Quinolines from oximes

The photochemistry of a number of arylidenecyclopentanone oxime 0 - acetates and methyl ethers has been investigated. Irradiation of several of these compounds in methanol leads to initial E-Z geometrical isomérisation and ultimately to the formation of nitrogen containing heterocycles via a 671-electron photocyclisation process followed by an elimination. The photocyclisation has been investigated for aryl groups containing both electron withdrawing and electron donating substituents. Cyclisation is not observed in the case of electron withdrawing groups such as 2-(4- cyanobenzylidene)cyclopentanone oxime O-acetate, 2-(3-cyanobenzylidene) cyclopentanone oxime O-acetate, 2-(3-fluorobenzylidene)cyclopentanone oxime O-acetate and 2-(3-chlorobenzylidene)cyclopentanone oxime O-acetate, whereas the presence of electron donating groups such as 2-(3- methoxybenzylidene)cyclopentanone oxime O-acetate and 2-(3- methylbenzylidene)cyclopentanone oxime O-acetate facilitates the reaction. The regiospecificity of the reaction has also been investigated, and in all cases where the photocyclisation proceeds, only one product is isolated. Both acetates and methyl ethers yield the same cyclised photoproducts. The photoreactivity of the arylidenecyclopentanone oxime O-acetates has also been investigated in natural sunlight at the Plataforma Solar de Almería (PSA) in the south of Spain. The photoreactions proceed in the same manner as in the laboratory yielding the desired products. Reasonable conversions are achieved, and the apparatus available at the PSA makes large scale and inexpensive heterocycle syntheses achievable

Quinoline synthesis: scope and regiochemistry of photocyclisation of substituted benzylidenecyclopentanone O-alkyl and O-acetyloximes

Irradiation of substituted 2-benzylidenecyclopentanone O-alkyl and O-acetyloximes in methanol provides a convenient synthesis of alkyl, alkoxy, hydroxy, acetoxy, amino, dimethylamino and benzo substituted annulated quinolines. para-Substituents yield 6-substituted-2,3-dihydro-1H-cyclopenta[b]quinolines with 8-substituted products being obtained from ortho-substituted starting materials. Reactions of meta-substituted precursors are highly regioselective, with alkyl substituents leading to 5-substituted 2,3-dihydro-1H-cyclopenta[b]quinolines and more strongly electron-donating substituents generally resulting in 7-substituted products. 2-Furylmethylene and 2-thienylmethylene analogues yield annulated furo- and thieno-[2,3e]pyridines respectively. Sequential E- to Z-benzylidene group isomerisation and six [pi]-electron cyclisation steps result in formation of a short-lived dihydroquinoline intermediate which spontaneously aromatises by elimination of an alcohol or acetic acid. For 2-benzylidenecyclopentanone O-allyloxime, singlet excited states are involved in both steps

Personal protective equipment-induced systemic hypercapnic hypoxaemia: translational implications for impaired cognitive–clinical functional performance

Background: Personal protective equipment (PPE) adversely affects pulmonary gas exchange and may result in systemic hypercapnic hypoxaemia and headache. This study aimed to determine what extent PPE affects cerebral symptoms, global cerebral blood flow, and cognitive functional performance.Methods: Higher surgical trainees participated in a randomized, repeated-measures, crossover study, completing 60 min of laparoscopic surgical simulation in both standard operating attire and type 3 PPE. Measurements were collected at baseline and after 60 min of simulation. The primary outcome measure was headache. Headache was examined using the validated visual analogue scale (VAS) and Environmental Symptoms Questionnaire C (ESQ-C), global cerebral blood flow with duplex ultrasonography, and visuospatial and executive gross/fine motor function with grooved peg board (GPB) and laparoscopic bead (LSB) board tasks.Results: Thirty-one higher surgical trainees (20 men, 11 women) completed the study. Compared with standard operating attire, PPE increased headache assessment scores (mean(s.d.) VAS score 3.5(5.6) versus 13.0(3.7), P < 0.001; ESQ-C score 1.3(2.0) versus 5.9(5.1), P < 0.001) and was associated with poorer completion times for GPB-D (61.4(12.0) versus 71.1(12.4) s; P = 0.034) and LSB (192.5(66.9) versus 270.7(135.3) s; P = 0.025) tasks. Wearing PPE increased heart rate (82.5(13.6) versus 93.5(13.0) beats/min; P = 0.022) and skin temperature (36.6(0.4) versus 37.1(0.5)°C; P < 0.001), but decreased peripheral oxygen saturation (97.9(0.8) versus 96.8(1.0) per cent; P < 0.001). Female higher surgical trainees exhibited higher peripheral oxygen saturation across all conditions. No differences were observed in global cerebral blood flow as a function of attire, time or sex.Conclusion: Despite no marked changes in global cerebral blood flow, type 3 PPE was associated with increased headache scores and cerebral symptoms (VAS and ESQ-C) alongside impaired executive motor function highlighting the clinical implications of PPEinduced impairment for cognitive–clinical performance

Enhanced stress resilience training for UK surgical trainees; Effect and evolution evaluated

Introduction Core Surgical Training (CST) programs are associated with high burnout. This study aimed to assess the influence of Enhanced Stress Resilience Training (ESRT) over a 2-year period in a single UK Statutory Education Body. Method CSTs participated in 5-weeks of formal ESRT to address work stressors. The primary outcome measure was career progression related to curriculum metrics and National Training Number (NTN) appointment. Secondary measures related to burnout using validated psychological inventories. Results Of 42 CSTs, 13 engaged fully with ESRT (31.0%; male 8, female 5, median age 28 year.), 11 engaged partially, and 18 did not. ESRT engagement was associated with better NTN appointment (ESRT 8/13 (61.5%) vs. not 1/18 (5.6%), p = 0.025), less burnout [aMBI; mean 5.14 (SD ± 2.35) vs. 3.14 (±2.25), F 6.637, p = 0.002, η p 2 =0.167], less stress [PSS-10; 19.22 (±5.91) vs. 15.79 (±5.47), F 8.740, p < 0.001, η p 2 =0.200], but more mindfulness [CAMS-R; 19.22 (±5.91) vs. 20.57 (±2.93), F 3.201, p = 0.047, η p 2 =0.084]. On multivariable analysis, Improving Surgical Training (run-through CST) program (OR 5.2 (95% CI 1.42-28.41, p = 0.022), MRCS pass (OR 17.128 (95% CI 1.48-197.11, p = 0.023) and ESRT engagement (OR 13.249, 95% CI 2.08-84.58, p = 0.006) were independently associated with NTN success. Discussion ESRT was associated with less stress and burnout, better mindfulness, and most importantly 13-fold better career progression

Trainee perspective of the causes of stress and burnout in surgical training: a qualitative study from Wales

Objectives Stress and burn-out among surgical trainees has been reported most prevalent in core surgical trainees (CST) and female trainees in particular. This study aimed to identify factors perceived by CSTs to be associated with stress and burnout in those at risk. Design An open-ended questionnaire was distributed to 79 CSTs and two researchers categorised responses independently, according to Michie’s model of workplace stress. Setting A UK regional postgraduate medical region (Wales). Participants Sixty-three responses were received; 42 males, 21 females. The response rate was 79.7%. Results Inter-rater reliability was good (k=0.792 (79.2%), p<0.001). The most common theme of Michie’s model related to CST stress and burnout was career development, with most statements associated with curriculum, examination and academic demands required to attain a CST certificate of completion of training, and higher surgical national training number appointment. This was closely followed by those intrinsic to the job with recurrent discussion around the difficulties balancing work perceived to be service provision (ward work and on-calls), outpatient clinic and operative experience. Conversely, the most common themes relevant to stress and burnout among female trainees were associated with relationships at work (primarily the male-dominated nature of surgery), extraorganisational factors (family–work life balance) and individual characteristics (personality and physiological differences). Conclusion CSTs’ perceptions regarding the causes of National Health Service related stress and burnout are numerous, and these findings provide a basis for the development of targeted stressor counter-measures to improve training and well-being

Protocol for a systematic review of the effects of schools and school-environment interventions on health: evidence mapping and syntheses

Background: Schools may have important effects on students' and staff's health. Rather than treating schools merely as sites for health education, 'school-environment' interventions treat schools as settings which influence health. Evidence concerning the effects of such interventions has not been recently synthesised. Methods/design: Systematic review aiming to map and synthesise evidence on what theories and conceptual frameworks are most commonly used to inform school-environment interventions or explain school-level influences on health; what effects school-environment interventions have on health/health inequalities; how feasible and acceptable are school-environment interventions; what effects other school-level factors have on health; and through what processes school-level influences affect health. We will examine interventions aiming to promote health by modifying schools' physical, social or cultural environment via actions focused on school policies and practices relating to education, pastoral care and other aspects of schools beyond merely providing health education. Participants are staff and students age 4-18 years. We will review published research unrestricted by language, year or source. Searching will involve electronic databases including Embase, ERIC, PubMed, PsycInfo and Social Science Citation Index using natural-language phrases plus reference/citation checking. Stage 1 will map studies descriptively by focus and methods. Stage 2 will involve additional inclusion criteria, quality assessment and data extraction undertaken by two reviewers in parallel. Evidence will be synthesised narratively and statistically where appropriate (undertaking subgroup analyses and meta-regression and where no significant heterogeneity of effect sizes is found, pooling these to calculate a final effect size). Discussion: We anticipate: finding a large number of studies missed by previous reviews; that non-intervention studies of school effects examine a greater breadth of determinants than are addressed by intervention studies; and that intervention effect estimates are greater than for school-based health curriculum interventions without school-environment components

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Global wealth disparities drive adherence to COVID-safe pathways in head and neck cancer surgery

Peer reviewe

Characterisation of in-hospital complications associated with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol UK: a prospective, multicentre cohort study

Background: COVID-19 is a multisystem disease and patients who survive might have in-hospital complications. These complications are likely to have important short-term and long-term consequences for patients, health-care utilisation, health-care system preparedness, and society amidst the ongoing COVID-19 pandemic. Our aim was to characterise the extent and effect of COVID-19 complications, particularly in those who survive, using the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK. Methods: We did a prospective, multicentre cohort study in 302 UK health-care facilities. Adult patients aged 19 years or older, with confirmed or highly suspected SARS-CoV-2 infection leading to COVID-19 were included in the study. The primary outcome of this study was the incidence of in-hospital complications, defined as organ-specific diagnoses occurring alone or in addition to any hallmarks of COVID-19 illness. We used multilevel logistic regression and survival models to explore associations between these outcomes and in-hospital complications, age, and pre-existing comorbidities. Findings: Between Jan 17 and Aug 4, 2020, 80 388 patients were included in the study. Of the patients admitted to hospital for management of COVID-19, 49·7% (36 367 of 73 197) had at least one complication. The mean age of our cohort was 71·1 years (SD 18·7), with 56·0% (41 025 of 73 197) being male and 81·0% (59 289 of 73 197) having at least one comorbidity. Males and those aged older than 60 years were most likely to have a complication (aged ≥60 years: 54·5% [16 579 of 30 416] in males and 48·2% [11 707 of 24 288] in females; aged &lt;60 years: 48·8% [5179 of 10 609] in males and 36·6% [2814 of 7689] in females). Renal (24·3%, 17 752 of 73 197), complex respiratory (18·4%, 13 486 of 73 197), and systemic (16·3%, 11 895 of 73 197) complications were the most frequent. Cardiovascular (12·3%, 8973 of 73 197), neurological (4·3%, 3115 of 73 197), and gastrointestinal or liver (0·8%, 7901 of 73 197) complications were also reported. Interpretation: Complications and worse functional outcomes in patients admitted to hospital with COVID-19 are high, even in young, previously healthy individuals. Acute complications are associated with reduced ability to self-care at discharge, with neurological complications being associated with the worst functional outcomes. COVID-19 complications are likely to cause a substantial strain on health and social care in the coming years. These data will help in the design and provision of services aimed at the post-hospitalisation care of patients with COVID-19. Funding: National Institute for Health Research and the UK Medical Research Council