Scavengers in islets fuel diabetic autoimmunity.

Autoreactive lymphocytes that infiltrate the pancreatic islet environment and target ß cells are primary drivers of type 1 diabetes. In this issue of Immunity, Srivastava et al.1 examine the role of the islet microenvironment in autoimmunity and find that the scavenging receptor CXCL16 on islet-resident macrophages uptakes oxidized low-density lipoproteins and promotes the differentiation and survival of infiltrating pathogenic CD8+ T cells.

Epigenetic Alteration of Smooth Muscle Cells Regulates Endothelin-Dependent Blood Pressure and Hypertensive Arterial Remodeling.

Long-standing hypertension (HTN) affects multiple organ systems and leads to pathologic arterial remodeling, which is driven largely by smooth muscle cell (SMC) plasticity. Although genome wide association studies (GWAS) have identified numerous variants associated with changes in blood pressure in humans, only a small percentage of these variants actually cause HTN. In order to identify relevant genes important in SMC function in HTN, we screened three separate human GWAS and Mendelian randomization studies to identify SNPs located within non-coding gene regions, focusing on genes encoding epigenetic enzymes, as these have been recently identified to control SMC fate in cardiovascular disease. We identified SNPs rs62059712 and rs74480102 in the promoter of the human JMJD3 gene and show that the minor C allele increases JMJD3 transcription in SMCs via increased SP1 binding to the JMJD3 promoter. Using our novel SMC-specific Jmjd3-deficient murine model ( Jmjd3 flox/flox Myh11 CreERT ), we show that loss of Jmjd3 in SMCs results in HTN, mechanistically, due to decreased EDNRB expression and a compensatory increase in EDNRA expression. As a translational corollary, through single cell RNA-sequencing (scRNA-seq) of human arteries, we found strong correlation between JMJD3 and EDNRB expression in SMCs. Further, we identified that JMJD3 is required for SMC-specific gene expression, and loss of JMJD3 in SMCs in the setting of HTN results in increased arterial remodeling by promoting the SMC synthetic phenotype. Our findings link a HTN-associated human DNA variant with regulation of SMC plasticity, revealing therapeutic targets that may be used in the screening and/or personalized treatment of HTN.

Efficacy and immunogenicity of a single dose of human papillomavirus vaccine compared to multidose vaccination regimens or no vaccination: An updated systematic review of evidence from clinical trials.

Objectives: This study systematically reviewed the published literature from clinical trials on the efficacy and immunogenicity of single-dose HPV vaccination compared to multidose schedules or no HPV vaccination. Methods: Four databases were searched for relevant articles published from Jan-1999 to Feb-2023. Articles were assessed for eligibility for inclusion using pre-defined criteria. Relevant data were extracted from eligible articles and a descriptive quality assessment was performed for each study. A narrative data synthesis was conducted, examining HPV infection, other clinical outcomes and immunogenicity responses by dose schedule. Results: Fifteen articles reporting data from six studies (all in healthy young females) were included. One article was included from each of three studies that prospectively randomised participants to receive a single HPV vaccine dose versus one or more comparator schedule(s). The other 12 articles reported data from three studies that randomised participants to receive multidose HPV vaccine (or control vaccine) schedules; in those studies, some participants failed to complete their allocated schedule, and evaluations were conducted to compare participants who actually received one, two or three doses. Across all efficacy studies, the incidence or prevalence of HPV16/18 infection was very low among HPV-vaccinated participants, regardless of the number of doses received; with no evidence for a difference between dose groups. In immunogenicity studies, HPV16/18 antibody seropositivity rates were high among all HPV-vaccinated participants. Antibody levels were significantly lower with one dose compared to two or three doses, but levels with one dose were stable and sustained to 11 years post-vaccination. Conclusions: Results from this review support recent World Health Organization recommendations allowing either one- or two-dose HPV vaccination in healthy young females. Longer-term efficacy and immunogenicity data from ongoing studies are awaited. Randomised trials of single-dose HPV-vaccination are urgently needed in other populations, e.g. boys, older females and people with HIV.

Diabetic wound keratinocytes induce macrophage JMJD3-mediated Nlrp3 expression via IL-1R signaling.

Macrophage (Mφ) plasticity is critical for normal wound repair; however, in type 2 diabetic wounds, Mφs persist in a low-grade inflammatory state that prevents the resolution of wound inflammation. Increased NLRP3 inflammasome activity has been shown in diabetic wound Mφs; however, the molecular mechanisms regulating NLRP3 expression and activity are unclear. Here, we identified that diabetic wound keratinocytes induce Nlrp3 gene expression in wound Mφs through IL-1 receptor-mediated signaling, resulting in enhanced inflammasome activation in the presence of PAMPs and DAMPs. We found that IL-1 alpha is increased in human and murine wound diabetic keratinocytes compared to non-diabetic controls and directly induces Mφ Nlrp3 expression through IL-1 receptor signaling. Mechanistically, we report that the histone demethylase, JMJD3, is increased in wound Mφs late post-injury and is induced by IL-1 alpha from diabetic wound keratinocytes, resulting in Nlrp3 transcriptional activation through an H3K27me3-mediated mechanism. Using genetically engineered mice deficient in JMJD3 in myeloid cells (Jmjd3fl/fllyz2cre+), we demonstrate that JMJD3 controls Mφ-mediated Nlrp3 expression during diabetic wound healing. Thus, our data suggest a role for keratinocyte-mediated IL-1 alpha/IL-1R signaling in driving enhanced NLRP3 inflammasome activity in wound Mφs. These data also highlight the importance of cell crosstalk in wound tissues and identify JMJD3 and the ILR signaling cascade as important upstream therapeutic targets for Mφ NLRP3 inflammasome hyperactivity in nonhealing diabetic wounds.

Histone demethylase JARID1C/KDM5C regulates Th17 cells by increasing IL-6 expression in diabetic plasmacytoid dendritic cells.

Plasmacytoid dendritic cells (pDCs) are first responders to tissue injury, where they prime naive T cells. The role of pDCs in physiologic wound repair has been examined, but little is known about pDCs in diabetic wound tissue and their interactions with naive CD4+ T cells. Diabetic wounds are characterized by increased levels of inflammatory IL-17A cytokine, partly due to increased Th17 CD4+ cells. This increased IL-17A cytokine, in excess, impairs tissue repair. Here, using human tissue and murine wound healing models, we found that diabetic wound pDCs produced excess IL-6 and TGF-ß and that these cytokines skewed naive CD4+ T cells toward a Th17 inflammatory phenotype following cutaneous injury. Further, we identified that increased IL-6 cytokine production by diabetic wound pDCs is regulated by a histone demethylase, Jumonji AT-rich interactive domain 1C histone demethylase (JARID1C). Decreased JARID1C increased IL-6 transcription in diabetic pDCs, and this process was regulated upstream by an IFN-I/TYK2/JAK1,3 signaling pathway. When inhibited in nondiabetic wound pDCs, JARID1C skewed naive CD4+ T cells toward a Th17 phenotype and increased IL-17A production. Together, this suggests that diabetic wound pDCs are epigenetically altered to increase IL-6 expression that then affects T cell phenotype. These findings identify a therapeutically manipulable pathway in diabetic wounds.

Obesity Inhibits Alveolar Macrophage Responses to Pseudomonas aeruginosa Pneumonia via Upregulation of Prostaglandin E2 in Male, but Not Female, Mice.

Obesity is associated with increased morbidity and mortality during bacterial pneumonia. Cyclooxygenase-2 (COX-2) and PGE2 have been shown to be upregulated in patients who are obese. In this study, we investigated the role of obesity and PGE2 in bacterial pneumonia and how inhibition of PGE2 improves antibacterial functions of macrophages. C57BL/6J male and female mice were fed either a normal diet (ND) or high-fat diet (HFD) for 16 wk. After this time, animals were infected with Pseudomonas aeruginosa in the lung. In uninfected animals, alveolar macrophages were extracted for either RNA analysis or to be cultured ex vivo for functional analysis. HFD resulted in changes in immune cell numbers in both noninfected and infected animals. HFD animals had increased bacterial burden compared with ND animals; however, male HFD animals had higher bacterial burden compared with HFD females. Alveolar macrophages from HFD males had decreased ability to phagocytize and kill bacteria and were shown to have increased cyclooxygenase-2 and PGE2. Treating male, but not female, alveolar macrophages with PGE2 leads to increases in cAMP and decreased bacterial phagocytosis. Treatment with lumiracoxib-conjugated nanocarriers targeting alveolar macrophages improves bacterial phagocytosis and clearance in both ND and HFD male animals. Our study highlights that obesity leads to worse morbidity during bacterial pneumonia in male mice because of elevated PGE2. In addition, we uncover a sex difference in both obesity and infection, because females produce high basal PGE2 but because of a failure to signal via cAMP do not display impaired phagocytosis.

Factors predicting mortality in hospitalised HIV-negative children with lower-chest-wall indrawing pneumonia and implications for management.

INTRODUCTION: In 2012, the World Health Organization revised treatment guidelines for childhood pneumonia with lower chest wall indrawing (LCWI) but no 'danger signs', to recommend home-based treatment. We analysed data from children hospitalized with LCWI pneumonia in the Pneumonia Etiology Research for Child Health (PERCH) study to identify sub-groups with high odds of mortality, who might continue to benefit from hospital management but may not be admitted by staff implementing the 2012 guidelines. We compare the proportion of deaths identified using the criteria in the 2012 guidelines, and the proportion of deaths identified using an alternative set of criteria from our model. METHODS: PERCH enrolled a cohort of 2189 HIV-negative children aged 2-59 months who were admitted to hospital with LCWI pneumonia (without obvious cyanosis, inability to feed, vomiting, convulsions, lethargy or head nodding) between 2011-2014 in Kenya, Zambia, South Africa, Mali, The Gambia, Bangladesh, and Thailand. We analysed risk factors for mortality among these cases using predictive logistic regression. Malnutrition was defined as mid-upper-arm circumference <125mm or weight-for-age z-score <-2. RESULTS: Among 2189 cases, 76 (3·6%) died. Mortality was associated with oxygen saturation <92% (aOR 3·33, 1·99-5·99), HIV negative but exposed status (4·59, 1·81-11·7), moderate or severe malnutrition (6·85, 3·22-14·6) and younger age (infants compared to children 12-59 months old, OR 2·03, 95%CI 1·05-3·93). At least one of three risk factors: hypoxaemia, HIV exposure, or malnutrition identified 807 children in this population, 40% of LCWI pneumonia cases and identified 86% of the children who died in hospital (65/76). Risk factors identified using the 2012 WHO treatment guidelines identified 66% of the children who died in hospital (n = 50/76). CONCLUSIONS: Although it focuses on treatment failure in hospital, this study supports the proposal for better risk stratification of children with LCWI pneumonia. Those who have hypoxaemia, any malnutrition or those who were born to HIV positive mothers, experience poorer outcomes than other children with LCWI pneumonia. Consistent identification of these risk factors should be prioritised and children with at least one of these risk factors should not be managed in the community.

Quantifying potential marine debris sources and potential threats to penguins on the West Antarctic Peninsula.

Marine pollution is becoming ubiquitous in the environment. Observations of pollution on beaches, in the coastal ocean, and in organisms in the Antarctic are becoming distressingly common. Increasing human activity, growing tourism, and an expanding krill fishing industry along the West Antarctic Peninsula all represent potential sources of plastic pollution and other debris (collectively referred to as debris) to the region. However, the sources of these pollutants from point (pollutants released from discrete sources) versus non-point (pollutants from a large area rather than a specific source) sources are poorly understood. We used buoyant simulated particles released in a high-resolution physical ocean model to quantify pollutant loads throughout the region. We considered non-point sources of debris from the Antarctic Circumpolar Current, Bellingshausen Sea, Weddell Sea, and point source pollution from human activities including tourism, research, and fishing. We also determined possible origins for observed debris based on data from the Southern Ocean Observing System and Palmer Long-Term Ecological Research program. Our results indicate that point source pollution released in the coastal Antarctic is more likely to serve as a source for observed debris than non-point sources, and that the dominant source of pollution is region-specific. Penguin colonies in the South Shetland and Elephant Islands had the greatest debris load from point sources whereas loads from non-point sources were greatest around the southernmost colonies. Penguin colonies at Cornwallis Island and Fort Point were exposed to the highest theoretical debris loads. While these results do not include physical processes such as windage and Stokes Drift that are known to impact debris distributions and transport in the coastal ocean, these results provide critical insights to building an effective stratified sampling and monitoring effort to better understand debris distributions, concentrations, and origins throughout the West Antarctic Peninsula.

Biofilm-derived oxylipin 10-HOME mediated immune response in women with breast implants.

Breast implant illness (BII) is a poorly understood disease in which patients develop symptoms typical of autoimmune conditions following breast implantation. There is no known underlying cause, and patients often resort to breast implant removal and capsulectomy to alleviate symptoms. In this issue of the JCI, Khan and colleagues examined 86 breast explants from patients that reported BII symptoms and 55 control explants. The BII group showed a disproportionally high degree of biofilm, which was associated with oxylipin (10-HOME) on the implant surfaces. Injections of 10-HOME in the mammary fat pad of a murine model recapitulated BII symptoms and increased Th1 cell populations. Notably, macrophages in the periprosthetic tissue from BII patients were more likely to exhibit a proinflammatory phenotype, and naive T cells exposed to 10-HOME caused naive macrophages to differentiate to a proinflammatory phenotype. This work provides a pathophysiologic mechanism for a currently understudied and poorly characterized disease.

Current Status and Principles for the Treatment and Prevention of Diabetic Foot Ulcers in the Cardiovascular Patient Population: A Scientific Statement From the American Heart Association.

Despite the known higher risk of cardiovascular disease in individuals with type 2 diabetes, the pathophysiology and optimal management of diabetic foot ulcers (DFUs), a leading complication associated with diabetes, is complex and continues to evolve. Complications of type 2 diabetes, such as DFUs, are a major cause of morbidity and mortality and the leading cause of major lower extremity amputation in the United States. There has recently been a strong focus on the prevention and early treatment of DFUs, leading to the development of multidisciplinary diabetic wound and amputation prevention clinics across the country. Mounting evidence has shown that, despite these efforts, amputations associated with DFUs continue to increase. Furthermore, due to increasing patient complexity of management secondary to comorbid conditions, such as cardiovascular disease, the management of peripheral artery disease associated with DFUs has become increasingly difficult, and care delivery is often episodic and fragmented. Although structured, process-specific approaches exist at individual institutions for the management of DFUs in the cardiovascular patient population, there is insufficient awareness of these principles in the general medicine communities. Furthermore, there is growing interest in better understanding the mechanistic underpinnings of DFUs to better define personalized medicine to improve outcomes. The goals of this scientific statement are to provide salient background information on the complex pathogenesis and current management of DFUs in cardiovascular patients, to guide therapeutic and preventive strategies and future research directions, and to inform public policy makers on health disparities and other barriers to improving and advancing care in this expanding patient population.

Transforming the Future of Surgeon-Scientists.

OBJECTIVE: To create a blueprint for surgical department leaders, academic institutions, and funding agencies to optimally support surgeon-scientists. BACKGROUND: Scientific contributions by surgeons have been transformative across many medical disciplines. Surgeon-scientists provide a distinct approach and mindset toward key scientific questions. However, lack of institutional support, pressure for increased clinical productivity, and growing administrative burden are major challenges for the surgeon-scientist, as is the time-consuming nature of surgical training and practice. METHODS: An American Surgical Association Research Sustainability Task Force was created to outline a blueprint for sustainable science in surgery. Leaders from top NIH-sponsored departments of surgery engaged in video and in-person meetings between January and April 2023. A strength, weakness, opportunities, threats analysis was performed, and workgroups focused on the roles of surgeons, the department and institutions, and funding agencies. RESULTS: Taskforce recommendations: (1) SURGEONS: Growth mindset : identifying research focus, long-term planning, patience/tenacity, team science, collaborations with disparate experts; Skill set : align skills and research, fill critical skill gaps, develop team leadership skills; DEPARTMENT OF SURGERY (DOS): (2) MENTORSHIP: Chair : mentor-mentee matching/regular meetings/accountability, review of junior faculty progress, mentorship training requirement, recognition of mentorship (eg, relative value unit equivalent, awards; Mentor: dedicated time, relevant scientific expertise, extramural funding, experience and/or trained as mentor, trusted advisor; Mentee : enthusiastic/eager, proactive, open to feedback, clear about goals; (3) FINANCIAL SUSTAINABILITY: diversification of research portfolio, identification of matching funding sources, departmental resource awards (eg, T-/P-grants), leveraging of institutional resources, negotiation of formalized/formulaic funds flow investment from academic medical center toward science, philanthropy; (4) STRUCTURAL/STRATEGIC SUPPORT: Structural: grants administrative support, biostats/bioinformatics support, clinical trial and research support, regulatory support, shared departmental laboratory space/equipment; Strategic: hiring diverse surgeon-scientist/scientists faculty across DOS, strategic faculty retention/ recruitment, philanthropy, career development support, progress tracking, grant writing support, DOS-wide research meetings, regular DOS strategic research planning; (5) COMMUNITY AND CULTURE: Community: right mix of faculty, connection surgeon with broad scientific community; Culture: building research infrastructure, financial support for research, projecting importance of research (awards, grand rounds, shoutouts); (6) THE ROLE OF INSTITUTIONS: Foundation: research space co-location, flexible start-up packages, courses/mock study section, awards, diverse institutional mentorship teams; Nurture: institutional infrastructure, funding (eg, endowed chairs), promotion friendly toward surgeon-scientists, surgeon-scientists in institutional leadership positions; Expectations: RVU target relief, salary gap funding, competitive starting salaries, longitudinal salary strategy; (7) THE ROLE OF FUNDING AGENCIES: change surgeon research training paradigm, offer alternate awards to K-awards, increasing salary cap to reflect market reality, time extension for surgeon early-stage investigator status, surgeon representation on study section, focused award strategies for professional societies/foundations. CONCLUSIONS: Authentic recommitment from surgeon leaders with intentional and ambitious actions from institutions, corporations, funders, and society is essential in order to reap the essential benefits of surgeon-scientists toward advancements of science.

Descriptions and patterns in opportunistic marine debris collected near Palmer Station, Antarctica.

Observations of marine debris in Antarctica have been increasing; however, impacts, distributions, sources, and transport pathways of debris remain poorly understood. Here, we describe the spatial distribution, types, and potential origins of marine debris in 2022/2023 near Palmer Station, Antarctica. We opportunistically collected 135 pieces of marine debris with the majority of items found along shorelines (90 %), some found in/near seabird nests/colonies (7 %) and few on inland rocky terrain (3 %). Plastic and abandoned, lost, or discarded fishing gear dominated observed debris. Results suggest that wind and the Antarctic Coastal Current may be a major pathway for debris. This study is the first assessment of marine debris in this region and suggests that oceanography, weather patterns, and shoreline geomorphology could play a role in determining where debris will accumulate. Continued tracking of debris and development of structured surveys is important for understanding the impacts of human activities in a biological hotspot.

Continuity and Rupture in Crisis: from Ebola to COVID-19 in Sierra Leone and the eastern Democratic Republic of the Congo.

This article examines the experience of healthcare professionals working in primary healthcare provision during the first wave of the COVID-19 pandemic in North Kivu, the Democratic Republic of the Congo, and in Kambia District, Sierra Leone. Drawing on ethnographic observation, interviews and focus groups, we explore everyday narratives of 'crisis' in these two regions which had recently seen Ebola epidemics. In describing the impact of COVID-19 on their life, work, and relationships with patients, healthcare workers made sense of the pandemic in relation to broader experiences of structural economic and political crisis, as well as differing experiences of recent Ebola epidemics. There were contradictory experiences of rupture and continuity: whilst COVID-19 disrupted routine health provision and exacerbated tensions with patients, the pandemic was also described as continuity, interacting with broader structural problems and longer-term experiences of 'crisis'. In effect, healthcare workers experienced the COVID-19 pandemic at the crossroads between the exceptional and the everyday, where states of exception brought by emergency measures shed new light on long-standing tensions and structural crisis.

SARS-CoV-2 seroprevalence and implications for population immunity: Evidence from two Health and Demographic Surveillance System sites in Kenya, February-December 2022.

BACKGROUND: We sought to estimate SARS-CoV-2 antibody seroprevalence within representative samples of the Kenyan population during the third year of the COVID-19 pandemic and the second year of COVID-19 vaccine use. METHODS: We conducted cross-sectional serosurveys among randomly selected, age-stratified samples of Health and Demographic Surveillance System (HDSS) residents in Kilifi and Nairobi. Anti-spike (anti-S) immunoglobulin G (IgG) serostatus was measured using a validated in-house ELISA and antibody concentrations estimated with reference to the WHO International Standard for anti-SARS-CoV-2 immunoglobulin. RESULTS: HDSS residents were sampled in February-June 2022 (Kilifi HDSS N = 852; Nairobi Urban HDSS N = 851) and in August-December 2022 (N = 850 for both sites). Population-weighted coverage for ≥1 doses of COVID-19 vaccine were 11.1% (9.1-13.2%) among Kilifi HDSS residents by November 2022 and 34.2% (30.7-37.6%) among Nairobi Urban HDSS residents by December 2022. Population-weighted anti-S IgG seroprevalence among Kilifi HDSS residents increased from 69.1% (65.8-72.3%) by May 2022 to 77.4% (74.4-80.2%) by November 2022. Within the Nairobi Urban HDSS, seroprevalence by June 2022 was 88.5% (86.1-90.6%), comparable with seroprevalence by December 2022 (92.2%; 90.2-93.9%). For both surveys, seroprevalence was significantly lower among Kilifi HDSS residents than among Nairobi Urban HDSS residents, as were antibody concentrations (p < 0.001). CONCLUSION: More than 70% of Kilifi residents and 90% of Nairobi residents were seropositive for anti-S IgG by the end of 2022. There is a potential immunity gap in rural Kenya; implementation of interventions to improve COVID-19 vaccine uptake among sub-groups at increased risk of severe COVID-19 in rural settings is recommended.

Symptom prevalence and secondary attack rate of SARS-CoV-2 in rural Kenyan households: A prospective cohort study.

BACKGROUND: We estimated the secondary attack rate of SARS-CoV-2 among household contacts of PCR-confirmed cases of COVID-19 in rural Kenya and analysed risk factors for transmission. METHODS: We enrolled incident PCR-confirmed cases and their household members. At baseline, a questionnaire, a blood sample, and naso-oropharyngeal swabs were collected. Household members were followed 4, 7, 10, 14, 21 and 28 days after the date of the first PCR-positive in the household; naso-oropharyngeal swabs were collected at each visit and used to define secondary cases. Blood samples were collected every 1-2 weeks. Symptoms were collected in a daily symptom diary. We used binomial regression to estimate secondary attack rates and survival analysis to analyse risk factors for transmission. RESULTS: A total of 119 households with at least one positive household member were enrolled between October 2020 and September 2022, comprising 503 household members; 226 remained in follow-up at day 14 (45%). A total of 43 secondary cases arose within 14 days of identification of the primary case, and 81 household members remained negative. The 7-day secondary attack rate was 4% (95% CI 1%-10%), the 14-day secondary attack rate was 28% (95% CI 17%-40%). Of 38 secondary cases with data, eight reported symptoms (21%, 95% CI 8%-34%). Antibody to SARS-CoV-2 spike protein at enrolment was not associated with risk of becoming a secondary case. CONCLUSION: Households in our setting experienced a lower 7-day attack rate than a recent meta-analysis indicated as the global average (23%-43% depending on variant), and infection is mostly asymptomatic in our setting.

2023 Vascular Research Initiatives Conference: Structural and Immune Cells in Vascular Disease.

The 2023 Vascular Research Initiatives Conference (VRIC) was held in Boston, Massachusetts, and coincided with the first day of Vascular Discovery 2023, hosted by the American Heart Association. VRIC attracts vascular clinicians, surgeon-scientists, and basic science researchers to a common arena to facilitate the exchange of basic and translational science to stimulate and inspire participants to study and find solutions to vascular conditions. The theme of the conference this year was "Structural and Immune Cells in Vascular Disease." Abstract sessions focused on venous disease, vascular regeneration, stem cells and wound healing, aortopathies, and the role of the immune system in atherosclerosis. A moderated translational science panel included talks from Dr Chiara Giannarelli and Dr Bhama Ramkhelawon. Recipients of Society for Vascular Surgery partner grants and National Institutes of Health K08 awardees presented their progress reports, and the Resident Research and VRIC Trainee Awardees were acknowledged. The Alexander W. Clowes Distinguished Lecture, entitled "Co-stimulatory Immune Checkpoints in Atherosclerosis: Novel Immunotherapeutic Targets to Combat Atherosclerotic Cardiovascular Disease" was given by Dr Ester Lutgens. VRIC continues to foster interdisciplinary collaborations across the translational field of vascular disease.

Population immunity to pneumococcal serotypes in Kilifi, Kenya, before and 6 years after the introduction of PCV10 with a catch-up campaign: an observational study of cross-sectional serosurveys.

BACKGROUND: In Kilifi (Kenya), a pneumococcal conjugate vaccine (PCV10) was introduced in 2011 in infants (aged <1 year, 3 + 0 schedule) with a catch-up campaign in children aged 1-4 years. We aimed to measure the effect of PCV10 on population immunity. METHODS: In this observational study, repeated cross-sectional serosurveys were conducted in independent random samples of 500 children younger than 15 years every 2 years between 2009 and 2017. During these surveys, blood samples were collected by venesection. Concentrations of anti-capsular IgGs against vaccine serotypes (VTs) 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F, and against serotypes 6A and 19A, were assayed by ELISA. We plotted the geometric mean concentrations (GMCs) by birth year to visualise age-specific antibody profiles. In infants, IgG concentrations of 0·35 µg/mL or higher were considered protective. FINDINGS: Of 3673 volunteers approached, 2152 submitted samples for analysis across the five surveys. Vaccine introduction resulted in an increase in the proportion of young children with protective IgG concentrations, compared with before vaccine introduction (from 0-33% of infants with VT-specific levels over the correlate of protection in 2009, to 60-94% of infants in 2011). However, among those vaccinated in infancy, GMCs of all ten VTs had waned rapidly by the age of 1, but rose again later in childhood. GMCs among children aged 10-14 years were consistently high over time (eg, the range of GMCs across survey rounds were between 0·45 µg/mL and 1·00 µg/mL for VT 23F and between 2·00 µg/mL and 3·11 µg/mL for VT 19F). INTERPRETATION: PCV10 in a 3 + 0 schedule elicited protective IgG levels during infancy, when disease risk is high. The high antibody levels in children aged 10-14 years might indicate continued exposure to vaccine serotypes due to residual carriage or to memory responses to cross-reactive antigens. Despite rapid waning of IgG after vaccination, disease incidence among young children in this setting remains low, suggesting that lower thresholds of antibody, or other markers of immunity (eg, memory B cells), may be needed to assess population protection among children who have aged past infancy. FUNDING: Gavi, the Vaccine Alliance; Wellcome Trust.

Quantifying Antarctic krill connectivity across the West Antarctic Peninsula and its role in large-scale Pygoscelis penguin population dynamics.

Antarctic krill (Euphausia superba) are considered a keystone species for higher trophic level predators along the West Antarctic Peninsula (WAP) during the austral summer. The connectivity of krill may play a critical role in predator biogeography, especially for central-place foragers such as the Pygoscelis spp. penguins that breed along the WAP during the austral summer. Antarctic krill are also heavily fished commercially; therefore, understanding population connectivity of krill is critical to effective management. Here, we used a physical ocean model to examine adult krill connectivity in this region using simulated krill with realistic diel vertical migration behaviors across four austral summers. Our results indicate that krill north and south of Low Island and the southern Bransfield Strait are nearly isolated from each other and that persistent current features play a role in this lack of inter-region connectivity. Transit and entrainment times were not correlated with penguin populations at the large spatial scales examined. However, long transit times and reduced entrainment correlate spatially with the areas where krill fishing is most intense, which heightens the risk that krill fishing may lead to limited krill availability for predators.

Satisfaction With Participation in the First STEPS Behavioral Intervention: Experiences of Parents of Young Children With Newly Diagnosed Type 1 Diabetes.

OBJECTIVE: Parents of young children with new-onset type 1 diabetes (T1D) often experience significant distress and struggle with T1D management during a challenging developmental stage. The First STEPS (Study of Type 1 in Early childhood and Parenting Support) trial evaluated a stepped-care behavioral intervention comprising increasingly intensive intervention steps (peer parent coach, cognitive-behavioral counseling, consultations with diabetes educator and psychologist) based on need. The intervention improved parental depressive symptoms compared to usual care. Subsequently, we examined parent satisfaction with the intervention to guide potential implementation and refinement for future trials. METHODS: Participants were 157 parents of young children newly diagnosed with T1D. At 9 months post randomization, n = 153 completed satisfaction questionnaires and n = 17 completed qualitative interviews. Satisfaction ratings about trial procedures and each intervention step were summarized. We used thematic analysis with the interview transcripts to generate themes related to participants' experiences in the trial overall and intervention specifically. We explored differences in themes between participants who did versus did not respond to the intervention and among those who experienced different intervention steps. RESULTS: Most participants in both arms rated study participation and methods positively (>95%), and those completing interviews described high satisfaction with study procedures overall, retention incentives, and contact with study staff. Intervention participants' satisfaction ratings were high across steps. Two qualitative themes reflected satisfaction with the intervention enhancing self-efficacy and social support. CONCLUSIONS: High satisfaction suggests implementing a stepped-care behavioral intervention as part of routine clinical care following T1D diagnosis would be well received.

Psychological disorders and positive mental health in gender-diverse youth.

An estimated 1.8% of U.S. adolescents identify as transgender, and when using expansive language to include diverse identities along the gender continuum (e.g., nonbinary, gender fluid), rates may be notably higher. Gender-diverse youth (GDY) experience significantly elevated rates of depression, anxiety, suicidality, and eating disorders relative to the general population. Youth with autism spectrum disorders also appear to report diverse gender identities at higher rates than neurotypical youth. Gender-minoritized stress, including distal (e.g., transgender related stigma and discrimination) and proximal (e.g., social or familial rejection due to gender-diverse identity) stressors, increase risk for mental health disorders among GDY, and gender affirmation mitigates risk. Gender-affirming medical and behavioral health care is associated with enhanced resilience and positive mental health outcomes for GDY.