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Abstract Human iPSC-derived cardiomyocytes (hiPSC-CMs) have proven invaluable for cardiac disease modeling and regeneration. Challenges with quality, inter-batch consistency, cryopreservation and scale remain, reducing experimental reproducibility and clinical translation. Here, we report a robust stirred suspension cardiac differentiation protocol, and we perform extensive morphological and functional characterization of the resulting bioreactor-differentiated iPSC-CMs (bCMs). Across multiple different iPSC lines, the protocol produces 1.2E6/mL bCMs with ~94% purity. bCMs have high viability after cryo-recovery (>90%) and predominantly ventricular identity. Compared to standard monolayer-differentiated CMs, bCMs are more reproducible across batches and have more mature functional properties. The protocol also works with magnetically stirred spinner flasks, which are more economical and scalable than bioreactors. Minor protocol modifications generate cardiac organoids fully in suspension culture. These reproducible, scalable, and resource-efficient approaches to generate iPSC-CMs and organoids will expand their applications, and our benchmark data will enable comparison to cells produced by other cardiac differentiation protocols.

Abstract Since late 2021, highly pathogenic avian influenza (HPAI) viruses of A/goose/Guangdong/1/1996 (H5N1) lineage have caused widespread mortality in wild birds and poultry in the United States. Concomitant with the spread of HPAI viruses in birds are increasing numbers of mammalian infections, including wild and captive mesocarnivores and carnivores with central nervous system involvement. Here we report HPAI, A(H5N1) of clade 2.3.4.4b, in a common bottlenose dolphin (Tursiops truncatus) from Florida, United States. Pathological findings include neuronal necrosis and inflammation of the brain and meninges, and quantitative real time RT-PCR reveal the brain carried the highest viral load. Virus isolated from the brain contains a S246N neuraminidase substitution which leads to reduced inhibition by neuraminidase inhibitor oseltamivir. The increased prevalence of A(H5N1) viruses in atypical avian hosts and its cross-species transmission into mammalian species highlights the public health importance of continued disease surveillance and biosecurity protocols.

This was intended to be the first in a series of three articles examining the development of the RAF High Command during the Second World War; unfortunately, due to illness only the first article was completed. Reproduced here the article covers the period from 1932 until the outbreak of war in 1939, shedding new light on the re-organisations of the Air Ministry in 1934, the RAF Command structure in 1936, and the tri-service debate in 1937 concerning the RAF proposal to establish a Supreme Air Commander. It challenges the established historiography casting a different perspective on RAF reforms, and as such offers a fresh starting point for analysing the RAF’s High Command structure and organisation as the Second World War approached. The subsequent two articles were intended to assess the development of RAF High Command practice as the war unfolded and operational challenges were met. Nonetheless, as is characteristic of the author it presents a challenging contribution to the history of the RAF as wartime approached.

In the context of service provisioning, the integration of Network Functions Virtualization (NFV) enhances the flexibility, scalability, and programmability of telecommunication networks. However, this integration introduces challenges, particularly in optimizing the placement of Virtualized Network Functions (VNFs) within the NFV Infrastructure (NFVI). Existing studies have predominantly focused on well-connected, mains-powered ecosystems like datacentres and cloud networks. In contrast, the aim of this paper is to identify a solution that distributes and deploys a Wireless Mesh Network (WMN) as the backbone for a disaster management communication and service infrastructure. Given the mobility of mesh routers in such scenarios, these devices are often battery-powered. Consequently, the placement of VNFs directly impacts the energy consumption in the network and, subsequently, its lifetime. The proposed solution for the energy-efficient placement of VNF is formulated as a multi-objective optimization problem. This context introduces different approaches and proposes a heuristic algorithm to optimize the placement of VNFs. The evaluation results indicate that the proposed algorithm outperforms prior alternatives in various scenarios. Notably, it surpasses established methods like the Nondominated Sorting Genetic Algorithm II (NSGA-II), commonly used to solve similar problems. This research signifies a significant advancement in addressing the specific challenges associated with NFV integration in wireless mesh networks, particularly in disaster management contexts.

Abstract Ancient DNA is a valuable tool for investigating genetic and evolutionary history that can also provide detailed profiles of the lives of ancient individuals. In this study, we develop a generalised computational approach to detect aneuploidies (atypical autosomal and sex chromosome karyotypes) in the ancient genetic record and distinguish such karyotypes from contamination. We confirm that aneuploidies can be detected even in low-coverage genomes ( ~ 0.0001-fold), common in ancient DNA. We apply this method to ancient skeletal remains from Britain to document the first instance of mosaic Turner syndrome (45,X0/46,XX) in the ancient genetic record in an Iron Age individual sequenced to average 9-fold coverage, the earliest known incidence of an individual with a 47,XYY karyotype from the Early Medieval period, as well as individuals with Klinefelter (47,XXY) and Down syndrome (47,XY, + 21). Overall, our approach provides an accessible and automated framework allowing for the detection of individuals with aneuploidies, which extends previous binary approaches. This tool can facilitate the interpretation of burial context and living conditions, as well as elucidate past perceptions of biological sex and people with diverse biological traits.

River estuaries along western Hudson Bay, Canada, are important summer habitats for beluga whales (Delphinapterus leucus (Pallas, 1776)) and subject to increasing industrial development activities including vessel traffic. The feasibility of establishing a National Marine Conservation Area (NMCA) in western Hudson Bay is under consideration, requiring baseline studies and habitat monitoring. In this study, beluga whale locations were identified using aerial photographs collected during summer 2018 of the Seal, Knife, Churchill, and Nelson River estuaries. Sentinel 2 wavelength bands were used to outline river plume boundaries for the Seal, Knife, and Churchill Rivers. Multiple discriminant analysis was used to differentiate between beluga habitat areas according to their environmental characteristics including concentration of total suspended sediments (TSS), and coloured dissolved organic matter (CDOM). The Seal River estuary, Knife River estuary, Churchill River outer estuary, Churchill River estuary, and Nelson River estuary were identified as distinct habitat areas. Resource selection functions and model selection were used to determine that habitat variables related to prey availability were important for beluga habitat selection, including TSS, CDOM, and the distance to river mouth or river plume. Identification of preferred habitat and habitat areas in this study are imperative for future management decisions including establishment of an NMCA.

The COVID-19 pandemic exposed and reinforced the structural crisis in paid and unpaid care work. On the one hand, pandemic-related closures of schools and childcare facilities increased the fragility of unpaid care arrangements, which are mainly organised by women. On the other hand, high infection and hospitalisation rates exacerbated the difficult working conditions in health-care professions, ranging from low wages and long working hours to high levels of mental and physical stress. Drawing on interviews conducted in an ongoing project in the German and Austrian health-care sector, this article investigates, from a gender perspective, how employees in health-care professions, who are at the very centre of both the unpaid and paid care crises, experienced this precarious situation during the pandemic. We suggest that the female-dominated sectors of paid and unpaid care work experienced further devaluation during the COVID-19 pandemic, while attempts to valorise their work were rather short-lived. We further argue that the structural crisis in paid care work is threatening the functionality of the health-care sector.

Abstract To mitigate COVID-19-related shortage of treatment capacity, the hepatopancreatobiliary (HPB) unit of the Royal Free Hospital London (RFHL) transferred its practice to independent hospitals in Central London through the North Central London Cancer Alliance. The aim of this study was to critically assess this strategy and evaluate perioperative outcomes. Prospectively collected data were reviewed on all patients who were treated under the RFHL HPB unit in six hospitals between November 2020 and October 2021. A total of 1541 patients were included, as follows: 1246 (81%) at the RFHL, 41 (3%) at the Chase Farm Hospital, 23 (2%) at the Whittington Hospital, 207 (13%) at the Princess Grace Hospital, 12 (1%) at the Wellington Hospital and 12 (1%) at the Lister Hospital, Chelsea. Across all institutions, overall complication rate were 40%, major complication (Clavien–Dindo grade ≥ 3a) rate were 11% and mortality rates were 1.4%, respectively. In COVID-19-positive patients (n = 28), compared with negative patients, complication rate and mortality rates were increased tenfold. Outsourcing HPB patients, including their specialist care, to surrounding institutions was safe and ensured ongoing treatment with comparable outcomes among the institutions during the COVID-19 pandemic. Due to the lack of direct comparison with a non-pandemic cohort, these results can strictly only be applied within a pandemic setting.

Abstract Background Thrombocytopenia is a common laboratory abnormality in dogs, and numerous diseases have been associated with its development. Estimates for the sensitivity and specificity of the degree of reduction of platelet concentration for the diagnosis of primary immune‐mediated thrombocytopenia (pITP) have not been reported. Objectives To report the prevalence of different causes of thrombocytopenia in dogs in the United Kingdom and to investigate the utility of platelet concentration to differentiate causes of thrombocytopenia. Methods Medical records of 762 dogs with thrombocytopenia presented to seven referral hospitals from January 2017 to December 2018 were retrospectively reviewed. Cases were assigned into the following categories: pITP, infectious diseases, neoplasia, inflammatory/other immune‐mediated disorders and miscellaneous causes. The prevalence of the different categories was estimated, and platelet concentrations were compared. Receiver‐operating characteristic (ROC) curves were used to investigate the utility of platelet concentration to differentiate between causes of thrombocytopenia. Results The most common disease category associated with thrombocytopenia was neoplasia (27.3%), followed by miscellaneous causes (26.9%), pITP (18.8%), inflammatory/immune‐mediated disorders (14.4%) and infectious diseases (12.6%). Dogs with pITP had significantly lower platelet concentrations (median 8 × 109/L, range: 0–70 × 109/L) than dogs in the other four categories. Platelet concentration was useful for distinguishing pITP from other causes of thrombocytopenia (area under ROC curve = 0.89, 95% confidence interval 0.87, 0.92), with a platelet concentration ≤12 × 109/L being 60% sensitive and 90% specific. Conclusions Severe thrombocytopenia was highly specific for a diagnosis of pITP, which was more prevalent in this UK population of thrombocytopenic dogs compared with previous epidemiological studies. Conversely, the proportion of dogs with infectious diseases was lower than in previous reports from other locations.

Influenza virological surveillance was conducted in Bangladesh from January to December 2021 in live poultry markets (LPMs) and in Tanguar Haor, a wetland region where domestic ducks have frequent contact with migratory birds. The predominant viruses circulating in LPMs were low pathogenic avian influenza (LPAI) H9N2 and clade 2.3.2.1a highly pathogenic avian influenza (HPAI) H5N1 viruses. Additional LPAIs were found in both LPM (H4N6) and Tanguar Haor wetlands (H7N7). Genetic analyses of these LPAIs strongly suggested long-distance movement of viruses along the Central Asian migratory bird flyway. We also detected a novel clade 2.3.4.4b H5N1 virus from ducks in free-range farms in Tanguar Haor that was similar to viruses first detected in October 2020 in The Netherlands but with a different PB2. Identification of clade 2.3.4.4b HPAI H5N1 viruses in Tanguar Haor provides continued support of the role of migratory birds in transboundary movement of influenza A viruses (IAV), including HPAI viruses. Domestic ducks in free range farm in wetland areas, like Tangua Haor, serve as a conduit for the introduction of LPAI and HPAI viruses into Bangladesh. Clade 2.3.4.4b viruses have dominated in many regions of the world since mid-2021, and it remains to be seen if these viruses will replace the endemic clade 2.3.2.1a H5N1 viruses in Bangladesh.

ABSTRACTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve after its emergence. Given its importance in viral infection and vaccine development, mutations in the viral Spike gene have been studied extensively; however, the impact of mutations outside the Spike gene are poorly understood. Here, we report that a triple deletion (ΔSGF or ΔLSG) in nonstructural protein 6 (nsp6) independently acquired in Alpha and Omicron sublineages of SARS-CoV-2 augments nsp6-mediated antagonism of type-I interferon (IFN-I) signaling. Specifically, these triple deletions enhance the ability of mutant nsp6 to suppress phosphorylation of STAT1 and STAT2. A parental SARS-CoV-2 USA-WA1/2020 strain containing the nsp6 ΔSGF deletion (ΔSGF-WA1) shows reduced susceptibility to IFN-I treatment in vitro, outcompetes the parental strain in human primary airway cultures, and increases virulence in mice; however, the ΔSGF-WA1 virus is less virulent than the Alpha variant (which has the nsp6 ΔSGF deletion and additional mutations in other genes). Analyses of host responses from ΔSGF-WA1-infected mice and primary airway cultures reveal activation of pathways indicative of a cytokine storm. These results provide evidence that mutations outside the Spike protein affect virus-host interactions and may alter pathogenesis of SARS-CoV-2 variants in humans.

Background The incidence of childhood cancer has risen by 15% since the 1990s. Early diagnosis is key to optimising outcomes, however diagnostic delays are widely reported. Presenting symptoms are often non-specific causing a diagnostic dilemma for clinicians. This Delphi consensus process was conducted to develop a new clinical guideline for children and young people presenting with signs/symptoms suggestive of a bone or abdominal tumour.Methods Invitation emails were sent to primary and secondary healthcare professionals to join the Delphi panel. 65 statements were derived from evidence review by a multidisciplinary team. Participants were asked to rank their level of agreement with each statement on a 9-point Likert scale (1=strongly disagree, 9=strongly agree), with responses ≥7 taken to indicate agreement. Statements not reaching consensus were rewritten and reissued in a subsequent round.Results All statements achieved consensus after two rounds. 96/133 (72%) participants responded to round 1 (R1) and 69/96 (72%) completed round 2 (R2). 62/65 (94%) statements achieved consensus in R1 with 29/65 (47%) gaining more than 90% consensus. Three statements did not reach consensus scoring between 61% and 69%. All reached numerical consensus at the end of R2. Strong consensus was reached on best practice of conducting the consultation, acknowledging parental instinct and obtaining telephone advice from a paediatrician to decide the timing and place of review, rather than adult cancer urgent referral pathways. Dissensus in statements was due to unachievable targets within primary care and valid concerns over a potential overinvestigation of abdominal pain.Conclusions This consensus process has consolidated statements that will be included in a new clinical guideline for suspected bone and abdominal tumours for use in both primary and secondary care. This evidence base will be translated into awareness tools for the public as part of the Child Cancer Smart national awareness campaign.

Abstract Extinct lineages of Yersinia pestis, the causative agent of the plague, have been identified in several individuals from Eurasia between 5000 and 2500 years before present (BP). One of these, termed the ‘LNBA lineage’ (Late Neolithic and Bronze Age), has been suggested to have spread into Europe with human groups expanding from the Eurasian steppe. Here, we show that the LNBA plague was spread to Europe’s northwestern periphery by sequencing three Yersinia pestis genomes from Britain, all dating to ~4000 cal BP. Two individuals were from an unusual mass burial context in Charterhouse Warren, Somerset, and one individual was from a single burial under a ring cairn monument in Levens, Cumbria. To our knowledge, this represents the earliest evidence of LNBA plague in Britain documented to date. All three British Yersinia pestis genomes belong to a sublineage previously observed in Bronze Age individuals from Central Europe that had lost the putative virulence factor yapC. This sublineage is later found in Eastern Asia ~3200 cal BP. While the severity of the disease is currently unclear, the wide geographic distribution within a few centuries suggests substantial transmissibility.

In recent years, many urban areas in low and middle income countries have experienced major dengue epidemics, and the city of Dhaka, the capital city of Bangladesh, is one of them. Understanding models based on land cover and land use in urban areas in relation to vector abundance and possible disease transmission can be a major epidemiological tool in identifying disease incidence and prevalence. Demographic and human behavioral factors can also play a role in determining microenvironments for entomological distribution—which is a major risk factor for epidemicity. Data collected from a cross-sectional entomological survey in the city of Dhaka during the monsoon season of 2012 and two serological surveys—one pre-monsoon and another post-monsoon in 2012—were analyzed in this study. A total of 898 households and 1003 containers with water were inspected, and 1380 Ae. aegypti pupae and 4174 larvae were counted in these containers. All Stegomyia indices were found to be the highest in the central business and residential mixed zone. The odds ratios of risk factors for seroprevalence, including sex, age, self-reported febrile illness during the previous six months, and travel during the last six months, were calculated; age distribution was found to be a highly significant risk factor (p = value < 0.0001). The study offers clear patterns of dengue viral transmission, disease dynamics, and their association with critical spatial dimensions.

Abstract Potassium dihydrogen phosphate (KDP) and its deuterated analog (DKDP) are unique nonlinear optical materials for high power laser systems. They are used widely for frequency conversion and polarization control by virtue of the ability to grow optical-quality crystals at apertures suitable for fusion-class laser systems. Existing methods for freeform figuring of KDP/DKDP optics do not produce surfaces with sufficient laser-induced–damage thresholds (LIDT’s) for operation in the ultraviolet portion of high-peak-power laser systems. In this work, we investigate fluid jet polishing (FJP) using a nonaqueous slurry as a sub-aperture finishing method for producing freeform KDP surfaces. This method was used to selectively polish surface areas to different depths on the same substrate with removals ranging from 0.16 μm to 5.13 μm. The finished surfaces demonstrated a slight increase in roughness as the removal depth increased along with a small number of fracture pits. Laser damage testing with 351 nm, 1 ns pulses demonstrated excellent surface damage thresholds, with the highest values in areas devoid of fracture pits. This work demonstrates, for the first time, a method that enables fabrication of a waveplate that provides tailored polarization randomization that can be scaled to meter-sized optics. Furthermore, this method is based on FJP technology that incorporates a nonaqueous slurry specially designed for use with KDP. This novel nonaqueous FJP process can be also used for figuring other types of materials that exhibit similar challenging inherent properties such as softness, brittleness, water-solubility, and temperature sensitivity.

While there is a large body of literature focusing on global-level flood hazard management, including preparedness, response, and recovery, there is a lack of research examining the patterns and dynamics of community-level flood management with a focus on local engagement and institutional mechanism. The present research explores how local communities mobilize themselves, both individually and institutionally, to respond to emerging flood-related situations and recover from their impacts. A case study approach was applied to investigate two towns in the Red River Valley of Manitoba, Canada: St. Adolphe and Ste. Agathe. Data collection consisted of in-depth interviews and oral histories provided by local residents, in addition to analysis of secondary official records and documents. The findings revealed that local community-level flood preparedness, response, and recovery in the Province of Manitoba are primarily designed, governed, managed, and evaluated by the provincial government authorities using a top-down approach. The non-participatory nature of this approach makes community members reluctant to engage with precautionary and response measures, which in turn results in undesired losses and damages. It is recommended that the Government of Manitoba develop and implement a collaborative and participatory community-level flood management approach that draws upon the accumulated experiential knowledge of local stakeholders and institutions.

Abstract An effective approach is reported to enhance the stability of inverted organo‐tin halide perovskite photovoltaics based on capping the cathode with a thin layer of bismuth. Using this simple approach, unencapsulated devices retain up to 70% of their peak power conversion efficiency after up to 100 h testing under continuous one sun solar illumination in ambient air and under electrical load, which is exceptional stability for an unencapsulated organo‐tin halide perovskite photovoltaic device tested in ambient air. The bismuth capping layer is shown to have two functions: First, it blocks corrosion of the metal cathode by iodine gas formed when those parts of the perovskite layer not protected by the cathode degrade. Second, it sequesters iodine gas by seeding its deposition on top of the bismuth capping layer, thereby keeping it away from the electro‐active parts of the device. The high affinity of iodine for bismuth is shown to correlate with the high polarizability of bismuth and the prevalence of the (012) crystal face at its surface. Bismuth is ideal for this purpose, because it is environmentally benign, non‐toxic, stable, cheap, and can be deposited by simple thermal evaporation at low temperature immediately after deposition of the cathode.

Layered nickel-rich lithium transition-metal oxides (LiNi_{x}Mn_{y}Co_{1−x−y}O_{2}; where x ≥ 0.8), with single-crystalline morphology, are promising future high-energy-density Li-ion battery cathodes due to their ability to mitigate particle-cracking-induced degradation. This is due to the absence of grain boundaries in these materials, which prevents the build-up of bulk crystallographic strain during electrochemical cycling. Compared to their polycrystalline counterparts, there is a need to study single-crystalline Ni-rich cathodes using operando x-ray methods in uncompromised machine-manufactured industrylike full cells to understand their bulk degradation mechanisms as a function of different electrochemical cycling protocols. This can help us identify factors to improve their long-term performance. Here, through in-house operando x-ray studies of pilot-line-built LiNi_{0.8}Mn_{0.1}Co_{0.1}O_{2}–graphite A7 pouch cells, it is shown that their electrochemical-capacity fade under harsh conditions (2.5–4.4 V and 40 °C for 100 cycles at a C/3 rate) primarily stems from the high-voltage reconstruction of the cathode surface from a layered to a cubic (rock-salt) phase that impedes the Li^{+} kinetics and increases cell impedance. Postmortem electron and x-ray microscopy show that these cathodes can withstand severe anisotropic structural changes and show no cracking when cycled under such conditions. Comparing these results to those from commercial Li-ion cells with surface-modified single-crystalline Ni-rich cathodes, it is identified that cathode surface passivation can mitigate this type of degradation and prolong cycle life. In addition to furthering our understanding of degradation in single-crystalline Ni-rich cathodes, this work also accentuates the need for practically relevant and reproducible fundamental investigations of Li-ion cells and presents a methodology for achieving this.

Layered hybrid perovskites (LPKs) are promising as alternatives or additives to 3D metal halide perovskites for optoelectronic applications including photovoltaic cells, LEDs and lasers due to their increased stability. However, high exciton binding energies in these materials mean that excitons are the majority species under the operating conditions of many devices. Although the efficiency of devices that incorporate LPKs has been increasing, much is still unknown about the interplay of excitons and free charge-carriers in these materials, which is vital information for understanding how optoelectronic properties dictate device efficiency. In this work, we employ optical pump/THz probe spectroscopy (OPTP) and visible transient absorption spectroscopy (TAS) to analyse the optoelectronic properties and charge-carrier dynamics of phenylethylammonium lead iodide (PEA) _2 PbI _4 . By combining these techniques, we are able to disentangle the contributions from excitons and free charge-carriers. We observe fast cooling of free charge-carriers and exciton formation on a timescale of ∼400 fs followed by slower bimolecular recombination of residual free charge-carriers with a rate constant k _2 ∼ 10 ^9 cm ^3 s ^−1 . Excitons recombine via two monomolecular processes with lifetimes t _1 ∼ 11 ps and t _2 ∼ 83 ps. Furthermore, we detect signatures of exciton–phonon coupling in the transient absorption kinetic traces. These findings provide new insight into the interplay between free charge-carriers and excitons as well as a possible mechanism to further understand the charge-carrier dynamics in LPKs.

Introduction: One in three adults in the United States 20 years of age or older has prediabetes mellitus (pre-DM), and many pre-DM patients will develop type 2 diabetes mellitus within 5 years. Cinnamon is used to lower blood sugar levels; however, results on its effectiveness are mixed. Diabetic blood glucose control is mainly monitored by either fasting blood glucose or hemoglobin A1c (HbA1c). The HbA1c test reflects the average blood glucose levels over the past 2?3 months. In this study, we investigated whether cinnamon supplements would influence HbA1c levels in prediabetic subjects. Methods: Fifty-two prediabetic subjects 18?70 years old qualified for this study. The treatment (TX) group (n?=?30) received two 500?mg capsules of cinnamon daily, while the CON group (n?=?22) did not receive any cinnamon supplement. Thirty-three subjects completed this study in 10 weeks (TX, n?=?20; CON, n?=?13). At the beginning and end of the study, HbA1c levels, body mass index (BMI), and percent body fat (PBF) of the subjects were also determined. Results: The Mann-Whitney U test for use with two independent groups indicated no statistically significant difference between the TX and CON groups based on HbA1c levels U?=?123.50, p?=?0.810; BMI U?=?112, p?=?0.507; and PBF U?=?119, p?=?0.685. Conclusion: The results of this pilot study showed that there were no statistically significant differences between the TX group taking the cinnamon supplements versus the CON group not taking cinnamon supplements in regard to HbA1c levels, BMI, or PBF. Future studies with longer study duration for HbA1c testing are warranted to determine the effects of cinnamon on lowering HbA1c in prediabetics.

Abstract Background The effects of filgotinib on patient-reported outcomes (PROs) from 3 trials in patients with active rheumatoid arthritis were investigated. Methods Methotrexate (MTX)-naïve patients received filgotinib 200 or 100 mg plus MTX (FIL200+MTX, FIL100+MTX), filgotinib 200 mg monotherapy (FIL200), or MTX monotherapy through 52 weeks (NCT02886728). Patients with inadequate response (IR) to MTX (MTX-IR) received FIL200+MTX, FIL100+MTX, adalimumab 40 mg +MTX (ADA+MTX), or placebo (PBO)+MTX (rerandomized to FIL200+MTX or FIL100+MTX at week 24) through 52 weeks (NCT02889796). Patients with IR to biologic disease-modifying antirheumatic drugs (bDMARD-IR) received FIL200 or FIL100 or PBO with background stable conventional synthetic (cs) DMARDs for up to 24 weeks (NCT02873936). PROs included Health Assessment Questionnaire-Disability Index (HAQ-DI), Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) physical/mental component summary (PCS/MCS), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), Work Productivity and Activity Impairment Questionnaire-Rheumatoid Arthritis (WPAI-RA), and Patient Global Assessment of Disease Activity (PtGA). Data are reported as least-squares mean changes from baseline with standard error to the timepoint representing each study’s primary endpoint. All statistical comparisons are of filgotinib groups vs their respective control groups. Results At week 24, among MTX-naïve patients, change from baseline (standard deviation) in HAQ-DI was − 1.00 (0.03; P < 0.001) with FIL200+MTX, − 0.94 (0.04; P < 0.01) with FIL100+MTX, and − 0.91 (0.04; P < 0.05) with FIL200 alone compared with − 0.81 (0.03) with MTX alone. At week 12, among MTX-IR patients, change from baseline in HAQ-DI was − 0.69 (0.04; P < 0.001 vs PBO+MTX, P < 0.05 vs ADA) with FIL200+MTX, − 0.57 (0.04; P < 0.001 vs placebo) with FIL100+MTX, and − 0.60 (0.04) with ADA vs − 0.40 (0.04) with PBO+MTX. At week 12, among bDMARD-IR patients, change from baseline in HAQ-DI was − 0.50 (0.06; P < 0.001) with FIL200+csDMARD and − 0.46 (0.05; P < 0.001) with FIL100+csDMARD vs − 0.19 (0.06) with placebo+csDMARD. Changes in SF-36 PCS and MCS, FACIT-Fatigue, WPAI, and PtGA tended to favor filgotinib over PBO, MTX, and ADA. Greater proportions of patients experienced clinically meaningful differences with either dosage of FIL in combination with csDMARDs (including MTX) and with FIL200 monotherapy vs comparators. Conclusions Filgotinib provided improvements in PROs across patient populations. These findings suggest filgotinib can be an effective treatment option for patients with insufficient response to MTX or bDMARDs and patients who are MTX-naïve. Trial registration ClinicalTrials.gov , FINCH 1, NCT02889796 , first posted September 7, 2016; FINCH 2, NCT02873936 , first posted August 22, 2016, retrospectively registered; FINCH 3, NCT02886728 , first posted September 1, 2016, retrospectively registered.

AimsTo determine an imaging protocol that can be used to assess the distribution of infusate in children with DIPG treated with CED.Methods13 children diagnosed with DIPG received between 3.8 and 5.7 ml of infusate, through two pairs of catheters to encompass tumor volume on day 1 of cycle one of treatment. Volumetric T2-weighted (T2W) and diffusion-weighted MRI imaging (DWI) were performed before and after day 1 of CED. Apparent diffusion coefficient (ADC) maps were calculated. The tumor volume pre and post CED was automatically segmented on T2W and ADC on the basis of signal intensity. The ADC maps pre and post infusion were aligned and subtracted to visualize the infusate distribution.ResultsThere was a significant increase (p < 0.001) in mean ADC and T2W signal intensity (SI) ratio and a significant (p < 0.001) increase in mean tumor volume defined by ADC and T2W SI post infusion (mean ADC volume pre: 19.8 ml, post: 24.4 ml; mean T2W volume pre: 19.4 ml, post: 23.4 ml). A significant correlation (p < 0.001) between infusate volume and difference in ADC/T2W SI defined tumor volume was observed (ADC, r = 0.76; T2W, r = 0.70). Finally, pixel-by-pixel subtraction of the ADC maps pre and post infusion demonstrated a volume of high signal intensity, presumed infusate distribution.ConclusionsADC and T2W MRI are proposed as a combined parameter method for evaluation of CED infusate distribution in brainstem tumors in future clinical trials.

Background: Anticholinergic (ACH) burden is a risk factor for negative health outcomes among older adults. Several medications contribute to ACH burden, including antimuscarinics used to manage overactive bladder (OAB). Objectives: This study aimed to understand the extent of ACH burden in an OAB population in the United States. Design: Non-interventional retrospective analysis. Methods: Adults with OAB whose care providers participated in the American Urological Association Quality (AQUA) Registry between 2014 and 2020 were included in this study. An adapted version of the Pharmacy Quality Alliance (PQA) measure of anticholinergic polypharmacy (poly-ACH) was used to assess ACH burden. The primary outcome was the annual prevalence of poly-ACH, and a secondary outcome was the percentage of patients taking 0, 1, 2, 3, 4, or ⩾ 5 ACH medications by calendar year. Analyses were stratified by age category at diagnosis and sex. Results: The sample comprised 552,840 patients with OAB. The mean age at initial OAB diagnosis was 65.7 years (58.2% male; 57.4% white). Prevalence of poly-ACH was highest in 2015 (3.7%) and lowest in 2020 (1.9%). Patients prescribed no ACH medications made up the largest proportion of each cohort, while those prescribed five or more comprised the smallest. The trend of decreasing proportions of patients taking increasing numbers of ACH medications was consistent. The proportion of patients prescribed no ACH medications increased from 63.3% in 2014 to 74.6% in 2020. The percentage of those prescribed three or more ACHs remained largely unchanged. Poly-ACH was highest among younger individuals (

Abstract Mitochondrial dysfunction and bioenergetics failure are common pathological hallmarks in Huntington’s disease (HD) and aging. In the present study, we used the YAC128 murine model of HD to examine the effects of mutant huntingtin on mitochondrial parameters related to aging in brain and skeletal muscle. We have conducted a cross-sectional natural history study of mitochondrial DNA changes in the YAC128 mouse. Here, we first show that the mitochondrial volume fraction appears to increase in the axons and dendrite regions adjacent to the striatal neuron cell bodies in old mice. Mitochondrial DNA copy number (mtDNAcn) was used as a proxy measure for mitochondrial biogenesis and function. We observed that the mtDNAcn changes significantly with age and genotype in a tissue-specific manner. We found a positive correlation between aging and the mtDNAcn in striatum and skeletal muscle but not in cortex. Notably, the YAC128 mice had lower mtDNAcn in cortex and skeletal muscle. We further show that mtDNA deletions are present in striatal and skeletal muscle tissue in both young and aged YAC128 and WT mice. Tracking gene expression levels cross-sectionally in mice allowed us to identify contributions of age and genotype to transcriptional variance in mitochondria-related genes. These findings provide insights into the role of mitochondrial dynamics in HD pathogenesis in both brain and skeletal muscle, and suggest that mtDNAcn in skeletal muscle tissue may be a potential biomarker that should be investigated further in human HD.

The invasive emerald ash borer (Agrilus planipennis Fairmaire; Coleoptera: Buprestidae) has killed tens of millions of ash (Fraxinus spp.) trees across North America. A. planipennis was first detected in Winnipeg, Manitoba in 2017 and has the potential to become a serious threat to the city's ash canopy which accounts for ~30% of the public tree inventory. The goal of this study was to predict when adult A. planipennis emergence and peak activity would occur in Winnipeg to help logistical planning for the implementation of a city-wide management program. The management program would focus on detection and limiting the spread of the beetle with the objective of preserving ash trees as long as possible allowing for more proactive management of the EAB infestation. To predict adult emergence and peak activity of A. planipennis, we used local weather station data to calculate the number of degree-days accumulated in each year for the 1970–2019 period using three different degree-day accumulation models. Developmental thresholds for A. planipennis were derived from previous North American studies. The estimated mean emergence dates for the 50-year period were June 14 ± 8.5 days (double sine model), June 14 ± 8.5 days (single sine model), and June 19 ± 9.1 days (standard model) whereas the peak activity dates were July 16 ± 8.8 days (double sine model), July 17 ± 8.7 days (single sine model), and July 21 ± 9.4 days (standard model). Meteorological records indicate that temperatures in the Winnipeg region have increased over the study period. However, our predicted emergence dates do not significantly differ over the 50 years examined in the study, although estimated peak activity dates are significantly earlier, suggesting that EAB movement may benefit from climate change. The results from this study will provide managers with information regarding the temporal behavior of A. plannipennis in Winnipeg allowing for improved timing of control measures and monitoring, thereby extending the projected life span of a significant ash tree population within the Winnipeg urban region. The management model developed for Winnipeg could serve as an example for other locations in the prairie region of North America.

Nearshore water quality can be highly impacted by anthropogenic activities ongoing along the coast, the effects of which on natural environments can be permanent and irreversible, with consequences for ecosystem biodiversity and functioning, as well as for associated services. Benthic filter feeders (e.g., mussels) provide several services for coastal regions, including improving water quality by reducing eutrophication, being a major source of food for humans, and as a habitat-forming species. Here, we seek to understand the role of benthic filter feeders in enhancing water quality in an urban coastal system in order to assess their role as ecosystem service providers and how they should be included in ecosystem-based evaluations. Using as a model False Bay, South Africa’s largest natural bay and a socio-economic hotspot, this multidisciplinary study was designed to identify possible pollution sources to a highly-urbanised coastal region, assess their effects on several biological and biogeochemical parameters, and evaluate the role of mussels in mitigating these anthropogenic inputs. We consider several sources of pollution, including nutrient loading from wastewater and river outflows, heavy metals, and aerosol deposition. We find that pollutant inputs are largely attenuated by the circulation of the bay and by the presence of filter feeders that bioaccumulate contaminants, thereby removing them from coastal waters. Our work thus emphasizes the potential for mussels and natural abiotic processes to ameliorate anthropogenic impacts, although these mitigation strategies are not without environmental risk. We recommend that such information should be included in national assessments used to develop appropriate strategies and policies for coastal environmental management and conservation.

Collegiality and the contribution to the sustenance of the academy through academic citizenship are central to commonly held conceptions of what it is to be a university. This study investigates the articulation and recognition of academic citizenship through institutional promotion criteria, including both traditional research and teaching-focussed career pathways. The study adopts a qualitative research approach and examines promotion criteria from a sample of 55 mid-sized universities in the UK. Findings point to a progressive shift in formal recognition of service activities associated with citizenship as part of the core academic workload. Institutional service is pervasive across all academic roles and levels, student service is largely invisible, and activities associated with public service are most notably acknowledged in traditional academic roles at the professorial level. The evolving nature of expectations of citizenship necessitates a more nuanced consideration of the core dimensions of an academic role and citizenship activities to ensure equity and inclusivity in career progression.

Abstract Female primates signal impending ovulation with a suite of sexual signals. Studies of these signals have focussed on visual, and to a lesser extent, acoustic signals, neglecting olfactory signals. We aimed to investigate the information content of female olfactory signals in captive olive baboons (Papio anubis) and relate these to the female fertile period. We studied eight adult females living in four groups at the CNRS Station de Primatologie, Rousset-sur-Arc, France. We used vaginal cytology to detect ovulation. We investigated the volatile component of odour signals using solid-phase microextraction and gas chromatography-mass spectrometry. We found a total of 74 volatile compounds, of which we tentatively identified 25, including several ketones, alcohols, aldehydes, terpenes, volatile fatty acids and hydrocarbons that have been identified in odour profiles of other primates. Our results show that vaginal odour intensity differs with sexual cycle stage suggesting that odour might play a role in signalling female baboon fertility. We found differences in vaginal odour between females living in all-female and in mixed sex groups but we could not distinguish the effects of group composition, female age and identity. This study of olfactory signalling improves our understanding of how female primates advertise their sexual receptivity.

In general, much is known about patterns relating to flood risk reduction, coping, and adaptation in various types of communities; however, knowledge of their drivers—which are critical for building community resilience to natural hazards—is limited. The present study investigates the influencing factors of coping and adaptation measures vis-a-vis flood hazards at the community level and examines their interrelationships. This work employs a “case study” approach and analyzes two towns—St. Adolphe and Ste. Agathe—in the Red River Valley in the province of Manitoba, Canada. Data collection consisted of in-depth interviews with key informants and obtaining oral histories from the locals, along with an examination of secondary official records and documents. The results revealed that the major drivers of local-level coping and adaptation include functioning partnerships among stakeholders, strong institutional structures that facilitate interactive learning, knowledge co-production, resources sharing, communication and information sharing, and infrastructure supports. It was observed that an institutional atmosphere conducive to spontaneous network development yields diverse coping and adaptation strategies. To improve the outcomes of coping and adaptation measures, close collaboration between community-based groups and formal and quasi-formal institutions, and transparency in decision-making processes are vital.

Migratory birds play a major role in spreading influenza viruses over long distances. We report highly pathogenic avian influenza A(H5N6) viruses in migratory and resident ducks in Bangladesh. The viruses were genetically similar to viruses detected in wild birds in China and Mongolia, suggesting migration-associated dissemination of these zoonotic pathogens.

BackgroundMultimorbidity, which is associated with significant negative outcomes for individuals and health care systems, is increasing in the United Kingdom. However, there is a lack of knowledge about the risk factors (including health, behavior, and environment) for multimorbidity over time. An interdisciplinary approach is essential, as data science, artificial intelligence, and engineering concepts (digital twins) can identify key risk factors throughout the life course, potentially enabling personalized simulation of life-course risk for the development of multimorbidity. Predicting the risk of developing clusters of health conditions before they occur would add clinical value by enabling targeted early preventive interventions, advancing personalized care to improve outcomes, and reducing the burden on health care systems. ObjectiveThis study aims to identify key risk factors that predict multimorbidity throughout the life course by developing an intelligent agent using digital twins so that early interventions can be delivered to improve health outcomes. The objectives of this study are to identify key predictors of lifetime risk of multimorbidity, create a series of simulated computational digital twins that predict risk levels for specific clusters of factors, and test the feasibility of the system. MethodsThis study will use machine learning to develop digital twins by identifying key risk factors throughout the life course that predict the risk of later multimorbidity. The first stage of the development will be the training of a base predictive model. Data from the National Child Development Study, the North West London Integrated Care Record, the Clinical Practice Research Datalink, and Cerner’s Real World Data will be split into subsets for training and validation, which will be done following the k-fold cross-validation procedure and assessed with the Prediction Model Risk of Bias Assessment Tool (PROBAST). In addition, 2 data sets—the Early-Life Data Cross-linkage in Research study and the Children and Young People’s Health Partnership randomized controlled trial—will be used to develop a series of digital twin personas that simulate clusters of factors to predict different risk levels of developing multimorbidity. ResultsThe expected results are a validated model, a series of digital twin personas, and a proof-of-concept assessment. ConclusionsDigital twins could provide an individualized early warning system that predicts the risk of future health conditions and recommends the most effective intervention to minimize that risk. These insights could significantly improve an individual’s quality of life and healthy life expectancy and reduce population-level health burdens. International Registered Report Identifier (IRRID)PRR1-10.2196/35738

BackgroundThe incidence of major surgery is on the rise globally, and more than 20% of patients are readmitted to hospital following discharge from hospital. During their hospital stay, patients are monitored for early detection of clinical deterioration, which includes regularly measuring physiological parameters such as blood pressure, heart rate, respiratory rate, temperature, and pulse oximetry. This monitoring ceases upon hospital discharge, as patients are deemed clinically stable. Monitoring after discharge is relevant to detect adverse events occurring in the home setting and can be made possible through the development of digital technologies and mobile networks. Smartwatches and other technological devices allow patients to self-measure physiological parameters in the home setting, and Bluetooth connectivity can facilitate the automatic collection and transfer of this data to a secure server with minimal input from the patient. ObjectiveThis paper presents the protocol for the DREAMPath (Domiciliary Recovery After Medicalization Pathway) study, which aims to measure compliance with a multidevice remote monitoring kit after discharge from hospital following major surgery. MethodsDREAMPath is a single-center, prospective, observational, cohort study, comprising 30 patients undergoing major intracavity surgery. The primary outcome is to assess patient compliance with wearable and interactive smart technology in the first 30 days following discharge from hospital after major surgery. Secondary outcomes will explore the relation between unplanned health care events and physiological data collected in the study, as well as to explore a similar relationship with daily patient-reported outcome measures (Quality of Recovery–15 score). Secondary outcomes will be analyzed using appropriate regression methods. Cardiopulmonary exercise testing data will also be collected to assess correlations with wearable device data. ResultsRecruitment was halted due to COVID-19 restrictions and will progress once research staff are back from redeployment. We expect that the study will be completed in the first quarter of 2022. ConclusionsDigital health solutions have been recently made possible due to technological advances, but urgency in rollout has been expedited due to COVID-19. The DREAMPath study will inform readers about the feasibility of remote monitoring for a patient group that is at an increased risk of acute deterioration. Trial RegistrationISRCTN Registry ISRCTN62293620; https://www.isrctn.com/ISRCTN62293620 International Registered Report Identifier (IRRID)DERR1-10.2196/30638

Abstract Background Individual surgical risk assessment (ISRA) enhances patient care experience and outcomes by informing shared decision-making, strengthening the consent process, and supporting clinical management. Neither the use of individual pre-surgical risk assessment tools nor the rate of individual risk assessment documentation is known. The primary endpoint of this study was to determine the rate of physician documented ISRAs, with or without a named ISRA tool, within the records of patients with poor outcomes. Secondary endpoints of this work included the effects of age, sex, race, ASA class, and time and type of surgery on the rate of documented presurgical risk. Methods The records of non-obstetric surgical patients within 22 community-based private hospitals in Arizona, Colorado, Nebraska, Nevada, and Wyoming, between January 1 and December 31, 2017, were evaluated. A two-sample proportion test was used to identify the difference between surgical documentation and anesthesiology documentation of risk. Logistic regression was used to analyze both individual and group effects associated with secondary endpoints. Results Seven hundred fifty-six of 140,756 inpatient charts met inclusion criteria (0.54%, 95% CI 0.50 to 0.58%). ISRAs were documented by 16.08% of surgeons and 4.76% of anesthesiologists (p < 0.0001, 95% CI −0.002 to 0.228). Cardiac surgeons documented ISRAs more frequently than non-cardiac surgeons (25.87% vs 16.15%) [p = 0.0086, R-squared = 0.970%]. Elective surgical patients were more likely than emergency surgical patients (19.57 vs 12.03%) to have risk documented (p = 0.023, R-squared = 0.730%). Patients over the age of 65 were more likely than patients under the age of 65 to have ISRA documentation (20.31 vs 14.61%) [p = 0.043, R-squared = 0.580%]. Only 10 of 756 (1.3%) records included documentation of a named ISRA tool. Conclusions The observed rate of documented ISRA in our sample was extremely low. Surgeons were more likely than anesthesiologists to document ISRA. As these individualized risk assessment discussions form the bedrock of perioperative informed consent, the rate and quality of risk documentation must be improved.