嗜铬细胞瘤的分子遗传学研究

嗜铬细胞瘤和副神经节瘤为自主神经系统肿瘤。以前估计约10%-15%的嗜铬细胞瘤由遗传因素导致,但近年来的研究显示RET,VHL,SDHB, SDHC, SDHD等易感基因的胚系突变率已近30%。鉴于此,建议进行遗传检查。本文就各遗传综合症,相关基因结构,与嗜铬细胞瘤相关的基因变异,基因型与表型的关联以及可能的发病机制等研究进展等作一综述。     

Interrogation of selected genes influencing serum LDL-Cholesterol levels in patients with well characterized NAFLD

BackgroundThe clinical significance of rare mutations in LDL metabolism genes on nonalcoholic fatty liver disease (NAFLD) severity is not well understood.ObjectiveTo examine the significance of mutations in LDL metabolism genes including apolipoprotein B (APOB), proprotein convertase subtilisin kexin 9 (PCSK9) and LDL receptor (LDLR) in patients with NAFLD.MethodsPatients with biopsy-confirmed NAFLD from the NASH Clinical Research Network studies were stratified into 3 groups of LDL-C (≤50 mg/dL, 130–150 mg/dL, ≥ 190 mg/dL) and then 120 (40 per group) were randomly selected from the strata. We examined the presence of mutations on LDL genes and analyzed its association with selected NAFLD-related features. Multivariable analyses were adjusted for age, race, gender and use of statins.ResultsAmong 40 patients with LDL-C ≤ 50 mg/dL, 7 (18%) patients had heterozygous variants in APOB and 2 had heterozygous variants in PCSK9 (5%). We also found heterozygous mutations in 3 (8%) patients with LDL-C ≥ 190 mg/dL; 2 and 1 located in LDLR and APOE genes, respectively. Compared to wild-type controls with LDL-C ≤ 50, APOB carriers displayed higher levels of alanine aminotransferase (85.86 ± 35.14 U/L vs 45.61 ± 20.84 U/L, Adj. P = 0.002) and steatosis >66% (57% vs 24%, Adj. P = 0.050). These associations remained statistically significant after excluding statin users. Other histological features of NAFLD severity were not different between wild-type controls and APOB mutation carriers.ConclusionMutations in the APOB gene are common among NAFLD patients with very low LDL-C and may be associated with increased aminotransferase levels and steatosis severity.     

Defining the clinical validity of genes reported to cause pulmonary arterial hypertension

PurposePulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy with significant cardiopulmonary morbidity and mortality. Genetic testing is currently recommended for adults diagnosed with heritable, idiopathic, anorexigen-, hereditary hemorrhagic telangiectasia–, and congenital heart disease–associated PAH, PAH with overt features of venous/capillary involvement, and all children diagnosed with PAH. Variants in at least 27 genes have putative evidence for PAH causality. Rigorous assessment of the evidence is needed to inform genetic testing.MethodsAn international panel of experts in PAH applied a semi-quantitative scoring system developed by the NIH Clinical Genome Resource to classify the relative strength of evidence supporting PAH gene-disease relationships based on genetic and experimental evidence.ResultsTwelve genes (BMPR2, ACVRL1, ATP13A3, CAV1, EIF2AK4, ENG, GDF2, KCNK3, KDR, SMAD9, SOX17, and TBX4) were classified as having definitive evidence and 3 genes (ABCC8, GGCX, and TET2) with moderate evidence. Six genes (AQP1, BMP10, FBLN2, KLF2, KLK1, and PDGFD) were classified as having limited evidence for causal effects of variants. TOPBP1 was classified as having no known PAH relationship. Five genes (BMPR1A, BMPR1B, NOTCH3, SMAD1, and SMAD4) were disputed because of a paucity of genetic evidence over time.ConclusionWe recommend that genetic testing includes all genes with definitive evidence and that caution be taken in the interpretation of variants identified in genes with moderate or limited evidence. Genes with no known evidence for PAH or disputed genes should not be included in genetic testing.     

Clinical implications of high-risk mutations in drug resistant tuberculosis (DR-TB): An observational cohort study

Genotype MTBDRsl [SL-LPA] was endorsed as a tool for early diagnosis of fluoroquinolones (FQ) and injectable second-line TB drugs (SLID) resistance in DR-TB. Correlation between specific genetic mutations using this tool and clinical outcome has not hitherto been studied in India. We conducted a observational cohort study to evaluate the predictive value of specific mutations for bad outcome. Our study identified 15 different types of gyrA mutations, commonest being A90V and D94G. Poor outcome was associated with mutations D94G and D94N/D94Y.Most XDR-TB patients harbored the high risk mutation of A1401G. Hence information of specific mutations using SL-LPA can help prognosticate and design appropriate treatment regimens.     

A retrospective analysis the clinic data and follow-up of non-invasive prenatal test in detection of fetal chromosomal aneuploidy in more than 40,000 cases in a single prenatal diagnosis center

ObjectiveTo evaluate the efficacy of non-invasive prenatal test (NIPT) in the detection of chromosomal aneuploidy according to the follow-up information from a single prenatal diagnosis center.MethodsA total of 40,311 cases were retrospectively reviewed. The screening was performed using a BGI protocol, pre-test and post-test genetic counseling was provided, and the pregnancy outcomes were recorded. The results of NIPT and clinical follow-up data were analyzed together with the pregnancy outcomes, confirmatory testing results, and ultrasound findings.ResultsOf the 40,311cases were includes in the study, successful follow-up was conducted in 468 (1.16%) cases with high risk, 225 (0.56%) cases with rare autosomal trisomy (RAT) and copy number variation (CNV). 39,572 (98.17%) cases with low risk and 623 (1.57%) cases of which were confirmed with adverse pregnancy outcomes. 46 (0.1%) cases with failed tests. Among them, 398 (84.7%) cases with high-risk results chose invasive testing, revealing 198 true positive cases. In cases with RAT and CNV results, 189 cases underwent invasive testing, revealing 5 cases RAT and 4 pathogenic CNVs.ConclusionsNIPT appears to be effective in detecting the fetal chromosomal aneuploidies T21, T18 and SCAs, but it exist false positive/negative cases, unconfirmed high-risk cfDNA results, and the high false positive rate in cases with RAT and CNV results implied the limitations of this screening method. Our study showed the importance to associate cfDNA screening results with clinical follow-up data and provided information that may help with result interpretation, genetic counseling and the decision making in clinic.     

The triglyceride to HDL-cholesterol ratio and chronic graft failure in renal transplantation

BackgroundTransplant vasculopathy (TV) is a major contributing factor to chronic graft failure in renal transplant recipients (RTR). TV lesions resemble atherosclerosis in several ways, and it is plausible to believe that some risk factors influence both atherosclerotic plaque formation and formation of TV.ObjectiveThe objective of this prospective longitudinal study was to determine if dyslipidemia reflected by the triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) ratio is prospectively associated with death censored chronic graft failure in RTR.Method454 prospectively included RTR with a functioning graft for at least one year, were followed for a median of 7 years. RTR were matched based on propensity scores to avoid potential confounding and subsequently the association of the TG/HDL-C ratio with the endpoint chronic graft failure, defined as return to dialysis or re-transplantation, was investigated.ResultsLinear regression analysis showed that concentration of insulin, male gender, BMI and number of antihypertensives predict the TG/HDL-C ratio. Cox regression showed that the TG/HDL-C ratio is associated with chronic graft failure (HR = 1.43, 95%CI = 1.12–1.84, p = 0.005) in competing risk analysis for mortality. Interaction testing indicated that the relationship of the TG/HDL-C ratio with graft failure is stronger in subjects with a higher insulin concentration.ConclusionOur results demonstrate that the TG/HDL-C ratio has the potential to act as a predictive clinical biomarker. Furthermore, there is a need for closer attention to lipid management in RTR in clinical practice with a focus on triglyceride metabolism.     

Effect of delay in processing and storage temperature on diagnosis of SARS-CoV-2 by RTPCR testing

PurposeA large number of new molecular or virology laboratories have been established to increase the testing capacity for SARS-CoV-2. Due to heavy workload, there is delay in testing of samples. In order to avoid the negative effect of delayed testing on RTPCR results guidelines are issued from WHO and CDC to transport samples in cold chain. However, in pandemic situations the recommended guidelines for transport and storage conditions are often compromised. This study was conducted to evaluate the effect of sample storage conditions at different temperatures on the results of RT PCR test.MethodsTotal 275 samples were included in this study, among these 126 samples tested positive and 149 samples tested negative. All samples were aliquoted into two and the aliquotes stored in duplicate at 4 ?°C and room temperature. All aliquots stored at both the temperatures were tested by RTPCR every 24 hours up to 5 days.ResultsDiagnostic accuracy decreased from day1 to day 5 at both the storage temperatures i,e 4 ?°C and room temperature in comparison to the initial day results. Positivity decreased on an average of 9.02% at 4 ?°C and at 9.27% at room temperature per day. Among total 126 positive samples on an average false negative and failure of internal control at 4 ?°C and room temperature was 8.86%, 8.22% and 3.64%, and 4.12%, respectively. All the samples with CT value ?< ?30 remained positive at both temperatures up to 5 days. Few samples with >30 CT value showed variable results i.e. positive, negative or internal control failure from day 1 (2nd day after sample collection) onwards.ConclusionsThere was no significant difference between RT PCR results of samples stored at 4 ?°C and room temperature up to 5 days of collection. However internal control failure was more in samples stored at room temperature. Therefore, samples received without cold chain also may be processed by RTPCR and should not be rejected.     

Under-correction of preoperative varus alignment does not lead to a difference in in-vivo bone loading in 3D-SPECT/CT compared to neutral alignment

BackgroundThe aim was to investigate the correlation of bone tracer uptake (BTU) in SPECT/CT and changes in coronal knee alignment after total knee arthroplasty (TKA). We questioned if undercorrection of preoperative varus alignment leads to a difference in BTU compared to neutral alignment.MethodsConsecutive 66 patients who received SPECT/CT before and after TKA were retrospectively included. Adjusted mechanical alignment was the alignment target. The alignment of the knee was measured on 3D-CT by selecting standardized landmarks. Maximum (mean ± SD) and relative BTU (ratio to the reference) were recorded using a previously validated localization scheme (p < 0.05).ResultsIn the native group, 20 knees were aligned (30.3%) in valgus (HKA > 181.5°), 12 (18.2%) in neutral (178.5°-181.5°) and 34 (51.5%) in varus (HKA < 178°). Overall TKA changed the alignment towards neutral. 48.5% remained in the same groups, whereas 50% of native valgus and 33% of varus knees changed to neutral after TKA. In native varus alignment mean BTU was significantly higher in some medial tibial and femoral regions (fem1ia (p = 0.010), fem1ip (p = 0.002), tib1a.mid (p = 0.005), tib1a.tray (p = 0.000), tib1p.tray (p = 0.000)); in native valgus alignment mean BTU was higher in the corresponding lateral tibial and femoral regions (fem2ip (p = 0.001), tib2a.tray (p = 0.011), tib2p.tray (p = 0.002)). After TKA, a significant decrease in femoral and tibial BTU (femoral preoperative BTU 1.64 +/-0.69; femoral postoperative BTU 0.95 +/-0.42; p = 0.000// tibial preoperative BTU 1.65 +/- 0.93; tibial postoperative BTU 1.16 +/- 0.48; p = 0.000) and an increase in patellar BTU was observed (p = 0.025). Native varus alignment correlated with a higher medial BTU decrease medially. Undercorrection of preoperative varus alignment showed no higher BTU after TKA.ConclusionPreoperative varus alignment correlated with a higher decrease in BTU in specific femoral and tibial medial regions. Preoperative valgus alignment correlated with a higher decrease in the corresponding lateral regions. Undercorrection of preoperative varus alignment did not lead to higher bone loading reflected by BTU after TKA.     

Low incidence of hepatitis B virus reactivation in patients with hematological malignancies receiving novel anticancer drugs: A report from a high epidemic area and literature review

BackgroundMore and more novel anticancer drugs have been approved for patients with hematological malignancies in recent years, but HBV reactivation (HBV-R) data in this population is very scarce. This study aimed to evaluated HBV-R risk in patients with hematological malignancies receiving novel anticancer drugs.MethodsHBV markers and serum HBV DNA levels of patients with hematological malignancies receiving novel anticancer drugs in a tertiary cancer hospital were retrospectively collected. HBV-R risk in the whole cohort and subgroups was described. The relevant literature was reviewed to make a pooled analysis.ResultsOf 845 patients receiving novel anticancer drugs, 258 (30.5%) were considered at risk for HBV-R. The median duration of exposure to novel drugs was 5.6 (0.1–67.6) months. The incidence of HBV-R was 2.1% in patients with past HBV infection without prophylactic antiviral treatment (PAT) and 1.2% in all patients at risk of HBV-R. In a pooled analysis of 11 studies with 464 patients, the incidence of HBV-R was 2.4% (95% CI: 1.3–4.2) in all at-risk patients receiving novel anticancer drugs and 0.6% (95% CI: 0.03–3.5) in patients with anticancer drugs plus PAT. The incidence of death due to HBV-R was 0.4% (95% CI: 0.1–1.6) in all at-risk patients and 18.2% (95% CI: 3.2–47.7) in patients with HBV-R.ConclusionMost episodes of HBV-R are preventable, and most cases with HBV-R are manageable. We recommend that novel anticancer drugs should not be intentionally avoided when treating cancer patients with HBV infection.     

Are There Regional Differences in Triple Negative Breast Cancer among Non-Hispanic Black Women?

BackgroundNon-Hispanic black women (NHB) are diagnosed with triple negative breast cancer (TNBC) more often than other ethnic or racial groups in the United States (US). This study describes regional differences in TNBC incidence among NHB women in the US from 2011 to 2015.MethodsWe analyzed data from the United States Cancer Statistics (USCS) that includes incidence data from the Centers for Disease Control and Prevention's National Program of Cancer Registries (NPCR) and the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) programs.ResultsCompared to the incidence rate for NHB women in the South, rates were significantly lower in the Northeast (22.6 per 100,000), higher in the Midwest (25.5 per 100,000) and similar in the West. These regional differences might be explained by genetic admixture among people with different geographic ancestral origins.ConclusionsResults from this study highlight the need to extend etiological research and evidence-based cancer prevention and control efforts to women at high risk of this disease in order to decrease cancer disparities.     

Applications of next-generation sequencing in hematologic malignancies

In the last decade, next-generation sequencing (NGS) has rapidly progressed from a research method to a core component of standard-of-care clinical testing. In oncology, tumor sequencing provides a critical tool to detect somatic driver mutations that not only characterize disease but also impact therapeutic decision-making. Here, we review the important role of NGS in the evaluation of hematopoietic neoplasms. We discuss technical and practical considerations relevant in somatic mutation testing, emphasizing issues unique to blood cancers. Then, we describe how NGS data is being used to facilitate diagnosis, inform prognosis, guide therapy selection, and even monitor disease. This broad overview highlights the transformative impacts NGS data provides throughout the clinical course of patients with hematologic malignancies.     

ATP7B variant spectrum in a French pediatric Wilson disease cohort

Background/aimThe spectrum of ATP7B variants varies significantly according to geographic distribution, and there is insufficient data on the variants observed in the French population.MethodsClinical data of 113 children included in the French WD national registry were gathered from March 01, 1995 to July 01, 2020. Data included epidemiological, clinical, laboratory, genetics.ResultsDiagnosis was made at a mean age of 11.0 ± 4.1 years (range 1–18 years). At diagnosis, 91 patients (79.8 %) had hepatic manifestations, 18 (15.8 %) presented neurological manifestations, and 4 patients (3.5 %) were asymptomatic. Only 29 patients (25 %) were homozygous for a variant. We have found a total of 102 different variants including 14 novel variants. Recurrent variant p.His1069Gln was the most prevalent, n = 31 alleles (14,2%), with only seven homozygous; in contrast 55% of variants are identified in only one family. 45% were truncating variants. In respect of mutated exon, the three most prevalent were exon 14 (16.5%), exon 8 (13.8%), and exon 3 (11.5%). When considering patients with two Nonsense / Frameshift variants as a group and those with two Missense variants, we found significantly lower ceruloplasmin for the former: 2.8 ± 0.7 mg/dl vs 8.4 ± 5mg/dl (p<0.05).Conclusionp.His1069Gln is the most frequent variant (14,2%) and exons 14, 8, and 2 of the ATP7B gene account for 41.7% of total variants. However, there is significant heterogeneity in the French population concerning the other ATP7B variants. Nonsense / Frameshift variants were associated with lower ceruloplasmin levels.     

Risk of failure in dual therapy versus triple therapy in naïve HIV patients: a systematic review and meta-analysis

ObjectivesSeveral attempts have been made to test different drug-sparing strategies to reduce the drug-burden and drug-related toxicities. The objective of this meta-analysis was to evaluate the relative risk (RR) of failure of dual therapies compared to triple therapies in HIV-naïve patients.MethodsWe searched MEDLINE, Google Scholar and the Cochrane Library. The following criteria were used: present data from original articles comparing the two treatment regimens; published from January 2007 up to January, 2020. No language or study design restriction was applied. Subjects were HIV-positive naïve patients treated with dual or triple antiretroviral therapy (ART). A systematic review and meta-analysis was performed. Treatment failure (TF) was the primary outcome evaluated; heterogeneity was assessed using the Q statistic and I².ResultsFourteen studies were included, allowing a meta-analysis on 5205 patients. The meta-analysis performed on studies that presented data at 48 weeks showed that the RR of TF (RR > 1 favouring triple therapy) in 10 studies was 1.20 (95% confidence interval (CI): 0.91–1.59, I²: 49.2%); the RR of virological failure (VF) in eight studies was 1.54 (95% CI: 0.84–2.86, I²: 54%); the RR of adverse drug reaction leading to discontinuation of the regimen at 48 weeks in eight studies was 0.76 (95% CI: 0.43–1.33, I²: 17.7%). In patients with less than 200 CD4+, the RR of TF in two studies without maraviroc was 2.09 (95% CI: 1.05–4.17, I²: 0.0%). Regarding the studies at 96 weeks there was no difference except in rate of development of resistance, RR 1.94 (95% CI: 1.06–3.53, I²: 6.2%).ConclusionDual therapies are as effective as those with three drugs, showing no difference according to the different dual therapies, except in patients with less than 200 CD4; however, they are associated with a higher selection of resistance-associated mutations at 96 weeks of therapy.     

Performance characteristics of two new rapid HIV diagnostic assays and use of test band reader

PurposeAccurate HIV diagnosis is essential for appropriate patient care. This present study evaluated the performance of two different new rapid HIV diagnostic tests; 1) TRUSTline HIV-1/2 Ab rapid test (Athenese-DxPvt. Ltd, Chennai, India)and 2) OnSite HIV 1/2 Ab Plus Combo Rapid Test (CTK Biotech Inc., San Diego, USA) and also validated ALTA Rapid Test Reader (RTR-1) (CTK Biotech Inc., San Diego, USA), the device is a user-friendly and image-analysis based qualitative/semi-quantitative tabletop reader.MethodsA total of n ?= ?500 characterized specimens were used for this evaluation and the results of the new test kits (TRUSTline and OnSite) were also compared with 4^th generation ELISA kit (Genescreen?Ultra HIV Ag-Ab ELISA) and 3 other commercially available rapid tests that were in the market; 1)SD Bioline? HIV 1/2 3.0, 2) Aspen® HIV 1/2 Rapid Ab Test and 3) Diagnostic enterprises HIVTRI-DOT. The test band intensities of the TRUSTline and OnSite tests were measured in an ALTA rapid test reader and compared with the naked eye reading.ResultsThe sensitivity, specificity, positive predictive value, negative predictive value and efficacy of TRUSTline and OnSite were 100%, 99.6%, 99.5%, 100% and 99.8% and 100%, 100%, 100%, 100% and 100% respectively.ConclusionsThe ‘TRUSTline HIV-1/2’ and ‘OnSite HIV 1/2' kits are suitable to use in the HIV testing algorithm. Use of the ALTA rapid test reader could be user's friendly in the field level testing in resource-limited settings”.     

Preoperative morphologic changes of the medial meniscus correlate with suture translations during knee flexion in pullout repair of medial meniscus posterior root tear

BackgroundMedial meniscus (MM) translates and extrudes posteriorly during knee flexion in MM posterior root tear (MMPRT) knees, and transtibial pullout repair of MMPRT has been performed to regulate the MM extrusion. This study aimed to calculate each suture translation during knee flexion in transtibial pullout repair of MMPRT, and to investigate the morphologic features of the MM that lead to longer suture translations during knee flexion.MethodsThirty patients with MMPRT who met the operative indication of pullout repair were enrolled and investigated prospectively. Pullout repair was performed by using two simple stitches (outer and inner sutures) and an all-inside suture in the posteromedial part of the MM. Each suture’s translation from 0° to 90° of knee flexion was measured intraoperatively. The MM morphologic features, including MM medial extrusion (MMME) and MM posterior height (MMPH), were measured using preoperative magnetic resonance imaging, and the correlation between these values and each suture translation was evaluated.ResultsThe average outer, inner, and all-inside suture translations were 4.8 mm, 3.9 mm, and 1.3 mm, respectively. Significant correlations were observed between the outer suture translation and MMME, and MMPH (p < 0.001 and <0.01, respectively). The thresholds for preoperative MMME and MMPH for longer outer suture translations (≥6 mm) were 2.1 mm and 5.4 mm, respectively.ConclusionsPreoperative longer MMME and higher MMPH were associated with longer meniscus translations during knee flexion during MMPRT repair.     

Prevalence of lymphedema among Anderson-Fabry disease patients: A report from the Fabry registry

BackgroundAnderson-Fabry disease (AFD) is a rare X-linked lysosomal storage disease due to a genetic variation in the α-galactosidase A (GLA) gene. As a result, the activity of the α-galactosidase A (AGAL-A) enzyme is reduced or absent, which causes sphingolipid deposition within different body parts. AFD typically manifests with cardiovascular, renal, cerebrovascular, and dermatologic involvement. Lymphedema is caused by sphingolipid deposition within lymphatics. Lymphedema can cause intolerable pain and limit daily activities. Very limited data exist on lymphedema in AFD patients.MethodsUsing data from the Fabry Registry (NCT00196742) with 7671 patients included (44% males and 56% females), we analyzed the prevalence of lymphedema among AFD patients who were ever assessed for lymphedema and studied the age of first reported lymphedema. Additionally, we assessed whether patients received AFD-specific treatment at some point during their clinical course. The data was stratified by gender and phenotype.ResultsOur study showed that lymphedema occurred in 16.5% of the Fabry Registry patients who were ever assessed for lymphedema (n = 5487). Male patients when compared to female patient have higher prevalence (21.7% vs 12.7%) and experienced lymphedema at a younger age (median age at first reported lymphedema of 43.7 vs 51.7 years). When compared to other phenotypes, classic phenotype has the highest prevalence of lymphedema with the earliest reported lymphedema. Among those who reported lymphedema, 84.5% received AFD-specific treatment during their clinical course.ConclusionsLymphedema is a common manifestation of AFD in both genders, with a tendency to present later in female patients. Recognition of lymphedema can offer an important opportunity for intervention and potential impact on associated morbidity. Additional future studies are needed to characterize the clinical implications of lymphedema in AFD patients and identify additional treatment options for this growing population.     

Rising prevalence of food allergies in Taiwan: An epidemiological study

BackgroundFood allergies are becoming more prevalent globally. The purpose of this study was to investigate the epidemiology of food allergies in Taiwan.MethodsIn 2017, a food allergy questionnaire was administered to 6–7-year-old children, 13–14-year-old adolescents, and their parents in Taipei. The results were compared to those from a previous survey conducted in 2004.ResultsA total of 16,200 questionnaires were completed, revealing a rise in the prevalence of food allergies from 7.7% to 10.4% in the pediatric group and from 6.4% to 12.5% in the adult group. Peanut allergies also increased to 1.1%. Shrimp and crabs were the most common allergens, with urticaria being the most common symptom. Shortness of breath or wheezing occurred in 10% of individuals, while 2.1% experienced syncope or shock, and 0.1% were admitted to an intensive care unit. Personal history of allergic rhinitis and atopic dermatitis, as well as family histories of food allergies, were risk factors for food allergy in 6–7-year-old children. In the 13–14-year-old group, personal history of asthma, allergic rhinitis, or atopic dermatitis, recent use of acetaminophen, and living with dogs were risk factors. Females, personal histories of asthma, allergic rhinitis, atopic dermatitis, and moist and damp at home were risk factors in adults. Breastfeeding was a protective factor in 6–7-year-old children.ConclusionThe increasing prevalence of food allergies, including peanut allergies, in Taiwan warrants attention from physicians to provide appropriate care and education to patients with food allergies. The protective effect of breastfeeding against food allergies shall be emphasized.     

Cardiomyopathy prevalence exceeds 30% in individuals with TTN variants and early atrial fibrillation

PurposeTTN truncating variants (TTNtvs) represent the largest known genetic cause of dilated cardiomyopathies (DCMs), however their penetrance for DCM in general populations is low. More broadly, patients with cardiomyopathies (CMs) often exhibit other cardiac conditions, such as atrial fibrillation (Afib), which has also been linked to TTNtvs. This retrospective analysis aims to characterize the relationship between different cardiac conditions in those with TTNtvs and identify individuals with the highest risk of DCM.MethodsIn this work we leverage longitudinal electronic health record and exome sequencing data from approximately 450,000 individuals in 2 health systems to statistically confirm and pinpoint the genetic footprint of TTNtv-related diagnoses aside from CM, such as Afib, and determine whether vetting additional significantly associated phenotypes better stratifies CM risk across those with TTNtvs. We focused on TTNtvs in exons with a percentage spliced in >90% (hiPSI TTNtvs), a representation of constitutive cardiac expression.ResultsWhen controlling for CM and Afib, other cardiac conditions retained only nominal association with TTNtvs. A sliding window analysis of TTNtvs across the locus confirms that the association is specific to hiPSI exons for both CM and Afib, with no meaningful associations in percent spliced in ≤90% exons (loPSI TTNtvs). The combination of hiPSI TTNtv status and early Afib diagnosis (before age 60) found a subset of TTNtv individuals at high risk for CM. The prevalence of CM in this subset was 33%, a rate that was 3.5 fold higher than that in individuals with hiPSI TTNtvs (9% prevalence), 5-fold higher than that in individuals without TTNtvs with early Afib (6% prevalence), and 80-fold higher than that in the general population.ConclusionOur retrospective analyses revealed that those with hiPSI TTNtvs and early Afib (～1/2900) have a high prevalence of CM (33%), far exceeding that in other individuals with TTNtvs and in those without TTNtvs with an early Afib diagnosis. These results show that combining phenotypic information along with genomic population screening can identify patients at higher risk for progressing to symptomatic heart failure.     

Molecular epidemiology of norovirus variants detected in children under five years of age in Hyderabad,India

PurposeNoroviruses are common viral agents in acute diarrhea in all age groups worldwide. Norovirus has been classified into 10 genogroups, GI to GX with over 48 genotypes among them the GII.4 genotype has evolved over time with a clear pattern of periodic variant replacement. Immunity is strain or genotype specific with little or no protection conferred across genogroups. The present study was aimed to determine the epidemiology, prevalent genotypes of norovirus in children below five years of age in the Hyderabad region, India.MethodsThe stool samples and clinical data were collected from 458 children below 5 years of age comprising of cases with acute gastroenteritis (n ?= ?366) and a control group (n ?= ?92) admitted to the pediatric ward. All the samples were tested for Norovirus by ELISA and RT-PCR. Sequencing was done for predominant strains.Results10.3% (n ?= ?38) of cases and 3.2% (n ?= ?3) of the control group were found to be Norovirus positive. Predominant genotypes were GII-82.5% followed by GI-12.5%.ConclusionSequencing and Phylogenetic analyses of 20 GII.4 strains was done. All of the isolates are clustered away from published the GII.4 variants thus suggesting the appearance of a new variant.     

Variability of interferon-γ release assays in people at high risk of tuberculosis infection or progression to tuberculosis disease living in the United States

ObjectivesInterferon-γ release assays, including T-SPOT.TB (TSPOT) and QuantiFERON Gold In-Tube (QFT), are important diagnostic tools for tuberculosis infection, but little work has been done to study the performance of these tests in populations prioritized for tuberculosis testing in the United States, especially those other than health care personnel.MethodsParticipants were enrolled as part of a large, prospective cohort of people at high risk of tuberculosis infection or progression to tuberculosis disease. All participants were administered a tuberculin skin test, TSPOT, and QFT test. A subset of participants had their QFT (n = 919) and TSPOT (n = 885) tests repeated when they returned to get their tuberculin skin test read 2 to 3 days later (repeat study). A total of 531 participants had a TSPOT performed twice on the same sample taken at the same time (split study).ResultsThe QFT repeat test interpretations were discordant (one test positive and the other negative) for 6.4% of participants (59 of 919), and the TSPOT tests were discordant for 60 of 885 participants in the repeat study (6.8%) and 41 of 531 participants in the split study (7.7%). There was a high degree of variability in the quantitative test results for both QFT and TSPOT, and discordance was not associated with both test results being near the established cut-offs. Furthermore, the proportion of discordance was similar when comparing participants in both the TSPOT repeat and TSPOT split studies.DiscussionBoth QFT and TSPOT were 6% to 8% discordant. The results should be interpreted with caution, particularly when seeing a conversion or reversion in serial testing.