Liver regulatory mechanisms of noncoding variants at lipid and metabolic trait loci.

Genome-wide association studies (GWASs) have identified hundreds of risk loci for liver disease and lipid-related metabolic traits, although identifying their target genes and molecular mechanisms remains challenging. We predicted target genes at GWAS signals by integrating them with molecular quantitative trait loci for liver gene expression (eQTL) and liver chromatin accessibility QTL (caQTL). We predicted specific regulatory caQTL variants at four GWAS signals located near EFHD1, LITAF, ZNF329, and GPR180. Using transcriptional reporter assays, we determined that caQTL variants rs13395911, rs11644920, rs34003091, and rs9556404 exhibit allelic differences in regulatory activity. We also performed a protein binding assay for rs13395911 and found that FOXA2 differentially interacts with the alleles of rs13395911. For variants rs13395911 and rs11644920 in putative enhancer regulatory elements, we used CRISPRi to demonstrate that repression of the enhancers altered the expression of the predicted target and/or nearby genes. Repression of the element at rs13395911 reduced the expression of EFHD1, and repression of the element at rs11644920 reduced the expression of LITAF, SNN, and TXNDC11. Finally, we showed that EFHD1 is a metabolically active gene in HepG2 cells. Together, these results provide key steps to connect genetic variants with cellular mechanisms and help elucidate the causes of liver disease.

Mental health-related structural stigma and discrimination in health and social policies in Nepal: A scoping review and synthesis.

AIMS: National policies can be used to reveal structural stigma and discrimination in relation to mental health. This review assesses how structural stigma and discrimination are manifested in the policies and legislations of Government of Nepal. METHODS: Scoping review methodology was followed to review policy documents (acts of parliament, legislation, policies, strategies, guidelines and official directives) drafted or amended after 2010. RESULTS: Eighty-nine policies were identified related to health, social welfare, development and regulations which were relevant to people with psychosocial and mental disabilities or have addressed the mental health agendas. Several critical policy failings and gaps are revealed, such as the use of stigmatizing language (e.g., 'insane' or 'lunatic'), inconsistencies within and between policies, deviation from international protocols defining legal capacity and consent, lack of inclusion of the mental health agenda in larger development policies and lack of cost-effective interventions and identification of financing mechanisms. Provisions for people living with mental health conditions included adequate standard of living; attaining standard mental health; the right to exercise legal capacity, liberty and security; freedom from torture or discrimination; and right to live independently. However, other policies contradicted these rights, such as prohibiting marriage, candidacy for and retention of positions of authority and vulnerability to imprisonment. CONCLUSION: Mental health-related structural stigma and discrimination in Nepal can be identified through the use of discriminator language and provisions in the policies. The structural stigma and discrimination may be addressed through revision of the discriminating policies, integrating the mental health agenda into larger national and provincial policies, and streamlining policies to comply with national and international protocols.

Left ventricle hypertrophy and re-modeling in children with essential hypertension: does the race matter?

BACKGROUND: This is the first study to report on the impact of race on differences in the prevalence of echocardiographic left ventricular hypertrophy and left ventricular adaptation at the time of diagnosis of essential hypertension in children. METHODS: This cross-sectional, single-centre study included patients aged 3-18 years who had newly diagnosed essential hypertension. Echocardiography was used to assess left ventricular mass index and left ventricular relative wall thickness. An left ventricular mass index > the 95th percentile for age and gender, and an left ventricular relative wall thickness > 0.42, were used to diagnose left ventricular hypertrophy and concentric adaptation. Various echocardiographic parameters were compared between African Americans and Caucasians. RESULTS: The study included 422 patients (289 African Americans and 133 Caucasians) diagnosed with essential hypertension at a median age of 14.6 (interquartile range; 12.1-16.3) years. Eighty-eight patients (20.9%) had left ventricular hypertrophy. There was no statistically significant difference in the prevalence of left ventricular hypertrophy between African Americans and Caucasians (22.5% versus 17.3%, p=0.22). The median left ventricular relative wall thickness was 0.35 (0.29-0.43), and 114 patients (27.0%) had an left ventricular relative wall thickness > 0.42. The presence of an left ventricular relative wall thickness > 0.42 was significantly higher among African Americans compared to Caucasians (30.1% versus 20.3%, p = 0.04). The African American race was a strong predictor for an left ventricular relative wall thickness > 0.42 (odds ratio 1.7, p = 0.04), but not for left ventricular mass index > the 95th percentile (p = 0.22). Overweight/obesity was a strong predictor for an left ventricular mass index > the 95th percentile. CONCLUSIONS: There was no difference in the prevalence of left ventricular hypertrophy in children with essential hypertension of different races. Obesity, rather than being African American, is associated with left ventricular hypertrophy.

Defining MRI Superiority over CT for Colorectal and Neuroendocrine Liver Metastases.

BACKGROUND: We compared CT and MRI for staging metastatic colorectal or neuroendocrine liver metastases (CRLMs and NELMs, respectively) to assess their impact on tumor burden. METHODS: A prospectively maintained database was queried for patients who underwent both imaging modalities within 3 months, with two blinded radiologists (R1 and R2) independently assessing the images for liver lesions. To minimize recall bias, studies were grouped by modality, and were randomized and evaluated separately. RESULTS: Our query yielded 76 patients (42 CRLMs; 34 NELMs) with low interrater variability (intraclass correlation coefficients: CT = 0.941, MRI = 0.975). For CRLMs, there were no significant differences in lesion number or size between CT and MRI. However, in NELMs, Eovist®-enhanced MRI detected more lesions (R1: 14.3 vs. 12.1, p = 0.02; R2: 14.4 vs. 12.4, p = 0.01) and smaller lesions (R1: 5.7 vs. 4.4, p = 0.03; R2: 4.8 vs. 2.9, p = 0.02) than CT. CONCLUSIONS: CT and MRI are equivalent for CRLMs, but for NELMs, MRI outperforms CT in detecting more and smaller lesions, potentially influencing treatment planning and surgery.

A domain-agnostic approach for characterization of lifelong learning systems.

Despite the advancement of machine learning techniques in recent years, state-of-the-art systems lack robustness to "real world" events, where the input distributions and tasks encountered by the deployed systems will not be limited to the original training context, and systems will instead need to adapt to novel distributions and tasks while deployed. This critical gap may be addressed through the development of "Lifelong Learning" systems that are capable of (1) Continuous Learning, (2) Transfer and Adaptation, and (3) Scalability. Unfortunately, efforts to improve these capabilities are typically treated as distinct areas of research that are assessed independently, without regard to the impact of each separate capability on other aspects of the system. We instead propose a holistic approach, using a suite of metrics and an evaluation framework to assess Lifelong Learning in a principled way that is agnostic to specific domains or system techniques. Through five case studies, we show that this suite of metrics can inform the development of varied and complex Lifelong Learning systems. We highlight how the proposed suite of metrics quantifies performance trade-offs present during Lifelong Learning system development - both the widely discussed Stability-Plasticity dilemma and the newly proposed relationship between Sample Efficient and Robust Learning. Further, we make recommendations for the formulation and use of metrics to guide the continuing development of Lifelong Learning systems and assess their progress in the future.

A Unique High-Output Cardiac Hypertrophy Phenotype Arising From Low Systemic Vascular Resistance in Cantu Syndrome.

Background Cardiomegaly caused by left ventricular hypertrophy is a risk factor for development of congestive heart failure, classically associated with decreased systolic and/or diastolic ventricular function. Less attention has been given to the phenotype of left ventricular hypertrophy with enhanced ventricular function and increased cardiac output, which is potentially associated with high-output heart failure. Lack of recognition may pose diagnostic ambiguity and management complexities. Methods and Results We sought to systematically characterize high-output cardiac hypertrophy in subjects with Cantu syndrome (CS), caused by gain-of-function variants in ABCC9, which encodes cardiovascular KATP (ATP-sensitive potassium) channel subunits. We studied the cardiovascular phenotype longitudinally in 31 subjects with CS with confirmed ABCC9 variants (median [interquartile range] age 8 years [3-32 years], body mass index 19.9 [16.5-22.9], 16 male subjects). Subjects with CS presented with significant left ventricular hypertrophy (left ventricular mass index 86.7 [57.7-103.0] g/m2 in CS, n=30; 26.6 [24.1-32.8] g/m2 in controls, n=17; P<0.0001) and low blood pressure (systolic 94.5 [90-103] mm Hg in CS, n=17; 109 [98-115] mm Hg in controls, n=17; P=0.0301; diastolic 60 [56-66] mm Hg in CS, n=17; 69 [65-72] mm Hg in control, n=17; P=0.0063). Most (21/31) subjects with CS exhibited eccentric hypertrophy with normal left ventricular wall thickness. Congestive heart failure symptoms were evident in 4 of the 5 subjects with CS aged >40 years on long-term follow-up. Conclusions The data define the natural history of high-output cardiac hypertrophy resulting from decreased systemic vascular resistance in subjects with CS, a defining population for long-term consequences of high-output hypertrophy caused by low systemic vascular resistance, and the potential for progression to high-output heart failure.

Ross Syndrome Presenting as Heat Exhaustion: A Report of Two Cases.

Ross syndrome is a rare clinical disorder of sweating associated with tonic pupil and areflexia. There are very few case reports of Ross syndrome in dermatology literature, most presenting with patchy hyperhidrosis. Here, we report two isolated cases who had presented to the emergency department with heat exhaustion. Multidisciplinary evaluations of the first case revealed focal anhidrosis, patchy hyperhidrosis, postural hypotension, absent deep tendon reflex, and tonic pupil while the second case had similar features except for postural hypotension, prompting the diagnosis of Ross syndrome. Presentation of these two patients highlights the importance of a high index of suspicion of dysautonomic disorder, interdisciplinary workup of a case of patchy anhidrosis, or hyperhidrosis, which may get missed in busy outpatient department (OPD) visit.

Comparison of Suture-Based and Collagen-Based Vascular Closure Devices for Large Bore Arteriotomies-A Meta-Analysis of Bleeding and Vascular Outcomes.

BACKGROUND: Large bore access procedures rely on vascular closure devices to minimize access site complications. Suture-based vascular closure devices (S-VCD) such as ProGlide and ProStar XL have been readily used, but recently, newer generation collagen-based vascular closure devices (C-VCD) such as MANTA have been introduced. Data on comparisons of these devices are limited. METHODS: PubMed, Scopus and Cochrane were searched for articles on vascular closure devices using keywords, ("Vascular closure devices" OR "MANTA" OR "ProStar XL" OR "ProGlide") AND ("outcomes") that resulted in a total of 875 studies. Studies were included if bleeding or vascular complications as defined by Valve Academic Research Consortium-2 were compared between the two types of VCDs. The event level data were pooled across trials to calculate the Odds Ratio (OR) with 95% CI, and analysis was done with Review Manager 5.4 using random effects model. RESULTS: Pooled analyses from these nine studies resulted in a total of 3410 patients, out of which 2855 were available for analysis. A total of 1229 received C-VCD and 1626 received S- VCD. Among the patients who received C-VCD, the bleeding complications (major and minor) were similar to patients who received S-VCD ((OR: 0.70 (0.35-1.39), p = 0.31, I2 = 55%), OR: 0.92 (0.53-1.61), p = 0.77, I2 = 65%)). The vascular complications (major and minor) in patients who received C-VCD were also similar to patients who received S-VCD ((OR: 1.01 (0.48-2.12), p = 0.98, I2 = 52%), (OR: 0.90 (0.62-1.30), p = 0.56, I2 = 35%)). CONCLUSIONS: Bleeding and vascular complications after large bore arteriotomy closure with collagen-based vascular closure devices are similar to suture-based vascular closure devices.

Declining Trend of Transapical Access for Transcatheter Aortic Valve Replacement in Patients with Aortic Stenosis.

Introduction: The last decade has witnessed major evolution and shifts in the use of transcatheter aortic valve replacement (TAVR) for severe aortic stenosis (AS). Included among the shifts has been the advent of alternative access sites for TAVR. Consequently, transapical access (TA) has become significantly less common. This study analyzes in detail the trend of TA access for TAVR over the course of 7 years. Methods: The national inpatient sample database was reviewed from 2011-2017 and patients with AS were identified by using validated ICD 9-CM and ICD 10-CM codes. Patients who underwent TAVR through TA access were classified as TA-TAVR, and any procedure other than TA access was classified as non-TA-TAVR. We compared the yearly trends of TA-TAVR to those of non-TA-TAVR as the primary outcome. Results: A total of 3,693,231 patients were identified with a diagnosis of AS. 129,821 patients underwent TAVR, of which 10,158 (7.8%) underwent TA-TAVR and 119,663 (92.2%) underwent non-TA-TAVR. After peaking in 2013 at 27.7%, the volume of TA-TAVR declined to 1.92% in 2017 (p < 0.0001). Non-TA-TAVR started in 2013 at 72.2% and consistently increased to 98.1% in 2017. In-patient mortality decreased from a peak of 5.53% in 2014 to 3.18 in 2017 (p=0.6) in the TA-TAVR group and from a peak of 4.51% in 2013 to 1.24% in 2017 (p=0.0001) in the non-TA-TAVR group. Conclusion: This study highlights a steady decline in TA access for TAVR, higher inpatient mortality, increased length of stay, and higher costs compared to non-TA-TAVR.

Intravascular ultrasound guided transcatheter electrosurgical revascularization of an interrupted aortic arch.

Interrupted aortic arch is a rare (prevalence 1:100000) but malignant cause of secondary hypertension, with late sequela of early myocardial infarction, stroke, and heart failure. We present the case of a 49-year-old male patient with aortic interruption successfully treated by intravascular ultrasound guided transcatheter electrosurgical wire crossing and revascularization using a covered stent. Learning objective: Transcatheter electrosurgical wire techniques utilizing intravascular ultrasound facilitate safe and effective percutaneous revascularization of complex aortic coarctation patients.

A rare case of persistent lateral marginal vein of Servelle in Klippel Trenaunay Syndrome: A successful surgical management.

INTRODUCTION AND IMPORTANCE: Klippel-Trenaunay Syndrome (KTS) is a rare congenital vascular disorder characterized by capillary malformation, varicosities, and tissue overgrowth. It usually affects the unilateral lower extremities manifesting commonly as pain, localized rise of temperature, and venous tortuosity. However, in severe cases, ulceration, cellulitis, and chronic lymphatic malformation may be present. Management is mostly supportive and involves the use of compression stockings. CASE PRESENTATION: Here, we report a case of KTS with a persistent lateral marginal vein of Servelle managed with radiofrequency ablation along with sclerotherapy of selected perforators. On a two-year follow-up, the symptoms had resolved and Doppler ultrasonography revealed resolution of the defective vein along with the absence of incompetent perforators. CLINICAL DISCUSSION: In cases with venous malformation with the persistence of embryonic avalvular venous structures, like the lateral marginal vein of Servelle, surgical intervention is warranted especially at a younger age to reduce the risk of future thromboembolic events and recurrence. CONCLUSION: Varicosities of the lateral marginal vein of Servelle can be managed successfully by radiofrequency ablation and adjunct sclerotherapy in selected cases.

Successful Treatment of Refractory Chronic Bullous Disease of Childhood with Rituximab.

Chronic bullous disease of childhood is a rare subepidermal bullous disease with a hallmark of linear IgA deposition along basement membrane zone seen on direct immunofluorescence. We report a case of a 2-year-old male child, who had recurrent and multiple bullous eruptions over body and he was not responding to conventional therapy. He had earlier developed a drug reaction to dapsone which is considered the drug of choice for this condition. We report successful management of this case with injection rituximab which is a chimeric monoclonal antibody against CD20, which is primarily found on the surface of B cells.

Pandemic Operating Room Supply Shortage and Surgical Site Infection: Considerations as We Emerge from the Coronavirus Disease 2019 Pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic created shortages of operating room (OR) supplies, forcing healthcare systems to make concessions regarding "standard" OR attire. At our institution, we were required to reduce shoe covers, reuse face masks, and allow washable head coverings. We determined if these changes affected surgical site infection (SSI) rates. STUDY DESIGN: A single institutional study was performed to compare the SSI rates reported to the National Healthcare Safety Network in the 2 years preceding COVID-19 (PRE, January 1, 2018, to December 31, 2020) with the first 12 months after the pandemic (POST, April 1, 2020, to March 31, 2021). We confirmed our findings using propensity score matching and multivariate analysis. RESULTS: Elimination of traditional shoe covers, disposable head covers, and single-use face masks was associated with a decreased SSI rate from 5.1% PRE to 2.6% POST (p < 0.001). Furthermore, this was despite a 14% increase in surgical volume and an increase in the number of contaminated/dirty cases (2.2% PRE vs 7.4% POST, p < 0.001). Use of disposable face masks decreased by 4.3-fold during this period from 3.5 million/y PRE to 0.8 million/y POST. Of note, inpatient hand hygiene throughout the hospital increased from 71% PRE to 85% POST (p < 0.001). CONCLUSIONS: This analysis has practical applications as we emerge from the pandemic and make decisions regarding OR attire. These data suggest that disposable head covers and shoe covers and frequent changes of face masks are unnecessary, and discontinuation of these practices will have significant cost and environmental implications. These data also reinforce the importance of good hand hygiene for infection prevention.