In some eukaryotes, germline and somatic genomes differ dramatically in their composition. Here we characterise a major germline-soma dissimilarity caused by a germline-restricted chromosome (GRC) in ...songbirds. We show that the zebra finch GRC contains >115 genes paralogous to single-copy genes on 18 autosomes and the Z chromosome, and is enriched in genes involved in female gonad development. Many genes are likely functional, evidenced by expression in testes and ovaries at the RNA and protein level. Using comparative genomics, we show that genes have been added to the GRC over millions of years of evolution, with embryonic development genes bicc1 and trim71 dating to the ancestor of songbirds and dozens of other genes added very recently. The somatic elimination of this evolutionarily dynamic chromosome in songbirds implies a unique mechanism to minimise genetic conflict between germline and soma, relevant to antagonistic pleiotropy, an evolutionary process underlying ageing and sexual traits.
Current trends suggest that significant gender disparities exist within Science, Technology, Engineering, and Mathematics (STEM) education at university, with female students being underrepresented ...in physics, but more equally represented in life sciences (e.g., biology, medicine). To understand these trends, it is important to consider the context in which students make decisions about which university courses to enrol in. The current study seeks to investigate gender differences in STEM through a unique approach that combines network analysis of student enrollment data with an interpretive lens based on the sociological theory of Pierre Bourdieu. We generate a network of courses taken by around 9000 undergraduate physics students (from 2009 to 2014) to quantify Bourdieu's concept of field. We identify the fields in which physics students participate by constructing a weighted co-enrollment network and finding communities within it. We then use odds ratios to report gender differences in transverse movements between different academic fields, and non-parametric tests to assess gender differences in vertical movements (changes in students' achievement rankings within a field). Odds ratios comparing the likelihood of progression from one field to another indicate that female students were more likely to make transverse movements into life science fields. We also found that university physics did a poor job in attracting high achieving students, and especially high achieving female students. Of the students who did choose to study physics at university, low and middle achieving female high school students were more likely to decrease their relative rank in their first year compared to their male counterparts. Low achieving female students were also less likely to continue with physics after their first year compared to their male counterparts. Results and implications are discussed in the context of Bourdieu's theory, and previous research. We argue that in order to remove constraints on female students' study choices, the field of physics needs to provide a culture in which all students feel like they belong.
A 9-month regimen of isoniazid can prevent active tuberculosis in persons with latent tuberculosis infection. However, the regimen has been associated with poor adherence rates and with toxic ...effects.
In an open-label trial conducted in nine countries, we randomly assigned adults with latent tuberculosis infection to receive treatment with a 4-month regimen of rifampin or a 9-month regimen of isoniazid for the prevention of confirmed active tuberculosis within 28 months after randomization. Noninferiority and potential superiority were assessed. Secondary outcomes included clinically diagnosed active tuberculosis, adverse events of grades 3 to 5, and completion of the treatment regimen. Outcomes were adjudicated by independent review panels.
Among the 3443 patients in the rifampin group, confirmed active tuberculosis developed in 4 and clinically diagnosed active tuberculosis developed in 4 during 7732 person-years of follow-up, as compared with 4 and 5 patients, respectively, among 3416 patients in the isoniazid group during 7652 person-years of follow-up. The rate differences (rifampin minus isoniazid) were less than 0.01 cases per 100 person-years (95% confidence interval CI, -0.14 to 0.16) for confirmed active tuberculosis and less than 0.01 cases per 100 person-years (95% CI, -0.23 to 0.22) for confirmed or clinically diagnosed tuberculosis. The upper boundaries of the 95% confidence interval for the rate differences of the confirmed cases and for the confirmed or clinically diagnosed cases of tuberculosis were less than the prespecified noninferiority margin of 0.75 percentage points in cumulative incidence; the rifampin regimen was not superior to the isoniazid regimen. The difference in the treatment-completion rates was 15.1 percentage points (95% CI, 12.7 to 17.4). The rate differences for adverse events of grade 3 to 5 occurring within 146 days (120% of the 4-month planned duration of the rifampin regimen) were -1.1 percentage points (95% CI, -1.9 to -0.4) for all events and -1.2 percentage points (95% CI, -1.7 to -0.7) for hepatotoxic events.
The 4-month regimen of rifampin was not inferior to the 9-month regimen of isoniazid for the prevention of active tuberculosis and was associated with a higher rate of treatment completion and better safety. (Funded by the Canadian Institutes of Health Research and the Australian National Health and Medical Research Council; ClinicalTrials.gov number, NCT00931736 .).
An expansion of the hexanucleotide GGGGCC repeat in the first intron of C9ORF72 gene was recently linked to amyotrophic lateral sclerosis. It is not known if the mutation results in a gain of ...function, a loss of function or if, perhaps both mechanisms are linked to pathogenesis. We generated a genetic model of ALS to explore the biological consequences of a null mutation of the Caenorhabditis elegans C9ORF72 orthologue, F18A1.6, also called alfa-1. alfa-1 mutants displayed age-dependent motility defects leading to paralysis and the specific degeneration of GABAergic motor neurons. alfa-1 mutants showed differential susceptibility to environmental stress where osmotic stress provoked neurodegeneration. Finally, we observed that the motor defects caused by loss of alfa-1 were additive with the toxicity caused by mutant TDP-43 proteins, but not by the mutant FUS proteins. These data suggest that a loss of alfa-1/C9ORF72 expression may contribute to motor neuron degeneration in a pathway associated with other known ALS genes.
Bioelectronic devices must be fast and sensitive to interact with the rapid, low-amplitude signals generated by neural tissue. They should also be biocompatible and soft, and should exhibit long-term ...stability in physiologic environments. Here, we develop an enhancement-mode, internal ion-gated organic electrochemical transistor (e-IGT) based on a reversible redox reaction and hydrated ion reservoirs within the conducting polymer channel, which enable long-term stable operation and shortened ion transit time. E-IGT transient responses depend on hole rather than ion mobility, and combine with high transconductance to result in a gain-bandwidth product that is several orders of magnitude above that of other ion-based transistors. We used these transistors to acquire a wide range of electrophysiological signals, including in vivo recording of neural action potentials, and to create soft, biocompatible, long-term implantable neural processing units for the real-time detection of epileptic discharges. E-IGTs offer a safe, reliable and high-performance building block for chronically implanted bioelectronics, with a spatiotemporal resolution at the scale of individual neurons.
The management of inflammatory bowel disease (IBD) has changed since the mid‐1990s (e.g., use of thiopurines/anti‐TNFα agents, improved surveillance programs), possibly affecting cancer risk. To ...establish current cancer risk in IBD, updates are warranted from cohorts covering this time span, and detailed enough to study associations with phenotype and medication. We studied intestinal‐, extra‐intestinal‐ and overall cancer risk in the Dutch population‐based IBDSL cohort. In total, 1,157 Crohn's disease (CD) and 1,644 ulcerative colitis (UC) patients were diagnosed between 1991 and 2011, and followed until 2013. Standardized incidence ratios (SIRs) were calculated for CD and UC separately, as well as for gender‐, phenotype‐, disease duration‐, diagnosis era‐ and medication groups. We found an increased risk for colorectal cancer in CD patients with colon involvement (SIR 2.97; 95% CI 1.08–6.46), but not in the total CD or UC population. In addition, CD patients were at increased risk for hematologic‐ (2.41; 1.04–4.76), overall skin‐ (1.55; 1.06–2.19), skin squamous cell‐ (SCC; 3.83; 1.83–7.04) and overall cancer (1.28; 1.01–1.60), whereas UC patients had no increased risk for extra‐intestinal‐ and overall cancer. Finally, in a medication analysis on CD and UC together, long‐term immunosuppression exposure (>12 months) was associated with an increased risk for hematologic cancer, non‐Hodgkin lymphoma, SCC and overall cancer, and this increase was mainly attributed to thiopurines. IBD patients with long‐term immunosuppression exposure can be considered as having a higher cancer risk, and our data support the advice in recent IBD guidelines to consider skin cancer screening in these patients.
What's new?
The management of inflammatory bowel disease (IBD) has changed markedly since the mid‐1990s, possibly affecting cancer risk. To establish current cancer risk, updates are warranted from cohorts covering this timespan and detailed enough to study associations with phenotype and medication. Here, using the Dutch population‐based IBDSL cohort, the authors found that colorectal cancer risk is currently lower in both CD and UC than previously mentioned in literature. CD patients however show an increased overall cancer risk. Altogether, long‐term immunosuppression exposure brings an additional cancer risk to IBD patients, a finding that may be relevant in other auto‐immune diseases with similar medication.
Although one may not always see it, social life often involves choices that make people act in ways that are mindful of others or not. We adopt an interdependence theoretical approach to the novel ...concept of social mindfulness, which we conceptualize in terms of other-regarding choices involving both skill (to see it, e.g., theory of mind, perspective taking) and will (to do it, e.g., empathic concern, prosocial orientation) to act mindfully toward another person's control over outcomes. We operationalized social mindfulness in a new social decision-making paradigm that focuses on leaving or limiting choice options for others that we tested across 7 studies. Studies 1a through 1c showed that people with other-oriented mindsets left interdependent others more choice than people with self-oriented and/or unspecified mindsets. Studies 2a and 2b revealed that people developed more favorable judgments of a socially mindful than of a socially unmindful person. Study 3 revealed that unknown others with trustworthy (vs. untrustworthy) faces were met with more social mindfulness. Study 4 revealed that social mindfulness could be traced in personality by being positively related to Honesty-Humility and Agreeableness (HEXACO Personality Inventory-Revised) as well as to Empathy (Interpersonal Reactivity Index) and a prosocial value orientation (SVO). Together, these studies contribute to explaining how social mindfulness can help people to navigate the social world by aiming to maximize other people's control over their situational outcomes.
Abstract
Background
Surgeons urgently need guidance on how to deliver surgical services safely and effectively during the COVID-19 pandemic. The aim was to identify the key domains that should be ...considered when developing pandemic preparedness plans for surgical services.
Methods
A scoping search was conducted to identify published articles relating to management of surgical patients during pandemics. Key informant interviews were conducted with surgeons and anaesthetists with direct experience of working during infectious disease outbreaks, in order to identify key challenges and solutions to delivering effective surgical services during the COVID-19 pandemic.
Results
Thirteen articles were identified from the scoping search, and surgeons and anaesthetists representing 11 territories were interviewed. To mount an effective response to COVID-19, a pandemic response plan for surgical services should be developed in advance. Key domains that should be included are: provision of staff training (such as patient transfers, donning and doffing personal protection equipment, recognizing and managing COVID-19 infection); support for the overall hospital response to COVID-19 (reduction in non-urgent activities such as clinics, endoscopy, non-urgent elective surgery); establishment of a team-based approach for running emergency services; and recognition and management of COVID-19 infection in patients treated as an emergency and those who have had surgery. A backlog of procedures after the end of the COVID-19 pandemic is inevitable, and hospitals should plan how to address this effectively to ensure that patients having elective treatment have the best possible outcomes.
Conclusion
Hospitals should prepare detailed context-specific pandemic preparedness plans addressing the identified domains. Specific guidance should be updated continuously to reflect emerging evidence during the COVID-19 pandemic.
Graphical Abstract
During pandemics, surgical services need to balance supporting the whole hospital response and minimizing the risk of nosocomial spread of COVID-19 against continuing care for acute surgical conditions and managing urgent elective surgery. This article identifies the key considerations that should be included in pandemic plans for surgical services.
Graphical Abstract
Best available advice
Summary Background 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. Methods 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. Findings 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). Interpretation 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. Funding Cancer Research UK.
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