Search

Background: Prompt and efficient identification and stratification of patients who are frail is important, as this cohort are at high risk of adverse healthcare outcomes. Numerous frailty screening tools have been developed to support their identification across different settings, yet relatively few have emerged for use in emergency departments (EDs). This protocol provides details for a systematic review aiming to synthesize the accumulated evidence regarding the diagnostic accuracy and clinimetric properties of frailty screening instruments to identify frail older adults in EDs. Methods: Six electronic databases will be searched from January 2000 to March 2021. Eligible studies will include adults aged ≥60 years screened in EDs with any available screening instrument to identify frailty (even if not originally designed for this purpose). Studies, including case-control, longitudinal, and cohort studies, will be included, where instruments are compared to a reference standard to explore diagnostic accuracy. Predictive accuracy for a selection of outcomes, including mortality, institutionalization, and readmission, will be assessed. Clinical and methodological heterogeneity will be examined, and a random effects meta-analysis performed if appropriate. Conclusion: Understanding whether frailty screening on presentation to EDs is accurate in identifying frailty, and predicting these outcomes is important for decision-making and targeting appropriate management.

Background Adverse drug reactions (ADRs) are common and have serious repercussions for older-adults. This descriptive-analysis elucidates clinical presentations, severity and responsible drugs of incident ADRs in the SENATOR (Software ENgine for the Assessment & optimization of drug and non-drug Therapy in Older peRsons) phase I feasibility study. Methods SENATOR-phase-I was a European multicentre-prospective-observational study. Participants were ≥ 65 years, experiencing acute-hospitalisation and on pharmacological treatment for ≥ 3 conditions. Adverse events (AEs) were identified by trigger list at recruitment, day-14/discharge and classified as ADRs when association with an administered drug was adjudicated as being probable/certain, according to the World Health Organization Uppsala Monitoring Centre ADR causality criteria. Results Of 644 participants recruited, 382 (59.1%) experienced 732 AEs, 363 AEs (49.6%) being incident. 139 participants (21.6%) experienced 177 (48.8%) ADRs. Full drug details were recorded in 156 patients (88%). Cardiovascular-system drugs accounted for one-third of ADRs (55, 35.3%). Five drug classes caused three-quarters of ADRs (135, 76.3%); diuretics 28.2% (furosemide 24.4%), opioid analgesics 16.7%, anti-bacterials for systemic use 14.1%, anti-thrombotic agents 10.3%, and drugs used in diabetes 7%. 68 patients (10.6%) experienced 81 (45.8%) clinically significant moderate-severe ADRs. Significant serum electrolyte disturbance (32, 18.1%), acute kidney injury [AKI] (22, 12.4%), unspecified adverse event (UAE; 21, 11.9%), dyspepsia/nausea/vomiting (20, 11.3%), new-onset major constipation (19, 10.7%) were the most common presentations of ADRs, accounting for 114, (64.4%) of all ADRs. In moderate-severe ADRs; AKI (12, 14.8%), acute bleeding (11, 13.6%), new-onset major constipation (11, 13.6%), UAE (11, 13.6%), significant serum electrolyte disturbance (10, 12.4%) were the most common presentations. Conclusion This analysis highlights that; 1-in-5 older adults will experience an incident ADR during acute hospitalisation. 1-in-10 patients experience moderate-severe incident ADRs. 3-of-4 ADRs were caused by 5 drug classes (diuretics, opioids, anti-bacterials, anti-thrombotics and anti-diabetic agents). This study allows for identification of potentially high risk medications which could be targeted for future ADR prevention.

Background Multi-morbidity and polypharmacy increase the risk of non-trivial adverse drug reactions (ADRs) in older people during hospitalization. Despite this, there are no established interventions for hospital-acquired ADR prevention. Methods We undertook a pragmatic, multi-national, parallel arm prospective randomized open-label, blinded endpoint (PROBE) controlled trial enrolling patients at six European medical centres. We randomized 1,537 older medical and surgical patients with multi-morbidity and polypharmacy on admission in a 1:1 ratio to SENATOR software-guided medication optimization plus standard care (intervention, n = 772, mean number of daily medications = 9.34) or standard care alone (control, n = 765, mean number of daily medications = 9.23) using block randomization stratified by site and admission type. Attending clinicians in the intervention arm received SENATOR-generated advice at a single time point with recommendations they could choose to adopt or not. The primary endpoint was occurrence of probable or certain ADRs within 14 days of randomization. Secondary endpoints were primary endpoint derivatives; tertiary endpoints included all-cause mortality, re-hospitalization, composite healthcare utilization and health-related quality of life. Results For the primary endpoint, there was no difference between the intervention and control groups (24.5 vs. 24.8%; OR 0.98; 95% CI 0.77–1.24; P = 0.88). Similarly, with secondary and tertiary endpoints, there were no significant differences. Among attending clinicians in the intervention group, implementation of SENATOR software-generated medication advice points was poor (~15%). Conclusions In this trial, uptake of software-generated medication advice to minimize ADRs was poor and did not reduce ADR incidence during index hospitalization.

International audience

Purpose Clostridium difficile has been reported to occur in the gastrointestinal tract of 50% of Cystic Fibrosis (CF) subjects, however, clinical C. difficile infection (CDI) is a rare occurrence in this cohort despite the presence of toxigenic and hypervirulent ribotypes. Here, we present the first longitudinal, multicentre analysis of C. difficile prevalence among adult CF subjects. Methodology Faecal samples were collected from adults with CF (selected based on confirmed Pseudomonas aeruginosa pulmonary colonisation) from Ireland, UK and Belgium as part of the CFMATTERS clinical research trial (grant No. 603038) and from non-CF controls. Faecal samples were collected on enrolment, at three monthly intervals, during pulmonary exacerbation and three months post exacerbation. C. difficile was isolated from faecal samples by ethanol shocking followed by culturing on cycloserine cefoxitin egg yolk agar. Isolates were characterised in terms of ribotype, toxin type and antibiotic susceptibility to antibiotics routinely used in the treatment of CDI (metronidazole and vancomycin) and those implicated in induction of CDI (ciprofloxacin and moxifloxacin). Results Prevalence of C. difficile among CF subjects in the three sites was similar ranging from 47% to 50% at baseline, while the healthy control cohort had a carriage rate of 7.1%. Including subjects who were positive for C. difficile at any time point there was a higher carriage rate of 71.4%, 66.7% and 63.2% in Ireland, UK, and Belgium, respectively. Ribotyping of 80 isolates from 45 CF persons, over multiple time points revealed 23 distinct ribotypes with two ribotypes (046 and 078) shared by all centres. The proportion of toxigenic isolates varied across the sites, ranging from 66.7% in Ireland to 52.9% in Belgium and 100% in the UK. Antibiotic susceptibility rates to vancomycin, metronidazole, ciprofloxacin and moxifloxacin was 100%, 97.5%, 1.3% and 63.8%, respectively. Conclusions This study demonstrates the highest carriage rate of C. difficile to date in a CF cohort. Longitudinal data show that C. difficile can be a transient inhabitant of the CF gut, changing both in terms of strain and excretion rates.

The aim of this trial is to evaluate the effect of SENATOR software on incident, adverse drug reactions (ADRs) in older, multimorbid, hospitalized patients. The SENATOR software produces a report designed to optimize older patients’ current prescriptions by applying the published STOPP and START criteria, highlighting drug-drug and drug-disease interactions and providing non-pharmacological recommendations aimed at reducing the risk of incident delirium. We will conduct a multinational, pragmatic, parallel arm Prospective Randomized Open-label, Blinded Endpoint (PROBE) controlled trial. Patients with acute illnesses are screened for recruitment within 48 h of arrival to hospital and enrolled if they meet the relevant entry criteria. Participants’ medical history, current prescriptions, select laboratory tests, electrocardiogram, cognitive status and functional status are collected and entered into a dedicated trial database. Patients are individually randomized with equal allocation ratio. Randomization is stratified by site and medical versus surgical admission, and uses random block sizes. Patients randomized to either arm receive standard routine pharmaceutical clinical care as it exists in each site. Additionally, in the intervention arm an individualized SENATOR-generated medication advice report based on the participant’s clinical and medication data is placed in their medical record and a senior medical staff member is requested to review it and adopt any of its recommendations that they judge appropriate. The trial’s primary outcome is the proportion of patients experiencing at least one adjudicated probable or certain, non-trivial ADR, during the index hospitalization, assessed at 14 days post-randomization or at index hospital discharge if it occurs earlier. Potential ADRs are identified retrospectively by the site researchers who complete a Potential Endpoint Form (one per type of event) that is adjudicated by a blinded, expert committee. All occurrences of 12 pre-specified events, which represent the majority of ADRs, are reported to the committee along with other suspected ADRs. Participants are followed up 12 (+/− 4) weeks post-index hospital discharge to assess medication quality and healthcare utilization. This is the first clinical trial to examine the effectiveness of a software intervention on incident ADRs and associated healthcare costs during hospitalization in older people with multi-morbidity and polypharmacy. Clinicaltrials.gov NCT02097654 , 27 March 2014.

Background: Adverse drug reactions (ADRs) are common in older adults and frequently have serious clinical and economic consequences. This study was conducted as a feasibility study for a randomized control trial (RCT) that will investigate the efficacy of a software engine to optimize medications and reduce incident (in-hospital) ADRs. This study’s objectives were to (i) establish current incident ADR rates across the six sites participating in the forthcoming RCT and (ii) assess whether incident ADRs are predictable. Methods: This was a multicentre, prospective observational study involving six European hospitals. Adults aged ⩾ 65 years, hospitalized with an acute illness and on pharmacological treatment for three or more conditions were eligible for inclusion. Adverse events (AEs) were captured using a trigger list of 12 common ADRs. An AE was deemed an ADR when its association with an administered drug was adjudicated as being probable/certain, according to the World Health Organization Uppsala Monitoring Centre causality assessment. The proportion of patients experiencing at least one, probable/certain, incident ADR within 14 days of enrolment/discharge was recorded. Results: A total of 644 patients were recruited, evenly split by sex and overwhelmingly of White ethnicity. Over 80% of admissions were medical. The median number of chronic conditions was five (interquartile range 4–6), with eight or more conditions present in approximately 10%. The mean number of prescribed medications was 9.9 (standard deviation 3.8), which correlated strongly with the number of conditions ( r = 0.54, p < 0.0001). A total of 732 AEs were recorded in 382 patients, of which 363 were incident. The majority of events were classified as probably or possibly drug related, with heterogeneity across sites (χ2 = 88.567, df = 20, p value < 0.001). Out of 644 patients, 139 (21.6%; 95% confidence interval 18.5–25.0%) experienced an ADR. Serum electrolyte abnormalities were the most common ADR. The ADRROP (ADR Risk in Older People) and GerontoNet ADR risk scales correctly predicted ADR occurrence in 61% and 60% of patients, respectively. Conclusion: This feasibility study established the rates of incident ADRs across the six study sites. The ADR predictive power of ADRROP and GerontoNet ADR risk scales were limited in this population.

Cystic Fibrosis (CF) and its treatment result in an altered gut microbiota composition compared to non-CF controls. However, the impact of this on gut microbiota functionality has not been extensively characterised. Our aim was to conduct a proof-of-principle study to investigate if measurable changes in gut microbiota functionality occur in adult CF patients compared to controls. Metagenomic DNA was extracted from faecal samples from six CF patients and six non-CF controls and shotgun metagenomic sequencing was performed on the MiSeq platform. Metabolomic analysis using gas chromatography-mass spectrometry was conducted on faecal water. The gut microbiota of the CF group was significantly different compared to the non-CF controls, with significantly increased Firmicutes and decreased Bacteroidetes. Functionality was altered, with higher pathway abundances and gene families involved in lipid (e.g. PWY 6284 unsaturated fatty acid biosynthesis (p = 0.016)) and xenobiotic metabolism (e.g. PWY-5430 meta-cleavage pathway of aromatic compounds (p = 0.004)) in CF patients compared to the controls. Significant differences in metabolites occurred between the two groups. This proof-of-principle study demonstrates that measurable changes in gut microbiota functionality occur in CF patients compared to controls. Larger studies are thus needed to interrogate this further.

Introduction In November 2016, the Integrated Addendum to ICH-GCP E6 (R2) will advise trial sponsors to develop a risk-based approach to clinical trial monitoring. This new process is commonly known as risk based monitoring (RBM). To date, a variety of tools have been developed to guide RBM. However, a gold standard approach does not exist. This review aims to identify and examine RBM tools. Methods Review of published and grey literature using a detailed search-strategy and cross-checking of reference lists. This review included academic and commercial instruments that met the Organisation for Economic Co-operation and Development (OECD) classification of RBM tools. Results Ninety-one potential RBM tools were identified and 24 were eligible for inclusion. These tools were published between 2000 and 2015. Eight tools were paper based or electronic questionnaires and 16 operated as Service as a System (SaaS). Risk associated with the investigational medicinal product (IMP), phase of the clinical trial and study population were examined by all tools and suitable mitigation guidance through on-site and centralised monitoring was provided. Conclusion RBM tools for clinical trials are relatively new, their features and use varies widely and they continue to evolve. This makes it difficult to identify the “best” RBM technique or tool. For example, equivalence testing is required to determine if RBM strategies directed by paper based and SaaS based RBM tools are comparable. Such research could be embedded within multi-centre clinical trials and conducted as a SWAT (Study within a Trial).

This study aimed to quantify the effect of cardiac hypertrophy induced with isoprenaline and caffeine on reflex regulation of renal sympathetic nerve activity by the arterial and cardiopulmonary baroreceptors. Male Wistar rats, untreated or given water containing caffeine and subcutaneous (s.c.) isoprenaline every 72 h for 2 weeks or thyroxine s.c. for 7 days, were anaesthetized and prepared for measurement of renal sympathetic nerve activity or cardiac indices. Both isoprenaline-caffeine and thyroxine treatment blunted weight gain but increased heart weight and heart weight to body weight ratio by 40 and 14% (both P

The present study compared the cardiovascular and renal actions of γ(2) -melanocyte-stimulating hormone (γ(2) MSH) with those of the synthetic analogue [Nle(3) ,d-Phe(6) ]-γ(2) MSH (NDP-γ(2) MSH) and explored the effects of high dietary salt intake on the renal actions of NDP-γ(2) MSH. Both peptides were infused systemically (3-1000 nmol/kg) and intrarenally (500 fmol/min) into innervated and renally denervated rats fed either a normal (0.4% NaCl) or high-salt (4% NaCl; HS) diet. Mean arterial pressure (MAP), glomerular filtration rate (GFR), urinary sodium excretion (U(N) (a) V), urinary output (UV) and fractional sodium excretion were determined, as was expression of the melanocortin MC(3) receptor in inner medullary collecting duct (IMCD) epithelial cells. Both renal and systemic infusion of γ(2) MSH increased MAP by 23 ± 2% and 54 ± 4%, respectively, but equivalent doses of NDP-γ(2) MSH had no significant pressor effects. Both peptides had similar natriuretic and diuretic effects in rats fed a normal salt diet. However, NDP-γ(2) MSH increased U(N) (a) V and UV by two- to threefold in rats fed the normal salt diet and by six- to sevenfold in rats fed the HS diet. Furthermore, NDP-γ(2) MSH induced a 3.5-fold increase in GFR only in rats fed the HS diet. These renal effects of NDP-γ(2) MSH were not abolished by prior renal denervation. Rats fed the HS diet also exhibited a 4.5-fold increase in MC(3) receptor expression in IMCD epithelial cells. Intrarenal infusion of NDP-γ(2) MSH induced the natriuretic but not the cardiovascular effects exhibited by γ(2) MSH. The renal activities may be attributed to a direct binding of NDP-γ(2) MSH to MC(3) receptors expressed in IMCD cells, leading to a potent natriuretic effect that is independent of renal innervation.