Outcomes of patients treated with low-dose flumazenil for benzodiazepine detoxification: A description of 26 participants.

INTRODUCTION: Benzodiazepines are commonly prescribed for a variety of indications and can be employed in the short- and long-term. While they are efficacious, issues arise from long-term use with the emergence of dependence and tolerance to doses within the therapeutic range and beyond. Discontinuation from benzodiazepines can be problematic for patients and may result in a withdrawal syndrome, which can be protracted and last months to years. METHODS: 26 participants received low-dose subcutaneous flumazenil infusions (4 mg/24 h for approximately eight days) as part of a randomised control crossover trial. Return to benzodiazepine use was assessed monthly for three months based on the benzodiazepine use in the previous week. Where data was not available, the treating psychiatrist examined patient files and clinical documents to determine benzodiazepine use. Withdrawal and craving scores were also measured. RESULTS: Abstinence rates from benzodiazepines at one-, two-, and three-month follow ups were 65.4 %, 50.0 %, and 46.2 % respectively. When considering patient files and clinical documents for those lost to follow-up, abstinence rates were higher at 73.1 %, 65.4 % and 61.5 % at the one-, two-, and three-month follow ups respectively. Withdrawal and craving scores were higher in those that had returned to any benzodiazepine use. CONCLUSION: Self-reported rates of abstinence from benzodiazepines at three months was between 46.2 % and 61.5 %. Flumazenil may yield greater success than benzodiazepine tapering from high dose benzodiazepine use (≥30 mg diazepam equivalent). Further research should compare abstinence rates after treatment with flumazenil compared to benzodiazepine tapering in high dose benzodiazepine users.

A double-blind randomised crossover trial of low-dose flumazenil for benzodiazepine withdrawal: A proof of concept.

INTRODUCTION: Benzodiazepines (BZD) are a class of anxiolytics with varying uses, which primarily act on the GABAA receptor resulting in hyperpolarisation. BZDs are often a difficult drug class to cease once neuroadaptation has occurred; recommendations usually involve gradual dose reductions at variable rates. A growing body of evidence has suggested that low-dose flumazenil, a GABAA receptor antagonist, may be a useful agent to allow for rapid detoxification. AIM: To collect pilot data on the safety and efficacy of low-dose subcutaneous flumazenil to reduce BZD use, withdrawal symptoms, and craving in participants taking above and below the therapeutic maximum diazepam equivalent of 30 mg to inform on sample size for future trials. METHOD: In a randomised double-blinded crossover study design, participants received low-dose flumazenil first (4 mg/24 h for approximately eight days) or placebo first. Groups were divided into those taking < 30 mg diazepam equivalent and ≥ 30 mg diazepam equivalent at baseline. Main outcome measures were percentage reduction in daily diazepam use, withdrawal symptoms, and craving scores from baseline, difference in diazepam use across the placebo first group, and flumazenil related adverse events. RESULTS: Twenty-eight participants were recruited and randomised to flumazenil first (n = 14) and placebo first (n = 14). In participants taking ≥ 30 mg diazepam equivalent at baseline (n = 15), flumazenil significantly reduced diazepam use by 30.5% (p = 0.024) compared to placebo. CONCLUSION: Low-dose flumazenil may aid in BZD detoxification in participants taking daily diazepam equivalent doses greater than or equal to the therapeutic maximum (≥30 mg) by reducing the need for diazepam.

An exploration of mercaptopurine/methotrexate tolerance during maintenance therapy in children with acute lymphoblastic leukemia.

PURPOSE: Mercaptopurine (6MP) and methotrexate (MTX) cause myelosuppression and interruptions in therapy in children with lymphoblastic leukemia (ALL). Length of time off of therapy is related to poorer outcomes. To date the dose at which most children tolerate these agents without drops in blood counts has not been identified. This study attempts to determine the maximum tolerated dose of both 6MP/MTX. METHODS: A retrospective chart review of 77 ALL children, median age 4.5 years. Time to first interruption and dose, along with total number of interruptions were collected. Absolute neutrophil and platelet counts recorded at time of interruption. Subgroup analysis of age, sex, diagnosis and risk stratification were also completed. REB approval was gained. RESULTS: Of the 77 patients that were studied, 9 of them had no treatment interruptions. Descriptive statistics are reported using Strata software. The mean number of interruptions during maintenance was 3.2, the mean time to first interruption was 149.8 days. The mean dose percent of MTX and 6MP at first interruption was 94.4% and 106% respectively. Maintenance therapy was interrupted independent of age, sex, diagnosis or disease risk stratification. CONCLUSION: Few patients complete maintenance therapy without interruptions at the current dose escalation schedules outlined by the Children's Oncology Group protocols. The interruptions are due in part to intolerance of dose escalations of MTX and 6 MP above 100%. Future research should investigate doses of 6MP and MTX in maintenance therapy in relation to leukemia outcomes.

Application of the Theoretical Domains Framework to identify factors that influence hand hygiene compliance in long-term care.

BACKGROUND: Healthcare worker (HCW) hand hygiene compliance is key to patient safety; however, compliance is suboptimal. Nevertheless hand hygiene compliance is not well studied in the long-term care setting. AIM: To apply a behaviour change framework, the Theoretical Domains Framework (TDF), to identify modifiable facilitators and barriers for HCW hand hygiene compliance in long-term care settings. METHODS: HCW hand hygiene compliance facilitators and barriers were examined using a questionnaire for HCWs from long-term care homes in Ontario, Canada. The questionnaire was informed by the TDF, which is based on a synthesis of constructs from a number of relevant psychological theories of behaviour change. FINDINGS: Barriers identified from the questionnaire aligned with the TDF domain environmental context and resources (time pressure, workload, and environmental controls). Facilitators identified from questionnaire results aligned with the TDF domains social/professional role and identity (it is what is expected of HCWs), and beliefs about consequences (risk of transmission of micro-organisms to self or others). CONCLUSION: There are several barriers to hand hygiene compliance that persist in long-term care. A behaviour change theory-informed framework such as the TDF can be helpful to identify those barriers. This study identified several key behavioural constructs aligned with the TDF that can be targeted when developing novel hand hygiene interventions.

Cerebral-placental-uterine ratio as novel predictor of late fetal growth restriction: prospective cohort study.

OBJECTIVE: Fetal growth restriction (FGR) is a major risk factor for stillbirth and most commonly arises from uteroplacental insufficiency. Despite clinical examination and third-trimester fetal biometry, cases of FGR often remain undetected antenatally. Placental insufficiency is known to be associated with altered blood flow resistance in maternal, placental and fetal vessels. The aim of this study was to evaluate the performance of individual and combined Doppler blood flow resistance measurements in the prediction of term small-for-gestational age and FGR. METHODS: This was a prospective study of 347 nulliparous women with a singleton pregnancy at 36 weeks' gestation in which fetal growth and Doppler measurements were obtained. Pulsatility indices (PI) of the uterine arteries (UtA), umbilical artery (UA) and fetal vessels were analyzed, individually and in combination, for prediction of birth weight < 10th , < 5th and < 3rd centiles. Doppler values were converted into centiles or multiples of the median (MoM) for gestational age. The sensitivities, positive and negative predictive values and odds ratios (OR) of the Doppler parameters for these birth weights at ∼ 90% specificity were assessed. Additionally, the correlations between Doppler measurements and other measures of placental insufficiency, namely fetal growth velocity and neonatal body fat measures, were analyzed. RESULTS: The Doppler combination most strongly associated with placental insufficiency was a newly generated parameter, which we have named the cerebral-placental-uterine ratio (CPUR). CPUR is the cerebroplacental ratio (CPR) (middle cerebral artery PI/UA-PI) divided by mean UtA-PI. CPUR MoM detected FGR better than did mean UtA-PI MoM or CPR MoM alone. At ∼ 90% specificity, low CPUR MoM had sensitivities of 50% for birth weight < 10th centile, 68% for < 5th centile and 89% for < 3rd centile. The respective sensitivities of low CPR MoM were 26%, 37% and 44% and those of high UtA-PI MoM were 34%, 47% and 67%. Low CPUR MoM was associated with birth weight < 10th centile with an OR of 9.1, < 5th centile with an OR of 17.3 and < 3rd centile with an OR of 57.0 (P < 0.0001 for all). CPUR MoM was also correlated most strongly with fetal growth velocity and neonatal body fat measures, as compared with CPR MoM or UtA-PI MoM alone. CONCLUSIONS: In this cohort, a novel Doppler variable combination, the CPUR (CPR/UtA-PI), had the strongest association with indicators of placental insufficiency. CPUR detected more cases of FGR than did any other Doppler parameter measured. If these results are replicated independently, this new parameter may lead to better identification of fetuses at increased risk of stillbirth that may benefit from obstetric intervention. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

T-bet controls intestinal mucosa immune responses via repression of type 2 innate lymphoid cell function.

Innate lymphoid cells (ILCs) play an important role in regulating immune responses at mucosal surfaces. The transcription factor T-bet is crucial for the function of ILC1s and NCR+ ILC3s and constitutive deletion of T-bet prevents the development of these subsets. Lack of T-bet in the absence of an adaptive immune system causes microbiota-dependent colitis to occur due to aberrant ILC3 responses. Thus, T-bet expression in the innate immune system has been considered to dampen pathogenic immune responses. Here, we show that T-bet plays an unexpected role in negatively regulating innate type 2 responses, in the context of an otherwise intact immune system. Selective loss of T-bet in ILCs leads to the expansion and increased activity of ILC2s, which has a functionally important impact on mucosal immunity, including enhanced protection from Trichinella spiralis infection and inflammatory colitis. Mechanistically, we show that T-bet controls the intestinal ILC pool through regulation of IL-7 receptor signalling. These data demonstrate that T-bet expression in ILCs acts as the key transcriptional checkpoint in regulating pathogenic vs. protective mucosal immune responses, which has significant implications for the understanding of the pathogenesis of inflammatory bowel diseases and intestinal infections.

Molecular alterations in prostate cancer and association with MRI features.

BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI) has been increasingly used for prostate cancer (PCa). Recent studies identified distinct molecular subclasses of PCa with recurrent genomic alterations. However, the associations between molecular alterations in PCa and characteristics on mpMRI are unknown. Therefore, the objective of this study was to investigate recurrent molecular alterations in PCa and their associations with mpMRI features. METHODS: Sixty-two PCa nodules >0.5 cm had a preoperative mpMRI. Nodules were evaluated for ERG rearrangement, PTEN deletion, SPINK1 overexpression, SPOP mutation and CHD1 deletion. Each PCa focus was matched to the corresponding location on mpMRI. Lesions were scored by single observer according to the PI-RADSv2 scale. RESULTS: Of the 62 nodules, 22 (35.5%) were ERG positive, 6 (9.7%) had SPINK1 overexpression, 6 (9.7%) had SPOP mutations, 4 (6.5%) had CHD1 deletions and 1 (1.6%) had PTEN deletion. All of the nodules with CHD1 deletions were not visible on mpMRI (P=0.037). All of the nodules with SPINK1 overexpression were visible on mpMRI, although the association was not statistically significant (P=0.06). There were no significant associations between any molecular alteration with the severity of the PI-RADS scores (all P>0.05). CONCLUSIONS: This investigation represents the first description of an association between recurrent molecular alterations and the characterization of PCa nodules on mpMRI. This study can be considered hypothesis-generating for future studies to rigorously evaluate the association of specific PCa molecular subclasses with imaging features and potentially define specific subsets of PCa for which the utility of MRI is higher or lower.

Recent advances in gut immunology.

In recent years, there have been significant advances in our understanding of the mucosal immune system. In addition to unravelling some of the complexities of this system, including the discovery of completely new cells types, further insights into the three-way interactions between mucosal immune cells, the intestinal epithelium and the microbial communities colonizing the GI tract promise to redefine our understanding of how intestinal homeostasis is maintained, but also how dysregulation of these highly integrated interactions conspires to cause disease. In this review, we will discuss major recent advances in the role of key immune players in the gut, including innate lymphoid cells (ILCs), mucosa-associated invariant T cells (MAIT cells) and cells of the mononuclear phagocyte system (MPS), including how these cells interact with the intestinal epithelial and their crosstalk with components of the intestinal microbiota, and how these interactions shape host health.

Regulation of human intestinal T-cell responses by type 1 interferon-STAT1 signaling is disrupted in inflammatory bowel disease.

Type 1 interferon (IFN-1) promotes regulatory T-cell function to suppress inflammation in the mouse intestine, but little is known about IFN-1 in the human gut. We therefore assessed the influence of IFN-1 on CD4+ T-cells isolated from human colon tissue obtained from healthy controls or patients with inflammatory bowel disease (IBD). Immunofluorescent imaging revealed constitutive expression of IFNß in human intestinal tissue, and colonic T-cells were responsive to exogenous IFN-1 as assessed by phosphorylation of signal transduction and activator of transcription 1 (pSTAT1) and induction of interferon stimulated genes (ISGs). Unlike their blood counterparts, intestinal T-cells from non-inflamed regions of IBD colon displayed enhanced responsiveness to IFN-1, increased frequency of pSTAT1+ cells, and greater induction of ISGs upon IFN-1 exposure in vitro. In healthy tissue, antibody neutralization of IFNß selectively reduced T-cell production of the pro-regulatory cytokine interleukin-10 (IL-10) and increased IFNγ synthesis. In contrast, neutralization of IFNß in IBD tissue cultures increased the frequency of T-cells producing inflammatory cytokines but did not alter IL-10 expression. These data support a role for endogenous IFN-1 as a context-dependent modulator of T-cell function that promotes regulatory activity in healthy human intestine, but indicate that the IFN-1/STAT1 pathway is dysregulated in inflammatory bowel disease.