<i>CYP3A</i> genetic variation and taxane-induced peripheral neuropathy: a systematic review, meta-analysis, and candidate gene study (vol 14, 1178421, 2023)

[This corrects the article DOI: 10.3389/fphar.2023.1178421.]

The relationship between lung disease severity and the sputum proteome in cystic fibrosis.

BackgroundProteomics can reveal molecular pathways of disease and provide translational perspectives to inform clinical decision making. Although several studies have previously reported the cystic fibrosis airway proteome, the relationship with severity of lung disease has not been characterised. The objectives of this observational study were to investigate differences in the CF sputum proteome associated with disease severity and identify potential markers of disease with translational potential.MethodsSputum samples from healthy volunteers and cystic fibrosis subjects (some prescribed modulator therapies) were analysed using liquid-chromatography tandem mass spectrometry. Severity of lung disease was based on baseline spirometry (percentage predicted forced expiratory volume in 1 s, FEV1%).ResultsMultiple sputum proteins (108 increased; 202 decreased) were differentially expressed in CF (n = 38) and healthy volunteers (n = 32). Using principal component analysis and hierarchical clustering, differences in sputum proteome were observed associated with progressive lung function impairment. In CF subjects, baseline FEV1% correlated with 87 proteins (positive correlation n = 20, negative n = 67); most were either neutrophil derived, or opposed neutrophil-driven oxidant and protease activity.ConclusionPredictable and quantifiable changes in the CF sputum proteome occurred associated with progressive lung function impairment, some of which might have value as markers of disease severity in CF sputum. Further work validating these markers in other patient cohorts and exploring their clinical utility is needed

DYNamic assessment of multi‐organ level dysfunction in patients recovering from COVID‐19: DYNAMO COVID‐19

We evaluated the impacts of COVID‐19 on multi‐organ and metabolic function in patients following severe hospitalised infection compared to controls. Patients (n = 21) without previous diabetes, cardiovascular or cerebrovascular disease were recruited 5–7 months post‐discharge alongside controls (n = 10) with similar age, sex and body mass. Perceived fatigue was estimated (Fatigue Severity Scale) and the following were conducted: oral glucose tolerance (OGTT) alongside whole‐body fuel oxidation, validated magnetic resonance imaging and spectroscopy during resting and supine controlled exercise, dual‐energy X‐ray absorptiometry, short physical performance battery (SPPB), intra‐muscular electromyography, quadriceps strength and fatigability, and daily step‐count. There was a greater insulin response (incremental area under the curve, median (inter‐quartile range)) during the OGTT in patients [18,289 (12,497–27,448) mIU/min/L] versus controls [8655 (7948–11,040) mIU/min/L], P &lt; 0.001. Blood glucose response and fasting and post‐prandial fuel oxidation rates were not different. This greater insulin resistance was not explained by differences in systemic inflammation or whole‐body/regional adiposity, but step‐count (P = 0.07) and SPPB scores (P = 0.004) were lower in patients. Liver volume was 28% greater in patients than controls, and fat fraction adjusted liver T1, a measure of inflammation, was raised in patients. Patients displayed greater perceived fatigue scores, though leg muscle volume, strength, force‐loss, motor unit properties and post‐exercise muscle phosphocreatine resynthesis were comparable. Further, cardiac and cerebral architecture and function (at rest and on exercise) were not different. In this cross‐sectional study, individuals without known previous morbidity who survived severe COVID‐19 exhibited greater insulin resistance, pointing to a need for physical function intervention in recovery

Novel <i>GREM1 </i>Variations in Sub-Saharan African Patients With Cleft Lip and/or Cleft Palate

Objective: Cleft lip and/or cleft palate (CL/P) are congenital anomalies of the face and have multifactorial etiology, with both environmental and genetic risk factors playing crucial roles. Though at least 40 loci have attained genomewide significant association with nonsyndromic CL/P, these loci largely reside in noncoding regions of the human genome, and subsequent resequencing studies of neighboring candidate genes have revealed only a limited number of etiologic coding variants. The present study was conducted to identify etiologic coding variants in GREM1, a locus that has been shown to be largely associated with cleft of both lip and soft palate. Patients and Method: We resequenced DNA from 397 sub-Saharan Africans with CL/P and 192 controls using Sanger sequencing. Following analyses of the sequence data, we observed 2 novel coding variants in GREM1. These variants were not found in the 192 African controls and have never been previously reported in any public genetic variant database that includes more than 5000 combined African and African American controls or from the CL/P literature. Results: The novel variants include p.Pro164Ser in an individual with soft palate cleft only and p.Gly61Asp in an individual with bilateral cleft lip and palate. The proband with the p.Gly61Asp GREM1 variant is a van der Woude (VWS) case who also has an etiologic variant in IRF6 gene. Conclusion: Our study demonstrated that there is low number of etiologic coding variants in GREM1, confirming earlier suggestions that variants in regulatory elements may largely account for the association between this locus and CL/P. </jats:sec

Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal carcinoma treatment (ICON8): primary progression free survival analysis results from a GCIG phase 3 randomised controlled trial

Background: Carboplatin and paclitaxel administered every 3 weeks is standard-of-care first-line chemotherapy for epithelial ovarian cancer. The Japanese JGOG3016 trial showed a significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly carboplatin. In this study, we aimed to compare efficacy and safety of two dose-dense weekly regimens to standard 3-weekly chemotherapy in a predominantly European population with epithelial ovarian cancer. Methods: In this phase 3 trial, women with newly diagnosed International Federation of Gynecology and Obstetrics stage IC–IV epithelial ovarian cancer were randomly assigned to group 1 (carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m2 paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m2 paclitaxel weekly), or group 3 (carboplatin AUC2 and 80 mg/m2 paclitaxel weekly). Written informed consent was provided by all women who entered the trial. The protocol had the appropriate national research ethics committee approval for the countries where the study was conducted. Patients entered the trial after immediate primary surgery, or before neoadjuvant chemotherapy with subsequent planned delayed primary surgery. The trial coprimary outcomes were progression-free survival and overall survival. Data analyses were done on an intention-to-treat basis, and were powered to detect a hazard ratio of 0·75 in progression-free survival. The main comparisons were between the control group (group 1) and each of the weekly research groups (groups 2 and 3). Findings: Between June 6, 2011, and Nov 28, 2014, 1566 women were randomly assigned to treatment. 72% (365), completed six protocol-defined treatment cycles in group 1, 60% (305) in group 2, and 63% (322) in group 3, although 90% (454), 89% (454), and 85% (437) completed six platinum-based chemotherapy cycles, respectively. Paclitaxel dose intensification was achieved with weekly treatment (median total paclitaxel dose 1010 mg/m2 in group 1; 1233 mg/m2 in group 2; 1274 mg/m2 in group 3). By February, 2017, 1018 (65%) patients had experienced disease progression. No significant progression-free survival increase was observed with either weekly regimen (restricted mean survival time 24·4 months [97·5% CI 23·0–26·0] in group 1, 24·9 months [24·0–25·9] in group 2, 25·3 months [23·9–26·9] in group 3; median progression-free survival 17·7 months [IQR 10·6–not reached] in group 1, 20·8 months [11·9–59·0] in group 2, 21·0 months [12·0–54·0] in group 3; log-rank p=0·35 for group 2 vs group 1; group 3 vs 1 p=0·51). Although grade 3 or 4 toxic effects increased with weekly treatment, these effects were predominantly uncomplicated. Febrile neutropenia and sensory neuropathy incidences were similar across groups. Interpretation Weekly dose-dense chemotherapy can be delivered successfully as first-line treatment for epithelial ovarian cancer but does not significantly improve progression-free survival compared with standard 3-weekly chemotherapy in predominantly European populations. Funding: Cancer Research UK, Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, Cancer Australia

To what extent can behaviour change techniques be identified within an adaptable implementation package for primary care? A prospective directed content analysis

Interpreting evaluations of complex interventions can be difficult without sufficient description of key intervention content. We aimed to develop an implementation package for primary care which could be delivered using typically available resources and could be adapted to target determinants of behaviour for each of four quality indicators: diabetes control, blood pressure control, anticoagulation for atrial fibrillation and risky prescribing. We describe the development and prospective verification of behaviour change techniques (BCTs) embedded within the adaptable implementation packages

Making new genetic diagnoses with old data:iterative reanalysis and reporting from genome-wide data in 1,133 families with developmental disorders

Purpose Given the rapid pace of discovery in rare disease genomics, it is likely that improvements in diagnostic yield can be made by systematically reanalyzing previously generated genomic sequence data in light of new knowledge. Methods We tested this hypothesis in the United Kingdom–wide Deciphering Developmental Disorders study, where in 2014 we reported a diagnostic yield of 27% through whole-exome sequencing of 1,133 children with severe developmental disorders and their parents. We reanalyzed existing data using improved variant calling methodologies, novel variant detection algorithms, updated variant annotation, evidence-based filtering strategies, and newly discovered disease-associated genes. Results We are now able to diagnose an additional 182 individuals, taking our overall diagnostic yield to 454/1,133 (40%), and another 43 (4%) have a finding of uncertain clinical significance. The majority of these new diagnoses are due to novel developmental disorder–associated genes discovered since our original publication. Conclusion This study highlights the importance of coupling large-scale research with clinical practice, and of discussing the possibility of iterative reanalysis and recontact with patients and health professionals at an early stage. We estimate that implementing parent–offspring whole-exome sequencing as a first-line diagnostic test for developmental disorders would diagnose >50% of patients.</p

A psychosocial goal-setting and manualised support intervention for independence in dementia (NIDUS-Family) versus goal setting and routine care: a single-masked, phase 3, superiority, randomised controlled trial

Summary Background Although national guidelines recommend that everyone with dementia receives personalised post-diagnostic support, few do. Unlike previous interventions that improved personalised outcomes in people with dementia, the NIDUS-Family intervention is fully manualised and deliverable by trained and supervised, non-clinical facilitators. We aimed to investigate the effectiveness of home-based goal setting plus NIDUS-Family in supporting the attainment of personalised goals set by people with dementia and their carers. Methods We did a two-arm, single-masked, multi-site, randomised, clinical trial recruiting patient–carer dyads from community settings. We randomly assigned dyads to either home-based goal setting plus NIDUS-Family or goal setting and routine care (control). Randomisation was blocked and stratified by site (2:1; intervention to control), with allocations assigned via a remote web-based system. NIDUS-Family is tailored to goals set by dyads by selecting modules involving behavioural interventions, carer support, psychoeducation, communication and coping skills, enablement, and environmental adaptations. The intervention involved six to eight video-call or telephone sessions (or in person when COVID-19-related restrictions allowed) over 6 months, then telephone follow-ups every 2–3 months for 6 months. The primary outcome was carer-rated goal attainment scaling (GAS) score at 12 months. Analyses were done by intention to treat. This trial is registered with the ISRCTN registry, ISRCTN11425138. Findings Between April 30, 2020, and May 9, 2021, we assessed 1083 potential dyads for eligibility, 781 (72·1%) of whom were excluded. Of 302 eligible dyads, we randomly assigned 98 (32·4%) to the control group and 204 (67·5%) to the intervention group. The mean age of participants with dementia was 79·9 years (SD 8·2), 169 (56%) were women, and 133 (44%) were men. 247 (82%) dyads completed the primary outcome, which favoured the intervention (mean GAS score at 12 months 58·7 [SD 13·0; n=163] vs 49·0 [14·1; n=84]; adjusted difference in means 10·23 [95% CI 5·75–14·71]; p<0·001). 31 (15·2%) participants in the intervention group and 14 (14·3%) in the control group experienced serious adverse events. Interpretation To our knowledge, NIDUS-Family is the first readily scalable intervention for people with dementia and their family carers that improves attainment of personalised goals. We therefore recommend that it be implemented in health and care services