Collapsing focal segmental glomerulosclerosis (FSGS), also known as collapsing glomerulopathy (CG), is the most aggressive variant of FSGS and is characterized by a rapid progression to kidney failure. Understanding CG pathogenesis represents a key step for the development of targeted therapies. Previous work implicated the telomerase protein component TERT in CG pathogenesis, as transgenic TERT expression in adult mice resulted in a CG resembling that seen in human primary CG and HIV-associated nephropathy (HIVAN). Here, we used the telomerase-induced mouse model of CG (i-TERTci mice) to identify mechanisms to inhibit CG pathogenesis. Inactivation of WIP1 phosphatase, a p53 target acting in a negative feedback loop, blocked disease initiation in i-TERTci mice. Repression of disease initiation upon WIP1 deficiency was associated with senescence enhancement and required transforming growth factor-ß functions. The efficacy of a pharmacologic treatment to reduce disease severity in both i-TERTci mice and in a mouse model of HIVAN (Tg26 mice) was then assessed. Pharmacologic inhibition of WIP1 enzymatic activity in either the telomerase mice with CG or in the Tg26 mice promoted partial remission of proteinuria and ameliorated kidney histopathologic features. Histological as well as high-throughput sequencing methods further showed that selective inhibition of WIP1 does not promote kidney fibrosis or inflammation. Thus, our findings suggest that targeting WIP1 may be an effective therapeutic strategy for patients with CG.

The expanded spectrum of human disease associated with GREB1L likely includes complex congenital heart disease.

OBJECTIVE: GREB1L has been linked prenatally to Potter's sequence, as well as less severe anomalies of the kidney, uterus, inner ear, and heart. The full phenotypic spectrum is unknown. The purpose of this study was to characterize known and novel pre- and postnatal phenotypes associated with GREB1L. METHODS: We solicited cases from the Fetal Sequencing Consortium, screened a population-based genomic database, and conducted a comprehensive literature search to identify disease cases associated with GREB1L. We present a detailed phenotypic spectrum and molecular changes. RESULTS: One hundred twenty-seven individuals with 51 unique pathogenic or likely pathogenic GREB1L variants were identified. 24 (47%) variants were associated with isolated kidney anomalies, 19 (37%) with anomalies of multiple systems, including one case of hypoplastic left heart syndrome, five (10%) with isolated sensorineural hearing loss, two (4%) with isolated uterine agenesis; and one (2%) with isolated tetralogy of Fallot. CONCLUSION: GREB1L may cause complex congenital heart disease (CHD) in humans. Clinicians should consider GREB1L testing in the setting of CHD, and cardiac screening in the setting of GREB1L variants.

Direct Reprogramming of Hepatocytes Into JAK/Stat-Dependent LGR5+ Liver Cells Able to Initiate Intrahepatic Cholangiocarcinoma.

Somatic cells that have been partially reprogrammed by the factors Oct4, Sox2, Klf4, and cMyc (OSKM) have been demonstrated to be potentially tumorigenic in vitro and in vivo due to the acquisition of cancer-associated genomic alterations and the absence of OSKM clearance over time. In the present study, we obtained partially reprogrammed, SSEA1-negative cells by transducing murine hepatocytes with Δ1Δ3-deleted adenoviruses that expressed the 4 OSKM factors. We observed that, under long-term 2D and 3D culture conditions, hepatocytes could be converted into LGR5-positive cells with self-renewal capacity that was dependent on 3 cross-signaling pathways: IL6/Jak/Stat3, LGR5/R-spondin, and Wnt/ß-catenin. Following engraftment in syngeneic mice, LGR5-positive cells that expressed the cancer markers CD51, CD166, and CD73 were capable of forming invasive and metastatic tumors reminiscent of intrahepatic cholangiocarcinoma (ICC): they were positive for CK19 and CK7, featured associations of cord-like structures, and contained cuboidal and atypical cells with dissimilar degrees of pleomorphism and mitosis. The LGR5+-derived tumors exhibited a highly vascularized stroma with substantial fibrosis. In addition, we identified pro-angiogenic factors and signaling pathways involved in neo-angiogenesis and vascular development, which represent potential new targets for anti-angiogenic strategies to overcome tumor resistance to current ICC treatments.

Cell specification and functional interactions in the pig blastocyst inferred from single-cell transcriptomics and uterine fluids proteomics.

The embryonic development of the pig comprises a long in utero pre- and peri-implantation development, which dramatically differs from mice and humans. During this peri-implantation period, a complex series of paracrine signals establishes an intimate dialogue between the embryo and the uterus. To better understand the biology of the pig blastocyst during this period, we generated a large dataset of single-cell RNAseq from early and hatched blastocysts, spheroid and ovoid conceptus and proteomic datasets from corresponding uterine fluids. Our results confirm the molecular specificity and functionality of the three main cell populations. We also discovered two previously unknown subpopulations of the trophectoderm, one characterised by the expression of LRP2, which could represent progenitor cells, and the other, expressing pro-apoptotic markers, which could correspond to the Rauber's layer. Our work provides new insights into the biology of these populations, their reciprocal functional interactions, and the molecular dialogue with the maternal uterine environment.