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Abstract Background The relationship between epigenomics and plant specialised metabolism remains largely unexplored despite the fundamental importance of epigenomics in gene regulation and, potentially, yield of products of plant specialised metabolic pathways. The glandular trichomes of Cannabis sativa are an emerging model system that produce large quantities of cannabinoid and terpenoid specialised metabolites with known medicinal and commercial value. To address this lack of epigenomic data, we mapped H3K4 trimethylation, H3K56 acetylation, H3K27 trimethylation post-translational modifications and the histone variant H2A.Z, using chromatin immunoprecipitation, in C. sativa glandular trichomes, leaf, and stem tissues. Corresponding transcriptomic (RNA-seq) datasets were integrated, and tissue-specific analyses conducted to relate chromatin states to glandular trichome specific gene expression. Results The promoters of cannabinoid and terpenoid biosynthetic genes, specialised metabolite transporter genes, defence related genes, and starch and sucrose metabolism were enriched specifically in trichomes for histone marks H3K4me3 and H3K56ac, consistent with active transcription. We identified putative trichome-specific enhancer elements by identifying intergenic regions of H3K56ac enrichment, a histone mark that maintains enhancer accessibility, then associated these to putative target genes using the tissue specific gene transcriptomic data. Bi-valent chromatin loci specific to glandular trichomes, marked with H3K4 trimethylation and H3K27 trimethylation, were associated with genes of MAPK signalling pathways and plant specialised metabolism pathways, supporting recent hypotheses that implicate bi-valent chromatin in plant defence. The histone variant H2A.Z was largely found in intergenic regions and enriched in chromatin that contained genes involved in DNA homeostasis. Conclusion We report the first genome-wide histone post-translational modification maps for C. sativa glandular trichomes, and more broadly for glandular trichomes in plants. Our findings have implications in plant adaptation and stress responses and provide a basis for enhancer-mediated, targeted, gene transformation studies in plant glandular trichomes.

Abstract Introduction The goal of this economic model is to estimate an economically justifiable price (EJP) for using donanemab for the treatment of early symptomatic Alzheimer’s disease (AD) in the United States based on clinical data from the phase 3 TRAILBLAZER-ALZ 2 trial (NCT04437511). Methods We adapted an AD Markov state-transition model developed by the Institute for Clinical and Economic Review to estimate the EJP for donanemab at different willingness-to-pay (WTP) thresholds from the health care system perspective and the societal perspective as co-base cases. Results Assuming a WTP threshold of $150,000 per quality-adjusted life-year (QALY) gained, the model estimates a 1-year (13-dose) EJP for donanemab of $80,538 from the health care system perspective and $91,126 from the societal perspective; at a WTP threshold of $100,000 per QALY gained, the model estimates a 1-year (13-dose) EJP for donanemab of $44,691 from the health care system perspective and $55,419 from the societal perspective. Mean total treatment costs per patient at the $150,000 per QALY gained EJP derived from the health care system perspective were estimated at $77,812 based on the average number of doses of donanemab patients received in the co-base case analysis. One-way sensitivity analysis (OWSA) indicated that treatment efficacy, disease severity at the time of treatment initiation, and duration of treatment effect were the main drivers of the potential EJP. Conclusions Results from this modeling simulation informed by the TRAILBLAZER-ALZ 2 study support an EJP for limited-duration treatment with donanemab that exceeds per-dose list prices for currently available amyloid-targeting therapies, implying potentially lower lifetime costs and better value for money.

Abstract The extended period of coexistence between Neanderthals and Homo sapiens in Europe coincided with the emergence of regionally distinctive lithic industries, signalling the onset of the Upper Palaeolithic. The Iberian Peninsula was on the periphery of pioneering Upper Palaeolithic developments, with archaeological remains primarily found in northern territories. We report the discovery of an initial Upper Palaeolithic lithic industry at Cueva Millán in the hinterlands of Iberia. This industry, termed here Arlanzian, not only represents the earliest and southernmost evidence of such industries in Iberia but also lacks a direct counterpart. However, it exhibits chronological and technological parallels with the lithic industries associated with the earliest expansion of Homo sapiens throughout Eurasia. We interpret this as potential evidence of its intrusive nature, but not necessarily associated with a migration event, as more complex scenarios derived from inter-population connectivity must be also considered. The biological identity of the Arlanzian makers remains unknown, but they coexisted with declining Neanderthal groups from neighbouring territories.

Multistage hydraulic fracturing of horizontal wells (MFHW) is a promising technology for controlling coal burst caused by thick and hard roofs in China. However, challenges remain regarding the MFHW control mechanism of coal burst and assessment of the associated fracturing effects. In this study, these challenges were investigated through numerical modelling and field applications, based on the actual operating parameters of MFHW for hard roofs in a Chinese coal mine. A damage parameter (D) is proposed to assess the degree of hydraulic fracturing in the roof. The mechanisms and effects of MFHW for controlling coal burst are analyzed using microseismic (MS) data and front-abutment stress distribution. Results show that the degree of fracturing can be categorized into lightly-fractured (D≤0.3), moderately fractured (0.3

Ji Eun Song,1 Eunjeong Ji,2 Nak-Hyun Kim,1,3 Jung Hun Ohn,1,3 Yejee Lim,1,3 Jongchan Lee,1,3 Hye Won Kim,1,3 Sun-Wook Kim,1,3 Jiwon Ryu,1,3 Hee-Sun Park,1,3 Eun Sun Kim1,3 1Hospital Medicine Center, Seoul National University Bundang Hospital, Seongnam, Republic of Korea; 2Medical Research Collaborating Center, Seoul National University Bundang Hospital, Seongnam, Republic of Korea; 3Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of KoreaCorrespondence: Eun Sun Kim, Department of Internal Medicine, Seoul National University Bundang Hospital, 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea, Email apolio3700@gmail.comPurpose: Older patients have a higher risk of aspiration pneumonia and mortality if they are hospitalized. We aimed to assess the effectiveness of an aspiration prevention quality improvement (QI) program that utilizes the Gugging Swallowing Screen (GUSS) in older patients.Patients and Methods: This retrospective cohort study was conducted in an acute medical care unit of a tertiary hospital in South Korea. The study used one-to-one propensity matching and included 96 patients who received the QI program and 96 who did not. All patients were aged 65 years or older and had risk factors for aspiration, including neurological and non-neurological disorders, neuromuscular disorders, impaired airway defenses, and dysphagia due to esophageal or gastrointestinal disorders. The primary outcomes included the duration of the fasting period during hospitalization, changes in nutritional status before admission and at discharge, in-hospital mortality, and readmission due to pneumonia within 90 days.Results: Fasting period, changes in weight and albumin levels upon discharge after hospitalization, and length of stay did not differ significantly between patients in the GUSS and non-GUSS groups. However, the risk of readmission within 90 days was significantly lower in patients who underwent the GUSS than in those who did not (hazard ratio, 0.085; 95% confidence interval, 0.025– 0.290; p = 0.001).Conclusion: The GUSS aspiration prevention program effectively prevented readmission due to pneumonia within 90 days in older patients with acute illnesses. This implies that the adoption of efficient aspiration prevention methods in older patients with acute illnesses could play a pivotal role by enhancing patient outcomes and potentially mitigating the healthcare costs linked to readmissions.Keywords: aspiration pneumonia, older patients, gugging swallowing screen, prevention, quality improvement

Abstract Background Recruitment for clinical trials and large-scale studies is challenging, especially for patients with complex conditions like chronic pain. Email recruitment has the potential to increase efficiency, to reduce costs, and to improve access for underrepresented patient populations. The objective of this study was to examine the effectiveness, efficiency, and equitability of email versus postal mail recruitment for the Learning to Apply Mindfulness to Pain (LAMP) study, a three-site clinical trial of mindfulness-based interventions for chronic pain. Methods Patients with chronic pain diagnoses were recruited from three United States Department of Veterans Affairs (VA) facilities using the VA electronic health record (EHR). Recruitment materials were sent using either postal mail (n = 7986) or email (n = 19,333). Patients in the email recruitment group were also mailed introductory postcards before any emails. Mailing addresses and email addresses were obtained from the EHR. Effectiveness was measured by the response rate of patients who logged into the secure LAMP study website. Efficiency was measured by the number of days from when the recruitment materials were sent to when patients logged into the LAMP portal as well as the estimated costs of each recruitment approach. To assess equitability, we examined whether email recruitment was less effective for underrepresented populations, based on demographic information from the EHR. Results Effectiveness—unadjusted response rates were greater for email versus postal-mail recruitment (18.9% versus 6.3%), and adjusted response rates were over three times greater for email recruitment (RR = 3.5, 95% CI 3.1–3.8) based on a multivariable analysis controlling for age, gender, race, ethnicity, rurality, and site. Efficiency—email recruitment had a significantly lower mean response time (1 day versus 8 days) and a lower cost. Equity—email recruitment led to higher response rates for all subpopulations, including older, non-White, Hispanic, rural, and female Veterans. Conclusions Email recruitment is an effective, efficient, and equitable way to recruit VA patients to large-scale, chronic pain clinical trials. Trial registration Clinical Trial Registration Number: NCT04526158. Patient enrollment began on December 4, 2020.

3-Phenyl-2-(thiophen-3-yl)-2,3-dihydro-4H-pyrido[3,2-e][1,3]thiazin-4-one (C17H12N2OS2, 1) and 2-(1H-indol-3-yl)-3-phenyl-2,3-dihydro-4H-pyrido[3,2-e][1,3]thiazin-4-one 0.438-hydrate (C21H15N3OS·0.438H2O, 2) crystallize in space groups P21/n and C2/c, respectively. The asymmetric unit in each case is comprised of two parent molecules, albeit of mixed chirality in the case of 1 and of similar chirality in 2 with the enantiomers occupying the neighboring asymmetric units. Structure 2 also has water molecules (partial occupancies) that form continuous channels along the b-axis direction. The thiazine rings in both structures exhibit an envelope conformation. Intermolecular interactions in 1 are defined only by C—H...O and C—H...N hydrogen bonds between crystallographically independent molecules. In 2, hydrogen bonds of the type N—H...O between independent molecules and C—H...N(π) type, and π–π stacking interactions between the pyridine rings of symmetry-related molecules are observed.

Background: Reconstruction of the proximal tibia following resection of malignant bone tumors in pediatric patients is traditionally limited to osteoarticular allografts or endoprostheses. Endoprostheses typically require resection or disruption of the distal femoral physis, which can lead to a leg length discrepancy (LLD). We introduce a novel form of proximal tibia limb reconstruction using a Compress® tibia hemiarthroplasty, which spares the distal femoral physis. Methods: We retrospectively reviewed 5 patients who underwent proximal tibia osteosarcoma resection and reconstruction with a custom Compress® proximal tibia hemiarthroplasty. Data on function, survival, LLD, complications, and patient-reported outcomes were collected. Results: Mean age at resection was 10.4 years [range: 8.8-12.9 years]. Mean implant survival was 59 months [range: 34-83 months]. One patient developed a deep infection, and two patients required implant lengthening. Both were later converted to a rotating hinged total knee arthroplasty (RHTKA) ​> ​58 months after index surgery. At the last follow-up, all living patients had knee range of motion from 0 to 110°, walked unassisted, and had no LLD or knee instability. Mean Toronto Extremity Salvage Score was 90 [range: 80-97]. Conclusions: Proximal tibia hemiarthroplasty reconstruction after tumor resection in skeletally immature patients preserves the distal femoral physis and may potentially reduce LLD and delay conversion to an RHTKA until after skeletal maturity. Key Concepts: (1) Osteosarcoma is the most common primary malignant bone tumor in children, arising most frequently around the knee. (2) Complete resection often requires excising the adjacent growth plate, creating a challenge for reconstruction in growing children to maintain function and avoid significant limb length inequality. (3) The custom expandable tibia hemiarthroplasty is a novel reconstruction option for skeletally immature patients requiring resection of the proximal tibia. (4) Although future research is needed, results of this study suggest that tibia hemiarthroplasty is a reasonable reconstruction option in growing children requiring oncologic resection of a primary bone tumor from the proximal tibia. Level of Evidence: Case series, Level IV

BackgroundShort sleep and obstructive sleep apnea are underrecognized strains on the public health infrastructure. In the United States, over 35% of adults report short sleep and more than 80% of individuals with obstructive sleep apnea remain undiagnosed. The associations between inadequate sleep and cardiometabolic disease risk factors have garnered increased attention. However, challenges persist in modeling sleep-associated cardiometabolic disease risk factors. ObjectiveThis study aimed to report early findings from the Short Sleep Undermines Cardiometabolic Health-Public Health Observational study (SLUMBRx-PONS). MethodsData for the SLUMBRx-PONS study were collected cross-sectionally and longitudinally from a nonclinical, rural community sample (n=47) in the southeast United States. Measures included 7 consecutive nights of wrist-based actigraphy (eg, mean of 7 consecutive nights of total sleep time [TST7N]), 1 night of sleep apnea home testing (eg, apnea-hypopnea index [AHI]), and a cross-sectional clinical sample of anthropometric (eg, BMI), cardiovascular (eg, blood pressure), and blood-based biomarkers (eg, triglycerides and glucose). Correlational analyses and regression models assessed the relationships between the cardiometabolic disease risk factors and the sleep indices (eg, TST7N and AHI). Linear regression models were constructed to examine associations between significant cardiometabolic indices of TST7N (model 1) and AHI (model 2). ResultsCorrelational assessment in model 1 identified significant associations between TST7N and AHI (r=–0.45, P=.004), BMI (r=–0.38, P=.02), systolic blood pressure (r=0.40, P=.01), and diastolic blood pressure (r=0.32, P=.049). Pertaining to model 1, composite measures of AHI, BMI, systolic blood pressure, and diastolic blood pressure accounted for 25.1% of the variance in TST7N (R2adjusted=0.25; F2,38=7.37; P=.002). Correlational analyses in model 2 revealed significant relationships between AHI and TST7N (r=–0.45, P

Hypoxic-ischemic encephalopathy (HIE) in neonates causes mortality and neurologic morbidity, including poor cognition with a complex neuropathology. Injury to the cholinergic basal forebrain and its rich innervation of cerebral cortex may also drive cognitive pathology. It is uncertain whether genes associated with adult cognition-related neurodegeneration worsen outcomes after neonatal HIE. We hypothesized that neocortical damage caused by neonatal HI in mice is ushered by persistent cholinergic innervation and interneuron (IN) pathology that correlates with cognitive outcome and is exacerbated by genes linked to Alzheimer's disease. We subjected non-transgenic (nTg) C57Bl6 mice and mice transgenically (Tg) expressing human mutant amyloid precursor protein (APP-Swedish variant) and mutant presenilin (PS1-ΔE9) to the Rice-Vannucci HI model on postnatal day 10 (P10). nTg and Tg mice with sham procedure were controls. Visual discrimination (VD) was tested for cognition. Cortical and hippocampal cholinergic axonal and IN pathology and Aβ plaques, identified by immunohistochemistry for choline acetyltransferase (ChAT) and 6E10 antibody respectively, were counted at P210. Simple ChAT+ axonal swellings were present in all sham and HI groups; Tg mice had more than their nTg counterparts, but HI did not affect the number of axonal swellings in APP/PS1 Tg mice. In contrast, complex ChAT+ neuritic clusters (NC) occurred only in Tg mice; HI increased that burden. The abundance of ChAT+ clusters in specific regions correlated with decreased VD. The frequency of attritional ChAT+ INs in the entorhinal cortex (EC) was increased in Tg shams relative to their nTg counterparts, but HI obviated this difference. Cholinergic IN pathology in EC correlated with NC number. The Aβ deposition in APP/PS1 Tg mice was not exacerbated by HI, nor did it correlate with other metrics. Adult APP/PS1 Tg mice have significant cortical cholinergic axon and EC ChAT+ IN pathologies; some pathology was exacerbated by neonatal HI and correlated with VD. Mechanisms of neonatal HI induced cognitive deficits and cortical neuropathology may be modulated by genetic risk, perhaps accounting for some of the variability in outcomes.

Woo-Youn Kim,1,2 Anna Baek,1 Yoonhee Kim,1 Yewon Suh,1,2 Eunsook Lee,1 Eunkyung Euni Lee,1,2 Ju-Yeun Lee,1,2 Jongchan Lee,3– 5 Hee Sun Park,3– 5 Eun Sun Kim,3– 5 Yejee Lim,3– 5 Nak-Hyun Kim,3– 5 Jung Hun Ohn,3– 5 Sun-wook Kim,3– 5 Jiwon Ryu,3– 5 Hye Won Kim3– 5 1Department of Pharmacy, Seoul National University Bundang Hospital, Seongnam, South Korea; 2College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea; 3Division of General Internal Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea; 4Hospital Medicine Center, Seoul National University Bundang Hospital, Seongnam, South Korea; 5Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South KoreaCorrespondence: Hye Won Kim, Email kimhwhw@gmail.comBackground: Transitional medication safety is crucial, as miscommunication about medication changes can lead to significant risks. Unclear or incomplete documentation during care transitions can result in outdated or incorrect medication lists at discharge, potentially causing medication errors, adverse drug events, and inadequate patient education. These issues are exacerbated by extended hospital stays and multiple care events, making accurate medication recall challenging at discharge.Objective: Thus, we aimed to investigate how real-time documentation of in-hospital medication changes prevents undocumented medication changes at discharge and improves physician-pharmacist communication.Methods: We conducted a retrospective cohort study in a tertiary hospital. Two pharmacists reviewed medical records of patients admitted to the acute medical unit from April to June 2020. In-hospital medication discrepancies were determined by comparing preadmission and hospitalization medication lists and it was verified whether the physician’s intent of medication changes was clarified by documentation. By a documentation rate of medication changes of 100% and < 100%, respectively, fully documented (FD) and partially documented (PD) groups were defined. Any undocumented medication changes at discharge were considered a “documentation error at discharge”. Pharmacists’ survey was conducted to assess the impact of appropriate documentation on the pharmacists.Results: After reviewing 400 medication records, patients were categorized into FD (61.3%) and PD (38.8%) groups. Documentation errors at discharge were significantly higher in the PD than in the FD group. Factors associated with documentation errors at discharge included belonging to the PD group, discharge from a non-hospitalist-managed ward, and having three or more intentional discrepancies. Pharmacists showed favorable attitudes towards physician’s documentation.Conclusion: Appropriate documentation of in-hospital medication changes, facilitated by free-text communication, significantly decreased documentation errors at discharge. This analysis underlines the importance of communication between pharmacists and hospitalists in improving patient safety during transitions of care.Plain language summary: During transitions of care, communication failures among healthcare professionals can lead to medication errors. Therefore, effective sharing of information is essential, especially when intentional changes in prescription orders are made. Documenting medication changes facilitates real-time communication, potentially improving medication reconciliation and reducing discrepancies. However, inadequate documentation of medication changes is common in clinical practice. This retrospective cohort study underlines the importance of real-time documentation of in-hospital medication changes. There was a significant reduction in documentation errors at discharge in fully documented group, where real-time documentation of medication changes was more prevalent. Pharmacists showed favorable attitudes toward the physician’s real-time documenting of medication changes because it provided valuable information on understanding the physician’s intent and improving communication and also saved time for pharmacists. This study concludes that physicians’ documentation on medication changes may reduce documentation errors at discharge, meaning that proper documentation of medication changes could enhance patient safety through effective communication.Keywords: medication reconciliation, medication safety, transitions in care, hospital information systems, hospital discharge, quality audit

Yul Hee Kim,1 Han-Seul Kim,1 Hyeung Kyoo Kim,2 Soo Young Kim,2 Jeonghun Lee,2 You Chan Kim,1 Young Joon Park1 1Department of Dermatology, Ajou University School of Medicine, Suwon, Republic of Korea; 2Department of Surgery, Ajou University School of Medicine, Suwon, Republic of KoreaCorrespondence: Young Joon Park, Department of Dermatology, Ajou University Hospital, 164, World Cup-ro, Yeongtong-gu, Suwon-si, Gyeonggi-Do, Suwon, Republic of Korea, Tel +82-31-219-5187, Email aro@ajou.ac.krPurpose: Early intervention of surgical scars with a pulsed dye laser is known to effectively prevent pathologic scars. Despite multiple reports on the effectiveness of the treatment, very few studies have demonstrated its appropriate initiation timing. In this study, our objective was to determine the optimal timing for initiating laser treatment following thyroidectomy.Methods: This study retrospectively analyzed 91 patients undergoing pulsed dye laser treatment post-thyroidectomy, grouping them by treatment initiation timing. The patients underwent treatment at intervals of 3– 4 weeks with at least five sessions. Those with a high pliability score were injected with intralesional corticosteroids. The Antera 3D® skin imaging analyzer was used to assess biophysical parameters.Results: The total Vancouver Scar Scale score significantly reduced after treatment in all groups. The Vancouver Scar Scale score reduction rate was significantly higher after treatment in the group for which the treatment was initiated within 3 weeks of surgery. The pigmentation and erythema score analyzed by Antera 3D® was also lower in this group.Conclusion: Early intervention using a pulsed dye laser within 3 weeks of thyroidectomy can substantially inhibit pathological scar development, providing physicians with a guide for optimal treatment commencement.Keywords: hypertrophic scars, laser treatment of scar, scar, pulsed dye laser

Tail biting is a multifactorial behavior that causes welfare and economic challenges in swine production. As of 2024, research exploring the influence of pig social structure on the development of tail biting is limited. The objective of this study was to explore whether social structures of pigs from different litter origins can impact tail biting and, ultimately, tail damage. Pigs (n = 96) were grouped (eight pigs/pen) based on their litter origin: non-littermates (NLM), half-littermates, and littermates (LM). Tail injury scores were assessed twice weekly from 10 to 24 weeks of age, with a maximal tail injury score (MTS) over the study period being used to evaluate victimization by tail biting. Pig behavior was video-recorded at 15, 19, and 23 weeks of age. Association networks based on lying behavior and tail biting interaction networks were evaluated at pen-and pig-levels using social network analysis. Pigs in LM pens experienced higher median MTS compared to pigs in NLM pens (Median = 1.5; Interquartile range = 1–2; p = 0.009). Within association networks, NLM pens had lower degree centralization measures than other pens at both 15 (Estimated marginal mean [EMM] = 0.07; 95% CI = 0.02–0.12; p = 0.003) and 23 weeks (EMM = 0.09; 95% CI = 0.04–0.14; p = 0.01) and pigs in NLM pens had higher weighted degree centrality than those in other pens (EMM = 1.00; 95% CI = 0.90–1.11; p = 0.002), suggesting pigs in NLM pens had more uniform, stronger, and more connections with their pen-mates. In tail biting networks, increased weighted in-degree centrality was associated with increased odds of pigs receiving a more severe MTS (OR = 1.56; 95% CI = 1.08–2.27; p = 0.02). Pigs with increased weighted out-degree centrality tended to have increased odds of receiving a more severe MTS (OR = 1.19; 95% CI = 0.97–1.48; p = 0.09). These preliminary data suggest a potential relationship between social structures and tail biting in growing-finishing pigs.

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.

Jonghoo Lee,1,&ast; Jae-Uk Song2,&ast; 1Department of Internal Medicine, Jeju National University Hospital, Jeju National University School of Medicine, Jeju, Republic of Korea; 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea&ast;These authors contributed equally to this workCorrespondence: Jonghoo Lee, Department of Internal Medicine, Jeju National University Hospital, Jeju National University School of Medicine, Jeju, Republic of Korea, Email lovlet@jejunu.ac.krBackground: The clinical efficacy of roflumilast, an oral phosphodiesterase-4 inhibitor, has been demonstrated in patients with severe chronic obstructive pulmonary disease (COPD). However, roflumilast has shown frequent adverse drug reactions (ADRs). This study was performed to investigate the dosing strategy that will improve adherence to roflumilast in COPD.Methods: We conducted a systematic review and meta-analysis using PubMed, Embase, and Cochrane Central Register. The dosing strategy for roflumilast was classified into a dose-escalation group and a low-dose group. We investigated clinical outcomes according to dosing strategy.Results: Five clinical trials involving 2424 patients were included. Both the dose-escalation and the low-dose groups showed a decrease in discontinuation rate compared to the standard dosing group for roflumilast (risk ratio [RR], 0.81; 95% confidence interval [CI], 0.67– 0.97; P = 0.02 and RR, 0.62; 95% CI, 0.48– 0.80; P < 0.01, respectively). In the two strategies, the pooled proportions of discontinuation were 27.9% and 11.7%, respectively. Although the pooled proportion of any ADR was not statistically decreased in the two strategies, diarrhea was significantly reduced in the low-dose group compared to the standard group (RR, 0.58; 95% CI, 0.42– 0.82; P < 0.01). The pooled incidence of acute exacerbations was similar between the low-dose and the standard groups (22.9% and 20.1%, respectively; P = 0.27).Conclusion: Our findings show that the two alternative dosing strategies might have the benefit of improving adherence to roflumilast in COPD. Further large-scale trials are required to support our findings.Keywords: drug tolerance, meta-analysis, phosphodiesterase 4 inhibitor, pulmonary disease, chronic obstructive, roflumilast

Jiwon Lee,1 Dong Woo Han,1 Na Young Kim,2 Keun-Su Kim,3 Yunil Yang,1 Juyeon Yang,4 Hye Sun Lee,4 Myoung Hwa Kim1 1Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, Republic of Korea; 2Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea; 3Department of Neurosurgery, Spine and Spinal Cord Institute, Gangnam Severance Spine Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea; 4Department of Research Affairs, Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, Republic of KoreaCorrespondence: Myoung Hwa Kim, Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, Republic of Korea, Fax +82-2-3463-0940, Email KMH2050@yuhs.acPurpose: Remimazolam is a newly developed ultra-short-acting benzodiazepine. We compared overall functional recovery, including the postoperative Quality of Recovery-15 (QoR-15) questionnaire scores, between balanced inhalational anesthesia using sevoflurane and total intravenous anesthesia (TIVA) with remimazolam in patients undergoing anterior cervical discectomy and fusion (ACDF).Patients and Methods: Seventy-two patients were randomized to the remimazolam (group R) or sevoflurane (group S) group. The primary outcome was the total QoR-15 score on postoperative day (POD) 1. We also assessed the total QoR-15 score on POD2, sub-scores of the QoR-15, perioperative parameters, and postoperative recovery profiles. Group-time interaction effects on the QoR-15 and its sub-scores were analyzed using a linear mixed model.Results: The total QoR-15 score on POD1 (120.2 in group R vs 114.3 in group S, P=0.189) was not statistically different between the groups. There were no significant group-time interaction effects on total QoR-15 scores. Instead, patients in group R showed significantly better sub-scores in psychological and postoperative nausea and vomiting (PONV) items on POD1, as well as a lower degree of PONV, than those in group S. Among the five dimensions of the QoR-15, a significant group-time interaction effect was observed for psychological support. Group R showed significantly less changeability in blood pressure and heart rate with a lower dose of intraoperatively administered vasopressor than group S.Conclusion: Considering QoR-15, including PONV reduction, and intraoperative hemodynamic stability, remimazolam can be used as the novel and safe anesthetic agent for maintaining general anesthesia instead of sevoflurane in patients undergoing ACDF.Plain Language Summary: Compared with balanced anesthesia using sevoflurane, total intravenous anesthesia with remimazolam showed better aspects for psychological support and postoperative nausea/vomiting in the quality of recovery and hemodynamic stability.Despite comparable total Quality of Recovery-15 scores, remimazolam-based total intravenous anesthesia could be a secure and suitable choice for patients undergoing cervical spine surgery.Keywords: cervical spine surgery, quality of recovery, remimazolam, sevoflurane, total intravenous anesthesia

Recovery from respiratory pneumococcal infections generates lung-localized protection against heterotypic bacteria, mediated by resident memory lymphocytes. Optimal protection in mice requires re-exposure to pneumococcus within days of initial infection. Serial surface marker phenotyping of B cell populations in a model of pneumococcal heterotypic immunity revealed that bacterial re-exposure stimulates the immediate accumulation of dynamic and heterogeneous populations of B cells in the lung, and is essential for the establishment of lung resident memory B (BRM) cells. The B cells in the early wave were activated, proliferating locally, and associated with both CD4+ T cells and CXCL13. Antagonist- and antibody-mediated interventions were implemented during this early timeframe to demonstrate that lymphocyte recirculation, CD4+ cells, and CD40 ligand (CD40L) signaling were all needed for lung BRM cell establishment, whereas CXCL13 signaling was not. While most prominent as aggregates in the loose connective tissue of bronchovascular bundles, morphometry and live lung imaging analyses showed that lung BRM cells were equally numerous as single cells dispersed throughout the alveolar septae. We propose that CD40L signaling from antigen-stimulated CD4+ T cells in the infected lung is critical to establishment of local BRM cells, which subsequently protect the airways and parenchyma against future potential infections.

Amphibians are routinely collected from the wild and added into managed care and public display facilities; however, there is a gap in understanding how these practices might alter the diversity and composition of skin microbial communities on these animals. The aim of this study was to evaluate and compare skin microbial communities of spring peeper frogs (Pseudacris crucifer) from acquisition in the wild through the end of their quarantine period and identify microbial taxa with antifungal properties. From an original group of seventy-six frogs, cohorts of ten were swabbed when acquired in the wild, upon transport from the wild, and swabbed throughout a 9-week quarantine period while under managed care. An immediate loss of microbial richness and diversity was evident upon transfer of the frogs from their original environment and continued throughout subsequent sampling time-points during quarantine. Importantly, antifungal taxa comprised significantly more of the overall skin community after the frogs were moved from the wild, largely due to members of the family Moraxellaceae. Overall, our findings demonstrate that amphibian skin microbiome changes immediately on removal from the wild, and that these changes persist throughout quarantine while being housed under managed care. This may play a pivotal role in the development of dermatological disease and have implications in the health and immune function of amphibians.

Summary: Patients afflicted with Stimulator of interferon gene (STING) gain-of-function mutations frequently present with debilitating interstitial lung disease (ILD) that is recapitulated in mice expressing the STINGV154M mutation (VM). Prior radiation chimera studies revealed an unexpected and critical role for non-hematopoietic cells in initiating ILD. To identify STING-expressing non-hematopoietic cell types required for the development of ILD, we use a conditional knockin (CKI) model and direct expression of the VM allele to hematopoietic cells, fibroblasts, epithelial cells, or endothelial cells. Only endothelial cell-targeted VM expression results in enhanced recruitment of immune cells to the lung associated with elevated chemokine expression and the formation of bronchus-associated lymphoid tissue, as seen in the parental VM strain. These findings reveal the importance of endothelial cells as instigators of STING-driven lung disease and suggest that therapeutic targeting of STING inhibitors to endothelial cells could potentially mitigate inflammation in the lungs of STING-associated vasculopathy with onset in infancy (SAVI) patients or patients afflicted with other ILD-related disorders.

Jeongmin Lee, Junho Choi, Juyoung Kim, Kayoung Lee College of Nursing, Gachon University, Incheon, South KoreaCorrespondence: Kayoung Lee, College of Nursing, Gachon University, Health Science Building, Room&num; 412, 191 Hambakmoero, Yeonsu-gu, Incheon, 21936, South Korea, Tel: +82-32-820-4227, Email kayolee@gachon.ac.krBackground: During COVID-19, nursing students experienced variations in on-site clinical practice, such as a combination of on-site and non-face-to-face clinical practice. Although on-site clinical practice is critical for increasing nurses’ clinical self-efficacy and developing professional nursing values, there is a lack of knowledge that reflects the current clinical practice environment.Aim: To examine the relationship between on-site clinical practice, nursing professional values, and nursing clinical self-efficacy during the COVID-19 pandemic.Methods: This study is a cross-sectional correlational study design. Demographic characteristics, on-site clinical practice, nursing professional values, and nursing clinical self-efficacy were assessed using an online survey from October 3, 2022, to November 6, 2022. Data were analyzed using descriptive statistics, ANOVA, t-test, Pearson’s correlation coefficient, and multiple regression.Results: Of the 86 participants, 18 (20.9%) were male and 68 (79.1%) were female. The duration of the participants’ average participation in on-site clinical practice was 39.67 days (61.04%). Nursing professional values significantly influenced clinical self-efficacy (β=0.379, p< 0.001). However, on-site clinical practice was not significantly related to clinical self-efficacy (β=0.051, p=0.611). In terms of nursing clinical self-efficacy, measuring blood glucose had the highest score. On the other hand, establishing and maintaining intravenous catheters had the lowest scores.Conclusion: Nursing students’ professional values were significantly associated with nursing clinical self-efficacy; however, the extent of involvement in on-site clinical practice during the pandemic did not have a significant impact on nursing clinical self-efficacy. Given that this study focused on a single university, it is imperative to replicate this research using diverse samples in the future. In addition, there is a need to establish a range of teaching and learning approaches for clinical practice, including simulation, online learning, and the use of state-of-the-art technology for faculty-student feedback strategies, in anticipation of the need for alternative practices.Keywords: clinical practice, COVID-19, self-efficacy, professionalism, nursing education, nursing students

The effects that mycobiomes have on physiological traits in turfgrasses are poorly understood. Drought tolerance, an economically and ecologically important trait, can be influenced by symbiotic fungi. In this two-year study, we evaluated the mycobiome associated with tall fescue exposed to prolonged periods of drought stress in a rainout shelter. Twelve plants, comprising six sets of half-sibs (progenies having one parent in common), one exhibiting a drought-tolerant phenotype and the other a drought-susceptible phenotype, were selected for analysis each year. The mycobiomes associated with the shoot, root, and rhizosphere soil were evaluated for each tall fescue half-sib pair using both short-read Illumina MiSeq and long-read Oxford Nanopore Technology (ONT) MinION sequencing pipelines. Both platforms sequenced portions of the fungal nuclear ribosomal RNA genes. The Illumina MiSeq sequenced the internal transcribed spacer region (ITS, 600 bp), while the ONT MinION covered the small subunit, ITS, and partial large subunit (4,600 bp). Both sequencing pipelines revealed that the mycobiomes associated with the roots, shoots, and soil were significantly different. The ONT MinION pipeline identified more diverse fungal lineages and had higher taxonomic resolution than the Illumina pipeline. Our results also indicated that root pathogens may play a more important role than endophytic or mycorrhizal symbionts in tall fescue drought stress tolerance.

Abstract NLRP3 induces caspase-1-dependent pyroptotic cell death to drive inflammation. Aberrant activity of NLRP3 occurs in many human diseases. NLRP3 activation induces ASC polymerization into a single, micron-scale perinuclear punctum. Higher resolution imaging of this signaling platform is needed to understand how it induces pyroptosis. Here, we apply correlative cryo-light microscopy and cryo-electron tomography to visualize ASC/caspase-1 in NLRP3-activated cells. The puncta are composed of branched ASC filaments, with a tubular core formed by the pyrin domain. Ribosomes and Golgi-like or endosomal vesicles permeate the filament network, consistent with roles for these organelles in NLRP3 activation. Mitochondria are not associated with ASC but have outer-membrane discontinuities the same size as gasdermin D pores, consistent with our data showing gasdermin D associates with mitochondria and contributes to mitochondrial depolarization.

Abstract Background Liver abscesses (LAs) are one of the most common and important problems faced by the beef industry. The most efficacious method for the prevention of LAs in North America is through dietary inclusion of low doses of antimicrobial drugs such as tylosin, but the mechanisms by which this treatment prevents LAs are not fully understood. LAs are believed to result from mucosal barrier dysfunction in the gastrointestinal tract (GIT) allowing bacterial translocation to the liver via the portal vein, yet differences in the GIT microbiome of cattle with and without LAs have not been explored. Here, we characterized microbial communities from LAs, rumen, ileum, and colon from the same cattle for the first time. Results Results demonstrate that tylosin supplementation was associated with differences in microbial community structure in the rumen and small intestine, largely because of differences in the predominance of Clostridia. Importantly, we show for the first time that microbial communities from multiple LAs in one animal’s liver are highly similar, suggesting that abscesses found at different locations in the liver may originate from a localized source in the GIT (rather than disparate locations). A large portion of abscesses were dominated by microbial taxa that were most abundant in the hindgut. Further, we identified taxa throughout the GIT that were differentially abundant between animals with and without liver abscesses. Bifidobacterium spp.—a bacteria commonly associated with a healthy GIT in several species—were more abundant in the rumen and ileum of animals without LAs compared to those with LAs. Conclusions Together these results provide the first direct comparison of GIT and LA microbial communities within the same animal, add considerable evidence to the hypothesis that some LA microbial communities arise from the hindgut, and suggest that barrier dysfunction throughout the GIT may be the underlying cause of LA formation in cattle.

Kyoung Sun Park,1 Changnyun Kim,2 Joo Won Kim,3 Sang‐Don Kim,4 Jee Young Lee,5 Yoon Jae Lee,5 Jinho Lee,1 Min Ji Kim,6 Young Eun Choi,6 Changsop Yang,7 Chang-Hyun Han,7,8,&ast; In-Hyuk Ha5,&ast; 1Jaseng Hospital of Korean Medicine, Seoul, Republic of Korea; 2Daejeon Jaseng Hospital of Korean Medicine, Daejeon, Republic of Korea; 3Bucheon Jaseng Hospital of Korean Medicine, Bucheon, Republic of Korea; 4Haeundae Jaseng Hospital of Korean Medicine, Busan, Republic of Korea; 5Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul, Republic of Korea; 6Clinical Research Coordinating Team, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea; 7Clinical Medicine Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea; 8Korean Convergence Medical Science, Korea Institute of Oriental Medicine School, University of Science & Technology, Daejeon, Republic of Korea&ast;These authors contributed equally to this workCorrespondence: Chang-Hyun Han, Clinical Medicine Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea, Tel +82 42 868 9498, Email chhan@kiom.re.kr In-Hyuk Ha, Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul, Republic of Korea, Tel +82 2 2222 2740, Email hanihata@gmail.comPurpose: Chronic lower back pain (LBP) is a major global health concern. Pharmacopuncture has been widely used to treat LBP in Korea; however, randomized clinical trials (RCT) or active control have not been conducted to evaluate its effectiveness. Therefore, this RCT aimed to compare the effectiveness of pharmacopuncture and physical therapy (PT) for the treatment of chronic LBP.Patients and Methods: A two-arm, parallel, and multicenter RCT was conducted at four hospitals of Korean medicine. Participants with chronic LBP were randomly assigned at a 1:1 ratio using block randomization to undergo 10 sessions of pharmacopuncture or PT over 5 weeks and followed up for 25 weeks. The numerical rating scale (NRS) and visual analog scale scores of LBP and radiating leg pain and the Oswestry disability index (ODI), 5-level EuroQol-5 dimension (EQ-5D-5L), and the patient global impression of change were recorded at baseline and at 6, 13, and 25 weeks. An intention-to-treat analysis was conducted as the primary analysis using a linear mixed model.Results: One-hundred patients (mean age, 49.27 years; 58 women) were recruited. At 6 weeks after randomization, pharmacopuncture showed statistically superior results compared with PT in LBP (difference in NRS, 1.54; 95% CI, 0.94– 2.13), function (difference in ODI, 4.52%; 95% CI, 0.93– 8.11%), and quality of life (difference in EQ-5D-5L) scores (− 0.05; 95% CI, − 0.08 to − 0.01). This effect persisted for 25 weeks. In the survival analysis for participants with at least a 50% reduction in the NRS scores of LBP during the 182-day follow-up, the pharmacopuncture group showed significantly faster recovery than the PT group (P< 0.001, Log rank test).Conclusion: Pharmacopuncture significantly reduced pain and improved functional outcomes and quality of life in patients with low back pain compared with physical therapy. Based on the findings of this study, pharmacopuncture could be recommended as a treatment for patients with chronic low back pain.Keywords: low back pain, pharmacopuncture, physiotherapy, Oswestry disability index, Roland–Morris disability questionnaire, pragmatic randomized controlled trial

Sora Mun,1 Seungyeon Lee,2 Yeeun Yun,3 Eun-Jeong Joo,4,5 Hee-Gyoo Kang,1– 3 Jiyeong Lee1,3 1Department of Biomedical Laboratory Science, College of Health Sciences, Eulji University, Gyeonggi, Republic of Korea; 2Department of Senior Healthcare, Graduate School, Eulji University, Gyeonggi, Republic of Korea; 3Department of Biomedical Laboratory Science, Graduate School, Eulji University, Gyeonggi, Republic of Korea; 4Department of Neuropsychiatry, School of Medicine, Eulji University, Daejeon, Republic of Korea; 5Department of Psychiatry, Uijeongbu Eulji Medical Center, Eulji University, Gyeonggi, Republic of KoreaCorrespondence: Hee-Gyoo Kang, Department of Biomedical Laboratory Science, College of Health Sciences, Eulji University, 553 Sanseong-daero, Sujeong-gu, Seongnam-si, Gyeonggi-do, Republic of Korea, Tel +82-31-740-7315, Email kanghg@eulji.ac.kr Jiyeong Lee, Department of Biomedical Laboratory Science, College of Health Sciences, Eulji University, 712 Dongil-ro, Uijeongbu-si, Gyeonggi-do, Republic of Korea, Tel +82-31-951-3862, Email leejiyeong@eulji.ac.krPurpose: Depressive mood is a major psychiatric symptom that causes serious disturbances in daily life. Unlike physical symptoms, psychiatric symptoms are more difficult to evaluate objectively. Therefore, we aimed to discover biomarkers that reflect changes in serum protein metabolism during a clinical depressive mood.Methods: Serum protein profiling was conducted in participants who were not experiencing a current depressive episode (healthy individuals and patients in remission). Serum proteins were identified and quantified using liquid chromatography–tandem mass spectrometry. Differentially expressed proteins with a p-value < 0.05 were selected, and candidate biomarkers were verified using multiple reaction monitoring analysis for absolute quantification.Results: Apolipoprotein A-IV levels were lower in the group with a current episode of depression than in the remission and healthy control groups. Further, fibronectin levels were also lower in the group with a current episode of depression than in the healthy control group but not in the remission group.Conclusion: We found that apolipoprotein A-IV-mediated inflammation is involved in clinical depressive moods, possibly by inducing neurological changes in the brain. Therefore, apolipoprotein A-IV and fibronectin levels may be explored as potentially novel biomarkers for detecting a current episode of depression.Keywords: biomarkers, depression, liquid chromatography–tandem mass spectrometry, inflammation, neuroinflammation, serum proteomics

Demis Zelelew,1 Milkyas Endale,1 Yadessa Melaku,1 Teshome Geremew,2 Rajalakshmanan Eswaramoorthy,3 Lemma Teshome Tufa,1,4 Youngeun Choi,5 Jaebeom Lee5 1Department of Applied Chemistry, School of Applied Natural Science, Adama Science and Technology University, Adama, Ethiopia; 2Department of Applied Biology, School of Applied Natural Science, Adama Science and Technology University, Adama, Ethiopia; 3Department of Biomaterials, Saveetha Dental College and Hospital, Saveetha University, Chennai, 600 077, India; 4Research Institute of Materials Chemistry, Chungnam National University, Daejeon, 34134, Republic of Korea; 5Department of Chemistry, Department of Chemistry Engineering and Applied Chemistry, Chungnam National University, Daejeon, 34134, Republic of KoreaCorrespondence: Milkyas Endale; Demis Zelelew, Department of Applied Chemistry, School of Applied Natural Science, Adama Science and Technology University, P.O. Box 1888, Adama, Ethiopia, Email milkyas.endale@astu.edu.et; milkyasendale@yahoo.com; demis1921zelelew@gmail.comBackground: Heterocyclic analogs of curcumin have a wide range of therapeutic potential and the ability to control the activity of a variety of metabolic enzymes.Methods: 1H-NMR and 13C-NMR spectroscopic techniques were used to determine the structures of synthesized compounds. The agar disc diffusion method and α-amylase inhibition assay were used to examine the antibacterial and anti-diabetic potential of the compounds against α-amylase enzyme inhibitory activity, respectively. DPPH-free radical scavenging and lipid peroxidation inhibition assays were used to assess the in vitro antioxidant potential.Results and Discussion: In this work, nine heterocyclic analogs derived from curcumin precursors under ultrasonic irradiation were synthesized in excellent yields (81.4– 93.7%) with improved reaction time. Results of antibacterial activities revealed that compounds 8, and 11 displayed mean inhibition zone of 13.00± 0.57, and 19.66± 00 mm, respectively, compared to amoxicillin (12.87± 1.41 mm) at 500 μg/mL against E. coli, while compounds 8, 11 and 16 displayed mean inhibition zone of 17.67± 0.57, 14.33± 0.57 and 23.33± 00 mm, respectively, compared to amoxicillin (13.75± 1.83 mm) at 500 μg/mL against P. aeruginosa. Compound 11 displayed a mean inhibition zone of 11.33± 0.57 mm compared to amoxicillin (10.75± 1.83 mm) at 500 μg/mL against S. aureus. Compound 11 displayed higher binding affinities of − 7.5 and − 8.3 Kcal/mol with penicillin-binding proteins (PBPs) and β-lactamases producing bacterial strains, compared to amoxicillin (− 7.2 and − 7.9 Kcal/mol, respectively), these results are in good agreement with the in vitro antibacterial activities. In vitro antidiabetic potential on α-amylase enzyme revealed that compounds 11 (IC50=7.59 μg/mL) and 16 (IC50=4.08 μg/mL) have higher inhibitory activities than acarbose (IC50=8.0 μg/mL). Compound 8 showed promising antioxidant inhibition efficacy of DPPH (IC50 = 2.44 g/mL) compared to ascorbic acid (IC50=1.24 g/mL), while compound 16 revealed 89.9± 20.42% inhibition of peroxide generation showing its potential in reducing the development of lipid peroxides. In silico molecular docking analysis, results are in good agreement with in vitro biological activity. In silico ADMET profiles suggested the adequate oral drug-likeness potential of the compounds without adverse effects.Conclusion: According to our findings, both biological activities and in silico computational studies results demonstrated that compounds 8, 11, and 16 are promising α-amylase inhibitors and antibacterial agents against E. coli, P. aeruginosa, and S. aureus, whereas compound 8 was found to be a promising antioxidant agent.Keywords: ultrasonic-irradiation, α-amylase, antibacterial, antioxidant, heterocyclic curcumin analogs, molecular docking, ADMET prediction

Prina Donga,1 Bruno Emond,2 Carmine Rossi,2 Brahim K Bookhart,1 Johnnie Lee,1 Gabrielle Caron-Lapointe,2 Fangzhou Wei,3 Marie-Hélène Lafeuille2 1Janssen Scientific Affairs, LLC, Titusville, NJ, USA; 2Analysis Group, Inc, Montréal, QC, Canada; 3Analysis Group, Inc, Menlo Park, CA, USACorrespondence: Carmine Rossi, Analysis Group, Inc, 1190 Avenue des Canadiens-de-Montréal, Tour Deloitte, Suite 1500, Montréal, QC, H3B 0G7, Canada, Tel +1 514-871-4233, Email carmine.rossi@analysisgroup.comIntroduction: Integrase strand transfer inhibitor-based regimens (eg, containing dolutegravir [DTG]) are associated with weight/body mass index (BMI) increases among people living with HIV-1 (PLWH). Assessing antiretroviral therapy (ART)-related weight/BMI changes is challenging, as PLWH may experience return-to-health weight gain as a result of viral suppression. This retrospective, longitudinal real-world study compared weight/BMI outcomes among overweight/obese (BMI ≥ 25 kg/m2; thus excluding return-to-health weight/BMI changes), treatment-naïve PLWH who initiated darunavir (DRV)/cobicistat (c)/emtricitabine (FTC)/tenofovir alafenamide (TAF) or DTG + FTC/TAF.Methods: Treatment-naïve PLWH with BMI ≥ 25 kg/m2 who initiated DRV/c/FTC/TAF or DTG + FTC/TAF (index date) had ≥ 12 months of baseline observation and ≥ 1 weight/BMI measurement in baseline and post-index periods in the Symphony Health IDV® database (07/17/2017– 12/31/2021) were included. Inverse probability of treatment weighting (IPTW) was used to balance differences in baseline characteristics between cohorts. On-treatment time-to-weight/BMI increases ≥ 5% were compared between cohorts using weighted adjusted Cox models.Results: Post-IPTW, 76 overweight/obese DRV/c/FTC/TAF-treated (mean age = 51.2 years, 30.7% female, 35.6% Black, mean baseline BMI = 33.2 kg/m2) and 88 overweight/obese DTG + FTC/TAF-treated PLWH (mean age = 51.5 years, 31.4% female, 31.4% Black, mean baseline BMI = 32.7 kg/m2) were included. The median [interquartile range] time from ART initiation to weight/BMI increase ≥ 5% was shorter for the DTG + FTC/TAF cohort (21.8 [9.9, 32.3] months) than the DRV/c/FTC/TAF cohort (median and interquartile times not reached; Kaplan–Meier rate at 21.8 months = 20.8%). Over the entire follow-up, overweight/obese PLWH initiating DTG + FTC/TAF had a more than twofold greater risk of experiencing weight/BMI increase ≥ 5% compared to those initiating DRV/c/FTC/TAF (hazard ratio [95% confidence interval]=2.43 [1.02; 7.04]; p = 0.036).Conclusion: Overweight/obese PLWH who initiated DTG + FTC/TAF had significantly greater risk of weight/BMI increase ≥ 5% compared to similar PLWH who initiated DRV/c/FTC/TAF and had shorter time-to-weight/BMI increase ≥ 5%, suggesting a need for additional monitoring to assess the risk of weight gain-related cardiometabolic disease.Keywords: human immunodeficiency virus, weight gain, BMI, darunavir, dolutegravir, observational study

IntroductionLoss of proteasome function, proteinopathy, and proteotoxicity may cause neurodegeneration across the human lifespan in several forms of brain injury and disease. Drugs that activate brain proteasomes in vivo could thus have a broad therapeutic impact in neurology.MethodsUsing pigs, a clinically relevant large animal with a functionally compartmental gyrencephalic cerebral cortex, we evaluated the localization and biochemical activity of brain proteasomes and tested the ability of small molecules to activate brain proteasomes.ResultsBy Western blotting, proteasome protein subunit PSMB5 and PSMA3 levels were similar in different pig brain regions. Immunohistochemistry for PSMB5 showed localization in the cytoplasm (diffuse and particulate) and nucleus (cytoplasm

Few formulas have been used in exercise physiology as extensively as the Fick formula, which calculates the rate of oxygen consumption (i.e., V.O2) as the product of cardiac output (Q.) and the difference in oxygen content in arterial and mixed venous blood (Δav¯O2). Unfortunately, the physiology of maximum V.O2 (V.O2MAX) is often misinterpreted due to a lack of appreciation for the limitations represented by the oft-ignored superscript annotations in the Fick formula. The purpose of this perspective is to explain the meaning of the superscript annotations and highlight how such annotations influence proper interpretation of V.O2MAX physiology with the Fick formula. First, we explain the significance of the overdots above V.O2 and Q., which indicate a measure per unit of time. As we will show, the presence of an overdot above Q. and lack of one above Δav¯O2 denotes they are different types of ratios and should be interpreted in the context of one another—not in contrast to each other as is commonplace. Second, we discuss the significance of the overline above the “v¯” in Δav¯O2, which indicates the venous sample is an average of blood that comes from mixed sources. The mixed nature of the venous sample has major implications for interpreting the influence of oxygen diffusion and blood flow heterogeneity on V.O2MAX. Ultimately, we give recommendations and insights for using the Fick formula to calculate V.O2 and interpret V.O2MAX physiology.

BackgroundPost-traumatic stress disorder (PTSD) and chronic pain are highly prevalent comorbid conditions. Veterans dually burdened by PTSD and chronic pain experience more severe outcomes compared to either disorder alone. Few studies have enrolled enough women Veterans to test gender differences in pain outcomes [catastrophizing, intensity, interference] by the severity of PTSD symptoms.AimExamine gender differences in the association between PTSD symptoms and pain outcomes among Veterans enrolled in a chronic pain clinical trial.MethodsParticipants were 421 men and 386 women Veterans with chronic pain who provided complete data on PTSD symptoms and pain outcomes. We used hierarchical linear regression models to examine gender differences in pain outcomes by PTSD symptoms.ResultsAdjusted multivariable models indicated that PTSD symptoms were associated with higher levels of pain catastrophizing (0.57, 95% CI [0.51, 0.63]), pain intensity (0.30, 95% CI [0.24, 0.37]), and pain interference (0.46, 95% CI [0.39, 0.52]). No evidence suggesting gender differences in this association were found in either the crude or adjusted models (all interaction p-valuesConclusionThese findings may reflect the underlying mutual maintenance of these conditions whereby the sensation of pain could trigger PTSD symptoms, particularly if the trauma and pain are associated with the same event. Clinical implications and opportunities testing relevant treatments that may benefit both chronic pain and PTSD are discussed.

Previous research on stabilization methods for microbiome investigations has largely focused on human fecal samples. There are a few studies using feces from other species, but no published studies investigating preservation of samples collected from cattle. Given that microbial taxa are differentially impacted during storage it is warranted to study impacts of preservation methods on microbial communities found in samples outside of human fecal samples. Here we tested methods of preserving bovine fecal respiratory specimens for up to 2 weeks at four temperatures (room temperature, 4°C, -20°C, and -80°C) by comparing microbial diversity and community composition to samples extracted immediately after collection. Importantly, fecal specimens preserved and analyzed were technical replicates, providing a look at the effects of preservation method in the absence of biological variation. We found that preservation with the OMNIgene®•GUT kit resulted in community structure most like that of fresh samples extracted immediately, even when stored at room temperature (~20°C). Samples that were flash-frozen without added preservation solution were the next most representative of original communities, while samples preserved with ethanol were the least representative. These results contradict previous reports that ethanol is effective in preserving fecal communities and suggest for studies investigating cattle either flash-freezing of samples without preservative or preservation with OMNIgene®•GUT will yield more representative microbial communities.

Hyocheong Chae,1,2,&ast; Hongmin Chu,1,3,&ast; Junghun Lee,1 Hagdong Kim,1 Dongha Kim,1 Sebong Park,1 Kwanghwan Lim,1 Minsu Jeong,1 Kyungho Kang,1 Gyeongchan Kim,1 Joo Hyun Lee,1 Sehun Jung,1 Jaehyo Kim,4 Yongjoo Kim,5 Myungseok Ryu1,6 On behalf of Korean Medical Society of Acupotomology KM Doctors Group1Departmental Research Committee, Korean Medical Society of Acupotomology, Seoul, Republic of Korea; 2Sunyujae Korean Medicine Clinic, Yongin, Republic of Korea; 3Department of Korean Internal Medicine, College of Korean Medicine, Wonkwang University, Iksan, Republic of Korea; 4Department of Meridian & Acupoint, College of Korean Medicine, Wonkwang University, Iksan, Republic of Korea; 5College of Korean Medicine, Sangji University, Wonju, Republic of Korea; 6Clinic Department, Daemyeong Korean Medicine Clinic, Seoul, Republic of Korea&ast;These authors contributed equally to this workCorrespondence: Myungseok Ryu, Clinic Department of Daemyung Korean Medicine Clinic, Wonwoo b/d 3rd fl, Yangpyeong-ro, Yeongdeungpo-gu, Seoul, 07208, Republic of Korea, Tel +82-2-2671-7191, Fax +82-2-2676-1297, Email yeonbu16@gmail.comObjective: Shoulder pain is a common complaint in outpatient clinics and can result in an inability to work or perform household activities, leading to significant socioeconomic burden. Acupotomy, as one kind acupuncture that has flat knife-shaped tip, has been widely used for treating shoulder pain. However, despite the widespread use of acupotomy in primary medical institutions, large sample size clinical trials have not sufficiently been performed. In this respect, this multi-center retrospective study aimed to investigate the effectiveness and safety of acupotomy in reducing shoulder pain and disability using data from multi-center primary care clinics.Methods: This study was conducted in 25 Korean medicine clinics affiliated with the Korean Medical Society of Acupotomology, Republic of Korea, from August 2021 to December 2021. The medical records of patients who visited the clinics complaining of shoulder pain were gathered, and among them were those of patients who underwent acupotomy treatment and those who received acupuncture combined therapy. The Numeric Rating Scale (NRS), SPADI (Shoulder Pain and Disability Index), Range of Motion (ROM) and adverse event were evaluated at each visit. A linear mixed-effects models and paired t-test were used to identify the effectiveness of the treatment.Results: Overall analysis showed that the NRS score of patients decreased from 4.95 ± 1.97 before treatment to 3.78 ± 2.03 after treatment (n = 332, difference in NRS score, 1.17; 95% CI: 0.96– 1.38, t = 10.89 p < 0.001). SPADI score decreased from 19.05 ± 20.44 at baseline before treatment to 12.12 ± 17.26 after the last visit, which was statistically significant (n = 332, mean difference in SPADI score, 6.93; 95% CI: 4.71– 9.15, t = 6.150, p < 0.001). No serious adverse event was reported in both groups.Conclusion: This study showed the effectiveness of acupotomy therapy for shoulder pain, and as the treatment sessions increased, the effect of pain reduction and shoulder function improvement were also increased.Keywords: acupotomy, shoulder pain, retrospective study, multicenter study

It has been found that some six- and seven-membered 2,3-diaryl-2,3-dihydro-1,3-thiaza-4-ones will undergo acid-catalyzed reaction with water when dissolved in chloroform to give dimeric ring-opened thioacetals. In this communication, initial exploration of this reaction is reported.

Bovine respiratory disease (BRD) is a leading cause of disease in feedlot and stocker calves with Mannheimia haemolytica (MH) as one of the most common etiologies. One of the most effective means of controlling BRD is through metaphylaxis, which involves administering antimicrobials to all animals at high risk of developing BRD. However, increasing prevalence of multidrug resistant (MDR) MH may reduce efficacy of metaphylaxis due to decreased susceptibility to drugs used for metaphylaxis. Primarily, this study aimed to determine the effect of tulathromycin metaphylaxis and subsequent BRD treatment on antimicrobial resistance (AMR) in MH isolated from stocker calves. Secondary objectives included evaluating the effect of metaphylaxis and treatment for BRD on animal health and comparing the genetic relationship of MH isolated. Crossbred beef heifers (n = 331, mean weight = 232, SD = 17.8 kg) at high risk for BRD were randomly assigned to receive tulathromycin metaphylaxis (META, n = 167) or not (NO META, n = 164). Nasopharyngeal swabs were collected for MH isolation, antimicrobial susceptibility testing and whole genome sequencing at arrival and 3 (WK3) and 10 (WK10) weeks later. Mixed-effects logistic regression was used to identify risk factors for isolation of MH and MDR MH (resistant to ≥3 antimicrobial drug classes) at 3 and 10 weeks, BRD morbidity, and crude mortality. Animals in the META group had higher odds of isolation of MDR MH at 3 weeks [OR (95% CI) = 13.08 (5–30.9), p

The racemic mixture of the title compound, C19H19NO3S, crystallizes in space group P\overline{1} with two homochiral molecules in each asymmetric unit. The seven-membered ring in both molecules is in a pucker-chair conformation. The extended structure exhibits C—H...O hydrogen bonds, of which two connect crystallographically independent molecules to generate a chain propagating along the b-axis direction. One C—H grouping of the cyclopropyl ring is in close contact with the phenyl ring of the neighboring independent molecule in C—H...π type interactions with carbon atom–ring-centroid distances of 3.544 (5) and 3.596 (4) Å. Other interactions are of the parallel–reciprocal type, with the chiral carbon atom of one molecule donating a proton to an oxygen atom of the sulfone group of a symmetry-related molecule and vice-versa. Symmetry-related molecular pairs also exhibit T-type interactions between aromatic rings with interplanar angles of 74.2 (2) and 69.2 (2)° and intercentroid distances of 4.965 (4) and 5.114 (4) Å.

Background Heavy menstrual bleeding affects one in four women and negatively impacts quality of life. The levonorgestrel-releasing intrauterine system is an effective long-term treatment but is discontinued by many due to unpredictable bleeding, or adverse effects. The selective progesterone receptor modulator ulipristal acetate is used to treat symptomatic fibroids but long-term efficacy for the symptom of heavy menstrual bleeding, irrespective of presence of fibroids, is unknown. Objectives To determine whether ulipristal acetate is more effective at reducing the burden of heavy menstrual bleeding than levonorgestrel-releasing intrauterine system after 12 months of treatment in women with and without fibroids. We investigated mechanism of action of ulipristal acetate in a subset of 20 women. Design Randomised, open-label, parallel group, multicentre trial with embedded mechanistic study. Setting Ten UK hospitals. Participants Women with heavy menstrual bleeding aged 18 and over with no contraindications to levonorgestrel-releasing intrauterine system or ulipristal acetate. Interventions Three 12-week treatment cycles of 5 mg ulipristal acetate daily, separated by 4-week treatment-free intervals, or continuous levonorgestrel-releasing intrauterine system following allocation in a 1 : 1 ratio using a web-based minimisation procedure. Main trial outcome measures Primary outcome was quality-of-life measured by menorrhagia multi-attribute scale at 12 months. Secondary outcomes included menstrual bleeding and patient satisfaction. Impact on fibroid size, endometrial appearance and liver function was also collected. Mechanistic study outcome Cellular markers for endometrial cell structure and function, determined from endometrial biopsies; volume of uterus and fibroids and microcirculation parameters were determined from magnetic resonance images. Results Sample size was increased from 220 to 302 as a result of temporary halt to recruitment due to concerns of ulipristal acetate hepatoxicity. Subsequent withdrawal of ulipristal acetate and the COVID-19 pandemic led to a premature closure of recruitment, with 118 women randomised to each treatment and 103 women completing 12-month menorrhagia multi-attribute scale scores prior to this point. Primary outcome scores substantially improved in both arms, but at 12 months there was no evidence of a difference between those receiving three cycles of ulipristal acetate [median score category: 76–99, interquartile range (51–75 to 100), n = 53] and levonorgestrel-releasing intrauterine system [median score category: 76–99, interquartile range (51–75 to 100), n = 50; adjusted odds ratio 0.55, 95% confidence interval 0.26 to 1.17; p = 0.12]. Rates of amenorrhoea were much higher in those allocated ulipristal acetate compared with the levonorgestrel-releasing intrauterine system (12 months: 64% vs. 25%, adjusted odds ratio 7.12, 95% confidence interval 2.29 to 22.2). There was no evidence of a difference in other participant-reported outcomes. There were no cases of endometrial malignancy and no hepatotoxicity due to ulipristal acetate use. Mechanistic study results Ulipristal acetate produced a reversible reduction in endometrial cell proliferation, as well as reversible alteration of other endometrial cellular markers. Ulipristal acetate did not produce a reduction in the volume of the uterus irrespective of coexisting fibroids, nor an effect on uterine microvascular blood flow. Limitations The urgent safety measures and premature closure of recruitment impacted final sample size. Conclusions We found no evidence of a difference in quality of life between the two treatments, but ulipristal acetate was superior to levonorgestrel-releasing intrauterine system at inducing amenorrhoea. Ulipristal acetate currently has restricted availability due to concerns regarding hepatotoxicity. Future work There is a need to develop new, safe, effective and fertility-sparing medical treatments for heavy menstrual bleeding. The observed acceptability and effectiveness of ulipristal acetate warrants further research into the selective progesterone receptor modulator class of pharmacological agents. Study registration This trial is registered as ISRCTN 20426843. Plain language summary What is the problem? Heavy menstrual bleeding is a common condition that affects the lives of many women. A hormone-releasing coil, fitted inside the womb, is effective in making periods lighter but can make them less regular. A medicine called ulipristal acetate or UPA, taken as a pill, has been shown to reduce rapidly menstrual bleeding in women with large, non-cancerous tumours in the womb, known as fibroids. It was not known whether UPA is effective in women who have heavy periods but do not have fibroids of any significant size. What did we plan to do? To find out which treatment was better at controlling heavy periods, 236 women were enrolled in a clinical trial where they received either the hormone coil or UPA. The choice of treatment was made at random by a computer rather than the wishes of researchers or patients, to ensure a fair comparison. Participants completed questionnaires about their symptoms and life quality at intervals up to 1 year. Twice during the trial, medicines regulatory authorities raised safety concerns about UPA causing liver problems. This resulted in the introduction of regular blood tests. The second time, recruitment to the trial stopped early. What did we find? Both treatments improved the symptoms of heavy menstrual bleeding in the majority of women. We found no evidence that UPA was better overall after 1 year of treatment, compared with the hormone coil, although fewer women on UPA continued to have periods. Laboratory studies on samples taken from the lining of the womb showed temporary changes due to UPA, which disappeared after treatment stopped. What does this mean? Both treatments improve the symptoms of menstrual bleeding and general wellbeing. Because of safety concerns UPA is not available for all women with heavy menstrual bleeding and new, safer medical treatments are needed. Scientific summary Background Heavy menstrual bleeding (HMB) is the most common gynaecological problem in women of reproductive age, affecting one in four women, and has adverse profound impact on health-related quality of life. Common causes of HMB include structural abnormalities such as uterine fibroids, adenomyosis and dysfunction of the endometrium. The levonorgestrel-releasing intrauterine system (LNG-IUS) is a proven, effective long-term treatment but about one-third of women cease use by two years due to unpredictable bleeding, hormonal adverse effects or lack of effectiveness. Furthermore, fibroids can make the LNG-IUS less effective. Alternative medical options for HMB exist, but are either less effective or associated with unacceptable adverse effects. Surgical interventions are effective at inducing bleeding control and improving quality of life but are typically incompatible with future fertility. Effective long-term medical treatments for women with HMB are needed. A class of drugs called selective progesterone receptor modulators (SPRMs) have potential to provide an effective oral treatment for HMB. SPRMs bind with progesterone receptors, resulting in tissue-specific effects in both myometrial and overlying endometrial tissue as well as shrinking uterine fibroids. The SPRM ulipristal acetate (UPA) has been successfully used to treat fibroids, but we do not know how effective UPA is for the treatment of women with HMB who do not have fibroids. Furthermore, there are uncertainties regarding the mechanism and location of action of UPA, as well as its longer-term safety. SPRMs induce distinctive, non-physiological endometrial changes, which can be confused with endometrial hyperplasia. More recently there has been concern regarding the potential for UPA to cause drug-induced liver injury (DILI). Post marketing surveillance reports resulted in a temporary halt in UPA use in 2018 and 2020. Use of UPA has since been reinstated since January 2021, albeit in a restricted context, reflecting the paucity of existing alternatives for HMB. Given these uncertainties, we designed the UCON trial to evaluate the safety, tolerability and effectiveness of UPA on HMB and to understand its mechanism of action. Clinical objectives Primary objective: to determine whether UPA is more effective at reducing the burden of HMB symptoms than LNG-IUS after 12 months of treatment. Secondary objectives: Ascertain whether UPA use beyond 3 months’ and up to 12 months’ duration is associated with histological changes to the endometrium and, if so, whether this compromises safety. Ascertain whether UPA is more effective than LNG-IUS in relation to menstrual blood loss, sexual activity, generic quality of life, satisfaction with treatment, patient-reported adverse events, and compliance at 3, 6 and 12 months. Determine the response to UPA and LNG-IUS treatment difference in the presence of uterine fibroids in terms of (1) alleviation of HMB and (2) change in uterine/fibroid volume. Collect data on liver function in women taking UPA, once safety concerns were raised. Mechanism of action study objectives To understand how UPA causes a reduction in menstrual bleeding and uterine/fibroid volume in women with HMB, we determined whether UPA administration: Alters endometrial cell function (e.g., and not limited to, proliferation, apoptosis, expression of steroid receptors, tumour suppressors and inflammatory mediators). Reduces blood plasma flow in the endometrium, uterine myometrium and fibroid tissue. Alters the volume fraction of the extracellular matrix in these tissues. Reduces uterine and fibroid volume. Design This was a randomised, open-label, parallel group, multicentre trial with embedded mechanistic study. Methods Setting The trial recruited participants in 10 sites in NHS hospital settings across the UK between 2015 and 2020. The mechanism of action study was conducted solely at the Edinburgh site. Participants For the main trial, informed consent was sought from premenopausal women (aged 18–50 years) with self-reported HMB, no contraindications to LNG-IUS or UPA. Those with uterine size greater than equivalent 14-week size or with submucosal fibroids >2cm were excluded. Other exclusion criteria relating to use of other treatments and current health status were applied, including history of severe hepatic impairment. Screening and randomisation Participants were recruited in gynaecology clinics by research nurses who screened patient referral letters. Following consent, haemoglobin and circulating estradiol levels were assessed, clinical history elicited and transvaginal and/or abdominal ultrasound and endometrial biopsy were obtained if not previously performed. Following this, and confirmation of eligibility, randomisation was via a web-based central service based at Birmingham Clinical Trials Unit to allocate women in a 1 : 1 ratio using a minimisation algorithm. Screened patients in Edinburgh were offered the opportunity to participate in the mechanistic study. Interventions and follow-up Those allocated to UPA received three courses of treatment, each course comprising a daily 5-mg oral dose for 12 weeks followed by a four-week break. Those allocated to the LNG-IUS had it fitted in hospital or primary care. Participants allocated to UPA returned to hospital to collect their repeat prescription at 3 and 6 months, and may have been seen by a member of the care team if required. They were then seen in clinic at 12 months for ultrasound scan (USS) and haemoglobin/serum estradiol measurement. Those allocated to the LNG-IUS group attended USS at 12 months. Follow-up at interim time points was conducted by postal questionnaire. Those partaking in the mechanism of action study underwent magnetic resonance imaging (MRI) following randomisation and at the end of treatment cycles two and three. An additional endometrial biopsy was obtained at the end of treatment cycle two. Outcome measures Primary Condition-specific quality of life score as measured by the menorrhagia multi-attribute scale (MMAS) questionnaire at 12 months. Summary scores range from 0 (worst affected) to 100 (not affected). Secondary Condition-specific quality of life score as measured by MMAS at 3 and 6 months Menstrual bleeding (pictorial blood loss assessment chart)* Cycle regularity (ordinal four-point scale)* Duration of period (ordinal three option scale)* Pelvic pain during periods, intercourse and at other times (visual analogue scales; 0 = best outcome, 10 = worse outcome)* Uterine fibroid symptom and quality of life instrument (only given to women diagnosed with fibroids)* Sexual function (sexual activity questionnaire)* Generic quality of life (EQ-5D-5L)* Satisfaction with treatment outcome (five-point Likert scale) Participant rating of effect of treatment on HMB over 12 months (four-point Likert scale) Whether participant is willing to recommend the treatment to a friend (yes/no) Surgical intervention Adherence to trial treatments and reasons for changing treatment, as reported by the participant Serious adverse events and reactions Uterine volume, evidence of adenomyosis, presence of fibroids, largest fibroid volume, endometrial thickness, endometrial appearance, evidence of ovarian cysts at 12 months (USS) Endometrial biopsy at 12 months (UPA group only) Liver function tests, from 20 March 2018 every four weeks (UPA group only) Haemoglobin and serum estradiol at 12 months * assessed at 3, 6 and 12 months Mechanism of action A: Effects on cellular markers of endometrial steroid receptors and metabolising enzymes (governing local endometrial steroid [ligand] availability), cell proliferation, cell survival (apoptosis); detection of genes implicated in control of proliferation in endometrium; B: Effects on uterine/fibroid structure addressed by obtaining volume measurements for the whole uterus, and for the total volume of fibroids when present, by using high resolution structural MRI and stereology; and C: Uterine vascularity using dynamic contrast-enhanced MRI (DCE-MRI). Urgent safety measures In November 2017, the European Medicines Agency (EMA) issued an urgent drug alert for UPA due to a small number of reports of serious liver injury. A detailed investigation by the regulatory authorities was undertaken and it was found that eight reports of serious liver injury were reported in Europe from an estimated 740,000 women using UPA for uterine fibroids. Restrictions on prescribing UPA were subsequently issued and the trial sponsor implemented an urgent safety measure (USM) in February 2018, which halted recruitment. Those allocated UPA were allowed to complete their current course of UPA treatment but not commence any further outstanding courses. In addition, they commenced monthly assessment of LFTs (as well as a post treatment test approximately 2 weeks after the last course of UPA). In August 2018, the halt on UPA prescribing was lifted and recruitment to UCON resumed in October 2018 with additional safety measures in place, including exclusion of those with any history of liver disease [defined as levels of alanine transaminase (ALT) or aspartate aminotransferase (AST) of more than two times the upper limit of normal] and LFT monitoring as described above. UPA was stopped if women had an ALT or AST more than three times the upper limit of normal and a hepatology opinion was sought. In March 2020, the EMA temporarily suspended use of UPA a second time due to ongoing concerns regarding hepatotoxicity and a further USM was issued. All treatment courses of UPA were immediately stopped. In view of the second USM, the investigators, in discussion with the funder, chose premature closure of recruitment to the study but planned follow-up actions continued as per protocol. Statistical considerations The study was powered to detect a clinically useful difference in MMAS score (13 points) between the two groups at twelve months. To detect a difference of this size [0.5 standard deviations (SDs)] with 90% power (p = 0.05) would require 86 women in each group (172 in total). To allow for a 20% loss to follow-up or pregnancy, the sample size was inflated to 220 women. Following the initial USM, this figure was inflated to 302 women to ensure that there were adequate responses in the primary analysis population (defined below) to detect the same size of difference. The original planned primary analysis population comprised all participants, regardless of adherence to treatment, employing suitable regression models to estimate difference between groups. The enforced non-compliance as a result of the withdrawal of UPA had substantial implications for the validity of the data reported by participants. It was therefore necessary to redefine analysis populations, considering the restrictions that prevented women taking their courses of UPA might influence their responses and any other new potential biases that may be apparent in either group due to, for example, knowledge of the safety concerns around UPA. The primary analysis population would now comprise participants with questionnaire responses received prior to the first USM (12 February 2018), along with questionnaire responses from participants recruited following the study restart (18 October 2018) provided that the responses were returned before the second USM (17 March 2020). Results Main trial A total of 4471 women were approached for the study, with 236 consented and randomised, of whom 181 (77%) returned primary outcome data at 12 months (103 within the primary analysis population). Baseline data were comparable between groups; 92% were white, 34% had fibroids and 8% adenomyosis. In the primary analysis population, MMAS scores substantially improved in both arms, but at 12 months there was no evidence of a difference between the UPA [median score category: 76–99, IQR (51–75 to 100), n = 53] and LNG-IUS [median score category: 76–99, IQR (51–75 to 100), n = 50] groups (adjusted OR 0.55, 95% CI 0.26 to 1.17; p = 0.12). Rates of amenorrhoea where much higher in those allocated UPA compared with LNG-IUS at each time point (3 months: 56% vs. 5%, adjusted OR 29.3, 95% CI 7.37 to 116; 6 months 53% vs. 10%, adjusted OR 11.7 95% CI 3.78 to 36.0; 12 months: 64% vs. 25%, adjusted OR 7.12, 95% CI 2.29 to 22.2). There was no evidence of a difference in the other patient-reported outcomes although there was considerable uncertainty. In those with uterine fibroids, there were no changes in fibroid or uterine volume in either treatment group at 12 months. On endometrial biopsy, seven participants (8%) had evidence of progesterone receptor modulator associated endometrial changes (PAEC) at 12 months, although none was observed at a further 6 months post treatment; there were no cases of endometrial malignancy. Rates of serious adverse events were low, and no patients required admission to hospital for management of deranged liver function tests due to UPA use. Mechanism of action study Effects of UPA administration on the uterus: UPA produced a reduction in cell proliferation in the endometrium, as well as alteration of other local endometrial cellular markers (steroid receptor and steroid metabolising enzyme expression) creating a local endometrial oestrogenic environment. The effects on endometrial cellular markers were reversed upon withdrawal of UPA treatment. Stereological analysis in 19 patients showed that UPA did not produce a reduction in the volume of the uterus, irrespective of coexisting fibroids or adenomyosis. DCE-MRI in 15 patients showed that UPA appears not to have an effect on uterine blood flow. If adenomyosis was present in the uterus, there was a significant increase in plasma volume in the endometrium. However, one of the five women with adenomyosis also had fibroids. Effects of UPA administration on uterine fibroids: DCE-MRI studies showed that UPA produced an average reduction in plasma volume in 11 fibroids, which may be interpreted as being due to a reduction in extracellular matrix components. This finding was not supported by stereological analysis, which failed to show a reduction in the total volume of fibroids in eight patients. However, it should be noted that the number of subjects studied is small. Conclusions Both UPA and LNG-IUS alleviated the adverse impact of heavy menstrual bleeding on quality of life but we found no evidence of a difference between groups over 12 months. UPA was evidently superior to LNG-IUS in terms of inducing amenorrhoea. We observed no difference in reduction in the volume of the uterus, whether or not fibroids were present and no difference in change in the volume of fibroids was observed. Analysis of selected markers of endometrial cellular function demonstrated UPA modulation of the progesterone receptor, resulting in molecular and cellular alteration in steroid receptors within the endometrium, consistent with the development of a local (endometrial) oestrogenic microenvironment. Despite this, there is no evidence of pathological endometrial changes. We demonstrated that alteration in the endometrial microenvironment reverses on cessation of UPA treatment, a key factor for a medical treatment of HMB, particularly for those who wish to preserve fertility. UPA now has restricted availability due to concerns regarding hepatotoxicity. Findings from this study may offer insights into mechanism of action of other SPRM class members. New, effective and acceptable oral medical treatment options are needed to address an important unmet clinical need. Recommendations for research Further studies of medical treatments for HMB Developing other SPRMs, not associated with DILI Other hormonal/non-hormonal medical treatments for HMB Patient populations that encompass both the symptoms of HMB and underlying aetiologies, including structurally normal uterus, adenomyosis and small fibroids Study design with outcome measures impact on menstrual bleeding pattern, pelvic pain and impact on haemoglobin and iron-deficiency, as well as quality of life Qualitative studies to determine what are the most important outcomes to women who suffer HMB Study registration This trial is registered as ISRCTN 20426843. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation Programme and will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No. 8. See the NIHR Journals Library website for further project information.

Abstract Efforts to preserve, protect and restore ecosystems are hindered by long delays between data collection and analysis. Threats to ecosystems can go undetected for years or decades as a result. Real‐time data can help solve this issue but significant technical barriers exist. For example, automated camera traps are widely used for ecosystem monitoring but it is challenging to transmit images for real‐time analysis where there is no reliable cellular or WiFi connectivity. We modified an off‐the‐shelf camera trap (Bushnell™) and customised existing open‐source hardware to create a ‘smart’ camera trap system. Images captured by the camera trap are instantly labelled by an artificial intelligence model and an ‘alert’ containing the image label and other metadata is then delivered to the end‐user within minutes over the Iridium satellite network. We present results from testing in the Netherlands, Europe, and from a pilot test in a closed‐canopy forest in Gabon, Central Africa. All reference materials required to build the system are provided in open‐source repositories. Results show the system can operate for a minimum of 3 months without intervention when capturing a median of 17.23 images per day. The median time‐difference between image capture and receiving an alert was 7.35 min, though some outliers showed delays of 5‐days or more when the system was incorrectly positioned and unable to connect to the Iridium network. We anticipate significant developments in this field and hope that the solutions presented here, and the lessons learned, can be used to inform future advances. New artificial intelligence models and the addition of other sensors such as microphones will expand the system's potential for other, real‐time use cases including real‐time biodiversity monitoring, wild resource management and detecting illegal human activities in protected areas.

The title sulfones, 2,3-diphenyl-2,3-dihydro-4H-1,3-benzothiazine-1,1,4-trione, C20H15NO3S, and 2,3-diphenyl-2,3-dihydro-4H-pyrido[3,2-e][1,3]thiazine-1,1,4-trione, C19H14N2O3S, crystallize in space group P21/n with two molecules in each of the asymmetric units and have almost identical unit cells and extended structures. In both structures, the thiazine rings exhibit a screw-boat pucker. The intermolecular interactions observed are C—H...O-type hydrogen bonds and parallel partial π–π stacking between the fused aromatic rings (benzo- or pyrido-) of the core of the molecules within each asymmetric unit, and also connecting to molecules with translational periodicity in the a-axis direction in what can be described as columns (two per asymmetric unit) of stacked molecules with alternating chirality. The pendant phenyl groups of both molecules do not participate in aromatic ring interactions.

The syntheses and crystal structures of two thiazinone compounds, namely, rac-2,3-diphenyl-2,3,5,6-tetrahydro-4H-1,3-thiazine-1,1,4-trione, C16H15NO3S, in its racemic form, and N-[(2S,5R)-1,1,4-trioxo-2,3-diphenyl-1,3-thiazinan-5-yl]acetamide, C18H18N2O4S, in an enantiopure form, are reported. The thiazine rings in the two structures differ in their puckering, as a half-chair in the first and a boat pucker in the second. The extended structures for both compounds have only C—H...O-type interactions between symmetry-related molecules, and exhibit no π–π stacking interactions in spite of each having two phenyl rings.

DC microgrids (DCMGs), typically envisioned with high bandwidth communications, may well expand their application range by considering additional autonomous control strategies, especially to increase resiliency in contingency situation. These strategies are based on the droop control methods, enabling voltage regulation and proportional load sharing based only on local measurements. Control challenges arise when coordinating the output of multiple DCMGs, each composed of several distributed energy resources through bus-to-bus transactional converters. This paper proposes an autonomous control strategy for transactional converters when multiple DCMGs are connected through a common bus. This control strategy seeks to match the external bus voltage with the internal bus voltage, balancing power. Three case scenarios are considered: standalone operation of each DCMG, excess generation on one DCMG, and generation deficit in one DCMG. Results using Sandia National Laboratories’ Secure Scalable Microgrid Simulink library, and models developed in MATLAB are compared. These results demonstrated that the proposed control strategy supported the advantage of seamless operation with and without local generation-load mismatches and expanded the range of autonomous operation between DCMGs.

Wonil Park,1,2 Jaesung Lee,1 Kwangseok Hong,3 Hun-Young Park,4,5 Saejong Park,6 Nahyun Kim,1 Jonghoon Park1 1Exercise Nutrition and Biochemistry Laboratory, Department of Physical Education, Korea University, Seoul, South Korea; 2Physical Education Laboratory, Chung-Ang University, Seoul, South Korea; 3Department of Physical Education, College of Education, Chung-Ang University, Seoul, South Korea; 4Department of Sports Medicine and Science, Graduate School, Konkuk University, Seoul, South Korea; 5Physical Activity and Performance Institute (PAPI), Konkuk University, Seoul, South Korea; 6Department of Sports Science, Korea Institute of Sport Science, Seoul, South KoreaCorrespondence: Jonghoon Park, Exercise Nutrition and Biochemistry Laboratory, Department of Physical Education, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, South Korea, Tel/Fax +82 (2) 3290-2315, Email jonghoonp@korea.ac.krPurpose: Preventive or therapeutic interventions are key to maintaining independence in pre-frail and/or frail elderly. Therefore, we investigated whether multi-component interventions were effective in physical fitness levels and vascular functions in pre-frail older women.Patients and Methods: Sixty participants aged ≥ 65 years (81.5 ± 4.3 yrs) were divided equally into control group, diet group, aerobic exercise and diet group, and aerobic exercise with electromyostimulation and diet group. For 8 weeks, the participants received a set of protein-added meals twice daily on weekdays. The aerobic exercise groups performed 45 mins of stepping exercise at 50– 70% of the maximal heart rate for 3 days/week, and the aerobic exercise with electromyostimulation was applied on each limb in 8 weeks. Blood pressure, physical fitness, cardiovascular biomarkers, pulse wave velocity, and flow-mediated dilation were measured before and after the 8-week.Results: There were no group differences in age, height, weight, body mass index, free fat mass, and %body fat at baseline. The right grip strength significantly increased in the diet group, aerobic exercise and diet group, and aerobic exercise with electromyostimulation and diet group (p < 0.05). Short physical performance battery, 6-min walking distance, and flow-mediated dilation significantly increased in the aerobic exercise and diet group and aerobic exercise with electromyostimulation and diet group (p < 0.05). Blood pressure and pulse wave velocity did not differ between interventions. High-density lipoprotein-cholesterol levels significantly increased after 8 weeks in all intervention groups (p < 0.05). There were no significant differences in glucose, HbA1c, total cholesterol, low-density lipoprotein-cholesterol, triglyceride, insulin, Homeostatic Model Assessment for Insulin Resistance, nitric oxide, and C-reactive protein levels.Conclusion: These results show that multi-component interventions appear to improve physical fitness and vascular function in pre-frail older women. Thus, possible strategies to prevent early frailty including proper nutrition and exercise may be needed.Keywords: pre-frail, protein-added, aerobic exercise, electromyostimulation, physical fitness, vascular function

Hee Jeong Kim,1,&ast; Jisun Lee,1,2,&ast; Hyun Jung Lee1,2 1Department of Obstetrics and Gynecology, Kyungpook National University Hospital, Daegu, Republic of Korea; 2Department of Obstetrics and Gynecology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea&ast;These authors contributed equally to this workCorrespondence: Hyun Jung Lee, Department of Obstetrics and Gynecology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea, Tel +821035328741, Fax +82534237905, Email hyunjunglee@knu.ac.krAbstract: In patients with acute abdomen, especially during pregnancy, it is difficult to suspect myoma torsion initially due to its rarity. However, when these patients have a solid mass in the pelvis, torsion of uterine fibroids or adnexa and large infarct inside leiomyoma are the main diagnoses that must be differentiated. We report a case of uterine myoma torsion mimicking ovarian torsion in the second trimester of pregnancy that was successfully managed by laparoscopic myomectomy. A 31-year-old pregnant woman with severe right lower abdominal pain at 21 + 2 weeks of gestation was transferred. On ultrasonography, the appendix appeared normal but a solid mass (7.0× 4.0 cm) containing a cystic portion was observed on the right side of the uterus. The mass had no blood flow and tenderness appeared on the transducer pressure. Pelvic magnetic resonance imaging revealed a 7 cm edematous mass with low signal intensity on T2-weighted image, instead of a normal-looking right ovary. These findings led to suspicion of right ovarian torsion. One day after admission, the patient’s symptoms worsened with acute elevation in C-reactive protein (CRP) (4.55 mg/dL) and neutrophile-to-lymphocyte ratio (NLR) (10.1), despite the use of analgesics and tocolytics, and uterine contractions were not controlled. Emergency surgery was performed, and the final diagnosis was a uterine leiomyoma torsion. Laparoscopic myomectomy was successfully performed, and symptoms were relieved after operation. She had full term vaginal delivery without complication. The differential diagnosis between myoma torsion and ovarian torsion is challenging in patients with acute abdomen during pregnancy. To exclude ovarian torsion, a comparison with an asymptomatic contralateral normal ovary will be very helpful. When fibroids are found in mothers with an acute abdomen, follow-up of NLR and CRP is related to preterm labor and can be a reference point for considering surgery.Keywords: ovarian torsion, leiomyoma, pregnancy, laparoscopy, myomectomy

Abstract Palaeontological animal bone deposits are rarely investigated through research partnerships where the local First Nations communities have a defining hand in both the research questions asked and the research processes. Here we report research undertaken through such a partnership approach at the iconic archaeological site of Cloggs Cave (GunaiKurnai Country, East Gippsland), in the southern foothills of SE Australia's Great Dividing Range. A new excavation was combined with detailed chronometric dating, high‐resolution 3D mapping and geomorphological studies. This allowed interpretation of a sequence of stratigraphic layers spanning from a lowermost excavated mixed layer dated to between 25,640 and 48,470 cal BP, to a dense set of uppermost, ash layers dated to between 1460 and 3360 cal BP. This long and well‐dated chronostratigraphic sequence enabled temporal trends in the abundant small mammal remains to be examined. The fossil assemblage consists of at least 31 taxa of mammals which change in proportions through time. Despite clear evidence that the Old Ancestors repeatedly carried vegetation into the cave to fuel cool fires (no visible vegetation grows in Cloggs Cave), we observed little to no evidence of cooking fires or calcined bone, suggesting that people had little involvement with the accumulation of the faunal remains. Small mammal bones were most likely deposited in the cave by large disc‐faced owls, Tyto novaehollandae (Masked Owl) or Tyto tenebricosa (Sooty Owl). Despite being well dated and largely undisturbed, the Cloggs Cave assemblage does not appear to track known Late Quaternary environmental change. Instead, the complex geomorphology of the area fostered a vegetation mosaic that supported mammals with divergent habitat preferences. The faunal deposit suggests a local ancestral landscape characterised by a resilient mosaic of habitats that persisted over thousands of years, signalling that the Old Ancestors burned landscape fires to encourage and manage patches of different vegetation types and ages within and through periods of climate change. Read the free Plain Language Summary for this article on the Journal blog.

Yoonmi Ji,1 Tae Young Choi,1 Jonghun Lee,1 Seoyoung Yoon,1 Geun Hui Won,1 Hyerin Jeong,2 Seung Wan Kang,2,3 Jun Won Kim1 1Department of Psychiatry, Daegu Catholic University School of Medicine, Daegu, Republic of Korea; 2iMediSync Inc, Seoul, Republic of Korea; 3National Standard Reference Data Center for Korean EEG, Seoul National University College of Nursing, Seoul, Republic of KoreaCorrespondence: Jun Won Kim, Department of Psychiatry, Daegu Catholic University School of Medicine, 3056-6 Daemyeong-4 dong, Nam-gu, Daegu, 705-718, Republic of Korea, Tel +82-53-650-4786, Fax +82-53-623-1694, Email f_affection@naver.comPurpose: This study used quantitative electroencephalography (QEEG) to investigate the characteristics of attention-deficit/hyperactivity disorder (ADHD) subtypes in children.Patients and Methods: There were 69 subjects (42 with ADHD and 27 neurotypical (NT)) in this study. A semi-structured interview was conducted with each participant for psychiatric diagnostic evaluation. We measured the absolute and relative power in 19 channels and analyzed QEEG using the following frequency ranges: delta (1– 4 Hz), theta (4– 8 Hz), alpha 1 (8– 10 Hz), alpha 2 (10– 12 Hz), beta 1 (12– 15 Hz), beta 2 (15– 20 Hz), beta 3 (20– 30 Hz), and gamma (30– 45 Hz). Group analyses and EEG noise preprocessing were conducted using iSyncBrain, a cloud-based, artificial intelligence EEG analysis platform. Analysis of covariance adjusted for IQ, age, and sex was used.Results: QEEG analysis revealed three ADHD subtypes, characterized by (A) elevated relative fast alpha and beta power, (B) elevated absolute slow frequency (delta and theta power), or (C) elevated absolute and relative beta power. A significant difference was found in the Korean ADHD Rating Scale (K-ARS) among the four groups (df=3, F=8.004, p< 0.001); group C had the highest score (25.31± 11.16), followed by group A (21.67± 13.18). The score of group B (12.64± 7.84) was similar to that of the NT group (11.07± 6.12) and did not reach the cut-off point of the K-ARS. In the Wender–Utah Rating Scale (WURS), group B score (55.82± 23.17) was significantly higher than the NT group score (42.81± 13.26).Conclusion: These results indicate that children with ADHD do not constitute a neurophysiologically homogenous group. Children with QEEG subtype B (elevated slow frequency) may be difficult to distinguish from normal children using the K-ARS, which is the most common screening tool for ADHD. Moreover, parents of children with this subtype may be less sensitive to observing ADHD symptoms.Keywords: attention-deficit/hyperactivity disorder, quantitative electroencephalography, subtype, clinical characteristics

Jungmin Lee,1 Jhordin James C Montegrico2 1School of Nursing, Hallym University, Chuncheon, Gangwon-do, 24252, South Korea; 2School of Nursing, University of North Carolina at Charlotte, Charlotte, NC, 28223, USACorrespondence: Jungmin Lee, School of Nursing, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-do, 24252, South Korea, Tel +82-33-248-2728, Email j_lee0624@hallym.ac.krBackground and Purpose: Currently, no instrument exists to measure condom use behavior among Korean college students. This study aims to create a cross-cultural adaptation of the English version of the sexual risk behavior beliefs and self-efficacy (SRBBS) instrument into Korean and examine the psychological properties of the translated version.Methods: Participants included 169 female college students recruited using convenience sampling techniques. Validity and reliability were examined using item and factor analyses and Cronbach’s alpha. Seventeen items were ultimately selected for analysis.Results: Four factors were extracted through factor analysis, representing 63.80% of the variance. Following two modifications, it showed a good model fit in the KR-SRBBS.Conclusion: The KR-SRBBS may be suitable for evaluating sexual behavior and self-efficacy among female college students.Keywords: factor analysis, psychometrics, self-efficacy, sexual behavior, women

The supplementation of live yeast in pig diets is common in the post-weaning phase due to its prebiotic and probiotic effects, but little is known regarding the potential of feeding live yeast to gestating or lactating sows for transferring such benefits to their offspring through maternal programming. The objective of this study was to investigate the effects of live yeast supplementation in sow diets during late gestation and lactation on their reproductive performance and its impact on offspring performance and gut microbiomes in the post-weaning period. Three dietary treatments were imposed on 92 mixed-parity sows during late gestation and lactation based upon the inclusion level of live yeast in corn/soybean meal-based diets: Control (0% yeast), Low (0.1% yeast), and High (0.5% yeast). Nursery pigs in the Low group displayed the highest feed intake in the post-weaning period and greater total gain and average daily gain in comparison to pigs in the High group. The gut microbiomes of nursery pigs differed in composition according to maternal dietary treatment groups at days 4 and 28 post weaning, highlighting higher abundances of bacterial genera typically associated with fermentation roles in the gut microbiomes of offspring of yeast-fed sows. These results indicate that the supplementation of live yeast in sow diets, depending on the inclusion level, may result in beneficial performance and specific microbiome traits for their offspring in the post-weaning period.

XTE J1829−098 is a transient X-ray pulsar with a period of ∼7.8 s. It is a candidate Be star system, although the evidence for this is not yet definitive. We investigated the twenty-year-long X-ray light curve using the Rossi X-ray Timing Explorer Proportional Counter Array (PCA), Neil Gehrels Swift Observatory Burst Alert Telescope, and the Monitor of All-sky X-ray Image. We find that all three light curves are clearly modulated on the ∼244 days orbital period previously reported from PCA monitoring observations, with outbursts confined to a narrow phase range. The light curves also show that XTE J1829−098 was in an inactive state between approximately 2008 December and 2018 April, and no strong outbursts occurred. Such behavior is typical of Be X-ray binary systems, with the absence of outbursts likely related to the dissipation of the Be star's decretion disk. The mean outburst shapes can be approximated with a triangular profile and, from a joint fit of this to all three light curves, we refine the orbital period to 243.95 ± 0.04 days. The mean outburst profile does not show any asymmetry and has a total phase duration of 0.140 ± 0.007. However, the PCA light curve shows that there is considerable cycle-to-cycle variability of the individual outbursts. We compare the properties of XTE J1829−098 with other sources that show short phase-duration outbursts, in particular GS 1843−02 (2S 1845−024), which has a very similar orbital period, but longer pulse period, and whose orbit is known to be highly eccentric.

We confirm a massive sub-Neptune-sized planet on a P = 22.8 days orbit around the star TOI-1824 ( T _eff = 5200 K, V = 9.7 mag). TESS first identified TOI-1824 b (formerly TOI-1824.01) as an object of interest in 2020 April after two transits in Sector 22 were matched with a single transit in Sector 21. TOI-1824 was subsequently targeted for ground-based Doppler monitoring with Keck-HIRES and APF-Levy. Using a joint model of the TESS photometry, radial velocities, and Ca ii H and K emission measurements as an activity indicator, we find that TOI-1824 b is an unusually dense sub-Neptune. The planet has a radius R _p = 2.63 ± 0.15 R _⊕ and mass M _p = 18.5 ± 3.2 M _⊕ , implying a bulk density of 5.6 ± 1.4 g cm ^−3 . TOI-1824 b's mass and radius situate it near a small group of “superdense sub-Neptunes” ( R _p ≲ 3 R _⊕ and M _p ≳ 20 M _⊕ ). While the formation mechanism of superdense sub-Neptunes is a mystery, one possible explanation is the constructive collision of primordial icy cores; such giant impacts would drive atmospheric escape and could help explain these planets' apparent lack of massive envelopes. We discuss TOI-1824 b in the context of these overdense planets, whose unique location in the exoplanet mass–radius plane make them a potentially valuable tracer of planet formation.

The Transiting Exoplanet Survey Satellite (TESS) has discovered hundreds of new worlds, with TESS planet candidates now outnumbering the total number of confirmed planets from Kepler. Owing to differences in survey design, TESS continues to provide planets that are better suited for subsequent follow-up studies, including mass measurement through radial velocity (RV) observations, compared to Kepler targets. In this work, we present the TESS-Keck Survey’s (TKS) Mass Catalog: a uniform analysis of all TKS RV survey data that has resulted in mass constraints for 126 planets and candidate signals. This includes 58 mass measurements that have reached ≥5 σ precision. We confirm or validate 32 new planets from the TESS mission either by significant mass measurement (15) or statistical validation (17), and we find no evidence of likely false positives among our entire sample. This work also serves as a data release for all previously unpublished TKS survey data, including 9,204 RV measurements and associated activity indicators over our three-year survey. We took the opportunity to assess the performance of our survey and found that we achieved many of our goals, including measuring the mass of 38 small (

JWST has ushered in an era of unprecedented ability to characterize exoplanetary atmospheres. While there are over 5000 confirmed planets, more than 4000 Transiting Exoplanet Survey Satellite (TESS) planet candidates are still unconfirmed and many of the best planets for atmospheric characterization may remain to be identified. We present a sample of TESS planets and planet candidates that we identify as “best-in-class” for transmission and emission spectroscopy with JWST. These targets are sorted into bins across equilibrium temperature T _eq and planetary radius R _p and are ranked by a transmission and an emission spectroscopy metric (TSM and ESM, respectively) within each bin. We perform cuts for expected signal size and stellar brightness to remove suboptimal targets for JWST. Of the 194 targets in the resulting sample, 103 are unconfirmed TESS planet candidates, also known as TESS Objects of Interest (TOIs). We perform vetting and statistical validation analyses on these 103 targets to determine which are likely planets and which are likely false positives, incorporating ground-based follow-up from the TESS Follow-up Observation Program to aid the vetting and validation process. We statistically validate 18 TOIs, marginally validate 31 TOIs to varying levels of confidence, deem 29 TOIs likely false positives, and leave the dispositions for four TOIs as inconclusive. Twenty-one of the 103 TOIs were confirmed independently over the course of our analysis. We intend for this work to serve as a community resource and motivate formal confirmation and mass measurements of each validated planet. We encourage more detailed analysis of individual targets by the community.