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What is this summary about? This is a summary of an article about part of a clinical study for the BNT162b2 COVID-19 vaccine, also called the Pfizer-BioNTech vaccine. The article was published in the New England Journal of Medicine in May 2021. This summary describes how the vaccine worked in participants 12- to 15-years old. The part of the study described in the article is ongoing and expected to finish March 2023. This means that the final results may be different from the results included in this summary. What happened in this study? The part of the study described in this summary included participants 12- to 15-years old who had no serious health issues. The BNT162b2 vaccine had already been studied in participants 16 years of age or older. In this part of the study, the researchers wanted to find out: How effective and safe the vaccine was in participants 12- to 15-years old. What the immune response to the vaccine and the vaccine safety were like in 12- to 15-year-olds compared with 16- to 25-year-olds. How well the vaccine prevented SARS-CoV-2 infections in participants who received the vaccine compared to those who did not. This is also called efficacy of the BNT162b2 vaccine Half of the participants in this study received 2 injections of the BNT162b2 vaccine and half received 2 injections of a placebo in a muscle of the upper arm. The placebo looked like the BNT162b2 vaccine but did not have any active vaccine in it. What were the results? BNT162b2 had a favorable safety profile. The most common reactions were pain at the injection site, fatigue, and headache. None of the participants had serious reactions to the vaccine. The 12- to 15-year-old participants' immune system responses to the BNT162b2 vaccine were as good as or stronger than the 16- to 25-year-old participants' immune responses. The participants who received the BNT162b2 vaccine were less likely to get COVID-19 compared with the participants who got the placebo. Clinical Trial Registration: NCT04368728 ( ClinicalTrials.gov )

Dengue is a worsening global public health problem. The vector-viral-host interactions driving the pathogenesis of dengue are multi-dimensional. Sequential dengue virus (DENV) infections with different DENV types significantly increase the risk of severe disease. Treatment is supportive in nature as there are no licensed anti-DENV antivirals or immuno-therapeutics. A single dengue vaccine has widely been licensed with two others in advanced clinical development. Dengvaxia® has been licensed in numerous countries but uptake has been slow as a result of safety signals noted in the youngest recipients and those who were dengue naïve at the time of vaccination.In this review, the current state of dengue vaccine and antiviral drug development will be discussed as well as new developments in controlled human infection models to support product development.The world needs a safe and efficacious tetravalent dengue vaccine capable of protecting multiple different populations across a broad age range and different flavivirus immunologic backgrounds. Safe and effective antivirals are also needed to prevent or attenuate dengue disease in the unvaccinated, in cases of vaccine failure, or in high-risk populations.

What is this summary about? This is a summary of an article about part of a clinical study for the BNT162b2 COVID-19 vaccine, also called the Pfizer-BioNTech vaccine. The article was published in the New England Journal of Medicine in September 2021. The part of the study described in the article began in July 2020 and is ongoing. This means that the final results may be different from the results included in this summary. What happened in this study? The participants in this study received 2 injections of either the BNT162b2 vaccine or a placebo, 21 days apart. The placebo looked like the BNT162b2 vaccine but had no active vaccine in it. None of the trial participants or study teams knew who received vaccine or placebo. What were the results? Most of the reactions to the injections were mild or moderate and lasted for a short period of time. The most common reactions were pain at the injection site, extreme tiredness (fatigue), and headache. These reactions usually happened in the first 7 days after receiving a vaccine dose. A small number of participants had severe reactions to the vaccine. Compared to participants who received the placebo, participants who received the BNT162b2 vaccine were much less likely to become ill if they were infected with the virus that causes COVID-19. The vaccine also had very good efficacy at preventing severe COVID-19. Participants in South Africa who received the BNT162b2 vaccine were less likely to become ill after infection with the beta variant of the virus compared to participants who received the placebo. The beta variant was very common in South Africa when the study was taking place. Clinical Trial Registration: NCT04368728 ( ClinicalTrials.gov )

Conventional methods for quantifying and phenotyping antigen-specific lymphocytes can rapidly deplete irreplaceable specimens. This is due to the fact that antigen-specific T and B cells have historically been analyzed in independent assays each requiring millions of cells. A technique that facilitates the simultaneous detection of antigen-specific T and B cells would allow for more thorough immune profiling with significantly reduced sample requirements. To this end, we developed the B and T cell tandem lymphocyte evaluation (BATTLE) assay, which allows for the simultaneous identification of SARS-CoV-2 Spike reactive T and B cells using an activation induced marker (AIM) T cell assay and dual-color B cell antigen probes. Using this assay, we demonstrate that antigen-specific B and T cell subsets can be identified simultaneously using conventional flow cytometry platforms and provide insight into the differential effects of mRNA vaccination on B and T cell populations following natural SARS-CoV-2 infection.

Background: The posterior scapular muscles eccentrically contract to disperse the high forces observed in the deceleration phase of pitching. Muscular adaptations often occur following chronic eccentric loading, however, no study has evaluated the adaptations of the posterior scapular muscles with regard to throwing and their relationship with humeral retroversion (HR) in professional pitchers. Hypothesis: Significant chronic adaptations in muscle thickness (MT) and strength of the trapezius and rhomboids would be observed in healthy professional baseball pitchers, and there would be a significant relationship between humeral adaptations (ie, HR) and posterior scapular muscle adaptations (ie, strength and MT). Study Design: Cross-sectional; Level 3. Methods: A total of 28 healthy male professional baseball pitchers (age, 22 ± 2 years; mass, 95 ± 17 kg; height, 190 ± 7 cm) were included in the study. Bilateral isometric muscle strength of the upper trapezius (UT), middle trapezius, lower trapezius (LT), and rhomboids was measured during a maximum voluntary isometric contraction. Diagnostic ultrasound images of the UT, middle trapezius, LT, rhomboid major, and rhomboid minor muscles were collected bilaterally to measure MT. HR was also quantified bilaterally with ultrasound. Paired sample t tests were used to compare dominant and nondominant strength and MT. Pearson correlation coefficients were used to assess the relationship between HR, isometric strength, and MT. Results: A significantly increased MT of the LT was found on the dominant arm compared with the nondominant arm (5.4 ± 1.1 mm vs 4.4 ± 1.5 mm; P = 0.00). The Pearson correlation coefficient demonstrated a significant weak negative relationship between HR and rhomboid major MT ( P = 0.03; R = −0.36), and a significant weak negative correlation between HR and middle trapezius isometric strength ( P = 0.03; R = −0.37). Conclusion: LT thickness was greater in the throwing arm compared with the nonthrowing arm of pitchers, suggesting a positive adaptation of the LT. Interestingly, there was a weak negative relationship between HR and both rhomboid major MT and middle trapezius isometric strength. This negative relationship suggests that since increased HR leads to decreased internal rotation range of motion during deceleration, the scapula may be forced into anterior tilt and protraction, which can place excessive eccentric load on the rhomboid major and middle trapezius.

Dengue is a major global public health problem requiring a safe and efficacious vaccine as the foundation of a comprehensive countermeasure strategy. Despite decades of attempts, the world has a single dengue vaccine licensed in numerous countries, but restrictions and conditions of its use have deterred uptake. Recently, clinical efficacy data has been revealed for two additional dengue vaccine candidates and the data appears encouraging. In this perspective I discuss dengue, the complexities of dengue vaccine development, early development setbacks, and how the latest data from the field may be cause for measured optimism. Finally, I provide some perspectives on evaluating dengue vaccine performance and how the pursuit of the perfect dengue vaccine may prevent advancement of vaccines which are good enough.

Dengue represents a growing public health burden worldwide, accounting for approximately 100 million symptomatic cases and tens of thousands of fatalities yearly. Prior infection with one serotype of dengue virus (DENV) is the greatest known risk factor for severe disease upon secondary infection with a heterologous serotype, a risk which increases as serotypes co-circulate in endemic regions. This disease risk is thought to be mediated by IgG-isotype antibodies raised during a primary infection, which poorly neutralize heterologous DENV serotypes and instead opsonize virions for uptake by FcγR-bearing cells. This antibody-dependent enhancement (ADE) of infection leads to a larger proportion of susceptible cells infected, higher viremia and greater immunopathology. We have previously characterized the induction of a serum IgA response, along with the typical IgM and IgG responses, during dengue infection, and have shown that DENV-reactive IgA can neutralize DENV and competitively antagonize IgG-mediated ADE. Here, we evaluate the potential for IgA itself to cause ADE. We show that IgG, but not IgA, mediated ADE of infection in cells expressing both FcαR and FcγRs. IgG-mediated ADE stimulated significantly higher pro-inflammatory cytokine production by primary human macrophages, while IgA did not affect, or slightly suppressed, this production. Mechanistically, we show that DENV/IgG immune complexes bind susceptible cells significantly more efficiently than DENV/IgA complexes or virus alone. Finally, we show that over the course of primary dengue infection, the expression of FcγRI (CD64) increases during the period of acute viremia, while FcγRIIa (CD32) and FcαR (CD89) expression decreases, thereby further limiting the ability of IgA to facilitate ADE in the presence of DENV. Overall, these data illustrate the distinct protective role of IgA during ADE of dengue infection and highlight the potential therapeutic and prognostic value of DENV-specific IgA.

Introduction Individuals with an underlying malignancy have high risk of poor COVID-19 outcomes. In clinical trials, COVID-19 vaccines were safe and efficacious against infection, hospitalization, and death, but most trials excluded participants with cancer. We report results from participants with a history of past or active neoplasm (malignant or benign/unknown) and up to 6 months’ follow-up post-dose 2 from the placebo-controlled, observer-blinded trial of the 2-dose BNT162b2 mRNA COVID-19 vaccine. Patients and methods Between July 2020–January 2021, 46,429 participants aged ≥12 years were randomized at 152 sites in 6 countries. Healthy participants with pre-existing stable neoplasm could participate; those receiving immunosuppressive therapy were excluded. Data are reported for participants, aged ≥16 years for safety and ≥12 years for efficacy, who had any history of neoplasm at baseline (data cut-off: March 13, 2021). Adverse-event (AE) data are controlled for follow-up time before unblinding and reported as incidence rates (IRs) per 100 person-years follow-up. Results At baseline, 3813 participants had a history of neoplasm; most common malignancies were breast (n = 460), prostate (n = 362), and melanoma (n = 223). Four BNT162b2 and 71 placebo recipients developed COVID-19 from 7 days post-dose 2; vaccine efficacy was 94.4% (95% CI: 85.2, 98.5) after up to 6 months’ follow-up post-dose 2. This compares favorably with vaccine efficacy of 91.1% in the overall trial population after the same follow-up. AEs were reported at IRs of 95.4 (BNT162b2) and 48.3 (placebo) per 100 person-years. Most common AEs were reactogenicity events (injection-site pain, fatigue, pyrexia). Three BNT162b2 and 1 placebo recipients withdrew because of vaccine-related AEs. No vaccine-related deaths were reported. Conclusion In participants with past or active neoplasms, BNT162b2 vaccine has a similar efficacy and safety profile as in the overall trial population. These results can inform BNT162b2 use during the COVID-19 pandemic and future trials in participants with cancer. Clinical trial number: NCT04368728

Background: Previous research has demonstrated that muscle synergy structure can adapt owing to training and injury; however, muscle synergies have not been evaluated in baseball players. Hypothesis: The throwing arm would have a similar muscle synergy structure but different levels of individual muscle activity within each synergy, relative to the nonthrowing arm. Study Design: Cross-sectional study in a controlled laboratory setting. Methods: Fourteen healthy competitive baseball players were included. Participants were tested bilaterally during a center-out planar reaching task using the KINARM robot, where kinematic data and surface electromyography data from 14 glenohumeral and scapular muscles were synchronized. Principal component analysis was used to extract muscle synergies, the variance accounted for (VAF) of each synergy, and individual muscle coefficients. The dominant (DOM) arm was compared with the nondominant (NDOM) arm using paired t tests for all dependent variables. Results: The same number of muscle synergies were extracted on the DOM and NDOM arms, along with no differences in VAF. In the first synergy, the infraspinatus (DOM 0.798 vs NDOM 0.587, P = 0.038) and lower trapezius (DOM 0.872 vs NDOM 0.480, P = 0.005) muscle coefficients significantly increased on the DOM arm. The second synergy had a significantly increased anterior deltoid (DOM 0.764 vs NDOM 0.374, P = 0.003) and a significantly decreased posterior deltoid (DOM −0.069 vs NDOM 0.197, P = 0.041) muscle coefficient on the DOM arm. Conclusion: The DOM shoulder exhibits a higher proportion of infraspinatus and lower trapezius muscle activation during the external rotation and abduction synergy. Also, the DOM shoulder has increased muscle activation of the teres major and latissimus dorsi during the internal rotation synergy, and increased muscle activation of the pectoralis major during the cross-body adduction synergy, compared with the NDOM shoulder. Clinical Relevance: By exploring these neuromuscular adaptations, the improved understanding of muscle synergy adaptations in baseball players will help optimize injury prevention and rehabilitation techniques.

Background: The relationship between posterior capsule adaptations and soft tissue glenohumeral internal rotation deficit (GIRD) in healthy pitchers remains unclear. Purpose/Hypothesis: This study aimed to identify if posterior capsule thickness (PCT) was associated with soft tissue GIRD in healthy pitchers. We hypothesized that there would be a positive relationship between soft tissue GIRD and PCT in the dominant arm, no relationship between soft tissue GIRD and PCT in the nondominant arm, and a strong positive relationship between soft tissue GIRD and the bilateral difference in PCT (posterior capsule hypertrophy [PCH]). Study Design: Cross-sectional study; Level of evidence, 3. Methods: A total of 45 healthy collegiate and professional pitchers were included. Glenohumeral internal rotation and external rotation range of motion, humeral retroversion, and PCT were measured bilaterally. PCT was determined for unilateral posterior capsule measurements, and PCH of the throwing shoulder was calculated as the bilateral difference in PCT. Soft tissue GIRD was calculated as the sum of clinical GIRD and the bilateral difference in humeral retroversion. Pearson correlation coefficients were determined to evaluate the relationships between dominant arm PCT, nondominant arm PCT, and PCH and soft tissue GIRD. Results: Pearson correlations showed that both dominant arm PCT ( R = −0.13; P = .378) and nondominant arm PCT ( R = 0.21; P = .165) were not related to soft tissue GIRD. However, Pearson correlations did show that the amount of PCH was moderately related to soft tissue GIRD ( R = 0.40; P = .007). Therefore, as the posterior capsule hypertrophied, soft tissue GIRD moderately increased. Conclusion: Increased PCH was associated with an increase in soft tissue GIRD in healthy pitchers. If PCT measurements are feasible, clinicians should consider performing bilateral ultrasound assessments to isolate posterior capsule adaptations (ie, PCH). This will allow clinicians to identify pitchers with potentially maladaptive structural adaptations and optimize management strategies throughout the season to counteract them.

Dengue virus (DENV) infection risk is known to vary substantially, even across small communities, with infections in and around the home driving transmission. However, It remains unclear how the immune status of an individual or household dictate this risk in part due to transmission being dominated by subclinical infections. In this study, we used demographic, household characteristic, and serological data from a multigenerational cohort study of 2860 individuals from 470 households in Kamphaeng Phet, Thailand, to determine the incidence and risk factors for DENV infections. We used hemagglutination inhibition (HAI) antibody titers measured in sequential serum samples to identify subclinical infections through a gradient boosted regression model. This approach identified ∼10% more cases than commonly used methods with approximately 90% of all infections being subclinical. As expected, we found that having higher DENV antibody titers was protective against infection. Individuals were additionally protected if other household members had higher titers suggesting that there are indirect effects of household immunity on the individuals found within a household. Our study provides a framework for inferring subclinical infections and characterizing the epidemiology of DENV infection in households.

Objectives: To describe the burden and sources of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) infection among healthcare personnel (HCP), such as occupational role, work setting, vaccination status, and patient contact between March 2020 through May 2022. Design: Active prospective surveillance. Setting: Large tertiary-care teaching institution with inpatient and ambulatory care services. Results: We identified 4,430 cases among HCPs between March 1, 2020, through May 31, 2022. The median age of this cohort was 37 years (range, 18–89); 2,840 (64.1%) were female; and 2,907 (65.6%) were white. Most of the infected HCP were in the general medicine department, followed by ancillary departments and support staff. Less than 10% of HCP SARS-CoV-2–positive cases worked on a COVID-19 unit. Of the reported SARS-CoV-2 exposures, 2,571 (58.0%) were from an unknown source, 1,185 (26.8%) were from a household source, 458 (10.3%) were from a community source, and 211 (4.8%) were healthcare exposures. A higher proportion of cases with reported healthcare exposures was vaccinated with only 1 or 2 doses, whereas a higher proportion of cases with reported household exposure was vaccinated and boosted, and a higher proportion of community cases with reported and unknown exposures were unvaccinated (P < .0001). HCP exposure to SARS-CoV-2 correlated with community-level transmission regardless of type of reported exposure. Conclusions: The healthcare setting was not an important source of perceived COVID-19 exposure among our HCPs. Most HCPs were not able to definitively identify the source of their COVID-19, followed by suspected household and community exposures. HCP with community or unknown exposure were more likely to be unvaccinated.

Background BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine encoding a prefusion-stabilized, membrane-anchored severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) full-length spike protein. BNT162b2 is highly efficacious against coronavirus disease 2019 (Covid-19) and is currently approved, conditionally approved, or authorized for emergency use worldwide. At the time of initial authorization, data beyond 2 months after vaccination were unavailable. Methods In an ongoing, placebo-controlled, observer-blinded, multinational, pivotal efficacy trial, we randomly assigned 44,165 participants 16 years of age or older and 2264 participants 12 to 15 years of age to receive two 30-μg doses, at 21 days apart, of BNT162b2 or placebo. The trial end points were vaccine efficacy against laboratory-confirmed Covid-19 and safety, which were both evaluated through 6 months after vaccination. Results BNT162b2 continued to be safe and have an acceptable adverse-event profile. Few participants had adverse events leading to withdrawal from the trial. Vaccine efficacy against Covid-19 was 91.3% (95% confidence interval [CI], 89.0 to 93.2) through 6 months of follow-up among the participants without evidence of previous SARS-CoV-2 infection who could be evaluated. There was a gradual decline in vaccine efficacy. Vaccine efficacy of 86 to 100% was seen across countries and in populations with diverse ages, sexes, race or ethnic groups, and risk factors for Covid-19 among participants without evidence of previous infection with SARS-CoV-2. Vaccine efficacy against severe disease was 96.7% (95% CI, 80.3 to 99.9). In South Africa, where the SARS-CoV-2 variant of concern B.1.351 (or beta) was predominant, a vaccine efficacy of 100% (95% CI, 53.5 to 100) was observed. Conclusions Through 6 months of follow-up and despite a gradual decline in vaccine efficacy, BNT162b2 had a favorable safety profile and was highly efficacious in preventing Covid-19. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.)

Background New York State adopted a COVID-19 vaccination requirement for all healthcare workers in September 2021, but they allowed medical exemptions. We examined reasons and frequency of medical exemption requests in an academic medical center. Methods We conducted active surveillance of all medical exemption requests in a tertiary care academic center in Central NY. Age, gender, reason for request, prior acceptance of other required vaccines, letter of support from employee provider, adjudication of the request, and impact of the decision on COVID-19 vaccine acceptance were collected prospectively since the mandate became effective. Results Among 8,776 HCWs, 108 requested medical exemptions, among those 57 (53%) were denied, 39 (36%) were granted temporary exemption, and 12 (11%) were permanent (Table). Females were more likely to request medical exemptions compared to males, 92 (85%) versus 16 (15%), respectively. Overall, 94 (87%) of the HCWs had a letter from their provider in support of their exemption. Nevertheless, only 47% of those qualified for permanent or temporary exemption using CDC guidelines. The most common reasons for requesting exemption included: having natural immunity, receiving monoclonal antibodies, experiencing a common reaction to previous COVID-19 vaccination, and having an underlying medical condition (Figure 1). The majority of individuals who had a request denied or who received a temporary medical exemption were subsequently vaccinated, 63% and 79%, respectively (Figure 2). Demographic and other characteristics among health care workers (HCW) requesting medical exemptions. Table Reasons for requesting medical exemption from COVID-19 vaccination requirement by request determination. Figure 1 COVID-19 vaccine uptake among health care workers (HCW) requesting medical exemptions to COVID-19 vaccination. *One HCW received alternative COVID-19 vaccine. Figure 2 Conclusion Females were more likely to request a medical exemption to vaccination and their requests were often supported by their providers. Future efforts should focus on educating both health care providers and the public about actual medical contraindications or precautions to vaccination to improve overall vaccination rates. Disclosures Jana Shaw, MD,MS,MPH, Pfizer: Advisor/Consultant Stephen J. Thomas, MD, Clover: case adjudication committee (compensated for time)|EdJen: Advisor/Consultant|Icosavax: data monitoring (compensated for time)|Island Pharma: Ownership Interest|Merck: Advisor/Consultant|Moderna: chair, safety monitoring committee (compensated for time)|New Day Diagnostics: Honoraria|Pfizer: Advisor/Consultant|PrimeVax: Ownership Interest|Sanofi Pasteur: Advisor/Consultant|Takeda: Advisor/Consultant|Takeda: case adjudication committee (compensated for time)|Vaxxinity: data monitoring committee (compensated for time).

Background Introduction: Health care personnel (HCP) are at increased risk for SARS-CoV-2 exposure. However, the exposure sources among HCP are poorly understood. Methods Design: We conducted active surveillance for all employed HCP newly diagnosed with COVID-19 between March 2020 and February 2022. We inquired about their sources of exposure using a standardized health department checklist and CDC guidance for managing healthcare personnel with SARS-CoV-2 infection or exposure. Results Among all 8,766 HCP, 2,220 (25.3%) tested positive. Among positive cases, 749 (33.7%), 651 (29.3%), and 221 (10%) were among ancillary services HCP, RNs, and allied HCP, respectively (Table 1). The majority of the sources of exposures were unknown (57.8%), followed by household (26.2%), community (10.5%), and health care (5.5%), respectively. The incidence of COVID-19 increased with level of patient contact regardless of source of exposure. The majority of the cases, N=1054 (47.5%), occurred among HCP who were not up-to-date on COVID-19 vaccines and had unknown exposure, and vaccination status varied by source of exposure (Table 2). HCP COVID-19 cases mirrored transmission in the community (Figure). Table 1.Incidence of COVID-19 Among Employed HCP Overall and by Exposure Type (N=8766)Table 2.Vaccine status among Employed HCP Covid-19 Cases by Source of Exposure (N=2220)Figure.HCP COVID-19 cases by exposure type (Left Axis) in the Central New York region (Right Axis) between March 2020 and February 2022. Conclusion The majority of HCP cases had no known exposure to SARS-CoV-2 and were not up-to-date on COVID-19 vaccines highlighting the importance of vaccination as the single most effective mean to COVID-19 prevention among HCP. Disclosures Jana Shaw, MD,MS,MPH, Pfizer: Advisor/Consultant Stephen J. Thomas, MD, Clover: case adjudication committee (compensated for time)|EdJen: Advisor/Consultant|Icosavax: data monitoring (compensated for time)|Island Pharma: Ownership Interest|Merck: Advisor/Consultant|Moderna: chair, safety monitoring committee (compensated for time)|New Day Diagnostics: Honoraria|Pfizer: Advisor/Consultant|PrimeVax: Ownership Interest|Sanofi Pasteur: Advisor/Consultant|Takeda: Advisor/Consultant|Takeda: case adjudication committee (compensated for time)|Vaxxinity: data monitoring committee (compensated for time).

The preferred antibiotic salvage regimen for persistent methicillin-resistant Staphylococcus aureus bacteremia (MRSAB) is unclear. We sought to evaluate the effectiveness and safety of vancomycin plus ceftaroline for persistent MRSAB. The primary outcome was time to MRSAB clearance post-ceftaroline initiation. Secondary outcomes included microbiological cure, hospital length of stay, 90-day readmission for MRSAB, 90-day all-cause mortality, MRSAB-related mortality, and incidence of antibiotic-associated adverse effects.Single-center, retrospective cohort study between January 1, 2016, and December 31, 2021.State University of New York Upstate University Hospital, a 748-bed tertiary care, academic medical center in Syracuse, NY.Adult patients were included if they had blood cultures positive for MRSA ≥72 h, received vancomycin monotherapy initially, and received vancomycin plus ceftaroline for ≥24 h. Patients were excluded if they received other anti-MRSA antibiotics, were pregnant, or were incarcerated. Of the 178 patients identified, 30 unique patients were evaluated.Patients were medically complex with a median Pitt bacteremia score of 3, 63.3% (19/30) were admitted to the intensive care unit, and 66.7% (20/30) had infective endocarditis. Vancomycin-associated acute kidney injury was observed in 10% (3/30) of patients, which resulted in dose adjustments. No patients experienced ceftaroline-associated neutropenia or Clostridioides difficile infection, but 6.7% (2/30) developed a rash attributed to ceftaroline. Median time to MRSAB clearance post-ceftaroline initiation was 2.6 days. Microbiologic cure occurred in nearly all patients 96.7% (29/30). Median hospital length of stay was 19.5 days, and 6.7% (2/30) of patients had 90-day readmission for MRSAB. 90-day all-cause mortality and MRSAB-related mortality occurred in 26.7% (8/30) and 13.3% (4/30) of patients, respectively.Vancomycin plus ceftaroline may represent an effective and well-tolerated salvage regimen option for persistent MRSAB.

Dengue human infection models present an opportunity to explore a vaccine, antiviral, or immuno-compound’s potential for clinical benefit in a controlled setting. Herein, we report the outcome of a phase 1, open-label assessment of a DENV-3 challenge model. In this study, 9 participants received a subcutaneous inoculation with 0.5ml of a 1.4×103PFU/ml suspension of the DENV-3 strain CH53489. All subjects developed RNAemia within 7 days of inoculation, with peak titers ranging from 3.13×104to 7.02×108GE/ml. Symptoms and clinical lab abnormalities consistent with mild dengue infection were observed in all subjects. DENV-3 specific seroconversion was observed by 14 days after inoculation, along with DENV-3 specific memory T cell responses. RNAseq and serum cytokine analysis revealed the presence of an antiviral transcriptional and cytokine response to infection that overlapped with the period of viremia. The magnitude and frequency of clinical and immunologic endpoints correlated with an individual’s peak viral titer.

Dengue virus (DENV) infections are major causes of morbidity and mortality throughout the tropics and subtropics. More than 400 million infections are estimated to occur every year, resulting in nearly 100 million symptomatic infections and more than 20,000 deaths. Early immune response kinetics to infection remain unclear, in large part due to the variable incubation period exhibited by the DENVs after introduction into a susceptible host. To fill this knowledge gap, we performed a comprehensive virologic and immunologic analysis of individuals experimentally infected with the underattenuated DENV-1 strain 45AZ5. This analysis captured both the kinetics and composition of the innate, humoral, and cellular immune responses elicited by experimental DENV-1 infection, as well as virologic and clinical features. We observed a robust DENV-specific immunoglobulin A (IgA) antibody response that manifested between the appearance of DENV-specific IgM and IgG in all challenged individuals, as well as the presence of a non-neutralizing/NS1-specific antibody response that was delayed relative to the appearance of DENV virion–specific humoral immunity. RNA sequencing analysis revealed discrete and temporally restricted gene modules that correlated with acute viremia and the induction of adaptive immunity. Our analysis provides a detailed description, in time and space, of the evolving matrix of DENV-elicited human inflammation and immunity and reveals several previously unappreciated immunological aspects of primary DENV-1 infection that can inform countermeasure development and evaluation.

Dengue control approaches are best informed by granular spatial epidemiology of these viruses, yet reconstruction of inter- and intra-household transmissions is limited when analyzing case count, serologic, or genomic consensus sequence data. To determine viral spread on a finer spatial scale, we extended phylogenomic discrete trait analyses to reconstructions of house-to-house transmissions within a prospective cluster study in Kamphaeng Phet, Thailand. For additional resolution and transmission confirmation, we mapped dengue intra-host single nucleotide variants on the taxa of these time-scaled phylogenies. This approach confirmed 19 household transmissions and revealed that dengue disperses an average of 70 m per day between households in these communities. We describe an evolutionary biology framework for the resolution of dengue transmissions that cannot be differentiated based on epidemiologic and consensus genome data alone. This framework can be used as a public health tool to inform control approaches and enable precise tracing of dengue transmissions.

Background: Because of the large forces and high frequency of throwing, the upper extremity experiences repetitive stresses that lead to acute and chronic adaptations. While the importance of pennation angle and muscle thickness as predictors of muscle force production has been shown in other populations and other joints, there has been little research done that examines these variables in the shoulders of baseball players. Purpose: (1) To examine the chronic effect pitching has on the rotator cuff muscle architecture (pennation angle and muscle thickness) in healthy professional baseball pitchers, and (2) to examine the correlation between muscle architecture and clinical measures of strength and range of motion (ROM). Study Design: Cross-sectional study; Level of evidence, 3. Methods: Twenty-eight healthy professional pitchers were recruited during the 2019 spring training. Internal rotation (IR) and external rotation (ER) strength were measured with a handheld dynamometer and IR and ER ROM were measured with an inclinometer. A diagnostic ultrasound machine was utilized to capture images of humeral retroversion, as well as the pennation angle and muscle thickness of the infraspinatus and teres minor muscles. ImageJ software was used to quantify the pennation angle and muscle thickness. Results: There were no significant differences between the dominant and nondominant arms for ER or IR strength. Also, no pennation angle and muscle thickness differences were found between the dominant and nondominant arms. A weak positive relationship between infraspinatus muscle thickness (superficial and total) and ER strength ( P = .016, R = 0.287 and P = .009, R = 0.316) and a moderate negative relationship between soft tissue glenohumeral internal rotation deficit (GIRD) and the bilateral difference of the teres minor deep pennation angle ( R = −0.477, P = .008) were observed. No other significant relationships were noted. Conclusion: Our results are contrary to current literature as we expected to see a stronger dominant arm, with a larger pennation angle and greater muscle thickness. Interestingly, we found that ER strength was positively related to only the thickness of the infraspinatus muscle, and that soft tissue GIRD was positively related to only the side-to-side adaptation of the pennation angle within the deep portion of the teres minor. This suggests that when posterior shoulder tightness occurs, specifically the architecture of the teres minor muscle is involved. However, the organization to which these players belonged has a very extensive training protocol throughout the year that emphasizes bilateral training during a large majority of the exercises. Therefore, the results may not be generalizable to all professional players.

Cefiderocol is a novel siderophore cephalosporin that forms a complex with extracellular free ferric iron, which leads to transportation across the outer cell membrane to exert its bactericidal activity through cell wall synthesis inhibition. This pharmacological property has rendered cefiderocol active against several clinically relevant MDR Gram-negative bacteria as evidenced by several in vitro and in vivo studies. Cefiderocol was first approved by the US FDA on 14 November 2019 for the treatment of complicated urinary tract infections. On 28 September 2020, cefiderocol was approved for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. The FDA-approved indications are based on clinical data from the APEKS-cUTI, APEKS-NP and CREDIBLE-CR trials. In APEKS-cUTI, cefiderocol demonstrated non-inferiority to imipenem/cilastatin for the treatment of complicated urinary tract infection caused by MDR Gram-negative bacteria. In APEKS-NP, cefiderocol demonstrated non-inferiority to meropenem for treatment of nosocomial pneumonia. However, in CREDIBLE-CR, higher all-cause mortality was observed with cefiderocol compared with best available therapy for the treatment of severe infections caused by Gram-negative bacteria, primarily in the subset of patients with Acinetobacter spp. infections. Several case reports/series have demonstrated clinical success with cefiderocol for a variety of severe infections. The purpose of this article is to review available data on the mechanism of action, in vitro and in vivo data, pharmacokinetics, pharmacodynamics, susceptibility testing, efficacy and safety of cefiderocol to address its role in therapy.

Background As a priority group, healthcare personnel (HCP) will be key to the success of coronavirus disease 2019 (COVID-19) vaccination programs. This study assessed HCP willingness to get vaccinated and identified specific concerns that would undermine vaccination efforts. Methods We conducted a cross-sectional survey of HCP, including clinical and nonclinical staff, researchers, and trainees, between 23 November and 5 December 2020. The survey evaluated attitudes, beliefs, and willingness to get vaccinated. Results There were 5287 respondents with a mean (SD) age of 42.5 (13.56) years; 72.8% were female (n = 3842). Overall, 57.5 % of individuals expressed intent to receive COVID-19 vaccine; 80.4% were physicians and scientists representing the largest group. 33.6% of registered nurses, 31.6% of allied health professionals, and 32% of master’s level clinicians were unsure they would take the vaccine (P Conclusions We observed that self-reported willingness to receive vaccination against COVID-19 differs by hospital roles, with physicians and research scientists showing the highest acceptance. These findings highlight important heterogeneity in personal attitudes among HCPs around COVID-19 vaccines and highlight a need for tailored communication strategies.

Background Dengue is a global health problem and the development of a tetravalent dengue vaccine with durable protection is a high priority. A heterologous prime-boost strategy has the advantage of eliciting immune responses through different mechanisms and therefore may be superior to homologous prime-boost strategies for generating durable tetravalent immunity. Methods In this phase 1 first-in-human heterologous prime-boost study, 80 volunteers were assigned to 4 groups and received a tetravalent dengue virus (DENV-1–4) purified inactivated vaccine (TDENV-PIV) with alum adjuvant and a tetravalent dengue virus (DENV-1–4) live attenuated vaccine (TDENV-LAV) in different orders and dosing schedules (28 or 180 days apart). Results All vaccination regimens had acceptable safety profiles and there were no vaccine-related serious adverse events. TDEN-PIV followed by TDEN-LAV induced higher neutralizing antibody titers and a higher rate of tetravalent seroconversions compared to TDEN-LAV followed by TDEN-PIV. Both TDEN-PIV followed by TDEN-LAV groups demonstrated 100% tetravalent seroconversion 28 days following the booster dose, which was maintained for most of these subjects through the day 180 measurement. Conclusions A heterologous prime-boost vaccination strategy for dengue merits additional evaluation for safety, immunogenicity, and potential for clinical benefit. Clinical Trials Registration NCT02239614.

Summary Background The development of an effective vaccine against Zika virus remains a public health priority. A Zika purified inactivated virus (ZPIV) vaccine candidate has been shown to protect animals against Zika virus challenge and to be well tolerated and immunogenic in humans up to 8 weeks of follow-up. We aimed to assess the safety and immunogenicity of ZPIV in humans up to 52 weeks of follow-up when given via standard or accelerated vaccination schedules. Methods We did a single-centre, double-blind, randomised controlled, phase 1 trial in healthy adults aged 18–50 years with no known history of flavivirus vaccination or infection at Beth Israel Deaconess Medical Center in Boston, MA, USA. Participants were sequentially enrolled into one of three groups: ZPIV given at weeks 0 and 4 (standard regimen), weeks 0 and 2 (accelerated regimen), or week 0 alone (single-dose regimen). Within each group, participants were randomly assigned using a computer-generated randomisation schedule to receive an intramuscular injection of 5 μg ZPIV or saline placebo, in a ratio of 5:1. The sponsor, clinical staff, investigators, participants, and laboratory personnel were masked to treatment assignment. The primary endpoint was safety up to day 364 after final dose administration, and secondary endpoints were proportion of participants with positive humoral immune responses (50% microneutralisation titre [MN50] ≥100) and geometric mean MN50 at observed peak response (ie, the highest neutralising antibody level observed for an individual participant across all timepoints) and week 28. All participants who received at least one dose of ZPIV or placebo were included in the safety population; the analysis of immunogenicity at observed peak included all participants who received at least one dose of ZPIV or placebo and had any adverse events or immunogenicity data after dosing. The week 28 immunogenicity analysis population consisted of all participants who received ZPIV or placebo and had immunogenicity data available at week 28. This trial is registered with ClinicalTrials.gov , NCT02937233 . Findings Between Dec 8, 2016, and May 17, 2017, 12 participants were enrolled into each group and then randomly assigned to vaccine (n=10) or placebo (n=2). There were no serious or grade 3 treatment-related adverse events. The most common reactions among the 30 participants who received the vaccine were injection-site pain (24 [80%]), fatigue (16 [53%]), and headache (14 [46%]). A positive response at observed peak titre was detected in all participants who received ZPIV via the standard regimen, in eight (80%) of ten participants who received ZPIV via the accelerated regimen, and in none of the ten participants who received ZPIV via the single-dose regimen. The geometric mean of all individual participants' observed peak values was 1153·9 (95% CI 455·2–2925·2) in the standard regimen group, 517·7 (142·9–1875·6) in the accelerated regimen group, and 6·3 (3·7–10·8) in the single-dose regimen group. At week 28, a positive response was observed in one (13%) of eight participants who received ZPIV via the standard regimen and in no participant who received ZPIV via the accelerated (n=7) or single-dose (n=10) regimens. The geomteric mean titre (GMT) at this timepoint was 13·9 (95% CI 3·5–55·1) in the standard regimen group and 6·9 (4·0–11·9) in the accelerated regimen group; antibody titres were undetectable at 28 weeks in participants who received ZPIV via the single-dose regimen. For all vaccine schedules, GMTs peaked 2 weeks after the final vaccination and declined to less than 100 by study week 16. There was no difference in observed peak GMTs between the standard 4-week and the accelerated 2-week boosting regimens (p=0·4494). Interpretation ZPIV was safe and well tolerated in humans up to 52 weeks of follow-up. ZPIV immunogenicity required two doses and was not durable. Additional studies of ZPIV to optimise dosing schedules are ongoing. Funding The Henry M Jackson Foundation for the Advancement of Military Medicine.

Background Humeral retrotorsion (HRT) is one bony adaptation that occurs in overhead athletes. This bony adaptation often leads to bilateral changes in range of motion at the glenohumeral joint. Because HRT can create different stress environments on the surrounding tissue, it may play a role in upper-limb injury and pain profiles. Therefore, the aim of this review was to examine whether HRT plays a role in shoulder and elbow injury profiles. Methods Two separate critical appraisal tools were administered: the Newcastle-Ottawa Scale (case control) and the Appraisal Tool for Cross-sectional Studies. The primary author extracted all data and obtained means and standard deviations for each outcome. Cohen d effect sizes (ESs) were calculated (ES [95% confidence interval]) for all HRT measurements including nondominant, dominant, and side-to-side differences. Finally, the Strength of Recommendation Taxonomy was used to evaluate the overall strength of the recommendation. Results Nine articles were included in this review. Large ESs were present in 2 studies on examination of symptomatic and asymptomatic dominant HRT and ranged between 0.83 (0.08-1.55) and –2.57 (–3.66 to 1.99). The majority of all ESs for all HRT measurements were moderate or low, rendering comparisons between asymptomatic and symptomatic cohorts that were not clinically meaningful. Conclusion The Strength of Recommendation Taxonomy rating was C based on inconsistent findings. Differences in sports populations and definitions of injuries across studies may be one reason for the varying ESs. HRT does occur in the overhead population, but the degree to which this HRT starts to affect upper-limb injury is unknown and is more than likely player specific and multifactorial.

Zika is an arboviral illness caused by infection with the Zika flavivirus. Transmission most commonly occurs during a feeding event involving an infected Aedes mosquito or vertical transmission between an infected mother to her fetus. Infection outcomes range from asymptomatic to devastating neurologic injuries in children infected in utero. The recognition of Congenital Zika Syndrome prompted the declaration of an international health emergency and a call to rapidly develop medical countermeasures such as vaccines and therapeutics. A flurry of research and development activity in industry, government, non-governmental organizations, and academia during the most recent Zika epidemic (2015) stimulated the development of a number of vaccine candidate prototypes, generation of pre-clinical data, and the conduct of early phase human trials. The safety and immunogenicity of different vaccine platforms were demonstrated and mouse and non-human primate passive transfer studies hinted at the potential for clinical benefit in humans and defining an immune correlate of protection. A rapid decline in regional transmission, however, prevented the conduct a clinical endpoint efficacy trial. The pathway to licensure of a Zika vaccine remains unclear.

Controlled human infection models can be helpful to study pathogenesis and immune responses as a basis for the development of vaccines. In controlled human infection models, human challenge agents are used to infect healthy volunteers, therefore, ethical considerations include that the exposure studies need to be safe and results should be meaningful, e.g. contribute to a better cure. Both in the US and in Europe, the level of Good Manufacturing Practice required is related to the phase of the study ('sliding scale Good Manufacturing Practice'), and, hence, is much more open to speedy drug development than anticipated. Recommendations included: the development of guidelines for human challenge agents; a focus on strain selection, in particular with regard to strain infectivity, stability and purity; the use of whole genome sequencing; a reference repository of challenge agents, the need for early exchange with regulators to ensure acceptability of strain selection and manufacturing for later drug development; sharing of models and challenge agents.

Background Dengue human infection models (DHIM) have been used as a safe means to test the viability of prophylaxis and therapeutics. Methods A phase 1 study of 12 healthy adult volunteers using a challenge virus, DENV-1-LVHC strain 45AZ5, was performed. A dose escalating design was used to determine the safety and performance profile of the challenge virus. Subjects were evaluated extensively until 28 days and then out to 6 months. Results Twelve subjects received the challenge virus: 6 with 0.5 mL of 6.5 × 103 plaque-forming units (PFU)/mL (low-dose group) and 6 with 0.5 mL of 6.5 × 104 PFU/mL (mid-dose group). All except 1 in the low-dose group developed detectable viremia. For all subjects the mean incubation period was 5.9 days (range 5–9 days) and mean time of viremia was 6.8 days (range 3–9 days). Mean peak for all subjects was 1.6 × 107 genome equivalents (GE)/mL (range 4.6 × 103 to 5 × 107 GE/mL). There were no serious adverse events or long-term safety signals noted. Conclusions We conclude that DENV-1-LVHC was well-tolerated, resulted in an uncomplicated dengue illness, and may be a suitable DHIM for therapeutic and prophylactic product testing. Clinical Trials Registration NCT02372175.

While the pathoetiology is disputed, a wide array of treatments is available to treat tendinopathy. The most common treatments found in the literature include therapeutic modalities, exercise protocols, and surgical interventions; however, their effectiveness remains ambiguous. The purpose of this study was to perform a systematic review of systematic reviews to determine the ability of therapeutic interventions to improve pain and dysfunction in patients with tendinopathy regardless of type or location. Five databases were searched for systematic reviews containing only randomized control trials to determine the effectiveness of treatments for tendinopathies based on pain and patient-reported outcomes. Systematic reviews were assessed via the Assessment of Multiple Systematic Reviews (AMSTAR) for methodological quality. From the database search, 3,295 articles were found, 107 passed the initial inclusion criteria. After further review, 25 systematic reviews were included in the final qualitative analysis. The AMSTAR scores were relatively high (8.8 ± 1.0) across the 25 systematic reviews. Eccentric exercises were the most common and consistently effective treatment for tendinopathy across systematic reviews. Low-level laser therapy and extracorporeal shockwave therapy demonstrated moderate effectiveness, while platelet-rich plasma injections demonstrated inconclusive evidence on their ability to decrease tendinopathy-related pain and improve function. Corticosteroids also showed some effectiveness for short-term pain, but for the long-term use deemed ineffective and at times contraindicated. Regarding surgical options, minimally invasive procedures were more effective compared to open surgical interventions. When treating tendinopathy regardless of location, eccentric exercises were the best treatment option to improve tendinopathy-related pain and improve self-reported function.

BACKGROUND Obstructive sleep apnea (OSA), nocturnal hypertension, and nondipping systolic blood pressure (BP) are each highly prevalent among African Americans. However, few data are available on the association between OSA and nighttime BP in this population. METHODS We examined the association of OSA with nighttime BP among African Americans who completed 24-hour ambulatory BP monitoring (ABPM) at Exam 1 (2000–2004) of the Jackson Heart Study (JHS) and subsequently participated in the JHS Sleep Study (2012–2016). Type 3 home sleep apnea testing was used to assess OSA measures, including respiratory event index (REI4%) and percent sleep time RESULTS Among 206 participants who completed ABPM and participated in the Jackson Heart Sleep Study, 50.5% had nocturnal hypertension and 26.2% had moderate to severe OSA (REI4% ≥15 events/hour). After multivariable adjustment, each SD (13.3 events/hour) increase in REI4% was associated with 1.75 mm Hg higher nighttime DBP (95% confidence interval (CI): 0.38, 3.11) and a prevalence ratio of 1.11 (95% CI: 1.00, 1.24) for nocturnal hypertension. Each SD (10.4%) increase in nocturnal hypoxemia was associated with a 1.91 mm Hg higher nighttime SBP (95% CI: 0.15, 3.66). CONCLUSIONS Severity of OSA and nocturnal hypoxemia were associated with high nighttime BP in African American participants in the JHS.

Four formulations of an investigational tetravalent dengue purified inactivated vaccine, administered as two doses one month (M) apart, were previously shown to be immunogenic and well-tolerated up to M13 of the phase I study NCT01702857. Here, we report results of the follow-up from M14 to year (Y) 3. One hundred healthy Puerto Rican adults, predominantly dengue virus (DENV)–primed, were randomized 1:1:1:1:1 to receive placebo or vaccine formulations: 1 μg/serotype/dose adjuvanted with aluminum, AS01E or AS03B, or aluminum-adjuvanted 4 μg/serotype/dose. No serious adverse events occurred. Two medically-attended potential immune-mediated disease cases, vaccination unrelated, were reported (groups 1 µg+Alum and 1 µg+AS03B). Of 14 instances of suspected dengue, none were laboratory confirmed. Geometric mean neutralizing antibody titers against DENV 1-4 waned from M14, but remained above pre-vaccination levels for DENV 1-3, with the highest values for group 1 µg+AS03B: 1220.1, 920.5, 819.4, and 940.5 (Y2), and 1329.3, 1169.2, 1219.8, and 718.9 (Y3). All formulations appeared to be safe and immunogenic during the 3-year follow-up.

Background: Due to high training volume, competitive swimmers incur shoulder pain and injury1, but certain physical characteristics, such as shoulder ROM and endurance, and tissue adaptations such as posterior capsule thickness (PCT) and supraspinatus tendon structure may also be risk factors. Decreased endurance and ROM have been found in competitive swimmers along with being related to pain2. However, no longitudinal studies have examined pain and disability, range of motion, training volume, shoulder endurance and tendon structure over the course of a competitive season. Purpose: The purpose of this study was to: 1) to assess shoulder pain and disability, internal rotation (IR) and external rotation (ER) and horizontal adduction (HADD) ROM, and posterior shoulder endurance longitudinally over a competitive collegiate season, and 2) determine if there is a relationship between swimming yardage, supraspinatus tendon organization and posterior capsule thickness. Methods: 17 male and 13 female Division III swimmers aged 19.6 ± 1.1 years participated. Pain and disability were assessed using the Penn Shoulder Score and the Disability of Arm Shoulder Hand sports module. Internal rotation (IR), external rotation (ER), and horizontal adduction (HA) were measured using a digital inclinometer. Shoulder endurance was measured using the Posterior Shoulder Endurance Test (PSET). Anterior, center, and posterior supraspinatus tendon images were collected by locating the anterior aspect of the tendon insertion and moving posteriorly. The ultrasound images were analyzed using custom MATlab software to quantify tissue organization. All measures were found in the beginning (T1), middle (T2), and end (T3) of the season. Repeated measure ANOVAs were used to compare longitudinal changes across time. If p-values were found to be ≤ 0.05, follow-up paired t-tests with Bonferroni corrections were used to compare T1, T2, and T3. This protocol was IRB-approved and participants signed a written consent form. Results: An increase in swimming yardage from T1 to T2 was followed by a significant decrease in yardage to finish the swimming season (Table 1). Disability decreased and endurance increased throughout the season with no observed changes in pain. IR and HA ROM decreased significantly between all timepoint comparisons. Tendon banding frequency did not change over time (Table 2). Discussion: Large amounts of IR during the pull phase and late initiation of ER during the recovery phase have been associated with a high risk of impingement4. The relationship between pain, disability, and range of motion may suggest that a reduction of IR could protect the swimmers’ shoulder by limiting impingement through the pull and recovery phases. However, further investigation is required to confirm. The lack of statistical significance longitudinally in tendon organization is not surprising since there were no changes in pain, a decrease in disability, and an increase in endurance. Conclusion/Clinical Relevance: Further research is required to understand the relationship between training volume, tendon organization, and disability. Collegiate swimmers demonstrate increased endurance and decreased disability over the course of the season. It may suggest that the loss of ROM is a positive adaptation and may be protective.

Funder: Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Funder: Military Infectious Disease Research Program, Funder: Armed Forces Health Surveillance Branch, Neutralizing antibodies are important correlates of protection against dengue. Yet, determinants of variation in neutralization across strains within the four dengue virus serotypes (DENV1-4) is imperfectly understood. Studies focus on structural DENV proteins, especially the envelope (E), the primary target of anti-DENV antibodies. Although changes in immune recognition (antigenicity) are often attributed to variation in epitope residues, viral processes influencing conformation and epitope accessibility also affect neutralizability, suggesting possible modulating roles of nonstructural proteins. We estimated effects of residue changes in all 10 DENV proteins on antigenic distances between 348 DENV collected from individuals living in Bangkok, Thailand (1994-2014). Antigenic distances were derived from response of each virus to a panel of twenty non-human primate antisera. Across 100 estimations, excluding 10% of virus pairs each time, 77 of 295 positions with residue variability in E consistently conferred antigenic effects; 52 were within ±3 sites of known binding sites of neutralizing human monoclonal antibodies, exceeding expectations from random assignments of effects to sites (p = 0.037). Effects were also identified for 16 sites on the stem/anchor of E which were only recently shown to become exposed under physiological conditions. For all proteins, except nonstructural protein 2A (NS2A), root-mean-squared-error (RMSE) in predicting distances between pairs held out in each estimation did not outperform sequences of equal length derived from all proteins or E, suggesting that antigenic signals present were likely through linkage with E. Adjusted for E, we identified 62/219 sites embedding the excess signals in NS2A. Concatenating these sites to E additionally explained 3.4% to 4.0% of observed variance in antigenic distances compared to E alone (50.5% to 50.8%); RMSE outperformed concatenating E with sites from any protein of the virus (ΔRMSE, 95%IQR: 0.01, 0.05). Our results support examining antigenic determinants beyond the DENV surface.

Despite successful return-to-sport (RTS) outcomes after posteromedial osteophyte resection, one possible consequence of osteophyte removal is increased stress on the ulnar collateral ligament (UCL), leading to a UCL injury. It is currently unknown how often overhead athletes who undergo isolated posteromedial osteophyte resection subsequently require UCL reconstruction (UCLR). Therefore, the purpose of this study was to report outcomes following arthroscopic resection of posteromedial osteophytes in overhead athletes and determine whether overhead athletes who underwent arthroscopic posteromedial osteophyte resection for posteromedial impingement went on to require UCL surgery. We hypothesized that there would be a high rate of RTS following osteophyte resection and that players who underwent arthroscopic posteromedial osteophyte resection would have a10% risk of requiring subsequent UCLR or UCL repair.All patients who underwent elbow arthroscopy from 2010-2020 at a single institution were reviewed. Patients were included if they underwent isolated arthroscopic posteromedial osteophyte resection without concomitant UCL surgery, were overhead athletes at the onset of posteromedial impingement symptoms, and had no history of elbow surgery. Primary outcomes included RTS rate, complications, and subsequent shoulder and/or elbow injury and surgery, as well as several patient-reported outcome measures (Kerlan-Jobe Orthopaedic Clinic score, Timmerman-Andrews elbow score, and Conway-Jobe score).Overall, 36 overhead athletes were evaluated at 5.1 ± 3.4 years postoperatively, including 28 baseball pitchers, 3 baseball catchers, 3 softball players, 1 tennis player, and 1 volleyball player. Of the overhead athletes, 77% were able to RTS; the mean Kerlan-Jobe Orthopaedic Clinic and satisfaction scores were 70 and 75, respectively; and 89% of athletes had either excellent (73%) or good (16%) Conway-Jobe scores at long-term follow-up. Subsequent UCLR was required in 18% of baseball pitchers (n = 5) at a median of 13 months postoperatively. Of the 5 UCLRs, 3 were performed shortly after posteromedial osteophyte resection (6, 7, and 13 months postoperatively) whereas the other 2 were performed at 6.2 and 7.5 years postoperatively.Following arthroscopic posteromedial osteophyte resection, 77% of athletes were able to RTS. Baseball pitchers who undergo arthroscopic resection of posteromedial osteophytes for posteromedial impingement have an 18% risk of subsequent UCLR.

mRNA vaccines have been shown to be safe and effective in individuals with cancer. It is unclear, however, if systemic anti-cancer therapy impacts the coordinated cellular and humoral immune responses elicited by SARS-CoV-2 mRNA vaccines. To fill this knowledge gap, we assessed SARS-CoV-2 mRNA vaccine-elicited immunity in a cohort of patients with advanced solid tumors either under observation or receiving systemic anti-cancer therapy. This analysis revealed that SARS-CoV-2 mRNA vaccine-elicited cellular and humoral immunity was not significantly different in individuals with cancer receiving systemic anti-cancer therapy relative to individuals under observation. Furthermore, even though some patients exhibited suboptimal antibody titers after vaccination, SARS-CoV-2 specific cellular immune responses were still detected. These data suggest that antibody titers offer an incomplete picture of vaccine-elicited SARS-CoV-2 immunity in cancer patients undergoing active systemic anti-cancer therapy, and that vaccine-elicited cellular immunity exists even in the absence of significant quantities of SARS-CoV-2 specific antibodies.

Background: Purposeful rehabilitation before surgery (prehabilitation) has been researched and implemented in the treatment of anterior cruciate ligament tears. However, it is unclear whether prehabilitation would affect outcomes for baseball pitchers with partial ulnar collateral ligament (UCL) tears. Purpose/Hypothesis: The purpose of this study was to determine whether baseball pitchers with partial UCL tears who completed ≥4 weeks of prehabilitation (prehab group) have different return to play (RTP) outcomes than pitchers with 0 to 3 weeks of preoperative physical therapy (no prehab group). We hypothesized that pitchers in the prehab group would have similar RTP rates compared with pitchers in the no prehab group. Study Design: Cohort study; Level of evidence, 3. Methods: Baseball pitchers of all competitive levels who underwent primary UCL reconstruction (UCLR) or UCL repair between 2010 and 2019 were included. Physician chart notes, magnetic resonance images, and operative notes were screened to confirm primary UCLR or UCL repair of a partial UCL tear and to identify whether the nonoperative treatment had been attempted. Patients were contacted via RedCap for postoperative complications, reoperations, RTP, and patient-reported outcomes (Kerlan-Jobe Orthopaedic Clinic score, Andrews-Timmerman score, Conway-Jobe score, and satisfaction). Results: Overall, 105 baseball pitchers (n = 55 prehab group; n = 50 no prehab group) were included and evaluated at 3.4 ± 2.5 years postoperatively. Six pitchers underwent UCL repair, and 99 pitchers underwent UCLR. All demographic characteristics were similar between groups except the prehab group received a gracilis graft more frequently (76.5% vs 51.2%; P = .038). The RTP rate (prehab [88.1%] vs no prehab [93.8%]; P = .465) was similar between groups. All other postoperative outcomes were also similar between groups, including revision rates and patient-reported outcomes. Conclusion: Postoperative and patient-reported outcomes did not differ significantly between pitchers with partial UCL tears who performed rehabilitation before UCL surgery and pitchers who did not attempt a significant period of rehabilitation before UCL surgery. Clinicians should feel comfortable recommending rehabilitation for patients with partial UCL tears who wish to attempt a period of nonoperative treatment, as postoperative outcomes are not affected if UCL surgery is later needed.

Background: Acute adaptations in clinical measures of range of motion and strength have been found after baseball pitching; however, there is a lack of research concerning the physiological mechanism responsible for these changes. Adaptations in muscle architecture of the infraspinatus and teres minor may serve as the structural changes responsible for these clinical measure changes. Purpose: To longitudinally assess the acute changes in range of motion, strength, and muscle architecture of the infraspinatus and teres minor muscles in baseball pitchers after a simulated baseball game. Additionally, we examined the relationship between muscle architecture and changes in clinical measures of range of motion and strength. Study Design: Controlled laboratory study. Methods: Ten healthy nonvarsity collegiate club baseball pitchers (mean ± SD; age, 20.1 ± 1.10 years) were examined pre-pitching, immediately after pitching, and each subsequent day for 5 days after pitching in a simulated baseball game. A digital inclinometer and handheld dynamometer were used to assess range of motion and strength, respectively. Diagnostic ultrasound was used to assess pennation angle and muscle thickness of the infraspinatus and teres minor at rest and at maximal contraction. Results: Internal rotation range of motion significantly decreased immediately and did not return to baseline until 4 days after pitching ( P≤ .05). External rotation strength also immediately decreased and returned on the third day after pitching ( P≤ .05). Moreover, the resting pennation angle of the superficial and deep portions of the infraspinatus increased immediately after pitching, with the superficial portion returning to baseline on day 4 and the deep portion returning on day 5 ( P≤ .05). Furthermore, the pennation angle changes of the infraspinatus and thickness of the teres minor were predictive of the loss of internal rotation range of motion after pitching ( R2 = 0.419; P≤ .05). Conclusion: This study found diminished internal rotation range of motion and external rotation strength after pitching, with alterations in muscle architecture of the infraspinatus. The pennation angle increase in the infraspinatus at rest is indicative of increased tension in the muscle, which was found to be the underlying mechanism for the clinical loss of internal rotation range of motion. This was demonstrated by the inverse relationship between internal rotation range of motion and the pennation angle of the superficial and deep fibers of the infraspinatus. Clinical Relevance: Clinicians should consider recovery time after pitching to prevent chronic losses of shoulder range of motion and strength. Identification of the underlying mechanisms of range of motion loss after pitching allows clinicians to optimize recovery strategies in baseball pitchers.

Dengue virus (DENV) infections are significant sources of morbidity and mortality throughout the tropics and subtropics. Over 400 million infections are estimated to occur every year, resulting in nearly 100 million symptomatic infections and over 20,000 deaths. Early immune response kinetics to infection remain unclear, in large part due to the variable incubation period exhibited by the DENVs after introduction into a susceptible host. To fill this knowledge gap, we performed a comprehensive virologic and immunologic analysis of individuals experimentally infected with the under-attenuated DENV-1 strain 45AZ5. This analysis captured both the kinetics and composition of the innate, humoral, and cellular immune responses elicited by experimental DENV-1 infection, as well as virologic and clinical features. Revealed in this analysis was a robust DENV-specific IgA antibody response that manifested between the appearance of DENV-specific IgM and IgG in all challenged individuals, as well as the presence of a non-neutralizing/NS1-specific antibody response that was delayed relative to the appearance of DENV-virion specific humoral immunity. RNAseq analysis also revealed several distinct and temporally-restricted gene modules that allowed for the identification and differentiation of the innate and adaptive immune response to DENV-infection. Our analysis provides a detailed description, in time and space, of the evolving matrix of DENV-elicited human inflammation and immunity and reveals several previously unappreciated immunological aspects of primary DENV-1 infection that can inform countermeasure development and evaluation.

Background Percussive therapy is hypothesized to speed recovery by delivering gentle, rhythmic pulses to soft tissue. However, patients often present with a differential soreness response after percussive therapy, which may lead to altered clinical outcomes. Purpose To compare the acute effects of percussion therapy on passive range of motion (ROM) and tissue-specific ultrasound measures (pennation angle [PA] and muscle thickness [MT]) between healthy individuals responding positively vs. negatively to percussive therapy performed on the dominant arm posterior rotator cuff. Study Design Cross-sectional laboratory study Methods Fifty-five healthy individuals were assessed on a subjective soreness scale before and after a five-minute percussive therapy session on the dominant arm posterior rotator cuff muscles. Participants with no change or a decrease in muscle soreness were assigned to the positive response group and participants who reported an increase in muscle soreness were assigned to the negative response group. Passive internal rotation (IR) and external rotation (ER) ROM and strength, and muscle architecture of the infraspinatus and teres minor were measured via ultrasound on the dominant shoulder. All dependent variables were collected before percussive therapy, and 20 minutes following percussive therapy. Results The positive response group had greater improvements than the negative response group in dominant arm IR ROM (2.3° positive vs. -1.3° negative, p=0.021) and IR strength (1.1 lbs vs. -1.2 lbs, p=0.011) after percussive therapy. No differences in ER strength or ROM were observed between groups. Regarding muscle architecture, the positive group had a lesser change in teres minor MT (0.00 mm vs. 0.11 mm, p=0.019) after percussive therapy. All other muscle architecture changes were not statistically different between groups. Conclusion Participants with a positive response to percussive therapy had increased dominant arm IR ROM and IR strength, and decreased teres minor MT, after percussive therapy compared to the negative response participants. Level of Evidence III

Conventional methods for quantifying and phenotyping antigen-specific lymphocytes can rapidly deplete irreplaceable specimens. This is due to the fact that antigen-specific T and B cells have historically been analyzed in independent assays each requiring millions of cells. A technique that facilitates the simultaneous detection of antigen-specific T and B cells would allow for more thorough immune profiling with significantly reduced sample requirements. To this end, we developed the B And T cell Tandem Lymphocyte Evaluation (BATTLE) assay, which allows for the simultaneous identification of SARS-CoV-2 Spike reactive T and B cells using an optimized Activation Induced Marker (AIM) T cell assay and dual-color B cell antigen probes. Using this assay, we demonstrate that antigen-specific B and T cell subsets can be identified simultaneously using conventional flow cytometry platforms and provide insight into the differential effects of mRNA vaccination on B and T cell populations following natural SARS-CoV-2 infection.

Dengue virus (DENV) is a prevalent human pathogen, infecting approximately 400 million individuals per year and causing symptomatic disease in approximately 100 million. A distinct feature of dengue is the increased risk for severe disease in some individuals with preexisting DENV-specific immunity. One proposed mechanism for this phenomenon is antibody-dependent enhancement (ADE), in which poorly-neutralizing IgG antibodies from a prior infection opsonize DENV to increase infection of Fcgamma receptor-bearing cells. While IgM and IgG are the most commonly studied DENV-reactive antibody isotypes, our group and others have described the induction of DENV-specific serum IgA responses during dengue. We hypothesized that monomeric IgA would be able to neutralize DENV without the possibility of ADE. To test this, we synthesized IgG and IgA versions of two different DENV-reactive monoclonal antibodies. We demonstrate that isotype-switching does not affect the antigen binding and neutralization properties of the two mAbs. We show that DENV-reactive IgG, but not IgA, mediates ADE in an Fcgamma receptor-positive K562 cells. Furthermore, we show that IgA potently antagonizes the ADE activity of IgG. These results suggest that levels of serum DENV-reactive IgA induced by DENV infection might regulate the overall ADE activity of DENV-immune plasmain vivoand warrants further study as a predictor of disease risk and/or therapeutic.

Population adoption of social distancing measures during the COVID-19 pandemic is at times deficient, increasing the risk of SARS-CoV-2 transmission. Healthcare workers and those living in areas of intense transmission may benefit from implementing biosafety measures in their daily lives. A mixed-methods approach, combining components of single negotiation text and the Delphi method, was used to create a COVID-19 biosafety-at-home protocol. A consensus building coordinator liaised with 12 experts to develop the protocol over 11 iterations. Experts had more than 200 years of combined experience in epidemiology, virology, infectious disease prevention, and public health. A flyer, created from the final protocol, was professionally designed and initially distributed via social media and institutional websites/emails in Ecuador beginning on May 2, 2020. Since then, it has been distributed in other countries, reaching ∼7,000 people. Translating research laboratory biosafety measures for the home/street environment might be challenging. The biosafety-at-home flyer addresses this challenge in a user-friendly format.

Difficulties inherent in the identification of immune correlates of protection or severe disease have challenged the development and evaluation of dengue vaccines. There persist substantial gaps in knowledge about the complex effects of age and sequential dengue virus (DENV) exposures on these correlations. To address these gaps, we were conducting a novel family-based cohort-cluster study for DENV transmission in Kamphaeng Phet, Thailand. The study began in 2015 and is funded until at least 2023. As of May 2019, 2,870 individuals in 485 families were actively enrolled. The families comprise at least 1 child born into the study as a newborn, 1 other child, a parent, and a grandparent. The median age of enrolled participants is 21 years (range 0–93 years). Active surveillance is performed to detect acute dengue illnesses, and annual blood testing identifies subclinical seroconversions. Extended follow-up of this cohort will detect sequential infections and correlate antibody kinetics and sequence of infections with disease outcomes. The central goal of this prospective study is to characterize how different DENV exposure histories within multigenerational family units, from DENV-naive infants to grandparents with multiple prior DENV exposures, affect transmission, disease, and protection at the level of the individual, household, and community.

Dengue is the world’s most prevalent and important arboviral disease. More than 50% of the world’s population lives at daily risk of infection and it is estimated more than 95 million people a year seek medical care following infection. Severe disease can manifest as plasma leakage and potential for clinically significant hemorrhage, shock, and death. Treatment is supportive and there is currently no licensed anti-dengue virus prophylactic or therapeutic compound. A single dengue vaccine, Sanofi Pasteur’s Dengvaxia®, has been licensed in 20 countries but uptake has been poor. A safety signal in dengue seronegative vaccine recipients stimulated an international re-look at the vaccine performance profile, new World Health Organization recommendations for use, and controversy in the Philippines involving the government, regulatory agencies, Sanofi Pasteur, clinicians responsible for testing and administering the vaccine, and the parents of vaccinated children. In this review, we provide an overview of Dengvaxia’s® development and discuss what has been learned about product performance since its licensure.

Summary Background Middle East respiratory syndrome (MERS) coronavirus causes a highly fatal lower-respiratory tract infection. There are as yet no licensed MERS vaccines or therapeutics. This study (WRAIR-2274) assessed the safety, tolerability, and immunogenicity of the GLS-5300 MERS coronavirus DNA vaccine in healthy adults. Methods This study was a phase 1, open-label, single-arm, dose-escalation study of GLS-5300 done at the Walter Reed Army Institute for Research Clinical Trials Center (Silver Spring, MD, USA). We enrolled healthy adults aged 18–50 years; exclusion criteria included previous infection or treatment of MERS. Eligible participants were enrolled sequentially using a dose-escalation protocol to receive 0·67 mg, 2 mg, or 6 mg GLS-5300 administered by trained clinical site staff via a single intramuscular 1 mL injection at each vaccination at baseline, week 4, and week 12 followed immediately by co-localised intramuscular electroporation. Enrolment into the higher dose groups occurred after a safety monitoring committee reviewed the data following vaccination of the first five participants at the previous lower dose in each group. The primary outcome of the study was safety, assessed in all participants who received at least one study treatment and for whom post-dose study data were available, during the vaccination period with follow-up through to 48 weeks after dose 3. Safety was measured by the incidence of adverse events; administration site reactions and pain; and changes in safety laboratory parameters. The secondary outcome was immunogenicity. This trial is registered at ClinicalTrials.gov (number NCT02670187) and is completed. Findings Between Feb 17 and July 22, 2016, we enrolled 75 individuals and allocated 25 each to 0·67 mg, 2 mg, or 6 mg GLS-5300. No vaccine-associated serious adverse events were reported. The most common adverse events were injection-site reactions, reported in 70 participants (93%) of 75. Overall, 73 participants (97%) of 75 reported at least one solicited adverse event; the most common systemic symptoms were headache (five [20%] with 0·67 mg, 11 [44%] with 2 mg, and seven [28%] with 6 mg), and malaise or fatigue (five [20%] with 0·67 mg, seven [28%] with 2 mg, and two [8%] with 6 mg). The most common local solicited symptoms were administration site pain (23 [92%] with all three doses) and tenderness (21 [84%] with all three doses). Most solicited symptoms were reported as mild (19 [76%] with 0·67 mg, 20 [80%] with 2 mg, and 17 [68%] with 6 mg) and were self-limiting. Unsolicited symptoms were reported for 56 participants (75%) of 75 and were deemed treatment-related for 26 (35%). The most common unsolicited adverse events were infections, occurring in 27 participants (36%); six (8%) were deemed possibly related to study treatment. There were no laboratory abnormalities of grade 3 or higher that were related to study treatment; laboratory abnormalities were uncommon, except for 15 increases in creatine phosphokinase in 14 participants (three participants in the 0·67 mg group, three in the 2 mg group, and seven in the 6 mg group). Of these 15 increases, five (33%) were deemed possibly related to study treatment (one in the 2 mg group and four in the 6 mg group). Seroconversion measured by S1-ELISA occurred in 59 (86%) of 69 participants and 61 (94%) of 65 participants after two and three vaccinations, respectively. Neutralising antibodies were detected in 34 (50%) of 68 participants. T-cell responses were detected in 47 (71%) of 66 participants after two vaccinations and in 44 (76%) of 58 participants after three vaccinations. There were no differences in immune responses between dose groups after 6 weeks. At week 60, vaccine-induced humoral and cellular responses were detected in 51 (77%) of 66 participants and 42 (64%) of 66, respectively. Interpretation The GLS-5300 MERS coronavirus vaccine was well tolerated with no vaccine-associated serious adverse events. Immune responses were dose-independent, detected in more than 85% of participants after two vaccinations, and durable through 1 year of follow-up. The data support further development of the GLS-5300 vaccine, including additional studies to test the efficacy of GLS-5300 in a region endemic for MERS coronavirus. Funding US Department of the Army and GeneOne Life Science.