Identification of Novel Potent NSD2-PWWP1 Ligands Using Structure-Based Design and Computational Approaches.

Dysregulation of histone methyl transferase nuclear receptor-binding SET domain 2 (NSD2) has been implicated in several hematological and solid malignancies. NSD2 is a large multidomain protein that carries histone writing and histone reading functions. To date, identifying inhibitors of the enzymatic activity of NSD2 has proven challenging in terms of potency and SET domain selectivity. Inhibition of the NSD2-PWWP1 domain using small molecules has been considered as an alternative approach to reduce NSD2-unregulated activity. In this article, we present novel computational chemistry approaches, encompassing free energy perturbation coupled to machine learning (FEP/ML) models as well as virtual screening (VS) activities, to identify high-affinity NSD2 PWWP1 binders. Through these activities, we have identified the most potent NSD2-PWWP1 binder reported so far in the literature: compound 34 (pIC50 = 8.2). The compounds identified herein represent useful tools for studying the role of PWWP1 domains for inhibition of human NSD2.

Impact of medication dosage on Helicobacter pylori eradication rates among pediatric patients.

OBJECTIVES: Helicobacter pylori rates of eradication to common first-line regimens continue to decline globally. Prescription of the appropriate medication dosage is an important consideration, particularly in the pediatric population due to medication weight-based dosing. Limited data is available on the impact of guideline-recommended weight-based dosing on the successful eradication of H. pylori in children. METHODS: Retrospective study of patients with histologic evidence of H. pylori from two pediatric tertiary care centers in New England. We excluded patients who were not treated or those missing eradication data. We compared the eradication rates of patients prescribed recommended weight-based dosages, duration, and frequency of treatment with those who were not. RESULTS: One hundred forty-four patients were included. The overall eradication rate was 73.6% (106/144). All treatment regimens were properly prescribed for 14 days. There was a high rate of improper weight-based dosing: proton pump inhibitor (PPI) 31.2% (45/144), amoxicillin 31.7% (39/123), metronidazole (MET) 19.4% (12/62), clarithromycin (CLA) 23.9% (22/70), tetracycline 50% (6/12), bismuth 26.1% (6/23). When PPIs were properly weight-dosed, there was a 78.8% eradication rate that dropped to 62.2% with suboptimal dosing (p = 0.036, OR: 2.26, CI: 1.04-4.87). When amoxicillin was properly weight-dosed, successful eradication was achieved in 81% versus only 53.8% when improperly dosed (p = 0.002; OR: 3.64, CI: 1.58-8.37). There was no statistically significant impact on eradication rates with improper weight-based dosing of MET, CLA, tetracycline, or bismuth. CONCLUSION: Proper weight-based dosing of amoxicillin and PPI is important for the successful eradication of H. pylori among children in the New England area.

Implementation of point-of-care molecular testing for respiratory viruses in congregate living settings.

OBJECTIVE: To implement and evaluate a point-of-care (POC) molecular testing platform for respiratory viruses in congregate living settings (CLS). DESIGN: Prospective quality improvement study. SETTING: Seven CLS, including three nursing homes and four independent-living facilities. PARTICIPANTS: Residents of CLS. METHODS: A POC platform for COVID-19, influenza A and B, and respiratory syncytial virus was implemented at participating CLS from December 1, 2022 to April 15, 2023. Residents with respiratory symptoms underwent paired testing, with respiratory specimens tested first with the POC platform and then delivered to an off-site laboratory for multiplex respiratory virus panel (MRVP) polymerase chain reaction (PCR) as per standard protocol. Turn-around time and diagnostic accuracy of the POC platform were compared against MRVP PCR. In an exploratory analysis, time to outbreak declaration among participating CLS was compared against a convenience sample of 19 CLS that did not use the POC platform. RESULTS: A total of 290 specimens that underwent paired testing were included. Turn-around time to result was significantly shorter with the POC platform compared to MRVP PCR, with median difference of 36.2 hours (interquartile range 21.8-46.4 hours). The POC platform had excellent diagnostic accuracy compared to MRVP PCR, with area under the curve statistic of .96. Time to outbreak declaration was shorter in CLS that used the POC platform compared to CLS that did not. CONCLUSION: Rapid POC testing platforms for respiratory viruses can be implemented in CLS, with high diagnostic accuracy, expedited turn-around times, and shorter time to outbreak declaration.

Predictors of SARS-CoV-2 transmission in congregate living settings: a multicenter prospective study.

BACKGROUND: Older adults residing in congregate living settings (CLS) such as nursing homes and independent living facilities remain at increased risk of morbidity and mortality from coronavirus disease 2019. We performed a prospective multicenter study of consecutive severe acute respiratory coronavirus virus 2 (SARS-CoV-2) exposures to identify predictors of transmission in this setting. METHODS: Consecutive resident SARS-CoV-2 exposures across 17 CLS were prospectively characterized from 1 September 2022 to 1 March 2023, including factors related to environment, source, and exposed resident. Room size, humidity, and ventilation were measured in locations where exposures occurred. Predictors were incorporated in a generalized estimating equation model adjusting for the correlation within CLS. RESULTS: Among 670 consecutive exposures to SARS-CoV-2 across 17 CLS, transmission occurred among 328 (49.0%). Increased risk was associated with nursing homes (odds ratio (OR) = 90.8; 95% CI, 7.8-1047.4), Jack and Jill rooms (OR = 2.2; 95% CI, 1.3-3.6), from source who was pre-symptomatic (OR = 11.2; 95% CI, 4.1-30.9), symptomatic (OR = 6.5; 95% CI, 1.4-29.9), or rapid antigen test positive (OR = 35.6; 95% CI, 5.6-225.6), and in the presence of secondary exposure (OR = 6.3; 95% CI, 1.6-24.0). Exposure in dining room was associated with reduced risk (OR = 0.02; 95% CI, 0.005-0.08) as was medium room size (OR = 0.3; 95% CI, 0.2-0.6). Recent vaccination of exposed resident (OR = 0.5; 95% CI, 0.3-1.0) and increased ventilation of room (OR = 0.9; 95% CI, 0.8-1.0) were marginally associated with reduced risk. CONCLUSION: Prospective assessment of SARS-CoV-2 exposures in CLS suggests that source characteristics and location of exposure are most predictive of resident transmission. These findings can inform risk assessment and further opportunities to prevent transmission in CLS.

Regulation of Versican Expression in Macrophages is Mediated by Canonical Type I Interferon Signaling via ISGF3.

Growing evidence supports a role for versican as an important component of the inflammatory response, with both pro- and anti-inflammatory roles depending on the specific context of the system or disease under investigation. Our goal is to understand the regulation of macrophage-derived versican and the role it plays in innate immunity. In previous work, we showed that LPS triggers a signaling cascade involving TLR4, the Trif adaptor, type I interferons, and the type I interferon receptor, leading to increased versican expression by macrophages. In the present study, we used a combination of chromatin immunoprecipitation, siRNA, chemical inhibitors, and mouse model approaches to investigate the regulatory events downstream of the type I interferon receptor to better define the mechanism controlling versican expression. Results indicate that transcriptional regulation by canonical type I interferon signaling via the heterotrimeric transcription factor, ISGF3, controls versican expression in macrophages exposed to LPS. This pathway is not dependent on MAPK signaling, which has been shown to regulate versican expression in other cell types. The stability of versican mRNA may also contribute to prolonged versican expression in macrophages. These findings strongly support a role for macrophage-derived versican as a type I interferon-stimulated gene and further our understanding of versican's role in regulating inflammation.

ER stress and lipid imbalance drive diabetic embryonic cardiomyopathy in an organoid model of human heart development.

Congenital heart defects are the most prevalent human birth defects, and their incidence is exacerbated by maternal health conditions, such as diabetes during the first trimester (pregestational diabetes). Our understanding of the pathology of these disorders is hindered by a lack of human models and the inaccessibility of embryonic tissue. Using an advanced human heart organoid system, we simulated embryonic heart development under pregestational diabetes-like conditions. These organoids developed pathophysiological features observed in mouse and human studies before, including ROS-mediated stress and cardiomyocyte hypertrophy. scRNA-seq revealed cardiac cell-type-specific dysfunction affecting epicardial and cardiomyocyte populations and alterations in the endoplasmic reticulum and very-long-chain fatty acid lipid metabolism. Imaging and lipidomics confirmed these findings and showed that dyslipidemia was linked to fatty acid desaturase 2 mRNA decay dependent on IRE1-RIDD signaling. Targeting IRE1 or restoring lipid levels partially reversed the effects of pregestational diabetes, offering potential preventive and therapeutic strategies in humans.

Inter-alpha-trypsin inhibitor (IαI) and hyaluronan modifications enhance the innate immune response to influenza virus in the lung.

The inter-alpha-trypsin inhibitor (IαI) complex is composed of the bikunin core protein with a single chondroitin sulfate (CS) attached and one or two heavy chains (HCs) covalently linked to the CS chain. The HCs from IαI can be transferred to hyaluronan (HA) through a TNFα-stimulated gene-6 (TSG-6) dependent process to form an HC•HA matrix. Previous studies reported increased IαI, HA, and HC•HA complexes in mouse bronchoalveolar lavage fluid (BALF) post-influenza infection. However, the expression and incorporation of HCs into the HA matrix of the lungs during the clinical course of influenza A virus (IAV) infection and the biological significance of the HC•HA matrix are poorly understood. The present study aimed to better understand the composition of HC•HA matrices in mice infected with IAV and how these matrices regulate the host pulmonary immune response. In IAV infected mice bikunin, HC1-3, TSG-6, and HAS1-3 all show increased gene expression at various times during a 12-day clinical course. The increased accumulation of IαI and HA was confirmed in the lungs of infected mice using immunohistochemistry and quantitative digital pathology. Western blots confirmed increases in the IαI components in BALF and lung tissue at 6 days post-infection (dpi). Interestingly, HCs and bikunin recovered from BALF and plasma from mice 6 dpi with IAV, displayed differences in the HC composition by Western blot analysis and differences in bikunin's CS chain sulfation patterns by mass spectrometry analysis. This strongly suggests that the IαI components were synthesized in the lungs rather than translocated from the vascular compartment. HA was significantly increased in BALF at 6 dpi, and the HA recovered in BALF and lung tissues were modified with HCs indicating the presence of an HC•HA matrix. In vitro experiments using polyinosinic-polycytidylic acid (poly(I:C)) treated mouse lung fibroblasts (MLF) showed that modification of HA with HCs increased cell-associated HA, and that this increase was due to the retention of HA in the MLF glycocalyx. In vitro studies of leukocyte adhesion showed differential binding of lymphoid (Hut78), monocyte (U937), and neutrophil (dHL60) cell lines to HA and HC•HA matrices. Hut78 cells adhered to immobilized HA in a size and concentration-dependent manner. In contrast, the binding of dHL60 and U937 cells depended on generating a HC•HA matrix by MLF. Our in vivo findings, using multiple bronchoalveolar lavages, correlated with our in vitro findings in that lymphoid cells bound more tightly to the HA-glycocalyx in the lungs of influenza-infected mice than neutrophils and mononuclear phagocytes (MNPs). The neutrophils and MNPs were associated with a HC•HA matrix and were more readily lavaged from the lungs. In conclusion, this work shows increased IαI and HA accumulation and the formation of a HC•HA matrix in mouse lungs post-IAV infection. The formation of HA and HC•HA matrices could potentially create specific microenvironments in the lungs for immune cell recruitment and activation during IAV infection.

Influenza outbreak management tabletop exercise for congregate living settings.

We conducted a tabletop exercise on influenza outbreak preparedness that engaged a large group of congregate living settings (CLS), with improvements in self-reported knowledge and readiness. This proactive approach to responding to communicable disease threats has potential to build infection prevention and control capacity beyond COVID-19 in the CLS sector.

Optimal Delivery Management for the Prevention of Early Neonatal SARS-CoV-2 Infection: Systematic Review and Meta-analysis.

OBJECTIVE: Delivery management interventions (DMIs) were recommended to prevent delivery-associated transmission of maternal SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) to infants without evidence of effect on early neonatal SARS-CoV-2 infection (ENI) and neonatal death <28 days of life (ND). This systematic review describes different DMI combinations and the frequency of ENI and ND. STUDY DESIGN: Individual patient data were collected from articles published from January 1, 2020 to December 31, 2021 from Cochrane review databases, Medline, and Google Scholar. Article inclusion criteria were: documented maternal SARS-CoV-2 polymerase chain reaction (PCR)-positive status 10 days before delivery or symptomatic at delivery with a positive test within 48 hours, known delivery method, and known infant SARS-CoV-2 PCR result. Primary outcomes were ENI (positive PCR at 12 hours to 10 days) and ND. All characteristics were pooled using the DerSimonian-Laird inverse variance method. Primary outcome analyses were performed using logit transformation and random effect. Pooled results were expressed as percentages (95% confidence intervals). Continuity correction was applied for all pooled results if any included study has 0 event. RESULTS: A total of 11,075 publications were screened. 117 publications representing 244 infants and 230 mothers were included. All publications were case reports. ENI and ND were reported in 23.4% (18.2-29.18) and 2.1% (0.67-4.72) of cases, respectively. Among cases with available information, DMIs were reported for physical environment (85-100%), delivery-specific interventions (47-100%), and infant care practices (80-100%). No significant comparisons could be performed between different DMI combinations due to small sample size. CONCLUSION: The evidence supporting any DMI in SARS-CoV-2-infected mothers to prevent ENI or ND is extremely limited. Limitations of this meta-analysis include high risk of bias, small sample size, and large confidence intervals. This identifies the need for multinational database generation and specific studies designed to provide evidence of DMI guidelines best suited to prevent transmission from mother to neonate. KEY POINTS: · In this review we analyzed 2 years of maternal SARS-CoV-2 published cases.. · We assessed association of delivery management interventions with infant SARS-CoV-2 infection.. · We found no evidence supporting any DMI for that purpose..

Discovery, Optimization, and Biological Evaluation of Arylpyridones as Cbl-b Inhibitors.

Casitas B-lymphoma proto-oncogene-b (Cbl-b), a member of the Cbl family of RING finger E3 ubiquitin ligases, has been demonstrated to play a central role in regulating effector T-cell function. Multiple studies using gene-targeting approaches have provided direct evidence that Cbl-b negatively regulates T, B, and NK cell activation via a ubiquitin-mediated protein modulation. Thus, inhibition of Cbl-b ligase activity can lead to immune activation and has therapeutic potential in immuno-oncology. Herein, we describe the discovery and optimization of an arylpyridone series as Cbl-b inhibitors by structure-based drug discovery to afford compound 31. This compound binds to Cbl-b with an IC50 value of 30 nM and induces IL-2 production in T-cells with an EC50 value of 230 nM. Compound 31 also shows robust intracellular target engagement demonstrated through inhibition of Cbl-b autoubiquitination, inhibition of ubiquitin transfer to ZAP70, and the cellular modulation of phosphorylation of a downstream signal within the TCR axis.

Debilitating lower back pain during menses unexpectedly resolved after treatment of subclinical temporomandibular disorder: a case report.

This case report describes a patient in whom debilitating lower back pain that always occurred during menses resolved when she received treatment for subclinical temporomandibular disorder (TMD). The patient was diagnosed with subclinical TMD and facial myalgia based on the results of clinical and radiographic examinations. She was treated with maxillary (nighttime) and mandibular (daytime) dental orthotics to provide stabilization and decompression of the temporomandibular joints. After 12 weeks of appliance therapy, which resulted in resolution of the TMD symptoms, the patient reported that the debilitating lower back pain she experienced during menses had ceased. Her back pain did not return after the use of the mandibular appliance was discontinued. The authors discuss how neurologic, postural, inflammatory, and qi flow changes attributed to the patient's TMD treatment may have contributed to the cessation of the patient's menses-related lower back pain.

Integration of hospital with congregate care homes in response to the COVID-19 pandemic.

Background: The coronavirus disease 2019 (COVID-19) pandemic has highlighted the need to improve the safety of the environments where we care for older adults in Canada. After providing assistance during the first wave, many Ontario hospitals formally partnered with local congregate care homes in a "hub and spoke" model during second pandemic wave onward. The objective of this article is to describe the implementation and longitudinal outcomes of residents in one hub and spoke model composed of a hospital partnered with 18 congregate care homes including four long-term care and 14 retirement or other congregate care homes. Intervention: Homes were provided continuous seven-day per week access to hospital support, including infection prevention and control (IPAC), testing, vaccine delivery and clinical support as needed. Any COVID-19 exposure or transmission triggered a same-day meeting to implement initial control measures. A minimum of weekly on-site visits occurred for long-term care homes and biweekly for other congregate care homes, with up to daily on-site presence during outbreaks. Outcomes: Case detection among residents increased following implementation in context of increased testing, then decreased post-immunization until the Omicron wave when it peaked. After adjusting for the correlation within homes, COVID-related mortality decreased following implementation (OR=0.51, 95% CI, 0.30-0.88; p=0.01). In secondary analysis, homes without pre-existing IPAC programs had higher baseline COVID-related mortality rate (OR=19.19, 95% CI, 4.66-79.02; p<0.001) and saw a larger overall decrease during implementation (3.76% to 0.37%-0.98%) as compared to homes with pre-existing IPAC programs (0.21% to 0.57%-0.90%). Conclusion: The outcomes for older adults residing in congregate care homes improved steadily throughout the COVID-19 pandemic. While this finding is multifactorial, integration with a local hospital partner supported key interventions known to protect residents.

Evaluation of a respiratory care protocol including less invasive surfactant administration in preterm infants.

BACKGROUND: Respiratory care protocol including less invasive ssurfactant administration (LISA) in ≤29 weeks' gestational age (GA) infants introduced in October 2018. METHODS: Retrospective study of infants admitted on continuous positive airway pressure (CPAP) October 2018 to December 2021. Maternal and neonatal variables were compared between infants managed on CPAP with and without LISA. Infants who received LISA and subsequently required mechanical ventilation (MV) within 72 h of life (HOL) [LISA failure (LF)] were compared with those who required no MV [LISA success (LS)]. RESULTS: 249 infants were admitted on CPAP, 5 were intubated prior to LISA, 143 required LISA and 101 remained on CPAP without surfactant. Of those receiving LISA, 108 were LS and 35 were LF. Compared to LS, LF infants were of lower GA and birth weight, required higher fractional inspired oxygen (FiO2), and CPAP level at birth, admission, one HOL, and an hour after LISA. Moreover, LF infants had higher mortality and morbidity. Together GA ≤ 25 weeks' and FiO2 ≥ 0.3 an hour after LISA best predicted LF. CONCLUSIONS: Over 80% of infants admitted on CPAP avoided MV within 72 HOL. Early predictors of LF provide targets for future interventions to decrease need for MV in preterm infants. IMPACT: Less invasive surfactant administration (LISA) decreases the need for mechanical ventilation (MV) and improves outcomes. However, some infants require MV within 72 h of life (HOL) despite LISA (LISA failure). Over 80% of ≤29 weeks' gestational age (GA) infants can be successfully managed on CPAP with or without surfactant in the first 72 HOL. A combination of factors including ≤25 weeks' GA and fraction of inspired oxygen ≥0.3 an hour after LISA predict LISA failure. Evaluation of a noninvasive respiratory support strategy including LISA provides targets for intervention to decrease need for MV in preterm infants.

Discovery of a Novel Benzodiazepine Series of Cbl-b Inhibitors for the Enhancement of Antitumor Immunity.

Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b) is a RING finger E3 ligase that is responsible for repressing T-cell, natural killer (NK) cell, and B-cell activation. The robust antitumor activity observed in Cbl-b deficient mice arising from elevated T-cell and NK-cell activity justified our discovery effort toward Cbl-b inhibitors that might show therapeutic promise in immuno-oncology, where activation of the immune system can drive the recognition and killing of cancer cells. We undertook a high-throughput screening campaign followed by structure-enabled optimization to develop a novel benzodiazepine series of potent Cbl-b inhibitors. This series displayed nanomolar levels of biochemical potency, as well as potent T-cell activation. The functional activity of this class of Cbl-b inhibitors was further corroborated with ubiquitin-based cellular assays.

Implementation of morbidity and mortality conference in a community hospital NICU and narrative review.

Background: The process of morbidity and mortality review (MMR) is recognized as an essential component of quality improvement, patient safety, attitudes towards patient safety, and continuing education. Despite the common use of MMR for all disciplines of medical care, recommendations have not been published regarding the implementation of MMR in a community hospital setting in the United States. Objectives: Review the literature on MMR conferences. Describe the implementation of an MMR conference in a community hospital neonatal intensive care unit (NICU). Conclusions: The establishment of a case overview method of MMR is feasible for a community hospital NICU. It increases staff and physician group awareness and education over common and complex mortality and morbidity etiologies, improves staff participation with unit management, links case presentation with open discussion and action items, and identifies opportunities for systemic changes to improve patient care.

Impairment Types and Combinations Among Adolescents and Young Adults with Disabilities: Colorado 2014-2018.

OBJECTIVE: Understanding the types of functional challenges faced by adolescents and young adults with disabilities (AYA-WD) can help payers, clinicians, community-based service providers, and policymakers recognize and meet needs. This paper describes state-level prevalence rates for 1) AYA-WD overall and for 2) impairment types singly and in combinations; and 3) examines how rates may differ between those insured by Medicaid versus commercial insurance. METHODS: This descriptive study uses Colorado's All Payer Claims Dataset 2014-2018 to identify insured 10- to 26-year-olds (Medicaid only: 333,931; commercially only: 392,444). It then applies the previously validated Children with Disabilities Algorithm (CWDA) and its companion, the Diagnosis-to-Impairment-Type Algorithm (DITA), to compare state-level prevalence rates by insurance source for disability overall and for each of five impairment types singly and in combination. RESULTS: Disability prevalence was greater among the Medicaid-insured AYA-WD by +7.6% points (pp)-Medicaid: 11.9% (47,654/333,931), commercial: 4.3% (16,907/392,444). Most AYA-WD had a single impairment, but the prevalence of AYA-WD with two or more impairments was greater among the Medicaid-insured than the commercially insured (+9.9 pp; Medicaid: 33.5% [15,963/47,654], commercial: 23.7% [3992/16, 907]), as was the prevalence of impairment types that were physical (+6.7 pp; Medicaid: 54.7% [26,054/47,654], commercial: 48.0% [8121/16,907]); developmental (+4.1 pp; Medicaid: 35.4% [16,874/47,654], commercial: 31.3% [5290/16,907]); psychiatric (+6.7 pp; Medicaid 21.3% [10,175/47,654], commercial: 14.6% [2470/16,907]), and intellectual (+9.3 pp; Medicaid: 26.2% [12,501/47,654], commercial: 16.9% [2858/16,907]). CONCLUSIONS: CWDA and DITA can be used to understand the rates at which impairment types and combinations occur in a population with childhood-onset disabilities.

Use of Electronic Clinical Data to Track Incidence and Mortality for SARS-CoV-2-Associated Sepsis.

Importance: Efforts to quantify the burden of SARS-CoV-2-associated sepsis have been limited by inconsistent definitions and underrecognition of viral sepsis. Objective: To describe the incidence and outcomes of SARS-CoV-2-associated sepsis vs presumed bacterial sepsis using objective electronic clinical criteria. Design, Setting, and Participants: This retrospective cohort study included adults hospitalized at 5 Massachusetts hospitals between March 2020 and November 2022. Exposures: SARS-CoV-2-associated sepsis was defined as a positive SARS-CoV-2 polymerase chain reaction test and concurrent organ dysfunction (ie, oxygen support above simple nasal cannula, vasopressors, elevated lactate level, rise in creatine or bilirubin level, and/or decline in platelets). Presumed bacterial sepsis was defined by modified US Centers for Disease Control and Prevention adult sepsis event criteria (ie, blood culture order, sustained treatment with antibiotics, and organ dysfunction using identical thresholds as for SARS-CoV-2-associated sepsis). Main Outcomes and Measures: Trends in the quarterly incidence (ie, proportion of hospitalizations) and in-hospital mortality for SARS-CoV-2-associated and presumed bacterial sepsis were assessed using negative binomial and logistic regression models. Results: This study included 431 017 hospital encounters from 261 595 individuals (mean [SD] age 57.9 [19.8] years, 241 131 (55.9%) females, 286 397 [66.5%] from academic hospital site). Of these encounters, 23 276 (5.4%) were from SARS-CoV-2, 6558 (1.5%) had SARS-CoV-2-associated sepsis, and 30 604 patients (7.1%) had presumed bacterial sepsis without SARS-CoV-2 infection. Crude in-hospital mortality for SARS-CoV-2-associated sepsis declined from 490 of 1469 (33.4%) in the first quarter to 67 of 450 (14.9%) in the last (adjusted odds ratio [aOR], 0.88 [95% CI, 0.85-0.90] per quarter). Crude mortality for presumed bacterial sepsis was 4451 of 30 604 patients (14.5%) and stable across quarters (aOR, 1.00 [95% CI, 0.99-1.01]). Medical record reviews of 200 SARS-CoV-2-positive hospitalizations confirmed electronic health record (EHR)-based SARS-CoV-2-associated sepsis criteria performed well relative to sepsis-3 criteria (90.6% [95% CI, 80.7%-96.5%] sensitivity; 91.2% [95% CI, 85.1%-95.4%] specificity). Conclusions and Relevance: In this retrospective cohort study of hospitalized adults, SARS-CoV-2 accounted for approximately 1 in 6 cases of sepsis during the first 33 months of the COVID-19 pandemic. In-hospital mortality rates for SARS-CoV-2-associated sepsis were high but declined over time and ultimately were similar to presumed bacterial sepsis. These findings highlight the high burden of SARS-CoV-2-associated sepsis and demonstrate the utility of EHR-based algorithms to conduct surveillance for viral and bacterial sepsis.

ER stress and lipid imbalance drive embryonic cardiomyopathy in a human heart organoid model of pregestational diabetes.

Congenital heart defects constitute the most common birth defect in humans, affecting approximately 1% of all live births. The incidence of congenital heart defects is exacerbated by maternal conditions, such as diabetes during the first trimester. Our ability to mechanistically understand these disorders is severely limited by the lack of human models and the inaccessibility to human tissue at relevant stages. Here, we used an advanced human heart organoid model that recapitulates complex aspects of heart development during the first trimester to model the effects of pregestational diabetes in the human embryonic heart. We observed that heart organoids in diabetic conditions develop pathophysiological hallmarks like those previously reported in mouse and human studies, including ROS-mediated stress and cardiomyocyte hypertrophy, among others. Single cell RNA-seq revealed cardiac cell type specific-dysfunction affecting epicardial and cardiomyocyte populations, and suggested alterations in endoplasmic reticulum function and very long chain fatty acid lipid metabolism. Confocal imaging and LC-MS lipidomics confirmed our observations and showed that dyslipidemia was mediated by fatty acid desaturase 2 (FADS2) mRNA decay dependent on IRE1-RIDD signaling. We also found that the effects of pregestational diabetes could be reversed to a significant extent using drug interventions targeting either IRE1 or restoring healthy lipid levels within organoids, opening the door to new preventative and therapeutic strategies in humans.

External Validation of a Clinical Score to Differentiate Takotsubo Syndrome From Non-ST-Elevation Myocardial Infarction in Women.

BACKGROUND AND AIMS: Clinical presentation of Takotsubo Syndrome (TS) mimics acute coronary syndrome (ACS). A score to differentiate TS from ACS would be helpful to facilitate appropriate investigation and management. We have previously developed a clinical score (NSTE-Takotsubo Score) to distinguish women with non-ST-segment elevation myocardial infarction (NSTEMI) from TS with non-ST-segment elevation (NSTE-TS). This study sought to assess the diagnostic validity of this score in an external validation cohort. METHODS: The external cohort consisted of women with NSTE-TS (n=110) and NSTEMI (n=113) from two major tertiary hospitals in New Zealand. The five variables in the arithmetic score (range -6 to +5) and their relative weights are: T-wave inversion (TWI) in ≥6 leads (3 points), recent stress (2 points), diabetes mellitus (DM) (-1 point), prior cardiovascular disease (CVD) (-2 points) and presence of ST depression (-3 points). Two clinicians blinded to the diagnoses calculated the score using clinical and electrocardiogram (ECG) data on day 1 post-admission. RESULTS: The NSTE-Takotsubo Score discriminated well between NSTE-TS and NSTEMI. The sensitivity and specificity of a score ≥1 to distinguish NSTE-TS from NSTEMI were 78% and 85%, respectively. The area under the receiver operator curve was 0.78 (95% CI 0.72 to 0.84). CONCLUSION: In an external validation cohort, the NSTE-Takotsubo Score was easy to apply and useful to identify women likely to have NSTE-TS on day 1 post-admission.

Impact of changing case definitions for coronavirus disease 2019 (COVID-19) hospitalization on pandemic metrics.

OBJECTIVE: To examine the impact of commonly used case definitions for coronavirus disease 2019 (COVID-19) hospitalizations on case counts and outcomes. DESIGN, PATIENTS, AND SETTING: Retrospective analysis of all adults hospitalized between March 1, 2020, and March 1, 2022, at 5 Massachusetts acute-care hospitals. INTERVENTIONS: We applied 6 commonly used definitions of COVID-19 hospitalization: positive severe acute respiratory coronavirus virus 2 (SARS-CoV-2) polymerase chain reaction (PCR) assay within 14 days of admission, PCR plus dexamethasone administration, PCR plus remdesivir, PCR plus hypoxemia, institutional COVID-19 flag, or COVID-19 International Classification of Disease, Tenth Revision (ICD-10) codes. Outcomes included case counts and in-hospital mortality. Overall, 100 PCR-positive cases were reviewed to determine each definition's accuracy for distinguishing primary or contributing versus incidental COVID-19 hospitalizations. RESULTS: Of 306,387 hospital encounters, 15,436 (5.0%) met the PCR-based definition. COVID-19 hospitalization counts varied substantially between definitions: 4,628 (1.5% of all encounters) for PCR plus dexamethasone, 5,757 (1.9%) for PCR plus remdesivir, 11,801 (3.9%) for PCR plus hypoxemia, 15,673 (5.1%) for institutional flags, and 15,868 (5.2%) for ICD-10 codes. Definitions requiring dexamethasone, hypoxemia, or remdesivir selected sicker patients compared to PCR alone (mortality rates 12.2%, 10.7%, and 8.8% vs 8.3%, respectively). Definitions requiring PCR plus remdesivir or dexamethasone did not detect a reduction in in-hospital mortality associated with the SARS-CoV-2 Omicron variant. ICD-10 codes had the highest sensitivity (98.4%) but low specificity (39.5%) for distinguishing primary or contributing versus incidental COVID-19 hospitalizations. PCR plus dexamethasone had the highest specificity (92.1%) but low sensitivity (35.5%). CONCLUSIONS: Commonly used definitions for COVID-19 hospitalizations generate variable case counts and outcomes and differentiate poorly between primary or contributing versus incidental COVID-19 hospitalizations. Surveillance definitions that better capture and delineate COVID-19-associated hospitalizations are needed.