Low-dose dengue virus 3 human challenge model: a phase 1 open-label study.

Dengue human infection models present an opportunity to explore the potential of a vaccine, anti-viral or immuno-compound for clinical benefit in a controlled setting. Here we report the outcome of a phase 1 open-label assessment of a low-dose dengue virus 3 (DENV-3) challenge model (NCT04298138), in which nine participants received a subcutaneous inoculation with 0.5 ml of a 1.4 × 103 plaque-forming unit per ml suspension of the attenuated DENV-3 strain CH53489. The primary and secondary endpoints of the study were to assess the safety of this DENV-3 strain in healthy flavivirus-seronegative individuals. All participants developed RNAaemia within 7 days after inoculation with peak titre ranging from 3.13 × 104 to 7.02 × 108 genome equivalents per ml. Solicited symptoms such as fever and rash, clinical laboratory abnormalities such as lymphopenia and thrombocytopenia, and self-reported symptoms such as myalgia were consistent with mild-to-moderate dengue in all volunteers. DENV-3-specific seroconversion and memory T cell responses were observed within 14 days after inoculation as assessed by enzyme-linked immunosorbent assay and interferon-gamma-based enzyme-linked immunospot. RNA sequencing and serum cytokine analysis revealed anti-viral responses that overlapped with the period of viraemia. The magnitude and frequency of clinical and immunologic endpoints correlated with an individual's peak viral titre.

Protective efficacy of a Zika purified inactivated virus vaccine candidate during pregnancy in marmosets.

Zika virus (ZIKV) infection during pregnancy poses significant threats to maternal and fetal health, leading to intrauterine fetal demise and severe developmental malformations that constitute congenital Zika syndrome (CZS). As such, the development of a safe and effective ZIKV vaccine is a critical public health priority. However, the safety and efficacy of such a vaccine during pregnancy remain uncertain. Historically, the conduct of clinical trials in pregnant women has been challenging. Therefore, clinically relevant animal pregnancy models are in high demand for testing vaccine efficacy. We previously reported that a marmoset pregnancy model of ZIKV infection consistently demonstrated vertical transmission from mother to fetus during pregnancy. Using this marmoset model, we also showed that vertical transmission could be prevented by pre-pregnancy vaccination with Zika purified inactivated virus (ZPIV) vaccine. Here, we further examined the efficacy of ZPIV vaccination during pregnancy. Vaccination during pregnancy elicited virus neutralizing antibody responses that were comparable to those elicited by pre-pregnancy vaccination. Vaccination also reduced placental pathology, viral burden and vertical transmission of ZIKV during pregnancy, without causing adverse effects. These results provide key insights into the safety and efficacy of ZPIV vaccination during pregnancy and demonstrate positive effects of vaccination on the reduction of ZIKV infection, an important advance in preparedness for future ZIKV outbreaks.

Zika purified inactivated virus (ZPIV) vaccine reduced vertical transmission in pregnant immunocompetent mice.

Zika virus (ZIKV) is a significant threat to pregnant women and their fetuses as it can cause severe birth defects and congenital neurodevelopmental disorders, referred to as congenital Zika syndrome (CZS). Thus, a safe and effective ZIKV vaccine for pregnant women to prevent in utero ZIKV infection is of utmost importance. Murine models of ZIKV infection are limited by the fact that immunocompetent mice are resistant to ZIKV infection. As such, interferon-deficient mice have been used in some preclinical studies to test the efficacy of ZIKV vaccine candidates against lethal virus challenge. However, interferon-deficient mouse models have limitations in assessing the immunogenicity of vaccines, necessitating the use of immunocompetent mouse pregnancy models. Using the human stat2 knock-in (hSTAT2KI) mouse pregnancy model, we show that vaccination with a purified formalin-inactivated Zika virus (ZPIV) vaccine prior to pregnancy successfully prevented vertical transmission. In addition, maternal immunity protected offspring against postnatal challenge for up to 28 days. Furthermore, passive transfer of human IgG purified from hyper-immune sera of ZPIV vaccinees prevented maternal and fetal ZIKV infection, providing strong evidence that the neutralizing antibody response may serve as a meaningful correlate of protection.

A five-year quasi-experimental study to evaluate the impact of empiric antibiotic order sets on antibiotic use metrics among hospitalized adult patients.

OBJECTIVE: Evaluation of adult antibiotic order sets (AOSs) on antibiotic stewardship metrics has been limited. The primary outcome was to evaluate the standardized antimicrobial administration ratio (SAAR). Secondary outcomes included antibiotic days of therapy (DOT) per 1,000 patient days (PD); selected antibiotic use; AOS utilization; Clostridioides difficile infection (CDI) cases; and clinicians' perceptions of the AOS via a survey following the final study phase. DESIGN: This 5-year, single-center, quasi-experimental study comprised 5 phases from 2017 to 2022 over 10-month periods between August 1 and May 31. SETTING: The study was conducted in a 752-bed tertiary care, academic medical center. INTERVENTION: Our institution implemented AOSs in the electronic medical record (EMR) for common infections among hospitalized adults. RESULTS: For the primary outcome, a statistically significant decreases in SAAR were detected from phase 1 to phase 5 (1.0 vs 0.90; P < .001). A statistically significant decreases were detected in DOT per 1,000 PD (4,884 vs 3,939; P = .001), fluoroquinolone orders (407 vs 175; P < .001), carbapenem orders (147 vs 106; P = .024), and clindamycin orders (113 vs 73; P = .01). No statistically significant change in mean vancomycin orders was detected (991 vs 902; P = .221). A statistically significant decrease in CDI cases was also detected (7.8, vs 2.4; P = .002) but may have been attributable to changes in CDI case diagnosis. Clinicians indicated that the AOSs were easy to use overall and that they helped them select the appropriate antibiotics. CONCLUSIONS: Implementing AOS into the EMR was associated with a statistically significant reduction in SAAR, antibiotic DOT per 1,000 PD, selected antibiotic orders, and CDI cases.

Household immunity and individual risk of infection with dengue virus in a prospective, longitudinal cohort study.

Although it is known that household infections drive the transmission of dengue virus (DENV), it is unclear how household composition and the immune status of inhabitants affect the individual risk of infection. Most population-based studies to date have focused on paediatric cohorts because more severe forms of dengue mainly occur in children, and the role of adults in dengue transmission is understudied. Here we analysed data from a multigenerational cohort study of 470 households, comprising 2,860 individuals, in Kamphaeng Phet, Thailand, to evaluate risk factors for DENV infection. Using a gradient-boosted regression model trained on annual haemagglutination inhibition antibody titre inputs, we identified 1,049 infections, 90% of which were subclinical. By analysing imputed infections, we found that individual antibody titres, household composition and antibody titres of other members in the same household affect an individual's risk of DENV infection. Those individuals living in households with high average antibody titres, or households with more adults, had a reduced risk of infection. We propose that herd immunity to dengue acts at the household level and may provide insight into the drivers of the recent change in the shifting age distribution of dengue cases in Thailand.

DENV-specific IgA contributes protective and non-pathologic function during antibody-dependent enhancement of DENV infection.

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.

Daptomycin Plus Oxacillin for Persistent Methicillin-Susceptible Staphylococcus aureus Bacteremia.

BACKGROUND: The preferred antibiotic salvage regimen for persistent methicillin-susceptible Staphylococcus aureus bacteremia (MSSAB) is unclear. Ertapenem with cefazolin or an antistaphylococcal penicillin has been primarily described, but identifying alternative carbapenem-sparing options may support antibiotic stewardship efforts and decrease the risk of antibiotic-associated Clostridioides difficile infection. OBJECTIVE: We sought to evaluate the effectiveness and safety of daptomycin plus oxacillin (D/O) for persistent MSSAB. METHODS: This was a single-center, retrospective cohort of patients with persistent MSSAB who received D/O between January 1, 2014, and January 1, 2023. Adult patients were included if they had blood cultures positive for MSSA ≥72 hours and received D/O combination for ≥48 hours. Patients were excluded if they were pregnant, incarcerated, or received another antibiotic considered to have excellent activity against MSSA. The primary outcome was time to MSSA bacteremia clearance post-daptomycin initiation. Secondary outcomes included microbiological cure, hospital length of stay, 90-day all-cause mortality, MSSA bacteremia-related mortality, 90-day readmission for MSSAB, and incidence of antibiotic-associated adverse effects. Time to MSSAB clearance post-D/O initiation was plotted using Kaplan-Meier estimation. RESULTS: Seven unique patient encounters were identified including 4 with endocarditis. Despite a median MSSA bacteremia duration of 7.8 days, median clearance was 2 days post-daptomycin initiation. All achieved microbiological cure, and no adverse effects were reported. Ninety-day all-cause mortality, MSSAB-related mortality, and 90-day readmission for MSSAB occurred in 28.6%, 14.3%, and 14.3% of patients, respectively. CONCLUSIONS AND RELEVANCE: D/O was an effective, well-tolerated salvage regimen in this cohort and may represent a carbapenem-sparing option for persistent MSSAB.

Zika-specific neutralizing antibodies targeting inter-dimer envelope epitopes.

Zika virus (ZIKV) is an emerging pathogen that causes devastating congenital defects. The overlapping epidemiology and immunologic cross-reactivity between ZIKV and dengue virus (DENV) pose complex challenges to vaccine design, given the potential for antibody-dependent enhancement of disease. Therefore, classification of ZIKV-specific antibody targets is of notable value. From a ZIKV-infected rhesus macaque, we identify ZIKV-reactive B cells and isolate potent neutralizing monoclonal antibodies (mAbs) with no cross-reactivity to DENV. We group these mAbs into four distinct antigenic groups targeting ZIKV-specific cross-protomer epitopes on the envelope glycoprotein. Co-crystal structures of representative mAbs in complex with ZIKV envelope glycoprotein reveal envelope-dimer epitope and unique dimer-dimer epitope targeting. All four specificities are serologically identified in convalescent humans following ZIKV infection, and representative mAbs from all four groups protect against ZIKV replication in mice. These results provide key insights into ZIKV-specific antigenicity and have implications for ZIKV vaccine, diagnostic, and therapeutic development.

Safety and immunogenicity of a purified inactivated Zika virus vaccine candidate in adults primed with a Japanese encephalitis virus or yellow fever virus vaccine in the USA: a phase 1, randomised, double-blind, placebo-controlled clinical trial.

BACKGROUND: Zika virus infection is a threat to at-risk populations, causing major birth defects and serious neurological complications. Development of a safe and efficacious Zika virus vaccine is, therefore, a global health priority. Assessment of heterologous flavivirus vaccination is important given co-circulation of Japanese encephalitis virus and yellow fever virus with Zika virus. We investigated the effect of priming flavivirus naive participants with a licensed flavivirus vaccine on the safety and immunogenicity of a purified inactivated Zika vaccine (ZPIV). METHODS: This phase 1, placebo-controlled, double-blind trial was done at the Walter Reed Army Institute of Research Clinical Trials Center in Silver Spring, MD, USA. Eligible participants were healthy adults aged 18-49 years, with no detectable evidence of previous flavivirus exposure (by infection or vaccination), as measured by a microneutralisation assay. Individuals with serological evidence of HIV, hepatitis B, or hepatitis C infection were excluded, as were pregnant or breastfeeding women. Participants were recruited sequentially into one of three groups (1:1:1) to receive no primer, two doses of intramuscular Japanese encephalitis virus vaccine (IXIARO), or a single dose of subcutaneous yellow fever virus vaccine (YF-VAX). Within each group, participants were randomly assigned (4:1) to receive intramuscular ZPIV or placebo. Priming vaccinations were given 72-96 days before ZPIV. ZPIV was administered either two or three times, at days 0, 28, and 196-234. The primary outcome was occurrence of solicited systemic and local adverse events along with serious adverse events and adverse events of special interest. These data were analysed in all participants receiving at least one dose of ZPIV or placebo. Secondary outcomes included measurement of neutralizing antibody responses following ZPIV vaccination in all volunteers with available post-vaccination data. This trial is registered at ClinicalTrials.gov, NCT02963909. FINDINGS: Between Nov 7, 2016, and Oct 30, 2018, 134 participants were assessed for eligibility. 21 did not meet inclusion criteria, 29 met exclusion criteria, and ten declined to participate. 75 participants were recruited and randomly assigned. 35 (47%) of 75 participants were male and 40 (53%) were female. 25 (33%) of 75 participants identified as Black or African American and 42 (56%) identified as White. These proportions and other baseline characteristics were similar between groups. There were no statistically significant differences in age, gender, race, or BMI between those who did and did not opt into the third dose. All participants received the planned priming IXIARO and YF-VAX vaccinations, but one participant who received YF-VAX dropped out before receipt of the first dose of ZPIV. 50 participants received a third dose of ZPIV or placebo, including 14 flavivirus-naive people, 17 people primed with Japanese encephalitis virus vaccine, and 19 participants primed with yellow fever vaccine. Vaccinations were well tolerated across groups. Pain at the injection site was the only adverse event reported more frequently in participants who received ZPIV than in those who received placebo (39 [65%] of 60 participants, 95% CI 51·6-76·9 who received ZPIV vs three [21·4%] of 14 who received placebo; 4·7-50·8; p=0·006). No patients had an adverse event of special interest or serious adverse event related to study treatment. At day 57, the flavivirus-naive volunteers had an 88% (63·6-98·5, 15 of 17) seroconversion rate (neutralising antibody titre ≥1:10) and geometric mean neutralising antibody titre (GMT) against Zika virus of 100·8 (39·7-255·7). In the Japanese encephalitis vaccine-primed group, the day 57 seroconversion rate was 31·6% (95% CI 12·6-56·6, six of 19) and GMT was 11·8 (6·1-22·8). Participants primed with YF-VAX had a seroconversion rate of 25% (95% CI 8·7-49·1, five of 20) and GMT of 6·6 (5·2-8·4). Humoral immune responses rose substantially following a third dose of ZPIV, with seroconversion rates of 100% (69·2-100; ten of ten), 92·9% (66·1-99·8; 13 of 14), and 60% (32·2-83·7, nine of 15) and GMTs of 511·5 (177·6-1473·6), 174·2 (51·6-587·6), and 79 (19·0-326·8) in the flavivirus naive, Japanese encephalitis vaccine-primed, and yellow fever vaccine-primed groups, respectively. INTERPRETATION: We found ZPIV to be well tolerated in flavivirus naive and primed adults but that immunogenicity varied significantly according to antecedent flavivirus vaccination status. Immune bias towards the flavivirus antigen of initial exposure and the timing of vaccination may have impacted responses. A third ZPIV dose overcame much, but not all, of the discrepancy in immunogenicity. The results of this phase 1 clinical trial have implications for further evaluation of ZPIV's immunisation schedule and use of concomitant vaccinations. FUNDING: Department of Defense, Defense Health Agency; National Institute of Allergy and Infectious Diseases; and Division of Microbiology and Infectious Disease.

Does Prehabilitation Before Surgery Affect Return to Sport in Baseball Pitchers With Partial Ulnar Collateral Ligament Tears?

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.

Sources of coronavirus disease 2019 (COVID-19) exposure among healthcare personnel (HCP) in a large tertiary-care medical center.

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.

Is new dengue vaccine efficacy data a relief or cause for concern?

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.

Identifying the underlying mechanisms responsible for glenohumeral internal rotation in professional baseball pitchers.

Background and Hypothesis: Glenohumeral internal rotation deficit has been identified as a significant risk factor for upper-extremity injuries in pitchers across all ages. Humeral retroversion (HR), posterior capsule thickness (PCT), and posterior rotator cuff muscle pennation angle (PA) have been independently associated with internal rotation range of motion (IR ROM); however, these anatomic structures have not been collectively measured in baseball pitchers to determine the underlying mechanisms responsible for IR ROM. Therefore, the purpose of this study was to determine the contributions of HR, PCT, and posterior rotator cuff PA on IR ROM during a preseason evaluation in healthy professional baseball pitchers. The authors hypothesized that HR, PCT, and posterior rotator cuff PA would have a significant contribution to IR ROM. Methods: This is a cross-sectional study. Healthy professional pitchers from a single organization were recruited at the beginning of the 2021 Major League Baseball Spring Training. Participants received bilateral IR ROM assessment while laying supine with the shoulder at 90 degrees of abduction and the scapula stabilized. Ultrasound imaging was also performed bilaterally to assess HR, PCT, infraspinatus (superficial + deep) PA, and teres minor (superficial + deep) PA. All ultrasound imaging processes were performed utilizing previously published, highly reliable techniques. A stepwise regression was performed, which included both arms to determine the mechanisms of IR ROM. Results: Overall, 49 pitchers (88 shoulders) with an average age of 22.5 ± 2.2 years were included in the final data analysis. Stepwise linear regression found that only HR and PCT were associated with the preseason IR ROM. There was a moderate relationship between HR and PCT relative to IR ROM (R = 0.535, P < .001). Conclusion: HR and PCT were found to be the primary mechanisms responsible for the preseason glenohumeral IR ROM. The posterior rotator cuff was not found to be significantly related to IR ROM. Future research evaluating these anatomic structures longitudinally-both acutely and chronically-will help clinicians optimize ROM management throughout the season. As glenohumeral internal rotation deficit can have harmful effects in baseball pitchers, understanding which anatomic structures are most responsible for IR ROM is important for injury prevention and treatment.

Bivalent Omicron BA.1-Adapted BNT162b2 Booster in Adults Older than 55 Years.

BACKGROUND: The emergence of immune-escape variants of severe acute respiratory syndrome coronavirus 2 warrants the use of sequence-adapted vaccines to provide protection against coronavirus disease 2019. METHODS: In an ongoing phase 3 trial, adults older than 55 years who had previously received three 30-µg doses of the BNT162b2 vaccine were randomly assigned to receive 30 µg or 60 µg of BNT162b2, 30 µg or 60 µg of monovalent B.1.1.529 (omicron) BA.1-adapted BNT162b2 (monovalent BA.1), or 30 µg (15 µg of BNT162b2 + 15 µg of monovalent BA.1) or 60 µg (30 µg of BNT162b2 + 30 µg of monovalent BA.1) of BA.1-adapted BNT162b2 (bivalent BA.1). Primary objectives were to determine superiority (with respect to 50% neutralizing titer [NT50] against BA.1) and noninferiority (with respect to seroresponse) of the BA.1-adapted vaccines to BNT162b2 (30 µg). A secondary objective was to determine noninferiority of bivalent BA.1 to BNT162b2 (30 µg) with respect to neutralizing activity against the ancestral strain. Exploratory analyses assessed immune responses against omicron BA.4, BA.5, and BA.2.75 subvariants. RESULTS: A total of 1846 participants underwent randomization. At 1 month after vaccination, bivalent BA.1 (30 µg and 60 µg) and monovalent BA.1 (60 µg) showed neutralizing activity against BA.1 superior to that of BNT162b2 (30 µg), with NT50 geometric mean ratios (GMRs) of 1.56 (95% confidence interval [CI], 1.17 to 2.08), 1.97 (95% CI, 1.45 to 2.68), and 3.15 (95% CI, 2.38 to 4.16), respectively. Bivalent BA.1 (both doses) and monovalent BA.1 (60 µg) were also noninferior to BNT162b2 (30 µg) with respect to seroresponse against BA.1; between-group differences ranged from 10.9 to 29.1 percentage points. Bivalent BA.1 (either dose) was noninferior to BNT162b2 (30 µg) with respect to neutralizing activity against the ancestral strain, with NT50 GMRs of 0.99 (95% CI, 0.82 to 1.20) and 1.30 (95% CI, 1.07 to 1.58), respectively. BA.4-BA.5 and BA.2.75 neutralizing titers were numerically higher with 30-µg bivalent BA.1 than with 30-µg BNT162b2. The safety profile of either dose of monovalent or bivalent BA.1 was similar to that of BNT162b2 (30 µg). Adverse events were more common in the 30-µg monovalent-BA.1 (8.5%) and 60-µg bivalent-BA.1 (10.4%) groups than in the other groups (3.6 to 6.6%). CONCLUSIONS: The candidate monovalent or bivalent omicron BA.1-adapted vaccines had a safety profile similar to that of BNT162b2 (30 µg), induced substantial neutralizing responses against ancestral and omicron BA.1 strains, and, to a lesser extent, neutralized BA.4, BA.5, and BA.2.75 strains. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04955626.).

Chronic Effects of Pitching on Muscle Thickness and Strength of the Scapular Stabilizers in Professional Baseball Players.

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.

Chronic Adaptations of Shoulder Muscle Synergies in Healthy Baseball Players.

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.

The Effects of Fatigue on Muscle Synergies in the Shoulders of Baseball Players.

BACKGROUND: Muscle synergies are defined as the central nervous system's organizational structure for movement. Muscle synergies change after muscular fatigue, with certain synergies assuming the primary role to compensate for fatigue within another muscle synergy. Owing to the high eccentric forces imposed upon the external rotators (ie, posterior rotator cuff), pitchers that continue to throw while fatigued are at a significantly higher risk of shoulder and/or elbow injury; however, the neuromuscular compensation strategies of baseball players in response to fatigue are currently unknown. HYPOTHESIS: Players would utilize the same muscle synergy structure following external rotation (ER) fatigue; however, muscle coefficients of nonfatigued muscles would increase (ie, compensate for the external rotators) after fatigue. STUDY DESIGN: Cross-sectional study conducted in a controlled, laboratory setting. METHODS: Nine players from an intercollegiate competitive club baseball team voluntarily participated in this study. Surface electromyography was used on 14 muscles of the glenohumeral and scapulothoracic joints of the dominant arm during a reaching protocol. Players completed a baseline reaching protocol (prefatigue), then an ER fatigue protocol until maximum concentric ER was reduced by 40%, and finally repeated the same reaching protocol (postfatigue). Principal component analysis was used to extract muscle synergies, the variance accounted for (VAF) of each synergy, and muscle coefficients. Prefatigue was compared with postfatigue using paired t tests for all dependent variables. RESULTS: Four muscle synergies were extracted for both pre- and postfatigue. The VAF for the ER/abduction synergy decreased significantly (prefatigue, 34.6%; postfatigue, 32.4%; P = 0.03), showing a decreased reliance on ER/abduction during the reaching task after fatigue. Within synergy 1, the pectoralis major muscle coefficient (-0.489 vs -0.552; P = 0.01; effect size = 1.68) decreased significantly from prefatigue to postfatigue, indicating that the pectoralis major assumed more of an antagonist role during ER/abduction. Within synergy 2 (forward reaching), there were no significant changes in VAF or muscle coefficients observed. For the third synergy, muscle coefficients increased for the serratus anterior (P = 0.02) and middle deltoid (P = 0.01), whereas in the fourth synergy, the pectoralis major (P = 0.01) increased and teres major (P = 0.01) and biceps brachii (P = 0.05) muscle coefficients decreased. CONCLUSION: The decreased VAF of the ER/abduction synergy after fatigue indicate that other muscles within that synergy could not fully compensate to maintain function. Interestingly, the changes in muscle coefficients suggest that players relied less on the internal rotation (IR) synergy and more on the cross-body synergy following fatigue. This may be due to imbalances between ER and IR while maintaining balance between cross-abduction and adduction. CLINICAL RELEVANCE: Clinicians may consider implementing low-load, high-repetition training programs to develop posterior shoulder endurance and prolong the onset of muscular fatigue.

Outcomes following arthroscopic posteromedial osteophyte resection and risk of future ulnar collateral ligament reconstruction.

BACKGROUND AND HYPOTHESIS: 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 a >10% risk of requiring subsequent UCLR or UCL repair. MATERIALS AND METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Vancomycin plus ceftaroline for persistent methicillin-resistant Staphylococcus aureus bacteremia.

STUDY OBJECTIVE: 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. DESIGN: Single-center, retrospective cohort study between January 1, 2016, and December 31, 2021. SETTING: State University of New York Upstate University Hospital, a 748-bed tertiary care, academic medical center in Syracuse, NY. PATIENTS: 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. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: Vancomycin plus ceftaroline may represent an effective and well-tolerated salvage regimen option for persistent MRSAB.

Biologics for dengue prevention: up-to-date.

INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.