Risk Assessment and Prevention of Falls in Older Community-Dwelling Adults: A Review.

Importance: Falls are reported by more than 14 million US adults aged 65 years or older annually and can result in substantial morbidity, mortality, and health care expenditures. Observations: Falls result from age-related physiologic changes compounded by multiple intrinsic and extrinsic risk factors. Major modifiable risk factors among community-dwelling older adults include gait and balance disorders, orthostatic hypotension, sensory impairment, medications, and environmental hazards. Guidelines recommend that individuals who report a fall in the prior year, have concerns about falling, or have gait speed less than 0.8 to 1 m/s should receive fall prevention interventions. In a meta-analysis of 59 randomized clinical trials (RCTs) in average-risk to high-risk populations, exercise interventions to reduce falls were associated with 655 falls per 1000 patient-years in intervention groups vs 850 falls per 1000 patient-years in nonexercise control groups (rate ratio [RR] for falls, 0.77; 95% CI, 0.71-0.83; risk ratio for number of people who fall, 0.85; 95% CI, 0.81-0.89; risk difference, 7.2%; 95% CI, 5.2%-9.1%), with most trials assessing balance and functional exercises. In a meta-analysis of 43 RCTs of interventions that systematically assessed and addressed multiple risk factors among individuals at high risk, multifactorial interventions were associated with 1784 falls per 1000 patient-years in intervention groups vs 2317 falls per 1000 patient-years in control groups (RR, 0.77; 95% CI, 0.67-0.87) without a significant difference in the number of individuals who fell. Other interventions associated with decreased falls in meta-analysis of RCTs and quasi-randomized trials include surgery to remove cataracts (8 studies with 1834 patients; risk ratio [RR], 0.68; 95% CI, 0.48-0.96), multicomponent podiatry interventions (3 studies with 1358 patients; RR, 0.77; 95% CI, 0.61-0.99), and environmental modifications for individuals at high risk (12 studies with 5293 patients; RR, 0.74; 95% CI, 0.61-0.91). Meta-analysis of RCTs of programs to stop medications associated with falls have not found a significant reduction, although deprescribing is a component of many successful multifactorial interventions. Conclusions and Relevance: More than 25% of older adults fall each year, and falls are the leading cause of injury-related death in persons aged 65 years or older. Functional exercises to improve leg strength and balance are recommended for fall prevention in average-risk to high-risk populations. Multifactorial risk reduction based on a systematic clinical assessment for modifiable risk factors may reduce fall rates among those at high risk.

Postprandial lipid and vascular responses following consumption of a commercially-relevant interesterified palmitic acid-rich spread in comparison to functionally-equivalent non-interesterified spread and spreadable butter: a randomised controlled trial in healthy adults.

Background: Interesterification is an industrial processing technique used widely where hard fats are essential for functionality and consumer acceptability, e.g. margarines and lower fat spreads. Objective: The aim of this study was to compare acute cardiovascular effects of functionally equivalent spreads (similar solid fat content) made with interesterified (IE) or non-IE palm-based fats, or spreadable butter. Methods: A randomised, controlled, 4-armed crossover, double-blind study (25 men, 25 women; 35-75 years; healthy; mean BMI 24.5, SD 3.8), compared effects of mixed nutrient meals containing 50 g fat from functionally equivalent products [IE spread, non-IE spread and spreadable butter (SB), with rapeseed oil (RO) as a reference treatment: with 16.7%, 27.9%, 19.3% and 4% palmitic acid, respectively] on 8 h postprandial changes in plasma triacylglycerol (TAG) and endothelial dysfunction (flow-mediated dilatation; FMD). Circulating reactive oxygen species (estimated using a neutrophil oxidative burst assay), glucose, insulin, NEFA, lipoprotein particle profiles, inflammatory markers (glycoprotein acetylation (Glyc-A) and IL-6), and biomarkers of endotoxemia were measured. Results: Postprandial plasma TAG concentrations after test meals were similar. However following RO versus the 3 spreads, there were significantly higher postprandial apolipoprotein B concentrations, and small HDL and LDL particle concentrations, and lower postprandial extra-large, large, and medium HDL particle concentrations, as well as smaller average HDL and LDL particle sizes. There were no differences following IE compared to the other spreads. Postprandial FMD% did not decrease after high-fat test meals, and there were no differences between treatments. Postprandial serum IL-6 increased similarly after test meals, but RO provoked a greater increase in postprandial concentrations of glycoprotein acetyls (GlycA), as well as 8 h sCD14, an endotoxemia marker. All other postprandial outcomes were not different between treatments. Conclusions: In healthy adults, a commercially-available IE-based spread did not evoke a different postprandial triacylglycerol, lipoprotein subclass, oxidative stress, inflammatory or endotoxemic response to functionally-equivalent, but compositionally-distinct alternative spreads. Clinical trial registry number: NCT03438084 (https://ClinicalTrials.gov).

New insights in the mechanisms of weight-loss maintenance: Summary from a Pennington symposium.

Obesity is a chronic disease that affects more than 650 million adults worldwide. Obesity not only is a significant health concern on its own, but predisposes to cardiometabolic comorbidities, including coronary heart disease, dyslipidemia, hypertension, type 2 diabetes, and some cancers. Lifestyle interventions effectively promote weight loss of 5% to 10%, and pharmacological and surgical interventions even more, with some novel approved drugs inducing up to an average of 25% weight loss. Yet, maintaining weight loss over the long-term remains extremely challenging, and subsequent weight gain is typical. The mechanisms underlying weight regain remain to be fully elucidated. The purpose of this Pennington Biomedical Scientific Symposium was to review and highlight the complex interplay between the physiological, behavioral, and environmental systems controlling energy intake and expenditure. Each of these contributions were further discussed in the context of weight-loss maintenance, and systems-level viewpoints were highlighted to interpret gaps in current approaches. The invited speakers built upon the science of obesity and weight loss to collectively propose future research directions that will aid in revealing the complicated mechanisms involved in the weight-reduced state.

The secondary bile acid isoursodeoxycholate correlates with post-prandial lipemia, inflammation, and appetite and changes post-bariatric surgery.

Primary and secondary bile acids (BAs) influence metabolism and inflammation, and the gut microbiome modulates levels of BAs. We systematically explore the host genetic, gut microbial, and habitual dietary contribution to a panel of 19 serum and 15 stool BAs in two population-based cohorts (TwinsUK, n = 2,382; ZOE PREDICT-1, n = 327) and assess changes post-bariatric surgery and after nutritional interventions. We report that BAs have a moderately heritable genetic component, and the gut microbiome accurately predicts their levels in serum and stool. The secondary BA isoursodeoxycholate (isoUDCA) can be explained mostly by gut microbes (area under the receiver operating characteristic curve [AUC] = ∼80%) and associates with post-prandial lipemia and inflammation (GlycA). Furthermore, circulating isoUDCA decreases significantly 1 year after bariatric surgery (ß = -0.72, p = 1 × 10-5) and in response to fiber supplementation (ß = -0.37, p < 0.03) but not omega-3 supplementation. In healthy individuals, isoUDCA fasting levels correlate with pre-meal appetite (p < 1 × 10-4). Our findings indicate an important role for isoUDCA in lipid metabolism, appetite, and, potentially, cardiometabolic risk.

How people wake up is associated with previous night's sleep together with physical activity and food intake.

How people wake up and regain alertness in the hours after sleep is related to how they are sleeping, eating, and exercising. Here, in a prospective longitudinal study of 833 twins and genetically unrelated adults, we demonstrate that how effectively an individual awakens in the hours following sleep is not associated with their genetics, but instead, four independent factors: sleep quantity/quality the night before, physical activity the day prior, a breakfast rich in carbohydrate, and a lower blood glucose response following breakfast. Furthermore, an individual's set-point of daily alertness is related to the quality of their sleep, their positive emotional state, and their age. Together, these findings reveal a set of non-genetic (i.e., not fixed) factors associated with daily alertness that are modifiable.

Menopause is associated with postprandial metabolism, metabolic health and lifestyle: The ZOE PREDICT study.

BACKGROUND: The menopause transition is associated with unfavourable alterations in health. However, postprandial metabolic changes and their mediating factors are poorly understood. METHODS: The PREDICT 1 UK cohort (n=1002; pre- n=366, peri- n=55, and post-menopausal females n=206) assessed phenotypic characteristics, anthropometric, diet and gut microbiome data, and fasting and postprandial (0-6 h) cardiometabolic blood measurements, including continuous glucose monitoring (CGM) data. Differences between menopausal groups were assessed in the cohort and in an age-matched subgroup, adjusting for age, BMI, menopausal hormone therapy (MHT) use, and smoking status. FINDINGS: Post-menopausal females had higher fasting blood measures (glucose, HbA1c and inflammation (GlycA), 6%, 5% and 4% respectively), sugar intakes (12%) and poorer sleep (12%) compared with pre-menopausal females (p<0.05 for all). Postprandial metabolic responses for glucose2hiauc and insulin2hiauc were higher (42% and 4% respectively) and CGM measures (glycaemic variability and time in range) were unfavourable post- versus pre-menopause (p<0.05 for all). In age-matched subgroups (n=150), postprandial glucose responses remained higher post-menopause (peak0-2h 4%). MHT was associated with favourable visceral fat, fasting (glucose and insulin) and postprandial (triglyceride6hiauc) measures. Mediation analysis showed that associations between menopause and metabolic health indicators (visceral fat, GlycA360mins and glycaemia (peak0-2h)) were in part mediated by diet and gut bacterial species. INTERPRETATION: Findings from this large scale, in-depth nutrition metabolic study of menopause, support the importance of monitoring risk factors for type-2 diabetes and cardiovascular disease in mid-life to older women to reduce morbidity and mortality associated with oestrogen decline. FUNDING: Zoe Ltd.

The impact of almonds and almond processing on gastrointestinal physiology, luminal microbiology, and gastrointestinal symptoms: a randomized controlled trial and mastication study.

BACKGROUND: Almonds contain lipid, fiber, and polyphenols and possess physicochemical properties that affect nutrient bioaccessibility, which are hypothesized to affect gut physiology and microbiota. OBJECTIVES: To investigate the impact of whole almonds and ground almonds (almond flour) on fecal bifidobacteria (primary outcome), gut microbiota composition, and gut transit time. METHODS: Healthy adults (n = 87) participated in a parallel, 3-arm randomized controlled trial. Participants received whole almonds (56 g/d), ground almonds (56 g/d), or an isocaloric control in place of habitual snacks for 4 wk. Gut microbiota composition and diversity (16S rRNA gene sequencing), SCFAs (GC), volatile organic compounds (GC-MS), gut transit time (wireless motility capsule), stool output and gut symptoms (7-d diary) were measured at baseline and endpoint. The impact of almond form on particle size distribution (PSD) and predicted lipid release was measured (n = 31). RESULTS: Modified intention-to-treat analysis was performed on 79 participants. There were no significant differences in mean ± SD abundance of fecal bifidobacteria after consumption of whole almonds (8.7% ± 7.7%), ground almonds (7.8% ± 6.9%), or control (13.0% ± 10.2%; q = 0.613). Consumption of almonds (whole and ground pooled) resulted in higher mean ± SD butyrate (24.1 ± 15.0 µmol/g) than control (18.2 ± 9.1 µmol/g; P = 0.046). There was no effect of almonds on gut microbiota at the phylum level or diversity, gut transit time, stool consistency, or gut symptoms. Almond form (whole compared with ground) had no effect on study outcomes. Ground almonds resulted in significantly smaller PSD and higher mean ± SD predicted lipid release (10.4% ± 1.8%) than whole almonds (9.3% ± 2.0%; P = 0.017). CONCLUSIONS: Almond consumption has limited impact on microbiota composition but increases butyrate in adults, suggesting positive alterations to microbiota functionality. Almonds can be incorporated into the diet to increase fiber consumption without gut symptoms.This trial was registered at clinicaltrials.gov as NCT03581812.

Screening for phenotypic outliers identifies an unusually low concentration of a ß-lactoglobulin B protein isoform in bovine milk caused by a synonymous SNP.

BACKGROUND: Milk samples from 10,641 dairy cattle were screened by a mass spectrometry method for extreme concentrations of the A or B isoforms of the whey protein, ß-lactoglobulin (BLG), to identify causative genetic variation driving changes in BLG concentration. RESULTS: A cohort of cows, from a single sire family, was identified that produced milk containing a low concentration of the BLG B protein isoform. A genome-wide association study (GWAS) of BLG B protein isoform concentration in milk from AB heterozygous cows, detected a group of highly significant single nucleotide polymorphisms (SNPs) within or close to the BLG gene. Among these was a synonymous G/A variation at position + 78 bp in exon 1 of the BLG gene (chr11:103256256G > A). The effect of the A allele of this SNP (which we named B') on BLG expression was evaluated in a luciferase reporter assay in transfected CHO-K1 and MCF-7 cells. In both cell types, the presence of the B' allele in a plasmid containing the bovine BLG gene from -922 to + 898 bp (relative to the transcription initiation site) resulted in a 60% relative reduction in mRNA expression, compared to the plasmid containing the wild-type B sequence allele. Examination of a mammary RNAseq dataset (n = 391) identified 14 heterozygous carriers of the B' allele which were homozygous for the BLG B protein isoform (BB'). The level of expression of the BLG B' allele was 41.9 ± 1.0% of that of the wild-type BLG B allele. Milk samples from three cows, homozygous for the A allele at chr11:103,256,256 (B'B'), were analysed (HPLC) and showed BLG concentrations of 1.04, 1.26 and 1.83 g/L relative to a mean of 4.84 g/L in milk from 16 herd contemporaries of mixed (A and B) BLG genotypes. The mechanism by which B' downregulates milk BLG concentration remains to be determined. CONCLUSIONS: High-throughput screening and identification of outliers, enabled the discovery of a synonymous G > A mutation in exon 1 of the B allele of the BLG gene (B'), which reduced the milk concentration of ß-lactoglobulin B protein isoform, by more than 50%. Milk from cows carrying the B' allele is expected to have improved processing characteristics, particularly for cheese-making.

Influence of information provided prior to switching from Humira to biosimilar adalimumab on UK patients' satisfaction: a cross-sectional survey by patient organisations.

OBJECTIVES: To investigate the perceptions and experiences of people with specific immune-mediated inflammatory diseases during the process of switching from Humira to biosimilar adalimumab. DESIGN: Cross-sectional survey. SETTING: An anonymised, self-administered, web-based survey. PARTICIPANTS: The participants were drawn from members and non-members of either the National Rheumatoid Arthritis Society, the National Axial Spondyloarthritis Society, Crohn's and Colitis UK, or Psoriasis Association. Birdshot Uveitis Society and Olivia's Vision also signposted to the survey links. RESULTS: A total of 899 people living with various immune mediated inflammatory diseases participated in this survey. Thirty-four per cent of respondents reported poor overall satisfaction with their biosimilar adalimumab after the switch, associated with complaints related to the switching process including lack of shared decision making, scarcity of information provided by or signposted to by the department instigating the switch as well as lack of training with the new injection device. Where training with the new device had been provided, there were significantly reduced reports of pain when injecting the new biosimilar (OR 0.20, 95% CI 0.07 to 0.55), side effects (OR 0.17, 95% CI 0.06 to 0.47) and difficulty in using the new injection device (OR 0.25, 95% CI 0.15 to 0.41). Self-reported side effects were reduced by (OR 0.13, 95% CI 0.05 to 0.38) when written information was provided by healthcare professionals and by (OR 0.15, 95% CI 0.05 to 0.42) with provision of verbal information. Difficulty in using the new injection device was also reduced by provision of satisfactory information such as written documents (OR 0.38, 95% CI 0.23 to 0.63) or by verbal communication with healthcare professionals (OR 0.45, 95% CI 0.27 to 0.73). Finally, provision of satisfactory written or verbal information was associated with a reduction in any negative perception regarding symptom control with the new biosimilar by (OR 0.05, 95% CI 0.004 to 0.57) and by (OR 0.15, 95% CI 0.03 to 0.84), respectively. CONCLUSIONS: Patient reported experiences of the process of switching from originator to biosimilar emphasise the importance of clear communication, training and information in order to optimise perception and maximise achievable outcomes with the new treatment.

Improving shared decision-making for osteoporosis pharmacologic therapy in nursing homes: a qualitative analysis.

Decisions on whether to use pharmacologic osteoporosis therapy in skilled nursing facility residents are complex and require shared decision-making. Residents, proxies, and staff desire individualized fracture risk estimates that consider advanced age, dementia, and mobility. They want options for reducing administration burden, monitoring instructions, and periodic reassessment of risk vs. benefit. PURPOSE: Decisions about pharmacologic osteoporosis treatment in nursing home (NH) residents with advanced age and multimorbidity are complex and should occur using shared decision-making. Our objective was to identify processes and tools to improve shared decision-making about pharmacologic osteoporosis treatment in NHs. METHODS: Qualitative analysis of data collected in three NHs from residents at high fracture risk, their proxies, nursing assistants, nurses, and one nurse practitioner (n = 28). Interviews explored participants' stories, attitudes, and experiences with oral osteoporosis medication management. Framework analysis was used to identify barriers to shared decision-making regarding osteoporosis treatment in this setting. RESULTS: Participants wanted individualized fracture risk estimates that consider immobility, advanced age, and comorbid dementia. Residents and proxies expected nursing staff to be involved in the decision-making; nursing staff wished to be informed on the relative risks vs. benefits of medications and given monitoring instructions. Two important competing demands to address during the shared decision-making process were burdensome administration requirements and polypharmacy. Participants wanted to reassess pharmacologic treatment appropriateness over time as clinical status or goals of care change. CONCLUSIONS: Shared decision-making using strategies and tools identified in this analysis may move osteoporosis pharmacologic treatment in NHs and for other older adults with multimorbidity from inappropriate inertia to appropriate prescribing or appropriate inaction.

Epigenetic Age Acceleration and Change in Frailty in MOBILIZE Boston.

Age-associated changes in DNA methylation have been implicated as 1 mechanism to explain the development of frailty; however, previous cross-sectional studies of epigenetic age acceleration (eAA) and frailty have had inconsistent findings. Few longitudinal studies have considered the association of eAA with change in frailty. We sought to determine the association between eAA and change in frailty in the MOBILIZE Boston cohort. Participants were assessed at 2 visits 12-18 months apart. Intrinsic, extrinsic, GrimAge, and PhenoAge eAA were assessed from whole-blood DNA methylation at baseline using the Infinium 450k array. Frailty was assessed by a continuous frailty score based on the frailty phenotype and by frailty index (FI). Analysis was by correlation and linear regression with adjustment for age, sex, smoking status, and body mass index. Three hundred and ninety-five participants with a frailty score and 431 with an FI had epigenetic and follow-up frailty measures. Mean (standard deviation) ages were 77.8 (5.49) and 77.9 (5.47) for the frailty score and the FI cohorts respectively, and 232 (58.7%) and 257 (59.6%) were female. All participants with epigenetic data identified as White. Baseline frailty score was not correlated with intrinsic or extrinsic eAA, but was correlated with PhenoAge and, even after adjustment for covariates, GrimAge. Baseline FI was correlated with extrinsic, GrimAge, and PhenoAge eAA with and without adjustment. No eAA measure was associated with change in frailty, with or without adjustment. Our results suggest that no eAA measure was associated with change in frailty. Further studies should consider longer periods of follow-up and repeated eAA measurement.

The relationship between diet and sleep in 2-y-old children: Results from Growing Up in New Zealand.

OBJECTIVES: This study aimed to examine the relationship between dietary practices and sleep in young children. METHODS: In this study, 2-y-old children (n = 6327) and their mothers were enrolled at birth and during pregnancy, respectively. The study obtained maternal demographic, health, and lifestyle data during late pregnancy. Parents reported the 2-y-old child's dietary practices on a food frequency questionnaire, as well as sleep duration and night-waking frequency. Measures of dietary intake quantified servings per day for each food group (grouped as low/moderate/high intake). Sleep measures were as inadequate sleep when <11 h sleep in a 24-h period and increased night waking when waking ≥2 times per night. Multivariable logistic regression analyses examined associations between toddler diet and sleep, which were described using adjusted odds ratios (ORs) and 95% confidence intervals. RESULTS: In this study, 2-y-old children (n = 6288) slept for a mean of 12.3 hours (standard deviation: ±1.5 hours) over a 24-h period, with 734 children (12%) getting <11 h of sleep in 24 h. Increased night waking occurred in 1063 children (17%). Compared with low intake, high soft drink/snack/fast food intake was associated with inadequate sleep (OR: 1.37) and increased night waking (OR: 1.34). High milk/cheese/yoghurt intake (OR: 1.55) was associated with increased odds of night waking, but moderate (OR: 0.81) or high (OR: 0.78) vegetable intake was associated with decreased odds of night waking. Exposure to screens (OR: 1.28) and heavy maternal cigarette smoking (OR: 2.20) were also associated with inadequate sleep and increased night waking, respectively. CONCLUSIONS: At age 2 y, higher consumption of soft drinks/snacks/fast foods is associated with shorter, more disrupted sleep. Conversely, higher vegetable consumption is associated with less disrupted sleep. Dietary modifications may improve toddlers' sleep.

Discontinuation of beta-blockers among nursing home residents at end of life.

BACKGROUND: Given limited life expectancy of nursing home (NH) residents, harms of continuing beta-blockers (BBs) may outweigh clinical benefits. Our objective was to describe beta-blocker discontinuation for NH residents during the last year of life, and identify characteristics associated with earlier discontinuation. METHODS: This was a retrospective cohort study that included all long-stay residents in fee-for-service Medicare who died in 2016 and were prescribed oral BBs 1 year before death. Beta-blocker discontinuation was defined as a gap in medication on hand for ≥45 days per Medicare Part D claims, measured from the last date drug was on hand. Comorbidities were obtained from Chronic Condition Warehouse, and other characteristics from the Minimum Data Set. Kaplan-Meier curves were used to describe time to first discontinuation. Findings were stratified by cardiac diagnoses, perceived life expectancy of <6 months, or elevated mortality index. RESULTS: Eighty-eight thousand two hundred and eighty-four residents were prescribed ≥1 daily BB 12 months before death. Mean age was 84.1 years and 69.2% were female. Of these, 60,573 residents (68.6%) remained on a BB in the last 45 days of life, and 57,880 residents (65.6%) had ≥1 cardiac diagnosis. Only 5239 residents (5.9%) had elevated mortality index, whereas 16,798 residents (19.0%) had perceived poor prognosis. In the last year of life, there was no difference in beta-blocker discontinuation pattern between residents with and without cardiac diagnoses. Residents with perceived poor prognosis and elevated mortality index discontinued BBs earlier. For example, mean time until discontinuation among residents with poor perceived prognosis was 245 versus 279 days in residents without such prognosis (p < 0.0001). CONCLUSIONS: BBs are commonly prescribed to NH residents in the final year of life. Overall, discontinuation occurs earlier in residents for whom clinicians perceive limited life expectancy, suggesting that improved prognostication may offer an important opportunity to reduce polypharmacy toward end of life.

Risk factors for injuries in New Zealand older adults with complex needs: a national population retrospective study.

BACKGROUND: Falls and falls-related injuries are common among older adults. Injuries in older adults lead to poor outcomes and lower quality of life. The objective of our study was to identify factors associated with fall-related injuries among home care clients in New Zealand. METHODS: The study cohort consisted of 75,484 community-dwelling people aged 65 years or older who underwent an interRAI home care assessment between June 2012 and June 2018 in New Zealand. The injuries included for analysis were fracture of the distal radius, hip fracture, pelvic fracture, proximal humerus fracture, subarachnoid haemorrhage, traumatic subdural haematoma, and vertebral fracture. Unadjusted and adjusted competing risk regression models were used to identify factors associated with fall-related injuries. RESULTS: A total of 7414 (9.8%) people sustained a falls-related injury over the 6-year period, and most injuries sustained were hip fractures (4735 63.9%). The rate of injurious falls was 47 per 1000 person-years. The factors associated with injury were female sex, older age, living alone, Parkinson's disease, stroke/CVA, falls, unsteady gait, tobacco use, and being underweight. Cancer, dyspnoea, high BMI, and a decrease in the amount of food or fluid usually consumed, were associated with a reduced risk of sustaining an injury. After censoring hip fractures the risks associated with other types of injury were sex, age, previous falls, dyspnoea, tobacco use, and BMI. CONCLUSIONS: While it is important to reduce the risk of falls, it is especially important to reduce the risk of falls-related injuries. Knowledge of risk factors associated with these types of injuries can help to develop focused intervention programmes and development of a predictive model to identify those who would benefit from intervention programmes.

PCSK9 Activity Is Potentiated Through HDL Binding.

Rationale: Proprotein convertase subtilisin/kexin type 9 (PCSK9) circulates in a free and lipoprotein-bound form, yet the functional consequence of the association between PCSK9 and high-density lipoprotein (HDL) remains unexplored. Objective: This study sought to interrogate the novel relationship between PCSK9 and HDL in humans. Methods and Results: Comparing lipoprotein and apolipoprotein profiles by nuclear magnetic resonance and targeted mass spectrometry measurements with PCSK9 levels in the community-based Bruneck (n=656) study revealed a positive association of plasma PCSK9 with small HDL, alongside a highly significant positive correlation between plasma levels of PCSK9 and apolipoprotein-C3, an inhibitor of lipoprotein lipase. The latter association was replicated in an independent cohort, the SAPHIR study (n=270). Thus, PCSK9-HDL association was determined during the postprandial response in two dietary studies (n=20 participants each, 8 times points). Peak triglyceride levels coincided with an attenuation of the PCSK9-HDL association, a loss of apolipoprotein-C3 from HDL and lower levels of small HDL as measured by nuclear magnetic resonance. Crosslinking mass spectrometry (XLMS) upon isolated HDL identified PCSK9 as a potential HDL-binding partner. PCSK9 association with HDL was confirmed through size-exclusion chromatography and immuno-isolation. Quantitative proteomics upon HDL isolated from patients with coronary artery disease (n=172) returned PCSK9 as a core member of the HDL proteome. Combined interrogation of the HDL proteome and lipidome revealed a distinct cluster of PCSK9, phospholipid transfer protein, clusterin and apolipoprotein-E within the HDL proteome, that was altered by sex and positively correlated with sphingomyelin content. Mechanistically, HDL facilitated PCSK9-mediated low-density lipoprotein receptor degradation and reduced low-density lipoprotein uptake through the modulation of PCSK9 internalisation and multimerisation. Conclusions: This study reports HDL as a binder of PCSK9 and regulator of its function. The combination of -omic technologies revealed postprandial lipaemia as a driver of PCSK9 and apolipoprotein-C3 release from HDL.

Palmitic acid-rich oils with and without interesterification lower postprandial lipemia and increase atherogenic lipoproteins compared with a MUFA-rich oil: A randomized controlled trial.

BACKGROUND: Interesterified (IE) fats are widely used in place of trans fats; however, little is known about their metabolism. OBJECTIVES: To test the impact of a commonly consumed IE compared with a non-IE equivalent fat on in vivo postprandial and in vitro lipid metabolism, compared with a reference oil [rapeseed oil (RO)]. METHODS: A double-blinded, 3-phase crossover, randomized controlled trial was performed in healthy adults (n = 20) aged 45-75 y. Postprandial plasma triacylglycerol and lipoprotein responses (including stable isotope tracing) to a test meal (50 g fat) were evaluated over 8 h. The test fats were IE 80:20 palm stearin/palm kernel fat, an identical non-IE fat, and RO (control). In vitro, mechanisms of digestion were explored using a dynamic gastric model (DGM). RESULTS: Plasma triacylglycerol 8-h incremental area under the curves were lower following non-IE compared with RO [-1.7 mmol/L⋅h (95% CI: -3.3, -0.0)], but there were no differences between IE and RO or IE and non-IE. LDL particles were smaller following IE and non-IE compared with RO (P = 0.005). Extra extra large, extra large, and large VLDL particle concentrations were higher following IE and non-IE compared with RO at 6-8 h (P < 0.05). No differences in the appearance of [13C]palmitic acid in plasma triacylglycerol were observed between IE and non-IE fats. DGM revealed differences in phase separation of the IE and non-IE meals and delayed release of SFAs compared with RO. CONCLUSIONS: Interesterification did not modify fat digestion, postprandial lipemia, or lipid metabolism measured by stable isotope and DGM analysis. Despite the lower lipemia following the SFA-rich fats, increased proatherogenic large triacylglycerol-rich lipoprotein remnant and small LDL particles following the SFA-rich fats relative to RO adds a new postprandial dimension to the mechanistic evidence linking SFAs to cardiovascular disease risk.

High intake of vegetables is linked to lower white blood cell profile and the effect is mediated by the gut microbiome.

BACKGROUND: Chronic inflammation, which can be modulated by diet, is linked to high white blood cell counts and correlates with higher cardiometabolic risk and risk of more severe infections, as in the case of COVID-19. METHODS: Here, we assessed the association between white blood cell profile (lymphocytes, basophils, eosinophils, neutrophils, monocytes and total white blood cells) as markers of chronic inflammation, habitual diet and gut microbiome composition (determined by sequencing of the 16S RNA) in 986 healthy individuals from the PREDICT-1 nutritional intervention study. We then investigated whether the gut microbiome mediates part of the benefits of vegetable intake on lymphocyte counts. RESULTS: Higher levels of white blood cells, lymphocytes and basophils were all significantly correlated with lower habitual intake of vegetables, with vegetable intake explaining between 3.59 and 6.58% of variation in white blood cells after adjusting for covariates and multiple testing using false discovery rate (q < 0.1). No such association was seen with fruit intake. A mediation analysis found that 20.00% of the effect of vegetable intake on lymphocyte counts was mediated by one bacterial genus, Collinsella, known to increase with the intake of processed foods and previously associated with fatty liver disease. We further correlated white blood cells to other inflammatory markers including IL6 and GlycA, fasting and post-prandial glucose levels and found a significant relationship between inflammation and diet. CONCLUSION: A habitual diet high in vegetables, but not fruits, is linked to a lower inflammatory profile for white blood cells, and a fifth of the effect is mediated by the genus Collinsella. TRIAL REGISTRATION: The ClinicalTrials.gov registration identifier is NCT03479866 .

Whole almond consumption is associated with better diet quality and cardiovascular disease risk factors in the UK adult population: National Diet and Nutrition Survey (NDNS) 2008-2017.

PURPOSE:  This work aimed to estimate whole almond consumption in a nationally representative UK survey population and examine associations with diet quality and cardiovascular disease (CVD) risk. METHODS:  Four-day food record data from the National Diet and Nutrition Survey (NDNS) 2008-2017 (n = 6802, age ≥ 19 year) were analyzed to investigate associations between whole almond consumption and diet quality, measured by the modified Mediterranean Diet Score (MDS) and modified Healthy Diet Score (HDS), and CVD risk markers, using survey-adjusted multivariable linear regression. RESULTS:  Whole almond consumption was reported in 7.6% of the population. Median intake in whole almond consumers was 5.0 g/day (IQR 9.3). Consumers had higher diet quality scores relative to non-consumers; higher intakes of protein, total fat, monounsaturated, n-3 and n-6 polyunsaturated fats, fiber, folate, vitamin C, vitamin E, potassium, magnesium, phosphorus, and iron; and lower intakes of trans-fatty acids, total carbohydrate, sugar, and sodium. BMI and WC were lower in whole almond consumers compared to non-consumers: 25.5 kg/m2 (95% CI 24.9, 26.2) vs 26.3 kg/m2 (25.9, 26.7), and 88.0 cm (86.2, 89.8) vs 90.1 cm (89.1, 91.2), respectively. However, there were no dose-related fully adjusted significant associations between increasing almond intake (g per 1000 kcal energy intake) and lower CVD risk markers. CONCLUSIONS:  Almond intake is low in the UK population, but consumption was associated with better dietary quality and lower CVD risk factors. Habitual consumption of whole almonds should be encouraged as part of a healthy diet.

Nuts and their Effect on Gut Microbiota, Gut Function and Symptoms in Adults: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

Nuts contain fibre, unsaturated fatty acids and polyphenols that may impact the composition of the gut microbiota and overall gut health. This study aimed to assess the impact of nuts on gut microbiota, gut function and gut symptoms via a systematic review and meta-analysis of randomised controlled trials (RCTs) in healthy adults. Eligible RCTs were identified by systematic searches of five electronic databases, hand searching of conference abstracts, clinical trials databases, back-searching reference lists and contact with key stakeholders. Eligible studies were RCTs administering tree nuts or peanuts in comparison to control, measuring any outcome related to faecal microbiota, function or symptoms. Two reviewers independently screened papers, performed data extraction and risk of bias assessment. Outcome data were synthesised as weighted mean difference (WMD) or standardised mean difference (SMD) using a random effects model. This review was registered on PROSPERO (CRD42019138169). Eight studies reporting nine RCTs were included, investigating almonds (n = 5), walnuts (n = 3) and pistachios (n = 1). Nut consumption significantly increased Clostridium (SMD: 0.40; 95% CI, 0.10, 0.71; p = 0.01), Dialister (SMD: 0.44; 95% CI, 0.13, 0.75; p = 0.005), Lachnospira (SMD: 0.33; 95% CI, 0.02, 0.64; p = 0.03) and Roseburia (SMD: 0.36; 95% CI, 0.10, 0.62; p = 0.006), and significantly decreased Parabacteroides (SMD: -0.31; 95% CI, -0.62, -0.00; p = 0.05). There was no effect of nuts on bacterial phyla, diversity or stool output. Further parallel design RCTs, powered to detect changes in faecal microbiota and incorporating functional and clinical outcomes, are needed.

Tree nut snack consumption is associated with better diet quality and CVD risk in the UK adult population: National Diet and Nutrition Survey (NDNS) 2008-2014.

OBJECTIVES: To examine associations of tree nut snack (TNS) consumption with diet quality and cardiovascular disease (CVD) risk in UK adults from National Diet and Nutrition Survey (NDNS) 2008-2014. DESIGN: Cross-sectional analysis using data from 4-d food diaries, blood samples and physical measurements for CVD risk markers. To estimate diet quality, modified Mediterranean Diet Score (MDS) and modified Healthy Diet Score (HDS) were applied. Associations of TNS consumption with diet quality and markers of CVD risk were investigated using survey-adjusted multivariable linear regression adjusted for sex, age, ethnicity, socio-economic and smoking status, region of residency and total energy and alcohol intake. SETTING: UK free-living population. SUBJECTS: 4738 adults (≥19 years). RESULTS: TNS consumers had higher modified MDS and HDS relative to non-consumers. TNS consumers also had lower BMI, WC, SBP and DBP and higher HDL compared to non-consumers, although a dose-related fully adjusted significant association between increasing nut intake (g per 4184 kJ/1000 kcal energy intake) and lower marker of CVD risk was only observed for SBP. TNS consumption was also associated with higher intake of total fat, mono-, n-3 and n-6 polyunsaturated fatty acids, fibre, vitamin A, thiamin, folate, vitamin C, vitamin E, potassium, magnesium, phosphorus, selenium and iron; and lower intake of saturated fatty acids, trans fatty acids, total carbohydrate, starch, free sugar, sodium and chloride. CONCLUSIONS: TNS consumers report better dietary quality and consumption was associated with lower CVD risk factors. Encouraging replacement of less healthy snacks with TNS should be encouraged as part of general dietary guidelines.