Adiposity, fat-free mass and incident heart failure in 500 000 individuals.

BACKGROUND AND AIMS: The independent role of body fat distribution and fat-free mass in heart failure (HF) risk is unclear. We investigated the role of different body composition compartments in risk of HF. METHODS: Present analyses include 428 087 participants (mean age 55.9 years, 44% male) from the UK Biobank. Associations of long-term average levels of body composition measures with incident HF were determined using adjusted Cox proportional hazards regression models. RESULTS: Over a median follow-up of 13.8 years, there were 10 455 first-ever incident HF events. Overall, HF risk was more strongly associated with central adiposity (waist circumference (WC) adjusted for body mass index (BMI); HR 1.38, 95% CI 1.32 to 1.45) than general adiposity (BMI adjusted for WC; HR 1.22, 95% CI 1.16 to 1.27). Although dual X-ray absorptiometry-derived body fat remained positively related to HF after adjustment for fat-free mass (HR 1.37, 95% CI 1.18 to 1.59), the association of fat-free mass with HF was substantially attenuated by fat mass (HR 1.12, 95% CI 1.01 to 1.26) while visceral fat (VAT) remained associated with HF independent of subcutaneous fat (HR 1.20, 95% CI 1.09 to 1.33). In analyses of HF subtypes, HF with preserved ejection fraction was independently associated with all fat measures (eg, VAT: HR 1.23, 95% CI 1.12 to 1.35; body fat: HR 1.36, 95% CI 1.17 to 1.57) while HF with reduced ejection fraction was not independently associated with fat measures (eg, VAT: HR 1.29, 95% CI 0.98 to 1.68; body fat: HR 1.29, 95% CI 0.80 to 2.07). CONCLUSIONS: This large-scale study shows that excess adiposity and fat mass are associated with higher HF risk while the association of fat-free mass with HF could be explained largely by its correlation with fat mass. The study also describes the independent relevance of body fat distribution to HF subtypes, suggesting different mechanisms may be driving their aetiopathogenesis.

MiR-214-3p Regulates Piezo1, Lysyl Oxidases and Mitochondrial Function in Human Cardiac Fibroblasts.

Cardiac fibroblasts are pivotal regulators of cardiac homeostasis and are essential in the repair of the heart after myocardial infarction (MI), but their function can also become dysregulated, leading to adverse cardiac remodelling involving both fibrosis and hypertrophy. MicroRNAs (miRNAs) are noncoding RNAs that target mRNAs to prevent their translation, with specific miRNAs showing differential expression and regulation in cardiovascular disease. Here, we show that miR-214-3p is enriched in the fibroblast fraction of the murine heart, and its levels are increased with cardiac remodelling associated with heart failure, or in the acute phase after experimental MI. Tandem mass tagging proteomics and in-silico network analyses were used to explore protein targets regulated by miR-214-3p in cultured human cardiac fibroblasts from multiple donors. Overexpression of miR-214-3p by miRNA mimics resulted in decreased expression and activity of the Piezo1 mechanosensitive cation channel, increased expression of the entire lysyl oxidase (LOX) family of collagen cross-linking enzymes, and decreased expression of an array of mitochondrial proteins, including mitofusin-2 (MFN2), resulting in mitochondrial dysfunction, as measured by citrate synthase and Seahorse mitochondrial respiration assays. Collectively, our data suggest that miR-214-3p is an important regulator of cardiac fibroblast phenotypes and functions key to cardiac remodelling, and that this miRNA represents a potential therapeutic target in cardiovascular disease.

Emergency department attendances and inpatient admissions due to mpox infection, England, 2022.

OBJECTIVES: In 2022, a global outbreak of mpox was reported. In the UK, it predominantly affected gay, bisexual and men who have sex with men (GBMSM). The study objectives were to describe the impact of the mpox outbreak on healthcare service usage in England in 2022, particularly emergency department (ED) attendance, inpatient admission and a number of bed days. Additionally, we wanted to explore whether pre-exposure prophylaxis (PrEP) usage, as a marker of condomless anal intercourse, which increases the risk of sexually transmitted infections associated with compromised skin integrity, was associated with higher ED attendance or hospital attendance. METHODS: Data on adult males with laboratory-confirmed mpox were linked with hospital records and described. Using routinely collected data and self-reported exposure data (including PrEP usage) from surveillance questionnaires, multinomial regression was used to estimate adjusted relative risk ratios (aRRRs) with 95% CIs for ED attendance and hospital admission compared with those not admitted. RESULTS: Among 3542 adult males with mpox during May to December 2022, 544 (15.4%) attended ED and 202 (5.7%) were admitted to the hospital. London had the most cases (2393, 68.7%), ED attendances (391, 71.9%) and hospital admissions (121, 59.9%). In multinomial regression, we found strong evidence that compared with people living with HIV, the aRRR for hospital admissions was higher in those not using PrEP (6.9 (95% CI 2.3 to 20.6) vs 4.9 (95% CI 1.7 to 14.1)). The aRRR for ED attendance was 0.63 (95% CI 0.36 to 1.1) for those not using PrEP versus 0.49 (95% CI 0.31 to 0.79). CONCLUSIONS: This outbreak had a considerable impact on health services, particularly in high-incidence areas. Commissioners of sexual and healthcare services should review plans for healthcare provision for similar sexually transmitted infection or novel outbreaks among GBMSM or naïve populations in the future. Further studies are needed to confirm and identify reasons for the higher likelihood of hospital admission seen for GBMSM without HIV infection.

Auto-loaded TRAIL-exosomes derived from induced neural stem cells for brain cancer therapy.

Transdifferentiation (TD), a somatic cell reprogramming process that eliminates pluripotent intermediates, creates cells that are ideal for personalized anti-cancer therapy. Here, we provide the first evidence that extracellular vesicles (EVs) from TD-derived induced neural stem cells (Exo-iNSCs) are an efficacious treatment strategy for brain cancer. We found that genetically engineered iNSCs generated EVs loaded with the tumoricidal gene product TRAIL at nearly twice the rate as their parental fibroblasts, and the TRAIL produced by iNSCs were naturally loaded into the lumen of EVs and arrayed across their outer membrane (Exo-iNSC-TRAIL). Uptake studies in ex vivo organotypic brain slice cultures showed Exo-iNSC-TRAIL selectively accumulates within tumor foci, and co-culture assays showed that Exo-iNSC-TRAIL killed metastatic and primary brain cancer cells more effectively than free TRAIL. In an orthotopic mouse model of brain cancer, Exo-iNSC-TRAIL reduced breast-to-brain tumor xenografts around 3000-fold greater than treatment with free TRAIL, with all Exo-iNSC-TRAIL treated animals surviving through 90 days post-treatment. In additional in vivo testing against aggressive U87 and invasive GBM8 glioblastoma tumors, Exo-iNSC-TRAIL also induced a statistically significant increase in survival. These studies establish a new easily generated, stable, tumor-targeted EV to efficaciously treat multiple forms of brain cancer.

Auto-loaded TRAIL-exosomes derived from induced neural stem cells for brain cancer therapy.

Transdifferentiation (TD), a somatic cell reprogramming process that eliminates pluripotent intermediates, creates cells that are ideal for personalized anti-cancer therapy. Here, we provide the first evidence that extracellular vesicles (EVs) from TD-derived induced neural stem cells (Exo-iNSCs) are an efficacious treatment strategy for brain cancer. We found that genetically engineered iNSCs generated EVs loaded with the tumoricidal gene product TRAIL at nearly twice the rate of their parental fibroblasts, and TRAIL produced by iNSCs was naturally loaded into the lumen of EVs and arrayed across their outer membrane (Exo-iNSC-TRAIL). Uptake studies in ex vivo organotypic brain slice cultures showed that Exo-iNSC-TRAIL selectively accumulates within tumor foci, and co-culture assays demonstrated that Exo-iNSC-TRAIL killed metastatic and primary brain cancer cells more effectively than free TRAIL. In an orthotopic mouse model of brain cancer, Exo-iNSC-TRAIL reduced breast-to-brain tumor xenografts by approximately 3000-fold compared to treatment with free TRAIL, with all Exo-iNSC-TRAIL treated animals surviving through 90 days post-treatment. In additional in vivo testing against aggressive U87 and invasive GBM8 glioblastoma tumors, Exo-iNSC-TRAIL also induced a statistically significant increase in survival. These studies establish a novel, easily generated, stable, tumor-targeted EV to efficaciously treat multiple forms of brain cancer.

Designing, piloting and evaluating (through a matched pre- and post-implementation survey) a targeted e-learning resource on antimicrobial resistance for public health professionals.

BACKGROUND: Antimicrobial resistance (AMR) is a significant global public health threat and key priority for the public health, especially health protection, workforce to lead by example. There is a paucity of learning resources on this for public health professionals (PHPs) in the UK. This project aimed to develop and disseminate a tailored interactive learning resource and evaluate impact on self-reported intention to change behaviour. METHODS: Learning objectives were agreed, content developed by the multi-disciplinary team and piloted by PHPs in 2022 alongside a matched pre- and post-implementation evaluation survey. Questions were mapped to the capability-opportunity-motivation-behaviour change model. Before and after responses were calculated to compare change in self-reported knowledge, understanding and behaviour. Significance of change in binary responses was estimated. RESULTS: The resource was delivered using an interactive, user-friendly and cost-free internal platform. Thirty-one PHPs completed the pilot e-learning and survey. Perceived and actual knowledge increased in parallel. Actual knowledge on AMR burden increased from 6.45 to 35.48% (P = 0.004). Self-reported confidence to explain AMR to others improved by 0.71 (95% CI; 0.38-1.04: P = 0.0001) Likert points on a five-point scale. Motivation to advocate for antimicrobial stewardship (AMS) in day-to-day work, improved by 0.71 (95% CI; 0.34-1.08: P < 0.00001) Likert points. Case scenarios were well-received as an effective way to apply theory to practice. CONCLUSION: Ensuring a well-informed and confident public health workforce is vital for reducing the AMR threat and advocating for AMS with the public and partner organizations. This targeted e-learning module is an effective additional learning medium in contributing to PHPs knowledge, understanding and self-reported intention to change behaviours.

The HLA-II immunopeptidome of SARS-CoV-2.

Targeted synthetic vaccines have the potential to transform our response to viral outbreaks, yet the design of these vaccines requires a comprehensive knowledge of viral immunogens. Here, we report severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) peptides that are naturally processed and loaded onto human leukocyte antigen-II (HLA-II) complexes in infected cells. We identify over 500 unique viral peptides from canonical proteins as well as from overlapping internal open reading frames. Most HLA-II peptides colocalize with known CD4+ T cell epitopes in coronavirus disease 2019 patients, including 2 reported immunodominant regions in the SARS-CoV-2 membrane protein. Overall, our analyses show that HLA-I and HLA-II pathways target distinct viral proteins, with the structural proteins accounting for most of the HLA-II peptidome and nonstructural and noncanonical proteins accounting for the majority of the HLA-I peptidome. These findings highlight the need for a vaccine design that incorporates multiple viral elements harboring CD4+ and CD8+ T cell epitopes to maximize vaccine effectiveness.

Point-of-care ultrasound as a diagnostic tool in respiratory assessment in awake paediatric patients: a comparative study.

BACKGROUND: Chest X-ray (CXR) has typically been the main investigation in children with suspected respiratory pathology. Recent advances in lung point-of-care ultrasound (POCUS) have shown the potential for it to be comparative, if not better, than CXR. The objective of this study was to compare CXR with lung POCUS in children with respiratory illness in a ward-based setting at a paediatric teaching hospital. METHODS: Any child <18 years of age presenting to Southampton Children's Hospital requiring a CXR for clinical reasons also had lung POCUS performed. CXR was reported by a consultant paediatric radiologist and lung POCUS was reviewed retrospectively by a blinded POCUS clinician, with only the clinical information provided on the CXR request. Comparisons were made between the CXR and lung POCUS findings. RESULTS: 100 paired lung POCUS and CXR were included in the study. 30% of lung POCUS were normal with 97% of these having a normal CXR. 70% of cases had POCUS abnormalities with 96% of POCUS cases identifying comparative lung pathology. Lung POCUS therefore had a sensitivity of 98.51% and a specificity of 87.9% with a diagnostic accuracy of 95% when compared with the CXR report. CONCLUSIONS: Lung POCUS has excellent diagnostic accuracy. The diagnosis of normal lung on POCUS when performed by a trained practitioner can reliably reduce the need for a CXR, thus reducing CXR use and radiation exposure in children. An abnormal lung POCUS could then either give the diagnosis or lead to a CXR with the expectation of clinically relevant findings.

Independent relevance of adiposity measures to coronary heart disease risk among 0.5 million adults in UK Biobank.

BACKGROUND: Evidence on body fat distribution shows opposing effects of waist circumference (WC) and hip circumference (HC) for coronary heart disease (CHD). We aimed to investigate the causality and the shape of such associations. METHODS: UK Biobank is a prospective cohort study of 0.5 million adults aged 40-69 years recruited between 2006 and 2010. Adjusted hazard ratios (HRs) for the associations of measured and genetically predicted body mass index (BMI), WC, HC and waist-to-hip ratio with incident CHD were obtained from Cox models. Mendelian randomization (MR) was used to assess causality. The analysis included 456 495 participants (26 225 first-ever CHD events) without prior CHD. RESULTS: All measures of adiposity demonstrated strong, positive and approximately log-linear associations with CHD risk over a median follow-up of 12.7 years. For HC, however, the association became inverse given the BMI and WC (HR per usual SD 0.95, 95% CI 0.93-0.97). Associations for BMI and WC remained independently positive after adjustment for other adiposity measures and were similar (1.14, 1.13-1.16 and 1.18, 1.15-1.20, respectively), with WC displaying stronger associations among women. Blood pressure, plasma lipids and dysglycaemia accounted for much of the observed excess risk. MR results were generally consistent with the observational, implying causality. CONCLUSIONS: Body fat distribution measures displayed similar associations with CHD risk as BMI except for HC, which was inversely associated with CHD risk (given WC and BMI). These findings suggest that different measures of body fat distribution likely influence CHD risk through both overlapping and independent mechanisms.

Is Height2.7 Appropriate for Indexation of Left Ventricular Mass in Healthy Adolescents? The Importance of Sex Differences.

BACKGROUND: Left ventricular mass (LVM) is an important predictor of cardiovascular risk. In adolescence, LVM is commonly indexed to height2.7, although some evidence suggests that this may not fully account for sex differences. METHODS: We investigated appropriate allometric scaling of LVM to height, total lean mass, and body surface area, in a UK birth cohort of 2039 healthy adolescents (17±1 years). Allometric relationships were determined by linear regression stratified by sex, following log transformation of x and y variables [log(y)=a+b×log(x)], b is the allometric exponent. RESULTS: Log (LVM) showed linear relationships with log(height) and log(lean mass). Biased estimates of slope resulted when the sexes were pooled. The exponents were lower than the conventional estimate of 2.7 for males (mean [95% CI]=1.66 [1.30-2.03]) and females (1.58 [1.27-1.90]). When LVM was indexed to lean mass, the exponent was 1.16 (1.05-1.26) for males and 1.07 (0.97-1.16) for females. When LVM was indexed to estimated body surface area, the exponent was 1.53 (1.40-1.66) for males and 1.34 (1.24-1.45) for females. CONCLUSIONS: Allometric exponents derived from pooled data, including men and women without adjustment for sex were biased, possibly due to sex differences in body composition. We suggest that when assessing LVM, clinicians should consider body size, body composition, sex, and age. Our observations may also have implications for the identification of young individuals with cardiac hypertrophy.

The HLA-II immunopeptidome of SARS-CoV-2.

Targeted synthetic vaccines have the potential to transform our response to viral outbreaks; yet the design of these vaccines requires a comprehensive knowledge of viral immunogens, including T-cell epitopes. Having previously mapped the SARS-CoV-2 HLA-I landscape, here we report viral peptides that are naturally processed and loaded onto HLA-II complexes in infected cells. We identified over 500 unique viral peptides from canonical proteins, as well as from overlapping internal open reading frames (ORFs), revealing, for the first time, the contribution of internal ORFs to the HLA-II peptide repertoire. Most HLA-II peptides co-localized with the known CD4+ T cell epitopes in COVID-19 patients. We also observed that two reported immunodominant regions in the SARS-CoV-2 membrane protein are formed at the level of HLA-II presentation. Overall, our analyses show that HLA-I and HLA-II pathways target distinct viral proteins, with the structural proteins accounting for most of the HLA-II peptidome and non-structural and non-canonical proteins accounting for the majority of the HLA-I peptidome. These findings highlight the need for a vaccine design that incorporates multiple viral elements harboring CD4+ and CD8+ T cell epitopes to maximize the vaccine effectiveness.

Body composition and risk factors for cardiovascular disease in global multi-ethnic populations.

BACKGROUND: No large-scale studies have compared associations between body composition and cardiovascular risk factors across multi-ethnic populations. METHODS: Population-based surveys included 30,721 Malay, 10,865 Indian and 25,296 Chinese adults from The Malaysian Cohort, and 413,737 White adults from UK Biobank. Sex-specific linear regression models estimated associations of anthropometry and body composition (body mass index [BMI], waist circumference [WC], fat mass, appendicular lean mass) with systolic blood pressure (SBP), low-density lipoprotein cholesterol (LDL-C), triglycerides and HbA1c. RESULTS: Compared to Malay and Indian participants, Chinese adults had lower BMI and fat mass while White participants were taller with more appendicular lean mass. For BMI and fat mass, positive associations with SBP and HbA1c were strongest among the Chinese and Malay and weaker in White participants. Associations with triglycerides were considerably weaker in those of Indian ethnicity (eg 0.09 [0.02] mmol/L per 5 kg/m2 BMI in men, vs 0.38 [0.02] in Chinese). For appendicular lean mass, there were weak associations among men; but stronger positive associations with SBP, triglycerides, and HbA1c, and inverse associations with LDL-C, among Malay and Indian women. Associations between WC and risk factors were generally strongest in Chinese and weakest in Indian ethnicities, although this pattern was reversed for HbA1c. CONCLUSION: There were distinct patterns of adiposity and body composition and cardiovascular risk factors across ethnic groups. We need to better understand the mechanisms relating body composition with cardiovascular risk to attenuate the increasing global burden of obesity-related disease.

Body Composition and Risk of Incident Heart Failure in 1 Million Adults: A Systematic Review and Dose-Response Meta-Analysis of Prospective Cohort Studies.

Background The aim of this systematic review was to quantify the associations between body composition measures and risk of incident heart failure (HF) and its subtypes in the general population. Methods and Results We searched Medline, Embase, and Global Health databases from each database inception to January 19, 2023 for prospective studies reporting on body composition and HF risk. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The Newcastle-Ottawa scale was used to assess the risk of bias of included studies. Fixed-effects models were used for meta-analysis. Thirty-five studies were included (ntotal=1 137 044; ncases=34 422). Summary relative risk (RR) per 5-kg/m2 higher body mass index was 1.42 (95% CI, 1.40-1.42; 𝜁2=0.02, I2=94.4%), 1.28 (95% CI, 1.26-1.31; 𝜁2=0.01, I2=75.8%) per 10-cm higher waist circumference, and 1.33 (95% CI, 1.28-1.37; 𝜁2=0.04, I2=94.9%) per 0.1-unit higher waist-hip ratio. Pooled estimates of the few studies that reported on regional fat suggested significant positive association between HF risk and both visceral fat (RR, 1.08 [95% CI, 1.04-1.12]) and pericardial fat (RR, 1.08 [95% CI, 1.06-1.10]). Among HF subtypes, associations were stronger for HF with preserved ejection fraction than HF with reduced ejection fraction. No study reported on lean mass. Conclusions Pooled data suggested strong associations between adiposity and HF. The association with adiposity is stronger for HF with preserved ejection fraction than HF with reduced ejection fraction, indicating that different mechanisms may be at play in etiopathogenesis of HF subtypes. Future studies are needed to investigate role of regional fat mass and lean mass in HF risk. Registration Information REGISTRATION: URL: www.crd.york.ac.uk/prospero/. Unique identifier: CRD42020224584.

Hybrid immunity in older adults is associated with reduced SARS-CoV-2 infections following BNT162b2 COVID-19 immunisation.

BACKGROUND: Older adults, particularly in long-term care facilities (LTCF), remain at considerable risk from SARS-CoV-2. Data on the protective effect and mechanisms of hybrid immunity are skewed towards young adults precluding targeted vaccination strategies. METHODS: A single-centre longitudinal seroprevalence vaccine response study was conducted with 280 LCTF participants (median 82 yrs, IQR 76-88 yrs; 95.4% male). Screening by SARS-CoV-2 polymerase chain reaction with weekly asymptomatic/symptomatic testing (March 2020-October 2021) and serology pre-/post-two-dose Pfizer-BioNTech BNT162b2 vaccination for (i) anti-nucleocapsid, (ii) quantified anti-receptor binding domain (RBD) antibodies at three time-intervals, (iii) pseudovirus neutralisation, and (iv) inhibition by anti-RBD competitive ELISA were conducted. Neutralisation activity: antibody titre relationship was assessed via beta linear-log regression and RBD antibody-binding inhibition: post-vaccine infection relationship by Wilcoxon rank sum test. RESULTS: Here we show neutralising antibody titres are 9.2-fold (95% CI 5.8-14.5) higher associated with hybrid immunity (p < 0.00001); +7.5-fold (95% CI 4.6-12.1) with asymptomatic infection; +20.3-fold, 95% (CI 9.7-42.5) with symptomatic infection. A strong association is observed between antibody titre: neutralising activity (p < 0.00001) and rising anti-RBD antibody titre: RBD antibody-binding inhibition (p < 0.001), although 18/169 (10.7%) participants with high anti-RBD titre (>100BAU/ml), show inhibition <75%. Higher RBD antibody-binding inhibition values are associated with hybrid immunity and reduced likelihood of infection (p = 0.003). CONCLUSIONS: Hybrid immunity in older adults was associated with considerably higher antibody titres, neutralisation and inhibition capacity. Instances of high anti-RBD titre with lower inhibition suggests antibody quantity and quality as independent potential correlates of protection, highlighting added value of measuring inhibition over antibody titre alone to inform vaccine strategy.

Older adults continue to be at risk of COVID-19, particularly in residential care home settings. We investigated the effect of infection and vaccination on antibody development and subsequent SARS-CoV-2 infection in older adults. Antibodies are proteins that the immune system produces on infection or vaccination that can help respond to subsequent infection with SARS-CoV-2. We found that older adults produce antibodies to SARS-CoV-2 after 2-doses of Pfizer BioNTech BNT162b2 vaccine. The strongest immune responses were seen among those older adults who also had prior history of infection. The results highlight the importance of both antibody quality and quantity when considering possible indicators of protection against COVID-19 and supports the need for a third, booster, vaccination in this age group..

HLA-II immunopeptidome profiling and deep learning reveal features of antigenicity to inform antigen discovery.

CD4+ T cell responses are exquisitely antigen specific and directed toward peptide epitopes displayed by human leukocyte antigen class II (HLA-II) on antigen-presenting cells. Underrepresentation of diverse alleles in ligand databases and an incomplete understanding of factors affecting antigen presentation in vivo have limited progress in defining principles of peptide immunogenicity. Here, we employed monoallelic immunopeptidomics to identify 358,024 HLA-II binders, with a particular focus on HLA-DQ and HLA-DP. We uncovered peptide-binding patterns across a spectrum of binding affinities and enrichment of structural antigen features. These aspects underpinned the development of context-aware predictor of T cell antigens (CAPTAn), a deep learning model that predicts peptide antigens based on their affinity to HLA-II and full sequence of their source proteins. CAPTAn was instrumental in discovering prevalent T cell epitopes from bacteria in the human microbiome and a pan-variant epitope from SARS-CoV-2. Together CAPTAn and associated datasets present a resource for antigen discovery and the unraveling genetic associations of HLA alleles with immunopathologies.

Workflow enabling deepscale immunopeptidome, proteome, ubiquitylome, phosphoproteome, and acetylome analyses of sample-limited tissues.

Serial multi-omic analysis of proteome, phosphoproteome, and acetylome provides insights into changes in protein expression, cell signaling, cross-talk and epigenetic pathways involved in disease pathology and treatment. However, ubiquitylome and HLA peptidome data collection used to understand protein degradation and antigen presentation have not together been serialized, and instead require separate samples for parallel processing using distinct protocols. Here we present MONTE, a highly sensitive multi-omic native tissue enrichment workflow, that enables serial, deep-scale analysis of HLA-I and HLA-II immunopeptidome, ubiquitylome, proteome, phosphoproteome, and acetylome from the same tissue sample. We demonstrate that the depth of coverage and quantitative precision of each 'ome is not compromised by serialization, and the addition of HLA immunopeptidomics enables the identification of peptides derived from cancer/testis antigens and patient specific neoantigens. We evaluate the technical feasibility of the MONTE workflow using a small cohort of patient lung adenocarcinoma tumors.

Chemical Communication and Protocell-Matrix Dynamics in Segregated Colloidosome Micro-Colonies.

Despite an emerging catalogue of collective behaviours in communities of homogeneously distributed cell-like objects, microscale protocell colonies with spatially segregated populations have received minimal attention. Here, we use microfluidics to fabricate Janus-like calcium alginate hydrogel microspheres with spatially partitioned populations of enzyme-containing inorganic colloidosomes and investigate their potential as integrated platforms for domain-mediated chemical communication and programmable protocell-matrix dynamics. Diffusive chemical signalling within the segregated communities gives rise to increased initial enzyme kinetics compared with a homogeneous distribution of protocells. We employ competing enzyme-mediated hydrogel crosslinking and decrosslinking reactions in different domains of the partitioned colonies to undertake selective expulsion of a specific protocell population from the community. Our results offer new possibilities for the design and construction of spatially organized cytomimetic consortia capable of endogenous chemical processing and protocell-environment interactivity.

Independent Relevance of Different Measures of Adiposity for Carotid Intima-Media Thickness in 40 000 Adults in UK Biobank.

Background Uncertainty persists about carotid intima-media thickness (CIMT) as a marker of subclinical atherosclerosis and the independent relevance of different measures of adiposity for CIMT. We assessed the independent relevance of general adiposity (body mass index), central adiposity (waist circumference), and body composition (fat mass index and fat-free mass index) with CIMT among adults in the United Kingdom. Methods and Results Multivariable linear regression of cross-sectional analyses of UK Biobank assessed the mean percentage difference in CIMT associated with equivalent differences in adiposity measures. To assess independent associations, body mass index and waist circumference were mutually adjusted, as were fat mass index and fat-free mass index. Among 39 367 participants (mean [SD] age 64 [8] years, 52% female, 97% White), median (interquartile range) CIMT was 0.65 (0.14) mm in women and 0.69 (0.18) mm in men. All adiposity measures were linearly and positively associated with CIMT after adjusting for confounders. Fat-free mass index was most strongly associated with CIMT after adjustment for fat mass index (% difference in CIMT: 1.23 [95% CI 0.93-1.53] women; 3.44 [3.01-3.86] men), while associations of fat mass index were attenuated after adjustment for fat-free mass index (0.28 [-0.02, 0.58] women; -0.59 [-0.99, -0.18] men). After mutual adjustment, body mass index remained positively associated with CIMT, but waist circumference was completely attenuated. Conclusions Fat-free mass index was the adiposity measure most strongly associated with CIMT, suggesting that CIMT may reflect vascular compensatory remodeling rather than atherosclerosis. Hence, screening for subclinical atherosclerosis should evaluate carotid plaques in addition to CIMT.

Enablers and barriers to workplace breastfeeding in the Armed Forces: a systematic review.

INTRODUCTION: The UK has no legislation protecting employees' access to breastfeeding facilities. Without specific breastfeeding policy, provisions to access workplace facilities can be inconsistent and negatively impact employees' breastfeeding duration, retention and morale, particularly servicewomen who work in varied and demanding military environments. This is an important policy area for the British Army to retain talented and trained soldiers. METHODS: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement principles, PubMed, Embase, CINAHL and Pro-Quest Databases were searched for studies relevant to accessing appropriate breastfeeding facilities in UK workplaces and high-income countries' Armed Forces. Factors acting as barriers and enablers to accessing facilities were identified. UK government and Armed Forces' websites were searched for grey literature on existing policies and guidance for accessing facilities. RESULTS: Barriers and enablers to access from 16 studies were described by three thematic areas: attitudes to breastfeeding, facility provisions and use of facilities. Factors which employers could influence included specific breastfeeding policy, universal workplace education, existence of suitable facilities and individualised breastfeeding plans. The key areas for policy development identified were clearly defined responsibilities; individualised risk assessments and breastfeeding plans; appropriate, but flexible, facility provision and access; signposting of relevant workplace accommodations; and physical fitness provisions. CONCLUSIONS: Five recommendations are presented: development, implementation and evaluation of breastfeeding policy; universal workplace breastfeeding education; the need for breastfeeding risk assessments and plans based on individual breastfeeding practice; written minimal and ideal standards for breastfeeding facilities and access, which considers workplace locations; and exceptions from deployment and physical fitness testing.

A Micro-Longitudinal Study of Naps, Sleep Disturbance, and Headache Severity in Women with Chronic Migraine.

OBJECTIVE: To examine the relationship between headaches, naps, and nocturnal sleep in women with chronic migraine (CM) using micro-longitudinal data from diaries and actigraphy. METHODS: 20 women with CM and 20 age and sex-matched healthy controls (HC) completed self-report questionnaires, electronic diaries, and wrist actigraphy over a 4-week period. Between-group comparisons were conducted with naps (frequency and duration) as the primary variable of interest. Within-group analyses were conducted on the CM group using hierarchical linear mixed models to examine the temporal relationships between headache severity, sleep behaviors, and sleep parameters. The primary variables of interest were naps (number and duration) and nocturnal sleep efficiency (diary and actigraphy). RESULTS: The CM group reported significantly more days with naps (25.85%) compared to the HC group (9.03%) during the study period (p = .0025). Within-group analyses in CM revealed that greater headache severity was associated with longer nap duration (p = .0037) and longer nap duration was associated with lower sleep efficiency measured using diaries (p = .0014) and actigraphy (p < .0001). CONCLUSIONS: Napping is more frequent in CM than HC and nap duration in CM is associated with headache severity and nocturnal sleep disturbance. These findings provide initial support for the hypothesis that daytime napping is a behavioral coping strategy used in CM that could contribute to insomnia.