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Background: To determine the effect of stress maneuvers/interventions on ultrasound liver stiffness measurements (LSMs) in patients with Fontan circulation and healthy controls., Methods: In this prospective, IRB-approved study of 10 patients after Fontan palliation and 10 healthy controls, ultrasound 2D shear-wave elastography LSMs were acquired at baseline and after maximum inspiration, expiration, standing, handgrip, aerobic exercise, i.v. fluid (500 mL normal saline) administration, and i.v. furosemide (20 mg) administration. Absolute and percent change in LSM were compared between baseline and each maneuver, and then from fluid infusion to after diuresis., Results: Median ages were 25.5 and 26 years in the post-Fontan and control groups (p = 0.796). LSMs after Fontan were higher at baseline (2.6 vs. 1.3 m/s) and with all maneuvers compared to controls (all p < 0.001). Changes in LSM with maneuvers, exercise, fluid, or diuresis were not significant when compared to baseline in post-Fontan patients. LSM in controls increased with inspiration (+0.02 m/s, 1.6%, p = 0.03), standing (+0.07 m/s, 5.5%, p = 0.03), and fluid administration (+0.10 m/s, 7.8%, p = 0.002), and decreased 60 minutes after diuretic administration (-0.05 m/s, -3.9%, p = 0.01) compared to baseline. LSM after diuretic administration significantly decreased when compared to after i.v. fluid administration at 30 minutes (-0.79 m/s, -26.5%, p = 0.004) and 60 minutes (-0.78 m/s, -26.2%, p = 0.017) for patients after Fontan and controls at 15 minutes (-0.12 m/s, -8.70%, p = 0.002), 30 minutes (-0.15 m/s, -10.9%, p = 0.003), and 60 minutes (-0.1 m/s, -10.9%, p = 0.005)., Conclusions: LSM after Fontan is higher with more variability compared to controls. Diuresis is associated with significantly decreased liver stiffness in both patients after Fontan and controls, with the suggestion of a greater effect in Fontan patients., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Clozapine is the most effective medication for the management of treatment-resistant schizophrenia and schizoaffective disorder, and its discontinuation can pose significant challenges in treatment. We present a patient with a diagnosis of schizoaffective disorder who was stable on clozapine for a decade until discontinuation due to thrombocytopenia. She experienced a relapse of her illness, presenting with psychotic and catatonic features with poor oral intake and physical health complications requiring a lengthy admission to the hospital. There was a poor response to alternative antipsychotics and a full course of electroconvulsive therapy. Intramuscular (IM) clozapine was initiated due to catatonia and refusal to accept oral medications. After receiving 10 doses of IM clozapine, she started accepting oral clozapine and made a full recovery within a few weeks. The low platelet count was persistent, and a bone marrow biopsy showed results consistent with immune thrombocytopenia being the cause of that low platelet count., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Dengue is a mosquito-borne, acute febrile illness caused by dengue viruses. The association between hematological malignancies and dengue infection is obscure, and the literature on this occurrence is also limited. We report two cases of acute leukaemia following dengue infection in a recent outbreak in Nepal. Our case reports suggest a possible association of acute leukaemia with dengue infection. The relationship should be explored further with observational studies., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2024 Anushka Agrawal et al.)

Introduction: The rise of antimicrobial resistance represents a critical threat to global health, exacerbated by the excessive and inappropriate dispensing and use of antimicrobial drugs, notably antibiotics, which specifically target bacterial infections. The surge in antibiotic consumption globally is particularly concerning in low-income and middle-income countries (LMICs), where informal healthcare providers (IPs) play a vital role in the healthcare landscape. Often the initial point of contact for healthcare-seeking individuals, IPs play a crucial role in delivering primary care services in these regions. Despite the prevalent dispensing of antibiotics by IPs in many LMICs, as highlighted by existing research, there remains a gap in the comprehensive synthesis of antibiotic dispensing practices and the influencing factors among IPs. Hence, this scoping review seeks to map and consolidate the literature regarding antibiotic dispensing and its drivers among IPs in LMICs., Methods and Analysis: This review will follow the Joanna Briggs Institute guideline for scoping review. A comprehensive search across nine electronic databases (MEDLINE, EMBASE, SCOPUS, Global Health, CINAHL, Web of Science, LILACS, AJOL and IMSEAR) will be performed, supplemented by manual searches of reference lists of eligible publications. The search strategy will impose no constraints on study design, methodology, publication date or language. The study selection process will be reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. The findings on antibiotic dispensing and its patterns will be synthesised and reported descriptively using tables, visuals and a narrative summary. Additionally, factors influencing antibiotic dispensing will be elucidated through both inductive and deductive content analysis methods., Ethics and Dissemination: Ethical approval is not required for scoping reviews. The findings will be disseminated through peer-reviewed publications and presentations at relevant conferences., Competing Interests: Competing interests: MP is supported by a Tier 1 Canada Research Chair in Epidemiology and Global Health. SG holds a Tier 2 Canada Research Chair in Communicable Disease Epidemiology., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The increasing prevalence of cannabis worldwide requires awareness of a potential, less recognized, paradoxical entity, the cannabinoid hyperemesis syndrome (CHS). This includes cyclic episodes of nausea, vomiting, and compulsive hot water bathing for alleviation in individuals with chronic cannabis use. An 18-year-old male with daily and prolonged cannabis use has excessive nausea and vomiting, is diagnosed with CHS, and is further complicated by severe and rapidly fluctuating hypophosphatemia. He was successfully managed with intravenous (IV) antiemetic (metoclopramide) and IV normal saline in the emergency department. Hypophosphatemia was treated with IV phosphorous. Although hypophosphatemia in CHS is a rare encounter, the authors share their experience to promote broader recognition and insight into successful management., Competing Interests: The authors declare that they have no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press.)

Competing Interests: We declare no competing interests. We thank Neena Joshi, Bethany-Kate Lewis, and Laetitia Bosio for their support in drafting and editing this Comment.

Introduction: Significant heterogeneity exists within the tumor-infiltrating CD8 T cell population, and exhausted T cells harbor a subpopulation that may be replicating and may retain signatures of activation, with potential functional consequences in tumor progression. Dysfunctional immunity in the tumor microenvironment is associated with poor cancer outcomes, making exploration of these exhausted T cell subpopulations critical to the improvement of therapeutic approaches., Methods: To investigate mechanisms associated with terminally exhausted T cells, we sorted and performed transcriptional profiling of CD8 + tumor-infiltrating lymphocytes (TILs) co-expressing the exhaustion markers PD-1 and TIM-3 from large-volume melanoma tumors. We additionally performed immunologic phenotyping and functional validation, including at the single-cell level, to identify potential mechanisms that underlie their dysfunctional phenotype., Results: We identified novel dysregulated pathways in CD8 + PD-1 + TIM-3 + cells that have not been well studied in TILs; these include bile acid and peroxisome pathway-related metabolism and mammalian target of rapamycin (mTOR) signaling pathways, which are highly correlated with immune checkpoint receptor expression., Discussion: Based on bioinformatic integration of immunophenotypic data and network analysis, we propose unexpected targets for therapies to rescue the immune response to tumors in melanoma., Competing Interests: BG is a consultant/advisory board member for Merck. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cameron, Richardson, Golden, Phoon, Tamilselvan, Pfannenstiel, Thapaliya, Roversi, Gao, Zagore, Cameron and Gastman.)

Background: The relationship between pancreatic fat on imaging and metabolic co-morbidities has not been established in pediatrics. We sought to investigate the relationship between pancreatic fat measured by MRI and endocrine/exocrine dysfunctions along with the metabolic co-morbidities in a cohort of children., Objective: To investigate relationships between pancreatic fat quantified by MRI and endocrine and exocrine conditions and metabolic co-morbidities in a cohort of children. MATERIALS AND METHODS: This was a retrospective review of pediatric patients (n = 187) who had a clinically indicated MRI examination between May 2018 and February 2020. After 51 patients without useable imaging data were excluded, the remaining 136 subjects comprised the study sample. Laboratory studies were assessed if collected within 6 months of MRI and patient charts were reviewed for demographic and clinical information. MRI proton density fat fraction (PDFF) sequence had been acquired according to manufacturer's specified parameters at a slice thickness of 3 mm. Two blinded radiologists independently collected PDFF data., Results: The median age at MRI was 12.1 (IQR: 9.0-14.8) years and the majority of patients were Caucasian (79%), followed by African American and Hispanic at 12% and 11% respectively. There was a higher median pancreas fat fraction in patients with exocrine conditions (chronic pancreatitis or exocrine insufficiency) compared to those without (3.5% vs 2.2%, p = 0.03). There was also a higher median fat fraction in the head of pancreas in patients with endocrine insufficient conditions (insulin resistance, pre-diabetes, type 1 and type 2 diabetes) compared to those without endocrine insufficiency when excluding patients with active acute pancreatitis (3.5% vs 2.0%, p = 0.04). Patients with BMI > 85% had higher mean fat fraction compared to patients with BMI ≤ 85% (head: 3.8 vs 2.4%, p = 0.01; body: 3.8 vs 2.5%, p = 0.005; tail: 3.7 vs 2.7%, p = 0.049; overall pancreas fat fraction: 3.8 vs 2.6%, p = 0.002)., Conclusion: Pancreas fat is elevated in patients with BMI > 85% and in those with exocrine and endocrine insufficiencies., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: We sought to evaluate associations between Magnetic Resonance Imaging (MRI) findings, exocrine pancreatic insufficiency (EPI) and endocrine insufficiency (prediabetes or diabetes) in children., Methods: This was a retrospective study that included patients<21 years of age who underwent MRI and endoscopic pancreatic function testing (ePFT; reference standard for pancreatic exocrine function) within 3 months. MRI variables included pancreas parenchymal volume, secreted fluid volume in response to secretin, and T1 relaxation time. Data were analyzed for the full sample as well as the subset without acute pancreatitis (AP) at the time of imaging., Results: Of 72 patients, 56% (40/72) were female with median age 11.4 years. A 5 mL decrease in pancreas parenchymal volume was associated with increased odds of exocrine pancreatic dysfunction by both ePFT (OR = 1.16, p = 0.02 full sample; OR = 1.29, p = 0.01 no-AP subset), and fecal elastase (OR = 1.16, p = 0.04 full sample; OR = 1.23, p = 0.02 no-AP subset). Pancreas parenchymal volume had an AUC 0.71 (95% CI: 0.59, 0.83) for predicting exocrine pancreatic dysfunction by ePFT and when combined with sex and presence of AP had an AUC of 0.82 (95% CI: 0.72, 0.92). Regarding endocrine function, decreased pancreas parenchymal volume was associated with increased odds of diabetes (OR = 1.16, p = 0.03), and T1 relaxation time predicted glycemic outcomes with an AUC 0.78 (95% CI: 0.55-1), 91% specificity and 73% sensitivity., Conclusions: Pancreas parenchymal volume is an MRI marker of exocrine and endocrine pancreatic dysfunction in children. A model including sex, AP, and pancreas volume best predicted exocrine status. T1 relaxation time is also an MRI marker of endocrine insufficiency., Competing Interests: Declaration of competing interest None to declare., (Copyright © 2023 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Introduction: Mass psychogenic illness (MPI), also known as mass hysteria (MH), is a mental health disorder that frequently occurs in Nepal. It primarily affects female students in government high schools and occurs during the course of the school day over a few days without corresponding organic causes., Purpose of the Study: This study set out to evaluate and give neuroeducation with the goal of preventing and/or managing MPI after documenting the existing state of knowledge regarding MPI., Materials and Methods: A total of 234 female students in grades 6 through 10 who attended MH-affected schools (SMH, n = 119) and schools without a mass hysteria history (SNOMH, n = 114) participated in this mass hysteria awareness study. Participants received written pre- and posttests formatted as questionnaires before and after receiving neuroeducation by watching a drama, viewing a human brain-spinal cord model demonstration, and attending an instructive lecture on the human neurological system, stress, and mass hysteria., Results: Our neuroeducation awareness study on mass hysteria was found to be effective among all of the participants from both SMH and SNOMH. The results indicated that the aforementioned neuroeducation tools are more effective in improving knowledge about mental stress differently in different grades of SMH and SNOMH students. The basic understanding of the human neurological system was not improved by the neuroeducation tool, according to our findings., Conclusion: Our study suggests that using day-structured neuroeducational tools might be an efficient way to treat mass psychogenic illness in Nepal., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors.)

Background: COVID-19 disease-related coagulopathy and thromboembolic complication, an important aspect of the disease pathophysiology, are frequent and associated with poor outcomes, particularly significant in hospitalized patients. Undoubtedly, anticoagulation forms a cornerstone for the management of hospitalized COVID-19 patients, but the appropriate dosing has been inconclusive and a subject of research. We aim to review existing literature and compare safety and efficacy outcomes of prophylactic and therapeutic dose anticoagulation in such patients., Methods: We did a systematic review and meta-analysis to compare the efficacy and safety of prophylactic dose anticoagulation when compared with therapeutic dosing in hospitalized COVID-19 patients. We searched PubMed, Google Scholar, EMBASE and COCHRANE databases from 2019 to 2021, without any restriction by language. We screened records, extracted data and assessed the risk of bias in the studies. RCTs that directly compare therapeutic and prophylactic anticoagulants dosing and are not placebo-controlled trials were included. Analyses of data were conducted using the Mantel-Haenszel random-effects model (DerSimonian-Laird analysis). The study is registered with PROSPERO (CRD42021265948)., Results: We included three studies in the final quantitative analysis. The incidence of thromboembolic events in therapeutic anticoagulation was lower in comparison with prophylactic anticoagulation in hospitalized COVID-19 patients and reached statistical significance [RR 1·45, 95% CI (1.07, 1.97) I 2 -0%], whereas major bleeding as an adverse event was found lower in prophylactic anticoagulation in comparison with therapeutic anticoagulation that was statistically significant [RR 0·42, 95% CI(0.19, 0.93) I 2 -0%]., Conclusion: Our study shows that therapeutic dose anticoagulation is more effective in preventing thromboembolic events than prophylactic dose but significantly increases the risk of major bleeding as an adverse event. So, the risk-benefit ratio must be considered while using either of them., (© 2022 The Authors. The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

BACKGROUND. Multiple ultrasound platforms now provide quantitative measures of hepatic steatosis. One such measure is the ultrasound-derived fat fraction (UDFF), which combines attenuation and backscatter quantification. OBJECTIVE. The purpose of this study was to characterize agreement between UDFF and MRI proton-density fat fraction (PDFF) measurements. METHODS. This prospective cross-sectional study enrolled 56 overweight and obese adolescents and adults (age ≥ 16 years) who underwent investigational ultrasound (deep abdominal transducer) and MRI examinations of the liver during a single visit from August 2020 to October 2020. Ultrasound examinations included three UDFF acquisitions of five measurements each (15 measurements total), and an overall median of medians was computed (UDFF overall ). MRI examinations included three PDFF acquisitions with calculation of an overall median PDFF. Spearman rank-order correlation was computed between UDFF and MRI PDFF measurements. Intraclass correlation coefficients and Bland-Altman difference plots were used to assess agreement. ROC curves were used to assess diagnostic performance of UDFF for detecting MRI PDFF of 5.5% or more. RESULTS. Median participant age was 32.5 years (IQR, 24.0-39.0 years); 40 participants were female, and 16 were male. A total of 34 (60.7%) participants had an MRI PDFF of 5.5% or more. UDFF overall was 10.5% (IQR, 5.0-20.0%); median MRI PDFF was 6.1% (IQR, 3.4-13.7%). UDFF overall was positively associated with MRI PDFF (ρ, 0.82; p < .001; intraclass correlation coefficient, 0.84 [95% CI, 0.59-0.93]). Mean bias between UDFF and PDFF was 4.0% (95% limits of agreement, -7.9% to 15.9%), with similar bias if summarizing UDFF by the first five measurements (4.4%), first three measurements (4.4%), or first measurement (4.6%). UDFF overall AUC was 0.90 (95% CI, 0.79-0.96) for MRI PDFF of 5.5% or more; AUC was not significantly different when it was based on the number of UDFF measurements ( p = .11-.97 for all pairwise AUC comparisons). UDFF overall cutoff of more than 5% had sensitivity of 94.1% and specificity of 63.6% for diagnosing MRI PDFF of 5.5% or more. CONCLUSION. Measurements of hepatic steatosis using UDFF show strong agreement with measurements by MRI PDFF. A UDFF overall cutoff of more than 5% provides high AUC and sensitivity, albeit low specificity, for detection of MRI PDFF of 5.5% or more. CLINICAL IMPACT. UDFF may have a clinical role in detection of hepatic steatosis. A reduced number of individual measurements is likely sufficient for determining an overall UDFF value. TRIAL REGISTRATION. ClinicalTrials.gov: NCT04523584.

The development of prostate-specific membrane antigen (PSMA) ligands labeled with radionuclides is a ground-breaking achievement in the management of prostate cancer. With the increasing use of 68 Gallium-PSMA and 18 F-DCFPyL (Pylarify) and their approval by the Food and Drug Administration (FDA), other PSMA agents and their unique characteristics are also being studied. Two other PSMA agents, namely 177 Lutetium-PSMA ( 177 Lu-PSMA) and 225 Actinium-PSMA ( 225 Ac-PSMA), are currently drawing the researcher's attention mainly due to their theranostic importance. Studies focusing on the essential characteristics of these two emerging radiotracers are relatively lacking. Hence, this review article, beginning with a brief introduction, intends to provide insights on the mechanism, efficacy, adverse effects, usefulness, including theranostic implications, and limitations of these two emerging PSMA agents. The 177 Lu-PSMA is commercially accessible, is well tolerated, and has been found to lower prostate-specific antigen (PSA) levels while improving patients' quality of life. It also reduces pain and the requirement for analgesics and is safe for advanced diseases. However, despite its potential advantages, around one-third of patients do not respond satisfactorily to this costly treatment; it is still challenging to personalize this therapy and predict its outcome. Similarly, 225 Ac is compatible with antibody-based targeting vectors, releasing four extremely hazardous high-energy emissions with a longer half-life of 10 days. It has made 225 Ac-PSMA therapy useful for tumors resistant to standard treatments, with a better response than 177 Lu-PSMA. Dosimetry studies show a good biochemical response without toxicity in patients with advanced metastatic castration-resistant prostate cancer (mCRPC). However, it can potentially cause significant damage to healthy tissues if not retained at the tumor site. Encapsulating radionuclides in a nano-carrier, hastening the absorption by tumor cells, and local delivery might all help reduce the harmful consequences. Both have advantages and disadvantages. The choice of PSMA agents may rely on desired qualities, cost, and convenience, among other factors. Further research is warranted in order to better understand their ideal use in clinical settings., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Alam et al.)

Background Acute cholecystitis is one of the commonest surgical disease. The rapid diagnosis at its early stage is one of the crucial factor in patient care and management. Objective To evaluate the role of magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography (MRCP) in the diagnosis or exclusion of acute cholecystitis, coexisting choledocholithiasis, and acute pancreatitis in emergency setting. Method This study was conducted in the department of radiodiagnosis B and C teaching hospital, Birtamod, Nepal from July 2016 to November 2019. Patients, clinically diagnosed as acute cholecystitis or biliary condition with positive Murphy's sign with or without jaundice and deranged Liver Function Test, raised Leucocyte counts were evaluated by Magnetic Resonance imaging. The sensitivity, specificity, Positive Productive Value (PPV), Negative Productive Value (NPV) were calculated for the diagnosis of acute cholecystitis. Data was entered and analysed by using SPSS version 20. Result There were 40 patients included in our study. Among them 27 (67.5%) were females and 13 (32.5%) male. The age of the patients ranged from 16 years to 79 years, mean age 49.4 years. Majority of the patients were in the age group of 40-60 years (57.5%). The overall sensitivity, specificity, Positive Productive Value and Negative Productive Value of Magnetic Resonance imaging diagnosis of acute cholecystitis were 100%, 66.6%, 94.4% and 100% respectively. Acute cholecystitis associated with gall stone disease were common and found in 72.5% cases, with sensitivity 96.5%, specificity 27.7%, Positive Productive Value 77.7% and Negative Productive Value 75.0%. Conclusion Magnetic resonance imaging (MRI)/Magnetic resonance cholangiopancreatography (MRCP) is an excellent tool for the evaluation of biliary pathology and can be used for the preoperative evaluation of acute cholecystitis at the emergency setting.

The complete absence of limbs is a rare occurrence. Though the causes are various, it is hard to elicit most of the time. They are usually diagnosed via anomaly scan but the lack of access to the same can often lead to a term presentation. It is still not uncommon to receive pregnant patients at term to the hospital or in labour as the first antenatal visit. Increasing the feasibility of the scan can help in the early diagnosis and management. Here, we report a rare combination of limb defects that we managed in a district-level hospital and highlight the difficulties in the management and referral of the patients while working in rural areas., Keywords: amelia; antenatal care; congenital limb deformities; fetal ultrasonography.

Background: Accurate assessment of renal function is important in the care of children with cancer because renal function has implications for anti-tumor medication dosing and eligibility for clinical trials., Objective: To characterize agreement between serum estimates of glomerular filtration rate (GFR) and a reference standard of radioisotopic GFR in a large pediatric oncology cohort., Materials and Methods: We conducted a retrospective cross-sectional study of children who had both radioisotopic GFR ( 99m Tc-diethylenetriaminepentaacetic acid, or 99m Tc-DTPA) and serum labs (creatinine, cystatin C) obtained <7 days apart between January 2017 and August 2019. We calculated estimated GFR from serum labs using published equations and calculated agreement using intraclass correlation coefficient (ICC) and Bland-Altman analysis with univariate regression to define predictors of agreement., Results: We included 272 pairs of data. Mean patient age was (mean ± standard deviation) 7.8±5.7 years. Mean radioisotopic GFR was 112±33 mL/min/1.73 m 2 . Absolute agreement between radioisotopic GFR and serum estimates was only fair (ICC=0.46-0.58) with a mean difference of -26.6 to +0.12 mL/min/1.73 m 2 . For radioisotopic GFR measurements <60 mL/min/1.73 m 2 , mean differences were greater, with serum estimates overestimating GFR by a mean of 21.5-39.6 mL/min/1.73 m 2 . In multivariable modeling, significant predictors of agreement included age, height, acute kidney injury and tumor type. Sensitivity of serum estimates was 14-29% for a GFR <60 mL/min/1.73 m 2 ., Conclusion: Agreement between radioisotopic GFR and serum estimates of GFR is only fair and serum estimates of GFR have poor sensitivity for clinically relevant GFR <60 mL/min/1.73 m 2 . Radioisotopic measurement of GFR likely remains necessary to assess renal function in pediatric oncology patients with decreased renal function., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Essential thrombocythemia, a myeloproliferative condition with an increased number of circulating platelets, is a rare hematological malignancy. The aim of the study is to find out the prevalence of essential thrombocythemia among patients with myeloproliferative neoplasms presenting in haematology unit of a tertiary care centre., Methods: This was a descriptive cross-sectional study at a tertiary care centre from September, 2020 to September, 2021 (Reference number: 48 (6-11) E2077/076). All the patients with a diagnosis of essential thrombocythemia and willing to give consent were included in the study while the patients with incomplete investigations were excluded. A sample size of 72 patients was taken and convenience sampling was done. Data were entered in Microsoft Excel 2010 and analysis was done by the Statistical Package for the Social Sciences Version 22.0. Point estimate at 95% Confidence Interval was calculated along with frequency and proportion for binary data along with mean and standard deviation for continuous data., Results: Among 72 patients with myeloproliferative neoplasms, the prevalence of essential thrombocythemia was found to be 17 (23.61%) (13.80-33.42 at a 95% Confidence Interval). The mean age of patients was 55.41±11.20 years with a male to female ratio of 9:8. The mean hemoglobin level and platelet count in patients were found to be 11.20±2.1 g/dl and 677000±262067.70 cells/mm3. Twelve (70.58%) of total patients were under low risk of essential thrombocythemia while 3 (17.64%) of them were at high risk., Conclusions: The prevalence of essential thrombocythemia was similar to other studies done in similar settings., Keywords: essential thrombocythemia; hematology; mutation.

Acute ischemic stroke (AIS) is a fatal and debilitating condition killing 2.7 million people each year worldwide. The most commonly used treatment modality for AIS is intravenous thrombolysis (IVT) with alteplase which is indicated for those presenting within 4.5 h of onset. Due to a lack of reliable evidence on harm or benefit, the 2019 American Heart Association/American Stroke Association (AHA/ASA) guidelines consider a history of previous intracranial hemorrhage (ICH) as potentially harmful and no longer an absolute contraindication for IVT in patients with AIS, and the U.S. Food and Drug Administration (FDA) removed chronic ICH as a specific contraindication for IVT from the label in 2015. Despite a shift in guidelines, physicians frequently face the dilemmatic choice whether to administer IVT in this subset of patients due to the risk of symptomatic intracranial hemorrhage (SICH). The benefit of IVT in such patients has not been thoroughly investigated, and there are only a few studies on the subject in the literature to date. We conducted the present meta-analysis in an aim to provide solid evidence on the efficacy and safety of IVT for treating AIS in patients with a history of remote ICH. Our meta-analysis found that IVT improves functional outcomes in AIS patients with prior remote ICH without increasing SICH or all-cause mortality. These findings may contribute to the decision-making process for IVT administration in AIS patients., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Immune checkpoint inhibitor (ICI) therapy continues to revolutionize melanoma treatment, but only a subset of patients respond. Major efforts are underway to develop minimally invasive predictive assays of ICI response. Using single-cell transcriptomics, we discovered a unique CD8 T cell blood/tumor-shared subpopulation in melanoma patients with high levels of oxidative phosphorylation (OXPHOS), the ectonucleotidases CD38 and CD39, and both exhaustion and cytotoxicity markers. We called this population with high levels of OXPHOS "CD8+ TOXPHOS cells." We validated that higher levels of OXPHOS in tumor- and peripheral blood-derived CD8+ TOXPHOS cells correlated with ICI resistance in melanoma patients. We then developed an ICI therapy response predictive model using a transcriptomic profile of CD8+ TOXPHOS cells. This model is capable of discerning responders from nonresponders using either tumor or peripheral blood CD8 T cells with high accuracy in multiple validation cohorts. In sum, CD8+ TOXPHOS cells represent a critical immune population to assess ICI response with the potential to be a new target to improve outcomes in melanoma patients., Competing Interests: Disclosures: P. Funchain reported grants from Pfizer and Bristol Myers Squibb and personal fees from Eisai outside the submitted work. A. Rodriguez reported non-financial support from Lipid Genomics during the conduct of the study and non-financial support from Lipid Genomics outside the submitted work; in addition, A. Rodriguez had a patent to LAG3 issued (Lipid Genomics). No other disclosures were reported., (© 2021 Li et al.)

Background: Deep learning Computed Tomography (CT) reconstruction (DLR) algorithms promise to improve image quality but the impact on clinical diagnostic performance remains to be demonstrated. We aimed to compare DLR to standard iterative reconstruction for detection of urolithiasis by unenhanced CT in children and young adults., Methods: This was an IRB approved retrospective study involving post-hoc reconstruction of clinically acquired unenhanced abdomen/pelvis CT scans. Images were reconstructed with six different manufacturer-standard DLR algorithms and reformatted in 3 planes (axial, sagittal, and coronal) at 3 mm intervals. De-identified reconstructions were loaded as independent examinations for review by 3 blinded radiologists (R1, R2, R3) tasked with identifying and measuring all stones. Results were compared to the clinical iterative reconstruction images as a reference standard. IntraClass correlation coefficients and kappa (k) statistics were used to quantify agreement., Results: CT data for 14 patients (mean age: 17.3 ± 3.4 years, 5 males and 9 females, weight class: 31-70 kg (n = 6), 71-100 kg (n = 7), > 100 kg (n = 1)) were reconstructed into 84 total exams. 7 patients had urinary tract calculi. Interobserver agreement on the presence of any urinary tract calculus was substantial to almost perfect (k = 0.71-1) for all DLR algorithms. Agreement with the reference standard on number of calculi was excellent (ICC = 0.78-0.96) and agreement on the size of the largest calculus was fair to excellent (ICC = 0.51-0.97) depending on reviewer and DLR algorithm., Conclusion: Deep learning reconstruction of unenhanced CT images allows similar renal stone detectability compared to iterative reconstruction., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Pathways to care studies are feasible and tested means of finding the actual routes taken by patients before reaching proper care. In view of the predominance of nonprofessional service providers and the lack of previous large studies on pathways in Nepal, this multicenter study is needed. The aim of the study was to trace the various pathways and carers involved in mental health care; assess clinical variables such as the duration of untreated illness, clinical presentation and treatment; and compare geographically and culturally diverse landscapes., Methods: This was a cross-sectional, convenience sampling study performed at 14 centers where new cases were being taken. The World Health Organization Study of the Pathways-to-Care Schedule was applied. The Nepali version of the encounter form was used. The data were collected between 17 September and 16 October 2020 and were analyzed using the Statistical Package for the Social Sciences (SPSS). Additionally, perspectives from local investigators were collected and discussed., Results: Most of the first carers were native/religious faith healers (28.2%), followed by psychiatrists (26%). The median duration for the first psychiatric consultation was 3 weeks. The duration of untreated illness was 30.72 ± 80.34 (median: 4) weeks, and the time taken for this journey was 94.99 ± 274.58 (median: 30) min. The longest delay from the onset of illness to psychiatric care was for epilepsy {90.0 ± 199.0 (median: 25.5)} weeks, followed by neurotic illness {22.89 ± 73.45 (median: 2)} and psychotic illness {10.54 ± 18.28 (median: 2)} weeks. Overall, most patients with severe mental illnesses (SMIs) had their first contact with faithhealers (49%), then met with medical doctors (13%) or psychiatrists (28%). Marked differences in clinical presentation surfaced when hilly centers were compared with the Terai belt., Conclusions: Faith healers, general practitioners and hospital doctors are major carers, and the means of educating them for proper referral can be considered. The investigators see several hindrances and opportunities in the studied pathways. The employment of more mental health professionals and better mental health advocacy, public awareness programs and school education are suggested strategies to improve proper mental health care., (© 2021. The Author(s).)

BACKGROUND . CT is the imaging modality of choice to identify lung metastasis. OBJECTIVE . The purpose of this study was to evaluate the performance of reduced-dose CT for the detection of lung nodules in children and young adults with cancer. METHODS . This prospective study enrolled patients 4-21 years old with known or suspected malignancy who were undergoing clinically indicated chest CT. Study participants underwent an additional investigational reduced-dose chest CT examination in the same imaging encounter. Separated deidentified CT examinations were reviewed in blinded fashion by three independent radiologists. One reviewer performed a subsequent secondary review to match nodules between the standard- and reduced-dose examinations. Diagnostic performance was computed for the reduced-dose examinations using the clinical examinations as the reference standard. Intraobserver agreement and interobserver agreement were calculated using Cohen kappa. RESULTS . A total of 78 patients (44 male patients and 34 female patients; mean age, 15.2 ± 3.8 [SD] years) were enrolled. The mean estimated effective dose was 1.8 ± 1.1 mSv for clinical CT and 0.3 ± 0.1 mSv for reduced-dose CT, which is an 83% dose reduction. Forty-five of the 78 (58%) patients had 162 total lung nodules (mean size, 3.4 ± 3.3 mm) detected on the clinical CT examinations. A total of 92% of nodules were visible on reduced-dose CT. The sensitivity and specificity of reduced-dose CT for nodules ranged from 63% to 77% and from 80% to 90%, respectively, across the three reviewers. Intraob-server agreement between clinical CT and reduced-dose CT was moderate to substantial for the presence of nodules (κ = 0.45-0.67) and was good to excellent for the number of nodules (κ = 0.68-0.84) and nodule size (κ = 0.69-0.86). Interobserver agreement for the presence of nodules was moderate for both reduced-dose (κ = 0.53) and clinical (κ = 0.54) CT. A median of one nodule was present on clinical CT in patients with a falsely negative reduced-dose CT examination. CONCLUSION . Reduced-dose CT depicts more than 90% of lung nodules in children and young adults with cancer. Reviewers identified the presence of nodules with moderate sensitivity and high specificity. CLINICAL IMPACT . CT performed at a 0.3-mSv mean effective dose has acceptable diagnostic performance for lung nodule detection in children and young adults and has the potential to reduce patient dose or expand CT utilization (e.g., to replace radiography in screening or monitoring protocols). TRIAL REGISTRATION . ClinicalTrials.gov NCT03681873.

Background: Diabetes mellitus (DM) is associated with adverse clinical outcomes and high mortality in patients with coronavirus disease 2019 (COVID-19). The relationship between diabetes and COVID-19 is known to be bidirectional., Aim: To analyze the rate of new-onset diabetes in COVID-19 patients and compare the clinical outcomes of new-onset diabetes, pre-existing diabetes, hyperglycemic, and non-diabetes among COVID-19 patients., Methods: We used the Meta-analysis of Observational Studies in Epidemiology statement for the present meta-analysis. Online databases were searched for all peer-reviewed articles published until November 6, 2020. Articles were screened using Covidence and data extracted. Further analysis was done using comprehensive meta-analysis. Among the 128 studies detected after thorough database searching, seven were included in the quantitative analysis. The proportion was reported with 95% confidence interval (CI) and heterogeneity was assessed using I 2 ., Results: Analysis showed that 19.70% (CI: 10.93-32.91) of COVID-19 patients had associated DM, and 25.23% (CI: 19.07-32.58) had associated hyperglycemia. The overall mortality rate was 15.36% (CI: 12.57-18.68) of all COVID-19 cases, irrespective of their DM status. The mortality rate was 9.26% among non-diabetic patients, 10.59% among patients with COVID-19 associated hyperglycemia, 16.03% among known DM patients, and 24.96% among COVID-19 associated DM patients. The overall occurrence of adverse events was 20.52% (CI: 14.21-28.70) among COVID-19 patients in the included studies, 15.29% among non-diabetic patients, 20.41% among patients with COVID-19 associated hyperglycemia, 20.69% among known DM patients, and 45.85% among new-onset DM. Meta-regression showed an increasing rate of mortality among new hyperglycemic patients, known diabetics, and new-onset DM patients in comparison to those without diabetes., Conclusion: A significantly higher rate of new onset DM and hyperglycemia was observed. Higher mortality rates and adverse events were seen in patients with new-onset DM and hyperglycemia than in the non-diabetic population., Competing Interests: Conflict-of-interest statement: The authors declare that they have no competing interests., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective: To determine the prevalence of underreporting of hepatic steatosis found incidentally on computed tomography (CT)., Study Design: Retrospective cross-sectional study including patients <18 years of age who had undergone unenhanced abdominal CT for evaluation of nephrolithiasis. Hepatic and splenic attenuation were measured independently by 2 reviewers. Hepatic steatosis was defined using various previously established criteria (4 original criteria designed to detect moderate/severe steatosis and 3 secondary criteria designed to identify mild steatosis). Radiology reports and clinical notes were reviewed for documentation of steatosis. Serum alanine aminotransferase levels were collected. Kappa statistics were used to assess agreement between reviewers., Results: A total of 584 patients were included. Agreement between reviewers' measurements for categorical classification of presence of steatosis was excellent (kappa statistic agreement >87%). The prevalence of hepatic steatosis ranged from 3% to 35%, depending on the criterion. Using absolute liver attenuation <48 Hounsfield units (most likely reflective of the truth, given alanine aminotransferase distribution and body mass index data), the prevalence was 7% (n = 42). Steatosis was reported for only 12 of 42 (28%) of these patients and was documented in clinical notes in only 3 of those cases., Conclusions: Hepatic steatosis is underreported as an incidental finding of CT for nephrolithiasis. Given the prevalence and silent nature of nonalcoholic fatty liver disease, a high level of suspicion is needed, so as not to miss the opportunity to identify steatosis in childhood., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Sickle cell anemia (SCA) is an inherited autosomal recessive disease. It is caused due to point mutation that substitutes glutamate with valine at the sixth amino acid position of the beta chain of hemoglobin molecules leading to the sickling of the red blood cells and decreased structural deformability. Silent cerebral infarcts are the most common neurological complication of SCA, while overt stroke comprises substantial burden in patients with SCA. This meta-analysis aimed to find the pooled prevalence of overt stroke in SCA patients and discuss the importance of screening them. PubMed, Embase, and Google Scholar were the electronic databases used to search the studies. A total of 765 articles were retrieved upon detailed searching in the abovementioned databases. After a series of removing duplicate articles, title and abstract screening, and full-text review, 20 articles were found eligible and included in the study. The total number of participants from all the included studies was 3,956, and pooled prevalence of stroke in patients with sickle cell anemia in Asia was found to be 5% (95% CI: 4%, 6%) with a range from 1 to 41%. Stroke occurrence in sickle cell anemia patients is an emergency complication that needs immediate intervention and management. Because of the high prevalence of stroke in patients with sickle cell anemia, clinicians should focus on its prevention and treatment strategies., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Sandip Kuikel et al.)

Background and Aims: Despite the high clinical significance of sarcopenia in alcohol-associated cirrhosis, there are currently no effective therapies because the underlying mechanisms are poorly understood. We determined the mechanisms of ethanol-induced impaired phosphorylation of mechanistic target of rapamycin complex 1 (mTORC1) and adenosine monophosphate-activated protein kinase (AMPK) with consequent dysregulated skeletal muscle protein homeostasis (balance between protein synthesis and breakdown)., Approach and Results: Differentiated murine myotubes, gastrocnemius muscle from mice with loss and gain of function of regulatory genes following ethanol treatment, and skeletal muscle from patients with alcohol-associated cirrhosis were used. Ethanol increases skeletal muscle autophagy by dephosphorylating mTORC1, circumventing the classical kinase regulation by protein kinase B (Akt). Concurrently and paradoxically, ethanol exposure results in dephosphorylation and inhibition of AMPK, an activator of autophagy and inhibitor of mTORC1 signaling. However, AMPK remains inactive with ethanol exposure despite lower cellular and tissue adenosine triphosphate, indicating a "pseudofed" state. We identified protein phosphatase (PP) 2A as a key mediator of ethanol-induced signaling and functional perturbations using loss and gain of function studies. Ethanol impairs binding of endogenous inhibitor of PP2A to PP2A, resulting in methylation and targeting of PP2A to cause dephosphorylation of mTORC1 and AMPK. Activity of phosphoinositide 3-kinase-γ (PI3Kγ), a negative regulator of PP2A, was decreased in response to ethanol. Ethanol-induced molecular and phenotypic perturbations in wild-type mice were observed in PI3Kγ -/- mice even at baseline. Importantly, overexpressing kinase-active PI3Kγ but not the kinase-dead mutant reversed ethanol-induced molecular perturbations., Conclusions: Our study describes the mechanistic underpinnings for ethanol-mediated dysregulation of protein homeostasis by PP2A that leads to sarcopenia with a potential for therapeutic approaches by targeting the PI3Kγ-PP2A axis., (© 2020 by the American Association for the Study of Liver Diseases.)

Background: Electrocardiographic (ECG) characteristics of patients with isolated hypomagnesemia are not well defined. We aimed to investigate these ECG characteristics in order to define clearly the features of isolated hypomagnesemia., Hypothesis: Lower serum magnesium could affect ECG parameters after excluding potential confounders., Methods: This retrospective study was of patients with low serum magnesium <0.65 mmol/L compared with the same patients after restoration to normal serum magnesium. Patients with hypokalemia, hypocalcemia and other electrolyte disturbances were excluded. ECG parameters manually determined and analyzed were P wave dispersion, PR interval, QRS duration, ST-T changes, T wave amplitude, T peak-to-end interval (Tpe), corrected Tpe (Tpec), QT, corrected QT (QTc), QT peak corrected (QTpc) and Tpe dispersion, Tpe/QT ratio., Results: Two-hundred-and-fourteen patients with isolated hypomagnesemia were identified with 50 of them (56.9 ± 13.6 years; 25 males) being eligible for final analysis from 270,997 patients presenting April 2011-October 2017. In the period of isolated hypomagnesemia, P wave duration was found prolonged ( p ≤ 0.02); as was QTc (439 ± 27 vs. 433 ± 22, p = 0.01). Tpec (122 ± 24vs. 111 ± 22, p = 0.000) and Tpe/QT ratio (0.29 ± 0.05 vs. 0.27 ± 0.05, p = 0.000) were increased. QTpc decreased during hypomagnesemia (334 ± 28 vs. 342 ± 21, p = 0.02). However, no significant differences were found in PR interval, QRS duration (85 ± 12 ms vs. 86 ± 12 ms, p = 0.122) and ST-T segments between the patients and their own controls., Conclusions: In patients with isolated hypomagnesemia, P wave duration, QTc, Tpec, and Tpe/QT ratio suggesting atrial depolarization and ventricular repolarization dispersion were significantly increased compared with normal magnesium levels in the same patients after restoration to normal levels., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yang, Chen, Duan, Thapaliya, Gao, Dong, Yin, Yang, Zhang, Tan, Hui, Wang, Sutton and Xia.)

Background: Combined use of furosemide with albumin is an approved therapy to overcome diuretic resistance in treatment of ascites in decompensated chronic liver disease. Bolus dosing of diuretics has its own limitations due to pre-existing hypotension, post diuretic sodium retention and braking phenomenon. Slow albumin and furosemide Infusion has been shown to mobilize large ascites with improved diuresis and hemodynamic stability in decompensated chronic liver disease. This study was undertaken to compare efficacy and safety of infusion therapy vs bolus therapy in term the management of refractory ascites., Methods: Decompensated chronic liver disease patients with refractory ascites were randomly assigned into two groups of 15 each - Bolus therapy (intravenous albumin and furosemide as boluses) and Infusion therapy (furosemide infusion at 2mg/hour and albumin at 2g/hour for three days). Diuresis, natriuresis, change in abdominal girth and body weight, and hemodynamic stability (change in SBP) were compared between the two groups., Results: Infusion therapy, as compared to bolus therapy, showed a significantly better diuresis (mean urinary output increment 483ml vs 243ml, p <0.001), natriuresis (mean urinary sodium excretion increment 35.2 mEq/L vs 16.6 mEq/L, p = 0.004),decrease in abdominal circumference (6.1cm vs 3.0cm, p<0.001) and decrease in body weight (5.53 Kg vs 2.86 Kg, p < 0.001). The complications of renal impairment were also lower in the Infusion group., Conclusion: Infusion of furosemide and albumin is a potential safer and effective therapeutic option in the management of refractory ascites with better natriuresis, higher urine output, and higher decrement in abdominal circumference and body weight, and lesser side effects.