Publications by authors named "Stephen J Thomas"

171 Publications

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine through 6 Months.

N Engl J Med 2021 Sep 15. Epub 2021 Sep 15.

From the State University of New York, Upstate Medical University, Syracuse (S.J.T.), and Vaccine Research and Development, Pfizer, Pearl River (J.A., A.G., K.A.S., K.K., S.B., W.V.K., D.C., Q.Y., P.L., P.R.D., W.C.G., K.U.J.) - both in New York; Associação Obras Sociais Irmã Dulce and Oswaldo Cruz Foundation, Bahia (E.D.M.), and iTrials-Hospital Militar Central (G.P.M.) and Fundacion INFANT, Buenos Aires (F.P.P.) - all in Brazil; Centro Paulista de Investigação Clinica, São Paulo (C.Z.); Vaccine Research and Development, Pfizer, Hurley, United Kingdom (N.K., S.L., R.B.); Vaccine Research and Development (J.L.P., X.X.) and Worldwide Safety, Safety Surveillance, and Risk Management (D.B.T., S.M.), Pfizer, Collegeville, PA; Global Product Development, Pfizer, Peapack, NJ (S.R.); Cincinnati Children's Hospital, Cincinnati (R.W.F.); Johns Hopkins Bloomberg School of Public Health, Baltimore (L.L.H.); BioNTech, Mainz (Ö.T., U.Ş.) and Medizentrum Essen Borbeck, Essen (A.S.) - both in Germany; Tiervlei Trial Centre, Karl Bremer Hospital, Cape Town, South Africa (H.N.); Hacettepe University, Ankara, Turkey (S.Ü.); and Worldwide Safety, Safety Surveillance, and Risk Management, Pfizer, Groton, CT (D.B.T., S.M.).

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.).
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http://dx.doi.org/10.1056/NEJMoa2110345DOI Listing
September 2021

Health Care Personnel (HCP) attitudes about COVID-19 vaccination after emergency use authorization.

Clin Infect Dis 2021 Sep 1. Epub 2021 Sep 1.

Department of Medicine, SUNY Upstate Medical University, Syracuse, NY, USA.

Background: We previously reported on COVID-19 vaccination intent among HCP before emergency use authorization. We found widespread hesitancy and a substantial proportion of HCP did not intend to vaccinate.

Methods: We conducted a cross-sectional survey of HCP, including clinical and non-clinical staff, researchers, and trainees between February 21 and March 19, 2021. The survey evaluated vaccine attitudes, beliefs, intent and acceptance.

Results: Overall, 3,981 (87.7%) of respondents had already received a COVID-19 vaccine or planned to get vaccinated. There were significant differences in vaccine acceptance by gender, age, race, and hospital role. Males (93.7%) were more likely than females (89.8%) to report vaccine acceptance (p<0.001). Mean age was higher among those reporting vaccine acceptance (p<0.001). Physicians and scientists showed the highest acceptance rate (97.3%), while staff in ancillary services showed the lowest acceptance rate (79.9%). Unvaccinated respondents were more likely to be females, to have refused vaccines in the past due to reasons other than illness or allergy, to care for COVID-19 patients, or to rely on themselves when making vaccination decision. Vaccine acceptance was more than twice previous intent among Black respondents, an increase from 30.8% to 73.8%, and across all hospital roles with all >80% vaccine acceptance.

Conclusions: The majority of HCP were vaccinated, much higher than reporting intent before vaccine was available. However, many HCP-particularly ancillary services-are still hesitant. Feasible and effective interventions to address the hesitant, including individually-tailored education strategies are needed, or vaccine can be mandated.
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http://dx.doi.org/10.1093/cid/ciab731DOI Listing
September 2021

Correlation between reported dengue illness history and seropositivity in rural Thailand.

PLoS Negl Trop Dis 2021 Jun 15;15(6):e0009459. Epub 2021 Jun 15.

State University of New York Upstate Medical University, Syracuse, New York, United States of America.

In the latest World Health Organization (WHO) recommendation for Dengvaxia implementation, either serological testing or a person's history of prior dengue illness may be used as supporting evidence to identify dengue virus (DENV)-immune individuals eligible for vaccination, in areas with limited capacity for laboratory confirmation. This analysis aimed to estimate the concordance between self-reported dengue illness histories and seropositivity in a prospective cohort study for dengue virus infection in Kamphaeng Phet province, a dengue-endemic area in northern Thailand. The study enrolled 2,076 subjects from 516 multigenerational families, with a median age of 30.6 years (range 0-90 years). Individual and family member dengue illness histories were obtained by questionnaire. Seropositivity was defined based on hemagglutination inhibition (HAI) assays. Overall seropositivity for DENV was 86.5% among those aged 9-45 years, which increased with age. 18.5% of participants reported a history of dengue illness prior to enrollment; 30.1% reported a previous DENV infection in the family, and 40.1% reported DENV infection in either themselves or a family member. Relative to seropositivity by HAI in the vaccine candidate group, the sensitivity and specificity of individual prior dengue illness history were 18.5% and 81.6%, respectively; sensitivity and specificity of reported dengue illness in a family member were 29.8% and 68.0%, and of either the individual or a family member were 40.1% and 60.5%. Notably, 13.4% of individuals reporting prior dengue illness were seronegative. Given the high occurrence of asymptomatic and mild DENV infection, self-reported dengue illness history is poorly sensitive for prior exposure and may misclassify individuals as 'exposed' when they were not. This analysis highlights that a simple, highly sensitive, and highly specific test for determining serostatus prior to Dengvaxia vaccination is urgently needed.
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http://dx.doi.org/10.1371/journal.pntd.0009459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232416PMC
June 2021

Persistent COVID-19 Symptoms Minimally Impact the Development of SARS-CoV-2-Specific T Cell Immunity.

Viruses 2021 05 15;13(5). Epub 2021 May 15.

Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA.

SARS-CoV-2 represents an unprecedented public health challenge. While the majority of SARS-CoV-2-infected individuals with mild-to-moderate COVID-19 resolve their infection with few complications, some individuals experience prolonged symptoms lasting for weeks after initial diagnosis. Persistent viral infections are commonly accompanied by immunologic dysregulation, but it is unclear if persistent COVID-19 impacts the development of virus-specific cellular immunity. To this end, we analyzed SARS-CoV-2-specific cellular immunity in convalescent COVID-19 patients who experienced eight days or fewer of COVID-19 symptoms or symptoms persisting for 18 days or more. We observed that persistent COVID-19 symptoms were not associated with the development of an overtly dysregulated cellular immune response. Furthermore, we observed that reactivity against the N protein from SARS-CoV-2 correlates with the amount of reactivity against the seasonal human coronaviruses 229E and NL63. These results provide insight into the processes that regulate the development of cellular immunity against SARS-CoV-2 and related human coronaviruses.
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http://dx.doi.org/10.3390/v13050916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155927PMC
May 2021

Safety, Immunogenicity, and Efficacy of the BNT162b2 Covid-19 Vaccine in Adolescents.

N Engl J Med 2021 07 27;385(3):239-250. Epub 2021 May 27.

From Cincinnati Children's Hospital, Cincinnati (R.W.F.); Kaiser Permanente Vaccine Study Center, Oakland (N.P.K.), and the California Research Foundation, San Diego (D.M.B.) - both in California; Vaccine Research and Development, Pfizer, Hurley, United Kingdom (N.K., S.L., R.B.); Vaccine Research and Development, Pfizer, Pearl River (A.G., J.A., K.A.S., K.K., W.V.K., D.C., P.R.D., K.U.J., W.C.G.), and SUNY Upstate Medical University, Syracuse (S.J.T.) - both in New York; Vaccine Research and Development (J.L.P., H.M., X.X.) and Worldwide Safety, Safety Surveillance and Risk Management (S.M.), Pfizer, Collegeville, PA; Duke Human Vaccine Institute, Durham, NC (E.B.W.); Senders Pediatrics, South Euclid, OH (S.S.); Clinical Research Professionals, Chesterfield, MO (T.J.); BioNTech, Mainz, Germany (Ö.T., U.Ş.); and Worldwide Safety, Safety Surveillance and Risk Management, Pfizer, Groton, CT (D.B.T.).

Background: Until very recently, vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had not been authorized for emergency use in persons younger than 16 years of age. Safe, effective vaccines are needed to protect this population, facilitate in-person learning and socialization, and contribute to herd immunity.

Methods: In this ongoing multinational, placebo-controlled, observer-blinded trial, we randomly assigned participants in a 1:1 ratio to receive two injections, 21 days apart, of 30 μg of BNT162b2 or placebo. Noninferiority of the immune response to BNT162b2 in 12-to-15-year-old participants as compared with that in 16-to-25-year-old participants was an immunogenicity objective. Safety (reactogenicity and adverse events) and efficacy against confirmed coronavirus disease 2019 (Covid-19; onset, ≥7 days after dose 2) in the 12-to-15-year-old cohort were assessed.

Results: Overall, 2260 adolescents 12 to 15 years of age received injections; 1131 received BNT162b2, and 1129 received placebo. As has been found in other age groups, BNT162b2 had a favorable safety and side-effect profile, with mainly transient mild-to-moderate reactogenicity (predominantly injection-site pain [in 79 to 86% of participants], fatigue [in 60 to 66%], and headache [in 55 to 65%]); there were no vaccine-related serious adverse events and few overall severe adverse events. The geometric mean ratio of SARS-CoV-2 50% neutralizing titers after dose 2 in 12-to-15-year-old participants relative to 16-to-25-year-old participants was 1.76 (95% confidence interval [CI], 1.47 to 2.10), which met the noninferiority criterion of a lower boundary of the two-sided 95% confidence interval greater than 0.67 and indicated a greater response in the 12-to-15-year-old cohort. Among participants without evidence of previous SARS-CoV-2 infection, no Covid-19 cases with an onset of 7 or more days after dose 2 were noted among BNT162b2 recipients, and 16 cases occurred among placebo recipients. The observed vaccine efficacy was 100% (95% CI, 75.3 to 100).

Conclusions: The BNT162b2 vaccine in 12-to-15-year-old recipients had a favorable safety profile, produced a greater immune response than in young adults, and was highly effective against Covid-19. (Funded by BioNTech and Pfizer; C4591001 ClinicalTrials.gov number, NCT04368728.).
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http://dx.doi.org/10.1056/NEJMoa2107456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174030PMC
July 2021

Precision Tracing of Household Dengue Spread Using Inter- and Intra-Host Viral Variation Data, Kamphaeng Phet, Thailand.

Emerg Infect Dis 2021 06;27(6):1637-1644

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.
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http://dx.doi.org/10.3201/eid2706.204323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153871PMC
June 2021

Team Science: American Heart Association's Hypertension Strategically Focused Research Network Experience.

Hypertension 2021 Jun 3;77(6):1857-1866. Epub 2021 May 3.

Internal Medicine (T.A.K., S.K.), Medical College of Wisconsin, Milwaukee, WI.

In 2015, the American Heart Association awarded 4-year funding for a Strategically Focused Research Network focused on hypertension composed of 4 Centers: Cincinnati Children's Hospital, Medical College of Wisconsin, University of Alabama at Birmingham, and University of Iowa. Each center proposed 3 integrated (basic, clinical, and population science) projects around a single area of focus relevant to hypertension. Along with scientific progress, the American Heart Association put a significant emphasis on training of next-generation hypertension researchers by sponsoring 3 postdoctoral fellows per center over 4 years. With the center projects being spread across the continuum of basic, clinical, and population sciences, postdoctoral fellows were expected to garner experience in various types of research methodologies. The American Heart Association also provided a number of leadership development opportunities for fellows and investigators in these centers. In addition, collaboration was highly encouraged among the centers (both within and outside the network) with the American Heart Association providing multiple opportunities for meeting and expanding associations. The area of focus for the Cincinnati Children's Hospital Center was hypertension and target organ damage in children utilizing ambulatory blood pressure measurements. The Medical College of Wisconsin Center focused on epigenetic modifications and their role in pathogenesis of hypertension using human and animal studies. The University of Alabama at Birmingham Center's areas of research were diurnal blood pressure patterns and clock genes. The University of Iowa Center evaluated copeptin as a possible early biomarker for preeclampsia and vascular endothelial function during pregnancy. In this review, challenges faced and successes achieved by the investigators of each of the centers are presented.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16296DOI Listing
June 2021

Master swimmers with shoulder pain and disability have altered functional and structural measures.

J Athl Train 2021 Apr 13. Epub 2021 Apr 13.

Arcadia University, Glenside, PA.

Context: Supraspinatus tendinopathy and shoulder pain are common in competitive youth swimmers; however, no studies have investigated clinical and structural factors contributing to shoulder pain and disability in master level swimmers.

Objective: The objectives of this study were: 1) to determine the prevalence of shoulder pain and disability in master level swimmers, 2) to identify the most provocative special tests for shoulder pain, and 3) to determine if shoulder clinical and tissue specific measures, training variables and volume vary between those with and without shoulder pain, dissatisfaction and disability.

Design: Cross-sectional.

Setting: Collegiate swimming facilities.

Patients Or Other Participants: Thirty-nine adult masters level swimmers were evaluated and included in the data analysis.

Main Outcome Measures: A survey of demographics, training, and pain and disability ratings using the Penn Shoulder Score and Disability of Arm Shoulder Hand sports module. Swimmers underwent a clinical exam including shoulder passive range of motion (PROM), posterior shoulder endurance test (PSET), supraspinatus tendon structure and posterior capsule thickness. One-way ANOVAs were used to compare demographics, clinical and structural findings between those with significant pain, dissatisfaction and disability (+PDD) and those without (-PDD).

Results: Fifteen percent of subjects reported pain at rest, 28% with normal activities (eating, dressing), and 69% with strenuous activities (sports) and 50% reported disability. The +PDD group had less shoulder internal rotation (10°), less ER (8°), and completed less yardage per day and per year. There were significant differences in the supraspinatus tendon structure between the +PDD and -PDD groups.

Conclusion: Masters swimmers with pain and disability are able to self-limit yardage and likely why they recorded less yardage. The reduced shoulder motion (IR and ER) without posterior capsule differences may be due to rotator cuff muscle/tendon restrictions and the supraspinatus tendon structure may indicate degeneration caused by previous overuse resulting in pain.
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http://dx.doi.org/10.4085/1062-6050-0067.21DOI Listing
April 2021

Return-to-Play and Competitive Outcomes After Ulnar Collateral Ligament Reconstruction Among Baseball Players: A Systematic Review.

Orthop J Sports Med 2020 Dec 28;8(12):2325967120966310. Epub 2020 Dec 28.

Penn Throwing Clinic, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Background: Ulnar collateral ligament (UCL) reconstruction (UCLR) is very common in baseball. However, no review has compared the return-to-play (RTP) and in-game performance statistics of pitchers after primary and revision UCLR as well as of position players after UCLR.

Purpose: To review, synthesize, and evaluate the published literature on outcomes after UCLR in baseball players to determine RTP and competitive outcomes among various populations of baseball players.

Study Design: Systematic review; Level of evidence, 4.

Methods: A literature search including studies between 1980 and November 4, 2019, was conducted for articles that included the following terms: ulnar collateral ligament, elbow, medial collateral ligament, Tommy John surgery, throwing athletes, baseball pitchers, biomechanics, and performance. To be included, studies must have evaluated baseball players at any level who underwent UCLR (primary or revision) and assessed RTP and/or competitive outcomes.

Results: A total of 29 studies with relatively high methodological quality met the inclusion criteria. After primary UCLR, Major League Baseball (MLB) pitchers returned to play in 80% to 97% of cases in approximately 12 months; however, return to the same level of play (RTSP) was less frequent and took longer, with 67% to 87% of MLB pitchers returning in about 15 months. RTP rates for MLB pitchers after revision UCLR were slightly lower, ranging from 77% to 85%, while RTSP rates ranged from 55% to 78%. RTP rates for catchers (59%-80%) were generally lower than RTP rates for infielders (76%) and outfielders (89%). All studies found a decrease in pitching workloads after UCLR. Fastball usage may also decrease after UCLR. Changes in earned run average and walks plus hits per inning pitched were inconclusive.

Conclusion: Pitchers returned to play after UCLR in approximately 12 months and generally took longer to return to their same level of play. Pitchers also returned to play less frequently after revision UCLR. After both primary and revision UCLR, professional pitchers experienced decreased workloads and potentially decreased fastball usage as well. Catchers may RTP after UCLR less frequently than pitchers, infielders, and outfielders possibly because of the frequency of throwing in the position. These results will help guide clinical decision making and patient education when treating UCL tears in baseball players.
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http://dx.doi.org/10.1177/2325967120966310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905078PMC
December 2020

Pre-existing Immunity to Japanese Encephalitis Virus Alters CD4 T Cell Responses to Zika Virus Inactivated Vaccine.

Front Immunol 2021 24;12:640190. Epub 2021 Feb 24.

Cellular Immunology Section, US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States.

The epidemic spread of Zika virus (ZIKV), associated with devastating neurologic syndromes, has driven the development of multiple ZIKV vaccines candidates. An effective vaccine should induce ZIKV-specific T cell responses, which are shown to improve the establishment of humoral immunity and contribute to viral clearance. Here we investigated how previous immunization against Japanese encephalitis virus (JEV) and yellow fever virus (YFV) influences T cell responses elicited by a Zika purified-inactivated virus (ZPIV) vaccine. We demonstrate that three doses of ZPIV vaccine elicited robust CD4 T cell responses to ZIKV structural proteins, while ZIKV-specific CD4 T cells in pre-immunized individuals with JEV vaccine, but not YFV vaccine, were more durable and directed predominantly toward conserved epitopes, which elicited Th1 and Th2 cytokine production. In addition, T cell receptor repertoire analysis revealed preferential expansion of cross-reactive clonotypes between JEV and ZIKV, suggesting that pre-existing immunity against JEV may prime the establishment of stronger CD4 T cell responses to ZPIV vaccination. These CD4 T cell responses correlated with titers of ZIKV-neutralizing antibodies in the JEV pre-vaccinated group, but not in flavivirus-naïve or YFV pre-vaccinated individuals, suggesting a stronger contribution of CD4 T cells in the generation of neutralizing antibodies in the context of JEV-ZIKV cross-reactivity.
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http://dx.doi.org/10.3389/fimmu.2021.640190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943459PMC
February 2021

Chronic Adaptations of the Posterior Rotator Cuff in Professional Pitchers.

Am J Sports Med 2021 03 16;49(4):892-898. Epub 2021 Feb 16.

Rothman Orthopaedic Institute, Bryn Mawr, Pennsylvania, USA.

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 ( = .016, = 0.287 and = .009, = 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 ( = -0.477, = .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.
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http://dx.doi.org/10.1177/0363546520988688DOI Listing
March 2021

Cefiderocol: a novel siderophore cephalosporin for multidrug-resistant Gram-negative bacterial infections.

J Antimicrob Chemother 2021 05;76(6):1379-1391

State University of New York Upstate University Hospital, Syracuse, NY, USA.

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.
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http://dx.doi.org/10.1093/jac/dkab015DOI Listing
May 2021

Temporally integrated single cell RNA sequencing analysis of PBMC from experimental and natural primary human DENV-1 infections.

PLoS Pathog 2021 01 29;17(1):e1009240. Epub 2021 Jan 29.

Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.

Dengue human infection studies present an opportunity to address many longstanding questions in the field of flavivirus biology. However, limited data are available on how the immunological and transcriptional response elicited by an attenuated challenge virus compares to that associated with a wild-type DENV infection. To determine the kinetic transcriptional signature associated with experimental primary DENV-1 infection and to assess how closely this profile correlates with the transcriptional signature accompanying natural primary DENV-1 infection, we utilized scRNAseq to analyze PBMC from individuals enrolled in a DENV-1 human challenge study and from individuals experiencing a natural primary DENV-1 infection. While both experimental and natural primary DENV-1 infection resulted in overlapping patterns of inflammatory gene upregulation, natural primary DENV-1 infection was accompanied with a more pronounced suppression in gene products associated with protein translation and mitochondrial function, principally in monocytes. This suggests that the immune response elicited by experimental and natural primary DENV infection are similar, but that natural primary DENV-1 infection has a more pronounced impact on basic cellular processes to induce a multi-layered anti-viral state.
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http://dx.doi.org/10.1371/journal.ppat.1009240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875406PMC
January 2021

Assessment of U.S. health care personnel (HCP) attitudes towards COVID-19 vaccination in a large university health care system.

Clin Infect Dis 2021 Jan 25. Epub 2021 Jan 25.

Department of Public Health and Preventive Medicine, SUNY Upstate Medical University, Syracuse, NY.

Background: As a priority group, healthcare personnel (HCP) will be key to success of COVID-19 vaccination programs. The purpose of this study was to assess HCP willingness to get vaccinated and identify specific concerns that would undermine vaccination efforts.

Methods: We conducted a cross-sectional survey of HCP, including clinical and non-clinical staff, researchers, and trainees between November 23 rd ,2020 and December 5 th ,2020. The survey evaluated attitudes, beliefs and willingness to get vaccinated.

Results: A total of 5287 respondents had a mean age of 42.5 years (SD=13.56), and were 72.8% 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<.001). Respondents who were older, males, White, or Asian were more likely to get vaccinated compared to other groups. Vaccine safety, potential adverse events, efficacy and speed of vaccine development dominated concerns listed by participants. Fewer (54.0%) providers of direct care vs. non-care providers (62.4%), and 52.0% of those who had provided care for COVID-19 patients (vs. 60.6% of those who had not) indicated they would take the vaccine if offered (p<.001).

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.
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http://dx.doi.org/10.1093/cid/ciab054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929026PMC
January 2021

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine.

N Engl J Med 2020 12 10;383(27):2603-2615. Epub 2020 Dec 10.

From Fundacion INFANT (F.P.P.) and iTrials-Hospital Militar Central (G.P.M.), Buenos Aires; State University of New York, Upstate Medical University, Syracuse (S.J.T.), and Vaccine Research and Development, Pfizer, Pearl River (J.A., A.G., K.A.S., K.K., W.V.K., D.C., P.R.D., K.U.J., W.C.G.) - both in New York; Vaccine Research and Development, Pfizer, Hurley, United Kingdom (N.K., S.L., R.B.); Vaccine Research and Development (J.L.P., P.L.) and Worldwide Safety, Safety Surveillance and Risk Management (S.M.), Pfizer, Collegeville, PA; Associação Obras Sociais Irmã Dulce and Oswaldo Cruz Foundation, Bahia (E.D.M.), and Centro Paulista de Investigação Clinica, São Paulo (C.Z.) - both in Brazil; Global Product Development, Pfizer, Peapack, NJ (S.R.); Cincinnati Children's Hospital, Cincinnati (R.W.F.); Johns Hopkins Bloomberg School of Public Health, Baltimore (L.L.H.); BioNTech, Mainz (ÖT., U.Ş.), and Medizentrum Essen Borbeck, Essen (A.S.) - both in Germany; Tiervlei Trial Centre, Karl Bremer Hospital, Cape Town, South Africa (H.N.); Hacettepe University, Ankara, Turkey (S.Ü.); and Worldwide Safety, Safety Surveillance and Risk Management, Pfizer, Groton, CT (D.B.T.).

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently.

Methods: In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 μg per dose). BNT162b2 is a lipid nanoparticle-formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary end points were efficacy of the vaccine against laboratory-confirmed Covid-19 and safety.

Results: A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups.

Conclusions: A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.).
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http://dx.doi.org/10.1056/NEJMoa2034577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745181PMC
December 2020

Changes in clinical measures and tissue adaptations in collegiate swimmers across a competitive season.

J Shoulder Elbow Surg 2020 Nov 9;29(11):2375-2384. Epub 2020 Jun 9.

Department of Health and Rehabilitation Sciences, Temple University, Philadelphia, PA, USA.

Background: Competitive swimmers incur shoulder pain and injury. Physical characteristics such as shoulder range of motion (ROM) and endurance and tissue adaptations such as posterior capsule thickness (PCT) may be risk factors in addition to high training volume.

Hypothesis/purpose: 1) To identify the most provocative special test and prevalence of positive special tests for shoulder impingement tests in a group of collegiate swimmers, (2) to assess shoulder pain and disability, internal rotation (IR) and external rotation, and horizontal adduction (HADD) ROM and posterior shoulder endurance longitudinally over a competitive collegiate season, and (3) determine if there is a relationship between swimming yardage, supraspinatus tendon organization, and PCT.

Methods: Thirty Division III swimmers were tested poolside at the beginning (T1), middle (T2), and end (T3) of their season. Dependent variables included pain and disability, shoulder ROM, Posterior Shoulder Endurance Test (PSET) value, and PCT. Analyses of variance with follow-up t tests compared measures over time, and Pearson correlation coefficients were performed.

Results: Despite increased swimming yardage, disability was reduced from T1 to T3 (P = .003). There was a reduction in bilateral IR and HADD ROM from T1 to T3. PSET values increased on the right from T1 to T3 (P = .014). There was a significant positive correlation between swimming yardage at T1 and T2 and PCT at T3 (P = .034, P = .028).

Conclusion: A loss of shoulder IR and HADD was observed across the season concurrent with less swimming-related disability, which may indicate a favorable adaptation. Improved PSET scores over the season is consistent with prior research linking endurance and less pain and disability.
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http://dx.doi.org/10.1016/j.jse.2020.03.028DOI Listing
November 2020

Immunogenicity of a Live-Attenuated Dengue Vaccine Using a Heterologous Prime-Boost Strategy in a Phase 1 Randomized Clinical Trial.

J Infect Dis 2021 May;223(10):1707-1716

Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.

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.
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http://dx.doi.org/10.1093/infdis/jiaa603DOI Listing
May 2021

Zika vaccine pre-clinical and clinical data review with perspectives on the future development.

Hum Vaccin Immunother 2020 10 23;16(10):2524-2536. Epub 2020 Jul 23.

Department of Pathology and Sealy Institute for Vaccine Sciences, University of Texas Medical Branch , Galveston, TX, USA.

Zika is an arboviral illness caused by infection with the Zika flavivirus. Transmission most commonly occurs during a feeding event involving an infected 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.
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http://dx.doi.org/10.1080/21645515.2020.1730657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644220PMC
October 2020

Social Distancing Metrics and Estimates of SARS-CoV-2 Transmission Rates: Associations Between Mobile Telephone Data Tracking and R.

J Public Health Manag Pract 2020 Nov/Dec;26(6):606-612

Department of Public Health & Preventive Medicine (Drs Morley, Shaw, Stewart, and Wang), Department of Family Medicine (Dr Morley), Department of Psychiatry & Behavioral Sciences (Dr Morley), Department of Medicine (Drs Anderson and Thomas), Institute for Global Health & Translational Science (Drs Anderson and Thomas), Department of Microbiology and Immunology (Drs Anderson and Thomas), Department of Pediatrics, Division of Pediatric Infectious Disease (Dr Shaw), Department of Urology (Dr Stewart), and Department of Geriatrics (Dr Stewart), SUNY Upstate Medical University, Syracuse, New York.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). In the absence of robust preventive or curative strategies, the implementation of social distancing has been a key component of limiting the spread of the virus.

Methods: Daily estimates of R(t) were calculated and compared with measures of social distancing made publicly available by Unacast. Daily generated variables representing an overall grade for distancing, changes in distances traveled, encounters between individuals, and daily visitation, were modeled as predictors of average R value for the following week, using linear regression techniques for 8 counties surrounding the city of Syracuse, New York. Supplementary analysis examined differences between counties.

Results: A total of 225 observations were available across the 8 counties, with 166 meeting the mean R(t) < 3 outlier criterion for the regression models. Measurements for distance (β = 1.002, P = .012), visitation (β = .887, P = .017), and encounters (β = 1.070, P = .001) were each predictors of R(t) for the following week. Mean R(t) drops when overall distancing grades move from D+ to C-. These trends were significant (P < .001 for each).

Conclusions: Social distancing, when assessed by free and publicly available measures such as those shared by Unacast, has an impact on viral transmission rates. The scorecard may also be useful for public messaging about social distance, in hospital planning, and in the interpretation of epidemiological models.
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http://dx.doi.org/10.1097/PHH.0000000000001240DOI Listing
October 2020

Safety and immunogenicity of a Zika purified inactivated virus vaccine given via standard, accelerated, or shortened schedules: a single-centre, double-blind, sequential-group, randomised, placebo-controlled, phase 1 trial.

Lancet Infect Dis 2020 09 6;20(9):1061-1070. Epub 2020 May 6.

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. Electronic address:

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 [MN] ≥100) and geometric mean MN 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.
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http://dx.doi.org/10.1016/S1473-3099(20)30085-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472641PMC
September 2020

Biosafety at Home: How to Translate Biomedical Laboratory Safety Precautions for Everyday Use in the Context of COVID-19.

Am J Trop Med Hyg 2020 08 26;103(2):838-840. Epub 2020 Jun 26.

Medical Entomology and Tropical Medicine Laboratory LEMMT, School of Biological and Environmental Sciences, Universidad San Francisco de Quito, Quito, Ecuador.

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.
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http://dx.doi.org/10.4269/ajtmh.20-0677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410461PMC
August 2020

A Phase 1, Open-Label Assessment of a Dengue Virus-1 Live Virus Human Challenge Strain.

J Infect Dis 2021 02;223(2):258-267

Institute for Global Health and Translational Science, Department of Microbiology and Immunology, and Department of Public Health and Preventive Medicine, State University of New York, Upstate Medical University, Syracuse, New York, USA.

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.
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http://dx.doi.org/10.1093/infdis/jiaa351DOI Listing
February 2021

Clinical management of tendinopathy: A systematic review of systematic reviews evaluating the effectiveness of tendinopathy treatments.

Scand J Med Sci Sports 2020 Oct 18;30(10):1810-1826. Epub 2020 Jun 18.

School of Health and Kinesiology, University of Nebraska at Omaha, Omaha, Nebraska, USA.

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.
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http://dx.doi.org/10.1111/sms.13734DOI Listing
October 2020

Safety and Immunogenicity of an AS03-Adjuvanted Inactivated Tetravalent Dengue Virus Vaccine Administered on Varying Schedules to Healthy U.S. Adults: A Phase 1/2 Randomized Study.

Am J Trop Med Hyg 2020 07 23;103(1):132-141. Epub 2020 Apr 23.

GSK, Rockville, Maryland.

Dengue disease and its causative agents, the dengue viruses (DENV-1-4), cause high morbidity in tropical and subtropical regions. We evaluated three dosing regimens of the investigational tetravalent AS03-adjuvanted dengue-purified inactivated vaccine (DPIV+AS03). In this phase 1/2, observer-blind, placebo-controlled study (NCT02421367), 140 healthy adults were randomized 1:1:2 to receive DPIV+AS03 according to the following regimens: 0-1 month (M), 0-1-6 M, or 0-3 M. Participants received DPIV+AS03 or placebo at M0, M1, M3, and M6 according to their dosing schedule. Primary objectives were 1) to evaluate the safety of DPIV+AS03 for 28 days (D) after each dose; 2) to demonstrate the added value of a booster dose (0-1-6 M versus 0-1 M) based on neutralizing antibody titers to each DENV type (DENV-1-4) at 28 D after the last dose; and, if this objective was met, 3) to demonstrate the benefit of a longer interval between the first and second doses (0-1 M versus 0-3 M). Adverse events (AEs) within 7 D after vaccination tended to be more frequent after DPIV+AS03 doses than placebo; the number of grade 3 AEs was low (≤ 4.5% after DPIV+AS03; ≤ 2.9% after placebo), with no obvious differences across groups. Within 28 D following each dose, the frequency of unsolicited AEs after DPIV+AS03 appeared higher for three-dose (0-1-6 M) than two-dose (0-1 M and 0-3 M) regimens. No serious AEs were considered related to vaccination, and no potential immune-mediated diseases were reported during the study. All three schedules were well tolerated. Both primary immunogenicity objectives were demonstrated. The 0-3 M and 0-1-6 M regimens were more immunogenic than the 0-1 M regimen.
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http://dx.doi.org/10.4269/ajtmh.19-0738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356407PMC
July 2020

Does humeral torsion play a role in shoulder and elbow injury profiles of overhead athletes: a systematic review.

J Shoulder Elbow Surg 2020 Aug 20;29(8):1712-1725. Epub 2020 Apr 20.

Department of Health & Human Performance, Texas State University, San Marcos, TX, USA.

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.
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http://dx.doi.org/10.1016/j.jse.2020.01.080DOI Listing
August 2020

Transcriptional and clonal characterization of B cell plasmablast diversity following primary and secondary natural DENV infection.

EBioMedicine 2020 Apr 18;54:102733. Epub 2020 Apr 18.

Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United States.

Antibody-mediated humoral immunity is thought to play a central role in mediating the immunopathogenesis of acute DENV infection, but limited data are available on the diversity, specificity, and functionality of the antibody response at the molecular level elicited by primary or secondary DENV infection. In order to close this functional gap in our understanding of DENV-specific humoral immunity, we utilized high-throughput single cell RNA sequencing to investigate B cells circulating in both primary and secondary natural DENV infections. We captured full-length paired immunoglobulin receptor sequence data from 9,027 B cells from a total of 6 subjects, including 2,717 plasmablasts. In addition to IgG and IgM class-switched cells, we unexpectedly found a high proportion of the DENV-elicited plasmablasts expressing IgA, principally in individuals with primary DENV infections. These IgA class-switched cells were extensively hypermutated even in individuals with a serologically confirmed primary DENV infection. Utilizing a combination of conventional biochemical assays and high-throughput shotgun mutagenesis, we determined that DENV-reactive IgA class-switched antibodies represent a significant fraction of DENV-reactive Igs generated in response to DENV infection, and that they exhibit a comparable epitope specificity to DENV-reactive IgG antibodies. These results provide insight into the molecular-level diversity of DENV-elicited humoral immunity and identify a heretofore unappreciated IgA plasmablast response to DENV infection.
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http://dx.doi.org/10.1016/j.ebiom.2020.102733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170960PMC
April 2020

When Can One Vaccinate with a Live Vaccine after Wild-Type Dengue Infection?

Vaccines (Basel) 2020 Apr 9;8(2). Epub 2020 Apr 9.

Institute for Global Health and Translational Sciences, Upstate Medical University, State University of New York, Syracuse, NY 13210, USA.

Recommendations have been issued for vaccinating with the Sanofi Pasteur tetravalent dengue vaccine (CYD-TDV, Dengvaxia) individuals aged from 9 to 45/60 years old with a prior dengue virus (DENV) infection and living in endemic countries/areas. One question linked to these recommendations is to determine when it is possible to start vaccination after laboratory confirmed wild-type DENV infection, and this question can be relevant to any live vaccine to be used in endemic areas. To address it, we reviewed and discussed the immunological and practical considerations of live vaccination in this context. Firstly, the nature and kinetics of immune responses triggered by primary or secondary DENV infection may positively or negatively impact subsequent live vaccine take and associated clinical benefit, depending on when vaccination is performed after infection. Secondly, regarding practical aspects, the "easiest" situation would correspond to a confirmed acute dengue fever, only requiring knowing when the patient should come back for vaccination. However, in most cases, it will not be possible to firmly establish the actual date of infection and vaccination may have to take place during well-defined periods, regardless of when prior infection occurred. Evidence that informs health authorities and medical practitioners in formulating vaccine policies and implementing vaccine programs is thus needed. The present work reviewed the different elements of the guidance and proposes some key conclusions and recommendations.
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http://dx.doi.org/10.3390/vaccines8020174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349415PMC
April 2020

Route of inoculation and mosquito vector exposure modulate dengue virus replication kinetics and immune responses in rhesus macaques.

PLoS Negl Trop Dis 2020 04 8;14(4):e0008191. Epub 2020 Apr 8.

GSK Vaccines, Rixensart, Belgium.

Dengue virus (DENV) is transmitted by infectious mosquitoes during blood-feeding via saliva containing biologically-active proteins. Here, we examined the effect of varying DENV infection modality in rhesus macaques in order to improve the DENV nonhuman primate (NHP) challenge model. NHPs were exposed to DENV-1 via subcutaneous or intradermal inoculation of virus only, intradermal inoculation of virus and salivary gland extract, or infectious mosquito feeding. The infectious mosquito feeding group exhibited delayed onset of viremia, greater viral loads, and altered clinical and immune responses compared to other groups. After 15 months, NHPs in the subcutaneous and infectious mosquito feeding groups were re-exposed to either DENV-1 or DENV-2. Viral replication and neutralizing antibody following homologous challenge were suggestive of sterilizing immunity, whereas heterologous challenge resulted in productive, yet reduced, DENV-2 replication and boosted neutralizing antibody. These results show that a more transmission-relevant exposure modality resulted in viral replication closer to that observed in humans.
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http://dx.doi.org/10.1371/journal.pntd.0008191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141610PMC
April 2020

Determining the Impact of the Opioid Crisis on a Tertiary-Care Hospital in Central New York to Identify Critical Areas of Intervention in the Local Community.

J Addict 2020 12;2020:3956187. Epub 2020 Mar 12.

Departments of Medicine, Pathology, Public Health and Microbiology and Immunology, State University of New York, Upstate Medical University, Syracuse, USA.

Background: Central New York has been afflicted by the heroin epidemic with an increase in overdose deaths involving opioids.

Objective: The objective of the study was to understand the epidemiology of hospitalizations related to a diagnosis of opioid use (OU).

Design: The study was designed as a retrospective analysis of hospitalized patients admitted from January 1, 2008, to December 30, 2018, using ICD-9 and 10 codes for heroin or opiate use, overdose, or poisoning. . The study was conducted in a tertiary-care and teaching hospital located in Central New York. . Hospitalized patients were included as study participants.

Results: Opioid use-related admissions increased from .05/100 hospital admissions in 2008 to a peak of 2.9/100 in 2018, a 58-fold increase. There were 49 deaths over the 11-year period for an overall case fatality of 1.2 per 100 OU admissions. The median age for all years was 40 years (SD of 13.7 years), and admissions were largely white caucasians (67.0% of all admissions). The mean length of stay was 8.55 days (SD 12 days), with a range of 1 to 153 days. The most frequent discharge diagnosis was due to infections (15.0% of discharge diagnoses) followed by trauma (5.8% of discharge diagnoses). Methicillin-resistant was more common in patients with OU (58.1%) than in patients with non-OU (43%) ( < 0.0001 by chi-square with Yates' correction). Spatial analysis was performed by zip code and demonstrated regional hotspots for OU-related admissions. . The limitations of this study are its retrospective nature and largely numerator-based analysis. The use of ICD codes underrepresents the true burden due to underreporting and failure to code appropriately. This study focuses on patients who are hospitalized for a medical reason with a secondary diagnosis of opioid use and does not include patients who present to the emergency room with an overdose underrepresenting the true burden of the problem.

Conclusions: Our results demonstrate the impact of the opioid epidemic in one tertiary-care center and the need to prepare for the costs and resources to address addiction care for this population.
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http://dx.doi.org/10.1155/2020/3956187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7091543PMC
March 2020

Safety and Immunogenicity of Different Formulations of a Tetravalent Dengue Purified Inactivated Vaccine in Healthy Adults from Puerto Rico: Final Results after 3 Years of Follow-Up from a Randomized, Placebo-Controlled Phase I Study.

Am J Trop Med Hyg 2020 05;102(5):951-954

Walter Reed Army Institute of Research, Silver Spring, Maryland.

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, AS01 or AS03, 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+AS03). 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+AS03: 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.
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http://dx.doi.org/10.4269/ajtmh.19-0461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204593PMC
May 2020
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