Revisiting \u3ci\u3eThe Handmaid’s Tale\u3c/i\u3e: Feminist Theory Meets Empirical Research on Surrogate Mothers

After briefly reviewing laws on surrogate motherhood in Canada, the United States, and Britain, the authors consider nearly 40 empirical research studies on the characteristics and experiences of women who have been surrogate mothers. Empiricism meets feminist theory as we revisit arguments against surrogacy arrangements, including the inability to give informed consent, the inherently exploitative nature of the arrangements, and the dangers of commodification. In light of our observations based on the empirical research, we argue that it may be time to review Canadian surrogacy laws

Molecular techniques for the detection of colorectal cancer cells in the peritoneal cavity

Colorectal cancer is a major health problem, and many patients relapse despite apparently curative treatment. Local recurrence is an important factor, and is more common when cancer cells are present on the free serosal surface or circumferential resection margin. We hypothesised that detecting tumour cells in the peritoneal cavity during surgery (in peritoneal washings) or post-operatively (in drain fluids) would act as a marker for risk of local recurrence, and that the use of molecular biological techniques would allow for the sensitive detection of such cells. We collected samples of colorectal tumours, with washings from the peritoneal cavity at the start and end of surgery, and fluid from the surgical drain on the first and second postoperative day. Epithelial cells in the peritoneal samples were enriched using magnetic cell separation (MACS). Using mutation specific PCR or a Mismatch Ligation Assay we detected common mutations of K-ras, TP53, APe and BRAF in primary tumour samples, and when such a mutation was found, we studied the peritoneal samples from that patient for the same mutation. We detected 23 mutations in 22 (out of 46) tumours from 21 patients. In 16 patients, at least one of the peritoneal samples gave a positive result for the same mutant DNA. Using MACS increased the proportion of positive samples. Half of the patients with positive peritoneal samples had Dukes' stage A or B tumours. Follow up is not yet long enough to allow conclusions to be drawn on the significance of these results. We have described techniques allowing mutations to be characterised in half of colorectal tumours and have demonstrated the presence of cells with the same mutation in peritoneal samples from three-quarters of patients. Longer follow up will show whether our tests are too sensitive, or whether they provide useful information about likely local recurrence

Acute coronary syndrome in the older adults

Coronary heart disease remains the leading cause of death in the developed world. Advanced age is the single strongest risk factor for coronary artery disease (CAD) and independent predictor for poor outcomes following an acute coronary syndrome (ACS). ACS refers to a spectrum of conditions compatible with acute myocardial ischemia and/or infarction due to various degrees of reduction in coronary blood flow as a result of plaque rupture/erosion and thrombosis formation or supply and demand mismatch. Unstable angina and non-ST segment elevation myocardial infarction are often continuous and clinically indistinguishable, collectively referred as non-ST elevation ACS (NSTE-ACS). An abrupt total occlusion of a coronary artery causing transmural myocardial ischemia/necrosis and displaying ST segment elevation or new left bundle branch block on a12-lead ECG leads to the diagnosis of ST segment elevation myocardial infarction (STEMI). NSTE-ACS and STEMI require acute cardiac care. Professional societies have established guidelines for high quality contemporary care for ACS patients, i.e., American Heart Association/American College of Cardiology guidelines for STEMI and NSTE-ACS, European Society of Cardiology guidelines for STEMI and NSTE-ACS, and the United Kingdom National Institute for Health and Care Excellence guidelines for STEMI and NSTE-ACS.[1]–[6] Implementation of evidence-based therapies has significantly decreased mortality and morbidities of ACS.[3],[7],[8] However, these advancements in ACS management have not equally improved outcomes for older adults. Vulnerable older patients continue to be at high risk of poor outcomes, are less likely to receive evidence based care, and have high mortality rates regardless of treatments given.[9],[10] These disparities and challenges in caring for ACS in older adults are well recognized.[11]–[13] This review summarizes the increasing burden and persistent unfavorable outcome of ACS in older adults, and discusses the clinical presentation, diagnosis and strategies for medical and invasive therapy

Stable ischemic heart disease in the older adults

Ischemic heart disease is caused by atherosclerotic and/or thrombotic obstruction of coronary arteries. Clinical spectrum of ischemic heart disease expands from asymptomatic atherosclerosis of coronary arteries to acute coronary syndromes (ACS) including unstable angina, acute myocardial infarction (non-ST elevation myocardial infarction and ST elevation myocardial infarction). Stable ischemic heart disease (SIHD) refers to patients with known or suspected SIHD who have no recent or acute changes in their symptomatic status, suggesting no active thrombotic process is underway. These patients include those with (1) recent-onset or stable angina or ischemic equivalent symptoms, such as dyspnea or arm pain with exertion; (2) post-ACS stabilized after revascularization or medical therapy; and (3) asymptomatic SIHD diagnosed by abnormal stress tests or imaging studies. This review summarizes clinical features and management of SIHD in the older adult. ACS in older adults is not considered in this review

Investigating the impact of a 20mph speed limit intervention on road traffic collisions, casualties, speed and volume in Belfast, UK: 3-year follow-up outcomes of a natural experiment

Background: Evidence regarding the effectiveness of 20 miles per hour (mph) speed limit interventions is limited, and rarely have long-term outcomes been assessed. We investigate the effect of a 20 mph speed limit intervention on road traffic collisions, casualties, speed and volume at 1 and 3 years post-implementation. Methods: An observational, repeated cross-sectional design was implemented, using routinely collected data for road traffic collisions, casualties, speed and volume. We evaluated difference-in-differences in collisions and casualties (intervention vs control) across three different time series and traffic speed and volume pre-implementation, at 1 and 3 years post-implementation. Results: Small reductions in road traffic collisions were observed at year 1 (3%; p=0.82) and year 3 post-implementation (15%; p=0.31) at the intervention site. Difference-in-differences analyses showed no statistically significant differences between the intervention and control sites over time for road traffic collisions. There were 16% (p=0.18) and 22% (p=0.06) reductions in casualty rates at years 1 and 3 post-implementation, respectively, at the intervention site. Results showed little change in mean traffic speed at year 1 (0.2 mph, 95% CI −0.3 to 2.4, p=0.14) and year 3 post-implementation (0.8, 95% CI −1.5 to 2.5, p=0.17). For traffic volume, a decrease in 57 vehicles per week was observed at year 1 (95% CI –162 to −14, p<0.00) and 71 vehicles at year 3 (95% CI −213 to 1, p=0.05) post-implementation. Conclusion: A 20 mph speed limit intervention implemented at city centre scale had little impact on long-term outcomes including road traffic collisions, casualties and speed, except for a reduction in traffic volume. Policymakers considering implementing 20 mph speed limit interventions should consider the fidelity, context and scale of implementation

Anatomy of Escherichia coli σ(70) promoters

Information theory was used to build a promoter model that accounts for the −10, the −35 and the uncertainty of the gap between them on a common scale. Helical face assignment indicated that base −7, rather than −11, of the −10 may be flipping to initiate transcription. We found that the sequence conservation of σ(70) binding sites is 6.5 ± 0.1 bits. Some promoters lack a −35 region, but have a 6.7 ± 0.2 bit extended −10, almost the same information as the bipartite promoter. These results and similarities between the contacts in the extended −10 binding and the −35 suggest that the flexible bipartite σ factor evolved from a simpler polymerase. Binding predicted by the bipartite model is enriched around 35 bases upstream of the translational start. This distance is the smallest 5′ mRNA leader necessary for ribosome binding, suggesting that selective pressure minimizes transcript length. The promoter model was combined with models of the transcription factors Fur and Lrp to locate new promoters, to quantify promoter strengths, and to predict activation and repression. Finally, the DNA-bending proteins Fis, H-NS and IHF frequently have sites within one DNA persistence length from the −35, so bending allows distal activators to reach the polymerase

The Wor1-like Protein Fgp1 Regulates Pathogenicity, Toxin Synthesis and Reproduction in the Phytopathogenic Fungus Fusarium graminearum

WOR1 is a gene for a conserved fungal regulatory protein controlling the dimorphic switch and pathogenicity determents in Candida albicans and its ortholog in the plant pathogen Fusarium oxysporum, called SGE1, is required for pathogenicity and expression of key plant effector proteins. F. graminearum, an important pathogen of cereals, is not known to employ switching and no effector proteins from F. graminearum have been found to date that are required for infection. In this study, the potential role of the WOR1-like gene in pathogenesis was tested in this toxigenic fungus. Deletion of the WOR1 ortholog (called FGP1) in F. graminearum results in greatly reduced pathogenicity and loss of trichothecene toxin accumulation in infected wheat plants and in vitro. The loss of toxin accumulation alone may be sufficient to explain the loss of pathogenicity to wheat. Under toxin-inducing conditions, expression of genes for trichothecene biosynthesis and many other genes are not detected or detected at lower levels in Δfgp1 strains. FGP1 is also involved in the developmental processes of conidium formation and sexual reproduction and modulates a morphological change that accompanies mycotoxin production in vitro. The Wor1-like proteins in Fusarium species have highly conserved N-terminal regions and remarkably divergent C-termini. Interchanging the N- and C- terminal portions of proteins from F. oxysporum and F. graminearum resulted in partial to complete loss of function. Wor1-like proteins are conserved but have evolved to regulate pathogenicity in a range of fungi, likely by adaptations to the C-terminal portion of the protein

The contribution of X-linked coding variation to severe developmental disorders

Abstract: Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication