A blueprint for a multi-disease, multi-domain Bayesian adaptive platform trial incorporating adult and paediatric subgroups: the Staphylococcus aureus Network Adaptive Platform trial.

The Staphylococcus aureus Network Adaptive Platform (SNAP) trial is a multifactorial Bayesian adaptive platform trial that aims to improve the way that S. aureus bloodstream infection, a globally common and severe infectious disease, is treated. In a world first, the SNAP trial will simultaneously investigate the effects of multiple intervention modalities within multiple groups of participants with different forms of S. aureus bloodstream infection. Here, we formalise the trial structure, modelling approach, and decision rules that will be used for the SNAP trial. By summarising the statistical principles governing the design, our hope is that the SNAP trial will serve as an adaptable template that can be used to improve comparative effectiveness research efficiency in other disease areas.Trial registration NCT05137119 . Registered on 30 November 2021.

Acute exercise affects dual-energy X-ray absorptiometry body composition estimates but not standardised ultrasound measurements of subcutaneous adipose tissue.

Ultrasound has been demonstrated to be a highly accurate and reliable tool for measuring subcutaneous adipose tissue thickness and is robust against changes in hydration status or acute food or fluid intake. However, the effect of prior acute exercise is unexamined. This study examined the impact of an acute endurance exercise and resistance exercise session on standardised brightness-mode ultrasound measurements of subcutaneous adipose tissue thickness compared to skinfolds and dual-energy X-ray absorptiometry body composition estimates. In a randomised cross-over design, 30 active adults (24.2 ± 4.9 years) undertook physique assessment via standardised brightness-mode ultrasound, skinfolds and dual-energy X-ray absorptiometry before, immediately and 45 min after an acute endurance or resistance exercise session. The mean sum of eight subcutaneous adipose tissue thickness measured via standardised brightness-mode ultrasound increased (0.6 mm, p = 0.04) immediately postendurance exercise but was not meaningful when evaluated against the technical error of measurement of the investigator. A significant (p = 0.01) but not meaningful decrease in the sum of eight skinfolds occurred immediately (-1.1 ± 0.4 mm) and 45 min (-1.3 ± 0.4 mm) postresistance exercise. Comparatively, endurance exercise elicited a meaningful decrease of total mass (460 ± 30 g) and trunk lean mass (680 ± 90 g) dual-energy X-ray absorptiometry estimates. Findings from this study indicate standardised client presentation may be unnecessary when employing either standardised brightness-mode ultrasound or skinfolds for body composition assessment unlike dual-energy X-ray absorptiometry.

Predicting the causative pathogen among children with pneumonia using a causal Bayesian network.

BACKGROUND: Pneumonia remains a leading cause of hospitalization and death among young children worldwide, and the diagnostic challenge of differentiating bacterial from non-bacterial pneumonia is the main driver of antibiotic use for treating pneumonia in children. Causal Bayesian networks (BNs) serve as powerful tools for this problem as they provide clear maps of probabilistic relationships between variables and produce results in an explainable way by incorporating both domain expert knowledge and numerical data. METHODS: We used domain expert knowledge and data in combination and iteratively, to construct, parameterise and validate a causal BN to predict causative pathogens for childhood pneumonia. Expert knowledge elicitation occurred through a series of group workshops, surveys and one-on-one meetings involving 6-8 experts from diverse domain areas. The model performance was evaluated based on both quantitative metrics and qualitative expert validation. Sensitivity analyses were conducted to investigate how the target output is influenced by varying key assumptions of a particularly high degree of uncertainty around data or domain expert knowledge. RESULTS: Designed to apply to a cohort of children with X-ray confirmed pneumonia who presented to a tertiary paediatric hospital in Australia, the resulting BN offers explainable and quantitative predictions on a range of variables of interest, including the diagnosis of bacterial pneumonia, detection of respiratory pathogens in the nasopharynx, and the clinical phenotype of a pneumonia episode. Satisfactory numeric performance has been achieved including an area under the receiver operating characteristic curve of 0.8 in predicting clinically-confirmed bacterial pneumonia with sensitivity 88% and specificity 66% given certain input scenarios (i.e., information that is available and entered into the model) and trade-off preferences (i.e., relative weightings of the consequences of false positive versus false negative predictions). We specifically highlight that a desirable model output threshold for practical use is very dependent upon different input scenarios and trade-off preferences. Three commonly encountered scenarios were presented to demonstrate the potential usefulness of the BN outputs in various clinical pictures. CONCLUSIONS: To our knowledge, this is the first causal model developed to help determine the causative pathogen for paediatric pneumonia. We have shown how the method works and how it would help decision making on the use of antibiotics, providing insight into how computational model predictions may be translated to actionable decisions in practice. We discussed key next steps including external validation, adaptation and implementation. Our model framework and the methodological approach can be adapted beyond our context to broad respiratory infections and geographical and healthcare settings.

The short term safety of COVID-19 vaccines in Australia: AusVaxSafety active surveillance, February - August 2021.

OBJECTIVE: To assess the short term safety of the COVID-19 vaccines Comirnaty (Pfizer-BioNTech BNT162b2) and Vaxzevria (AstraZeneca ChAdOx1) in Australia. DESIGN: Prospective observational cohort study; online surveys by AusVaxSafety, a national active vaccine safety surveillance system, three and eight days after vaccination. SETTING, PARTICIPANTS: People aged 16 years or more who received COVID-19 vaccines at sentinel vaccination hubs, general practices, or Aboriginal Community Controlled Health Organisation clinics, 22 February - 30 August 2021. MAIN OUTCOME MEASURES: Primary outcome: proportion of respondents who reported any adverse event following immunisation (AEFI) 0-3 days after vaccination. SECONDARY OUTCOMES: proportions of respondents who reported specific adverse events or medical review for AEFI within seven days of vaccination; impact on usual daily activities; recovery. RESULTS: 4 851 480 people received COVID-19 vaccines at participating sentinel sites during the study period (25% of all COVID-19 vaccine doses administered in Australia to 30 August 2021). 3 035 983 people responded to both surveys (response rate, 62.6%); 35.9% of respondents reported one or more AEFI 0-3 days after Comirnaty dose 1, 54.7% after Comirnaty dose 2, 52.8% after Vaxzevria dose 1, and 22.0% after Vaxzevria dose 2. Local pain, fatigue, headache, and myalgia were the most frequently reported symptoms. After adjusting for demographic characteristics, vaccination site type, jurisdiction, and self-reported medical conditions, the odds of reporting any AEFI were higher for women than men (range of adjusted odd ratios [aORs], by vaccine and dose, 1.53-1.84), for people with a history of anaphylaxis (aOR range, 1.28-1.45), and for people reporting certain underlying conditions, including obesity (aOR range, 1.15-1.75), immunodeficiency (aOR range, 1.04-2.24), or chronic inflammatory disease (aOR range, 1.05-1.75). 0.9% of respondents sought medical advice in the three days following vaccination, most frequently after Comirnaty dose 2 (1.4%) and Vaxzevria dose 1 (1.2%). CONCLUSION: AusVaxSafety active surveillance affirms the short term safety profile of Comirnaty and Vaxzevria vaccines in a large population sample during the first six months of the Australian COVID-19 vaccination program.

Short- versus standard-course intravenous antibiotics for peri-prosthetic joint infections managed with debridement and implant retention: a randomised pilot trial using a desirability of outcome ranking (DOOR) endpoint.

BACKGROUND: Peri-prosthetic joint infection (PJI) is a devastating complication of joint replacement surgery. Determining the optimal duration of intravenous (IV) antibiotics for PJI managed with debridement and implant retention (DAIR) is a research priority. METHODS: Patients undergoing DAIR for early and late-acute PJI of the hip or knee were randomised to receive 2 (short-course) or 6 (standard-course) weeks of IV antibiotics, with both groups completing 12 weeks of antibiotics in total. The primary endpoint of this pilot, open-label, randomised trial was a 7-point ordinal desirability of outcome ranking (DOOR) score, which accounted for mortality, clinical cure and treatment adverse events at 12 months. Duration of IV treatment was used as a tiebreaker, with shorter courses ranked higher. Outcome adjudication was performed by expert clinicians blinded to the allocated intervention (Australia and New Zealand Clinical Trials Registry ACTRN12617000127303). RESULTS: 60 patients were recruited; 31 and 29 were allocated to short- and standard-course treatment, respectively. All had an evaluable outcome at 12 months and were analysed by intention-to-treat. Clinical cure was demonstrated in 44 (73%) overall; 22 (71%) in the short-course group and 22 (76%) in the standard-care group (P=0.77). Using the DOOR approach, the probability that short- was better than standard-course treatment was 59.7% (95% confidence interval 45.1-74.3). CONCLUSIONS: In selected patients with early and late-acute PJI managed with DAIR, shorter courses of IV antibiotics may be appropriate. Due to small sample size, these data accord with, but do not confirm, results from other international trials of early transition to oral antibiotics.

Food and fluid intake and hydration status does not affect ultrasound measurements of subcutaneous adipose tissue in active adults.

OBJECTIVES: To investigate the impact of acute food and fluid intake or hydration status on the standardised brightness-mode ultrasound measurement of subcutaneous adipose tissue thickness. DESIGN: Thirty active adults (female n = 10) participated in a randomised cross over study. METHODS: Participants completed three body composition assessment sessions via standardised brightness-mode ultrasound and Dual-energy X-ray absorptiometry. Participants were assessed under standardised presentation during 'food only' and 'food plus water' sessions at baseline and reassessed after their allotted intake. 'Hypohydration plus water' was undertaken in a hypohydrated state at baseline and reassessed after water intake. RESULTS: The sum of eight subcutaneous adipose tissue thickness was lower when measured after 'food only' or 'food plus water' compared to baseline (-0.1 to -0.9 mm; p < 0.01). However, these changes were less than the 95% confidence interval of the technical error of measurement of the investigator. Body mass, dual-energy x-ray absorptiometry total and trunk mass, lean mass and trunk lean mass estimates increased (p < 0.01) following 'food only' or 'food plus water', and decreased with hypohydration (p < 0.01). Total and regional fat mass estimates were not impacted. CONCLUSIONS: The sum of eight subcutaneous adipose tissue thickness measured via standardised brightness-mode ultrasound was unaffected by acute food and fluid consumption or hydration status changes. Comparatively, these interventions altered dual-energy x-ray absorptiometry body composition estimates, especially that of lean mass components. Standardised brightness-mode ultrasound can therefore be used to monitor changes in fat patterning when standardised client presentation is not practically achievable.

Measures of body composition via Dual-energy X-ray absorptiometry, ultrasound and skinfolds are not impacted by the menstrual cycle in active eumenorrheic females.

OBJECTIVES: (1) Compare changes in body composition estimates over the menstrual cycle in active females using Dual-energy X-ray absorptiometry, standardised brightness-mode ultrasound and skinfolds (2) Compare the predictability of Dual-energy X-ray absorptiometry fat mass estimate via standardised brightness-mode ultrasound versus skinfolds measurements. DESIGN: Thirty active females (27 ±â€¯5 y) with regularly occurring menstrual cycles participated in a cross sectional study. METHODS: Participants completed four assessment sessions scheduled according to each individual's menstrual cycle. These sessions took place during their (1) early follicular, (2) mid-to-late follicular, (3) mid-luteal and (4) second early follicular phases. Body composition estimates were acquired using Dual-energy X-ray absorptiometry, subcutaneous adipose tissue thickness was measured at eight sites using standardised brightness-mode ultrasound and skinfolds. RESULTS: The sum of eight subcutaneous adipose tissue thickness measured using standardised brightness-mode ultrasound and skinfolds were not different between the cycle phases (p > 0.05). Body mass and Dual-energy X-ray absorptiometry total mass estimate as well as Dual-energy X-ray absorptiometry estimates of total and regional lean and fat mass were also not different between cycle phases (p > 0.05) and any changes were within the 95% confidence intervals of their respective least significant change values. CONCLUSIONS: There were no true and meaningful changes in the sum of eight subcutaneous adipose tissue thickness measured via standardised brightness-mode ultrasound and skinfolds or Dual-energy X-ray absorptiometry total and regional tissue mass estimates across the menstrual cycle in active eumenorrheic females. Body composition may thus be assessed via these methods in this population at any cycle phase with standardised participant presentation.

Reduction in Maternal Energy Intake during Lactation Decreased Maternal Body Weight and Concentrations of Leptin, Insulin and Adiponectin in Human Milk without Affecting Milk Production, Milk Macronutrient Composition or Infant Growth.

Maternal diet has the potential to affect human milk (HM) composition, but very few studies have directly assessed the effect of maternal diets on HM composition. The primary aim of this study was to assess the effect of improving dietary quality in lactating women over 2 weeks on the concentrations of macronutrients and metabolic hormones in HM. The secondary aims were to assess the impact of the dietary intervention on 24 h milk production, maternal body composition and infant growth. Fifteen women completed a 1-week baseline period followed by a 2-week dietary intervention phase targeted towards reducing fat and sugar intake. Maternal anthropometric and body composition and infant growth measurements were performed weekly. Total 24 h milk production was measured before and after the dietary intervention, and HM samples were collected daily. Maternal intakes of energy (-33%), carbohydrate (-22%), sugar (-29%), fat (-54%) and saturated fat (-63%) were significantly reduced during the dietary intervention. HM insulin, leptin and adiponectin concentrations were 10-25% lower at the end of the dietary intervention, but HM concentrations of macronutrients were unaffected. Maternal body weight (-1.8%) and fat mass (-6.3%) were significantly reduced at the end of the dietary intervention, but there were no effects on 24 h milk production or infant growth. These results suggest that reducing maternal energy, carbohydrate, fat and sugar intake over a 2-week period is associated with significant reductions in HM insulin, leptin and adiponectin concentrations. These changes may be secondary to decreases in maternal weight and fat mass. The limited studies to date that have investigated the association between metabolic hormone concentrations in HM and infant growth raise the possibility that the changes in HM composition observed in the current study could impact infant growth and adiposity, but further studies are required to confirm this hypothesis.

Daily variation of macronutrient concentrations in mature human milk over 3 weeks.

Human milk (HM) composition is known to be highly variable, both between individuals and across the duration of lactation. It is less clear, however, to what extent fat, lactose and protein concentrations in HM change daily over shorter time periods in mature HM, and no studies have evaluated this to date. The aim of this study was to systematically assess and compare HM macronutrient concentrations in samples collected at different times of day, from left and right breasts and daily across a 3-week period in the same woman. Fifteen lactating women (1.6-4.9 months postpartum) collected daily pre-feed HM samples from both breasts each morning for 21 consecutive days and completed intensive sampling once a week (morning, afternoon and evening samples) during this period. Concentrations of fat, protein and lactose in HM did not differ according to time of day, day of week or breast used for collection. The results of this study suggest that pre-feed samples collected at any point across a 3-week period and from either the left or right breast provide comparable measures of fat, protein and lactose concentrations in mature HM, in pragmatic studies where women are collecting their own HM samples.Clinical trial registration: Australian New Zealand Clinical Trials Registry (ACTRN12619000606189).

Nipple shield use does not impact sucking dynamics in breastfeeding infants of mothers with nipple pain.

Nipple shields (shield) may reduce pain during breastfeeding, but the impact on infant sucking dynamics is not known. We examined the effects of shield use on sucking dynamics, milk removal and nipple pain in two groups of breastfeeding dyads: pain group (PG): shield used for nipple pain; comparison group (CG): no breastfeeding difficulties. Twenty PG (6 ± 4 weeks postnatal) and 28 CG dyads (8 ± 6 weeks postnatal) attended 2 monitored breastfeeding sessions with shield use randomised. Within-subject outcomes were compared. PG: shield use did not affect intra-oral vacuum (peak p = 0.17, baseline p = 0.59), sucking frequency (p = 0.20) or milk transfer (40 mL vs 48 mL, p = 0.80; percentage of available milk removed (PAMR) 55% vs 57%, p = 0.88), and reduced McGill pain scores (p = 0.012). CG: shield use increased non-nutritive sucking (10% more, p = 0.049), and reduced nutritive sucking (18% less, p = 0.017) and milk transfer (63 mL vs 31 mL p < 0.001, PAMR 65% vs 36% p < 0.001). For both groups, feeding duration increased by 2 min (p < 0.0001) and non-nutritive portions of the feed increased with shield use.Conclusion: Nipple shield use improved maternal comfort and did not impact milk removal or sucking strength in PG, but significantly reduced milk transfer and nutritive sucking in CG. What is Known: • Mothers report that nipple shields reduce nipple pain and enable continued breastfeeding. • Concerns that nipple shield use may reduce milk transfer and alter infant sucking patterns are based on limited published evidence. What is New: • Nipple shield use is associated with a 25% reduction in pain scores in breastfeeding mothers with chronic nipple pain. • Milk transfer is not reduced in dyads that regularly use a shield for chronic nipple pain. • Intra-oral vacuums are not impacted by nipple shield use in mothers experiencing pain.

Centrifugation does not remove bacteria from the fat fraction of human milk.

Analysis of the human milk microbiome is complicated by the presence of a variable quantity of fat. The fat fraction of human milk is typically discarded prior to analysis. It is assumed that all cells are pelleted out of human milk by high speed centrifugation; however, studies of bovine milk have reported that bacteria may remain trapped within the fat fraction. Here, the bacterial DNA profiles of the fat fraction and cell pellet of human milk (n = 10) were analysed. Human and bacterial DNA was consistently recovered from the fat fraction of human milk (average of 12.4% and 32.7%, respectively). Staphylococcus epidermidis was significantly more abundant in the cell pellet compared to the fat fraction (P = 0.038), and three low-abundance species (< 5% relative abundance) were recovered from one fraction only. However, inclusion of fat reduced the efficiency of DNA extraction by 39%. Culture-based methods were used to quantify the distribution of an exogenously added strain of Staphylococcus aureus in human milk fractions. S. aureus was consistently recovered from the fat fraction (average 28.9%). Bacterial DNA profiles generated from skim milk or cell pellets are not representative of the entire human milk microbiome. These data have critical implications for the design of future work in this field.

Dietary pattern trajectories across adolescence and early adulthood and their associations with childhood and parental factors.

BACKGROUND: Although adolescent dietary patterns tend to be of poor quality, it is unclear whether dietary patterns established in adolescence persist into adulthood. OBJECTIVES: We examined trajectories across adolescence and early adulthood for 2 major dietary patterns and their associations with childhood and parental factors. METHODS: Using data from the Western Australian Pregnancy Cohort (Raine Study), intakes of 38 food groups were estimated at ages 14, 17, 20 and 22 y in 1414 participants using evaluated FFQs. Using factor analysis, 2 major dietary patterns (healthy and Western) were consistently identified across follow-ups. Sex-specific group-based modeling assessed the variation in individual dietary pattern z scores to identify group trajectories for each pattern between ages 14 and 22 y and to assess their associations with childhood and parental factors. RESULTS: Two major trajectory groups were identified for each pattern. Between ages 14 and 22 y, a majority of the cohort (70% males, 73% females) formed a trajectory group with consistently low z scores for the healthy dietary pattern. The remainder had trajectories showing either declining (27% females) or reasonably consistent healthy dietary pattern z scores (30% males). For the Western dietary pattern, the majority formed trajectories with reasonably consistent average scores (79% males, 81% females) or low scores that declined over time. However, 21% of males had a trajectory of steady, marked increases in Western dietary pattern scores over time. A lower maternal education and higher BMI (in kg/m2) were positively associated with consistently lower scores of the healthy dietary pattern. Lower family income, family functioning score, maternal age, and being in a single-parent family were positively related to higher scores of the Western dietary pattern. CONCLUSIONS: Poor dietary patterns established in adolescence are likely to track into early adulthood, particularly in males. This study highlights the transition between adolescence and early adulthood as a critical period and the populations that could benefit from dietary interventions.

Performance of Predictive Equations and Biochemical Measures Quantifying Net Endogenous Acid Production and the Potential Renal Acid Load.

INTRODUCTION: A limited number of studies have assessed the accuracy and precision of methods for determining the net endogenous acid production (NEAP) and its components. We aimed to investigate the performance of methods quantifying the diet dependent acid-base load. METHODS: Data from metabolic balance studies enabled calculations of NEAP according to the biochemical measures (of net acid excretion [NAE], urinary net endogenous acid production [UNEAP], and urinary potential renal acid load [UPRAL]) as well as estimative diet equations (by Frassetto et al., Remer and Manz, Sebastian et al., and Lemann) that were compared among themselves in healthy participants fed both acid and base forming diets for 6 days each. RESULTS: Seventeen participants (mean ± SD age, 60 ± 8 years; body mass index, 23 ± 2 kg/m2) provided 102 twenty-four-hour urine samples for analysis (NAE, 39 ± 38 mEq/d [range, -9 to 95 mEq/d]). Bland-Altman analysis comparing UNEAP to NAE showed good accuracy (bias, -2 mEq/d [95% confidence interval {CI}, -8 to 3]) and modest precision (limits of agreement, -32 to 28 mEq/d). Accurate diet equations included potential renal acid load (PRAL) by Sebastian et al. (bias, -4 mEq/d [95% CI, -8 to 0]) as well as NEAP by Lemann et al. (bias, 4 mEq/d [95% CI, -1 to 9]) and Remer and Manz (bias, -1 mEq/d [95% CI, -6 to 3]). CONCLUSIONS: Researchers are encouraged to collect measures of UPRAL and UNEAP; however, investigators drawing conclusions between the diet-dependent acid-base load and human health should consider the limitations within all methods.