Social Isolation and Sleep: Manifestation During COVID-19 Quarantines

Although researchers have investigated the impact of social isolation on well-being, the recent quarantines due to COVID-19 resulted in a social isolation environment that was unique to any examined in the past. Because sleep is one of the endogenous drives that impacts short and long-term health and well-being, it is important to consider how social isolation during the COVID-19 government-mandated quarantines affected sleep and sleep habits. A number of researchers have addressed this question during the last 2 years by examining several concepts related to possible changes in sleep during the quarantines. To best understand these recent results, the current mini review provides a background on the pre-pandemic literature on the effects of social isolation and loneliness with a focus on sleep and then summarizes the recent literature on sleep and sleep habits. In general, sleep was negatively impacted for many people during the pandemics but not all. One group that seemed to benefit from the pandemic in terms of sleep patterns, were younger people who could more easily adapt their sleep times to match their internal chronobiology. Given the potential broad impact of sleep on health and well-being, better understanding how social isolation impacts sleep is an important consideration for individuals, work organizations, and governments

SurgiCal Obesity Treatment Study (SCOTS) : a prospective, observational cohort study on health and socioeconomic burden in treatment-seeking individuals with severe obesity in Scotland, UK

Objectives: There is a lack of evidence to inform the delivery and follow-up of bariatric surgery for people with severe obesity. The SurgiCal Obesity Treatment Study (SCOTS) is a national longitudinal cohort of people undergoing bariatric surgery. Here, we describe characteristics of the recruited SCOTS cohort, and the relationship between health and socioeconomic status with body mass index (BMI) and age. Participants/Methods: 445 participants scheduled for bariatric surgery at any of 14 centres in Scotland, UK, were recruited between 2013 and 2016 for this longitudinal cohort study (1 withdrawal); 249 completed health-related preoperative patient-reported outcome measures. Regression models were used to estimate the effect of a 10-unit increase in age or BMI, adjusting for sex, smoking and socioeconomic status. Results: Mean age was 46 years and median BMI was 47 kg/m2. For each 10 kg/m2 higher BMI, there was a change of −5.2 (95% CI −6.9 to –3.5; p<0.0001) in Rand 12-item Short Form Survey Physical Component Summary (SF-12 PCS), −0.1 (95% CI −0.2 to –0.1; p<0.0001) in EuroQoL 5-level EQ-5D version index score and 14.2 (95% CI 10.7 to 17.7; p<0.0001) in Impact of Weight on Quality of Life-Lite Physical Function Score. We observed a 3.1 times higher use of specialist aids and equipment at home (OR: 3.1, 95% CI 1.9 to 5.0; p<0.0001). Broadly, similar results were seen for each 10-year higher age, including a change of −2.1 (95% CI −3.7 to –0.5; p<0.01) in SF-12 PCS. Conclusions: A higher BMI combined with older age is associated with poor physical functioning and quality of life in people seeking bariatric surgery treatment. Policy-makers must consider the health and care needs of these individuals and invest to provide increased access to effective weight management. Trial registration number: ISRCTN47072588

RA-MAP, molecular immunological landscapes in early rheumatoid arthritis and healthy vaccine recipients

Rheumatoid arthritis (RA) is a chronic inflammatory disorder with poorly defined aetiology characterised by synovial inflammation with variable disease severity and drug responsiveness. To investigate the peripheral blood immune cell landscape of early, drug naive RA, we performed comprehensive clinical and molecular profiling of 267 RA patients and 52 healthy vaccine recipients for up to 18 months to establish a high quality sample biobank including plasma, serum, peripheral blood cells, urine, genomic DNA, RNA from whole blood, lymphocyte and monocyte subsets. We have performed extensive multi-omic immune phenotyping, including genomic, metabolomic, proteomic, transcriptomic and autoantibody profiling. We anticipate that these detailed clinical and molecular data will serve as a fundamental resource offering insights into immune-mediated disease pathogenesis, progression and therapeutic response, ultimately contributing to the development and application of targeted therapies for RA.</p

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

National survey: Developing a common approach to grading of practice in pre-registration midwifery

This paper presents the final phase of a national project exploring grading of practice in programmes leading to registration as a midwife in the United Kingdom. The aim was to develop a generic framework for grading practice, enhancing standardisation while enabling flexibility in application of current and new educational standards. A mixed method on-line survey considered existing practice assessment tools, factors contributing to robust and reliable assessment and perceptions of two assessment tools developed by the research team: a 'Lexicon Framework' and 'Rubric', which were tested through scenarios. Participants included 170 midwifery and nursing academics, clinicians and students, representing 20 universities in the UK. Seven key themes emerged, from which an 'Evidence Based Model for Professional Practice Assessment' was developed. The proposed tools were overall positively evaluated and demonstrated a good level of reliability. A national tool to standardise midwifery practice assessment is recommended, and scope for transferability of our tools to all midwifery programmes and to nursing was identified. Other recommendations include engagement of key stakeholders in development of practice assessment documentation, and maintaining the professional purpose of grading practice as central to the process. A set of key principles for assessing practice is presented

A Six Year, Low-resolution, Multibroadband Transit Photometry Study of HD 189733b

Transmission spectroscopy offers an invaluable opportunity to characterize the atmospheres of exoplanets. We present new ground-based optical transmission spectra of the hot Jupiter HD 189733b, derived from nine transits observed over a six year time span (2016–2021) using near-simultaneous $u^{\prime} g^{\prime} r^{\prime} i^{\prime}$ broadband observations. We achieve an average (best) precision of 435 (280) ppm by implementing an optical diffuser on the prime focus spectrograph from the 2.3 m Wyoming Infrared Observatory telescope. The data provide new measurements of the apparent planetary radius with respect to the stellar radius, the spectral index of atmospheric opacity, and the time variability of the two quantities. Our results indicate an enhanced spectral slope in the optical regime ≈2.4 times steeper than would be expected from canonical Rayleigh scattering and that is consistent with earlier measurements of a super-Rayleigh slope (SRS). While the effect of stellar activity on the transmission spectrum complicates the measurement of the spectral slope, our multiepoch data set over six years can measure and average over stellar variations, yielding a mean spectral index of −9.9 ± 4.4. The 1200 K equilibrium temperature of HD 189733b places it in a sweet spot for the formation of SRSs and is consistent with vigorously mixing hazes in the atmosphere. Additionally, we find variations in the depth of the lightcurve during two of the transits, explainable as an increase in occulted star spots during June 2021. Although the star is active, the mean level of stellar activity does not seem to vary dramatically over our six years of observations, leading us to conclude that the variability in stellar activity is modest at most

Identifying potential high-risk zones for land-derived plastic litter to marine megafauna and key habitats within the North Atlantic

The pervasive use of plastic in modern society has led to plastic litter becoming ubiquitous within the ocean. Land-based sources of plastic litter are thought to account for the majority of plastic pollution in the marine environment, with plastic bags, bottles, wrappers, food containers and cutlery among the most common items found. In the marine environment, plastic is a transboundary pollutant, with the potential to cause damage far beyond the political borders from where it originated, making the management of this global pollutant particularly complex. In this study, the risks of land-derived plastic litter (LDPL) to major groups of marine megafauna – seabirds, cetaceans, pinnipeds, elasmobranchs, turtles, sirenians, tuna and billfish – and a selection of productive and biodiverse biogenic habitats – coral reefs, mangroves, seagrass, saltmarsh and kelp beds – were analysed using a Spatial Risk Assessment approach. The approach combines metrics for vulnerability (mechanism of harm for megafauna group or habitat), hazard (plastic abundance) and exposure (distribution of group or habitat). Several potential high-risk zones (HRZs) across the North Atlantic were highlighted, including the Azores, the UK, the French and US Atlantic coasts, and the US Gulf of Mexico. Whilst much of the modelled LDPL driving risk in the UK originated from domestic sources, in other HRZs, such as the Azores archipelago and the US Gulf of Mexico, plastic originated almost exclusively from external (non-domestic) sources. LDPL from Caribbean islands - some of the largest generators of marine plastic pollution in the dataset of river plastic emissions used in the study - was noted as a significant input to HRZs across both sides of the Atlantic. These findings highlight the potential of Spatial Risk Assessment analyses to determine the location of HRZs and understand where plastic debris monitoring and management should be prioritised, enabling more efficient deployment of interventions and mitigation measures.</p

Macrophage-released pyrimidines inhibit gemcitabine therapy in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDA) is characterized by abundant infiltration of tumor-associated macrophages (TAMs). TAMs have been reported to drive resistance to gemcitabine, a frontline chemotherapy in PDA, though the mechanism of this resistance remains unclear. Profiling metabolite exchange, we demonstrate that macrophages programmed by PDA cells release a spectrum of pyrimidine species. These include deoxycytidine, which inhibits gemcitabine through molecular competition at the level of drug uptake and metabolism. Accordingly, genetic or pharmacological depletion of TAMs in murine models of PDA sensitizes these tumors to gemcitabine. Consistent with this, patients with low macrophage burden demonstrate superior response to gemcitabine treatment. Together, these findings provide insights into the role of macrophages in pancreatic cancer therapy and have potential to inform the design of future treatments. Additionally, we report that pyrimidine release is a general function of alternatively activated macrophage cells, suggesting an unknown physiological role of pyrimidine exchange by immune cells

Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial

BackgroundPatients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma have high survival when treated with radiotherapy plus cisplatin. Whether replacement of cisplatin with cetuximab-an antibody against the epidermal growth factor receptor-can preserve high survival and reduce treatment toxicity is unknown. We investigated whether cetuximab would maintain a high proportion of patient survival and reduce acute and late toxicity.MethodsRTOG 1016 was a randomised, multicentre, non-inferiority trial at 182 health-care centres in the USA and Canada. Eligibility criteria included histologically confirmed HPV-positive oropharyngeal carcinoma; American Joint Committee on Cancer 7th edition clinical categories T1-T2, N2a-N3 M0 or T3-T4, N0-N3 M0; Zubrod performance status 0 or 1; age at least 18 years; and adequate bone marrow, hepatic, and renal function. We randomly assigned patients (1:1) to receive either radiotherapy plus cetuximab or radiotherapy plus cisplatin. Randomisation was balanced by using randomly permuted blocks, and patients were stratified by T category (T1-T2 vs T3-T4), N category (N0-N2a vs N2b-N3), Zubrod performance status (0 vs 1), and tobacco smoking history (≤10 pack-years vs &gt;10 pack-years). Patients were assigned to receive either intravenous cetuximab at a loading dose of 400 mg/m2 5-7 days before radiotherapy initiation, followed by cetuximab 250 mg/m2 weekly for seven doses (total 2150 mg/m2), or cisplatin 100 mg/m2 on days 1 and 22 of radiotherapy (total 200 mg/m2). All patients received accelerated intensity-modulated radiotherapy delivered at 70 Gy in 35 fractions over 6 weeks at six fractions per week (with two fractions given on one day, at least 6 h apart). The primary endpoint was overall survival, defined as time from randomisation to death from any cause, with non-inferiority margin 1·45. Primary analysis was based on the modified intention-to-treat approach, whereby all patients meeting eligibility criteria are included. This study is registered with ClinicalTrials.gov, number NCT01302834.FindingsBetween June 9, 2011, and July 31, 2014, 987 patients were enrolled, of whom 849 were randomly assigned to receive radiotherapy plus cetuximab (n=425) or radiotherapy plus cisplatin (n=424). 399 patients assigned to receive cetuximab and 406 patients assigned to receive cisplatin were subsequently eligible. After median follow-up duration of 4·5 years, radiotherapy plus cetuximab did not meet the non-inferiority criteria for overall survival (hazard ratio [HR] 1·45, one-sided 95% upper CI 1·94; p=0·5056 for non-inferiority; one-sided log-rank p=0·0163). Estimated 5-year overall survival was 77·9% (95% CI 73·4-82·5) in the cetuximab group versus 84·6% (80·6-88·6) in the cisplatin group. Progression-free survival was significantly lower in the cetuximab group compared with the cisplatin group (HR 1·72, 95% CI 1·29-2·29; p=0·0002; 5-year progression-free survival 67·3%, 95% CI 62·4-72·2 vs 78·4%, 73·8-83·0), and locoregional failure was significantly higher in the cetuximab group compared with the cisplatin group (HR 2·05, 95% CI 1·35-3·10; 5-year proportions 17·3%, 95% CI 13·7-21·4 vs 9·9%, 6·9-13·6). Proportions of acute moderate to severe toxicity (77·4%, 95% CI 73·0-81·5 vs 81·7%, 77·5-85·3; p=0·1586) and late moderate to severe toxicity (16·5%, 95% CI 12·9-20·7 vs 20·4%, 16·4-24·8; p=0·1904) were similar between the cetuximab and cisplatin groups.InterpretationFor patients with HPV-positive oropharyngeal carcinoma, radiotherapy plus cetuximab showed inferior overall survival and progression-free survival compared with radiotherapy plus cisplatin. Radiotherapy plus cisplatin is the standard of care for eligible patients with HPV-positive oropharyngeal carcinoma.FundingNational Cancer Institute USA, Eli Lilly, and The Oral Cancer Foundation