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.

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.

Exploration of the P1 residue in 3CL protease inhibitors leading to the discovery of a 2-tetrahydrofuran P1 replacement.

The virally encoded 3C-like protease (3CLpro) is a well-validated drug target for the inhibition of coronaviruses including Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Most inhibitors of 3CLpro are peptidomimetic, with a γ-lactam in place of Gln at the P1 position of the pseudopeptide chain. An effort was pursued to identify a viable alternative to the γ-lactam P1 mimetic which would improve physicochemical properties while retaining affinity for the target. Discovery of a 2-tetrahydrofuran as a suitable P1 replacement that is a potent enzymatic inhibitor of 3CLpro in SARS-CoV-2 virus is described herein.

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.

The Management of Children and Youth With Pediatric Mental and Behavioral Health Emergencies.

Mental and behavioral health (MBH) emergencies in children and youth continue to increasingly affect not only the emergency department (ED), but the entire spectrum of emergency medical services for children, from prehospital services to the community. Inadequate community and institutional infrastructure to care for children and youth with MBH conditions makes the ED an essential part of the health care safety net for these patients. As a result, an increasing number of children and youth are referred to the ED for evaluation of a broad spectrum of MBH emergencies, from depression and suicidality to disruptive and aggressive behavior. However, challenges in providing optimal care to these patients include lack of personnel, capacity, and infrastructure, challenges with timely access to a mental health professional, the nature of a busy ED environment, and paucity of outpatient post-ED discharge resources. These factors contribute to prolonged ED stays and boarding, which negatively affects patient care and ED operations. Strategies to improve care for MBH emergencies, including systems level coordination of care, is therefore essential. The goal of this policy statement and its companion technical report is to highlight strategies, resources, and recommendations for improving emergency care delivery for pediatric MBH.

Evaluating an Integrated Local System Response to the COVID-19 Pandemic: Case Study of East Toronto Health Partners.

Introduction: East Toronto Health Partners (ETHP) is a network of organizations that serve residents of East Toronto, Ontario, Canada. ETHP is a newly formed integrated model of care in which hospital, primary care, community providers and patients/families work together to improve population health. We describe and evaluate the evolution of this emerging integrated care system as it responded to a global health crisis. Description: This paper begins by describing ETHP's pandemic response mapping out over two years of data. To evaluate the response, semi-structured interviews were conducted with 30 decision makers, clinicians, staff, and volunteers who were part of the response. The interviews were thematically analyzed, and emergent themes mapped onto the nine pillars of integrated care. Discussion: The ETHP pandemic response evolved rapidly. Early siloed responses gave way to collaborative efforts and equity emerged as a central priority. New alliances formed, resources were shared, leaders emerged, and community members stepped forward to contribute. Interviewees identified positives as well as many opportunities for improvement post-pandemic. Conclusion: The pandemic was a catalyst for change in East Toronto that accelerated existing initiatives to achieve integrated care. The East Toronto experience may serve as a useful guide for other emerging integrated care systems.

Resident Communication With Patients and Families Preferring Languages Other Than English.

OBJECTIVES: Patients and families preferring languages other than English (LOE) often experience inequitable communication with their health care providers, including the underutilization of professional interpretation. This study had 2 aims: to characterize resident-perceived communication with families preferring LOE and to evaluate the impact of language preference on frequency of resident interactions with hospitalized patients and families. METHODS: This was a cross-sectional study at a quaternary care children's hospital. We developed a questionnaire for residents regarding their interactions with patients preferring LOE. We concurrently developed a communication tracking tool to measure the frequency of resident communication events with hospitalized patients. Data were analyzed with logistic and Poisson regression models. RESULTS: Questionnaire results demonstrated a high level of resident comfort with interpretation, though more than 30% of residents reported "sometimes" or "usually" communicating with families preferring LOE without appropriate interpretation (response rate, 47%). The communication tracking tool was completed by 36 unique residents regarding 151 patients, with a 95% completion rate. Results demonstrated that patients and families preferring LOE were less likely to be present on rounds compared with their counterparts preferring English (adjusted odds ratio, 0.17; 95% confidence interval [CI], 0.07-0.39). Similarly, patients and families preferring LOE were less likely to receive a resident update after rounds (adjusted odds ratio, 0.29; 95% CI, 0.13-0.62) and received fewer resident updates overall (incidence rate ratio, 0.45; 95% CI, 0.30-0.69). CONCLUSIONS: Hospitalized patients and families preferring LOE experience significant communication-related inequities. Ongoing efforts are needed to promote equitable communication with this population and should consider the unique role of residents.

Improving Identification of Interpreter Need in the Pediatric Emergency Department.

OBJECTIVE: Patients with limited English proficiency (LEP) benefit from the appropriate use of medical interpreters. A multidisciplinary quality improvement team sought to improve communication with patients with LEP within a pediatric emergency department (ED). Specifically, the team aimed to improve the early identification of patients and caregivers with LEP, the utilization of interpreter services for those identified, and documentation of interpreter use in the patient chart. METHODS: Using clinical observations and data review, the project team identified key processes for improvement in the ED workflow and introduced interventions to increase identification of language needs and offer interpreter services. These include a new triage screening question, an icon on the ED track board that communicates language needs to staff, an electronic health record (EHR) alert with information on how to obtain interpreter services, and a new template to prompt correct documentation in the ED provider's note. Outcomes were tracked using statistical process control charts. RESULTS: All study measures met special cause for improvement during the 6-month study period and have been sustained during surveillance data collection. Identification rates for patients with LEP during triage increased from 60% to 77%. Interpreter utilization increased from 77% to 86%. The documentation of interpreter use increased from 38% to 73%. CONCLUSION: Using improvement methods, a multidisciplinary team increased the identification of patients and caregivers with LEP in an ED. Integration of this information into the EHR allowed for the targeted prompting of providers to use interpreter services and to correctly document their use.

NRF2 Activation Reprograms Defects in Oxidative Metabolism to Restore Macrophage Function in Chronic Obstructive Pulmonary Disease.

Rationale: Chronic obstructive pulmonary disease (COPD) is a disease characterized by persistent airway inflammation and disordered macrophage function. The extent to which alterations in macrophage bioenergetics contribute to impaired antioxidant responses and disease pathogenesis has yet to be fully delineated. Objectives: Through the study of COPD alveolar macrophages (AMs) and peripheral monocyte-derived macrophages (MDMs), we sought to establish if intrinsic defects in core metabolic processes drive macrophage dysfunction and redox imbalance. Methods: AMs and MDMs from donors with COPD and healthy donors underwent functional, metabolic, and transcriptional profiling. Measurements and Main Results: We observed that AMs and MDMs from donors with COPD display a critical depletion in glycolytic- and mitochondrial respiration-derived energy reserves and an overreliance on glycolysis as a source for ATP, resulting in reduced energy status. Defects in oxidative metabolism extend to an impaired redox balance associated with defective expression of the NADPH-generating enzyme, ME1 (malic enzyme 1), a known target of the antioxidant transcription factor NRF2 (nuclear factor erythroid 2-related factor 2). Consequently, selective activation of NRF2 resets the COPD transcriptome, resulting in increased generation of TCA cycle intermediaries, improved energetic status, favorable redox balance, and recovery of macrophage function. Conclusions: In COPD, an inherent loss of metabolic plasticity leads to metabolic exhaustion and reduced redox capacity, which can be rescued by activation of the NRF2 pathway. Targeting these defects, via NRF2 augmentation, may therefore present an attractive therapeutic strategy for the treatment of the aberrant airway inflammation described in COPD.

Access to Critical Health Information for Children During Emergencies: Emergency Information Forms and Beyond.

ABSTRACT: Children with chronic medical conditions rely on complex management plans for problems that cause them to be at increased risk for suboptimal outcomes in emergency situations. The emergency information form (EIF) is a medical summary that provides rapid access to critical information to physicians and other members of the health care team so that optimal emergency medical care can be provided. This statement describes an updated approach to EIFs and the information they contain. Essential common data elements are reviewed, integration with electronic health records is discussed, and broadening the rapid availability and use of health data for all children and youth is proposed. A broader approach to data accessibility and use could extend the benefits of rapid access to critical information for all children receiving emergency care as well as further facilitating emergency preparedness during disaster management.

Television-Related Head Injuries in Children: A Secondary Analysis of a Large Cohort Study of Head-Injured Children in the Pediatric Emergency Care Applied Research Network.

OBJECTIVE: The objective of the study was to describe the epidemiology, cranial computed tomography (CT) findings, and clinical outcomes of children with blunt head trauma after television tip-over injuries. METHODS: We performed a secondary analysis of children younger than 18 years prospectively evaluated for blunt head trauma at 25 emergency departments (EDs) in the Pediatric Emergency Care Applied Research Network from June 2004 to September 2006. Children injured from falling televisions were included. Patients were excluded if injuries occurred more than 24 hours before ED evaluation or if neuroimaging was obtained before evaluation. Data collected included age, race, sex, cranial CT findings, and clinical outcomes. Clinically important traumatic brain injuries (ciTBIs) were defined as death from TBI, neurosurgery, intubation for more than 24 hours for the TBI, or hospital admission of 2 nights or more for the head injury, in association with TBI on CT. RESULTS: A total of 43,904 children were enrolled into the primary study and 218 (0.5%; 95% confidence interval [CI], 0.4% to 0.6%) were struck by falling televisions. The median (interquartile range) age of the 218 patients was 3.1 (1.9-4.9) years. Seventy-five (34%) of the 218 underwent CT scanning. Ten (13.3%; 95% CI, 6.6% to 23.2%) of the 75 patients with an ED CT had traumatic findings on cranial CT scan. Six patients met the criteria for ciTBI. Three of these patients died. All 6 patients with ciTBIs were younger than 5 years. CONCLUSIONS: Television tip-overs may cause ciTBIs in children, including death, and the most severe injuries occur in children 5 years or younger. These injuries may be preventable by simple preventive measures such as anchoring television sets with straps.

Fragment-Guided Discovery of Pyrazole Carboxylic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2 Related Factor 2 (KEAP1:NRF2) Protein-Protein Interaction.

The NRF2-mediated cytoprotective response is central to cellular homoeostasis, and there is increasing interest in developing small-molecule activators of this pathway as therapeutics for diseases involving chronic oxidative stress. The protein KEAP1, which regulates NRF2, is a key point for pharmacological intervention, and we recently described the use of fragment-based drug discovery to develop a tool compound that directly disrupts the protein-protein interaction between NRF2 and KEAP1. We now present the identification of a second, chemically distinct series of KEAP1 inhibitors, which provided an alternative chemotype for lead optimization. Pharmacophoric information from our original fragment screen was used to identify new hit matter through database searching and to evolve this into a new lead with high target affinity and cell-based activity. We highlight how knowledge obtained from fragment-based approaches can be used to focus additional screening campaigns in order to de-risk projects through the rapid identification of novel chemical series.

Dynamical correlation energy of metals in large basis sets from downfolding and composite approaches.

Coupled-cluster theory with single and double excitations (CCSD) is a promising ab initio method for the electronic structure of three-dimensional metals, for which second-order perturbation theory (MP2) diverges in the thermodynamic limit. However, due to the high cost and poor convergence of CCSD with respect to basis size, applying CCSD to periodic systems often leads to large basis set errors. In a common "composite" method, MP2 is used to recover the missing dynamical correlation energy through a focal-point correction, but the inadequacy of finite-order perturbation theory for metals raises questions about this approach. Here, we describe how high-energy excitations treated by MP2 can be "downfolded" into a low-energy active space to be treated by CCSD. Comparing how the composite and downfolding approaches perform for the uniform electron gas, we find that the latter converges more quickly with respect to the basis set size. Nonetheless, the composite approach is surprisingly accurate because it removes the problematic MP2 treatment of double excitations near the Fermi surface. Using this method to estimate the CCSD correlation energy in the combined complete basis set and thermodynamic limits, we find that CCSD recovers 85%-90% of the exact correlation energy at rs = 4. We also test the composite approach with the direct random-phase approximation used in place of MP2, yielding a method that is typically (but not always) more cost effective due to the smaller number of orbitals that need to be included in the more expensive CCSD calculation.

Detection of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) in outpatients: A multicenter comparison of self-collected saline gargle, oral swab, and combined oral-anterior nasal swab to a provider collected nasopharyngeal swab.

BACKGROUND: Widespread testing for severe acute respiratory coronavirus virus 2 (SARS-CoV-2) is necessary to curb the spread of coronavirus disease 2019 (COVID-19), but testing is undermined when the only option is a nasopharyngeal swab. Self-collected swab techniques can overcome many of the disadvantages of a nasopharyngeal swab, but they require evaluation. METHODS: Three self-collected non-nasopharyngeal swab techniques (saline gargle, oral swab and combined oral-anterior nasal swab) were compared to a nasopharyngeal swab for SARS-CoV-2 detection at multiple COVID-19 assessment centers in Toronto, Canada. The performance characteristics of each test were assessed. RESULTS: The adjusted sensitivity of the saline gargle was 0.90 (95% CI 0.86-0.94), the oral swab was 0.82 (95% CI, 0.72-0.89) and the combined oral-anterior nasal swab was 0.87 (95% CI, 0.77-0.93) compared to a nasopharyngeal swab, which demonstrated a sensitivity of ˜90% when all positive tests were the reference standard. The median cycle threshold values for the SARS-CoV-2 E-gene for concordant and discordant saline gargle specimens were 17 and 31 (P < .001), for the oral swabs these values were 17 and 28 (P < .001), and for oral-anterior nasal swabs these values were 18 and 31 (P = .007). CONCLUSIONS: Self-collected saline gargle and an oral-anterior nasal swab have a similar sensitivity to a nasopharyngeal swab for the detection of SARS-CoV-2. These alternative collection techniques are cheap and can eliminate barriers to testing, particularly in underserved populations.

Structure-Activity and Structure-Conformation Relationships of Aryl Propionic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1/Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1/NRF2) Protein-Protein Interaction.

The KEAP1-NRF2-mediated cytoprotective response plays a key role in cellular homoeostasis. Insufficient NRF2 signaling during chronic oxidative stress may be associated with the pathophysiology of several diseases with an inflammatory component, and pathway activation through direct modulation of the KEAP1-NRF2 protein-protein interaction is being increasingly explored as a potential therapeutic strategy. Nevertheless, the physicochemical nature of the KEAP1-NRF2 interface suggests that achieving high affinity for a cell-penetrant druglike inhibitor might be challenging. We recently reported the discovery of a highly potent tool compound which was used to probe the biology associated with directly disrupting the interaction of NRF2 with the KEAP1 Kelch domain. We now present a detailed account of the medicinal chemistry campaign leading to this molecule, which included exploration and optimization of protein-ligand interactions in three energetic "hot spots" identified by fragment screening. In particular, we also discuss how consideration of ligand conformational stabilization was important to its development and present evidence for preorganization of the lead compound which may contribute to its high affinity and cellular activity.

Discovery of a crystalline sulforaphane analog with good solid-state stability and engagement of the Nrf2 pathway in vitro and in vivo.

The antioxidant natural product sulforaphane (SFN) is an oil with poor aqueous and thermal stability. Recent work with SFN has sought to optimize methods of formulation for oral and topical administration. Herein we report the design of new analogs of SFN with the goal of improving stability and drug-like properties. Lead compounds were selected based on potency in a cellular screen and physicochemical properties. Among these, 12 had good aqueous solubility, permeability and long-term solid-state stability at 23 °C. Compound 12 also displayed comparable or better efficacy in cellular assays relative to SFN and had in vivo activity in a mouse cigarette smoke challenge model of acute oxidative stress.

Quality Improvement Initiative to Improve Abuse Screening Among Infants With Extremity Fractures.

OBJECTIVES: The aim of this study was to evaluate the effectiveness of clinical pathway implementation and quality improvement (QI) interventions to increase the percentage of infants with extremity fractures undergoing evaluation for suspected physical abuse, including skeletal survey (SS), and consultation with social work, and/or Child Protection Team. METHODS: Charts were retrospectively reviewed to establish percentage of infants less than 12 months old with extremity fractures undergoing an SS and consultation during the prepathway (January 1, 2012 to December 31, 2013) and postpathway (January 1, 2014 to June 30, 2015) periods. Using an Ishikawa framework, key process drivers were identified and additional QI interventions (clinical decision support and provider education) were developed and implemented. Impact of QI interventions on study metrics during active QI (July 1, 2015 to June 30, 2016) and post-QI periods (July 1, 2016 to December 31, 2016) was monitored using statistical process control charts. Logistic regression assessed predictors of obtaining an SS, consultation use, and occult fracture detection. RESULTS: Skeletal survey use pre- and postpathway averaged 40%, surpassing 60% on average during active QI and post-QI periods. Consultation performance averaged 46% pre- and postpathway, increasing to nearly 67% during active QI; consultation performance decreased during post-QI to 60%. A lack of trauma history and presence of femur or humerus fracture were associated with increased SS use and consultation (both P < 0.001). Overall 20% of SS revealed occult fractures.

Centers for Disease Control and Prevention Guideline on the Diagnosis and Management of Mild Traumatic Brain Injury Among Children.

Importance: Mild traumatic brain injury (mTBI), or concussion, in children is a rapidly growing public health concern because epidemiologic data indicate a marked increase in the number of emergency department visits for mTBI over the past decade. However, no evidence-based clinical guidelines have been developed to date for diagnosing and managing pediatric mTBI in the United States. Objective: To provide a guideline based on a previous systematic review of the literature to obtain and assess evidence toward developing clinical recommendations for health care professionals related to the diagnosis, prognosis, and management/treatment of pediatric mTBI. Evidence Review: The Centers for Disease Control and Prevention (CDC) National Center for Injury Prevention and Control Board of Scientific Counselors, a federal advisory committee, established the Pediatric Mild Traumatic Brain Injury Guideline Workgroup. The workgroup drafted recommendations based on the evidence that was obtained and assessed within the systematic review, as well as related evidence, scientific principles, and expert inference. This information includes selected studies published since the evidence review was conducted that were deemed by the workgroup to be relevant to the recommendations. The dates of the initial literature search were January 1, 1990, to November 30, 2012, and the dates of the updated literature search were December 1, 2012, to July 31, 2015. Findings: The CDC guideline includes 19 sets of recommendations on the diagnosis, prognosis, and management/treatment of pediatric mTBI that were assigned a level of obligation (ie, must, should, or may) based on confidence in the evidence. Recommendations address imaging, symptom scales, cognitive testing, and standardized assessment for diagnosis; history and risk factor assessment, monitoring, and counseling for prognosis; and patient/family education, rest, support, return to school, and symptom management for treatment. Conclusions and Relevance: This guideline identifies the best practices for mTBI based on the current evidence; updates should be made as the body of evidence grows. In addition to the development of the guideline, CDC has created user-friendly guideline implementation materials that are concise and actionable. Evaluation of the guideline and implementation materials is crucial in understanding the influence of the recommendations.