Hybrid Immunity and SARS-CoV-2 Antibodies: Results of the HEROES-RECOVER Prospective Cohort Study.

BACKGROUND: There are limited data on whether hybrid immunity differs by count and order of immunity-conferring events (infection with severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] or vaccination against coronavirus disease 2019 [COVID-19]). From a multi-site cohort of frontline workers, we examined the heterogeneity of the effect of hybrid immunity on SARS-CoV-2 antibody levels. METHODS: Exposures included event count and event order, categorized into 7 permutations. Outcome was level of serum antibodies against receptor-binding domain (RBD) of the ancestral SARS-CoV-2 spike protein (total RBD-binding immunoglobulin). Means were examined up to 365 days after each of the first to seventh events. RESULTS: Analysis included 5793 participants measured from 7 August 2020 to 15 April 2023. Hybrid immunity from infection before 1 or 2 vaccine doses elicited modestly superior antibody responses after the second and third events (compared with infections or vaccine doses alone). This superiority was not repeated after additional events. Among adults infected before vaccination, adjusted geometric mean ratios (95% confidence interval [CI]) of anti-RBD early response (versus vaccinated only) were 1.23 (1.14-1.33), 1.09 (1.03-1.14), 0.87 (.81-.94), and 0.99 (.85-1.15) after the second to fifth events, respectively. Post-vaccination infections elicited superior responses; adjusted geometric mean ratios (95% CI) of anti-RBD early response (versus vaccinated only) were 0.93 (.75-1.17), 1.11 (1.06-1.16), 1.17 (1.11-1.24), and 1.20 (1.07-1.34) after the second to fifth events, respectively. CONCLUSIONS: Evidence of heterogeneity in antibody levels by permutations of infection and vaccination history could inform COVID-19 vaccination policy.

Prevention and Attenuation of Covid-19 with the BNT162b2 and mRNA-1273 Vaccines.

BACKGROUND: Information is limited regarding the effectiveness of the two-dose messenger RNA (mRNA) vaccines BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) in preventing infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and in attenuating coronavirus disease 2019 (Covid-19) when administered in real-world conditions. METHODS: We conducted a prospective cohort study involving 3975 health care personnel, first responders, and other essential and frontline workers. From December 14, 2020, to April 10, 2021, the participants completed weekly SARS-CoV-2 testing by providing mid-turbinate nasal swabs for qualitative and quantitative reverse-transcriptase-polymerase-chain-reaction (RT-PCR) analysis. The formula for calculating vaccine effectiveness was 100% × (1 - hazard ratio for SARS-CoV-2 infection in vaccinated vs. unvaccinated participants), with adjustments for the propensity to be vaccinated, study site, occupation, and local viral circulation. RESULTS: SARS-CoV-2 was detected in 204 participants (5%), of whom 5 were fully vaccinated (≥14 days after dose 2), 11 partially vaccinated (≥14 days after dose 1 and <14 days after dose 2), and 156 unvaccinated; the 32 participants with indeterminate vaccination status (<14 days after dose 1) were excluded. Adjusted vaccine effectiveness was 91% (95% confidence interval [CI], 76 to 97) with full vaccination and 81% (95% CI, 64 to 90) with partial vaccination. Among participants with SARS-CoV-2 infection, the mean viral RNA load was 40% lower (95% CI, 16 to 57) in partially or fully vaccinated participants than in unvaccinated participants. In addition, the risk of febrile symptoms was 58% lower (relative risk, 0.42; 95% CI, 0.18 to 0.98) and the duration of illness was shorter, with 2.3 fewer days spent sick in bed (95% CI, 0.8 to 3.7). CONCLUSIONS: Authorized mRNA vaccines were highly effective among working-age adults in preventing SARS-CoV-2 infection when administered in real-world conditions, and the vaccines attenuated the viral RNA load, risk of febrile symptoms, and duration of illness among those who had breakthrough infection despite vaccination. (Funded by the National Center for Immunization and Respiratory Diseases and the Centers for Disease Control and Prevention.).

Cell and gene therapy investment: evolution and future outlook on investor perspectives.

BACKGROUND AIMS: To better understand the attitudes and behaviors of investors involved in funding cell and gene therapy (CGT) businesses, the Business Development and Finance) subcommittee of International Society for Cell and Gene Therapy, in collaboration with Truist Securities, conducted a broad survey of the investment community in late 2021. METHODS: This survey follows a similar study that this group executed in 2018, and the longitudinal comparisons between the two time periods provide insights into how investor behavior in the CGT field has evolved. RESULTS: The vast majority of investor respondents are specialist biotech investors who are primarily active in deploying capital in North America and Europe. There was a notable increase in the proportion of investors actively deploying capital in China and Japan between 2018 and 2021. The percentage of respondents' portfolios dedicated to CGT companies has also increased in this period, reflecting a noteworthy trend in the therapeutic landscape. CONCLUSIONS: Clinically significant data remain the dominant force behind investment decisions, whereas competition from other drug modalities has now emerged as the most-cited barrier to making a CGT investment, eclipsing safety concerns as the most significant barrier to investment in 2018. Concerns around manufacturing and scale-up have also increased in prominence amongst the investment community. Gene-editing technologies are attracting investors as the most compelling new CGT technology. This survey also revealed that most investors expect to increase their level of investment in allogeneic technologies relative to autologous products in the coming years.

Risk Factors for Reinfection with SARS-CoV-2 Omicron Variant among Previously Infected Frontline Workers.

In a cohort of essential workers in the United States previously infected with SARS-CoV-2, risk factors for reinfection included being unvaccinated, infrequent mask use, time since first infection, and being non-Hispanic Black. Protecting workers from reinfection requires a multipronged approach including up-to-date vaccination, mask use as recommended, and reduction in underlying health disparities.

Disease and social factors associated with healthcare utilization for the treatment of SARS-CoV-2 infections in a longitudinal cohort of essential workers in Arizona.

BACKGROUND: Demands on health systems due to COVID-19 are substantial, but drivers of healthcare utilization are not well defined in non-severe SARS-CoV-2 infections. Among a prospective cohort of frontline workers from July 2020 to February 2023, we assessed predictors of healthcare utilization during SARS-CoV-2 infection. METHODS: Weekly specimens tested via real-time reverse transcriptase polymerase chain reaction analysis. Participants reported sociodemographic, health status information, and illness experience information. Primary outcome was healthcare utilization during SARS-CoV-2 infection. Predictors included sociodemographic characteristics, baseline health status, and measures of illness severity. Multivariable logistic regression was utilized to generate odds ratios for predictors of healthcare utilization. RESULTS: 1,923 SARS-CoV-2 infections (1,276 first infections and 647 reinfections from 4,208 participants): 1221 (63.5%) individuals were between 40 and 65 years old; 1115 (58.0%) were female; 449 (23.3%) were Hispanic and 1305 (67.9%) non-Hispanic White. 294 (15.3%) individuals sought medical care during first infection, 106 (5.5%) during reinfection. Sociodemographic and baseline health characteristics were not associated with healthcare utilization during infections from any variant for first infections, while age (OR 1.04, 95%CI 1.01-1.07) was during Omicron reinfection. In first infection, number of symptoms (OR 1.16, 95%CI 1.00-1.36 in Origin/Alpha, OR 1.12, 95%CI 1.00-1.49 in Delta, OR 1.09, 95%CI 1.01-1.16 in Omicron), number of days spent in bed (OR 1.13, 95%CI 1.02-1.33 in Origin/Alpha, OR 1.23, 95%CI 1.00-1.59 in Delta, OR 1.12, 95%CI 1.03-1.22 in Omicron), and illness duration (OR 1.01, 95%CI 1.00-1.04 in Origin/Alpha, OR 1.01, 95%CI 1.00-1.03 in Delta, OR 1.01, 95%CI 1.00-1.02 in Omicron) were related to healthcare utilization for all variants. Number of days in bed (OR 1.12, 95%CI 1.01-1.27), illness duration (OR 1.01, 95%CI 1.00-1.02), and hours of work missed (OR 2.24, 95%CI 1.11-4.74) were positively associated with healthcare utilization during Omicron reinfection. CONCLUSION: The main factors associated with healthcare utilization for SARS-CoV-2 infection were symptom severity and duration. Practices and therapeutics aimed at decreasing these factors would be most helpful in easing the burden on health systems.

Effectiveness of 2-Dose BNT162b2 (Pfizer BioNTech) mRNA Vaccine in Preventing SARS-CoV-2 Infection Among Children Aged 5-11 Years and Adolescents Aged 12-15 Years - PROTECT Cohort, July 2021-February 2022.

The BNT162b2 (Pfizer-BioNTech) mRNA COVID-19 vaccine was recommended by CDC's Advisory Committee on Immunization Practices for persons aged 12-15 years (referred to as adolescents in this report) on May 12, 2021, and for children aged 5-11 years on November 2, 2021 (1-4). Real-world data on vaccine effectiveness (VE) in these age groups are needed, especially because when the B.1.1.529 (Omicron) variant became predominant in the United States in December 2021, early investigations of VE demonstrated a decline in protection against symptomatic infection for adolescents aged 12-15 years and adults* (5). The PROTECT† prospective cohort of 1,364 children and adolescents aged 5-15 years was tested weekly for SARS-CoV-2, irrespective of symptoms, and upon COVID-19-associated illness during July 25, 2021-February 12, 2022. Among unvaccinated participants (i.e., those who had received no COVID-19 vaccine doses) with any laboratory-confirmed SARS-CoV-2 infection, those with B.1.617.2 (Delta) variant infections were more likely to report COVID-19 symptoms (66%) than were those with Omicron infections (49%). Among fully vaccinated children aged 5-11 years, VE against any symptomatic and asymptomatic Omicron infection 14-82 days (the longest interval after dose 2 in this age group) after receipt of dose 2 of the Pfizer-BioNTech vaccine was 31% (95% CI = 9%-48%), adjusted for sociodemographic characteristics, health information, frequency of social contact, mask use, location, and local virus circulation. Among adolescents aged 12-15 years, adjusted VE 14-149 days after dose 2 was 87% (95% CI = 49%-97%) against symptomatic and asymptomatic Delta infection and 59% (95% CI = 22%-79%) against Omicron infection. Fully vaccinated participants with Omicron infection spent an average of one half day less sick in bed than did unvaccinated participants with Omicron infection. All eligible children and adolescents should remain up to date with recommended COVID-19 vaccinations.

Association of mRNA Vaccination With Clinical and Virologic Features of COVID-19 Among US Essential and Frontline Workers.

Importance: Data on the epidemiology of mild to moderately severe COVID-19 are needed to inform public health guidance. Objective: To evaluate associations between 2 or 3 doses of mRNA COVID-19 vaccine and attenuation of symptoms and viral RNA load across SARS-CoV-2 viral lineages. Design, Setting, and Participants: A prospective cohort study of essential and frontline workers in Arizona, Florida, Minnesota, Oregon, Texas, and Utah with COVID-19 infection confirmed by reverse transcriptase-polymerase chain reaction testing and lineage classified by whole genome sequencing of specimens self-collected weekly and at COVID-19 illness symptom onset. This analysis was conducted among 1199 participants with SARS-CoV-2 from December 14, 2020, to April 19, 2022, with follow-up until May 9, 2022, reported. Exposures: SARS-CoV-2 lineage (origin strain, Delta variant, Omicron variant) and COVID-19 vaccination status. Main Outcomes and Measures: Clinical outcomes included presence of symptoms, specific symptoms (including fever or chills), illness duration, and medical care seeking. Virologic outcomes included viral load by quantitative reverse transcriptase-polymerase chain reaction testing along with viral viability. Results: Among 1199 participants with COVID-19 infection (714 [59.5%] women; median age, 41 years), 14.0% were infected with the origin strain, 24.0% with the Delta variant, and 62.0% with the Omicron variant. Participants vaccinated with the second vaccine dose 14 to 149 days before Delta infection were significantly less likely to be symptomatic compared with unvaccinated participants (21/27 [77.8%] vs 74/77 [96.1%]; OR, 0.13 [95% CI, 0-0.6]) and, when symptomatic, those vaccinated with the third dose 7 to 149 days before infection were significantly less likely to report fever or chills (5/13 [38.5%] vs 62/73 [84.9%]; OR, 0.07 [95% CI, 0.0-0.3]) and reported significantly fewer days of symptoms (10.2 vs 16.4; difference, -6.1 [95% CI, -11.8 to -0.4] days). Among those with Omicron infection, the risk of symptomatic infection did not differ significantly for the 2-dose vaccination status vs unvaccinated status and was significantly higher for the 3-dose recipients vs those who were unvaccinated (327/370 [88.4%] vs 85/107 [79.4%]; OR, 2.0 [95% CI, 1.1-3.5]). Among symptomatic Omicron infections, those vaccinated with the third dose 7 to 149 days before infection compared with those who were unvaccinated were significantly less likely to report fever or chills (160/311 [51.5%] vs 64/81 [79.0%]; OR, 0.25 [95% CI, 0.1-0.5]) or seek medical care (45/308 [14.6%] vs 20/81 [24.7%]; OR, 0.45 [95% CI, 0.2-0.9]). Participants with Delta and Omicron infections who received the second dose 14 to 149 days before infection had a significantly lower mean viral load compared with unvaccinated participants (3 vs 4.1 log10 copies/µL; difference, -1.0 [95% CI, -1.7 to -0.2] for Delta and 2.8 vs 3.5 log10 copies/µL, difference, -1.0 [95% CI, -1.7 to -0.3] for Omicron). Conclusions and Relevance: In a cohort of US essential and frontline workers with SARS-CoV-2 infections, recent vaccination with 2 or 3 mRNA vaccine doses less than 150 days before infection with Delta or Omicron variants, compared with being unvaccinated, was associated with attenuated symptoms, duration of illness, medical care seeking, or viral load for some comparisons, although the precision and statistical significance of specific estimates varied.

Cell and gene therapy: a snapshot of investor perspectives.

In a collaborative effort between the Commercialization Committee of the International Society for Cell & Gene Therapy (ISCT) and Bloomberg Intelligence, a broad survey of the investment community was executed in order to understand investor perceptions of companies that develop cell and gene therapies (CGTs) and gauge the trajectory of future investment. A broad spectrum of investors responded to the survey, including both health care specialists and generalist investors across a wide range of fund sizes and geographies. A majority of survey respondents have limited exposure to CGTs in their health care portfolios today, which highlights the opportunity to increase awareness of this burgeoning field in the investment community. The survey established that clinically significant data are the most important consideration when making an investment in this area, whereas safety concerns were highlighted as the most prominent barrier to making an investment. Challenges with manufacturing and scale-up were also ranked as a significant concern. The majority of investors hold the belief that both autologous and allogeneic cell therapies can co-exist. The detailed findings of this survey will help to provide a foundation for educational content that the ISCT Commercialization Committee can bring forth to further the investment in CGTs through the newly created Investigators to Investors program.

Interim Estimate of Vaccine Effectiveness of BNT162b2 (Pfizer-BioNTech) Vaccine in Preventing SARS-CoV-2 Infection Among Adolescents Aged 12-17 Years - Arizona, July-December 2021.

The BNT162b2 (Pfizer-BioNTech) mRNA COVID-19 vaccine has demonstrated high efficacy in preventing infection with SARS-CoV-2 (the virus that causes COVID-19) in randomized placebo-controlled Phase III trials in persons aged 12-17 years (referred to as adolescents in this report) (1); however, data on real-word vaccine effectiveness (VE) among adolescents are limited (1-3). As of December 2021, the Pfizer-BioNTech vaccine is approved by the Food and Drug Administration (FDA) for adolescents aged 16-17 years and under FDA emergency use authorization for those aged 12-15 years. In a prospective cohort in Arizona, 243 adolescents aged 12-17 years were tested for SARS-CoV-2 by reverse transcription-polymerase chain reaction (RT-PCR) each week, irrespective of symptoms, and upon onset of COVID-19-like illness during July 25-December 4, 2021; the SARS-CoV-2 B.1.617.2 (Delta) variant was the predominant strain during this study period. During the study, 190 adolescents contributed fully vaccinated person-time (≥14 days after receiving 2 doses of Pfizer-BioNTech vaccine), 30 contributed partially vaccinated person-time (receipt of 1 dose or receipt of 2 doses but with the second dose completed <14 days earlier), and 66 contributed unvaccinated person-time. Using the Cox proportional-hazards model, the estimated VE of full Pfizer-BioNTech vaccination for preventing SARS-CoV-2 infection was 92% (95% CI = 79%-97%), adjusted for sociodemographic characteristics, health information, frequency of social contact, mask use, location, and local virus circulation. These findings from a real-world setting indicate that 2 doses of Pfizer-BioNTech vaccine are highly effective in preventing SARS-CoV-2 infection among Arizona adolescents. CDC recommends COVID-19 vaccination for all eligible persons in the United States, including persons aged 12-17 years.

Interim Estimates of Vaccine Effectiveness of BNT162b2 and mRNA-1273 COVID-19 Vaccines in Preventing SARS-CoV-2 Infection Among Health Care Personnel, First Responders, and Other Essential and Frontline Workers - Eight U.S. Locations, December 2020-March 2021.

Messenger RNA (mRNA) BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) COVID-19 vaccines have been shown to be effective in preventing symptomatic COVID-19 in randomized placebo-controlled Phase III trials (1,2); however, the benefits of these vaccines for preventing asymptomatic and symptomatic SARS-CoV-2 (the virus that causes COVID-19) infection, particularly when administered in real-world conditions, is less well understood. Using prospective cohorts of health care personnel, first responders, and other essential and frontline workers* in eight U.S. locations during December 14, 2020-March 13, 2021, CDC routinely tested for SARS-CoV-2 infections every week regardless of symptom status and at the onset of symptoms consistent with COVID-19-associated illness. Among 3,950 participants with no previous laboratory documentation of SARS-CoV-2 infection, 2,479 (62.8%) received both recommended mRNA doses and 477 (12.1%) received only one dose of mRNA vaccine.† Among unvaccinated participants, 1.38 SARS-CoV-2 infections were confirmed by reverse transcription-polymerase chain reaction (RT-PCR) per 1,000 person-days.§ In contrast, among fully immunized (≥14 days after second dose) persons, 0.04 infections per 1,000 person-days were reported, and among partially immunized (≥14 days after first dose and before second dose) persons, 0.19 infections per 1,000 person-days were reported. Estimated mRNA vaccine effectiveness for prevention of infection, adjusted for study site, was 90% for full immunization and 80% for partial immunization. These findings indicate that authorized mRNA COVID-19 vaccines are effective for preventing SARS-CoV-2 infection, regardless of symptom status, among working-age adults in real-world conditions. COVID-19 vaccination is recommended for all eligible persons.

Living at the Confluence of Stigmas: PrEP Awareness and Feasibility Among People Who Inject Drugs in Two Predominantly Rural States.

We explored knowledge, beliefs, and acceptability of pre-exposure prophylaxis (PrEP) for HIV prevention with reference to stigma among people who inject drugs (PWID) in two predominately rural U.S. states. We conducted interviews with 65 current or former PWID aged 18 years or older and living in Arizona or Indiana. Most (63%) of the interviewees were not aware of PrEP. They often confused PrEP with HIV treatment, and many believed that PrEP was only for sexual risk or gay sexual risk. Once they understood that PrEP was recommended for PWID, the participants held a positive view of PrEP and felt that a once-daily pill was feasible. Experiences of stigma about drug use remained a crucial barrier to accessing healthcare and PrEP. This was often linked with anticipated or expressed homophobia. PrEP interventions among PWID must focus on education and the confluence of stigmas in which PWID find themselves when considering PrEP.

RESUMEN: Exploramos el conocimiento, las creencias y la aceptabilidad de la profilaxis previa a la exposición (PrEP) para la prevención del VIH con referencia al estigma entre las personas que inyectan drogas (PWID) en dos Estados Unidos predominantemente rurales. estados. Realizamos entrevistas con 65 PWID actuales o anteriores de 18 años o más y viviendo en Arizona o Indiana. Más (63%) de los entrevistados no estaban al tanto de la PrEP. A menudo confundieron la PrEP con el tratamiento del VIH, y muchos creían que la PrEP era sólo por riesgo sexual o riesgo sexual gay. Una vez que entendieron que la PrEP se recomendaba para PWID, los participantes tenían una visión positiva de la PrEP y sentían que una vez-píldora diaria era factible. Las experiencias de estigma sobre el consumo de drogas siguieron siendo una barrera crucial para acceder a la atención médica y a la PrEP. Esto a menudo estaba relacionado con la homofobia anticipada o expresada. Las intervenciones de la PrEP entre PWID deben centrarse en la educación y la confluencia de estigmas en los que PWID se encuentra al considerar la PrEP.

Health promotion interventions for African Americans delivered in U.S. barbershops and hair salons- a systematic review.

BACKGROUND: African American adults suffer disproportionately from obesity-related chronic diseases, particularly at younger ages. In order to close the gap in these health disparities, efforts to develop and test culturally appropriate interventions are critical. METHODS: A PRISMA-guided systematic review was conducted to identify and critically evaluate health promotion interventions for African Americans delivered in barbershops and hair salons. Subject headings and keywords used to search for synonyms of 'barbershops,' 'hair salons,' and 'African Americans' identified all relevant articles (from inception onwards) from six databases: Academic Search Ultimate, Cumulative Index of Nursing and Allied Health Literature (CINAHL), Embase, PsycINFO, PubMed, Web of Science (Science Citation Index and Social Sciences Citation Index). Experimental and quasi-experimental studies for adult (> 18 years) African Americans delivered in barbershops and hair salons that evaluated interventions focused on risk reduction/management of obesity-related chronic disease: cardiovascular disease, cancer, and type 2 diabetes were included. Analyses were conducted in 2020. RESULTS: Fourteen studies met criteria for inclusion. Ten studies hosted interventions in a barbershop setting while four took place in hair salons. There was substantial variability among interventions and outcomes with cancer the most commonly studied disease state (n = 7; 50%), followed by hypertension (n = 5; 35.7%). Most reported outcomes were focused on behavior change (n = 10) with only four studies reporting clinical outcomes. CONCLUSIONS: Health promotion interventions delivered in barbershops/hair salons show promise for meeting cancer screening recommendations and managing hypertension in African Americans. More studies are needed that focus on diabetes and obesity and utilize the hair salon as a site for intervention delivery. TRIAL REGISTRATION: PROSPERO CRD42020159050 .

Managerial process improvement: a lean approach to eliminating medication delivery.

PURPOSE: Statistical evidence shows that medication errors are a major cause of injuries that concerns all health care oganizations. Despite all the efforts to improve the quality of care, the lack of understanding and inability of management to design a robust system that will strategically target those factors is a major cause of distress. The paper aims to discuss these issues. DESIGN/METHODOLOGY/APPROACH: Achieving optimum organizational performance requires two key variables; work process factors and human performance factors. The approach is that healthcare administrators must take in account both variables in designing a strategy to reduce medication errors. However, strategies that will combat such phenomena require that managers and administrators understand the key factors that are causing medication delivery errors. FINDINGS: The authors recommend that healthcare organizations implement the Toyota Production System (TPS) combined with human performance improvement (HPI) methodologies to eliminate medication delivery errors in hospitals. ORIGINALITY/VALUE: Despite all the efforts to improve the quality of care, there continues to be a lack of understanding and the ability of management to design a robust system that will strategically target those factors associated with medication errors. This paper proposes a solution to an ambiguous workflow process using the TPS combined with the HPI system.

Production of site-specific antibody-drug conjugates using optimized non-natural amino acids in a cell-free expression system.

Antibody-drug conjugates (ADCs) are a targeted chemotherapeutic currently at the cutting edge of oncology medicine. These hybrid molecules consist of a tumor antigen-specific antibody coupled to a chemotherapeutic small molecule. Through targeted delivery of potent cytotoxins, ADCs exhibit improved therapeutic index and enhanced efficacy relative to traditional chemotherapies and monoclonal antibody therapies. The currently FDA-approved ADCs, Kadcyla (Immunogen/Roche) and Adcetris (Seattle Genetics), are produced by conjugation to surface-exposed lysines, or partial disulfide reduction and conjugation to free cysteines, respectively. These stochastic modes of conjugation lead to heterogeneous drug products with varied numbers of drugs conjugated across several possible sites. As a consequence, the field has limited understanding of the relationships between the site and extent of drug loading and ADC attributes such as efficacy, safety, pharmacokinetics, and immunogenicity. A robust platform for rapid production of ADCs with defined and uniform sites of drug conjugation would enable such studies. We have established a cell-free protein expression system for production of antibody drug conjugates through site-specific incorporation of the optimized non-natural amino acid, para-azidomethyl-l-phenylalanine (pAMF). By using our cell-free protein synthesis platform to directly screen a library of aaRS variants, we have discovered a novel variant of the Methanococcus jannaschii tyrosyl tRNA synthetase (TyrRS), with a high activity and specificity toward pAMF. We demonstrate that site-specific incorporation of pAMF facilitates near complete conjugation of a DBCO-PEG-monomethyl auristatin (DBCO-PEG-MMAF) drug to the tumor-specific, Her2-binding IgG Trastuzumab using strain-promoted azide-alkyne cycloaddition (SPAAC) copper-free click chemistry. The resultant ADCs proved highly potent in in vitro cell cytotoxicity assays.

Determinants of differentials in pneumonia mortality in the UK and France.

Pneumonia is one of the major causes of death in the world. Age-adjusted mortality from pneumonia in the United Kingdom was three times higher than it was in France in 2004. The purpose of this article is to find the underlying determinants of pneumonia mortality differences between these two countries. The main research question is "what are the determinants of pneumonia mortality in the UK and France?" Reviewing the underlying determinants of health inequalities, we expected that behavioral factors, environmental factors, and the health care system would account for the differences, but they do not actually account for much of the differences in Pneumonia mortality between the UK and France. The main difference is due to data quality problems particularly relating to diagnosis and certification in both countries.

Longitudinal parental perception of COVID-19 vaccines for children in a multi-site, cohort study.

OBJECTIVES: Pediatric COVID-19 vaccine hesitancy and uptake is not well understood. Among parents of a prospective cohort of children aged 6 months-17 years, we assessed COVID-19 vaccine knowledge, attitudes, and practices (KAP), and uptake over 15 months. METHODS: The PROTECT study collected sociodemographic characteristics of children at enrollment and COVID-19 vaccination data and parental KAPs quarterly. Univariable and multivariable logistic regression models were used to test the effect of KAPs on vaccine uptake; McNemar's test for paired samples was used to evaluate KAP change over time. RESULTS: A total of 2,837 children were enrolled, with more than half (61 %) vaccinated by October 2022. Positive parental beliefs about vaccine safety and effectiveness strongly predicted vaccine uptake among children aged 5-11 years (aOR 13.1, 95 % CI 8.5-20.4 and aOR 6.4, 95 % CI 4.3-9.6, respectively) and children aged 12+ years (aOR 7.0, 95 % CI 3.8-13.0 and aOR 8.9, 95 % CI 4.4-18.0). Compared to enrollment, at follow-up parents (of vaccinated and unvaccinated children) reported higher self-assessed vaccine knowledge, but more negative beliefs towards vaccine safety, effectiveness, and trust in government. Parents unlikely to vaccinate their children at enrollment reported more positive beliefs on vaccine knowledge, safety, and effectiveness at follow-up. CONCLUSION: The PROTECT cohort allows for an examination of factors driving vaccine uptake and how beliefs about COVID-19 and the COVID-19 vaccines change over time. Findings of the current analysis suggest that these beliefs change over time and policies aiming to increase vaccine uptake should focus on vaccine safety and effectiveness.

Evaluating Immunologic and Illness Outcomes of SARS-CoV-2 Infection in Vaccinated and Unvaccinated Children Aged ≥ 5 Years, in a Multisite Longitudinal Cohort.

Hybrid immunity, as a result of infection and vaccination to SARS-CoV-2, has been well studied in adults but limited evidence is available in children. We evaluated the antibody responses to primary SARS-CoV-2 infection among vaccinated and unvaccinated children aged ≥ 5 years. METHODS: A longitudinal cohort study of children aged ≥ 5 was conducted during August 2021-August 2022, at sites in Arizona, Texas, Utah, and Florida. Children submitted weekly nasal swabs for PCR testing and provided sera 14-59 days after PCR-confirmed SARS-CoV-2 infection. Antibodies were measured by ELISA against the receptor-binding domain (RBD) and S2 domain of ancestral Spike (WA1), in addition to Omicron (BA.2) RBD, following infection in children, with and without prior monovalent ancestral mRNA COVID-19 vaccination. RESULTS: Among the 257 participants aged 5 to 18 years, 166 (65%) had received at least two mRNA COVID-19 vaccine doses ≥ 14 days prior to infection. Of these, 53 occurred during Delta predominance, with 37 (70%) unvaccinated at the time of infection. The remaining 204 infections occurred during Omicron predominance, with 53 (26%) participants unvaccinated. After adjusting for weight, age, symptomatic infection, and gender, significantly higher mean RBD AUC values were observed among the vaccinated group compared to the unvaccinated group for both WA1 and Omicron (p < 0.0001). A smaller percentage of vaccinated children reported fever during illness, with 55 (33%) reporting fever compared to 44 (48%) unvaccinated children reporting fever (p = 0.021). CONCLUSIONS: Children with vaccine-induced immunity at the time of SARS-CoV-2 infection had higher antibody levels during convalescence and experienced less fever compared to unvaccinated children during infection.

COVID-19 Across Pandemic Variant Periods: The Severe Acute Respiratory Infection-Preparedness (SARI-PREP) Study.

IMPORTANCE: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has evolved through multiple phases in the United States, with significant differences in patient centered outcomes with improvements in hospital strain, medical countermeasures, and overall understanding of the disease. We describe how patient characteristics changed and care progressed over the various pandemic phases; we also emphasize the need for an ongoing clinical network to improve the understanding of known and novel respiratory viral diseases. OBJECTIVES: To describe how patient characteristics and care evolved across the various COVID-19 pandemic periods in those hospitalized with viral severe acute respiratory infection (SARI). DESIGN: Severe Acute Respiratory Infection-Preparedness (SARI-PREP) is a Centers for Disease Control and Prevention Foundation-funded, Society of Critical Care Medicine Discovery-housed, longitudinal multicenter cohort study of viral pneumonia. We defined SARI patients as those hospitalized with laboratory-confirmed respiratory viral infection and an acute syndrome of fever, cough, and radiographic infiltrates or hypoxemia. We collected patient-level data including demographic characteristics, comorbidities, acute physiologic measures, serum and respiratory specimens, therapeutics, and outcomes. Outcomes were described across four pandemic variant periods based on a SARS-CoV-2 sequenced subsample: pre-Delta, Delta, Omicron BA.1, and Omicron post-BA.1. SETTING: Multicenter cohort of adult patients admitted to an acute care ward or ICU from seven hospitals representing diverse geographic regions across the United States. PARTICIPANTS: Patients with SARI caused by infection with respiratory viruses. MAIN OUTCOMES AND RESULTS: Eight hundred seventy-four adult patients with SARI were enrolled at seven study hospitals between March 2020 and April 2023. Most patients (780, 89%) had SARS-CoV-2 infection. Across the COVID-19 cohort, median age was 60 years (interquartile range, 48.0-71.0 yr) and 66% were male. Almost half (430, 49%) of the study population belonged to underserved communities. Most patients (76.5%) were admitted to the ICU, 52.5% received mechanical ventilation, and observed hospital mortality was 25.5%. As the pandemic progressed, we observed decreases in ICU utilization (94% to 58%), hospital length of stay (median, 26.0 to 8.5 d), and hospital mortality (32% to 12%), while the number of comorbid conditions increased. CONCLUSIONS AND RELEVANCE: We describe increasing comorbidities but improved outcomes across pandemic variant periods, in the setting of multiple factors, including evolving care delivery, countermeasures, and viral variants. An understanding of patient-level factors may inform treatment options for subsequent variants and future novel pathogens.

Health information technology capacity at federally qualified health centers: a mechanism for improving quality of care.

BACKGROUND: The adoption of health information technology has been recommended as a viable mechanism for improving quality of care and patient health outcomes. However, the capacity of health information technology (i.e., availability and use of multiple and advanced functionalities), particularly in federally qualified health centers (FQHCs) on improving quality of care is not well understood. We examined associations between health information technology (HIT) capacity at FQHCs and quality of care, measured by the receipt of discharge summary, frequency of patients receiving reminders/notifications for preventive care/follow-up care, and timely appointment for specialty care. METHODS: The analyses used 2009 data from the National Survey of Federally Qualified Health Centers. The study included 776 of the FQHCs that participated in the survey. We examined the extent of HIT use and tested the hypothesis that level of HIT capacity is associated with quality of care. Multivariable logistic regressions, reporting unadjusted and adjusted odds ratios, were used to examine whether 'FQHCs' HIT capacity' is associated with the outcome measures. RESULTS: The results showed a positive association between health information technology capacity and quality of care. FQHCs with higher HIT capacity were significantly more likely to have improved quality of care, measured by the receipt of discharge summaries (OR=1.43; CI=1.01, 2.40), the use of a patient notification system for preventive and follow-up care (OR=1.74; CI=1.23, 2.45), and timely appointment for specialty care (OR=1.77; CI=1.24, 2.53). CONCLUSIONS: Our findings highlight the promise of HIT in improving quality of care, particularly for vulnerable populations who seek care at FQHCs. The results also show that FQHCs may not be maximizing the benefits of HIT. Efforts to implement HIT must include strategies that facilitate the implementation of comprehensive and advanced functionalities, as well as promote meaningful use of these systems. Further examination of the role of health information systems in clinical decision-making and improvements in patient outcomes are needed to better understand the benefits of HIT in improving overall quality of care.