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While macrolides are among the frequently prescribed antibiotics for pregnant women, evidence of their fetal safety remains conflicting. This study aimed to evaluate the risk of major congenital malformations (MCM) after first-trimester exposure to macrolides compared with amoxicillin, focusing on specific MCM subtypes. This nationwide cohort study used data from the Mother-Child EPI-MERES Register nested in the French Health Data System (SNDS). Pregnancies linked with their singleton live-born infants from January 1, 2010, and December 31, 2020, were included. The macrolide exposure group comprised pregnancies with one or more prescriptions filled for systemic macrolides (erythromycin, spiramycin, roxithromycin, josamycin, clarithromycin, and azithromycin) during the first trimester. The comparator group comprised pregnancies exposed to amoxicillin during the first trimester. Adjusted relative risks (aRR) and 95% CI were estimated by log-binomial regression for any MCM overall and individual MCMs with a prevalence of at least one per 10,000 live-born infants in the macrolide exposure group. Among 7,644,579 eligible pregnancies, 140,708 exposed to macrolides and 592,652 exposed to amoxicillin were included. After adjustment for measured confounders, macrolide exposure during the first trimester was not associated with any MCM overall (aRR 1.00, 95% CI 0.96 to 1.05) compared with amoxicillin. Specifically, no increased risk was found for most individual MCMs. However, an increase in the risk for spina bifida (aRR 1.82, 95% CI 1.22 to 2.71) and syndactyly (aRR 1.65, 95% CI 1.06 to 2.58) was observed. The adjusted risk difference per 10,000 live-born infants was 1.15 (95% CI 0.26 to 2.05) for spina bifida and 0.87 (95% CI 0.01 to 1.72) for syndactyly. Sensitivity analyses consistently yielded elevated point estimates for these two MCMs, despite wide confidence intervals and small numbers of events. Residual confounding by indication is possible. The findings indicate that macrolide exposure during the first trimester is not strongly associated with an increased risk for most individual MCMs, which is reassuring. However, an increased risk of spina bifida and syndactyly remains possible. Future studies are required to investigate these observations further as evidence continues to grow.

Maturation age and size have important fitness consequences through their effects on survival probabilities and body sizes. The evolution of maturation reaction norms in response to environmental covariation in growth and mortality is therefore a key subject of life-history theory. The eco-evolutionary model we present and analyze here incorporates critical features that earlier studies of evolving maturation reaction norms have often neglected: the trade-off between growth and reproduction, source-sink population structure, and population regulation through density-dependent growth and fecundity. We report the following findings. First, the evolutionarily optimal age at maturation can be decomposed into the sum of a density-dependent and a density-independent component. These components measure, respectively, the hypothetical negative age at which an individual’s length would be 0 and the delay in maturation relative to this offset. Second, along any growth trajectory, individuals mature earlier when mortality is higher. This allows us to deduce, third, how the shapes of evolutionarily optimal maturation reaction norms depend on the covariation between growth and mortality (positive or negative, linear or curvilinear, and deterministic or probabilistic). Providing eco-evolutionary explanations for many alternative reaction-norm shapes, our results appear to be in good agreement with current empirical knowledge on maturation dynamics.

Fishing may induce neutral and adaptive evolution affecting life‐history traits, and molecular evidence has shown that neutral genetic diversity has declined in some exploited populations. Here, we theoretically study the interplay between neutral and adaptive evolution caused by fishing. An individual‐based eco‐genetic model is devised that includes neutral and functional loci in a realistic ecological setting. In line with theoretical expectations, we find that fishing induces evolution towards slow growth, early maturation at small size and higher reproductive investment. We show, first, that the choice of genetic model (based on either quantitative genetics or gametic inheritance) influences the evolutionary recovery of traits after fishing ceases. Second, we analyse the influence of three factors possibly involved in the lack of evolutionary recovery: the strength of selection, the effect of genetic drift and the loss of adaptive potential. We find that evolutionary recovery is hampered by an association of weak selection differentials with reduced additive genetic variances. Third, the contribution of fisheries‐induced selection to the erosion of functional genetic diversity clearly dominates that of genetic drift only for the traits related to maturation. Together, our results highlight the importance of taking into account population genetic variability in predictions of eco‐evolutionary dynamics.

Introduction Thanks to antiretroviral treatment (ART), people living with HIV (PLHIV) are living longer and ageing. However, ageing involves increased risks of co‐morbidities, which also depend on when PLHIV individuals started ART. To tackle the HIV age‐related upcoming challenges, knowledge of the current and future age structure of the HIV population is needed. Here, we forecast the demographic profile of the adult population living with diagnosed HIV (aPLdHIV) in France until 2030, accounting for the impact of the ART initiation period on mortality. Methods We used national data from the French Hospital Database on HIV (ANRS CO4‐FHDH) and a sample of the National Health Data System to, first, characterize the aPLdHIV in 2018 and estimate their mortality rates according to age, sex and ART initiation period. Second, we used national HIV surveillance data to define three scenarios for the numbers of newly diagnosed HIV cases over 2019–2030: 30% decrease in HIV cases (S1), status quo situation (S2) and epidemic elimination (S3). We then combined these data using a matrix model, to project the age structure of aPLdHIV and time since ART initiation. Results In 2018, there was an estimated 161,125 aPLdHIV (33% women), of which 55% were aged 50 or older (50+), 22% aged 60+ and 8% aged 70+. In 2030, the aPLdHIV would grow to 195,246 for S1, 207,972 for S2 and 167,221 for S3. Whatever the scenario, in 2030, the estimated median time since ART initiation would increase and age distribution would shift towards older ages: with 65–72% aPLdHIV aged 50+, 42–48% 60+ and 17–19% 70+. This corresponds to ∼83,400 aPLdHIV (28% women) aged 60+, among which ∼69% started ART more than 20 years ago (i.e. before 2010) and ∼39% ≥30 years ago (i.e. before 2000), and to ∼33,100 aPLdHIV (27% women) aged 70+, among which ∼72% started ART ≥20 years ago and ∼43% ≥30 years ago. Conclusions By 2030, in France, close to 20% of the aPLdHIV will be aged 70+, of which >40% would have started ART more than 30 years ago. These estimates are essential to adapt co‐morbidities screening and anticipate resource provision in the aged care sector.

Introduction To close gaps in HIV prevention and care, knowledge about locations and populations most affected by HIV is essential. Here, we provide subnational and sub‐population estimates of three key HIV epidemiological indicators, which have been unavailable for most settings. Methods We used surveillance data on newly diagnosed HIV cases from 2004 to 2014 and back‐calculation modelling to estimate in France, at national and subnational levels, by exposure group and country of birth: the numbers of new HIV infections, the times to diagnosis, the numbers of undiagnosed HIV infections. The denominators used for rate calculations at national and subnational levels were based on population size (aged 18 to 64) estimates produced by the French National Institute of Statistics and Economic Studies and the latest national surveys on sexual behaviour and drug use. Results We estimated that, in 2014, national HIV incidence was 0.17‰ (95% confidence intervals (CI): 0.16 to 0.18) or 6607 (95% CI: 6057 to 7196) adults, undiagnosed HIV prevalence was 0.64‰ (95% CI: 0.57 to 0.70) or 24,197 (95% CI: 22,296 to 25,944) adults and median time to diagnosis over the 2011 to 2014 period was 3.3 years (interquartile range: 1.2 to 5.7). Three mainland regions, including the Paris region, out of the 27 French regions accounted for 56% of the total number of new and undiagnosed infections. Incidence and undiagnosed prevalence rates were 2‐ to 10‐fold higher than the national rates in three overseas regions and in the Paris region (p‐values < 0.001). Rates of incidence and undiagnosed prevalence were higher than the national rates for the following populations (p‐values < 0.001): born‐abroad men who have sex with men (MSM) (respectively, 108‐ and 78‐fold), French‐born MSM (62‐ and 44‐fold), born‐abroad persons who inject drugs (14‐ and 18‐fold), sub‐Saharan African‐born heterosexuals (women 15‐ and 15‐fold, men 11‐ and 13‐fold). Importantly, affected populations varied from one region to another, and in regions apparently less impacted by HIV, some populations could be as impacted as those living in most impacted regions. Conclusions In France, some regions and populations have been most impacted by HIV. Subnational and sub‐population estimates of key indicators are not only essential to adapt, design implement and evaluate tailored HIV interventions in France, but also elsewhere where similar heterogeneity is likely to exist.

Younger ages and smaller sizes at maturation have been observed in commercial fish stocks over the last century. We establish that age and length at 50% proportion mature (i.e. the proportion of mature individuals in a population or the probability that an individual is mature) decreased from the 1970s to the 2000s in North Sea cod Gadus morhua, haddock Melanogrammus aeglefinus and whiting Merlangius merlangus, but not in Norway pout Trisopterus esmarkii. The potential contributions of demography, phenotypic plasticity and evolution to these trends were assessed. First, maturation trends were extricated from demographic effects and growth-dependent plasticity by estimating probabilistic maturation reaction norms (PMRNs). PMRN midpoints have significantly shifted downwards at most ages for cod, haddock and whiting, but not for Norway pout. Second, increased temperature and food abundance, loosened trophic competition and relaxed social pressure may also trigger growth-independent plasticity in maturation. Principal component regression of PMRN midpoints on annual estimates of relevant environmental variables exhibiting a temporal trend suggest that, despite some evidence of environmental effects, PMRN trends were mostly independent of growth-independent plasticity in haddock, whiting and male cod, but not in female cod. According to these findings, evolution of maturation, potentially in response to fishing, is plausible in haddock, whiting and male cod, but unlikely for Norway pout, and does not explain trends in female cod maturation. In agreement with life-history theory, the maturation response was larger in fast-growing, late- and large-maturing species exhibiting moderate reproductive effort.

General practitioners (GPs) play a key role in reducing the hidden HIV-epidemic, but many diagnostic opportunities are missed in primary care. This study aimed at informing the development of an HIV-testing intervention for GPs in Flanders (Belgium) using formative research with a participatory approach. Through the active involvement of an advisory board and 16 group discussions with 122 Flemish GPs, GPs’ current HIV-testing practices and perceived practical relevance of 2 distinct HIV-testing strategies (i.e. provider-initiated testing of key populations and indicator condition-based testing) were explored in terms of their relevance and feasibility in routine primary care. Self-reported HIV-testing practices revealed that most tests performed were patient-initiated, pretest counseling was rarely done, and post-test counseling was offered mainly for patients with an HIV-diagnosis. GPs reported multiple barriers to provider-initiated HIV-testing, i.e. personal discomfort, fear of offending their patient, limited knowledge of benefits of early HIV-diagnosis, misconceptions about HIV-risks, lack of guidelines and time. Difficulties to identify patient’s sexual orientation or ethical concerns were mentioned as barriers for target group-based HIV testing. GPs assessed the current list of 64 indicator conditions as too difficult to integrate in routine care, deeming a reduced list of GP-relevant conditions as more feasible. Combined strategies (i.e. target group- and indicator-based testing) supported by official screening recommendations were perceived as successful strategies for provider-initiated HIV-testing in primary care. This formative research delivered qualitative evidence for the development of an HIV-testing intervention for primary care settings.

Introduction Increasing our knowledge on geographic areas and key populations most affected by HIV is essential to improve prevention and care and to ensure a more focused HIV response. Here, we estimated the prevalence of undiagnosed HIV infections in Belgium and its distribution across geographic areas and exposure groups. Methods We used surveillance data on newly diagnosed HIV cases and a previously developed back‐calculation model to estimate number and prevalence rates (per 10000) of undiagnosed HIV infections by exposure group at national and subnational levels. Belgium consists of three regions: Flanders, Brussels‐Capital Region and Wallonia. We produced estimates for Brussels‐Capital Region and Wallonia. For Flanders, we produced estimates for two sub‐regional areas: the province of Antwerp and the other provinces, because Antwerp is the second largest city after Brussels. Population sizes were determined using data from the Belgian Statistical Office and surveys on sexual behaviour and drug use. Results In Belgium, in 2015, an estimated 2818 (95% confidence interval: 2494 to 3208) individuals were living with undiagnosed HIV, that is, 15% of individuals living with HIV. The Brussels‐Capital Region and the province of Antwerp, which host the two biggest cities, accounted for ~60% of the undiagnosed infections, and had the highest undiagnosed prevalence rates per 10000: 12.0 (9.4 to 15.3) and 7.4 (5.6 to 9.8) respectively. Individuals with foreign nationality accounted for 56% of the total number of undiagnosed infections, and were the most affected populations in all areas in terms of undiagnosed prevalence rates. Specifically, men who have sex with men (MSM) with non‐European nationality were the most affected population in the province of Antwerp (853.4 (408.2 to 1641.9) undiagnosed infections per 10000), the Brussels‐Capital Region (543.9 (289.1 to 1019.1)), and the other provinces of Flanders (691.7 (235.5 to 1442.2)), while in Wallonia, it was heterosexual women with Sub‐Saharan African nationality (132.2 (90.6 to 178.5)). Conclusions Geographic areas hosting the biggest cities in Belgium accounted for the vast majority of undiagnosed HIV infections and individuals with foreign nationality were the most affected, especially MSM with non‐European nationality. This should be accounted for when tailoring prevention and testing programs. Furthermore, MSM with foreign nationality require more attention in Belgium, and certainly more generally in Europe.

This chapter first elaborates on the mechanisms by which fishing should affect population dynamics and characteristics. It then reviews the observed changes in life‐history traits, and investigates how the various mechanisms responsible for these changes. The most powerful method for understanding the mechanisms underlying changes in life‐history traits is the experimental approach. Because the results cannot be directly generalised to wild populations, field studies are also needed. Many have aimed at quantifying the magnitude of density‐dependent processes in life‐history traits variability. Recently, progress has also been made in estimating evolutionary changes. Fishing effects on populations introduce bias and uncertainty in stock size estimates. The chapter examines the extent of these errors, and how they could be corrected for in stock assessments and projections. It then discusses how life‐history traits themselves could be used as indicators for fisheries management, and examines the management tools available to mitigate fishing effects on populations.

Background The 2011 4th European Conference on Infections in Leukemia (ECIL4) guidelines recommend antibiotics de-escalation/discontinuation in selected febrile neutropenia (FN) patients. We aimed to assess the impact of an antimicrobial stewardship (AMS) program based on these guidelines on antibiotics use and clinical outcomes in high-risk FN patients. Methods We conducted an observational study in the hematology department of Cochin University Hospital in Paris, France. An ECIL4-based antibiotics de-escalation and discontinuation strategy was implemented jointly by the hematologists and the AMS team. The pre-intervention (January–October 2018) and post-intervention (January-October 2019) periods were compared. We retrospectively collected clinical and microbiological data. We compiled antibiotics consumptions via hospital pharmacy data and standardized them by calculating defined daily doses per 1000 patient-days. We analyzed the two-monthly antibiotic consumption using an interrupted time series method and built a composite endpoint for clinical outcomes based on transfer to the intensive care unit (ICU) and/or hospital death. Results Overall, 273 hospital stays (164 patients) in the pre-intervention and 217 (148 patients) in the post-intervention periods were analyzed. Patients were mainly hospitalized for intensive chemotherapy for acute leukemia or autologous stem-cell transplant for myeloma. Patients were slightly younger in the pre-intervention compared to the post-intervention period (median age 60.4 vs 65.2 years, p = 0.049), but otherwise comparable. After implementation of the AMS program, glycopeptide and carbapenem use decreased by 85% (p = 0.03) and 72% (p = 0.04), respectively. After adjustment on confounders, the risk of transfer to the ICU/death decreased significantly after implementation of the AMS program (post-intervention period: odds-ratio = 0.29, 95% Confidence Interval: 0.15–0.53, p < 0.001). Conclusion Implementation of a multidisciplinary AMS program for high-risk neutropenic patients was associated with lower carbapenem and glycopeptide use and improved clinical outcomes.