Are people with metabolically healthy obesity really healthy? A prospective cohort study of 381,363 UK Biobank participants.

AIMS/HYPOTHESIS: People with obesity and a normal metabolic profile are sometimes referred to as having 'metabolically healthy obesity' (MHO). However, whether this group of individuals are actually 'healthy' is uncertain. This study aims to examine the associations of MHO with a wide range of obesity-related outcomes. METHODS: This is a population-based prospective cohort study of 381,363 UK Biobank participants with a median follow-up of 11.2 years. MHO was defined as having a BMI ≥ 30 kg/m2 and at least four of the six metabolically healthy criteria. Outcomes included incident diabetes and incident and fatal atherosclerotic CVD (ASCVD), heart failure (HF) and respiratory diseases. RESULTS: Compared with people who were not obese at baseline, those with MHO had higher incident HF (HR 1.60; 95% CI 1.45, 1.75) and respiratory disease (HR 1.20; 95% CI 1.16, 1.25) rates, but not higher ASCVD. The associations of MHO were generally weaker for fatal outcomes and only significant for all-cause (HR 1.12; 95% CI 1.04, 1.21) and HF mortality rates (HR 1.44; 95% CI 1.09, 1.89). However, when compared with people who were metabolically healthy without obesity, participants with MHO had higher rates of incident diabetes (HR 4.32; 95% CI 3.83, 4.89), ASCVD (HR 1.18; 95% CI 1.10, 1.27), HF (HR 1.76; 95% CI 1.61, 1.92), respiratory diseases (HR 1.28; 95% CI 1.24, 1.33) and all-cause mortality (HR 1.22; 95% CI 1.14, 1.31). The results with a 5 year landmark analysis were similar. CONCLUSIONS/INTERPRETATION: Weight management should be recommended to all people with obesity, irrespective of their metabolic status, to lower risk of diabetes, ASCVD, HF and respiratory diseases. The term 'MHO' should be avoided as it is misleading and different strategies for risk stratification should be explored.

Wasting and Stunting in Infants and Young Children as Risk Factors for Subsequent Stunting or Mortality: Longitudinal Analysis of Data from Malawi, South Africa, and Pakistan.

BACKGROUND: Few studies have had sufficient longitudinal data to track how different malnourished states relate to mortality at different ages and interrelate over time. OBJECTIVES: This study aims to describe the RRs and proportions of mortality associated with wasting and stunting and the pathways into and out of these nutritional states. METHODS: Longitudinal growth data sets collected for children ages 0-24 months from Malawi, South Africa, and Pakistan were combined (n = 5088). Children were classified as deceased, wasted (weight for height < -2 SD; 1-4%), stunted (length < -2SD; 20-47%), or wasted and stunted (WaSt; 2-5%) at ages 3, 6, 9, 12, 18, and 24 months. Mixed-effects Cox models were used to study the association between nutritional status and mortality. RESULTS: By age 3 months, 20% of children were already stunted, rising to 49% by 24 months, while wasting (4.2% and 2.2% at 3 months, respectively) and WaSt (0.9% and 3.7% at 24 months, respectively) were less common. The HR for mortality in WaSt was 9.5 (95% CI, 5.9-15), but 60% of WaSt-associated mortality occurred at 3-6 months. Wasting or WaSt was associated with 10-23% of deaths beyond 6 months, but in the second year over half of deaths occurred in stunted, nonwasted children. Stunting persisted in 82% of children and wasting persisted in 44%. Wasted children were more likely than nonwasted, nonstunted children to become stunted (RR, 1.93; 95% CI, 1.7-2.2), but 94% of children who progressed to stunting had not been wasted in the prior period. CONCLUSIONS: WaSt greatly increased the risk of death, particularly in very young infants, but more deaths overall were associated with stunting. Most stunting appeared to be either intrauterine in origin or arose in children without prior wasting. Either stunting and wasting represent alternative responses to restricted nutrition, or stunting also has other, nonnutritional causes.

Functional diversification despite structural congruence in the HipBST toxin-antitoxin system of Legionella pneumophila.

IMPORTANCE: Toxin-antitoxin (TA) systems are parasitic genetic elements found in almost all bacterial genomes. They are exchanged horizontally between cells and are typically poorly conserved across closely related strains and species. Here, we report the characterization of a tripartite TA system in the bacterial pathogen Legionella pneumophila that is highly conserved across Legionella species genomes. This system (denoted HipBSTLp) is a distant homolog of the recently discovered split-HipA system in Escherichia coli (HipBSTEc). We present bioinformatic, molecular, and structural analyses of the divergence between these two systems and the functionality of this newly described TA system family. Furthermore, we provide evidence to refute previous claims that the toxin in this system (HipTLp) possesses bifunctionality as an L. pneumophila virulence protein. Overall, this work expands our understanding of the split-HipA system architecture and illustrates the potential for undiscovered biology in these abundant genetic elements.

Child maltreatment and incident mental disorders in middle and older ages: a retrospective UK Biobank cohort study.

BACKGROUND: Understanding the mental health consequences of child maltreatment at different life stages is important in accurately quantifying the burden of maltreatment. This study investigated the association between child maltreatment and incident mental disorders in middle and older age as well as the potential mediators and moderators. METHODS: This is a retrospective cohort study of 56,082 participants from UK Biobank. Child maltreatment was recalled using the Childhood Trauma Screener. Incident mental disorders, including depressive, anxiety and affective disorders, behavioural syndromes, post-traumatic stress disorder (PTSD), schizophrenia, substance abuse, and dementia, after baseline assessment were ascertained through linkage to primary care records. FINDINGS: There was a dose-response relationship between child maltreatment and mental disorder. Those who experienced three or more maltreatment types had the highest risk of all mental disorders (HR 1.85, 95% CI: 1.67-2.06) followed by those who experienced two (HR 1.48, 95% CI: 1.35-1.63) and then one (HR 1.26, 95% CI: 1.19-2.35). Child maltreatment was most strongly associated with PTSD (HR 1.59, 95% CI: 1.20-2.10 P=0.001). The excess risk was largely unexplained by the included mediators. The association between child maltreatment and all mental disorders were stronger among participants who binge drank (Pinteraction=0.003) or had few social visits (Pinteraction=0.003). INTERPRETATION: The mental health consequence of child maltreatment could last decades, even among those who had no recorded mental disorders in early adulthood. In the absence of strong mediators, prevention of child maltreatment remains the priority. FUNDING: Wellcome Trust Institutional Strategic Support Fund.