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Capecitabine monotherapy as palliation for advanced colorectal cancer (CRC) is generally well tolerated. Adding erlotinib, an EGFR-tyrosine kinase inhibitor, might improve efficacy versus capecitabine alone. 82 patients received capecitabine alone (Arm 1) or capecitabine with erlotinib (Arm 2). Median time-to-progression (TTP) in Arm 1 was 7.9 months versus 9.2 in Arm 2. In -wild type (WT) patients TTP was 8.4 and 11.7 months in Arms 1 and 2, respectively. In -mutated patients TTP was 7.4 and 1.9 months in Arms 1 and 2, respectively (p = 0.023). Arm 2 -WT patients, left-sided primaries, had an overall survival of 16.0 versus 12.1 months in right-sided primaries. Adding erlotinib to capecitabine increased TTP by 3.2 months in -WT patients. This study suggests that erlotinib harms patients with -mutated advanced CRC while it may provide benefit to those with -WT CRC. Further study of EGFR-tyrosine kinase inhibitors in patients with left-sided -WT CRC is warranted.

During the 20th century medical education has been largely preoccupied with discussions of the venues and methods for teaching. Little attention has been paid to what should be learned about the scientific paradigm underlying research and practice. A 17th century model has gradually produced an increasingly narrow, monocausal, reductionistic view of health and disease. Much good has resulted, but this \"belief system\" fails to accommodate or explain the meaning and impact on patients' health of diverse internal and external experiences and influences. During this period quantum mechanics and its ever-expanding capacity to accommodate new information and enhance understanding have superseded Newtonian physics in much scientific thinking. A broad range of historical and contemporary scientific literature is examined in support of four central questions in this three-part series: (1) Are there reasons to examine these matters now? (2) How is medical scientific thinking influenced by the general reorientation of science during the 20th century? (3) Are there reasons now to examine the impact of these changes on medicine? (4) Will a change of paradigm affect medical practice, research, and education? The extraordinarily productive contemporary biomedical model should be expanded beyond the physical and biological to incorporate meaningful information about how each patient's experiences impinge on health status. Family and other primary care physicians together with collaborators in the biological and behavioral sciences and other health professions should undertake rigorous research to establish the validity of the expanded paradigm espoused. Its impact on practice, research, education, and policies could be profound.

During the 20th century medical education has been preoccupied largely with discussions of the venues and methods for teaching. Little attention has been paid to what should be learned about the scientific paradigm underlying research and practice. A 17th century model has gradually produced a technically efficient but increasingly narrow, monocausal, reductionistic view of health and disease. This \"belief system\" fails to accommodate or explain the meaning and impact on patients' health of diverse internal and external experiences and influences. During this period new physics and systemic views of biosystems have extended the Newtonian scientific paradigm beyond its materialistic boundaries, which still determines most of the medical sciences. A broad range of historical and contemporary scientific literature is examined in support of four central questions addressed in this three-part series: Is there a reason to examine these matters now? How is medical scientific thinking influenced by the general reorientation of science during the 20th century? Is there is a reason to examine the impact of these changes on medicine now? Will a change of paradigm affect medical practice, research, and education? The extraordinarily productive contemporary biomedical model should be expanded to include meaningful information about how each patient's experiences impinge on health status. Family physicians, together with collaborators in the biological and behavioral sciences and other health professionals, should undertake rigorous research to establish the validity of the expanded paradigm espoused. Its impact could be profound on practice, research, education, and policies.

During the 20th century medical education has been largely preoccupied with discussions of the venues and methods for teaching. Little attention has been paid to what should be learned about the scientific paradigm underlying research and practice. A 17th century model has gradually produced an increasingly narrow, monocausal, reductionistic view of health and disease. Much good has resulted, but this \"belief system\" fails to accommodate or explain the meaning and impact on patients' health of diverse internal and external experiences and influences. During this period quantum mechanics and its ever-expanding capacity to accommodate new information and enhance understanding have superseded Newtonian physics in much scientific thinking. A broad range of historical and contemporary scientific literature is examined in support of four central questions in this three-part series: (1) Are there reasons to examine these matters now? (2) How is medical scientific thinking influenced by the general reorientation of science during the 20th century? (3) Are there reasons now to examine the impact of these changes on medicine? (4) Will a change of paradigm affect medical practice, research, and education? The extraordinarily productive contemporary biomedical model should be expanded beyond the physical and biological to incorporate meaningful information about how each patients experiences impinge on health status. Family and other primary care physicians together with collaborators in the biological and behavioral sciences and other health professions should undertake rigorous research to establish the validity of the expanded paradigm espoused. Its impact on practice, research, education, and policies could be profound.

Overall rating: Good Strengths: Fairly comprehensive Weaknesses: Some repetition. Coverage of systemic pharmacotherapy as related to anesthetic techniques could be better Audience: Those managing patients with cancer pain Although cancer is a common disease, many patients do not have their pain optimally managed. Fortunately, over the past 10 to 15 years, significant inroads have been made in dealing with this difficult problem.

Studies have suggested that evening dosing with antihypertensive therapy might have better outcomes than morning dosing. The Treatment in Morning versus Evening (TIME) study aimed to investigate whether evening dosing of usual antihypertensive medication improves major cardiovascular outcomes compared with morning dosing in patients with hypertension. The TIME study is a prospective, pragmatic, decentralised, parallel-group study in the UK, that recruited adults (aged ≥18 years) with hypertension and taking at least one antihypertensive medication. Eligible participants were randomly assigned (1:1), without restriction, stratification, or minimisation, to take all of their usual antihypertensive medications in either the morning (0600–1000 h) or in the evening (2000–0000 h). Participants were followed up for the composite primary endpoint of vascular death or hospitalisation for non-fatal myocardial infarction or non-fatal stroke. Endpoints were identified by participant report or record linkage to National Health Service datasets and were adjudicated by a committee masked to treatment allocation. The primary endpoint was assessed as the time to first occurrence of an event in the intention-to-treat population (ie, all participants randomly assigned to a treatment group). Safety was assessed in all participants who submitted at least one follow-up questionnaire. The study is registered with EudraCT (2011-001968-21) and ISRCTN (18157641), and is now complete. Between Dec 17, 2011, and June 5, 2018, 24 610 individuals were screened and 21 104 were randomly assigned to evening (n=10 503) or morning (n=10 601) dosing groups. Mean age at study entry was 65·1 years (SD 9·3); 12 136 (57·5%) participants were men; 8968 (42·5%) were women; 19 101 (90·5%) were White; 98 (0·5%) were Black, African, Caribbean, or Black British (ethnicity was not reported by 1637 [7·8%] participants); and 2725 (13·0%) had a previous cardiovascular disease. By the end of study follow-up (March 31, 2021), median follow-up was 5·2 years (IQR 4·9–5·7), and 529 (5·0%) of 10 503 participants assigned to evening treatment and 318 (3·0%) of 10 601 assigned to morning treatment had withdrawn from all follow-up. A primary endpoint event occurred in 362 (3·4%) participants assigned to evening treatment (0·69 events [95% CI 0·62–0·76] per 100 patient-years) and 390 (3·7%) assigned to morning treatment (0·72 events [95% CI 0·65–0·79] per 100 patient-years; unadjusted hazard ratio 0·95 [95% CI 0·83–1·10]; p=0·53). No safety concerns were identified. Evening dosing of usual antihypertensive medication was not different from morning dosing in terms of major cardiovascular outcomes. Patients can be advised that they can take their regular antihypertensive medications at a convenient time that minimises any undesirable effects. British Heart Foundation.

Allopurinol is a urate-lowering therapy used to treat patients with gout. Previous studies have shown that allopurinol has positive effects on several cardiovascular parameters. The ALL-HEART study aimed to determine whether allopurinol therapy improves major cardiovascular outcomes in patients with ischaemic heart disease. ALL-HEART was a multicentre, prospective, randomised, open-label, blinded-endpoint trial done in 18 regional centres in England and Scotland, with patients recruited from 424 primary care practices. Eligible patients were aged 60 years or older, with ischaemic heart disease but no history of gout. Participants were randomly assigned (1:1), using a central web-based randomisation system accessed via a web-based application or an interactive voice response system, to receive oral allopurinol up-titrated to a dose of 600 mg daily (300 mg daily in participants with moderate renal impairment at baseline) or to continue usual care. The primary outcome was the composite cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. The hazard ratio (allopurinol vs usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis (excluding randomly assigned patients later found to have met one of the exclusion criteria). The safety analysis population included all patients in the modified intention-to-treat usual care group and those who took at least one dose of randomised medication in the allopurinol group. This study is registered with the EU Clinical Trials Register, EudraCT 2013-003559-39, and ISRCTN, ISRCTN32017426. Between Feb 7, 2014, and Oct 2, 2017, 5937 participants were enrolled and then randomly assigned to receive allopurinol or usual care. After exclusion of 216 patients after randomisation, 5721 participants (mean age 72·0 years [SD 6·8], 4321 [75·5%] males, and 5676 [99·2%] white) were included in the modified intention-to-treat population, with 2853 in the allopurinol group and 2868 in the usual care group. Mean follow-up time in the study was 4·8 years (1·5). There was no evidence of a difference between the randomised treatment groups in the rates of the primary endpoint. 314 (11·0%) participants in the allopurinol group (2·47 events per 100 patient-years) and 325 (11·3%) in the usual care group (2·37 events per 100 patient-years) had a primary endpoint (hazard ratio [HR] 1·04 [95% CI 0·89–1·21], p=0·65). 288 (10·1%) participants in the allopurinol group and 303 (10·6%) participants in the usual care group died from any cause (HR 1·02 [95% CI 0·87–1·20], p=0·77). In this large, randomised clinical trial in patients aged 60 years or older with ischaemic heart disease but no history of gout, there was no difference in the primary outcome of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death between participants randomised to allopurinol therapy and those randomised to usual care. UK National Institute for Health and Care Research.

Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function–associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD. A genome-wide association study in more than 400,000 individuals identifies 139 new signals for lung function. These variants can predict chronic obstructive pulmonary disease in independent, transancestral cohorts.

Human population isolates provide a snapshot of the impact of historical demographic processes on population genetics. Such data facilitate studies of the functional impact of rare sequence variants on biomedical phenotypes, as strong genetic drift can result in higher frequencies of variants that are otherwise rare. We present the first whole genome sequencing (WGS) study of the VIKING cohort, a representative collection of samples from the isolated Shetland population in northern Scotland, and explore how its genetic characteristics compare to a mainland Scottish population. Our analyses reveal the strong contributions played by the founder effect and genetic drift in shaping genomic variation in the VIKING cohort. About one tenth of all high-quality variants discovered are unique to the VIKING cohort or are seen at frequencies at least ten fold higher than in more cosmopolitan control populations. Multiple lines of evidence also suggest relaxation of purifying selection during the evolutionary history of the Shetland isolate. We demonstrate enrichment of ultra-rare VIKING variants in exonic regions and for the first time we also show that ultra-rare variants are enriched within regulatory regions, particularly promoters, suggesting that gene expression patterns may diverge relatively rapidly in human isolates.

Peroxisomes are organelles that perform diverse metabolic functions in different organisms, but a common function is β-oxidation of a variety of long chain aliphatic, branched, and aromatic carboxylic acids. Import of substrates into peroxisomes for β-oxidation is mediated by ATP binding cassette (ABC) transporter proteins of subfamily D, which includes the human adrenoleukodystropy protein (ALDP) defective in X-linked adrenoleukodystrophy (X-ALD). Whether substrates are transported as CoA esters or free acids has been a matter of debate. Using COMATOSE (CTS), a plant representative of the ABCD family, we demonstrate that there is a functional and physical interaction between the ABC transporter and the peroxisomal long chain acyl-CoA synthetases (LACS)6 and -7. We expressed recombinant CTS in insect cells and showed that membranes from infected cells possess fatty acyl-CoA thioesterase activity, which is stimulated by ATP. A mutant, in which Serine 810 is replaced by asparagine (S810N) is defective in fatty acid degradation in vivo, retains ATPase activity but has strongly reduced thioesterase activity, providing strong evidence for the biological relevance of this activity. Thus, CTS, and most likely the other ABCD family members, represent rare examples of polytopic membrane proteins with an intrinsic additional enzymatic function that may regulate the entry of substrates into the β-oxidation pathway. The cleavage of CoA raises questions about the side of the membrane where this occurs and this is discussed in the context of the peroxisomal coenzyme A (CoA) budget.