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Background: Disparities exist in underrepresented in medicine (URiM) resident representation. This review examines recent trends in resident diversity, URiM recruitment strategies, and identifies research gaps in equity, diversity, and inclusion (EDI) for URiM residents., Methods: MEDLINE, EMBASE, Web of Science, and ERIC databases were searched for studies published from 2017 to 2022 on URiM resident prevalence and recruitment initiatives., Results: 3634 abstracts were reviewed, and 52 articles were included. 35 (67 ​%) studies reported on prevalence of URiM residents, demonstrating URiM resident composition is lower than residency applicant demographics, particularly in surgery. Seventeen (33 ​%) studies reported on URiM recruitment interventions, such as visiting clerkship programs, holistic review, and targeted outreach, and demonstrated success in increasing recruitment of URiM candidates to programs., Conclusions: URiM residents remain disproportionately underrepresented, and markedly so among surgical residency programs. Further research should focus on implementing EDI interventions in surgery and assess URiM resident attrition post-matriculation., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Most smokers who achieve short-term abstinence relapse even when aided by evidence-based cessation treatment. Mobile health presents a promising but largely untested avenue for providing adjunct behavioral support for relapse prevention. This paper presents the rationale and design of a randomized controlled trial aimed at evaluating the effectiveness of personalized mobile chat messaging support for relapse prevention among people who recently quit smoking., Methods: This is a two-arm, assessor-blinded, randomized controlled trial conducted in two clinic-based smoking cessation services in Hong Kong. An estimated 586 daily tobacco users who have abstained for 3 to 30 days will be randomized (1:1) to intervention group or control group. Both groups receive standard-of-care smoking cessation treatment from the services. The intervention group additionally receives 3-month relapse prevention support via mobile chat messaging, including cessation advice delivered by a live counselor and access to a supportive chatbot via WhatsApp. The control group receives text messaging on generic cessation advice for 3 months as attention control. The primary outcome is tobacco abstinence verified by an exhaled carbon monoxide of <5 parts per million or a negative salivary cotinine test at 6 months after randomization. Secondary outcomes include self-reported 6-month prolonged tobacco abstinence, 7-day point-prevalent abstinence, and relapse rate. The primary analyses will be by intention-to-treat, assuming participants with missing data are non-abstinent. This trial is registered with ClinicalTrials.gov (NCT05370352) and follows CONSORT-EHEALTH., Conclusion: This trial will provide new evidence on the effectiveness of mobile chat messaging as a scalable and accessible intervention for relapse prevention., 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) 2024.)

Introduction: Real-Time Gated Proton Therapy (RGPT) is an active motion management technique that utilizes treatment gating and tumor tracking via fiducial markers. When performing RGPT treatment for prostate cancer, it is essential to account for the CTV displacement relative to the body in the clinical workflow. The workflow at the National Cancer Centre Singapore (NCCS) includes bone matching via CT-CBCT images, followed by fiducial matching via pulsed fluoroscopy (soft tissue matching), and finally, a robustness evaluation procedure to determine if the difference is within an allowable tolerance. In this study, we compare two CTV translation methods for robustness evaluation: (1) an in-house translation algorithm and (2) the RayStation "simulate organ motion" Deformable image registration (DIR) algorithm., Methods: Nine RGPT prostate patient plans with CTV volumes ranging from 17.1 to 96.72 cm 2 were included in this study. An in-house translation algorithm and "simulate organ motion" DIR RayStation algorithm were used to generate CTV shifts along R-L, I-S, and P-A axes between ± $ \pm $ 10 mm at 2 mm steps. At each step, dose metrics, which include CTV D max , CTV D 95% , and CTV D 98% , were extracted and used as comparative metrics for CTV target coverage and hot spot evaluation., Results: Across all axes, there were no statistically significant differences between the two algorithms for all three dose metrics: CTV D max (P = 0.92, P = 0.91, and P = 0.47), CTV D 95% (P = 0.97, P = 0.22, and P = 0.33), and CTV D 98% (P = 0.85, P = 0.33, and P = 0.36). Further, the in-house translation algorithm evaluation time was less than 10 s, two orders of magnitude faster than the DIR algorithm., Conclusion: Our results demonstrate that the simpler in-house algorithm performs equivalently to the realistic DIR algorithm when simulating CTV motion in prostate cancers. Furthermore, the in-house algorithm completes the robustness evaluation two orders of magnitude faster than the DIR algorithm. This significant reduction in evaluation time is crucial especially when preparatory time efficiency is of paramount importance in a busy clinic., (© 2024 The Author(s). Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Objectives: To summarize current evidence of high-dose influenza vaccine (HD-IV) vs standard-dose (SD-IV) regarding severe clinical outcomes., Methods: A prespecified meta-analysis was conducted to assess relative vaccine effectiveness (rVE) of HD-IV vs SD-IV in reducing the rates of (1) pneumonia and influenza (P&I) hospitalization, (2) all hospitalizations, and (3) all-cause death in adults ≥ 65 years in randomized controlled trials. Pooled effect sizes were estimated using fixed-effects models with the inverse variance method., Results: Five randomized trials were included encompassing 105,685 individuals. HD-IV vs SD-IV reduced P&I hospitalizations (rVE: 23.5 %, [95 %CI: 12.3 to 33.2]). HD-IV vs SD-IV also reduced rate of all-cause hospitalizations (rVE: 7.3 %, [95 %CI: 4.5 to 10.0]). No significant differences were observed in death rates (rVE = 1.6 % ([95 %CI: -2.0 to 5.0]) in HD-IV vs SD-IV. Sensitivity analyses omitting trials with participants sharing the same comorbidity, trials with ≥ 100 events, and random-effects models provided comparable estimates for all outcomes., Conclusions: HD-IV reduced the incidence of P&I and all-cause hospitalization vs SD-IV in adults ≥ 65 years in randomized trials, through no significant difference was observed in all-cause death rates. These findings, supported by evidence from several randomized studies, can benefit from replication in a fully powered, individually randomized trial., Competing Interests: Declaration of Competing Interest KGS has served on advisory boards for Sanofi. MML, RH, and MD are full-time employees of Sanofi and may hold stocks and/or shares in the company. SDS has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi, Theracos, US2. AI and consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Puretech Health. TBS is chief investigator of the Boston Scientific financed ”DANLOGIC-HF” trial, the Sanofi financed “NUDGE-FLU” trial, the Sanofi financed “DANFLU-1″ trial, the Sanofi financed “DANFLU-2″ trial and steering committee member of the Boston Scientific sponsored “LUX-Dx TRENDS Evaluates Diagnostics Sensors in Heart Failure Patients Receiving Boston Scientific's Investigational ICM System” trial, the Amgen sponsored GALACTIC-HF trial, the Boehringer Ingelheim financed EASi-KIDNEY trial and served on advisory boards for Sanofi, Amgen, CSL Seqirus and GSK and received speaker honorariums from Bayer, Novartis, Sanofi, GE Healthcare and GSK and received research grants from Boston Scientific, GE Healthcare, AstraZeneca, Novo Nordisk, and Sanofi and consulted for Novo Nordisk, IQVIA and Parexel. The remaining authors have nothing to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Daily quality assurance is an integral part of a radiotherapy workflow to ensure the dose is delivered safely and accurately to the patient. It is performed before the first treatment of the day and needs to be time and cost efficient for a multiple gantries proton center. In this study, we introduced an efficient method to perform QA for output constancy, range verification, spot positioning accuracy and imaging and proton beam isocenter coincidence with DailyQA3., Methods: A stepped acrylic block of specific dimensions is fabricated and placed on top of the DailyQA3 device. Treatment plans comprising of two different spread-out Bragg peaks and five individual spots of 1.0 MU each are designed to be delivered to the device. A mathematical framework to measure the 2D distance between the detectors and individual spot is introduced and play an important role in realizing the spot positioning and centering QA. Lastly, a 5 months trends of the QA for two gantries are presented., Results: The outputs are monitored by two ion chambers in the DailyQA3 and a tolerance of ± 3 % $ \pm 3\% $ are used. The range of the SOBPs are monitored by the ratio of ion chamber signals and a tolerance of ± 1 mm $ \pm 1\ {\mathrm{mm}}$ is used. Four diodes at ± 10 cm $ \pm 10\ {\mathrm{cm}}$ from the central ion chambers are used for spot positioning QA, while the central ion chamber is used for imaging and proton beam isocenter coincidence QA. Using the framework, we determined the absolute signal threshold corresponding to the offset tolerance between the individual proton spot and the detector. A 1.5 mm $1.5\ {\mathrm{mm}}$ tolerances are used for both the positioning and centering QA. No violation of the tolerances is observed in the 5 months trends for both gantries., Conclusion: With the proposed approach, we can perform four QA items in the TG224 within 10 min., (© 2024 The Authors. Journal of Applied Clinical Medical Physics is published by Wiley Periodicals, Inc. on behalf of The American Association of Physicists in Medicine.)

Introduction: Real-time gated proton therapy (RGPT) is a motion management technique unique to the Hitachi particle therapy system. It uses pulsed fluoroscopy to track an implanted fiducial marker. There are currently no published guidelines on how to conduct the commissioning and quality assurance. In this work we reported on our centre's commissioning workflow and our daily and monthly QA procedures., Methods: Six commissioning measurements were designed for RGPT. The measurements include imaging qualities, fluoroscopic exposures, RGPT marker tracking accuracy, temporal gating latency, fiducial marker tracking fidelity and an end-to-end proton dosimetry measurement. Daily QA consists of one measurement on marker localization accuracy. Four months daily QA trends are presented. Monthly QA consists of three measurementson the gating latency, fluoroscopy imaging quality and dosimetry verification of gating operation with RGPT., Results: The RGPT was successfully commissioned in our centre. The air kerma rates were within 15 % from specifications and the marker tracking accuracies were within 0.245 mm. The gating latencies for turning the proton beam on and off were 119.5 and 50.0 ms respectively. The 0.4x10.0 mm 2 Gold Anchor TM gave the best tracking results with visibility up to 30 g/cm 2 . Gamma analysis showed that dose distribution of a moving and static detectors had a passing rate of more than 95 % at 3 %/3mm. The daily marker localization QA results were all less than 0.2 mm., Conclusion: This work could serve as a good reference for other upcoming Hitachi particle therapy centres who are interested to use RGPT as their motion management solution., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

In this study, we evaluated the implementation of a second-tier genetic screening test using an amplicon-based next-generation sequencing (NGS) panel in our laboratory during the period of 1 September 2021 to 31 August 2022 for the newborn screening (NBS) of six conditions for inborn errors of metabolism: citrullinemia type II (MIM #605814), systemic primary carnitine deficiency (MIM #212140), glutaric acidemia type I (MIM #231670), beta-ketothiolase deficiency (#203750), holocarboxylase synthetase deficiency (MIM #253270) and 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (MIM # 246450). The custom-designed NGS panel can detect sequence variants in the relevant genes and also specifically screen for the presence of the hotspot variant IVS16ins3kb of SLC25A13 by the copy number variant calling algorithm. Genetic second-tier tests were performed for 1.8% of a total of 22,883 NBS samples. The false positive rate for these six conditions after the NGS second-tier test was only 0.017%, and two cases of citrullinemia type II would have been missed as false negatives if only biochemical first-tier testing was performed. The confirmed true positive cases were citrullinemia type II ( n = 2) and systemic primary carnitine deficiency ( n = 1). The false positives were later confirmed to be carrier of citrullinemia type II ( n = 2), carrier of glutaric acidemia type I ( n = 1) and carrier of systemic primary carnitine deficiency ( n = 1). There were no false negatives reported. The incorporation of a second-tier genetic screening test by NGS greatly enhanced our program's performance with 5-working days turn-around time maintained as before. In addition, early genetic information is available at the time of recall to facilitate better clinical management and genetic counseling.

The continual distress of COVID-19 cannot be overemphasized. The pandemic economic and social costs are alarming, with recent attributed economic loss amounting to billions of dollars globally. This economic loss is partly driven by workplace absenteeism due to the disease. Influenza is believed to be a culprit in reinforcing this phenomenon as it may exist in the population concurrently with COVID-19 during the influenza season. Furthermore, their joint infection may increase workplace absenteeism leading to additional economic loss. The objective of this project will aim to quantify the collective impact of COVID-19 and influenza on workplace absenteeism via a mathematical compartmental disease model incorporating population screening and vaccination. Our results indicate that appropriate PCR testing and vaccination of both COVID-19 and seasonal influenza may significantly alleviate workplace absenteeism. However, with COVID-19 PCR testing, there may be a critical threshold where additional tests may result in diminishing returns. Regardless, we recommend on-going PCR testing as a public health intervention accompanying concurrent COVID-19 and influenza vaccination with the added caveat that sensitivity analyses will be necessary to determine the optimal thresholds for both testing and vaccine coverage. Overall, our results suggest that rates of COVID-19 vaccination and PCR testing capacity are important factors for reducing absenteeism, while the influenza vaccination rate and the transmission rates for both COVID-19 and influenza have lower and almost equal affect on absenteeism. We also use the model to estimate and quantify the (indirect) benefit that influenza immunization confers against COVID-19 transmission., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

This updated systematic review and meta -analysis of randomized and observational studies published up to April 2023 assessed the relative performance of high-dose inactivated influenza vaccine (HD-IIV) and standard-dose influenza vaccines (SD-IIV) against influenza-associated outcomes in older adults (≥65 years). The analysis included studies conducted over 12 influenza seasons (2009/2010 to 2019/2020, 2021/2022), including over 45 million individuals aged ≥ 65 years, and showed that HD-IIV provided significantly better protection than SD-IIV against influenza-like illness and influenza-related hospitalizations, as well as cardiovascular, cardiorespiratory, and all-cause hospitalizations. Subgroup analyses showed HD-IIV consistently provided better protection than SD-IIV against influenza outcomes across the age range (65+, 75+ 85+ years), and regardless of the predominantly circulating influenza strain and vaccine antigenic match/mismatch. Randomized studies continue to drive high-quality evidence on the effectiveness of high-dose inactivated influenza vaccine relative to SD-IIV against severe influenza outcomes in adults aged ≥ 65 years, supported by observational data., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JKHL, GKLL, JKY, MML, and SIS are employees of Sanofi, the manufacturer of the high-dose influenza vaccine, and may hold shares and/or stock options in the company., (© 2023 The Author(s).)

Background: Respiratory syncytial virus (RSV) is associated with substantial morbidity in the United States, especially among infants. Nirsevimab, an investigational long-acting monoclonal antibody, was evaluated as an immunoprophylactic strategy for infants in their first RSV season and for its potential impact on RSV-associated, medically attended lower respiratory tract illness (RSV-MALRTI) and associated costs., Methods: A static decision-analytic model of the US birth cohort during its first RSV season was developed to estimate nirsevimab's impact on RSV-related health events and costs; model inputs included US-specific costs and epidemiological data. Modelled RSV-related outcomes included primary care and emergency room visits, hospitalizations including intensive care unit admission and mechanical ventilations, and RSV-related mortality., Results: Under current standard of care, RSV caused 529 915 RSV-MALRTIs and 47 281 hospitalizations annually, representing $1.2 billion (2021 US dollars [USD]) in costs. Universal immunization of all infants with nirsevimab is expected to reduce 290 174 RSV-MALRTI, 24 986 hospitalizations, and expenditures of $612 million 2021 USD., Conclusions: An all-infant immunization strategy with nirsevimab could substantially reduce the health and economic burden for US infants during their first RSV season. While this reduction is driven by term infants, all infants, including palivizumab-eligible and preterm infants, would benefit from this strategy., Competing Interests: Potential conflicts of interest. A. K., M. B., and J. L. are employees of Sanofi and may hold shares and/or stock options in the company. A. S., R. M., S. M., and J. R. are salaried employees of Evidera and are not allowed to accept remuneration from any clients for their services. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Prior studies have established those elderly patients with chronic obstructive pulmonary disease (COPD) are at elevated risk for developing influenza-associated complications such as hospitalization, intensive-care admission, and death. This study sought to determine whether influenza vaccination could improve survival among elderly patients with COPD., Materials/methods: This study included Veterans (age ≥ 65 years) diagnosed with COPD that received care at the United States Veterans Health Administration (VHA) during four influenza seasons, from 2012-2013 to 2015-2016. We linked VHA electronic medical records and Medicare administrative files to Centers for Disease Control and Prevention National Death Index cause of death records as well as influenza surveillance data. A multivariable time-dependent Cox proportional hazards model was used to compare rates of mortality of recipients of influenza vaccination to those who did not have records of influenza vaccination. We estimated hazard ratios (HRs) adjusted for age, gender, race, socioeconomic status, comorbidities, and healthcare utilization., Results: Over a span of four influenza seasons, we included 1,856,970 person-seasons of observation where 1,199,275 (65%) had a record of influenza vaccination and 657,695 (35%) did not have a record of influenza vaccination. After adjusting for comorbidities, demographic and socioeconomic characteristics, influenza vaccination was associated with reduced risk of death during the most severe periods of influenza seasons: 75% all-cause (HR = 0.25; 95% CI: 0.24-0.26), 76% respiratory causes (HR = 0.24; 95% CI: 0.21-0.26), and 82% pneumonia/influenza cause (HR = 0.18; 95% CI: 0.13-0.26). A significant part of the effect could be attributed to "healthy vaccinee" bias as reduced risk of mortality was also found during the periods when there was no influenza activity and before patients received vaccination: 30% all-cause (HR = 0.70; 95% CI: 0.65-0.75), 32% respiratory causes (HR = 0.68; 95% CI: 0.60-0.78), and 51% pneumonia/influenza cause (HR = 0.49; 95% CI: 0.31-0.78). However, as a falsification study, we found that influenza vaccination had no impact on hospitalization due to urinary tract infection (HR = 0.97; 95% CI: 0.80-1.18)., Conclusions: Among elderly patients with COPD, influenza vaccination was associated with reduced risk for all-cause and cause-specific mortality., Competing Interests: Competing Interests Statement: YYX has received research funding from Sanofi Pasteur, Sanofi, Pfizer, Genentech, Janssen, VIR Biotechnology, and the Office of Rural Health Resource Center-Eastern Region. SMM has received research funding from Assurex, GSK, Merck, Pfizer, Roche and Sanofi, and is/was a member of advisory boards for GSK and Sanofi. JN, RVA, JKL, EWT and AC are employees of Sanofi Pasteur. The remaining authors have nothing to disclose. Affiliation with Sanofi Pasteur could be perceived as a potential conflict of interest because Sanofi Pasteur produces influenza vaccines.

Background: Influenza vaccine efficacy/effectiveness can vary from season to season due in part to the dominant circulating strains and antigenic matching. This study reviews the relative vaccine efficacy/effectiveness (rVE) of high-dose inactivated trivalent influenza vaccine (HD-IIV3) compared to standard-dose influenza vaccines (SD-IIV) in adults aged ≥ 65 years against influenza-associated outcomes. Additional sub-analyses of HD-IIV3 rVE were performed by the predominantly circulating influenza strain and the antigenic match or mismatch of the vaccine against the predominant circulating strains., Methods: An updated systematic review and meta-analysis was conducted for studies assessing the rVE of HD-IIV3 against probable/laboratory-confirmed influenza-like illness (ILI), hospital admissions, and death in adults aged ≥ 65 years. Results from individual seasons were extracted from the studies, and viral surveillance data were used to determine the dominant circulating strains and antigenic match for each season. Results were then stratified based on clinical outcomes and seasonal characteristics and meta-analyzed to estimate pooled rVEs of HD-IIV3., Results: 15 publications were meta-analyzed after screening 1,293 studies, providing data on 10 consecutive influenza seasons and over 22 million individuals receiving HD-IIV3 in randomized and observational settings. Across all influenza seasons, HD-IIV3 demonstrated improved protection against ILI compared to SD-IIV (rVE = 15.9%, 95% CI: 4.1-26.3%). HD-IIV3 was also more effective at preventing hospital admissions from all-causes (rVE = 8.4%, 95% CI: 5.7-11.0%), as well as influenza (rVE = 11.7%, 95% CI: 7.0-16.1%), pneumonia (rVE = 27.3%, 95% CI: 15.3-37.6%), combined pneumonia/influenza (rVE = 13.4%, 95% CI: 7.3-19.2%) and cardiorespiratory events (rVE = 17.9%, 95% CI: 15.0-20.8%). Reductions in mortality due to pneumonia/influenza (rVE = 39.9%, 95% CI: 18.6-55.6%) and cardiorespiratory causes (rVE = 27.7%, 95% CI: 13.2-32.0%) were also observed. Similar pooled rVEs were observed in both matched and mismatched seasons and in seasons where A/H3N2 or A/H1N1 strains were predominantly circulating., Conclusions: Evidence over 10 consecutive influenza seasons and in more than 34 million individuals aged ≥ 65 years suggests that HD-IIV3 is consistently more effective than SD-IIV at reducing influenza cases as well as influenza-associated clinical complications irrespective of circulating strain and antigenic match. A video summary of the article can be accessed via the Supplementary data link at the end of this article., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JL, GL, TS, SS, DG and AC are employees of Sanofi Pasteur, the manufacturer of the high-dose influenza vaccine. This work was supported by Sanofi Pasteur., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Previous studies established an association between laboratory-confirmed influenza infection (LCI) and hospitalization for acute myocardial infarction (AMI) but not causality. We aimed to explore the underlying mechanisms by adding biological mediators to an established study design used by earlier studies., Methods: With data on biomarkers, we used a self-controlled case-series design to evaluate the effect of LCI on hospitalization for AMI among Veterans Health Administration (VHA) patients. We included senior Veterans (age 65 years and older) with LCI between 2010 through 2015. Patient-level data from VHA electronic medical records were used to capture laboratory results, hospitalizations, and baseline patient characteristics. We defined the "risk interval" as the first 7 days after specimen collection and the "control interval" as 1 year before and 1 year after the risk interval. More importantly, using mediation analysis, we examined the role of abnormal white blood cell (WBC) and platelet count in the relationship between LCI and AMI to explore the thrombogenic nature of this association, thus potential causality., Results: We identified 391 hospitalizations for AMI that occurred within +/-1 year of a positive influenza test, of which 31 (31.1 admissions/week) occurred during the risk interval and 360 (3.5/per week) during the control interval, resulting in an incidence ratio (IR) for AMI admission of 8.89 (95% confidence interval [CI]: 6.16-12.84). In stratified analyses, AMI risk was significantly elevated among patients with high WBC count (IR, 12.43; 95% CI: 6.99-22.10) and high platelet count (IR, 15.89; 95% CI: 3.59-70.41)., Conclusion: We confirmed a significant association between LCI and AMI. The risk was elevated among those with high WBC or platelet count, suggesting a potential role for inflammation and platelet activation in the underlying mechanism., Competing Interests: YYX has received research funding from Sanofi Pasteur, Sanofi, Pfizer, Genentech, Janssen, VIR Biotechnology, and the Office of Rural Health Resource Center- Eastern Region. SMM has received research funding from Assurex, GSK, Merck, Pfizer, Roche and Sanofi, and is/was a member of advisory boards for GSK and Sanofi. RVA, JKL, EWT and AC are employees of Sanofi Pasteur. The remaining authors have nothing to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Planar cell polarity (PCP) pathway is crucial for tissue morphogenesis. Mutations in PCP genes cause multi-organ anomalies including dysplastic kidneys. Defective PCP signaling was postulated to contribute to cystogenesis in polycystic kidney disease. This work was undertaken to elucidate the role of the key PCP gene, Vangl2, in embryonic and postnatal renal tubules and ascertain whether its loss contributes to cyst formation and defective tubular function in mature animals. We generated mice with ubiquitous and collecting duct-restricted excision of Vangl2. We analyzed renal tubules in mutant and control mice at embryonic day E17.5 and postnatal days P1, P7, P30, P90, 6- and 9-month old animals. The collecting duct functions were analyzed in young and adult mutant and control mice. Loss of Vangl2 leads to profound tubular dilatation and microcysts in embryonic kidneys. Mechanistically, these abnormalities are caused by defective convergent extension (larger tubular cross-sectional area) and apical constriction (cuboidal cell shape and a reduction of activated actomyosin at the luminal surface). However, the embryonic tubule defects were rapidly resolved by Vangl2-independent mechanisms after birth. Normal collecting duct architecture and functions were found in young and mature animals. During embryogenesis, Vangl2 controls tubular size via convergent extension and apical constriction. However, rapidly after birth, PCP-dependent control of tubular size is switched to a PCP-independent regulatory mechanism. We conclude that loss of the Vangl2 gene is dispensable for tubular elongation and maintenance postnatally. It does not lead to cyst formation and is unlikely to contribute to polycystic kidney disease., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Recent research has demonstrated an association between obesity and migraine headaches. Furthermore, studies have demonstrated that migraine improvement can occur with significant weight loss. Given that bariatric surgery is the most effective intervention for obesity and obesity-related comorbidities, there is potential for bariatric surgery to improve migraine symptoms. The objective of this study was to conduct a systematic review and meta-analysis to determine the effect of bariatric surgery on migraine headaches., Methods: A comprehensive literature search from database inception to December 2018 was conducted for studies examining the effect of bariatric surgery on migraines. Patients of all ages who had a history of migraines undergoing primary bariatric surgery were included. Primary outcomes included migraine frequency, severity, and disability., Results: Four studies were included (n = 159). Frequency of migraines was markedly reduced after bariatric surgery, with fewer symptomatic days suffered by patients per month post-operatively (mean difference [MD] - 5.56 days, 95%CI 0.14 to 10.99, p = 0.04). The degree of migraine headache-related disability as measured by the Migraine Disability Assessment Scale (MIDAS) was also significantly lower following bariatric surgery (MD - 14.72, 95%CI 10.08 to 19.36, p < 0.001). The severity of migraine headache pain before and after surgery was reduced with borderline statistical significance (MD - 3.53, 95%CI - 0.12 to 7.17, p = 0.06)., Conclusion: Migraine severity, frequency, and headache-related disability were improved 6 months after bariatric surgery. However, this systematic review was limited by a low number of studies and larger high-quality, randomized trials are needed to determine the effect of bariatric surgery on migraine headaches.

Background: Unmeasured confounders are commonplace in observational studies conducted using real-world data. Prior event rate ratio (PERR) adjustment is a technique shown to perform well in addressing such confounding. However, it has been demonstrated that, in some circumstances, the PERR method actually increases rather than decreases bias. In this work, we seek to better understand the robustness of PERR adjustment., Methods: We begin with a Bayesian network representation of a generalized observational study, which is subject to unmeasured confounding. Previous work evaluating PERR performance used Monte Carlo simulation to calculate joint probabilities of interest within the study population. Here, we instead use a Bayesian networks framework., Results: Using this streamlined analytic approach, we are able to conduct probabilistic bias analysis (PBA) using large numbers of combinations of parameters and thus obtain a comprehensive picture of PERR performance. We apply our methodology to a recent study that used the PERR in evaluating elderly-specific high-dose (HD) influenza vaccine in the US Veterans Affairs population. That study obtained an HD relative effectiveness of 25% (95% CI: 2%-43%) against influenza- and pneumonia-associated hospitalization, relative to standard-dose influenza vaccine. In this instance, we find that the PERR-adjusted result is more like to underestimate rather than to overestimate the relative effectiveness of the intervention., Conclusions: Although the PERR is a powerful tool for mitigating the effects of unmeasured confounders, it is not infallible. Here, we develop some general guidance for when a PERR approach is appropriate and when PBA is a safer option., (© 2019 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.)

Background: Observational studies of the relative effectiveness of influenza vaccines are essential for public health decision making. Their estimates, however, are subject to bias due to unmeasured confounders. Instrumental variable (IV) methods can control for observed and unobserved confounders., Methods: We used linked electronic medical record databases in the Veterans Health Administration (VHA) as well as Medicare administrative files to examine the relative vaccine effectiveness (rVE) of high-dose influenza vaccine (HD) versus standard-dose influenza vaccines (SD) in preventing hospitalizations among VHA-enrolled Veterans ≥65 years of age during 5 influenza seasons (2010-2011 through 2014-2015). Using multivariable IV Poisson regression modeling to address unmeasured confounding and bias, we analyzed the data by each season and through longitudinal analysis of all five seasons., Findings: We included 3,638,924 person-influenza seasons of observation where 158,636 (4%) were among HD vaccine recipients and 3,480,288 (96%) were among SD vaccine recipients. Of the 1,728,562 Veterans, 1,702,824 (98.5%) were male and 1,299,412 (75%) were non-Hispanic white. Based on the longitudinal analysis of all five seasons, the IV-adjusted rVE estimate of HD vs. SD was 10% (95% CI, 8-12%) against all-cause hospitalization; 18% (95% CI, 15-21%) against cardiorespiratory-associated hospitalization; and 14% (95% CI, 6-22%) against influenza/pneumonia-associated hospitalization. The findings by season were similar., Interpretation: Our analysis of VHA clinical data collected from approximately 1.7 million Veterans 65 years and older during five seasons demonstrates that high-dose influenza vaccine is more effective than standard-dose influenza vaccines in preventing influenza- or pneumonia-associated hospitalizations, cardiorespiratory hospitalizations, and all-cause hospitalizations., (Published by Elsevier Ltd.)

Background: Acellular pertussis vaccine studies postulate that waning protection, particularly after the adolescent booster, is a major contributor to the increasing US pertussis incidence. However, these studies reported relative (ie, vs a population given prior doses of pertussis vaccine), not absolute (ie, vs a pertussis vaccine naïve population) efficacy following the adolescent booster. We aim to estimate the absolute protection offered by acellular pertussis vaccines., Methods: We conducted a systematic review of acellular pertussis vaccine effectiveness (VE) publications. Studies had to comply with the US schedule, evaluate clinical outcomes, and report VE over discrete time points. VE after the 5-dose childhood series and after the adolescent sixth-dose booster were extracted separately and pooled. All relative VE estimates were transformed to absolute estimates. VE waning was estimated using meta-regression modeling., Findings: Three studies reported VE after the childhood series and four after the adolescent booster. All booster studies reported relative VE (vs acellular pertussis vaccine-primed population). We estimate initial childhood series absolute VE is 91% (95% CI: 87% to 95%) and declines at 9.6% annually. Initial relative VE after adolescent boosting is 70% (95% CI: 54% to 86%) and declines at 45.3% annually. Initial absolute VE after adolescent boosting is 85% (95% CI: 84% to 86%) and declines at 11.7% (95% CI: 11.1% to 12.3%) annually., Interpretation: Acellular pertussis vaccine efficacy is initially high and wanes over time. Observational VE studies of boosting failed to recognize that they were measuring relative, not absolute, VE and the absolute VE in the boosted population is better than appreciated., Competing Interests: The authors have read the journal's policy and have the following conflicts: AC, HZ, TS, JL, AT, DJ, DM and MD were employees of Sanofi Pasteur during the conduct of the study. Sanofi Pasteur is a pharmaceutical company that manufactures pertussis vaccine. Mitacs is a not-for-profit organization that designs and funds research and training programs in Canada. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development, or marketed products to declare.

Background: We examined whether a high-dose inactivated influenza vaccine was more efficacious in preventing hospitalizations than a standard-dose vaccine in the Veterans Health Administration (VHA) senior population., Methods: This study estimated the relative vaccine effectiveness (rVE) of high dose versus standard dose using a retrospective cohort of VHA patients 65 years of age or older in the 2015-2016 influenza season. To adjust for measured confounders, we matched each high-dose recipient with up to 4 standard-dose recipients vaccinated at the same location within a 2-week period and having 2 or more pre-existing medical comorbidities. We used the previous event rate ratio method (PERR), a type of difference-in-differences analysis, to adjust for unmeasured confounders., Results: We evaluated 104965 standard-dose and 125776 high-dose recipients; matching decreased the population to 49091 standard-dose and 24682 high-dose recipients. The matched, PERR-adjusted rVE was 25% (95% confidence interval [CI], 2%-43%) against influenza- or pneumonia-associated hospitalization, 7% (95% CI, -2% to 14%) against all-cause hospitalization, 14% (95% CI, -8% to 32%) against influenza- or pneumonia-associated outpatient visit, 5% (95% CI, 2%-8%) against all-cause outpatient visit, and 38% (95% CI, -5% to 65%) against laboratory-confirmed influenza., Conclusions: In protecting senior VHA patients against influenza- or pneumonia-associated hospitalization, a high-dose influenza vaccine is more effective than a standard-dose vaccine.

Background: Influenza is responsible for a significant disease burden annually, especially in older adults. This study reviews the relative vaccine efficacy or effectiveness (rVE) of high-dose inactivated trivalent influenza vaccine (HD-IIV3) compared to standard-dose influenza vaccines (SD-IIV3) in adults ≥65 against influenza-associated outcomes to inform evidence-based decision-making to shift clinical practice and standard of care in this population., Methods: A systematic review was conducted for studies assessing the rVE of HD-IIV3 against probable/laboratory-confirmed influenza-like illness (ILI), hospital admissions, and death in adults ≥65. Results from individual seasons were meta-analyzed and a random-effects model was used to estimate pooled rVEs., Results: After screening 992 studies, seven studies were meta-analyzed. HD-IIV3 demonstrated better protection against ILI compared to SD-IIV3 (rVE = 19.5%; 95% CI: 8.6-29.0%). HD-IIV3 was also more effective at preventing hospital admissions from all-causes (rVE = 9.1%; 95% CI: 2.4-15.3%), as well as from influenza (rVE = 17.8%; 95% CI: 8.1-26.5%), pneumonia (rVE = 24.3%, 95% CI: 13.9-33.4%), and cardiorespiratory events (rVE = 18.2%; 95% CI: 6.8-28.1%). rVE against post-influenza mortality was 22.2% (95% CI: -18.2-48.8%) and 2.5% (95% CI: -5.2-9.5%) against all-cause mortality., Conclusions: Available evidence suggests HD-IIV3 is more effective than SD-IIV3 at reducing the clinical outcomes associated with influenza infection in older adults and should be considered for routine use in the 65+ population.