Ambient pollen exposure and pollen allergy symptom severity in the EPOCHAL study.

BACKGROUND: Ambient pollen exposure causes nasal, ocular, and pulmonary symptoms in allergic individuals, but the shape of the exposure-response association is not well characterized. We evaluated this association and determined (1) whether symptom severity differs between subpopulations; (2) how the association changes over the course of the pollen season; and (3) which pollen exposure time lags affect symptoms. METHODS: Adult study participants (n = 396) repeatedly scored severity of nasal, ocular, and pulmonary allergic symptoms, resulting in three composite symptom scores. We calculated hourly individually relevant pollen exposure to seven allergenic plants (alder, ash, birch, hazel, grasses, mugwort, and ragweed) considering personal sensitization and exposure time lags of up to 96 h. We fitted generalized additive mixed models, with a random personal intercept, adjusting for weather and air pollution as potential time-varying confounders. RESULTS: We identified a clear nonlinear positive association between pollen exposure and ocular and nasal symptom severity in the pollen allergy group: Symptom severity increased steeply with increasing exposure initially, but attenuated beyond approximately 80 pollen/m3. We found no evidence of an exposure threshold, below which no symptoms occur. While recent pollen exposure in the last approximately 5 h affected symptoms most, associations lingered for up to 60 h. Grass pollen exposure (compared to tree pollen) and younger age (18-30 years, as opposed to 30-65 years) were both associated with higher nasal and ocular symptom severity. CONCLUSIONS: The lack of a threshold and attenuated dose-response curve may have implications for pollen warning systems, which may be revised to include multiday pollen concentrations in the future.

Association between short-term pollen exposure and blood pressure in adults: A repeated-measures study.

BACKGROUND: Recent studies have related high pollen concentrations to increased cardiovascular morbidity and mortality, yet very little research concerns pre-clinical cardiovascular health, including effects on blood pressure (BP). The EPOCHAL panel study investigated the exposure-response relationship between ambient pollen exposure and systolic and diastolic BP in adults. METHODS: BP was measured in 302 adults with and in 94 without pollen allergy during the pollen season, on approximately 16 days per person (6253 observations). Average individually-relevant pollen exposure in the 96 h prior to each BP measurement was calculated by summing up the averages of all ambient pollen concentrations to which the individual was found to be sensitized in a skin prick test, and which originated from seven highly allergenic pollen types (hazel, alder, birch, ash, grasses, mugwort and ragweed). Generalized additive mixed models were used to study the association between mean individually-relevant pollen exposure in the last 96 h and BP, adjusting for individual and environmental time-varying covariates. Effect modification by pollen allergy status, sex and BMI was evaluated. RESULTS: Positive non-linear associations between individually-relevant pollen exposure and both systolic and diastolic BP were found in the allergic but not in the non-allergic group. BP increased sharply for exposures from zero to 60/80 pollen/m3 (diastolic/systolic BP), followed by a tempered further increase at higher concentrations. Increases of 2.00 mmHg [95% confidence interval (CI): 0.80-3.19] in systolic and 1.51 mmHg [95% CI: 0.58-2.45] in diastolic BP were associated with 96-h average pollen exposure of 400 pollen/m3, compared to no exposure. Obesity and female sex were associated with larger BP increases. CONCLUSIONS: The finding that short-term pollen concentration is associated with increased systolic and diastolic BP in persons with pollen allergy strengthens the evidence that pollen may cause systemic health effects and trigger cardiovascular events.

A cohort analysis of residential radon exposure and melanoma incidence in Switzerland.

Radon is a radioactive noble gas found in Earth's crust. It accumulates in buildings, and accounts for approximately half the ionizing radiation dose received by humans. The skin is considerably exposed to ionizing radiation from radon. We aimed to evaluate the association between residential radon exposure and melanoma and squamous cell carcinoma incidence. The study included 1.3 million adults (20 years and older) from the Swiss National Cohort who were residents of the cantons of Vaud, Neuchâtel, Valais, Geneva, Fribourg, and Ticino at the study baseline (December 04, 2000). Cases of primary tumours of skin (melanoma and squamous cell carcinoma) were identified using data from cantonal cancer registries. Long-term residential radon and ambient solar ultraviolet radiation exposures were assigned to each individual's address at baseline. Cox proportional hazard models with age as time scale, adjusted for canton, socioeconomic position, demographic data available in the census, and outdoor occupation were applied. Total and age specific effects were calculated, in the full population and in non-movers, and potential effect modifiers were tested. In total 4937 incident cases of melanoma occurred during an average 8.9 years of follow-up. Across all ages, no increased risk of malignant melanoma or squamous cell carcinoma incidence in relation to residential radon was found. An association was only observed for melanoma incidence in the youngest age group of 20-29 year olds (1.68 [95% CI: 1.29, 2.19] 100 Bq/m3 radon). This association was mainly in women, and in those with low socio-economic position. Residential radon exposure might be a relevant risk factor for melanoma, especially for young adults. However, the results must be interpreted with caution as this finding is based on a relatively small number of melanoma cases. Accumulation of radon is preventable, and measures to reduce exposure and communicate the risks remain important to convey to the public.

Long-term development of loneliness in older people and associations with stringency of COVID-19 measures: an observational cohort study.

BACKGROUND: Most longitudinal studies found heightened feelings of loneliness in older people in spring 2020 compared to times before the pandemic. However, longer-term effects are more disputed. We, therefore, investigated changes in loneliness in older people throughout the first 21 months of the COVID-19 pandemic in Switzerland and examined the association between the stringency of COVID-19 measures and feelings of loneliness. METHODS: We assessed loneliness (3-item University of California Los Angeles (UCLA) loneliness scale) in a nationally representative longitudinal observational online survey. Older people (65-79 years) were surveyed between March 2020 and December 2021. Proportions of people feeling lonely (UCLA loneliness scale >6) were compared in two stringent phases ('lockdown', Oxford University stringency index ≥55) and two less restricted phases. Additionally, we explored the situation of potentially more susceptible subgroups (living alone, women, chronic and mental diseases, low educational level and low income). RESULTS: Phases with stringent measures were associated with higher levels of loneliness in older people. People living alone, women, people with noncommunicable or mental disease diagnoses and lower income show consistently higher levels of loneliness. However, the differences are not accentuated in phases with more stringent measures. We found little differences between subgroups with varying educational levels. CONCLUSIONS: Even in a country with relatively less stringent COVID-19 measures like Switzerland, an increase in the proportion of older people that feel lonely could be found during phases with more stringent COVID-19 measures. Lockdown phases should, therefore, be accompanied by evidence-based interventions to relieve loneliness to avoid adverse short- and long-term consequences.

Pre-referral rectal artesunate is no "magic bullet" in weak health systems.

Severe malaria is a potentially fatal condition that requires urgent treatment. In a clinical trial, a sub-group of children treated with rectal artesunate (RAS) before being referred to a health facility had an increased chance of survival. We recently published in BMC Medicine results of the CARAMAL Project that did not find the same protective effect of pre-referral RAS implemented at scale under real-world conditions in three African countries. Instead, CARAMAL identified serious health system shortfalls that impacted the entire continuum of care, constraining the effectiveness of RAS. Correspondence to the article criticized the observational study design and the alleged interpretation and consequences of our findings.Here, we clarify that we do not dispute the life-saving potential of RAS, and discuss the methodological criticism. We acknowledge the potential for confounding in observational studies. Nevertheless, the totality of CARAMAL evidence is in full support of our conclusion that the conditions under which RAS can be beneficial were not met in our settings, as children often failed to complete referral and post-referral treatment was inadequate.The criticism did not appear to acknowledge the realities of highly malarious settings documented in detail in the CARAMAL project. Suggesting that trial-demonstrated efficacy is sufficient to warrant large-scale deployment of pre-referral RAS ignores the paramount importance of functioning health systems for its delivery, for completing post-referral treatment, and for achieving complete cure. Presenting RAS as a "magic bullet" distracts from the most urgent priority: fixing health systems so they can provide a functioning continuum of care and save the lives of sick children.The data underlying our publication is freely accessible on Zenodo.

Effectiveness of rectal artesunate as pre-referral treatment for severe malaria in children under 5 years of age: a multi-country observational study.

BACKGROUND: To prevent child deaths from severe malaria, early parenteral treatment is essential. Yet, in remote rural areas, accessing facilities offering parenteral antimalarials may be difficult. A randomised controlled trial found pre-referral treatment with rectal artesunate (RAS) to reduce deaths and disability in children who arrived at a referral facility with delay. This study examined the effectiveness of pre-referral RAS treatment implemented through routine procedures of established community-based health care systems. METHODS: An observational study accompanied the roll-out of RAS in the Democratic Republic of the Congo (DRC), Nigeria and Uganda. Children <5 years of age presenting to a community-based health provider with a positive malaria test and signs of severe malaria were enrolled and followed up during admission and after 28 days to assess their health status and treatment history. The primary outcome was death; covariates of interest included RAS use, referral completion, and post-referral treatment. RESULTS: Post-roll-out, RAS was administered to 88% of patients in DRC, 52% in Nigeria, and 70% in Uganda. The overall case fatality rate (CFR) was 6.7% (135/2011) in DRC, 11.7% (69/589) in Nigeria, and 0.5% (19/3686) in Uganda; 13.8% (865/6286) of patients were sick on day 28. The CFR was higher after RAS roll-out in Nigeria (16.1 vs. 4.2%) and stable in DRC (6.7 vs. 6.6%) and Uganda (0.7 vs. 0.3%). In DRC and Nigeria, children receiving RAS were more likely to die than those not receiving RAS (aOR=3.06, 95% CI 1.35-6.92 and aOR=2.16, 95% CI 1.11-4.21, respectively). Only in Uganda, RAS users were less likely to be dead or sick at follow-up (aOR=0.60, 95% CI 0.45-0.79). Post-referral parenteral antimalarials plus oral artemisinin-based combination therapy (ACT), a proxy for appropriate post-referral treatment, was protective. However, in referral health facilities, ACT was not consistently administered after parenteral treatment (DRC 68.4%, Nigeria 0%, Uganda 70.9%). CONCLUSIONS: Implemented at scale to the recommended target group, pre-referral RAS had no beneficial effect on child survival in three highly malaria-endemic settings. RAS is unlikely to reduce malaria deaths unless health system issues such as referral and quality of care at all levels are addressed. TRIAL REGISTRATION: The study is registered on ClinicalTrials.gov : NCT03568344.

Non-communicable disease prevention in Kosovo: quantitative and qualitative assessment of uptake and barriers of an intervention for healthier lifestyles in primary healthcare.

BACKGROUND: Smoking, physical inactivity, low fruit and vegetable consumption, and obesity are common in Kosovo. Their prevention is a priority to relieve the health system of from costly non-communicable disease treatments. The Accessible Quality Healthcare project is implementing a primary healthcare intervention that entails nurse-guided motivational counselling to facilitate change in the domains of smoking, diet, alcohol consumption and physical inactivity for at-risk patients. This study quantitatively assesses the uptake of motivational counselling and the distribution of health behaviours and stages of health behaviour change of the participants according to the intervention, as well as qualitatively describes experiences and perceived benefits of motivational counselling. METHODS: Study participants (n = 907) were recruited consecutively in 2019 from patients visiting the Main Family Medical Centres in 12 municipalities participating in the Kosovo Non-Communicable Disease Cohort study as part of the Accessible Quality Healthcare project. For the quantitative study, we used baseline and first follow-up data on smoking status, physical inactivity, obesity, fruit and vegetable as well as alcohol consumption, uptake of counselling, and stages for behavioural change. For the qualitative study, in-depth interviews were conducted with a subset of 26 cohort participants who had undergone motivational counselling. RESULTS: Motivational counselling was obtained by only 22% of the eligible participants in the intervention municipalities. Unhealthy behaviours are high even in persons who underwent counselling (of whom 13% are smokers; 86% physically inactive; 93% with inadequate fruit and vegetable consumption; and 61% are obese); only the rate of smoking was lower in those who obtained counselling. Among smokers, over 80% were still in the pre-contemplation phase of behaviour change. More advanced stages of behaviour change were observed among the highly prevalent group of inactive persons and participants with poor dietary habits, among the 5 intervention municipalities. According to the qualitative study results, the participants who obtained motivational counselling were very satisfied with the services but requested additional services such as group physical activity sessions and specialized services for smoking cessation. CONCLUSIONS: More tailored and additional primary health care approaches in accordance with patients' views need to be considered for the motivational counselling intervention to reach patients and efficiently facilitate lifestyle behaviour change.

Mediators of gender effects on depression among cardiovascular disease patients in Palestine.

BACKGROUND: Among patients suffering from coronary heart disease (CHD) and comorbid depression, women experience a higher burden compared to men. Little is known on the characteristics that differentiate men and women with both diseases and whether these factors mediate gender effects on depression. This study assessed whether women are more likely to suffer from depression and which characteristics mediate gender effects on depression among a cardiac population in Palestine, specifically addressing the role of post-traumatic stress disorder (PTSD). METHODS: Using a cross-sectional design, patients consecutively admitted with a CHD to one of the four main hospitals in Nablus, Palestine, were interviewed using a structured questionnaire with validated instruments. Data was also obtained from hospital medical records. Patients were assessed for depression using the Cardiac Depression Scale (CDS). Bivariate analysis was conducted to compare characteristics of women and men with and without depressive symptoms. Mediators (direct and indirect effects) of the association between gender and depression were evaluated using a structural equation model (SEM). RESULTS: Women were more likely to suffer from severe depression than men (28.7% vs. 18.8%). Female gender was positively associated with higher PTSD symptoms, comorbidities, somatic symptoms and income, and with lower resilience, self-esteem, quality of life, education, prevalence of smoking and physical activity. Structural equation modeling revealed negative indirect effects of gender on depression (CDS score) through resilience, self-esteem and physical activity, whereas positive indirect effects of gender on depression were observed through PTSD, comorbidities, somatic symptoms and smoking. There was no direct effect of gender on depression. CONCLUSION: This study found a higher prevalence of severe depression in female patients with cardiac disease compared to male cardiac patients. Our findings provide novel information on mediating factors of the association between gender and depression among cardiac patients, in particular PTSD. The results emphasize the need for further research on potential mediating factors that could account for gender differences in depression and the need to provide support programs for female patients with comorbid CHD and depression to improve their psycho-social well-being.

Ribosomal Peptide Syntheses from Activated Substrates Reveal Rate Limitation by an Unexpected Step at the Peptidyl Site.

Protein synthesis (translation) is central to cellular function and antibiotic development. Interestingly, the key chemical step of translation, peptide bond formation, is among the slower enzymatic reactions. The reason for this remains controversial because of reliance on studies using highly modified, severely minimized, or unreactive substrate analogues. Here, we investigated this problem by fast kinetics using full-length aminoacyl-tRNA substrates with atomic substitutions that activated the ester electrophile. While trifluoro substitution of hydrogens in nonconserved positions of the peptidyl-site substrate dramatically increased the ester reactivity in solution assays, a large hastening of the combined rates of ribosomal accommodation and peptidyl transfer was observed only with a slowly reacting aminoacyl-site nucleophile, proline. With a fast-reacting A-site nucleophile, phenylalanine, effects did not correlate at all with electrophilicities. As effects were observed using the same, natural, aminoacyl-tRNA at the A site and all rates of accommodation/peptidyl transfer were pH dependent, we concluded that rate limitation was not by A-site accommodation but rather by peptidyl transfer and a hitherto unexpected step at the P site. This new slow step, which we term P-site accommodation, has implications for the activation or inhibition of ribosome function in vitro and in vivo.

A tRNA body with high affinity for EF-Tu hastens ribosomal incorporation of unnatural amino acids.

There is evidence that tRNA bodies have evolved to reduce differences between aminoacyl-tRNAs in their affinity to EF-Tu. Here, we study the kinetics of incorporation of L-amino acids (AAs) Phe, Ala allyl-glycine (aG), methyl-serine (mS), and biotinyl-lysine (bK) using a tRNA(Ala)-based body (tRNA(AlaB)) with a high affinity for EF-Tu. Results are compared with previous data on the kinetics of incorporation of the same AAs using a tRNA(PheB) body with a comparatively low affinity for EF-Tu. All incorporations exhibited fast and slow phases, reflecting the equilibrium fraction of AA-tRNA in active ternary complex with EF-Tu:GTP before the incorporation reaction. Increasing the concentration of EF-Tu increased the amplitude of the fast phase and left its rate unaltered. This allowed estimation of the affinity of each AA-tRNA to EF-Tu:GTP during translation, showing about a 10-fold higher EF-Tu affinity for AA-tRNAs formed from the tRNA(AlaB) body than from the tRNA(PheB) body. At ∼1 µM EF-Tu, tRNA(AlaB) conferred considerably faster incorporation kinetics than tRNA(PheB), especially in the case of the bulky bK. In contrast, the swap to the tRNA(AlaB) body did not increase the fast phase fraction of N-methyl-Phe incorporation, suggesting that the slow incorporation of N-methyl-Phe had a different cause than low EF-Tu:GTP affinity. The total time for AA-tRNA release from EF-Tu:GDP, accommodation, and peptidyl transfer on the ribosome was similar for the tRNA(AlaB) and tRNA(PheB) bodies. We conclude that a tRNA body with high EF-Tu affinity can greatly improve incorporation of unnatural AAs in a potentially generalizable manner.

Kinetics of tRNA(Pyl) -mediated amber suppression in Escherichia coli translation reveals unexpected limiting steps and competing reactions.

The utility of ribosomal incorporation of unnatural amino acids (AAs) in vivo is generally restricted by low efficiencies, even with the most widely used suppressor tRNA(Pyl) . Because of the difficulties of studying incorporation in vivo, almost nothing is known about the limiting steps after tRNA charging. Here, we measured the kinetics of all subsequent steps using a purified Escherichia coli translation system. Dipeptide formation from initiator fMet-tRNA(fMet) and tRNA(Pyl) charged with allylglycine or methylserine displayed unexpectedly sluggish biphasic kinetics, ∼30-fold slower than for native substrates. The amplitude of the fast phases increased with increasing EF-Tu concentration, allowing measurement of Kd values of EF-Tu binding, both of which were ∼25-fold weaker than normal. However, binding could be increased ∼30-fold by lowering temperature. The fast phase rates were limited by the surprisingly ∼10-fold less efficient binding of EF-Tu:GTP:AA-tRNA(Pyl) ternary complex to the ribosomes, not GTP hydrolysis or peptide bond formation. Furthermore, processivity was unexpectedly impaired as ∼40% of the dipeptidyl-tRNA(Pyl) could not be elongated to tripeptide. Dipeptide formation was slow enough that termination due to misreading the UAG codon by non-cognate RF2 became very significant. This new understanding provides a framework for improving unnatural AA incorporation by amber suppression. Biotechnol. Bioeng. 2016;113: 1552-1559. © 2015 Wiley Periodicals, Inc.

Transition-state stabilization in Escherichia coli ribonuclease P RNA-mediated cleavage of model substrates.

We have used model substrates carrying modified nucleotides at the site immediately 5' of the canonical RNase P cleavage site, the -1 position, to study Escherichia coli RNase P RNA-mediated cleavage. We show that the nucleobase at -1 is not essential but its presence and identity contribute to efficiency, fidelity of cleavage and stabilization of the transition state. When U or C is present at -1, the carbonyl oxygen at C2 on the nucleobase contributes to transition-state stabilization, and thus acts as a positive determinant. For substrates with purines at -1, an exocyclic amine at C2 on the nucleobase promotes cleavage at an alternative site and it has a negative impact on cleavage at the canonical site. We also provide new insights into the interaction between E. coli RNase P RNA and the -1 residue in the substrate. Our findings will be discussed using a model where bacterial RNase P cleavage proceeds through a conformational-assisted mechanism that positions the metal(II)-activated H2O for an in-line attack on the phosphorous atom that leads to breakage of the phosphodiester bond.

Facile synthesis of N-acyl-aminoacyl-pCpA for preparation of mischarged fully ribo tRNA.

Chemical synthesis of N-acyl-aminoacyl-pdCpA and its ligation to tRNA(minus CA) is widely used for the preparation of unnatural aminoacyl-tRNA substrates for ribosomal translation. However, the presence of the unnatural deoxyribose can decrease incorporation yield in translation and there is no straightforward method for chemical synthesis of the natural ribo version. Here, we show that pCpA is surprisingly stable to treatment with strong organic bases provided that anhydrous conditions are used. This allowed development of a facile method for chemical aminoacylation of pCpA. Preparative synthesis of pCpA was also simplified by using t-butyl-dithiomethyl protecting group methodology, and a more reliable pCpA postpurification treatment method was developed. Such aminoacyl-pCpA analogues ligated to tRNA(minus CA) transcripts are highly active in a purified translation system, demonstrating utility of our synthetic method.

Weekend physical activity profiles and their relationship with quality of life: The SOPHYA cohort of Swiss children and adolescents.

INTRODUCTION: Quality of life (QoL) is an important health indicator among children and adolescents. Evidence on the effect of physical activity (PA)-related behaviors on QoL among youth remains inconsistent. Conventional accelerometer-derived PA metrics and guidelines with a focus on whole weeks may not adequately characterize QoL relevant PA behavior. OBJECTIVE: This study aims to a) identify clusters of accelerometer-derived PA profiles during weekend days among children and adolescents living in Switzerland, b) assess their cross-sectional and predictive association with overall QoL and its dimensions, and c) investigate whether the associations of QoL with the newly identified clusters persist upon adjustment for the commonly used PA metrics moderate-to-vigorous physical activity (MVPA) and time spent in sedentary behavior (SB). METHODS: The population-based Swiss children's Objectively measured PHYsical Activity (SOPHYA) cohort among children and adolescents aged 6 to 16 years was initiated at baseline in 2013. PA and QoL information was obtained twice over a five-year follow-up period. The primary endpoint is the overall QoL score and its six dimension scores obtained by KINDL® questionnaire. The primary predictor is the cluster membership of accelerometer-derived weekend PA profile. Clusters were obtained by applying the k-medoid algorithm to the distance matrix of profiles obtained by pairwise alignments of PA time series using the Dynamic Time Warping (DTW) algorithm. Secondary predictors are accelerometer-derived conventional PA metrics MVPA and SB from two combined weekend days. Linear regression models were applied to assess a) the cross-sectional association between PA cluster membership and QoL at baseline and b) the predictive association between PA cluster membership at baseline and QoL at follow-up, adjusting for baseline QoL. RESULTS: The study sample for deriving PA profile clusters consisted of 51.4% girls and had an average age of 10.9 [SD 2.5] years). The elbow and silhouette methods indicated that weekend PA profiles are best classified in two or four clusters. The most differentiating characteristic for the two-clusters classification ("lower activity" and "high activity"), and the four-clusters classification ("inactive", "low activity", "medium activity", and "high activity"), respectively was the participant's mean counts per 15-seconds epoch. Participants assigned to high activity clusters were younger and more often male. Neither the clustered PA profiles nor MVPA or SB were cross-sectionally or predictively associated with overall QoL. The only association of a conventional PA metrics with QoL while adjusting for cluster membership was observed between MVPA during the weekend days and social well-being with a mean score difference of 2.4 (95%CI: 0.3 to 4.5; p = 0.025). CONCLUSION: The absence of strong associations of PA metrics for the weekend with QoL, except for the positive association between MVPA during the weekend days and social well-being, is in line with results from two randomized studies not showing efficacy of PA interventions on youth QoL. But because PA decreases with age, its promotion and relevance to QoL remain important research topics. Larger longitudinal study samples with more than two follow-up time points of children and adolescents are needed to derive new novel accelerometer-derived PA profiles and to associate them with QoL dimensions.

Randomised controlled trial on the effect of social support on disease control, mental health and health-related quality of life in people with diabetes from Côte d'Ivoire: the SoDDiCo study protocol.

INTRODUCTION: Diabetes mellitus (DM) and its severe complications contribute significantly to disability and, hence, burden of disease. Poor mental health, a frequent DM consequence, may hinder successful diabetes control in low-income and middle-income countries (LMICs). Evidence suggests social support as a cost-effective tool to improve diabetes self-management, behaviour and mental health. However, its real-world application in LMICs has rarely been tested. We aim to investigate the effect of a social support intervention on disease control, mental health and health-related quality of life in people with diabetes from Côte d'Ivoire (SoDDiCo) through a randomised controlled trial. METHODS AND ANALYSIS: The trial will take place in the Centre Antidiabétique d'Abidjan, Institut National de Santé Publique, Abidjan, Côte d'Ivoire. We will prospectively randomise up to 1500 people with newly diagnosed diabetes into two parallel arms: intervention (routine care+family supporter accompanying clinical management) and control (routine care), using gender-stratified blocked randomisation with random block sizes of 10, 16, 20 and 24. Participants will undergo baseline, 3-month and 12-month postrandomisation assessments. The primary study outcome will be glycated haemoglobin (HbA1c). Secondary outcomes will include glycaemic control (HbA1c<7.0%), presence at follow-up visits, mental health and quality of life scores. Using intention-to-treat framework, we will assess the impact of the family support intervention on these endpoints over the course of the 1-year follow-up. Effect modification by baseline social capital will be assessed. ETHICS AND DISSEMINATION: The SoDDiCo trial was approved by the Ethikkommission Nordwest- und Zentralschweiz (ref: AO_2021-00041; approved: 12 July 2021) and by Comité National d'Éthique des Sciences de la Vie et de la Santé (ref: 049-22/MSHPCMU/CNESVS-kp; approved: 20 April 2022). The randomised intervention trial will follow good clinical practice guidelines. All results will be made available to the public through abstracts at conferences as well as through peer-reviewed articles. International guidelines for authorship will be respected. TRIAL REGISTRATION NUMBER: ISRCTN10901121, ISRCTN registry.

Cross-Sectional but Not Prospective Association of Accelerometry-Derived Physical Activity With Quality of Life in Children and Adolescents.

Objectives: This study aims to quantify the cross-sectional and prospective associations between quality of life (QoL) and moderate-to-vigorous physical activity (MVPA). Methods: This study was based on the Swiss children's Objectively measured PHYsical Activity cohort. The primary endpoint is the overall QoL score and its six dimensions. The main predictor is the average time spent in MVPA per day. Linear mixed effects and linear regression models respectively were used to investigate the cross-sectional and prospective associations between MVPA and QoL. Results: There were 352 participants in the study with complete data from baseline (2013-2015) and follow-up (2019). MVPA was positively associated with overall QoL and physical wellbeing (p = 0.023 and 0.002 respectively). The between-subject MVPA was positively associated with the overall QoL, physical wellbeing, and social wellbeing (p = 0.030, 0.017, and 0.028 respectively). Within-subject MVPA was positively associated with physical wellbeing and functioning at school (p = 0.039 and 0.013 respectively). Baseline MVPA was not associated with QoL 5 years later. Conclusion: Future longitudinal studies should employ shorter follow-up times and repeat measurements to assess the PA and QoL association.

On genetic specificity in symbiont-mediated host-parasite coevolution.

Existing theory of host-parasite interactions has identified the genetic specificity of interaction as a key variable affecting the outcome of coevolution. The Matching Alleles (MA) and Gene For Gene (GFG) models have been extensively studied as the canonical examples of specific and non-specific interaction. The generality of these models has recently been challenged by uncovering real-world host-parasite systems exhibiting specificity patterns that fit neither MA nor GFG, and by the discovery of symbiotic bacteria protecting insect hosts against parasites. In the present paper we address both challenges, simulating a large number of non-canonical models of host-parasite interactions that explicitly incorporate symbiont-based host resistance. To assess the genetic specialisation in these hybrid models, we develop a quantitative index of specificity applicable to any coevolutionary model based on a fitness matrix. We find qualitative and quantitative effects of host-parasite and symbiont-parasite specificities on genotype frequency dynamics, allele survival, and mean host and parasite fitnesses.

Understanding diarrhoeal diseases in response to climate variability and drought in Cape Town, South Africa: a mixed methods approach.

BACKGROUND: The climate of southern Africa is expected to become hotter and drier with more frequent severe droughts and the incidence of diarrhoea to increase. From 2015 to 2018, Cape Town, South Africa, experienced a severe drought which resulted in extreme water conservation efforts. We aimed to gain a more holistic understanding of the relationship between diarrhoea in young children and climate variability in a system stressed by water scarcity. METHODS: Using a mixed-methods approach, we explored diarrhoeal disease incidence in children under 5 years between 2010 to 2019 in Cape Town, primarily in the public health system through routinely collected diarrhoeal incidence and weather station data. We developed a negative binomial regression model to understand the relationship between temperature, precipitation, and relative humidity on incidence of diarrhoea with dehydration. We conducted in-depth interviews with stakeholders in the fields of health, environment, and human development on perceptions around diarrhoea and health-related interventions both prior to and over the drought, and analysed them through the framework method. RESULTS: From diarrhoeal incidence data, the diarrhoea with dehydration incidence decreased over the decade studied, e.g. reduction of 64.7% in 2019 [95% confidence interval (CI): 5.5-7.2%] compared to 2010, with no increase during the severe drought period. Over the hot dry diarrhoeal season (November to May), the monthly diarrhoea with dehydration incidence increased by 7.4% (95% CI: 4.5-10.3%) per 1 °C increase in temperature and 2.6% (95% CI: 1.7-3.5%) per 1% increase in relative humidity in the unlagged model. Stakeholder interviews found that extensive and sustained diarrhoeal interventions were perceived to be responsible for the overall reduction in diarrhoeal incidence and mortality over the prior decade. During the drought, as diarrhoeal interventions were maintained, the expected increase in incidence in the public health sector did not occur. CONCLUSIONS: We found that that diarrhoeal incidence has decreased over the last decade and that incidence is strongly influenced by local temperature and humidity, particularly over the hot dry season. While climate change and extreme weather events especially stress systems supporting vulnerable populations such as young children, maintaining strong and consistent public health interventions helps to reduce negative health impacts.

Prospective association between depressive symptoms and blood-pressure related outcomes in Kosovo.

Kosovo has the lowest life expectancy in the Western Balkans, where cardiovascular disease (CVD) accounts for over half of all deaths. Depression also contributes to disability in the country, with a prevalence of moderate to severe symptoms reported as high as 42% in the general population. Although the mechanisms are not yet well understood, evidence suggests that depression is an independent risk factor for CVD. Our study assessed the prospective association between depressive symptoms and blood pressure (BP)-related outcomes among primary healthcare users in Kosovo to understand the role of BP in the relationship between depression and CVD. We included 648 primary healthcare users from the KOSCO study. The presence of depressive symptoms was defined as moderate to very severe depressive symptoms (DASS-21 depressive symptoms score ≥14). Multivariable censored regression models assessed prospective associations between baseline depressive symptoms and changes in systolic and diastolic BP while taking hypertension treatment into consideration. Multivariable logistic regression models assessed prospective associations between baseline depressive symptoms and hypertension diagnosis among normotensive patients (n = 226) as well as uncontrolled hypertension in hypertensive patients (n = 422) at follow-up. Depressive symptoms were associated with attenuated diastolic BP (ß = -2.84, 95%-CI -4.64 to -1.05, p = 0.002) over a year of follow-up in our fully adjusted model, although the association with systolic BP (ß = -1.98, 95%-CI -5.48 to 1.28, p = 0.23) did not meet statistical significance. We found no statistically significant association of depressive symptoms with hypertension diagnosis among initially normotensive people (OR = 1.68, 95%-CI 0.41 to 6.98, p = 0.48), nor with hypertension control among initially hypertensive people (OR = 0.69, 95%-CI 0.34 to 1.41, p = 0.31). Our findings are not consistent with increased BP as an underlying mechanism between depression and elevated CVD risk and contribute valuable evidence to cardiovascular epidemiology, where the mechanisms between depression, hypertension and CVD are yet to be elucidated.