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Abstract Background Endometriosis affects 1 in 10 women, many of whom have surgery for persistent pain. Recurrence of symptoms following an operation is common. Although hormonal treatment can reduce this risk, there is uncertainty about the best option. Objectives To evaluate the clinical and cost-effectiveness of long-acting progestogen therapy compared with the combined oral contraceptive pill in preventing recurrence of endometriosis-related pain and quality of life. Design A multicentre, open, randomised trial with parallel economic evaluation. The final design was informed by a pilot study, qualitative exploration of women’s lived experience of endometriosis and a pretrial economic model. Setting Thirty-four United Kingdom hospitals. Participants Women of reproductive age undergoing conservative surgery for endometriosis. Interventions Long-acting progestogen reversible contraceptive (either 150 mg depot medroxyprogesterone acetate or 52 mg levonorgestrel-releasing intrauterine system) or combined oral contraceptive pill (30 µg ethinylestradiol, 150 µg levonorgestrel). Main outcome measures The primary outcome was the pain domain of the Endometriosis Health Profile-30 questionnaire at 36 months post randomisation. The economic evaluation estimated the cost per quality-adjusted life-years gained. Results Four hundred and five women were randomised to receive either long-acting reversible contraceptive (N = 205) or combined oral contraceptive pill (N = 200). Pain scores improved in both groups (24 and 23 points on average) compared with preoperative values but there was no difference between the two (adjusted mean difference: −0.8, 95% confidence interval −5.7 to 4.2; p = 0.76). The long-acting reversible contraceptive group underwent fewer surgical procedures or second-line treatments compared with the combined oral contraceptive group (73 vs. 97; hazard ratio 0.67, 95% confidence interval 0.44 to 1.00). The mean adjusted quality-adjusted life-year difference between two arms was 0.043 (95% confidence interval −0.069 to 0.152) in favour of the combined oral contraceptive pill, although this cost an additional £533 (95% confidence interval 52 to 983) per woman. Limitations Limitations include the absence of a no-treatment group and the fact that many women changed treatments over the 3 years of follow-up. Use of telephone follow-up to collect primary outcome data in those who failed to return questionnaires resulted in missing data for secondary outcomes. The COVID pandemic may have affected rates of further surgical treatment. Conclusions At 36 months, women allocated to either intervention had comparable levels of pain, with both groups showing around a 40% improvement from presurgical levels. Although the combined oral contraceptive was cost-effective at a threshold of £20,000 per quality-adjusted life-year, the difference between the two was marginal and lower rates of repeat surgery might make long-acting reversible contraceptives preferable to some women. Future work Future research needs to focus on evaluating newer hormonal preparations, a more holistic approach to symptom suppression and identification of biomarkers to diagnose endometriosis and its recurrence. Trial registration This trial is registered as ISRCTN97865475. https://doi.org/10.1186/ISRCTN97865475. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/114/01) and is published in full in Health Technology Assessment; Vol. 28, No. 55. See the NIHR Funding and Awards website for further award information. The NIHR recognises that people have diverse gender identities, and in this report, the word ‘woman’ is used to describe patients or individuals whose sex assigned at birth was female, whether they identify as female, male or non-binary. Plain language summary What was the question? Endometriosis is a condition where cells similar to ones that line the womb are found elsewhere in the body. Endometriosis affects 1 in 10 women, many of whom have surgery for persistent pain. Unfortunately, symptoms often return and some women will need repeat operations. Hormonal contraceptives can prevent the return of endometriosis-related pain: either long-acting reversible contraceptives (injections or a coil, fitted inside the womb) or the combined oral contraceptive pill (often called ‘the pill’). We do not know which is the best option. The aim of this trial was to find out which of these two hormone treatments was more effective in terms of symptom relief, avoidance of further surgery and costs. What did we do? Four hundred and five women with endometriosis, who were not intending to get pregnant, participated in a clinical trial. Half of the participants took long-acting reversible contraceptives, and the other half took the pill for 3 years following endometriosis surgery. The choice of treatment was made at random by a computer to ensure a fair comparison, although those allocated to the long-acting contraceptive could choose between injections or the coil. Participants completed questionnaires about their symptoms and life quality at intervals up to 3 years. What did we find? Both treatments were equally good at reducing pain but more women using the pill had repeat operations. The pill was a little more costly overall but associated with a slightly higher quality of life. What does this mean? Both treatments are equally effective in reducing pain up to 3 years after surgery for endometriosis. The differences in costs are small and the choice of treatment should be based on personal preference. Scientific summary Background Endometriosis, which affects up to 1 in 10 women, is characterised by the proliferation of endometrial cells outside the uterus, usually within the pelvis. These endometriotic deposits undergo cyclical proliferation in response to ovarian oestrogen, resulting in internal bleeding, scarring and adhesion formation, which causes pain and has a serious impact on quality of life in affected women. Surgical removal or destruction of endometriotic tissue is currently the preferred treatment but the risk of recurrence is high. Recurrence can be controlled by post-surgical hormonal treatment to reduce circulating levels of oestrogen but there is uncertainty as to the clinical and cost-effectiveness of two commonly used modalities: long-acting reversible contraceptive (LARC) and the combined oral contraceptive pill (COCP). Progestogen-based LARCs used in the trial were the levonorgestrel-releasing intrauterine system (LNG-IUS) or depot medroxyprogesterone acetate injection (DMPA). Objectives To evaluate the clinical and cost-effectiveness of LARCs compared with COCP in preventing recurrence of endometriosis-related pain and quality of life. Design A multicentre, open, randomised trial with parallel economic evaluation. The final design was informed by a pilot study, qualitative exploration of women’s lived experience of endometriosis and a pretrial economic model. Setting Thirty-four NHS hospitals within the UK. Participants Women of reproductive age undergoing laparoscopic surgery for pelvic pain due to endometriosis were eligible if they fulfilled the following criteria: Inclusion criteria: Aged 16–45 years. No immediate plans to conceive. Scheduled for laparoscopic conservative surgery, or diagnostic laparoscopy with concurrent surgery if endometriosis is found, for pelvic pain associated with endometriosis. Willing to be randomised to one long-acting progestogen (LNG-IUS or DMPA) and COCP. The following women were also eligible if they had recurrent pain and were to have conservative surgery for endometriosis: Had one or more previous diagnostic laparoscopies. Had previous laparoscopic conservative surgery for endometriosis, provided that this did not involve rectovaginal dissection or bowel resection. Used postoperative medical treatment, including the treatment options included in the trial. Previous use of treatment options included in the trial as contraceptives. Use of preoperative gonadotropin-releasing hormone analogues (GnRHa), provided that this was stopped at least 4 weeks prior to laparoscopy. Exclusion criteria: No endometriosis identified at diagnostic laparoscopy. Infertility. Any plans for further elective endometriosis surgery (for deep disease or endometrioma). Contraindications to the use of hormonal treatment with oestrogen or progestogens. Suspicion of malignancy. Interventions Four hundred and five women were randomised in a one-to-one ratio via secure internet facility to either LARCs or COCP. The LARC was either 150 mg DMPA or 52 mg LNG-IUS. The COCP formulation contained 30 µg ethinylestradiol and 150 µg levonorgestrel. The LARC (LNG-IUS or DMPA) was selected before randomisation by the patient if a preference was apparent (or alternatively allocated randomly if there was no opinion). Outcome measures Primary outcome Pain as evaluated by the pain domain of the Endometriosis Health Profile – 30-item (EHP-30) questionnaire at 36 months post randomisation. Secondary outcomes (evaluated at 6 months, 1, 2 and 3 years): The four core domains of the EHP-30 questionnaire (control and powerlessness; emotional well-being; social support; self-image). The six modular domains of the EHP-30 (work; relationships with family; sexual relationships; feelings about medical profession; feelings about treatment; feelings about infertility). Pelvic pain measured by visual analogue scale (VAS) during periods; during intercourse; at any time. Responses to the question ‘compared to 1 month ago, would you say your pelvic pain has “Got much better”, “Got a little better”, “Not changed much”, “Got worse”’. Fatigue, as measured by Fatigue Severity Scale (FSS) score. Menstrual regularity. Generic quality of life questionnaire [EuroQol-5 Dimensions, five-level version (EQ-5D-5L)], including index and thermometer scores. Capabilities, as a measure of well-being (ICEpop CAPability, ICECAP measure). Further therapeutic surgery or second-line treatment for endometriosis as a proxy for recurrence or ‘treatment failure’, defined as having undergone hysterectomy, surgery for endometriosis, laparoscopy or taking GnRHa treatment. Discontinuation rates of randomised treatment (time to first treatment change), with reasons for change. Serious adverse events. The economic evaluation estimated the cost per quality-adjusted life-years (QALYs) gained. Sample size To detect an 8-point difference on the EHP-30 pain domain with 90% power (p = 0.05) and assuming the standard deviation (SD) to be 22 points required 160 participants per group, 320 in total. To account for any loss to follow-up (estimated to be 20%), this target was inflated to 400. Eight points is equivalent to 0.36 SD, which can be considered halfway between a small (0.2 SD) to moderate (0.5 SD) effect size. This size of sample would also give us good power (80%) to detect a 10-point difference in the two stratified analyses of LNG-IUS versus COCP and DMPA versus COCP provided that these subgroups had a roughly even split. Results A total of 405 women were allocated to receive either LARC (N = 205) or COCP (N = 200) following laparoscopic surgery for endometriosis. The two randomised groups were comparable in terms of age [29.6 years (6.7 years) vs. 29.3 years (6.6 years)]; body mass index [27.0 kg/m2 (10.6 kg/m2) vs. 26.3 kg/m2 (5.5 kg/m2)]; early-stage endometriosis: stages I and II (79% vs. 79%); complete surgical excision (92% vs. 90%); white ethnicity (91% vs. 92%) and previous hormonal treatment (27% vs. 23%). Pain scores improved in both groups (24 and 23 points on average) compared with preoperative values but there was no statistically significant difference between LARC and COCP at 3 years [adjusted mean difference: −0.8; 95% confidence interval (CI) −5.7 to 4.2; p = 0.76]. The choice of LARC (LNG-IUS or DMPA) did not alter these findings. Most of the other domains of the EHP-30 were improved in both groups at all time points compared with preoperative scores, with no consistent evidence of any difference between groups when estimates of uncertainty were considered. Women in the LARC group had fewer surgical procedures or second-line treatments compared with those taking COCP (73 vs. 97 events, occurring in 50 vs. 61 women due to repeat interventions), translating to a 33% reduction in time to treatment failure [hazard ratio (HR) 0.67, 95% CI 0.44 to 1.00]. Participants in the LARC group had a slightly higher mean EQ-5D-5L score at 36 months compared with those in the COCP arm (0.693 and 0.686, respectively). The mean adjusted imputed QALY difference between the two arms was 0.043 (95% CI −0.069 to 0.152) in favour of COCP, where participants in LARC group had a lower QALY value than those randomised to COCP (1.937 and 1.976, respectively). Despite this, the COCP group was estimated to be more expensive than the LARC group by £533 (95% CI 52 to 983) per woman over 36 months of follow-up. Limitations In the absence of a no-treatment arm, we were unable to demonstrate the effect of surgery alone on preventing recurrence of pain symptoms. While we are able to comment on the effectiveness of a strategy of postoperative prescription of LARC versus COCP, the true impact of these interventions is difficult to gauge as the prolonged duration of follow-up meant that many women had discontinued their allocated treatments. The predominance of white women in the recruited sample limits our ability to be confident about how our results might apply to women from other ethnic backgrounds. Use of telephone follow-up to collect primary outcome data in those who failed to return full questionnaires resulted in missing data for some of the secondary outcomes. While all patients were recruited prior to the COVID-19 pandemic, the number of women who required further surgery may be underestimated, given the negative impact of COVID-19 on waiting lists for elective surgery throughout the UK. It is possible that this may have led to an increase in the use of GnRHa treatment by women who were unable to access surgery for their symptoms. Conclusions At 36 months, women allocated to LARCs or COCP had comparable levels of pain, with both groups showing around 40% improvement from presurgical levels. Although COCP is likely to be considered more cost-effective at a threshold of £20,000 per QALY, the difference between the two is marginal. LARCs may be preferred by some women as they are associated with lower rates of surgery, particular hysterectomy and operations for recurrence of endometriosis. Future work Future research needs to focus on evaluating newer hormonal preparations, a more holistic approach to symptom suppression and identification of biomarkers to diagnose endometriosis and its recurrence. Active measures need to be adopted to improve the inclusivity of clinical research and ensure that the ethnic mix within participants mirror that of the general population. Trial registration This trial is registered as ISRCTN97865475. https://doi.org/10.1186/ISRCTN97865475. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/114/01) and is published in full in Health Technology Assessment; Vol. 28, No. 55. See the NIHR Funding and Awards website for further award information.

INTRODUCTION:Surface electromyography (sEMG) is the measurement of the electrical activity of the skeletal muscle tissue detected at the skin's surface. Typically, a bipolar electrode configuration is used. Most muscles have pennate and/or curved fibres, meaning it is not always feasible to align the bipolar electrodes along the fibres direction. Hence, there is a need to explore how different electrode designs can affect sEMG measurements. METHOD:A three layer finite element (skin, fat, muscle) muscle model was used to explore different electrode designs. The implemented model used as source signal an experimentally recorded intramuscular EMG taken from the biceps brachii muscle of one healthy male. A wavelet based intensity analysis of the simulated sEMG signal was performed to analyze the power of the signal in the time and frequency domain. RESULTS:The model showed muscle tissue causing a bandwidth reduction (to 20-92- Hz). The inter-electrode distance (IED) and the electrode orientation relative to the fibres affected the total power but not the frequency filtering response. The effect of significant misalignment between the electrodes and the fibres (60°-90°) could be reduced by increasing the IED (25-30 mm), which attenuates signal cancellation. When modelling pennated fibres, the muscle tissue started to act as a low pass filter. The effect of different IED seems to be enhanced in the pennated model, while the filtering response is changed considerably only when the electrodes are close to the signal termination within the model. For pennation angle greater than 20°, more than 50% of the source signal was attenuated, which can be compensated by increasing the IED to 25 mm. CONCLUSION:Differences in tissue filtering properties, shown in our model, indicates that different electrode designs should be considered for muscle with different geometric properties (i.e. pennated muscles).

BACKGROUND: Mutations at positions 2142 or 2143 in the two-copy 23S ribosomal RNA gene of Helicobacter pylori are highly predictive of in vitro clarithromycin resistance and failure of clarithromycin-containing treatment regimens.

ABSTRACT: This study examined the influence of feeding frequency on the morphology of the reproductive tract in broiler breeder hens, with a focus on the liver, ovary, and oviduct. A total of 364 hens and 52 roosters, starting at 31 wk of age and continuing until the end of their 38th week, were divided into 13 groups with varying feeding frequencies (1, 2, or 3 times daily). Significant changes in reproductive and metabolic parameters were observed, where feeding hens twice or thrice daily resulted in significantly reduced ovary weight and follicle counts (P < 0.001), while liver weight increased (P < 0.05). These findings suggesting complex interactions between feeding practices and reproductive efficiency.

Abstract Background Effective stakeholder engagement in health research is increasingly being recognised and promoted as an important pathway to closing the gap between knowledge production and its use in health systems. However, little is known about its process and impacts, particularly in low-and middle-income countries. This opinion piece draws on the stakeholder engagement experiences from a global health research programme on Chronic Obstructive Pulmonary Disease (COPD) led by clinician researchers in Brazil, China, Georgia and North Macedonia, and presents the process, outcomes and lessons learned. Main body Each country team was supported with an overarching engagement protocol and mentored to develop a tailored plan. Patient involvement in research was previously limited in all countries, requiring intensive efforts through personal communication, meetings, advisory groups and social media. Accredited training programmes were effective incentives for participation from healthcare providers; and aligning research findings with competing policy priorities enabled interest and dialogue with decision-makers. The COVID-19 pandemic severely limited possibilities for planned engagement, although remote methods were used where possible. Planned and persistent engagement contributed to shared knowledge and commitment to change, including raised patient and public awareness about COPD, improved skills and practice of healthcare providers, increased interest and support from clinical leaders, and dialogue for integrating COPD services into national policy and practice. Conclusion Stakeholder engagement enabled relevant local actors to produce and utilise knowledge for small wins such as improving day-to-day practice and for long-term goals of equitable access to COPD care. For it to be successful and sustained, stakeholder engagement needs to be valued and integrated throughout the research and knowledge generation process, complete with dedicated resources, contextualised and flexible planning, and commitment.

Coastal environments are complex systems that are influenced by a combination of natural processes and human activities. Scientific interest in the effects of coastal erosion/accretion and climatic change-related processes has greatly increased in recent decades due to the growing human development along coastal areas. This paper investigates the state and evolution of beach–dune systems for the 1977–2001 and 2001–2019 periods of the Mediterranean coast of Andalusia (Spain) using two different proxies: the dune toe line, which was used to track foredunes evolution, and the high-water line, which was used to assess shoreline evolution. Results showed a general erosional behavior of the studied beach–dune systems and identified cases where the main trend was altered through human interventions. During the 1977–2001 period, foredunes essentially showed erosion (54%), accretion (24%), and stability (22%) and shorelines showed accretion (40%) and erosion and stability (34% each). During the 2001–2019 period, foredunes essentially showed erosion (42%), stability (30%), and accretion (28%), and shorelines showed erosion (40%), accretion (34%), and stability (26%). Combining the evolution classes of each proxy (dune toe/shoreline) allows the behavior of both shoreline proxies to be assessed together and provides insights additional to those derived from the use of a single proxy. In this regard, Erosion/erosion (EE) and Accretion/accretion (AA) were the most frequent behaviors in the first and second periods. The results obtained provide additional insights on the nature and drivers of coastal change that aid local coastal managers and administrations in understanding erosion processes. The method can be applied to other areas around the world where a similar database is available.

Biological control uses naturally occurring antagonists such as bacteria or fungi for environmentally friendly control of plant pathogens. Bacillus spp. have been used for biocontrol of numerous plant and insect pests and are well-known to synthesize a variety of bioactive secondary metabolites. We hypothesized that bacteria isolated from agricultural soil would be effective antagonists of soilborne fungal pathogens. Here, we show that the Delaware soil isolate Bacillus velezensis strain S4 has in vitro activity against soilborne and foliar plant pathogenic fungi, including two with a large host range, and one oomycete. Further, this strain shows putative protease and cellulase activity, consistent with our prior finding that the genome of this organism is highly enriched in antifungal and antimicrobial biosynthetic gene clusters. We demonstrate that this bacterium causes changes to the fungal and oomycete hyphae at the inhibition zone, with some of the hyphae forming bubble-like structures and irregular branching. We tested strain S4 against Magnaporthe oryzae spores, which typically form germ tubes and penetration structures called appressoria, on the surface of the leaf. Our results suggest that after 12 hours of incubation with the bacterium, fungal spores form germ tubes, but instead of producing appressoria, they appear to form rounded, bubble-like structures. Future work will investigate whether a single antifungal molecule induces all these effects, or if they are the result of a combination of bacterially produced antimicrobials.

Abstract Introduction In 2019, smoking prevalence in North Macedonia was one of the world’s highest at around 46% in adults. However, access to smoking cessation treatment is limited and no co-ordinated smoking cessation programmes are provided in primary care. Methods We conducted a three parallel-armed randomised controlled trial (n = 1368) to investigate effectiveness and cost-effectiveness of lung age (LA) or exhaled carbon monoxide (CO) feedback combined with very brief advice (VBA) to prompt smoking cessation compared with VBA alone, delivered by GPs in primary care in North Macedonia. All participants who decided to attempt to quit smoking were advised about accessing smoking cessation medications and were also offered behavioural support as part of the “ACT” component of VBA. Participants were aged ≥ 35 years, smoked ≥ 10 cigarettes per day, were recruited from 31 GP practices regardless of motivation to quit and were randomised (1:1:1) using a sequence generated before the start of recruitment. The primary outcome was biochemically validated 7-day point prevalence abstinence at 4 weeks (wks). Participants and GPs were not blinded to allocation after randomisation, however outcome assessors were blind to treatment allocation. Results There was no evidence of a difference in biochemically confirmed quitting between intervention and control at 4wks (VBA + LA RR 0.90 (97.5%CI: 0.35, 2.27); VBA + CO RR 1.04 (97.5%CI: 0.44, 2.44)), however the absolute number of quitters was small (VBA + LA 1.6%, VBA + CO 1.8%, VBA 1.8%). A similar lack of effect was observed at 12 and 26wks, apart from in the VBA + LA arm where the point estimate was significant but the confidence intervals were very wide. In both treatment arms, a larger proportion reported a reduction in cigarettes smoked per day at 4wks (VBA + LA 1.30 (1.10, 1.54); VBA + CO 1.23 (1.03, 1.49)) compared with VBA. The point estimates indicated a similar direction of effect at 12wks and 26wks, but differences were not statistically significant. Quantitative process measures indicated high fidelity to the intervention delivery protocols, but low uptake of behavioural and pharmacological support. VBA was the dominant intervention in the health economic analyses. Conclusion Overall, there was no evidence that adding LA or CO to VBA increased quit rates. However, a small effect cannot be ruled out as the proportion quitting was low and therefore estimates were imprecise. There was some evidence that participants in the intervention arms were more likely to reduce the amount smoked, at least in the short term. More research is needed to find effective ways to support quitting in settings like North Macedonia where a strong smoking culture persists. Trial registration The trial was registered at http://www.isrctn.com (ISRCTN54228638) on the 07/09/2018.

Abstract Background Endometriosis affects 190 million women and those assigned female at birth worldwide. For some, it is associated with debilitating chronic pelvic pain. Diagnosis of endometriosis is often achieved through diagnostic laparoscopy. However, when isolated superficial peritoneal endometriosis (SPE), the most common endometriosis subtype, is identified during laparoscopy, limited evidence exists to support the common decision to surgically remove it via excision or ablation. Improved understanding of the impact of surgical removal of isolated SPE for the management of chronic pelvic pain in women is required. Here, we describe our protocol for a multi-centre trial to determine the effectiveness of surgical removal of isolated SPE for the management of endometriosis-associated pain. Methods We plan to undertake a multi-centre participant-blind parallel-group randomised controlled clinical and cost-effectiveness trial with internal pilot. We plan to randomise 400 participants from up to 70 National Health Service Hospitals in the UK. Participants with chronic pelvic pain awaiting diagnostic laparoscopy for suspected endometriosis will be consented by the clinical research team. If isolated SPE is identified at laparoscopy, and deep or ovarian endometriosis is not seen, participants will be randomised intraoperatively (1:1) to surgical removal (by excision or ablation or both, according to surgeons’ preference) versus diagnostic laparoscopy alone. Randomisation with block-stratification will be used. Participants will be given a diagnosis but will not be informed of the procedure they received until 12 months post-randomisation, unless required. Post-operative medical treatment will be according to participants’ preference. Participants will be asked to complete validated pain and quality of life questionnaires at 3, 6 and 12 months after randomisation. Our primary outcome is the pain domain of the Endometriosis Health Profile-30 (EHP-30), via a between randomised group comparison of adjusted means at 12 months. Assuming a standard deviation of 22 points around the pain score, 90% power, 5% significance and 20% missing data, 400 participants are required to be randomised to detect an 8-point pain score difference. Discussion This trial aims to provide high quality evidence of the clinical and cost-effectiveness of surgical removal of isolated SPE. Trial registration ISRCTN registry ISRCTN27244948. Registered 6 April 2021.

Abstract Fundamental knowledge gaps exist about the plasticity of cells from adult soma and the potential diversity of body shape and behavior in living constructs derived from genetically wild‐type cells. Here anthrobots are introduced, a spheroid‐shaped multicellular biological robot (biobot) platform with diameters ranging from 30 to 500 microns and cilia‐powered locomotive abilities. Each Anthrobot begins as a single cell, derived from the adult human lung, and self‐constructs into a multicellular motile biobot after being cultured in extra cellular matrix for 2 weeks and transferred into a minimally viscous habitat. Anthrobots exhibit diverse behaviors with motility patterns ranging from tight loops to straight lines and speeds ranging from 5–50 microns s−1. The anatomical investigations reveal that this behavioral diversity is significantly correlated with their morphological diversity. Anthrobots can assume morphologies with fully polarized or wholly ciliated bodies and spherical or ellipsoidal shapes, each related to a distinct movement type. Anthrobots are found to be capable of traversing, and inducing rapid repair of scratches in, cultured human neural cell sheets in vitro. By controlling microenvironmental cues in bulk, novel structures, with new and unexpected behavior and biomedically‐relevant capabilities, can be discovered in morphogenetic processes without direct genetic editing or manual sculpting.

Abstract Flow direction modeling consists of (a) an accurate representation of the river network and (b) digital elevation model (DEM) processing to preserve characteristics with hydrological significance. In part 1 of our study, we presented a mesh‐independent approach to representing river networks on different types of meshes. This follow‐up part 2 study presents a novel DEM processing approach for flow direction modeling. This approach consists of (a) a topological relationship‐based hybrid breaching‐filling method to conduct stream burning for the river network and (b) a modified depression removal method for rivers and hillslopes. Our methods reduce modifications to surface elevations and provide a robust two‐step procedure to remove local depressions in DEM. They are mesh‐independent and can be applied to both structured and unstructured meshes. We applied our new methods with different model configurations to the Susquehanna River Basin. The results show that topological relationship‐based stream burning and depression‐filling methods can reproduce the correct river networks, providing high‐quality flow direction and other characteristics for hydrologic and Earth system models.

Summary: Background: In patients with idiopathic inflammatory myopathies (IIM), autoantibodies are associated with specific clinical phenotypes suggesting a pathogenic role of adaptive immunity. We explored if autoantibody profiles are associated with specific HLA genetic variants and clinical manifestations in IIM. Methods: We included 1348 IIM patients and determined the occurrence of 14 myositis-specific or –associated autoantibodies. We used unsupervised cluster analysis to identify autoantibody-defined subgroups and logistic regression to estimate associations with clinical manifestations, HLA-DRB1, HLA-DQA1, HLA-DQB1 alleles, and amino acids imputed from genetic information of HLA class II and I molecules. Findings: We identified eight subgroups with the following dominant autoantibodies: anti-Ro52, -U1RNP, -PM/Scl, -Mi2, -Jo1, -Jo1/Ro52, -TIF1γ or negative for all analysed autoantibodies. Associations with HLA-DRB1∗11, HLA-DRB1∗15, HLA-DQA1∗03, and HLA-DQB1∗03 were present in the anti-U1RNP-dominated subgroup. HLA-DRB1∗03, HLA-DQA1∗05, and HLA-DQB1∗02 alleles were overrepresented in the anti-PM/Scl and anti-Jo1/Ro52-dominated subgroups. HLA-DRB1∗16, HLA-DRB1∗07 alleles were most frequent in anti-Mi2 and HLA-DRB1∗01 and HLA-DRB1∗07 alleles in the anti-TIF1γ subgroup. The HLA-DRB1∗13, HLA-DQA1∗01 and HLA-DQB1∗06 alleles were overrepresented in the negative subgroup. Significant signals from variations in class I molecules were detected in the subgroups dominated by anti-Mi2, anti-Jo1/Ro52, anti-TIF1γ, and the negative subgroup. Interpretation: Distinct HLA class II and I associations were observed for almost all autoantibody-defined subgroups. The associations support autoantibody profiles use for classifying IIM which would likely reflect underlying pathogenic mechanisms better than classifications based on clinical symptoms and/or histopathological features. Funding: See a detailed list of funding bodies in the Acknowledgements section at the end of the manuscript.

The production of meltwater from glacier ice, which is exposed at the margins of land ice during the summer, is responsible for a large proportion of glacier mass loss. The rate of meltwater production from glacier ice is especially sensitive to its physical structure and chemical composition which combine to determine the albedo of glacier ice. However, the optical properties of near-surface glacier ice are not well known since most prior work has focused on laboratory-grown ice or deep cores. Here, we demonstrate a measurement technique based on diffuse propagation of nanosecond-duration laser pulses in near-surface glacier ice that enables the independent measurement of the scattering and absorption coefficients, allowing for a complete description of the processes governing radiative transfer. We employ a photon-counting detector to overcome the high losses associated with diffuse optics. The instrument is highly portable and rugged, making it optimally suited for deployment in remote regions. A set of measurements taken on Crook and Collier Glaciers, Oregon, serves as a demonstration of the technique. These measurements provide insight into both physical structure and composition of near-surface glacier ice and open new avenues for the analysis of light-absorbing impurities and remote sensing of the cryosphere.

Abstract In Brazil, prevalence of diagnosed COPD among adults aged 40 years and over is 16% although over 70% of cases remain undiagnosed. Hypertension is common and well-recorded in primary care, and frequently co-exists with COPD because of common causes such as tobacco smoking, therefore we conducted a cross-sectional screening test accuracy study in nine Basic Health Units in Brazil, among hypertensive patients aged ≥40 years to identify the optimum screening test/combinations to detect undiagnosed COPD. We compared six index tests (four screening questionnaires, microspirometer and peak flow) against the reference test defined as those below the lower limit of normal (LLN-GLI) on quality diagnostic spirometry, with confirmed COPD at clinical review. Of 1162 participants, 6.8% (n = 79) had clinically confirmed COPD. Peak flow had a higher specificity but lower sensitivity than microspirometry (sensitivity 44.3% [95% CI 33.1, 55.9], specificity 95.5% [95% CI 94.1, 96.6]). SBQ performed well compared to the other questionnaires (sensitivity 75.9% [95% CI 65.0, 84.9], specificity 59.2% [95% CI 56.2, 62.1]). A strategy requiring both SBQ and peak flow to be positive yielded sensitivity of 39.2% (95% CI 28.4, 50.9) and specificity of 97.0% (95% CI 95.7, 97.9). The use of simple screening tests was feasible within the Brazilian primary care setting. The combination of SBQ and peak flow appeared most efficient, when considering performance of the test, cost and ease of use (costing £1690 (5554 R$) with 26.7 cases detected per 1,000 patients). However, the choice of screening tests depends on the clinical setting and availability of resources. ISRCTN registration number: 11377960.

Abstract COPD is increasingly common in China but is poorly understood by patients, medications are not used as prescribed and there is no access to recommended non-pharmacological treatment. We explored COPD patients’ and general practitioners’ (GPs) knowledge of COPD, views on its management and the acceptability of a flexible lung health service (LHS) offering health education, exercise, self-management, smoking cessation and mental health support. Using a convergent mixed methods design, data were collected from patients and GPs using focus groups (FGs) in four Chinese cities, questionnaires were also used to collect data from patients. FGs were audio-recorded and transcribed. Quantitative data were analysed descriptively, thematic framework analysis was used for the qualitative data. Two-hundred fifty-one patients completed the questionnaire; 39 patients and 30 GPs participated in ten separate FGs. Three overarching themes were identified: patients’ lack of knowledge/understanding of COPD, current management of COPD not meeting patients’ needs and LHS design, which was well received by patients and GPs. Participants wanted COPD education, TaiChi, psychological support and WeChat for social support. 39% of survey responders did not know what to do when their breathing worsened and 24% did not know how to use their inhalers. 36% of survey respondents requested guided relaxation. Overall, participants did not fully understand the implications of COPD and current treatment was sub-optimal. There was support for developing a culturally appropriate intervention meeting Chinese patients’ needs, health beliefs, and local healthcare delivery. Further research should explore the feasibility of such a service.

Abstract River networks are important features in surface hydrology. However, accurately representing river networks in spatially distributed hydrologic and Earth system models is often sensitive to the model's spatial resolution. Specifically, river networks are often misrepresented because of the mismatch between the model's spatial resolution and river network details, resulting in significant uncertainty in the projected flow direction. In this study, we developed a topological relationship‐based river network representation method for spatially distributed hydrologic models. This novel method uses (a) graph theory algorithms to simplify real‐world vector‐based river networks and assist in mesh generation; and (b) a topological relationship‐based method to reconstruct conceptual river networks. The main advantages of our method are that (a) it combines the strengths of vector‐based and DEM raster‐based river network extraction methods; and (b) it is mesh‐independent and can be applied to both structured and unstructured meshes. This method paves a path for advanced terrain analysis and hydrologic modeling across different scales.

Anegada, the easternmost island of the Virgin Islands group (Caribbean Sea), is a low Pleistocene carbonate platform surrounded by Horseshoe Reef, the world’s third-largest fringing reef. The western part of the island consists of an extensive beachridge plain (>40 ridges). The sandy carbonate shoreline exists in three morphodynamic domains that exhibit distinctive behaviour over the 59-year study period (1953 to 2012). The northern shore is dominated by westerly longshore drift under fair-weather conditions and cross-shore sediment transport during high-energy events. Storm wave run-up and high nearshore sediment availability contribute to the construction of shore-parallel beachridges. The western end of the island is affected by refracted waves that drive strong erosion and sediment transport. This is reflected in a succession of alternating rapid shoreline recession and progradation phases over the study period. The south–central shoreline is exposed to low wave energy and is stable and colonised by mangroves. The fringing reef plays a dominant role in mesoscale shoreline morphodynamics, both as a sediment source and in wave energy dissipation. Quasi-stable points and embayments suggest a strong influence of the reef framework in controlling the shoreline’s morphology and position. Sediment transfer from the reef to the shoreline appears to take place via shore-oblique, linear sediment transport pathways that develop across the lagoon in response to the modification of incoming waves. Cannibalisation of the shoreline sediment over the past 50 years is leading to straightening of the shoreline planform. This is counter to the long-term (Holocene) development of beachridges and suggests a change from a strongly positive to negative sediment budget.

Abstract Introduction There is relatively little published on the effects of COVID-19 on respiratory physiology, particularly breathing patterns. We sought to determine if there were lasting detrimental effect following hospital discharge and if these related to the severity of COVID-19. Methods We reviewed lung function and breathing patterns in COVID-19 survivors > 3 months after discharge, comparing patients who had been admitted to the intensive therapy unit (ITU) (n = 47) to those who just received ward treatments (n = 45). Lung function included spirometry and gas transfer and breathing patterns were measured with structured light plethysmography. Continuous data were compared with an independent t-test or Mann Whitney-U test (depending on distribution) and nominal data were compared using a Fisher’s exact test (for 2 categories in 2 groups) or a chi-squared test (for > 2 categories in 2 groups). A p-value of

Supraglacial lakes and rivers dominate the storage and transport of meltwater on the southwest Greenland Ice Sheet (GrIS) surface. Despite functioning as interconnected hydrologic networks, supraglacial lakes and rivers are commonly studied as independent features, resulting in an incomplete understanding of their collective impact on meltwater storage and routing. We use Landsat 8 satellite imagery to assess the seasonal evolution of supraglacial lakes and rivers on the southwest GrIS during the 2015 melt season. Remotely sensed meltwater areas and volumes are compared with surface runoff simulations from three climate models (MERRA-2, MAR 3.6 and RACMO 2.3), and with in situ observations of proglacial discharge in the Watson River. We find: (1) at elevations >1600 m, 21% of supraglacial lakes and 28% of supraglacial rivers drain into moulins, signifying the presence of high-elevation surface-to-bed meltwater connections even during a colder-than-average melt season; (2) while supraglacial lakes dominate instantaneous surface meltwater storage, supraglacial rivers dominate total surface meltwater area and discharge; (3) the combined surface area of supraglacial lakes and rivers is strongly correlated with modeled surface runoff; and (4) of the three models examined here, MERRA-2 runoff yields the highest overall correlation with observed proglacial discharge in the Watson River.

Recent work has identified complex perennial supraglacial stream and river networks in areas of the Greenland Ice Sheet (GrIS) ablation zone. Current surface mass balance (SMB) models appear to overestimate meltwater runoff in these networks compared to in-channel measurements of supraglacial discharge. Here, we constrain SMB models using the hillslope river routing model (HRR), a spatially explicit flow routing model used in terrestrial hydrology, in a 63 km2 supraglacial river catchment in southwest Greenland. HRR conserves water mass and momentum and explicitly accounts for hillslope routing (i.e., flow over ice and/or firn on the GrIS), and we produce hourly flows for nearly 10 000 channels given inputs of an ice surface digital elevation model (DEM), a remotely sensed supraglacial channel network, SMB-modeled runoff, and an in situ discharge dataset used for calibration. Model calibration yields a Nash–Sutcliffe efficiency as high as 0.92 and physically realistic parameters. We confirm earlier assertions that SMB runoff exceeds the conserved mass of water measured in this catchment (by 12 %–59 %) and that large channels do not dewater overnight despite a diurnal shutdown of SMB runoff production. We further test hillslope routing and network density controls on channel discharge and conclude that explicitly including hillslope flow and routing runoff through a realistic fine-channel network (as opposed to excluding hillslope flow and using a coarse-channel network) produces the most accurate results. Modeling complex surface water processes is thus both possible and necessary to accurately simulate the timing and magnitude of supraglacial channel flows, and we highlight a need for additional in situ discharge datasets to better calibrate and apply this method elsewhere on the ice sheet.

Light transmission into bare glacial ice affects surface energy balance, biophotochemistry, and light detection and ranging (lidar) laser elevation measurements but has not previously been reported for the Greenland Ice Sheet. We present measurements of spectral transmittance at 350–900 nm in bare glacial ice collected at a field site in the western Greenland ablation zone (67.15∘ N, 50.02∘ W). Empirical irradiance attenuation coefficients at 350–750 nm are ∼ 0.9–8.0 m−1 for ice at 12–124 cm depth. The absorption minimum is at ∼ 390–397 nm, in agreement with snow transmission measurements in Antarctica and optical mapping of deep ice at the South Pole. From 350–530 nm, our empirical attenuation coefficients are nearly 1 order of magnitude larger than theoretical values for optically pure ice. The estimated absorption coefficient at 400 nm suggests the ice volume contained a light-absorbing particle concentration equivalent to ∼ 1–2 parts per billion (ppb) of black carbon, which is similar to pre-industrial values found in remote polar snow. The equivalent mineral dust concentration is ∼ 300–600 ppb, which is similar to values for Northern Hemisphere warm periods with low aeolian activity inferred from ice cores. For a layer of quasi-granular white ice (weathering crust) extending from the surface to ∼ 10 cm depth, attenuation coefficients are 1.5 to 4 times larger than for deeper bubbly ice. Owing to higher attenuation in this layer of near-surface granular ice, optical penetration depth at 532 nm is 14 cm (20 %) lower than asymptotic attenuation lengths for optically pure bubbly ice. In addition to the traditional concept of light scattering on air bubbles, our results imply that the granular near-surface ice microstructure of weathering crust is an important control on radiative transfer in bare ice on the Greenland Ice Sheet ablation zone, and we provide new values of flux attenuation, absorption, and scattering coefficients to support model development and validation.

Evidence for sea-level change during and around Marine Isotope Stage (MIS) 5e (ca. 125 ka) in southern Africa derives from a wide variety of geomorphic and sedimentological sea-level indicators, supported in the past 2 decades by absolute chronological control, particularly on littoral deposits, some of which have a quantifiable relationship to former sea level. In addition to these proxies, data provided by both terrestrial (dune sediments and archaeological remains) and marine (lagoonal and nearshore littoral sediments) limiting points provide broad constraints on sea level. Here, we review publications describing such data points. Using the framework of the World Atlas of Last Interglacial Shorelines, we insert in a standardized database (https://doi.org/10.5281/zenodo.4459297, Cooper and Green, 2020) all the elements available to assess former palaeo-relative sea level (palaeo-RSL) and the chronological constraints associated with them (including uncertainties). Overall, we reviewed 71 studies, from which we extracted 39 sea-level indicators and 26 limiting points. As far as age attribution is concerned, early analysis of molluscs and whole-rock beachrock samples using U series allowed dating of several sea-level indicators during the 1980s, but the more widespread application of optically stimulated luminescence (OSL) dating since 2004 has yielded many more (and more accurate) sea-level indicators from several sites. This has helped resolve the nature and timing of MIS 5e shorelines and has the potential to further elucidate the apparent presence of two or more sea-level peaks at several South African sites during this interval. The standardized sea-level database presented in this paper is the first of its kind for this region. Future research should be directed to improve the stratigraphic description of last interglacial shorelines and to obtain better dating, high-accuracy elevation measurements with better palaeo-RSL interpretation.

Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of liver damage directly related to diabetes, obesity, and metabolic syndrome. The (pro)renin receptor (PRR) has recently been demonstrated to play a role in glucose and lipid metabolism. Here, we test the hypothesis that the PRR regulates the development of diet-induced hepatic steatosis and fibrosis. C57Bl/6J mice were fed a high-fat diet (HFD) or normal-fat diet (NFD) with matching calories for 6 weeks. An 8-week methionine choline-deficient (MCD) diet was used to induce fibrosis. Two weeks following diet treatment, mice were implanted with a subcutaneous osmotic pump delivering either the peptide PRR antagonist, PRO20, or scrambled peptide for 4 or 6 weeks. Mice fed a 6-week HFD exhibited increased liver lipid accumulation and liver triglyceride content compared with NFD-fed mice. Importantly, PRO20 treatment reduced hepatic lipid accumulation in HFD-fed mice without affecting body weight or blood glucose. Furthermore, PRR antagonism attenuated HFD-induced steatosis, particularly microvesicular steatosis. In the MCD diet model, the percentage of collagen area was reduced in PRO20-treated compared with control mice. PRO20 treatment also significantly decreased levels of liver alanine aminotransferase, an indicator of liver damage, in MCD-fed mice compared with controls. Mechanistically, we found that PRR antagonism prevented HFD-induced increases in PPARγ and glycerol-3-phosphate acyltransferase 3 expression in the liver. Taken together, our findings establish the involvement of the PRR in liver triglyceride synthesis and suggest the therapeutic potential of PRR antagonism for the treatment of liver steatosis and fibrosis in NAFLD.

The propensity for Saccharomyces cerevisiae yeast to ferment sugars into ethanol and CO2 has long been useful in the production of a wide range of food and drink. In the production of alcoholic beverages, the yeast strain selected for fermentation is crucial because not all strains are equally proficient in tolerating fermentation stresses. One potential mechanism by which domesticated yeast may have adapted to fermentation stresses is through changes in the expression of stress response genes. MED15 is a general transcriptional regulator and RNA Pol II Mediator complex subunit which modulates the expression of many metabolic and stress response genes. In this study, we explore the role of MED15 in alcoholic fermentation. In addition, we ask whether MED15 alleles from wine, sake or palm wine yeast improve fermentation activity and grape juice fermentation stress responses. And last, we investigate to what extent any differences in activity are due to allelic differences in the lengths of three polyglutamine tracts in MED15. We find that strains lacking MED15 are deficient in fermentation and fermentation stress responses and that MED15 alleles from alcoholic beverage yeast strains can improve both the fermentation capacity and the response to ethanol stresses when transplanted into a standard laboratory strain. Finally, we find that polyglutamine tract length in the Med15 protein is one determinant in the efficiency of the alcoholic fermentation process. These data lead to a working model in which polyglutamine tract length and other types of variability within transcriptional hubs like the Mediator subunit, Med15, may contribute to a reservoir of transcriptional profiles that may provide a fitness benefit in the face of environmental fluctuations.

The brain renin-angiotensin system plays important roles in blood pressure and cardiovascular regulation. There are two isoforms of prorenin in the brain: the classic secreted form (prorenin/sREN) encoded by renin-a, and an intracellular form (icREN) encoded by renin-b. Emerging evidence indicates the importance of renin-b in cardiovascular and metabolic regulation. However, the role of endogenous brain prorenin in the development of salt-sensitive hypertension remains undefined. In this study, we test the hypothesis that renin-a produced locally in the brain contributes to the pathogenesis of hypertension. Using RNAscope, we report for the first time that renin mRNA is expressed in several regions of the brain, including the subfornical organ (SFO), the paraventricular nucleus of the hypothalamus (PVN), and the brainstem, where it is found in glutamatergic, GABAergic, cholinergic, and tyrosine hydroxylase-positive neurons. Notably, we found that renin mRNA was significantly elevated in the SFO and PVN in a mouse model of DOCA-salt–induced hypertension. To examine the functional importance of renin-a in the SFO, we selectively ablated renin-a in the SFO in renin-a–floxed mice using a Cre-lox strategy. Importantly, renin-a ablation in the SFO attenuated the maintenance of DOCA-salt–induced hypertension and improved autonomic function without affecting fluid or sodium intake. Molecularly, ablation of renin-a prevented the DOCA-salt–induced elevation in NADPH oxidase 2 (NOX2) in the SFO without affecting NOX4 or angiotensin II type 1 and 2 receptors. Collectively, our findings demonstrate that endogenous renin-a within the SFO is important for the pathogenesis of salt-sensitive hypertension.

Tidal breathing measurements can be used to identify changes in respiratory status. Structured light plethysmography (SLP) is a non-contact tidal breathing measurement technique. Lack of reference equations for SLP parameters makes clinical decision-making difficult. We have developed a set of growth-adjusted reference equations for seven clinically pertinent parameters of respiratory rate (fR), inspiratory time (tI), expiratory time (tE), duty cycle (tI/total breath time), phase (thoraco-abdominal asynchrony (TAA)), relative thoracic contribution (RTC) and tidal inspiratory/expiratory flow at 50% volume (IE50). Reference equations were developed based on a cohort of 198 seated healthy subjects (age 2–75 years, height 82–194 cm, 108 males). We adopted the same methodological approach as the Global Lung Function Initiative (GLI) report on spirometric reference equations. 5 min of tidal breathing was recorded per subject. Parameters were summarised with their medians. The supplementary material provided is an integral part of this work and a reference range calculator is provided therein. We found predicted fR to decrease with age and height rapidly in the first 20 years and slowly thereafter. Expected tI, tE and RTC followed the opposite trend. RTC was 6.7% higher in females. Duty cycle increased with age, peaked at 13 years and decreased thereafter. TAA was high and variable in early life and declined rapidly with age. Predicted IE50 was constant, as it did not correlate with growth. These reference ranges for seven key measures ensure that clinicians and researchers can identify tidal breathing patterns in disease and better understand and interpret SLP and tidal breathing data.

Abstract Chlorisondamine (CSD) has been used to assess the neurogenic contribution to blood pressure (BP) and vasomotor sympathetic tone in animal models. It is assumed that the reduction in BP following CSD administration is associated to decreases in cardiac output (CO) and peripheral resistance, reflecting cardiac and vasomotor sympathetic tone, respectively. Surprisingly, this has not been characterized experimentally in mice, despite the extensive use of this animal model in cardiovascular research. We hypothesize that a specific dose of CSD can selectively block the sympathetic vasomotor tone. To test this hypothesis, we evaluated the effects of different doses of CSD (intraperitoneal) on BP and heart rate (HR) using telemetry, and on CO using echocardiography. BP and HR in normotensive C57Bl/6J mice reduced to a similar extent by all CSD doses tested (1–6 mg/kg). CSD at 6 mg/kg also reduced CO without affecting left ventricular stroke volume or fractional shortening. On the other hand, lower doses of CSD (1 and 2 mg/kg) produced significantly larger BP and HR reductions in DOCA‐salt–induced hypertensive mice, indicating a greater neurogenic BP response. In addition, all doses of CSD reduced CO in hypertensive mice. Our data suggest that the BP response to CSD in mice likely reflects reduced CO and vasomotor sympathetic tone. We conclude that CSD can be used to assess the neurogenic contribution to BP in mice but may not be appropriate for specifically estimating vasomotor sympathetic tone.

Gliosis and fibrosis after spinal cord injury (SCI) lead to formation of a scar that is an impediment to axonal regeneration. Fibrotic scarring is characterized by the accumulation of fibronectin, collagen, and fibroblasts at the lesion site. The mechanisms regulating fibrotic scarring after SCI and its effects on axonal elongation and functional recovery are not well understood. In this study, we examined the effects of eliminating an isoform of fibronectin containing the Extra Domain A domain (FnEDA) on both fibrosis and on functional recovery after contusion SCI using male and female FnEDA-null mice. Eliminating FnEDA did not reduce the acute fibrotic response but markedly diminished chronic fibrotic scarring after SCI. Glial scarring was unchanged after SCI in FnEDA-null mice. We found that FnEDA was important for the long-term stability of the assembled fibronectin matrix during both the subacute and chronic phases of SCI. Motor functional recovery was significantly improved, and there were increased numbers of axons in the lesion site compared to wildtype mice, suggesting that the chronic fibrotic response is detrimental to recovery. Our data provide insight into the mechanisms of fibrosis after SCI and suggest that disruption of fibronectin matrix stability by targeting FnEDA represents a potential therapeutic strategy for promoting recovery after SCI.