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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Emerging and re-emerging infectious diseases are an expanding global threat to public health, security, and economies. Increasing populations, urbanization, deforestation, climate change, anti-vaccination movements, war, and international travel are some of the contributing factors to this trend. The recent Ebola, MERS-CoV, and Zika outbreaks demonstrated we are insufficiently prepared to respond with proven safe and effective countermeasures (i.e., vaccines and therapeutics). The State University of New York Upstate Medical University and the Trudeau Institute convened a summit of key opinion and thought leaders in the life sciences and biomedical research and development enterprises to explore global biopreparedness challenges, take an inventory of existing capabilities and capacities related to preparation and response, assess current "gaps," and prospect what could be done to improve our position. Herein we describe the summit proceedings, "Translational Immunology Supporting Biomedical Countermeasure Development for Emerging Vector-borne Viral Diseases," held October 2-3, 2018, at the Trudeau Institute in Saranac Lake, NY.

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

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.

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.

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.)

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.

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., Author summary Dengue Human Challenge Models allow for the analysis of host/virus interactions under highly controlled experimental conditions. However, it is unclear how close the immune response generated by an attenuated challenge virus compares to that generated by a naturally acquired DENV infection. In this study, we utilized single cell RNA sequencing to assess the immune response generated by both experimental and natural primary DENV-1 infections. This analysis suggests that the immune response elicited by experiential and natural primary DENV-1 infections are similar, but that natural DENV-1 infection has a more pronounced impact on basic cellular processes to induce a multi-layered anti-viral state.

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.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.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.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.).

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 (s = 1.002, P = .012), visitation (s = .887, P = .017), and encounters (s = 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.

BACKGROUND: Suboptimal sleep, including insufficient/long sleep duration and poor sleep quality, is a risk factor for cardiovascular disease (CVD) common but there is little information among African Americans, a group with a disproportionate CVD burden. The current study examined the association between suboptimal sleep and incident CVD among African Americans. METHODS: This study included 4,522 African Americans without CVD at baseline (2000–2004) of the Jackson Heart Study (JHS). Self-reported sleep duration was defined as very short (

Recommendations have been issued for vaccinating with the Sanofi Pasteur tetravalent dengue vaccine (CYD-TDV, Dengvaxia&reg, ) 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 &ldquo, easiest&rdquo, 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.

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., Author summary Dengue virus is transmitted into the skin of humans by mosquitoes as they take a blood meal. In contrast, many animal models are infected in the laboratory using a syringe to inject below the skin. Here, we looked at how different routes and methods of infection altered dengue infection in rhesus macaques. We found that infection via mosquito feeding resulted in a number of changes compared to other routes and methods, including a delay in the time to detection of dengue virus and overall greater quantities of dengue virus in the blood, and changes in the amounts of various components of blood that have been associated with dengue disease in humans. After 15 months, we exposed the macaques again to either the same or a different type of dengue virus. We found that animals exposed to the same type of dengue virus were protected from infection, whereas those animals exposed to a different type were only partially protected. Overall, our results show that dengue virus delivery using the natural transmission vector, mosquitoes, results in infection that is closer to what is observed in humans and may influence the interpretation of future studies of candidate vaccines.

Background Baseball pitching places tremendous forces on the arm, which may lead to structural tissue adaptations that are represented by changes in rotational range of motion (ROM). These adaptations often include both bony and soft tissue; however, the contribution of each tissue to the change in motion is not always clinically attainable. The purposes of this study were to determine the adaptations of ROM, bone, and soft tissue bilaterally and to examine the correlation between clinical ROM and humeral retroversion (HR)–corrected ROM. We hypothesized that glenohumeral internal rotation (IR) and total motion would be decreased and glenohumeral external rotation (ER), posterior capsule thickness (PCT), and HR would be increased in the dominant arm; that HR-corrected ROM would be significantly different than clinical ROM; and that HR-corrected ROM would be correlated with total motion difference. Methods Thirty professional baseball pitchers participated in this study. HR, PCT, and glenohumeral IR and ER were evaluated in the dominant and nondominant shoulders of each subject. Results The dominant arm exhibited significantly more retroversion, ER, and PCT than the nondominant arm. The dominant arm also had significantly less IR and total motion than the nondominant arm. The total ROM difference was significantly correlated with both HR-corrected glenohumeral IR deficit and ER gain. Conclusion HR-corrected glenohumeral IR deficit and ER gain may more accurately reflect the contribution of soft-tissue changes to ROM. Unfortunately, measurement of HR is not always clinically attainable, making clinical management difficult.

Licensing and decisions on public health use of a vaccine rely on a robust clinical development program that permits a risk-benefit assessment of the product in the target population. Studies undertaken early in clinical development, as well as well-designed pivotal trials, allow for this robust characterization. In 2012, WHO published guidelines on the quality, safety and efficacy of live attenuated dengue tetravalent vaccines. Subsequently, efficacy and longer-term follow-up data have become available from two Phase 3 trials of a dengue vaccine, conducted in parallel, and the vaccine was licensed in December 2015. The findings and interpretation of the results from these trials released both before and after licensure have highlighted key complexities for tetravalent dengue vaccines, including concerns vaccination could increase the incidence of dengue disease in certain subpopulations. This report summarizes clinical and regulatory points for consideration that may guide vaccine developers on some aspects of trial design and facilitate regulatory review to enable broader public health recommendations for second-generation dengue vaccines. Published version

The dengue virus (DENV) vaccines that are licensed or in clinical development consist of DENV serotype 1-4 tetravalent formulations given simultaneously and are not acquired sequentially like natural infections. It is unclear what effect this has on development of protective levels of immunity to all four serotypes. Serotype-specific neutralizing antibody (NAb) is considered the most relevant correlate of protection from dengue disease. Here we assessed levels of serotype-specific and cross-reactive NAb in immune sera from 10 subjects vaccinated with a live attenuated tetravalent DENV vaccine developed at the Walter Reed Army Institute of Research. The majority of subjects NAb responses to DENV-2 and DENV-4 were type-specific, while their NAb responses to DENV-1 and DENV-3 were primarily cross-reactive. Vaccine virus RNAemia has been most frequently detected for DENV-2 and DENV-4 in vaccinated subjects, strongly suggesting that replication is important for eliciting serotype-specific immunity.

Objective We determined differences in the prevalence of blood pressure (BP) phenotypes and the association of these phenotypes with left ventricular hypertrophy (LVH) for individuals who fulfilled and did not fulfill various criteria used for defining a complete ambulatory blood pressure monitoring (ABPM) recording. Methods We analyzed data for 1141 participants from the Jackson Heart Study. Criteria evaluated included having greater than or equal to 80% of planned readings with more than or equal to one reading per hour (Spanish ABPM Registry criteria), more than or equal to 70% of planned readings with a minimum of 20 daytime and seven nighttime readings (2013 European Society of Hypertension criteria), greater than or equal to 14 daytime and greater than or equal to seven nighttime readings (2003 European Society of Hypertension criteria), more than or equal to 10 daytime and more than or equal to 5 nighttime readings (International Database of Ambulatory Blood Pressure in Relation to Cardiovascular Outcome criteria), and greater than or equal to 14 daytime readings (UK National Institute of Health and Clinical Excellence criteria). Results Between 45.0% (Spanish ABPM Registry) and 91.8% (UK National Institute of Health and Clinical Excellence) of the participants fulfilled the different criteria for a complete ABPM recording. Across the various criteria evaluated, 55.5-57.8% of participants had nocturnal hypertension and 62.8-66.8% had nondipping systolic BP. Among participants with clinic-measured systolic/diastolic BP of more than or equal to 140/90 mmHg, 22.9-26.5% had white-coat hypertension. The prevalence of daytime, 24-h, sustained, and masked hypertension differed by up to 2% for participants fulfilling each criterion. The association of BP phenotypes with LVH was similar for participants who fulfilled versus those who did not fulfill different criteria (each P>0.05). Conclusion Irrespective of the criteria used for defining a complete ABPM recording, the prevalence of BP phenotypes and their association with LVH were similar.

A rotator cuff tear is a common injury in athletes and workers who repeatedly perform overhead movements, and it is not uncommon for this demographic to return to activity shortly after treatment. A biceps tenotomy is often performed in the presence of a rotator cuff tear to help reduce pain and improve joint function. However, the effect of this procedure on the surrounding tissues in the glenohumeral joint is unknown. Therefore, the purpose of this study was to investigate the effect of a biceps tenotomy in the presence of a supraspinatus rotator cuff tear followed by overuse activity on ambulatory function and mechanical and histologic properties of the remaining rotator cuff tendons and glenoid cartilage. 46 rats underwent 4weeks of overuse activity to create a tendinopathic condition, then were randomized into two groups: unilateral detachment of the supraspinatus tendon or detachment of the supraspinatus and long head of the biceps tendons. Ambulatory measurements were performed throughout the 8weeks prior to euthanasia, followed by analysis of the properties of the remaining intact tendons and glenoid cartilage. Results demonstrate that shoulder function was not effected in the biceps tenotomy group. However, the intact tendons and glenoid cartilage showed altered mechanical and histologic properties. This study provides evidence from an animal model that does not support the use of tenotomy in the presence of a supraspinatus tendon rotator cuff tear, and provides a framework for physicians to better prescribe long-term treatment strategies for patients.

The safety and immunogenicity of four formulations of an investigational tetravalent dengue purified inactivated vaccine (DPIV), formulated at 1 or 4 μg with aluminum hydroxide (alum) or at 1 μg with an adjuvant system (AS01E or AS03B), were evaluated in a first-time-in-human, placebo-controlled, randomized, observer-blind, phase 1 trial in the continental United States. Two doses of vaccine or placebo were administered intramuscularly 4 weeks apart to 100 healthy adults 18-39 years of age, randomized 1:1:1:1:1 to receive one of four DPIV formulations or saline placebo. The response to a third dose was evaluated in a subset of nine participants remote from primary vaccination. Humoral immunogenicity was assessed using a 50% microneutralization assay. All DPIV formulations were well tolerated. No vaccine-related serious adverse events were observed through 12 months after the second vaccine dose. In all DPIV groups, geometric mean antibody titers peaked at Day 56, waned through 6 months after the second vaccine dose, and then stabilized. In the nine subjects where boosting was evaluated, a strong anamnestic response was observed. These results support continuation of the clinical development of this dengue vaccine candidate (clinicaltrials.gov: NCT01666652).

Two studies of messenger RNA Zika virus vaccines show that they protect against infection in animal models.

The Thai research study presented here was funded by an R01 award from the National Institutes of Health (PI: TE, GM83224-01A1). This Ecuadorian research study was supported, in part, by the Department of Defense Global Emerging Infection Surveillance (GEIS) grant (P0220_13_OT) and the Department of Medicine of SUNY Upstate Medical University. AS-I and SR were additionally supported by NSF DEB EEID 1518681 and NSF DEB RAPID 1641145. Dengue viruses (DENV) pose a significant and increasing threat to human health across broad regions of the globe. Currently, prevention, control, and treatment strategies are limited. Promising interventions are on the horizon, including multiple vaccine candidates under development and a renewed and innovative focus on controlling the vector, Aedes aegypti. However, significant gaps persist in our understanding of the similarities and differences in DENV epidemiology across regions of potential implementation and evaluation. In this manuscript, we highlight and compare findings from two analogous cluster-based studies for DENV transmission and pathogenesis conducted in Thailand and Ecuador to identify key features and questions for further pursuit. Despite a remarkably similar incidence of DENV infection among enrolled neighborhood contacts at the two sites, we note a higher occurrence of secondary infection and severe illness in Thailand compared to Ecuador. A higher force of infection in Thailand, defined as the incidence of infection among susceptible individuals, is suggested by the higher number of captured Aedes mosquitoes per household, the increasing proportion of asymptomatic infections with advancing age, and the high proportion of infections identified as secondary-type infections by serology. These observations should be confirmed in long-term, parallel prospective cohort studies conducted across regions, which would advantageously permit characterization of baseline immune status (susceptibility) and contemporaneous assessment of risks and risk factors for dengue illness. Publisher PDF

Dengue is a tropical disease transmitted by mosquitoes, and nearly half of the world’s population lives in areas where individuals are at risk of infection. Several vaccines for dengue are in development, including one which was recently licensed in several countries, although its utility is limited to people who have already been infected with one of the four dengue viruses. One major hurdle to understanding whether a dengue vaccine will work for everyone—before exposure—is the necessity of knowing which marker can be measured in the blood to signal that the individual has protective immunity. This report describes an approach measuring multiple different parts of immunity in order to characterize which signals one candidate vaccine imparted to a small number of human volunteers. This approach was designed to be able to be applied to any dengue vaccine study so that the data can be compared and used to inform future vaccine design and/or optimization strategies., Dengue is the most prevalent arboviral disease afflicting humans, and a vaccine appears to be the most rational means of control. Dengue vaccine development is in a critical phase, with the first vaccine licensed in some countries where dengue is endemic but demonstrating insufficient efficacy in immunologically naive populations. Since virus-neutralizing antibodies do not invariably correlate with vaccine efficacy, other markers that may predict protection, including cell-mediated immunity, are urgently needed. Previously, the Walter Reed Army Institute of Research developed a monovalent purified inactivated virus (PIV) vaccine candidate against dengue virus serotype 1 (DENV-1) adjuvanted with alum. The PIV vaccine was safe and immunogenic in a phase I dose escalation trial in healthy, flavivirus-naive adults in the United States. From that trial, peripheral blood mononuclear cells obtained at various time points pre- and postvaccination were used to measure DENV-1-specific T cell responses. After vaccination, a predominant CD4+ T cell-mediated response to peptide pools covering the DENV-1 structural proteins was observed. Over half (13/20) of the subjects produced interleukin-2 (IL-2) in response to DENV peptides, and the majority (17/20) demonstrated peptide-specific CD4+ T cell proliferation. In addition, analysis of postvaccination cell culture supernatants demonstrated an increased rate of production of cytokines, including gamma interferon (IFN-γ), IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Overall, the vaccine was found to have elicited DENV-specific CD4+ T cell responses as measured by enzyme-linked immunosorbent spot (ELISpot), intracellular cytokine staining (ICS), lymphocyte proliferation, and cytokine production assays. Thus, together with antibody readouts, the use of a multifaceted measurement of cell-mediated immune responses after vaccination is a useful strategy for more comprehensively characterizing immunity generated by dengue vaccines. IMPORTANCE Dengue is a tropical disease transmitted by mosquitoes, and nearly half of the world’s population lives in areas where individuals are at risk of infection. Several vaccines for dengue are in development, including one which was recently licensed in several countries, although its utility is limited to people who have already been infected with one of the four dengue viruses. One major hurdle to understanding whether a dengue vaccine will work for everyone—before exposure—is the necessity of knowing which marker can be measured in the blood to signal that the individual has protective immunity. This report describes an approach measuring multiple different parts of immunity in order to characterize which signals one candidate vaccine imparted to a small number of human volunteers. This approach was designed to be able to be applied to any dengue vaccine study so that the data can be compared and used to inform future vaccine design and/or optimization strategies.

ContextBaseball is played around the world, including in North America and Latin America. The repetitive and stressful act of throwing can lead to adaptations such as increased humeral retroversion (HR) in the throwing arm. This adaptation is often considered beneficial as it allows more glenohumeral external rotation during the cocking phase of pitching without soft tissue stretching. Therefore, it is speculated that throwing should be started at a young age to capitalize on this adaptation. Interestingly, athletes in different geographic regions of the world often begin organized baseball at different ages. However, range of motion (ROM), HR, and the starting age of baseball have never been examined based on geographic region.ObjectiveTo determine if ROM, HR, and the starting age of baseball players differed between professional baseball pitchers from North America and Latin America.DesignCross-sectional study.SettingClinical setting.Patients or Other ParticipantsThirty professional pitchers (North American = 19, Latin American = 11) with no current injury or surgery in the previous 6 months.Main Outcome Measure(s)Both ROM and HR were measured in the dominant and nondominant shoulder of each participant. The starting age for baseball was self-reported.ResultsThe Latin American group had more dominant-arm HR (8.7°; P = .034), more nondominant-arm external rotation (5.3°; P = .049), and a trend toward more nondominant-arm HR (6.5°; P = .058), yet they started playing baseball at a later age (by 3.7 years; P = .021) compared with the North American group.ConclusionsLatin American players had greater HR but started playing baseball at an older age. These findings contradict current thinking that HR would be more pronounced if baseball was started at a younger age. Additional research is required to better understand HR and the genetic, environmental, and nutritional factors that contribute to its development.

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. Setting. The study was conducted in a tertiary-care and teaching hospital located in Central New York. Patients. 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 Staphylococcus aureus was more common in patients with OU (58.1%) than in patients with non-OU (43%) (p<0.0001 by chi-square with Yates’ correction). Spatial analysis was performed by zip code and demonstrated regional hotspots for OU-related admissions. Limitations. 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.

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.

Background The World Health Organization recommends intradermal (ID) administration of rabies vaccine for preexposure prophylaxis. Methods In a randomized trial in adults assigned to 1 of 6 treatment groups (ID vs intramuscular [IM], 2 vs 3 doses, and controls), rabies neutralizing antibody titers were measured to 1 year postvaccination. Results ID vaccination produced acceptable antibody levels in all subjects (2- and 3-dose groups). At day 365, acceptable levels were 40% for IM and 50% for ID 2-dose schedule, and 70% for IM and 60% for ID 3-dose schedule. Conclusions ID rabies vaccination induces acceptable antibody titers at a fraction of the dose. Clinical Trials Registration NCT02374814.

Background Chloroquine can impair the immune responses to intradermal rabies vaccination. Current guidelines recommend an extra intramuscular dose be given for postexposure prophylaxis in previously unvaccinated persons taking any antimalarial drug. Methods We conducted a randomized, open-label, single-site study in 103 previously unvaccinated healthy adults age ≥18 to ≤60 years old to evaluate the effects of chloroquine, atovaquone/proguanil (Malarone), and doxycycline on the antibody response to a purified chick embryo cell vaccine, given on a postexposure prophylaxis schedule. All treatment groups received antimalarials 14 days prior to and during vaccination. Results All subjects achieved accepted neutralizing antibody titers of ≥0.5 IU/mL following the second rabies vaccination dose and maintained this protection through the duration of the study. We observed a reduction in rabies antibody geometric mean titer in the chloroquine versus control groups 28 days after vaccination: 2.3 versus 6.87 IU/mL, respectively (P < .001, t test). A significant difference was not observed for those taking Malarone or doxycycline. Conclusions We conclude that there is no reduction of rabies antibody response in subjects taking Malarone or doxycycline, but a significant reduction in those taking chloroquine; however, accepted antibody levels were achieved for all 3 antimalarials. Clinical Trials Registration NCT02564471.

Background Dengue is a global health problem requiring an effective, safe dengue vaccine. Methods We report the results of a phase II, randomized, open-label, single-center trial in adults aged 18 to 45 years in the United States designed to explore the effects of the Chimeric Yellow Fever Derived Tetravalent Dengue Vaccine (CYD-TDV, Dengvaxia) when administered on its designated schedule (months 0, 6, and 12) or on an accelerated dosing schedule (months 0, 2, and 6) and/or given before, or concomitantly with, a vaccine against Japanese encephalitis (JE). Results Based on dengue virus serotype-specific neutralizing antibody (NAb), the accelerated dosing schedule was comparable to the 0, 6, and 12-month schedule. Giving JE vaccine concurrently with CYD-TDV did not result in an increase in overall NAb titers. Immunophenotyping of peripheral blood mononuclear cells revealed an increase in activated CD8+ T cells after CYD-TDV vaccination, a phenomenon that was greatest for the JE vaccine primed. Conclusions We conclude that an accelerated dosing schedule of CYD-TDV results in essentially equivalent dengue serotype-specific NAb titers as the currently used schedule, and there may be an early benefit in antibody titers and activated CD8+ T cells by the administration of the JE vaccine before CYD-TDV vaccination.

Dengue virus infections have adversely impacted U.S. military operations since the Spanish-American War. The erosion of mission capabilities and lost duty days are underestimated. Appreciating the incidence and prevalence of dengue infections in U.S. military personnel is important to inform disease prevention strategies. Banked pre- and post-deployment serum samples from 1,000 U.S. military personnel with a single deployment to a dengue-endemic region were tested using a screening microneutralization assay to detect anti-dengue-virus-neutralizing antibodies. A total of 76 (7.6%) post-deployment samples were positive and 15 of the pre-deployment samples were negative. These figures represent an infection incidence of 1.5% and total of 17.6 seroconversions per 10,000 deployment months. These data represent a deploying military population with a relatively high background rate of dengue seropositivity, a low level of infection during deployment compared with background infection rates in the local populations, and the potential for worsening clinical attack rates with increased frequency of deployment. Additional studies are required to more clearly elucidate the dengue infection and disease risk in U.S. military personnel.

A recent unprecedented outbreak of Zika virus (ZIKV) in the Americas has been associated with microcephaly and other congenital malformations in infants as well as Guillain-Barre syndrome in adults. The development of a safe and effective ZIKV vaccine is therefore an urgent global health priority. Promising data from preclinical vaccine studies in mice and monkeys suggest that an effective vaccine will likely be possible, but important scientific challenges remain. Here we review the current state of ZIKV vaccine development. We discuss different vaccination strategies and, in the context of what has been learnt from other flavivirus vaccines, we highlight challenges facing clinical evaluation of ZIKV vaccine candidates.

The worst Ebola virus disease (EVD) outbreak in history has resulted in more than 28,000 cases and 11,000 deaths. We present the final results of two phase 1 trials of an attenuated, replication-competent, recombinant vesicular stomatitis virus (rVSV)-based vaccine candidate designed to prevent EVD.We conducted two phase 1, placebo-controlled, double-blind, dose-escalation trials of an rVSV-based vaccine candidate expressing the glycoprotein of a Zaire strain of Ebola virus (ZEBOV). A total of 39 adults at each site (78 participants in all) were consecutively enrolled into groups of 13. At each site, volunteers received one of three doses of the rVSV-ZEBOV vaccine (3 million plaque-forming units [PFU], 20 million PFU, or 100 million PFU) or placebo. Volunteers at one of the sites received a second dose at day 28. Safety and immunogenicity were assessed.The most common adverse events were injection-site pain, fatigue, myalgia, and headache. Transient rVSV viremia was noted in all the vaccine recipients after dose 1. The rates of adverse events and viremia were lower after the second dose than after the first dose. By day 28, all the vaccine recipients had seroconversion as assessed by an enzyme-linked immunosorbent assay (ELISA) against the glycoprotein of the ZEBOV-Kikwit strain. At day 28, geometric mean titers of antibodies against ZEBOV glycoprotein were higher in the groups that received 20 million PFU or 100 million PFU than in the group that received 3 million PFU, as assessed by ELISA and by pseudovirion neutralization assay. A second dose at 28 days after dose 1 significantly increased antibody titers at day 56, but the effect was diminished at 6 months.This Ebola vaccine candidate elicited anti-Ebola antibody responses. After vaccination, rVSV viremia occurred frequently but was transient. These results support further evaluation of the vaccine dose of 20 million PFU for preexposure prophylaxis and suggest that a second dose may boost antibody responses. (Funded by the National Institutes of Health and others; rVSV∆G-ZEBOV-GP ClinicalTrials.gov numbers, NCT02269423 and NCT02280408 .).

Background The natural time course for recovery of glenohumeral internal rotation (IR) loss after a throwing episode is unknown. In addition, the effect of the sleeper stretch on the time course for recovery of motion after a throwing episode has never been investigated. Therefore, the objectives of this study were to (1) to determine the natural time course for spontaneous recovery of IR after a throwing episode and (2) to evaluate the effect of the sleeper stretch on the time course for recovery of IR after a throwing episode. Methods The study participants were 17 male high school baseball pitchers (aged 17.7 ± 0.9 years). A crossover designed was used over a 2-week period. For week 1, glenohumeral IR and external rotation (ER) were evaluated in the dominant shoulder 1 day before a throwing episode and at 2 hours, 1 day, 2 days, 3 days, 4 days, and 5 days after pitching. During week 2, participants completed a sleeper stretch protocol before measurements. Results The natural time course of spontaneous recovery for IR after a throwing episode was 4 days. Stretching reduced the time course of recovery for IR to 2 days. Conclusion A sleeper stretch program for high school baseball pitchers can accelerate the recovery of commonly observed IR loss and also may mitigate the cumulative effects observed over the course of a season.

RANSTHORACIC ECHOCARDIOGRAPHY (TTE) is an important tool for evaluating and managing patients with worsening aortic stenosis. In almost every case, imaging is performed by a sonographer and interpreted by a cardiologist. It is rare for a patient’s cardiac pathology to be followed by an anesthesiology echocardiography team that performs and interprets the patient’s frequent TTE imaging and works as a team with the patient’s cardiologist. The authors describe a case of mild aortic stenosis discovered in a 70-year-old former cardiac anesthesiologist (T.S.) during a routine physical examination by his primary care physician (an internist/cardiologist). The aortic stenosis then was followed for 5 years by the anesthesia echocardiography team with frequent TTEs (ie, every 3-6 months) until the severity of the stenosis indicated valve replacement was required even though the patient’s symptoms were subtle and mild. Intraoperative echocardiography is an increasingly important tool, and it is now an accepted practice for anesthesiologists to perform transesophageal echocardiography (TEE) during surgery. While most anesthesia echocardiography is transesophageal, for those with sufficient skill and training, TTE can be put to good use in managing patients throughout the perioperative period, from the preoperative clinic through hospital discharge. 1 Although cardiologists usually follow patients with cardiac pathology that may require surgical correction, because of their skill and experience with TTE, some anesthesia echocardiography teams may be asked to assist in the followup imaging, management, and decisions these patients need to make about their subsequent surgical care.

Zika virus (ZIKV) is a flavivirus that is responsible for an unprecedented current epidemic in Brazil and the Americas1,2. ZIKV has been causally associated with fetal microcephaly, intrauterine growth restriction, and other birth defects in both humans3–8 and mice9–11. The rapid development of a safe and effective ZIKV vaccine is a global health priority1,2, but very little is currently known about ZIKV immunology and mechanisms of immune protection. Here we show that a single immunization of a plasmid DNA vaccine or a purified inactivated virus vaccine provides complete protection in susceptible mice against challenge with a ZIKV outbreak strain from northeast Brazil. This ZIKV strain has recently been shown to cross the placenta and to induce fetal microcephaly and other congenital malformations in mice11. We produced DNA vaccines expressing full-length ZIKV pre-membrane and envelope (prM-Env) as well as a series of deletion mutants. The full-length prM-Env DNA vaccine, but not the deletion mutants, afforded complete protection against ZIKV as measured by absence of detectable viremia following challenge, and protective efficacy correlated with Env-specific antibody titers. Adoptive transfer of purified IgG from vaccinated mice conferred passive protection, and CD4 and CD8 T lymphocyte depletion in vaccinated mice did not abrogate protective efficacy. These data demonstrate that protection against ZIKV challenge can be achieved by single-shot subunit and inactivated virus vaccines in mice and that Env-specific antibody titers represent key immunologic correlates of protection. Our findings suggest that the development of a ZIKV vaccine for humans will likely be readily achievable.

Background Sex differences may exist in cognitive faculties and neuromuscular strategies for maintaining joint stability. The purpose of this study was to assess whether preparatory and reactive knee stiffening strategies are affected differently in males and females exposed to sex-biased cognitive loads. Methods 20 male and 20 female volunteers were tested for knee joint stiffness and quadriceps and hamstring muscle activation patterns throughout a rapid eccentric knee extension perturbation. Participants were tested under 3 cognitive loads (Benton's Judgment of Line Orientation; Symbol Digit modalities Test; and Serial 7's) and a control condition. Apparent knee joint stiffness and muscle activation amplitude and timing were quantified throughout the perturbation across the 4 conditions. Findings Reactive knee stiffness values were significantly less during the cognitive tasks compared to the control condition (Judgment of Line Orientation = 0.034 Nm/deg/kg, Symbol Digit Modalities Test = 0.037 Nm/deg/kg, Serial 7's = 0.037 Nm/deg/kg, control = 0.048 Nm/deg/kg). Females had greater normalized total apparent stiffness than males. The quadriceps muscles had faster and greater activation than the hamstring muscles; however, no group differences were observed. No overall differences in muscle activation (magnitude and timing) were found between the cognitive loading tasks. Interpretation Cognitive loading may decrease the ability of healthy individuals to reactively stiffen their knee joint and appears to interfere with the normal stiffness regulation strategies. This may elucidate an extrinsic risk factor for non-contact knee ligament injury.

In 2014, the American Heart Association (AHA) announced the funding of a Strategically Focused Research Network (SFRN) focused on hypertension. Hypertension was chosen for a SFRN because interdisciplinary hypertension research has great potential to impact the AHA’s mission and 2020 goals of improving the cardiovascular health of all Americans by 20% while reducing deaths from cardiovascular disease (CVD) and stroke by 20% by 2020. Four centers with highly integrated basic, clinical, and population science projects were selected for the AHA SFRN: Cincinnati Children’s Hospital, Medical College of Wisconsin (MCW), University of Alabama at Birmingham (UAB), and University of Iowa (UI). The Cincinnati center is studying ambulatory blood pressure (BP) and hypertensive target organ damage in adolescents. The MCW center is studying epigenetics of hypertension by conducting studies of genome-wide DNA methylation patterns. The UAB center is studying racial differences in the prevalence and determinants of abnormal diurnal BP patterns. The UI center is studying copeptin, a possible early biomarker for preeclampsia and vascular endothelial function, and arterial stiffness changes occurring before and during preeclampsia. In this article, we provide an overview of the science being conducted at each center and describe the innovative training program incorporated into the SFRN. A goal of the Hypertension SFRN is to facilitate collaborative research. Therefore, we describe opportunities and resources available to researchers interested in collaborating with SFRN investigators. The AHA Hypertension SFRN has the potential to identify new approaches for the prevention and treatment of hypertension and, ultimately, improve the cardiovascular health of Americans. The SFRN is a mechanism initiated by the AHA to address key strategic issues as determined by the AHA Board of Directors. In 2014, hypertension was selected for a SFRN because improvement in its prevention and treatment has the potential to impact the AHA’s mission and 2020 goals: to …