Effect of Exercise Training on Prognosis in Community-acquired Pneumonia: A Randomized Controlled Trial.

OBJECTIVE: To investigate the effect of standard care (SoC) combined with supervised in-bed cycling (Bed-Cycle) or booklet exercises (Book-Exe) versus SoC in community-acquired pneumonia (CAP). METHODS: In this randomized controlled trial, 186 patients with CAP were assigned to SoC (n = 62), Bed-Cycle (n = 61), or Book-Exe (n = 63). Primary outcome length of stay (LOS) was analyzed with analysis of covariance. Secondary outcomes, 90-day readmission, and 180-day mortality were analyzed with Cox proportional hazard regression and readmission days with negative-binominal regression. RESULTS: LOS was -2% (95% CI: -24 to 25) and -1% (95% CI: -22 to 27) for Bed-Cycle and Book-Exe, compared with SoC. Ninety-day readmission was 35.6% for SoC, 27.6% for Bed-Cycle, and 21.3% for Book-Exe. Adjusted hazard ratio (aHR) for 90-day readmission was 0.63 (95% CI: .33-1.21) and 0.54 (95% CI: .27-1.08) for Bed-Cycle and Book-Exe compared with SoC. aHR for 90-day readmission for combined exercise was 0.59 (95% CI: .33-1.03) compared with SoC. aHR for 180-day mortality was 0.84 (95% CI: .27-2.60) and 0.82 (95% CI: .26-2.55) for Bed-Cycle and Book-Exe compared with SoC. Number of readmission days was 226 for SoC, 161 for Bed-Cycle, and 179 for Book-Exe. Incidence rate ratio for readmission days was 0.73 (95% CI: .48-1.10) and 0.77 (95% CI: .51-1.15) for Bed-Cycle and Book-Exe compared with SoC. CONCLUSIONS: Although supervised exercise training during admission with CAP did not reduce LOS or mortality, this trial suggests its potential to reduce readmission risk and number of readmission days. CLINICAL TRIALS REGISTRATION: NCT04094636.

Correlates of Plasma Citrulline, a Potential Marker of Enterocyte Mass, among Children with Stunting: A Cross-Sectional Study in Uganda.

BACKGROUND: Environmental enteric dysfunction (EED) is associated with stunting. Citrulline, produced in mature enterocytes, may be a valuable biomarker of small intestinal enterocyte mass in the context of EED. OBJECTIVES: We aimed to explore the correlates of plasma citrulline (p-cit) in children with stunting. METHODS: In a cross-sectional study using baseline data from the community-based MAGNUS (milk affecting growth, cognition and the gut in child stunting) trial (ISRCTN13093195), we explored potential correlates of p-cit in Ugandan children with stunting aged 12-59 mo. Using linear regression in univariate and multivariate models, we explored associations with socioeconomics, diet, micronutrient status, and water, sanitation, and hygiene characteristics. The influence of covariates age, fasting, and systemic inflammation were also explored. RESULTS: In 750 children, the mean ± standard deviation age was 32.0 ± 11.7 mo, and height-for-age z-score was -3.02 ± 0.74. P-cit, available for 730 children, differed according to time fasted and was 20.7 ± 8.9, 22.3 ± 10.6 and 24.2 ± 13.1 µmol/L if fasted <2, 2-5 and >5 h, respectively. Positive correlates of p-cit were age [0.07; 95% confidence interval (CI): 0.001, 0.15 µmol/L] and log10 serum insulin-like growth factor-1 (8.88; 95% CI: 5.09, 12.67 µmol/L). With adjustment for systemic inflammation, the association with serum insulin-like growth factor-1 reduced (4.98; 95% CI: 0.94, 9.03 µmol/L). Negative correlates of p-cit included food insecurity, wet season (-3.12; 95% CI: -4.97, -1.26 µmol/L), serum C-reactive protein (-0.15; 95% CI: -0.20, -0.10 µmol/L), serum α1-acid glycoprotein (-5.34; 95% CI: -6.98, -3.70 µmol/L) and anemia (-1.95; 95% CI: -3.72, -0.18 µmol/L). Among the negatively correlated water, sanitation, and hygiene characteristics was lack of soap for handwashing (-2.53; 95% CI: -4.82, -0.25 µmol/L). Many associations attenuated with adjustment for inflammation. CONCLUSIONS: Many of the correlates of p-cit are characteristic of populations with a high EED prevalence. Systemic inflammation is strongly associated with p-cit and is implicated in EED and stunting. Adjustment for systemic inflammation attenuates many associations, reflecting either confounding, mediation, or both. This study highlights the complex interplay between p-cit and systemic inflammation.

Correlates of Body Composition in Children with Stunting: A Cross-sectional Study in Uganda.

BACKGROUND: Development of body composition (BC) may be disrupted in children with stunting. Such disruption may affect the later risk of excess adiposity and metabolic health, yet few studies have investigated correlates of BC in children with stunting. OBJECTIVES: We aimed to investigate nutritional status, infection and inflammation, breastfeeding behaviors, and other factors as correlates of BC in children with stunting. METHODS: Among Ugandan children with a height-for-age z-score <-2, BC was estimated using bioelectrical impedance analysis and compared with United Kingdom references. We used multiple linear regression analysis to identify correlates of fat mass (FM), fat-free mass (FFM), FM-index (FMI), and FFM index (FFMI) and height, adjusting for gender and age. RESULTS: In 750 children aged 1-5 y, FMI was 0.46 (95% confidence interval [CI]: 0.38, 0.54] and FFMI 0.18 [95% CI: 0.11, 0.26) z-scores lower than United Kingdom references. Elevated serum α1-acid glycoprotein was associated with 1.14 [0.76, 1.52] cm lower height, 0.50 [0.35, 0.65] kg/m2 less FFMI, and 0.48 [0.31, 0.66] kg/m2 greater FMI. Similar, weaker, associations for elevated serum C-reactive protein were detected. A positive malaria rapid test was associated with 0.64 [0.25, 1.02] cm shorter height, but 0.36 [0.18, 0.54] kg/m2 greater FMI. Anemia (according to hemoglobin) was associated with 0.20 [0.07, 0.33] kg less FFM in proportion to shorter height. Longer breastfeeding duration was associated with 0.03 [0.02, 0.04] kg greater FFM per month, in proportion to greater height. CONCLUSIONS: These children exhibited deficits in FM and FFM, proportionally to their stunted height, compared with United Kingdom references. Systemic inflammation correlated inversely with linear growth and FFM but positively with fatness, making it a possible target for intervention where fat-free tissue accretion is desirable. Longer breastfeeding may offer protection to lean linear growth, but findings for micronutrients were less clear. Longitudinal studies are warranted to support these findings. The study was registered at www.isrctn.com (Ref. ISRCTN13093195).

The impact of an oral glucose load on IFN-γ-release in persons infected with Mycobacterium tuberculosis.

BACKGROUND AND OBJECTIVE: To diagnose tuberculosis infection (TBI), whole blood is incubated with M.tuberculosis (Mtb)-specific peptides and the release of interferon-γ (IFN-γ) is measured in IFN-γ-release assays (IGRAs). Hyperglycaemia and fluctuations in blood glucose may modulate IFN-γ-release. Here, we investigated if glucose intake affects IFN-γ-release or IGRA results in IGRAs taken during an oral glucose tolerance test (OGTT). METHODS: Persons with TB disease (TB) or TBI underwent a standard 75-g OGTT at the start and end of treatment for TB or TBI. Blood for the IGRA QuantiFERON-TB Gold Plus (QFT) containing Mtb-specific tubes (TB1 and TB2), a non-specific mitogen tube (MIT) and an empty control tube (NIL) was drawn at sample-timepoints -15 (baseline), 60, 90, 120 and 240 min during the OGTT. Blood glucose was measured in parallel at all timepoints. IFN-γ-release (after subtraction of NIL) at each timepoint was compared with baseline using linear-mixed-model analysis. RESULTS: Twenty-four OGTTs from 14 participants were included in the final analysis. Compared to baseline, IFN-γ-release was increased at sample-timepoint 240 min for TB1; geometric mean (95% confidence interval) 3.0 (1.5-6.2) vs 2.5 (1.4-4.4) IU/mL (p = 0.047), and MIT; 182.6 (103.3-322.9) vs 146.0 (84.0-254.1) IU/mL (p = 0.002). Plasma glucose levels were not associated with IFN-γ-release and the QFT test results were unaffected by the OGTT. CONCLUSION: Ingestion of glucose after a 10-h fast was associated with increased IFN-γ-release after 240 min in the MIT tube. However, there was no association between plasma glucose levels at the QFT sampling timepoint and IFN-γ-release. Furthermore, the QFT test results were not affected by glucose intake. The overall effect of an OGTT and prevailing plasma glucose levels on IFN-γ-release in IGRAs seem limited. TRIAL REGISTRATION: Trial registration ID: NCT04830462 ( https://clinicaltrials.gov/study/NCT04830462 ). Registration date: 05-Apr-2021.

Ethical self-efficacy among healthcare professionals caring for people with dementia: a brief pre- and post-report on the CARE intervention.

BACKGROUND: Interventions targeting healthcare professionals' confidence in managing ethical issues in dementia care are limited despite documented positive effects of educational programs on staff knowledge and self-efficacy. However, inconsistencies in the literature regarding the impact of educational programs underscore the need for targeted interventions. The CARE intervention, specifically designed to enhance confidence in ethical decision-making, aims to address this gap. This study evaluates the effectiveness of the CARE intervention in enhancing the ethical self-efficacy of healthcare professionals caring for people with dementia, particularly those with initially low levels of self-efficacy. METHODS: Using a non-experimental pre-post evaluation design, the CARE intervention was administered to healthcare professionals (n = 86), measuring ethical self-efficacy pre-and post-intervention. We hypothesized significant differences in ethical self-efficacy mean scores pre- and post-intervention for all participants, particularly those with low pre-measurement scores, whom we expected to benefit most from the intervention. Statistical analysis included paired t-tests and Wilcoxon tests for the low pre-measurement subgroup analysis. RESULTS: While no significant change was observed in the entire sample, participants with low initial self-efficacy showed a statistically significant improvement post-intervention. CONCLUSIONS: The CARE intervention holds promise in improving ethical self-efficacy among healthcare professionals with initial low confidence levels. Targeted interventions are essential in addressing confidence gaps in managing ethical challenges in dementia care, with implications for professional well-being and quality of care. Further research should explore long-term effects and expand sample size to enhance generalizability and sustainability of findings.

Simultaneous Inference Using Multiple Marginal Models.

This tutorial describes single-step low-dimensional simultaneous inference with a focus on the availability of adjusted p values and compatible confidence intervals for more than just the usual mean value comparisons. The basic idea is, first, to use the influence of correlation on the quantile of the multivariate t-distribution: the higher the less conservative. In addition, second, the estimability of the correlation matrix using the multiple marginal models approach (mmm) using multiple models in the class of linear up to generalized linear mixed models. The underlying maxT-test using mmm is discussed by means of several real data scenarios using selected R packages. Surprisingly, different features are highlighted, among them: (i) analyzing different-scaled, correlated, multiple endpoints, (ii) analyzing multiple correlated binary endpoints, (iii) modeling dose as qualitative factor and/or quantitative covariate, (iv) joint consideration of several tuning parameters within the poly-k trend test, (v) joint testing of dose and time, (vi) considering several effect sizes, (vii) joint testing of subgroups and overall population in multiarm randomized clinical trials with correlated primary endpoints, (viii) multiple linear mixed effect models, (ix) generalized estimating equations, and (x) nonlinear regression models.

Detection of a Chirality-Induced Spin Selective Quantum Capacitance in α-Helical Peptides.

Advanced Kelvin probe force microscopy simultaneously detects the quantum capacitance and surface potential of an α-helical peptide monolayer. These indicators shift when either the magnetic polarization or the enantiomer is toggled. A model based on a triangular quantum well in thermal and chemical equilibrium and electron-electron interactions allows for calculating the electrical potential profile from the measured data. The combination of the model and the measurements shows that no global charge transport is required to produce effects attributed to the chirality-induced spin selectivity effect. These experimental findings support the theoretical model of Fransson et al. Nano Letters 2021, 21 (7), 3026-3032. Measurements of the quantum capacitance represent a new way to test and refine theoretical models used to explain strong spin polarization due to chirality-induced spin selectivity.

The relationship between energy provided and growth during severe wasting treatment.

Treatment of severe acute malnutrition aims at producing quick catch-up growth in children to decrease their short-term mortality risk. The extent to which catch-up growth is influenced by the amount of energy provided is unclear. This study assessed whether energy provided at admission is associated with catch-up ponderal growth among children with mid-upper arm circumference (MUAC) < 115 mm at admission. We conducted a secondary data analysis an operational cohort in Mali. The children were treated with a simplified protocol providing 1000 kcal/day of therapeutic food until MUAC ≥ 115 mm was achieved for two consecutive weeks and 500 kcal/day thereafter until discharge with MUAC ≥ 125 mm for two consecutive weeks. Linear mixed-effects regression models were fitted to assess the relationship between energy provided at admission (kcal/kg/day) with weight gain velocity (g/kg/day) (primary outcome), change in MUAC -for-age z-score and change in weight-for-age z-score. Unadjusted models and models adjusted for sex, age, seasonality and MUAC at admission were fitted. Both models included the study site as a random effect. A 10 kcal/kg/day increase in energy provided at admission was associated with increments in all outcomes; for weight gain velocity, the mean (95% CI) increment was 0.340 [0.326, 0.354] g/kg/day and 0.466 [0.446, 0.485] g/kg/day in the unadjusted and adjusted analysis, respectively. A positive relationship exists between energy provided at admission and catch-up ponderal growth in children with MUAC < 115 mm treated using a simplified protocol. Determining the ideal weight gain rate remains essential for assessing the benefits and risks of increased energy intake during treatment.

Correlates of early child development among children with stunting: A cross-sectional study in Uganda.

Many children in low- and middle-income countries are not attaining their developmental potential. Stunting is associated with poor child development, but it is not known which correlates of stunting are impairing child development. We explored potential socioeconomic, nutritional, clinical, and household correlates of early child development among 12-59-month-old children with stunting in a cross-sectional study in Uganda. Development was assessed using the Malawi Development Assessment Tool (MDAT) across four domains of gross and fine motor, language, and social skills. Linear regression analysis was used to assess correlates of development in the four domains and total MDAT score. Of 750 children included, the median [interquartile range] age was 30 [23-41] months, 55% of the children resided in rural settings with 21% from female-headed households and 47% of mothers had no schooling. The mean ± standard deviation height-for-age z-score (HAZ) was -3.02 ± 0.74, 40% of the children had a positive malaria test and 65% were anaemic (haemoglobin < 110 g/L). One-third had children's books at home, majority (96%) used household objects to play with and most of them (70%) used toys as pretence items like those to mimic cooking. After age, sex, and site adjustments, HAZ (0.24, 95% confidence interval [CI]: 0.14-0.33) and head circumference (0.07, 95% CI: 0.02-0.12) were positive correlates of total MDAT score, whereas weight-for-height z-score (WHZ) was not. Current breastfeeding was associated with 0.41 (95% CI: 0.17-0.65) lower total MDAT score. Children from households with a single income earner had 0.22 (95% CI: 0.06-0.37) lower total MDAT score. Furthermore, severe food insecurity, inflammation and positive malaria test were associated with lower scores for motor development. All family care indicator subscales (FCIs) positively correlated with the total MDAT score and this association was independent of household's socioeconomic status. In conclusion, stunting degree, head circumference, number of household income earners and stimulation by improved FCIs correlate with early child development among stunted children. The negative association with prolonged breastfeeding is likely due to reverse causality. Identified correlates may inform initiatives to support children with stunting attain their development potential.

Effect of milk protein and whey permeate in large quantity lipid-based nutrient supplement on linear growth and body composition among stunted children: A randomized 2 × 2 factorial trial in Uganda.

BACKGROUND: Despite possible benefits for growth, milk is costly to include in foods for undernourished children. Furthermore, the relative effects of different milk components, milk protein (MP), and whey permeate (WP) are unclear. We aimed to assess the effects of MP and WP in lipid-based nutrient supplement (LNS), and of LNS itself, on linear growth and body composition among stunted children. METHODS AND FINDINGS: We performed a randomized, double-blind, 2 × 2 factorial trial among 12 to 59 months old stunted children in Uganda. Children were randomized to 4 formulations of LNS with MP or soy protein isolate and WP or maltodextrin (100 g/day for 12 weeks) or no supplementation. Investigators and outcome assessors were blinded; however, participants were only blinded to the ingredients in LNS. Data were analyzed based on intention-to-treat (ITT) using linear mixed-effects models adjusted for age, sex, season, and site. Primary outcomes were change in height and knee-heel length, and secondary outcomes included body composition by bioimpedance analysis (ISRCTN13093195). Between February and September 2020, we enrolled 750 children with a median age of 30 (interquartile range 23 to 41) months, with mean (± standard deviation) height-for-age z-score (HAZ) -3.02 ± 0.74 and 12.7% (95) were breastfed. The 750 children were randomized to LNS (n = 600) with or without MP (n = 299 versus n = 301) and WP (n = 301 versus n = 299), or no supplementation (n = 150); 736 (98.1%), evenly distributed between groups, completed 12-week follow-up. Eleven serious adverse events occurred in 10 (1.3%) children, mainly hospitalization with malaria and anemia, all deemed unrelated to the intervention. Unsupplemented children had 0.06 (95% confidence interval, CI [0.02, 0.10]; p = 0.015) decline in HAZ, accompanied by 0.29 (95% CI [0.20, 0.39]; p < 0.001) kg/m2 increase in fat mass index (FMI), but 0.06 (95% CI [-0.002; 0.12]; p = 0.057) kg/m2 decline in fat-free mass index (FFMI). There were no interactions between MP and WP. The main effects of MP were 0.03 (95% CI [-0.10, 0.16]; p = 0.662) cm in height and 0.2 (95% CI [-0.3, 0.7]; p = 0.389) mm in knee-heel length. The main effects of WP were -0.08 (95% CI [-0.21, 0.05]; p = 220) cm and -0.2 (95% CI [-0.7; 0.3]; p = 403) mm, respectively. Interactions were found between WP and breastfeeding with respect to linear growth (p < 0.02), due to positive effects among breastfed and negative effects among non-breastfed children. Overall, LNS resulted in 0.56 (95% CI [0.42, 0.70]; p < 0.001) cm height increase, corresponding to 0.17 (95% CI [0.13, 0.21]; p < 0.001) HAZ increase, and 0.21 (95% CI [0.14, 0.28]; p < 0.001) kg weight increase, of which 76.5% (95% CI [61.9; 91.1]) was fat-free mass. Using height-adjusted indicators, LNS increased FFMI (0.07 kg/m2, 95% CI [0.0001; 0.13]; p = 0.049), but not FMI (0.01 kg/m2, 95% CI [-0.10, 0.12]; p = 0.800). Main limitations were lack of blinding of caregivers and short study duration. CONCLUSIONS: Adding dairy to LNS has no additional effects on linear growth or body composition in stunted children aged 12 to 59 months. However, supplementation with LNS, irrespective of milk, supports linear catch-up growth and accretion of fat-free mass, but not fat mass. If left untreated, children already on a stunting trajectory gain fat at the expense of fat-free mass, thus nutrition programs to treat such children should be considered. TRIAL REGISTRATION: ISRCTN13093195.

Associations between Stunting, Wasting and Body Composition: A Longitudinal Study in 6- to 15-Month-Old Kenyan Children.

BACKGROUND: Early growth and body composition may influence the risk of obesity and health in adulthood. Few studies have examined how undernutrition is associated with body composition in early life. OBJECTIVES: We assessed stunting and wasting as correlates of body composition in young Kenyan children. METHODS: Nested in a randomized controlled nutrition trial, this longitudinal study assessed fat and fat-free mass (FM, FFM) using deuterium dilution technique among children at age 6 and 15 months. This trial was registered at http://controlled-trials.com/ (ISRCTN30012997). Cross-sectional and longitudinal associations between z-score categories of length-for-age (LAZ) or weight-for-length (WLZ) and FM, FFM, fat mass index (FMI), fat-free mass index (FFMI), triceps, and subscapular skinfolds were analyzed by linear mixed models. RESULTS: Among the 499 children enrolled, breastfeeding declined from 99% to 87%, stunting increased from 13% to 32%, and wasting remained at 2% to 3% between 6 and 15 mo. Compared with LAZ >0, stunted children had a 1.12 kg (95% CI: 0.88, 1.36; P < 0.001) lower FFM at 6 mo and increased to 1.59 kg (95% CI: 1.25, 1.94; P < 0.001) at 15 mo, corresponding to differences of 18% and 17%, respectively. When analyzing FFMI, the deficit in FFM tended to be less than proportional to children's height at 6 mo (P ≤ 0.060) but not at 15 mo (P > 0.40). Stunting was associated with 0.28 kg (95% CI: 0.09, 0.47; P = 0.004) lower FM at 6 mo. However, this association was not significant at 15 mo, and stunting was not associated with FMI at any time point. A lower WLZ was generally associated with lower FM, FFM, FMI, and FFMI at 6 and 15 mo. Differences in FFM, but not FM, increased with time, whereas FFMI differences did not change, and FMI differences generally decreased with time. CONCLUSIONS: Overall, low LAZ and WLZ among young Kenyan children were associated with reduced lean tissue, which may have long-term health consequences.

Serum cobalamin in children with moderate acute malnutrition in Burkina Faso: Secondary analysis of a randomized trial.

BACKGROUND: Among children with moderate acute malnutrition (MAM) the level of serum cobalamin (SC) and effect of food supplements are unknown. We aimed to assess prevalence and correlates of low SC in children with MAM, associations with hemoglobin and development, and effects of food supplements on SC. METHODS AND FINDINGS: A randomized 2 × 2 × 3 factorial trial was conducted in Burkina Faso. Children aged 6 to 23 months with MAM received 500 kcal/d as lipid-based nutrient supplement (LNS) or corn-soy blend (CSB), containing dehulled soy (DS) or soy isolate (SI) and 0%, 20%, or 50% of total protein from milk for 3 months. Randomization resulted in baseline equivalence between intervention groups. Data on hemoglobin and development were available at baseline. SC was available at baseline and after 3 and 6 months. SC was available from 1,192 (74.1%) of 1,609 children at baseline. The mean (±SD) age was 12.6 (±5.0) months, and 54% were females. Low mid-upper arm circumference (MUAC; <125 mm) was found in 80.4% (958) of the children and low weight-for-length z-score (WLZ; <-2) in 70.6% (841). Stunting was seen in 38.2% (456). Only 5.9% were not breastfed. Median (IQR) SC was 188 (137; 259) pmol/L. Two-thirds had SC ≤222 pmol/L, which was associated with lower hemoglobin. After age and sex adjustments, very low SC (<112 pmol/L) was associated with 0.21 (95% CI: 0.01; 0.41, p = 0.04) and 0.24 (95% CI: 0.06; 0.42, p = 0.01) z-score lower fine and gross motor development, respectively. SC data were available from 1,330 (85.9%) of 1,548 children followed up after 3 months and 398 (26.5%) of the 1,503 children after 6 months. Based on tobit regression, accounting for left censored data, and adjustments for correlates of missing data, the mean (95% CI) increments in SC from baseline to the 3- and 6-month follow-up were 72 (65; 79, p < 0.001) and 26 (16; 37, p < 0.001) pmol/L, respectively. The changes were similar among the 310 children with SC data at all 3 time points. Yet, the increase was 39 (20; 57, p < 0.001) pmol/L larger in children given LNS compared to CSB if based on SI (interaction, p < 0.001). No effect of milk was found. Four children died, and no child developed an allergic reaction to supplements. The main limitation of this study was that only SC was available as a marker of status and was missing from a quarter of the children. CONCLUSIONS: Low SC is prevalent among children with MAM and may contribute to impaired erythropoiesis and child development. The SC increase during supplementation was inadequate. The bioavailability and adequacy of cobalamin in food supplements should be reconsidered. TRIAL REGISTRATION: ISRCTN Registry ISRCTN42569496.

The Tukey trend test: Multiplicity adjustment using multiple marginal models.

In dose-response analysis, it is a challenge to choose appropriate linear or curvilinear shapes when considering multiple, differently scaled endpoints. It has been proposed to fit several marginal regression models that try sets of different transformations of the dose levels as explanatory variables for each endpoint. However, the multiple testing problem underlying this approach, involving correlated parameter estimates for the dose effect between and within endpoints, could only be adjusted heuristically. An asymptotic correction for multiple testing can be derived from the score functions of the marginal regression models. Based on a multivariate t-distribution, the correction provides a one-step adjustment of p-values that accounts for the correlation between estimates from different marginal models. The advantages of the proposed methodology are demonstrated through three example datasets, involving generalized linear models with differently scaled endpoints, differing covariates, and a mixed effect model and through simulation results. The methodology is implemented in an R package.

Fish oil supplementation may improve attention, working memory and attention-deficit/hyperactivity disorder symptoms in adults with autism spectrum disorder: a randomised crossover trial.

Marine n-3 fatty acids (n-3LCPUFA) have shown neurocognitive benefits in children with attention-deficit/hyperactivity disorder (ADHD), but few trials have examined effects in adults with autism spectrum disorder (ASD). We explored, if n-3LCPUFA affect cognitive functions in adults with ASD, and if effects are modified by comorbid ADHD. In a 2 × 4 week crossover study, twenty-six participants were randomised to sequence of supplementation with fish oil (FO, 5·2 g/d n-3PUFA) and safflower oil (SO). At baseline and after each period, we measured primary outcomes: attention (d2-test) and spatial working memory (Corsi test) and secondary outcomes: flexibility (Stroop word-colour test), ADHD symptoms (Conners scales), executive functions (Behavioural Inventory of Executive Function) and social behaviour (Social Responsiveness Scale). The dropout rate was 15 %. Compliance was 94 % and correlated with whole-blood n-3LCPUFA. Corsi scores improved by ∼0·3 × sd (P = 0·032) after FO v. SO, and the odds for d2 errors were 30 % lower (P = 0·016), which was supported by improved Conners scores of attention (P = 0·023). Improvement in Conners ADHD symptom score was limited to participants with ADHD (-3·5(-6·0; -1·0), n 10 v. -0·2(-2·5;2·2), n 11 without ADHD, Pinteraction = 0·096), who also improved their behavioural regulation index by 0·3 × sd after FO (Pinteraction = 0·016). Participants without ADHD gained most in d2 test performance (OR = 0·4(0·2;0·7) v. 0·9(0·6;1·3) in those with ADHD, Pinteraction = 0·002), but their executive function score was exacerbated after FO (5·9(0·0,11·8), Pinteraction = 0·039). Our results did not show any effects on ASD symptoms, but suggest that FO may improve attention and working memory in adults with ASD and ameliorate ADHD symptoms in those with comorbid ADHD.

The changing spectrum of microbial aetiology of respiratory tract infections in hospitalized patients before and during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic was met with strict containment measures. We hypothesized that societal infection control measures would impact the number of hospital admissions for respiratory tract infections, as well as, the spectrum of pathogens detected in patients with suspected community acquired pneumonia (CAP). METHODS: This study is based on aggregated surveillance data from electronic health records of patients admitted to the hospitals in Bergen Hospital Trust from January 2017 through June 2021, as well as, two prospective studies of patients with suspected CAP conducted prior to and during the COVID-19 pandemic (pre-COVID cohort versus COVID cohort, respectively). In the prospective cohorts, microbiological detections were ascertained by comprehensive PCR-testing in lower respiratory tract specimens. Mann-Whitney's U test was used to analyse continuous variables. Fisher's exact test was used for analysing categorical data. The number of admissions before and during the outbreak of SARS-CoV-2 was compared using two-sample t-tests on logarithmic transformed values. RESULTS: Admissions for respiratory tract infections declined after the outbreak of SARS-CoV-2 (p < 0.001). The pre-COVID and the COVID cohorts comprised 96 and 80 patients, respectively. The proportion of viruses detected in the COVID cohort was significantly lower compared with the pre-COVID cohort [21% vs 36%, difference of 14%, 95% CI 4% to 26%; p = 0.012], and the proportion of bacterial- and viral co-detections was less than half in the COVID cohort compared with the pre-COVID cohort (19% vs 45%, difference of 26%, 95% CI 13% to 41%; p < 0.001). The proportion of bacteria detected was similar (p = 0.162), however, a difference in the bacterial spectrum was observed in the two cohorts. Haemophilus influenzae was the most frequent bacterial detection in both cohorts, followed by Streptococcus pneumoniae in the pre-COVID and Staphylococcus aureus in the COVID cohort. CONCLUSION: During the first year of the COVID-19 pandemic, the number of admissions with pneumonia and the microbiological detections in patients with suspected CAP, differed from the preceding year. This suggests that infection control measures related to COVID-19 restrictions have an overall and specific impact on respiratory tract infections, beyond reducing the spread of SARS-CoV-2.

Individual participant data (IPD)-level meta-analysis of randomised controlled trials to estimate the vitamin D dietary requirements in dark-skinned individuals resident at high latitude.

CONTEXT AND PURPOSE: There is an urgent need to develop vitamin D dietary recommendations for dark-skinned populations resident at high latitude. Using data from randomised controlled trials (RCTs) with vitamin D3-supplements/fortified foods, we undertook an individual participant data-level meta-regression (IPD) analysis of the response of wintertime serum 25-hydroxyvitamin (25(OH)D) to total vitamin D intake among dark-skinned children and adults residing at ≥ 40° N and derived dietary requirement values for vitamin D. METHODS: IPD analysis using data from 677 dark-skinned participants (of Black or South Asian descent; ages 5-86 years) in 10 RCTs with vitamin D supplements/fortified foods identified via a systematic review and predefined eligibility criteria. Outcome measures were vitamin D intake estimates across a range of 25(OH)D thresholds. RESULTS: To maintain serum 25(OH)D concentrations ≥ 25 and 30 nmol/L in 97.5% of individuals, 23.9 and 27.3 µg/day of vitamin D, respectively, were required among South Asian and 24.1 and 33.2 µg/day, respectively, among Black participants. Overall, our age-stratified intake estimates did not exceed age-specific Tolerable Upper Intake Levels for vitamin D. The vitamin D intake required by dark-skinned individuals to maintain 97.5% of winter 25(OH)D concentrations ≥ 50 nmol/L was 66.8 µg/day. This intake predicted that the upper 2.5% of individuals could potentially achieve serum 25(OH)D concentrations ≥ 158 nmol/L, which has been linked to potential adverse effects in older adults in supplementation studies. CONCLUSIONS: Our IPD-derived vitamin D intakes required to maintain 97.5% of winter 25(OH)D concentrations ≥ 25, 30 and 50 nmol/L are substantially higher than the equivalent estimates for White individuals. These requirement estimates are also higher than those currently recommended internationally by several agencies, which are based predominantly on data from Whites and derived from standard meta-regression based on aggregate data. Much more work is needed in dark-skinned populations both in the dose-response relationship and risk characterisation for health outcomes. TRAIL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews (Registration Number: CRD42018097260).

Similar effects of milk protein and blends of milk and plant-based protein on appetite-related hormones in 7- to 8-year-old healthy Danish children: secondary analyses from the PROGRO randomised trial.

AIM: The effect of different protein sources on the appetite-related hormones in children is largely unknown. We investigated the effect of milk protein versus blends of milk and rapeseed protein on plasma leptin and adiponectin in children. METHODS: We included 88 Danish 7- to 8-year-old children randomised to receive 35 g protein/day for 4 weeks in 2018 as either milk protein or blends of milk and rapeseed protein (ratio 54:46 or 30:70). Outcomes included absolute and fat mass-adjusted adiponectin and leptin measured at baseline, Weeks 1 and 4. RESULTS: There was no difference in changes in absolute and fat mass-adjusted adiponectin and leptin after 1 or 4 weeks between the three groups (p ≥ 0.100). Leptin increased within all groups (p ≤ 0.046). Combining the three groups, leptin and fat mass-adjusted leptin increased by 23% (95% CI 11;35) and 17% (6.4;29) during the intervention respectively (both p ≤ 0.001). Adiponectin variables did not change during the intervention period. CONCLUSION: There were no differences between milk protein and blends of milk and rapeseed protein on absolute and fat mass-adjusted leptin and adiponectin in healthy children with a habitual intake of milk. However, leptin increased within all three groups. Future studies should further investigate effect on appetite-related hormones of rapeseed protein alone.

The PREVIEW intervention study: Results from a 3-year randomized 2 x 2 factorial multinational trial investigating the role of protein, glycaemic index and physical activity for prevention of type 2 diabetes.

AIM: To compare the impact of two long-term weight-maintenance diets, a high protein (HP) and low glycaemic index (GI) diet versus a moderate protein (MP) and moderate GI diet, combined with either high intensity (HI) or moderate intensity physical activity (PA), on the incidence of type 2 diabetes (T2D) after rapid weight loss. MATERIALS AND METHODS: A 3-year multicentre randomized trial in eight countries using a 2 x 2 diet-by-PA factorial design was conducted. Eight-week weight reduction was followed by a 3-year randomized weight-maintenance phase. In total, 2326 adults (age 25-70 years, body mass index ≥ 25 kg/m2 ) with prediabetes were enrolled. The primary endpoint was 3-year incidence of T2D analysed by diet treatment. Secondary outcomes included glucose, insulin, HbA1c and body weight. RESULTS: The total number of T2D cases was 62 and the cumulative incidence rate was 3.1%, with no significant differences between the two diets, PA or their combination. T2D incidence was similar across intervention centres, irrespective of attrition. Significantly fewer participants achieved normoglycaemia in the HP compared with the MP group (P < .0001). At 3 years, normoglycaemia was lowest in HP-HI (11.9%) compared with the other three groups (20.0%-21.0%, P < .05). There were no group differences in body weight change (-11% after 8-week weight reduction; -5% after 3-year weight maintenance) or in other secondary outcomes. CONCLUSIONS: Three-year incidence of T2D was much lower than predicted and did not differ between diets, PA or their combination. Maintaining the target intakes of protein and GI over 3 years was difficult, but the overall protocol combining weight loss, healthy eating and PA was successful in markedly reducing the risk of T2D. This is an important clinically relevant outcome.

Body weight and metabolic risk factors in patients with type 2 diabetes on a self-selected high-protein low-carbohydrate diet.

PURPOSE: We previously reported beneficial glucoregulatory effects of a fully provided carbohydrate-reduced, high-protein (CRHP) diet in patients with type 2 diabetes mellitus (T2DM) in a crossover 2 × 6-week trial, in which patients maintained their body weight. Here, we investigated physiological changes during an additional 6-month period on a self-selected and self-prepared CRHP diet. METHODS: Twenty-eight patients with T2DM were instructed to consume a CRHP diet (30% of energy from carbohydrate and 30% from protein) for 24 weeks, after an initial 2 × 6-week trial when all food was prepared and provided to them. Patients received dietary advice every 2 weeks. At weeks 0, 6, 12 and 36, they underwent a 3-h intravenous glucose tolerance test, a 4-h mixed meal test, and a 48-h continuous glucose monitoring. Liver, muscle, pancreas, and visceral fat contents were measured by magnetic resonance imaging. RESULTS: During the 24-week self-selected diet period (weeks 12-36), body weight, visceral fat, liver fat, and glycated haemoglobin were maintained at the same levels achieved at the end of the fully provided diet period, and were still lower than at baseline (P < 0.05). Postprandial insulinaemia and insulin secretion were significantly greater (P < 0.05). At week 36, fasting insulin and C-peptide levels increased (P < 0.01) and daily glycaemia decreased further (P < 0.05) when compared with the end of the fully provided diet period. CONCLUSION: Substituting dietary carbohydrate for protein and fat has metabolic benefits in patients with T2DM. These beneficial effects are maintained or augmented over the next 6 months when patients self-select and self-prepare this diet in a dietitian-supported setting. TRIAL REGISTRATION: ClinicalTrials.gov NCT02764021.

Individual participant data (IPD)-level meta-analysis of randomised controlled trials with vitamin D-fortified foods to estimate Dietary Reference Values for vitamin D.

CONTEXT AND PURPOSE: Individual participant data-level meta-regression (IPD) analysis is superior to meta-regression based on aggregate data in determining Dietary Reference Values (DRV) for vitamin D. Using data from randomized controlled trials (RCTs) with vitamin D3-fortified foods, we undertook an IPD analysis of the response of winter serum 25-hydroxyvitamin (25(OH)D) to total vitamin D intake among children and adults and derived DRV for vitamin D. METHODS: IPD analysis using data from 1429 participants (ages 2-89 years) in 11 RCTs with vitamin D-fortified foods identified via a systematic review and predefined eligibility criteria. Outcome measures were vitamin D DRV estimates across a range of serum 25(OH)D thresholds using unadjusted and adjusted models. RESULTS: Our IPD-derived estimates of vitamin D intakes required to maintain 97.5% of winter 25(OH)D concentrations ≥ 25 and ≥ 30 nmol/L are 6 and 12 µg/day, respectively (unadjusted model). The intake estimates to maintain 90%, 95% and 97.5% of concentrations ≥ 50 nmol/L are 33.4, 57.5 and 92.3 µg/day, respectively (unadjusted) and 17.0, 28.1 and 43.6 µg/day, respectively (adjusted for mean values for baseline serum 25(OH)D, age and BMI). CONCLUSIONS: IPD-derived vitamin D intakes required to maintain 90%, 95% and 97.5% of winter 25(OH)D concentrations ≥ 50 nmol/L are much higher than those derived from standard meta-regression based on aggregate data, due to the inability of the latter to capture between person-variability. Our IPD provides further evidence that using food-based approaches to achieve an intake of 12 µg/day could prevent vitamin D deficiency (i.e., serum 25(OH)D < 30 nmol/L) in the general population.