An intron variant of the GLI family zinc finger 3 (GLI3) gene differentiates resistance training-induced muscle fiber hypertrophy in younger men.

We examined the association between genotype and resistance training-induced changes (12 wk) in dual x-ray energy absorptiometry (DXA)-derived lean soft tissue mass (LSTM) as well as muscle fiber cross-sectional area (fCSA; vastus lateralis; n = 109; age = 22 ± 2 y, BMI = 24.7 ± 3.1 kg/m2 ). Over 315 000 genetic polymorphisms were interrogated from muscle using DNA microarrays. First, a targeted investigation was performed where single nucleotide polymorphisms (SNP) identified from a systematic literature review were related to changes in LSTM and fCSA. Next, genome-wide association (GWA) studies were performed to reveal associations between novel SNP targets with pre- to post-training change scores in mean fCSA and LSTM. Our targeted investigation revealed no genotype-by-time interactions for 12 common polymorphisms regarding the change in mean fCSA or change in LSTM. Our first GWA study indicated no SNP were associated with the change in LSTM. However, the second GWA study indicated two SNP exceeded the significance level with the change in mean fCSA (P = 6.9 × 10-7 for rs4675569, 1.7 × 10-6 for rs10263647). While the former target is not annotated (chr2:205936846 (GRCh38.p12)), the latter target (chr7:41971865 (GRCh38.p12)) is an intron variant of the GLI Family Zinc Finger 3 (GLI3) gene. Follow-up analyses indicated fCSA increases were greater in the T/C and C/C GLI3 genotypes than the T/T GLI3 genotype (P < .05). Data from the Auburn cohort also revealed participants with the T/C and C/C genotypes exhibited increases in satellite cell number with training (P < .05), whereas T/T participants did not. Additionally, those with the T/C and C/C genotypes achieved myonuclear addition in response to training (P < .05), whereas the T/T participants did not. In summary, this is the first GWA study to examine how polymorphisms associate with the change in hypertrophy measures following resistance training. Future studies are needed to determine if the GLI3 variant differentiates hypertrophic responses to resistance training given the potential link between this gene and satellite cell physiology.

Do multi-ingredient protein supplements augment resistance training-induced gains in skeletal muscle mass and strength? A systematic review and meta-analysis of 35 trials.

OBJECTIVE: To determine the effects of multi-ingredient protein (MIP) supplements on resistance exercise training (RT)-induced gains in muscle mass and strength compared with protein-only (PRO) or placebo supplementation. DATA SOURCES: Systematic search of MEDLINE, Embase, CINAHL and SPORTDiscus. ELIGIBILITY CRITERIA: Randomised controlled trials with interventions including RT ≥6 weeks in duration and a MIP supplement. DESIGN: Random effects meta-analyses were conducted to determine the effect of supplementation on fat-free mass (FFM), fat mass, one-repetition maximum (1RM) upper body and 1RM lower body muscular strength. Subgroup analyses compared the efficacy of MIP supplementation relative to training status and chronological age. RESULTS: The most common MIP supplements included protein with creatine (n=17) or vitamin D (n=10). Data from 35 trials with 1387 participants showed significant (p<0.05) increases in FFM (0.80 kg (95% CI 0.44 to 1.15)), 1RM lower body (4.22 kg (95% CI 0.79 to 7.64)) and 1RM upper body (2.56 kg (95% CI 0.79 to 4.33)) where a supplement was compared with all non-MIP supplemented conditions (means (95% CI)). Subgroup analyses indicated a greater effect of MIP supplements compared with all non-MIP supplements on FFM in untrained (0.95 kg (95% CI 0.51 to 1.39), p<0.0001) and older participants (0.77 kg (95% CI 0.11 to 1.43), p=0.02); taking MIP supplements was also associated with gains in 1RM upper body (1.56 kg (95% CI 0.80 to 2.33), p=0.01) in older adults. SUMMARY/CONCLUSIONS: When MIP supplements were combined with resistance exercise training, there were greater gains in FFM and strength in healthy adults than in counterparts who were supplemented with non-MIP. MIP supplements were not superior when directly compared with PRO supplements. The magnitude of effect of MIP supplements was greater (in absolute values) in untrained and elderly individuals undertaking RT than it was in trained individuals and in younger people. TRIAL REGISTRATION NUMBER: CRD42017081970.

Muscle fibre activation is unaffected by load and repetition duration when resistance exercise is performed to task failure.

KEY POINTS: Performing resistance exercise with heavier loads is often proposed to be necessary for the recruitment of larger motor units and activation of type II muscle fibres, leading to type II fibre hypertrophy. Indirect measures [surface electromyography (EMG)] have been used to support this thesis, although we propose that lighter loads lifted to task failure (i.e. volitional fatigue) result in the similar activation of type II fibres. In the present study, participants performed resistance exercise to task failure with heavier and lighter loads with both a normal and longer repetition duration (i.e. time under tension). Type I and type II muscle fibre glycogen depletion was determined by neither load, nor repetition duration during resistance exercise performed to task failure. Surface EMG amplitude was not related to muscle fibre glycogen depletion or anabolic signalling; however, muscle fibre glycogen depletion and anabolic signalling were related. Performing resistance exercise to task failure, regardless of load lifted or repetition duration, necessitates the activation of type II muscle fibres. ABSTRACT: Heavier loads (>60% of maximal strength) are considered to be necessary during resistance exercise (RE) to activate and stimulate hypertrophy of type II fibres. Support for this proposition comes from observation of higher surface electromyography (EMG) amplitudes during RE when lifting heavier vs. lighter loads. We aimed to determine the effect of RE, to task failure, with heavier vs. lighter loads and shorter or longer repetition durations on: EMG-derived variables, muscle fibre activation, and anabolic signalling. Ten recreationally-trained young men performed four unilateral RE conditions randomly on two occasions (two conditions, one per leg per visit). Muscle biopsies were taken from the vastus lateralis before and one hour after RE. Broadly, total time under load, number of repetitions, exercise volume, EMG amplitude (at the beginning and end of each set) and total EMG activity were significantly different between conditions (P < 0.05); however, neither glycogen depletion (in both type I and type II fibres), nor phosphorylation of relevant signalling proteins showed any difference between conditions. We conclude that muscle fibre activation and subsequent anabolic signalling are independent of load, repetition duration and surface EMG amplitude when RE is performed to task failure. The results of the present study provide evidence indicating that type I and type II fibres are activated when heavier and lighter loads are lifted to task failure. We propose that our results explain why RE training with higher or lower loads, when loads are lifted to task failure, leads to equivalent muscle hypertrophy and occurs in both type I and type II fibres.

Feedback regulation of Caulobacter crescentus holdfast synthesis by flagellum assembly via the holdfast inhibitor HfiA.

To permanently attach to surfaces, Caulobacter crescentusproduces a strong adhesive, the holdfast. The timing of holdfast synthesis is developmentally regulated by cell cycle cues. When C. crescentusis grown in a complex medium, holdfast synthesis can also be stimulated by surface sensing, in which swarmer cells rapidly synthesize holdfast in direct response to surface contact. In contrast to growth in complex medium, here we show that when cells are grown in a defined medium, surface contact does not trigger holdfast synthesis. Moreover, we show that in a defined medium, flagellum synthesis and regulation of holdfast production are linked. In these conditions, mutants lacking a flagellum attach to surfaces over time more efficiently than either wild-type strains or strains harboring a paralyzed flagellum. Enhanced adhesion in mutants lacking flagellar components is due to premature holdfast synthesis during the cell cycle and is regulated by the holdfast synthesis inhibitor HfiA. hfiA transcription is reduced in flagellar mutants and this reduction is modulated by the diguanylate cyclase developmental regulator PleD. We also show that, in contrast to previous predictions, flagella are not necessarily required for C. crescentus surface sensing in the absence of flow, and that arrest of flagellar rotation does not stimulate holdfast synthesis. Rather, our data support a model in which flagellum assembly feeds back to control holdfast synthesis via HfiA expression in a c-di-GMP-dependent manner under defined nutrient conditions.

Leucine metabolites do not attenuate training-induced inflammation in young resistance trained men.

Leucine metabolites may reduce training-induced inflammation; however, there is scant evidence for this assertion. We conducted a double-blind randomized controlled pragmatic trial where 40 male participants were allocated into 4 groups: α-hydroxyisocaproic acid group ([α-HICA], n = 10, Fat-free mass [FFM] = 62.0 ± 7.1 kg), ß-hydroxy-ß-methylbutyrate free acid group ([HMB-FA], n = 11, FFM = 62.7 ± 10.5 kg), calcium ß-hydroxy-ß-methylbutyrate group ([HMB-Ca], n = 9, FFM = 65.6 ± 10.1 kg) or placebo group ([PLA]; n = 10, FFM = 64.2 ± 5.7 kg). An 8-week whole-body resistance training routine (3 training sessions per week) was employed to induce gains in skeletal-muscle thickness. Skeletal muscle thickness (MT), one repetition maximum (1RM), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP) and tumour necrosis factor alpha (TNF-α) were assessed at baseline and at the end of weeks 4 and 8. Time-dependent increases were detected from baseline to week 8 for MT (vastus lateralis: p = 0.009; rectus femoris: p = 0.018), 1RM (back squat: α-HICA, 18.5% ± 18.9%; HMB-FA, 23.2% ± 16%; HMB-Ca, 10.5% ± 13.8%; PLA, 19.7% ± 9% and bench press: α-HICA, 13.8% ± 19.1%; HMB-FA, 15.5% ± 9.3%; HMB-Ca, 10% ± 10.4%; PLA, 14.4 ± 11.3%, both p < 0.001), IL-6, hsCRP (both p < 0.001) and TNF-α (p = 0.045). No differences were found between groups at any time point. No leucine metabolite attenuated inflammation during training. Additionally, backwards elimination regressions showed that no circulating inflammatory marker consistently shared variance with the change in any outcome. Using leucine metabolites to modulate inflammation cannot be recommended from the results obtained herein. Furthermore, increases in inflammatory markers, from training, do not correlate with any outcome variable and are likely the result of training adaptations.

Microvascular adaptations to resistance training are independent of load in resistance-trained young men.

Resistance training promotes microvasculature expansion; however, it remains unknown how different resistance training programs contribute to angiogenesis. Thus, we recruited experienced resistance-trained participants and determined the effect of 12 wk of either high-repetition/low-load or low-repetition/high-load resistance training performed to volitional fatigue on muscle microvasculature. Twenty men performed either a high-repetition [20-25 repetitions, 30-50% of 1-repetition maximum (1RM); n = 10] or a low-repetition (8-12 repetitions, 75-90% of 1RM; n = 10) resistance training program. Muscle biopsies were taken before and after resistance training, and immunohistochemistry was used to assess fiber type (I and II)-specific microvascular variables. High-repetition/low-load and low-repetition/high-load groups were not different in any variable before resistance training. Both protocols resulted in an increase in capillarization. Specifically, after resistance training, the capillary-to-fiber ratio, capillary contacts, and capillary-to-fiber perimeter exchange index were elevated, and sharing factor was reduced. These data demonstrate that resistance training performed to volitional failure, using either high repetition/low load or low repetition/high load, induced similar microvascular adaptations in recreationally resistance-trained young men.

Changes in Kidney Function Do Not Differ between Healthy Adults Consuming Higher- Compared with Lower- or Normal-Protein Diets: A Systematic Review and Meta-Analysis.

Background: Higher-protein (HP) diets are advocated for several reasons, including mitigation of sarcopenia, but their effects on kidney function are unclear. Objective: This meta-analysis was conducted to determine the effect of HP intakes on kidney function in healthy adults. Methods: We conducted a systematic review and meta-analysis of trials comparing HP (≥1.5 g/kg body weight or ≥20% energy intake or ≥100 g protein/d) with normal- or lower-protein (NLP; ≥5% less energy intake from protein/d compared with HP group) intakes on kidney function. Medline and EMBASE databases were searched. Randomized controlled trials comparing the effects of HP with NLP (>4 d duration) intakes on glomerular filtration rate (GFR) in adults without kidney disease were included. Results: A total of 2144 abstracts were reviewed, with 40 articles selected for full-text review; 28 of these were analyzed and included data from 1358 participants. Data were analyzed using random-effects meta-analysis (RevMan 5; The Cochrane Collaboration), meta-regression (STATA; StataCorp), and dose-response analysis (Prism; GraphPad). Analyses were conducted using postintervention (post) GFR and the change in GFR from preintervention to post. The post-only comparison showed a trivial effect for GFR to be higher after HP intakes [standardized mean difference (SMD): 0.19; 95% CI: 0.07, 0.31; P = 0.002]. The change in GFR did not differ between interventions (SMD: 0.11; 95% CI: -0.05, 0.27; P = 0.16). There was a linear relation between protein intake and GFR in the post-only comparison (r = 0.332, P = 0.03), but not between protein intake and the change in GFR (r = 0.184, P = 0.33). The main limitation of the current analysis is the unclear risk of selection bias of the included trials. Conclusions: Postintervention GFR comparisons indicate that HP diets result in higher GFRs; however, when changes in GFR were compared, dietary protein had no effect. Our analysis indicates that HP intakes do not adversely influence kidney function on GFR in healthy adults.

Defining anabolic resistance: implications for delivery of clinical care nutrition.

PURPOSE OF REVIEW: Skeletal muscle mass with aging, during critical care, and following critical care is a determinant of quality of life and survival. In this review, we discuss the mechanisms that underpin skeletal muscle atrophy and recommendations to offset skeletal muscle atrophy with aging and during, as well as following, critical care. RECENT FINDINGS: Anabolic resistance is responsible, in part, for skeletal muscle atrophy with aging, muscle disuse, and during disease states. Anabolic resistance describes the reduced stimulation of muscle protein synthesis to a given dose of protein/amino acids and contributes to declines in skeletal muscle mass. Physical inactivity induces: anabolic resistance (that is likely exacerbated with aging), insulin resistance, systemic inflammation, decreased satellite cell content, and decreased capillary density. Critical illness results in rapid skeletal muscle atrophy that is a result of both anabolic resistance and enhanced skeletal muscle breakdown. SUMMARY: Insofar as atrophic loss of skeletal muscle mass is concerned, anabolic resistance is a principal determinant of age-induced losses and appears to be a contributor to critical illness-induced skeletal muscle atrophy. Older individuals should perform exercise using both heavy and light loads three times per week, ingest at least 1.2 g of protein/kg/day, evenly distribute their meals into protein boluses of 0.40 g/kg, and consume protein within 2 h of retiring for sleep. During critical care, early, frequent, and multimodal physical therapies in combination with early, enteral, hypocaloric energy (∼10-15 kcal/kg/day), and high-protein (>1.2 g/kg/day) provision is recommended.

A systematic review, meta-analysis and meta-regression of the effect of protein supplementation on resistance training-induced gains in muscle mass and strength in healthy adults.

OBJECTIVE: We performed a systematic review, meta-analysis and meta-regression to determine if dietary protein supplementation augments resistance exercise training (RET)-induced gains in muscle mass and strength. DATA SOURCES: A systematic search of Medline, Embase, CINAHL and SportDiscus. ELIGIBILITY CRITERIA: Only randomised controlled trials with RET ≥6 weeks in duration and dietary protein supplementation. DESIGN: Random-effects meta-analyses and meta-regressions with four a priori determined covariates. Two-phase break point analysis was used to determine the relationship between total protein intake and changes in fat-free mass (FFM). RESULTS: Data from 49 studies with 1863 participants showed that dietary protein supplementation significantly (all p<0.05) increased changes (means (95% CI)) in: strength-one-repetition-maximum (2.49 kg (0.64, 4.33)), FFM (0.30 kg (0.09, 0.52)) and muscle size-muscle fibre cross-sectional area (CSA; 310 µm2 (51, 570)) and mid-femur CSA (7.2 mm2 (0.20, 14.30)) during periods of prolonged RET. The impact of protein supplementation on gains in FFM was reduced with increasing age (-0.01 kg (-0.02,-0.00), p=0.002) and was more effective in resistance-trained individuals (0.75 kg (0.09, 1.40), p=0.03). Protein supplementation beyond total protein intakes of 1.62 g/kg/day resulted in no further RET-induced gains in FFM. SUMMARY/CONCLUSION: Dietary protein supplementation significantly enhanced changes in muscle strength and size during prolonged RET in healthy adults. Increasing age reduces and training experience increases the efficacy of protein supplementation during RET. With protein supplementation, protein intakes at amounts greater than ~1.6 g/kg/day do not further contribute RET-induced gains in FFM.

STAAR: a randomised controlled trial of electronic adherence monitoring with reminder alarms and feedback to improve clinical outcomes for children with asthma.

BACKGROUND: Suboptimal adherence to inhaled steroids is common in children with asthma and is associated with poor disease control, reduced quality of life and even death. Previous studies using feedback of electronically monitored adherence data have demonstrated improved adherence, but have not demonstrated a significant impact on clinical outcomes. The aim of this study was to determine whether introduction of this approach into routine practice would result in improved clinical outcomes. METHODS: Children with asthma aged 6-16 years were randomised to the active intervention consisting of electronic adherence monitoring with daily reminder alarms together with feedback in the clinic regarding their inhaled corticosteroid (ICS) use or to the usual care arm with adherence monitoring alone. All children had poorly controlled asthma at baseline, taking ICS and long-acting ß-agonists. Subjects were seen in routine clinics every 3 months for 1 year. The primary outcome was the Asthma Control Questionnaire (ACQ) score. Secondary outcomes included adherence and markers of asthma morbidity. RESULTS: 77 of 90 children completed the study (39 interventions, 38 controls). Adherence in the intervention group was 70% vs 49% in the control group (p≤0.001). There was no significant difference in the change in ACQ, but children in the intervention group required significantly fewer courses of oral steroids (p=0.008) and fewer hospital admissions (p≤0.001). CONCLUSIONS: The results indicate that electronic adherence monitoring with feedback is likely to be of significant benefit in the routine management of poorly controlled asthmatic subjects. TRIAL REGISTRATION NUMBER: NCT02451709; pre-result.

Enteral Feeding with Human Milk Decreases Time to Discharge in Infants following Gastroschisis Repair.

OBJECTIVE: To assess the effect of enteral feeding with human milk on the time from initiation of feeds to discharge after gastroschisis repair through review of a multi-institutional database. STUDY DESIGN: Infants who underwent gastroschisis repair between 1997 and 2012 with data recorded in the Pediatrix Medical Group Clinical Data Warehouse were categorized into 4 groups based on the percentage of days fed human milk out of the number of days fed enterally. Cox proportional hazards regression modeling was performed to determine the adjusted effect of human milk on the time from initiation of feeds to discharge. RESULTS: Among 3082 infants, 659 (21%) were fed human milk on 0% of enteral feeding days, 766 (25%) were fed human milk on 1%-50% of enteral feeding days, 725 (24%) were fed human milk on 51%-99% of enteral feeding days, and 932 (30%) were fed human milk on 100% of enteral feeding days. Following adjustment, being fed human milk on 0% of enteral feeding days was associated with a significantly increased time to discharge compared with being fed human milk on 100% of enteral feeding days (hazard ratio [HR] for discharge per day, 0.46; 95% CI, 0.40-0.52). The same was found for infants fed human milk on 1%-50% of enteral feeding days (HR, 0.37; 95% CI, 0.32-0.41) and for infants fed human milk on 51%-99% of enteral feeding days (HR, 0.51; 95% CI, 0.46-0.57). CONCLUSION: The use of human milk for enteral feeding of infants following repair of gastroschisis significantly reduces the time to discharge from initiation of feeds.

The role of mitochondrial genes in ischemia-reperfusion injury: A systematic review of experimental studies.

Mitochondrial dysfunction contributes to pathological conditions like ischemia-reperfusion (IR) injury. To address the lack of effective therapeutic interventions for IR injury and potential knowledge gaps in the current literature, we systematically reviewed 3800 experimental studies across 5 databases and identified 20 mitochondrial genes impacting IR injury in various organs. Notably, CyPD, Nrf2, and GPX4 are well-studied genes consistently influencing IR injury outcomes. Emerging genes like ALDH2, BNIP3, and OPA1 are supported by human genetic evidence, thereby warranting further investigation. Findings of this review can inform future research directions and inspire therapeutic advancements.

A method to estimate the contribution of rare coding variants to complex trait heritability.

It has been postulated that rare coding variants (RVs; MAF < 0.01) contribute to the "missing" heritability of complex traits. We developed a framework, the Rare variant heritability (RARity) estimator, to assess RV heritability (h2RV) without assuming a particular genetic architecture. We applied RARity to 31 complex traits in the UK Biobank (n = 167,348) and showed that gene-level RV aggregation suffers from 79% (95% CI: 68-93%) loss of h2RV. Using unaggregated variants, 27 traits had h2RV > 5%, with height having the highest h2RV at 21.9% (95% CI: 19.0-24.8%). The total heritability, including common and rare variants, recovered pedigree-based estimates for 11 traits. RARity can estimate gene-level h2RV, enabling the assessment of gene-level characteristics and revealing 11, previously unreported, gene-phenotype relationships. Finally, we demonstrated that in silico pathogenicity prediction (variant-level) and gene-level annotations do not generally enrich for RVs that over-contribute to complex trait variance, and thus, innovative methods are needed to predict RV functionality.

Genome-wide study investigating effector genes and polygenic prediction for kidney function in persons with ancestry from Africa and the Americas.

Chronic kidney disease is a leading cause of death and disability globally and impacts individuals of African ancestry (AFR) or with ancestry in the Americas (AMS) who are under-represented in genome-wide association studies (GWASs) of kidney function. To address this bias, we conducted a large meta-analysis of GWASs of estimated glomerular filtration rate (eGFR) in 145,732 AFR and AMS individuals. We identified 41 loci at genome-wide significance (p < 5 × 10-8), of which two have not been previously reported in any ancestry group. We integrated fine-mapped loci with epigenomic and transcriptomic resources to highlight potential effector genes relevant to kidney physiology and disease, and reveal key regulatory elements and pathways involved in renal function and development. We demonstrate the varying but increased predictive power offered by a multi-ancestry polygenic score for eGFR and highlight the importance of population diversity in GWASs and multi-omics resources to enhance opportunities for clinical translation for all.

The HmrABCX pathway regulates the transition between motile and sessile lifestyles in Caulobacter crescentus by a HfiA-independent mechanism.

Through its cell cycle, the bacterium Caulobacter crescentus switches from a motile, free-living state, to a sessile surface-attached cell. During this coordinated process, cells undergo irreversible morphological changes, such as shedding of their polar flagellum and synthesis of an adhesive holdfast at the same pole. In this work, we used genetic screens to identify genes involved in the regulation of the motile to sessile lifestyle transition. We identified a predicted hybrid histidine kinase that inhibits biofilm formation and activates the motile lifestyle: HmrA (Holdfast and motility regulator A). Genetic screens and genomic localization led to the identification of additional genes that regulate the proportion of cells harboring an active flagellum or a holdfast and that form a putative phosphorelay pathway with HmrA. Further genetic analysis indicates that the Hmr pathway is independent of the holdfast synthesis regulator HfiA and may impact c-di-GMP synthesis through the diguanylate cyclase DgcB pathway. Finally, we provide evidence that the Hmr pathway is involved in the regulation of sessile-to-motile lifestyle as a function of environmental stresses, namely excess copper and non-optimal temperatures.

Precision medicine for cardiometabolic disease: a framework for clinical translation.

Cardiometabolic disease is a major threat to global health. Precision medicine has great potential to help to reduce the burden of this common and complex disease cluster, and to enhance contemporary evidence-based medicine. Its key pillars are diagnostics; prediction (of the primary disease); prevention (of the primary disease); prognosis (prediction of complications of the primary disease); treatment (of the primary disease or its complications); and monitoring (of risk exposure, treatment response, and disease progression or remission). To contextualise precision medicine in both research and clinical settings, and to encourage the successful translation of discovery science into clinical practice, in this Series paper we outline a model (the EPPOS model) that builds on contemporary evidence-based approaches; includes precision medicine that improves disease-related predictions by stratifying a cohort into subgroups of similar characteristics, or using participants' characteristics to model treatment outcomes directly; includes personalised medicine with the use of a person's data to objectively gauge the efficacy, safety, and tolerability of therapeutics; and subjectively tailors medical decisions to the individual's preferences, circumstances, and capabilities. Precision medicine requires a well functioning system comprised of multiple stakeholders, including health-care recipients, health-care providers, scientists, health economists, funders, innovators of medicines and technologies, regulators, and policy makers. Powerful computing infrastructures supporting appropriate analysis of large-scale, well curated, and accessible health databases that contain high-quality, multidimensional, time-series data will be required; so too will prospective cohort studies in diverse populations designed to generate novel hypotheses, and clinical trials designed to test them. Here, we carefully consider these topics and describe a framework for the integration of precision medicine in cardiometabolic disease.

The case for precision medicine in the prevention, diagnosis, and treatment of cardiometabolic diseases in low-income and middle-income countries.

Cardiometabolic diseases are the leading preventable causes of death in most geographies. The causes, clinical presentations, and pathogenesis of cardiometabolic diseases vary greatly worldwide, as do the resources and strategies needed to prevent and treat them. Therefore, there is no single solution and health care should be optimised, if not to the individual (ie, personalised health care), then at least to population subgroups (ie, precision medicine). This optimisation should involve tailoring health care to individual disease characteristics according to ethnicity, biology, behaviour, environment, and subjective person-level characteristics. The capacity and availability of local resources and infrastructures should also be considered. Evidence needed for equitable precision medicine cannot be generated without adequate data from all target populations, and the idea that research done in high-income countries will transfer adequately to low-income and middle-income countries (LMICs) is problematic, as many migration studies and transethnic comparisons have shown. However, most data for precision medicine research are derived from people of European ancestry living in high-income countries. In this Series paper, we discuss the case for precision medicine for cardiometabolic diseases in LMICs, the barriers and enablers, and key considerations for implementation. We focus on three propositions: first, failure to explore and implement precision medicine for cardiometabolic disease in LMICs will enhance global health disparities. Second, some LMICs might already be placed to implement cardiometabolic precision medicine under appropriate circumstances, owing to progress made in treating infectious diseases. Third, improvements in population health from precision medicine are most probably asymptotic; the greatest gains are more likely to be obtained in countries where health-care systems are less developed. We outline key recommendations for implementation of precision medicine approaches in LMICs.

Surrogate Adiposity Markers and Mortality.

Importance: Body mass index (BMI) is an easily obtained adiposity surrogate. However, there is variability in body composition and adipose tissue distribution between individuals with the same BMI, and there is controversy regarding the BMI associated with the lowest mortality risk. Objective: To evaluate which of BMI, fat mass index (FMI), and waist-to-hip (WHR) has the strongest and most consistent association with mortality. Design, Setting, and Participant: This cohort study used incident deaths from the UK Biobank (UKB; 2006-2022), which includes data from 22 clinical assessment centers across the United Kingdom. UKB British participants of British White ancestry (N = 387 672) were partitioned into a discovery cohort (n = 337 078) and validation cohort (n = 50 594), with the latter consisting of 25 297 deaths and 25 297 controls. The discovery cohort was used to derive genetically determined adiposity measures while the validation cohort was used for analyses. Exposure-outcome associations were analyzed through observational and mendelian randomization (MR) analyses. Exposures: BMI, FMI, and WHR. Main Outcomes and Measures: All-cause and cause-specific (cancer, cardiovascular disease [CVD], respiratory disease, or other causes) mortality. Results: There were 387 672 and 50 594 participants in our observational (mean [SD] age, 56.9 [8.0] years; 177 340 [45.9%] male, 210 332 [54.2%], female), and MR (mean [SD] age, 61.6 [6.2] years; 30 031 [59.3%] male, 20 563 [40.6%], female) analyses, respectively. Associations between measured BMI and FMI with all-cause mortality were J-shaped, whereas the association of WHR with all-cause mortality was linear using the hazard ratio (HR) scale (HR per SD increase of WHR, 1.41 [95% CI, 1.38-1.43]). Genetically determined WHR had a stronger association with all-cause mortality than BMI (odds ratio [OR] per SD increase of WHR, 1.51 [95% CI, 1.32-1.72]; OR per SD increase of BMI, 1.29 [95% CI, 1.20-1.38]; P for heterogeneity = .02). This association was stronger in male than female participants (OR, 1.89 [95% CI, 1.54-2.32]; P for heterogeneity = .01). Unlike BMI or FMI, the genetically determined WHR-all-cause mortality association was consistent irrespective of observed BMI. Conclusions and Relevance: In this cohort study, WHR had the strongest and most consistent association with mortality irrespective of BMI. Clinical recommendations should consider focusing on adiposity distribution compared with mass.