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Although most research on sleep and adolescent health has focused on how long each youth sleeps on average, variability in sleep duration may be just as problematic. Existing findings have been inconsistent and unable to address cause-effect relationships. This study piloted an experimental protocol to induce sleep variability and explore its impact on daytime sleepiness in adolescents. Healthy adolescents aged 14-17 participated in a 3-week, at-home protocol. Sleep was monitored by sleep diaries and actigraphy. Following a run-in period to stabilize wake times (set at 6:30am throughout the protocol), participants were randomly counterbalanced across two 5-night experimental conditions. Bedtimes were consistent at 11:00pm during the stable sleep condition (7.5-hour sleep period each night) but changed on alternating nights during the variable sleep condition (ranging from 9:30pm to 12:30am) so that sleep duration averaged 7.5 hours across the condition with a standard deviation of 1.37 hours. Difficulty waking was assessed each morning and daytime sleepiness was assessed by end-of-condition parent- and adolescent-reports. Of the 20 participants who completed the study, 16 met the predetermined adherence definition. For those who were adherent, there were no differences in overall sleep duration between the stable and variable sleep conditions (p>.05) but adolescents had 58.6 minutes greater night-to-night variation in sleep duration in the variable condition (p < .001). Across all nights, youth reported greater difficulty waking following nights of shorter assigned sleep (p = .004) and greater overall sleepiness during the variable condition (p = .03). It is feasible to experimentally vary how long adolescents sleep on a nightly basis while holding average sleep duration constant. Such a protocol will promote tests of the acute effects of day-to-day changes in sleep duration on health.

Background Obesity has played a central role in heightened coronavirus disease 2019 (COVID-19) risk and vaccine response. COVID-19 vaccine intention among those with a history of severe obesity, specifically those who have undergone bariatric surgery, has not been described. This study aims to examine early COVID-19 vaccine intention among mothers with a history of severe obesity who underwent bariatric surgery. Methods Sixty-four mothers ( M age  = 39.3 years) who underwent bariatric surgery ( M time since surgery  = 19.6 months) completed surveys online (November 2020–February 2021). Information obtained included their COVID-19 vaccine intention (vaccine ready, undecided, vaccine opposed). Analyses examined group differences in demographics, body mass index (BMI = kg/m 2 ), knowledge of obesity-related COVID-19 risk, flu vaccination history, general beliefs about vaccine safety/effectiveness, and factors increasing confidence/motivation to obtain a COVID-19 vaccine. Results Thirty-six (56.3%) mothers had severe obesity (≥ Class II [BMI =  ≥ 35 kg/m 2 ]). The majority were vaccine hesitant (undecided [ n  = 28; 43.8%]; vaccine opposed [ n  = 15; 23.4%]). Compared to the vaccine-ready group, vaccine-hesitant groups were younger ( p  < .05). For the vaccine opposed, recent flu vaccination rates ( p  = .012) and general belief that vaccines are safe ( p  = .028) were lower than expected. Among hesitant participants, no reported side effects and the health of self and others were endorsed as top factors increasing vaccine confidence and motivation respectively. Conclusions While preliminary, the prominence of early vaccine hesitancy in this sample of mothers who have undergone bariatric surgery, with most persisting with severe obesity, indicates a subgroup at high risk. Factors to address through targeted messaging and intervention were identified. Graphical abstract

Vaccine development efforts have recently focused on enabling strong immune responses to poorly immunogenic antigens, via display on multimerisation scaffolds or virus like particles (VLPs). Typically such studies demonstrate improved antibody titer comparing monomeric and nano-arrayed antigen. There are many such studies and scaffold technologies, but minimal side-by-side evaluation of platforms for both the amount and efficacy of antibodies induced. Here we present direct comparison of three leading platforms displaying the promising malaria transmission-blocking vaccine (TBV) target Pfs25. These platforms encompass the three important routes to antigen-scaffold linkage: genetic fusion, chemical cross-linking and plug-and-display SpyTag/SpyCatcher conjugation. We demonstrate that chemically-conjugated Qβ VLPs elicited the highest quantity of antibodies, while SpyCatcher-AP205-VLPs elicited the highest quality anti-Pfs25 antibodies for transmission blocking upon mosquito feeding. These quantative and qualitative features will guide future nanoassembly optimisation, as well as the development of the new generation of malaria vaccines targeting transmission.

Marine radiocarbon (14C) ages are an important geochronology tool for the understanding of past earthquakes and tsunamis that have impacted the coastline of New Zealand. To advance this field of research, we need an improved understanding of the radiocarbon marine reservoir correction for coastal waters of New Zealand. Here we report 170 new ΔR20 (1900–1950) measurements from around New Zealand made on pre-1950 marine shells and mollusks killed by the 1931 Napier earthquake. The influence of feeding method, living depth and environmental preference on ΔR is evaluated and we find no influence from these factors except for samples living at or around the high tide mark on rocky open coastlines, which tend to have anomalously low ΔR values. We examine how ΔR varies spatially around the New Zealand coastline and identify continuous stretches of coastline with statistically similar ΔR values. We recommend subdividing the New Zealand coast into four regions with different marine reservoir corrections: A: south and western South Island, ΔR20 –113 ± 33 yr, B: Cook Strait and western North Island, ΔR20 –171 ± 29 yr, C: northeastern North Island, ΔR20 –143 ± 18 yr, D: eastern North Island and eastern South Island, ΔR20 –70 ± 39 yr.

Background Limited evidence exists regarding the relationship between health literacy and health-related quality of life (HRQoL) in Australian patients from primary care. The objective of this study was to investigate the impact of health literacy on HRQoL in a large sample of patients without known vascular disease or diabetes and to examine whether the difference in HRQoL between low and high health literacy groups was clinically significant. Methods This was a cross-sectional study of baseline data from a cluster randomised trial. The study included 739 patients from 30 general practices across four Australian states conducted in 2012 and 2013 using the standard Short Form Health Survey (SF-12) version 2. SF-12 physical component score (PCS-12) and mental component score (MCS-12) are derived using the standard US algorithm. Health literacy was measured using the Health Literacy Management Scale (HeLMS). Multilevel regression analysis (patients at level 1 and general practices at level 2) was applied to relate PCS-12 and MCS-12 to patient reported life style risk behaviours including health literacy and demographic factors. Results Low health literacy patients were more likely to be smokers (12 % vs 6 %, P  = 0.005), do insufficient physical activity (63 % vs 47 %, P  < 0.001), be overweight (68 % vs 52 %, P  < 0.001), and have lower physical health and lower mental health with large clinically significant effect sizes of 0.56 (B (regression coefficient) = −5.4, P  < 0.001) and 0.78(B = -6.4, P  < 0.001) respectively after adjustment for confounding factors. Patients with insufficient physical activity were likely to have a lower physical health score (effect size = 0.42, B = −3.1, P  < 0.001) and lower mental health (effect size = 0.37, B = −2.6, P  < 0.001). Being overweight tended to be related to a lower PCS-12 (effect size = 0.41, B = −1.8, P  < 0.05). Less well-educated, unemployed and smoking patients with low health literacy reported worse physical health. Health literacy accounted for 45 and 70 % of the total between patient variance explained in PCS-12 and MCS-12 respectively. Conclusions Addressing health literacy related barriers to preventive care may help reduce some of the disparities in HRQoL. Recognising and tailoring health related communication to those with low health literacy may improve health outcomes including HRQoL in general practice.

Ian Tomlinson and colleagues identify a 40-kb duplication upstream of the gene that encodes the BMP antagonist GREM1 in families with hereditary mixed polyposis syndrome. The mutation is associated with increased allele-specific and ectopic expression of GREM1. Hereditary mixed polyposis syndrome (HMPS) is characterized by apparent autosomal dominant inheritance of multiple types of colorectal polyp, with colorectal carcinoma occurring in a high proportion of affected individuals. Here, we use genetic mapping, copy-number analysis, exclusion of mutations by high-throughput sequencing, gene expression analysis and functional assays to show that HMPS is caused by a duplication spanning the 3′ end of the SCG5 gene and a region upstream of the GREM1 locus. This unusual mutation is associated with increased allele-specific GREM1 expression. Whereas GREM1 is expressed in intestinal subepithelial myofibroblasts in controls, GREM1 is predominantly expressed in the epithelium of the large bowel in individuals with HMPS. The HMPS duplication contains predicted enhancer elements; some of these interact with the GREM1 promoter and can drive gene expression in vitro. Increased GREM1 expression is predicted to cause reduced bone morphogenetic protein (BMP) pathway activity, a mechanism that also underlies tumorigenesis in juvenile polyposis of the large bowel.

Objectives To investigate the proportion of clinical scenarios covered by EURO-2000 Guidelines and ESR iGuide , and assess compliance with both guidelines. Methods The clinical indication on archived request forms for head, chest, abdomen-pelvis, and spine CT examinations performed in three hospitals in January 2018 was retrospectively matched with EURO-2000 Guidelines and ESR iGuide . For clinical scenarios addressed in the guidelines, the compliance with the guidelines was assessed. Analysis was performed on pooled data from the three centres and further stratified by centre, body region, and prescriber’s specialisation. The differences in categorical data distributions between centres, body regions, and prescribers’ specialisations were assessed with paired McNemar’s χ 2 tests. Results A total of 6,812 requests for 7,217 CT examinations were analysed. Sixty-five percent of clinical situations that lead to prescribing CT examinations were addressed in EURO-2000 Guidelines compared with 81% for ESR iGuide . Proportions of clinical scenarios covered by the guidelines were statistically different between centres and body regions ( p < 0.001) and varied according to prescribers’ specialisations ( p ranging from < 0.001 to 0.531). Both EURO-2000 Guidelines and ESR iGuide encompassed more clinical scenarios in certain body regions, favouring, e.g. spine and head over abdomen and chest. The proportion of “unjustified examinations” was greater according to EURO-2000 Guidelines (46%) than ESR iGuide (23%) ( p < 0.001). Conclusions Both EURO-2000 Guidelines and ESR iGuide do not address numerous common clinical scenarios. The proportions of scenarios addressed differ according to the centre, body region, and prescribers’ specialisation. Any estimation of compliance with referral guidelines is therefore of relative significance. Key Points • ESR iGuide performs better than earlier EURO-2000 Guidelines for the coverage of all possible clinical scenarios leading to CT referrals. • Differences in coverage of clinical scenarios by both referral guidelines are observed for different body regions and/or prescribers’ subspecialties. • As referral guidelines are incomplete, any estimation of justified or unjustified CT requests is of relative significance.

Objectives To determine variability of volume computed tomographic dose index (CTDIvol) and dose–length product (DLP) data, and propose a minimum sample size to achieve an expected precision. Methods CTDIvol and DLP values of 19,875 consecutive CT acquisitions of abdomen (7268), thorax (3805), lumbar spine (3161), cervical spine (1515) and head (4106) were collected in two centers. Their variabilities were investigated according to sample size (10 to 1000 acquisitions) and patient body weight categories (no weight selection, 67–73 kg and 60–80 kg). The 95 % confidence interval in percentage of their median (CI95/med) value was calculated for increasing sample sizes. We deduced the sample size that set a 95 % CI lower than 10 % of the median (CI95/med ≤ 10 %). Results Sample size ensuring CI95/med ≤ 10 %, ranged from 15 to 900 depending on the body region and the dose descriptor considered. In sample sizes recommended by regulatory authorities (i.e., from 10–20 patients), mean CTDIvol and DLP of one sample ranged from 0.50 to 2.00 times its actual value extracted from 2000 samples. Conclusions The sampling error in CTDIvol and DLP means is high in dose surveys based on small samples of patients. Sample size should be increased at least tenfold to decrease this variability. Key Points • Variability of dose descriptors is high regardless of the body region . • Variability of dose descriptors depends on weight selection and the region scanned . • Larger samples would reduce sampling errors of radiation dose data in surveys . • Totally or partially disabling AEC reduces dose variability and increases patient dose . • Median values of dose descriptors depend on the body weight selection .

Preoperative (neoadjuvant) chemotherapy and radiotherapy are more effective than similar postoperative treatment for oesophageal, gastric, and rectal cancers, perhaps because of more effective micrometastasis eradication and reduced risk of incomplete excision and tumour cell shedding during surgery. The FOxTROT trial aims to investigate the feasibility, safety, and efficacy of preoperative chemotherapy for colon cancer. In the pilot stage of this randomised controlled trial, 150 patients with radiologically staged locally advanced (T3 with ≥5 mm invasion beyond the muscularis propria or T4) tumours from 35 UK centres were randomly assigned (2:1) to preoperative (three cycles of OxMdG [oxaliplatin 85 mg/m2, l-folinic acid 175 mg, fluorouracil 400 mg/m2 bolus, then 2400 mg/m2 by 46 h infusion] repeated at 2-weekly intervals followed by surgery and a further nine cycles of OxMdG) or standard postoperative chemotherapy (12 cycles of OxMdG). Patients with KRAS wild-type tumours were randomly assigned (1:1) to receive panitumumab (6 mg/kg; every 2 weeks with the first 6 weeks of chemotherapy) or not. Treatment allocation was through a central randomisation service using a minimised randomisation procedure including age, radiological T and N stage, site of tumour, and presence of defunctioning colostomy as stratification variables. Primary outcome measures of the pilot phase were feasibility, safety, and tolerance of preoperative therapy, and accuracy of radiological staging. Analysis was by intention to treat. This trial is registered, number ISRCTN 87163246. 96% (95 of 99) of patients started and 89% (85 of 95) completed preoperative chemotherapy with grade 3–4 gastrointestinal toxicity in 7% (seven of 94) of patients. All 99 tumours in the preoperative group were resected, with no significant differences in postoperative morbidity between the preoperative and control groups: 14% (14 of 99) versus 12% (six of 51) had complications prolonging hospital stay (p=0·81). 98% (50 of 51) of postoperative chemotherapy patients had T3 or more advanced tumours confirmed at post-resection pathology compared with 91% (90 of 99) of patients following preoperative chemotherapy (p=0·10). Preoperative therapy resulted in significant downstaging of TNM5 compared with the postoperative group (p=0·04), including two pathological complete responses, apical node involvement (1% [one of 98] vs 20% [ten of 50], p<0·0001), resection margin involvement (4% [four of 99] vs 20% [ten of 50], p=0·002), and blinded centrally scored tumour regression grading: 31% (29 of 94) vs 2% (one of 46) moderate or greater regression (p=0·0001). Preoperative chemotherapy for radiologically staged, locally advanced operable primary colon cancer is feasible with acceptable toxicity and perioperative morbidity. Proceeding to the phase 3 trial, to establish whether the encouraging pathological responses seen with preoperative therapy translates into improved long-term oncological outcome, is appropriate. Cancer Research UK.

The genetic and molecular basis of flagellar motility has been investigated for several decades, with innovative research strategies propelling advances at a steady pace. Furthermore, as the phenomenon is examined in diverse bacteria, new taxon-specific regulatory and structural features are being elucidated. Motility is also a straightforward bacterial phenotype that can allow undergraduate researchers to explore the palette of molecular genetic tools available to microbiologists. This study, driven primarily by undergraduate researchers, evaluated hundreds of flagellar motility mutants in the Gram-negative plant-associated bacterium Agrobacterium fabrum . The nearly saturating screen implicates a total of 37 genes in flagellar biosynthesis, including genes of previously unknown function.