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Abstract Background Children and young people (CYP) seen by child and adolescent mental health services (CAMHS) often experience safeguarding issues. Yet little is known about the volume and nature of these risks, including how different adversities or risks relate to one another. This exploratory study aims to bridge this gap, examining rates at entry to services and profiles of risk using a latent class analysis. Methods Data were extracted for CYP who received at least one risk assessment at CAMHs in South London between January 2007 and December 2017. In total, there were 21,688 risk assessments. Latent class analysis was used to identify profiles of risk from the risk assessments. Results Concerns about parent mental health (n = 5274; 24%), emotional abuse (n = 4487; 21%), violence towards others (n = 4210; 19%), destructive behaviour (n = 4005; 18%), and not attending school (n = 3762; 17%) were the most commonly identified risks. Six distinct profiles of risk were identified from the latent class analyses: (1) maltreatment and externalising behaviours, (2) maltreatment but low risk to self and others, (3) antisocial behaviour, (4) inadequate caregiver supervision and risk to self and others, (5) risk to self but not others, and (6) mental health needs but low risk. Conclusions These findings provide fresh insights into adverse experiences and risks identified by CAMHS. For professionals, the profiles identified in this study might provide insights into profiles of identified risks, in contrast to traditional cumulative approaches to risk. For researchers, these profiles may be fertile ground for hypothesis‐driven work on the association between adversity and later outcomes.

Introduction The ski binding plays an important role in ski mountaineering. When traveling uphill, the binding has an adjustable heel height known as the riser. Previous laboratory research reported joint kinematics and kinetics are influenced by riser height, however little is known about changes to muscle activity associated with differing joint motion. The purpose of this work was to assess riser height influence on kinematics and muscle activity at different slopes during on-snow skiing. Methods Three female and nine male recreational ski mountaineers (19-26 y) were tested on 5o and 16o gradients using no riser (0 cm) and riser (5.3 cm) at a submaximal 80% HRmax. Each subject used Backland 85 UL skis and Backland Bindings (Atomic Skis, Altenmarkt, Austria). Subjects skied for 6 min at each binding setting with the last 10 gait-cycles evaluating lower limb joint motion gathered from 2D-sagittal plane motion capture. Electromyography (EMG) collected unilaterally on the rectus femoris, biceps femoris, medial gastrocnemius and triceps brachii also. Results 5o slope: hip range of motion (ROM) decreased (p = .003), ankle ROM decreased (p = .005), stride length decreased (p = .004), rating of perceived exertion (RPE) increased (p = .02) for riser compared to no riser. At 16o slope: hip ROM decreased (p = .001), and RPE decreased (p = .004) for riser compared to no riser. HR, glide distance, velocity, EMG, and net mechanical efficiency were not different between riser heights on either slope. Discussion/Conclusion Lower body joint kinematics, step length and RPE varied significantly with riser height. Kinematic differences did not impact velocity or muscle activity when controlling pace. These results agree with previous findings showing minimal differences in EMG and HR while lower body kinematics and RPE changed with riser height.

Background: Perturbation-based balance training (PBT) is a promising fall risk reduction method that involves inducing unexpected perturbations to balance to train participants reactive balance control. Due to the unpredictable nature of PBT, its acceptability to older adults could present a barrier to the implementation of PBT in the community. Aim/Purpose: The purpose of this study was to assess the perceived acceptability of a community-based PBT program to both older adults and healthcare professionals (HCPs). Methods: Nineteen older adults (aged 69.6 ± 6.6 years, 17 women, 2 men) and three HCPs participated in the qualitative study. Participants completed four PBT sessions facilitated in conjunction with HCPs. Interviews, based on the theoretical framework of acceptability, were conducted before and after PBT and analyzed using template analysis. Results: PBT was perceived as effective by older adults and HCPs. However, HCPs perceived the equipment cost as a substantial barrier to feasibility in the community.

The effect of norovirus dose on outcomes such as virus shedding and symptoms after initial infection is not well understood. We performed a secondary analysis of a human challenge study by using Bayesian mixed-effects models. As the dose increased from 4.8 to 4,800 reverse transcription PCR units, the total amount of shed virus in feces increased from 4.5 × 1011 to 3.4 × 1012 genomic equivalent copies; in vomit, virus increased from 6.4 × 105 to 3.0 × 107 genomic equivalent copies. Onset time of viral shedding in feces decreased from 1.4 to 0.8 days, and time of peak viral shedding decreased from 2.3 to 1.5 days. Time to symptom onset decreased from 1.5 to 0.8 days. One type of symptom score increased. An increase in norovirus dose was associated with more rapid shedding and symptom onset and possibly increased severity. However, the effect on virus load and shedding was inconclusive.

ABSTRACT: Postnatal mortality among replacement stock has a detrimental effect on the social, economic, and environmental sustainability of dairy production. Calf mortality rates vary between countries and show differences in temporal trends; most, however, are characterized by high levels of between-farm variability. Explaining this variation can be difficult because herd-level information on management practices relevant to calf health is often not available. The Irish Johne's Control Programme (IJCP) contains a substantial on-farm monitoring program called the Veterinary Risk Assessment and Management Plan (VRAMP). Although this risk assessment is largely focused on factors relevant to the transmission of paratuberculosis, many of its principles are good practice biocontainment policies that are also advocated for the protection of calf health. The objectives of this study were (1) to quantify mortality in ear-tagged Irish dairy calves between 2016 and 2020 using both survival and risk approaches, (2) to determine risk factors for 100-d cumulative mortality hazard in ear-tagged Irish dairy calves between 2016 and 2020, (3) to determine whether 100-d cumulative mortality hazard was higher in ear-tagged calves within herds registered in the IJCP versus those that were not registered in the IJCP and whether there were differences between these cohorts over time, and (4) within IJCP herds, to determine whether VRAMP score or changes in VRAMP score were associated with 100-d cumulative mortality hazard. Excluding perinatal mortality, the overall 100-d cumulative mortality hazard was 4.1%. Calf mortality was consistently underestimated using risk approaches that did not account for calf censoring. Cox proportional hazards models showed that cumulative mortality hazard was greater in male calves; particularly, calves born to Jersey breed dams and those with a beef breed sire. Mortality hazard increased with increasing herd size, was highest in calves born in herds that contract-reared heifers, and lowest in those born in mixed dairy-beef enterprises. Mortality hazard decreased over time with the mortality hazard in 2020 being 0.83 times that of 2016. Mortality hazard was higher in IJCP-registered herds than nonregistered herds (hazard ratio 1.06, 95% CI 1.01–1.12), likely reflecting differences in herds that enrolled in the national program. However, we detected a significant interaction between IJCP status (enrolled vs. not enrolled) and year (hazard ratio 0.96, 95% CI 0.92–1.00), indicating that the decrease in mortality hazard between 2016 and 2020 was greater in IJCP herds versus non-IJCP herds. Finally, increasing VRAMP scores (indicating higher risk for paratuberculosis transmission) were positively associated with increased calf mortality hazard. Postnatal calf mortality rates in Irish dairy herds declined between 2016 and 2020. Our study suggests that implementation of recommended biocontainment practices to control paratuberculosis in IJCP herds was associated with a reduction in calf mortality hazard.

Abstract Background The establishment of new anatomy facilities needs to accommodate a combination of modern teaching modalities that best align with evidence-based best teaching practices. This article describes the process in which our state-of-the-art anatomy laboratories were designed and implemented, and how these facilities support aspects of modern anatomy education. Methods A list of best practices for anatomy education in a modern medical curriculum was summarized from the literature. To assess student satisfaction, a survey related to student perception of the anatomy facilities (5-point Likert scale) was conducted. Results Our educational modalities include a broad range of teaching approaches. The Instructional Studio houses prosected and plastinated specimens, and cadaveric dissections are performed. Each of our three Dry Laboratories allow for active learning and interaction between small student groups. The Webinar Room acts as a conference room for departmental and online meetings, discussions with students, and dialogues with affiliated hospitals via the internet. The Imaging Center is equipped with a Sectra® medical educational platform, CAE Vimedix® Virtual Medical Imaging Ultrasound Training System, and Philipps Lumify® Ultrasound devices to train students to conduct and interpret sonographic images. Moreover, the Complete Anatomy® program is made available to all our students. Conclusion The layout of our newly created Anatomy Facilities allows for all aspects of modern medical education mentioned in the literature. These educational modalities and teaching approaches are highly appreciated by our faculty and students. Moreover, these technologies allowed for a smooth transition from on-site anatomy teaching to online education during the COVID pandemic.

The year 2022 will herald approximately 100,000 new cases of cutaneous melanoma (CM), and over 7000 deaths from CM. Over the past 40 years, CM incidence has increased nearly six-fold; however, annual mortality has remained relatively constant. These trends encapsulate the phenomenon of overdiagnosis. Increased recognition of indolent lesions that appear histologically malignant may be leading to a melanoma epidemic. Enhanced melanoma awareness, screening efforts, physician uncertainty, medical-legal pressures, and diagnostic scrutiny using tools like immunohistochemical staining, mole mapping, dermoscopy, confocal microscopy, and molecular diagnostics contribute to increased CM diagnosis. As a result, current melanoma staging and treatment guidelines are being challenged. Existing standards fail to accurately identify histologically benign lesions that are lethal or, conversely, histologically malignant lesions that are innocuous. Healthcare systems and, more importantly, patients suffer from this diagnostic ambiguity that leads to the over-treatment of innocuous melanomas and under-treatment of aggressive melanomas. As dermatology continues to experience a shift towards earlier diagnosis of melanoma, management strategies must adapt. Herein, we review factors that may contribute to the increased incidence of melanoma, emphasize deficiencies in current staging systems, and provide insights into the future of melanoma management via precision medicine.

Abstract Although PAH is partially attributed to disordered metabolism, previous human studies have mostly examined circulating metabolites at a single time point, potentially overlooking crucial disease biology. Current knowledge gaps include an understanding of temporal changes that occur within and across relevant tissues, and whether observed metabolic changes might contribute to disease pathobiology. We utilized targeted tissue metabolomics in the Sugen hypoxia (SuHx) rodent model to investigate tissue‐specific metabolic relationships with pulmonary hypertensive features over time using regression modeling and time‐series analysis. Our hypotheses were that some metabolic changes would precede phenotypic changes, and that examining metabolic interactions across heart, lung, and liver tissues would yield insight into interconnected metabolic mechanisms. To support the relevance of our findings, we sought to establish links between SuHx tissue metabolomics and human PAH ‐omics data using bioinformatic predictions. Metabolic differences between and within tissue types were evident by Day 7 postinduction, demonstrating distinct tissue‐specific metabolism in experimental pulmonary hypertension. Various metabolites demonstrated significant tissue‐specific associations with hemodynamics and RV remodeling. Individual metabolite profiles were dynamic, and some metabolic shifts temporally preceded the emergence of overt pulmonary hypertension and RV remodeling. Metabolic interactions were observed such that abundance of several liver metabolites modulated lung and RV metabolite‐phenotype relationships. Taken all together, regression analyses, pathway analyses and time‐series analyses implicated aspartate and glutamate signaling and transport, glycine homeostasis, lung nucleotide abundance, and oxidative stress as relevant to early PAH pathobiology. These findings offer valuable insights into potential targets for early intervention in PAH.

Summary: Objective: Two techniques facilitate the transition in an alpine ski turn, extension (EXT) and flexion (FLEX). The purpose of this study is to compare NIRS, EMG, and RPE responses between EXT and FLEX in expert level skiers. Design: 24 Professional Ski Instructors of America Level III alpine ski instructors, examiners, and National Demonstration Team members completed one standardized run each of EXT and FLEX. A turn cycle, made of a right and left turn, was divided into four Phases. Methods: NIRS assessed HbO2 desaturation in the rectus femoris (RF) and vastus lateralis (VL). EMG was collected from the RF, VL, and gluteus medius (GM). Rating of Perceived Exertion (RPE, 0–10) assessed subjective exertion. Results: FLEX resulted in greater HbO2 desaturation in RF (−77.9 ​± ​21% vs. −67.5 ​± ​23%, p ​

Abstract In pulmonary artery hypertension (PAH), emerging evidence suggests that metabolic abnormalities may be contributing to cellular dysfunction in PAH. Metabolic abnormalities such as glycolytic shift have been observed intracellularly in several cell types in PAH, including microvacular endothelial cells (MVECs). Concurrently, metabolomics of human PAH samples has also revealed a variety of metabolic abnormalities; however the relationship between the intracellular metabolic abnormalities and the serum metabolome in PAH remains under investigation. In this study, we utilize the sugen/hypoxia (SuHx) rodent model of PAH to examine the RV, LV and MVEC intracellular metabolome (using targeted metabolomics) in normoxic and SuHx rats. We additionally validate key findings from our metabolomics experiments with data obtained from cell culture of normoxic and SuHx MVECs, as well as metabolomics of human serum samples from two different PAH patient cohorts. Taken together, our data, spanning rat serum, human serum and primary isolated rat MVECs reveal that: (1) key classes of amino acids (specifically, branched chain amino acids—BCAA) are lower in the pre‐capillary (i.e., RV) serum of SuHx rats (and humans); (2) intracellular amino acid levels (in particular BCAAs) are increased in SuHx‐MVECs; (3) there may be secretion rather than utilization of amino acids across the pulmonary microvasculature in PAH and (4) an oxidized glutathione gradient is present across the pulmonary vasculature, suggesting a novel fate for increased glutamine uptake (i.e., as a source of glutathione). in MVECs in PAH. In summary, these data reveal new insight into the shifts in amino acid metabolism occurring across the pulmonary circulation in PAH.

OBJECTIVES/GOALS: Older adults in rural communities are at an elevated risk of falling. Perturbation-Based Balance Training (PBT) is a highly effective fall prevention paradigm but its feasibility in the community is unknown. The purpose of this study was to determine the feasibility and acceptability of PBT to older adults and local clinicians in rural communities. METHODS/STUDY POPULATION: 19 older adults (60+ years) were recruited from communities in rural Montana to take part in a PBT program. The PBT program was implemented using a bespoke portable PBT treadmill developed by our research team and validated against commercial PBT treadmills. To increase ecological validity, the program was implemented by local clinicians. The PBT program lasted 6 weeks, with 1 session per week, participants received up to 35 trip perturbations per session. The feasibility and acceptability of PBT to participants and clinicians was assessed within the Theoretical Framework of Acceptability, prospectively and retrospectively via interviews and surveys, and concurrently via field notes. RESULTS/ANTICIPATED RESULTS: Data analysis is ongoing and will be complete by the time of presentation. Preliminary results suggest the portable PBT program was generally acceptable to older adults and local clinicians. Perceived effectiveness was generally positive and increased balance awareness and low burden are emerging as common themes. Local clinicians indicated the burden of implementing PBT was low, PBT fit within their views on fall prevention, and had a high level of perceived effectiveness. There appear to be a few limitations to feasibility, which are primarily related to the weight and transportation of the treadmill. We are currently working to refine the treadmill and lower its weight and are developing a grant with local clinicians and extension agents that would facilitate transportation to a broader network of communities. DISCUSSION/SIGNIFICANCE: Our preliminary findings suggest PBT is feasible in rural communities and accepted by older adults. Increased balance and fall awareness and low burden are emerging as important factors in the feasibility and acceptability of PBT. This study provides a foundation for future studies to translate other PBT modalities from the lab to the community.

Abstract Background and Aim Barrett's esophagus is associated with increased risk of esophageal adenocarcinoma. The optimal management of low‐grade dysplasia arising in Barrett's esophagus remains controversial. We performed a retrospective study from a tertiary referral center for Barrett's esophagus neoplasia, to estimate time to progression to high‐grade dysplasia/esophageal adenocarcinoma in patients with confirmed low‐grade dysplasia compared with those with downstaged low‐grade dysplasia from index presentation and referral. We analyzed risk factors for progression. Methods We analyzed consecutive patients with low‐grade dysplasia in Barrett's esophagus referred to a single tertiary center (July 2006–October 2018). Biopsies were reviewed by at least two expert pathologists. Results One hundred and forty‐seven patients referred with suspected low‐grade dysplasia were included. Forty‐two of 133 (32%) of all external referrals had confirmed low‐grade dysplasia after expert histopathology review. Multivariable analysis showed nodularity at index endoscopy (P

Wallerian degeneration (WD) is a conserved axonal self-destruction program implicated in several neurological diseases. WD is driven by the degradation of the NAD+ synthesizing enzyme NMNAT2, the buildup of its substrate NMN, and the activation of the NAD+ degrading SARM1, eventually leading to axonal fragmentation. The regulation and amenability of these events to therapeutic interventions remain unclear. Here we explored pharmacological strategies that modulate NMN and NAD+ metabolism, namely the inhibition of the NMN-synthesizing enzyme NAMPT, activation of the nicotinic acid riboside (NaR) salvage pathway and inhibition of the NMNAT2-degrading DLK MAPK pathway in an axotomy model in vitro. Results show that NAMPT and DLK inhibition cause a significant but time-dependent delay of WD. These time-dependent effects are related to NMNAT2 degradation and changes in NMN and NAD+ levels. Supplementation of NAMPT inhibition with NaR has an enhanced effect that does not depend on timing of intervention and leads to robust protection up to 4 days. Additional DLK inhibition extends this even further to 6 days. Metabolite analyses reveal complex effects indicating that NAMPT and MAPK inhibition act by reducing NMN levels, ameliorating NAD+ loss and suppressing SARM1 activity. Finally, the axonal NAD+/NMN ratio is highly predictive of cADPR levels, extending previous cell-free evidence on the allosteric regulation of SARM1. Our findings establish a window of axon protection extending several hours following injury. Moreover, we show prolonged protection by mixed treatments combining MAPK and NAMPT inhibition that proceed via complex effects on NAD+ metabolism and inhibition of SARM1.

Background Clinical risk factors in neonatal cardiac surgery do not fully capture discrepancies in outcomes. Targeted metabolomic analysis of plasma from neonates undergoing heart surgery with cardiopulmonary bypass was performed to determine associations with clinical outcomes. Methods and Result Samples and clinical variables from 149 neonates enrolled in the Corticosteroid Therapy in Neonates Undergoing Cardiopulmonary Bypass trial with surgical treatment for congenital heart disease between 2012 and 2016 were included. Blood samples were collected before skin incision, immediately after cardiopulmonary bypass, and 12 hours after surgery. Outcomes include composite morbidity/mortality (death, extracorporeal membrane oxygenation, cardiac arrest, acute kidney injury, and/or hepatic injury) and a cardiac composite (extracorporeal membrane oxygenation, cardiac arrest, or increase in lactate level), hepatic injury, and acute kidney injury. Targeted metabolite levels were determined by high‐resolution tandem liquid chromatography and mass spectrometry. Principal component and regression analyses were used to assess associations between metabolic profiles and outcomes, with 2 models created: a base clinical model and a base model+metabolites. Of the 193 metabolites examined, 40 were detected and quantified. The first principal component, principal component 1, was composed mostly of preoperative metabolites and was significantly associated with the composite morbidity/mortality, cardiac composite, and hepatic injury outcomes. In regression models, individual metabolites also improved model performance for the composite morbidity/mortality, cardiac composite, and hepatic injury outcomes. Significant disease pathways included myocardial injury (false discovery rate, 0.00091) and heart failure (false discovery rate, 0.041). Conclusions In neonatal cardiac surgery, perioperative metabolites were associated with postoperative outcomes and improved clinical model outcome associations. Preoperative metabolite levels alone may improve risk models and provide a basis for optimizing perioperative care.

Abstract Many studies report age as a risk factor for BoHV-1 infection or seropositivity. However, it is unclear whether this pattern reflects true epidemiological causation or is a consequence of study design and other issues. Here, we seek to understand the age-related dynamics of BoHV-1 seroprevalence in seasonal calving Irish dairy herds and provide decision support for the design and implementation of effective BoHV-1 testing strategies. We analysed seroprevalence data from dairy herds taken during two Irish seroprevalence surveys conducted between 2010 and 2017. Age-dependent seroprevalence profiles were constructed for herds that were seropositive and unvaccinated. Some of these profiles revealed a sudden increase in seroprevalence between adjacent age-cohorts, from absent or low to close to 100% of seropositive animals. By coupling the outcome of our data analysis with simulation output of an individual-based model at the herd scale, we have shown that these sudden increases are related to extensive virus circulation within a herd for a limited time, which may then subsequently remain latent over the following years. BoHV-1 outbreaks in dairy cattle herds affect animals independent of age and lead to almost 100% seroconversion in all age groups, or at least in all animals within a single epidemiological unit. In the absence of circulating infection, there is a year-on-year increase in the age-cohort at which seroprevalence changes from low to high. The findings of this study inform recommendations regarding testing regimes in the context of contingency planning or an eradication programme in seasonal calving dairy herds.

Background: A One Health approach requires integrative research to elucidate antimicrobial resistance (AMR) in the environment and the risks it poses to human health. Research on this topic involves experts from diverse backgrounds and professions. Shortcomings exist in terms of consistent, complete, and transparent reporting in many environmental studies. Standardized reporting will improve the quality of scientific papers, enable meta-analyses and enhance the communication among different experts. In this study, we aimed to generate a consensus of reporting standards for AMR research in wastewater and related aquatic environments. Methods: Based on a risk of bias assessment of the literature in a systematic review, we proposed a set of study quality indicators. We then used a multistep modified Delphi consensus to develop the EMBRACE-WATERS statement (rEporting antiMicroBial ResistAnCE in WATERS), a checklist of recommendations for reporting in studies of AMR in wastewater and related aquatic environments. Findings: Consensus was achieved among a multidisciplinary panel of twenty-one experts in three steps. The developed EMBRACE-WATERS statement incorporates 21 items. Each item contains essential elements of high-quality reporting and is followed by an explanation of their rationale and a reporting-example. The EMBRACE-WATERS statement is primarily intended to be used by investigators to ensure transparent and comprehensive reporting of their studies. It can also guide peer-reviewers and editors in evaluation of manuscripts on AMR in the aquatic environment. This statement is not intended to be used to guide investigators on the methodology of their research. Interpretation: We are hopeful that this statement will improve the reporting quality of future studies of AMR in wastewater and related aquatic environments. Its uptake would generate a common language to be used among researchers from different disciplines, thus advancing the One Health approach towards understanding AMR spread across aquatic environments. Similar initiatives are needed in other areas of One Health research.

The Irish Johne's Control Programme (IJCP) provides a long-term approach to the voluntary control of Johne's disease (JD) in Ireland, strongly supported by Irish cattle industry leadership. It leverages the establishment of Animal Health Ireland for control of animal diseases not regulated by the European Union. The IJCP has four objectives: facilitate protection against spread of JD to uninfected farms; reduce the level of infection when present; assure markets of JD control in Ireland; and improve calf health and farm biosecurity. Key IJCP elements are an annual veterinary risk assessment and management plan (VRAMP), annual whole herd test (WHT) by ELISA on blood or milk samples with ancillary faecal PCR testing of ELISA reactors, and Targeted Advisory Service on Animal Health (TASAH) investigations of infected herds. There are pathways for assurance of herds with continuing negative tests and for management of test-positive herds. Herdowners are responsible for on-farm activities, and specifically-trained (approved) veterinary practitioners have a pivotal role as technical advisors and service providers. The programme is supported by training of veterinarians, performance of testing in designated laboratories, documentation of policies and procedures, innovative data management for herd and test activities and for programme administration, training, and broad communication and awareness activities. Tools and systems are refined to address emerging issues and enhance the value of the programme. An Implementation Group comprising industry, government and technical leaders sets strategic direction and policy, advised by a Technical Working Group. Shared funding responsibilities are agreed by key stakeholders until 2022 to support herds in the programme to complete requirements. Herd registrations have increased steadily to exceed 1,800. National bulk tank milk surveillance is also being deployed to identify and recruit test-positive herds with the expectation that they have a relatively high proportion of seropositive animals. The programme will continue to innovate and improve to meet farmer and industry needs.

The COST action “Standardising output-based surveillance to control non-regulated diseases of cattle in the European Union (SOUND control),” aims to harmonise the results of surveillance and control programmes (CPs) for selected cattle diseases to facilitate safe trade and improve overall control of cattle infectious diseases. In this paper we aimed to provide an overview on the diversity of control for these diseases in Europe. A selected cattle disease was defined as an infectious disease of cattle with no or limited control at EU level, which is not included in the European Union Animal health law Categories A or B under Commission Implementing Regulation (EU) 2020/2002. A CP was defined as surveillance and/or intervention strategies designed to lower the incidence, prevalence, mortality or prove freedom from a specific disease in a region or country. Passive surveillance, and active surveillance of breeding bulls under Council Directive 88/407/EEC were not considered as CPs. A questionnaire was designed to obtain country-specific information about CPs for each disease. Animal health experts from 33 European countries completed the questionnaire. Overall, there are 23 diseases for which a CP exists in one or more of the countries studied. The diseases for which CPs exist in the highest number of countries are enzootic bovine leukosis, bluetongue, infectious bovine rhinotracheitis, bovine viral diarrhoea and anthrax (CPs reported by between 16 and 31 countries). Every participating country has on average, 6 CPs (min–max: 1–13) in place. Most programmes are implemented at a national level (86%) and are applied to both dairy and non-dairy cattle (75%). Approximately one-third of the CPs are voluntary, and the funding structure is divided between government and private resources. Countries that have eradicated diseases like enzootic bovine leukosis, bluetongue, infectious bovine rhinotracheitis and bovine viral diarrhoea have implemented CPs for other diseases to further improve the health status of cattle in their country. The control of the selected cattle diseases is very heterogenous in Europe. Therefore, the standardising of the outputs of these programmes to enable comparison represents a challenge.

A mandatory national Irish bovine viral diarrhoea (BVD) eradication programme, coordinated by Animal Health Ireland, commenced in 2013. Key decisions and programme review are undertaken by a cross-industry Implementation Group (BVDIG) supported by a Technical Working Group. Ear notch tissue is collected from all new-born calves using modified official identity tags, supplemented by additional blood sampling, including for confirmatory testing of calves with initial positive results and testing of their dams. Testing is delivered by private laboratories in conjunction with the National Reference Laboratory, with all results reported to a central database. This database manages key elements of the programme, issuing results to herdowners by short message service messaging supplemented by letters; assigning and exchanging animal-level statuses with government databases of the Department of Agriculture, Food and the Marine to enable legislated restrictions on animal movements; assigning negative herd status based on test results; generating regular reports for programme management and evaluation and providing herd-specific dashboards for a range of users. Legislation supporting the programme has been in place throughout but has not thus far mandated the slaughter of persistently infected (PI) calves. A key challenge in the early years, highlighted by modeling, was the retention of PI animals by some herd owners. This has largely been resolved by measures including graduated financial supports to encourage their early removal, herd-level movement restrictions, ongoing programme communications and the input of private veterinary practitioners (PVPs). A framework for funded investigations by PVPs in positive herds was developed to identify plausible sources of infection, to resolve the status of all animals in the herd and to agree up to three measures to prevent re-introduction of the virus. The prevalence of PI calves in 2013 was 0.66%, within 11.3% of herds, reducing in each subsequent year, to 0.03 and 0.55%, respectively, at the end of 2020. Recent regulatory changes within the European Union for the first time make provision for official approval of national eradication programmes, or recognition of BVD freedom, and planning is underway to seek approval and, in due course, recognition of freedom within this framework by 2023.

Various European Member States have implemented control or eradication programmes for endemic infectious diseases in cattle. The design of these programmes varies between countries and therefore comparison of the outputs of different control programmes is complex. Although output-based methods to estimate the confidence of freedom resulting from these programmes are under development, as yet there is no practical modeling framework applicable to a variety of infectious diseases. Therefore, a data collection tool was developed to evaluate data availability and quality and to collect actual input data required for such a modeling framework. The aim of the current paper is to present the key learnings from the process of the development of this data collection tool. The data collection tool was developed by experts from two international projects: STOC free (Surveillance Tool for Outcome-based Comparison of FREEdom from infection, www.stocfree.eu) and SOUND control (Standardizing OUtput-based surveillance to control Non-regulated Diseases of cattle in the EU, www.sound-control.eu). Initially a data collection tool was developed for assessment of freedom of bovine viral diarrhea virus in six Western European countries. This tool was then further generalized to enable inclusion of data for other cattle diseases i.e., infectious bovine rhinotracheitis and Johne's disease. Subsequently, the tool was pilot-tested by a Western and Eastern European country, discussed with animal health experts from 32 different European countries and further developed for use throughout Europe. The developed online data collection tool includes a wide range of variables that could reasonably influence confidence of freedom, including those relating to cattle demographics, risk factors for introduction and characteristics of disease control programmes. Our results highlight the fact that data requirements for different cattle diseases can be generalized and easily included in a data collection tool. However, there are large differences in data availability and comparability across European countries, presenting challenges to the development of a standardized data collection tool and modeling framework. These key learnings are important for development of any generic data collection tool for animal disease control purposes. Further, the results can facilitate development of output-based modeling frameworks that aim to calculate confidence of freedom from disease.

Background and study aims Cryoablation with the Cryoballoon device is a novel ablative therapy that uses cycles of freezing and thawing to induce cell death. This single-center prospective study evaluated the feasibility of the focal cryoablation device for the treatment of areas of refractory esophageal neoplasia in patients who had undergone first line endoscopic eradication therapy (EET). Complete remission of dysplasia (CR-D) and complete remission of intestinal metaplasia (CR-IM) at first follow-up endoscopy, durability of disease reversal, rates of stenosis and adverse events were studied. Patients and methods Eighteen cases were treated. At baseline, nine patients had low-grade dysplasia (LGD), six had high-grade dysplasia (HGD) and three had intramucosal carcinoma (IMC). Median length of dysplastic Barrett’s esophagus (BE) treated was 3 cm. The median number of ablations per patient was 11. Each selected area of visible dysplasia received 10 seconds of ablation. One session of cryoablation was performed per patient. Biopsies were performed at around 3 months post-ablation. Results CR-D was achieved in 78 % and CR-IM in 39 % of patients. There were no device malfunction or adverse events. Stenosis was noted in 11 % of cases. At a median follow up of 19-months, CR-D was maintained in 72 % of patients and CR-IM in 33 %. Conclusions Cryoablation appears to be a viable rescue strategy in patients with refractory neoplasia. It is well tolerated and successful in obtaining CR-D and CR-IM in patients with treatment-refractory BE. Further trials of dosimetry, efficacy and safety in treatment-naïve patients are underway.

Purpose: Ovarian cancer is the most fatal of all gynecologic cancers, with a high relapse rate regardless of stage. Women treated for ovarian cancer, therefore, likely have supportive care needs that extend well beyond the time frame of first-line therapy. Unfortunately, there is minimal data describing these needs. The purpose of this qualitative study is to understand the supportive care needs of women with ovarian care at the end of treatment. Methods: To better understand the issues faced by women with ovarian cancer, we conducted a public Twitter chat in collaboration with gynecologic cancer social media (#gyncsm). Both quantitative and qualitative analyses were performed. Results: The chat occurred over a 1-hour time frame on Twitter and resulted in more than 300 unique and original tweets from 43 participants during the chat and an additional 60 unique participants following the chat. Survivors and physicians represented 32% and 11% of participants, respectively; caregivers, advocates, and other clinicians represented the remaining participants. Participants noted deep interest in receiving support during survivorship and dissatisfaction with currently available resources. Sentiment analysis showed that participants viewed the support from social media in a positive light and also revealed negative sentiment around the lack of support from health care providers at the end of treatment. Conclusions: Themes derived from the Twitter chat revealed the unique experiences of individuals with ovarian cancer after treatment, including a heightened sense of vulnerability. Understanding these themes represents an opportunity for clinicians to better understand and address the needs of this patient community.

The existence, stage of eradication and design of control programmes (CPs) for diseases that are not regulated by the EU differ between Member States. When freedom from infection is reached or being pursued, safe trade is essential to protect or reach that status. The aim of STOC free, a collaborative project between six countries, is to develop and validate a framework that enables a transparent and standardized comparison of confidence of freedom for CPs across herds, regions or countries. The framework consists of a model combined with a tool to facilitate the collection of the necessary parameters. All relevant actions taken in a CP are included in a Bayesian network model, which allows prior distributions for most parameters. In addition, frequency of occurrence and risk estimates for factors that influence either the probability of introduction or temporary misclassification leading to delayed detection of the infection are included in the model. Bovine viral diarrhea virus (BVDV) is used as an example disease. Many countries have CPs in place for BVDV and although elements of the CPs are similar, biosecurity measures and testing protocols, including types of tests and testing frequency, as well as target groups, differ widely. Although the initially developed framework is based on BVDV, the aim is to make it sufficiently generic to be adaptable to CPs for other diseases and possibly other species. Thus, STOC free will result in a single general framework, adaptable to multiple disease CPs, which aims to enhance the safety of trade.

Floating-gate (FG) transistors are a primary means of providing nonvolatile digital memory in standard CMOS processes, but they are also key enablers for large-scale programmable analog systems, as well. Such programmable analog systems are often designed for battery-powered and resource-constrained applications, which require the memory cells to program quickly and with low infrastructural overhead. To meet these needs, we present a four-transistor analog floating-gate memory cell that offers both voltage and current outputs and has linear programming characteristics. Furthermore, we present a simple programming circuit that forces the memory cell to converge to targets with 13.0 bit resolution. Finally, we demonstrate how to use the FG memory cell and the programmer circuit in array configurations. We show how to program an array in either a serial or parallel fashion and demonstrate the effectiveness of the array programming with an application of a bandpass filter array.

Gastric adenocarcinoma is a disease that is often detected late, at a stage when curative treatment is unachievable. This must be addressed through changes in our approach to the identification of patients at increased risk by improving the detection and risk assessment of premalignant changes in the stomach, including chronic atrophic gastritis and intestinal metaplasia. Current guidelines recommend utilising random biopsies in a pathology-led approach in order to stage the extent and severity of gastritis and intestinal metaplasia. This random method is poorly reproducible and prone to sampling error and fails to acknowledge recent advances in our understanding of the progression to gastric cancer as a non-linear, branching evolutionary model. Data suggest that recent advances in endoscopic imaging modalities, such as narrow band imaging, can achieve a high degree of accuracy in the stomach for the diagnosis of these premalignant changes. In this review, we outline recent data to support a paradigm shift towards an endoscopy-led approach to diagnosis and staging of premalignant changes in the stomach. High-quality endoscopic interrogation of the chronically inflamed stomach mucosa, supported by targeted biopsies, will lead to more accurate risk assessment, with reduced rates of under or missed diagnoses.

Objective To assess the impact of an open fracture intervention bundle on clinical management and patient outcomes of adults in Malawi with open tibia fractures. Methods We conducted a before-and-after implementation study in Malawi in 2021 and 2022 to assess the impact of an open fracture intervention bundle, including a national education course for clinical officers and management guidelines for open fractures. We recruited 287 patients with open tibia fractures. The primary outcome was a before-and- after comparison of the self-reported short musculoskeletal function assessment score, a measure of patient function. Secondary outcomes included clinical management; and clinician knowledge and implementation evaluation outcomes of 57 health-care providers attending the course. We also constructed multilevel regression models to investigate associations between clinical knowledge, patient function, and implementation evaluation before and after the intervention. Findings The median patient function score at 1 year was 6.8 (interquartile range, IQR: 1.5 to 14.5) before intervention and 8.4 (IQR: 3.8 to 23.2) after intervention. Compared with baseline scores, we found clinicians' open fracture knowledge scores improved 1 year after the intervention was implemented (mean posterior difference: 1.6, 95% highest density interval: 0.9 to 2.4). However, we found no difference in most aspects of clinicians' open fracture management practice. Conclusion Despite possible improvement in clinician knowledge and positive evaluation of the intervention implementation, our study showed that there was no overall improvement in clinical management, and weak evidence of worsening patient function 1 year after injury, after implementation of the open fracture intervention bundle. Abstracts in [phrase omitted], Francais, [phrase omitted] and Espanol at the end of each article. [phrase omitted] Objectif Evaluer l'Impact d'un ensemble d'interventions relatives aux fractures ouvertes sur la prise en charge clinique et la sante des patients adultes souffrant d'une fracture ouverte du tibia au Malawi. Methodes Afin d'evaluer cet impact, nous avons mene une etude dans le pays en 2021 et 2022, avant et apres la mise en oeuvre, qui prevoyait un cours d'education national destine aux responsables cliniques et des directives de prise en charge des fractures ouvertes. Nous avons recrute 287 patients presentant des fractures ouvertes du tibia. Une comparaison avant/apres de la courte note d'evaluation de la fonction musculosquelettique autodeclaree, qui permet de determiner a quel point le patient est operationnel, constituait le critere d'evaluation principal. Les criteres d'evaluation secondaires incluaient la prise en charge clinique, ainsi que les resultats de l'evaluation des connaissances cliniques et de la mise en oeuvre pour 57 prestataires de soins de sante ayant participe au cours. Nous avons egalement elabore des modeles de regression multiniveaux en vue d'examiner les liens entre les connaissances cliniques, le degre operationnel du patient et l'evaluation de la mise en oeuvre avant et apres l'intervention. Resultats La note mediane de la fonction des patients a un an s'elevait a 6,8 (ecart interquartile, EI: 1,5 a 14,5) avant l'intervention et a 8,4 (EI: 3,8 a 23,2) apres l'intervention. En la comparant avec les notes initiales, nous avons decouvert que les connaissances des medecins en matiere de fractures ouvertes s'etaient ameliorees un an apres le deploiement de l'intervention (difference moyenne a posteriori: 1,6, intervalle de densite le plus eleve a 95%: 0,9 a 2,4). Toutefois, en ce qui concerne la prise en charge des fractures ouvertes par les medecins, nous n'avons observe aucune difference pour la plupart des aspects. Conclusion Malgre une possible amelioration des connaissances medicales et une intervention dont la mise en oeuvre a ete jugee positive, notre etude a montre qu'il n'existait aucune amelioration globale de la prise en charge clinique et peu d'elements indiquant une degradation de l'etat du patient un an apres sa blessure une fois que l'ensemble des interventions relatives aux fractures ouvertes a ete adopte. [phrase omitted] Objetivo Evaluar el Impacto de un paquete de Intervencion en fracturas abiertas sobre el manejo clinico y los resultados de los pacientes adultos en Malawi con fracturas abiertas de tibia. Metodos Se realizo un estudio de implementacion antes y despues en Malawi entre 2021 y 2022 para evaluar el impacto de un paquete de intervencion en fracturas abiertas, que incluye un curso nacional de educacion para funcionarios clinicos y directrices de manejo para fracturas abiertas. Se reclutaron 287 pacientes con fracturas abiertas de tibia. El resultado primario fue una comparacion antes y despues del puntaje breve de evaluacion de la funcion musculoesqueletica autoinformada, una medida de la funcion del paciente. Los resultados secundarios incluyeron: el manejo clinico; y los resultados de la evaluacion del conocimiento clinico y la implementacion de 57 profesionales sanitarios que asistieron al curso. Tambien se construyeron modelos de regresion multinivel para investigar las asociaciones entre el conocimiento clinico, la funcion del paciente y la evaluacion de la implementacion antes y despues de la intervencion. Resultados El puntaje medio de la funcion del paciente a un ano fue de 6,8 (rango intercuartilico, IQR: 1,5 a 14,5) antes de la intervencion y de 8,4 (IQR: 3,8 a 23,2) despues de la intervencion. En comparacion con los puntajes iniciales, se observo que los puntajes de conocimiento de fractura abierta de los medicos mejoraron un ano despues de la implementacion de la intervencion (diferencia posterior media: 1,6; intervalo de densidad mas alta del 95%: 0,9 a 2,4). Sin embargo, no se observaron diferencias en la mayoria de los aspectos de la practica clinica para el manejo de las fracturas abiertas. Conclusion A pesar de la posible mejora de los conocimientos de los medicos y de la evaluacion positiva de la implementacion de la intervencion, nuestro estudio mostro que no hubo una mejora general en el manejo clinico y pruebas debiles de empeoramiento de la funcion del paciente un ano despues de la lesion tras la implementacion del paquete de intervencion en fracturas abiertas., Introduction Economic growth, urbanization and increased road vehicle use have led to a rapid rise in the rates of road traffic incidents in low-income countries. (1) Open fractures are increasingly [...]

Induction of the kynurenine pathway (KP) of tryptophan catabolism has been proposed to contribute to T cell dysfunction during human/simian immunodeficiency virus (HIV/SIV) infection via depletion of local tryptophan levels and production of immunomodulatory KP metabolites. However, while changes in tryptophan and KP metabolites have been observed in plasma, their levels in lymphoid tissues and levels of enzymes downstream of indoleamine 2,3-dioxygenase (IDO1) have been relatively unexplored. We used our SIV-infected pigtailed macaque model to analyze longitudinal changes in KP metabolites and enzymes by gas chromatography/mass spectrometry and NanoString nCounter gene expression analysis, respectively, in spleen and blood compared to changes previously established in brain and CSF. We found that tryptophan levels were remarkably stable in tissue sites despite robust depletion in the circulating plasma and CSF. We also demonstrated that intracellular tryptophan reserves were maintained in cultured cells even in the presence of depleted extracellular tryptophan levels. Kynurenine, 3-hydroxykynurenine, quinolinic acid, and the KP enzymes all displayed highly divergent patterns in the sites examined, though IDO1 expression always correlated with local kynurenine/tryptophan ratios. Finally, we demonstrated by FACS that myeloid dendritic cells (mDCs) and cells of monocytic lineage were the highest producers of IDO1 in chronically infected spleens. Overall our study reveals insights into the tissue-specific regulation of KP enzymes and metabolites and, in particular, highlights the multiple mechanisms by which cells and tissues seek to prevent TRP starvation during inflammation.

Abstract Introduction We present a pair of approximately 50-minute, formative self-assessment, e-learning modules (histology quizzes) that evaluate student knowledge of basic histology and systems histology of the gastrointestinal (GI) tract. The modules integrate microscopic anatomy with cellular functions. Methods During the anatomy course, students are given four 50-minute lectures on histology with associated readings from the assigned textbook. During the GI course, students are given one 50-minute lecture accompanied by a reading assignment from the same textbook. The lecture learning objectives are consistent with the objectives of the Quizmaker modules. Subsequently, the relevant histology quiz is made available to the students. Although the assessments are formative, students are required to complete them with a passing grade of 80% in order to pass the course. Students are given unlimited attempts to achieve the passing grade. Results To date, a total of 320 students have completed the quizzes. The average of the Likert responses of the first-year medical students to the statement “The Histology and Radiology Quizmaker programs helped me to clarify concepts and identify areas of deficiency” was 4.3. Narrative comments were uniformly positive: students liked the program and greatly benefitted from it, suggested that the program be offered again and thanked the faculty for preparing it. Additional comments stated that the quizzes helped students recognize histological structures and study general histological concepts while integrating histology with other preclinical subjects. Discussion The Histology Quizmaker quizzes are very useful tools for formative self-assessment with immediate feedback, which are highly appreciated by the students. We plan to add similar histology tools in other second-year organ systems courses and in the third-year clinical clerkships to integrate the basic sciences with the clinical sciences.

As more countries engage in water reuse, either intended or de facto, there is an urgent need to more comprehensively evaluate resulting environmental and public health concerns. While antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARGs) are increasingly coming under the spotlight, as emerging contaminants, existing water reuse regulations and guidelines do not adequately address these concerns. This perspectives paper seeks to frame the various challenges that need to be resolved to identify meaningful and realistic target types and levels of antibiotic resistance benchmarks for water reuse. First, there is the need for standardized and agreed-upon methodologies to identify and quantify ARB and ARGs. Second, even if methodologies are available, identifying which ARB and ARGs to monitor that would best relate to the occurrence of disease burden remains unknown. Third, a framework tailored to assessing the risks associated with ARB and ARGs during reuse is urgently needed. Fourth, similar to protecting drinking water sources, strategies to prevent dissemination of ARB and ARGs via wastewater treatment and reuse are required to ensure that appropriate barriers are emplaced. Finally, current wastewater treatment technologies could benefit from modification or retrofit to more effectively remove ARB and ARGs while also producing a high quality product for water and resource recovery. This perspectives paper highlights the need to consider ARB and ARGs when evaluating the overall safety aspects of water reuse and ways by which this may be accomplished.

We describe an uncommon scenario where the femoral diaphysis was subjugated by previous long stemmed revision knee replacements limiting options for primary hip arthroplasty. A short stemmed pressfit femoral componet was implanted bilaterally. At 11 years the implants remain stable with improved clinical function. This case emphasizes the importance of preoperative templating and the utility of considering the use of unconventional stems in the management of unusual situations.

Recent advances in sensor and platform technologies, such as satellite systems, unmanned aerial vehicles (UAV), manned aerial platforms, and ground-based sensor networks have resulted in massive volumes of data being produced and collected about the earth. Processing, managing, and analyzing these data is one of the main challenges in 3D synthetic representation used in modeling and simulation (M&S) of the natural environment. M&S devices, such as flight simulators, traditionally require a variety of different databases to provide a synthetic representation of the world. M&S often requires integration of data from a variety of sources stored in different formats. Thus, for simulation of a complex synthetic environment, such as a 3D terrain model, tackling interoperability among its components (geospatial data, natural and man-made objects, dynamic and static models) is a critical challenge. Conventional approaches used local proprietary data models and formats. These approaches often lacked interoperability and created silos of content within the simulation community. Therefore, open geospatial standards are increasingly perceived as a means to promote interoperability and reusability for 3D M&S. In this paper, the Open Geospatial Consortium (OGC) CDB Standard is introduced. “CDB” originally referred to Common DataBase, which is currently considered as a name with no abbreviation in the OGC community. The OGC CDB is an international standard for structuring, modeling, and storing geospatial information required in high-performance modeling and simulation applications. CDB defines the core conceptual models, use cases, requirements, and specifications for employing geospatial data in 3D M&S. The main features of the OGC CDB Standard are described as the run-time performance, full plug-and-play interoperable geospatial data store, usefulness in 3D and dynamic simulation environment, ability to integrate proprietary and open-source data formats. Furthermore, compatibility with the OGC standards baseline reduces the complexity of discovering, transforming, and streaming geospatial data into the synthetic environment and makes them more widely acceptable to major geospatial data/software producers. This paper includes an overview of OGC CDB version 1.0, which defines a conceptual model and file structure for the storage, access, and modification of a multi-resolution 3D synthetic environment data store. Finally, this paper presents a perspective of future versions of the OGC CDB and what the steps are for humanizing the OGC CDB standard with the other OGC/ISO standards baseline.

Atrophic gastritis, whether caused by Helicobacter pylori infection or as a result of an autoimmune process, is associated with corpus atrophy. However, whereas atrophic gastritis caused by H. pylori involves the antrum, the antrum is spared in autoimmune gastritis. Here, we report the use of magnifying endoscopy to identify and distinguish atrophic gastritis caused by H. pylori from autoimmune gastritis. The mucosal pattern in autoimmune gastritis is that of closely arranged small round and oval pits, thus differing from the pattern seen in atrophic mucosa due to H. pylori infection. We speculate that this reflects differences in inflammation between the two types of gastritis. In autoimmune gastritis the inflammation is directed primarily against gastric glands, whereas in H. pylori infection the inflammation is directed against the bacteria on or near the surface and the damage initially affects the surface epithelium. During repair, the normal regular round pits are destroyed, whereas they remain largely intact in mucosa with autoimmune-associated atrophy. Confirmation of the features of autoimmune gastritis revealed by magnifying endoscopy would not only make the endoscopic diagnosis of autoimmune gastritis more accurate, but also help to elucidate changes in the surface epithelial structure of gastritis due to various causes.