Clinician-targeted interventions to influence antibiotic prescribing behaviour for acute respiratory infections in primary care: An overview of systematic reviews

Background: Antibiotic resistance is a worldwide health threat. Interventions that reduce antibiotic prescribing by clinicians are expected to reduce antibiotic resistance. Disparate interventions to change antibiotic prescribing behaviour for acute respiratory infections (ARIs) have been trialled and meta-analysed, but not yet synthesised in an overview. This overview synthesises evidence from systematic reviews, rather than individual trials. Objectives: To systematically review the existing evidence from systematic reviews on the effects of interventions aimed at influencing clinician antibiotic prescribing behaviour for ARIs in primary care. Methods: We searched the Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects (DARE), MEDLINE, Embase, CINAHL, PsycINFO, and Science Citation Index to June 2016. We also searched the reference lists of all included reviews. We ran a pre-publication search in May 2017 and placed additional studies in 'awaiting classification'. We included both Cochrane and non-Cochrane reviews of randomised controlled trials evaluating the effect of any clinician-focussed intervention on antibiotic prescribing behaviour in primary care. Two overview authors independently extracted data and assessed the methodological quality of included reviews using the ROBIS tool, with disagreements reached by consensus or by discussion with a third overview author. We used the GRADE system to assess the quality of evidence in included reviews. The results are presented as a narrative overview. Main results: We included eight reviews in this overview: five Cochrane Reviews (33 included trials) and three non-Cochrane reviews (11 included trials). Three reviews (all Cochrane Reviews) scored low risk across all the ROBIS domains in Phase 2 and low risk of bias overall. The remaining five reviews scored high risk on Domain 4 of Phase 2 because the 'Risk of bias' assessment had not been specifically considered and discussed in the review Results and Conclusions. The trials included in the reviews varied in both size and risk of bias. Interventions were compared to usual care. Moderate-quality evidence indicated that C-reactive protein (CRP) point-of-care testing (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.66 to 0.92, 3284 participants, 6 trials), shared decision making (odds ratio (OR) 0.44, 95% CI 0.26 to 0.75, 3274 participants, 3 trials; RR 0.64, 95% CI 0.49 to 0.84, 4623 participants, 2 trials; risk difference -18.44, 95% CI -27.24 to -9.65, 481,807 participants, 4 trials), and procalcitonin-guided management (adjusted OR 0.10, 95% CI 0.07 to 0.14, 1008 participants, 2 trials) probably reduce antibiotic prescribing in general practice. We found moderate-quality evidence that procalcitonin-guided management probably reduces antibiotic prescribing in emergency departments (adjusted OR 0.34, 95% CI 0.28 to 0.43, 2605 participants, 7 trials). The overall effect of these interventions was small (few achieving greater than 50% reduction in antibiotic prescribing, most about a quarter or less), but likely to be clinically important. Compared to usual care, shared decision making probably makes little or no difference to reconsultation for the same illness (RR 0.87, 95% CI 0.74 to 1.03, 1860 participants, 4 trials, moderate-quality evidence), and may make little or no difference to patient satisfaction (RR 0.86, 95% CI 0.57 to 1.30, 1110 participants, 2 trials, low-quality evidence). Similarly, CRP testing probably has little or no effect on patient satisfaction (RR 0.79, 95% CI 0.57 to 1.08, 689 participants, 2 trials, moderate-quality evidence) or reconsultation (RR 1.08, 95% CI 0.93 to 1.27, 5132 participants, 4 trials, moderate-quality evidence). Procalcitonin-guided management probably results in little or no difference in treatment failure in general practice compared to normal care (adjusted OR 0.95, 95% CI 0.73 to 1.24, 1008 participants, 2 trials, moderate-quality evidence), however it probably reduces treatment failure in the emergency department compared to usual care (adjusted OR 0.76, 95% CI 0.61 to 0.95, 2605 participants, 7 trials, moderate-quality evidence). The quality of evidence for interventions focused on clinician educational materials and decision support in reducing antibiotic prescribing in general practice was either low or very low (no pooled result reported) and trial results were highly heterogeneous, therefore we were unable draw conclusions about the effects of these interventions. The use of rapid viral diagnostics in emergency departments may have little or no effect on antibiotic prescribing (RR 0.86, 95% CI 0.61 to 1.22, 891 participants, 3 trials, low-quality evidence) and may result in little to no difference in reconsultation (RR 0.86, 95% CI 0.59 to 1.25, 200 participants, 1 trial, low-quality evidence). None of the trials in the included reviews reported on management costs for the treatment of an ARI or any associated complications. Authors' conclusions: We found evidence that CRP testing, shared decision making, and procalcitonin-guided management reduce antibiotic prescribing for patients with ARIs in primary care. These interventions may therefore reduce overall antibiotic consumption and consequently antibiotic resistance. There do not appear to be negative effects of these interventions on the outcomes of patient satisfaction and reconsultation, although there was limited measurement of these outcomes in the trials. This should be rectified in future trials. We could gather no information about the costs of management, and this along with the paucity of measurements meant that it was difficult to weigh the benefits and costs of implementing these interventions in practice. Most of this research was undertaken in high-income countries, and it may not generalise to other settings. The quality of evidence for the interventions of educational materials and tools for patients and clinicians was either low or very low, which prevented us from drawing any conclusions. High-quality trials are needed to further investigate these interventions. </p

Impact of FTO genotypes on BMI and weight in polycystic ovary syndrome : a systematic review and meta-analysis

Aims/hypothesis FTO gene single nucleotide polymorphisms (SNPs) have been shown to be associated with obesity-related traits and type 2 diabetes. Several small studies have suggested a greater than expected effect of the FTO rs9939609 SNP on weight in polycystic ovary syndrome (PCOS). We therefore aimed to examine the impact of FTO genotype on BMI and weight in PCOS. Methods A systematic search of medical databases (PubMed, EMBASE and Cochrane CENTRAL) was conducted up to the end of April 2011. Seven studies describing eight distinct PCOS cohorts were retrieved; seven were genotyped for SNP rs9939609 and one for SNP rs1421085. The per allele effect on BMI and body weight increase was calculated and subjected to meta-analysis. Results A total of 2,548 women with PCOS were included in the study; 762 were TT homozygotes, 1,253 had an AT/CT genotype, and 533 were AA/CC homozygotes. Each additional copy of the effect allele (A/C) increased the BMI by a mean of 0.19 z score units (95% CI 0.13, 0.24; p = 2.26 × 10−11) and body weight by a mean of 0.20 z score units (95% CI 0.14, 0.26; p = 1.02 × 10−10). This translated into an approximately 3.3 kg/m2 increase in BMI and an approximately 9.6 kg gain in body weight between TT and AA/CC homozygotes. The association between FTO genotypes and BMI was stronger in the cohorts with PCOS than in the general female populations from large genome-wide association studies. Deviation from an additive genetic model was observed in heavier populations. Conclusions/interpretation The effect of FTO SNPs on obesity-related traits in PCOS seems to be more than two times greater than the effect found in large population-based studies. This suggests an interaction between FTO and the metabolic context or polygenic background of PCOS

The modified NCEP ATP III criteria maybe better than the IDF criteria in diagnosing Metabolic Syndrome among Malays in Kuala Lumpur

<p>Abstract</p> <p>Background</p> <p>Metabolic Syndrome is associated with increased risk for type 2 diabetes and cardiovascular diseases. However, different diagnostic criteria have been recommended by different expert groups. In Malaysia, there is a lack of research comparing these different diagnostic criteria. Therefore, it is our aim to study the concordance between the IDF and the modified NCEP ATP III definitions of Metabolic Syndrome among a Malay cohort in Kuala Lumpur; and to demonstrate if all participants have the same cardiometabolic risks.</p> <p>Methods</p> <p>This was an analytical cross sectional study. Ethics approval was obtained and informed consent was given by all participants. Anthropometric measurements, blood pressure, fasting blood glucose and lipid profile were taken following standard protocols.</p> <p>Results</p> <p>Metabolic Syndrome was diagnosed in 41.4% and 38.2% participants using the modified NCEP and IDF criteria respectively. Among those diagnosed with Metabolic Syndrome by modified NCEP, 7.6% were missed by the IDF criteria. Participants diagnosed by the modified NCEP criteria had lower BMI and waist circumference but had higher cardiometabolic risks than those diagnosed with both criteria. Their blood pressure, glucose, total cholesterol and triglyceride were more adverse than the IDF group. This demonstrated that central obesity may not be a prerequisite for the development of increased cardiometabolic risks within this Malay cohort.</p> <p>Conclusion</p> <p>Metabolic syndrome is common in this Malay cohort regardless of the criterion used. The modified NCEP ATP III criteria may be more suitable in diagnosis of metabolic syndrome for this Malay cohort.</p

A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets

Objective: Gastric cancer is a major gastrointestinal malignancy for which targeted therapies are emerging as treatment options. This study sought to identify the most prevalent molecular targets in gastric cancer and to elucidate systematic patterns of exclusivity and co-occurrence among these targets, through comprehensive genomic analysis of a large panel of gastric cancers. Design: Using high-resolution single nucleotide polymorphism arrays, copy number alterations were profiled in a panel of 233 gastric cancers (193 primary tumours, 40 cell lines) and 98 primary matched gastric non-malignant samples. For selected alterations, their impact on gene expression and clinical outcome were evaluated. Results: 22 recurrent focal alterations (13 amplifications and nine deletions) were identified. These included both known targets (FGFR2, ERBB2) and also novel genes in gastric cancer (KLF5, GATA6). Receptor tyrosine kinase (RTK)/RAS alterations were found to be frequent in gastric cancer. This study also demonstrates, for the first time, that these alterations occur in a mutually exclusive fashion, with KRAS gene amplifications highlighting a clinically relevant but previously underappreciated gastric cancer subgroup. FGFR2-amplified gastric cancers were also shown to be sensitive to dovitinib, an orally bioavailable FGFR/VEGFR targeting agent, potentially representing a subtype-specific therapy for FGFR2-amplified gastric cancers. Conclusion: The study demonstrates the existence of five distinct gastric cancer patient subgroups, defined by the signature genomic alterations FGFR2 (9% of tumours), KRAS (9%), EGFR (8%), ERBB2 (7%) and MET (4%). Collectively, these subgroups suggest that at least 37% of gastric cancer patients may be potentially treatable by RTK/RAS directed therapies

What happens if you single out? An experiment

We present an experiment investigating the effects of singling out an individual on trust and trustworthiness. We find that (a) trustworthiness falls if there is a singled out subject; (b) non-singled out subjects discriminate against the singled out subject when they are not responsible of the distinct status of this person; (c) under a negative frame, the singled out subject returns significantly less; (d) under a positive frame, the singled out subject behaves bimodally, either selecting very low or very high return rates. Overall, singling out induces a negligible effect on trust but is potentially disruptive for trustworthiness

The Opportunities and Challenges of SME Manufacturing Automation: Safety and Ergonomics in Human–Robot Collaboration

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Increased S-nitrosylation and proteasomal degradation of caspase-3 during infection contribute to the persistence of adherent invasive escherichia coli (AIEC) in immune cells

Adherent invasive Escherichia coli (AIEC) have been implicated as a causative agent of Crohn's disease (CD) due to their isolation from the intestines of CD sufferers and their ability to persist in macrophages inducing granulomas. The rapid intracellular multiplication of AIEC sets it apart from other enteric pathogens such as Salmonella Typhimurium which after limited replication induce programmed cell death (PCD). Understanding the response of infected cells to the increased AIEC bacterial load and associated metabolic stress may offer insights into AIEC pathogenesis and its association with CD. Here we show that AIEC persistence within macrophages and dendritic cells is facilitated by increased proteasomal degradation of caspase-3. In addition S-nitrosylation of pro- and active forms of caspase-3, which can inhibit the enzymes activity, is increased in AIEC infected macrophages. This S-nitrosylated caspase-3 was seen to accumulate upon inhibition of the proteasome indicating an additional role for S-nitrosylation in inducing caspase-3 degradation in a manner independent of ubiquitination. In addition to the autophagic genetic defects that are linked to CD, this delay in apoptosis mediated in AIEC infected cells through increased degradation of caspase-3, may be an essential factor in its prolonged persistence in CD patients

AQP5 enriches for stem cells and cancer origins in the distal stomach

LGR5 marks resident adult epithelial stem cells at the gland base in the mouse pyloric stomach1, but the identity of the equivalent human stem cell population remains unknown owing to a lack of surface markers that facilitate its prospective isolation and validation. In mouse models of intestinal cancer, LGR5+ intestinal stem cells are major sources of cancer following hyperactivation of the WNT pathway2. However, the contribution of pyloric LGR5+ stem cells to gastric cancer following dysregulation of the WNT pathway—a frequent event in gastric cancer in humans3—is unknown. Here we use comparative profiling of LGR5+ stem cell populations along the mouse gastrointestinal tract to identify, and then functionally validate, the membrane protein AQP5 as a marker that enriches for mouse and human adult pyloric stem cells. We show that stem cells within the AQP5+ compartment are a source of WNT-driven, invasive gastric cancer in vivo, using newly generated Aqp5-creERT2 mouse models. Additionally, tumour-resident AQP5+ cells can selectively initiate organoid growth in vitro, which indicates that this population contains potential cancer stem cells. In humans, AQP5 is frequently expressed in primary intestinal and diffuse subtypes of gastric cancer (and in metastases of these subtypes), and often displays altered cellular localization compared with healthy tissue. These newly identified markers and mouse models will be an invaluable resource for deciphering the early formation of gastric cancer, and for isolating and characterizing human-stomach stem cells as a prerequisite for harnessing the regenerative-medicine potential of these cells in the clinic