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Abstract We use Mars Atmosphere and Volatile EvolutioN observations of the upstream solar wind, and Mars Express observations of ionospheric electron densities and magnetic fields, to study how the topside ionosphere (>320 km) of Mars is affected by variations in solar wind dynamic pressure. We find that high solar wind dynamic pressures result in the topside ionosphere being depleted of plasma at all solar zenith angles, coincident with increased induced magnetic field strengths. The depletion of topside plasma in response to high solar wind dynamic pressures is observed in both weak and strong crustal magnetic field regions. Taken together, our results suggest that high solar wind dynamic pressures lead to ionospheric compression, increased ion escape, and reduced day‐to‐night plasma transport in the high‐altitude nightside ionosphere.

Existing protected areas are anchors for conservation. Safeguarding flora and fauna within their peripheral areas is essential to maintaining their integrity and to potential increases to the area under effective conservation. With the decline in tropical forests, initiatives to increase the area of undisturbed forests under strict protection, particularly those neighboring protected areas, is of critical importance. Applied research has informed such land-management decisions for areas surrounding the Nouabalé-Ndoki National Park (NNNP) in Republic of Congo since the park's inception three decades ago. Here, we present results of the first systematic line transect survey of great ape nests conducted in the Djéké Triangle, a 100 km 2 unlogged continuous forest in the Kabo Forestry Management Unit adjacent to the NNNP. Distance sampling methods applied along 26 line transects on two different occasions (2016 and 2018, with total effort of 69.4 km) provided density estimates of 0.75 (95% confidence interval (CI) 0.52-1.09) and 0.61 (95% CI 0.40-0.92) chimpanzees/km 2 and 2.15 (95% CI 1.36-3.40) and 1.19 (95% CI 0.78-1.82) gorillas/km 2 for each of the two surveys, respectively. Estimated ape densities were compared to others across the landscape. The findings provide a unique baseline in an area that supports ongoing behavioral research and future gorilla tourism opportunities in the Djéké Triangle. More importantly, results provided empirical evidence of the environmental value and strategic conservation importance supporting inclusion of the Djéké Triangle into the NNNP in 2023. These long-term monitoring results inform best-practice standards and ape tourism certification., Competing Interests: Declarations Conflict of interest The authors declare no conflict of interest., (© 2024. The Author(s), under exclusive licence to Japan Monkey Centre.)

Background: An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with an attack rate of 55% (22/40 workers) occurred at a public-facing office in England from August to September 2021. Published evidence regarding outbreaks in office workplaces remains limited., Aims: To describe an investigation of workplace- and worker-related risk factors following an outbreak of SARS-CoV-2 in a public-facing office., Methods: The COVID-19 (coronavirus disease 2019) Outbreak Investigation to Understand Transmission (COVID-OUT) study undertook an investigation of the outbreak. This included surface sampling, occupational environmental assessment, molecular and serological testing of workers, and detailed questionnaires., Results: Despite existing COVID-19 control measures, surface sampling conducted during a self-imposed 2-week temporary office closure identified viral contamination (10/60 samples, 17% positive), particularly in a small, shared security office (6/9, 67% positive) and on a window handle in one open-plan office. Targeted enhanced cleaning was, therefore, undertaken before the office reopened. Repeat surface sampling after this identified only one positive (2%) sample. Ventilation was deemed adequate using carbon dioxide monitoring (typically ≤1000 ppm). Twelve workers (30%) responded to the COVID-OUT questionnaire, and all had been vaccinated with two doses. One-third of respondents (4/12) reported direct physical or close contact with members of the public; of these, 75% (3/4) reported a divider/screen between themselves and members of the public., Conclusions: The results highlight the potential utility of surface sampling to identify SARS-CoV-2 control deficiencies and the importance of evolving, site-specific risk assessments with layered COVID-19 mitigation strategies., (© Crown copyright 2023.)

Introduction: Equal access to medicines is crucial to ensuring public health, but access is difficult to measure, especially for infections where changes in infective species make treatment choices highly dynamic. This study investigated if the combination of infection prevalence with medicine efficacy and regulatory availability could access medicines access of topical onychomycosis medicines., Methods: Two databases, PubMed and Web of Science, were used to identify relevant information published between 1990 and 2019. For the meta-analysis, human onychomycosis investigations using PCR analysis were included. Reviewers independently selected eligible articles, extracted data and assessed the study quality. A random-effects meta-analysis model with a Freeman-Tukey transformation was employed to the PCR data. For the meta-analysis, the global infection trends and regional differences in the infective organisms were determined., Results: Of the 26 studies analysed, the PCR analysis in 18 studies confirmed onychomycosis in about half of the visually suspected cases (55%, CI 43%-67%). Across all 26 studies dermatophytes were the most prevalent infective organism (57%, CI 37%-76%), but a sub-group analysis showed yeasts predominated in females (31%, CI 0%-84%) (p < 0.0001), in fingernail infections (42%, CI 21%-65%) (p < 0.0001) and in arid countries (p < 0.0001). Combining these results with medicine efficacy data showed that residents from 83 of the 92 countries assessed (90%) could not access the most efficacious topical product, and 22% could not access any broad-spectrum agents. Countries in Africa had the poorest access to topical onychomycosis medicines., Conclusion: This study identified that access to effective topical products for onychomycosis is a global problem. This issue appeared to be due to under-representation of candida infections in pivotal clinical studies of topical onychomycosis products. A head-to-head multicentre study for topical efinaconazole or a novel broad spectrum topical agent is needed to help resolve these access problems., Protocol Registration: PROSPERO-CRD42023464744., (© 2024 The Author(s). Mycoses published by Wiley‐VCH GmbH.)

Background: Predictive biomarkers for immune checkpoint blockade in the second-line treatment of metastatic renal cell carcinoma (mRCC) are lacking., Materials and Methods: Patients with histologically confirmed RCC who started nivolumab after at least 4 months of tyrosine kinase inhibitors (TKIs) were recruited for this study. Serial tissue and blood samples were collected for immune biomarker evaluation. The primary endpoint was to determine the association of specific T-cell subsets with clinical outcomes tested using Wilcoxon rank sum for clinical benefit rate (CBR) and log-rank test for progression-free survival (PFS)., Results: Twenty patients were included in this trial with a median age of 64 years and followed-up for a median of 12 months. The median PFS for patients who received TKI was 13.8 months, while for those subsequently treated with nivolumab following TKI therapy, the median PFS was 2.6 months. CBR of nivolumab was 20% with two partial responses. Functionally active programmed cell death protein 1+ CD4+ T cells were enriched in non-responders ( q  = 0.003) and associated with worse PFS on nivolumab ( P  = 0.04). Responders showed a significant reduction in the effector CD4+T-cell (T EF ) fraction compared to non-responders at 3 months on nivolumab (0.40 versus 0.80, P  = 0.0005). CD127+CD4+ T cells were enriched in patients who developed immune-related adverse effects ( q  = 0.003). Using in-house validated multiplex immunohistochemistry for six markers, we measured tumour-associated immune cell densities in tissue samples . Responders to nivolumab showed a significantly higher mean of immune cell densities in tissue samples compared to non-responders (346 versus 87 cells/mm 2 , P  = 0.04)., Conclusions: In this small study, analysis of tissue-based and peripheral blood immune cell subsets predicted clinical outcomes of nivolumab. Further studies are warranted with larger populations to validate these observations., (© 2024 The Authors.)

Aims: We implemented magnetic resonance imaging-based image-guided adaptive brachytherapy (IGABT) for the management of cervical cancer at the Northern Centre for Cancer Care in January 2015. The Royal College of Radiologists recommended IGABT as the new standard of care for the management of cervical cancer in the UK in 2009, following earlier publication of recommendations of Groupe European de Curietherapie of the European Society for Radiotherapy and Oncology for three-dimensional magnetic resonance imaging-based IGABT. The purpose of this study was to investigate if the introduction of IGABT in the management of cervical cancer at our institute indeed improved the treatment outcomes with a better toxicity profile as compared with conventional brachytherapy (CBT)., Patients and Methods: A retrospective analysis of 213 patients with International Federation of Gynecology and Obstetrics stage IB-IVA cervical cancer treated with curative radiotherapy ± chemotherapy at the Northern Centre for Cancer Care was carried out for the period January 2010 to December 2019. Patients were categorised into three groups based on their brachytherapy planning process. Fifty-eight patients were treated with CBT, 35 patients were treated with retrospective brachytherapy (RBT) planning and 120 patients were treated with IGABT. Eighty-six per cent received concomitant chemotherapy with cisplatin. Outcome measures were local control rates, overall and progression-free survival, and impact on treatment-related toxicities., Results: The median follow-up was 36, 32 and 25 months for CBT, RBT and IGABT, respectively. Three-year local control achieved was 70.4, 77.8 and 86.9%, respectively. Three-year overall survival was 53.8, 61.1 and 86.2%, respectively. Grade 2 or 3 bladder and bowel toxicity was 8% and 10% in IGABT group versus 20% and 27% in the CBT group., Conclusion: Our analysis indicated that IGABT proved to be very effective in not only improving locoregional control, but also offered quality survivorship to these women, with a significant drop in radiation-related bladder and bowel toxicities., (Crown Copyright © 2022. Published by Elsevier Ltd. All rights reserved.)

Objective: Phosphorylation of insulin receptor substrate (IRS) 1 by tumor necrosis factor alpha (TNF-α) has been implicated as a factor contributing to insulin resistance. Administration of IL-15 reduces adipose tissue deposition in young rats and stimulates secretion of adiponectin, an insulin sensitizing hormone that inhibits the production and activity of TNF-α. We aimed at investigating the effects of age life-long moderate calorie restriction (CR) on IL-15 and TNF-α signaling in rat white adipose tissue (WAT)., Materials and Methods: Thirty-six 8-month-old, 18-month-old, and 29-month-old male Fischer344´Brown Norway F1 rats (6 per group) were either fed ad libitum (AL) or calorie restricted by 40%. The serum levels of IL-15 and IL-15 receptor α-chain (IL-15Rα) were increased by CR controls regardless of age. An opposite pattern was detected in WAT. In addition, CR reduced gene expression of TNF-α and cytosolic IRS1 serine phosphorylation in WAT, independently from age., Results: IL-15 signaling in WAT is increased over the course of aging in AL rats compared with CR rodents. Protein levels of IL-15Rα are greater in WAT of AL than in CR rats independently from age. This adaptation was paralleled by increased IRS1 phosphorylation through TNF-α-mediated insulin resistance. Adiponectin decreased at old age in AL rats, while no changes were evident in CR rats across age groups., Conclusions: IL-15 signaling could therefore represent a potential target for interventions to counteract metabolic alterations and the deterioration of body composition during aging.

Abnormal tau hyperphosphorylation and its aggregation into neurofibrillary tangles are a hallmark of tauopathies, neurodegenerative disorders that include Alzheimer's disease (AD). Active and passive Tau-immunotherapy has been proposed as a therapeutic approach to AD with mixed results. One of the limitations of active immunotherapy may be associated with the mediocre immunogenicity of vaccines that are not inducing therapeutically potent titers of antibodies. The aim of this study was to test the efficacy of an anti-tau vaccine, AV-1980R/A composed of N terminal peptide of this molecule fused with an immunogenic MultiTEP platform and formulated in a strong adjuvant, Advax CpG in a Tg4510 mouse model of tauopathy. Experimental mice were immunized with AV-1980R/A and a control group of mice were injected with adjuvant only. Nontransgenic and tetracycline transactivator (tTA) transgenic littermates were included as baseline controls to contrast with the tau phenotype. Active immunization with AV-1980R/A induced very strong anti-tau humoral immune responses in both nontransgenic and transgenic mice with evidence of IgG in brains of AV-1980R/A vaccinated mice. These experimental animals displayed an improvement in short-term memory during a novel object recognition test. However, impairments in other behavioral tasks were not prevented by AV-1980R/A vaccinations. At the same time, high titers of anti-tau antibodies reduced hyperphosphorylated pSer396 tau but did not lower the level of other phosphorylated tau species in the brains of AV-1980R/A vaccinated mice. These data indicate that active immunotherapy with an N-terminal Tau epitope was only partially effective in improving cognition and reducing pathology in the stringent Tg4510 mouse model of tauopathy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Study Question: Do human oocytes express voltage-gated proton channels?, Summary Answer: Human oocytes exhibit voltage-gated proton currents., What Is Known Already: Voltage-gated proton currents have been reported in human sperm, where they contribute to capacitation and motility. No such studies of human oocytes exist., Study Design, Size, Duration: Voltage-clamp studies were undertaken using entire oocytes and vesicles derived from oocytes and in excised patches of membrane from oocytes., Participants/materials, Setting, Methods: Frozen, thawed human metaphase II oocytes were obtained from material donated to the gamete repository at the Rush Center for Advanced Reproductive Care. Prior to patch clamping, oocytes were warmed and equilibrated. Formation of an electrically tight seal requires exposing bare oolemma. Sections of the zona pellucida (ZP) were removed using a laser, followed by repeated pipetting, to further separate the oocyte from the ZP. Patch-clamp studies were performed using the whole-cell configuration on oocytes or vesicles derived from oocytes, and using inside-out patches of membrane, under conditions optimized to detect voltage-gated proton currents., Main Results and the Role of Chance: Proton currents are present at significant levels in human oocytes where they exhibit properties similar to those reported in other human cells, as well as those in heterologous expression systems transfected with the HVCN1 gene that codes for the voltage-gated proton channel., Large Scale Data: N/A., Limitations, Reasons for Caution: Human oocytes are large cells, which limits our ability to control the intracellular solution. Subtle effects of cryopreservation by vitrification and subsequent warming on properties of HVCN1, the HVCN1 gene product, cannot be ruled out., Wider Implications of the Findings: Possible functions for voltage-gated proton channels in human oocytes may now be contemplated., Study Funding/competing Interest(s): NIH R35GM126902 (TED), Bears Care (DM). No competing interests., Trial Registration Number: N/A., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The spread of the Zika virus (ZIKV) in the Americas led to large outbreaks across the region and most of the Southern hemisphere. Of greatest concern were complications following acute infection during pregnancy. At the beginning of the outbreak, the risk to unborn babies and their clinical presentation was unclear. This report describes the methods and results of the UK surveillance response to assess the risk of ZIKV to children born to returning travellers. Established surveillance systems operating within the UK - the paediatric and obstetric surveillance units for rare diseases, and national laboratory monitoring - enabled rapid assessment of this emerging public health threat. A combined total of 11 women experiencing adverse pregnancy outcomes after possible ZIKV exposure were reported by the three surveillance systems; five miscarriages, two intrauterine deaths and four children with clinical presentations potentially associated with ZIKV infection. Sixteen women were diagnosed with ZIKV during pregnancy in the UK. Amongst the offspring of these women, there was unequivocal laboratory evidence of infection in only one child. In the UK, the number and risk of congenital ZIKV infection for travellers returning from ZIKV-affected countries is very small.

Osteonecrosis of the jaw (ONJ) is a rare, but severe, condition that has traditionally been associated with the use of bisphosphonates. We report what is, to our knowledge, the first case of ONJ secondary to the use of everolimus, in the absence of treatment with bisphosphonates in a 65-year-old man who was given it for immunosuppression after a renal transplant. After 18 months of treatment, he was diagnosed with severe ONJ and underwent radical debridement of the palate and complete dental clearance of the maxilla., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Purpose: In 1959, Maroteaux and Lamy initially designated pseudoachondroplasia as a distinct dysplasia different from achondroplasia the most common form of skeletal dysplasia. Pseudoachondroplasia is caused by a mutation in the collagen oligomeric matrix protein gene (COMP) gene on chromosome 19p13.1-p12 encoding the COMP. The COMP gene mutations result in rendering the articular and growth plate cartilages incapable of withstanding routine biomechanical loads with resultant deformity of the joints. The purpose of the study was to characterize the typical orthopaedic findings in pseudoachondroplasia., Methods: The charts and radiographs of 141 patients with pseudoachondroplasia were analyzed. This cohort, to our knowledge, represents the largest group of patients describing the typical orthopaedic manifestations of pseudoachondroplasia., Results: Patients with pseudoachondroplasia have normal craniofacial appearance with normal intelligence. Short stature is not present at birth and generally appears by two to four years of age. The condition is a form of spondyloepiphyseal dysplasia and the long bones are characterized by dysplastic changes in the epiphysis, metaphysis and vertebral bodies. Radiographically the long bones have altered the appearance and structure of the epiphyses with small irregularly formed or fragmented epiphyses or flattening. The metaphyseal regions of the long bones show flaring, widening or 'trumpeting'. The cervical (89%) and thoracic and lumbar vertebrae show either platyspondyly, ovoid, 'cod-fish' deformity or anterior 'beaking'. Kyphosis (28%), scoliosis (58%) and lumbar lordosis (100%) are commonly seen. The femoral head and acetabulum are severely dysplastic (100%). The knees show either genu valgum (22%), genu varum (56%) or 'windswept' deformity (22%)., Conclusion: Most commonly these distortions of the appendicular and the axial skeleton lead to premature arthritis particularly of the hips and often the knees not uncommonly in the 20- to 30-year-old age group., Level of Evidence: III.

In this study, the involvement of aluminum-based drinking water treatment residual (DWTR) as substrate in floating treatment wetland (FTW) to enhance its treatment performance was firstly proposed and trialed. A laboratory scale DWTR-FTW fed with synthetic wastewater containing COD, nitrogen (N), phosphorus (P) and mineral salts was operated in three stages of unplanted (1-30 days), planted (31-60 days) and aerated (61-135 days) modes. The results showed that the average removal rates of COD, total nitrogen (TN), total phosphorus (TP) in stage 3 were 88%, 85%, and 90.2%, respectively, indicating the outstanding purification performance of DWTR-FTW in comparison of traditional FTWs. The embedded DWTR enriches the biomass and robustly adsorbs P, while aeration supplies sufficient dissolved oxygen for the microorganism. The results revealed that 7.022 g P was accumulated in DWTR, which is 400 times higher than that in sediment and plants during the experimental period, reflecting that DWTR adsorption is the major P removal pathway in DWTR-FTW. Overall, DWTR-FTW could significantly remove pollutants, especially P, and provide an alternative pathway to enhance purification performance of FTW., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Atom probe tomography (APT) and scanning transmission electron microscopy (STEM) techniques were used to probe the long-time thermal stability of nm-scale Mn-Ni-Si precipitates (MNSPs) formed in intermediate and high Ni reactor pressure vessel steels under high fluence neutron irradiation at ≈320 °C. Post irradiation annealing (PIA) at 425 °C for up to 57 weeks was used to determine if the MNSPs are: (a) non-equilibrium solute clusters formed and sustained by radiation induced segregation (RIS); or, (b) equilibrium G or Γ 2 phases, that precipitate at accelerated rates due to radiation enhanced diffusion (RED). Note the latter is consistent with both thermodynamic models and x-ray diffraction (XRD) measurements. Both the experimental and an independently calibrated cluster dynamics (CD) model results show that the stability of the MNSPs is very sensitive to the alloy Ni and, to a lesser extent, Mn content. Thus, a small fraction of the largest MNSPs in the high Ni steel persist, and begin to coarsen at long times. These results suggest that the MNSPs remain a stable phase, even at 105 °C higher than they formed at, thus are most certainly equilibrium phases at much lower service relevant temperatures of ≈290 °C.

Introduction: This paper describes the funding rates established in Ontario to reflect best practices in hospital-based care delivery for these endoscopic procedures: colonoscopy, colonoscopy biopsy, gastroscopy, gastroscopy biopsy, and colonoscopy combined with gastroscopy., Methods: The funding rates are based on direct costs and were established using a micro-costing approach after receipt of inputs from 3 working groups and a review of the administrative data and literature, where applicable. The first group advised on nursing activities, time, and staffing ratios along the patient pathway for each of the procedures. The second group provided recommendations about the duration for each procedure, and the third group provided information about supplies and equipment, their use, and costs., Results: The resulting funding rates are $161.18 for colonoscopy and $151.08 for gastroscopy (without accompanying interventions), $16.06 for colonoscopy biopsy and $8.22 for gastroscopy biopsy (added to the respective procedures), and $207.26 for combined colonoscopy and gastroscopy. Detailed costs for each component embedded in the rates are also provided., Conclusions: The rates came into effect in April 2018. The process and outcomes described here allowed for a transparent pricing mechanism in which funding follows the patient, clinical expert consensus is the basis for practice, and providers and payers both understand the components., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none.

Brains of females are more sensitive to the acute catabolic actions of leptin. However, sex differences in the long-term physiological responses to central leptin receptor modulation are unknown. Accordingly, we centrally delivered a viral vector to overexpress leptin (Leptin), a neutral leptin receptor antagonist (Leptin-Antagonist) or a green fluorescence protein (GFP) (Control). We examined chronic changes in body weight and composition in male and female rats. Females displayed greater and sustained responses to Leptin, whereas males rapidly lost physiological effects and developed leptin resistance as confirmed by lower acute leptin-mediated phosphorylation of signal transducer and activator of transcription 3 (P-STAT3). Surprisingly, despite persistent physiological responses, Leptin-females also exhibited reduced acute leptin-mediated P-STAT3, suggesting an onset of leptin resistance near time of death. In line with this interpretation, Leptin-females and Control-females consumed the same amount of food on the last day of the experiment. Both Leptin-Antagonist groups gained similar percentages of their initial body weight and fat mass, whereas only Leptin-Antagonist-females gained lean body mass. Consequently, the lean/fat mass ratio with Leptin-Antagonist was preserved in females and decreased in males, suggesting a deterioration of body composition in males. In summary, the present study establishes that females are more responsive to long-term central leptin overexpression than males and that leptin antagonism has a greater physiological impact in males. The hormone environment may have played a role in these processes; however, future studies are needed to establish whether such physiological responses are mediated by female or male sex hormones., (© 2017 British Society for Neuroendocrinology.)

Indigenous, foodborne transmission of hepatitis E has been increasing across industrialised countries. Public Health England has conducted enhanced surveillance in England and Wales since 2003.This report gives an account of acute infections from 2010 to 2016 and describes modification made to the methods of surveillance to account for changes in reporting behaviours and improve ascertainment.

The presence of a first flush (FF) of suspended solids (SS) in stormwater runoff has important implications for the design of treatment facilities, as does the particle size of solids. Whilst numerous studies have examined the FF behaviour of SS, few have disaggregated FF trends by particle size. In this study, the FF behaviour of SS was investigated in five size ranges, sampled from an urban stormwater drainage system located in Dublin, Ireland. A weak FF was exhibited in the gross fraction of SS, with just two events from 14 transporting more than 50% of the SS mass in the first 25% of runoff, implying that treatment structures should be capable of removing SS throughout the storm event. In the majority of rain events, the FF strength increased with decreasing particle size, probably related to the lower intensities required to dislodge solids at the onset of rainfall. Although FF strength was correlated with rain event characteristics, prediction intervals were too broad to confirm FF presence based on rainfall data alone. Therefore, the design of smaller treatment volumes based on an assumption of FF must be justified by local monitoring data.