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Objectives: To develop a pragmatic twice daily lamivudine dosing strategy for preterm infants from 24 to 37 completed weeks of gestation., Methods: Data were combined from eight pharmacokinetic studies in neonates and infants receiving lamivudine oral solution. A population pharmacokinetic model was developed using non-linear mixed effects regression. Different lamivudine dosing strategies, stratified by gestational age at birth (GA) bands, were simulated in a virtual population of preterm infants, aimed at maintaining lamivudine drug exposures (AUC0-12) within a reference target range of 2.95 to 13.25 µg·h/mL, prior to switching to WHO-weight band doses when ≥4 weeks of age and weighing ≥3 kg., Results: A total of 154 infants (59% female) contributed 858 lamivudine plasma concentrations. Median (range) GA at birth was 38 (27-41) weeks. At the time of first pharmacokinetic sampling infants were older with median postnatal age (PNA) of 6.3 (0.52-26.6) weeks. Lamivudine concentrations were described by a one-compartment model, with CL/F and V/F allometrically scaled to weight. Maturation of CL/F was described using an Emax model based on PNA. CL/F was also adjusted on GA to allow extrapolation for extreme prematurity. Simulations predicted an optimal lamivudine dosing for infants GA ≥24 to <30 weeks of 2 mg/kg twice daily from birth until weighing 3 kg; and for GA ≥30 to <37 weeks, 2 mg/kg twice daily for the first 4 weeks of life, followed by 4 mg/kg twice daily until weighing 3 kg., Conclusions: Model-based predictions support twice daily pragmatic GA band dosing of lamivudine for preterm infants, but clinical validation is warranted., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The practice of medicine in recent years has emphasized the use of evidence-based clinical guidelines to help inform treatment decisions. Since its development in 2004, the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach has offered a systematic process for reviewing and summarizing the certainty of evidence found in the medical literature regarding various treatment options. To develop truly patient-centered care guidelines, this appraisal of the certainty of evidence must be combined with an understanding of the balance between benefits and harms, patient preferences, equity, feasibility, cost-effectiveness, and policy implications. This review examines each of these domains in detail, exploring the process and benefits of developing relevant, patient-focused guidelines directly applicable to the practice of modern medicine., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Goals: We aimed to evaluate whether direct access colonoscopy (DAC) is noninferior to office-scheduled colonoscopy (OSC) for achieving successful colonoscopy., Background: DAC may improve access to colonoscopy. We developed an algorithm assessing eligibility, risk for inadequate preparation, and need for nursing/navigator assistance., Study: This was a retrospective, single-center study of DAC and OSC patients from June 5, 2018, to July 31, 2019. Patients were 45 to 75 years old with an indication of screening or surveillance. A successful colonoscopy met 3 criteria: complete colonoscopy (cecum, anastomosis, or ileum), adequate preparation (Boston Score ≥2/segment), and performed <90 days from initial patient contact. Unsuccessful colonoscopy did not meet ≥1 criteria. Secondary end points included days to successful colonoscopy, preparation quality, polyp detection, and 10-year recall rate. Noninferiority against risk ratio value of 0.85 was tested using 1-sided alpha of 0.05., Results: A total of 1823 DAC and 828 OSC patients were eligible. DAC patients were younger, with a greater proportion of black patients and screening indications. For the outcome of successful colonoscopy, DAC was noninferior to OSC (DAC vs. OSC: 62.7% vs. 57.1%, RR 1.16, 95% LCL 1.09, P=0.001). For DAC, days to colonoscopy were fewer, and likelihood of 10-year recall after negative screening greater. Boston Score and polyp detection were similar for groups. Black patients were less likely to achieve successful colonoscopy; otherwise, groups were similar. For unsuccessful colonoscopies, proportionally more DAC patients canceled or no-showed while more OSC patients scheduled >90 days. DAC remained noninferior to OSC at 180 days., Conclusions: DAC was noninferior to OSC for achieving successful colonoscopy, comparing similarly in quality and efficiency outcomes., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: ADVANCE compared 3 World Health Organization-recommended first-line regimens in participants with HIV who were antiretroviral naive., Methods: This randomized, open-label, noninferiority trial enrolled participants living with HIV with no antiretroviral exposure in the previous 6 months to 1 of the following arms: tenofovir alafenamide (TAF) / emtricitabine (FTC) + dolutegravir (DTG) (2 tablets), tenofovir disoproxil fumarate (TDF) / FTC + DTG (2 tablets), or a fixed-dose combination of TDF / FTC / efavirenz (EFV) (1 tablet). We report the final safety and efficacy data up to 192 weeks., Results: Repeat consent from the original 351 participants randomized to each arm was obtained from 230 participants (66%) in the TAF/FTC + DTG arm, 209 (60%) in the TDF/FTC + DTG arm, and 183 (52%) in the TDF/FTC/EFV arm. At 192 weeks, 213 (61%) of the original 351 participants in the TAF/FTC + DTG arm, 195 (56%) in the TDF/FTC + DTG arm, and 172 (49%) in the TDF/FTC/EFV arm had confirmed RNA <50 copies/mL, with low virologic failure in all groups and no significant integrase inhibitor mutations in any arm. Mean weight gain was 8.9 kg (SD, 7.1) in the TAF/FTC + DTG arm, 5.9 kg (SD, 7.1) in the TDF/FTC + DTG arm, and 3.2 kg (SD, 8.1) in the TDF/FTC/EFV arm at 192 weeks from baseline and was greatest among women, those taking TAF, and those with lower baseline CD4 counts. The weight trajectory slowed after week 96. There were few clinical events and minor laboratory changes and differences among arms after 96 weeks. There were no significant differences in treatment-emergent hypertension or pregnancy outcomes by arm., Conclusions: High viral suppression was seen across arms, with no resistance to DTG. Weight gain continued but slowed after 96 weeks, with few clinical events or laboratory changes., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The picture naming task is common both as a clinical task and as a method to study the neural bases of speech production in the healthy brain. However, this task is not reflective of most naturally occurring productions, which tend to happen within a context, typically in dialogue in response to someone else's production. How the brain basis of the classic "confrontation picture naming" task compares to the planning of utterances in dialogue is not known. Here we used magnetoencephalography (MEG) to measure neural activity associated with language production using the classic picture naming task as well as a minimal variant of the task, intended as more interactive or dialogue-like. We assessed how neural activity is affected by the interactive context in children, teenagers, and adults. The general pattern was that in adults, the interactive task elicited a robust sustained increase of activity in frontal and temporal cortices bilaterally, as compared to simple picture naming. This increase was present only in the left hemisphere in teenagers and was absent in children, who, in fact, showed the reverse effect. Thus our findings suggest a robustly bilateral neural basis for the coordination of interaction and a very slow developmental timeline for this network., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Goldman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Women/females report more adverse events (AE) following immunization than men/males for many vaccines, including the influenza and COVID-19 vaccines. This discrepancy is often dismissed as a reporting bias, yet the relative contributions of biological sex and gender are poorly understood. We investigated the roles of sex and gender in the rate of AE following administration of the high-dose seasonal influenza vaccine to older adults (≥ 75 years) using an AE questionnaire administered 5-8 days post-vaccination. Participant sex (male or female) was determined by self-report and a gender score questionnaire was used to assign participants to one of four gender categories (feminine, masculine, androgynous, or undifferentiated). Sex steroid hormones and inflammatory cytokines were measured in plasma samples collected prior to vaccination to generate hypotheses as to the biological mechanism underpinning the AE reported., Results: A total of 423 vaccines were administered to 173 participants over four influenza seasons (2019-22) and gender data were available for 339 of these vaccinations (2020-22). At least one AE was reported following 105 vaccinations (25%), by 23 males and 82 females. The majority of AE occurred at the site of injection, were mild, and transient. The odds of experiencing an AE were 3-fold greater in females than males and decreased with age to a greater extent in females than males. The effects of gender, however, were not statistically significant, supporting a central role of biological sex in the occurrence of AE. In males, estradiol was significantly associated with IL-6 and with the probability of experiencing an AE. Both associations were absent in females, suggesting a sex-specific effect of estradiol on the occurrence of AE that supports the finding of a biological sex difference., Conclusions: These data support a larger role for biological sex than for gender in the occurrence of AE following influenza vaccination in older adults and provide an initial investigation of hormonal mechanisms that may mediate this sex difference. This study highlights the complexities of measuring gender and the importance of assessing AE separately for males and females to better understand how vaccination strategies can be tailored to different subsets of the population., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objective: The Pulmonary Embolism Quality-of-Life (PEmb-QoL) questionnaire assesses quality of life (QoL) after pulmonary embolism (PE). We aimed to determine whether any clinical or pathophysiologic features of PE were associated with worse PEmb-QoL scores 1 month after PE., Methods: In this prospective multicenter registry, we conducted PEmb-QoL questionnaires. We determined differences in QoL domain scores for four primary variables: clinical deterioration (death, cardiac arrest, respiratory failure, hypotension requiring fluid bolus, catecholamine support, or new dysrhythmia), right ventricular dysfunction (RVD), PE risk stratification, and subsequent rehospitalization. For overall QoL score, we fit a multivariable regression model that included these four primary variables as independent variables., Results: Of 788 PE patients participating in QoL assessments, 156 (19.8%) had a clinical deterioration event, 236 (30.7%) had RVD of which 38 (16.1%) had escalated interventions. For those without and with clinical deterioration, social limitations had mean (±SD) scores of 2.07 (±1.27) and 2.36 (±1.47), respectively (p = 0.027). For intensity of complaints, mean (±SD) scores for patients without RVD (4.32 ± 2.69) were significantly higher than for those with RVD with or without reperfusion interventions (3.82 ± 1.81 and 3.83 ± 2.11, respectively; p = 0.043). There were no domain score differences between PE risk stratification groups. All domain scores were worse for patients with rehospitalization versus without. By multivariable analysis, worse total PEmb-QoL scores with effect sizes were subsequent rehospitalization 11.29 (6.68-15.89), chronic obstructive pulmonary disease (COPD) 8.17 (3.91-12.43), and longer index hospital length of stay 0.06 (0.03-0.08)., Conclusions: Acute clinical deterioration, RVD, and PE severity were not predictors of QoL at 1 month post-PE. Independent predictors of worsened QoL were rehospitalization, COPD, and index hospital length of stay., (© 2023 The Authors. Academic Emergency Medicine published by Wiley Periodicals LLC on behalf of Society for Academic Emergency Medicine.)

Background: Seasonal influenza causes significant morbidity and mortality with a disproportionately high disease burden in older adults. Strain-specific hemagglutination-inhibition (HAI) antibody titer is a well-established measure of humoral immunity against influenza and pre-vaccination HAI titer is a valuable indicator of pre-existing humoral immunity at the beginning of each influenza season in highly vaccinated older adults. While vaccine-induced HAI antibody titers are known to wane over time, accurate assessment of their interseason waning has been challenging. This is because pre-vaccination HAI titers are routinely measured using current season vaccine strain antigens instead of the prior season vaccines with which individuals were immunized; as such, they do not accurately represent residual antibody titers from prior season vaccination. This study took advantage of available pre-vaccination HAI titers measured using both current and prior season vaccine strain antigens in a longitudinal influenza immunization study with participants enrolled for multiple consecutive influenza seasons from 2014 through 2017. Influenza A virus (IAV) H3N2 and influenza B virus (IBV) strains in the vaccine formula changed in 2015 and again in 2016 season. IAV H1N1 vaccine strain remained the same from 2014 through 2016 seasons, but changed in 2017. We also investigated factors contributing to pre-existing humoral immunity., Results: Interseason waning of HAI titers was evident, but rates of waning varied among vaccine strains and study seasons, from 18% (p = .43) to 61% (p < .01). Rates of waning were noticeably greater when pre-vaccination HAI titers were measured by the routine approach, i.e., using current season vaccine strain antigens, from 33% (p = .12) to 83% (p < .01), adjusting for age at prior study season, sex, race, and education. This was largely because the routinely measured pre-vaccination HAI titers underrepresented residual HAI titers from prior season vaccinations. Moreover, interseason antibody waning and prior season post-vaccination HAI titers had significant and independent associations with pre-vaccination HAI titers., Conclusions: The routinely measured pre-vaccination HAI titer overestimates interseason HAI antibody waning as it underestimates residual antibody titers from prior season vaccination when virus strains in the vaccine formula change. Moreover, interseason antibody waning and prior season post-vaccination HAI titers independently contribute to pre-existing humoral immunity in this highly vaccinated, community-dwelling older adult population., (© 2023. The Author(s).)

Objectives: Existing pulmonary embolism (PE) risk scores were developed to predict death within weeks, but not more proximate adverse events. We determined the ability of 3 PE risk stratification tools (simplified pulmonary embolism severity index [sPESI], 2019 European Society of Cardiology guidelines [ESC], and PE short-term clinical outcomes risk estimation [PE-SCORE]) to predict 5-day clinical deterioration after emergency department (ED) diagnosis of PE., Methods: We analyzed data from six EDs on ED patients with confirmed PE. Clinical deterioration was defined as death, respiratory failure, cardiac arrest, new dysrhythmia, sustained hypotension requiring vasopressors or volume resuscitation, or escalated intervention within 5 days of PE diagnosis. We determined sensitivity and specificity of sPESI, ESC, and PE-SCORE for predicting clinical deterioration., Results: Of 1569 patients, 24.5% had clinical deterioration within 5 days. sPESI, ESC, and PE-SCORE classifications were low-risk in 558 (35.6%), 167 (10.6%), and 309 (19.6%), respectively. Sensitivities of sPESI, ESC, and PE-SCORE for clinical deterioration were 81.8 (78, 85.7), 98.7 (97.6, 99.8), and 96.1 (94.2, 98), respectively. Specificities of sPESI, ESC, and PE-SCORE for clinical deterioration were 41.2 (38.4, 44), 13.7 (11.7, 15.6), and 24.8 (22.4, 27.3). Areas under the curve were 61.5 (59.1, 63.9), 56.2 (55.1, 57.3), and 60.5 (58.9, 62.0). Negative predictive values were 87.5 (84.7, 90.2), 97 (94.4, 99.6), and 95.1 (92.7, 97.5)., Conclusions: ESC and PE-SCORE were better than sPESI for detecting clinical deterioration within 5 days after PE diagnosis., Competing Interests: Jason T. Nomura is an ultrasound consultant for Philips. The other authors disclose no conflicts of interest., (© 2023 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Background: We aimed to determine vaccine hesitancy and the main barriers associated with the 2019 novel coronavirus, SARS-CoV-2 (COVID-19) vaccination among families of children diagnosed with food/drug/environmental allergies., Methods: Between May and June 2021, we approached 146 families seen at the outpatient allergy clinic at the Montreal Children's Hospital and a community allergy practice were invited to complete an anonymous online survey on COVID-19 and vaccination attitudes and behaviour. Uni and multivariable logistic regressions were compared to estimate factors associated with vaccine hesitancy., Results: Among all patients, 24.1% reported vaccine hesitancy. The large majority of parents (95.2%) believed that vaccines work. The most common barrier to vaccination was fear of adverse side effects (57.0%). One-third of participants (31.5%) reported that a history of food, venom and drug allergy was a contraindication for COVID-19 vaccination. Fifty-nine (60.8%) participants stated that the dissemination of additional information would increase their willingness to be vaccinated. Most (96.9%) parents reported that their children's vaccinations were up to date. Hesitant families were more likely to be parents of children aged 6-10 years, be of Asian descent, report that mRNA vaccines are riskier than traditional vaccines, and report that the vaccine should not be given if the child has a history of allergic reaction to vaccines., Conclusion: Vaccine hesitancy exists mainly among certain ethnic groups and families with young children. Allergies to food, venom and drug allergy are commonly perceived as contraindications for COVID-19 vaccination. Knowledge translation activities addressing parental concerns will help increase vaccination rates., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Gooding, Protudjer, Gabrielli, Mulé, Shand, Zhang, McCusker, Noya, Harvey, Chalifour, Sicard, Abrams, Amiel, Ngo, Bonnici, MacDonald and Ben-Shoshan.)

Background: Intimate partner violence (IPV) is associated with suboptimal HIV treatment outcomes, but its distribution and risk factors among certain subpopulations of people living with HIV in resource-limited settings are not well known. We examined the prevalence, incidence, and recurrence of IPV and its association with adverse childhood experiences (ACEs) among pregnant/breastfeeding women living with HIV in Malawi., Methods: This study used longitudinal data for 455 pregnant women living with HIV continuously enrolled in the VITAL Start trial. IPV was assessed at baseline and months 1, 6, and 12 using the widely validated WHO IPV survey. Forms of IPV assessed were physical IPV, emotional IPV, and sexual IPV measured as prevalence, incidence, and recurrence. ACE histories were assessed using WHO's ACE International Questionnaire (ACE-IQ) tool. Logistic and log-binomial regressions were used in multivariable analyses that controlled for factors such as depression and alcohol use., Results: Participants' mean age was 27.6 ± 5.7 years. Forty-three percent (43%) reported IPV prevalence, 13% reported IPV incidence, and another 13% reported IPV recurrence, with emotional IPV being the most commonly reported IPV type. Over 96% reported experiencing ⩾1 ACE. In regression analysis, cumulative ACE scores were significantly associated with IPV prevalence and IPV recurrence and in both cases, the magnitude of association was greatest for sexual IPV compared with physical IPV and emotional IPV. ACE scores were not significantly associated with IPV incidence., Conclusions: IPV is highly prevalent among pregnant women living with HIV and continues to occur throughout the pregnancy and postpartum period; its graded relationship with ACEs is a concern in resource-limited settings where HIV/AIDS remains a public health concern. Strategies aimed to address the needs of pregnant/breastfeeding women living with HIV may benefit from the regular screening of this population for IPV and ACE, including in antenatal care clinics., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2023.)

Objectives: We sought to determine associations of early electrocardiogram (ECG) patterns with clinical deterioration (CD) within 5 days and with RV abnormality (abnlRV) by echocardiography in pulmonary embolism (PE)., Methods: In this prospective, multicenter study of newly confirmed PE patients, early echocardiography and initial ECG were examined. Initial ECG patterns included lead-specific ST-segment elevation (STE) or depression (STD), T-wave inversion (TWI), supraventricular tachycardia (SVT), sinus tachycardia, and right bundle branch block as complete (cRBBB) or incomplete (iRBBB). We defined CD as respiratory failure, hypotension, dysrhythmia, cardiac arrest, escalated PE intervention, or death within 5 days. We calculated odds ratios (ORs) for CD and abnlRV with univariate and full multivariate models in the presence of other variables., Results: Of 1676 patients, 1629 (97.2%) had both ECG and GDE; 415/1676 (24.7%) had CD, and 529/1629 (32.4%) had abnlRV. AbnlRV had an OR for CD of 4.25 (3.35, 5.38). By univariable analysis, the absence of abnormal ECG patterns had OR for CD and abnlRV of 0.34 (0.26, 0.44; p < 0.001) and 0.24 (0.18, 0.31; p < 0.001), respectively. By multivariable analyses, one ECG pattern had a significant OR for CD: SVT 2.87 (1.66, 5.00). Significant ORS for abnlRV were: TWI V 2-4 4.0 (2.64, 6.12), iRBBB 2.63 (1.59, 4.38), STE aVR 2.42 (1.58, 3.74), S1-Q3-T3 2.42 (1.70, 3.47), and sinus tachycardia 1.68 (1.14, 2.49)., Conclusions: SVT was an independent predictor of CD. TWI V 2-4 , iRBBB, STE aVR, sinus tachycardia, and S1-Q3-T3 were independent predictors of abnlRV. Finding one or more of these ECG patterns may increase considerations for performance of echocardiography to look for RV abnormalities and, if present, inform concerns for early clinical deterioration., (© 2022 The Authors. Academic Emergency Medicine published by Wiley Periodicals LLC on behalf of Society for Academic Emergency Medicine.)

Introduction: Adverse childhood experiences (ACEs) have been linked to common mental disorders (CMDs) such as anxiety and depressive thoughts. We examined the prevalence of ACEs and their association with CMDs among pregnant women living with HIV (PWLHIV) in Malawi-an HIV endemic resource-limited setting., Methods: This is a cross-sectional study of 798 PWLHIV enrolled in the VITAL Start trial in Malawi (10/2018 to 06/2021) (NCT03654898). ACE histories were assessed using WHO's Adverse Childhood Experiences International Questionnaire (ACE-IQ) tool. Depressive symptoms (somatic complaints, reduced vital energy, anxiety, and depressive thoughts) were assessed using WHO's Self Reporting Questionnaire 20-Item (SRQ-20) tool. Log-binomial regressions were used to examine the association between cumulative ACEs and each depressive symptom, as well as identify ACEs driving this association., Results: The mean age of our sample was 27.5 years. Over 95 % reported having experienced ≥1 ACE. On average, each participant reported four ACEs; 11 % reported sexual abuse. About 52 % and 44 % reported anxiety and depressive thoughts, respectively. In regressions, cumulative ACE scores were significantly associated with depressive symptoms-even after adjusting for multiple testing. This association was primarily driven by reports of sexual abuse., Limitations: Data on maternal ACEs were self-reported and could suffer from measurement error because of recall bias., Conclusions: ACEs are widespread and have a graded relationship with depressive symptoms in motherhood. Sexual abuse was found to be a primary driver of this association. Earlier recognition of ACEs and provision of trauma-informed interventions to improve care in PWLHIV may reduce negative mental health sequelae., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Male sex and old age are risk factors for severe coronavirus disease 2019, but the intersection of sex and aging on antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines has not been characterized., Methods: Plasma samples were collected from older adults (aged 75-98 years) before and after 3 doses of SARS-CoV-2 mRNA vaccination, and from younger adults (aged 18-74 years) post-dose 2, for comparison. Antibody binding to SARS-CoV-2 antigens (spike protein [S], S receptor-binding domain, and nucleocapsid), functional activity against S, and live-virus neutralization were measured against the vaccine virus and the Alpha, Delta, and Omicron variants of concern (VOCs)., Results: Vaccination induced greater antibody titers in older females than in older males, with both age and frailty associated with reduced antibody responses in males but not females. Responses declined significantly in the 6 months after the second dose. The third dose restored functional antibody responses and eliminated disparities caused by sex, age, and frailty in older adults. Responses to the VOCs, particularly the Omicron variant, were significantly reduced relative to the vaccine virus, with older males having lower titers to the VOCs than older females. Older adults had lower responses to the vaccine and VOC viruses than younger adults, with greater disparities in males than in females., Conclusions: Older and frail males may be more vulnerable to breakthrough infections owing to low antibody responses before receipt of a third vaccine dose. Promoting third dose coverage in older adults, especially males, is crucial to protecting this vulnerable population., Competing Interests: Potential conflicts of interest. I. S., M. L., C. W., S. Y., and A. P. received funding for their institution from NIAID/NIH (grants N272201400007C and 75N93021C00045) and from the CDC (grant 75D30121C11061). A. J. K., S. M. C., and M. J. B. received grant support from the National Institute for Innovation in Manufacturing Biopharmaceuticals consortium, which that went to their institution. R. M. was supported by the Office of Research on women's Health and the NIA, NIH (grant U54AG062333). A. M. M. has received grants or contracts from the Agency for Healthcare Research and Quality, the CDC, the NIH, and Merck. A. H. K. received NIAID funding (grant K08AI156021) and consulting fees from Roche. S. X. L. received NIH grants for their institution (grants U54AG062333, R01AI108907, R21AG059742, UH2AG056933, U01AI35042, R01AG060825, and U01AI165826); funding for their institution from Cybersecurity and Infrastructure Security Agency, MMAAP, the Sanofi Pasteur grant project and the Howard and Abby Milstein Foundation; and honoraria for participating in the Sanofi Pasteur COVID-19 Vaccine International Advisory Board, the Sanofi Pasteur Speakers Bureau for Influenza Vaccines, and the GSK Speakers Bureau for Herpes Zoster Vaccine Shingrix. They are also the president of the MMAAP foundation. S. L. K. received support from the NIA/NIH (grant U54AG062333) and NIH/National Cancer Institute/NIH (grant U54CA260492) and is a board member for the NIH’s Advisory Committee on Research on women's Health and an editor for PloS Pathogens and the Journal of Virology. All other authors report no potential conflicts., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

Objectives: Identifying right ventricle (RV) abnormalities is important to stratifying pulmonary embolism (PE) severity. Disposition decisions are influenced by concerns about early deterioration. Triaging strategies, like the Simplified Pulmonary Embolism Severity Index (sPESI), do not include RV assessments as predictors or early deterioration as outcome(s). We aimed to (1) determine if RV assessment variables add prognostic accuracy for 5-day clinical deterioration in patients classified low risk by sPESI, and (2) determine the prognostic importance of RV assessments compared to other variables and to each other., Methods: We identified low risk sPESI patients (sPESI = 0) from a prospective PE registry. From a large field of candidate variables, we developed, and compared prognostic accuracy of, full and reduced random forest models (with and without RV assessment variables, respectively) on a validation database. We reported variable importance plots from full random forest and provided odds ratios for statistical inference of importance from multivariable logistic regression. Outcomes were death, cardiac arrest, hypotension, dysrhythmia, or respiratory failure within 5 days of PE., Results: Of 1736 patients, 610 (35.1%) were low risk by sPESI and 72 (11.8%) experienced early deterioration. Of the 610, RV abnormality was present in 157 (25.7%) by CT, 121 (19.8%) by echocardiography, 132 (21.6%) by natriuretic peptide, and 107 (17.5%) by troponin. For deterioration, the receiver operating characteristics for full and reduced random forest prognostic models were 0.80 (0.77-0.82) and 0.71 (0.68-0.73), respectively. RV assessments were the top four in the variable importance plot for the random forest model. Echocardiography and CT significantly increased predicted probability of 5-day clinical deterioration by the multivariable logistic regression., Conclusions: A PE triaging strategy with RV imaging assessments had superior prognostic performance at classifying low risk for 5-day clinical deterioration versus one without., (© 2022 Society for Academic Emergency Medicine.)

Context: Most epidemiological research on eczema has largely relied on patient survey data. With the increasing use of electronic medical records (EMR) in primary care, there has been a shift in epidemiological research towards the use of validated case definitions to study disease., Objective: Apply a validated case definition for eczema to EMR data from primary care providers participating in the Canadian Primary Care Sentential Surveillance Network (CPCSSN) to determine the prevalence of diagnosed eczema in Canada and describe patient's characteristics including risk factors and comorbidities., Study Design: Cross-sectional study., Dataset: EMR data from 1,574 primary care providers in seven Canadian provinces., Population Studied: Patient records were examined for those with at least one encounter with a family physician, nurse practitioner or community pediatrician participating in CPCSSN between January 1, 2017, and December 31, 2019 (N= 689,301 patients)., Outcome Measures: Primary outcome was lifetime prevalence of eczema. Secondary outcomes were demographics of eczema patients and the association between eczema and various comorbidities., Results: Descriptive statistics revealed a lifetime prevalence of documented eczema of 11.6% overall, 15.1% in those <19 years, and 11.5% in those >19 years. Patients with eczema were more likely to be smokers. Using the Material and Social Deprivation Index we found eczema was more prevalent among the least materially and socially deprived quintiles. In logistic regression, female patients (OR, 1.29; 95% CI, 1.27-1.32) and patients <19 years (OR, 1.27; 95% CI, 1.19-1.35) had higher odds of eczema compared to male patients and patients aged >19 years. Patients with comorbidities such as rhinitis (OR, 2.11; 95% CI, 2.06-2.17), asthma (OR, 1.4; 95% CI, 1.37-1.43), any allergy (OR, 1.09, 95% CI 1.06-1.11), COPD (OR, 1.1; 95% CI, 1.06-1.14) and anxiety (OR, 1.66; 95% CI, 1.63-1.69) had higher odds of eczema compared to patients without these comorbidities. Depression (OR, 0.96; 95% CI, 0.94-0.98) and obesity (OR, 0.96; 95% CI, 0.94-0.98) were negatively associated with a diagnosis of eczema., Conclusion: This is the first study in Canada to determine the prevalence of primary care provider documented eczema using EMR data. This study can inform and improve disease surveillance as well as future studies exploring burden of illness, trends or interventions related to eczema care in Canada., Competing Interests: Authors report none, (Annals of Family Medicine, Inc.)

Context: Choosing Wisely Canada (CWC) aims to engage healthcare providers to reduce unnecessary care. Reducing overuse of antimicrobials and antipsychotics in patients with dementia in primary care settings remains an ongoing challenge. Audit and Feedback (A&F) interventions can facilitate practice change but can be improved by understanding factors affecting the likelihood of uptake of the feedback. Objective: To assess the impact of A&F interventions to reduce unnecessary prescribing of antibiotics and antipsychotics use and evaluate whether practice changes remain stable over time. Design: Clustered randomized controlled trial. Dataset: The Manitoba Primary Care Research Network (MaPCReN), a practice-based network that includes a repository containing de-identified EMR data from over 288,000 Manitobans. Population: Primary care providers participating in MaPCReN were randomized to three A&F groups: 1) Information on the relevant CWC recommendations; 2) practice specific data along with general information regarding the CWC recommendations 3) No CWC information. Outcome Measures: Statistics demonstrating changes in target prescriptions. Multivariate regression assessed characteristics of providers with improved prescribing. Results: 182 primary care providers were evaluated, 86.3% decreased the number of target prescriptions. More providers decreased prescribing in group1 (88.9%) or group2 (94.0%) compared to the control group 3 (76.7%) (p-value 0.02). There was no statistically significant difference between practice specific feedback and generic CWC information. An average of 46 antibiotic medications per provider were prescribed for viral indications in 2014/2015. This dropped to 15 in 2016/17 and was 18 in 2018/19. An average of 3 antipsychotic medications were prescribed for patients with dementia in 2014/2015. This dropped 7% in 2016/17 and remained stable in 2018/19. There were no statistically significant provider characteristics when considering all providers with improved prescribing, but male, rural and fee for service providers were more likely to decrease prescribing greater than the mean. Conclusion: Both practice specific and generic A&F information sent directly to primary care providers by a trusted source reduced potentially unnecessary prescriptions. This supports ongoing engagement with primary care providers in practice-based research networks to improve care and promote sustained practice changes., Competing Interests: Authors report none., (© 2021 Annals of Family Medicine, Inc.)

Oral pre-exposure prophylaxis (PrEP) is recommended for persons at substantial risk for HIV, including female sex workers (FSW), men who have sex with men (MSM), people who inject drugs (PWID), and transgender women (TGW). We report on a PrEP demonstration project at seven clinics in the Democratic Republic of the Congo. Routinely collected data were abstracted to assess PrEP uptake, scheduled visit attendance, and self-reported adherence. Between February and May 2018, 469 eligible clients were offered daily oral PrEP; 75.1% accepted: 78.7% FSW, 20.5% MSM, and 0.9% TGW. Two percent also identified as PWID. Attendance was 64.5% at one-month visits; 82.1% at three-month visits; and among 47.7% of clients who initiated PrEP at least six months before data abstraction, 85.8% at six-month visits. Among 66.3% of clients with at least one adherence assessment, 39% self-reported low adherence. Results demonstrate the acceptability of PrEP delivered in healthcare settings serving FSW, MSM, PWID, and TGW.

Older adults (≥65 years of age) bear a significant burden of severe disease and mortality associated with influenza, despite relatively high annual vaccination coverage and substantial pre-existing immunity to influenza. To test the hypothesis that host factors, including age and sex, play a role in determining the effect of repeated vaccination and levels of pre-existing humoral immunity to influenza, we evaluated pre- and post-vaccination strain-specific hemagglutination inhibition (HAI) titers in adults over 75 years of age who received a high-dose influenza vaccine in at least four out of six influenza seasons. Pre-vaccination titers, rather than host factors and repeated vaccination were significantly associated with post-vaccination HAI titer outcomes, and displayed an age-by-sex interaction. Pre-vaccination titers to H1N1 remained constant with age. Titers to H3N2 and influenza B viruses decreased substantially with age in males, whereas titers in females remained constant with age. Our findings highlight the importance of pre-existing immunity in this highly vaccinated older adult population and suggest that older males are particularly vulnerable to reduced pre-existing humoral immunity to influenza., (© 2021. The Author(s).)

Background: We compared the cost-effectiveness of pediatric provider-initiated HIV testing and counseling (PITC) vs no PITC in a range of clinical care settings in South Africa., Methods: We used the Cost-Effectiveness of Preventing AIDS Complications Pediatric model to simulate a cohort of children, aged 2-10 years, presenting for care in 4 settings (outpatient, malnutrition, inpatient, tuberculosis clinic) with varying prevalence of undiagnosed HIV (1.0%, 15.0%, 17.5%, 50.0%, respectively). We compared "PITC" (routine testing offered to all patients; 97% acceptance and 71% linkage to care after HIV diagnosis) with no PITC. Model outcomes included life expectancy, lifetime costs, and incremental cost-effectiveness ratios (ICERs) from the health care system perspective and the proportion of children with HIV (CWH) diagnosed, on antiretroviral therapy (ART), and virally suppressed. We assumed a threshold of $3200/year of life saved (YLS) to determine cost-effectiveness. Sensitivity analyses varied the age distribution of children seeking care and costs for PITC, HIV care, and ART., Results: PITC improved the proportion of CWH diagnosed (45.2% to 83.2%), on ART (40.8% to 80.4%), and virally suppressed (32.6% to 63.7%) at 1 year in all settings. PITC increased life expectancy by 0.1-0.7 years for children seeking care (including those with and without HIV). In all settings, the ICER of PITC vs no PITC was very similar, ranging from $710 to $1240/YLS. PITC remained cost-effective unless undiagnosed HIV prevalence was <0.2%., Conclusions: Routine testing improves HIV clinical outcomes and is cost-effective in South Africa if the prevalence of undiagnosed HIV among children exceeds 0.2%. These findings support current recommendations for PITC in outpatient, inpatient, tuberculosis, and malnutrition clinical settings., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objective: Many adolescents and young adults (AYA) have unmet HIV prevention needs. We describe the Prevention and Treatment through a Comprehensive Care Continuum for HIV-affected Adolescents in Resource Constrained Settings (PATC3H) consortium organization, transition milestones, and youth engagement strategies. The PATC3H consortium focuses on reducing HIV incidence and related health disparities among AYA., Design and Methods: Organizational data were obtained from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and supplemented with a brief survey completed by study principal investigators. Transition from the initial phase (years 1 and 2) to the subsequent phase (years 3 and 5) was contingent on meeting prespecified milestones. We reviewed the structure and function of the research consortium, identified shared elements of transition milestones, and examined common youth engagement strategies., Results: The PATC3H consortium supports eight research studies through a milestone transition mechanism. The consortium includes AYA HIV research studies in seven countries - Brazil, Kenya, Mozambique, Nigeria, South Africa, Uganda, and Zambia. The NIH request for applications required transition milestones that included early consultation with stakeholders. The transition milestones required by NIH for the eight studies included early consultation with health and policy stakeholders, pilot intervention data, and commitment from national government stakeholders. All studies provided multiple pathways for AYA engagement, including AYA advisory boards and youth-led research studies., Conclusion: Data suggest that requiring milestones to transition to the final phase may have facilitated health and policy stakeholder engagement and enhanced formative assessment of regulatory protocols. These data have implications for designing engaged research studies in low and middle-income countries., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Develop and validate a prognostic model for clinical deterioration or death within days of pulmonary embolism (PE) diagnosis using point-of-care criteria., Methods: We used prospective registry data from six emergency departments. The primary composite outcome was death or deterioration (respiratory failure, cardiac arrest, new dysrhythmia, sustained hypotension, and rescue reperfusion intervention) within 5 days. Candidate predictors included laboratory and imaging right ventricle (RV) assessments. The prognostic model was developed from 935 PE patients. Univariable analysis of 138 candidate variables was followed by penalized and standard logistic regression on 26 retained variables, and then tested with a validation database (N = 801)., Results: Logistic regression yielded a nine-variable model, then simplified to a nine-point tool (PE-SCORE): one point each for abnormal RV by echocardiography, abnormal RV by computed tomography, systolic blood pressure < 100 mmHg, dysrhythmia, suspected/confirmed systemic infection, syncope, medico-social admission reason, abnormal heart rate, and two points for creatinine greater than 2.0 mg/dL. In the development database, 22.4% had the primary outcome. Prognostic accuracy of logistic regression model versus PE-SCORE model: 0.83 (0.80, 0.86) vs. 0.78 (0.75, 0.82) using area under the curve (AUC) and 0.61 (0.57, 0.64) vs. 0.50 (0.39, 0.60) using precision-recall curve (AUCpr). In the validation database, 26.6% had the primary outcome. PE-SCORE had AUC 0.77 (0.73, 0.81) and AUCpr 0.63 (0.43, 0.81). As points increased, outcome proportions increased: a score of zero had 2% outcome, whereas scores of six and above had ≥ 69.6% outcomes. In the validation dataset, PE-SCORE zero had 8% outcome [no deaths], whereas all patients with PE-SCORE of six and above had the primary outcome., Conclusions: PE-SCORE model identifies PE patients at low- and high-risk for deterioration and may help guide decisions about early outpatient management versus need for hospital-based monitoring., Competing Interests: The authors have declared that no competing interests exist.