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A 30-year-old man was referred by a general ophthalmologist for retina examination owing to his high myopia status. His presenting visual acuity in the right eye was 6/6 with a refraction of −2.75 dioptre sphere (DS), −2.75 dioptre cylinder (DC) at 170° and that in the left eye was 6/9 with a

To describe the clinical and imaging features in a series of patients diagnosed with macular coloboma (MC) and intrachoroidal cavitation (ICC).Patients diagnosed with MC based on clinical examination between June 2017 and July 2021 were retrieved from the electronic medical record system and were included in the study. Colour fundus photographs, optical coherence tomography (OCT) and Multicolour® imaging scans of these patients were analysed.We identified 16 eyes of 11 patients with MC on fundus examination. Based on OCT imaging features, conforming variant of MC was seen in 9 (56%) eyes and non-conforming variant in 7 (44%) eyes. No eyes with MC in the study showed features of both conforming and non-conforming varieties simultaneously. In the non-conforming variety of MC with presence of intercalary membrane break, ICC was identified in 5 (71%) of these eyes. ICC in MC appeared as flat, dark greenish areas with or without an orange-coloured boundary abutting the margin of the coloboma on Multicolour® imaging.In 31% eyes, ICC was seen in non-conforming type of MC and was well-identified on Multicolour® imaging. It appears that presence of intercalary membrane break and detachment are prerequisites for developing ICC.

Tuberculosis (TB) disease causes significant morbidity, mortality, and public health impacts. Prevention of latent tuberculosis infection (LTBI) in children reduces the burden of disease.The Texas Children's Mobile Clinic Program's (TC-MCP's) mission is to provide high-quality health care to underresourced children within the community setting. The TC-MCP serves a large foreign-born pediatric population. The need for an LTBI treatment program arose when caring for this high-risk population.The TC-MCP providers collaborated with nationally recognized pediatric TB experts as well as local health departments that provide medications free of cost. The TC-MCP placed tuberculin skin tests (TSTs) on patients with risk factors for TB. TST-positive patients had an interferon-γ release assay (IGRA) performed. IGRA-positive patients had a chest radiograph (CXR) obtained. Children with positive IGRA and normal CXR were included in the LTBI program, which consisted of TC-MCP outpatient visits and 12 once-weekly doses of isoniazid/rifapentine (3HP) provided by local health departments.From January 2018 to March 2020, 785 TC-MCP patients received TSTs, of which 38 (4.8%) were positive. An additional 7 positive TSTs were identified from outside facilities. In addition to the 45 positive TSTs, 4 TC-MCP patients with follow-up difficulties had IGRAs done as the initial test. Of these 49 IGRAs done, 13 patients had a positive IGRA. An additional 6 patients with positive IGRAs from outside facilities were identified. Nineteen patients (36.5%) were diagnosed with LTBI; of whom, 18 completed 3HP therapy through the TC-MCP. Eighty-three percent (15/18) completed at least 2 in-person visits.Underresourced children at higher risk for TB benefit from a mobile clinic's unique reach. By utilizing community partnerships, mobile clinics can successfully fill gaps in the health care system where marginalized populations may be missed.

Background AKI is an important complication post cardiac surgery in children. An early diagnosis can help in mitigating complications and allow for prognostication. Urinary albumin:creatinine ratio (ACR) as a biomarker can provide a cheaper and more accessible AKI risk assessment and prediction. There is a paucity of paediatric literature regarding its utility. Methods This was a prospective observational study, enrolling all children aged 1 month to 18 years, who underwent cardiac surgery, with use of cardiopulmonary bypass. Cohort was divided into groups 75.8 mg/g) predicted post-operative AKI after adjusting for clinical variables (adjusted RR, 11.71; 1.85–16.59). In the group aged 141.3 mg/g) predicted post-operative AKI in unadjusted analysis but not after adjusting for clinical variables (RR, 2.78; 0.70–6.65). For AKI risk prediction, AUC (95% CI) was highest after combining clinical model and pre-operative ACR for groups aged < 2 years [0.805 (0.713-0.896)] and ≥ 2 years [0.872 (0.772–0.973)]. Conclusions This study provides evidence for use of albuminuria as a feasible biomarker in AKI prediction in children post cardiac surgery, especially when added to a clinical model. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information. Supplementary Information The online version contains supplementary material available at 10.1007/s00467-021-05219-0.

Transplant centers hesitate to transplant patients with cognitive impairment. It is unclear if pre-kidney transplant (KT) cognitive screening can predict post-KT cognitive function.We evaluated pre- to post-KT cognitive function with the Montreal Cognitive Assessment (MoCA) in a cohort of 108 patients. We used an adjusted logistic regression model to assess pre- to post-KT changes in cognitive status (continuous variable) and a linear mixed model to assess changes in MoCA scores (categorical variable) pre- to post- KT.The average pre- and post-KT MoCA scores were 25.3 ± 3.0 and 26.4 ± 2.8, respectively. Final pre-KT score did not predict post-KT cognitive status (OR = 1.08; 95% CI: .92-1.26; P = .35). 32% of the patients with a final pre-KT score ≥26 had at least one post-KT score 26. Conversely, 61% of the patients with a final pre-KT score 26 had at least one post KT score ≥26. In the linear mixed model analysis, the final pre-KT score was associated with a small, clinically insignificant (β = .34; 95% CI: .19-.49; P .001) effect on the post-KT score.A low pre-KT MoCA score is not a strong independent predictor of post-KT cognitive function and should not preclude patients from receiving a KT.

Little is known about the physiology of latent Mycobacterium tuberculosis infection. We studied the mutational rates of 24 index tuberculosis (TB) cases and their latently infected household contacts who developed active TB up to 5.25 years later, as an indication of bacterial physiological state and possible generation times during latent TB infection in humans. Here we report that the rate of new mutations in the M. tuberculosis genome decline dramatically after two years of latent infection (two-sided p, Here, Colangeli et al. use a human household contact cohort to measure the rate of mutation and evolution of Mycobacterium tuberculosis strains and find that long term latency is characterized by reduced mutation rates compared to latency in the first year, coinciding with clinical risk of developing active TB.

Objective To determine if use of a health literacy low-inference, self-assessment measure (LISAM), promoted behavior change as measured by increased use of health literacy communication skills (HLCS). Methods The LISAM is a tool used by educators to self-assess their performances after giving a lecture. The tool is low inference because it self-assesses behaviors that are specific, with little room for subjectivity. Forty-four third-year medical students self-assessed HLCS using a LISAM modified to include health literacy communication skills (LISAM-HLCS). Self-assessment followed participation in an audio recorded, standardized patient encounter and again after listening to the recording. Students also created 3 written goals for improvement. This session was repeated 1 week later. Results At Session 2, 71.4% of students met at least 2 of their 3 self-created objectives. The 3 most commonly created objectives were using teach-back, asking more open ended questions, and obtaining patient input into the management plan. Use of the LISAM increased HLCS use at Session 2 versus Session 1 as assessed by both students and study investigators (P Conclusions Without faculty present, students met and adjusted objectives, catalyzing changes in HLCS. The LISAM-HLCS has the potential to empower students to improve communication skills and to reduce dependence on faculty observations.

Cancer stem cells (CSCs) are cells within tumors that maintain the ability to self-renew, drive tumor growth, and contribute to therapeutic resistance and cancer recurrence. In this study, we investigate the role of Zinc finger and SCAN domain containing 4 (ZSCAN4) in human head and neck squamous cell carcinoma (HNSCC). The murine Zscan4 is involved in telomere maintenance and genomic stability of mouse embryonic stem cells. Our data indicate that the human ZSCAN4 is enriched for, marks and is co-expressed with CSC markers in HNSCC. We show that transient ZSCAN4 induction for just 2 days increases CSC frequency both in vitro and in vivo and leads to upregulation of pluripotency and CSC factors. Importantly, we define for the first time the role of ZSCAN4 in altering the epigenetic profile and regulating the chromatin state. Our data show that ZSCAN4 leads to a functional histone 3 hyperacetylation at the promoters of OCT3/4 and NANOG, leading to an upregulation of CSC factors. Consistently, ZSCAN4 depletion leads to downregulation of CSC markers, decreased ability to form tumorspheres and severely affects tumor growth. Our study suggests that ZSCAN4 plays an important role in the maintenance of the CSC phenotype, indicating it is a potential therapeutic target in HNSCC.

To report Multicolour® imaging (MCI) findings in commotio retinae (CR) involving macula and correlate topographically with outer retinal layers on optical coherence tomography (OCT).This retrospective study included participants with CR involving macula without any other type of traumatic maculopathy and imaged with OCT and MCI.The study included 16 eyes of 16 patients (14 males). Age of presentation ranged from 7 to 56 years and presenting vision ranged from 6/6 to 6/24. On OCT, increased reflectivity and obliteration of hyporeflective ellipsoid zone (EZ) and interdigitation zone (IZ) at CR region were seen. Fovea and other retinal layers were spared. On MCI, white areas due to hyperreflectance corresponding to CR were noted on individual colour reflectance channels and on composite multicolour image. In all cases, foveal reflectance pattern was unaffected. The affection of the EZ and IZ at the CR on OCT was associated with increased reflectance on individual wavelength colour channels on MCI. Foveal sparing on MCI correlated with photoreceptor layer sparing at the fovea on OCT. In 6 (38%) cases with follow-up details, normal reflectivity of EZ and IZ was noted in the region of previous CR as early as 1-week post-presentation. White coloration on multicolour image showed resolution.Foveal sparing was common and rod-dominated areas were affected in CR. Corresponding changes on MCI showed hyperreflectance areas on individual wavelength colour channels. Studies combined with photoreceptor-specific electrophysiological tests, adaptive optics imaging and histological evidences would be required in future.

Corona virus disease (COVID-19) has been associated with a variety of ophthalmic manifestations including acute macular neuroretinopathy and paracentral middle maculopathy. Posterior segment manifestations after post COVID-19 vaccinations have been reported.A 25- year-old Asian Indian female developed sequential bilateral AMN following a single dose of COVISHIELD™ vaccine. On investigations she was found to have a β thalassemia trait. Presentation started unilaterally and progressed to the other eye after a month. On clinical examination, the fundus was apparently normal in both eyes. Significant changes suggestive of AMN were seen on multimodal imaging of the posterior segment of the respective eye at the time of involvement which resolved spontaneously in due course.We report a temporal association of COVID-19 vaccination and AMN.

Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. The FBXW7 neurodevelopmental syndrome is distinguished by global developmental delay, borderline to severe intellectual disability, hypotonia, and gastrointestinal issues. Brain imaging detailed variable underlying structural abnormalities affecting the cerebellum, corpus collosum, and white matter. A crystal-structure model of FBXW7 predicted that missense variants were clustered at the substrate-binding surface of the WD40 domain and that these might reduce FBXW7 substrate binding affinity. Expression of recombinant FBXW7 missense variants in cultured cells demonstrated impaired CYCLIN E1 and CYCLIN E2 turnover. Pan-neuronal knockdown of the Drosophila ortholog, archipelago, impaired learning and neuronal function. Collectively, the data presented herein provide compelling evidence of an F-Box protein-related, phenotypically variable neurodevelopmental disorder associated with monoallelic variants in FBXW7.

Sarcopenia is associated with adverse outcomes in end-stage kidney disease. We evaluated if pretransplant sarcopenia affects posttransplant outcomes in kidney transplant (KT) recipients.In this single-center retrospective study of adult patients with end-stage kidney disease, we analyzed the association between pre-KT psoas muscle cross-sectional area and critical posttransplant outcomes of decline in estimated glomerular filtration rate (eGFR), graft loss, rehospitalization, and mortality using Cox proportional hazard model adjusted for age, sex, and race.Pre-KT abdomen and pelvic computed tomography scans performed during evaluation for KT eligibility were available for 573 KT recipients. Of these, 465 KT recipients received kidney alone transplant, 71 received simultaneous liver kidney transplant (SLK), and 37 received simultaneous pancreas kidney transplant (SPK). Patients were 49 (SD, 13) years old, 16% Black, and 60% men. For kidney alone transplant recipients, a higher psoas muscle cross-sectional area was associated with a shorter length of hospitalization (β coefficient = -0.003; 95% CI, -0.005 to -0.0007). Conversely, pre-KT psoas muscle cross-sectional area did not predict decline in eGFR, graft loss, mortality, or early rehospitalization. For SLK recipients, psoas muscle cross-sectional area did not predict any of the priori outcomes. For SPK recipients, higher pretransplant psoas muscle cross-sectional area predicted a longer length of hospitalization (β coefficient = 0.03; 95% CI, 0.01-0.05). There was no association between psoas muscle cross-sectional area and other outcomes assessed.Pretransplant psoas muscle cross-sectional areas are not predictive of post-transplant decline in eGFR, graft loss, rehospitalization or mortality in kidney alone, SPK, or SLK transplants.

Purpose Exome sequencing often identifies pathogenic genetic variants in patients with undiagnosed diseases. Nevertheless, frequent findings of variants of uncertain significance necessitate additional efforts to establish causality before reaching a conclusive diagnosis. To provide comprehensive genomic testing to patients with undiagnosed disease, we established an Individualized Medicine Clinic, which offered clinical exome testing and included a Translational Omics Program (TOP) that provided variant curation, research activities, or research exome sequencing. Methods From 2012 to 2018, 1101 unselected patients with undiagnosed diseases received exome testing. Outcomes were reviewed to assess impact of the TOP and patient characteristics on diagnostic rates through descriptive and multivariate analyses. Results The overall diagnostic yield was 24.9% (274 of 1101 patients), with 174 (15.8% of 1101) diagnosed on the basis of clinical exome sequencing alone. Four hundred twenty-three patients with nondiagnostic or without access to clinical exome sequencing were evaluated by the TOP, with 100 (9% of 1101) patients receiving a diagnosis, accounting for 36.5% of the diagnostic yield. The identification of a genetic diagnosis was influenced by the age at time of testing and the disease phenotype of the patient. Conclusion Integration of translational research activities into clinical practice of a tertiary medical center can significantly increase the diagnostic yield of patients with undiagnosed disease.

OBJECTIVES: Primary failure of eruption (PFE) is a genetic disorder exhibiting the cessation of tooth eruption. Loss-of-function mutations in parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor (PTH/PTHrP receptor, PPR) were reported as the underlying cause of this disorder in humans. We showed in a PFE mouse model that PTHrP-PPR signaling is responsible for normal dental follicle cell differentiation and tooth eruption. However, the mechanism underlying the eruption defect in PFE remains undefined. In this descriptive study, we aim to chronologically observe tooth eruption and root formation of mouse PFE molars through 3D microCT analyses. SETTING AND SAMPLE POPULATION: Two individuals with PFE were recruited at Showa University. A mouse PFE model was generated by deleting PPR specifically in PTHrP-expressing dental follicle and divided into three groups, PPR(fl/fl);R26R(tdTomato/+)(Control), PTHrP-creER;PPR(fl/+);R26R(tdTomato/+)(cHet), and PTHrP-creER;PRR(fl/fl);R26R(tdTomato/+)(cKO). MATERIALS AND METHODS: Images from human PFE subjects were acquired by CBCT. All groups of mouse samples were studied at postnatal days 14, 25, 91, and 182 after a tamoxifen pulse at P3, and superimposition of 3D microCT images among three groups was rendered. RESULTS: Mouse and human PFE molars exhibited a similar presentation in the 3D CT analyses. The quantitative analysis in mice demonstrated a statistically significant decrease in the eruption height of cKO first and second molars compared to other groups after postnatal day 25. Additionally, cKO molars demonstrated significantly shortened roots with dilacerations associated with the reduced interradicular bone height. CONCLUSIONS: Mouse PFE molars erupt at a much slower rate compared to normal molars, associated with shortened and dilacerated roots and defective interradicular bones.

Most patients with colorectal cancer die as a result of the disease spreading to other organs. However, no prevalent mutations have been associated with metastatic colorectal cancers. Instead, particular features of the tumour microenvironment, such as lack of T-cell infiltration, low type 1 T-helper cell (T

There is paucity of evidence on cost of antiretroviral therapy (ART) delivered through the public sector in India. Moreover, the Government of India is considering changing the criteria for introduction of ART to HIV patients, which is likely to have significant economic implications. In this paper, we assess the health system cost of ART services at two levels of health care delivery. Bottom-up costing was used to collect data on capital and recurrent resources consumed over a period of one year (April 2014–March 2015). Capital costs were annualized and shared costs apportioned to calculate annual and unit costs of providing ART care. Sensitivity analysis was undertaken to measure the extent of uncertainty in input prices. The annual per capita cost of ART therapy was INR 48,975 (USD738) in the Centre of Excellence (COE) and INR 24,954 (USD376) in the ART centre. Drugs contributed around 70% and 65% of total annual cost, followed by human resource (19% each) and capital cost (7%; 12%) in COE and ART centres, respectively. These provide a comprehensive assessment of the cost of ART care in India. The study estimates could be used for planning of services, as well as undertaking further cost-effectiveness studies.

Alzheimer's Disease (AD) is an age-related disease with modifiable risk factors such as hypertension, hypercholesterolemia, obesity, and physical inactivity influencing the onset and progression. There is however, no direct evidence that reducing these risk factors prevents or slows AD. The Risk Reduction for Alzheimer's Disease (rrAD) trial is designed to study the independent and combined effects of intensive pharmacological control of blood pressure and cholesterol and exercise training on neurocognitive function. Six hundred and forty cognitively normal older adults age 60 to 85 years with hypertension and increased risk for dementia will be enrolled. Participants are randomized into one of four intervention group for two years: usual care, Intensive Reduction of Vascular Risk factors (IRVR) with blood pressure and cholesterol reduction, exercise training (EX), and IRVR+EX. Neurocognitive function is measured at baseline, 6, 12, 18, and 24 months; brain MRIs are obtained at baseline and 24 months. We hypothesize that both IRVR and EX will improve global cognitive function, while IRVR+EX will provide a greater benefit than either IRVR or EX alone. We also hypothesize that IRVR and EX will slow brain atrophy, improve brain structural and functional connectivity, and improve brain perfusion. Finally, we will explore the mechanisms by which study interventions impact neurocognition and brain. If rrAD interventions are shown to be safe, practical, and successful, our study will have a significant impact on reducing the risks of AD in older adults. NCT Registration: NCT02913664

Determination of viral load through cycle threshold (Ct) values may act as a predictor of severity and outcomes in patients with corona virus disease 2019 (COVID-19). However, variable literature is available regarding this relationship. Our study attempted to explore this association and the effect of various socio-demographic and clinical parameters on severity and outcome of COVID-19. Retrospective analysis of records of 731 patients whose nasopharyngeal/ oropharyngeal swabs were subjected to cartridge based nucleic acid amplification (CBNAAT) on Cepheid Xpert Xpress SARS-Cov-2 was done. Cycle threshold (Ct) values of N2 and E genes were studied in relation to severity and outcome of COVID-19. The viral load as determined by Ct values was classified as high (32). Association of socio-demographic and clinical parameters with respect to severity and outcome was also studied. Severity and mortality were significantly more in elder individuals, those belonging to the rural background, those with symptoms >7 days in duration before presentation and those with increasing number of co-morbidities (Severity: p32, in comparison when it was upto 25, and when between 25.1 and 32 (severity: p=0.032 and 0.003 respectively, mortality: p=0.018 and

Tuberculosis (TB) infection of the Sternoclavicular joint (SCJ) is a rare entity, with 1–2% of all osteo-articular cases reported. We report a series of three cases of TB of the SCJ, in the patients presented with swelling of SCJ. Cytology showed chronic granulomatous pathology in all three cases, with one patient having Cartridge base nucleic acid amplification test positive for TB and another one having acid fast bacilli positive on Ziehl Neelsen staining. All three were put on antitubercular treatment (ATT) that resulted in significant improvement. A high index of suspicion of TB to be maintained in cases with swellings at unusual sites especially in high burden countries like India. Similarly, gradually progressive osteoarticular swellings without systemic features should also raise suspicion of tubercular etiology, as diagnosis was delayed for about 4 months in two of our cases and about 1 year in the third case. The application of newer technologies such as CBNAAT can help in early microbiological confirmation of paucibacillary disease leading to early diagnosis and prevention of possible complications.

T-wave inversions (TWI) in inferolateral electrocardiogram (ECG) leads (II, III, aVF, V5-V6) are often suggestive of cardiac pathology in adult patients. They are a common reason of additional testing in pediatric patients. The goal of the study is to determine correlation of exercise stress test T-wave response with diagnosis of cardiac pathology. This is a retrospective review of pediatric patients 21 years with the finding of baseline TWI in inferior (II, III, avF) and/or lateral (V5-V6) leads on 12-lead ECG. All patients underwent treadmill exercise stress test (EST) and an echocardiogram within 1 year of each other. Demographics, baseline ECG findings, echocardiogram results, and EST data were recorded. T-wave reversion was considered complete if T waves demonstrated normalization during exercise, partial if there was minimal improvement, and no response if there was no change or worsening of inversions. In our cohort of 72 patients with a mean age 14.6 (± 2.9) years and 61% males, 59 (82%) had a structurally normal heart. Thirteen patients had evidence of structural or functional heart disease. Of the 59 patients, 83% had either complete or partial T-wave response. Among the 13 patients with heart disease, two patients had genetic testing consistent with risk for hypertrophic cardiomyopathy and had complete and partial response on EST. Exercise stress testing for TWI in pediatric patients has low sensitivity and specificity for the diagnosis of cardiac disease and routine use in this patient population may not be indicated.

Introduction The launch of injectable shorter regimens under Programmatic Management of Drug Resistant Tuberculosis (PMDT) guidelines 2017 under Revised National Tuberculosis Control Program (RNTCP) was a welcome step as it decreased the duration of treatment significantly in Drug Resistant Tuberculosis (DRTB) patients. The objective of the present study was to evaluate the treatment outcomes of patients started on injectable shorter regimens from March 2018 to May, 2019. Methods Retrospective study which scrutinized medical records of 85 patients started on injectable shorter regimen was conducted. Necessary information on possible patient and disease related predicting factors like age, gender, weight, HIV status, presence of diabetes mellitus (DM), anemia, gap between diagnosis and initiation of treatment, duration of intensive phase (IP) and time of sputum conversion was retrieved, and analyzed for possible association with treatment outcomes. Results 56.5% had successful treatment outcomes. Age, gender, BMI, diabetic/anemic status and gap between diagnosis and initiation of treatment had no statistically significant relationship with the final outcomes. Duration of IP, sputum conversion and time of outcome during the course of illness emerged as significant factors in successful outcomes. Conclusion The injectable shorter regimens were suitable for a variety of population irrespective of demographic disparities. Patients need to be followed closely as microbiological parameters serve as early indicators of unsuccessful outcomes. These regimens can serve as an alternate choice in patients not tolerating the all oral shorter Bedaquiline containing shorter regimen. Similar such options with combinations of different drugs for individualizing treatment regimens is the need of the hour.

Background Whether mild to moderately low estimated glomerular filtration rate (eGFR) is associated with cognitive decline in older adults is not clear. We evaluated changes in cognition in relation to baseline eGFR in older adults participating in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Methods This is a longitudinal secondary analysis of an established observational cohort. We used data from the ADNI, an National Institutes of Health–funded, multicenter longitudinal observational study that includes participants with and without cognitive impairment who were administered a comprehensive battery of neuropsychological tests every 6 months. We related the Chronic Kidney Disease Epidemiology Collaboration eGFR with previously validated cognition composite scores for memory (ADNI-Mem) and executive function (ADNI-EF) in multivariable linear regression analysis adjusted for age, sex, race and level of education. Results A total of 1127 ADNI participants (mean age 74 ± 7 years, 57% men, 97% Caucasian, mean follow-up 6 ± 2.6 years) were included in the analysis. The mean baseline eGFR was 76 ± 19 mL/min/1.73 m2, with 6% with eGFR 90 mL/min/1.73 m2 at baseline. Both ADNI-Mem and ADNI-EF scores declined over time. In the multivariable linear regression model, older age (β = −0.117, P = 0.01), female sex (β = 0.312, P < 0.001) and lower education (β = 0.079, P < 0.001) were associated with a decline in ADNI-Mem scores, whereas baseline eGFR (each 10 mL/min/1.73 m2 change) was not {β = −0.03 [confidence interval (CI) −0.06–0.001], P = 0.11}. Similarly, older age (β = −0.278, P < 0.001) and lower education (β = 0.099, P < 0.001) were associated with a decline in ADNI-EF scores, whereas baseline eGFR was not [β = 0.004 (95% CI −0.04–0.04), P = 0.84]. Conclusions In this cohort from the ADNI study, there was no association between baseline eGFR and cognitive decline in older adults with mild to moderately low eGFR.

Introduction: The Ocular manifestations of coronavirus disease 2019 (COVID-19) reported include conjunctivitis, conjunctival hyperemia, chemosis, epiphora, episcleritis, retinal manifestations included cotton wool spots (CWS), micro-hemorrhages, papillophlebitis and neuro-ophthalmic manifestations.Purpose: To report post COVID-19 ophthalmic manifestations using multimodal imaging.Results: A 66-year-old Asian Indian male presented to us with bilateral blurring of vision, RE>LE, of 3 days following a diagnosis of COVID-19 disease. Corrected distance visual acuity were 20/2666 and 20/25 in the right (RE) and left (LE) eyes respectively. He had bilateral anterior chamber inflammation with a relative afferent pupillary defect in the RE. RE showed central retinal artery occlusion(CRAO) with CWS, few flame-shaped retinal hemorrhages and disc edema and hyperemia. LE had disc edema and hyperemia, few flame-shaped retinal hemorrhages, cystoid changes and CWS. A diagnosis of bilateral panuveitis and papillitis with CRAO in the RE was made.Conclusion: Our patient developed a vascular occlusion with panuveitis, which possibly represents an immune mediated event following COVID-19. Patients should be warned about possible ophthalmic sequelae even after recovery.

Allergic rhinitis (AR) is a chronic allergen specific, IgE-mediated hypersensitivity disorder which significantly impairs the quality of life in affected patients. Many aeroallergens and molds are responsible for AR. This study was conducted to find prevalence of Aspergillus fumigatus skin hypersensitivity in patients of AR by skin prick test (SPT). 150 clinically diagnosed AR patients visiting our OPD were enrolled. Skin hypersensitivity for Aspergillus f. was done by SPT in all the enrolled patients. Chi square test and Student’s t-test were applied for statistical analysis. Out of 150 patients, 60 (40%) were positive for Aspergillus fumigatus SPT. Majority of the positive patients had persistent AR and among those 39/60 (65%) had moderate to severe persistent AR and 12/60 (20%) had mild persistent AR. Our study concluded that there is high (40%) prevalence of Aspergillus f. skin hypersensitivity among AR patients. The hypersensitivity to Aspergillus f. was found more in severe AR patients and it was statistically significant.

Background The progressive risk of graft failure in pediatric heart transplantation (PHT) necessitates close surveillance for rejection and coronary allograft vasculopathy (CAV). The current gold standard of surveillance via invasive coronary angiography is costly, imperfect and associated with complications. Our goal was to assess the safety and feasibility of a comprehensive multi-parametric CMR protocol with regadenoson stress perfusion in PHT and evaluate for associations with clinical history of rejection and CAV. Methods We performed a retrospective review of 26 PHT recipients who underwent stress CMR with tissue characterization and compared with 18 age-matched healthy controls. CMR protocol included myocardial T2, T1 and extracellular volume (ECV) mapping, late gadolinium enhancement (LGE), qualitative and semi-quantitative stress perfusion (myocardial perfusion reserve index; MPRI) and strain imaging. Clinical, demographics, rejection score and CAV history were recorded and correlated with CMR parameters. Results Mean age at transplant was 9.3 ± 5.5 years and median duration since transplant was 5.1 years (IQR 7.5 years). One patient had active rejection at the time of CMR, 11/26 (42%) had CAV 1 and 1/26 (4%) had CAV 2. Biventricular volumes were smaller and cardiac output higher in PHT vs. healthy controls. Global T1 (1053 ± 42 ms vs 986 ± 42 ms; p Conclusion In a PHT population with low incidence of rejection or high-grade CAV, CMR demonstrates important differences in myocardial structure, function and perfusion compared to age-matched healthy controls. Regadenoson stress perfusion CMR could be safely and reliably performed. Increasing T2 values were associated with worsening left ventricular function and increasing T1/ECV values were associated with rejection history and low-grade CAV. These findings warrant larger prospective studies to further define the role of CMR in PHT graft surveillance.

Objectives Assess the impact of heterogeneity among established sepsis criteria (Sepsis-1, Sepsis-3, Centers for Disease Control and Prevention Adult Sepsis Event, and Centers for Medicare and Medicaid severe sepsis core measure 1) through the comparison of corresponding sepsis cohorts. Design Retrospective analysis of data extracted from electronic health record. Setting Single, tertiary-care center in St. Louis, MO. Patients Adult, nonsurgical inpatients admitted between January 1, 2012, and January 6, 2018. Interventions None. Measurements and main results In the electronic health record data, 286,759 encounters met inclusion criteria across the study period. Application of established sepsis criteria yielded cohorts varying in prevalence: Centers for Disease Control and Prevention Adult Sepsis Event (4.4%), Centers for Medicare and Medicaid severe sepsis core measure 1 (4.8%), International Classification of Disease code (7.2%), Sepsis-3 (7.5%), and Sepsis-1 (11.3%). Between the two modern established criteria, Sepsis-3 (n = 21,550) and Centers for Disease Control and Prevention Adult Sepsis Event (n = 12,494), the size of the overlap was 7,763. The sepsis cohorts also varied in time from admission to sepsis onset (hr): Sepsis-1 (2.9), Sepsis-3 (4.1), Centers for Disease Control and Prevention Adult Sepsis Event (4.6), and Centers for Medicare and Medicaid severe sepsis core measure 1 (7.6); sepsis discharge International Classification of Disease code rate: Sepsis-1 (37.4%), Sepsis-3 (40.1%), Centers for Medicare and Medicaid severe sepsis core measure 1 (48.5%), and Centers for Disease Control and Prevention Adult Sepsis Event (54.5%); and inhospital mortality rate: Sepsis-1 (13.6%), Sepsis-3 (18.8%), International Classification of Disease code (20.4%), Centers for Medicare and Medicaid severe sepsis core measure 1 (22.5%), and Centers for Disease Control and Prevention Adult Sepsis Event (24.1%). Conclusions The application of commonly used sepsis definitions on a single population produced sepsis cohorts with low agreement, significantly different baseline demographics, and clinical outcomes.

Since the first heart transplant in 1967, there has been significant progress in this field of cardiac transplantation. Approximately 600 pediatric heart transplants are performed every year worldwide. With the increasing number of pediatric heart transplant patients, and given the few tertiary care pediatric transplant centers, adult and pediatric emergency department (ED) providers are increasingly engaged in the care of pediatric heart transplant recipients in the ED.The aim of this article is to review common ED scenarios pertinent to the pediatric heart transplant patients.There are complications unique to this population, such as rejection, opportunistic infections, and medication side effects, that require special considerations, and it is helpful for the emergency medicine (EM) provider to have knowledge about them.The unique immunological challenges in these patients, including rejection and medication side effects and opportunistic infections, make this population fragile, and the knowledge of these challenges is helpful for EM providers.

Background In an effort to encourage Family Planning (FP) adoption, since 1952, the Government of India has been implementing various centrally sponsored schemes that offer financial incentives (FIs) to acceptors as well as service providers, for services related to certain FP methods. However, understanding of the role of FIs on uptake of FP services, and the quality of FP services provided, is limited and mixed. Methods A qualitative descriptive study was conducted in Chatra and Palamu districts of Jharkhand state. A total of 64 interviews involving multiple stakeholders were conducted. The stakeholders included recent FP acceptors or clients, FP service providers of public health facilities including Accredited Social Healthcare Activists (ASHAs), government health officials managing FP programs at the district and state level, and members of development partners supporting FP programs in Jharkhand. Data analysis included both inductive and deductive strategies. It was done using the software Atlas ti version 8. Results It has emerged that there is a strong felt need for FP among majority of the clients, and FIs may be a motivator for uptake of FP methods only among those belonging to the lower socio economic strata. For ASHAs, FI is the primary motivator for providing FP related services. There may be a tendency among them and the nurses to promote methods which have more financial incentives linked with them. There are mixed opinions on discontinuing FIs for clients or replacing them with non-financial incentives. Delays in payment of FIs to both clients and the ASHAs is a common issue and adversely effects the program. Conclusion FIs for clients have limited influence on their decision to take up a FP method while different amounts of FIs for ASHAs and nurses, linked with different FP methods, may be influencing their service provision. More research is needed to determine the effect of discontinuing FI for FP services.

ObjectivesTo systematically analyse the effect of pharmacological treatment of hypertension (HTN) on cognitive decline in older adults.MethodsRandomised, placebo-controlled trials with a prespecified quantitative outcome of cognition and a pharmacological intervention for at least 12 months to treat HTN in older adults (>60 years). Our primary outcome was change in cognition with pharmacological treatment of HTN. Standardised mean difference (SMD) was used to analyse different outcomes reported in the selected studies. We searched PubMed CENTRAL and the Cochrane Library from inception to 6 July 2020. Two independent reviewers assessed trial quality and extracted data. Internal and external validity of the studies was assessed.ResultsNine randomised controlled trials with 34 994 participants were included in the final analysis. The net SMD for change in cognition was −0.049 (CI: −0.078 to −0.019) indicating that treatment of HTN decreased cognitive decline. Heterogeneity was low with an I² of 6%.DiscussionCurrent evidence does not indicate worsening of cognition with treatment of HTN. Treatment of HTN in older adults may reduce cognitive decline. These results have important implications in clinical management of patients at risk for dementia.PROSPERO registration numberCRD42020139750.

TB is a global disease and the leading cause of death among infectious diseases worldwide. TB was considered incurable till the mid 19th century. The major landmark in the treatment was the discovery of Rifampicin which has led to shorter courses of therapy as compared to the previous regimens which also consisted of injectables. Although, treatment for TB is evolving expeditiously today but a lot needs to be done as far as drug resistant TB (DRTB) is concerned. Non-standard regimens in private sector, lack of access to drug susceptibility testing, delay in the treatment, poor follow up and default in the treatment has led to emergence DRTB. Addition of newer drugs like bedaquiline and delamanid has made oral regimen possible in DRTB as well. Encouraging results of BPaL regimen for extensively drug resistant TB (XDR-TB) may prove to be a game changer. The target of TB elimination by 2025 is onerous considering the huge population, rising DRTB patients and private sector non engagement in the programme despite implementation of second largest national programme of the world.

Pleural effusion is rarely encountered in patients of allergic bronchopulmonary aspergillosis (ABPA). We report the case of a 17-year-old male who presented with complaints of fever, cough and increasing shortness of breath for 3 weeks. Patient had breathlessness with seasonal variation. Patient had right lower lobe consolidation with pleural effusion which did not respond to antibiotics. Pleural fluid was exudate with neutrophilic predominance and low ADA. Skin prick test for Aspergillus fumigatus was positive, both total IgE and specific IgE against Aspergillus fumigatus were raised.

Introduction Learning effective communication, particularly jargon avoidance, is important for medical training. Standardized methods exist to identify jargon but there is room to further refine those methods to define medical jargon and expand categorization. This project aims to classify jargon words as having a plain language alternative or not, to both standardize the definition of jargon and as a foundation for teaching jargon avoidance. Methods We analyzed 123 transcribed encounters between standardized patients and medical students to quantify and categorize medical jargon using a stepwise process based on published literature. This process eliminated common words (based on New Dale-Chall list) without distinct medical meaning. Uncommon words and words with distinct medical meanings found in Stedman’s Medical Dictionary were considered jargon. Jargon words were cross-referenced with the Plain Language Thesaurus to identify plain language alternatives. Results This process identified 310 jargon words, 102 with plain language alternative from the 123 encounters. Conclusion We objectively classified jargon into distinct categories with a novel focus on jargon words with and without plain language alternatives. Practice implications This objective classification system serves as an important step in gaining a comprehensive understanding of jargon use which is essential to improving and teaching communication skills.

BackgroundChronic kidney disease (CKD) is associated with cognitive impairment and dementia. We examined whether this relationship hold true in older adults, who have a higher prevalence of both CKD and dementia.Design, setting, participants, and measurementsWe conducted a cross-sectional secondary analysis of an established observational cohort. We analyzed data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), an NIH funded, multicenter longitudinal observational study, which includes participants with normal and impaired cognition and assesses cognition with a comprehensive battery of neuropsychological tests. We included a non-probability sample of all ADNI participants with serum creatinine measurements at baseline (N = 1181). Using multivariable linear regression analysis, we related the CKD Epidemiology Collaboration equation eGFR with validated composite scores for memory (ADNI-mem) and executive function (ADNI-EF).ResultsFor the 1181 ADNI participants, the mean age was 73.7 ± 7.1 years. Mean estimated glomerular filtration rate (eGFR) was 76.4 ± 19.7; 6% had eGFR90 ml/min/1.73 m2. The mean ADNI-Mem score was 0.241 ± 0.874 and mean ADNI-EF score was 0.160 ± 1.026. In separate multivariable linear regression models, adjusted for age, sex, race education and BMI, there was no association between each 10 ml/ min/1.73 m2 higher eGFR and ADNI-Mem (β -0.02, 95% CI -0.04, 0.02, p = 0.56) or ADNI-EF (β 0.01, 95% CI -0.03, 0.05, p = 0.69) scores.ConclusionWe did not observe an association between eGFR and cognition in the older ADNI participants.

Background Mobile Clinics represent an untapped resource for our healthcare system. The COVID-19 pandemic has exacerbated its limitations. Mobile health clinic programs in the US already play important, albeit under-appreciated roles in the healthcare system. They provide access to healthcare especially for displaced or isolated individuals; they offer versatility in the setting of a damaged or inadequate healthcare infrastructure; and, as a longstanding community-based service delivery model, they fill gaps in the healthcare safety-net, reaching social-economically underserved populations in both urban and rural areas. Despite an increasing body of evidence of the unique value of this highly adaptable model of care, mobile clinics are not widely supported. This has resulted in a missed opportunity to deploy mobile clinics during national emergencies such as the COVID-19 pandemic, as well as using these already existing, and trusted programs to overcome barriers to access that are experienced by under-resourced communities. Main text In March, the Mobile Healthcare Association and Mobile Health Map, a program of Harvard Medical School’s Family Van, hosted a webinar of over 300 mobile health providers, sharing their experiences, challenges and best practices of responding to COVID 19. They demonstrated the untapped potential of this sector of the healthcare system in responding to healthcare crises. A Call to Action: The flexibility and adaptability of mobile clinics make them ideal partners in responding to pandemics, such as COVID-19. In this commentary we propose three approaches to support further expansion and integration of mobile health clinics into the healthcare system: First, demonstrate the economic contribution of mobile clinics to the healthcare system. Second, expand the number of mobile clinic programs and integrate them into the healthcare infrastructure and emergency preparedness. Third, expand their use of technology to facilitate this integration. Conclusions Understanding the economic and social impact that mobile clinics are having in our communities should provide the evidence to justify policies that will enable expansion and optimal integration of mobile clinics into our healthcare delivery system, and help us address current and future health crises.

BackgroundChronic kidney disease (CKD) is associated with abnormalities in cerebral blood flow (CBF), cerebral neurochemical concentrations and white matter integrity, each of which are associated with adverse clinical consequences in the non-CKD population, and may explain the high prevalence of dementia and stroke in end stage kidney disease (ESKD). Since cognition improves after kidney transplantation (KT), we examined these brain abnormalities pre-to post-KT to identify potential reversibility in ESKD-associated brain abnormalities.MethodsWe measured the effects of KT on CBF assessed by arterial spin labeling, cerebral neurochemical concentrations (N-acetylaspartate, choline, glutamate and glutamine, myoinositol and total creatine) measured by magnetic resonance spectroscopic imaging, and white matter integrity measured by fractional anisotropy (FA) and mean diffusivity (MD) with diffusion tensor imaging. We used a linear mixed model analysis to compare longitudinal, repeated brain MRI measurements pre-KT, and 3 months and 12 months post-KT, and also compared findings with healthy controls.Results29 ESKD patients and 19 age-matched healthy controls participated in the study. 22 patients underwent post-KT MRI. CBF, which was higher pre-KT than in controls (p=0.003), decreased post-KT (pConclusionsBrain abnormalities in CKD are reversible and normalize with KT. Further studies are needed to understand the mechanisms underlying these brain abnormalities and to explore interventions to mitigate them even in patients who cannot be transplanted.Significance statementKidney disease is accompanied by brain structural and physiological abnormalities and increased risk of dementia and stroke. Renal replacement therapy with dialysis does not normalize these brain abnormalities. We evaluated these brain abnormalities before and after kidney transplantation and demonstrated that unlike dialysis, kidney transplantation normalizes cerebral blood flow, neurochemical concentrations and white matter integrity. These changes persist beyond initial post-transplantation period and thus cannot be attributed to peri-procedural interventions like steroids. These results indicate reversibility of brain abnormalities in kidney disease. Further studies are needed to understand the mechanisms underlying these abnormalities and explore interventions for prevention and mitigation in patients who cannot be transplanted.

Inhibitory control, the ability to inhibit impulsive responses and irrelevant stimuli, enables high level functioning and activities of daily living. The Simon task probes inhibition using interfering stimuli, i.e., cues spatially presented on the opposite side of the indicated response; incongruent response times (RT) are slower than congruent RTs. Operational applicability of the Simon task beyond finger/hand manipulations and visual/auditory cues is unclear, but important to consider as new technologies provide tactile cues and require motor responses from the lower extremity (e.g., exoskeletons). In this study, twenty participants completed the Simon task under four conditions, each combination of two cue (visual/tactile) and response (upper/lower-extremity) modalities. RT were significantly longer for incongruent than congruent cues across cue-response pairs. However, alternative cue-response pairs yielded slower RT and decreased accuracy for tactile cues and lower-extremity responses. Results support operational usage of the Simon task to probe inhibition using tactile cues and lower-extremity responses relevant for new technologies like exoskeletons and immersive environments.

Formation of functional skeletal tissues requires highly organized steps of mesenchymal progenitor cell differentiation. The dental follicle (DF) surrounding the developing tooth harbors mesenchymal progenitor cells for various differentiated cells constituting the tooth root–bone interface and coordinates tooth eruption in a manner dependent on signaling by parathyroid hormone-related peptide (PTHrP) and the PTH/PTHrP receptor (PPR). However, the identity of mesenchymal progenitor cells in the DF and how they are regulated by PTHrP-PPR signaling remain unknown. Here, we show that the PTHrP-PPR autocrine signal maintains physiological cell fates of DF mesenchymal progenitor cells to establish the functional periodontal attachment apparatus and orchestrates tooth eruption. A single-cell RNA-seq analysis revealed cellular heterogeneity of PTHrP + cells, wherein PTHrP + DF subpopulations abundantly express PPR. Cell lineage analysis using tamoxifen-inducible PTHrP-creER mice revealed that PTHrP + DF cells differentiate into cementoblasts on the acellular cementum, periodontal ligament cells, and alveolar cryptal bone osteoblasts during tooth root formation. PPR deficiency induced a cell fate shift of PTHrP + DF mesenchymal progenitor cells to nonphysiological cementoblast-like cells precociously forming the cellular cementum on the root surface associated with up-regulation of Mef2c and matrix proteins, resulting in loss of the proper periodontal attachment apparatus and primary failure of tooth eruption, closely resembling human genetic conditions caused by PPR mutations. These findings reveal a unique mechanism whereby proper cell fates of mesenchymal progenitor cells are tightly maintained by an autocrine system mediated by PTHrP-PPR signaling to achieve functional formation of skeletal tissues.

A sophisticated intracellular trafficking pathway in humans is used to tailor vitamin B(12) into its active cofactor forms, and to deliver it to two known B(12-)dependent enzymes. Herein, we report an unexpected strategy for cellular retention of B(12), an essential and reactive cofactor. If methylmalonyl-CoA mutase is unavailable to accept the coenzyme B(12) product of adenosyltransferase, the latter catalyzes homolytic scission of the cobalt−carbon bond in an unconventional reversal of the nucleophilic displacement reaction that was used to make it. The resulting homolysis product binds more tightly to adenosyltransferase than does coenzyme B(12), facilitating cofactor retention. We have trapped, and characterized spectroscopically, an intermediate in which the cobalt−carbon bond is weakened prior to being broken. The physiological relevance of this sacrificial catalytic activity for cofactor retention is supported by the significantly lower coenzyme B(12) concentration in patients with dysfunctional methylmalonyl-CoA mutase but normal adenosyltransferase activity.

The US prevalence of childhood obesity remains high with ~ 1 in five children diagnosed with obesity, and rates of obesity are likely higher in uninsured and Medicaid populations than in those with private insurance. To understand the impact of an obesity intervention, an established mobile clinic program conducted a study to determine whether a FitKids Mobile Lifestyle Modification Program could reach overweight and obese uninsured children. Eighty-six children (ages 8-18 years) participated in the FitKids study over two trial periods. The first trial consisted of four total visits, but subsequent visits after the initial visit had poor turnout. Through telephonic interviews, parents described positive aspects of the program: (1) providers' individual attention to their child, (2) increased knowledge about obesity, nutrition, and diet, (3) and parent and child were motivated to be more active. The most common barriers noted for return visits were (1) personal/family factors, (2) scheduling issues, and (3) distance to the clinic. As quality improvement, for the second trial, total number of visits was reduced from 4 to 3 visits and reminder calls were instituted. Percentage of children who returned for the third visit (67.5% for Trial 1 and 62.5% for Trial 2) was not improved despite quality improvement interventions. Mobile clinics provide a unique solution to reach underserved overweight and obese children to help them create a more active and healthy lifestyle, but more research is needed to understand how best to optimize programs.

To test the non-inferiority of an alternative to the Apgar score. The Neonatal Resuscitation and Adaptation Score (NRAS) was recorded in parallel to the Apgar score by a resuscitation team at deliveries. Correlation between the systems was assessed, as well as the predictive ability of NRAS and Apgar scores for mortality or short-term morbidities. A total of 340 infants were in the study group. The two scores correlated strongly (r = 0.87 and 0.83 at 1 and 5 min, respectively). Those needing ventilation at 48 h of life had a 5-min NRAS

Asparagine synthetase deficiency is a rare inborn error of metabolism caused by a defect in ASNS, a gene encoding asparagine synthetase. It manifests with a severe neurological phenotype manifesting as severe developmental delay, congenital microcephaly, spasticity and refractory seizures. To date, nineteen patients from twelve unrelated families have been identified. Majority of the mutations are missense and nonsense mutations in homozygous or compound heterozygous state. We add another case from India which harbored a novel homozygous missense variation in exon 11 and compare the current case with previously reported cases.

Background Patients treated with dialysis have high rates of brain infarcts, brain atrophy, and white matter disease. There are limited data regarding the presence of more subtle damage to brain white matter. Methods In the Cognition and Dialysis Study, we compared brain structure using diffusion tensor imaging in hemodialysis (HD) patients to individuals without known kidney disease, using tract based spatial statistics (TBSS) to compare Fractional Anisotropy (FA) and Mean Diffusivity (MD). Statistical comparison of each overlaid voxel was age controlled using a permutation based corrected p value of

Background Cognitive impairment is common in patients treated with hemodialysis. The trajectory of cognitive function and risk factors for cognitive decline remain uncertain in this population. Study Design Longitudinal cohort. Setting & Participants 314 prevalent hemodialysis patients. Predictors Age, sex, race, education level, hemodialysis vintage, cause of end-stage renal disease, and baseline history of cardiovascular disease. Outcomes Cognitive function as determined by a comprehensive neurocognitive battery, administered at baseline and yearly when possible. Individual cognitive test results were reduced into 2 domain scores using principal components analysis, representing memory and executive function, which were used as our coprimary outcomes and by definition have a mean of zero and SD of 1. Results Mean age was 63 years; 54% were men, 22% were black, and 90% had at least a high school education. During a median follow-up of 2.1 (IQR, 0.9-4.2) years, 196 had at least 1 follow-up test, 156 died, and 43 received a kidney transplant. Linear mixed models and joint models, which accounted for competing risks from death, dropout, or kidney transplantation, showed nearly identical results. The joint model demonstrated a decline in executive function (−0.09 [95% CI, −0.13 to −0.05] SD per year), whereas memory improved slightly (0.05 [95% CI, 0.02 to 0.08] SD per year). A significant yearly decline was also seen in the Mini-Mental State Examination score (median change, −0.41; 95% CI, −0.57 to −0.25). Older age was the only significant risk factor for steeper executive function decline (−0.04 [95% CI, −0.06 to −0.02] SD steeper annual decline for each 10 years of age). Limitations Prevalent hemodialysis patients only, limited follow-up testing due to high mortality rate, and exclusion of participants with severe cognitive deficits or dementia. Conclusions Prevalent hemodialysis patients demonstrate significant cognitive decline, particularly within tests of executive function. Older age was the only statistically significant risk factor for steeper cognitive decline, which may have important clinical consequences for patient management and education. Future studies should evaluate strategies to maintain or improve cognitive function.

Background There is a high prevalence of cognitive impairment in dialysis patients. The prevalence of cognitive impairment after kidney transplantation is unknown. Methods Study Design: Cross-sectional study. Setting and Participants: Single center study of prevalent kidney transplant recipients from a transplant clinic in a large academic center. Intervention: Assessment of cognition using the Montreal Cognitive Assessment (MoCA). Demographic and clinical variables associated with cognitive impairment were also examined. Outcomes and Measurements: a) Prevalence of cognitive impairment defined by a MoCA score of

Pathogenic variants in the XPC complex subunit, DNA damage recognition, and repair factor (XPC) are the cause of xeroderma pigmentosum, group C (MIM: 278720). Xeroderma pigmentosum is an inherited condition characterized by hypersensitivity to ultraviolet (UV) irradiation and increased risk of skin cancer due to a defect in nucleotide excision repair (NER). Here we describe an individual with a novel missense variant and deletion of exons 14–15 in XPC presenting with a history of recurrent melanomas. The proband is a 39-yr-old female evaluated through the Mayo Clinic Department of Clinical Genomics. Prior to age 36, she had more than 60 skin biopsies that showed dysplastic nevi, many of which had atypia. At age 36 she presented with her first melanoma in situ, and since then has had more than 10 melanomas. The proband underwent research whole-exome sequencing (WES) through the Mayo Clinic's Center for Individualized Medicine and a novel heterozygous variant of uncertain significance (VUS) in XPC (c.1709T > G, p.Val570Gly) was identified. Clinical confirmation pursued via XPC gene sequencing and deletion/duplication analysis of XPC revealed a pathogenic heterozygous deletion of ∼1 kb within XPC, including exons 14 and 15. Research studies determined the alterations to be in trans. Although variants in XPC generally result in early-onset skin cancer in childhood, the proband is atypical in that she did not present with her first melanoma until age 36. Review of the patient's clinical, pathological, and genetic findings points to a diagnosis of delayed presentation of xeroderma pigmentosum.

PURPOSE: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). METHODS: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. RESULTS: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. CONCLUSION: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila. ispartof: GENETICS IN MEDICINE vol:21 issue:12 pages:2723-2733 ispartof: location:United States status: published

Purpose: This study characterizes the clinical and genetic features of nine unrelated patients with de novo variants in the NR4A2 gene. Methods: Variants were identified and de novo origins were confirmed through trio exome sequencing in all but one patient. Targeted RNA sequencing was performed for one variant to confirm its splicing effect. Independent discoveries were shared through GeneMatcher. Results: Missense and loss-of-function variants in NR4A2 were identified in patients from eight unrelated families. One patient carried a larger deletion including adjacent genes. The cases presented with developmental delay, hypotonia (six cases), and epilepsy (six cases). De novo status was confirmed for eight patients. One variant was demonstrated to affect splicing and result in expression of abnormal transcripts likely subject to nonsense-mediated decay. Conclusion: Our study underscores the importance of NR4A2 as a disease gene for neurodevelopmental disorders and epilepsy. The identified variants are likely causative of the seizures and additional developmental phenotypes in these patients.

Mycobacterium tuberculosis can adapt to changing environments by non-heritable mechanisms. Frame-shifting insertions and deletions (indels) may also participate in adaptation through gene disruption, which could be reversed by secondary introduction of a frame-restoring indel. We present ScarTrek, a program that scans genomic data for indels, including those that together disrupt and restore a gene’s reading frame, producing “frame-shift scars” suggestive of reversible gene inactivation. We use ScarTrek to analyze 5977 clinical M. tuberculosis isolates. We show that indel frequency inversely correlates with genomic linguistic complexity and varies with gene-position and gene-essentiality. Using ScarTrek, we detect 74 unique frame-shift scars in 48 genes, with a 3.74% population-level incidence of unique scar events. We find multiple scars in the ESX-1 gene cluster. Six scars show evidence of convergent evolution while the rest shared a common ancestor. Our results suggest that sequential indels are a mechanism for reversible gene silencing and adaptation in M. tuberculosis., Bacterial adaptation through frame-shifting insertions and deletions (indels) could be reversed by secondary introduction of a frame-restoring indel. Here, the authors develop ScarTrek, a program that scans genomic data for different indels, and analyze 5977 clinical M. tuberculosis isolates for indel frequency.