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Background: Smoking and alcohol misuse are lifestyle factors that can be controlled and have significant health effects. Both these factors increase the risk of developing conditions such as diabetes mellitus because they affect glucose metabolism and can interfere with blood glucose control in individuals with diabetes. Research on tobacco and alcohol use and specific health outcomes among adults with prediabetes or type 2 diabetes mellitus (T2DM) could provide valuable information leading to more efficient treatment and management of this disease., Objectives: To assess the association between tobacco and alcohol use and specific health outcomes among South African adults with prediabetes or T2DM., Methods: Data from the 2016 South African Demographic and Health Survey were analysed using Stata v17. Participants were classified into prediabetes or T2DM groups, based on a glycated haemoglobin cut-off of 5.7% or self-report of a previous diagnosis of T2DM. Exposures of interest were self-reported current tobacco smoking and problem/risky alcohol use. The associations between these exposures and health outcomes in the different groups were assessed using multivariable logistic regression analysis. We adjusted for specific confounders in the regression models., Results: Of a total of 6 108 participants (mean (standard deviation) age 41 (19) years), 72.2% (n=4 409) had prediabetes and 27.8% (n=1 699) T2DM; 17.7% (n=1 084) were current smokers and 9.3% (n=565) reported problem/risky alcohol use. Current smoking was significantly associated with 40% increased odds of shortness of breath (adjusted odds ratio (aOR) 1.40; 95% confidence interval (CI) 1.1 - 1.7; p<0.001) and 67% increased odds of chronic obstructive pulmonary disease (COPD)/asthma (aOR 1.67; 95% CI 1.2 - 2.2; p<0.001). Problem/risky alcohol use was significantly associated with 40% increased odds of COPD/asthma (aOR 1.40; 95% CI 1.1 - 1.7; p=0.001) and 92% increased odds of having cancer (aOR 1.92; 95% CI 1.5 - 2.5; p<0.001)., Conclusion: There is a need for targeted smoking cessation programmes and alcohol misuse counselling among individuals living with diabetes and prediabetes.

Context: Cardiovascular disease (CVD) is the leading cause of mortality for US women; lack of health insurance contributes to poor control of risk factors and increased mortality. Health coaching including motivational interviewing can support primary and secondary CVD prevention, but among uninsured women, improving health outcomes is dependent on successfully reaching priority populations., Objective: We evaluated the implementation and reach of health coaching with motivational interviewing among clients in the Illinois WISEWOMAN Program (IWP), a CVD screening and risk-reduction program for uninsured women aged 40 to 64., Intervention: Following CVD screening, motivational interviewing is offered to all IWP clients via four 30-min one-on-one health coaching sessions to offer personalized guidance on setting and achieving health behavior goals., Setting: Our analysis included clients from the eight community-based Illinois agencies that implemented IWP from 2019 to 2023., Design and Measures: We assessed client demographic and baseline health characteristics among all IWP clients, those who participated in health coaching by attending at least one session, and those who completed health coaching by attending at least three of four sessions. We also assessed health coaching participation and completion by agency and examined agency-specific associations between client characteristics and health coaching participation and completion., Results: Among IWP enrollees (n = 3094), 89.7% participated in at least one health coaching session but only 31.4% completed health coaching by attending at least three sessions. Over 90% of IWP clients participated in at least one health coaching session at 4 IWP agencies. Further, over 85% of health coaching participants completed health coaching at four agencies. Across agencies, no client-level characteristics were consistently associated with health coaching participation or completion., Conclusions: High motivational interviewing participation rates support its acceptability among uninsured women, but agency-level community-level barriers likely prevent client engagement in multiple sessions. Reducing CVD risk requires working with partner agencies to address barriers to reaching the priority population., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc.)

Introduction: Hypertension is a major factor related to morbidity and mortality in middle- and high‑income countries., Objectives: The aim of the study was to assess the incidence and prevalence of registered hypertension in Poland in the years 2018-2022., Patients and Methods: We used the public payer claims database to assess incidence and prevalence of registered hypertension. Definition of hypertension was based on the International Classification of Diseases, 10th Revision codes from I10 to I15., Results: The number of registered hypertension cases during the analyzed period varied from 10.9 to 11 million. The prevalence was 0.5%, 0.5%, 0.5%, 0.4%, and 0.4% (P <0.001) in children (age <18 years) and 34.4%, 34.8%, 34.9%, 35.2%, and 35.2% (P <0.001) among adults in 2018, 2019, 2020, 2021, and 2022, respectively. In 2022, the mean (SD) age of persons with registered hypertension was 66.2 (14.1) years in women and 60.8 (14.8) years in men (P <0.001). The highest incidence of registered hypertension was found in men aged 55-59 years and in women aged 50-54 years. In the population aged up to 54 years, the registered prevalence of hypertension was higher among men, while in older age groups it was higher in women, reaching 94% and 87% in the oldest groups of women and men, respectively., Conclusions: In 2022, the number of patients with registered hypertension in Poland was close to 11 million, while the prevalence was 35.2% in adults and 0.4% in children. In the population under the age of 55 years, hypertension is more common in men, while women predominate in the older age groups.

Malaria is a life-threatening disease of global health importance, particularly in sub-Saharan Africa. The growth inhibition assay (GIA) is routinely used to evaluate, prioritize, and quantify the efficacy of malaria blood-stage vaccine candidates but does not reliably predict either naturally acquired or vaccine-induced protection. Controlled human malaria challenge studies in semi-immune volunteers provide an unparalleled opportunity to robustly identify mechanistic correlates of protection. We leveraged this platform to undertake a head-to-head comparison of seven functional antibody assays that are relevant to immunity against the erythrocytic merozoite stage of Plasmodium falciparum. Fc-mediated effector functions were strongly associated with protection from clinical symptoms of malaria and exponential parasite multiplication, while the gold standard GIA was not. The breadth of Fc-mediated effector function discriminated clinical immunity following the challenge. These findings present a shift in the understanding of the mechanisms that underpin immunity to malaria and have important implications for vaccine development., Competing Interests: Declaration of interests In the CHMI-SIKA team, Y.A., P.F.B., S.L.H., E.R.J., B.K.L.S., and T.L.R. are salaried, full-time employees of Sanaria Inc., the manufacturer of Sanaria PfSPZ Challenge. Thus, all authors associated with Sanaria Inc. have potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The merozoite surface protein 1 (MSP1) is the most abundant protein on the surface of the invasive merozoite stages of Plasmodium falciparum and has long been considered a key target of protective immunity. We used samples from a single controlled human malaria challenge study to test whether the full-length version of MSP1 (MSP1 FL ) induced antibodies that mediated Fc-IgG functional activity in five independent assays. We found that anti-MSP1 FL antibodies induced complement fixation via C1q, monocyte-mediated phagocytosis, neutrophil respiratory burst, and natural killer cell degranulation as well as IFNγ production. Activity in each of these assays was strongly associated with protection. The breadth of MSP1-specific Fc-mediated effector functions was more strongly associated with protection than the individual measures and closely mirrored what we have previously reported using the same assays against merozoites. Our findings suggest that MSP1 FL is an important target of functional antibodies that contribute to a protective immune response against malaria., (© 2024 Rosenkranz et al.)

Objectives: This study aimed to evaluate competing risks and functional ability measures among patients who had a stroke., Design: A joint model comprising two related submodels was applied: a cause-specific hazard submodel for competing drop-out and stroke-related death risks, and a partial proportional odd submodel for longitudinal functional ability., Setting: Felege Hiwot Referral Hospital, Ethiopia., Participants: The study included 400 patients who had a stroke from the medical ward outpatient stroke unit at Felege Hiwot Referral Hospital, who were treated from September 2018 to August 2021., Results: Among the 400 patients who had a stroke, 146 (36.5%) died and 88 (22%) dropped out. At baseline, 14% of patients had no symptoms and/or disability while 24% had slight disability, and 25% had severe disability. Most patients (37.04%) exhibited moderate functional ability. The presence of diabetes increased the cause-specific hazard of death by 3.95 times (95% CI 2.16 to 7.24) but decreased the cause-specific hazard of drop-out by 95% (aHR 0.05; 95% CI 0.01 to 0.46) compared with non-diabetic patients who had a stroke., Conclusion: A substantial proportion of patients who had a stroke experienced mortality and drop-out during the study period, highlighting the importance of considering competing risks in stroke research. Age, diabetes, white cell count and stroke complications were significant covariates affecting both longitudinal and survival submodels. Compared with stand-alone models, the joint competing risk modelling technique offers comprehensive insights into the disease's transition pattern., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Malaria transmission intensity affects the development of naturally acquired immunity to malaria. An absolute correlate measure of protection against malaria is lacking. However, antibody-mediated functions against Plasmodium falciparum correlate with protection against malaria. In children, antibody-mediated functions against P. falciparum decline with reduced exposure. It is unclear whether adults maintain antibody-mediated functions as malaria transmission declines. This study assessed antibody-dependent respiratory burst (ADRB) in individuals from an area with declining malaria transmission. In an age-matched analysis, we compare ADRB activity during high versus low malaria transmission periods. Age significantly predicted higher ADRB activity in the high ( p < 0.001) and low ( p < 0.001) malaria transmission periods. ADRB activity was higher during the high compared to the low malaria transmission period in older children and adults. Only older adults during the high malaria transmission period had their median ADRB activity above the ADRB cut-off. Ongoing P. falciparum infection influenced ADRB activity during the low ( p = 0.01) but not the high ( p = 0.29) malaria transmission period. These findings propose that naturally acquired immunity to P. falciparum is affected in children and adults as malaria transmission declines, implying that vaccines will be necessary to induce and maintain protection against malaria.

Background: Shigellosis mainly affects children under 5 years of age living in low- and middle-income countries, who are the target population for vaccination. There are, however, limited data available to define the appropriate timing for vaccine administration in this age group. Information on antibody responses following natural infection, proxy for exposure, could help guide vaccination strategies., Methods: We undertook a retrospective analysis of antibodies to five of the most prevalent Shigella serotypes among children aged <5 years in Kenya. Serum samples from a cross-sectional serosurvey in three Kenyan sites (Nairobi, Siaya, and Kilifi) were analyzed by standardized ELISA to measure IgG against Shigella sonnei and Shigella flexneri 1b, 2a, 3a, and 6. We identified factors associated with seropositivity to each Shigella serotype, including seropositivity to other Shigella serotypes., Results: A total of 474 samples, one for each participant, were analyzed: Nairobi ( n = 169), Siaya ( n = 185), and Kilifi ( n = 120). The median age of the participants was 13.4 months (IQR 7.0-35.6), and the male:female ratio was 1:1. Geometric mean concentrations (GMCs) for each serotype increased with age, mostly in the second year of life. The overall seroprevalence of IgG antibodies increased with age except for S. flexneri 6 which was high across all age subgroups. In the second year of life, there was a statistically significant increase of antibody GMCs against all five serotypes ( p = 0.01-0.0001) and a significant increase of seroprevalence for S. flexneri 2a ( p = 0.006), S. flexneri 3a ( p = 0.006), and S. sonnei ( p = 0.05) compared with the second part of the first year of life. Among all possible pairwise comparisons of antibody seropositivity, there was a significant association between S. flexneri 1b and 2a (OR = 6.75, 95% CI 3-14, p < 0.001) and between S. flexneri 1b and 3a (OR = 23.85, 95% CI 11-54, p < 0.001)., Conclusion: Children living in low- and middle-income settings such as Kenya are exposed to Shigella infection starting from the first year of life and acquire serotype-specific antibodies against multiple serotypes. The data from this study suggest that Shigella vaccination should be targeted to infants, ideally at 6 or at least 9 months of age, to ensure children are protected in the second year of life when exposure significantly increases., Competing Interests: Authors OR, PF, FN, AA, UN, VC, and FM are employees of GSK group of companies. LM and AP were employees of GSK group of companies when the study was performed. LM is currently employed by U.S. Pharmacopeia Convention. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kapulu, Muthumbi, Otieno, Rossi, Ferruzzi, Necchi, Acquaviva, Martin, Orindi, Mwai, Kibet, Mwanzu, Bigogo, Verani, Mbae, Nyundo, Agoti, Nakakana, Conti, Bejon, Kariuki, Scott, Micoli and Podda.)

Background: Ideal number of children (INC) is the number of children that a woman or man would have if they could go back to the time when they did not have any children and could choose accurately the number of children to have in their total life. Despite numerous studies on the prevalence and associated factors of the ideal number of children, there is a lack of studies that incorporated spatial and multilevel analysis. Thus, this study was aimed at the spatial and multilevel analysis of an ideal number of children and associated factors., Methods: The study design was a cross-sectional study in which the data was obtained from Ethiopian Demographic and Health Survey (EDHS) in 2016. About 13,961 women ages 15-49 who fulfill the inclusion criterion were considered. A negative binomial regression model that incorporates spatial and multilevel analysis was employed., Results: About 33 and 12.8% of the women had four and six ideal numbers of children respectively. The highest INC per woman was recorded in Oromia region 5055 (36.1%) and the lowest in Harare 35(0.2%). The INC per woman is high in rural 10,726 (76.6%) areas as compared to urban areas 3277(23.4%). The ideal number of children was spatially clustered (Global Moran's I = 0.1439, p < .00043). Significant hotspot clusters were found in the Somali region such as in Afder, Shabelle, Korahe, and Doolo zone., Conclusion: The spatial analysis revealed a significant clustering of the ideal number of children in the Ethiopia zone. Specifically, higher INC was observed in the Somali region, specifically in the Afder, Shabelle, Korahe, and Doolo zones. Among the various factors considered, women's age, region, place of residence, women's education level, contraception use, religion, marital status, family size, and age at first birth year were identified as significant predictors of the ideal number of children. These findings indicate that these factors play a crucial role in shaping reproductive preferences and decisions among women in the study population. Based on these findings, responsible bodies should prioritize targeted interventions and policies in high-risk regions to address women's specific reproductive needs., (© 2023. The Author(s).)

Introduction: Detailed analyses of genetic diversity, antigenic variability, protein localization and immunological responses are vital for the prioritization of novel malaria vaccine candidates. Comprehensive approaches to determine the most appropriate antigen variants needed to provide broad protection are challenging and consequently rarely undertaken., Methods: Here, we characterized PF3D7&#95;1136200, which we named Asparagine-Rich Merozoite Antigen (ARMA) based on the analysis of its sequence, localization and immunogenicity. We analyzed IgG and IgM responses against the common variants of ARMA in independent prospective cohort studies in Burkina Faso (N = 228), Kenya (N = 252) and Mali (N = 195) using a custom microarray, Div-KILCHIP., Results: We found a marked population structure between parasites from Africa and Asia. African isolates shared 34 common haplotypes, including a dominant pair although the overall selection pressure was directional (Tajima's D = -2.57; Fu and Li's F = -9.69; P < 0.02). ARMA was localized to the merozoite surface, IgG antibodies induced Fc-mediated degranulation of natural killer cells and strongly inhibited parasite growth in vitro. We found profound serological diversity, but IgG and IgM responses were highly correlated and a hierarchical clustering analysis identified only three major serogroups. Protective IgG and IgM antibodies appeared to target both cross-reactive and distinct epitopes across variants. However, combinations of IgG and IgM antibodies against selected variants were associated with complete protection against clinical episodes of malaria., Discussion: Our systematic strategy exploits genomic data to deduce the handful of antigen variants with the strongest potential to induce broad protection and may be broadly applicable to other complex pathogens for which effective vaccines remain elusive., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest, (Copyright © 2023 Niaré, Chege, Rosenkranz, Mwai, Saßmannshausen, Odera, Nyamako, Tuju, Alfred, Waitumbi, Ogutu, Sirima, Awandare, Kouriba, Rayner and Osier.)

Introduction: Gestational diabetes mellitus (GDM) is associated with adverse perinatal outcomes. Approaches to screening for GDM continue to evolve, introducing potential variability of care. This study explored the impact of these variations on GDM counselling and screening from the perspectives of pregnant individuals., Methods: Following a Corbin and Strauss approach to qualitative, grounded theory we recruited 28 individuals from three cities in Ontario, Canada who had a singleton pregnancy under the care of either a midwife, family physician or obstetrician. Convenience and purposive sampling techniques were used. Semi-structured telephone interviews were conducted and transcribed verbatim between March and December 2020. Transcripts were analysed inductively resulting in codes, categories and themes., Results: Three themes were derived from the data about GDM screening and counselling: 'informing oneself', 'deciding' and 'screening'. All participants, regardless of geographical region, or antenatal care provider, moved through these three steps during the GDM counselling and screening process. Differences in counselling approaches between pregnancy care providers were noted throughout the 'informing' and 'deciding' stages of care. Factors influencing these differences included communication, healthcare autonomy and patient motivation to engage with health services. No differences were noted within care provider groups across the three geographic regions. Participant experiences of GDM screening were influenced by logistical challenges and personal preferences towards testing., Conclusion: Informing oneself about GDM may be a crucial step for facilitating decision-making and screening uptake, with an emphasis on information provision to facilitate patient autonomy and motivation., Patient or Public Contribution: Participants of our study included patients and service users. Participants were actively involved in the study design due to the qualitative, patient-centred nature of the research methods employed. Analysis of results was structured according to the emergent themes of the data which were grounded in patient perspectives and experiences., (© 2023 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Background: Antenatal care (ANC) is a maternal health care service given by skilled health professionals to pregnant women. Women may give birth at home or in health institutions. Home delivery care (DC) increases the likelihood of mortality of the mother and the newborn. Globally, each year nearly 303,000 maternal deaths occurred from complications of pregnancy and childbirth. Ethiopia alone accounted for 13,000 deaths, which disproportionately affects women living in different places of the country. Thus, this study aimed to assess the spatiotemporal patterns and associated factors of antenatal and delivery care utilization in Ethiopia., Method: This study used the 2000 to 2016 EDHS (Ethiopian and Demographic Health Survey) data as a source. A total weighted sample of 30,762 women (7966 in 2000, 7297 in 2005, 7908 in 2011, and 7591 in 2016) was used. The separate and bivariate logistic regression analyses with and without the spatial effect were modeled using SAS version 9.4 and ArcGIS version 10.8., Results: The spatial distribution of ANC and DC was non-random in Ethiopia. The overall odds ratio of ANC and DC was 2.09. In 2016, 31.8% and 33.2% of women had ANC and DC respectively. The estimated odds of following ANC among mothers from middle and rich households were 1.346 and 1.679 times the estimated odds of following ANC among mothers from poor households respectively. Women who had attained higher education were 1.56 and 2.03 times more likely to have ANC and DC respectively compared to women who had no formal education., Conclusions: Despite the government's report that women now have better access to maternal health care, a sizable proportion of women continue to give birth at home without going to the advised antenatal care appointment. Women and husbands with low education, having non-working partners, religion, regions of dwelling, residing in rural, lower birth order, low birth interval, unable to access mass media, low wealth status, and earlier EDHS survey years were significant predictors that hinder antenatal and delivery care utilization simultaneously in Ethiopia. Whereas the spatial variable significantly affects antenatal care and being unable to access mobile phones lead to low utilization of delivery care. We recommend that policymakers, planners, and researchers consider these variables and the spatiotemporal distribution of ANC and DC to reduce maternal mortality in Ethiopia. Besides, it is recommended that further studies use the latest EDHS survey data., (© 2023. The Author(s).)

Natural killer (NK) cells are potent immune effectors that can be activated via antibody-mediated Fc receptor engagement. Using multiparameter flow cytometry, we found that NK cells degranulate and release IFN-γ upon stimulation with antibody-opsonized Plasmodium falciparum merozoites. Antibody-dependent NK (Ab-NK) activity was largely strain transcending and enhanced invasion inhibition into erythrocytes. Ab-NK was associated with the successful control of parasitemia after experimental malaria challenge in African adults. In an independent cohort study in children, Ab-NK increased with age, was boosted by concurrent P. falciparum infections, and was associated with a lower risk of clinical episodes of malaria. Nine of the 14 vaccine candidates tested induced Ab-NK, including some less well-characterized antigens: P41, P113, MSP11, RHOPH3, and Pf &#95;11363200. These data highlight an important role of Ab-NK activity in immunity against malaria and provide a potential mechanism for evaluating vaccine candidates.

Objectives: The objective of this study was to evaluate any association between culture site / culture result / pathogen and incident PsA or psoriasis., Methods: Records of all samples sent for culture from a large population during a 3-year period were linked with nationwide registry data on diagnoses and death over a 15-year period. The main outcomes of interest were incident diagnoses of PsA and psoriasis, defined by International Classification of Diseases (ICD) codes. The effect of culture site, culture result (positive vs negative), and pathogen (Streptococcus vs negative culture) on the risk of developing PsA and psoriasis was calculated using Cox proportional hazards models adjusted for age and gender., Results: A total of 313 235 bacterial cultures from 128 982 individuals were analysed. Comparing individuals with pharyngeal cultures to those with urine cultures, the hazard ratio for incident PsA was 8.78 [95% confidence interval (CI) 3.23, 23.91] and for incident psoriasis it was 8.00 (95% CI 5.28, 12.12). Most of the risk was concentrated in the first 50 days after the culture date. Increased risk was also found when comparing individuals with cultures from the pharynx with those with cultures from the nasopharynx and blood. An association with streptococci was not found, neither in the pharynx nor at any other site. A positive bacterial culture from any site was associated with reduced risk for both PsA and psoriasis., Conclusion: There is a strong site-specific association between pharyngeal culture samples and an increased risk of PsA and psoriasis, regardless of the pathogen. This may indicate that the site of infection, rather than the pathogen, is associated with increased risk., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The impact of the COVID-19 pandemic on participation in and availability of cardiac rehabilitation (CR) is unknown., Methods: Among eligible Medicare fee-for-service beneficiaries, we evaluated, by month, the number of CR sessions attended per 100 000 beneficiaries, individuals eligible to initiate CR, and centers offering in-person CR between January 2019 and December 2021. We compared these outcomes between 2 periods: December 1, 2019 through February 28, 2020 (period 1, before declaration of the pandemic-related national emergency) and October 1, 2021 through December 31, 2021 (period 2, the latest period for which data are currently available)., Results: In period 1, Medicare beneficiaries participated in (mean±SD) 895±84 CR sessions per 100 000 beneficiaries each month. After the national emergency was declared, CR participation sharply declined to 56 CR sessions per 100 000 beneficiaries in April 2020. CR participation recovered gradually through December 2021 but remained lower than prepandemic levels (period 2: 698±29 CR sessions per month per 100 000 beneficiaries, P =0.02). Declines in CR participation were most marked among dual Medicare and Medicaid enrollees and patients residing in rural areas or socially vulnerable communities. There was no statistically significant change in CR eligibility between the 2 periods. Compared with 2618±5 CR centers in period 1, there were 2464±7 in period 2 ( P <0.01). Compared with CR centers that survived the pandemic, 220 CR centers that closed were more likely to be affiliated with public hospitals, located in rural areas, and serve the most socially vulnerable communities., Conclusions: The COVID-19 pandemic was associated with a persistent decline in CR participation and the closure of CR centers, which disproportionately affected rural and low-income patients and the most socially vulnerable communities. Innovation in CR financing and delivery is urgently needed to equitably enhance CR participation among Medicare beneficiaries.

Background: Partial anomalous pulmonary venous return (PAPVR) is a rare condition that may lead to pulmonary arterial hypertension (PAH). We sought to determine the prevalence of PAPVR, the follow-up rate of incidentally discovered PAPVR, the repercussions of volume and pressure overload on the right ventricle (RV), and the prevalence and predictors of PAH., Methods and Results: Fifty PAPVR patients aged ≥18 years were included. All underwent transthoracic echocardiography and multislice imaging. PAPVR prevalence was 0.2% (23/13,606 chest computed tomography reports). Of the 26 incidentally diagnosed patients, 14 (54%) did not have a cardiac follow-up. Seven (14%) patients had PAH, of whom one third (28%) had Eisenmenger syndrome. The left-to-right shunt ratio (Qp/Qs) was the only predictor of PAH. PAPVR-induced volume overload led to increased right chamber volumes (RV basal diameter 45±8 mm, RV mid-diameter 38±9 mm, RV/left ventricle ratio 1.2 ± 0.2, indexed RV end-diastolic area 14±4 cm 2 /m 2 , indexed RV end-systolic area 8.6 ± 3.2 cm 2 /m 2 ) and increased RV functional parameters (tricuspid annular plane systolic excursion 27±5 mm, fractional area change [FAC] 42 ± 10%, global longitudinal strain [GLS] -22 ± 5). In contrast, PAH-induced pressure overload had no impact on right heart volumes, but on RV functional parameters, which were decreased compared to non-PAH patients (FAC 35 ± 13% vs. 43 ± 10%, p  = 0.049; GLS -18 ± 5 vs. -23 ± 4%, p  = 0.01)., Conclusions: PAPVR prevalence was 0.2%. When incidentally diagnosed, its management was often neglected despite potentially serious consequences (14% PAH). Only the Qp/Qs ratio was predictive of PAH. PAPVR-induced volume overload was shown to increase right heart volumes, while PAH-induced pressure overload caused alterations of RV functional parameters., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nour Rahnama reports financial support was provided by 10.13039/501100011068Saint-Luc Foundation., (© 2022 The Authors.)

Background: Asymptomatic carriage of malaria parasites is common in high transmission intensity areas and confounds clinical case definitions for research studies. This is important for investigations that aim to identify immune correlates of protection from clinical malaria. The proportion of fevers attributable to malaria parasites is widely used to define different thresholds of parasite density associated with febrile episodes. The varying intensity of malaria transmission was investigated to check whether it had a significant impact on the parasite density thresholds. The same dataset was used to explore an alternative statistical approach, using the probability of developing fevers as a choice over threshold cut-offs. The former has been reported to increase predictive power., Methods: Data from children monitored longitudinally between 2005 and 2017 from Junju and Chonyi in Kilifi, Kenya were used. Performance comparison of Bayesian-latent class and logistic power models in estimating malaria attributable fractions and probabilities of having fever given a parasite density with changing malaria transmission intensity was done using Junju cohort. Zero-inflated beta regressions were used to assess the impact of using probabilities to evaluate anti-merozoite antibodies as correlates of protection, compared with multilevel binary regression using data from Chonyi and Junju., Results: Malaria transmission intensity declined from over 49% to 5% between 2006 and 2017, respectively. During this period, malaria attributable fraction varied between 27-59% using logistic regression compared to 10-36% with the Bayesian latent class approach. Both models estimated similar patterns of fevers attributable to malaria with changing transmission intensities. The Bayesian latent class model performed well in estimating the probabilities of having fever, while the latter was efficient in determining the parasite density threshold. However, compared to the logistic power model, the Bayesian algorithm yielded lower estimates for both attributable fractions and probabilities of fever. In modelling the association of merozoite antibodies and clinical malaria, both approaches resulted in comparable estimates, but the utilization of probabilities had a better statistical fit., Conclusions: Malaria attributable fractions, varied with an overall decline in the malaria transmission intensity in this setting but did not significantly impact the outcomes of analyses aimed at identifying immune correlates of protection. These data confirm the statistical advantage of using probabilities over binary data., (© 2022. The Author(s).)

Background: Covaxin/BBV152 is one of the most widely used vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and one of the few vaccines used extensively in low- and middle-income countries (LMIC)., Methods: We investigated the effect of Covaxin on the SARS-CoV-2 specific IgG and IgA and neutralizing antibody (NAb) levels at baseline (M0) and at Months 1 (M1), 2 (M2), 3 (M3), 4 (M4), 6 (M6) and 12 (M12) following vaccination in healthcare workers. In addition, we also examined the NAb levels against variant lineages of B.1.617.2 (Delta, India), B.1.617.2.1 (Delta Plus, India), B.1.351 (Beta, SA), B.1.1.7 (Alpha, UK) and B.1.1.529 (Omicron)., Results: Covaxin induces enhanced SARS-CoV-2 binding antibodies of IgG and IgA responses against both spike (S) and nucleocapsid (N) antigens at M1, M2, M3, M4, M6 and M12 in comparison with M0. Our data also reveal that NAb levels against the ancestral strain (Wuhan, wild type) are elevated and sustained at M1, M2, M3, M4, M6 and M12 in comparison with M0 and against variant lineages of B.1.617.2 (Delta, India), B.1.617.2.1 (Delta Plus, India), B.1.351 (Beta, SA) and B.1.1.7 (Alpha, UK) are elevated at M3, M6 and M12 in comparison with M0. However, NAb levels against B.1.1.529 (Omicron) was consistently below the limit of detection except at M12., Conclusion: Thus, Covaxin induces an enhanced humoral immune response, with persistence till at least 12 months post-vaccination against most SARS-CoV-2 variants., (© International Society of Travel Medicine 2022. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The T-lymphocyte-mediated inflammation in Crohn's disease can be assessed by quantifying CD3-positive T-lymphocyte counts in colonic sections. We developed and validated a process to reliably quantify immunohistochemical marker-positive cells in a high-throughput setting using whole slide images (WSIs) of CD3-immunostained colonic and ileal tissue sections. In regions of interest (ROIs) and/or whole tissue sections of 40 WSIs from 36 patients with Crohn's disease, CD3-positive cells were quantified by an expert gastrointestinal pathologist (gold standard) and by image analysis algorithms developed with software from 3 independent vendors. Semiautomated quantification of CD3-positive cell counts estimated in 1 ROI per section were accurate when compared with manual analysis (Pearson correlation coefficient, 0.877 to 0.925). Biological variability was acceptable in digitally determined CD3-positive cell measures between 2 to 5 ROIs annotated on the same tissue section (coefficient of variation <25%). Results from computer-aided analysis of CD3-positive T lymphocytes in a whole tissue section and the average of results from 2 to 5 ROIs per tissue section lacked reliability (overestimation or underestimation and systematic bias), suggesting that absolute quantification of CD3-positive T lymphocytes in a whole tissue section may be more accurate. Semiautomated image analysis in WSIs demonstrated reproducible CD3-positive cell measures across 3 independent algorithms. A computer-aided digital image analysis method was developed and validated to quantify CD3-positive T lymphocytes in colonic and ileal biopsy sections from patients with Crohn's disease. Results support consideration of this digital analysis method for use in future Crohn's disease clinical studies., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Ring-infected erythrocytes are the predominant asexual stage in the peripheral circulation but are rarely investigated in the context of acquired immunity against Plasmodium falciparum malaria. Here we compare antibody-dependent phagocytosis of ring-infected parasite cultures in samples from a controlled human malaria infection (CHMI) study (NCT02739763). Protected volunteers did not develop clinical symptoms, maintained parasitaemia below a predefined threshold of 500 parasites/μl and were not treated until the end of the study. Antibody-dependent phagocytosis of both ring-infected and uninfected erythrocytes from parasite cultures was strongly correlated with protection. A surface proteomic analysis revealed the presence of merozoite proteins including erythrocyte binding antigen-175 and -140 on ring-infected and uninfected erythrocytes, providing an additional antibody-mediated protective mechanism for their activity beyond invasion-inhibition. Competition phagocytosis assays support the hypothesis that merozoite antigens are the key mediators of this functional activity. Targeting ring-stage parasites may contribute to the control of parasitaemia and prevention of clinical malaria., (© 2022. The Author(s).)

Malaria and invasive non-typhoidal Salmonella (NTS) are life-threatening infections that often co-exist in African children. The iron-regulatory hormone hepcidin is highly upregulated during malaria and controls the availability of iron, a critical nutrient for bacterial growth. We investigated the relationship between Plasmodium falciparum malaria and NTS bacteremia in all pediatric admissions aged <5 years between August 1998 and October 2019 (n=75,034). We then assayed hepcidin and measures of iron status in five groups: (1) children with concomitant severe malarial anemia (SMA) and NTS (SMA+NTS, n=16); and in matched children with (2) SMA (n=33); (3) NTS (n=33); (4) cerebral malaria (CM, n=34); and (5) community-based children. SMA and severe anemia without malaria were associated with a 2-fold or more increased risk of NTS bacteremia, while other malaria phenotypes were not associated with increased NTS risk. Children with SMA had lower hepcidin/ferritin ratios (0.10; interquartile range [IQR]: 0.03-0.19) than those with CM (0.24; IQR: 0.14-0.69; P=0.006) or asymptomatic malaria (0.19; IQR: 0.09-0.46; P=0.01) indicating suppressed hepcidin levels. Children with SMA+NTS had lower hepcidin levels (9.3 ng/mL; IQR: 4.7-49.8) and hepcidin/ferritin ratios (0.03; IQR: 0.01-0.22) than those with NTS alone (105.8 ng/mL; IQR: 17.3-233.3; P=0.02 and 0.31; IQR: 0.06-0.66; P=0.007, respectively). Since hepcidin degrades ferroportin on the Salmonella-containing vacuole, we hypothesize that reduced hepcidin in children with SMA might contribute to NTS growth by modulating iron availability for bacterial growth. Further studies are needed to understand how the hepcidin-ferroportin axis might mediate susceptibility to NTS in severely anemic children.

Context: Public Health 3.0 described the need for public health agencies and the public health workforce to transform and obtain new skills and approaches to address the social determinants of health (SDOH) through cross-sectoral partnerships and collective action., Objective: To assess the current state of local health departments' Public Health 3.0 alignment through interventions and initiatives documented in community health improvement plans (CHIPs)., Method: We conducted a content analysis of Illinois CHIPs from July to November 2020. A coding framework aligned with Public Health 3.0 concepts was developed on the basis of constructs from the literature, faculty expertise, and preliminary reviews of the CHIPs. Two researchers deductively coded for health priorities and interventions in Microsoft Excel 2016 and calculated the number of CHIPs in which each code appeared., Results: Ninety CHIPs representing 98 counties across the state were analyzed; 2 CHIPs were excluded because of a lack of strategies. Our content analysis found that 13% (n = 12) of CHIPs had explicit priorities related to SDOH and 12% (n = 11) included interventions that addressed socioeconomic factors. Ten percent (n = 9) of CHIPs proposed multilevel multicomponent interventions. Eighty-nine percent (n = 80) of CHIPs included community-level interventions, and 53% (n = 48) of CHIPs included policy, systems, and environmental strategies focused on specific health content. The majority of CHIPs (96%; n = 86) had at least 1 partnership strategy. Thirty-two percent (n = 29) of CHIPs mentioned the use of an evidence-based strategy., Conclusions: Our content analysis found opportunities to improve Illinois public health agencies' Public Health 3.0 capacities and capability. Findings are limited to this data source and definitions of the Public Health 3.0 attributes, leaving room for practice and research opportunities to develop operational definitions of Public Health 3.0; capacity building to improve the public health workforce readiness; and research and evaluation to measure improvements., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Context: There are multiple calls for public health agency role and workforce transformation to increase capacity to orchestrate cross-sectoral partnerships that set and implement strategies addressing the structural and social determinants of health. Mobilizing for Action through Planning and Partnerships (MAPP) may be one tool for collective action to improve population health and equity. However, little is known about the Action Cycle in MAPP and implementation of resulting community health improvement plans., Objective: To explore the characteristics of MAPP users who completed the MAPP Action Cycle and factors that facilitated or inhibited implementation activities during this phase., Methods: We used a sequential participatory mixed-methods design involving 2 phases of data collection. The first data collection phase included a Web-based survey using Qualtrics. The second data collection phase included qualitative key-informant interviews and focus groups. A national public health and health care advisory group informed the evaluation throughout the entire process to ground the process in practice and experience., Results: This study showed that some MAPP participants do not conduct implementation activities as defined by the MAPP Action Cycle and of those who do, implementation activity varies by participant experiences conducting MAPP and accreditation status. The MAPP users who completed 3 or more rounds of MAPP were more likely to align and integrate MAPP within their agencies as well as organize a collaborative implementation process with partners. More resources and skills in planning that facilitate long-range partnerships were noted as key to implementation., Conclusions: Opportunity remains to improve implementation in MAPP. National leaders should explore and build capacity and infrastructure within public health agencies and with their partners to create a system of readiness and an infrastructure that support implementation over time., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background Artificial intelligence (AI) applications for cancer imaging conceptually begin with automated tumor detection, which can provide the foundation for downstream AI tasks. However, supervised training requires many image annotations, and performing dedicated post hoc image labeling is burdensome and costly. Purpose To investigate whether clinically generated image annotations can be data mined from the picture archiving and communication system (PACS), automatically curated, and used for semisupervised training of a brain MRI tumor detection model. Materials and Methods In this retrospective study, the cancer center PACS was mined for brain MRI scans acquired between January 2012 and December 2017 and included all annotated axial T1 postcontrast images. Line annotations were converted to boxes, excluding boxes shorter than 1 cm or longer than 7 cm. The resulting boxes were used for supervised training of object detection models using RetinaNet and Mask region-based convolutional neural network (R-CNN) architectures. The best-performing model trained from the mined data set was used to detect unannotated tumors on training images themselves (self-labeling), automatically correcting many of the missing labels. After self-labeling, new models were trained using this expanded data set. Models were scored for precision, recall, and F 1 using a held-out test data set comprising 754 manually labeled images from 100 patients (403 intra-axial and 56 extra-axial enhancing tumors). Model F 1 scores were compared using bootstrap resampling. Results The PACS query extracted 31 150 line annotations, yielding 11 880 boxes that met inclusion criteria. This mined data set was used to train models, yielding F 1 scores of 0.886 for RetinaNet and 0.908 for Mask R-CNN. Self-labeling added 18 562 training boxes, improving model F 1 scores to 0.935 ( P < .001) and 0.954 ( P < .001), respectively. Conclusion The application of semisupervised learning to mined image annotations significantly improved tumor detection performance, achieving an excellent F 1 score of 0.954. This development pipeline can be extended for other imaging modalities, repurposing unused data silos to potentially enable automated tumor detection across radiologic modalities. © RSNA, 2022 Online supplemental material is available for this article.

Survivors of critical illness frequently require increased healthcare resources after hospital discharge. We undertook a systematic review and meta-analysis to assess hospital re-admission rates following critical care admission and to explore potential re-admission risk factors. We searched the MEDLINE, Embase and CINAHL databases on 05 March 2020. Our search strategy incorporated controlled vocabulary and text words for hospital re-admission and critical illness, limited to the English language. Two reviewers independently applied eligibility criteria and assessed quality using the Newcastle Ottawa Score checklist and extracted data. The primary outcome was acute hospital re-admission in the year after critical care discharge. Of the 8851 studies screened, 87 met inclusion criteria and 41 were used within the meta-analysis. The analysis incorporated data from 3,897,597 patients and 741,664 re-admission episodes. Pooled estimates for hospital re-admission after critical illness were 16.9% (95%CI: 13.3-21.2%) at 30 days; 31.0% (95%CI: 24.3-38.6%) at 90 days; 29.6% (95%CI: 24.5-35.2%) at six months; and 53.3% (95%CI: 44.4-62.0%) at 12 months. Significant heterogeneity was observed across included studies. Three risk factors were associated with excess acute care rehospitalisation one year after discharge: the presence of comorbidities; events during initial hospitalisation (e.g. the presence of delirium and duration of mechanical ventilation); and subsequent infection after hospital discharge. Hospital re-admission is common in survivors of critical illness. Careful attention to the management of pre-existing comorbidities during transitions of care may help reduce healthcare utilisation after critical care discharge. Future research should determine if targeted interventions for at-risk critical care survivors can reduce the risk of subsequent rehospitalisation., (© 2021 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists.)

Strengthening malaria surveillance is a key intervention needed to reduce the global disease burden. Reliable serological markers of recent malaria exposure could improve current surveillance methods by allowing for accurate estimates of infection incidence from limited data. We studied the IgG antibody response to 111 Plasmodium falciparum proteins in 65 adult travellers followed longitudinally after a natural malaria infection in complete absence of re-exposure. We identified a combination of five serological markers that detect exposure within the previous three months with >80% sensitivity and specificity. Using mathematical modelling, we examined the antibody kinetics and determined that responses informative of recent exposure display several distinct characteristics: rapid initial boosting and decay, less inter-individual variation in response kinetics, and minimal persistence over time. Such serological exposure markers could be incorporated into routine malaria surveillance to guide efforts for malaria control and elimination., (© 2022. The Author(s).)

Rationale: Chronically critically ill patients admitted to a long-term acute care hospital (LTACH) setting are a vulnerable population of intensive care unit (ICU) survivors. Little is known of the goals and functional outcomes achieved by patients after rehabilitation in the LTACH setting. Objectives: We sought to examine patient goals and functional outcomes, including swallowing function, among ICU survivors admitted to an LTACH with a tracheostomy. Methods: This was a prospective observational cohort study of chronic critically ill LTACH patients. Results: Fifty older subjects with a median duration of intubation before tracheostomy of 13 days were enrolled. ICU-acquired weakness and cognitive impairment were present in 40 (80%) and 36 (72%) patients, as measured by the Medical Research Council scale and Montreal Cognitive Assessment, respectively. Mental health problems were also common, with 16 (32%) patients experiencing moderate to severe anxiety, 9 (18%) experiencing moderate to severe depression, and 11 (22%) reporting symptoms consistent with post-traumatic stress disorder, according to the Hospital Anxiety and Depression Scale and Post-Traumatic Stress Syndrome 10-Questions Inventory, respectively. Pharyngeal dysfunction, as measured by Fiberoptic Endoscopic Evaluation of Swallow examination, was present in 37 (74%) patients. Patient goals, in decreasing order of frequency, included eating and drinking, speaking, walking, returning home, and toileting. By LTACH discharge, goal attainment was variable, with 97% of those who ranked speaking as important being able to speak and 88% of those who ranked eating and drinking as important being able to eat and drink but with only 21% being able to walk and only 18% being able to self-toilet. Discharge to the home or acute rehabilitation setting, achieved in 52% of the population, was associated with greater strength, as measured by the total Medical Research Council score ( P  = 0.002) as well as by the European 5-dimension, 5-level health-related quality of life instrument domains of mobility ( P  = 0.008) and self-care ( P  = 0.04). Conclusions: Goal attainment during this period of recovery was variable. The ability to speak, eat, and drink, frequently identified as goals by these patients, were achieved, whereas functional goals such as walking were rarely achieved. These findings highlight the importance of identifying patient goals and setting realistic expectations informed by functional assessments when rehabilitating this vulnerable patient population in the LTACH and subsequent post-acute care settings.

Objective: Large data on the clinical characteristics and outcome of COVID-19 in the Indian population are scarce. We analysed the factors associated with mortality in a cohort of moderately and severely ill patients with COVID-19 enrolled in a randomised trial on convalescent plasma., Design: Secondary analysis of data from a Phase II, Open Label, Randomized Controlled Trial to Assess the Safety and Efficacy of Convalescent Plasma to Limit COVID-19 Associated Complications in Moderate Disease., Setting: 39 public and private hospitals across India during the study period from 22 April to 14 July 2020., Participants: Of the 464 patients recruited, two were lost to follow-up, nine withdrew consent and two patients did not receive the intervention after randomisation. The cohort of 451 participants with known outcome at 28 days was analysed., Primary Outcome Measure: Factors associated with all-cause mortality at 28 days after enrolment., Results: The mean (SD) age was 51±12.4 years; 76.7% were males. Admission Sequential Organ Failure Assessment score was 2.4±1.1. Non-invasive ventilation, invasive ventilation and vasopressor therapy were required in 98.9%, 8.4% and 4.0%, respectively. The 28-day mortality was 14.4%. Median time from symptom onset to hospital admission was similar in survivors (4 days; IQR 3-7) and non-survivors (4 days; IQR 3-6). Patients with two or more comorbidities had 2.25 (95% CI 1.18 to 4.29, p=0.014) times risk of death. When compared with survivors, admission interleukin-6 levels were higher (p<0.001) in non-survivors and increased further on day 3. On multivariable Fine and Gray model, severity of illness (subdistribution HR 1.22, 95% CI 1.11 to 1.35, p<0.001), PaO 2 /FiO 2 ratio <100 (3.47, 1.64-7.37, p=0.001), neutrophil lymphocyte ratio >10 (9.97, 3.65-27.13, p<0.001), D-dimer >1.0 mg/L (2.50, 1.14-5.48, p=0.022), ferritin ≥500 ng/mL (2.67, 1.44-4.96, p=0.002) and lactate dehydrogenase ≥450 IU/L (2.96, 1.60-5.45, p=0.001) were significantly associated with death., Conclusion: In this cohort of moderately and severely ill patients with COVID-19, severity of illness, underlying comorbidities and elevated levels of inflammatory markers were significantly associated with death., Trial Registration Number: CTRI/2020/04/024775., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Steroid-resistant nephrotic syndrome (SRNS) is a burden in the country due to the progressive severity of chronic kidney disease (CKD). Calcineurin inhibitors (CNIs) or monoclonal antibodies are currently recommended for the treatment of this disease. In developing countries, steroid and cyclophosphamide (CPA) are available drugs used during the treatment. This study aims to provide a non-invasive modality that can be used to predict the response of SRNS children to CPA therapy. Subsequently, the proteinuria duration was shortened to reduce the risk of glomerular damage. The present study aims to determine whether there is a correlation between baseline serum TGFB and proteinuria in SRNS children six months after receiving CPA treatment. The author hypothesized that there would be a negative correlation between those variables., Method: A prospective-cohort-study was conducted at Hasan Sadikin General Hospital Bandung, Indonesia. A total of 88 SRNS children, aged 1 to 18 were accessed for serum TGF-β level before receiving CPA therapy for six months, and clinical signs were observed. Furthermore, after six months of CPA treatment, the subjects were divided into CPA responder and non-responder based on the presence of proteinuria, then the data were analyzed using multiple logistic regression to adjust age and gender., Results: There was a statistically significant relationship between TGF-β and the risk of non-response to CPA therapy, after accounting for age, gender, baseline GFR, baseline ureum, and baseline urinary protein, the adjusted-OR was 1.051 (95% CI 1.007, 1.097, p = 0.022)., Conclusion: The high level of serum TGF-β obtained prior to CPA administration are reliable data for estimating adverse results on CPA therapy. Based on these results, a high baseline TGF-β level correlates with the poor response of CPA therapy., Competing Interests: Conflict of interest The authors declare that they have no competing interests., (© the Author(s).)

Protein microarrays are versatile tools for high throughput study of the human proteome, but systematic and non-systematic sources of bias constrain optimal interpretation and the ultimate utility of the data. Published guidelines to limit technical variability whilst maintaining important biological variation favour DNA-based microarrays that often differ fundamentally in their experimental design. Rigorous tools to guide background correction, the quantification of within-sample variation, normalisation, and batch correction specifically for protein microarrays are limited, require extensive investigation and are not centrally accessible. Here, we develop a generic one-stop-shop pre-processing suite for protein microarrays that is compatible with data from the major protein microarray scanners. Our graphical and tabular interfaces facilitate a detailed inspection of data and are coupled with supporting guidelines that enable users to select the most appropriate algorithms to systematically address bias arising in customized experiments. The localization and distribution of background signal intensities determine the optimal correction strategy. A novel function overcomes the limitations in the interpretation of the coefficient of variation when signal intensities are at the lower end of the detection threshold. We demonstrate essential considerations in the experimental design and their impact on a range of algorithms for normalization and minimization of batch effects. Our user-friendly interactive web-based platform eliminates the need for prowess in programming. The open-source R interface includes illustrative examples, generates an auditable record, enables reproducibility, and can incorporate additional custom scripts through its online repository. This versatility will enhance its broad uptake in the infectious disease and vaccine development community., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Background: Iron overload in severe β -thalassemia is a serious complication that occurs during the course of the disease. Information about the iron status during initial illness with β -thalassemia major seemed to be limited. This study is aimed at analyzing iron status, serum hepcidin, and growth differentiation factor 15 (GDF15) levels in newly diagnosed β -thalassemia major., Methods: A case-control study was performed at Dr. Hasan Sadikin General Hospital, which included 41 children with newly diagnosed β -thalassemia major. Age- and sex-matched controls were enrolled. The subjects had no blood transfusion, had normal liver function, and had no sign of inflammation. The groups were compared in terms of the levels of hemoglobin (Hb), serum ferritin (SF), transferrin saturation (TS), serum hepcidin, and GDF15 as iron homeostasis parameters., Results: Of the 41 newly diagnosed β -thalassemia major patients, those who were less than 24 months old had significantly lower median Hb levels than controls (5.0 vs. 11.7 g/dL, P < 0.001). The median SF and TS levels were significantly higher than those in controls (315.0 vs. 29.0 ng/mL, P < 0.001; 70.6 vs. 16.5%, P < 0.001), and median hepcidin was at the normal limit, but the value was higher in patients (251.0 vs. 123.1 ng/mL, P < 0.001). The median GDF15 level was significantly higher in patients (2,095.3 vs. 342.4 pg/mL, P < 0.001). There was a positive correlation between SF-TS, SF-hepcidin, TS-hepcidin, SF-GDF15, TS-GDF15, and hepcidin-GDF15 ( P < 0.001)., Conclusion: In newly diagnosed β -thalassemia major, an increase in iron status occurred. This may be caused by increased iron absorption due to massive erythropoietic activity, characterized by an increase in GDF15 levels, which does not cause hepcidin suppression. The iron homeostasis response seems to be physiologically indicated by a tendency to increase hepcidin levels., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Susi Susanah et al.)

Study Question: How does the risk of cardiovascular disease (CVD) vary with type and age of menopause?, Summary Answer: Earlier surgical menopause (e.g. <45 years) poses additional increased risk of incident CVD events, compared to women with natural menopause at the same age, and HRT use reduced the risk of CVD in women with early surgical menopause., What Is Known Already: Earlier age at menopause has been linked to an increased risk of CVD mortality and all-cause mortality, but the extent that this risk of CVD varies by type of menopause and the role of postmenopausal HRT use in reducing this risk is unclear., Study Design, Size, Duration: Pooled individual-level data of 203 767 postmenopausal women from 10 observational studies that contribute to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE) consortium were included in the analysis., Participants/materials, Setting, Methods: Postmenopausal women who had reported menopause (type and age of menopause) and information on non-fatal CVD events were included. Type of menopause (natural menopause and surgical menopause) and age at menopause (categorised as <35, 35-39, 40-44, 45-49, 50-54 and ≥55 years) were exposures of interest. Natural menopause was defined as absence of menstruation over a period of 12 months (no hysterectomy and/or oophorectomy) and surgical menopause as removal of both ovaries. The study outcome was the first non-fatal CVD (defined as either incident coronary heart disease (CHD) or stroke) event ascertained from hospital medical records or self-reported. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CI for non-fatal CVD events associated with natural menopause and surgical menopause., Main Results and the Role of Chance: Compared with natural menopause, surgical menopause was associated with over 20% higher risk of CVD (HR 1.22, 95% CI 1.16-1.28). After the stratified analysis by age at menopause, a graded relationship for incident CVD was observed with lower age at menopause in both types of natural and surgical menopause. There was also a significant interaction between type of menopause and age at menopause (P < 0.001). Compared with natural menopause at 50-54 years, women with surgical menopause before 35 (2.55, 2.22-2.94) and 35-39 years (1.91, 1.71-2.14) had higher risk of CVD than those with natural menopause (1.59, 1.23-2.05 and 1.51, 1.33-1.72, respectively). Women who experienced surgical menopause at earlier age (<50 years) and took HRT had lower risk of incident CHD than those who were not users of HRT., Limitations, Reasons for Caution: Self-reported data on type and age of menopause, no information on indication for the surgery (e.g. endometriosis and fibroids) and the exclusion of fatal CVD events may bias our results., Wider Implications of the Findings: In clinical practice, women who experienced natural menopause or had surgical menopause at an earlier age need close monitoring and engagement for preventive health measures and early diagnosis of CVD. Our findings also suggested that timing of menopause should be considered as an important factor in risk assessment of CVD for women. The findings on CVD lend some support to the position that elective bilateral oophorectomy (surgical menopause) at hysterectomy for benign diseases should be discouraged based on an increased risk of CVD., Study Funding/competing Interest(s): InterLACE project is funded by the Australian National Health and Medical Research Council project grant (APP1027196). GDM is supported by Australian National Health and Medical Research Council Principal Research Fellowship (APP1121844). There are no competing interests., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: Biosimilar approval, such as Inflectra™ (CT-P13) for treating ulcerative colitis (UC) and Crohn's disease (CD), has reduced direct drug costs. Though clinicians are comfortable with biosimilar use in treatment-naïve patients, there are concerns in some jurisdictions that there are insufficient data from well-controlled trials to support non-medical switching. A systematic review, along with a critical assessment of the study design, was conducted to assess the potential impact of switching stable CD/UC patients from infliximab to CT-P13., Methods: A literature search using PubMed and abstracts/posters from 3 major gastroenterology conferences from 2014 to 2018 was completed. Two individual reviewers extracted data from each relevant report and compiled it into evidence tables to facilitate descriptive analyses. Key randomized trial and observational study designs were critically assessed to contextualize data relevance., Results: A total of 49 reports (3 randomized controlled trials, 40 observational trials, and 1 case series) were included. Most studies revealed no efficacy, safety, or immunogenicity concerns with non-medical switch. Limitations of supporting data include a small number of randomized controlled trials; predominance of observational studies with varying outcome assessments and lack of appropriate controls; and scarcity of research on biosimilar switch long-term effects., Conclusions: The majority of studies suggested non-medical switch is safe. However, clinicians and regulatory bodies should be aware of differences and limitations in study designs when making inferences about the risks and benefits of switching stable IBD patients to biosimilars.

Venetoclax, a small molecule inhibitor of BCL-2, has promising pre-clinical and early clinical activity in relapsed refractory multiple myeloma (RRMM). However, the clinical use of venetoclax remains under evaluation. We performed a single-center, retrospective analysis of patients with RRMM treated with off-label venetoclax. Forty-seven patients with a median of seven lines of prior therapy were identified. Most patients (87%) received venetoclax plus proteasome inhibitor, though there was heterogeneity in the venetoclax-containing regimen patients received, and 38% had known t(11;14). The overall response rate (ORR) was 39%, with 17% achieving ≥ very good partial response (VGPR). In the t(11;14) cohort, the ORR was 71%, with 24% achieving ≥ VGPR. The median progression-free survival was 2.1 months and overall survival was 15.6 months. One treatment-related death (related to infection) occurred. Venetoclax appears safe and efficacious in patients with RRMM, especially in those with t(11;14). Prospective trials are ongoing to further evaluate this treatment.

Background: A high prevalence of working while ill (presenteeism) has been documented among health care workers (HCWs). However, previous evidence is primarily based on nonspecific causes of sickness and self-reported data. Our study examined presenteeism among HCWs with laboratory-confirmed influenza., Methods: The data pertaining to laboratory-confirmed influenza cases and history of sick leave among HCWs in Queensland, Australia, were collected from 2009-2015. The incidence and duration of sick leave around the time of disease confirmation were analyzed. The associations of factors, such as job category and employment status, on presenteeism were assessed with regression analyses., Results: The overall sick leave incidence was 85.9% in the laboratory-confirmed periods, which translates that 14.1% of HCWs were working while ill with influenza. Among medical doctors, approximately one-quarter of them were attending work in the period. A shorter duration of leave was also observed among medical doctors and full-time employees compared with other HCWs and part-time employees., Conclusions: Presenteeism among HCWs with influenza put both HCWs and patients at risk by increasing potential for transmission. Our findings emphasize the importance of an integrated approach including both HCW sick leave management and vaccination for strategic prevention and control of nosocomial influenza infection., (Copyright © 2019. Published by Elsevier Inc.)

Competing Interests: Dr Feagan has been a consultant to AbbVie, Janssen, and Takeda Pharmaceuticals.

In a deinstitutionalised mental health care system, those with mental illness require complex, multidisciplinary and intersectoral care at the primary or community service setting. This paper describes an Evidence Map of different strategies to strengthen the provision of mental health care at the primary health care (PHC) setting, the quality of the evidence, and knowledge gaps. Electronic and reference searching yielded 2666 articles of which 306 qualified for data extraction. A systematic review methodology identified nine different strategies that strengthen the provision of mental healthcare and these strategies are mapped in line with the outcomes they affect. The top three strategies that were reported the most, included strategies to empower families, carers and patients; integration of care or collaborative interventions; and e-health interventions. The least reported strategy was task shifting. The Evidence Map further shows the amount and quality of evidence supporting each of the listed strategies, and this helps to inform policy design and research priorities around mental health. This is the first systematic Evidence Map to show the different strategies that strengthen the provision of mental healthcare at PHC setting and the impact these strategies have on patient, hospital and societal level indicators., Competing Interests: The authors have declared that no competing interests exist.

Background: Pacemakers have become the standard of care in patients with severe bradycardia and conduction abnormalities. The survival and premature mortality can be assessed using the years of life lost (YLLs)., Aims: The aim of the study was to analyze mortality trends over the period from 1999 to 2015 among patients implanted with a dual‑chamber (DDD) pacemaker who were inhabitants of Małopolska Province., Methods: This was a retrospective study of records collected from consecutive patients who underwent de novo DDD pacemaker implantation at a single center between 1984 and 2014. Inclusion criteria were residence status in Małopolska Province at the latest follow‑up visit and death between 1999 and 2015. The standard expected years of life lost per death was used to calculate YLLs. Time trends were evaluated with joinpoint models and presented as an average annual percentage change (AAPC)., Results: Among a total of 3932 consecutive patients implanted with a DDD pacemaker, 1211 patients met the inclusion criteria. We noted an increase in the mean age at implant from 70 years in 1999 to 75.5 years in 2015 (AAPC, 0.6%; P <0.05), the number of years lived after DDD pacemaker implantation from 2.6 years to 8.2 years (AAPC, 7.4%; P <0.05), and the mean age at death from 72.6 years to 83.8 years (AAPC, 0.89%; P <0.05). Finally, we observed a reduction of the YLLs per death from 17.4 years in 1999 to 9 years in 2015 (AAPC, -4%; P <0.05). All trends were significant for both men and women., Conclusions: In the 17‑year follow‑up, we showed significant changes in analyzed trends, in particular a reduction in the YLLs per death.

Background: Interventions to block malaria transmission from humans to mosquitoes are currently in development. To be successfully implemented, key populations need to be identified where the use of these transmission-blocking and/or reducing strategies will have greatest impact. Methods: We used data from a longitudinally monitored cohort of children from Kilifi county located along the Kenyan coast collected between 1998-2016 to describe the distribution and prevalence of gametocytaemia in relation to transmission intensity, time and age. Data from 2,223 children accounting for 9,134 person-years of follow-up assessed during cross-sectional surveys for asexual parasites and gametocytes were used in logistic regression models to identify factors predictive of gametocyte carriage in this cohort. Results: Our analysis showed that children 1-5 years of age were more likely to carry microscopically detectable gametocytes than their older counterparts. Carrying asexual parasites and recent episodes of clinical malaria were also strong predictors of gametocyte carriage. The prevalence of asexual parasites and of gametocyte carriage declined over time, and after 2006, when artemisinin combination therapy (ACT) was introduced, recent episodes of clinical malaria ceased to be a predictor of gametocyte carriage.  Conclusions: Gametocyte carriage in children in Kilifi has fallen over time.  Previous episodes of clinical malaria may contribute to the development of carriage, but this appears to be mitigated by the use of ACTs highlighting the impact that gametocidal antimalarials can have in reducing the overall prevalence of gametocytaemia when targeted on acute febrile illness., Competing Interests: No competing interests were disclosed.

Background: Ecological factors are important indicators for tuberculosis (TB) notification. However, consolidation of evidence on the effect of altitude and temperature on TB notification rate has not yet been done. The aim of this review is to illustrate the effect of altitude and temperature on TB notification rate., Methods: Electronic searches were undertaken from PubMed, EMBASE, and Scopus databases. Hand searches of bibliographies of retrieved papers provided additional references. A review was performed using the Meta-analysis Of Observational Studies in Epidemiology guideline., Results: Nine articles from various geographic regions were included in the study. Five out of nine studies showed the effect of altitude and four articles identified temperature effects. Results showed that TB notification rates were lower at higher altitude and higher at a higher temperature., Conclusion: This review provides qualitative evidence that TB notification rates increase with temperature and decrease with altitude. The findings of this review will encourage policymakers and program managers to consider seasonality and altitude differences in the design and implementation of TB prevention and control strategies., Competing Interests: There are no conflicts of interest.

Objectives: This study evaluates the real-world effectiveness of Diagnose-Intervene-Verify-Adjust (DIVA), an innovative quality improvement mode, in improving primary healthcare (PHC) bottlenecks impeding health system performance in Kaduna, a northern Nigerian state., Design: An embedded mixed method study design involving participant observation., Setting: PHCs in 23 local government areas of Kaduna state, Nigeria., Participants: 138 PHC managers across the state (PHC directors and programme managers in the 23 local governments)., Intervention: DIVA is a four-step improvement model in which 'Diagnose' identifies constraints to effective coverage, 'Intervene' develops/implements action plans addressing constraints, while 'Verify/Adjust' monitor performance and revise plans., Primary and Secondary Outcome Measures: The model, as adapted in Nigeria, is designed to evaluate and improve the availability of health commodities, human resources, geographical accessibility, acceptability, continuous utilisation and quality of four PHC interventions (immunisation, integrated management of childhood illnesses, antenatal care and skilled birth attendance)., Results: 183 bottlenecks were identified by local government teams across all interventions in 2013. 41% of bottlenecks concern human resources. Geographical access and availability of commodities ranked least. Availability of commodities was the most improved determinant although among the least constrained, probably indicating skewed implementation of operational plans. 1562 activities were planned to address identified bottlenecks in the state, of which only 568 (36%) were completely implemented CONCLUSION: Our study demonstrates that PHC planning using the DIVA model can potentially improve health system performance. However, effective implementation is critical and may require some central government oversight., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Female Hodgkin lymphoma (HL) patients treated with chest radiotherapy (RT) have a very high risk of breast cancer. The contribution of genetic factors to this risk is unclear. We therefore examined 211 155 germline single-nucleotide polymorphisms (SNPs) for gene-radiation interaction on breast cancer risk in a case-only analysis including 327 breast cancer patients after chest RT for HL and 4671 first primary breast cancer patients. Nine SNPs showed statistically significant interaction with RT on breast cancer risk (false discovery rate, <20%), of which 1 SNP in the PVT1 oncogene attained the Bonferroni threshold for statistical significance. A polygenic risk score (PRS) composed of these SNPs (RT-interaction-PRS) and a previously published breast cancer PRS (BC-PRS) derived in the general population were evaluated in a case-control analysis comprising the 327 chest-irradiated HL patients with breast cancer and 491 chest-irradiated HL patients without breast cancer. Patients in the highest tertile of the RT-interaction-PRS had a 1.6-fold higher breast cancer risk than those in the lowest tertile. Remarkably, we observed a fourfold increased RT-induced breast cancer risk in the highest compared with the lowest decile of the BC-PRS. On a continuous scale, breast cancer risk increased 1.4-fold per standard deviation of the BC-PRS, similar to the effect size found in the general population. This study demonstrates that genetic factors influence breast cancer risk after chest RT for HL. Given the high absolute breast cancer risk in radiation-exposed women, these results can have important implications for the management of current HL survivors and future patients., (© 2019 by The American Society of Hematology.)