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Plain Language SummaryWhat is the context?The WHO added the pneumococcal conjugate vaccine and the rotavirus vaccine in the recommended vaccination schedule of all countries in 2007 and 2009, respectively.Previous studies estimated the public health benefit of these vaccines by approximating the number of children who received them.What is new?We used an alternative approach to estimate the benefit based on actual number of doses of the vaccines, human rotavirus vaccine (HRV; Rotarix) and pneumococcal polysaccharide protein D-conjugate vaccine (PHiD-CV; Synflorix) delivered to each country considered.The study analyzed data from children under 5 years of age in 60 Gavi-supported countries by identifying the number of vaccine doses delivered, estimating the number of children fully covered, applying the country-specific disease epidemiology, estimating the number of severe disease cases and deaths avoided.From 2009 to 2019, approximately 143 million children were vaccinated with HRV avoiding an estimated 18.7 million severe rotavirus disease cases and 153,000 deaths.From 2011 to 2019, about 146 million children were vaccinated with pneumococcal vaccine avoiding an estimated 5.0 million severe pneumococcal disease cases and 587,000 deaths.What is the impact?The benefit of HRV and PHiD-CV in Gavi-supported countries is often estimated based on assumptions of vaccine coverage rates.A modeling approach based on doses delivered by the vaccine manufacturer can provide an additional view on the potential vaccine benefits and improve planning, contribution, and sustainability of the immunization programs at a country level.In 2019, HRV and PHiD-CV together averted nine cases of severe disease each minute and one child death every 4 minutes. Vaccine impact models against rotavirus disease (RD) and pneumococcal disease (PD) in low- and middle-income countries assume vaccine coverage based on other vaccines. We propose to assess the impact on severe disease cases and deaths avoided based on vaccine doses delivered by one manufacturer to Gavi-supported countries. From the number of human rotavirus vaccine (HRV) and pneumococcal polysaccharide protein D-conjugate vaccine (PHiD-CV) doses delivered, we estimated the averted burden of disease 1) in a specific year and 2) for all children vaccinated during the study period followed-up until 5 years (y) of age. Uncertainty of the estimated impact was assessed in a probabilistic sensitivity analysis using Monte-Carlo simulations to provide 95% confidence intervals. From 2009 to 2019, approximately 143 million children received HRV in 57 Gavi-supported countries, avoiding an estimated 18.7 million severe RD cases and 153,000, deaths. From 2011 to 2019, approximately 146 million children received PHiD-CV in 36 countries, avoiding an estimated 5.0 million severe PD cases and 587,000 deaths. The number of severe cases and deaths averted for all children vaccinated during the study period until 5 years of age were about 23.2 million and 190,000, respectively, for HRV, and 6.6 million and 749,000, respectively, for PHiD-CV. Models based on doses delivered help to assess the impact of vaccination, plan vaccination programs and understand public health benefits. In 2019, HRV and PHiD-CV doses delivered over a 5-y period may have, on average, averted nine severe disease cases every minute and one child death every 4 min. GlaxoSmithKline Biologicals SA funded this study and was involved in all stages of study conduct, including analysis of the data. GlaxoSmithKline Biologicals SA also paid all costs associated with the development and publication of this manuscript. The authors would like to thank Tathyana Giannotti Cousseau for her input regarding the initiation, collection of the actual sales volume per year and assessment of various methodologies adopted by Supranational agencies like Gavi and John Hopkins for “Lives Saved” model. The authors would also like to thank Business & Decision Life Sciences platform for editorial assistance and manuscript coordination, on behalf of GSK, and TVF communications platform for the design support for the digital illustration, on behalf of GSK. Mary Greenacre (An Sgriobhadair Ltd) provided writing support for this literature review.

ispartof: INTENSIVE CARE MEDICINE vol:47 issue:3 pages:344-348 ispartof: location:United States status: published

Background The SARS-CoV-2/COVID-19 pandemic has claimed nearly 900,000 lives worldwide and infected more than 27 million people. Researchers worldwide are studying ways to decrease SARS-CoV-2 transmission and COVID-19 related deaths. Several studies found altitude having a negative association with both COVID-19 incidence and deaths. Ecuadorian data was used to explore the relationship between altitude and COVID-19. Methods This is an ecological study examining province-level data. To explore a relationship between altitude and COVID-19, this study utilized publicly available COVID-19 data and population statistics. ANOVA, correlation statistics, and a multivariate linear model explored the relationship between different Ecuadorian altitudes against incidence, mortality, and case-fatality rates. Population statistics attributed to COVID-19 were included in the linear model to control for confounding factors. Results Statistically significant differences were observed in the regions of Amazónica, Sierra, Costa of Ecuador for incidence, mortality, and case fatality rates, suggesting an association between altitude and SARS-CoV-2 transmission and COVID-19 disease severity (p-value ≤0.05). In univariate analysis, altitude had a negative association to mortality rate with a 1-unit change in altitude resulting in the decrease of 0.006 units in mortality rate (p-value = 0.03). The multiple linear models adjusted for population statistics showed a statistically significant negative association of altitude with mortality rate (p-value = 0.01) with a 1-unit change in altitude resulting in the decrease in mortality rate by 0.015 units. Overall, the model helped in explaining 50% (R2 = 0.4962) of the variance in mortality rate. Conclusion Altitude may have an effect on COVID-19 mortality rates. However, based on our model and R2 value, the relationship between our variables of interest and COVID-19 mortality may be nonlinear. More research is needed to understand why altitude may have a protective effect against COVID-19 mortality and how this may be applicable in a clinical setting.

BackgroundWe evaluated prevaccine pandemic period COVID-19 death risk factors among nursing home (NH) residents.MethodsIn a retrospective cohort study covering Medicare fee-for-service beneficiaries aged ≥65 years residing in US NHs, we estimated adjusted hazard ratios (HRs) using multivariate Cox proportional hazards regressions.ResultsAmong 608251 elderly NH residents, 57398 (9.4%) died of COVID-19–related illness 1 April to 22 December 2020; 46.9% (26893) of these deaths occurred without prior COVID-19 hospitalizations. We observed a consistently increasing age trend for COVID-19 deaths. Racial/ethnic minorities shared similarly high risk of NH COVID-19 deaths with whites. NH facility characteristics for-profit ownership and low health inspection ratings were associated with higher death risk. Resident characteristics (male [HR, 1.69], end-stage renal disease [HR, 1.42], cognitive impairment [HR, 1.34], and immunocompromised status [HR, 1.20]) were death risk factors. Other individual-level characteristics were less predictive of death than in community-dwelling population.ConclusionsLow NH health inspection ratings and private ownership contributed to COVID-19 death risks. Nearly half of NH COVID-19 deaths occurred without prior COVID-19 hospitalization and older residents were less likely to get hospitalized with COVID-19. No substantial differences were observed by race/ethnicity and socioeconomic status for NH COVID-19 deaths.

ObjectiveTo estimate the effectiveness of messenger RNA (mRNA) booster doses during the period of Delta and Omicron variant dominance.DesignWe conducted a matched test-negative case–control study to estimate the vaccine effectiveness (VE) of three and two doses of mRNA vaccines against infection (regardless of symptoms) and against COVID-19-related hospitalisation and death.SettingVeterans Health Administration.ParticipantsWe used electronic health record data from 114 640 veterans who had a SARS-CoV-2 test during November 2021–January 2022. Patients were largely 65 years or older (52%), male (88%) and non-Hispanic white (59%).Main outcome measuresFirst positive result for a SARS-CoV-2 PCR or antigen test.ResultsAgainst infection, booster doses had higher estimated VE (64%, 95% CI 63 to 65) than two-dose vaccination (12%, 95% CI 10 to 15) during the Omicron period. For the Delta period, the VE against infection was 90% (95% CI 88 to 92) among boosted vaccinees, higher than the VE among two-dose vaccinees (54%, 95% CI 50 to 57). Against hospitalisation, booster dose VE was 89% (95% CI 88 to 91) during Omicron and 94% (95% CI 90 to 96) during Delta; two-dose VE was 63% (95% CI 58 to 67) during Omicron and 75% (95% CI 69 to 80) during Delta. Against death, the VE with a booster dose was 94% (95% CI 90 to 96) during Omicron and 96% (95% CI 87 to 99) during Delta.ConclusionsAmong an older, mostly male, population with comorbidities, we found that an mRNA vaccine booster was highly effective against infection, hospitalisation and death. Although the effectiveness of booster vaccination against infection was moderately higher against Delta than against the Omicron SARS-CoV-2 variant, effectiveness against severe disease and death was similarly high against both variants.

BackgroundShingrix (recombinant zoster vaccine) was licensed to prevent herpes zoster, dispensed as 2 doses given 2–6 months apart among adults aged ≥50 years. Clinical trials yielded efficacy of >90% for confirmed herpes zoster, but post-market performance has not been evaluated. Efficacy of a single dose and a delayed second dose and efficacy among persons with autoimmune or immunosuppressive conditions have not been studied. We aimed to assess post-market vaccine effectiveness of Shingrix.MethodsWe conducted a cohort study among Medicare Part D community-dwelling beneficiaries aged >65 years. Herpes zoster was identified using a medical office visit diagnosis with treatment, and postherpetic neuralgia was identified using a validated algorithm. We used inverse probability of treatment weighting to improve cohort balance and marginal structural models to estimate hazard ratios.ResultsWe found a vaccine effectiveness of 70.1% (95% confidence interval [CI], 68.6–71.5) and 56.9% (95% CI, 55.0–58.8) for 2 and 1 doses, respectively. The 2-dose vaccine effectiveness was not significantly lower for beneficiaries aged >80 years, for second doses received at ≥180 days, or for individuals with autoimmune conditions. The vaccine was also effective among individuals with immunosuppressive conditions. Two-dose vaccine effectiveness against postherpetic neuralgia was 76.0% (95% CI, 68.4–81.8).ConclusionsThis large real-world observational study of the effectiveness of Shingrix demonstrates the benefit of completing the 2-dose regimen. Second doses administered beyond the recommended 6 months did not impair effectiveness. Our effectiveness estimates were lower than the clinical trials estimates, likely due to differences in outcome specificity.

ImportancePrevious studies have analyzed effectiveness of booster mRNA Covid-19 vaccination and compared it with 2-dose primary series for both Delta and Omicron variants. Observational studies that estimate effectiveness by comparing outcomes among vaccinated and unvaccinated individuals may suffer from residual confounding and exposure misclassification.ObjectiveTo estimate relative effectiveness of booster vaccination versus the 2-dose primary series with self-controlled study designDesign, Setting and ParticipantsWe used the Veterans Health Administration (VHA) Corporate Data Warehouse to identify U.S. Veterans enrolled in care ≥2 years who received the 2-dose primary mRNA Covid-19 vaccine series and a mRNA Covid-19 booster following expanded recommendation for booster vaccination, and who had a positive SARS-CoV-2 test during the Delta (9/23/2021-11/30/2021) or Omicron (1/1/22-3/1/22) predominant period. Among them, we conducted a self-controlled risk interval (SCRI) analysis to compare odds of SARS-CoV-2 infection during a booster exposure interval versus a control interval.Exposurescontrol interval (days 4-6 post-booster vaccination, presumably prior to gain of booster immunity), and booster exposure interval (days 14-16 post-booster vaccination, presumably following gain of booster immunity)Outcomes and MeasuresPositive PCR or antigen SARS-CoV-2 test. Separately for Delta and Omicron periods, we used conditional logistic regression to calculate odds ratios (OR) of a positive test for the booster versus control interval and calculated relative effectiveness of booster versus 2-dose primary series as (1-OR)*100. The SCRI approach implicitly controlled for time-fixed confounders.ResultsWe found 42 individuals with a positive SARS-CoV-2 test in the control interval and 14 in the booster exposure interval during Delta period, and 137 and 66, respectively, in Omicron period. For the booster versus 2-dose primary series, the odds of infection were 70% (95%CI: 42%, 84%) lower during the Delta period and 56% (95%CI: 38%, 67%) lower during Omicron. Results were similar for ages ConclusionsBooster vaccination was more effective relative to a 2-dose primary series, the relative effectiveness was consistent across age groups and was higher during the Delta predominant period than during the Omicron period.

Background Approximately 50 000 influenza-associated deaths occur annually in the United States, overwhelmingly among individuals aged ≥65 years. Although vaccination is the primary prevention tool, investigations have shown low vaccine effectiveness (VE) in recent years, particularly among the elderly. We analyzed the relative VE (RVE) of all influenza vaccines among Medicare beneficiaries aged ≥65 years to prevent influenza hospital encounters during the 2019–2020 season. Methods Retrospective cohort study using Poisson regression and inverse probability of treatment weighting (IPTW). Exposures included egg-based high-dose trivalent (HD-IIV3), egg-based adjuvanted trivalent (aIIV3), egg-based standard dose (SD) quadrivalent (IIV4), cell-based SD quadrivalent (cIIV4), and recombinant quadrivalent (RIV4) influenza vaccines. Results We studied 12.7 million vaccinated beneficiaries. Following IPTW, cohorts were well balanced for all covariates and health-seeking behavior indicators. In the adjusted analysis, RIV4 (RVE, 13.3%; 95% CI, 7.4–18.9%), aIIV3 (RVE, 8.2%; 95% CI, 4.2–12.0%), and HD-IIV3 (RVE, 6.8%; 95% CI, 3.3–10.1%) were significantly more effective in preventing hospital encounters than the reference egg-based SD IIV4, while cIIV4 was not significantly more effective than IIV4 (RVE, 2.8%; 95% CI, −2.8%, 8.2%). Our results were consistent across all analyses. Conclusions In this influenza B-Victoria and A(H1N1)–dominated season, RIV4 was moderately more effective than other vaccines, while HD-IIV3 and aIIV3 were more effective than the IIV4 vaccines, highlighting the contributions of antigen amount and adjuvant use to VE. Egg adaptation likely did not substantially affect our RVE evaluation. Our findings, specific to the 2019–2020 season, should be evaluated in other studies using virological case confirmation.

Community-acquired pneumonia (CAP) is a common infection with significant morbidity and mortality. In January 2017, Poland introduced pneumococcal conjugate vaccine (PCV) into their national immunisation programme to protect children against invasive pneumococcal disease. This study was designed to investigate pneumonia-related hospitalisation rates and trends from 2009 to 2016 prior to the introduction of nationally funded PCV vaccination.Using national public statistic data available from the National Institute of Public Health - National Institute of Hygiene, annual hospitalisation rates for pneumonia were analysed, categorised by aetiology and age (2, 2-3, 4-5, 6-19, 20-59, 60+ years). Trends over time were assessed, as well as in-hospital mortality.The overall hospitalisation rate due to pneumonia varied between 325.9 and 372.2/100,000 population. Higher rates of hospitalisation were seen in older adults and children ≤5 years. Trends were observed when analysing hospitalisations by pneumonia aetiology within age groups: between 2009 and 2016, Streptococcus pneumoniae hospitalisations significantly increased for children aged2, 2-3, and 4-5 years, from 5.3 to 12.4, 5.2 to 8.2, and 1.9 to 4.6/100,000 population respectively. Whereas hospitalisations due to Haemophilus influenzae pneumonia decreased significantly from 7.8 to 1.8 and 4.8 to 1.9/100,000 children aged2 and 2-3 years respectively. The numbers of in-hospital deaths increased from 5578 in 2009 to 8149 in 2016, with85% of deaths in the 60+ age group.This is the first national study of pneumonia hospitalisations in Poland, providing the baseline data from which to investigate the impact of the change in vaccination policy on pneumonia hospitalisations in Poland.

Otitis media (OM) is a common disease of childhood and available pneumococcal conjugate vaccines (PCVs), with different compositions, could have different impact on OM reduction. This systematic literature review evaluated available data describing the efficacy, effectiveness, and impact of 10-valent pneumococcalPlain Language Summary

Emotional dysregulation is a core feature of borderline personality disorder (BPD); it is, for example, known to influence one’s ability to read other people’s facial expressions. We investigated behavioral and neurophysiological foundations of emotional face processing in individuals with BPD and in healthy controls, taking participants’ sex into account. 62 individuals with BPD (25 men, 37 women) and 49 healthy controls (20 men, 29 women) completed an emotion classification task with faces depicting blends of angry and happy expressions while the electroencephalogram was recorded. The cortical activity (late positive potential, P3/LPP) was evaluated using source modeling. Compared to healthy controls, individuals with BPD responded slower to happy but not to angry faces; further, they showed more anger ratings in happy but not in angry faces, especially in those with high ambiguity. Men had lower anger ratings than women and responded slower to angry but not happy faces. The P3/LPP was larger in healthy controls than in individuals with BPD, and larger in women than in men; moreover, women but not men produced enlarged P3/LPP responses to angry vs. happy faces. Sex did not interact with behavioral or P3/LPP-related differences between healthy controls and individuals with BPD. Together, BPD-related alterations in behavioral and P3/LPP correlates of emotional face processing exist in both men and women, supposedly without sex-related interactions. Results point to a general ‘negativity bias’ in women. Source modeling is well suited to investigate effects of participant and stimulus characteristics on the P3/LPP generators.

Background: The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has precipitated the worst global pandemic in a century, which has caused millions of infections and deaths as well as massive economic repercussions. Objective: As with any pathogenic virus, it is crucial to understand its unique interactions with the human immune system so that pharmaceutical and prophylactic interventions can be deployed to effectively control the pandemic. Methods: A literature search by using PubMed was conducted in 2020 with variants of the terms “COVID-19,” “SARS-CoV-2,” and “immunological response.” English language articles that presented original data about the immunologic response to coronavirus disease 2019 (COVID-19) were selected for review. This article reviewed the current understanding of the innate and adaptive immune responses to SARS-CoV-2 infection, including their relationship to current therapeutic and diagnostic strategies. Results: SARS-CoV-2 uses several unique molecular techniques to evade detection by the innate immune system early in the course of infection, and upregulation of these innate immune pathways may possibly accelerate the time to recovery and prevent severe disease. Although the majority of cases results in the patients' recovery, a significant proportion of infections result in deaths prompted by the host's inflammatory overreaction to the infection, a response that can be attenuated with corticosteroids and potentially other immune modulators. Conclusion: Current work by the scientific community to further understand how SARS-CoV-2 interacts with the human immune system will be invaluable to our response and preparedness for future coronavirus pandemics.

Key Points Question What was the COVID-19 vaccination coverage and estimated mRNA COVID-19 vaccine effectiveness (VE) among US veterans in the first 3 months following vaccine rollout? Findings In this case-control study including 6 647 733 veterans, 23% of veterans received at least 1 COVID-19 vaccination during the first 3 months of vaccine rollout. VE against infection was estimated to be 95% for full vaccination; estimated VE against COVID-19-related hospitalization was 91%, and there were no COVID-19–related deaths among fully vaccinated veterans. Meaning These findings suggest that early vaccination rollout for veterans was efficient, and estimated VE was high for this diverse US population., This case-control study describes the scope of the mRNA COVID-19 vaccination rollout and estimates the association between vaccination and reductions in SARS-CoV-2 infections among veterans during the first 3 months of vaccine rollout., Importance Effectiveness of mRNA vaccinations in a diverse older population with high comorbidity is unknown. Objectives To describe the scope of the COVID-19 vaccination rollout among US veterans, and to estimate mRNA COVID-19 vaccine effectiveness (VE) as measured by rates of SARS-CoV-2 infection. Design, Setting, and Participants This matched test–negative case-control study was conducted using SARS-CoV-2 test results at Veterans Health Administration sites from December 14, 2020, to March 14, 2021. Vaccine coverage was estimated for all veterans. VE against SARS-CoV-2 infection and COVID-19–related hospitalization and death were estimated using electronic health records from veterans who routinely sought care at a VHA facility and had a test result positive for SARS-CoV-2 (cases) or negative for SARS-CoV-2 (controls). Cases and controls were matched on time of test and geographic region. Data were analyzed from May to July 2021. Exposures Vaccination status, defined as unvaccinated, partially vaccinated (≥14 days after first dose until second dose), or fully vaccinated (≥14 days after second dose), at time of test. Main Outcomes and Measures The main outcome of interest was a positive result for SARS-CoV-2 on a polymerase chain reaction or antigen test. Secondary outcomes included COVID-19–related hospitalization and death, defined by discharge data and proximity of event to positive test result. VE was estimated from odds ratios for SARS-CoV-2 infection with 95% CIs. Results Among 6 647 733 veterans included (3 350 373 veterans [50%] aged ≥65 years; 6 014 798 [90%] men and 632 935 [10%] women; 461 645 Hispanic veterans of any race [7%], 1 102 471 non-Hispanic Black veterans [17%], and 4 361 621 non-Hispanic White veterans [66%]), 1 363 180 (21%) received at least 1 COVID-19 vaccination by March 7, 2021. In this period, during which the share of SARS-CoV-2 variants Alpha, Epsilon, and Iota had started to increase in the US, estimates of COVID-19 VE against infection, regardless of symptoms, was 95% (95% CI, 93%-96%) for full vaccination and 64% (95% CI, 59%-68%) for partial vaccination. Estimated VE against COVID-19–related hospitalization for full vaccination was 91% (95% CI 83%-95%); there were no deaths among veterans who were fully vaccinated. VE against infection was similar across subpopulations (non-Hispanic Black, 94% [95% CI, 88%-97%]; Hispanic [any race], 83% [95% CI, 45%-95%]; non-Hispanic White, 92% [95% CI 88%-94%]; rural, 94% [95% CI, 89%-96%]; urban, 93% 95% CI, 89%-95%]). Conclusions and Relevance For veterans of all racial and ethnic subgroups living in urban or rural areas, mRNA vaccination was associated with substantially decreased risk of COVID-19 infection and hospitalization, with no deaths among fully vaccinated veterans.

Objectives This community-based study explores the syndemic nature of HIV/AIDS risk and resilience among Indigenous Kichwa communities in the province of Imbabura, Ecuador. This study elucidates individual and community-level factors that serve to exacerbate HIV/AIDS risk, as they relate to underlying macrolevel, structural forces. Critically, this study also elicited opportunities for community-based opportunities for resiliency from HIV/AIDS. Study design Exploratory qualitative study. Methods Guided by syndemic theory, a qualitative study was conducted to explore HIV risk and resilience among Indigenous Kichwa communities in the Northern Andean highlands of Ecuador. Eight focus groups (n = 59) with men and women from two communities were conducted. The data were analyzed using applied thematic analysis techniques. Results Identified risk factors for HIV/AIDS centered around the following themes: (1) parents leaving the community for work, (2) alcohol and drug consumption, (3) unprotected sex, and (4) barriers to health care. Identified HIV/AIDS resiliency factors included the preservation of Indigenous culture and family-focused interventions. Conclusions The identified risk factors for HIV/AIDS are interrelated within a complex syndemic relationship. The mutually reinforcing individual-level risk factors of substance abuse and risky sexual behavior coalesce with violence to exacerbate the risk for HIV/AIDS acquisition among Ecuadorian Highland Indigenous communities. Moreover, HIV/AIDS risk prevails in the macrolevel context of disproportionate unemployment among Indigenous peoples and a systematically fragmented healthcare system. It is critical that public health professionals work to revolutionize the systematic discrimination that underpins indigenous health disparities at-large.

Background The nutrition transition continues to affect populations throughout the world. The added impact of market integration and urbanization exacerbates the impact of the nutrition transition upon Indigenous populations worldwide. Objectives This study aims to explore the nutritional concerns of the urban Kichwas community residing in the Andes highlands of Ecuador. Study design This is a qualitative study. Methods Eight focus groups were conducted with Kichwas men and women in November 2015 in the Imbabura province of the Andes in Ecuador. Data analysis Applied thematic analysis was used to analyze findings regarding nutrition. Results The participants shared concerns regarding increased intake of fast food, poor meal timing, and a shift in the child's food preferences that rejects traditional foods. They attributed these concerns to urbanization resulting from an increase in dual-income households and a loss of cultural identity. Conclusions Synergistic cultural factors are related to nutritional concerns voiced by the urban Kichwas community. Public health implications Syndemic theory is a useful interpretive lens regarding nutritional trends within the Kichwas communities as they relate to the increased risk of chronic disease.

Background Guillain-Barre syndrome (GBS) is a serious acute demyelinating disease, an increased risk of which was found after the 1976 swine flu vaccinations. The U.S. Food and Drug Administration, in collaboration with the Centers for Medicare & Medicaid Services, has been conducting active surveillance for GBS after influenza vaccinations of Medicare Fee-For-Service beneficiaries since 2009. Methods We conducted active surveillance for GBS claims in the 2015–2016 and 2016–2017 influenza seasons using the Updating Sequential Probability Ratio Test (USPRT) to monitor for signals of GBS risk. We performed self-controlled risk interval (SCRI) analyses at the end of both seasons, including chart confirmation in the 2015–2016 season, to estimate the odds ratio of GBS risk. We used 1–42 and 8–21 days post-vaccination as primary and secondary risk windows, respectively, and 43–84 days post-vaccination as the control window. Results Over 13 million beneficiaries were vaccinated in each season. USPRT found a low magnitude signal for GBS in both seasons. SCRI analyses did not find excess GBS risk following any influenza vaccine for days 1–42 post-vaccination in either season. In the 2015–2016 season, for the 8–21 day window, our chart-confirmation showed an attributable GBS risk of 0.87 (95% CI: 0.16, 1.49) and 1.68 (95% CI: 0.69, 2.41) cases per million vaccinees after all seasonal and high dose (HD) vaccines, respectively, an elevated GBS risk for beneficiaries aged ≥75 years following all seasonal vaccines (OR: 2.25; 95% CI: 1.15, 4.39) and HD vaccine (OR: 3.67, 95% CI: 1.52, 8.85), and an elevated GBS risk for males who received seasonal vaccines (OR: 2.18; 95% CI: 1.15, 4.15) and HD vaccine (OR: 3.33; 95% CI: 1.35, 8.20). The finding of elevated GBS risk with advancing age and in males is consistent with literature; however, a distinction between HD and SD was a new finding. In the 2016–17 season, for the 8–21 day window, attributed cases showed an attributable GBS risk of 0.87 (95% CI: 0.03, 1.61) and 1.11 (95% CI: 0.00, 2.01) cases per million vaccinees after all seasonal and HD vaccines, respectively. We found no excess GBS risk for standard dose vaccines in the 8–21 day window in either season. Conclusions Our primary analysis finding of no excess GBS risk during both seasons was reassuring. The slightly elevated GBS risk, although in the expected range, in the 8–21 day window after all seasonal and high dose vaccines, but not after standard dose vaccines is hypothesis-generating because the difference may be due to vaccine factors such as antigen amount or strains in various seasons or due to host factors.

BackgroundStudies have found that the high-dose influenza vaccine has a higher relative vaccine effectiveness (RVE) versus standard-dose vaccines in some seasons. We evaluated the effect of age on the RVE of high-dose versus standard-dose influenza vaccines among Medicare beneficiaries.MethodsA 6-season retrospective cohort study from 2012 to 2018 among Medicare beneficiaries aged ≥65 years was performed. Poisson regression was used to evaluate the effect of age on the RVE of high-dose versus standard-dose influenza vaccines in preventing influenza-related hospitalizations.ResultsThe study included >19 million vaccinated beneficiaries in a community pharmacy setting. The Poisson models indicated a slightly increasing trend in RVE with age in all seasons. The high-dose vaccine was more effective than standard-dose vaccines in preventing influenza-related hospital encounters (ie, influenza-related inpatient stays and emergency department visits) in the 2012–2013 (RVE, 23.1%; 95% confidence interval [CI], 17.6%–28.3%), 2013–2014 (RVE, 15.3%; 95% CI, 7.8%–22.3%), 2014–2015 (RVE, 8.9%; 95% CI, 5.6%–12.1%), and 2016–2017 (RVE, 12.6%; 95% CI, 6.3%–18.4%) seasons and was at least as effective in all other seasons. We also found that the high-dose vaccine was consistently more effective than standard-dose vaccines across all seasons for people aged ≥85 years. Similar trends were observed for influenza-related inpatient stays.ConclusionsThe RVE of high-dose versus standard-dose influenza vaccines increases with age.

Background: No head-to-head studies are currently available comparing pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) with 13-valent pneumococcal conjugate vaccine (PCV-13). This study explored the feasibility of using network meta-analysis (NMA) to conduct an indirect comparison of the relative efficacy or effectiveness of the two vaccines. Methods: A systematic literature search was conducted for published randomized controlled trials (RCTs) and non-RCT studies reporting data on vaccine efficacy or effectiveness against invasive pneumococcal disease in children aged

Purpose Medicare claims can provide real-world evidence (RWE) to support the Food and Drug Administration's ability to conduct postapproval studies to validate products' safety and effectiveness. However, Medicare claims do not contain comprehensive information on some important sources of bias. Thus, we piloted an approach using the Medicare Current Beneficiary Survey (MCBS), a nationally representative survey of the Medicare population, to (a) assess cohort balance with respect to unmeasured confounders in a herpes zoster vaccine (HZV) effectiveness claims-based study and (b) augment Medicare claims with MCBS data to include unmeasured covariates. Methods We reanalyzed data from our published HZV effectiveness Medicare analysis, using linkages to MCBS to obtain information on impaired mobility, education, and health-seeking behavior. We assessed survey variable balance between the matched cohorts and selected imbalanced variables for model adjustment, applying multiple imputation by chained equations (MICE) to impute these potential unmeasured confounders. Results The original HZV effectiveness study cohorts appeared well balanced with respect to variables we selected from the MCBS. Our imputed results showed slight shifts in HZV effectiveness point estimates with wider confidence intervals, but indicated no statistically significant differences from the original study estimates. Conclusions Our innovative use of linked survey data to assess cohort balance and our imputation approach to augment Medicare claims with MCBS data to include unmeasured covariates provide potential solutions for addressing bias related to unmeasured confounding in large database studies, thus adding new tools for RWE studies.

Using Medicare claims data on prescriptions of oseltamivir dispensed to people 65 years old and older, we present a descriptive analysis of patterns of influenza activity in the United States for 579 core-based statistical areas (CBSAs) from the 2010–2011 through the 2015–2016 influenza seasons. During this time, 1,010,819 beneficiaries received a prescription of oseltamivir, ranging from 45,888 in 2011–2012 to 380,745 in 2014–2015. For each season, the peak weekly number of prescriptions correlated with the total number of prescriptions (Pearson’s r ≥ 0.88). The variance in peak timing decreased with increasing severity (p

Background: Mexican Americans are at increased risk of developing mild cognitive impairment (MCI) and Alzheimer’s disease compared to non-Hispanic whites. This study sought to examine the relationship between vascular risk, depression, and cognition in Mexican American elders. Methods: Data from 470 (390 normal controls, 80 MCI patients) Mexican Americans enrolled in the Health and Aging Brain among Latino Elders (HABLE) study were used. The cardiovascular risk was assessed by the Framingham Risk Score. Cognition was assessed with a neuropsychological battery, and depression was assessed based on scores from the Geriatric Depression Scale (GDS). ANOVAs were utilized to determine the differences in neuropsychological scores of normal controls with and without depression and CVD risk (low vs. high). Follow-up logistic regression was conducted to determine MCI risk. Results: The results of this study indicated that comorbid depression and a high CVD risk were associated with poorer cognitive performance in Mexican Americans. Depressed women with high CVD risk were more likely to have executive dysfunction, language deficits, and poorer global cognition than nondepressed women with a high CVD risk. In Mexican American men, those with a high vascular risk and depression were more likely to have executive dysfunction and poorer immediate memory than the nondepressed high-risk group. Higher GDS scores (OR = 1.10; 95% CI 1.02–1.10, p = 0.001) and higher vascular risk scores (OR = 1.05; 95% CI 1.02–1.10, p = 0.001) significantly predicted MCI status in Mexican Americans. Conclusion: The results of this study indicated that comorbid depression and a high CVD risk were associated with poorer cognitive performance and increased risk of MCI in Mexican Americans.

Background The low influenza vaccine effectiveness (VE) observed during the A(H3N2)-dominated 2017–2018 season may be due to vaccine virus adaptation to growth in eggs. We compared the effectiveness of cell-cultured and egg-based vaccines among Medicare beneficiaries. Methods Retrospective cohort study on Medicare beneficiaries aged ≥65 years who received an influenza vaccine (cell-cultured, egg-based quadrivalent; egg-based high-dose, adjuvanted, or standard-dose trivalent) during the 2017–2018 season. We used Poisson regression to evaluate relative VE (RVE) in preventing influenza-related hospital encounters. Results Of >13 million beneficiaries, RVE for cell-cultured vaccines relative to egg-based quadrivalent vaccines was 10% (95% confidence interval [CI], 7%–13%). In a midseason interim analysis, this estimate was 16.5% (95% CI, 10.3%–22.2%). In a 5-way comparison, cell-cultured (RVE, 11%; 95% CI, 8%–14%) and egg-based high-dose (RVE, 9%; 95% CI, 7%–11%) vaccines were more effective than egg-based quadrivalent vaccines. Conclusions The modest VE difference between cell-cultured and egg-based vaccines only partially explains the low overall VE reported by the Centers for Disease Control and Prevention, suggesting that egg adaptation was not the main contributor to the low VE found among individuals aged ≥65 years. The midseason interim analysis we performed demonstrates that our methods can be used to evaluate VE actively during the influenza season.

Background There are theoretical concerns that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) could increase the risk of severe Covid-19. Objective To determine if ACEIs and ARBs are associated with an increased risk of Covid-19 hospitalization overall, or hospitalization involving intensive care unit (ICU) admission, invasive mechanical ventilation, or death. Design Observational case-control study. Participants Medicare beneficiaries aged ≥ 66 years with hypertension, treated with ACEIs, ARBs, calcium channel blockers (CCBs), or thiazide diuretics. Main Measures Adjusted odds ratios (OR) and 95% confidence intervals (CI) for the outcomes of Covid-19 hospitalization, or hospitalization involving ICU admission, invasive mechanical ventilation, or death. Results A total of 35,300 cases of hospitalized Covid-19 were matched to 228,228 controls on calendar date and neighborhood of residence. The median age of cases was 79 years, 57.4% were female, and the median duration of hospitalization was 8 days (interquartile range 5–12). ACEIs and ARBs were associated with a slight reduction in Covid-19 hospitalization risk compared with treatment with other first-line antihypertensives (OR for ACEIs 0.95, 95% CI 0.92–0.98; OR for ARBs 0.94, 95% CI 0.90–0.97). Similar results were obtained for hospitalizations involving ICU admission, invasive mechanical ventilation, or death. There were no meaningful differences in risk for ACEIs compared with ARBs. In an analysis restricted to monotherapy with a first-line agent, CCBs were associated with a small increased risk of Covid-19 hospitalization compared with ACEIs (OR 1.09, 95% CI 1.04–1.14), ARBs (OR 1.10, 95% CI 1.05–1.15), or thiazide diuretics (OR 1.11, 95% CI 1.03–1.19). Conclusions ACEIs and ARBs were not associated with an increased risk of Covid-19 hospitalization or with hospitalization involving ICU admission, invasive mechanical ventilation, or death. The finding of a small increased risk of Covid-19 hospitalization with CCBs was unexpected and could be due to residual confounding. Supplementary Information The online version contains supplementary material available at 10.1007/s11606-021-07155-z.

Under-detection of HIV/AIDS still burdens many low- and middle-income countries (LMICs). Our randomized trial investigated the effects of financial incentives and a behavioral nudge to induce HIV testing and learning HIV status in Ecuador. In the control group, 12.2% of participants agreed to testing, and 5.3% learned results. A financial incentive paid at testing increased the fraction of participants tested by 50.1 percentage points (95% CI 38.8 to 61.4) and the fraction who learned their status by 8.9 percentage points (95% CI 5.3 to 12.5); the nudge had no effect. The HIV-positive rate was 1.2% in the control group, and incentives prompted a 4.7 percentage point (95% CI 0.5 to 8.9) higher proportion of HIV-positive detection. Incentives also induced earlier testing, suggesting reduced procrastination. This suggests that information with appropriately timed small financial incentives can improve HIV testing and detection of new cases in the general population in LMIC settings.

The worldwide implementation of pneumococcal conjugate vaccines (PCVs) in children has reduced the overall pneumococcal disease burden. Two PCVs are widely available for infant vaccination: the pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) and the 13-valent PCV (PCV13). While these PCVs differ in serotype composition (PCV13 includes polysaccharides of serotypes 3, 6A and 19A; PHiD-CV does not), their impact on the overall pneumococcal disease burden in children is comparable. This commentary summarizes the evidence of comparability between PHiD-CV and PCV13 and explores why differences in serotype composition may not necessarily translate into a differential clinical impact. Both vaccines confer similarly high protection against disease caused by vaccine serotypes and lead to a partial replacement by non-vaccine serotypes. PHiD-CV does not protect against serotype 3 disease (not included in the vaccine) and PCV13's effect on this serotype has been inconsistent. PHiD-CV provides some cross-protection against disease caused by vaccine-related serotype 19A but neither vaccine has fully controlled 19A disease. While protection against 19A is higher for PCV13 than PHiD-CV, replacement by non-PCV13 serotypes in settings with a PCV13 program appears to compensate for this difference. This results in a similar residual overall disease burden with both vaccines.

Background Glioblastoma (GBM) is the most common primary brain tumor in adults with a median survival of approximately 15 months; therefore, more effective treatment options for GBM are required. To identify new drugs targeting GBMs, we performed a high-throughput drug screen using patient-derived neurospheres cultured to preferentially retain their glioblastoma stem cell (GSC) phenotype. Methods High-throughput drug screening was performed on GSCs followed by a dose-response assay of the 5 identified original “hits.” A PI3K/mTOR dependency to a proteasome inhibitor (carfilzomib), was confirmed by genetic and pharmacologic experiments. Proteasome Inhibition Response Signatures were derived from proteomic and bioinformatic analysis. Molecular mechanism of action was determined using three-dimensional (3D) GBM-organoids and preclinical orthotopic models. Results We found that GSCs were highly sensitive to proteasome inhibition due to an underlying dependency on an increased protein synthesis rate, and loss of autophagy, associated with PTEN loss and activation of the PI3K/mTOR pathway. In contrast, combinatory inhibition of autophagy and the proteasome resulted in enhanced cytotoxicity specifically in GSCs that did express PTEN. Finally, proteasome inhibition specifically increased cell death markers in 3D GBM-organoids, suppressed tumor growth, and increased survival of mice orthotopically engrafted with GSCs. As perturbations of the PI3K/mTOR pathway occur in nearly 50% of GBMs, these findings suggest that a significant fraction of these tumors could be vulnerable to proteasome inhibition. Conclusions Proteasome inhibition is a potential synthetic lethal therapeutic strategy for GBM with proteasome addiction due to a high protein synthesis rate and autophagy deficiency.

Background Leptospira are shed into the environment via urine of infected animals. Rivers are thought to be an important risk factor for transmission to humans, though much is unknown about the types of environment or characteristics that favor survival. To address this, we screened for Leptospira DNA in two rivers in rural Ecuador where Leptospirosis is endemic. Results We collected 112 longitudinal samples and recorded pH, temperature, river depth, precipitation, and dissolved oxygen. We also performed a series of three experiments designed to provide insight into Leptospira presence in the soil. In the first soil experiment, we characterized prevalence and co-occurrence of Leptospira with other bacterial taxa in the soil at dispersed sites along the rivers (n = 64). In the second soil experiment, we collected 24 river samples and 48 soil samples at three points along eight transects to compare the likelihood of finding Leptospira in the river and on the shore at different distances from the river. In a third experiment, we tested whether Leptospira presence is associated with soil moisture by collecting 25 soil samples from two different sites. In our river experiment, we found pathogenic Leptospira in only 4 (3.7%) of samples. In contrast, pathogenic Leptospira species were found in 22% of shore soil at dispersed sites, 16.7% of soil samples (compared to 4.2% of river samples) in the transects, and 40% of soil samples to test for associations with soil moisture. Conclusions Our data are limited to two sites in a highly endemic area, but the scarcity of Leptospira DNA in the river is not consistent with the widespread contention of the importance of river water for leptospirosis transmission. While Leptospira may be shed directly into the river, onto the shores, or washed into the river from more remote sites, massive dilution and limited persistence in rivers may reduce the environmental load and therefore, the epidemiological significance of such sources. It is also possible that transmission may occur more frequently on shores where people are liable to be barefoot. Molecular studies that further explore the role of rivers and water bodies in the epidemiology of leptospirosis are needed.

Streptococcus pneumoniae is a major cause of morbidity and mortality, especially amongst young children and the elderly. Childhood implementation of pneumococcal conjugate vaccines (PCVs) significantly reduced the incidence of invasive pneumococcal disease (IPD), while several nonvaccine serotypes remained substantial. Although there is evidence of the impact of higher-valent PCVs on serotype 19A, 19A IPD burden and antibiotic resistance remain a major concern post-vaccination. We performed a systematic literature review to analyze the frequency and clonal distribution of serotype 19A isolates in the pre– and post-PCV era worldwide providing a scientific background on the factors that influence multidrug resistance in pneumococcal isolates. Serotype 19A IPD incidence increased in all regions following the introduction of the 7-valent PCV. The higher-valent PCVs have reduced the rates of 19A IPD isolates, but several circulating strains with diverse antibiotic resistance prevailed. Heterogeneous clonal distribution in serotype 19A was observed within countries and regions, irrespective of higher-valent PCV used. An increase of 19A isolates from pre- to post-vaccination periods were associated with frequently occurring serotype switching events and with the prevalence of multidrug resistant strains. Rational antibiotic policies must be implemented to control the emergence of resistance. Plain Language Summary What is the context? Streptococcus pneumoniae is a major cause of pneumococcal diseases especially amongst young children and the elderly. Vaccination with pneumococcal conjugate vaccines has significantly reduced the incidence of invasive pneumococcal disease worldwide. However, the invasive pneumococcal disease remains an important health problem due to the increase of nonvaccine serotypes. Serotype 19A is predominant in many countries worldwide. Factors contributing to its prevalence include serotype replacement, the emergence of clones with multidrug resistance due to antibiotic overuse, and potential bacteria adaptation in response to the vaccine. What is new? We performed a systematic literature review to 1) analyze the incidence and clonal distribution of serotype 19A isolates pre- and post-vaccination worldwide, and to collect data evaluating antimicrobial resistance patterns displayed by the clones of serotype 19A. We found that 1) clonal distribution in serotype 19A was heterogeneous within countries and regions, irrespective of the vaccine used; 2) the diversity of 19A isolates increased after vaccination. It was associated with frequent serotype switching events and with the prevalence of multidrug resistant strains. What is the impact? Implementation of policies to educate on sustainable antibiotic use and infectious prevention measures may help control the emergence of antibiotic resistance. High-quality active surveillance and future molecular epidemiology studies are needed to understand rapid genetic changes.

The current study was performed to evaluate risk factors for severe coronavirus disease 2019 (COVID-19) outcomes among Medicare beneficiaries during the pandemic's early phase.In a retrospective cohort study covering Medicare fee-for-service beneficiaries, we separated out elderly residents in nursing homes (NHs) and those with end-stage renal disease (ESRD) from the primary study population of individuals age ≥65 years. Outcomes included COVID-19 hospital encounters and COVID-19-associated deaths. We estimated adjusted odds ratios (ORs) using logistic regression.We analyzed 25 333 329 elderly non-NH beneficiaries without ESRD, 653 966 elderly NH residents, and 292 302 patients with ESRD. COVID-related death rates (per 10 000) were much higher among elderly NH residents (275.7) and patients with ESRD (60.8) than in the primary study population (5.0). Regression-adjusted clinical predictors of death among the primary population included immunocompromised status (OR, 1.43), frailty index conditions such as cognitive impairment (3.16), and other comorbid conditions, including congestive heart failure (1.30). Demographic-related risk factors included male sex (OR, 1.77), older age (3.09 for 80- vs 65-year-olds), Medicaid dual-eligibility status (2.17), and racial/ethnic minority. Compared with whites, ORs were higher for blacks (2.47), Hispanics (3.11), and Native Americans (5.82). Results for COVID-19 hospital encounters were consistent.Frailty, comorbid conditions, and race/ethnicity were strong risk factors for COVID-19 hospitalization and death among the US elderly.

Alcohol abuse has been identified as a risk factor for contracting human immunodeficiency virus (HIV) and accelerating disease progression. Our study aims to determine alcohol consumption rates among Ecuadorian HIV positive (HIV+) patients prior to diagnosis to evaluate its impact as an independent risk factor for contracting HIV. Additionally, we will examine post-diagnosis consumption rates among the HIV+ population. We provided anonymous questionnaires to 300 HIV+ patients and 600 internal medicine patients at 3 hospitals in Quito, Ecuador. Questionnaires quantified alcohol usage prior to HIV diagnosis, at time of diagnosis, and post-diagnosis while accounting for other potential HIV risk factors. We then determined frequencies of alcohol consumption and confounding variables. Finally, we performed a multivariable logistic regression controlling for confounders to determine the statistical significance of alcohol consumption as an independent risk factor for HIV. Our results showed increased odds for contracting HIV among those who drank daily (OR 5.3, CI 2.0–14.0) and those who consumed 6 or more alcoholic beverages on days they drank (OR 5.0, CI 3.1–8.2). Through multivariable analysis, we found that abstaining from binge drinking was a protective factor with an OR 0.5 (0.3–0.96). The percentage of HIV+ patients abstaining from alcohol increased from 30% twelve months prior to diagnosis to 57% after diagnosis. Our results show that alcohol abuse significantly increases the risk of contracting HIV. We found that prior to diagnosis, HIV patients consistently drank more frequently and a greater amount than the control group. Alcohol use significantly decreased among HIV+ patients after diagnosis.

The Human Leucocyte Antigen (HLA) locus and other DNA sequence variants identified in Genome-Wide Association (GWA) studies explain around 50% of the heritability of celiac disease (CD). However, the pathogenesis of CD could be driven by other layers of genomic information independent from sequence variation, such as DNA methylation, and it is possible that allele-specific methylation explains part of the SNP associations. Since the DNA methylation landscape is expected to be different among cell types, we analyzed the methylome of the epithelial and immune cell populations of duodenal biopsies in CD patients and controls separately. We found a cell type-specific methylation signature that includes genes mapping to the HLA region, namely TAP1 and HLA-B. We also performed Immunochip SNP genotyping of the same samples and interrogated the expression of some of the affected genes. Our analysis revealed that the epithelial methylome is characterized by the loss of CpG island (CGI) boundaries, often associated to altered gene expression, and by the increased variability of the methylation across the samples. The overlap between differentially methylated positions (DMPs) and CD-associated SNPs or variants contributing to methylation quantitative trait loci (mQTLs) is minimal. In contrast, there is a notable enrichment of mQTLs among the most significant CD-associated SNPs. Our results support the notion that DNA methylation alterations constitute a genotype-independent event and confirm its role in the HLA region (apart from the well-known, DQ allele-specific effect). Finally, we find that a fraction of the CD-associated variants could exert its phenotypic effect through DNA methylation. The authors thank the technical and human support provided by SGIker of the UPV/EHU and the Genomics Platform at the CIC bioGUNE. We also thank Dr Florence Le Calvez-Kelm and Mr Geoffroy Durand from the Genetic Cancer Susceptibility group (IARC, Lyon) for their help with the HM450 beadchip assays. The work was funded by ISCIII Research Project Grants PI13/01201 and PI16/00258, cofunded by the European Union ERDF/ESF "A way to make Europe" co-financed by the Spanish Ministry of Economy and Competitiveness -http://www.mineco.gob.es/-and by the European Union ERDF/ESF "A way to make Europe" and project 2011/111034 from the Basque Department of Health -http://www.euskadi.eus/gobierno-vasco/departamento-salud/inicio/-to J.R.B. N.F.J. was supported by an IARC Postodctoral Fellowship (FP7 Marie Curie Actions-People-COFUND) and a Postdoctoral Fellowship from the Basque Department of Education -http://training.iarc.fr/en/fellowships/postdoc.php-.I.R.G.and A.J.M. are supported by Predoctoral Fellowship grants from the UPV/EHU and the Basque Department of Education -http://www.euskadi.eus/gobierno-vasco/departamento-educacion/-, respectively. S.E. was supported by the abovementioned IARC Postdoctoral Fellowship program. ACR is an Ikerbasque Research Fellow -http://www.ikerbasque.net/-.The funding bodies had no role in the design of the study and collection, analysis, and interpretation of data nor in writing the manuscript.

Introduction: There is a paucity of information on cancer among Indigenous populations in Latin America.Methods: Guided by tenets of community engaged research and syndemic theory, we conducted eig...

Introduction: Pneumococcal conjugate vaccine (PCV) impact studies have reported substantial reductions in the incidence of invasive pneumococcal disease (IPD) after implementation of childhood PCV programs. Heterogeneity in surveillance systems, local epidemiology and PCV programs hampers comparisons between studies. We aimed to better understand the impact of childhood PCV programs on overall IPD and serotype distribution. Areas covered: We analyzed the impact of PCV programs on the incidence of overall IPD, and the distribution of vaccine serotypes (VT) and non-vaccine serotypes (NVT) in children Expert commentary: After introduction of pediatric PCV programs, the residual overall IPD burden in children was low and in a narrow range across countries with high vaccination coverage, irrespective of differences in PCV programs and pneumococcal epidemiology. Effects on overall IPD were more variable in the elderly. Whereas IPD was mainly due to VTs before PCV introduction, NVTs are the major contributor today in children and adults. Read the transcript Watch the video on Vimeo

BACKGROUND Over 34 million residents of the United States aged 65 years and older are also Medicare prescription drug beneficiaries. Medical claims records for this age group potentially provide a wealth of data for better understanding influenza epidemiology. OBJECTIVE The purpose of this study was to evaluate data on oseltamivir dispensing extracted from medical claims records as an indicator of influenza activity in the United States for the 2010-11 through 2014-15 influenza seasons. METHODS We used Centers for Medicare and Medicaid Services (CMS) medical claims data to evaluate the weekly number of therapeutic oseltamivir prescriptions dispensed following a rapid influenza diagnostic test among beneficiaries 65 years old and older as an indicator of influenza timing and intensity. We compared the temporal changes in this indicator to changes in the proportion of influenza-like illnesses among outpatient visits in the US Outpatient Influenza-like Illness Surveillance Network (ILINet) by administrative regions defined by the US Department of Health and Human Services. Using the moving epidemic method, we determined intensity thresholds and categorized the severity of seasons for both CMS and ILINet data. RESULTS Centers for Medicare and Medicaid Services oseltamivir data and ILINet data were strongly correlated by administrative region (median Spearman's ρ = 0.78; interquartile range = 0.73-0.80). CMS oseltamivir data and ILINet data substantially agreed (Cohen's weighted κ = 0.62) as to the seasonal severity across administrative regions. CONCLUSIONS Our results support the use of oseltamivir dispensing in medical claims data as an indicator of US influenza activity.

Clinicians often encounter patients with apparently discordant echocardiographic findings, severe aortic stenosis (SAS) defined by aortic valve area (AVA) despite a low mean gradient. A new classification according to flow state and pressure gradient has been proposed. We sought to assess the prevalence, characteristics and outcomes of patients with asymptomatic SAS with preserved left-ventricular ejection fraction (LVEF) according to flow and gradient.In total 442 patients with SAS (AVAi0.6 cm2/m2) and LVEF ≥50% (mean age 80+11years, 54,5% female) were included. Patients were classified according to flow state (≥ or35ml/mOur study confirms the high prevalence and worse prognosis of LF/LG SAS. Clinicians must be aware of this entity to ensure appropriate patient management.

Celiac disease is a chronic autoimmune condition triggered by dietary gluten in genetically predisposed individuals and the treatment is a strict gluten-free diet. The major predisposing genes are HLA-DQA1 and HLA-DQB1, but these are not sufficient for disease development. One of the candidate genes worth studying is interleukin (IL)-15 gene, together with its specific receptor, IL-15Rα, as they participate in promoting lymphocyte signaling and survival, and the establishment of appropriate conditions for villous atrophy, then acting as key players in the immunopathogenesis of CD. Here we analyze IL-15 and IL-15Rα genes in samples from the Spanish Consortium for Genetics of Celiac Disease (CEGEC) collection, identifying two regulatory single-nucleotide polymorphisms (SNP) that might be associated with celiac disease: rs4956400 (p-value 0.0112, OR 1.21, 95% CI 1.04–1.40) and rs11100722 (p-value 0.0087, OR 1.24, 95% CI 1.06–1.45), both located upstream the IL15 gene. When the expression of both genes was assessed, these two SNPs were found to be correlated with IL-15 higher protein expression. Besides, rs8177655 from IL15RA was also associated to mRNA IL-15 expression in CD patients. Finally, three SNPs from IL15RA intronic regions, rs2296141, rs3136614 and rs3181148, and another from its 3’UTR region, rs2229135, could be related to the age of diagnosis of celiac disease patients., This study was performed thanks to the grants from the Junta de Castilla y León (VA016A10-2), Instituto de Salud Carlos III FEDER (PI10/01647 and PI13/01201), Basque Dpt. of Health (2011/111034) and FPI-University of Valladolid.

Background Tens of millions of seniors are at risk of herpes zoster (HZ) and its complications. Live attenuated herpes zoster vaccine (HZV) reduces that risk, although questions regarding effectiveness and durability of protection in routine clinical practice remain. We used Medicare data to investigate HZV effectiveness (VE) and its durability. Methods This retrospective cohort study included beneficiaries ages ≥65 years during January 2007 through July 2014. Multiple adjustments to account for potential bias were made. HZV-vaccinated beneficiaries were matched to unvaccinated beneficiaries (primary analysis) and to HZV-unvaccinated beneficiaries who had received pneumococcal vaccination (secondary analysis). HZ outcomes in community and hospital settings were analyzed, including ophthalmic zoster (OZ) and postherpetic neuralgia (PHN). Results Among eligible beneficiaries (average age 77 years), the primary analysis found VE for community HZ of 33% (95% CI: 32%-35%) and 19% (95% CI: 17%-22%), for the first 3, and subsequent 4+ years postvaccination, respectively. In the secondary analysis, VE was, respectively, 37% (95% CI: 36%-39%) and 22% (95% CI: 20%-25%). In the primary analysis, VE for PHN was 57% (95% CI: 52%-61%) and 45% (95% CI: 36%-53%) in the first 3 and subsequent 4+ years, respectively; VE for hospitalized HZ was, respectively, 74% (95% CI: 67%-79%) and 55% (95% CI: 39%-67%). Differences in VE by age group were not significant. Conclusions In both the primary and secondary analyses, HZV provided protection against HZ across all ages, but effectiveness declined over time. VE was higher and better preserved over time for PHN and HZ-associated hospitalizations than for community HZ.

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Objective This study aims to compare a shorter cold ischemia time with the present one in relation to the complications developed in liver transplantations. Design This is a retrospective, observational study of orthotopic liver transplantations performed with grafts from brain-dead donors during 12 months at a University Hospital (Seville). We compare incidence rates of complications (reperfusion syndrome, arterial and biliary complications, and prostaglandin requirements) between two groups according to cold ischemia times (group A 6 hours). Results Sixty cases were included. There were more males in both groups as donors (55.5%) and recipients (75%). The median age was higher in group B in two cases. The Model for End-stage Liver Disease score was higher in patients with a shorter cold ischemia time, with a median of 20 hours (range, 16 to 26.5 hours). We observed that reperfusion syndrome (3.4% vs. 13.3%; P = .353), vascular complications (6.9% vs. 24.1%; P = .144), biliary tract complications (13.8% vs. 20.7%; P = .730), and prostaglandin requirements (3.4% vs. 20.7%; P = .102) were more common in group B, although without reaching statistical significance. After uni- and multivariate analyses, cold ischemia time longer than 6 hours was the only risk factor to develop complications (odds ratio: 3.578; 95% confidence interval: 1.125 to 11.374, P = .031). Conclusion According to the results of our analysis, cold ischemia times longer than 6 hours, as tends to be the usual procedure in most centers, imply higher rates of complications after liver transplantation.

BackgroundStudies among individuals ages ≥65 years have found a moderately higher relative vaccine effectiveness (RVE) for the high-dose (HD) influenza vaccine compared with standard-dose (SD) products for most seasons. Studies during the A(H3N2)-dominated 2017–2018 season showed slightly higher RVE for the cell-cultured vaccine compared with SD egg-based vaccines. We investigated the RVE of influenza vaccines among Medicare beneficiaries ages ≥65 years during the 2018–2019 season.MethodsThis is a retrospective cohort study using inverse probability of treatment weighting and Poisson regression to evaluate RVE in preventing influenza hospital encounters.ResultsAmong 12 777 214 beneficiaries, the egg-based adjuvanted (RVE, 7.7%; 95% confidence interval [CI], 3.9%–11.4%) and HD (RVE, 4.9%; 95% CI, 1.7%–8.1%) vaccines were marginally more effective than the egg-based quadrivalent vaccines. The cell-cultured quadrivalent vaccine was not significantly more effective than the egg-based quadrivalent vaccine (RVE, 2.5%; 95% CI, −2.4% to 7.3%).ConclusionsWe did not find major effectiveness differences between licensed vaccines used among the elderly during the 2018–2019 season. Consistent with prior research, we found that the egg-based adjuvanted and HD vaccines were slightly more effective than the egg-based quadrivalent vaccines.

The epidermal growth factor receptor (EGFR) is overexpressed in numerous solid tumors and is the subject of extensive therapeutic efforts. Much of the research on EGFR is focused on protein dynamics and downstream signaling, however few studies have explored its transcriptional regulation. Here, we identified two enhancers (CE1 and CE2) present within the first intron of the EGFR gene in models of glioblastoma (GBM) and head and neck squamous cell carcinoma (HNSCC). CE1 and CE2 contain open chromatin and H3K27Ac histone marks, enhance transcription in reporter assays, and interact with the EGFR promoter. Enhancer genetic deletion by CRISPR/Cas9 significantly reduces EGFR transcript levels, with double deletion exercising an additive effect. Targeted repression of CE1 and CE2 by dCas9-KRAB demonstrates repression of transcription similar to that of genomic deletion. We identify AP-1 transcription factor family members in concert with BET bromodomain proteins as modulators of CE1 and CE2 activity in HNSCC and GBM through de novo motif identification and validate their presence. Genetic inhibition of AP-1 or pharmacologic disruption of BET/AP-1 binding results in downregulated EGFR protein and transcript levels, confirming a role for these factors in CE1 and CE2. Our results identify and characterize these novel enhancers, shedding light on the role that epigenetic mechanisms play in regulating EGFR transcription in EGFR-dependent cancers. IMPLICATIONS: We identify critical constituent enhancers present in the first intron of the EGFR gene, and provide rationale for therapeutic targeting of EGFR intron 1 enhancers through perturbation of AP-1 and BET in EGFR-positive malignancies.

Introduction: Facial expressions and vocal intonation are key signals in the communication of emotions. Individuals with posttraumatic stress disorder (PTSD) are known to show an impaired perception of facial emotions. So far, research on multimodal emotional stimuli or the priming effects on emotion processing has been absent in PTSD. Therefore, we conducted a study to investigate the influence of vocal priming on facial emotion processing and classification in PTSD using electroencephalography. Methods: Twenty-one women with PTSD compared to 28 healthy women were asked to classify emotion-morphed faces with predominantly angry, ambiguous, or predominantly happy expressions primed by either an angry or a happy voice. Responses and reaction times as well as the N170, a component reflecting configural face processing, were analyzed. Results: Patients with PTSD were slower in classifying emotional faces that were primed by either an angry or happy voice compared to the healthy controls (HCs; η2 = 0.14). Additionally, patients with PTSD were faster in classifying facial expressions after angry compared to happy vocal primes (η2 = 0.14). HCs did not show this effect. Correlation analyses revealed positive associations between emotion (dys-)regulation and reaction times in patients with PTSD but not in HCs (r = 0.64–0.76). Furthermore, patients with PTSD showed greater N170 amplitudes for predominantly angry and ambiguous faces than HCs (η2 = 0.07). Conclusion: Data suggest that patients with PTSD experience more difficulties when processing complex social stimuli than HCs. The altered processing of complex social-emotional signals could amplify PTSD symptoms, thus qualifying as an explicit therapy target.

To identify candidate genes in celiac disease (CD), we reanalyzed the whole Immunochip CD cohort using a different approach that clusters individuals based on immunoancestry prior to disease association analysis, rather than by geographical origin. We detected 636 new associated SNPs (P