Background As global aging accelerates, routinely assessing the functional status and morbidity burden of older patients becomes paramount. The aim of this study is to assess the validity of the comprehensive clinical and functional Health Assessment Tool (HAT) based on four cohorts of older adults (60 + years) from the Swedish National study on Aging and Care (SNAC) spanning urban, suburban, and rural areas.Methods The HAT integrates five health indicators (gait speed, global cognition, number of chronic diseases, and basic and instrumental activities of daily living), providing an individual-level score between 0 and 10. The tool was constructed using nominal response models, first separately for each cohort and then in a harmonized dataset. Outcomes included all-cause mortality over a maximum follow-up of 16 years and unplanned hospital admissions over a maximum of 3 years of follow-up. The predictive capacity was assessed through the area under the curve (AUC) using logistic regressions. For time to death, Cox regressions were performed, and Harrell's C-indices were reported. Results from the four cohorts were pooled using individual participant data meta-analysis and compared with those from the harmonized dataset.Results The HAT demonstrated high predictive capacity across all cohorts as well as in the harmonized dataset. In the harmonized dataset, the AUC was 0.84 (95% CI 0.81-0.87) for 1-year mortality, 0.81 (95% CI 0.80-0.83) for 3-year mortality, 0.80 (95% CI 0.79-0.82) for 5-year mortality, 0.69 (95% CI 0.67-0.70) for 1-year unplanned admissions, and 0.69 (95% CI 0.68-0.70) for 3-year unplanned admissions. The Harrell's C for time-to-death throughout 16 years of follow-up was 0.75 (95% CI 0.74-0.75).Conclusions The HAT is a highly predictive, clinically intuitive, and externally valid instrument with potential for better addressing older adults' health needs and optimizing risk stratification at the population level.

Background: As global aging accelerates, routinely assessing the functional status and morbidity burden of older patients becomes paramount. The aim of this study is to assess the validity of the comprehensive clinical and functional Health Assessment Tool (HAT) based on four cohorts of older adults (60 + years) from the Swedish National study on Aging and Care (SNAC) spanning urban, suburban, and rural areas.

Methods: The HAT integrates five health indicators (gait speed, global cognition, number of chronic diseases, and basic and instrumental activities of daily living), providing an individual-level score between 0 and 10. The tool was constructed using nominal response models, first separately for each cohort and then in a harmonized dataset. Outcomes included all-cause mortality over a maximum follow-up of 16 years and unplanned hospital admissions over a maximum of 3 years of follow-up. The predictive capacity was assessed through the area under the curve (AUC) using logistic regressions. For time to death, Cox regressions were performed, and Harrell’s C-indices were reported. Results from the four cohorts were pooled using individual participant data meta-analysis and compared with those from the harmonized dataset.

Results: The HAT demonstrated high predictive capacity across all cohorts as well as in the harmonized dataset. In the harmonized dataset, the AUC was 0.84 (95% CI 0.81–0.87) for 1-year mortality, 0.81 (95% CI 0.80–0.83) for 3-year mortality, 0.80 (95% CI 0.79–0.82) for 5-year mortality, 0.69 (95% CI 0.67–0.70) for 1-year unplanned admissions, and 0.69 (95% CI 0.68–0.70) for 3-year unplanned admissions. The Harrell’s C for time-to-death throughout 16 years of follow-up was 0.75 (95% CI 0.74–0.75).

Conclusions: The HAT is a highly predictive, clinically intuitive, and externally valid instrument with potential for better addressing older adults’ health needs and optimizing risk stratification at the population level. © The Author(s) 2024.

Background: Artemisinin-resistant Plasmodium falciparum has emerged in the Greater Mekong sub-region and poses a major global public health threat. Slow parasite clearance is a key clinical manifestation of reduced susceptibility to artemisinin. This study was designed to establish the baseline values for clearance in patients from Sub-Saharan African countries with uncomplicated malaria treated with artemisinin-based combination therapies (ACTs). Methods: A literature review in PubMed was conducted in March 2013 to identify all prospective clinical trials (uncontrolled trials, controlled trials and randomized controlled trials), including ACTs conducted in Sub-Saharan Africa, between 1960 and 2012. Individual patient data from these studies were shared with the WorldWide Antimalarial Resistance Network (WWARN) and pooled using an a priori statistical analytical plan. Factors affecting early parasitological response were investigated using logistic regression with study sites fitted as a random effect. The risk of bias in included studies was evaluated based on study design, methodology and missing data. Results: In total, 29,493 patients from 84 clinical trials were included in the analysis, treated with artemether-lumefantrine (n = 13,664), artesunate-amodiaquine (n = 11,337) and dihydroartemisinin-piperaquine (n = 4,492). The overall parasite clearance rate was rapid. The parasite positivity rate (PPR) decreased from 59.7 % (95 % CI: 54.5-64.9) on day 1 to 6.7 % (95 % CI: 4.8-8.7) on day 2 and 0.9 % (95 % CI: 0.5-1.2) on day 3. The 95th percentile of observed day 3 PPR was 5.3 %. Independent risk factors predictive of day 3 positivity were: high baseline parasitaemia (adjusted odds ratio (AOR) = 1.16 (95 % CI: 1.08-1.25); per 2-fold increase in parasite density, P <0.001); fever (>37.5 degrees C) (AOR = 1.50 (95 % CI: 1.06-2.13), P = 0.022); severe anaemia (AOR = 2.04 (95 % CI: 1.21-3.44), P = 0.008); areas of low/moderate transmission setting (AOR = 2.71 (95 % CI: 1.38-5.36), P = 0.004); and treatment with the loose formulation of artesunate-amodiaquine (AOR = 2.27 (95 % CI: 1.14-4.51), P = 0.020, compared to dihydroartemisinin-piperaquine). Conclusions: The three ACTs assessed in this analysis continue to achieve rapid early parasitological clearance across the sites assessed in Sub-Saharan Africa. A threshold of 5 % day 3 parasite positivity from a minimum sample size of 50 patients provides a more sensitive benchmark in Sub-Saharan Africa compared to the current recommended threshold of 10 % to trigger further investigation of artemisinin susceptibility.

Background: Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria. Methods: Individual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites. Results: Forty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P < 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and region; treatment with loose NFDC-25 was associated with a 3.5-fold greater risk of recrudescence by day 28 (adjusted hazard ratio, AHR = 3.51 [95% CI: 2.02-6.12], P < 0.001) compared to FDC, and treatment with loose NFDC-30 was associated with a higher risk of recrudescence at only three sites. Conclusions: There was substantial variation in the total dose of amodiaquine administered in different AS-AQ combination regimens. Fixed dose AS-AQ combinations ensure optimal dosing and provide higher antimalarial treatment efficacy than the loose individual tablets in all age categories.

Background: Environmental factors, including infectious agents, are speculated to play a role in the rising prevalence and the geographic distribution of celiac disease, an autoimmune disorder. In the USA and Sweden where the regional variation in the frequency of celiac disease has been studied, a similarity with the geographic distribution of Lyme disease, an emerging multisystemic infection caused by Borrelia burgdorferi spirochetes, has been found, thus raising the possibility of a link. We aimed to determine if infection with Borrelia contributes to an increased risk of celiac disease.

Methods: Biopsy reports from all of Sweden's pathology departments were used to identify 15,769 individuals with celiac disease. Through linkage to the nationwide Patient Register, we compared the rate of earlier occurrence of Lyme disease in the patients with celiac disease to that in 78,331 matched controls. To further assess the temporal relationship between Borrelia infection and celiac disease, we also examined the risk of subsequent Lyme disease in patients with a diagnosis of celiac disease.

Results: Twenty-five individuals (0.16%) with celiac disease had a prior diagnosis of Lyme disease, whereas 79 (0.5%) had a subsequent diagnosis of Lyme disease. A modest association between Lyme disease and celiac disease was seen both before (odds ratio, 1.61; 95% confidence interval (CI), 1.06-2.47) and after the diagnosis of celiac disease (hazard ratio, 1.82; 95% CI, 1.40-2.35), with the risk of disease being highest in the first year of follow-up.

Conclusions: Only a minor fraction of the celiac disease patient population had a prior diagnosis of Lyme disease. The similar association between Lyme disease and celiac disease both before and after the diagnosis of celiac disease is strongly suggestive of surveillance bias as a likely contributor. Taken together, the data indicate that Borrelia infection is not a substantive risk factor in the development of celiac disease.

BACKGROUND: Selenium-dependent deiodinases play a central role in thyroid hormone regulation and metabolism. In many European countries, insufficient selenium intake may consequently lead to adverse effects on thyroid function. In this randomised placebo-controlled double-blind study, we examined the effect of supplementation with selenium and coenzyme Q₁₀ on thyroid hormonal status, cardiovascular (CV) mortality and health-related quality of life (Hr-QoL).

METHODS: Free T3, free T4, reverse T3, and TSH were determined in 414 individuals at baseline, and the effect of selenium yeast (200 µg/day) and coenzyme Q₁₀ (200 mg/day) supplementation on hormone concentrations, CV mortality and Hr-QoL was evaluated after 48 months using Short Form 36 (SF-36). Pre-intervention plasma selenium was low, mean 67 µg/L, corresponding to an estimated intake of 35 µg/day. Changes in concentrations of thyroid hormones following the intervention were assessed using T-tests, repeated measures of variance, and ANCOVA analyses.

RESULTS: In the total population, the group with the lowest selenium concentration at baseline presented with significantly higher levels of TSH and lower levels of fT3 as compared to subjects with the highest selenium concentration. Supplementation with selenium and coenzyme Q₁₀ for 4 years significantly increased fT3 and rT3, decreased fT4, and diminished the increase in TSH levels compared with placebo treatment (p = 0.03, all). In the placebo group, TSH and fT4 values above the median were associated with an increase in 10-year CV mortality, as compared with the mortality rate among those with TSH and fT4 below the median (p < 0.04, both), with no difference in mortality rate according to TSH and fT4 levels in the active intervention group. Similarly, TSH > median and fT3 < median were associated with a decline in mental Hr-QoL measures vs. TSH < and fT3 > median in the placebo group during 4 years of follow-up, but this was wiped out in the active group.

CONCLUSIONS: Supplementation with selenium and coenzyme Q₁₀ had a beneficial effect on thyroid hormones with respect to CV mortality and Hr-QoL outcomes. The initial deficient selenium status was associated with an impaired thyroid function and the changes in thyroid hormone levels can be explained by increased activity of deiodinases. We conclude that a substantial part of the elderly study population might suffer from suboptimal thyroidal function with adverse clinical implications due to selenium deficiency.

TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov and has the identifier NCT01443780. Since it was not mandatory to register at the time the study began, the study has been registered retrospectively.

Background Selenium-dependent deiodinases play a central role in thyroid hormone regulation and metabolism. In many European countries, insufficient selenium intake may consequently lead to adverse effects on thyroid function. In this randomised placebo-controlled double-blind study, we examined the effect of supplementation with selenium and coenzyme Q(10) on thyroid hormonal status, cardiovascular (CV) mortality and health-related quality of life (Hr-QoL). Methods Free T3, free T4, reverse T3, and TSH were determined in 414 individuals at baseline, and the effect of selenium yeast (200 mu g/day) and coenzyme Q(10) (200 mg/day) supplementation on hormone concentrations, CV mortality and Hr-QoL was evaluated after 48 months using Short Form 36 (SF-36). Pre-intervention plasma selenium was low, mean 67 mu g/L, corresponding to an estimated intake of 35 mu g/day. Changes in concentrations of thyroid hormones following the intervention were assessed using T-tests, repeated measures of variance, and ANCOVA analyses. Results In the total population, the group with the lowest selenium concentration at baseline presented with significantly higher levels of TSH and lower levels of fT3 as compared to subjects with the highest selenium concentration. Supplementation with selenium and coenzyme Q(10) for 4 years significantly increased fT3 and rT3, decreased fT4, and diminished the increase in TSH levels compared with placebo treatment (p = 0.03, all). In the placebo group, TSH and fT4 values above the median were associated with an increase in 10-year CV mortality, as compared with the mortality rate among those with TSH and fT4 below the median (p &lt; 0.04, both), with no difference in mortality rate according to TSH and fT4 levels in the active intervention group. Similarly, TSH &gt; median and fT3 &lt; median were associated with a decline in mental Hr-QoL measures vs. TSH &lt; and fT3 &gt; median in the placebo group during 4 years of follow-up, but this was wiped out in the active group. Conclusions Supplementation with selenium and coenzyme Q(10) had a beneficial effect on thyroid hormones with respect to CV mortality and Hr-QoL outcomes. The initial deficient selenium status was associated with an impaired thyroid function and the changes in thyroid hormone levels can be explained by increased activity of deiodinases. We conclude that a substantial part of the elderly study population might suffer from suboptimal thyroidal function with adverse clinical implications due to selenium deficiency. Trial registration This study was registered at ClinicalTrials.gov and has the identifier NCT01443780. Since it was not mandatory to register at the time the study began, the study has been registered retrospectively.

BACKGROUND: Excess body weight, physical activity, smoking, alcohol consumption and certain dietary factors are individually related to colorectal cancer (CRC) risk; however, little is known about their joint effects. The aim of this study was to develop a healthy lifestyle index (HLI) composed of five potentially modifiable lifestyle factors - healthy weight, physical activity, non-smoking, limited alcohol consumption and a healthy diet, and to explore the association of this index with CRC incidence using data collected within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. METHODS: In the EPIC cohort, a total of 347,237 men and women, 25- to 70-years old, provided dietary and lifestyle information at study baseline (1992 to 2000). Over a median follow-up time of 12 years, 3,759 incident CRC cases were identified. The association between a HLI and CRC risk was evaluated using Cox proportional hazards regression models and population attributable risks (PARs) have been calculated. RESULTS: After accounting for study centre, age, sex and education, compared with 0 or 1 healthy lifestyle factors, the hazard ratio (HR) for CRC was 0.87 (95% confidence interval (CI): 0.44 to 0.77) for two factors, 0.79 (95% CI: 0.70 to 0.89) for three factors, 0.66 (95% CI: 0.58 to 0.75) for four factors and 0.63 (95% CI: 0.54 to 0.74) for five factors; P-trend <0.0001. The associations were present for both colon and rectal cancers, HRs, 0.61 (95% CI: 0.50 to 0.74; P for trend <0.0001) for colon cancer and 0.68 (95% CI: 0.53 to 0.88; P-trend <0.0001) for rectal cancer, respectively (P-difference by cancer sub-site = 0.10). Overall, 16% of the new CRC cases (22% in men and 11% in women) were attributable to not adhering to a combination of all five healthy lifestyle behaviours included in the index. CONCLUSIONS: Combined lifestyle factors are associated with a lower incidence of CRC in European populations characterized by western lifestyles. Prevention strategies considering complex targeting of multiple lifestyle factors may provide practical means for improved CRC prevention.

Background: Nutrition and lifestyle have been long established as risk factors for colorectal cancer (CRC). Modifiable lifestyle behaviours bear potential to minimize long-term CRC risk; however, translation of lifestyle information into individualized CRC risk assessment has not been implemented. Lifestyle-based risk models may aid the identification of high-risk individuals, guide referral to screening and motivate behaviour change. We therefore developed and validated a lifestyle-based CRC risk prediction algorithm in an asymptomatic European population.

Methods: The model was based on data from 255,482 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) study aged 19 to 70 years who were free of cancer at study baseline (1992–2000) and were followed up to 31 September 2010. The model was validated in a sample comprising 74,403 participants selected among five EPIC centres. Over a median follow-up time of 15 years, there were 3645 and 981 colorectal cancer cases in the derivation and validation samples, respectively. Variable selection algorithms in Cox proportional hazard regression and random survival forest (RSF) were used to identify the best predictors among plausible predictor variables. Measures of discrimination and calibration were calculated in derivation and validation samples. To facilitate model communication, a nomogram and a web-based application were developed.

Results: The final selection model included age, waist circumference, height, smoking, alcohol consumption, physical activity, vegetables, dairy products, processed meat, and sugar and confectionary. The risk score demonstrated good discrimination overall and in sex-specific models. Harrell’s C-index was 0.710 in the derivation cohort and 0.714 in the validation cohort. The model was well calibrated and showed strong agreement between predicted and observed risk. Random survival forest analysis suggested high model robustness. Beyond age, lifestyle data led to improved model performance overall (continuous net reclassification improvement = 0.307 (95% CI 0.264–0.352)), and especially for young individuals below 45 years (continuous net reclassification improvement = 0.364 (95% CI 0.084–0.575)).

Conclusions: LiFeCRC score based on age and lifestyle data accurately identifies individuals at risk for incident colorectal cancer in European populations and could contribute to improved prevention through motivating lifestyle change at an individual level.

Background: Plasmodium falciparum infections with slow parasite clearance following artemisinin-based therapies are widespread in the Greater Mekong Subregion. A molecular marker of the slow clearance phenotype has been identified: single genetic changes within the propeller region of the Kelch13 protein (pfk13; Pf3D7_1343700). Global searches have identified almost 200 different non-synonymous mutant pfk13 genotypes. Most mutations occur at low prevalence and have uncertain functional significance. To characterize the impact of different pfk13 mutations on parasite clearance, we conducted an individual patient data meta-analysis of the associations between parasite clearance half-life (PC_1/2) and pfk13 genotype based on a large set of individual patient records from Asia and Africa.

Methods: A systematic literature review following the PRISMA protocol was conducted to identify studies published between 2000 and 2017 which included frequent parasite counts and pfk13 genotyping. Four databases (Ovid Medline, PubMed, Ovid Embase, and Web of Science Core Collection) were searched. Eighteen studies (15 from Asia, 2 from Africa, and one multicenter study with sites on both continents) met inclusion criteria and were shared. Associations between the log transformed PC_1/2 values and pfk13 genotype were assessed using multivariable regression models with random effects for study site.

Results: Both the pfk13 genotypes and the PC_1/2 were available from 3250 (95%) patients (n=3012 from Asia (93%), n=238 from Africa (7%)). Among Asian isolates, all pfk13 propeller region mutant alleles observed in five or more specific isolates were associated with a 1.5- to 2.7-fold longer geometric mean PC_1/2 compared to the PC_1/2 of wild type isolates (all p≤0.002). In addition, mutant allele E252Q located in the P. falciparum region of pfk13 was associated with 1.5-fold (95%CI 1.4-1.6) longer PC_1/2. None of the isolates from four countries in Africa showed a significant difference between the PC_1/2 of parasites with or without pfk13 propeller region mutations.Previously, the association of six pfk13 propeller mutant alleles with delayed parasite clearance had been confirmed. This analysis demonstrates that 15 additional pfk13 alleles are associated strongly with the slow-clearing phenotype in Southeast Asia.

Conclusion: Pooled analysis associated 20 pfk13 propeller region mutant alleles with the slow clearance phenotype, including 15 mutations not confirmed previously.

Internet-administered cognitive behavior therapy is a promising new way to deliver psychological treatment. There are an increasing number of controlled trials in various fields such as anxiety disorders, mood disorders and health conditions such as headache and insomnia. Among the advantages for the field of cognitive behavior therapy is the dissemination of the treatment, being able to access treatment from a distance, and possibilities to tailor the interventions. To date, studies in which large effects have been obtained have included patient support from a clinician. Recent trials suggest that this support may come from non-clinicians and that therapist effects are minimal. Since studies also suggest that internet-delivered cognitive behavior therapy can be equally effective as face-to-face cognitive behavior therapy, this is a finding that may have implications for CBT practitioners. However, there are other aspects to consider for implementation, as while clinicians may hold positive attitudes towards internet-delivered CBT a recent study suggested that patients are more skeptical and may prefer face-to-face treatment. In the present work, I argue that internet-delivered CBT may help to increase adherence to treatment protocols, that training can be facilitated by means of internet support, and that research on internet interventions can lead to new insights regarding what happens in regular CBT. Moreover, I conclude that internet-delivered CBT works best when support is provided, leaving an important role for clinicians who can incorporate internet treatment in their services. However, I also warn against disseminating internet-delivered CBT to patients for whom it is not suitable, and that clinical skills may suffer if clinicians are trained and practice mainly using the internet.

Background

Infant neurodevelopment in the first years after birth is determined by multiple factors, including parental care and maternal mental wellbeing. In this study, we aim to assess the impact of persistent maternal depressive symptoms during the first 3 months postpartum on infant neurodevelopment at 6 months.

Methods

Using a longitudinal cohort design, 1253 mother-infant pairs were followed up at 7, 45, and 90 days to assess postpartum depressive symptoms using the Edinburgh Postnatal Depression Scale (EPDS); infants were followed up at 6 months to assess neuro-developmental status using the WHO's Infant and Young Child Development (IYCD) tool. A generalized linear regression model was used to assess the association between persistent postpartum depressive symptoms and infant neurodevelopmental delay at 6 months. A generalized linear mixed model (GLMM) with a hospital as a random intercept was used to assess the persistent postpartum depressive symptoms with an IYCD score. Linear regression was used to compare the IYCD scores between exposure groups.

Results

In the study population, 7.5% of mothers had persistent depressive symptoms, and 7.5% of infants had neurodevelopmental delay. Infants born to mothers with persistent depressive symptoms had a higher proportion of neurodevelopmental delay than infants born to women without persistent symptoms (48.6% vs 5.1%; p < 0.001). In the adjusted regression model, infants whose mothers had persistent depressive symptoms at 7, 45, and 90 days had a 5.21-fold increased risk of neurodevelopmental delay (aRR, 5.21; 95% CI, 3.17, 8.55). Mean scores in the motor domain (12.7 vs 15.2; p < 0.001) and language domain (6.4 vs 8.5; p < 0.001) were significant when a mother had persistent depression vs. no depression. Mean scores in the general behavioral domain (5.9 vs 10.4, p < 0.001) and the socio-emotional domain (15.4 vs 17.7; p < 0.001) were significantly different when a mother had persistent depression vs no persistent depression.

Conclusions

Our results suggest that 6-month-old infants are at higher risk for neurodevelopment delays if their mother reports persistent symptoms of depression from 7 to 90 days postpartum. The neurodevelopmental delay can be observed in all functional domains. Preventive intervention to reduce maternal postpartum depression may reduce the impact on infant developmental delay.

Background Frailty has been identified as a risk factor for cognitive impairment and dementia. However, it is not known whether familial factors, such as genetics and shared environmental factors, underlie this association. We analyzed the association between frailty and the risk of dementia in a large twin cohort and examined the role of familial factors in the association. Methods The Rockwood frailty index (FI) based on 44 health deficits was used to assess frailty. The population-level association between FI and the risk of all-cause dementia was analyzed in 41,550 participants of the Screening Across the Lifespan Twin (SALT) study (full sample, aged 41-97 years at baseline), using Cox and competing risk models. A subsample of 10,487 SALT participants aged 65 and older who received a cognitive assessment (cognitive sample) was used in a sensitivity analysis to assess the effect of baseline cognitive level on the FI-dementia association. To analyze the influence of familial effects on the FI-dementia association, a within-pair analysis was performed. The within-pair model was also used to assess whether the risk conferred by frailty varies by age at FI assessment. Results A total of 3183 individuals were diagnosed with dementia during the 19-year follow-up. A 10% increase in FI was associated with an increased risk of dementia (hazard ratio [HR] 1.17 (95% confidence interval [CI] 1.07, 1.18)) in the full sample adjusted for age, sex, education, and tobacco use. A significant association was likewise found in the cognitive sample, with an HR of 1.13 (95% CI 1.09, 1.20), adjusted for age, sex, and cognitive level at baseline. The associations were not attenuated when adjusted for APOE e4 carrier status or considering the competing risk of death. After adjusting for familial effects, we found no evidence for statistically significant attenuation of the effect. The risk conferred by higher FI on dementia was constant after age 50 until very old age. Conclusions A higher level of frailty predicts the risk of dementia and the association appears independent of familial factors. Targeting frailty might thus contribute to preventing or delaying dementia.

Background: Mesenchymal stem cells (MSCs) have been promoted as an attractive option to use as cellular delivery vehicles to carry anti-tumor agents, owing to their ability to home into tumor sites and secrete cytokines. Multiple isolated populations have been described as MSCs, but despite extensive in vitro characterization, little is known about their in vivo behavior. The aim of this study was to investigate the efficacy and efficiency of different MSC lineages derived from five different sources (bone marrow, adipose tissue, epithelial endometrium, stroma endometrium, and amniotic membrane), in order to assess their adequacy for cell-based anti-tumor therapies. Our study shows the crucial importance of understanding the interaction between MSCs and tumor cells, and provides both information and a methodological approach, which could be used to develop safer and more accurate targeted therapeutic applications. Methods: We first measured the in vivo migration capacity and effect on tumor growth of the different MSCs using two imaging techniques: (i) single-photon emission computed tomography combined with computed tomography (SPECT-CT), using the human sodium iodine symporter gene (hNIS) and (ii) magnetic resonance imaging using superparamagnetic iron oxide. We then sought correlations between these parameters and expression of pluripotency-related or migration-related genes. Results: Our results show that migration of human bone marrow-derived MSCs was significantly reduced and slower than that obtained with the other MSCs assayed and also with human induced pluripotent stem cells (hiPSCs). The qPCR data clearly show that MSCs and hiPSCs exert a very different pluripotency pattern, which correlates with the differences observed in their engraftment capacity and with their effects on tumor growth. Conclusion: This study reveals differences in MSC recruitment/migration toward the tumor site and the corresponding effects on tumor growth. Three observations stand out: 1) tracking of the stem cell is essential to check the safety and efficacy of cell therapies; 2) the MSC lineage to be used in the cell therapy needs to be carefully chosen to balance efficacy and safety for a particular tumor type; and 3) different pluripotency and mobility patterns can be linked to the engraftment capacity of the MSCs, and should be checked as part of the clinical characterization of the lineage.

Background: The ubiquity of Internet connectivity, and widespread unmet needs, requires investigations of digital interventions for people seeking help with their drinking. The objective of this study was to test the effectiveness of a digital alcohol intervention compared to existing online resources for help seekers. Methods: This parallel randomised controlled trial included 2129 risky drinkers with access to a mobile phone and aged 18 years or older. Randomised sub-studies investigated consent procedures and control group design. Simple computerised randomisation was used. Participants were aware of allocation after randomisation; research personnel were not. The digital intervention was designed around weekly monitoring of alcohol consumption followed by feedback and tools for behaviour change. Primary outcomes were total weekly consumption (TWC) and frequency of heavy episodic drinking (HED), measured 2 and 4 months post-randomisation. Results: Between 25/04/2019 and 26/11/2020, 2129 participants were randomised (intervention: 1063, control: 1066). Negative binomial regression was used to contrast groups, with both Bayesian and maximum likelihood inference. The posterior median incidence rate ratio (IRR) of TWC was 0.89 (95% CI = 0.81;0.99, 98.2% probability of effect, P-value = 0.033) at 2 months among 1557 participants and 0.77 (95% CI = 0.69;0.86, &gt; 99.9% probability of effect, P-value &lt; 0.001) at 4 months among 1429 participants. For HED, the IRR was 0.83 (95% CI = 0.75;0.93, &gt; 99.9% probability of effect, P-value = 0.0009) at 2 months among 1548 participants and 0.71 (95% CI = 0.63;0.79, probability of effect &gt; 99.9%, P-value &lt; 0.0001) at 4 months among 1424 participants. Analyses with imputed data were not markedly different. Conclusions: A digital alcohol intervention produced self-reported behaviour change among online help seekers in the general population. The internal and external validity of this trial is strong, subject to carefully considered study limitations arguably inherent to trials of this nature. Limitations include higher than anticipated attrition to follow-up and lack of blinding.

Substantial global progress in the control of malaria in recent years has led to increased commitment to its potential elimination. Whether this is possible in high transmission areas of sub-Saharan Africa remains unclear. Zanzibar represents a unique case study of such attempt, where modern tools and strategies for malaria treatment and vector control have been deployed since 2003. We have studied temporal trends of comprehensive malariometric indices in two districts with over 100,000 inhabitants each. The analyses included triangulation of data from annual community-based cross-sectional surveys, health management information systems, vital registry and entomological sentinel surveys. The interventions, with sustained high-community uptake, were temporally associated with a major malaria decline, most pronounced between 2004 and 2007 and followed by a sustained state of low transmission. In 2015, the Plasmodium falciparum community prevalence of 0.43% (95% CI 0.23-0.73) by microscopy or rapid diagnostic test represented 96% reduction compared with that in 2003. The P. falciparum and P. malariae prevalence by PCR was 1.8% (95% CI 1.3-2.3), and the annual P. falciparum incidence was estimated to 8 infections including 2.8 clinical episodes per 1000 inhabitants. The total parasite load decreased over 1000-fold (99.9%) between 2003 and 2015. The incidence of symptomatic malaria at health facilities decreased by 94% with a trend towards relatively higher incidence in age groups > 5 years, a more pronounced seasonality and with reported travel history to/from Tanzania mainland as a higher risk factor. All-cause mortality among children < 5 years decreased by 72% between 2002 and 2007 mainly following the introduction of artemisinin-based combination therapies whereas the main reduction in malaria incidence followed upon the vector control interventions from 2006. Human biting rates decreased by 98% with a major shift towards outdoor biting by Anopheles arabiensis. Zanzibar provides new evidence of the feasibility of reaching uniquely significant and sustainable malaria reduction (pre-elimination) in a previously high endemic region in sub-Saharan Africa. The data highlight constraints of optimistic prognostic modelling studies. New challenges, mainly with outdoor transmission, a large asymptomatic parasite reservoir and imported infections, require novel tools and reoriented strategies to prevent a rebound effect and achieve elimination.

Background Smoking continues to be a leading risk factor for several diseases globally. We hypothesised that an intervention delivered via text messages could help individuals who were looking to quit.Methods A two-arm, parallel-groups, randomised controlled trial was employed. Both groups received treatment as usual, with the intervention group also receiving a 12-week text messaging intervention. Participants were adult, weekly or more frequent smokers, recruited online and in primary health care centres. Research personnel were blinded, while participants were not. Primary outcomes were prolonged abstinence and point prevalence of abstinence, 3 and 6 months post-randomisation. All randomised participants were included in analyses.Results Between 18 September 2020 and 16 June 2022, we randomised 1012 participants (intervention: 505, control: 507). Outcome data was available for 67% (n = 682) of participants at 3 months and 64% (n = 643) at 6 months. At 3 months, the odds ratio (OR) of prolonged abstinence was 2.15 (95% compatibility interval [CoI] = 1.51; 3.06, probability of effect [POE] &gt; 99.9%, p &lt; 0.0001), and for point prevalence of abstinence, it was 1.70 (95% CoI = 1.18; 2.44, POE = 99.8%, p = 0.0034) in favour of the text messaging intervention. At 6 months, the OR of prolonged abstinence was 2.38 (95% CoI = 1.62; 3.57, POE &gt; 99.9%, p = &lt; 0.0001), and for point prevalence, it was 1.49 (95% CoI = 1.03; 2.14, POE = 98.3%, p = 0.0349) in favour of the text messaging intervention. Analyses with imputed data were not markedly different.Conclusions Amongst general population help-seekers-who on average had smoked for 25 years-access to a 12-week text messaging intervention produced higher rates of self-reported smoking abstinence in comparison to treatment as usual only. The intervention could be part of the societal response to the burden which smoking causes; however, findings are limited by risk of bias due to attrition, self-reported outcomes, and lack of blinding.

Background: Epidemiological studies of associations between metabolites and cancer risk have typically focused on specific cancer types separately. Here, we designed a multivariate pan-cancer analysis to identify metabolites potentially associated with multiple cancer types, while also allowing the investigation of cancer type-specific associations.

Methods: We analysed targeted metabolomics data available for 5828 matched case-control pairs from cancer-specific case-control studies on breast, colorectal, endometrial, gallbladder, kidney, localized and advanced prostate cancer, and hepatocellular carcinoma nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. From pre-diagnostic blood levels of an initial set of 117 metabolites, 33 cluster representatives of strongly correlated metabolites and 17 single metabolites were derived by hierarchical clustering. The mutually adjusted associations of the resulting 50 metabolites with cancer risk were examined in penalized conditional logistic regression models adjusted for body mass index, using the data-shared lasso penalty.

Results: Out of the 50 studied metabolites, (i) six were inversely associated with the risk of most cancer types: glutamine, butyrylcarnitine, lysophosphatidylcholine a C18:2, and three clusters of phosphatidylcholines (PCs); (ii) three were positively associated with most cancer types: proline, decanoylcarnitine, and one cluster of PCs; and (iii) 10 were specifically associated with particular cancer types, including histidine that was inversely associated with colorectal cancer risk and one cluster of sphingomyelins that was inversely associated with risk of hepatocellular carcinoma and positively with endometrial cancer risk.

Conclusions: These results could provide novel insights for the identification of pathways for cancer development, in particular those shared across different cancer types.

Background Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. Methods We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. Results In sex-specific MR analyses, higher BMI (per 4.2 kg/m(2)) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m(2)) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P <= 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. Conclusions Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.

BACKGROUND: Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood.

METHODS: We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models.

RESULTS: In sex-specific MR analyses, higher BMI (per 4.2 kg/m²) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m²) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles.

CONCLUSIONS: Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.

New Global Burden of Disease estimates for liver cirrhosis, published in BMC Medicine, suggest that cirrhosis caused over a million deaths in 2010, with a further million due to liver cancer and acute hepatitis. Cause-specific mortality data were very sparse for some regions, particularly in Africa, with no relevant mortality data for 58/187 countries. Liver disease involves infectious, malignant and chronic aetiologies with overlapping symptoms. Where available mortality data come from verbal autopsies, separating different types of liver disease is challenging. Cirrhosis is a disease of rich and poor alike; key public health risk factors such as alcohol consumption play an important role. Risk-reduction strategies such as controlling the price of alcohol are being widely discussed. Since these estimates used alcohol consumption as a covariate, they cannot be used to explore relationships between alcohol consumption and cirrhosis mortality. There is hope: coming generations of adults will have been vaccinated against hepatitis B, and this is envisaged to reduce the burden of fatal liver disease. But more complete civil registration globally is needed to fully understand the burden of liver disease.

BACKGROUND: Verbal Autopsy (VA) is widely viewed as the only immediate strategy for registering cause of death in much of Africa and Asia, where routine physician certification of deaths is not widely practiced. VA involves a lay interview with family or friends after a death, to record essential details of the circumstances. These data can then be processed automatically to arrive at standardized cause of death information.

METHODS: The Population Health Metrics Research Consortium (PHMRC) undertook a study at six tertiary hospitals in low- and middle-income countries which documented over 12,000 deaths clinically and subsequently undertook VA interviews. This dataset, now in the public domain, was compared with the WHO 2012 VA standard and the InterVA-4 interpretative model.

RESULTS: The PHMRC data covered 70% of the WHO 2012 VA input indicators, and categorized cause of death according to PHMRC definitions. After eliminating some problematic or incomplete records, 11,984 VAs were compared. Some of the PHMRC cause definitions, such as 'preterm delivery', differed substantially from the International Classification of Diseases, version 10 equivalent. There were some appreciable inconsistencies between the hospital and VA data, including 20% of the hospital maternal deaths being described as non-pregnant in the VA data. A high proportion of VA cases (66%) reported respiratory symptoms, but only 18% of assigned hospital causes were respiratory-related. Despite these issues, the concordance correlation coefficient between hospital and InterVA-4 cause of death categories was 0.61.

CONCLUSIONS: The PHMRC dataset is a valuable reference source for VA methods, but has to be interpreted with care. Inherently inconsistent cases should not be included when using these data to build other VA models. Conversely, models built from these data should be independently evaluated. It is important to distinguish between the internal and external validity of VA models. The effects of using tertiary hospital data, rather than the more usual application of VA to all-community deaths, are hard to evaluate. However, it would still be of value for VA method development to have further studies of population-based post-mortem examinations.

Background: Verbal autopsy is an increasingly important methodology for assigning causes to otherwise uncertified deaths, which amount to around 50% of global mortality and cause much uncertainty for health planning. The World Health Organization sets international standards for the structure of verbal autopsy interviews and for cause categories that can reasonably be derived from verbal autopsy data. In addition, computer models are needed to efficiently process large quantities of verbal autopsy interviews to assign causes of death in a standardised manner. Here, we present the InterVA-5 model, developed to align with the WHO-2016 verbal autopsy standard. This is a harmonising model that can process input data from WHO-2016, as well as earlier WHO-2012 and Tariff-2 formats, to generate standardised cause-specific mortality profiles for diverse contexts.

The software development involved building on the earlier InterVA-4 model, and the expanded knowledge base required for InterVA-5 was informed by analyses from a training dataset drawn from the Population Health Metrics Research Collaboration verbal autopsy reference dataset, as well as expert input.

Results: The new model was evaluated against a test dataset of 6130 cases from the Population Health Metrics Research Collaboration and 4009 cases from the Afghanistan National Mortality Survey dataset. Both of these sources contained around three quarters of the input items from the WHO-2016, WHO-2012 and Tariff-2 formats. Cause-specific mortality fractions across all applicable WHO cause categories were compared between causes assigned in participating tertiary hospitals and InterVA-5 in the test dataset, with concordance correlation coefficients of 0.92 for children and 0.86 for adults.

The InterVA-5 model’s capacity to handle different input formats was evaluated in the Afghanistan dataset, with concordance correlation coefficients of 0.97 and 0.96 between the WHO-2016 and the WHO-2012 format for children and adults respectively, and 0.92 and 0.87 between the WHO-2016 and the Tariff-2 format respectively.

Conclusions: Despite the inherent difficulties of determining “truth” in assigning cause of death, these findings suggest that the InterVA-5 model performs well and succeeds in harmonising across a range of input formats. As more primary data collected under WHO-2016 become available, it is likely that InterVA-5 will undergo minor re-versioning in the light of practical experience. The model is an important resource for measuring and evaluating cause-specific mortality globally.

Background: Much research in epidemiology has been focused on evaluating conventional methods of control strategies in the event of an epidemic or pandemic. Travel restrictions are often suggested as an efficient way to reduce the spread of a contagious disease that threatens public health, but few papers have studied in depth the effects of travel restrictions. In this study, we investigated what effect different levels of travel restrictions might have on the speed and geographical spread of an outbreak of a disease similar to severe acute respiratory syndrome (SARS). Methods: We used a stochastic simulation model incorporating survey data of travel patterns between municipalities in Sweden collected over 3 years. We tested scenarios of travel restrictions in which travel over distances > 50 km and 20 km would be banned, taking into account different levels of compliance. Results: We found that a ban on journeys > 50 km would drastically reduce the speed and geographical spread of outbreaks, even when compliance is < 100%. The result was found to be robust for different rates of intermunicipality transmission intensities. Conclusion: This study supports travel restrictions as an effective way to mitigate the effect of a future disease outbreak.

Background: The Mediterranean diet has been associated with lower risk of breast cancer (BC) but evidence from prospective studies on the role of Mediterranean diet on BC survival remains sparse and conflicting. We aimed to investigate whether adherence to Mediterranean diet prior to diagnosis is associated with overall and BC-specific mortality.

Methods: A total of 13,270 incident breast cancer cases were identified from an initial sample of 318,686 women in 9 countries from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Adherence to Mediterranean diet was estimated through the adapted relative Mediterranean diet (arMED), a 16-point score that includes 8 key components of the Mediterranean diet and excludes alcohol. The degree of adherence to arMED was classified as low (score 0–5), medium (score 6–8), and high (score 9–16). Multivariable Cox proportional hazards models were used to analyze the association between the arMED score and overall mortality, and Fine-Gray competing risks models were applied for BC-specific mortality.

Results: After a mean follow-up of 8.6 years from diagnosis, 2340 women died, including 1475 from breast cancer. Among all BC survivors, low compared to medium adherence to arMED score was associated with a 13% higher risk of all-cause mortality (HR 1.13, 95%CI 1.01–1.26). High compared to medium adherence to arMED showed a non-statistically significant association (HR 0.94; 95% CI 0.84–1.05). With no statistically significant departures from linearity, on a continuous scale, a 3-unit increase in the arMED score was associated with an 8% reduced risk of overall mortality (HR3-unit 0.92, 95% CI: 0.87–0.97). This result sustained when restricted to postmenopausal women and was stronger among metastatic BC cases (HR3-unit 0.81, 95% CI: 0.72–0.91).

Conclusions: Consuming a Mediterranean diet before BC diagnosis may improve long-term prognosis, particularly after menopause and in cases of metastatic breast cancer. Well-designed dietary interventions are needed to confirm these findings and define specific dietary recommendations.

Background: There is no consensus on the most efficient catheter ablation (CA) strategy for patients with atrial fibrillation (AF). The objective of this study was to compare the efficacy and safety of different CA strategies for AF ablation through network meta-analysis (NMA). Methods: A systematic search of PubMed, Web of Science, and CENTRAL was performed up to October 5th, 2020. Randomized controlled trials (RCT) comparing different CA approaches were included. Efficacy was defined as arrhythmia recurrence after CA and safety as any reported complication related to the procedure during a minimum follow-up time of 6 months. Results: In total, 67 RCTs (n = 9871) comparing 19 different CA strategies were included. The risk of recurrence was significantly decreased compared to pulmonary vein isolation (PVI) alone for PVI with renal denervation (RR: 0.60, CI: 0.38-0.94), PVI with ganglia-plexi ablation (RR: 0.62, CI: 0.41-0.94), PVI with additional ablation lines (RR: 0.8, CI: 0.68-0.95) and PVI in combination with bi-atrial modification (RR: 0.32, CI: 0.11-0.88). Strategies including PVI appeared superior to non-PVI strategies such as electrogram-based approaches. No significant differences in safety were observed. Conclusions: This NMA showed that PVI in combination with additional CA strategies, such as autonomic modulation and additional lines, seem to increase the efficacy of PVI alone. These strategies can be considered in treating patients with AF, since, additionally, no differences in safety were observed. This study provides decision-makers with comprehensive and comparative evidence about the efficacy and safety of different CA strategies.

BACKGROUND: Understanding the relationship between chronic pain conditions and suicidal behavior-suicide attempt, other intentional self-harm, and death by suicide-is imperative for suicide prevention efforts. Although chronic pain conditions are associated with suicidal behaviors, these associations might be attributed to unmeasured confounding or mediated via pain comorbidity.

METHODS: We linked a population-based Swedish twin study (N=17,148 twins) with 10 years of longitudinal, nationwide records of suicidal behavior from health and mortality registers through 2016. To investigate whether pain comorbidity versus specific pain conditions were more important for later suicidal behavior, we modeled a general factor of pain and two independent specific pain factors (measuring pain-related somatic symptoms and neck-shoulder pain, respectively) based on 9 self-reported chronic pain conditions. To examine whether the pain-suicidal behavior associations were attributable to familial confounding, we applied a co-twin control model.

RESULTS: Individuals scoring one standard deviation above the mean on the general pain factor had a 51% higher risk of experiencing suicidal behavior (odds ratio (OR), 1.51; 95% confidence interval (CI), 1.34-1.72). The specific factor of somatic pain was also associated with increased risk for suicidal behavior (OR, 1.80; 95% CI, 1.45-2.22]). However, after adjustment for familial confounding, the associations were greatly attenuated and not statistically significant within monozygotic twin pairs (general pain factor OR, 0.89; 95% CI, 0.59-1.33; somatic pain factor OR, 1.02; 95% CI, 0.49-2.11)

CONCLUSION: Clinicians might benefit from measuring not only specific types of pain, but also pain comorbidity; however, treating pain might not necessarily reduce future suicidal behavior, as the associations appeared attributable to familial confounding.

Background: Adverse childhood life events are associated with increased risks of hypertension, ischemic heart disease, and stroke later in life. Limited evidence also suggests that stress in adulthood may increase the risk of atrial fibrillation (AF). Whether childhood adversity may lead to the development of AF is unknown. We investigated whether the loss of a parent or sibling in childhood is associated with an increased risk of AF and compared this effect to that of similar losses in young adulthood.

Methods: We studied 6,394,975 live-born individuals included in the Danish (1973-2018) and Swedish Medical Birth Registers (1973-2014). We linked data from several national registers to obtain information on the death of parents and siblings and on personal and familial sociodemographic and health-related factors. We analyzed the association between bereavement and AF using Poisson regression.

Results: Loss of a parent or sibling was associated with an increased AF risk both when the loss occurred in childhood and in adulthood; the adjusted incident rate ratios and 95% confidence intervals were 1.24 (1.14-1.35) and 1.24 (1.16-1.33), respectively. Bereavement in childhood was associated with AF only if losses were due to cardiovascular diseases or other natural causes, while loss in adulthood was associated with AF not only in case of natural deaths, but also unnatural deaths. The associations did not differ substantially according to age at loss and whether the deceased was a parent or a sibling.

Conclusions: Bereavement both in childhood and in adulthood was associated with an increased AF risk.

Background Adverse childhood life events are associated with increased risks of hypertension, ischemic heart disease, and stroke later in life. Limited evidence also suggests that stress in adulthood may increase the risk of atrial fibrillation (AF). Whether childhood adversity may lead to the development of AF is unknown. We investigated whether the loss of a parent or sibling in childhood is associated with an increased risk of AF and compared this effect to that of similar losses in young adulthood.

Methods We studied 6,394,975 live-born individuals included in the Danish (1973–2018) and Swedish Medical Birth Registers (1973–2014). We linked data from several national registers to obtain information on the death of parents and siblings and on personal and familial sociodemographic and health-related factors. We analyzed the association between bereavement and AF using Poisson regression.

Results Loss of a parent or sibling was associated with an increased AF risk both when the loss occurred in childhood and in adulthood; the adjusted incident rate ratios and 95% confidence intervals were 1.24 (1.14–1.35) and 1.24 (1.16–1.33), respectively. Bereavement in childhood was associated with AF only if losses were due to cardiovascular diseases or other natural causes, while loss in adulthood was associated with AF not only in case of natural deaths, but also unnatural deaths. The associations did not differ substantially according to age at loss and whether the deceased was a parent or a sibling.

Conclusions Bereavement both in childhood and in adulthood was associated with an increased AF risk.

Background: Gestational diabetes mellitus (GDM) is associated with both short- and long-term risks, although it is unknown if risks vary by severity, timing, and duration of gestational hyperglycemia. We aimed to identify trajectories of random capillary glucose (RCG) levels throughout pregnancy and assess their associations with both obstetric/neonatal outcomes and children’s risk of neurodevelopmental conditions (NDCs) (i.e., autism, intellectual disability, and attention-deficit/hyperactivity disorders [ADHD]).

Methods: A population-based cohort study was conducted involving 76,228 children born to 68,768 mothers without pregestational diabetes. Group-based trajectory modeling was utilized to identify distinct glucose trajectories across RCG values throughout the course of pregnancy. The associations between these trajectory groups and obstetric/neonatal outcomes as well as children’s NDCs were then assessed using generalized estimating equation models with a logit link. The Benjamini-Hochberg (BH) procedure was employed to adjust P-values for multiple comparisons, controlling the false discovery rate (FDR).

Results: Five distinct glucose trajectory groups were identified, each with varying percentages diagnosed with GDM. Their associations with obstetric/neonatal outcomes as well as children’s NDCs varied. For example, when compared to the "Persistently Low" group, other groups exhibited varying degrees of increased risk for large-for-gestational-age babies, with the exception of the "High in Early Pregnancy" group. Compared to the "Persistently Low" group, all other trajectory groups were associated with NDC outcomes, except the “High in Mid-Pregnancy” group. However, none of the associations with offspring NDCs remained significant after accounting for the FDR correction.

Conclusions: Persistent high glucose levels or moderately elevated glucose levels throughout pregnancy, as well as transient states of hyperglycemia in early or mid-pregnancy, were found to be associated with increased risks of specific obstetric and neonatal complications, and potentially offspring NDCs. These risks varied depending on the severity, timing, duration, and management of hyperglycemia. The findings underscore the need for continuous surveillance and individualized management strategies for women displaying different glucose trajectories during pregnancy. Limitations such as potential residual confounding, the role of mediators, and small sample size should be addressed in future studies.

BACKGROUND: Gestational diabetes mellitus (GDM) is associated with both short- and long-term risks, although it is unknown if risks vary by severity, timing, and duration of gestational hyperglycemia. We aimed to identify trajectories of random capillary glucose (RCG) levels throughout pregnancy and assess their associations with both obstetric/neonatal outcomes and children's risk of neurodevelopmental conditions (NDCs) (i.e., autism, intellectual disability, and attention-deficit/hyperactivity disorders [ADHD]).

METHODS: A population-based cohort study was conducted involving 76,228 children born to 68,768 mothers without pregestational diabetes. Group-based trajectory modeling was utilized to identify distinct glucose trajectories across RCG values throughout the course of pregnancy. The associations between these trajectory groups and obstetric/neonatal outcomes as well as children's NDCs were then assessed using generalized estimating equation models with a logit link. The Benjamini-Hochberg (BH) procedure was employed to adjust P-values for multiple comparisons, controlling the false discovery rate (FDR).

RESULTS: Five distinct glucose trajectory groups were identified, each with varying percentages diagnosed with GDM. Their associations with obstetric/neonatal outcomes as well as children's NDCs varied. For example, when compared to the "Persistently Low" group, other groups exhibited varying degrees of increased risk for large-for-gestational-age babies, with the exception of the "High in Early Pregnancy" group. Compared to the "Persistently Low" group, all other trajectory groups were associated with NDC outcomes, except the "High in Mid-Pregnancy" group. However, none of the associations with offspring NDCs remained significant after accounting for the FDR correction.

CONCLUSIONS: Persistent high glucose levels or moderately elevated glucose levels throughout pregnancy, as well as transient states of hyperglycemia in early or mid-pregnancy, were found to be associated with increased risks of specific obstetric and neonatal complications, and potentially offspring NDCs. These risks varied depending on the severity, timing, duration, and management of hyperglycemia. The findings underscore the need for continuous surveillance and individualized management strategies for women displaying different glucose trajectories during pregnancy. Limitations such as potential residual confounding, the role of mediators, and small sample size should be addressed in future studies.

Background Prognostic models developed in general cohorts with a mixture of heart failure (HF) phenotypes, though more widely applicable, are also likely to yield larger prediction errors in settings where the HF phenotypes have substantially different baseline mortality rates or different predictor-outcome associations. This study sought to use individual participant data meta-analysis to develop an HF phenotype stratified model for predicting 1-year mortality in patients admitted with acute HF. Methods Four prospective European cohorts were used to develop an HF phenotype stratified model. Cox model with two rounds of backward elimination was used to derive the prognostic index. Weibull model was used to obtain the baseline hazard functions. The internal-external cross-validation (IECV) approach was used to evaluate the generalizability of the developed model in terms of discrimination and calibration. Results 3577 acute HF patients were included, of which 2368 were classified as having HF with reduced ejection fraction (EF) (HFrEF; EF &lt; 40%), 588 as having HF with midrange EF (HFmrEF; EF 40-49%), and 621 as having HF with preserved EF (HFpEF; EF &gt;= 50%). A total of 11 readily available variables built up the prognostic index. For four of these predictor variables, namely systolic blood pressure, serum creatinine, myocardial infarction, and diabetes, the effect differed across the three HF phenotypes. With a weighted IECV-adjusted AUC of 0.79 (0.74-0.83) for HFrEF, 0.74 (0.70-0.79) for HFmrEF, and 0.74 (0.71-0.77) for HFpEF, the model showed excellent discrimination. Moreover, there was a good agreement between the average observed and predicted 1-year mortality risks, especially after recalibration of the baseline mortality risks. Conclusions Our HF phenotype stratified model showed excellent generalizability across four European cohorts and may provide a useful tool in HF phenotype-specific clinical decision-making.

BACKGROUND: Physician-coded verbal autopsy (PCVA) is the most widely used method to determine causes of death (CODs) in countries where medical certification of death is uncommon. Computer-coded verbal autopsy (CCVA) methods have been proposed as a faster and cheaper alternative to PCVA, though they have not been widely compared to PCVA or to each other.

METHODS: We compared the performance of open-source random forest, open-source tariff method, InterVA-4, and the King-Lu method to PCVA on five datasets comprising over 24,000 verbal autopsies from low- and middle-income countries. Metrics to assess performance were positive predictive value and partial chance-corrected concordance at the individual level, and cause-specific mortality fraction accuracy and cause-specific mortality fraction error at the population level.

RESULTS: The positive predictive value for the most probable COD predicted by the four CCVA methods averaged about 43% to 44% across the datasets. The average positive predictive value improved for the top three most probable CODs, with greater improvements for open-source random forest (69%) and open-source tariff method (68%) than for InterVA-4 (62%). The average partial chance-corrected concordance for the most probable COD predicted by the open-source random forest, open-source tariff method and InterVA-4 were 41%, 40% and 41%, respectively, with better results for the top three most probable CODs. Performance generally improved with larger datasets. At the population level, the King-Lu method had the highest average cause-specific mortality fraction accuracy across all five datasets (91%), followed by InterVA-4 (72% across three datasets), open-source random forest (71%) and open-source tariff method (54%).

CONCLUSIONS: On an individual level, no single method was able to replicate the physician assignment of COD more than about half the time. At the population level, the King-Lu method was the best method to estimate cause-specific mortality fractions, though it does not assign individual CODs. Future testing should focus on combining different computer-coded verbal autopsy tools, paired with PCVA strengths. This includes using open-source tools applied to larger and varied datasets (especially those including a random sample of deaths drawn from the population), so as to establish the performance for age- and sex-specific CODs.

Background: An inverse relationship between allergies with glioma risk has been reported in several but not all epidemiological observational studies. We performed an analysis of genetic variants associated with atopy to assess the relationship with glioma risk using Mendelian randomisation (MR), an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.

Methods: Two-sample MR was undertaken using genome-wide association study data. We used single nucleotide polymorphisms (SNPs) associated with atopic dermatitis, asthma and hay fever, IgE levels, and self-reported allergy as instrumental variables. We calculated MR estimates for the odds ratio (OR) for each risk factor with glioma using SNP-glioma estimates from 12,488 cases and 18,169 controls, using inverse-variance weighting (IVW), maximum likelihood estimation (MLE), weighted median estimate (WME) and mode-based estimate (MBE) methods. Violation of MR assumptions due to directional pleiotropy were sought using MR-Egger regression and HEIDI-outlier analysis.

Results: Under IVW, MLE, WME and MBE methods, associations between glioma risk with asthma and hay fever, self-reported allergy and IgE levels were non-significant. An inverse relationship between atopic dermatitis and glioma risk was found by IVW (OR 0.96, 95% confidence interval (CI) 0.93-1.00, P = 0.041) and MLE (OR 0.96, 95% CI 0.94-0.99, P = 0.003), but not by WME (OR 0.96, 95% CI 0.91-1.01, P = 0.114) or MBE (OR 0.97, 95% CI 0.92-1.02, P = 0.194).

Conclusions: Our investigation does not provide strong evidence for relationship between atopy and the risk of developing glioma, but findings do not preclude a small effect in relation to atopic dermatitis. Our analysis also serves to illustrate the value of using several MR methods to derive robust conclusions.

BACKGROUND: Emerging research suggests that attention-deficit/hyperactivity disorder (ADHD) increases the risk for cardiovascular (CVDs) and metabolic disorders (i.e., cardiometabolic disorders) in adulthood. Yet, available studies are scarce and have mainly been focused on individuals receiving clinical ADHD diagnoses. We aimed to investigate the prospective associations of ADHD symptoms in young and mid-adulthood with subsequent cardiometabolic disorders and the underlying mechanisms.

METHODS: We studied 10,394 twins from the Swedish Twin Registry (STR), born between 1958 and 1985 without previous medical history of cardiometabolic disorders. They provided self-assessment of ADHD symptoms (score range 0-36) via a validated, DSM-IV-based scale in a web-based questionnaire/telephone interview within the Study of Twin Adults: Genes and Environment (STAGE), in 2005-2006 (aged 19-47 years), and were followed until the end of 2018 (33-59 years) to identify incident clinical diagnoses/medication prescriptions for cardiometabolic disorders acquired from Swedish national registers. We used Cox regression models to investigate the associations between ADHD symptoms score and cardiometabolic outcomes, with and without adjustment for relevant covariates, and a co-twin control design to study familial confounding.

RESULTS: A one-unit increase in the level of ADHD symptoms was associated with a 2% increase in the rate of CVDs (hazard ratio [HR] = 1.02, 95% confidence interval 1.01-1.04) and a 3% increase in the rate of metabolic disorders (HR = 1.03, 1.02-1.05), after adjusting for birth year and sex. The associations were no longer significant after adjusting for educational attainment, lifestyle factors, and comorbid psychiatric disorders. The associations remained significant after adjusting for familial factors shared by dizygotic twin pairs but became nonsignificant after adjusting for factors shared by monozygotic twin pairs. However, the strength of the associations attenuated significantly in monozygotic twins compared to dizygotic twins for CVDs only, suggesting genetic confounding.

CONCLUSIONS: ADHD symptom score is associated with a higher risk for cardiometabolic disorders, which may be explained by lower educational attainment, adverse lifestyle factors, and psychiatric comorbidities. Moreover, the associations appear to be partly confounded by shared genetic factors, especially for CVDs. Further research is needed to investigate the identified associations at the level of individual cardiometabolic disorders and to follow-up participants until a more advanced older age.

BACKGROUND: It has been repeatedly shown that men infected by SARS-CoV-2 face a twofold higher likelihood of dying, being hospitalized or admitted to the intensive care unit compared to women, despite taking into account relevant confounders. It has been hypothesized that these discrepancies are related to sex steroid hormone differences with estrogens being negatively correlated with disease severity. The objective of this study was therefore to evaluate COVID-19-related mortality and morbidity among peri- and postmenopausal women in relation to estrogen-containing menopause hormonal treatments (MHT).

METHODS: This is a national register-based matched cohort study performed in Sweden between January 1 to December 31, 2020. Study participants comprised women over the age of 53 years residing in Sweden. Exposure was defined as prescriptions of local estrogens, systemic estrogens with and without progestogens, progestogens alone, or tibolone. MHT users were then compared with a matched cohort of non-users. The primary outcome consisted of COVID-19 mortality, whereas the secondary outcomes included inpatient hospitalizations/outpatient visits and confirmed SARS-CoV-2 infection. Multivariable adjusted Cox regression-derived hazard ratios (HRs) were calculated.

RESULTS: Use of systemic estrogens alone is associated with increased COVID-19 mortality among older women (aHR 4.73, 1.22 to 18.32), but the association is no longer significant when discontinuation of estrogen use is accounted for. An increased risk for COVID-19 infection is further observed for women using combined systemic estrogens and progestogens (aHR 1.06, 1.00 to 1.13) or tibolone (aHR 1.21, 1.01 to 1.45). Use of local estrogens is associated with an increased risk for COVID-19-related death (aHR 2.02,1.45 to 2.81) as well as for all secondary outcomes.

CONCLUSIONS: Systemic or local use of estrogens does not decrease COVID-19 morbidity and mortality to premenopausal background levels. Excess risk for COVID-19 morbidity and mortality was noted among older women and those discontinuing systemic estrogens. Higher risk for death was also noted among women using local estrogens, for which non-causal mechanisms such as confounding by comorbidity or frailty seem to be the most plausible underlying explanations.

TRIAL REGISTRATION DETAILS: Not applicable.

Background

It has been repeatedly shown that men infected by SARS-CoV-2 face a twofold higher likelihood of dying, being hospitalized or admitted to the intensive care unit compared to women, despite taking into account relevant confounders. It has been hypothesized that these discrepancies are related to sex steroid hormone differences with estrogens being negatively correlated with disease severity. The objective of this study was therefore to evaluate COVID-19-related mortality and morbidity among peri- and postmenopausal women in relation to estrogen-containing menopause hormonal treatments (MHT).

Methods

This is a national register-based matched cohort study performed in Sweden between January 1 to December 31, 2020. Study participants comprised women over the age of 53 years residing in Sweden. Exposure was defined as prescriptions of local estrogens, systemic estrogens with and without progestogens, progestogens alone, or tibolone. MHT users were then compared with a matched cohort of non-users. The primary outcome consisted of COVID-19 mortality, whereas the secondary outcomes included inpatient hospitalizations/outpatient visits and confirmed SARS-CoV-2 infection. Multivariable adjusted Cox regression-derived hazard ratios (HRs) were calculated.

Results

Use of systemic estrogens alone is associated with increased COVID-19 mortality among older women (aHR 4.73, 1.22 to 18.32), but the association is no longer significant when discontinuation of estrogen use is accounted for. An increased risk for COVID-19 infection is further observed for women using combined systemic estrogens and progestogens (aHR 1.06, 1.00 to 1.13) or tibolone (aHR 1.21, 1.01 to 1.45). Use of local estrogens is associated with an increased risk for COVID-19-related death (aHR 2.02,1.45 to 2.81) as well as for all secondary outcomes.

Conclusions

Systemic or local use of estrogens does not decrease COVID-19 morbidity and mortality to premenopausal background levels. Excess risk for COVID-19 morbidity and mortality was noted among older women and those discontinuing systemic estrogens. Higher risk for death was also noted among women using local estrogens, for which non-causal mechanisms such as confounding by comorbidity or frailty seem to be the most plausible underlying explanations.

BackgroundThe ABC transporter P-glycoprotein (P-gp) is recognized as a site for drug-drug interactions and provides a mechanistic explanation for clinically relevant pharmacokinetic interactions with digoxin. The question of whether several P-gp inhibitors may have additive effects has not yet been addressed.

MethodsWe evaluated the effects on serum concentrations of digoxin (S-digoxin) in 618 patients undergoing therapeutic drug monitoring. P-gp inhibitors were classified as Class I, with a known effect on digoxin kinetics, or Class II, showing inhibition in vitro but no documented effect on digoxin kinetics in humans. Mean S-digoxin values were compared between groups of patients with different numbers of coadministered P-gp inhibitors by a univariate and a multivariate model, including the potential covariates age, sex, digoxin dose and total number of prescribed drugs.

ResultsA large proportion (47%) of the digoxin patients undergoing therapeutic drug monitoring had one or more P-gp inhibitor prescribed. In both univariate and multivariate analysis, S-digoxin increased in a stepwise fashion according to the number of coadministered P-gp inhibitors (all P values < 0.01 compared with no P-gp inhibitor). In multivariate analysis, S-digoxin levels were 1.26 ± 0.04, 1.51 ± 0.05, 1.59 ± 0.08 and 2.00 ± 0.25 nmol/L for zero, one, two and three P-gp inhibitors, respectively. The results were even more pronounced when we analyzed only Class I P-gp inhibitors (1.65 ± 0.07 for one and 1.83 ± 0.07 nmol/L for two).

ConclusionsPolypharmacy may lead to multiple drug-drug interactions at the same site, in this case P-gp. The S-digoxin levels increased in a stepwise fashion with an increasing number of coadministered P-gp inhibitors in patients taking P-gp inhibitors and digoxin concomitantly. As coadministration of digoxin and P-gp inhibitors is common, it is important to increase awareness about P-gp interactions among prescribing clinicians.

BACKGROUND: Delirium is a common and serious problem among acutely unwell persons. Although linked to higher rates of mortality, institutionalisation and dementia, it remains underdiagnosed. Careful consideration of its phenomenology is warranted to improve detection and therefore mitigate some of its clinical impact. The publication of the fifth edition of the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM-5) provides an opportunity to examine the constructs underlying delirium as a clinical entity.

DISCUSSION: Altered consciousness has been regarded as a core feature of delirium; the fact that consciousness itself should be physiologically disrupted due to acute illness attests to its clinical urgency. DSM-5 now operationalises 'consciousness' as 'changes in attention'. It should be recognised that attention relates to content of consciousness, but arousal corresponds to level of consciousness. Reduced arousal is also associated with adverse outcomes. Attention and arousal are hierarchically related; level of arousal must be sufficient before attention can be reasonably tested.

SUMMARY: Our conceptualisation of delirium must extend beyond what can be assessed through cognitive testing (attention) and accept that altered arousal is fundamental. Understanding the DSM-5 criteria explicitly in this way offers the most inclusive and clinically safe interpretation.

BACKGROUND: Leakage of bacterial products across the gut barrier may play a role in liver diseases which often precede the development of liver cancer. However, human studies, particularly from prospective settings, are lacking.

METHODS: We used a case-control study design nested within a large prospective cohort to assess the association between circulating levels of anti-lipopolysaccharide (LPS) and anti-flagellin immunoglobulin A (IgA) and G (IgG) (reflecting long-term exposures to LPS and flagellin, respectively) and risk of hepatocellular carcinoma. A total of 139 men and women diagnosed with hepatocellular carcinoma between 1992 and 2010 were matched to 139 control subjects. Multivariable rate ratios (RRs), including adjustment for potential confounders, hepatitis B/C positivity, and degree of liver dysfunction, were calculated with conditional logistic regression.

RESULTS:  = 0.021). This finding did not vary substantially by time from enrollment to diagnosis, and did not change after adjustment for chronic infection with hepatitis B and C viruses.

CONCLUSIONS: These novel findings, based on exposures up to several years prior to diagnosis, support a role for gut-derived bacterial products in hepatocellular carcinoma development. Further study into the role of gut barrier failure and exposure to bacterial products in liver diseases is warranted.

Background Homelessness has been associated with multiple detrimental health outcomes across observational studies. However, relatively few randomized controlled trials (RCTs) have been conducted on people who experience homelessness (PEH). Thus, this umbrella review ranked the credibility of evidence derived from systematic reviews (SRs) and meta-analyses (MAs) of observational studies investigating the associations between homelessness and any health outcome as well as RCTs targeting health needs in this population. Methods Several databases were systematically searched from inception through April 28, 2021. Any SR and/or MA reporting quantitative data and providing a control group were eligible for inclusion. The credibility of the evidence derived from observational studies was appraised by considering the significance level of the association and the largest study, the degree of heterogeneity, the presence of small-study effects as well as excess significance bias. The credibility of evidence was then ranked in five classes. For SRs and/or MAs of RCTs, we considered the level of significance and whether the prediction interval crossed the null. The AMSTAR-2 and AMSTAR-plus instruments were adopted to further assess the methodological quality of SRs and/or MAs. The Newcastle-Ottawa Scale (NOS) was employed to further appraise the methodological quality of prospective cohort studies only; a sensitivity analysis limited to higher quality studies was conducted. Results Out of 1549 references, 8 MAs and 2 SRs were included. Among those considering observational studies, 23 unique associations were appraised. Twelve of them were statistically significant at the p &lt;= 0.005 level. Included cases had worst health-related outcomes than controls, but only two associations reached a priori-defined criteria for convincing (class I) evidence namely hospitalization due to any cause among PEH diagnosed with HIV infection, and the occurrence of falls within the past year among PEH. According to the AMSTAR-2 instrument, the methodological quality of all included SRs and/or MAs was "critically low." Interventional studies were scant. Conclusion While homelessness has been repeatedly associated with detrimental health outcomes, only two associations met the criteria for convincing evidence. Furthermore, few RCTs were appraised by SRs and/or MAs. Our umbrella review also highlights the need to standardize definitions of homelessness to be incorporated by forthcoming studies to improve the external validity of the findings in this vulnerable population.

Obesity is a complex disease with multiple well-defined risk factors. Nevertheless, susceptibility to obesity and its sequelae within obesogenic environments varies greatly from one person to the next, suggesting a role for gene × environment interactions in the etiology of the disorder. Epigenetic regulation of the human genome provides a putative mechanism by which specific environmental exposures convey risk for obesity and other human diseases and is one possible mechanism that underlies the gene × environment/treatment interactions observed in epidemiological studies and clinical trials. A study published in BMC Medicine this month by Wang et al. reports on an examination of DNA methylation in peripheral blood leukocytes of lean and obese adolescents, comparing methylation patterns between the two groups. The authors identified two genes that were differentially methylated, both of which have roles in immune function. Here we overview the findings from this study in the context of those emerging from other recent genetic and epigenetic studies, discuss the strengths and weaknesses of the study and speculate on the future of epigenetics in chronic disease research.

BACKGROUND: Although lifestyle factors have been studied in relation to individual non-communicable diseases (NCDs), their association with development of a subsequent NCD, defined as multimorbidity, has been scarcely investigated. The aim of this study was to investigate associations between five lifestyle factors and incident multimorbidity of cancer and cardiometabolic diseases.

METHODS: In this prospective cohort study, 291,778 participants (64% women) from seven European countries, mostly aged 43 to 58 years and free of cancer, cardiovascular disease (CVD), and type 2 diabetes (T2D) at recruitment, were included. Incident multimorbidity of cancer and cardiometabolic diseases was defined as developing subsequently two diseases including first cancer at any site, CVD, and T2D in an individual. Multi-state modelling based on Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals (95% CI) of developing cancer, CVD, or T2D, and subsequent transitions to multimorbidity, in relation to body mass index (BMI), smoking status, alcohol intake, physical activity, adherence to the Mediterranean diet, and their combination as a healthy lifestyle index (HLI) score. Cumulative incidence functions (CIFs) were estimated to compute 10-year absolute risks for transitions from healthy to cancer at any site, CVD (both fatal and non-fatal), or T2D, and to subsequent multimorbidity after each of the three NCDs.

RESULTS: During a median follow-up of 11 years, 1910 men and 1334 women developed multimorbidity of cancer and cardiometabolic diseases. A higher HLI, reflecting healthy lifestyles, was strongly inversely associated with multimorbidity, with hazard ratios per 3-unit increment of 0.75 (95% CI, 0.71 to 0.81), 0.84 (0.79 to 0.90), and 0.82 (0.77 to 0.88) after cancer, CVD, and T2D, respectively. After T2D, the 10-year absolute risks of multimorbidity were 40% and 25% for men and women, respectively, with unhealthy lifestyle, and 30% and 18% for men and women with healthy lifestyles.

CONCLUSION: Pre-diagnostic healthy lifestyle behaviours were strongly inversely associated with the risk of cancer and cardiometabolic diseases, and with the prognosis of these diseases by reducing risk of multimorbidity.

Background: Circulating vitamin C concentrations have been associated with several cancers in observational studies, but little is known about the causal direction of the associations. This study aims to explore the potential causal relationship between circulating vitamin C and risk of five most common cancers in Europe.

Methods: We used summary-level data for genetic variants associated with plasma vitamin C in a large vitamin C genome-wide association study (GWAS) meta-analysis on 52,018 Europeans, and the corresponding associations with lung, breast, prostate, colon, and rectal cancer from GWAS consortia including up to 870,984 participants of European ancestry. We performed two-sample, bi-directional Mendelian randomization (MR) analyses using inverse-variance-weighted method as the primary approach, while using 6 additional methods (e.g., MR-Egger, weighted median-based, and mode-based methods) as sensitivity analysis to detect and adjust for pleiotropy. We also conducted a meta-analysis of prospective cohort studies and randomized controlled trials to examine the association of vitamin C intakes with cancer outcomes.

Results: The MR analysis showed no evidence of a causal association of circulating vitamin C concentration with any examined cancer. Although the odds ratio (OR) per one standard deviation increase in genetically predicted circulating vitamin C concentration was 1.34 (95% confidence interval 1.14 to 1.57) for breast cancer in the UK Biobank, this association could not be replicated in the Breast Cancer Association Consortium with an OR of 1.05 (0.94 to 1.17). Smoking initiation, as a positive control for our reverse MR analysis, showed a negative association with circulating vitamin C concentration. However, there was no strong evidence of a causal association of any examined cancer with circulating vitamin C. Sensitivity analysis using 6 different analytical approaches yielded similar results. Moreover, our MR results were consistent with the null findings from the meta-analysis exploring prospective associations of dietary or supplemental vitamin C intakes with cancer risk, except that higher dietary vitamin C intake, but not vitamin C supplement, was associated with a lower risk of lung cancer (risk ratio: 0.84, 95% confidence interval 0.71 to 0.99).

Conclusions: These findings provide no evidence to support that physiological-level circulating vitamin C has a large effect on risk of the five most common cancers in European populations, but we cannot rule out very small effect sizes.

Background:

The purpose of this study is to validate a new five-tiered prognostic classification system to better discriminate cancer-specific mortality in men diagnosed with primary non-metastatic prostate cancer.

Methods:

We applied a recently described five-strata model, the Cambridge Prognostic Groups (CPGs 1-5), in two international cohorts and tested prognostic performance against the current standard three-strata classification of low-, intermediate- or high-risk disease. Diagnostic clinico-pathological data for men obtained from the Prostate Cancer data Base Sweden (PCBaSe) and the Singapore Health Study were used. The main outcome measure was prostate cancer mortality (PCM) stratified by age group and treatment modality.

Results:

The PCBaSe cohort included 72,337 men, of whom 7162 died of prostate cancer. The CPG model successfully classified men with different risks of PCM with competing risk regression confirming significant intergroup distinction (p < 0.0001). The CPGs were significantly better at stratified prediction of PCM compared to the current three-tiered system (concordance index (C-index) 0.81 vs. 0.77, p < 0.0001). This superiority was maintained for every age group division (p < 0.0001). Also in the ethnically different Singapore cohort of 2550 men with 142 prostate cancer deaths, the CPG model outperformed the three strata categories (C-index 0.79 vs. 0.76, p < 0.0001). The model also retained superior prognostic discrimination in the treatment sub-groups: radical prostatectomy (n = 20,586), C-index 0.77 vs. 074; radiotherapy (n = 11,872), C-index 0.73 vs. 0.69; and conservative management (n = 14,950), C-index 0.74 vs. 0.73. The CPG groups that sub-divided the old intermediate-risk (CPG2 vs. CPG3) and high-risk categories (CPG4 vs. CPG5) significantly discriminated PCM outcomes after radical therapy or conservative management (p < 0.0001).

Conclusions:

This validation study of nearly 75,000 men confirms that the CPG five-tiered prognostic model has superior discrimination compared to the three-tiered model in predicting prostate cancer death across different age and treatment groups. Crucially, it identifies distinct sub-groups of men within the old intermediate-risk and high-risk criteria who have very different prognostic outcomes. We therefore propose adoption of the CPG model as a simple-to-use but more accurate prognostic stratification tool to help guide management for men with newly diagnosed prostate cancer.

Background: The purpose of this study is to validate a new five-tiered prognostic classification system to better discriminate cancer-specific mortality in men diagnosed with primary non-metastatic prostate cancer.

Methods: We applied a recently described five-strata model, the Cambridge Prognostic Groups (CPGs 1-5), in two international cohorts and tested prognostic performance against the current standard three-strata classification of low-, intermediate- or high-risk disease. Diagnostic clinico-pathological data for men obtained from the Prostate Cancer data Base Sweden (PCBaSe) and the Singapore Health Study were used. The main outcome measure was prostate cancer mortality (PCM) stratified by age group and treatment modality.

Results: The PCBaSe cohort included 72,337 men, of whom 7162 died of prostate cancer. The CPG model successfully classified men with different risks of PCM with competing risk regression confirming significant intergroup distinction (p < 0.0001). The CPGs were significantly better at stratified prediction of PCM compared to the current three-tiered system (concordance index (C-index) 0.81 vs. 0.77, p < 0.0001). This superiority was maintained for every age group division (p < 0.0001). Also in the ethnically different Singapore cohort of 2550 men with 142 prostate cancer deaths, the CPG model outperformed the three strata categories (C-index 0.79 vs. 0.76, p < 0.0001). The model also retained superior prognostic discrimination in the treatment sub-groups: radical prostatectomy (n =3D 20,586), C-index 0.77 vs. 074; radiotherapy (n =3D 11,872), C-index 0.73 vs. 0.69; and conservative management (n =3D 14,950), C-index 0.74 vs. 0.73. The CPG groups that sub-divided the old intermediate-risk (CPG2 vs. CPG3) and high-risk categories (CPG4 vs. CPG5) significantly discriminated PCM outcomes after radical therapy or conservative management (p < 0.0001).

Conclusions: This validation study of nearly 75,000 men confirms that the CPG five-tiered prognostic model has superior discrimination compared to the three-tiered model in predicting prostate cancer death across different age and treatment groups. Crucially, it identifies distinct sub-groups of men within the old intermediate-risk and high-risk criteria who have very different prognostic outcomes. We therefore propose adoption of the CPG model as a simple-to-use but more accurate prognostic stratification tool to help guide management for men with newly diagnosed prostate cancer.

Background: Metformin is a hypoglycaemic medication that has been proposed to treat or prevent preeclampsia. Combining national birth data from Scotland and Sweden, we investigated whether metformin used during pregnancy was associated with an altered risk of developing a hypertensive disorder of pregnancy.

Methods: We utilised data from two population-based cohorts: Scotland (2012-2018) and Sweden (2007-2019). Nulliparous women with gestational diabetes or type 2 diabetes who had birth outcome data linked with medications prescribed during pregnancy were included. The association between metformin prescription and hypertensive disorders of pregnancy was characterised using inverse probability weighted regression analysis, adjusting for variables that predict metformin use and potential confounders. Adverse neonatal outcomes were included as secondary outcomes.

Results: from both countries were then combined in a meta-analysis using a random effects model. Results The Scottish cohort included 3859 women with gestational diabetes or type 2 diabetes. Of these women, 30.8% (n = 1187) received at least one metformin prescription during pregnancy. For Sweden, 7771 women with gestational diabetes were included where 19.3% (1498) used metformin during pregnancy. Metformin prescription was not associated with an altered risk of any hypertensive disorder of pregnancy (Scotland adjusted relative risk (aRR) 0.88 [95% confidence interval (CI) 0.66-1.19]; Sweden aRR 1.08 [95% CI 0.86-1.37]) or preeclampsia (Scotland aRR 1.02 [95% CI 0.66-1.60]; Sweden aRR 1.00 [95% CI 0.72-1.39]). Combining adjusted results in a meta-analysis produced similar findings, with a pooled RR of 0.98 (95% CI 0.79-1.18) for any hypertensive disorder and RR 1.01 ([95% CI 0.73-1.28]) for preeclampsia. For neonatal outcomes, metformin was associated with a reduced risk of birthweight > 4500 g in Scotland (aRR 0.39 [95% CI 0.21-0.71]) but not in Sweden. There was no association between metformin and preterm birth or birthweight < 3rd or < 10th percentiles. Pooling results from both countries, metformin was not associated with adverse neonatal outcomes, including preterm birth (RR 1.00 [95% CI 0.89-1.13]), and birthweight < 10th percentile (RR 0.82 [95% CI 0.60-1.13]) or < 3rd percentile (RR 0.78 [95% CI 0.41-1.48]).

Conclusions: In this two-country analysis, metformin use in pregnancy among women with diabetes was not associated with an altered risk of developing any hypertensive disorder of pregnancy. In the combined meta-analysis, metformin was not associated with an altered risk of adverse neonatal outcomes.

Background: Postmenopausal hormone-replacement therapy (HRT) increases breast-cancer risk. The influence of HRT on the biology of the primary tumor, however, is not well understood.

Methods: We obtained breast-cancer gene expression profiles using Affymetrix human genome U133A arrays. We examined the relationship between HRT-regulated gene profiles, tumor characteristics, and recurrence-free survival in 72 postmenopausal women.

Results: HRT use in patients with estrogen receptor ( ER) protein positive tumors (n = 72) was associated with an altered regulation of 276 genes. Expression profiles based on these genes clustered ER-positive tumors into two molecular subclasses, one of which was associated with HRT use and had significantly better recurrence free survival despite lower ER levels. A comparison with external data suggested that gene regulation in tumors associated with HRT was negatively correlated with gene regulation induced by short-term estrogen exposure, but positively correlated with the effect of tamoxifen.

Conclusion: Our findings suggest that post-menopausal HRT use is associated with a distinct gene expression profile related to better recurrence-free survival and lower ER protein levels. Tentatively, HRT-associated gene expression in tumors resembles the effect of tamoxifen exposure on MCF-7 cells.

Background: Lithium is prescribed during pregnancy, but there is limited information about pregnancy and neonatal outcomes following in utero exposure. Thus, this study aimed to investigate the associations between lithium use and adverse pregnancy and neonatal outcomes.

Methods: This population-based cohort study examined associations between maternal lithium use and major adverse pregnancy and neonatal outcomes via inverse probability weighted propensity score regression models.

Results: Of 854,017 women included in this study, 434 (0.05%) used lithium during pregnancy. Among pre-specified primary outcomes, lithium use during pregnancy was associated with an increased risk of spontaneous preterm birth (8.7% vs 3.0%; adjusted relative risk [aRR] 2.64 95% CI 1.82, 3.82) and birth of a large for gestational age infant (9.0% vs 3.5%; aRR 2.64 95% CI 1.91, 3.66), but not preeclampsia nor birth of a small for gestational age infant. Among secondary outcomes, lithium use was associated with an increased risk of cardiac malformations (2.1% vs 0.8%; aRR 3.17 95% CI 1.64, 6.13). In an analysis restricted to pregnant women with a diagnosed psychiatric illness (n=9552), associations remained between lithium and spontaneous preterm birth, birth of a large for gestational age infant, and cardiovascular malformations; and a positive association with neonatal hypoglycaemia was also found. These associations were also apparent in a further analysis comparing women who continued lithium treatment during pregnancy to those who discontinued prior to pregnancy.

Conclusions: Lithium use during pregnancy is associated with an increased risk of spontaneous preterm birth and other adverse neonatal outcomes. These potential risks must be balanced against the important benefit of treatment and should be used to guide shared decision-making.

Background Lithium is the most effective treatment in bipolar disorder. Its use is limited by concerns about risk of chronic kidney disease (CKD). We aimed to develop a model to predict risk of CKD following lithium treatment initiation, by identifying individuals with a high-risk trajectory of kidney function. Methods We used United Kingdom Clinical Practice Research Datalink (CPRD) electronic health records (EHRs) from 2000 to 2018. CPRD Aurum for prediction model development and CPRD Gold for external validation. We used elastic net regularised regression to generate a prediction model from potential features. We performed discrimination and calibration assessments in an external validation data set. We included all patients aged >= 16 with bipolar disorder prescribed lithium. To be included patients had to have >= 1 year of follow-up before lithium initiation, >= 3 estimated glomerular filtration rate (eGFR) measures after lithium initiation (to be able to determine a trajectory) and a normal (>= 60 mL/min/1.73 m(2)) eGFR at lithium initiation (baseline). In the Aurum development cohort, 1609 fulfilled these criteria. The Gold external validation cohort included 934 patients. We included 44 potential baseline features in the prediction model, including sociodemographic, mental and physical health and drug treatment characteristics. We compared a full model with the 3-variable 5-year kidney failure risk equation (KFRE) and a 3-variable elastic net model. We used group-based trajectory modelling to identify latent trajectory groups for eGFR. We were interested in the group with deteriorating kidney function (the high-risk group). Results The high risk of deteriorating eGFR group included 191 (11.87%) of the Aurum cohort and 137 (14.67%) of the Gold cohort. Of these, 168 (87.96%) and 117 (85.40%) respectively developed CKD 3a or more severe during follow-up. The model, developed in Aurum, had a ROC area of 0.879 (95%CI 0.853-0.904) in the Gold external validation data set. At the empirical optimal cut-point defined in the development dataset, the model had a sensitivity of 0.91 (95%CI 0.84-0.97) and a specificity of 0.74 (95% CI 0.67-0.82). However, a 3-variable elastic net model (including only age, sex and baseline eGFR) performed similarly well (ROC area 0.888; 95%CI 0.864-0.912), as did the KFRE (ROC area 0.870; 95%CI 0.841-0.898). Conclusions Individuals at high risk of a poor eGFR trajectory can be identified before initiation of lithium treatment by a simple equation including age, sex and baseline eGFR. Risk was increased in individuals who were younger at commencement of lithium, female and had a lower baseline eGFR. We did not identify strong predicters of eGFR decline specific to lithium-treated patients. Notably, lithium duration and toxicity were not associated with high-risk trajectory.