Lung-Protective Ventilation for Pediatric Acute Respiratory Distress Syndrome: A Nonrandomized Controlled Trial.

OBJECTIVES: Despite the recommendation for lung-protective mechanical ventilation (LPMV) in pediatric acute respiratory distress syndrome (PARDS), there is a lack of robust supporting data and variable adherence in clinical practice. This study evaluates the impact of an LPMV protocol vs. standard care and adherence to LPMV elements on mortality. We hypothesized that LPMV strategies deployed as a pragmatic protocol reduces mortality in PARDS. DESIGN: Multicenter prospective before-and-after comparison design study. SETTING: Twenty-one PICUs. PATIENTS: Patients fulfilled the Pediatric Acute Lung Injury Consensus Conference 2015 definition of PARDS and were on invasive mechanical ventilation. INTERVENTIONS: The LPMV protocol included a limit on peak inspiratory pressure (PIP), delta/driving pressure (DP), tidal volume, positive end-expiratory pressure (PEEP) to Fio2 combinations of the low PEEP acute respiratory distress syndrome network table, permissive hypercarbia, and conservative oxygen targets. MEASUREMENTS AND MAIN RESULTS: There were 285 of 693 (41·1%) and 408 of 693 (58·9%) patients treated with and without the LPMV protocol, respectively. Median age and oxygenation index was 1.5 years (0.4-5.3 yr) and 10.9 years (7.0-18.6 yr), respectively. There was no difference in 60-day mortality between LPMV and non-LPMV protocol groups (65/285 [22.8%] vs. 115/406 [28.3%]; p = 0.104). However, total adherence score did improve in the LPMV compared to non-LPMV group (57.1 [40.0-66.7] vs. 47.6 [31.0-58.3]; p < 0·001). After adjusting for confounders, adherence to LPMV strategies (adjusted hazard ratio, 0.98; 95% CI, 0.97-0.99; p = 0.004) but not the LPMV protocol itself was associated with a reduced risk of 60-day mortality. Adherence to PIP, DP, and PEEP/Fio2 combinations were associated with reduced mortality. CONCLUSIONS: Adherence to LPMV elements over the first week of PARDS was associated with reduced mortality. Future work is needed to improve implementation of LPMV in order to improve adherence.

Cluster randomized trial designs for modeling time-varying intervention effects.

Stepped-wedge cluster randomized trials (SW-CRTs) are typically analyzed assuming a constant intervention effect. In practice, the intervention effect may vary as a function of exposure time, leading to biased results. The estimation of time-on-intervention (TOI) effects specifies separate discrete intervention effects for each elapsed period of exposure time since the intervention was first introduced. It has been demonstrated to produce results with minimum bias and nominal coverage probabilities in the analysis of SW-CRTs. Due to the design's staggered crossover, TOI effect variances are heteroskedastic in a SW-CRT. Accordingly, we hypothesize that alternative CRT designs will be more efficient at modeling certain TOI effects. We derive and compare the variance estimators of TOI effects between a SW-CRT, parallel CRT (P-CRT), parallel CRT with baseline (PB-CRT), and novel parallel CRT with baseline and an all-exposed period (PBAE-CRT). We also prove that the time-averaged TOI effect variance and point estimators are identical to that of the constant intervention effect in both P-CRTs and PB-CRTs. We then use data collected from a hospital disinvestment study to simulate and compare the differences in TOI effect estimates between the different CRT designs. Our results reveal that the SW-CRT has the most efficient estimator for the early TOI effect, whereas the PB-CRT typically has the most efficient estimator for the long-term and time-averaged TOI effects. Overall, the PB-CRT with TOI effects can be a more appropriate choice of CRT design for modeling intervention effects that vary by exposure time.

Estimation and reduction of bias in self-controlled case series with non-rare event dependent outcomes and heterogeneous populations.

The self-controlled case series (SCCS) is a commonly adopted study design in the assessment of vaccine and drug safety. Recurrent event data collected from SCCS studies are typically analyzed using the conditional Poisson model which assumes event times are independent within-cases. This assumption is violated in the presence of event dependence, where the occurrence of an event influences the probability and timing of subsequent events. When event dependence is suspected in an SCCS study, the standard recommendation is to include only the first event from each case in the analysis. However, first event analysis can still yield biased estimates of the exposure relative incidence if the outcome event is not rare. We first demonstrate that the bias in first event analysis can be even higher than previously assumed when subpopulations with different baseline incidence rates are present and describe an improved method for estimating this bias. Subsequently, we propose a novel partitioned analysis method and demonstrate how it can reduce this bias. We provide a recommendation to guide the number of partitions to use with the partitioned analysis, illustrate this recommendation with an example SCCS study of the association between beta-blockers and acute myocardial infarction, and compare the partitioned analysis against other SCCS analysis methods by simulation.

Estimation of trajectory of protective efficacy in infectious disease prevention trials using recurrent event times.

In studies of infectious disease prevention, the level of protective efficacy of medicinal products such as vaccines and prophylactic drugs tends to vary over time. Many products require administration of multiple doses at scheduled times, as opposed to one-off or continual intervention. Accurate information on the trajectory of the level of protective efficacy over time facilitates informed clinical recommendations and implementation strategies, for example, with respect to the timing of administration of the doses. Based on concepts from pharmacokinetic and pharmacodynamic modeling, we propose a non-linear function for modeling the trajectory after each dose. The cumulative effect of multiple doses of the products is captured by an additive series of the function. The model has the advantages of parsimony and interpretability, while remaining flexible in capturing features of the trajectories. We incorporate this series into the Andersen-Gill model for analysis of recurrent event time data and compare it with alternative parametric and non-parametric functions. We use data on clinical malaria disease episodes from a trial of four doses of an anti-malarial drug combination for chemoprevention to illustrate, and evaluate the performance of the methods using simulation. The proposed method out-performed the alternatives in the analysis of real data in terms of Akaike and Bayesian Information Criterion. It also accurately captured the features of the protective efficacy trajectory such as the area under curve in simulations. The proposed method has strong potential to enhance the evaluation of disease prevention measures and improve their implementation strategies.

ENABLE-SG (Educate, Nurture, Advise, Before Life Ends for Singapore) as a proactive palliative care model: protocol for a hybrid type 1 effectiveness-implementation randomized wait-list controlled trial.

BACKGROUND: Specialist palliative care is often provided late in the patient's disease trajectory in response to uncontrolled symptoms. Shifting from this reactionary illness-stress paradigm to a proactive health-wellness approach, the ENABLE (Educate, Nurture, Advise, Before Life Ends) telehealth model aims to enhance the coping, stress and symptom management, self-care, and advance care planning skills of patients with advanced cancers and their caregivers. The ENABLE model has been culturally adapted to Singapore (ENABLE-SG) and pilot-tested. A hybrid type 1 effectiveness-implementation design will be used to evaluate the effectiveness of ENABLE-SG while collecting real-world implementation data. METHODS: This single-centre, assessor-blind, wait-list (immediately vs. 6 months) randomized controlled trial will recruit 300 adult patients within 60 days of an advanced cancer diagnosis and their family caregivers from the National Cancer Centre of Singapore. ENABLE-SG comprises structured psychoeducational sessions with a telehealth coach, covering essential topics of early palliative care. Participants will be assessed at baseline and every 3 months until patient's death, 12 months (caregivers), or end of study (patients). The primary outcome is patient quality of life 6 months after baseline. Secondary patient-reported outcomes include mood, coping, palliative care concerns, and health status. Secondary caregiver-reported outcomes include caregiver quality of life, mood, coping, and care satisfaction. Mixed-effects regression modelling for repeated measurements will be used. To assess the effectiveness of ENABLE-SG versus usual care, patient and caregiver outcomes at 6 months will be compared. To compare earlier versus delayed ENABLE-SG, patient and caregiver outcomes at 12 months will be compared. Within the hybrid type 1 effectiveness-implementation design, implementation outcomes will be evaluated in both the early and delayed groups. Acceptability, adoption, appropriateness, and feasibility will be assessed using a feedback survey and semi-structured interviews with a purposive sample of patients, caregivers, and healthcare providers. Transcribed interviews will be analysed thematically. Other implementation outcomes of penetration, fidelity, and cost will be assessed using records of study-related processes and summarized using descriptive statistics. A cost-effectiveness analysis will also be conducted. DISCUSSION: This study will assess both effectiveness and implementation of ENABLE-SG. Insights into implementation processes can facilitate model expansion and upscaling. TRIAL REGISTRATION: Registered prospectively on ClinicalTrials.gov, NCT06044441. Registered on 21/09/2023.

Novel 3-arm wait-list controlled trial designs together with mixed-effects analysis improve precision of treatment effect estimators.

Clinical trialists have long been searching for approaches to increase statistical power without increasing sample size. Conventional wait-list controlled (WLC) trials are limited to two trial arms and two or three repeated measurements per person. These features limit statistical power. Furthermore, their analysis is usually based on analysis of covariance or mixed effects modelling, with a focus on estimating treatment effect at one time-period after initiation of therapy. We propose two 3-arm WLC trial designs together with a mixed-effects analysis framework. The designs require three or four repeated measurements per person. The analytic framework defines up to three treatment effect estimands, representing the effects at one to three time-periods after initiation of therapy. The precision (inverse of variance) of the treatment effect estimators in the new and conventional trial designs are analytically derived and evaluated in simulations. The results are interpreted in the context of a cognitive training trial in older people. The proposed designs and analysis methods increase the precision level of treatment effect estimators as compared to conventional designs and analyses. Given a target level of statistical power, the proposed methods require a smaller number of participants per trial than the conventional methods, without necessarily increasing the number of measurements per trial. Furthermore, the proposed analytic framework sheds light on the treatment effects at different times after initiation of therapy, which is not usually considered in conventional WLC trial analysis. In situations that a WLC trial is appropriate, the 3-arm designs are useful alternatives to existing 2-arm designs.

Modelling non-linear patterns of time-varying intervention effects on recurrent events in infectious disease prevention studies.

Protective efficacy of vaccines and pharmaceutical products for prevention of infectious diseases usually vary over time. Information on the trajectory of the level of protection is valuable. We consider a parsimonious, non-linear and non-monotonic function for modelling time-varying intervention effects and compare it with several alternatives. The cumulative effects of multiple doses of intervention over time can be captured by an additive series of the function. We apply it to the Andersen-Gill model for analysis of recurrent time-to-event data. We re-analyze data from a trial of intermittent preventive treatment for malaria to illustrate and evaluate the method by simulation.

Metabolic health status and fecundability in a Singapore preconception cohort study.

BACKGROUND: Obesity compromises metabolic health and female fertility, yet not all obese women are similar in metabolic status. The extent to which fecundability is influenced by the metabolic health status of women who are overweight or obese before conception is unknown. OBJECTIVE: This study aimed to: (1) determine the metabolic health status, and (2) examine the association between metabolic health status and fecundability of overweight and obese women trying to conceive in the Singapore PREconception Study of long-Term maternal and child Outcomes cohort study. STUDY DESIGN: We conducted a prospective preconception cohort study of Asian women (Chinese, Malay, and Indian) aged 18 to 45 years trying to conceive who were treated from 2015 to 2017 in KK Women's and Children's Hospital in Singapore (n=834). We defined women to have metabolically unhealthy status if they: (1) met 3 or more modified Joint Interim Statement metabolic syndrome criteria; or (2) had homeostasis model assessment-insulin resistance index ≥2.5. Body mass index was categorized as normal (18.5-22.9 kg/m2), overweight (23-27.4 kg/m2), or obese (≥27.5 kg/m2) on the basis of cutoff points for Asian populations. Fecundability was measured by time to pregnancy in menstrual cycles within a year of enrolment. Discrete-time proportional hazards models were used to estimate fecundability odds ratios, with adjustment for confounders and accounting for left truncation and right censoring. RESULTS: Of 232 overweight women, 28 (12.1%) and 25 (10.8%) were metabolically unhealthy by metabolic syndrome ≥3 criteria and homeostasis model assessment-insulin resistance ≥2.5, respectively. Of 175 obese women, 54 (30.9%) and 93 (53.1%) were metabolically unhealthy by metabolic syndrome ≥3 criteria and homeostasis model assessment-insulin resistance ≥2.5, respectively. Compared with metabolically healthy normal-weight women, lower fecundability was observed in metabolically unhealthy overweight women on the basis of metabolic syndrome criteria (fecundability odds ratios, 0.38 [95% confidence interval, 0.15-0.92]) and homeostasis model assessment-insulin resistance (fecundability odds ratios, 0.68 [95% confidence interval, 0.33-1.39]), with metabolic syndrome criteria showing a stronger association. Metabolically unhealthy obese women showed lower fecundability than the healthy normal-weight reference group by both metabolic syndrome (fecundability odds ratios, 0.35; 95% confidence interval, 0.17-0.72) and homeostasis model assessment-insulin resistance criteria (fecundability odds ratios, 0.43; 95% confidence interval, 0.26-0.71). Reduced fecundability was not observed in overweight or obese women who showed healthy metabolic profiles by either definition. CONCLUSION: Overweight or obesity was not synonymous with having metabolic syndrome or insulin resistance. In our preconception cohort, metabolically unhealthy overweight and obese women showed reduced fecundability, unlike their counterparts who were metabolically healthy. These findings suggest that metabolic health status, rather than simply being overweight and obese per se, plays an important role in fecundability.

Inclusion of unexposed clusters improves the precision of fixed effects analysis of stepped-wedge cluster randomized trials.

Stepped-wedge cluster randomized trials (SW-CRTs) are typically analyzed using mixed effects models. The fixed effects model is a useful alternative that controls for all time-invariant cluster-level confounders and has proper control of type I error when the number of clusters is small. In principle, all clusters in SW-CRTs are designed to eventually receive the intervention, but in real-world research, some trials can end with unexposed clusters (clusters that never received the intervention), such as when a trial is terminated early based on interim analysis results. Typically, unexposed clusters are expected to contribute no information to the fixed effects intervention effect estimator and are excluded from fixed effects analyses. In this article we mathematically prove that inclusion of unexposed clusters improves the precision of the fixed effects least squares dummy variable (LSDV) intervention effect estimator, re-analyze data from a recent SW-CRT of a novel palliative care intervention containing an unexposed cluster, and evaluate the methods by simulation. We found that including unexposed clusters improves the precision of the fixed effects LSDV intervention effect estimator in both real and simulated datasets. Our simulations also reveal an increase in power and decrease in root mean square error. These improvements are present even if the assumptions of constant residual variance and period effects are violated. In the case that a SW-CRT concludes with unexposed clusters, these unexposed clusters can be included in the fixed effects LSDV analysis to improve precision, power, and root mean square error.

Ratio estimators of intervention effects on event rates in cluster randomized trials.

We consider five asymptotically unbiased estimators of intervention effects on event rates in non-matched and matched-pair cluster randomized trials, including ratio of mean counts r1 , ratio of mean cluster-level event rates r2 , ratio of event rates r3 , double ratio of counts r4 , and double ratio of event rates r5 . In the absence of an indirect effect, they all estimate the direct effect of the intervention. Otherwise, r1 , r2, and r3 estimate the total effect, which comprises the direct and indirect effects, whereas r4 and r5 estimate the direct effect only. We derive the conditions under which each estimator is more precise or powerful than its alternatives. To control bias in studies with a small number of clusters, we propose a set of approximately unbiased estimators. We evaluate their properties by simulation and apply the methods to a trial of seasonal malaria chemoprevention. The approximately unbiased estimators are practically unbiased and their confidence intervals usually have coverage probability close to the nominal level; the asymptotically unbiased estimators perform well when the number of clusters is approximately 32 or more per trial arm. Despite its simplicity, r1 performs comparably with r2 and r3 in trials with a large but realistic number of clusters. When the variability of baseline event rate is large and there is no indirect effect, r4 and r5 tend to offer higher power than r1 , r2, and r3 . We discuss the implications of these findings to the planning and analysis of cluster randomized trials.

Investigating 5-Level EQ-5D (EQ-5D-5L) Values Based on Preferences of Patients With Heart Disease.

OBJECTIVES: Several studies have shown that patients with heart disease value hypothetical health states differently from the general population. We aimed to investigate the health preferences of patients with heart disease and develop a value set for the 5-level EQ-5D (EQ-5D-5L) based on these patient preferences. METHODS: Patients with confirmed heart disease were recruited from 2 hospitals in Singapore. A total of 86 EQ-5D-5L health states (10 per patient) were valued using a composite time trade-off method according to the international valuation protocol for EQ-5D-5L; 20-parameter linear models and 8-parameter cross-attribute level effects models with and without an N45 term (indicating whether any health state dimension at level 4 or 5 existed) were estimated. Each model included patient-specific random intercepts. Model performance was evaluated for out-of-sample and in-sample predictive accuracy in terms of root mean square error. The discriminative ability of the utility values was assessed using heart disease-related functional classes. RESULTS: A total of 576 patients were included in the analysis. The preferred model, with the lowest out-of-sample root mean square error, was a 20-parameter linear model including N45. Predicted utility values ranged from -0.727 for the worst state to 1 for full health; the value for the second-best state was 0.981. Utility values demonstrated good discriminative ability in differentiating among patients of varied functional classes. CONCLUSIONS: An EQ-5D-5L value set representing the preferences of patients with heart disease was developed. The value set could be used for patient-centric economic evaluation and health-related quality of life assessment for patients with heart disease.

Inclusion of unexposed subjects improves the precision and power of self-controlled case series method.

The self-controlled case series is an important method in the studies of the safety of biopharmaceutical products. It uses the conditional Poisson model to make comparison within persons. In models without adjustment for age (or other time-varying covariates), cases who are never exposed to the product do not contribute any information to the estimation. We provide analytic proof and simulation results that the inclusion of unexposed cases in the conditional Poisson model with age adjustment reduces the asymptotic variance of the estimator of the exposure effect and increases power. We re-analysed a vaccine safety dataset to illustrate.

Maternal meal irregularities during pregnancy and lifestyle correlates.

Meal regularity can influence metabolic health. However, habits of skipping and delaying meals are rarely studied among pregnant women. This study examined the incidence of maternal meal skipping and meal delaying, and their associated lifestyle patterns during pregnancy. Pregnant women in the second trimester (18-24 weeks' gestation; n = 90) were recruited from the antenatal clinics in KK Women's and Children's Hospital, Singapore, 2019-2020. Data on sociodemographic, lifestyle and dietary habits were collected. Firstly, principal component analysis was used to identify lifestyle patterns. Subsequently, multiple logistic regression model was used to examine the association of lifestyle patterns with meal skipping and delaying. In total, 32 (35.6%) women had irregular meals, in which 25 (27.8%) and 26 (28.9%) women reported meal skipping and meal delaying for at least 3 times a week, respectively. Women with 'poor sleep and emotion' pattern as characterized by higher scores for poor sleep, depression, anxiety, and stress symptoms were associated with higher odds of meal skipping (OR 1.99; 95% CI 1.13, 3.53) and meal delaying (2.50; 1.31, 4.79). 'Sedentary' pattern, as characterized by greater daily time spent on television and screen electronic devices, and 'weight and inactivity' pattern, as characterized by higher BMI and physical inactivity level, were not associated with meal regularity. In this study, almost one-third of women reporting meal irregularities during pregnancy. 'Poor sleep and emotion' pattern is associated with a higher incidence of meal skipping and delaying. These findings suggest the need to address sleep and emotional health in interventions promoting healthy nutrition specifically regular eating in pregnancy.

Associations between Gut Microbiota and Intestinal Inflammation, Permeability and Damage in Young Malawian Children.

BACKGROUND: Environmental enteric dysfunction (EED) is common in low- and middle-income countries and associated with childhood undernutrition. The composition of gut microbiota has been implicated in the pathogenesis of EED. Our aim was to assess the associations between gut microbiota and EED biomarkers in rural Malawian children. We hypothesized that there would be an inverse association between microbiota maturity and diversity and fecal concentrations of EED biomarkers. METHODS: We used data from fecal samples collected at 6, 18 and 30 months from 611 children who were followed up during a nutrition intervention trial. The primary time point for analysis was 18 months. Microbiota data were obtained through 16S rRNA sequencing and variables included microbiota maturity and diversity, phylogenetic dissimilarity and relative abundances of individual taxa. EED biomarkers included calprotectin (marker of inflammation), alpha-1 antitrypsin (intestinal permeability) and REG1B (intestinal damage). RESULTS: There was an inverse association between microbiota maturity and diversity and fecal concentrations of all 3 EED biomarkers at 18 months (p≤0.001). The results were similar at 30 months, while at 6 months inverse associations were found only with calprotectin and alpha-1 antitrypsin concentrations. At 18 months, EED biomarkers were not associated with phylogenetic dissimilarity, but at 6 and 30 months several associations were observed. Individual taxa predicting EED biomarker concentrations at 18 months included several Bifidobacterium and Enterobacteriaceae taxa as well as potentially displaced oral taxa. CONCLUSIONS: Our findings support the hypothesis of an inverse association between microbiota maturity and diversity and EED in rural Malawian children.

Chronic childhood undernutrition is an important public health concern that affects about 150 million children, mostly in low- and middle-income countries. Undernutrition is caused by insufficient nutrient intake and frequent infections, but there are also other underlying factors. One of these is a condition called environmental enteric dysfunction (EED), which is characterized by intestinal inflammation and damage without apparent clinical symptoms. EED is thought to be caused by the ingestion of pathogenic bacteria that leads to changes in the intestine such as increased permeability and decreased absorptive capacity. This might make the intestinal wall vulnerable to bacterial invasion and reduce the absorption of nutrients. Besides potentially pathogenic bacteria, there are many commensal bacteria in the gastrointestinal tract that have beneficial functions and that interact with the immune system. The aim of our study was to assess the associations between all these bacteria, that is the intestinal microbiota and biomarkers of EED. We used data from fecal samples collected from young children participating in a nutrition intervention trial in rural Malawi. Our findings support an inverse association between the diversity and maturity of the intestinal microbiota and biomarkers of EED. Additionally, we identified the differences at the level of individual bacterial taxa (groups of bacteria defined by genetic similarity) between participants with different levels of EED biomarkers. Due to the type of study, we cannot determine whether the observed associations represent a causal relationship between the intestinal microbiota and EED. This as well as the exact mechanisms behind these associations should be assessed in further studies.

Hope, bias and survival expectations of advanced cancer patients: A cross-sectional study.

OBJECTIVE: Many patients with advanced illness are unrealistically optimistic about their prognosis. We test for the presence of several cognitive biases, including optimism bias, illusion of superiority, self-deception, misattribution, and optimistic update bias, that could explain unrealistically optimistic prognostic beliefs among advanced cancer patients and quantifies the extent to which hope exacerbates these biases. METHODS: A cross-sectional survey was administered to 200 advanced cancer patients with physician-estimated prognoses of one year or less. Hope was measured using the Herth Hope Index (HHI). Hypotheses were tested using linear and logistic regressions and a structural-equation model. RESULTS: Results are consistent with the presence of optimism bias, illusion of superiority, self-deception, and misattribution. All of these biases are amplified by higher levels of hope. Each 1-point higher HHI is associated with a 6% (OR: 1.06; 95% CI: 1.01-1.11) greater odds of believing their illness is curable, a 0.33-year (95% CI: 0.17-0.49) longer expected survival, a 6% (OR: 1.06; 95% CI: 1.02-1.11) higher probability of believing that survival outcomes are better than the average patient, a 5% higher odds of believing primary intent of treatment is curative (OR: 1.05; 95% CI: 1.00-1.10), and a 12% (OR: 1.12; 95% CI: 1.05-1.17) higher odds of believing they are well-informed. Mediation analyses revealed that hope significantly mediates the effect of mental-well-being and loneliness on expected survival. CONCLUSIONS: Results suggest advanced cancer patients succumb to several cognitive biases which are exacerbated by greater levels of hope. As a result, they are susceptible to possible over-treatment and regret.

Comparing the effect of a consult model versus an integrated palliative care and medical oncology co-rounding model on health care utilization in an acute hospital - an open-label stepped-wedge cluster-randomized trial.

BACKGROUND: The benefit of specialist palliative care for cancer inpatients is established, but the best method to deliver specialist palliative care is unknown. AIM: To compare a consult model versus a co-rounding model; both provide the same content of specialist palliative care to individual patients but differ in the level of integration between palliative care and oncology clinicians. DESIGN: An open-label, cluster-randomized trial with stepped-wedge design. The primary outcome was hospital length of stay; secondary outcomes were 30-day readmissions and access to specialist palliative care. ClinicalTrials.gov number NCT03330509. SETTING/PARTICIPANTS: Cancer patients admitted to the oncology inpatient service of an acute hospital in Singapore. RESULTS: A total of 5681 admissions from December 2017 to July 2019 were included, of which 5295 involved stage 3-4 cancer and 1221 received specialist palliative care review. Admissions in the co-rounding model had a shorter hospital length of stay than those in the consult model by 0.70 days (95%CI -0.04 to 1.45, p = 0.065) for all admissions. In the sub-group of stage 3-4 cancer patients, the length of stay was 0.85 days shorter (95%CI 0.05-1.65, p = 0.038). In the sub-group of admissions that received specialist palliative care review, the length of stay was 2.62 days shorter (95%CI 0.63-4.61, p = 0.010). Hospital readmission within 30 days (OR1.03, 95%CI 0.79-1.35, p = 0.822) and access to specialist palliative care (OR1.19, 95%CI 0.90-1.58, p = 0.215) were similar between the consult and co-rounding models. CONCLUSIONS: The co-rounding model was associated with a shorter hospital length of stay. Readmissions within 30 days and access to specialist palliative care were similar.

Fecundability in reproductive aged women at risk of sexual dysfunction and associated risk factors: a prospective preconception cohort study.

BACKGROUND: Female sexual dysfunction (FSD) is a prevalent problem, affecting up to 41% of reproductive aged women worldwide. However, the association between female sexual function (FSF) and fecundability in women attempting to conceive remains unclear. We aimed 1) to examine the association between FSF in reproductive-aged preconception Asian women and fecundability, as measured by time-to-pregnancy in menstrual cycles, and 2) to examine lifestyle and behavioral factors associated with FSF. METHODS: From the Singapore PREconception Study of long-Term maternal and child Outcomes (S-PRESTO) prospective cohort, we evaluated FSF using the 6-item Female Sexual Function Index (FSFI-6) and ascertained time-to-pregnancy within a year of baseline assessment. We estimated fecundability ratio (FR) and 95% confidence interval (CI) using the discrete-time proportional hazards model, accounting for left-truncation and right censoring. We used multivariable logistic and linear regression models to identify potential factors related to FSF. RESULTS: Among 513 participants, 58.9% had low FSF as defined by a total FSFI-6 score at or below the median value of 22. Compared to women with high FSF, those with low FSF had a 27% reduction in fecundability (FR 0.73; 95% CI 0.54, 0.99), with adjustment for age, ethnicity, education, parity and body mass index. Overall, the FRs generally reduced with decreasing FSFI-6 scores. Physical activity, obesity, absence of probable depression and anxiety were independently associated with reduced odds of low FSF and increased FSFI-6 scores, after adjusting for sociodemographic characteristics. CONCLUSIONS: Low FSF is associated with a longer time-to-pregnancy. Early evaluation and optimization of FSF through increased physical activity and optimal mental health may help to improve female fecundity. The finding of obese women having improved FSF remains uncertain which warrants further investigations on plausibly mechanisms. In general, the current finding highlights the importance of addressing FSF in preconception care service for general women, which is currently lacking as part of the fertility promotion effort in the country.

Faecal regenerating 1B protein concentration is not associated with child growth in rural Malawi.

AIM: This study was designed to determine whether faecal regenerating 1B protein (REG1B) concentration is associated with physical growth among 6-30-month-old children in rural Malawi. METHODS: This was a secondary analysis from a randomised controlled trial in rural Malawi in which we followed-up 790 live-born infants from birth to 30 months of age. We collected anthropometric data at the age of 6, 12, 18, 24 and 30 months. We measured faecal REG1B concentration by enzyme-linked immunosorbent assay (ELISA) technique using stool samples collected at 6, 18 and 30 months of age. We assessed the association between faecal REG1B concentration and children's physical growth using linear regression and longitudinal data analysis. RESULTS: Of 790 live-born infants enrolled, 694 (87%) with at least one faecal REG1B concentration measurement were included in the analysis. Faecal REG1B concentration was not associated with the children's concurrent length-for-age z-score (LAZ), weight-for-age z-score (WAZ), weight-for-length z-score (WLZ) and mid-upper arm circumference-for-age z-score (MUACZ) at any time point (P > 0.05), nor with a change in their anthropometric indices in the subsequent 6-month period (P > 0.05). CONCLUSIONS: Faecal REG1B concentration is not associated with LAZ, WAZ, WLZ and MUACZ among 6-30-month-old infants and children in rural Malawi.

Validity and reliability of the English and translated Chinese versions of the Integrated Palliative care Outcome Scale (IPOS) in Singapore.

CONTEXT: Measurement of patient-centred outcomes enables clinicians to focus on patient and family priorities and enables quality of palliative care to be assessed. OBJECTIVES: This study aimed to evaluate the validity and reliability of the English and translated Chinese versions of the Integrated Palliative care Outcome Scale (IPOS) among advanced cancer patients in Singapore. METHODS: IPOS was forward and backward translated from English into Chinese. Structural validity was assessed by confirmatory factor analysis; known-group validity by comparing inpatients and community patients; construct validity by correlating IPOS with Edmonton Symptom Assessment System-revised (ESAS-r) and Functional Assessment of Cancer Therapy-General (FACT-G); internal consistency by Cronbach's alpha; inter-rater reliability between patient and staff responses; test-retest reliability of patient responses between two timepoints. RESULTS: One hundred eleven English-responding and 109 Chinese-responding patients participated. The three-factor structure (Physical Symptoms, Emotional Symptoms and Communication and Practical Issues) was confirmed with Comparative Fit Index and Tucker-Lewis-Index > 0.9 and Root Mean Square Error of Approximation < 0.08. Inpatients scored higher than outpatients as hypothesised. Construct validity (Pearson's correlation coefficient, r ≥ |0.608|) was shown between the related subscales of IPOS and FACT-G and ESAS-r. Internal consistency was confirmed for total and subscale scores (Cronbach's alpha≥0.84), except for the Communication and Practical Issues subscale (Cronbach's alpha = 0.29-0.65). Inter-rater reliability (Intra-class correlation coefficient [ICC] ≤ 0.43) between patient and staff responses was insufficient. Test-retest reliability was confirmed with Intra-class correlation coefficient ICC = 0.80 (English) and 0.88 (Chinese) for IPOS Total. CONCLUSION: IPOS in English and Chinese showed good validity, good internal consistency, and good test-retest reliability, except for the Communication and Practical Issues subscale. There was poor inter-rater reliability between patients and staff.

A feasible and acceptable multicultural psychosocial intervention targeting symptom management in the context of advanced breast cancer.

OBJECTIVE: Advanced breast cancer patients around the world experience high symptom burden (ie, distress, pain, and fatigue) and are in need of psychosocial interventions that target symptom management. This study examined the feasibility, acceptability, and engagement of a psychosocial intervention that uses cognitive-behavioral strategies along with mindfulness and values-based activity to enhance patients' ability to manage symptoms of advanced disease in a cross-cultural setting (United States and Singapore). Pre-treatment to post-treatment outcomes for distress, pain, and fatigue were compared between intervention recipients and waitlisted controls. METHODS: A pilot randomized controlled trial included women with advanced breast cancer (N = 85) that were recruited in the United States and Singapore. Participants either received the four session intervention or be put on waitlist. Descriptive statistics and effect size of symptom change were calculated. RESULTS: The psychosocial intervention was found to be feasible as indicated through successful trial accrual, low study attrition (15% ), and high intervention adherence (77% completed all sessions). Acceptability (ie, program satisfaction and cultural sensitivity) and engagement to the study intervention (ie, practice of skills taught) were also high. Anxiety, depression, and fatigue scores remained stable or improved among intervention participants while the same symptoms worsened in the control group. In general, effect sizes are larger in the US sample compared with the Singapore sample. CONCLUSIONS: The cognitive-behavioral, mindfulness, and values-based intervention is feasible, acceptable, and engaging for advanced breast cancer patients in a cross-cultural setting and has potential for efficacy. Further larger-scaled study of intervention efficacy is warranted.