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Summary: Background: Since 1992, when recombinant hepatitis B vaccine was introduced in China, government health officials have used nationally representative serological surveys to monitor progress in prevention and control of hepatitis B. In 2020, we conducted the fourth seroepidemiological survey, which for the first time included medical evaluation of the clinical status of HBsAg positive subjects over the age of 15 and their medical management. We report survey results in comparison with the three previous surveys. Methods: Consistent with previous national surveys, the 2020 survey used a stratified, three-stage cluster random sampling method to select for evaluation 1-69-year-olds in 120 national disease surveillance points. Blood samples were tested for HBsAg, anti-HBV surface antigen (anti-HBs), and anti-HBV core antigen (anti-HBc) in the National Hepatitis Laboratory of the Institute for Viral Disease Control and Prevention of China CDC. HBsAg positive subjects aged ≥15-year were evaluated for evidence of liver disease, and through face-to-face questionnaire-based survey, we determined the healthcare management cascade of HBV-infected individuals. Findings: HBsAg prevalence in 1–69-year-olds was 5.86%; in children 1–4 years of age, seroprevalence was 0.30%; 75 million people were living with HBV nationwide. Among HBsAg-positive individuals 15 years and older, expert medical examination found that 78.03% were HBsAg carriers with no evidence of liver damage, 19.63% had chronic HBV with liver enzyme abnormalities, 0.84% had evidence of cirrhosis, and 0.15% had evidence of liver cancer. 59.78% of HBsAg + individuals were aware that they were positive before the survey, 30 million were unaware; 38.25% of those who knew they were positive (17 million) had medical indications for antiviral treatment, and 17.33% of these individuals (3 million) were being treated with antivirals. Interpretation: The decline in HBsAg prevalence in the general population, from 9.72% in 1992 to 5.86% in 2020, and in 1–4-year-olds from 9.67% in 1992 to 0.30% in 2020, shows progress that continues on track toward WHO targets for prevention of new infections. Implementation of acceptable strategies to identify infected individuals and offer long-term medical monitoring and management will be important to prevent complications from hepatitis B infection and for meeting WHO cascade-of-care targets. Funding: The study was funded by the Major Science and Technology Special Project of China’s 13th 5-Year Plan (grant no. 2017ZX10105015); Central finance-operation of public health emergency response mechanism of Chinese Center for Disease Control and Prevention (131031001000200001, 102393220020010000017).

Abstract Chiral orbital currents (COC) underpin a novel colossal magnetoresistance in ferrimagnetic Mn3Si2Te6. Here we report the Hall effect in the COC state which exhibits the following unprecedented features: (1) A sharp, current-sensitive peak in the magnetic field dependence of the Hall resistivity, and (2) A current-sensitive scaling relation between the Hall conductivity σ xy and the longitudinal conductivity σ xx , namely, σ xy ∝ σ xx α with α reaching up to 5, which is exceptionally large compared to α ≤ 2 typical of all solids. The novel Hall responses along with a current-sensitive carrier density and a large Hall angle of 15% point to a giant, current-sensitive Hall effect that is unique to the COC state. Here, we show that a magnetic field induced by the fully developed COC combines with the applied magnetic field to exert the greatly enhanced transverse force on charge carriers, which dictates the COC Hall responses.

Abstract Background Immunization is a cornerstone of public health. Despite great success, China’s National Immunization Program (NIP) faces challenges, such as the integration of several World Health Organization-recommended vaccines and other systemic issues. The Innovation Laboratory for Vaccine Delivery Research (VaxLab), supported by the Bill & Melinda Gates Foundation and established in 2021 at Duke Kunshan University, focuses on enhancing China’s NIP through research and policy advocacy. This editorial aims to summarize the key findings of the manuscripts published in the collection contributed by VaxLab team and set the future research agenda. Key findings The collection contains eleven manuscripts discussing China’s immunization landscape and strategies to improve coverage, particularly for non-NIP vaccines like human papillomavirus vaccine (HPV), pneumococcal conjugate vaccine (PCV), Haemophilus influenzae type b vaccine (Hib), and rotavirus vaccines. Key findings include: (i) The COVID-19 vaccination campaign demonstrated China’s capacity for rapid, large-scale immunization efforts, suggesting potential for broader vaccine coverage improvements; (ii) Efforts in combating cervical cancer through the HPV vaccine indicate progress but also highlight challenges like vaccine supply and equitable access; (iii) The lag in adopting higher-valent paediatric combination vaccines in China needs attention to address regulatory and health system hurdles; (iv) Disparities in access to non-NIP vaccines underscore the need for government initiatives to improve vaccine coverage, especially for remote areas and marginalized populations; (v) Original studies emphasize the influence of caregivers’ knowledge, health workers’ financial incentives, and concerns about vaccine efficacy on immunization rates; (vi) Case studies from the Weifang City of China and Indonesia to introduce PCV offer insights on successful vaccine introduction strategies and the impact of innovative financing and government support. Conclusion The articles emphasize the need for government leadership, strategic policymaking, and public awareness to enhance vaccine coverage and equity. The VaxLab will continue strengthening China’s NIP by focusing on vaccine financing, emphasizing diversity, equity, and inclusion, and improving maternal vaccination coverage. Research will extend to Southeast Asian and Western Pacific regions, especially in middle-income countries facing challenges in vaccine financing and delivery. The collective efforts outlined in this collection show a commitment to evolving and adapting immunization strategies to meet global health goals and to provide equitable access to vaccines for all. Graphical Abstract

ATP-binding cassette (ABC) transport systems are crucial for bacteria to ensure sufficient uptake of nutrients that are not produced de novo or improve the energy balance. The cell surface of the pathobiont Streptococcus pneumoniae (pneumococcus) is decorated with a substantial array of ABC transporters, critically influencing nasopharyngeal colonization and invasive infections. Given the auxotrophic nature of pneumococci for certain amino acids, the Ami ABC transporter system, orchestrating oligopeptide uptake, becomes indispensable in host compartments lacking amino acids. The system comprises five exposed Oligopeptide Binding Proteins (OBPs) and four proteins building the ABC transporter channel. Here, we present a structural analysis of all the OBPs in this system. Multiple crystallographic structures, capturing both open and closed conformations along with complexes involving chemically synthesized peptides, have been solved at high resolution providing insights into the molecular basis of their diverse peptide specificities. Mass spectrometry analysis of oligopeptides demonstrates the unexpected remarkable promiscuity of some of these proteins when expressed in Escherichia coli, displaying affinity for a wide range of peptides. Finally, a model is proposed for the complete Ami transport system in complex with its various OBPs. We further disclosed, through in silico modelling, some essential structural changes facilitating oligopeptide transport into the cellular cytoplasm. Thus, the structural analysis of the Ami system provides valuable insights into the mechanism and specificity of oligopeptide binding by the different OBPs, shedding light on the intricacies of the uptake mechanism and the in vivo implications for this human pathogen.

Understanding the anatomical structure of a patient’s shoulder joint is essential in surgical decision-making, especially regarding glenohumeral bone loss. The use of various imaging techniques, such as magnetic resonance imaging (MRI) and computed tomography (CT), bring certain advantages and disadvantages in assessing joint structure. Before a surgical procedure, bone loss can be observed and measured using these imaging techniques in both 2-dimensional and 3-dimensional (3D) views. The ability to visualize the shoulder joint in a 3D manner, as commonly done with CT scans, is helpful in assessing bone loss; however, CT involves exposure to radiation, additional time, and greater costs. The process of obtaining a 3D view of the shoulder joint from an MRI, although less common, can be completed effectively to assess bone loss while also solving some issues surrounding CT scans. By loading MRI datasets into an image-reformation program, such as 3D Slicer, the anatomical structures can be segmented to create realistic 3D models of the shoulder joint. Surgical direction can be determined after bone loss measurements and structural assessment of these models, without the need for CT scans. This technique can also be applied to other skeletal joints, in addition to the shoulder.

Abstract The Tour Divide (TD) is a 4385 km ultra‐endurance bicycle race that follows the continental divide from Canada to Mexico. In this case study, we performed a comprehensive molecular and physiological profile before and after the completion of the TD. Assessments were performed 35 days before the start (Pre‐TD) and ∼36 h after the finish (Post‐TD). Total energy expenditure was assessed during the first 9 days by doubly labelled water (2H218O), abdominal and leg tissue volumes via MRI, and graded exercise tests to quantify fitness and substrate preference. Vastus lateralis muscle biopsies were taken to measure mitochondrial function via respirometry, and vascular function was assessed using Doppler ultrasound. The 47‐year‐old male subject took 16 days 7 h 45 min to complete the route. He rode an average of 16.8 h/day. Neither maximal O2 uptake nor maximal power output changed pre‐ to post‐TD. Measurement of total energy expenditure and dietary recall records suggested maintenance of energy balance, which was supported by the lack of change in body weight. The subject lost both appendicular and trunk fat mass and gained leg lean mass pre‐ to post‐TD. Skeletal muscle mitochondrial and vascular endothelial function decreased pre‐ to post‐TD. Overall, exercise performance was maintained despite reductions in muscle mitochondrial and vascular endothelial function post‐TD, suggesting a metabolic reserve in our highly trained athlete.

To assist gas distribution companies to effectively monitor their infrastructure and locate gas leaks, this paper considers the use of an Unmanned Aerial Vehicle (UAV) carrying a methane sensor to survey a region for gas leaks. As the UAV collects in situ measurements, it gathers evidence regarding the presence or absence of leaks in the region. To relate the UAV measurement to a region on the ground, we propose to use Upwind Survey Regions (USRs). If the UAV collects a measurement of high gas concentration, the USR represents a region that is likely to contain the leak. Likewise, if the UAV collects a measurement of low gas concentration, the USR represents a region that is likely to be clear of gas leaks. We propose a framework to process the measurements and produce a survey map indicating areas that can be reliably cleared of gas leaks and areas that may contain gas leaks. Our framework is composed of two steps: 1) mapping UAV measurements into USRs on the ground; and 2) fusing the various mapped USRs to produce the survey map. We discuss how USRs can be estimated and we test our framework using both simulated and real UAV flights.

Abstract China's immunization programs conducted a unified, tightly coordinated COVID-19 vaccination campaign during the dynamic COVID Zero period that reached well over 90% of the population with vaccines having > 90% effectiveness against serious-to-fatal COVID-19. The campaign was eight times the size of the annual routine national immunization program, administering 3.4 billion doses of vaccines while monitoring vaccine coverage, acceptability, safety, and effectiveness. Every asset of the routine immunization program had to be strengthened and expanded to attain high coverage and reach hundreds of millions of adults who had not been vaccinated since childhood. Program strengthening and expansion were in directions aligned with the World Health Organization's Immunization Agenda 2030, which has a vision that "everyone, everywhere, at every age fully benefits from vaccines for good health and well-being" and requires reaching all children, adolescents, and adults with lifesaving vaccines. Momentum from this campaign should not be lost but should be invested into achieving what is possible with a properly resourced national immunization program that is now proven to be capable of reaching everyone in the world’s largest country throughout the life course, and to do so with all vaccines recommended by the World Health Organization. Graphical Abstract

This study aimed to determine the impact of various fast-interrupting shakes on markers of glycemic control including glucose, β-hydroxybutyrate (BHB), insulin, glucagon, GLP-1, and GIP. Twenty-seven sedentary adults (twelve female, fifteen male) with overweight or obesity completed this study. One condition consisted of a 38-h water-only fast, and the other two conditions repeated this, but the fasts were interrupted at 24 h by either a high carbohydrate/low fat (HC/LF) shake or an isovolumetric and isocaloric low carbohydrate/high fat (LC/HF) shake. The water-only fast resulted in 135.3% more BHB compared to the HC/LF condition (p < 0.01) and 69.6% more compared to the LC/HF condition (p < 0.01). The LC/HF condition exhibited a 38.8% higher BHB level than the HC/LF condition (p < 0.01). The area under the curve for glucose was 14.2% higher in the HC/LF condition than in the water condition (p < 0.01) and 6.9% higher compared to the LC/HF condition (p < 0.01), with the LC/HF condition yielding 7.8% more glucose than the water condition (p < 0.01). At the 25-h mark, insulin and glucose-dependent insulinotropic polypeptide (GIP) were significantly elevated in the HC/LF condition compared to the LC/HF condition (p < 0.01 and p = 0.02, respectively) and compared to the water condition (p < 0.01). Furthermore, insulin, GLP-1, and GIP were increased in the LC/HF condition compared to the water condition at 25 h (p < 0.01, p = 0.015, and p < 0.01, respectively). By the 38-h time point, no differences were observed among the conditions for any of the analyzed hormones. While a LC/HF shake does not mimic a fast completely, it does preserve some of the metabolic changes including elevated BHB and glucagon, and decreased glucose and insulin compared to a HC/LF shake, implying a potential for improved metabolic health.

Abstract The botulinum neurotoxin serotype A (BoNT/A) cuts a single peptide bond in SNAP25, an activity used to treat a wide range of diseases. Reengineering the substrate specificity of BoNT/A’s protease domain (LC/A) could expand its therapeutic applications; however, LC/A’s extended substrate recognition (≈ 60 residues) challenges conventional approaches. We report a directed evolution method for retargeting LC/A and retaining its exquisite specificity. The resultant eight-mutation LC/A (omLC/A) has improved cleavage specificity and catalytic efficiency (1300- and 120-fold, respectively) for SNAP23 versus SNAP25 compared to a previously reported LC/A variant. Importantly, the BoNT/A holotoxin equipped with omLC/A retains its ability to form full-length holotoxin, infiltrate neurons, and cleave SNAP23. The identification of substrate control loops outside BoNT/A’s active site could guide the design of improved BoNT proteases and inhibitors.

ABSTRACT Streptococcus pneumoniae colonizes the human nasopharynx and causes several diseases. Pneumococcal vaccines target the polysaccharide capsule and prevent most serious disease, but there has been an increase in the prevalence of nonencapsulated S. pneumoniae (NESp). Previously, it was thought that a capsule was necessary to cause invasive disease. NESp strains expressing the oligopeptide transporters AliC and AliD have been isolated from patients with invasive disease. The AliC and AliD oligopeptide transporters regulate the expression of several genes, including choline binding protein AC (CbpAC) (a homolog of PspA), which aids in reducing C3b deposition. It is hypothesized that by altering CbpAC expression, AliC and AliD provide protection from classical complement-mediated clearance by reducing C-reactive protein (CRP) binding. Our study demonstrates that AliC and AliD regulate CbpAC expression in NESp and that AliD found in certain serotypes of encapsulated strains regulates PspA expression. C3b deposition was increased in the NESp ΔaliD and encapsulated mutants in comparison to the wild type. NESp strains expressing AliC and AliD have a significant decrease in C1q and CRP deposition in comparison to the ΔaliC ΔaliD mutant. The complement protein C1q is required for NESp clearance in a murine model and increases opsonophagocytosis. By regulating CbpAC expression, NESp inhibits CRP binding to the bacterial surface and blocks classical complement activation, leading to greater systemic survival and virulence. Due to the increase in the prevalence of NESp, it is important to gain a better understanding of NESp virulence mechanisms that aid in establishing disease and persistence within a host by avoiding clearance by the immune system. IMPORTANCE Streptococcus pneumoniae (pneumococcus) can cause a range of diseases. Although there is a robust pneumococcal vaccination program that reduces invasive pneumococcal disease by targeting various polysaccharide capsules, there has been an increase in the isolation of nonvaccine serotypes and nonencapsulated S. pneumoniae (NESp) strains. While most studies of pneumococcal pathogenesis have focused on encapsulated strains, there is little understanding of how NESp causes disease. NESp lacks a protective capsule but contains novel genes, such as aliC and aliD, which have been shown to regulate the expression of numerous genes and to be required for NESp virulence and immune evasion. Furthermore, NESp strains have high transformation efficiencies and harbor resistance to multiple drugs. This could be deleterious to current treatment strategies employed for pneumococcal disease as NESp can be a reservoir of drug resistance genes. Therefore, deciphering how NESp survives within a host and facilitates disease is a necessity that will allow the fabrication of improved, broad-spectrum treatments and preventatives against pneumococcal disease. Our study provides a better understanding of NESp virulence mechanisms during host-pathogen interactions through the examination of genes directly regulated by the NESp proteins AliC and AliD.

This cross-sectional investigation examined the relationship between sitting time and insulin resistance in 6931 U.S. adults. The mediating effects of several covariates were evaluated. Self-reported sitting time, measured in minutes per day, was the exposure variable. Insulin resistance (IR), indexed using the natural log of the homeostatic model assessment of insulin resistance (L-HOMA-IR), was the outcome variable. This study used data collected from the 2011–2018 National Health and Nutrition Examination Survey (NHANES). Results showed a strong, positive, dose-response association between sitting time and insulin resistance after adjusting for age, sex, race, and year of assessment (F=12.6, p

Background: Recognition of posterior glenohumeral instability has increased in young, athletic populations, leading to evolution in operative approaches to management. As with anterior instability surgery, successful treatment for these challenging injuries is dependent on understanding the key principles of pathology and restoration of the functional anatomy. Indications: Operative management of posterior glenohumeral instability is indicated for recurrent instability events or persistent pain refractory to physical therapy in the setting of posterior labral pathology with or without bone loss. Technique: In this video article, we present our approach to operative management of posterior glenohumeral instability in a young, athletic population, as developed through extensive experience in military and athlete populations and supported by research. Our approach to posterior glenohumeral instability is to restore the functional anatomy of the bone, labrum, and capsuloligamentous static restraints. We consider concomitant pathology and bone loss as components of these restraints that need to be restored to achieve a stable, painless shoulder. Using standard portals and tools, we prepare the glenoid and mobilize the labrum. When present, large osseous lesions can be restored using allograft distal tibia. We then repair and superiorize the inferior labrum, taking care to create a secure buttress against translation by positioning anchors at the edge of the chondral surface and everting the interior flap of tissue. If capsular pathology is present, this is also addressed. In the setting of significant posterior glenoid bone loss, we reconstruct the osseous support with a distal tibial allograft, which we perform arthroscopically and augment with labral repair. Using these techniques, surgeons can expect a low overall failure rate. In our young, highly active population, we observed 17.2% failure by 5 years, although this is dependent on multiple factors including age and bone loss. Discussion: Outcomes for posterior glenohumeral instability can be excellent with both nonoperative and operative treatments. When operative intervention is pursued, it is important to critically evaluate the anatomy, place portals considerately, and functionally restore the damaged structures. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.

Introduction: Traumatic anterior glenohumeral instability events result in a capsulolabral (Bankart lesion) and/or osseous injury with subsequent attritional bone loss, particularly with recurrence. Up to 88% of patients with recurrent instability experience glenoid bone loss, which predisposes to future dislocations and subluxations, even with arthroscopic capsulolabral repair. The surgical management of glenoid bone loss includes a number of different techniques such as the Latarjet or coracoid transfer as well as other osseous and osteoarticular autografts and allografts. However, operative management of shoulder instability has increasingly shifted toward arthroscopic approaches with preservation of anatomy when possible. Indications: Arthroscopic-assisted allograft distal tibia bone block augmentation to the anterior glenoid is indicated for revision anterior glenohumeral instability procedures with anterior bone loss and in primary cases of anterior instability with critical bone loss. Technique: Our technique for nonrigid arthroscopic anterior glenoid reconstruction with allograft distal tibia and anterior labral repair is performed preferentially in the lateral position without necessitating patient repositioning. The preplanned tibial bone block is prepared on a back table prior to the arthroscopic procedure. After creation of portals and elevation of labral tissue, a guide and drill are used to introduce a retrograde reamer which is deployed to create a perpendicular edge for apposition of the allograft tibia. The bone block is then introduced through a rotator interval portal by pulling sutures retrograde through glenoid bone tunnels and is secured to the prepared surface medial to the liberated labrum. The articular surface of the graft and glenoid are aligned and suture-based fixation is used to compress the bone block against the native glenoid. The anterior labral tissue is then mobilized over the graft and repaired to the native glenoid when possible. Description/Conclusion: The benefits of allograft tibia augmentation for anterior instability with glenoid bone loss include an anatomic joint surface restoration including articular cartilage, lack of donor site morbidity, and a minimally invasive arthroscopic approach. When performed arthroscopically and with nonrigid fixation, this technique permits concurrent anterior labral repair and anatomic reconstruction, safe graft passage without necessity of a far medial portal, and expeditious return to function.

Purpose – Forecasting techniques improve supply chain resilience by ensuring that the correct parts are available when required. In addition, accurate forecasts conserve precious resources and money by avoiding new start contracts to produce unforeseen part requests, reducing labor intensive cannibalization actions and ensuring consistent transportation modality streams where changes incur cost. This study explores the effectiveness of the United States Air Force’s current flying hour-based demand forecast by comparing it with a sortie-based demand forecast to predict future spare part needs. Design/methodology/approach – This study employs a correlation analysis to show that demand for reparable parts on certain aircraft has a stronger correlation to the number of sorties flown than the number of flying hours. The effect of using the number of sorties flown instead of flying hours is analyzed by employing sorties in the United States Air Force (USAF)’s current reparable parts forecasting model. A comparative analysis on D200 forecasting error is conducted across F-16 and B-52 fleets. Findings – This study finds that the USAF could improve its reparable parts forecast, and subsequently part availability, by employing a sortie-based demand rate for particular aircraft such as the F-16. Additionally, our findings indicate that forecasts for reparable parts on aircraft with low sortie count flying profiles, such as the B-52 fleet, perform better modeling demand as a function of flying hours. Thus, evidence is provided that the Air Force should employ multiple forecasting techniques across its possessed, organically supported aircraft fleets. The improvement of the forecast and subsequent decrease in forecast error will be presented in the Results and Discussion section. Research limitations/implications – This study is limited by the data-collection environment, which is only reported on an annual basis and is limited to 14 years of historical data. Furthermore, some observations were not included because significant data entry errors resulted in unusable observations. Originality/value – There are few studies addressing the time measure of USAF reparable component failures. To the best of the authors’ knowledge, there are no studies that analyze spare component demand as a function of sortie numbers and compare the results of forecasts made on a sortie-based demand signal to the current flying hour-based approach to spare parts forecasting. The sortie-based forecast is a novel methodology and is shown to outperform the current flying hour-based method for some aircraft fleets.

We estimated the symptomatic, PCR-confirmed secondary attack rate (SAR) for 2,382 close contacts of 476 symptomatic persons with coronavirus disease in Yichang, Hubei Province, China, identified during January 23–February 25, 2020. The SAR among all close contacts was 6.5%; among close contacts who lived with an index case-patient, the SAR was 10.8%; among close-contact spouses of index case-patients, the SAR was 15.9%. The SAR varied by close contact age, from 3.0% for those 60 years of age. Multilevel logistic regression showed that factors significantly associated with increased SAR were living together, being a spouse, and being >60 years of age. Multilevel regression did not support SAR differing significantly by whether the most recent contact occurred before or after the index case-patient’s onset of illness (p = 0.66). The relatively high SAR for coronavirus disease suggests relatively high virus transmissibility.

BackgroundBBIBP-CorV and CoronaVac inactivated COVID-19 vaccines are widely-used, World Health Organization-emergency-listed vaccines. Understanding antibody level changes over time after vaccination is important for booster dose policies. We evaluated neutralizing antibody (nAb) titers and associated factors for the first 12 months after primary-series vaccination with BBIBP-CorV and CoronaVac.MethodsOur study consisted of a set of cross-sectional sero-surveys in Zhejiang and Shanxi provinces, China. In 2021, we enrolled 1,527 consenting 18-59-year-olds who received two doses of BBIBP-CorV or CoronaVac 1, 3, 6, 9, or 12 months earlier and obtained blood samples and demographic and medical data. We obtained 6-month convalescent sera from 62 individuals in Hebei province. Serum nAb titers were measured by standard micro-neutralization cytopathic effect assay in Vero cells with ancestral SARS-CoV-2 strain HB01. We used the first WHO International Standard (IS) for anti-SARS-CoV-2 immunoglobulin (NIBSC code 20/136) to standardized geometric mean concentrations (IU/mL) derived from the nAb geometric mean titers (GMT over 1:4 was considered seropositive). We analyzed nAb titer trends using Chi-square and factors related to nAb titers with logistic regression and linear models.ResultsNumbers of subjects in each of the five month-groupings ranged from 100 to 200 for each vaccine and met group-specific target sample sizes. Seropositivity rates from BBIBP-CorV were 98.0% at 1 month and 53.5% at 12 months, and GMTs were 25.0 and 4.0. Respective seropositivity rates from CoronaVac were 90.0% and 62.5%, and GMTs were 20.2 and 4.1. One-, three-, six-, nine-, and twelve-month GMCs were 217.2, 84.1, 85.7, 44.6, and 10.9 IU/mL in BBIBP-CorV recipients and 195.7, 94.6, 51.7, 27.6, and 13.4 IU/mL in CoronaVac recipients. Six-month convalescent seropositivity was 95.2%; GMC was 108.9 IU/mL. Seropositivity and GMCs were associated with age, sex, and time since vaccination.ConclusionsNeutralizing Ab levels against ancestral SARS-CoV-2 from BBIBP-CorV or CoronaVac vaccination were similar and decreased with increasing time since vaccination; over half of 12-month post-vaccination subjects were seropositive. Seropositivity and GMCs from BBIBP-CorV and CoronaVac six and nine months after vaccination were similar to or slightly lower than in six-month convalescent sera. These real-world data suggest necessity of six-month booster doses.

Vector-mediated mutagenesis remains a major safety concern for many gene therapy clinical protocols. Indeed, lentiviral-based gene therapy treatments of hematologic disease can result in oligoclonal blood reconstitution in the transduced cell graft. Specifically, clonal expansion of hematopoietic stem cells (HSCs) highly expressing HMGA2, a chromatin architectural factor found in many human cancers, is reported in patients undergoing gene therapy for hematologic diseases, raising concerns about the safety of these integrations. Here, we show for the first time in vivo multilineage and multiclonal expansion of non-human primate HSCs expressing a 3’ UTR-truncated version of HMGA2 without evidence of any hematologic malignancy >7 years post-transplantation, which is significantly longer than most non-human gene therapy pre-clinical studies. This expansion is accompanied by an increase in HSC survival, cell cycle activation of downstream progenitors, and changes in gene expression led by the upregulation of IGF2BP2, a mRNA binding regulator of survival and proliferation. Thus, we conclude that prolonged ectopic expression of HMGA2 in hematopoietic progenitors is not sufficient to drive hematologic malignancy and is not an acute safety concern in lentiviral-based gene therapy clinical protocols.

We characterized the human β-like globin transgenes in two mouse models of sickle cell disease (SCD) and tested a genome-editing strategy to induce red blood cell fetal hemoglobin (HbF; α2γ2). Berkeley SCD mice contain four to 22 randomly arranged, fragmented copies of three human transgenes (HBA1, HBG2-HBG1-HBD-HBBS and a mini-locus control region) integrated into a single site of mouse chromosome 1. Cas9 disruption of the BCL11A repressor binding motif in the γ-globin gene (HBG1 and HBG2; HBG) promoters of Berkeley mouse hematopoietic stem cells (HSCs) caused extensive death from multiple double-strand DNA breaks. Long-range sequencing of Townes SCD mice verified that the endogenous Hbb genes were replaced by single-copy segments of human HBG1 and HBBS including proximal but not some distal gene-regulatory elements. Townes mouse HSCs were viable after Cas9 disruption of the HBG1 BCL11A binding motif but failed to induce HbF to therapeutic levels, contrasting with human HSCs. Our findings provide practical information on the genomic structures of two common mouse SCD models, illustrate their limitations for analyzing therapies to induce HbF and confirm the importance of distal DNA elements in human globin regulation. This article has an associated First Person interview with the first author of the paper.

Hunger and satiety are controlled by several physiological mechanisms, including pancreatic and gastrointestinal hormones. While the influence of exercise and fasting have been described individually, in relation to these hormones, there is a paucity of work showing the effects of the two modalities (fasting and exercise) combined. Twenty healthy adults (11 males, 9 females) completed both conditions of this study, each consisting of a 36-h water-only fast. One of the fasts began with treadmill exercise, and the differences between the conditions on various appetite hormones were measured every 12 h. The difference in the area under the curve between conditions for ghrelin was 211.8 ± 73.1 pg/mL (F = 8.40, p < 0.0105), and, for GLP-1, it was −1867.9 ± 850.4 pg/mL (F = 4.82, p < 0.0422). No significant differences were noted for areas under the curve between conditions for leptin, PP, PYY, insulin, or GIP. Initiating a fast with exercise lowers ghrelin concentrations and elevates GLP-1 concentrations. Given that ghrelin elicits feelings of hunger and GLP-1 signals feelings of satiety, adding exercise to the beginning of a fast may reduce some of the biological drive of hunger, which could make fasting more tolerable, leading to better adherence and more significant health outcomes.

Influenza vaccination coverage in pregnant women in China remains low. In this review, we first provide an overview of the evidence for the use of influenza vaccination during pregnancy. Second, we discuss influenza vaccination policy and barriers to increased seasonal influenza vaccination coverage in pregnant women in China. Third, we provide case studies of successes and challenges of programs for increasing seasonal influenza vaccination in pregnant women from other parts of Asia with lessons learned for China. Finally, we assess opportunities and challenges for increasing influenza vaccination coverage among pregnant women in China.

Background: Posterior glenoid bone loss occurs in more than two-thirds of patients with posterior glenohumeral instability, with 14% to 22% having greater than subcritical bone loss (13.5%), a marker for potential need for bony augmentation versus soft tissue-only procedures. Several techniques are described to augment either the version or volume of the glenoid surface including osteotomies, autograft transfers, and allograft tibia transfers. Indications: Arthroscopic-assisted allograft distal tibia bone block augmentation to the posterior glenoid is indicated for revision posterior instability procedures with posterior bone loss and in primary cases of posterior instability with critical bone loss. Technique Description: Arthroscopic posterior glenoid reconstruction with allograft distal tibia and posterior labral repair in the lateral position is presented. This technique uses standard instrument sets and requires no patient repositioning. The preplanned tibial bone block is prepared on a back table either prior to, or concurrently with, arthroscopic procedure. After creation of high posterior portal and standard anterior portal, a sucker-shaver and burr are used to create a perpendicular edge for apposition of the allograft tibia. The bone block is introduced through a longitudinal incision and underdelivered to the prepared surface under the liberated labrum. The articular surface of the graft and glenoid are aligned and cannulated screws are used to compress the bone block against the native glenoid. The posterior labral tissue is then mobilized over the graft and repaired to the native glenoid. Results: Arthroscopic distal tibial allograft augmentation for posterior bone loss restored stability and function in a small cohort of patients. Patients reported improved stability in the immediate postoperative course, with restoration of motion by 2 months. Push-ups, pull-ups, and return to full active duty without restrictions is allowed at 6 months postoperatively. Imaging at 3 months postoperatively has shown excellent graft healing. Discussion: The benefits of allograft tibia augmentation for posterior instability with glenoid bone loss include an anatomic joint surface restoration including articular cartilage, lack of donor site morbidity, and a minimally invasive approach. When performed arthroscopically, this technique permits concurrent posterior labral repair and anatomic reconstruction.

Background Progressive cardiac remodeling and worsening myocardial function over time have been proposed as potential mediators of heart failure in obesity. Methods and Results We serially assessed cardiac structure and function in 254 subjects participating in a longitudinal study of obesity. Demographic, clinical, laboratory, and echocardiographic features were determined at baseline and 2‐, 6‐, and 11‐year follow‐up. We measured body mass index (BMI) exposure as the area under the curve of the BMI at each of the 4 visits. At enrollment, mean age of the subjects was 47 years, 79% were women, mean BMI was 44 kg/m2, 26% had diabetes mellitus, 48% had hypertension, and 53% had hyperlipidemia. Between baseline and 11 years, BMI increased by 1.1 and 0.3 kg/m2 in men and women, respectively. There were modest increases in left ventricular (LV) end‐diastolic volume, LV mass, and left atrial volume, and significant decreases in early/late mitral diastolic flow velocity ratio and E wave deceleration time. However, there were no significant changes in LV ejection fraction or ratio of early mitral diastolic flow velocity/early mitral annular velocity, whereas right ventricular fractional area change increased. Significant predictors of the change in LV mass were male sex, baseline BMI, BMI area under the curve, and change in LV stroke volume, but not smoking, hypertension, or diabetes mellitus. Conclusions In long‐standing, persistent severe obesity, there was evidence of cardiac remodeling over a period of 11 years, but no clear worsening of systolic or diastolic function. Measures of remodeling were most strongly related to BMI. The observed changes might predispose to heart failure with preserved ejection fraction, but are not classic for an evolving dilated cardiomyopathy.

The association between mention of scientific research in popular media (e.g., the mainstream media or social media platforms) and scientific impact (e.g., citations) has yet to be fully explored. The purpose of this study was to clarify this relationship, while accounting for some other factors that likely influence scientific impact (e.g., the reputations of the scientists conducting the research and academic journal in which the research was published). To accomplish this purpose, approximately 800 peer-reviewed articles describing original research were evaluated for scientific impact, popular media attention, and reputations of the scientists/authors and publication venue. A structural equation model was produced describing the relationship between non-scientific impact (popular media) and scientific impact (citations), while accounting for author/scientist and journal reputation. The resulting model revealed a strong association between the amount of popular media attention given to a scientific research project and corresponding publication and the number of times that publication is cited in peer-reviewed scientific literature. These results indicate that (1) peer-reviewed scientific publications receiving more attention in non-scientific media are more likely to be cited than scientific publications receiving less popular media attention, and (2) the non-scientific media is associated with the scientific agenda. These results may inform scientists who increasingly use popular media to inform the general public and scientists concerning their scientific work. These results might also inform administrators of higher education and research funding mechanisms, who base decisions partly on scientific impact.

The main objective of the present study was to assess the association between participation in strength training and insulin resistance. Another goal was to assess the influence of several potential confounding variables on the strength training and insulin resistance relationship. Lastly, the influence of waist circumference, fat-free mass (kg), body fat percentage, and the fat-free mass index on the association between strength training and insulin resistance was assessed. This cross-sectional study included 6,561 randomly selected men and women in the U.S. Data were collected using the precise protocol established by NHANES. HOMA-IR was used as the outcome variable to index insulin resistance. Both time spent strength training and frequency of strength training bouts were used as exposure variables. There was not a statistically significant relationship between strength training and insulin resistance in women. However, before and after controlling for 11 potential confounding variables, men who reported no strength training had significantly higher levels of HOMA-IR compared to men who reported moderate or high levels of strength training (F=9.87, P

The need for closer linkages between scientific and programmatic areas focused on addressing vaccine-preventable and acute respiratory infections led to establishment of the National Center for Immunization and Respiratory Diseases (NCIRD) at the Centers for Disease Control and Prevention. During its first 10 years (2006–2015), NCIRD worked with partners to improve preparedness and response to pandemic influenza and other emergent respiratory infections, provide an evidence base for addition of 7 newly recommended vaccines, and modernize vaccine distribution. Clinical tools were developed for improved conversations with parents, which helped sustain childhood immunization as a social norm. Coverage increased for vaccines to protect adolescents against pertussis, meningococcal meningitis, and human papillomavirus–associated cancers. NCIRD programs supported outbreak response for new respiratory pathogens and oversaw response of the Centers for Disease Control and Prevention to the 2009 influenza A(H1N1) pandemic. Other national public health institutes might also find closer linkages between epidemiology, laboratory, and immunization programs useful.

Abstract Background As China approaches the elimination of measles, outbreaks of measles continue to occur. Healthcare workers (HCWs) are known to be at high risk of infection and transmission of measles virus. A measles outbreak occurred in a hospital in Xinjiang Uighur Autonomous Region of the People’s Republic of China. We report an investigation of this outbreak and its implications for measles elimination and outbreak preparedness. Methods We conducted a retrospective search for measles cases using hospital records. Information on cases was collected by interview, and was used to determine epidemiological linkages. We surveyed HCWs to determine their demographic characteristics, disease history and vaccination status, and knowledge about measles. Results We identified 19 cases, ages 18 to 45 years, in Hospital W between December 2015 and January 2016; 14 were laboratory-confirmed, and 5 were epidemiologically linked. The primary case was a 25-year-old neurology department nurse who developed a rash on 22 December 2015 that was reported on 11 January 2016. She continued working and living with her workmates in a dormitory during her measles transmission period. Among the 19 infected HCWs, 2 had received a dose of measles-containing vaccine (MCV) before the outbreak, and 16 had unknown vaccination status. Outbreak response immunization activities were started on 8 January in a non-selective manner by offering vaccine regardless of vaccination history; 605(68%) of 890 HCWs were vaccinated. The HCW survey had a 73% response rate (646/890); 41% of HCWs reported that they had received MCV before outbreak, and 56% exhibited good knowledge of measles symptoms, transmission, complications, and vaccination. Conclusions Low MCV coverage, low measles knowledge among HCWs, delayed reporting of measles cases, and absence of proper case management were associated with this outbreak. Training and vaccinating HCWs against measles are essential activities to prevent measles virus transmission among HCWs.

Abstract A new method has been developed for the isolation of 223,224,225Ra, in high yield and purity, from a proton irradiated 232Th matrix. Herein we report an all-aqueous process using multiple solid-supported adsorption steps including a citrate chelation method developed to remove >99.9% of the barium contaminants by activity from the final radium product. A procedure involving the use of three columns in succession was developed, and the separation of 223,224,225Ra from the thorium matrix was obtained with an overall recovery yield of 91 ± 3%, average radiochemical purity of 99.9%, and production yields that correspond to physical yields based on previously measured excitation functions.

The primary purpose of this investigation was to evaluate the relationship between milk-fat intake and obesity, particularly abdominal obesity, in 13,544 U.S. adults. A lesser objective was to measure the degree to which the association was influenced by multiple potential confounding variables. This cross-sectional study used data from the 2011–2016 National Health and Nutrition Examination Survey (NHANES). Quantity of milk-fat regularly consumed was the exposure variable. Sagittal abdominal diameter (SAD), a measure of abdominal obesity, and body mass index (BMI) were the outcome variables. Sagittal abdominal diameter is a strong predictor of visceral abdominal fat, when measured by computed tomography, and has been shown to predict cardiometabolic disorders better than BMI. After controlling for age, race, gender, physical activity, leisure computer use and gaming, alcohol habits, and cigarette use, significantly lower BMIs were associated with consistent non-fat and full-fat milk consumption (F = 4.1, p = 0.0063). A significantly lower SAD was associated only with regular consumption of non-fat milk (F = 5.0, p = 0.0019). No significant differences were detected between the other milk-fat groups or milk abstainers. In this nationally representative sample, only 19.6% of adults regularly consumed low-fat milk. In conclusion, consistent non-fat milk intake was predictive of lower levels of abdominal adiposity compared to consumption of higher levels of milk-fat.

We present a new formulation of the dynamical matrix method for computing the magnetic normal modes of a large system, resulting in a highly scalable approach. The motion equation, which takes into account external field, dipolar and ferromagnetic exchange interactions, is rewritten in the form of a generalized eigenvalue problem without any additional approximation. For its numerical implementation several solvers have been explored, along with preconditioning methods. This reformulation was conceived to extend the study of magnetization dynamics to a broader class of finer-mesh systems, such as three-dimensional, irregular or defective structures, which in recent times raised the interest among researchers. To test its effectiveness, we applied the method to investigate the magnetization dynamics of a hexagonal artificial spin-ice as a function of a geometric distortion parameter following the Fibonacci sequence. We found several important features characterizing the low frequency spin modes as the geometric distortion is gradually increased.

Objective: The rampant growth of obesity worldwide has stimulated explosive research into human metabolism. Energy expenditure has been shown to be altered by diets differing in macronutrient composition, with low-carbohydrate, ketogenic diets eliciting a significant increase over other interventions. The central aim of this study was to explore the effects of the ketone β-hydroxybutyrate (βHB) on mitochondrial bioenergetics in adipose tissue. Methods: We employed three distinct systems—namely, cell, rodent, and human models. Following exposure to elevated βHB, we obtained adipose tissue to quantify mitochondrial function. Results: In every model, βHB robustly increased mitochondrial respiration, including an increase of roughly 91% in cultured adipocytes, 113% in rodent subcutaneous adipose tissue (SAT), and 128% in human SAT. However, this occurred without a commensurate increase in adipose ATP production. Furthermore, in cultured adipocytes and rodent adipose, we quantified and observed an increase in the gene expression involved in mitochondrial biogenesis and uncoupling status following βHB exposure. Conclusions: In conclusion, βHB increases mitochondrial respiration, but not ATP production, in mammalian adipocytes, indicating altered mitochondrial coupling. These findings may partly explain the increased metabolic rate evident in states of elevated ketones, and may facilitate the development of novel anti-obesity interventions.

Differences in botulinum neurotoxin manufacturing, formulation, and potency evaluation can impact dose and biological activity, which ultimately affect duration of action. The potency of different labeled vials of incobotulinumtoxinA (Xeomin®; 50 U, 100 U, or 200 U vials; incobotA) versus onabotulinumtoxinA (BOTOX®; 100 U vial; onabotA) were compared on a unit-to-unit basis to assess biological activity using in vitro (light-chain activity high-performance liquid chromatography (LCA-HPLC) and cell-based potency assay (CBPA)) and in vivo (rat compound muscle action potential (CMAP) and mouse digit abduction score (DAS)) assays. Using LCA-HPLC, incobotA units displayed approximately 54% of the protease activity of label-stated equivalent onabotA units. Lower potency, reflected by higher EC50, ID50, and ED50 values (pooled mean ± SEM), was displayed by incobotA compared to onabotA in the CBPA (EC50: incobotA 7.6 ± 0.7 U/mL; onabotA 5.9 ± 0.5 U/mL), CMAP (ID50: incobotA 0.078 ± 0.005 U/rat; onabotA 0.053 ± 0.004 U/rat), and DAS (ED50: incobotA 14.2 ± 0.5 U/kg; onabotA 8.7 ± 0.3 U/kg) assays. Lastly, in the DAS assay, onabotA had a longer duration of action compared to incobotA when dosed at label-stated equivalent units. In summary, onabotA consistently displayed greater biological activity than incobotA in two in vitro and two in vivo assays. Differences in the assay results do not support dose interchangeability between the two products.

Marine protected areas (MPAs) form the cornerstone of marine conservation. Identifying which factors contribute to their success or failure is crucial considering the international conservation targets for 2020 and the limited funds generally available for marine conservation. We identified common factors of success and/or failure of MPA effectiveness using peer-reviewed publications and first-hand expert knowledge for 27 case studies around the world. We found that stakeholder engagement was considered to be the most important factor affecting MPA success, and equally, its absence, was the most important factor influencing failure. Conversely, while some factors were identified as critical for success, their absence was not considered a driver of failure, and vice versa. This mismatch provided the impetus for considering these factors more critically. Bearing in mind that most MPAs have multiple objectives, including non-biological, this highlights the need for the development and adoption of standardized effectiveness metrics, besides biological considerations, to measure factors contributing to the success or failure of MPAs to reach their objectives. Considering our conclusions, we suggest the development of specific protocols for the assessment of stakeholder engagement, the role of leadership, the capacity of enforcement and compliance with MPAs objectives. Moreover, factors defining the success and failure of MPAs should be assessed not only by technical experts and the relevant authorities, but also by other stakeholder groups whose compliance is critical for the successful functioning of an MPA. These factors should be considered along with appropriate ecological, social, and economic data and then incorporated into adaptive management to improve MPA effectiveness.

We report the microwave response of symmetric and asymmetric threefold clusters with nearly contacting segments that can serve as the node in a Kagome artificial spin ice lattice. The structures are patterned on a coplanar waveguide and consist of elongated and nearly-contacting ellipses with uniform thickness. Branches of the ferromagnetic resonance spectra display mode softening that correlates well with the calculations, whereas agreement between the measured and simulated static magnetization is more qualitative.

ABSTRACT Nonencapsulated Streptococcus pneumoniae (NESp) is an emerging human pathogen that colonizes the nasopharynx and is associated with noninvasive diseases such as otitis media (OM), conjunctivitis, and nonbacteremic pneumonia. Since capsule expression was previously thought to be necessary for establishment of invasive pneumococcal disease (IPD), serotype-specific polysaccharide capsules are targeted by currently licensed pneumococcal vaccines. Yet, NESp expressing oligopeptide binding proteins AliC and AliD have been isolated during IPD. Thus, we hypothesize AliC and AliD are major NESp virulence determinants that facilitate persistence and development of IPD. Our study reveals that NESp expressing AliC and AliD have intensified virulence compared to isogenic mutants. Specifically, we demonstrate AliC and AliD enhance murine nasopharyngeal colonization and pulmonary infection and are required for OM in a chinchilla model. Furthermore, AliC and AliD increase pneumococcal survival in chinchilla whole blood and aid in resistance to killing by human leukocytes. Comparative proteome analysis revealed significant alterations in protein levels when AliC and AliD were absent. Virulence-associated proteins, including a pneumococcal surface protein C variant (CbpAC), were significantly downregulated, while starvation response indicators were upregulated in the double mutant relative to wild-type levels. We also reveal that differentially expressed CbpAC was essential for NESp adherence to epithelial cells, virulence during OM, reduction of C3b deposition on the NESp surface, and binding to nonspecific IgA. Altogether, the rise in NESp prevalence urges the need to understand how NESp establishes disease and persists in a host. This study highlights the roles of AliC, AliD, and CbpAC in the pathogenesis of NESp. IMPORTANCE Despite the effective, widespread use of licensed pneumococcal vaccines over many decades, pneumococcal infections remain a worldwide burden resulting in high morbidity and mortality. NESp subpopulations are rapidly rising in the wake of capsule-targeted vaccine strategies, yet there is very little knowledge on NESp pathogenic potential and virulence mechanisms. Although NESp lacks a protective capsule, NESp lineages expressing AliC and AliD have been associated with systemic infections. Furthermore, higher antibiotic resistance rates and transformation efficiencies associated with emerging NESp threaten treatment strategies needed to control pneumococcal infections and transmission. Elucidating how NESp survives within a host and establishes disease is necessary for development of broadened pneumococcal prevention methods. Our study identifies virulence determinants and host survival mechanisms employed by NESp with a high pathogenic potential. Moreover, our study also identifies virulence determinants shared by NESp and encapsulated strains that may serve as broad prevention and therapeutic targets.

Streptococcus pneumoniae is an important human pathogen. To cause disease, it must first colonize the nasopharynx. The widespread use of pneumococcal-conjugate vaccines which target the capsular polysaccharide has led to decreased nasopharyngeal carriage of vaccine serotypes, but a concomitant increase in carriage of non-vaccine serotypes and nonencapsulated S. pneumoniae (NESp). Some NESp express pneumococcal surface protein K (PspK), a virulence factor shown to contribute to nasopharyngeal colonization. We present the case of a child with chronic adenoiditis caused by a PspK+ NESp. We tested the pneumococcal isolate, designated C144.66, for antimicrobial resistance, the presence of the pspK gene and the expression of PspK. Sequence typing and genome sequencing were performed. C144.66 was found to be resistant to erythromycin and displayed intermediate resistance to penicillin and trimethoprim/sulfamethoxazole. C144.66 has the pspK gene in place of the capsule locus. Additionally, PspK expression was confirmed by flow cytometry. NESp are a growing concern as an emerging human pathogen, as current pneumococcal vaccines do not confer immunity against them. An inability to vaccinate against NESp may result in increased carriage and associated pathology.

Marine protected areas (MPAs) are a well-established conservation strategy, employed around the world to protect important marine species and ecosystems and support the recovery of declining populations. The continental waters of North America contain remarkable biodiversity, but many species face increasing pressure from overexploitation, climate change, and other anthropogenic impacts. Canada, Mexico, and the USA have pledged to protect at least 10% of their marine and coastal waters by 2020 as signatories to the Convention on Biological Diversity, and have made efforts to establish MPAs. These MPAs vary widely in terms of levels of protection and designation processes; information that is not reflected in official statistics. To this end, we critically examined progress toward the CBD target for marine protection in continental North American waters to determine how well ocean ecosystems are protected by MPAs. We reviewed government data to determine whether MPAs met four criteria: legal designation, permanence, presence of an administrative structure, and a completed management plan. Sites that met all four criteria were categorized as “implemented.” Any sites that failed to meet one or more criterion were considered “incompletely implemented” and excluded from the analysis. We also calculated the amount of “fully-protected” MPAs in which all extractive uses are prohibited. We found that

Healthy oceans are essential to human survival and prosperity, yet oceans are severely impacted worldwide by anthropogenic threats including overfishing, climate change, industrialization, pollution, and habitat destruction. Marine protected areas (MPAs) have been implemented around the world and are effective conservation tools that can mitigate some of these threats and build resilience when designed and managed well. However, despite a rich scientific literature on MPA effectiveness, science is not the main driver behind the design and implementation of many MPAs, leading to variable MPA effectiveness and bias in global MPA representativity. As a result, the marine conservation community focuses on promoting the creation of more MPAs as well as more effective ones, however no structure to improve or accelerate effective MPA implementation currently exists. To safeguard marine ecosystems on a global scale and better monitor progress toward ecosystem protection, robust science-based criteria are needed for evaluating MPAs and synthesizing the extensive and interdisciplinary science on MPA effectiveness. This paper presents a strategic initiative led by Marine Conservation Institute called the Global Ocean Refuge System (GLORES). GLORES aims to set standards to improve the quality of MPAs and catalyze strong protection for at least 30% of the ocean by 2030. Such substantial increase in marine protection is needed to maintain the resilience of marine ecosystems and restore their benefits to people. GLORES provides a comprehensive strategy that employs the rich body of MPA science to scale up existing marine conservation efforts.

Streptococcus pneumoniae is commonly found in the human nasopharynx and is the causative agent of multiple diseases. Since invasive pneumococcal infections are associated with encapsulated pneumococci, the capsular polysaccharide is the target of licensed pneumococcal vaccines. However, there is an increasing distribution of non-vaccine serotypes, as well as nonencapsulated S. pneumoniae (NESp). Both encapsulated and nonencapsulated pneumococci possess the polyamine oligo-transport operon (potABCD). Previous research has shown inactivation of the pot operon in encapsulated pneumococci alters protein expression and leads to a significant reduction in pneumococcal murine colonization, but the role of the pot operon in NESp is unknown. Here, we demonstrate deletion of potD from the NESp NCC1 strain MNZ67 does impact expression of the key proteins pneumolysin and PspK, but it does not inhibit murine colonization. Additionally, we show the absence of potD significantly increases biofilm production, both in vitro and in vivo. In a chinchilla model of otitis media (OM), the absence of potD does not significantly affect MNZ67 virulence, but it does significantly reduce the pathogenesis of the virulent encapsulated strain TIGR4 (serotype 4). Deletion of potD also significantly reduced persistence of TIGR4 in the lungs but increased persistence of PIP01 in the lungs. We conclude the pot operon is important for the regulation of protein expression and biofilm formation in both encapsulated and NCC1 nonencapsulated Streptococcus pneumoniae. However, in contrast to encapsulated pneumococcal strains, polyamine acquisition via the pot operon is not required for MNZ67 murine colonization, persistence in the lungs, or full virulence in a model of OM. Therefore, NESp virulence regulation needs to be further established to identify potential NESp therapeutic targets.

In 2013, a resurgence of measles occurred in Beijing, China. The outbreaks occurred among adults and were associated with endemic genotype H1 and imported genotype D8 viruses. Migrant workers were disproportionately represented in the outbreaks; thus, vaccinating such workers against measles may be an effective strategy toward the elimination of this disease.

ABSTRACT While significant protection from pneumococcal disease has been achieved by the use of polysaccharide and polysaccharide-protein conjugate vaccines, capsule-independent protection has been limited by serotype replacement along with disease caused by nonencapsulated Streptococcus pneumoniae (NESp). NESp strains compose approximately 3% to 19% of asymptomatic carriage isolates and harbor multiple antibiotic resistance genes. Surface proteins unique to NESp enhance colonization and virulence despite the lack of a capsule even though the capsule has been thought to be required for pneumococcal pathogenesis. Genes for pneumococcal surface proteins replace the capsular polysaccharide (cps) locus in some NESp isolates, and these proteins aid in pneumococcal colonization and otitis media (OM). NESp strains have been isolated from patients with invasive and noninvasive pneumococcal disease, but noninvasive diseases, specifically, conjunctivitis (85%) and OM (8%), are of higher prevalence. Conjunctival strains are commonly of the so-called classical NESp lineages defined by multilocus sequence types (STs) ST344 and ST448, while sporadic NESp lineages such as ST1106 are more commonly isolated from patients with other diseases. Interestingly, sporadic lineages have significantly higher rates of recombination than classical lineages. Higher rates of recombination can lead to increased acquisition of antibiotic resistance and virulence factors, increasing the risk of disease and hindering treatment. NESp strains are a significant proportion of the pneumococcal population, can cause disease, and may be increasing in prevalence in the population due to effects on the pneumococcal niche caused by pneumococcal vaccines. Current vaccines are ineffective against NESp, and further research is necessary to develop vaccines effective against both encapsulated and nonencapsulated pneumococci.

Streptococcus pneumoniae infections result in a range of human diseases and are responsible for almost one million deaths annually. Pneumococcal disease is mediated in part through surface structures and an anti-phagocytic capsule. Recent studies have shown that nonencapsulated Streptococcus pneumoniae (NESp) make up a significant portion of the pneumococcal population and are able to cause disease. NESp lack some common surface proteins expressed by encapsulated pneumococci, but express surface proteins unique to NESp. A chinchilla model of otitis media (OM) was used to determine the effect various pneumococcal mutations have on pathogenesis in both NESp and encapsulated pneumococci. Epithelial cell adhesion and invasion assays were used to examine the effects in relation to deletion of intrinsic genes or expression of novel genes. A mouse model of colonization was also utilized for comparison of various pneumococcal mutants. It was determined that pneumococcal surface protein K (PspK) and pneumolysin (Ply) affect NESp middle ear pathogenesis, but only PspK affected epithelial cell adhesion. Experiments in an OM model were done with encapsulated strains testing the importance of native virulence factors and treatment of OM. First, a triple deletion of the common virulence factors PspA, PspC, and Ply, (ΔPAC), from an encapsulated background abolished virulence in an OM model while a PspC mutant had detectable, but reduced amounts of recoverable bacteria compared to wildtype. Next, treatment of OM was effective when starting antibiotic treatment within 24 hrs with resolution by 48 hrs post treatment. Expression of NESp-specific virulence factor PspK in an encapsulated strain has not been previously studied, and we showed significantly increased adhesion and invasion of human epithelial cells by pneumococci. Murine colonization was not significantly increased when an encapsulated strain expressed PspK, but colonization was increased when a capsule mutant expressed PspK. The ability of PspK expression to increase colonization in a capsule mutant despite no increase in adhesion can be attributed to other functions of PspK, such as sIgA binding or immune modulation. OM is a substantial economic burden, thus a better understanding of both encapsulated pneumococcal pathogenesis and the emerging pathogen NESp is necessary for effective prevention and treatment.

In winegrapes (Vitis spp.), fruit quality traits such as berry color, total soluble solids content (SS), malic acid content (MA), and yeast assimilable nitrogen (YAN) affect fermentation or wine quality, and are important traits in selecting new hybrid winegrape cultivars. Given the high genetic diversity and heterozygosity of Vitis species and their tendency to exhibit inbreeding depression, linkage map construction and quantitative trait locus (QTL) mapping has relied on F1 families with the use of simple sequence repeat (SSR) and other markers. This study presents the construction of a genetic map by single nucleotide polymorphisms identified through genotyping-by-sequencing (GBS) technology in an F2 mapping family of 424 progeny derived from a cross between the wild species V. riparia Michx. and the interspecific hybrid winegrape cultivar, 'Seyval'. The resulting map has 1449 markers spanning 2424 cM in genetic length across 19 linkage groups, covering 95% of the genome with an average distance between markers of 1.67 cM. Compared to an SSR map previously developed for this F2 family, these results represent an improved map covering a greater portion of the genome with higher marker density. The accuracy of the map was validated using the well-studied trait berry color. QTL affecting YAN, MA and SS related traits were detected. A joint MA and SS QTL spans a region with candidate genes involved in the malate metabolism pathway. We present an analytical pipeline for calling intercross GBS markers and a high-density linkage map for a large F2 family of the highly heterozygous Vitis genus. This study serves as a model for further genetic investigations of the molecular basis of additional unique characters of North American hybrid wine cultivars and to enhance the breeding process by marker-assisted selection. The GBS protocols for identifying intercross markers developed in this study can be adapted for other heterozygous species.

Abdominal obesity and low cardiorespiratory fitness (CRF) are associated with insulin resistance in older adults. Exercise is associated with improvement in insulin sensitivity. Whether this association is mediated by change in CRF and/or abdominal obesity is unclear. The current study is a secondary analysis of data from a randomized controlled trial in Kingston, Ontario. Sedentary older adults (60-80 years) (N = 80) who completed the exercise (N = 59) or control (N = 21) conditions for 6 months were included. CRF was measured using a treadmill test, adipose tissue (AT) by magnetic resonance imaging, and insulin sensitivity by hyperinsulinemic-euglycemic clamp. Waist circumference (WC) was measured at the iliac crest. Mediation analyses were used to assess whether abdominal AT and/or CRF mediated the exercise-induced change in insulin sensitivity. By comparison to controls, reduction (mean ± SD) was observed for visceral (-0.4 ± 0.4 kg) and abdominal subcutaneous (-0.4 ± 0.4) AT depots, WC (-4.1 ± 3.2 cm) and BMI (-0.9 ± 0.8 kg/m2) (p < 0.05). Insulin sensitivity (4.2 ± 5.2 M/I) and CRF (0.2 ± 0.3 L/min) improved in the exercise group (p < 0.05). All AT variables, BMI and WC were mediators of the change in insulin sensitivity (p < 0.05). After adjustment for change in total AT, abdominal AT remained a mediator with an effect ratio of 0.79 (p < 0.05), whereas total AT was not significant when adjusted for abdominal AT (p > 0.05). The effect ratio for change in WC and BMI combined (0.63, p