Promoting Alcohol Reduction in Non-Treatment Seeking parents (PAReNTS):a protocol for a pilot feasibility cluster randomised controlled trial of alcohol screening and brief interventions to reduce parental alcohol use disorders in vulnerable families

Brief alcohol advice intervention. (DOCX 1500 kb

A pilot feasibility cluster randomised controlled trial of screening and brief alcohol intervention to prevent hazardous drinking in young people aged 14-15 years in a high school setting (SIPS JR-HIGH)

Background: Approximately 33% of 15- to 16-year-olds in England report alcohol intoxication in the past month. This present work builds on the evidence base by focusing on Alcohol Screening and Brief Intervention (ASBI) to reduce hazardous drinking in younger adolescents. Objectives: To explore the feasibility and acceptability of a future definitive cluster randomised controlled trial (cRCT) of ASBI in a school setting to staff, young people and parents; to explore the fidelity of the interventions as delivered by school learning mentors; to estimate the parameters for the design of a definitive cRCT of brief alcohol intervention, including rates of eligibility, consent, participation and retention at 12 months; and to pilot the collection of cost and resource-use data to inform the cost-effectiveness/utility analysis in a definitive trial. Setting: Seven schools across one geographical area in North East England. Methods: Feasibility of trial processes, recruitment and retention and a qualitative evaluation examined facilitators and barriers to the use of ASBI approaches in the school setting in this age group. A three-arm pilot cRCT (with randomisation at the school level) with qualitative evaluation to assess the feasibility of a future definitive cRCT of the effectiveness and cost-effectiveness of ASBI in a school setting, with an integrated qualitative component. The trial ran in parallel with a repeated cross-sectional survey, which facilitated screening for the trial. Participants: Year 10 school pupils (aged 14–15 years). Interventions: Young people who screened positive on a single alcohol screening question, and consented to take part, were randomised to one of three groups: (1) feedback that their drinking habits may be risky and provision of an advice leaflet (control condition, n?=?two schools); (2) feedback as for the control condition plus a 30-minute brief interactive session, which combined structured advice and motivational interviewing techniques, delivered by the school learning mentor (intervention 1, n?=?two schools); or (3) feedback as for the control condition plus a 30-minute brief interactive session as for intervention 1 plus a 60-minute session involving family members delivered by the school learning mentor (intervention 2, n?=?three schools). Young people were followed up at 12 months. Main outcome measures: Feasibility and acceptability. Randomisation: Randomisation was carried out at the school level. Randomisation achieved balance on two school-level variables (numbers of pupils in school year and proportion receiving free school meals). Blinding: School staff, young people and researchers were not blind to the intervention allocated. Results: A total of 229 young people were eligible for the trial; 182 (79.5%) were randomised (control, n?=?53; intervention 1, n?=?54; intervention 2, n?=?75). Of the 75 randomised to intervention 2, 67 received intervention 1 (89%). Eight received both intervention 1 and intervention 2 (11%). In total, 160 out of 182 were successfully followed up at 12 months (88%). Interviews were carried out with six school lead liaisons, 13 learning mentors, 27 young people and seven parents (n?=?53). Analysis shows that the school setting is a feasible and acceptable place to carry out ASBI, with learning mentors seen as suitable people to do this. Intervention 2 was not seen as feasible or acceptable by school staff, parents or young people. Outcomes/conclusions: It is feasible and acceptable to carry out a trial of the effectiveness and cost-effectiveness of single-session ASBI with young people in the school setting, with learning mentors delivering the intervention. Future work should include a definitive study that does not include a parental arm

Intervention to reduce excessive alcohol consumption and improve comorbidity outcomes in hypertensive or depressed primary care patients: two parallel cluster randomized feasibility trials

Wilson, G. B. Wray, C. McGovern, R. Newbury-Birch, D. McColl, E. Crosland, A. Background Many primary care patients with raised blood pressure or depression drink potentially hazardous levels of alcohol. Brief interventions (BI) to reduce alcohol consumption may improve comorbid conditions and reduce the risk of future alcohol problems. However,research has not established their effectiveness in this patient population. This study aimed to establish the feasibility of definitive trials of BI to reduce excessive drinking in primary care patients with hypertension or mild to moderate depression. Methods Thirteen general practices in North East England were randomized to the intervention or control arm of one of two parallel pilot trials. Adult patients drinking excessively and diagnosed with hypertension or mild-to-moderate depression received the Alcohol Use Disorders Identification Test (AUDIT) by postal survey. Consenting respondents scoring more than 7 on AUDIT (score range 0 to 40) received brief alcohol consumption advice plus an information leaflet (intervention) or an information leaflet alone(control) with follow-up at six months. Measurements included the numbers of patients eligible, recruited, and retained, and the AUDIT score and systolic/diastolic blood pressure of each patient or the nine-item Patient Health Questionnaire (PHQ-9) score. Acceptability was assessed via practitioner feedback and patient willingness to be screened, recruited, and retained at follow-up. Results In the hypertension trial, 1709 of 33,813 adult patients(5.1%) were eligible and were surveyed. Among the eligible patients, 468 (27.4%) returned questionnaires; 166 (9.6% of those surveyed) screened positively on AUDIT and 83 (4.8% of those surveyed) were recruited (50.0% of positive screens). Sixty-seven cases (80.7% of recruited patients)completed follow-up at six months. In the depression trial, 1,044 of 73,146 adult patients(1.4%)were eligible and surveyed. Among these eligible patients, 215(20.6%)responded;104(10.0% of those surveyed)screened positively on AUDIT and 29 (2.8% of those surveyed) were recruited (27.9% of positive screens). Nineteen cases(65.5% of recruited patients)completed follow-up at six months. Conclusions Recruitment and retention rates were higher in the hypertension trial than in the depression trial. A full brief intervention trial appears feasible for primary care patients with hypertension who drink excessively. High AUDIT scores in the depression trial suggest the importance of alcohol intervention in this group. However, future work may require alternative screening and measurement procedures

Puffins, Pigs, Cod, and Barley: Palaeoeconomy at Undir Junkarinsfløtti, Sandoy, Faroe Islands

This paper reports on the zooarchaeological and archaeobotanical remains from the initial season of excavations at the Norse period site at Undir Junkarinsfløtti in the Faroe islands. These remains represent the first zooarchaeological analysis undertaken for the Faroes and only the third archaeobotanical assemblage published from the islands. The excavated deposits are described and the key findings from the palaeoenvironmental remains highlighted within the context of the wider North Atlantic environmental archaeology of the Norse period

Puffins, Pigs, Cod, and Barley: Palaeoeconomy at Undir Junkarinsfløtti, Sandoy, Faroe Islands

This paper reports on the zooarchaeological and archaeobotanical remains from the initial season of excavations at the Norse period site at Undir Junkarinsfløtti in the Faroe islands. These remains represent the first zooarchaeological analysis undertaken for the Faroes and only the third archaeobotanical assemblage published from the islands. The excavated deposits are described and the key findings from the palaeoenvironmental remains highlighted within the context of the wider North Atlantic environmental archaeology of the Norse period

Copy number of FCGR3B, which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake.

Copy number (CN) variation (CNV) has been shown to be common in regions of the genome coding for immune-related genes, and thus impacts upon polygenic autoimmunity. Low CN of FCGR3B has recently been associated with systemic lupus erythematosus (SLE). FcgammaRIIIb is a glycosylphosphatidylinositol-linked, low affinity receptor for IgG found predominantly on human neutrophils. We present novel data demonstrating that both in a family with FcgammaRIIIb-deficiency and in the normal population, FCGR3B CNV correlates with protein expression, with neutrophil uptake of and adherence to immune complexes, and with soluble serum FcgammaRIIIb. Reduced FcgammaRIIIb expression is thus likely to contribute to the impaired clearance of immune complexes, which is a feature of SLE, explaining the association between low FCGR3B CNV and SLE that we have confirmed in a Caucasian population. In contrast, antineutrophil cytoplasmic antibody-associated systemic vasculitis (AASV), a disease not associated with immune complex deposition, is associated with high FCGR3B CN. Thus, we define a role for FCGR3B CNV in immune complex clearance, a function that may explain why low FCGR3B CNV is associated with SLE, but not AASV. This is the first report of an association between disease-related gene CNV and variation in protein expression and function that may contribute to autoimmune disease susceptibility

Safety and Tolerability of SER-109 as an Investigational Microbiome Therapeutic in Adults With Recurrent Clostridioides difficile Infection: A Phase 3, Open-Label, Single-Arm Trial

IMPORTANCE: A safe and effective treatment for recurrent Clostridioides difficile infection (CDI) is urgently needed. Antibiotics kill toxin-producing bacteria but do not repair the disrupted microbiome, which promotes spore germination and infection recurrence. OBJECTIVES: To evaluate the safety and rate of CDI recurrence after administration of investigational microbiome therapeutic SER-109 through 24 weeks. DESIGN, SETTING, AND PARTICIPANTS: This phase 3, single-arm, open-label trial (ECOSPOR IV) was conducted at 72 US and Canadian outpatient sites from October 2017 to April 2022. Adults aged 18 years or older with recurrent CDI were enrolled in 2 cohorts: (1) rollover patients from the ECOSPOR III trial who had CDI recurrence diagnosed by toxin enzyme immunoassay (EIA) and (2) patients with at least 1 CDI recurrence (diagnosed by polymerase chain reaction [PCR] or toxin EIA), inclusive of their acute infection at study entry. INTERVENTIONS: SER-109 given orally as 4 capsules daily for 3 days following symptom resolution after antibiotic treatment for CDI. MAIN OUTCOMES AND MEASURES: The main outcomes were safety, measured as the rate of treatment-emergent adverse events (TEAEs) in all patients receiving any amount of SER-109, and cumulative rates of recurrent CDI (toxin-positive diarrhea requiring treatment) through week 24 in the intent-to-treat population. RESULTS: Of 351 patients screened, 263 were enrolled (180 [68.4%] female; mean [SD] age, 64.0 [15.7] years); 29 were in cohort 1 and 234 in cohort 2. Seventy-seven patients (29.3%) were enrolled with their first CDI recurrence. Overall, 141 patients (53.6%) had TEAEs, which were mostly mild to moderate and gastrointestinal. There were 8 deaths (3.0%) and 33 patients (12.5%) with serious TEAEs; none were considered treatment related by the investigators. Overall, 23 patients (8.7%; 95% CI, 5.6%-12.8%) had recurrent CDI at week 8 (4 of 29 [13.8%; 95% CI, 3.9%-31.7%] in cohort 1 and 19 of 234 [8.1%; 95% CI, 5.0%-12.4%] in cohort 2), and recurrent CDI rates remained low through 24 weeks (36 patients [13.7%; 95% CI, 9.8%-18.4%]). At week 8, recurrent CDI rates in patients with a first recurrence were similarly low (5 of 77 [6.5%; 95% CI, 2.1%-14.5%]) as in patients with 2 or more recurrences (18 of 186 [9.7%; 95% CI, 5.8%-14.9%]). Analyses by select baseline characteristics showed consistently low recurrent CDI rates in patients younger than 65 years vs 65 years or older (5 of 126 [4.0%; 95% CI, 1.3%-9.0%] vs 18 of 137 [13.1%; 95% CI, 8.0%-20.0%]) and patients enrolled based on positive PCR results (3 of 69 [4.3%; 95% CI, 0.9%-12.2%]) vs those with positive toxin EIA results (20 of 192 [10.4%; 95% CI, 6.5%-15.6%]). CONCLUSIONS AND RELEVANCE: In this trial, oral SER-109 was well tolerated in a patient population with recurrent CDI and prevalent comorbidities. The rate of recurrent CDI was low regardless of the number of prior recurrences, demographics, or diagnostic approach, supporting the beneficial impact of SER-109 for patients with CDI. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03183141

Detecting copy number status and uncovering subclonal markers in heterogeneous tumor biopsies

<p>Abstract</p> <p>Background</p> <p>Genomic aberrations can be used to determine cancer diagnosis and prognosis. Clinically relevant novel aberrations can be discovered using high-throughput assays such as Single Nucleotide Polymorphism (SNP) arrays and next-generation sequencing, which typically provide aggregate signals of many cells at once. However, heterogeneity of tumor subclones dramatically complicates the task of detecting aberrations.</p> <p>Results</p> <p>The aggregate signal of a population of subclones can be described as a linear system of equations. We employed a measure of allelic imbalance and total amount of DNA to characterize each locus by the copy number status (gain, loss or neither) of the strongest subclonal component. We designed simulated data to compare our measure to existing approaches and we analyzed SNP-arrays from 30 melanoma samples and transcriptome sequencing (RNA-Seq) from one melanoma sample.</p> <p>We showed that any system describing aggregate subclonal signals is underdetermined, leading to non-unique solutions for the exact copy number profile of subclones. For this reason, our illustrative measure was more robust than existing Hidden Markov Model (HMM) based tools in inferring the aberration status, as indicated by tests on simulated data. This higher robustness contributed in identifying numerous aberrations in several loci of melanoma samples. We validated the heterogeneity and aberration status within single biopsies by fluorescent <it>in situ </it>hybridization of four affected and transcriptionally up-regulated genes E2F8, ETV4, EZH2 and FAM84B in 11 melanoma cell lines. Heterogeneity was further demonstrated in the analysis of allelic imbalance changes along single exons from melanoma RNA-Seq.</p> <p>Conclusions</p> <p>These studies demonstrate how subclonal heterogeneity, prevalent in tumor samples, is reflected in aggregate signals measured by high-throughput techniques. Our proposed approach yields high robustness in detecting copy number alterations using high-throughput technologies and has the potential to identify specific subclonal markers from next-generation sequencing data.</p