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OBJECTIVE The pediatric sepsis literature lacks studies examining the inpatient setting, yet sepsis remains a leading cause of death in children’s hospitals. More information is needed about sepsis arising in patients already hospitalized to improve morbidity and mortality outcomes. This study describes the clinical characteristics, process measures, and outcomes of inpatient sepsis cases compared with emergency department (ED) sepsis cases within the Improving Pediatric Sepsis Outcomes data registry from 46 hospitals that care for children. METHODS This retrospective cohort study included Improving Pediatric Sepsis Outcomes sepsis cases from January 2017 to December 2019 with onset in inpatient or ED. We used descriptive statistics to compare inpatient and ED sepsis metrics and describe inpatient sepsis outcomes. RESULTS The cohort included 26 855 cases; 8.4% were inpatient and 91.6% were ED. Inpatient cases had higher sepsis-attributable mortality (2.0% vs 1.4%, P = .025), longer length of stay after sepsis recognition (9 vs 5 days, P <.001), more intensive care admissions (57.6% vs 54.1%, P = .002), and greater average vasopressor use (18.0% vs 13.6%, P <.001) compared with ED. In the inpatient cohort, >40% of cases had a time from arrival to recognition within 12 hours. In 21% of cases, this time was >96 hours. Improved adherence to sepsis treatment bundles over time was associated with improved 30-day sepsis-attributable mortality for inpatients with sepsis. CONCLUSIONS Inpatient sepsis cases had longer lengths of stay, more need for intensive care, and higher vasopressor use. Sepsis-attributable mortality was significantly higher in inpatient cases compared with ED cases and improved with improved sepsis bundle adherence.

ImportanceFalls and fractures are frequent and deleterious to the health of older people. Aspirin has been reported to reduce bone fragility and slow bone loss.ObjectiveTo determine if daily low-dose aspirin (100 mg) reduces the risk of fractures or serious falls (fall-related hospital presentations) in healthy older men and women.Design, Setting, and ParticipantsThis substudy of a double-blind, randomized, placebo-controlled trial studied older adult men and women in 16 major sites across southeastern Australia. The ASPREE-FRACTURE substudy was conducted as part of the Australian component of the ASPREE trial. Between 2010 and 2014 healthy (free of cardiovascular disease, dementia or physical disability), community-dwelling volunteers aged 70 years or older were recruited to participate in the ASPREE trial. Potentially eligible participants were identified by medical practitioners and trial personnel and were then sent a letter of invitation to participate. Interested participants were screened for suitability. Eligible participants with medical practitioner authorization and adherent to a 4-week run-in medication trial were randomized. Data were analyzed from October 17, 2019, to August 31, 2022.InterventionsParticipants in the intervention group received a daily dose of oral 100 mg enteric-coated (low-dose) aspirin. The control group received a daily identical enteric-coated placebo tablet.Main Outcomes and MeasuresThe primary outcome of ASPREE-FRACTURE was the occurrence of any fracture. The secondary outcome was serious fall resulting in hospital presentation.ResultsIn total, 16 703 people with a median (IQR) age of 74 (72-78) years were recruited, and 9179 (55.0%) were women. There were 8322 intervention participants and 8381 control participants included in the primary and secondary outcome analysis of 2865 fractures and 1688 serious falls over the median follow-up of 4.6 years. While there was no difference in the risk of first fracture between the intervention and control participants (hazard ratio, 0.97; 95% CI, 0.87-1.06; P = .50), aspirin was associated with a higher risk of serious falls (total falls 884 vs 804; incidence rate ratio, 1.17; 95% CI, 1.03-1.33; P = .01). Results remained unchanged in analyses that adjusted for covariates known to influence fracture and fall risk.Conclusions and RelevanceIn this substudy of a randomized clinical trial, the failure of low-dose aspirin to reduce the risk of fractures while increasing the risk of serious falls adds to evidence that this agent provides little favorable benefit in a healthy, White older adult population.Trial RegistrationThis substudy is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615000347561).

PURPOSE To describe a newly established international registry recruiting diverse patients with advanced prostate cancer across academic and community practices to address unmet needs in this population. PATIENTS AND METHODS Initiated in 2017, IRONMAN (International Registry for Men with Advanced Prostate Cancer) is a prospective cohort of patients with advanced prostate cancer. The study will enroll 5,000 patients with metastatic hormone-sensitive prostate cancer (mHSPC) or castration-resistant prostate cancer (CRPC), recruited from Australia, the Bahamas, Barbados, Brazil, Canada, Ireland, Jamaica, Kenya, Nigeria, Norway, South Africa, Spain, Sweden, Switzerland, the United Kingdom, and the United States. The study is collecting datatypes to study variation in care and treatment of advanced prostate cancer across countries and across academic, community-based, and government practices with a focus on clinical outcomes, patient-reported outcomes, epidemiologic data, biologic subtypes, and clinician questionnaires. RESULTS Through July 2022, 2,682 eligible patients were enrolled in 11 of 12 active countries. Sixty-six percent of patients have mHSPC, and 34% have CRPC. On the basis of self-report, 11% of patients are Black and 9% are Hispanic. Five Veterans Affairs Medical Centers are enrolling patients. Globally, 23% of patients report being veterans of military service. CONCLUSION To our knowledge, this is the first international cohort of people newly diagnosed with advanced prostate cancer designed to describe variations in patient management, experiences, and outcomes. IRONMAN aims to identify optimal treatment sequences to improve survival, understand patient-reported outcomes, and explore novel biomarkers to understand treatment resistance mechanisms. Insights from IRONMAN will inform and guide future clinical management of people with mHSPC and CRPC. This cohort study will provide real-world evidence to facilitate a better understanding of the survivorship of people with advanced prostate cancer.

ImportanceCytokine storm due to COVID-19 can cause high morbidity and mortality and may be more common in patients with cancer treated with immunotherapy (IO) due to immune system activation.ObjectiveTo determine the association of baseline immunosuppression and/or IO-based therapies with COVID-19 severity and cytokine storm in patients with cancer.Design, Setting, and ParticipantsThis registry-based retrospective cohort study included 12 046 patients reported to the COVID-19 and Cancer Consortium (CCC19) registry from March 2020 to May 2022. The CCC19 registry is a centralized international multi-institutional registry of patients with COVID-19 with a current or past diagnosis of cancer. Records analyzed included patients with active or previous cancer who had a laboratory-confirmed infection with SARS-CoV-2 by polymerase chain reaction and/or serologic findings.ExposuresImmunosuppression due to therapy; systemic anticancer therapy (IO or non-IO).Main Outcomes and MeasuresThe primary outcome was a 5-level ordinal scale of COVID-19 severity: no complications; hospitalized without requiring oxygen; hospitalized and required oxygen; intensive care unit admission and/or mechanical ventilation; death. The secondary outcome was the occurrence of cytokine storm.ResultsThe median age of the entire cohort was 65 years (interquartile range [IQR], 54-74) years and 6359 patients were female (52.8%) and 6598 (54.8%) were non-Hispanic White. A total of 599 (5.0%) patients received IO, whereas 4327 (35.9%) received non-IO systemic anticancer therapies, and 7120 (59.1%) did not receive any antineoplastic regimen within 3 months prior to COVID-19 diagnosis. Although no difference in COVID-19 severity and cytokine storm was found in the IO group compared with the untreated group in the total cohort (adjusted odds ratio [aOR], 0.80; 95% CI, 0.56-1.13, and aOR, 0.89; 95% CI, 0.41-1.93, respectively), patients with baseline immunosuppression treated with IO (vs untreated) had worse COVID-19 severity and cytokine storm (aOR, 3.33; 95% CI, 1.38-8.01, and aOR, 4.41; 95% CI, 1.71-11.38, respectively). Patients with immunosuppression receiving non-IO therapies (vs untreated) also had worse COVID-19 severity (aOR, 1.79; 95% CI, 1.36-2.35) and cytokine storm (aOR, 2.32; 95% CI, 1.42-3.79).Conclusions and RelevanceThis cohort study found that in patients with cancer and COVID-19, administration of systemic anticancer therapies, especially IO, in the context of baseline immunosuppression was associated with severe clinical outcomes and the development of cytokine storm.Trial RegistrationClinicalTrials.gov Identifier: NCT04354701

AbstractAutosomal dominant polycystic kidney disease (ADPKD) is driven by mutations in the PKD1 and PKD2 genes, and it is characterized by renal cyst formation, inflammation and fibrosis. Forkhead box protein M1 (FoxM1), a transcription factor of the Forkhead box (Fox) protein super family, has been reported to promote tumor formation, inflammation and fibrosis in many organs. However, the role and mechanism of FoxM1 in regulation of ADPKD progression is still poorly understood. Here, we show that FoxM1 is an important regulator of cyst growth in ADPKD. FoxM1 is upregulated in cyst-lining epithelial cells in Pkd1 mutant mouse kidneys and human ADPKD kidneys. FoxM1 promotes cystic renal epithelial cell proliferation by increasing the expression of Akt and Stat3 and the activation of ERK and Rb. FoxM1 also regulates cystic renal epithelial cell apoptosis through NF-κB signaling pathways. In addition, FoxM1 regulates the recruitment and retention of macrophages in Pkd1 mutant mouse kidneys, a process that is associated with FoxM1-mediated upregulation of monocyte chemotactic protein 1. Targeting FoxM1 with its specific inhibitor, FDI-6, delays cyst growth in rapidly progressing and slowly progressing Pkd1 mutant mouse kidneys. This study suggests that FoxM1 is a central and upstream regulator of ADPKD pathogenesis and provides a rationale for targeting FoxM1 as a therapeutic strategy for ADPKD treatment.

Abstract Background Patients taking chronic opioids are at high risk of opioid induced adrenal insufficiency (OIAI). Previously, we showed that the prevalence of OIAI was 9% based on low morning cortisol, corticotropin (ACTH), and dehydroepiandrosterone sulfate (DHEAS). Data on the overnight metyrapone test to diagnose OIAI are sparse. We aimed to determine the prevalence of OIAI using overnight metyrapone test and identify changes in the steroid metabolome of patients treated with opioids. Methods Cross-sectional study of adult patients treated with opioid therapy of at least 20 morphine milligram equivalents (MME)/day for at least 3 months. Measurements included ACTH, cortisol, and DHEAS. Overnight metyrapone test was administered in all patients, and 24h urine steroid profiling was optional (25 steroids measured by liquid chromatography mass spectrometry1). All patients completed the quality-of-life survey (AddiQoL). Prevalence of OIAI was defined as sum of post-metyrapone 11-deoxycortisol and cortisol of <15 mcg/dL. Result: In 22 patients (median age 59 years [range, 38-74], 9, 41% women), median MME was 33 (20-161) mg, and median cumulative opioid exposure was 245 (10-2550) mg*years. Following the overnight metyrapone test, 7 (32%) patients were diagnosed with OIAI. Patients with OIAI had lower DHEAS concentrations (median of 21 mcg/dL[ 5-113] vs 54 [22-173], p =0. 03), but not cortisol (median 10[5.3-16] mcg/dL vs 13[5.3-22], p=0. 06) or ACTH (median 27[8.1-51] pg/mL vs 26[5.9-55], p=0.8). Patients with OIAI were treated with higher daily MME (100 mg[30-150] vs 30[20-161], p=0. 03) and had a higher cumulative exposure to opioids (median, 660 mg*years [250-2250] vs 150 [10-1288], p =0. 01). AddiQol scores were similar between groups (median of 68[56-84] vs 73[48-83], p= 0.97). Urine steroid profiling was performed in 18 patients. Patients with OIAI demonstrated 4 times lower total urine glucocorticoids (16334 mcg/24h vs 4377 mcg/24h, p=0. 003), all <10% of the reference range, and 3 times lower total urinary androgens (median of 805 mcg/24h vs 2320 mcg/24h, p=0.14). Conclusion Prevalence of OIAI using overnight metyrapone test is high at 32%. Patients diagnosed with OIAI were treated with higher doses of MME/day and had a higher cumulative exposure to opioids when compared to those without OIAI. Applying 24h urine steroid profiling we showed that total glucocorticoids are 4 times lower in those with OIAI (and all <10% of reference ranges) as opposed to those without OIAI. We showed that baseline measurements of ACTH, DHEAS, and cortisol may incorrectly exclude OIAI, and a dynamic test, such as overnight metyrapone test is needed when suspicion for OIAI is high. | 1. Hines JM, Bancos I, Bancos C, et al. High-Resolution, Accurate-Mass (HRAM) Mass Spectrometry Urine Steroid Profiling in the Diagnosis of Adrenal Disorders. Clin Chem. 2017;63(12): 1824-1835. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

The majority of congenital cardiovascular disease including structural cardiac defects, abnormalities in cardiac function, and rhythm disturbances can be identified prenatally using screening obstetrical ultrasound with referral for fetal echocardiogram when indicated. Diagnosis of congenital heart disease in the fetus should prompt assessment for extracardiac abnormalities and associated genetic abnormalities once parental consent is obtained. Pediatric cardiologists, in conjunction with maternal-fetal medicine, neonatology, and cardiothoracic surgery subspecialists, should counsel families about the details of the congenital heart defect as well as prenatal and postnatal management. Prenatal diagnosis often leads to increased maternal depression and anxiety; however, it decreases morbidity and mortality for many congenital heart defects by allowing clinicians the opportunity to optimize prenatal care and plan delivery based on the specific lesion. Changes in prenatal care can include more frequent assessments through the remainder of the pregnancy, maternal medication administration, or, in selected cases, in utero cardiac catheter intervention or surgical procedures to optimize postnatal outcomes. Delivery planning may include changing the location, timing or mode of delivery to ensure that the neonate is delivered in the most appropriate hospital setting with the required level of hospital staff for immediate postnatal stabilization. Based on the specific congenital heart defect, prenatal echocardiogram assessment in late gestation can often aid in predicting the severity of postnatal instability and guide the medical or interventional level of care needed for immediate postnatal intervention to optimize the transition to postnatal circulation.

Abstract Background Pfizer-BioNTech COVID-19 vaccine received emergency use authorization for persons ≥ 16 years in December 2020 and for adolescents 12–15 years in May 2021. Despite the clear benefits and favorable safety profile, vaccine uptake in adolescents has been suboptimal. We sought to assess factors associated with COVID-19 non-vaccination in adolescents 12–18 years of age. Methods Between June 1, 2021 and April 29, 2022, we assessed factors associated with COVID-19 non-vaccination in hospitalized adolescents ages 12–18 years enrolled in the Overcoming COVID-19 vaccine effectiveness network. Demographic characteristics and clinical information were captured through parent interviews and/or electronic medical record abstraction; COVID-19 vaccination was assessed through documented sources. We assessed associations between receipt of the COVID-19 vaccine and demographic and clinical factors using univariate and multivariable logistic regression and estimated adjusted odds ratios (aOR) for each factor associated with non-vaccination. Results Among 1665 hospitalized adolescents without COVID-19, 56% were unvaccinated. Unvaccinated adolescents were younger (median age 15.1 years vs. 15.4 years, p < .01) and resided in areas with higher social vulnerability index (SVI) scores (median 0.6 vs 0.5, p < .001) than vaccinated adolescents. Residence in the Midwest [aOR 2.60 (95% CI: 1.80, 3.79)] or South [aOR 2.49 (95% CI: 1.77, 3.54)] US census regions, rarely or never receiving influenza vaccine [aOR 5.31 (95% CI: 3.81, 7.47)], and rarely or never taking precautions against COVID-19 [aOR 3.17 (95% CI: 1.94, 5.31)] were associated with non-vaccination against COVID-19. Conclusions Efforts to increase COVID-19 vaccination of adolescents should focus on persons with geographic, socioeconomic, and medical risk factors associated with non-vaccination.

Background: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. Methods: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. Results: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. Conclusions: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

Background Cardiac complications related to COVID‐19 in children and adolescents include ventricular dysfunction, myocarditis, coronary artery aneurysm, and bradyarrhythmias, but tachyarrhythmias are less understood. The goal of this study was to evaluate the frequency, characteristics, and outcomes of children and adolescents experiencing tachyarrhythmias while hospitalized for acute severe COVID‐19 or multisystem inflammatory syndrome in children. Methods and Results This study involved a case series of 63 patients with tachyarrhythmias reported in a public health surveillance registry of patients aged <21 years hospitalized from March 15, 2020, to December 31, 2021, at 63 US hospitals. Patients with tachyarrhythmias were compared with patients with severe COVID‐19–related complications without tachyarrhythmias. Tachyarrhythmias were reported in 22 of 1257 patients (1.8%) with acute COVID‐19 and 41 of 2343 (1.7%) patients with multisystem inflammatory syndrome in children. They included supraventricular tachycardia in 28 (44%), accelerated junctional rhythm in 9 (14%), and ventricular tachycardia in 38 (60%); >1 type was reported in 12 (19%). Registry patients with versus without tachyarrhythmia were older (median age, 15.4 [range, 10.4–17.4] versus 10.0 [range, 5.4–14.8] years) and had higher illness severity on hospital admission. Intervention for treatment of tachyarrhythmia was required in 37 (59%) patients and included antiarrhythmic medication (n=31, 49%), electrical cardioversion (n=11, 17%), cardiopulmonary resuscitation (n=8, 13%), and extracorporeal membrane oxygenation (n=9, 14%). Patients with tachyarrhythmias had longer hospital length of stay than those who did not, and 9 (14%) versus 77 (2%) died. Conclusions Tachyarrhythmias were a rare complication of acute severe COVID‐19 and multisystem inflammatory syndrome in children and adolescents and were associated with worse clinical outcomes, highlighting the importance of close monitoring, aggressive treatment, and postdischarge care.