Canine and feline P-glycoprotein deficiency: What we know and where we need to go.

In 2001 the molecular genetic basis of so-called "ivermectin sensitivity" in herding breed dogs was determined to be a P-glycoprotein deficiency caused by a genetic variant of the MDR1 (ABCB1) gene often called "the MDR1 mutation." We have learned a great deal about P-glycoprotein's role in drug disposition since that discovery, namely that P-glycoprotein transports many more drugs than just macrocyclic lactones that P-glycoprotein mediated drug transport is present in more places than just the blood brain barrier, that some cats have a genetic variant of MDR1 that results in P-glycoprotein deficiency, that P-glycoprotein dysfunction can occur as a result of drug-drug interactions in any dog or cat, and that the concept of P-glycoprotein "inhibitors" versus P-glycoprotein substrates is somewhat arbitrary and artificial. This paper will review these discoveries and discuss how they impact drug selection and dosing in dogs and cats with genetically mediated P-glycoprotein deficiency or P-glycoprotein dysfunction resulting from drug-drug interactions.

Global change re-structures alpine plant communities through interacting abiotic and biotic effects.

Global change is altering patterns of community assembly, with net outcomes dependent on species' responses to the abiotic environment, both directly and mediated through biotic interactions. Here, we assess alpine plant community responses in a 15-year factorial nitrogen addition, warming and snow manipulation experiment. We used a dynamic competition model to estimate the density-dependent and -independent processes underlying changes in species-group abundances over time. Density-dependent shifts in competitive interactions drove long-term changes in abundance of species-groups under global change while counteracting environmental drivers limited the growth response of the dominant species through density-independent mechanisms. Furthermore, competitive interactions shifted with the environment, primarily with nitrogen and drove non-linear abundance responses across environmental gradients. Our results highlight that global change can either reshuffle species hierarchies or further favour already-dominant species; predicting which outcome will occur requires incorporating both density-dependent and -independent mechanisms and how they interact across multiple global change factors.

Supplementing Dietary Fibers With a Low FODMAP Diet in Irritable Bowel Syndrome: A Randomized Controlled Crossover Trial.

BACKGROUND & AIMS: Institution of a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) in patients with irritable bowel syndrome (IBS) may lead to inadequate fiber intake. This trial aimed to investigate the effects of supplementing specific fibers concomitantly with a low FODMAP diet on relevant clinical and physiological indices in symptomatic patients with IBS. METHODS: A double-blind crossover trial was conducted in which 26 patients with IBS were randomly assigned to 1 of 3 low FODMAP diets differing only in total fiber content: control, 23 g/d; sugarcane bagasse, 33 g/d; or fiber combination (sugarcane bagasse with resistant starch), 45 g/d. Each diet lasted 14 days with most food provided and ≥21 days' washout between. Endpoints were assessed during baseline and dietary interventions. RESULTS: From a median IBS Severity Scoring System total score at baseline of 305, all diets reduced median scores by >50 with no differences in rates of symptom response between the diets: control (57%), sugarcane bagasse (67%), fiber combination (48%) (P = .459). Stool output was ∼50% higher during the fiber-supplemented vs control diets (P < .001 for both). While there were no overall differences overall in stool characteristics, descriptors, and water content, or in gastrointestinal transit times, supplementation with sugarcane bagasse normalized both low stool water content and slow colonic transit from during the control diet. CONCLUSIONS: Concomitant supplementation of fibers during initiation of a low FODMAP diet did not alter symptomatic response in patients with IBS but augmented stool bulk and normalized low stool water content and slow transit. Resistant starch did not exert additional symptomatic benefits over sugarcane bagasse alone. (Australia and New Zealand Clinical Trial Registry; Number, ACTRN12619000691145).

Comparing Costs and Outcomes of Treatments for Irritable Bowel Syndrome With Diarrhea: Cost-Benefit Analysis.

BACKGROUND: Irritable bowel syndrome (IBS) is one of the most expensive gastroenterological conditions and is an ideal target for developing a value-based care model. We assessed the comparative cost-benefit of treatments for IBS with diarrhea (IBS-D), the most common IBS subtype from insurer and patient perspectives. METHODS: We constructed a decision analytic model assessing trade-offs among guideline-recommended and recently FDA-approved drugs, supplements, low FODMAP diet, cognitive behavioral therapy (CBT). Outcomes and costs were derived from systematic reviews of clinical trials and national databases. Health-gains were represented using quality-adjusted life years (QALY). RESULTS: From an insurer perspective, on-label prescription drugs (rifaximin, eluxadoline, alosetron) were significantly more expensive than off-label treatments, low FODMAP, or CBT. Insurer treatment preferences were driven by average wholesale prescription drug prices and were not affected by health gains in sensitivity analysis within standard willingness-to-pay ranges up to $150,000/QALY-gained. From a patient perspective, prescription drug therapies and neuromodulators appeared preferable due to a reduction in lost wages due to IBS with effective therapy, and also considering out-of-pocket costs of low FODMAP food and out-of-pocket costs to attend CBT appointments. Comparative health outcomes exerted influence on treatment preferences from a patient perspective in cost-benefit analysis depending on a patients' willingness-to-pay threshold for additional health-gains, but health outcomes were less important than out-of-pocket costs at lower willingness-to-pay thresholds. CONCLUSIONS: Costs are critical determinants of IBS treatment value to patients and insurers, but different costs drive patient and insurer treatment preferences. Divergent cost drivers appear to explain misalignment between patient and insurer IBS treatment preferences in practice.

Diet as a therapeutic tool in chronic gastrointestinal disorders: Lessons from the FODMAP journey.

BACKGROUND AND AIM: Diet is a powerful tool in the management of gastrointestinal disorders, but developing diet therapies is fraught with challenge. This review discusses key lessons from the FODMAP diet journey. METHODS: Published literature and clinical experience were reviewed. RESULTS: Key to designing a varied, nutritionally adequate low-FODMAP diet was our accurate and comprehensive database of FODMAP composition, made universally accessible via our user-friendly, digital application. Our discovery that FODMAPs coexist with gluten in cereal products and subsequent gluten/fructan challenge studies in nonceliac gluten-sensitive populations highlighted issues of collinearity in the nutrient composition of food and confirmation bias in the interpretation of dietary studies. Despite numerous challenges in designing, funding, and executing dietary randomized controlled trials, efficacy of the low-FODMAP diet has been repeatedly demonstrated, and confirmed by real-world experience, giving this therapy credibility in the eyes of clinicians and researchers. Furthermore, real-world application of this diet saw the evolution of a safe and effective three-phased approach. Specialist dietitians must deliver this diet to optimize outcomes as they can target and tailor the therapy and to mitigate the key risks of compromising nutritional adequacy and precipitating disordered eating behaviors, skills outside the gastroenterologist's standard tool kit. While concurrent probiotics are ineffective, specific fiber supplements may improve short-term and long-term outcomes. CONCLUSIONS: The FODMAP diet is highly effective, but optimal outcomes are contingent on the involvement of a gastroenterological dietitian who can assess, educate, and monitor patients and manage risks associated with implementation of this restrictive diet.

A novel transdermal ketoprofen formulation for analgesia in cattle.

Ketoprofen is registered in many countries for injectable administration in cattle. Because it is soluble in a wide range of excipients, development of a novel transdermal (TD) ketoprofen formulation was pursued to provide a convenient and pain-free route of administration in cattle. One hundred and six excipient combinations were screened using in vitro techniques (Franz diffusion cells), with a 20%(w/v) ketoprofen formulation dissolved in a combination of 45%:45%(v/v) ethanol and isopropyl myristate (IPM) and 10%(v/v) eucalyptus oil achieving maximal penetration of ketoprofen through bovine skin. A bioavailability study was then conducted using a randomized cross-over design (n = 12), including IV, IM (both 3 mg/kg) and TD (10 mg/kg) ketoprofen formulations administered with a one-week washout period between administrations. The IV and IM formulation pharmacokinetic results were as expected. The CMAX , Tmax and AUC0-Last were significantly higher (arithmetic mean ± SD) after TD administration (20.0 ± 6.5 µg/ml, 115 ± 17 min and 3940 ± 1324 µg*min/ml, respectively), compared to IM (11.0 ± 4.0 µg/ml, 74 ± 43 min and 2376 ± 738 µg*min/ml, respectively), although there were no significant differences for T½ß . However, dose corrected values CMAX and AUCinf were significantly higher for IM compared to TD. The arithmetic mean bioavailability (F) of the transdermal formulation was 50%. The plasma concentration of the TD formulation at a dose of 10 mg/kg was similar to the IM formulation at 3 mg/kg by 30 min post-dosing with an arithmetic mean ± SD of 7.97 ± 4.38 vs. 8.02 ± 3.55 µg/ml, respectively. The TD formulation was generally well tolerated by cattle, although some local irritation along the site of application was noted after 12 h of exposure during the bioavailability study. Results indicate that this novel TD formulation provides a substantial improvement in administration convenience, may improve animal welfare and end-user safety through needle-free administration, and achieves similar plasma pharmacokinetics to the IM product when administered at 10 mg/kg.

Reduced social contact and attachment insecurity as predictors of loneliness during COVID-19: A two-month experience sampling study.

The impact of reduced social contact on mental health during the COVID-19 pandemic has been identified as a major public health concern. While personality factors such as attachment style have been associated with psychological distress during the pandemic, the longitudinal relevance of these factors and the role of daily social contact in mitigating distress remains poorly understood. This study evaluated the impact of social contact and attachment style on changes in loneliness over an 8-week experience sampling period during the COVID-19 pandemic. A general adult sample (n = 184) recruited online completed measures of psychological distress, attachment, and loneliness via smartphone. Loneliness and daily social contact were assessed twice per week for eight weeks, yielding 1124 unique observations. During the experience sampling period, proximal increases in loneliness were associated with decreased daily in-person contact. In contrast, participants who described themselves as having fewer interactions via text, phone, or videoconferencing, as well as those with higher anxious and avoidant attachment traits, reported greater experiences of loneliness over time. These findings suggest the relevance of both enduring personality characteristics and daily social behaviors as risk factors for loneliness during the pandemic, pointing to potential targets for clinical intervention and future empirical study.

Dietary fibres and IBS: translating functional characteristics to clinical value in the era of personalised medicine.

Clinical guidelines in the use of fibre supplementation for patients with IBS provide one-size-fits-all advice, which has limited value. This narrative review addresses data and concepts around the functional characteristics of fibre and subsequent physiological responses induced in patients with IBS with a view to exploring the application of such knowledge to the precision use of fibre supplements. The key findings are that first, individual fibres elicit highly distinct physiological responses that are associated with their functional characteristics rather than solubility. Second, the current evidence has focused on the use of fibres as a monotherapy for IBS symptoms overall without attempting to exploit these functional characteristics to elicit specific, symptom-targeted effects, or to use fibre types as adjunctive therapies. Personalisation of fibre therapies can therefore target several therapeutic goals. Proposed goals include achieving normalisation of bowel habit, modulation of gut microbiota function towards health and correction of microbial effects of other dietary therapies. To put into perspective, bulking fibres that are minimally fermented can offer utility in modulating indices of bowel habit; slowly fermented fibres may enhance the activities of the gut microbiota; and the combination of both fibres may potentially offer both benefits while optimising the activities of the microbiota throughout the different regions of the colon. In conclusion, understanding the GI responses to specific fibres, particularly in relation to the physiology of the individual, will be the future for personalising fibre therapy for enhancing the personalised management of patients with IBS.

Contrasting Clinician and Insurer Perspectives to Managing Irritable Bowel Syndrome: Multilevel Modeling Analysis.

INTRODUCTION: Insurance coverage is an important determinant of treatment choice in irritable bowel syndrome (IBS), often taking precedence over desired mechanisms of action or patient goals/values. We aimed to determine whether routine and algorithmic coverage restrictions are cost-effective from a commercial insurer perspective. METHODS: A multilevel microsimulation tracking costs and outcomes among 10 million hypothetical moderate-to-severe patients with IBS was developed to model all possible algorithms including common global IBS treatments (neuromodulators; low fermentable oligo-, di-, and mono-saccharides, and polyols; and cognitive behavioral therapy) and prescription drugs treating diarrhea-predominant IBS (IBS-D) or constipation-predominant IBS (IBS-C) over 1 year. RESULTS: Routinely using global IBS treatments (central neuromodulator; low fermentable oligo-, di-, and mono-saccharides, and polyols; and cognitive behavioral therapy) before US Food and Drug Administration-approved drug therapies resulted in per-patient cost savings of $9,034.59 for IBS-D and $2,972.83 for IBS-C over 1 year to insurers, compared with patients starting with on-label drug therapy. Health outcomes were similar, regardless of treatment sequence. Costs varied less than $200 per year, regardless of the global IBS treatment order. The most cost-saving and cost-effective IBS-D algorithm was rifaximin, then eluxadoline, followed by alosetron. The most cost-saving and cost-effective IBS-C algorithm was linaclotide, followed by either plecanatide or lubiprostone. In no scenario were prescription drugs routinely more cost-effective than global IBS treatments, despite a stronger level of evidence with prescription drugs. These findings were driven by higher prescription drug prices as compared to lower costs with global IBS treatments. DISCUSSION: From an insurer perspective, routine and algorithmic prescription drug coverage restrictions requiring failure of low-cost behavioral, dietary, and off-label treatments appear cost-effective. Efforts to address insurance coverage and drug pricing are needed so that healthcare providers can optimally care for patients with this common, heterogenous disorder.

Screening dietary fibres for fermentation characteristics and metabolic profiles using a rapid in vitro approach: implications for irritable bowel syndrome.

The therapeutic value of specific fibres is partly dependent on their fermentation characteristics. Some fibres are rapidly degraded with the generation of gases that induce symptoms in patients with irritable bowel syndrome (IBS), while more slowly or non-fermentable fibres may be more suitable. More work is needed to profile a comprehensive range of fibres to determine suitability for IBS. Using a rapid in vitro fermentation model, gas production and metabolite profiles of a range of established and novel fibres were compared. Fibre substrates (n 15) were added to faecal slurries from three healthy donors for 4 h with gas production measured using real-time headspace sampling. Concentrations of SCFA and ammonia were analysed using GC and enzymatic assay, respectively. Gas production followed three patterns: rapid (≥60 ml/g over 4 h) for fructans, carrot fibre and maize-derived xylo-oligosaccharide (XOS); mild (30-60 ml/g) for partially hydrolysed guar gum, almond shell-derived XOS and one type of high-amylose resistant starch 2 (RS2) and minimal (no differences with blank controls) for methylcellulose, another high-amylose RS2, acetylated or butyrylated RS2, RS4, acacia gum and sugarcane bagasse. Gas production correlated positively with total SCFA (r 0·80, P < 0·001) and negatively with ammonia concentrations (r -0·68, P < 0·001). Proportions of specific SCFA varied: fermentation of carrot fibre, XOS and acetylated RS2 favoured acetate, while fructans favoured butyrate. Gas production and metabolite profiles differed between fibre types and within fibre classes over a physiologically relevant 4-h time course. Several fibres resisted rapid fermentation and may be candidates for clinical trials in IBS patients.

Effects of fiber intake on intestinal pH, transit, and predicted oral mesalamine delivery in patients with ulcerative colitis.

BACKGROUND AND AIM: Limited data are available on the effects of fermentable fiber in altering intestinal pH and transit to predict efficacy-based delivery profiles of pH-dependent mesalamine coatings in ulcerative colitis (UC). This study aimed to examine regional pH and transit after acute changes in fermentable fiber intake in quiescent UC patients and their effects on drug release systems. METHODS: In a randomized, double-blind study, 18 patients with quiescent UC and 10 healthy controls were supplied meals high (13 g) or low (≤ 2 g) in fermentable fiber and subsequently ingested a wireless pH-motility capsule. After a ≥ 3-day washout, they crossed over to the other diet. Measurements of intestinal pH and transit were used to predict drug release for the various pH-dependent coatings. RESULTS: Increasing fermentable fiber intake lowered overall (median 6.2 [6.1-6.7] vs low: 6.9 [range or interquartile range: 6.4-7.4]; P = 0.01) and distal pH (7.8 [7.3-8.1] vs 8.2 [8.0-8.5]; P = 0.04) in controls. In UC patients, only cecal pH was decreased (high: 5.1 [4.8-5.5] vs low: 5.5 [5.3-5.7]; P < 0.01). Colonic transit in the UC cohort varied widely after a low-fiber intake but tended to normalize after the high fermentable fiber intake. Hypothetical coating dissolution profiles were heterogeneous in UC patients, with a multi-matrix delayed release system having the highest likelihood of patients (20-40%) with incomplete dissolution, and predominant small intestinal dissolution predicted for Eudragit L (94% patients) and S (44-69%). CONCLUSIONS: Patients with quiescent UC have abnormalities in intestinal pH and transit in response to acute changes in fermentable fiber intake. These have potentially detrimental effects on predicted luminal release patterns of pH-dependent 5-aminosalicylic acid release systems.

Sedatives for opioid withdrawal in newborn infants.

BACKGROUND: Neonatal abstinence syndrome (NAS) due to opioid withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss, seizures and neurodevelopmental problems. OBJECTIVES: To assess the effectiveness and safety of using a sedative versus control (placebo, usual treatment or non-pharmacological treatment) for NAS due to withdrawal from opioids and determine which type of sedative is most effective and safe for NAS due to withdrawal from opioids. SEARCH METHODS: We ran an updated search on 17 September 2020 in CENTRAL via CRS Web and MEDLINE via Ovid. We searched clinical trials databases, conference proceedings and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: We included trials enrolling infants with NAS born to mothers with an opioid dependence with more than 80% follow-up and using randomised, quasi-randomised and cluster-randomised allocation to sedative or control. DATA COLLECTION AND ANALYSIS: Three review authors assessed trial eligibility and risk of bias, and independently extracted data. We used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: We included 10 trials (581 infants) with NAS secondary to maternal opioid use in pregnancy. There were multiple comparisons of different sedatives and regimens. There were limited data available for use in sensitivity analysis of studies at low risk of bias. Phenobarbital versus supportive care: one study reported there may be little or no difference in treatment failure with phenobarbital and supportive care versus supportive care alone (risk ratio (RR) 2.73, 95% confidence interval (CI) 0.94 to 7.94; 62 participants; very low-certainty evidence). No infant had a clinical seizure. The study did not report mortality, neurodevelopmental disability and adverse events. There may be an increase in days' hospitalisation and treatment from use of phenobarbital (hospitalisation: mean difference (MD) 20.80, 95% CI 13.64 to 27.96; treatment: MD 17.90, 95% CI 11.98 to 23.82; both 62 participants; very low-certainty evidence). Phenobarbital versus diazepam: there may be a reduction in treatment failure with phenobarbital versus diazepam (RR 0.39, 95% CI 0.24 to 0.62; 139 participants; 2 studies; low-certainty evidence). The studies did not report mortality, neurodevelopmental disability and adverse events. One study reported there may be little or no difference in days' hospitalisation and treatment (hospitalisation: MD 3.89, 95% CI -1.20 to 8.98; 32 participants; treatment: MD 4.30, 95% CI -0.73 to 9.33; 31 participants; both low-certainty evidence). Phenobarbital versus chlorpromazine: there may be a reduction in treatment failure with phenobarbital versus chlorpromazine (RR 0.55, 95% CI 0.33 to 0.92; 138 participants; 2 studies; very low-certainty evidence), and no infant had a seizure. The studies did not report mortality and neurodevelopmental disability. One study reported there may be little or no difference in days' hospitalisation (MD 7.00, 95% CI -3.51 to 17.51; 87 participants; low-certainty evidence) and 0/100 infants had an adverse event. Phenobarbital and opioid versus opioid alone: one study reported no infants with treatment failure and no clinical seizures in either group (low-certainty evidence). The study did not report mortality, neurodevelopmental disability and adverse events. One study reported there may be a reduction in days' hospitalisation for infants treated with phenobarbital and opioid (MD -43.50, 95% CI -59.18 to -27.82; 20 participants; low-certainty evidence). Clonidine and opioid versus opioid alone: one study reported there may be little or no difference in treatment failure with clonidine and dilute tincture of opium (DTO) versus DTO alone (RR 0.09, 95% CI 0.01 to 1.59; 80 participants; very low-certainty evidence). All five infants with treatment failure were in the DTO group. There may be little or no difference in seizures (RR 0.14, 95% CI 0.01 to 2.68; 80 participants; very low-certainty evidence). All three infants with seizures were in the DTO group. There may be little or no difference in mortality after discharge (RR 7.00, 95% CI 0.37 to 131.28; 80 participants; very low-certainty evidence). All three deaths were in the clonidine and DTO group. The study did not report neurodevelopmental disability. There may be little or no difference in days' treatment (MD -4.00, 95% CI -8.33 to 0.33; 80 participants; very low-certainty evidence). One adverse event occurred in the clonidine and DTO group. There may be little or no difference in rebound NAS after stopping treatment, although all seven cases were in the clonidine and DTO group. Clonidine and opioid versus phenobarbital and opioid: there may be little or no difference in treatment failure (RR 2.27, 95% CI 0.98 to 5.25; 2 studies, 93 participants; very low-certainty evidence). One study reported one infant in the clonidine and morphine group had a seizure, and there were no infant mortalities. The studies did not report neurodevelopmental disability. There may be an increase in days' hospitalisation and days' treatment with clonidine and opioid versus phenobarbital and opioid(hospitalisation: MD 7.13, 95% CI 6.38 to 7.88; treatment: MD 7.57, 95% CI 3.97 to 11.17; both 2 studies, 91 participants; low-certainty evidence). There may be little or no difference in adverse events (RR 1.55, 95% CI 0.44 to 5.40; 2 studies, 93 participants; very low-certainty evidence). However, there was oversedation only in the phenobarbital and morphine group; and hypotension, rebound hypertension and rebound NAS only in the clonidine and morphine group. AUTHORS' CONCLUSIONS: There is very low-certainty evidence that phenobarbital increases duration of hospitalisation and treatment, but reduces days to regain birthweight and duration of supportive care each day compared to supportive care alone. There is low-certainty evidence that phenobarbital reduces treatment failure compared to diazepam and very low-certainty evidence that  phenobarbital reduces treatment failure compared to chlorpromazine. There is low-certainty evidence of an increase in days' hospitalisation and days' treatment with clonidine and opioid compared to phenobarbital and opioid. There are insufficient data to determine the safety and incidence of adverse events for infants treated with combinations of opioids and sedatives including phenobarbital and clonidine.

Opioid treatment for opioid withdrawal in newborn infants.

BACKGROUND: Neonatal abstinence syndrome (NAS) due to opioid withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss, seizures and neurodevelopmental problems. OBJECTIVES: To assess the effectiveness and safety of using an opioid for treatment of NAS due to withdrawal from opioids in newborn infants. SEARCH METHODS: We ran an updated search on 17 September 2020 in CENTRAL via Cochrane Register of Studies Web and MEDLINE via Ovid. We also searched clinical trials databases, conference proceedings and the reference lists of retrieved articles for eligible trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs), quasi- and cluster-RCTs which enrolled infants born to mothers with opioid dependence and who were experiencing NAS requiring treatment with an opioid. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trial eligibility and risk of bias, and independently extracted data. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included 16 trials (1110 infants) with NAS secondary to maternal opioid use in pregnancy. Seven studies at low risk of bias were included in sensitivity analysis. Opioid versus no treatment / usual care: a single trial (80 infants) of morphine and supportive care versus supportive care alone reported no difference in treatment failure (risk ratio (RR) 1.29, 95% confidence interval (CI) 0.41 to 4.07; very low certainty evidence). No infant had a seizure. The trial did not report mortality, neurodevelopmental disability and adverse events. Morphine increased days hospitalisation (mean difference (MD) 15.00, 95% CI 8.86 to 21.14; very low certainty evidence) and treatment (MD 12.50, 95% CI 7.52 to 17.48; very low certainty evidence), but decreased days to regain birthweight (MD -2.80, 95% CI -5.33 to -0.27) and duration (minutes) of supportive care each day (MD -197.20, 95% CI -274.15 to -120.25). Morphine versus methadone: there was no difference in treatment failure (RR 1.59, 95% CI 0.95 to 2.67; 2 studies, 147 infants; low certainty evidence). Seizures, neonatal or infant mortality and neurodevelopmental disability were not reported. A single study reported no difference in days hospitalisation (MD 1.40, 95% CI -3.08 to 5.88; 116 infants; low certainty evidence), whereas data from two studies found an increase in days treatment (MD 2.71, 95% CI 0.22 to 5.21; 147 infants; low certainty) for infants treated with morphine. A single study reported no difference in breastfeeding, adverse events, or out of home placement. Morphine versus sublingual buprenorphine: there was no difference in treatment failure (RR 0.79, 95% CI 0.36 to 1.74; 3 studies, 113 infants; very low certainty evidence). Neonatal or infant mortality and neurodevelopmental disability were not reported. There was moderate certainty evidence of an increase in days hospitalisation (MD 11.45, 95% CI 5.89 to 17.01; 3 studies, 113 infants), and days treatment (MD 12.79, 95% CI 7.57 to 18.00; 3 studies, 112 infants) for infants treated with morphine. A single adverse event (seizure) was reported in infants exposed to buprenorphine. Morphine versus diluted tincture of opium (DTO): a single study (33 infants) reported no difference in days hospitalisation, days treatment or weight gain (low certainty evidence). Opioid versus clonidine: a single study (31 infants) reported no infant with treatment failure in either group. This study did not report seizures, neonatal or infant mortality and neurodevelopmental disability. There was low certainty evidence for no difference in days hospitalisation or days treatment. This study did not report adverse events. Opioid versus diazepam: there was a reduction in treatment failure from use of an opioid (RR 0.43, 95% CI 0.23 to 0.80; 2 studies, 86 infants; low certainty evidence). Seizures, neonatal or infant mortality and neurodevelopmental disability were not reported. A single study of 34 infants comparing methadone versus diazepam reported no difference in days hospitalisation or days treatment (very low certainty evidence). Adverse events were not reported. Opioid versus phenobarbital: there was a reduction in treatment failure from use of an opioid (RR 0.51, 95% CI 0.35 to 0.74; 6 studies, 458 infants; moderate certainty evidence). Subgroup analysis found a reduction in treatment failure in trials titrating morphine to ≧ 0.5 mg/kg/day (RR 0.21, 95% CI 0.10 to 0.45; 3 studies, 230 infants), whereas a single study using morphine < 0.5 mg/kg/day reported no difference compared to use of phenobarbital (subgroup difference P = 0.05). Neonatal or infant mortality and neurodevelopmental disability were not reported. A single study (111 infants) of paregoric versus phenobarbital reported seven infants with seizures in the phenobarbital group, whereas no seizures were reported in two studies (170 infants) comparing morphine to phenobarbital. There was no difference in days hospitalisation or days treatment. A single study (96 infants) reported no adverse events in either group. Opioid versus chlorpromazine: there was a reduction in treatment failure from use of morphine versus chlorpromazine (RR 0.08, 95% CI 0.01 to 0.62; 1 study, 90 infants; moderate certainty evidence). No seizures were reported in either group. There was low certainty evidence for no difference in days treatment. This trial reported no adverse events in either group. None of the included studies reported time to control of NAS. Data for duration and severity of NAS were limited, and we were unable to use these data in quantitative synthesis. AUTHORS' CONCLUSIONS: Compared to supportive care alone, the addition of an opioid may increase duration of hospitalisation and treatment, but may reduce days to regain birthweight and the duration of supportive care each day. Use of an opioid may reduce treatment failure compared to phenobarbital, diazepam or chlorpromazine. Use of an opioid may have little or no effect on duration of hospitalisation or treatment compared to use of phenobarbital, diazepam or chlorpromazine. The type of opioid used may have little or no effect on the treatment failure rate. Use of buprenorphine probably reduces duration of hospitalisation and treatment compared to morphine, but there are no data for time to control NAS with buprenorphine, and insufficient evidence to determine safety. There is insufficient evidence to determine the effectiveness and safety of clonidine.

No Change in Risk for Antibiotic-Resistant Salmonellosis from Beef, United States, 2002-2010.

Restricting antibiotic use in food production animals is a target for reducing antimicrobial drug-resistant infections in humans. We used US surveillance data to estimate the probability of antibiotic-resistant nontyphoidal salmonellosis per meal made with beef during 2002-2010. Applying data for nontyphoidal Salmonella in raised-without-antibiotics cattle, we tested the effect of removing antibiotic use from all beef cattle production. We found an average of 1.2 (95% credible interval 0.6-4.2) antibiotic-resistant nontyphoidal salmonellosis cases per 1 million beef meals made with beef initially contaminated with antibiotic-resistant nontyphoidal Salmonella at slaughter or retail and 0.031 (95% credible interval 0.00018-0.14) cases per 1 million meals irrespective of beef contamination status. Neither outcome showed sustained change except for increases in 2003 and 2009 (>98% confidence) when larger or more outbreaks occurred. Switching all beef production to a raised-without-antibiotics system may not have a significant effect on antibiotic-resistant nontyphoidal salmonellosis (94.3% confidence).

The EAT-Lancet Commission's Dietary Composition May Not Prevent Noncommunicable Disease Mortality.

The recently published EAT-Lancet Commission report on dietary impacts on the environment suggested that their proposed diet could prevent more than 10 million annual premature mortalities from noncommunicable diseases globally. The report did not meet standards for transparency and replicability, nor did it fully account for statistical uncertainty. Our attempt to replicate the mortality calculations for the United States revealed flaws in the assumptions and methods used to estimate the avoided mortalities. After correcting some calculation errors and fully accounting for uncertainty in the avoided mortalities, the mortality reduction effect of the EAT-Lancet proposed diet in the USA is no greater than the impact of energy consumption changes that would prevent under-weight, over-weight, and obesity alone. As our findings call into question the global conclusions of the EAT-Lancet report, futher independent validation is needed before it can be used to inform dietary guidelines.

Successful elevation of circulating acetate and propionate by dietary modulation does not alter T-regulatory cell or cytokine profiles in healthy humans: a pilot study.

PURPOSE: Increased circulating concentrations of short-chain fatty acids (SCFA) achieved by ingestion of high-fibre diets is associated with anti-inflammatory effects through promotion of FoxP3+ regulatory T(reg) cells in mouse models. This study aimed to determine whether similar increments in blood SCFA levels can be achieved in humans and whether these are associated with similar immune modulatory effects. METHODS: In a pilot single-blinded, randomised, controlled cross-over study in ten healthy subjects, the effects were determined of high- (39 g/day) and low-fibre (18 g/day) intake (all food provided) on SCFA (gas chromatography), proportions of Treg cells (flow cytometry) and a panel of cytokines (multiplex methodology) measured in peripheral blood at day 5 of each diet. RESULTS: Actual fibre intake differed between the diets by 19 [16-21] g/day (P< 0.001). Median [range] total plasma SCFA levels with high-fibre intake were 174.5 [104.8-249.5] µmol/L, which were greater than those associated with low-fibre intake at 59.0 [26.5-79.9] (P < 0.001). Differences were significantly different for both acetate and propionate. The frequencies of total CD4 T cells and T-regulatory cells, and concentrations of inflammatory and anti-inflammatory cytokines were not significantly different between the dietary interventions. CONCLUSIONS: Plasma SCFA levels can be modulated by altering dietary fibre consumption in healthy individuals with increments similar to those achieved in murine studies. Five days of diet intervention did not result in changes in regulatory T-cell proportions and cytokine concentrations in peripheral blood, and may require longer duration of dietary change.

Correction to: A suite of automated tools to quantify hand and wrist motor function after cervical spinal cord injury.

The original article [1] contains several errors which the authors would like to rectify.

Fructan, Rather Than Gluten, Induces Symptoms in Patients With Self-Reported Non-Celiac Gluten Sensitivity.

BACKGROUND & AIMS: Non-celiac gluten sensitivity is characterized by symptom improvement after gluten withdrawal in absence of celiac disease. The mechanisms of non-celiac gluten sensitivity are unclear, and there are no biomarkers for this disorder. Foods with gluten often contain fructans, a type of fermentable oligo-, di-, monosaccharides and polyols. We aimed to investigate the effect of gluten and fructans separately in individuals with self-reported gluten sensitivity. METHODS: We performed a double-blind crossover challenge of 59 individuals on a self-instituted gluten-free diet, for whom celiac disease had been excluded. The study was performed at Oslo University Hospital in Norway from October 2014 through May 2016. Participants were randomly assigned to groups placed on diets containing gluten (5.7 g), fructans (2.1 g), or placebo, concealed in muesli bars, for 7 days. Following a minimum 7-day washout period (until the symptoms induced by the previous challenge were resolved), participants crossed over into a different group, until they completed all 3 challenges (gluten, fructan, and placebo). Symptoms were measured by Gastrointestinal Symptom Rating Scale Irritable Bowel Syndrome (GSRS-IBS) version. A linear mixed model for analysis was used. RESULTS: Overall GSRS-IBS scores differed significantly during gluten, fructan, and placebo challenges; mean values were 33.1 ± 13.3, 38.6 ± 12.3, and 34.3 ± 13.9, respectively (P = .04). Mean scores for GSRS-IBS bloating were 9.3 ± 3.5, 11.6 ± 3.5, and 10.1 ± 3.7, respectively, during the gluten, fructan, and placebo challenges (P = .004). The overall GSRS-IBS score for participants consuming fructans was significantly higher than for participants consuming gluten (P = .049), as was the GSRS bloating score (P = .003). Thirteen participants had the highest overall GSRS-IBS score after consuming gluten, 24 had the highest score after consuming fructan, and 22 had the highest score after consuming placebo. There was no difference in GSRS-IBS scores between gluten and placebo groups. CONCLUSIONS: In a randomized, double-blind, placebo-controlled crossover study of individuals with self-reported non-celiac gluten sensitivity, we found fructans to induce symptoms, measured by the GSRS-IBS. Clinicaltrials.gov no: NCT02464150.

A suite of automated tools to quantify hand and wrist motor function after cervical spinal cord injury.

BACKGROUND: Cervical spinal cord injury (cSCI) often causes chronic upper extremity disability. Reliable measurement of arm function is critical for development of therapies to improve recovery after cSCI. In this study, we report a suite of automated rehabilitative tools to allow simple, quantitative assessment of hand and wrist motor function. METHODS: We measured range of motion and force production using these devices in cSCI participants with a range of upper limb disability and in neurologically intact participants at two time points separated by approximately 4 months. Additionally, we determined whether measures collected with the rehabilitative tools correlated with standard upper limb assessments, including the Graded Redefined Assessment of Strength, Sensibility, and Prehension (GRASSP) and the Jebsen Hand Function Test (JHFT). RESULTS: We find that the rehabilitative devices are useful to provide assessment of upper limb function in physical units over time in SCI participants and are well-correlated with standard assessments. CONCLUSIONS: These results indicate that these tools represent a reliable system for longitudinal evaluation of upper extremity function after cSCI and may provide a framework to assess the efficacy of strategies aimed at improving recovery of upper limb function.

Vagus Nerve Stimulation Paired With Upper Limb Rehabilitation After Chronic Stroke.

Background and Purpose- We assessed safety, feasibility, and potential effects of vagus nerve stimulation (VNS) paired with rehabilitation for improving arm function after chronic stroke. Methods- We performed a randomized, multisite, double-blinded, sham-controlled pilot study. All participants were implanted with a VNS device and received 6-week in-clinic rehabilitation followed by a home exercise program. Randomization was to active VNS (n=8) or control VNS (n=9) paired with rehabilitation. Outcomes were assessed at days 1, 30, and 90 post-completion of in-clinic therapy. Results- All participants completed the course of therapy. There were 3 serious adverse events related to surgery. Average FMA-UE scores increased 7.6 with active VNS and 5.3 points with control at day 1 post-in-clinic therapy (difference, 2.3 points; CI, -1.8 to 6.4; P=0.20). At day 90, mean scores increased 9.5 points from baseline with active VNS, and the control scores improved by 3.8 (difference, 5.7 points; CI, -1.4 to 11.5; P=0.055). The clinically meaningful response rate of FMA-UE at day 90 was 88% with active VNS and 33% with control VNS ( P<0.05). Conclusions- VNS paired with rehabilitation was acceptably safe and feasible in participants with upper limb motor deficit after chronic ischemic stroke. A pivotal study of this therapy is justified. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT02243020.