Estrogen receptor-α and progesterone receptor are expressed in label-retaining mammary epithelial cells that divide asymmetrically and retain their template DNA strands

INTRODUCTION: Stem cells of somatic tissues are hypothesized to protect themselves from mutation and cancer risk through a process of selective segregation of their template DNA strands during asymmetric division. Mouse mammary epithelium contains label-retaining epithelial cells that divide asymmetrically and retain their template DNA. METHOD: Immunohistochemistry was used in murine mammary glands that had been labeled with [(3)H]thymidine during allometric growth to investigate the co-expression of DNA label retention and estrogen receptor (ER)-α or progesterone receptor (PR). Using the same methods, we investigated the co-localization of [(3)H]thymidine and ER-α or PR in mammary tissue from mice that had received treatment with estrogen, progesterone, and prolactin subsequent to a long chase period to identify label-retaining cells. RESULTS: Label-retaining epithelial cells (LRECs) comprised approximately 2.0% of the entire mammary epithelium. ER-α-positive and PR-positive cells represented about 30–40% of the LREC subpopulation. Administration of estrogen, progesterone, and prolactin altered the percentage of LRECs expressing ER-α. CONCLUSION: The results presented here support the premise that there is a subpopulation of LRECs in the murine mammary gland that is positive for ER-α and/or PR. This suggests that certain mammary LRECs (potentially stem cells) remain stably positive for these receptors, raising the possibility that LRECs comprise a hierarchy of asymmetrically cycling mammary stem/progenitor cells that are distinguished by the presence or absence of nuclear steroid receptor expression

The hypoxia that developed in a microtidal estuary following an extreme storm produced dramatic changes in the benthos

Runoff from an extreme storm on 22 March 2010 led, during the next 3 months, to the formation of a pronounced halocline and underlying hypoxia in the upper reaches of the microtidal Swan–Canning Estuary. Benthic macroinvertebrates were sampled between January 2010 and October 2011 at five sites along 10 km of this region. By mid-April, the number of species, total density, Simpson’s evenness index and taxonomic distinctness had declined markedly, crustaceans had disappeared and the densities of annelids and molluscs had declined slightly. These faunal attributes (except Simpson’s index) and species composition did not recover until after the end of the hypoxia. The survival of annelids and loss of crustaceans in this period reflects different sensitivities of these taxa to severe environmental stress. The results emphasise that microtidal estuaries with long residence times are highly vulnerable to the effects of environmental perturbations, particularly during warmer periods of the year

Statistical aspects of the TNK-S2B trial of tenecteplase versus alteplase in acute ischemic stroke: an efficient, dose-adaptive, seamless phase II/III design

Background TNK-S2B, an innovative, randomized, seamless phase II/III trial of tenecteplase versus rt-PA for acute ischemic stroke, terminated for slow enrollment before regulatory approval of use of phase II patients in phase III

Impact of COVID-19 on cardiac procedure activity in England and associated 30-day mortality

BACKGROUND: Limited data exists on the impact of COVID-19 on national changes in cardiac procedure activity, including patient characteristics and clinical outcomes before and during the COVID-19 pandemic. METHODS AND RESULTS: All major cardiac procedures (n = 374,899) performed between 1st January and 31st May for the years 2018, 2019 and 2020 were analysed, stratified by procedure type and time-period (pre-COVID: January-May 2018 and 2019 and January-February 2020 and COVID: March-May 2020). Multivariable logistic regression was performed to examine the odds ratio (OR) of 30-day mortality for procedures performed in the COVID period.Overall, there was a deficit of 45,501 procedures during the COVID period compared to the monthly averages (March-May) in 2018-2019. Cardiac catheterisation and device implantations were the most affected in terms of numbers (n = 19,637 and n = 10,453) whereas surgical procedures such as MVR, other valve replacement/repair, ASD/VSD repair and CABG were the most affected as a relative percentage difference (Δ) to previous years' averages. TAVR was the least affected (Δ-10.6%). No difference in 30-day mortality was observed between pre-COVID and COVID time-periods for all cardiac procedures except cardiac catheterisation (OR 1.25 95% confidence interval (CI) 1.07-1.47, p = 0.006) and cardiac device implantation (OR 1.35 95% CI 1.15-1.58, p < 0.001). CONCLUSION: Cardiac procedural activity has significantly declined across England during the COVID-19 pandemic, with a deficit in excess of 45000 procedures, without an increase in risk of mortality for most cardiac procedures performed during the pandemic. Major restructuring of cardiac services is necessary to deal with this deficit, which would inevitably impact long-term morbidity and mortality

“You have to change your whole life”: a qualitative study of the dynamics of treatment adherence among adults with tuberculosis in the United Kingdom

Karina Kielmann - ORCID: 0000-0001-5519-1658 https://orcid.org/0000-0001-5519-1658Aaron S. Karat - ORCID: 0000-0001-9643-664X https://orcid.org/0000-0001-9643-664XVoR deposited 2021-04-13.Maintaining adherence to treatment for tuberculosis (TB) is essential if the disease is to be eliminated. As part of formative research to develop an intervention to improve adherence, we documented the lived experiences of adults receiving anti-TB treatment (ATT) in three UK cities and examined how personal, social, and structural circumstances interacted to impact on individuals’ adherence to treatment. Using a topic guide that explored social circumstances and experiences of TB care, we conducted in-depth interviews with 18 adults (six women) who were being or had been treated for TB (patients) and four adults (all women) who were caring for a friend, relative, or partner being treated for TB (caregivers). We analysed transcripts using an adapted framework method that classified factors affecting adherence as personal, social, structural, health systems, or treatment-related. Eleven of 18 patients were born outside the UK (in South, Central, and East Asia, and Eastern and Southern Africa); among the seven who were UK-born, four were Black, Asian, or Minority Ethnic and three were White British. TB and its treatment were often disruptive: in addition to debilitating symptoms and side effects of ATT, participants faced job insecurity, unstable housing, stigma, social isolation, worsening mental health, and damaged relationships. Those who had a strong support network, stable employment, a routine that could easily be adapted, a trusting relationship with their TB team, and clear understanding of the need for treatment reported finding it easier to adhere to ATT. Changes in circumstances sometimes had dramatic effects on an individual’s ability to take ATT; participants described how the impact of certain acute events (e.g., the onset of side effects or fatigue, episodes of stigmatisation, loss of income) were amplified by their timing or through their interaction with other elements of the individual’s life. We suggest that the dynamic and fluctuating nature of these factors necessitates comprehensive and regular review of needs and potential problems, conducted before and during ATT; this, coupled with supportive measures that consider (and seek to mitigate) the influence of social and structural factors, may help improve adherence.This work was supported by the National Institute for Health Research (NIHR) Health Technology Assessment Programme, UK grant number 16/88/06.https://doi.org/10.1016/j.jctube.2021.10023323pubpu

Star Routing: Between Vehicle Routing and Vertex Cover

We consider an optimization problem posed by an actual newspaper company, which consists of computing a minimum length route for a delivery truck, such that the driver only stops at street crossings, each time delivering copies to all customers adjacent to the crossing. This can be modeled as an abstract problem that takes an unweighted simple graph $G = (V, E)$ and a subset of edges $X$ and asks for a shortest cycle, not necessarily simple, such that every edge of $X$ has an endpoint in the cycle. We show that the decision version of the problem is strongly NP-complete, even if $G$ is a grid graph. Regarding approximate solutions, we show that the general case of the problem is APX-hard, and thus no PTAS is possible unless P $=$ NP. Despite the hardness of approximation, we show that given any $\alpha$-approximation algorithm for metric TSP, we can build a $3\alpha$-approximation algorithm for our optimization problem, yielding a concrete $9/2$-approximation algorithm. The grid case is of particular importance, because it models a city map or some part of it. A usual scenario is having some neighborhood full of customers, which translates as an instance of the abstract problem where almost every edge of $G$ is in $X$. We model this property as $|E - X| = o(|E|)$, and for these instances we give a $(3/2 + \varepsilon)$-approximation algorithm, for any $\varepsilon > 0$, provided that the grid is sufficiently big.Comment: Accepted to the 12th Annual International Conference on Combinatorial Optimization and Applications (COCOA'18

Lagoonal littorinids: Shell shape and speciation

Variables related to shell shape have been measured in littorinids from brackish lagoons and coastal sites. After removal of size related effects, the data were analyzed using multivariate techniques. On Canonical Variate 1 there was good separation of the shells of the lagoonal animals from those of animals from the coast and a tidal lagoon. The former, for example, had lighter, and therefore thinner, shells for any given shell size and a smaller jugosity of the aperture lip. The lagoonal shells from Golam Head and the coastal animals from Robin Hood's Bay could each be separated clearly from the other samples. Although there are clear morphometric differences in the shells, it is not possible without appropriate breeding experiments to raise the lagoonal animals from L. saxatilis var. lagunae (L. tenebrosa) to species status. The importance of conserving lagoonal habitats is considered in terms of the preservation of biodiversit

Antibiotic usage in chronic rhinosinusitis: analysis of national primary care electronic health records

Background : The aim of this study was to analyse rates of antibiotic usage in chronic rhinosinusitis (CRS) in primary care in England and Wales and to identify trends in the choice of antibiotics prescribed. Methods : We used linked data from primary care EHRs, with diagnoses coded using the Read terminology (Clinical Practice Research Datalink) from consenting general practices, with (2) hospital care administrative records (Hospital Episode Statistics, HES recorded using ICD-10). Results : From the total of 88,317 cases of CRS identified, 40,462 (46%) had an antibiotic prescription within 5 days of their first CRS diagnosis. Of patients receiving a first line antibiotic within 5 days of CRS diagnosis, over 80%, in each CRS group, received a subsequent prescription for an antibiotic. Within 5 years of diagnosis, 9% are estimated to have had 5 or more antibiotics within 5 days of a CRS-related consultation. With data spanning almost 20 years, it was possible to discern trends in antibiotics prescriptions, with a clear increasing trend towards macrolide and tetracycline prescribing evident. Conclusions : While antibiotics may have been prescribed for acute exacerbations, we have found high rates of repeated antibiotic prescription in some patients with CRS in primary care. There is a need for stronger evidence on the role of antibiotics in CRS management

Antibiotic usage in chronic rhinosinusitis: analysis of national primary care electronic health records

BACKGROUND: The aim of this study was to analyse rates of antibiotic usage in chronic rhinosinusitis (CRS) in primary care in England and Wales and to identify trends in the choice of antibiotics prescribed. METHODS: We used linked data from primary care EHRs, with diagnoses coded using the Read terminology (Clinical Practice Research Datalink) from consenting general practices, with (2) hospital care administrative records (Hospital Episode Statistics, HES recorded using ICD-10). RESULTS: From the total of 88,317 cases of CRS identified, 40,462 (46%) had an antibiotic prescription within 5 days of their first CRS diagnosis. Of patients receiving a first line antibiotic within 5 days of CRS diagnosis, over 80%, in each CRS group, received a subsequent prescription for an antibiotic. Within 5 years of diagnosis, 9% are estimated to have had 5 or more antibiotics within 5 days of a CRS-related consultation. With data spanning almost 20 years, it was possible to discern trends in antibiotics prescriptions, with a clear increasing trend towards macrolide and tetracycline prescribing evident. CONCLUSIONS: While antibiotics may have been prescribed for acute exacerbations, we have found high rates of repeated antibiotic prescription in some patients with CRS in primary care. There is a need for stronger evidence on the role of antibiotics in CRS management