Background-The lack of evidence-based outcomes data leads to uncertainty in developing treatment regimens in children newly diagnosed with Ulcerative Colitis (UC). We hypothesized that pre-treatment clinical, transcriptomic, and microbial factors predict disease course. Methods-We performed an inception cohort study of 428 paediatric UC patients receiving standardised mesalazine or corticosteroids (CS), with pre-established criteria for escalation to thiopurines or anti-TNFα. RNA sequencing (n=206) defined pre-treatment rectal gene expression. 16S sequencing (n=343) characterized rectal/fecal microbiota. The primary outcome was Week 52 CS-free remission (SFR) with no therapy beyond mesalazine. Findings-Week 52 SFR was achieved in 150/400 (38%) participants; 74/400 (19%) received thiopurines alone, 12¾00 (31%) received anti-TNFα, and 25/400 (6%) colectomy. Lower baseline clinical severity, higher baseline hemoglobin, and Week 4 clinical remission were associated with achieving Week 52 SFR (logistic model AUC:0.70 (95% CI 0.65-0.75), specificity 77% (CI 71-82), n=386). Baseline severity and week 4 remission were validated inan independent cohort of 274 participants. An antimicrobial peptide gene signature (OR:0.6, p=0.002) and Ruminococcaceae (OR:1.4, p=0.04) and Sutterella (OR: 0.8, p=0.05) abundance were independently associated with SFR after adjusting for the clinical predictors. Amongst moderateto-severe patients, escalation to anti-TNFα was associated with increased baseline clinical severity and decreased hemoglobin, serum 25 (OH) D, and rectal eosinophils (logistic model AUC:0.78 (95% CI 0.72-0.84), specificity 85% (CI 78-93), n=232). A rectal transportgene signature (OR: 0.3, p=0.0006) and Oscillospira abundance (OR:0.6, p=0.02) were independently associated with escalation to anti-TNFα after adjusting for the clinical predictors. Interpretation-Our findings support the utility of using initial clinical activity and treatment response by 4 weeks to predict Week 52 CS-free remission with mesalazine alone in children newly diagnosed with UC. The development of personalized clinical and biological signatures holds the promise of informing UC therapeutic decisions.

Background Previous retrospective pediatric ulcerative colitis (UC) studies had limited ability to describe disease progression and identify predictors of treatment response. The PROTECT multicentre inception cohort aimed to identify characteristics associated with outcomes following standardized therapy after initial diagnosis. Methods We completed a prospective multicentre inception cohort study at 29 centres in the USA and Canada of paediatric patients aged 4–17 years newly diagnosed with UC who received initial standardized treatment with mesalamine or corticosteroids (CS) guided by the Pediatric UC Activity Index (PUCAI). The key outcomes for this analysis were week 12 CS-free remission, defined as PUCAI<10 and taking only mesalamine, and treatment escalation to anti-TNFα, immunomodulators or colectomy among those initially treated with intravenous (IV) CS. Independent predictors were identified through multivariable logistic regression using a per-protocol approach. Registered with clinicaltrials.gov: NCT01536535 Findings 428 children initiated mesalamine (n=136), oral CS (n=144), or IV CS (n=148) with initial mean ± standard deviation PUCAI of 31±13, 50±14, and 67±14, respectively (p<0.001). By week 12, CS-free remission taking mesalamine only was achieved by 48% (64/132) initiating with mesalamine, 33% (47/141) with oral CS, and 21% (30/143) with IV CS (p<0.001). Treatment escalation was required in 7% (9/132), 15% (21/141), and 36% (52/143), respectively (p<0.001); 8 patients, all initially treated with IV CS, received colectomy. Predictors of week 12 CS-free remission were baseline PUCAI <35 (odds ratio (OR) 2.4, 95% CI 1.4–4.2; p=0.002), higher baseline albumin by 1 g/dL increments among age < 12 years (4.1, 1.9–8.6; p=0.0003), and week 4 remission (6.3, 3.8–10.4; p<0.0001). Predictors of treatment escalation by week 12 in those initially treated with IV CS included baseline total Mayo score ≥11 (2.6, 0.9–7.2; p=0.068), rectal biopsy eosinophil count ≤32/high power field (4.6, 1.6–12.8; p=0.004), rectal biopsy surface villiform changes (3.1, 1.1–8.6; p=0.034) and not achieving week 4 remission (30.2, 6.4–144.2; p<0.0001). Interpretation Our findings provide guidelines to assess response of children newly diagnosed with UC to standardized initial therapy and identify predictors of treatment response and failure. These data suggest that additional therapeutic interventions may be warranted to improve early outcomes, especially in those presenting with severe disease and requiring intravenous corticosteroids.

BackgroundEvidence suggests that fasting, during which only water is consumed, results in potentially health promoting physiological effects. However, peer-reviewed research assessing the safety of water-only fasting is lacking. To address this, we conducted a chart review to describe adverse events (AEs) that occurred during medically supervised, water-only fasting.MethodsElectronic charts from patient visits to a residential medical facility from 2006 to 2011 were reviewed. Patients who were at least 21 years of age and water-only fasted for ≥2 consecutive days with a refeeding period equal to half of the fast length were included. Out of 2539 charts, 768 visits met our inclusion and exclusion criteria. AEs were abstracted from chart notes and classified according to CTCAE (v4.03) and MedDRA (v12.1) terminology. Descriptive analysis of AEs is reported.ResultsDuring the protocol period, the highest grade AE (HGAE) in 555 visits was a grade 2 event or lower, in 212 visits it was a grade 3 event, in 1 visit it was a grade 4 event, and there were no grade 5 events. There were 2 (0.002%) visits with a serious adverse event (SAE). The majority of AEs identified were mild (n = 4490, 75%) in nature and known reactions to fasting.ConclusionsTo our knowledge, this is the most comprehensive analysis of AEs experienced during medically supervised, water-only fasting conducted to date. Overall, our data indicate that the majority of AEs experienced were mild to moderate and known reactions to fasting. This suggests that the protocol used in this study can be safely implemented in a medical setting with minimal risk of a SAE.Electronic supplementary materialThe online version of this article (10.1186/s12906-018-2136-6) contains supplementary material, which is available to authorized users.

BackgroundEpidemiologic evidence, reinforced by clinical and laboratory studies, shows that the rich Western diet is the major underlying cause of death and disability (e.g, from cardiovascular disease and type 2 diabetes) in Western industrialized societies. The objective of this study is to document the effects that eating a low-fat (≤10% of calories), high-carbohydrate (~80% of calories), moderate-sodium, purely plant-based diet ad libitum for 7 days can have on the biomarkers of cardiovascular disease and type 2 diabetes.MethodsRetrospective analysis of measurements of weight, blood pressure, blood sugar, and blood lipids and estimation of cardiovascular disease risk at baseline and day 7 from 1615 participants in a 10-day residential dietary intervention program from 2002 to 2011. Wilcoxon’s signed-rank test was used for testing the significance of changes from baseline.ResultsThe median (interquartile range, IQR) weight loss was 1.4 (1.8) kg (p < .001). The median (IQR) decrease in total cholesterol was 22 (29) mg/dL (p < .001). Even though most antihypertensive and antihyperglycemic medications were reduced or discontinued at baseline, systolic blood pressure decreased by a median (IQR) of 8 (18) mm Hg (p < .001), diastolic blood pressure by a median (IQR) of 4 (10) mm Hg (p < .001), and blood glucose by a median (IQR) of 3 (11) mg/dL (p < .001). For patients whose risk of a cardiovascular event within 10 years was >7.5% at baseline, the risk dropped to 5.5% (>27%) at day 7 (p < .001).ConclusionsA low-fat, starch-based, vegan diet eaten ad libitum for 7 days results in significant favorable changes in commonly tested biomarkers that are used to predict future risks for cardiovascular disease and metabolic diseases.

Interference occurs when the treatment (or exposure) of one individual affects the outcomes of others. In some settings, it may be reasonable to assume that individuals can be partitioned into clusters such that there is no interference between individuals in different clusters, that is, there is partial interference. In observational studies with partial interference, inverse probability weighted (IPW) estimators have been something else different possible treatment effects. However, the validity of IPW estimators depends on the propensity score being known or correctly modelled. Alternatively, one can estimate the treatment effect using an outcome regression model. In this paper, we propose doubly robust (DR) estimators that utilize both models and are consistent and asymptotically normal if either model, but not necessarily both, is correctly specified. Empirical results are presented to demonstrate the DR property of the proposed estimators and the efficiency gain of DR over IPW estimators when both models are correctly specified. The different estimators are illustrated using data from a study examining the effects of cholera vaccination in Bangladesh.

M-estimation, or estimating equation, methods are widely applicable for point estimation and asymptotic inference. In this paper, we present an R package that can find roots and compute the empirical sandwich variance estimator for any set of user-specified, unbiased estimating equations. Examples from the M-estimation primer by Stefanski and Boos (2002) demonstrate use of the software. The package also includes a framework for finite sample, heteroscedastic, and autocorrelation variance corrections, and a website with an extensive collection of tutorials.

PurposeIn contrast to randomized clinical trials, comparative safety and effectiveness assessments of osteoporosis medications in clinical practice may be subject to confounding by indication. We used negative control outcomes to detect residual confounding when comparing osteoporosis medications.MethodsUsing MarketScan Commercial and Supplemental claims, we identified women aged ≥55 years who initiated an oral bisphosphonate (BP) (risedronate, alendronate, or ibandronate), denosumab (an injected biologic), or intravenous zoledronic acid (ZA) from October 1, 2010 to September 30, 2015. Women with Paget's disease or cancer were excluded. We compared individual oral BPs to each other, denosumab to ZA, denosumab to oral BPs, and ZA to oral BPs, with respect to 11 negative control outcomes identified by subject matter experts. We estimated the 12‐month cumulative risk difference (RD) using inverse probability of treatment and censoring weights.ResultsAmong 148 587 women, most initiated alendronate (57%), followed by ibandronate (12%), ZA (11%), risedronate (10%), and denosumab (10%). Compared with denosumab, patients initiating ZA had similar risks of all negative control outcomes. Compared with oral BPs, patients initiating denosumab had a higher risk of a wellness visit (RD = 1.2%, 95% CI: 0.4, 1.9) and a lower risk of receiving herpes zoster vaccine (RD = −0.6%, 95% CI: −1.1, −0.2). Comparing ZA with oral BP initiators resulted in two outcomes with positive associations.ConclusionsCaution is warranted when comparing injectable vs oral osteoporosis medications, given the potential for unmeasured confounding. Evaluating negative control outcomes could be a standard validity check prior to conducting comparative studies.

In causal inference, interference occurs when the treatment of one subject affects the outcome of other subjects. Interference can distort research conclusions about causal effects when not accounted for properly. In the absence of interference, inverse probability weighted (IPW) estimators are commonly used to estimate causal effects from observational data. Recently, IPW estimators have been extended to handle interference. Tchetgen Tchetgen and VanderWeele (2012) proposed IPW methods to estimate direct and indirect (or spillover) effects that allow for interference between individuals within groups. In this paper, we present inferference, an package that computes these IPW causal effect estimates when interference may be present within groups. We illustrate use of the package with examples from political science and infectious disease.