Resilience in Research:A guide to developing and managing your resilience and well-being in an academic environment

Academic environments can be complex and dynamic work places. Full of comradeship, yet also sometimes a solitary experience – and while there is a great sense of achievement in the research process to create new knowledge, there are the inevitable ups and downs to navigate through. At a superficial level, a research career, of any duration, can fluctuate from challenging, overwhelming and exciting, sometimes within the same day. Underneath this, there are more subtle factors that keep individuals going, through these ups and downs of research life. This self-resilience is different for everyone and what might excite or energise one colleague may dishearten another

Resilience in Research:A guide to developing and managing your resilience and well-being in an academic environment

Academic environments can be complex and dynamic work places. Full of comradeship, yet also sometimes a solitary experience – and while there is a great sense of achievement in the research process to create new knowledge, there are the inevitable ups and downs to navigate through. At a superficial level, a research career, of any duration, can fluctuate from challenging, overwhelming and exciting, sometimes within the same day. Underneath this, there are more subtle factors that keep individuals going, through these ups and downs of research life. This self-resilience is different for everyone and what might excite or energise one colleague may dishearten another

Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high grade ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: integrated analysis of data from Study 10 and ARIEL2

Objective: An integrated analysis was undertaken to characterize the antitumor activity and safety profile of the oral poly(ADP-ribose) polymerase inhibitor rucaparib in patients with relapsed high-grade ovarian carcinoma (HGOC). Methods: Eligible patients from Study 10 (NCT01482715) and ARIEL2 (NCT01891344) who received a starting dose of oral rucaparib 600 mg twice daily (BID) with or without food were included in these analyses. The integrated efficacy population included patients with HGOC and a deleterious germline or somatic BRCA1 or BRCA2 (BRCA1/2) mutation who received at least two prior chemotherapies and were sensitive, resistant, or refractory to platinum-based chemotherapy. The primary endpoint was investigator-assessed confirmed objective response rate (ORR). Secondary endpoints included duration of response (DOR) and progression-free survival (PFS). The integrated safety population included patients with HGOC who received at least one dose of rucaparib 600 mg BID, irrespective of BRCA1/2 mutation status and prior treatments. Results: In the efficacy population (n = 106), ORR was 53.8% (95% confidence interval [CI], 43.8–63.5); 8.5% and 45.3% of patients achieved complete and partial responses, respectively. Median DOR was 9.2 months (95% CI, 6.6–11.6). In the safety population (n = 377), the most frequent treatment-emergent adverse events (AEs) were nausea, asthenia/fatigue, vomiting, and anemia/hemoglobin decreased. The most common grade ≥ 3 treatment-emergent AE was anemia/hemoglobin decreased. Treatment-emergent AEs led to treatment interruption, dose reduction, and treatment discontinuation in 58.6%, 45.9%, and 9.8% of patients, respectively. No treatment-related deaths occurred. Conclusions: Rucaparib has antitumor activity in advanced BRCA1/2-mutated HGOC and a manageable safety profile

Ebola Virus Disease in Children, Sierra Leone, 2014-2015.

Little is known about potentially modifiable factors in Ebola virus disease in children. We undertook a retrospective cohort study of children <13 years old admitted to 11 Ebola holding units in the Western Area, Sierra Leone, during 2014-2015 to identify factors affecting outcome. Primary outcome was death or discharge after transfer to Ebola treatment centers. All 309 Ebola virus-positive children 2 days-12 years old were included; outcomes were available for 282 (91%). Case-fatality was 57%, and 55% of deaths occurred in Ebola holding units. Blood test results showed hypoglycemia and hepatic/renal dysfunction. Death occurred swiftly (median 3 days after admission) and was associated with younger age and diarrhea. Despite triangulation of information from multiple sources, data availability was limited, and we identified no modifiable factors substantially affecting death. In future Ebola virus disease epidemics, robust, rapid data collection is vital to determine effectiveness of interventions for children

Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Rucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma. Methods: In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries. Eligible patients were aged 18 years or older, had a platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma, had received at least two previous platinum-based chemotherapy regimens, had achieved complete or partial response to their last platinum-based regimen, had a cancer antigen 125 concentration of less than the upper limit of normal, had a performance status of 0–1, and had adequate organ function. Patients were ineligible if they had symptomatic or untreated central nervous system metastases, had received anticancer therapy 14 days or fewer before starting the study, or had received previous treatment with a poly(ADP-ribose) polymerase inhibitor. We randomly allocated patients 2:1 to receive oral rucaparib 600 mg twice daily or placebo in 28 day cycles using a computer-generated sequence (block size of six, stratified by homologous recombination repair gene mutation status, progression-free interval after the penultimate platinum-based regimen, and best response to the most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary outcome was investigator-assessed progression-free survival evaluated with use of an ordered step-down procedure for three nested cohorts: patients with BRCA mutations (carcinoma associated with deleterious germline or somatic BRCA mutations), patients with homologous recombination deficiencies (BRCA mutant or BRCA wild-type and high loss of heterozygosity), and the intention-to-treat population, assessed at screening and every 12 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01968213; enrolment is complete. Findings: Between April 7, 2014, and July 19, 2016, we randomly allocated 564 patients: 375 (66%) to rucaparib and 189 (34%) to placebo. Median progression-free survival in patients with a BRCA-mutant carcinoma was 16·6 months (95% CI 13·4–22·9; 130 [35%] patients) in the rucaparib group versus 5·4 months (3·4–6·7; 66 [35%] patients) in the placebo group (hazard ratio 0·23 [95% CI 0·16–0·34]; p&lt;0·0001). In patients with a homologous recombination deficient carcinoma (236 [63%] vs 118 [62%]), it was 13·6 months (10·9–16·2) versus 5·4 months (5·1–5·6; 0·32 [0·24–0·42]; p&lt;0·0001). In the intention-to-treat population, it was 10·8 months (8·3–11·4) versus 5·4 months (5·3–5·5; 0·36 [0·30–0·45]; p&lt;0·0001). Treatment-emergent adverse events of grade 3 or higher in the safety population (372 [99%] patients in the rucaparib group vs 189 [100%] in the placebo group) were reported in 209 (56%) patients in the rucaparib group versus 28 (15%) in the placebo group, the most common of which were anaemia or decreased haemoglobin concentration (70 [19%] vs one [1%]) and increased alanine or aspartate aminotransferase concentration (39 [10%] vs none). Interpretation: Across all primary analysis groups, rucaparib significantly improved progression-free survival in patients with platinum-sensitive ovarian cancer who had achieved a response to platinum-based chemotherapy. ARIEL3 provides further evidence that use of a poly(ADP-ribose) polymerase inhibitor in the maintenance treatment setting versus placebo could be considered a new standard of care for women with platinum-sensitive ovarian cancer following a complete or partial response to second-line or later platinum-based chemotherapy. Funding: Clovis Oncology

Development of a Pediatric Ebola Predictive Score, Sierra Leone1.

We compared children who were positive for Ebola virus disease (EVD) with those who were negative to derive a pediatric EVD predictor (PEP) score. We collected data on all children <13 years of age admitted to 11 Ebola holding units in Sierra Leone during August 2014-March 2015 and performed multivariable logistic regression. Among 1,054 children, 309 (29%) were EVD positive and 697 (66%) EVD negative, with 48 (5%) missing. Contact history, conjunctivitis, and age were the strongest positive predictors for EVD. The PEP score had an area under receiver operating characteristics curve of 0.80. A PEP score of 7/10 was 92% specific and 44% sensitive; 3/10 was 30% specific, 94% sensitive. The PEP score could correctly classify 79%-90% of children and could be used to facilitate triage into risk categories, depending on the sensitivity or specificity required

ARIEL4: An International, Multicenter, Randomized Phase 3 Study of the PARP Inhibitor Rucaparib vs Chemotherapy in Germline or Somatic BRCA1- or BRCA2-Mutated, Relapsed, High-Grade Ovarian Carcinoma

Описание In high-grade ovarian cancer, including fallopian tube and primary peritoneal cancers, approximately 18% of patients have tumors with a germline BRCA1 or BRCA2 mutation and approximately 7% of patients have tumors with a somatic BRCA1 or BRCA2 mutation1• The poly (ADP-ribose) polymerase (PARP) inhibitor rucaparib has demonstrated efficacy in tumors with homologous recombination deficiency (HRD), including a BRCA1 or BRCA2 mutation2-5–In cells with HRD, PARP inhibition results in accumulation of double-strand ..

The Clean pilot study: evaluation of an environmental hygiene intervention bundle in three Tanzanian hospitals.

BACKGROUND: Healthcare associated infections (HAI) are estimated to affect up to 15% of hospital inpatients in low-income countries (LICs). A critical but often neglected aspect of HAI prevention is basic environmental hygiene, particularly surface cleaning and linen management. TEACH CLEAN is an educational intervention aimed at improving environmental hygiene. We evaluated the effectiveness of this intervention in a pilot study in three high-volume maternity and newborn units in Dar es Salaam, Tanzania. METHODS: This study design prospectively evaluated the intervention as a whole, and offered a before-and-after comparison of the impact of the main training. We measured changes in microbiological cleanliness [Aerobic Colony Counts (ACC) and presence of Staphylococcus aureus] using dipslides, and physical cleaning action using gel dots. These were analysed with descriptive statistics and logistic regression models. We used qualitative (focus group discussions, in-depth interviews, and semi-structured observation) and quantitative (observation checklist) tools to measure why and how the intervention worked. We describe these findings across the themes of adaptation, fidelity, dose, reach and context. RESULTS: Microbiological cleanliness improved during the study period (ACC pre-training: 19%; post-training: 41%). The odds of cleanliness increased on average by 1.33 weekly during the pre-training period (CI = 1.11-1.60), and by 1.08 (CI = 1.03-1.13) during the post-training period. Cleaning action improved only in the pre-training period. Detection of S. aureus on hospital surfaces did not change substantially. The intervention was well received and considered feasible in this context. The major pitfalls in the implementation were the limited number of training sessions at the hospital level and the lack of supportive supervision. A systems barrier to implementation was lack of regular cleaning supplies. CONCLUSIONS: The evaluation suggests that improvements in microbiological cleanliness are possible using this intervention and can be sustained. Improved microbiological cleanliness is a key step on the pathway to infection prevention in hospitals. Future research should assess whether this bundle is cost-effective in reducing bacterial and viral transmission and infection using a rigorous study design

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist