Bigger is fitter? Quantitative genetic decomposition of selection reveals an adaptive evolutionary decline of body mass in a wild rodent population

This is the final version of the article. Available from the publisher via the DOI in this record.In natural populations, quantitative trait dynamics often do not appear to follow evolutionary predictions. Despite abundant examples of natural selection acting on heritable traits, conclusive evidence for contemporary adaptive evolution remains rare for wild vertebrate populations, and phenotypic stasis seems to be the norm. This so-called "stasis paradox" highlights our inability to predict evolutionary change, which is especially concerning within the context of rapid anthropogenic environmental change. While the causes underlying the stasis paradox are hotly debated, comprehensive attempts aiming at a resolution are lacking. Here, we apply a quantitative genetic framework to individual-based long-term data for a wild rodent population and show that despite a positive association between body mass and fitness, there has been a genetic change towards lower body mass. The latter represents an adaptive response to viability selection favouring juveniles growing up to become relatively small adults, i.e., with a low potential adult mass, which presumably complete their development earlier. This selection is particularly strong towards the end of the snow-free season, and it has intensified in recent years, coinciding which a change in snowfall patterns. Importantly, neither the negative evolutionary change, nor the selective pressures that drive it, are apparent on the phenotypic level, where they are masked by phenotypic plasticity and a non causal (i.e., non genetic) positive association between body mass and fitness, respectively. Estimating selection at the genetic level enabled us to uncover adaptive evolution in action and to identify the corresponding phenotypic selective pressure. We thereby demonstrate that natural populations can show a rapid and adaptive evolutionary response to a novel selective pressure, and that explicitly (quantitative) genetic models are able to provide us with an understanding of the causes and consequences of selection that is superior to purely phenotypic estimates of selection and evolutionary change.The study was funded by a Swiss National Science Foundation (http://www.snf.ch) project grant (31003A_141110) awarded to EP

Screening for Hepatocellular Carcinoma among adults with HIV/Hepatitis B coinfection in Zambia: A Pilot Study

Background & aims: Chronic hepatitis B virus (HBV) infection is the main cause of hepatocellular carcinoma (HCC) in sub-Saharan Africa (SSA). In an established cohort of HIV/HBV-coinfected individuals on antiretroviral therapy (ART), we piloted an HCC screening initiative at two outpatient clinics in Lusaka, Zambia. Methods: We performed abdominal ultrasound (AUS) and transient elastography in all patients. Results: Among 279 HIV/HBV-coinfected patients, 165 (59.1%) were men, median age was 34 years (interquartile range 28-39) and median CD4 count 246 cells/µl (112-355). While 102 (36.6%) individuals had elevated transaminases, 114 (40.9%) had HBV levels >2000 IU/mL and 59 (24.6%) significant fibrosis. On AUS, 75 (26.9%) participants had hepatomegaly and 69 (24.7%) peri-portal fibrosis. Five patients had a liver lesion >1cm, an indication for confirmatory imaging. Conclusions: In one of the first HCC screening initiatives in SSA, 2% of HIV/HBV-coinfected adults had significant liver lesions, and a quarter had findings suggestive of schistosomiasis-induced liver damage

Clusters of Sexual Behavior in Human Immunodeficiency Virus-positive Men Who Have Sex With Men Reveal Highly Dissimilar Time Trends.

Separately addressing specific groups of people who share patterns of behavioral change might increase the impact of behavioral interventions to prevent transmission of sexually transmitted infections. We propose a method based on machine learning to assist the identification of such groups among men who have sex with men (MSM). By means of unsupervised learning, we inferred "behavioral clusters" based on the recognition of similarities and differences in longitudinal patterns of condomless anal intercourse with nonsteady partners (nsCAI) in the HIV Cohort Study over the last 18 years. We then used supervised learning to investigate whether sociodemographic variables could predict cluster membership. We identified 4 behavioral clusters. The largest behavioral cluster (cluster 1) contained 53% of the study population and displayed the most stable behavior. Cluster 3 (17% of the study population) displayed consistently increasing nsCAI. Sociodemographic variables were predictive for both of these clusters. The other 2 clusters displayed more drastic changes: nsCAI frequency in cluster 2 (20% of the study population) was initially similar to that in cluster 3 but accelerated in 2010. Cluster 4 (10% of the study population) had significantly lower estimates of nsCAI than all other clusters until 2017, when it increased drastically, reaching 85% by the end of the study period. We identified highly dissimilar behavioral patterns across behavioral clusters, including drastic, atypical changes. The patterns suggest that the overall increase in the frequency of nsCAI is largely attributable to 2 clusters, accounting for a third of the population

The J-Curve in HIV: Low and Moderate Alcohol Intake Predicts Mortality but Not the Occurrence of Major Cardiovascular Events.

OBJECTIVES: In HIV-negative populations, light-to-moderate alcohol consumption is associated with a lower cardiovascular morbidity and mortality than alcohol abstention. Whether the same holds true for HIV-infected individuals has not been evaluated in detail. DESIGN: Cohort study. METHODS: Adults on antiretroviral therapy in the Swiss HIV Cohort Study with follow-up after August 2005 were included. We categorized alcohol consumption into: abstention or very low (<1 g/d), low (1-9 g/d), moderate (10-29 g/d in women and 10-39 g/d in men), and high alcohol intake. Cox proportional hazards models were used to describe the association between alcohol consumption and cardiovascular disease-free survival (combined endpoint), cardiovascular disease events (CADE) and overall survival. Baseline and time-updated risk factors for CADE were included in the models. RESULTS: Among 9741 individuals included, there were 788 events of major CADE or death during 46,719 patient-years of follow-up, corresponding to an incidence of 1.69 events/100 person-years. Follow-up according to alcohol consumption level was 51% no or very low, 20% low, 23% moderate, and 6% high intake. As compared with no or very low alcohol intake, low (hazard ratio 0.79, 95% confidence interval 0.63 to 0.98) and moderate alcohol intakes (0.78, 0.64 to 0.95) were associated with a lower incidence of the combined endpoint. There was no significant association between alcohol consumption and CADE. CONCLUSIONS: Compared with no or very low alcohol consumption, low and moderate intake associated with a better CADE-free survival. However, this result was mainly driven by mortality and the specific impact of drinking patterns and type of alcoholic beverage on this outcome remains to be determined

Clinical Outcomes in Persons Coinfected With Human Immunodeficiency Virus and Hepatitis C Virus: Impact of Hepatitis C Virus Treatment

Background: A hepatitis C (HCV) cure is associated with changes in lipids and inflammatory biomarkers, but its impact on clinical endpoints among treated human immunodeficiency virus (HIV)/HCV coinfected persons is unclear. / Methods: People living with HIV from EuroSIDA with a known HCV status after January 2001 were classified into strata based on time-updated HCV RNA measurements and HCV treatment, as either HCV antibody–negative; spontaneously resolved HCV; chronic, untreated HCV; cured HCV (HCV RNA–negative); or HCV treatment failures (HCV RNA–positive). Poisson regression was used to compare incidence rates between HCV groups for end-stage liver disease (ESLD; including hepatocellular carcinoma [HCC]), non–acquired immunodeficiency virus defining malignancy (NADM; excluding HCC), and cardiovascular disease (CVD). / Results: There were 16 618 persons included (median follow-up 8.3 years, interquartile range 3.1–13.7). There were 887 CVD, 902 NADM, and 436 ESLD events; crude incidence rates/1000 person-years follow-up were 6.4 (95% confidence interval [CI] 6.0–6.9) for CVD, 6.5 (95% CI 6.1–6.9) for NADM, and 3.1 (95% CI 2.8–3.4) for ESLD. After adjustment, there were no differences in incidence rates of NADM or CVD across the 5 groups. HCV-negative individuals (adjusted incidence rate ratio [aIRR] 0.22, 95% CI 0.14–0.34) and those with spontaneous clearance (aIRR 0.61, 95% CI 0.36–1.02) had reduced rates of ESLD compared to cured individuals. Persons with chronic, untreated HCV infections (aIRR 1.47, 95% CI 1.02–2.13) or treatment failure (aIRR 1.80, 95% CI 1.22–2.66) had significantly raised rates of ESLD, compared to those who were cured. / Conclusions: Incidences of NADM or CVD were independent of HCV group, whereas those cured had substantially lower incidences of ESLD, underlining the importance of successful HCV treatment for reducing ESLD

Chronic hepatitis B virus monoinfection at a university hospital in Zambia.

AIM: To characterize antiviral therapy eligibility among hepatitis B virus (HBV)-infected adults at a university hospital in Zambia. METHODS: Hepatitis B surface antigen-positive adults (n = 160) who were HIV-negative and referred to the hospital after a routine or clinically-driven HBV test were enrolled. Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), platelet count, hepatitis B e-antigen, and HBV DNA were measured. Liver fibrosis/cirrhosis was assessed by physical examination, AST-to-platelet ratio index, and transient elastography. In antiviral therapy-naïve individuals, we described HBV stages and antiviral therapy eligibility per World Health Organization (WHO) and by HBV test (routine vs clinical). Elevated ALT was > 19 in women and > 30 U/L in men. Among treatment-experienced individuals, we described medication side effects, adherence, and viral suppression. RESULTS: The median age was 33 years, 71.9% were men, and 30.9% were diagnosed with HBV through a clinically-driven test with the remainder identified via routine testing (at the blood bank, community events, etc.). Among 120 treatment-naïve individuals, 2.5% were categorized as immune tolerant, 11.7% were immune active, 35.6% were inactive carriers, and 46.7% had an indeterminate phenotype. Per WHO guidelines, 13 (10.8%) were eligible for immediate antiviral therapy. The odds of eligibility were eight times higher for those diagnosed at clinical vs routine settings (adjusted odds ratio, 8.33; 95%CI: 2.26-29.41). Among 40 treatment-experienced HBV patients, virtually all took tenofovir, and a history of mild side effects was reported in 20%. Though reported adherence was good, 12 of 29 (41.4%) had HBV DNA > 20 IU/mL. CONCLUSION: Approximately one in ten HBV-monoinfected Zambians were eligible for antivirals. Many had indeterminate phenotype and needed clinical follow-up.School of Medicine at University of Alabama at Birmingham; Fogarty International Center, No. K01TW009998; National Institute of Allergy and Infectious Diseases, U.S. National Institutes of Health, No. U01AI069924; and Swiss National Science Foundation (to Wandeler G), No. PZ0093_154730

Cryptic invasion drives phenotypic changes in central European threespine stickleback

Cryptic invasions are commonly associated with genetic changes of the native species or genetic lineage that the invaders replace. Phenotypic shifts resulting from cryptic invasions are less commonly reported given the relative paucity of historical specimens that document such phenotypic changes. Here, I study such a case in two populations of threespine stickleback from central Europe, comparing contemporary patterns of gene flow with phenotypic changes between historical and contemporary population samples. I find gene flow from an invasive lineage to be associated with significant phenotypic changes, where the degree of phenotypic change corresponds with the level of gene flow that a population receives. These findings underline the utility of combining genetic approaches with phenotypic data to estimate the impact of gene flow in systems where anthropogenic alterations have removed former geographic barriers promoting cryptic invasions

Height and timing of growth spurt during puberty in young people living with vertically acquired HIV in Europe and Thailand.

OBJECTIVE: The aim of this study was to describe growth during puberty in young people with vertically acquired HIV. DESIGN: Pooled data from 12 paediatric HIV cohorts in Europe and Thailand. METHODS: One thousand and ninety-four children initiating a nonnucleoside reverse transcriptase inhibitor or boosted protease inhibitor based regimen aged 1-10 years were included. Super Imposition by Translation And Rotation (SITAR) models described growth from age 8 years using three parameters (average height, timing and shape of the growth spurt), dependent on age and height-for-age z-score (HAZ) (WHO references) at antiretroviral therapy (ART) initiation. Multivariate regression explored characteristics associated with these three parameters. RESULTS: At ART initiation, median age and HAZ was 6.4 [interquartile range (IQR): 2.8, 9.0] years and -1.2 (IQR: -2.3 to -0.2), respectively. Median follow-up was 9.1 (IQR: 6.9, 11.4) years. In girls, older age and lower HAZ at ART initiation were independently associated with a growth spurt which occurred 0.41 (95% confidence interval 0.20-0.62) years later in children starting ART age 6 to 10 years compared with 1 to 2 years and 1.50 (1.21-1.78) years later in those starting with HAZ less than -3 compared with HAZ at least -1. Later growth spurts in girls resulted in continued height growth into later adolescence. In boys starting ART with HAZ less than -1, growth spurts were later in children starting ART in the oldest age group, but for HAZ at least -1, there was no association with age. Girls and boys who initiated ART with HAZ at least -1 maintained a similar height to the WHO reference mean. CONCLUSION: Stunting at ART initiation was associated with later growth spurts in girls. Children with HAZ at least -1 at ART initiation grew in height at the level expected in HIV negative children of a comparable age

Hepatitis delta infection among persons living with HIV in Europe

BACKGROUND AND AIMS: A high prevalence of hepatitis delta virus (HDV) infection, the most severe form of viral hepatitis, has been reported among persons living with HIV (PLWH) in Europe. We analysed data from a large HIV cohort collaboration to characterize HDV epidemiological trends across Europe, as well as its impact on clinical outcomes. METHODS: All PLWH with a positive hepatitis B surface antigen (HBsAg) in the Swiss HIV Cohort Study and EuroSIDA between 1988 and 2019 were tested for anti-HDV antibodies and, if positive, for HDV RNA. Demographic and clinical characteristics at initiation of antiretroviral therapy were compared between HDV-positive and HDV-negative individuals using descriptive statistics. The associations between HDV infection and overall mortality, liver-related mortality as well as hepatocellular carcinoma (HCC) were assessed using cumulative incidence plots and cause-specific multivariable Cox regression. RESULTS: Of 2793 HBsAg-positive participants, 1556 (56%) had stored serum available and were included. The prevalence of HDV coinfection was 15.2% (237/1556, 95% confidence interval [CI]: 13.5%–17.1%) and 66% (132/200) of HDV-positive individuals had active HDV replication. Among persons who inject drugs (PWID), the prevalence of HDV coinfection was 50.5% (182/360, 95% CI: 45.3%–55.7%), with similar estimates across Europe, compared to 4.7% (52/1109, 95% CI: 3.5%–5.9%) among other participants. During a median follow-up of 10.8 years (interquartile range 5.6–17.8), 82 (34.6%) HDV-positive and 265 (20.1%) HDV-negative individuals died. 41.5% (34/82) of deaths were liver-related in HDV-positive individuals compared to 17.7% (47/265) in HDV-negative individuals. HDV infection was associated with overall mortality (adjusted hazard ratio 1.6; 95% CI 1.2–2.1), liver-related death (2.9, 1.6–5.0) and HCC (6.3, 2.5–16.0). CONCLUSION: We found a very high prevalence of hepatitis delta among PWID across Europe. Among PLWH who do not inject drugs, the prevalence was similar to that reported from populations without HIV. HDV coinfection was associated with liver-related mortality and HCC incidence