Met World Health Organization Criteria Research Articles

Risk Stratified Treatment for Patients with Newly Diagnosed Juvenile Myelomonocytic Leukemia: A Phase 1/2 Non-Randomized Study of Trametinib and Azacitidine with or without Chemotherapy

Background: Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of childhood. The biochemical hallmark of JMML is aberrant signaling through the Ras pathway caused by initiating mutations in NF1, NRAS, KRAS, RRAS, RRAS2, SH2B3, PTPN11,or CBL. While hematopoietic stem cell transplantation (HSCT) can be curative, 5-year event-free survival of children with JMML after HSCT is only ~50%. Recently, several studies have identified mutational burden and DNA methylation as predictive of clinical outcomes in patients with JMML. In the T2020-004 phase 1/2 clinical trial, we will define lower-risk patients as those with one somatic alteration and low DNA methylation and high-risk patients as those with more than one somatic alteration or intermediate/high DNA methylation. Trametinib is an orally bioavailable, reversible, highly selective allosteric inhibitor of MEK1/2 in the Ras/MAPK signaling pathway. Trametinib is FDA-approved for the treatment of adults with advanced melanoma with BRAF V600E or V600K mutations and in children with Ras-mutant solid tumors in combination with dabrafenib. Clinical investigation of trametinib monotherapy via the Children's Oncology Group ADVL1521 phase 2 trial (NCT03190915) showed efficacy in children with relapsed/refractory JMML. Phase 2 clinical trial evaluation of azacitidine in children with newly-diagnosed JMML was also efficacious and led to its FDA approval. In this trial, trametinib will be tested in combination with azacitidine in lower-risk patients and in combination with azacitidine and chemotherapy for high-risk patients. Study Design and Methods: This is a non-randomized, risk stratified, Phase 1/2 study for patients with newly-diagnosed JMML (NCT05849662) conducted via the Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium with safety and efficacy phases for both lower-risk and high-risk cohorts. Lower-risk patients will receive trametinib once-daily for 28 days in combination with azacitidine administered daily for five days per cycle. Lower-risk patients can receive up to 12 cycles and will proceed to HSCT only if they experience progressive disease or relapse. High-risk patients will receive trametinib administered once-daily for 28 days in combination with azacitidine, fludarabine, and cytarabine (aza/FLA) administered daily for five days per cycle. High-risk patients will receive up to two cycles of therapy before proceeding to HSCT off protocol. Key Eligibility: Patients aged 1 month to 21 years who meet World Health Organization criteria for JMML will be eligible. Objectives: The primary safety objectives are to determine the safety of combining trametinib with azacitidine for lower-risk patients and combining trametinib with aza/FLA for high-risk patients. The secondary efficacy objectives are to determine the event-free survival for lower-risk patients in the absence of HSCT and the molecular response rates pre-HSCT for high-risk patients. Sample Size and Statistical Design: A rolling 6 trial design will be used during Phase 1 of the study to determine the recommended phase II dose (RP2D) of trametinib for lower-risk and high-risk patients in combination with their respective therapies. Starting trametinib dose is 0.032mg/kg daily if less than 6 years of age, or 0.025mg/kg daily if 6 years or older, with one dose level de-escalation if indicated. Phase II of the study involves lower-risk and high-risk cohort expansions at the RP2D of trametinib. Target accrual is 22 patients in the lower-risk arm and 42 patients in the high-risk arm. The study is open to accrual at all TACL consortium sites. We acknowledge the TACL Consortium's scientific contribution to and participation in this study, including participating member institutions, investigators, research teams, and the TACL Operations Center. Novartis Pharmaceuticals Corporation provided the investigative drug in support of this trial. This study is supported by the National Institute of Health, National Cancer Institute (R37CA266550), the Pediatric Cancer Research Foundation, and the Cannonball Kids Cancer Foundation.

A Rare Case of Triple Negative Essential Thrombocythemia Presenting with Splenic Infarction: A Diagnostic Conundrum

Introduction Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by significant thrombocytosis with high propensity for thrombosis formation as well as other vascular complications. Most myeloproliferative neoplasms including ET are associated with Janus kinase ( JAK2) mutation. Other commonly associated mutations include Calreticulin ( CALR) and Myeloproliferative leukemia virus oncogene ( MPL) mutations. About 17% of cases of ET lack mutations in these driver genes. This presents a clinical conundrum for clinicians on initiation of appropriate treatment for these patients. We report a rare presentation of triple-negative ET with splenic infarction. Case Summary A 66-year-old Hispanic female who presented with left sided abdominal pain that gradually worsened over the course of 1 week; she believed it was stomach cramps. Laboratory evaluations were pertinent for platelet counts of 2000 x 10 9/L, hemoglobin level was 10.9 g/dl, and leukocytosis (white blood cell count 13.2k/uL) without left shift. Further work-up with iron studies was unremarkable and molecular studies were negative for BCR-ABL 1, PDGFR alpha/beta, FGFR 1, JAK2 V617F (including exons 12-13), CALR and MPL. A bone marrow biopsy showed an increase in megakaryocytes with some atypical forms with “enlarged size and nuclear hyper lobulation, and mild patchy reticulin fibrosis” suggestive of myeloproliferative neoplasm. Computed Tomography of the abdomen and pelvis with contrast showed evidence of splenic infarct. The patient was started on oral aspirin 81mg and oral hydroxyurea 2000 mg daily. Due to poor response to hydroxyurea and aspirin, she eventually had two cycles of platelet apheresis, and her platelet count improved to 1000 x 10 9/L. A repeat bone marrow biopsy was subsequently done to confirm essential thrombocythemia. At the time of discharge, the patient was asymptomatic and platelet count had decreased to 892 × 10 9/L. Discussion Essential thrombocythemia (ET) is a rare but recognized cause of vascular complications including arterial and venous thrombosis. Triple negative ET is quite uncommon and can pose a great deal of diagnostic challenge which can impact timing of initiation of appropriate therapy. This clinical vignette exemplified the conundrum encountered in making a diagnosis of triple negative ET. Following the World Health Organization (WHO) 2016 criteria for diagnosis of ET, patient has to have all 4 of: sustained platelet counts >450 x 10 9/L, bone marrow biopsy showing increased number of enlarged and mature megakaryocytes with no significant increase or left shift of granulopoiesis or erythropoiesis, presence of driver mutations/clonal markers (including JAK2, CALR and MPL mutations) or absent of evidence of iron deficiency or cause for reactive thrombocytosis and not meeting WHO criteria for Polycythemia vera or other myeloid neoplasms. Our patient met criteria for ET with no driver mutation detected, hence triple negative ET. She was also classified as high-risk ET using the revised International Prognostic Score for Essential Thrombocytopenia (IPSET). Initial work up of this patient was not confirmatory of the essential thrombocythemia due to the bone marrow biopsy not clearly defining features as per WHO stipulations, thus, a more aggressive therapy was not pursued. This can pose a great deal of diagnostic challenge which can impact timing of initiation of appropriate therapy. This is not uncommon especially considering sampling challenge. Studies has shown that early initiation of cytoreductive therapy prophylactically in a high-risk patients can avert vascular complications of ET (including splenic infarction). The index patient responded slowly to platelet apheresis which can be an effective treatment in acute thrombotic complication of ET. Conclusion The diagnosis of triple negative essential thrombocythemia can pose a clinical challenge which impacts effective management of this myeloproliferative neoplasm. There is a dire need for further discussion on this conundrum to provide more applicable recommendations to avert the rare but fatal complications of ET. Platelet apheresis can be an option for emergency treatment in patients presenting with a major vascular complication like splenic infarction.

Abstract 13310: TTN Variants and Arrhythmic Risk Among Countywide Sudden Deaths: From the San Francisco Postmortem Systematic Investigation of Sudden Cardiac Death Study

Background: Titin, encoded by TTN , is a sarcomeric protein necessary for normal cardiac and skeletal muscle function. Truncating variants in the A-band are a frequent cause of isolated and familial dilated cardiomyopathy (DCM) in living cohorts. Whether variants outside of the A-band confer arrhythmic risk remains unclear. We investigated the yield and distribution of TTN variants in a postmortem study of presumed sudden cardiac deaths (pSCDs) in San Francisco County. Methods: From 2/1/2011 to 12/31/2017, the Postmortem Systematic Investigation of Sudden Cardiac Death study performed complete autopsies on 889 incident deaths (age 16-90) meeting World Health Organization criteria for SCD (pSCD). Using clinical records, autopsy findings, and family history, we performed deep phenotyping to adjudicate underlying arrhythmic “SAD” (potentially rescuable with defibrillation) or non-arrhythmic “non-SAD” (tamponade, overdose, etc.) cause of pSCD. We performed clinical whole exome testing on cases with next of kin consent. Results: Of the 322 pSCDs tested (196 SAD, 126 non-SAD), we detected 5 truncating/splice variants located in non-A-band regions (p=0.03 vs. none found in the A-band) in 4 cases, all SAD. No truncating/splice variants were detected in 47 cases with autopsy evidence of DCM (cardiomegaly and short axis > 3.5cm). Overall, 89 cases had at least 1 TTN variant of uncertain significance (VUS): 61 (68.5%) SADs and 28 (31.5%) non-SADs, with a trend towards more TTN VUSs among SADs (p =0.10). A total of 110 VUSs were found: 10 (9.1%) in the Z-disc, 38 (34.5%) in the I-band, 50 (45.5%) in the A-band, and 12 (10.9%) in the M-band. TTN VUSs clustered similarly throughout the gene in SADs and non-SADs. Conclusion: In this 7-year postmortem genetic study of unselected countywide sudden deaths using autopsy to adjudicate arrhythmic cause, we found TTN truncating/splice variants in non-A-band regions were associated with SAD and a trend toward association with SAD among TTN VUS carriers. In contrast to living cohorts with diagnosed DCM, no cases meeting autopsy criteria for DCM had a truncating/splice variant. Since non-survivors (i.e., SCDs) are underrepresented in DCM cohorts, our results suggest a potential role for non-A band TTN variants in arrhythmic risk.

Homelessness and Incidence and Causes of Sudden Death

Over 580 000 people in the US experience homelessness, with one of the largest concentrations residing in San Francisco, California. Unhoused individuals have a life expectancy of approximately 50 years, yet how sudden death contributes to this early mortality is unknown. To compare incidence and causes of sudden death by autopsy among housed and unhoused individuals in San Francisco County. This cohort study used data from the Postmortem Systematic Investigation of Sudden Cardiac Death (POST SCD) study, a prospective cohort of consecutive out-of-hospital cardiac arrest deaths countywide among individuals aged 18 to 90 years. Cases meeting World Health Organization criteria for presumed SCD underwent autopsy, toxicologic analysis, and medical record review. For rate calculations, all 525 incident SCDs in the initial cohort were used (February 1, 2011, to March 1, 2014). For analysis of causes, 343 SCDs (incident cases approximately every third day) were added from the extended cohort (March 1, 2014, to December 16, 2018). Data analysis was performed from July 1, 2022, to July 1, 2023. The main outcomes were incidence and causes of presumed SCD by housing status. Causes of sudden death were adjudicated as arrhythmic (potentially rescuable with implantable cardioverter-defibrillator), cardiac nonarrhythmic (eg, tamponade), or noncardiac (eg, overdose). A total of 868 presumed SCDs over 8 years were identified: 151 unhoused individuals (17.4%) and 717 housed individuals (82.6%). Unhoused individuals compared with housed individuals were younger (mean [SD] age, 56.7 [0.8] vs 61.0 [0.5] years, respectively) and more often male (132 [87.4%] vs 499 [69.6%]), with statistically significant racial differences. Paramedic response times were similar (mean [SD] time to arrival, unhoused individuals: 5.6 [0.4] minutes; housed individuals: 5.6 [0.2] minutes; P = .99), while proportion of witnessed sudden deaths was lower among unhoused individuals compared with housed individuals (27 [18.0%] vs 184 [25.7%], respectively, P = .04). Unhoused individuals had higher rates of sudden death (incidence rate ratio [IRR], 16.2; 95% CI, 5.1-51.2; P < .001) and arrhythmic death (IRR, 7.2; 95% CI, 1.3-40.1; P = .02). These associations remained statistically significant after adjustment for differences in age and sex. Noncardiac causes (96 [63.6%] vs 270 [37.7%], P < .001), including occult overdose (48 [31.8%] vs 90 [12.6%], P < .001), gastrointestinal causes (8 [5.3%] vs 15 [2.1%], P = .03), and infection (11 [7.3%] vs 20 [2.8%], P = .01), were more common among sudden deaths in unhoused individuals. A lower proportion of sudden deaths in unhoused individuals were due to arrhythmic causes (48 of 151 [31.8%] vs 420 of 717 [58.6%], P < .001), including acute and chronic coronary disease. In this cohort study among individuals who experienced sudden death in San Francisco County, homelessness was associated with greater risk of sudden death from both noncardiac causes and arrhythmic causes potentially preventable with a defibrillator.

Cardiometabolic health in adults born with very low birth weight—a sibling study

BackgroundPreterm survivors have increased risk for impaired cardiometabolic health. We assessed glucose regulation and cardiometabolic biomarkers in adult very low birth weight (VLBW, <1500 g) survivors, using siblings as controls.MethodsVLBW-participants were matched with term-born, same-sex siblings. At mean age 29.2 years (SD 3.9), 74 VLBW-adults and 70 siblings underwent a 2-h 75 g oral glucose tolerance test and blood tests for assessment of cardiometabolic biomarkers.ResultsOf participants, 23 (31%) VLBW and 11 (16%) sibling-controls met World Health Organization criteria for impaired glucose regulation (OR adjusted for age and sex 2.5, 95% CI: 1.1 to 5.8).Adjusting for age and sex, VLBW-participants showed 9.2% higher 2-h glucose (95% CI: 0.4% to 18.8%) than their siblings. Also, fasting (13.4%, −0.3% to 29.0%) and 2-h free fatty acids (15.6%, −2.4% to 36.9%) were higher in VLBW-participants. These differences were statistically significant only after further adjusting for confounders. No statistically significant differences were found regarding other measured biomarkers, including insulin resistance, atherogenic lipid profiles or liver tests.ConclusionsVLBW-adults showed more impaired fatty acid metabolism and glucose regulation. Differences in cardiometabolic biomarkers were smaller than in previous non-sibling studies. This may partly be explained by shared familial, genetic, or environmental factors.ImpactAt young adult age, odds for impaired glucose regulation were 3.4-fold in those born at very low birth weight, compared to same-sex term-born siblings.Taking into consideration possible unmeasured, shared familial confounders, we compared cardiometabolic markers in adults born preterm at very low birth weight with term-born siblings.Prematurity increased risk for impaired glucose regulation, unrelated to current participant characteristics, including body mass index.In contrast to previous studies, differences in insulin resistance were not apparent, suggesting that insulin resistance may partially be explained by factors shared between siblings. Also, common cardiometabolic biomarkers were similar within sibling pairs.

Cardiometabolic risk factors in young adults diagnosed with acute myocardial infarction

Abstract Funding Acknowledgements Type of funding sources: None. Background/introduction Morbidity and mortality associated with atherosclerotic cardiovascular diseases are prevalent in young patients. Meanwhile, traditional cardiovascular risk calculators underestimate disease risk in young adults. Purpose To characterize cardiometabolic risk factors and lipid levels in young adults with acute myocardial infarction. Setting: A multicenter, population-based analysis of patients diagnosed at our hospitals in Arizona, as well as our clinic health system spanning Minnesota and Wisconsin. Methods This is a retrospective cohort study including patients 18 to 50 years old diagnosed with acute myocardial infarction from October 1, 2015, to December 31, 2018. Parameters obtained included: Age, sex, ethnicity, body mass index, tobacco use, comorbid medical conditions, fasting blood glucose, hemoglobin A1c, lipid levels, and prescribed lipid-lowering therapy. Results Among 553 young patients diagnosed with acute myocardial infarction, the mean age at the time was 44.4 years, with men accounting for 69.1% of cases. The mean body mass index was 32.2 kg/m2. Hypertension, diabetes mellitus, and tobacco use were present in 64.7%, 25.9%, and 36.2% of patients. Insulin resistance, elevated triglycerides, and low HDL-C were present in 29.8%, 51.0%, and 62.8% of patients, respectively. Approximately 61.3% of patients within this cohort met World Health Organization criteria for diagnosis of metabolic syndrome. Mean LDL-C was 116 mg/dL and mean triglycerides were 190 mg/dL. Statin therapy was prescribed to 92 (16.6%) of patients prior to diagnosis of acute myocardial infarction, whereas 359 (67.3%) of patients met ACC/AHA criteria for lipid-lowering therapy. Within this subgroup receiving statin therapy, the mean serum LDL-C was 101 mg/dl, 26.1% had levels below 70 mg/dL, and 56.5% had LDL-C levels below 100 mg/dL. Thirty-four patients (6.1%) with LDL-C levels greater than 190 mg/dL, and 29 (85.3%) were not on lipid-lowering therapy. Conclusions and Relevance Multiple treatable risk factors were present in most young adults with acute myocardial infarction, including many with LDL-C levels below 100 mg/dL. Being overweight or obese was the most prevalent risk factor, while elevated non-HDL cholesterol was the most common lipid panel abnormality. In addition to known cardiometabolic risk factors, these findings build upon a growing body of evidence implicating triglyceride-rich lipoproteins in non-HDL and remnant cholesterol as an independent risk factor of ASCVD, which were common in this cohort of young patients presenting with myocardial infarction. In this cohort, lipid-lowering therapy was underutilized in young patients with known cardiometabolic risk factors, elevated estimated 10-year ASCVD risk, and individuals with phenotypic Familial Hypercholesterolemia.

A138 SERRATED POLYPOSIS SYNDROME IN INFLAMMATORY BOWEL DISEASE: A SEQUELAE OF CHRONIC DISEASE ACTIVITY OR NEW WHO PHENOTYPE?

Abstract Background Serrated polyposis syndrome (SPS) is a growing health concern with up to 1 in 125 universal screening program participants meeting diagnostic criteria. Conversely, SPS in inflammatory bowel disease (IBD) is rarely described in the literature, despite the predisposition for serrated epithelial change and serrated polyps in this population. Purpose To describe a case of World Health Organization (WHO) criterion I SPS in a patient with IBD, and discuss the existing literature on this rare occurrence. Method Case report and review of the literature. Result(s) Case Report A 53-year-old female with ulcerative colitis (UC; Phenotype: Left-sided; Duration of disease: 40 years; Medical therapy: sulfasalazine) undergoing regular endoscopic surveillance was recently found to have multiple serrated-class lesions including 6 in the sigmoid colon ranging between 8-30mm in size; this included 3 sessile serrated lesions (SSLs) between 20-30mm removed by piecemeal cold snare resection without complication and 2 residual large SSLs for staged endoscopic resection. No endoscopic disease activity was appreciated (Mayo 0), with histopathology of the sigmoid colon and rectum demonstrating chronic inactive colitis. Literature Review From 2008 to 2021, there are eleven reported cases of SPS in IBD. Six patients had UC and most were in remission for several decades at the time of SPS diagnosis. Most SPS cases met WHO criteria and fit within described phenotypes. While the case above meets WHO criterion I for SPS, the presence of large distal lesions is atypical, raising the question of whether chronic disease activity contributed to the development of these serrated lesions, given the known predisposition for serrated epithelial change and serrated lesions in patients with colonic IBD. Image Conclusion(s) SPS in patients with IBD is rare. Questions remain about the role of chronic disease activity contributing to the formation of serrated lesions, its clinical relevance, and optimal management strategy. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared

Tyrosine kinase inhibitors for the treatment of indolent systemic mastocytosis: Are we there yet?

Indolent systemic mastocytosis (ISM) is the most prevalent form of systemic mastocytosis. Many patients with ISM suffer from mast cell (MC) mediator-related symptoms. In a small number of patients, hematologic progression is seen in the follow-up. In some patients with ISM, symptoms arising from MC-derived mediators including gastrointestinal symptoms, anaphylaxis, and neuropsychiatric symptoms are kept under control with conventional mediator-targeting drugs or MC-stabilizing agents. However, in a substantial number of patients, the symptoms are refractory to such conventional therapy. For these patients, novel drugs and targeted approaches are considered. One reasonable approach may be to apply tyrosine kinase inhibitors directed against KIT and other key kinase targets expressed in neoplastic MCs in ISM. Because MCs in more than 90% of all patients with typical ISM display the KIT D816V mutant receptor, clinically effective KIT-targeting drugs have to be active against this mutant form of KIT. The 2 such most effective and well-studied agents currently available are midostaurin and avapritinib. Other KIT-targeting drugs, such as imatinib or masitinib, are less effective or even noneffective against KIT D816V and are thus recommended for use only in patients with other KIT mutant forms (noncodon 816 mutations) or with wild-type KIT. In the present article, we review the current state in the treatment of ISM with tyrosine kinase inhibitors, with special emphasis on treatment responses and potential adverse effects. In fact, all of these agents also have unique and common adverse effects, and their use to treat patients with ISM should be balanced against their toxicity and short- and long-term safety.

Abstract 10914: Refining Genotype-Phenotype Correlations for Post-Mortem Genetic Testing of Sudden Cardiac Death: From the POST SCD Study

Introduction: The POST SCD (POstmortem Systematic InvesTigation of Sudden Cardiac Death) Study is the only prospective unbiased sudden cardiac death (SCD) cohort to use comprehensive postmortem investigation to refine the SCD phenotype to true cardiac and arrhythmic causes. Most postmortem genetic testing focuses on genotypes while tolerating a SCD phenotype that is presumed cardiac. Hypothesis: We hypothesize that a comprehensive postmortem evaluation following presumed SCD will refine genotype-phenotype associations and interpretation of postmortem genetic testing. Methods: The POST SCD study prospectively identified all deaths attributed to out-of-hospital cardiac arrest between 18-90 years of age in San Francisco County between February 2011-March 2014 (20,440 deaths reviewed). Medical record review identified 525 presumed SCDs that met World Health Organization criteria. Comprehensive autopsy, toxicology, and histology ruled out non-arrhythmic causes (overdose, hemorrhage, PE) to arrive at 293 sudden arrhythmic deaths (SADs). In the first 30 SADs with high suspicion for heritable cause, a comprehensive 300-gene cardiac/arrhythmia panel was performed, then whole exome testing in cases with negative or non-contributory panel. Results: By pathologic criteria, the 30 autopsy-defined SADs (21 males [70%], median age 53 years) for genetic testing included dilated cardiomyopathy (37%), hypertrophic cardiomyopathy (HCM; 10%), hypertrophy without pathologic features of HCM (33%), primary electrical disease (10%), arrhythmogenic cardiomyopathy (3%), mitral valve prolapse (3%), or non-compaction (3%). In 3 SADs, we identified 4 pathogenic/likely pathogenic (P/LP) variants in APOB , MYBPC3 , GAA , and TTN , but 3 of 4 ( APOB, GAA , TTN ) were non-contributory to SCD. There were 61 variants of uncertain significance in 24 patients (80%). Further exome testing in 7 SADs identified no compelling variants. Conclusions: Postmortem genetic testing identified P/LP variants in 10% of autopsy-proven SADs with high suspicion for heritable cause, but detailed postmortem phenotyping excluded 75% as non-contributory to SCD. These results highlight the importance of comprehensive autopsy evaluation to refine genotype-phenotype correlations.

Prognosis factors for dengue shock syndrome in children

Background: Varied clinical manifestations, complex pathogenesis, and different viral serotypes make it difficult to predict the course of dengue disease. Many studies have been conducted on the prognostic factors for the occurrence of dengue shock syndrome (SSD), but all use the 2017 World Health Organization (WHO) guidelines. Aim: This study aims to determine the prognostic factors for the occurrence of SSD based on WHO guidelines in 2011. Method: Retrospective study using medical record data of pediatric patients aged 0 to &lt;18 years with a diagnosis of dengue fever dengue (DHF), SSD, and expanded dengue syndrome (EDS) that meet WHO criteria in 2011 at the reputable database from 2017 to December 2020. Independent variables, namely gender, age, nutritional status, secondary dengue infection, leukopenia, abdominal pain, gastrointestinal bleeding, hepatomegaly, and plasma leakage. Shock is the dependent variable. Multivariate analysis using logistic regression analysis. Results: Subjects who met the study criteria were 145 patients, 52 (35.8%) of whom had SSD. Five of 52 SSD patients went into shock during hospitalization. The bivariate analysis yielded significant factors including, malnutrition, overnutrition and obesity, gastrointestinal bleeding, hemoconcentration, ascites, leukocytes 5,000 mm 3, encephalopathy, enzyme elevation heart, and overload. The results of multivariate analysis showed that hemoconcentration variables and elevated liver enzymes were factors of SSD Prognosis. Conclusion: Hemoconcentration and elevated liver enzymes are prognostic factors for SSD.

Use of telehealth in home nutrition support: Challenges and advantages.

Coronavirus disease 2019 (COVID-19), after initially being detected in Wuhan, China in late 2019, quickly spread to most regions of the world, meeting World Health Organization criteria for a pandemic. Social distancing along with other measures implemented to control spread had a drastic impact on the provision of healthcare including deferred elective procedures and surgeries as well as delayed care and evaluation for emergent diagnoses such as heart attacks and strokes. In the home nutrition practice, patients began to delay routine laboratory tests and were canceling or deferring annual visits. Our group soon began to rapidly deploy telehealth to meet the needs of the home nutrition patients. Telehealth is not a new concept with descriptions of healthcare being provided at a distance with the use of telephone in the 1870s. However, widespread adoption has been limited because of regulation (licensure, prescriptions, credentialing, and privileges), lack of reimbursement, as well as adoption and availability of technology needed to carry out telehealth visits. As regulations and limits on reimbursements were waived during COVID-19 pandemic, our home nutrition practice began to evaluate core components of the care we provide for our patients and assess which could be successfully transitioned to telehealth. In addition to the history and regulation of telehealth, the current manuscript provides details regarding successful implementation of telehealth visits such as change management, selection of telehealth platform, scheduling and logistics, as well as carrying out the virtual visit including history and physical exam.

Sudden Cardiac Death and Myocardial Fibrosis, Determined by Autopsy, in Persons with HIV

BackgroundThe incidence of sudden cardiac death and sudden death caused by arrhythmia, as determined by autopsy, in persons with human immunodeficiency virus (HIV) infection has not been clearly established.MethodsBetween February 1, 2011, and September 16, 2016, we prospectively identified all new deaths due to out-of-hospital cardiac arrest among persons 18 to 90 years of age, with or without known HIV infection, for comprehensive autopsy and toxicologic and histologic testing. We compared the rates of sudden cardiac death and sudden death caused by arrhythmia between groups.ResultsOf 109 deaths from out-of-hospital cardiac arrest among 610 unexpected deaths in HIV-positive persons, 48 met World Health Organization criteria for presumed sudden cardiac death; of those, fewer than half (22) had an arrhythmic cause. A total of 505 presumed sudden cardiac deaths occurred between February 1, 2011, and March 1, 2014, in persons without known HIV infection. Observed incidence rates of presumed sudden cardiac death were 53.3 deaths per 100,000 person-years among persons with known HIV infection and 23.7 deaths per 100,000 person-years among persons without known HIV infection (incidence rate ratio, 2.25; 95% confidence interval [CI], 1.37 to 3.70). Observed incidence rates of sudden death caused by arrhythmia were 25.0 and 13.3 deaths per 100,000 person-years, respectively (incidence rate ratio, 1.87; 95% CI, 0.93 to 3.78). Among all presumed sudden cardiac deaths, death due to occult drug overdose was more common in persons with known HIV infection than in persons without known HIV infection (34% vs. 13%). Persons who were HIV-positive had higher histologic levels of interstitial myocardial fibrosis than persons without known HIV infection.ConclusionsIn this postmortem study, the rates of presumed sudden cardiac death and myocardial fibrosis were higher among HIV-positive persons than among those without known HIV infection. One third of apparent sudden cardiac deaths in HIV-positive persons were due to occult drug overdose. (Supported by the National Heart, Lung, and Blood Institute.)

Evaluation of the durability of long\u2010lasting insecticidal nets in Guatemala

BackgroundInsecticide-treated bed nets (ITNs) are widely used for the prevention and control of malaria. In Guatemala, since 2006, ITNs have been distributed free of charge in the highest risk malaria-endemic areas and constitute one of the primary vector control measures in the country. Despite relying on ITNs for almost 15 years, there is a lack of data to inform the timely replacement of ITNs whose effectiveness becomes diminished by routine use.MethodsThe survivorship, physical integrity, insecticide content and bio-efficacy of ITNs were assessed through cross-sectional surveys conducted at 18, 24 and 32 months after a 2012 distribution of PermaNet® 2.0 in a malaria focus in Guatemala. A working definition of ‘LLIN providing adequate protection’ was developed based on the combination of the previous parameters and usage of the net. A total of 988 ITNs were analysed (290 at 18 months, 349 at 24 months and 349 at 32 months).ResultsThe functional survivorship of bed nets decreased over time, from 92% at 18 months, to 81% at 24 months and 69% at 32 months. Independent of the time of the survey, less than 80% of the bed nets that were still present in the household were reported to have been used the night before. The proportion of bed nets categorized as “in good condition” per World Health Organization (WHO) guidelines of the total hole surface area, diminished from 77% to 18 months to 58% at 32 months. The portion of ITNs with deltamethrin concentration less than 10 mg/m2 increased over time. Among the bed nets for which bioassays were conducted, the percentage that met WHO criteria for efficacy dropped from 90% to 18 months to 52% at 32 months. The proportion of long-lasting insecticidal nets (LLINs) providing adequate protection was 38% at 24 months and 21% at 32 months.ConclusionsAt 32 months, only one in five of the LLINs distributed in the campaign provided adequate protection in terms of survivorship, physical integrity, bio-efficacy and usage. Efforts to encourage the community to retain, use, and properly care for the LLINs may improve their impact. Durability assessments should be included in future campaigns.

Factors Predisposing to Survival After Resuscitation for Sudden Cardiac Arrest

BackgroundIn the POST SCD study, the authors autopsied all World Health Organization (WHO)–defined sudden cardiac deaths (SCDs) and found that only 56% had an arrhythmic cause; resuscitated sudden cardiac arrests (SCAs) were excluded because they did not die suddenly. They hypothesized that causes underlying resuscitated SCAs would be similarly heterogeneous. ObjectivesThe aim of this study was to determine the causes and outcomes of resuscitated SCAs. MethodsThe authors identified all out-of-hospital cardiac arrests (OHCAs) from February 1, 2011, to January 1, 2015, of patients aged 18 to 90 years in San Francisco County. Resuscitated SCAs were OHCAs surviving to hospitalization and meeting WHO criteria for suddenness. Underlying cause was determined by comprehensive record review. ResultsThe authors identified 734 OHCAs over 48 months; 239 met SCA criteria, 133 (55.6%) were resuscitated to hospitalization, and 47 (19.7%) survived to discharge. Arrhythmic causes accounted for significantly more resuscitated SCAs overall (92 of 133, 69.1%), particularly among survivors (43 of 47, 91.5%), than WHO-defined SCDs in POST SCD (293 of 525, 55.8%; p < 0.004 for both). Among resuscitated SCAs, arrhythmic cause, ventricular tachycardia/fibrillation initial rhythm, and white race were independent predictors of survival. None of the resuscitated SCAs due to neurologic causes survived. ConclusionsIn this 4-year countywide study of OHCAs, only one-third were sudden, of which one-half were resuscitated to hospitalization and 1 in 5 survived to discharge. Arrhythmic cause predicted survival and nearly one-half of nonsurvivors had nonarrhythmic causes, suggesting that SCA survivors are not equivalent to SCDs. Early identification of nonarrhythmic SCAs, such as neurologic emergencies, may be a target to improve OHCA survival.

Randomized Trial of Amoxicillin for Pneumonia in Pakistan

BackgroundThe World Health Organization (WHO) recommends oral amoxicillin for patients who have pneumonia with tachypnea, yet trial data indicate that not using amoxicillin to treat this condition may be noninferior to using amoxicillin.MethodsWe conducted a double-blind, randomized, placebo-controlled noninferiority trial involving children at primary health care centers in low-income communities in Karachi, Pakistan. Children who were 2 to 59 months of age and who met WHO criteria for nonsevere pneumonia with tachypnea were randomly assigned to a 3-day course of a suspension of amoxicillin (the active control) of 50 mg per milliliter or matched volume of placebo (the test regimen), according to WHO weight bands (500 mg every 12 hours for a weight of 4 to <10 kg, 1000 mg every 12 hours for a weight of 10 to <14 kg, or 1500 mg every 12 hours for a weight of 14 to <20 kg). The primary outcome was treatment failure during the 3-day course of amoxicillin or placebo. The prespecified noninferiority margin was 1.75 percentage points.ResultsFrom November 9, 2014, through November 30, 2017, a total of 4002 children underwent randomization (1999 in the placebo group and 2003 in the amoxicillin group). In the per-protocol analysis, the incidence of treatment failure was 4.9% among placebo recipients (95 of 1927 children) and 2.6% among amoxicillin recipients (51 of 1929 children) (between-group difference, 2.3 percentage points; 95% confidence interval [CI], 0.9 to 3.7). Results were similar in the intention-to-treat analysis. The presence of fever and wheeze predicted treatment failure. The number needed to treat to prevent one treatment failure was 44 (95% CI, 31 to 80). One patient (<0.1%) in each group died. Relapse occurred in 40 children (2.2%) in the placebo group and in 58 children (3.1%) in the amoxicillin group.ConclusionsAmong children younger than 5 years of age with nonsevere pneumonia, the frequency of treatment failure was higher in the placebo group than in the amoxicillin group, a difference that did not meet the noninferiority margin for placebo. (Funded by the Joint Global Health Trials Scheme [of the Department for International Development, Medical Research Council, and Wellcome] and others; RETAPP ClinicalTrials.gov number, NCT02372461.)

Characteristics and Outcomes of 241 Births to Women With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection at Five New York City Medical Centers.

To describe the characteristics and birth outcomes of women with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as community spread in New York City was detected in March 2020. We performed a prospective cohort study of pregnant women with laboratory-confirmed SARS-CoV-2 infection who gave birth from March 13 to April 12, 2020, identified at five New York City medical centers. Demographic and clinical data from delivery hospitalization records were collected, and follow-up was completed on April 20, 2020. Among this cohort (241 women), using evolving criteria for testing, 61.4% of women were asymptomatic for coronavirus disease 2019 (COVID-19) at the time of admission. Throughout the delivery hospitalization, 26.5% of women met World Health Organization criteria for mild COVID-19, 26.1% for severe, and 5% for critical. Cesarean birth was the mode of delivery for 52.4% of women with severe and 91.7% with critical COVID-19. The singleton preterm birth rate was 14.6%. Admission to the intensive care unit was reported for 17 women (7.1%), and nine (3.7%) were intubated during their delivery hospitalization. There were no maternal deaths. Body mass index (BMI) 30 or higher was associated with COVID-19 severity (P=.001). Nearly all newborns tested negative for SARS-CoV-2 infection immediately after birth (97.5%). During the first month of the SARS-CoV-2 outbreak in New York City and with evolving testing criteria, most women with laboratory-confirmed infection admitted for delivery did not have symptoms of COVID-19. Almost one third of women who were asymptomatic on admission became symptomatic during their delivery hospitalization. Obesity was associated with COVID-19 severity. Disease severity was associated with higher rates of cesarean and preterm birth.

The therapeutic efficacy of 177Lu-DOTATATE/DOTATOC in advanced neuroendocrine tumors

Background:Somatostatin analog therapies showed great potential for patients suffering advanced neuroendocrine tumors (NETs). This study was aimed to evaluate the therapeutic efficacy of 177Lu-DOTATATE/DOTATOC (177Lu-octreotate/octreotide) peptide receptor radionuclide therapy (PRRT) in advanced or inoperable NETs patients.Methods:Pubmed, Web of Science, Embase and Cochrane Library were searched from 1950 to April 2019. Eligible studies should include randomized or nonrandomized controlled trials (RCTs)-based investigations of 177Lu-octreotate/octreotide PRRT for NETs. All these studies were assessed with Response Evaluation Criteria in Solid Tumors (RECIST), RECIST 1.1, Southwest Oncology Group (SWOG) criteria or World Health Organization (WHO) criteria. Disease response rates (DRRs) and disease control rates (DCRs) were calculated according to each response criteria group. DRRs were defined as the percentages of patients with complete response (CR) + partial response (PR), while DCRs represented the percentages of patients with CR+ PR+ stable disease (SD). The pooled proportions were calculated with either a fixed-effects model or a random-effects model depending on the test for heterogeneity.Results:A total of 22 studies (1758 patients) were included in this meta-analysis: 8 studies with 478 patients met RECIST criteria, 10 studies with 1127 patients met RECIST 1.1 criteria, 5 studies with 459 patients met SWOG criteria, and 1 study with 40 patients met WHO criteria, and among these articles 1 study met both RECIST and RECIST 1.1 criteria and 1 met both RECIST 1.1 and SWOG criteria. The pooled DRRs were 33.0% (95% CI: 25.0%-42.0%, I2 = 65%), 35.0% (95% CI: 26.0%-45.0%, I2 = 91%) and 25.0% (95% CI: 14.0%-36.0%, I2 = 84%) according to RECIST, RECIST 1.1 and SWOG criteria, respectively. The pooled DCRs were 79.0% (95% CI: 75.0%-83.0%, I2 = 97%), 83.0% (95% CI: 78.0%-88.0%, I2 = 0) and 82.0% (95% CI: 75.0%-89.0%, I2 = 91%), respectively.Conclusion:In advanced NETs patients, DRRs and DCRs were significantly elevated after initial treatment with 177Lu-DOTATATE PRRT, which shows that this treatment would be beneficial and promising for advanced or inoperable NETs patients.

Standardised shorter regimens versus individualised longer regimens for rifampin- or multidrug-resistant tuberculosis.

We sought to compare the effectiveness of two World Health Organization (WHO)-recommended regimens for the treatment of rifampin- or multidrug-resistant (RR/MDR) tuberculosis (TB): a standardised regimen of 9-12 months (the "shorter regimen") and individualised regimens of ≥20 months ("longer regimens").We collected individual patient data from observational studies identified through systematic reviews and a public call for data. We included patients meeting WHO eligibility criteria for the shorter regimen: not previously treated with second-line drugs, and with fluoroquinolone- and second-line injectable agent-susceptible RR/MDR-TB. We used propensity score matched, mixed effects meta-regression to calculate adjusted odds ratios and adjusted risk differences (aRDs) for failure or relapse, death within 12 months of treatment initiation and loss to follow-up.We included 2625 out of 3378 (77.7%) individuals from nine studies of shorter regimens and 2717 out of 13 104 (20.7%) individuals from 53 studies of longer regimens. Treatment success was higher with the shorter regimen than with longer regimens (pooled proportions 80.0% versus 75.3%), due to less loss to follow-up with the former (aRD -0.15, 95% CI -0.17- -0.12). The risk difference for failure or relapse was slightly higher with the shorter regimen overall (aRD 0.02, 95% CI 0-0.05) and greater in magnitude with baseline resistance to pyrazinamide (aRD 0.12, 95% CI 0.07-0.16), prothionamide/ethionamide (aRD 0.07, 95% CI -0.01-0.16) or ethambutol (aRD 0.09, 95% CI 0.04-0.13).In patients meeting WHO criteria for its use, the standardised shorter regimen was associated with substantially less loss to follow-up during treatment compared with individualised longer regimens and with more failure or relapse in the presence of resistance to component medications. Our findings support the need to improve access to reliable drug susceptibility testing.

Children with Congenital Heart Disease Are Active but Need to Keep Moving: A Cross-Sectional Study Using Wrist-Worn Physical Activity Trackers

To compare daily physical activity of children with congenital heart disease (CHD) with healthy peers measured using wearables bracelets in a large cohort. Additionally, subjectively estimated and objectively measured physical activity was compared. From September 2017 to May 2019, 162 children (11.8±3.2years; 60 girls) with various CHD participated in a self-estimated and wearable-based physical activity assessment. Step-count and moderate-to-vigorous physical activity were recorded with the Garminvivofit jr. for 7 consecutive days and compared with a reference cohort (RC) of 96 healthy children (10.9±3.8years; 49 girls). Children with CHD were active and 123 (75.9%) achieved 60minutes physical activity on a weekly average according to the World Health Organization criteria as 81 (84.3%) of the healthy peers did (P=.217). After correction for age, sex, and seasonal effects, only slightly lower step count (CHD: 10 206±3178 steps vs RC: 11 142±3136 steps; P=.040) but no lower moderate-to-vigorous physical activity (CHD: 80.5±25.6minutes/day vs RC: 81.5±25.3minutes/day; P=.767) occurred comparing CHD with RC. In children with CHD higher age (P=.004), overweight or obesity (P=.016), complex severity (P=.046), and total cavopulmonary connection (P=.027) were associated with not meeting World Health Organization criteria. Subjective estimation of daily moderate-to-vigorous physical activity was fairly correct in half of all children with CHD. Even though the majority is sufficiently active, physical activity needs to be promoted in overweight or obese patients, patients with complex CHD severity, and in particular in those with total cavopulmonary connection.

Characterisation of children hospitalised with pneumonia in central Vietnam: a prospective study.

Pneumonia is the most common reason for paediatric hospital admission in Vietnam. The potential value of using the World Health Organization (WHO) case management approach in Vietnam has not been documented.We performed a prospective descriptive study of all children (2-59 months) admitted with "pneumonia" (as assessed by the admitting clinician) to the Da Nang Hospital for Women and Children to characterise their disease profiles and assess risk factors for an adverse outcome. The disease profile was classified using WHO pneumonia criteria, with tachypnoea or chest indrawing as defining clinical signs. Adverse outcome was defined as death, intensive care unit admission, tertiary care transfer or hospital stay >10 days.Of 4206 admissions, 1758 (41.8%) were classified as "no pneumonia" using WHO criteria and only 252 (6.0%) met revised criteria for "severe pneumonia". The inpatient death rate was low (0.4% of admissions) with most deaths (11 out of 16; 68.8%) occurring in the "severe pneumonia" group. An adverse outcome was recorded in 18.7% of all admissions and 60.7% of the "severe pneumonia" group. Children were hospitalised for a median of 7 days at an average cost of 253 USD per admission. Risk factors for adverse outcome included WHO-classified "severe pneumonia", age <1 year, low birth weight, previous recent admission with an acute respiratory infection and recent tuberculosis exposure. Breastfeeding, day-care attendance and pre-admission antibiotic use were associated with reduced risk.Few hospital admissions met WHO criteria for "severe pneumonia", suggesting potential unnecessary hospitalisation and use of intravenous antibiotics. Better characterisation of the underlying diagnosis requires careful consideration.