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Abstract Background Peer workers are individuals who draw on their personal experiences in a professional capacity to support clients. Existing research on the role of peer workers in mental health, homelessness, and substance use services has primarily focused on their impact on client outcomes. This paper describes the development of peer workers as they transition into, through, and beyond this role. Utilising data from the Supporting Harm Reduction through Peer Support (SHARPS) study, where Peer Navigators supported people experiencing homelessness and substance use challenges, this paper explores the sense-making involved in an intensive peer support worker role, adaptation to organisational culture, and engagement with opportunities for professional advancement. Methods Semi-structured interviews with three Peer Navigators were conducted by two SHARPS study researchers at four time points in 2018 and 2019 corresponding with the beginning, middle, and end of the intervention. These data were analysed along with entries from the three Peer Navigators’ reflective diaries. Analysis followed a multi-stage approach to thematic analysis utilising both inductive and deductive processes. The Peer Navigators’ personal reflections have also been incorporated into the recommendations. Results The foundational training provided to the Peer Navigators before taking up their role helped to ensure readiness and build confidence. This training illuminated the dynamics of supporting individuals with complex health and social challenges. Integrating into diverse organisational environments, the Peer Navigators adapted to new professional expectations and consistently advocated for harm reduction and psychologically informed approaches, sometimes encountering resistance from other professionals. Establishing effective relationships with participants and professionals was essential and involved dealing with challenges such as overcoming personal biases and navigating systemic obstacles. the Peer Navigators benefitted from the specially designed training to support career progress with personal and professional development opportunities which enabled successful transitions beyond the SHARPS study. Conclusions Pre-work training, coupled with support and adherence to key principles, enabled the Peer Navigators to integrate effectively into diverse organisations. Quality relationships were vital in achieving client outcomes and supporting the professional growth of the Peer Navigators. These findings are important for services employing peer workers and underscore the importance of a commitment to training and continuing professional development.

Abstract It is known that the electromagnetic vacuum is responsible for the Lamb shift, which is a crucial phenomenon in quantum electrodynamics (QED). In circuit QED, the readout or bus resonators that are dispersively coupled can result in a significant Lamb shift of the qubit. However, previous approaches or proposals for controlling the Lamb shift in circuit QED demand overheads in circuit designs or non-perturbative renormalization of the system’s eigenbases, which can impose formidable limitations. In this work, we propose and demonstrate an all-microwave method for controlling the Lamb shift of fixed-frequency transmons. We employ the drive-induced longitudinal coupling between the transmon and resonator. By simply using an off-resonant monochromatic drive near the resonator frequency, we can control the net Lamb shift up to ±30 MHz and engineer it to zero with the drive-induced longitudinal coupling without facing the aforementioned challenges. Our work establishes an efficient way of engineering the fundamental effects of the electromagnetic vacuum and provides greater flexibility in non-parametric frequency controls of multilevel systems.

Abstract Background Veterans of the 1990–1991 Gulf War have experienced excess health problems, most prominently the multisymptom condition Gulf War illness (GWI). The Department of Veterans Affairs (VA) Cooperative Studies Program #2006 “Genomics of Gulf War Illness in Veterans” project was established to address important questions concerning pathobiological and genetic aspects of GWI. The current study evaluated patterns of chronic ill health/GWI in the VA Million Veteran Program (MVP) Gulf War veteran cohort in relation to wartime exposures and key features of deployment, 27–30 years after Gulf War service. Methods MVP participants who served in the 1990–1991 Gulf War completed the MVP Gulf War Era Survey in 2018–2020. Survey responses provided detailed information on veterans’ health, Gulf War exposures, and deployment time periods and locations. Analyses determined associations of three defined GWI/ill health outcomes with Gulf War deployment characteristics and exposures. Results The final cohort included 14,103 veterans; demographic and military characteristics of the sample were similar to the full population of U.S. 1990–1991 Gulf War veterans. Overall, a substantial number of veterans experienced chronic ill health, as indicated by three defined outcomes: 49% reported their health as fair or poor, 31% met Centers for Disease Control and Prevention criteria for severe GWI, and 20% had been diagnosed with GWI by a healthcare provider. Health outcomes varied consistently with veterans’ demographic and military characteristics, and with exposures during deployment. All outcomes were most prevalent among youngest veterans (

Abstract Background Medical training can be a challenging time for residents both professionally and personally. Resident support programs must be able to address a range of potential experiences, be accessible and easy to navigate, and consider the unique context of residency. Rigorous evaluation of resident support programs is needed to determine whether these programs are meeting these goals. Methods The Directors of Resident Support (DRS) program, launched in January 2021 at the Cumming School of Medicine at the University of Calgary, is a near-peer support model consisting of three faculty physicians, trained in peer support, who receive contacts from residents needing support for any issue. DRS physicians provide empathetic listening, referral to existing resources, and peer support for residents. A multisource evaluation of the DRS program, including field notes, data collection forms, and surveys, was guided by the Donabedian framework. Results There were 62 total contacts in the 2-year evaluation period which required a median 2 h to address (range 5 min to more than 40 h). The most common topic for contact was to discuss feedback or evaluation (n = 10, 24.4%) and the most common response was listening and support (n = 29, 70.7%). Residents also contacted DRS to discuss experiences of racism, physical assault, sexual harassment, and mental health crises. Residents (n = 13) rated a median score of 74 out of possible 100 for usefulness (interquartile range [IQR] 1-100, with higher scores suggesting greater usefulness). Free text survey responses suggested that residents felt validated by contact with the program though some residents felt that additional follow-up would have been helpful. Conclusion The DRS program has been well-utilized by residents for a variety of issues. Postgraduate Medical Education offices seeking to create resident support programs may anticipate that about 3% of residents may use a similar program per year and that the typical interaction would last 2 h, with a wide range. Feedback suggested that similar programs should have a formal process for follow-up with residents to ensure their concern was addressed and that resident supporters should have diverse lived experiences.

Abstract Background Pulmonary arterial hypertension is a life-threatening progressive disorder characterised by high blood pressure (hypertension) in the arteries of the lungs (pulmonary artery). Although treatable, there is no known cure for this rare disorder, and its exact cause is unknown. Mutations in the bone morphogenetic protein receptor type-2 (BMPR2) are the most common genetic cause of familial pulmonary arterial hypertension. This study represents the first-ever trial of treatments aimed at directly rescuing the BMPR2 pathway, repurposing two drugs that have shown promise at restoring levels of BMPR2 signalling: hydroxychloroquine and phenylbutyrate. Methods This three-armed phase II precision medicine study will investigate BMPR2 target engagement and explore the efficacy of two repurposed therapies in pulmonary arterial hypertension patients with BMPR2 mutations. Patients will be stratified based on two BMPR2 mutation classes: missense and haploinsufficient mutations. Eligible subjects will be randomised to one of the three arms (two active therapy arms and a placebo arm, all plus standard of care) following a Bayesian response-adaptive design implemented independently in each stratum and updated in response to a novel panel of primary biomarkers designed to assess biological modification of the disease. Discussion The results of this trial will provide the first randomised evidence of the efficacy of these therapies to rescue BMPR2 function and will efficiently explore the potential for a differential response of these therapies per mutation class to address causes rather than consequences of this rare disease. Trial registration The study has been registered with ISRCTN (ISRCTN10304915, 22/09/2023).

Abstract The type VI secretion system (T6SS) is a molecular machine utilised by many Gram-negative bacteria to deliver antibacterial toxins into adjacent cells. Here we present the structure of Tse15, a T6SS Rhs effector from the nosocomial pathogen Acinetobacter baumannii. Tse15 forms a triple layered β-cocoon Rhs domain with an N-terminal α-helical clade domain and an unfolded C-terminal toxin domain inside the Rhs cage. Tse15 is cleaved into three domains, through independent auto-cleavage events involving aspartyl protease activity for toxin self-cleavage and a nucleophilic glutamic acid for N-terminal clade cleavage. Proteomic analyses identified that significantly more peptides from the N-terminal clade and toxin domains were secreted than from the Rhs cage, suggesting toxin delivery often occurs without the cage. We propose the clade domain acts as an internal chaperone to mediate toxin tethering to the T6SS machinery. Conservation of the clade domain in other Gram-negative bacteria suggests this may be a common mechanism for delivery.

Yilin Feng,1 Nandini Venkateswaran,1 Amanda Steele,2 Eric D Rosenberg,3 Preeya K Gupta2,4 1Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA; 2Triangle Eye Consultants, Raleigh, NC, USA; 3Department of Ophthalmology, New York Medical College, Valhalla, NY, USA; 4Department of Ophthalmology, Tulane University, New Orleans, LA, USACorrespondence: Preeya K Gupta, Email preeyakgupta@gmail.comPurpose: To evaluate the impact of TearCare (TC) treatment on clinical, quality of life, and functional visual outcome metrics in patients with dry eye disease (DED) and meibomian gland disease (MGD).Methods: This is a prospective, single-center clinical trial. Adults with MGD and a DED diagnosis and tear break-up time (TBUT) < 10 seconds were included. All subjects had at least 20/40 vision and no surgery or new treatment for DED within 60 days prior to enrollment. All patients had one baseline visit prior to undergoing TC and one follow-up visit 1 month after TC. At each visit, the meibomian gland secretion score (MGSS), TBUT, and corneal fluorescein staining (KFL) were assessed. DED symptoms were evaluated using the Ocular Surface Disease Index (OSDI) questionnaire, Visual Function Questionnaire 25 (VFQ-25), and the Fatigue Severity Scale. Reading speed was determined through the International Reading Speed Texts (IReST), Minnesota Low Vision Reading Test (MNREAD), and Wilkins Rate of Reading Test (WRRT).Results: Thirty-two subjects were included. The average age was 55.9 years. Sixteen (52%) participants had a clinically significant improvement in reading speed after treatment with TC, defined as > 10 words per minute increase in their IReST score. Improvement on the IReST and the MNREAD reached statistical significance (p = 0.012 and p = 0.028, respectively). OSDI scores significantly decreased and VFQ-25 scores significantly increased after TC treatment (p < 0.001). All of the clinical exam parameters showed statistically significant improvements after treatment (p < 0.001).Conclusion: TC is an effective treatment both clinically and with respect to visual function. Patients who had TC exhibited improvements in quality of life and improved reading speed after a single treatment. This treatment should be frequently considered and utilized to reduce the disease burden of DED related to MGD.Keywords: thermal pulsation, tearcare, meibomian gland dysfunction, dry eye disease, reading speed

ABSTRACT: The objectives of this study were to determine the farm-level hyperketolactia (HKL) prevalence, as diagnosed from the milk BHB concentration, on dairy farms milking with an automated milking system (AMS) and to describe the farm-level housing, management, and nutritional risk factors associated with increased farm-average milk BHB and the within-herd HKL prevalence in the first 45 DIM. Canadian AMS farms (n = 162; eastern Canada, n = 8; Quebec, n = 24; Ontario, n = 75; western Canada n = 55) were visited once between April and September 2019 to record housing and herd management practices. The first test milk data for each cow under 45 DIM were collected, along with the final test of the previous lactations for all multiparous cows, from April 1, 2019, to September 30, 2020. The first test milk BHB was then used to classify each individual cow as having or not having HKL (milk BHB ≥0.15 mmol/L) at the time of testing. Milk fat and protein content, milk BHB, and HKL prevalence were summarized by farm and lactation group (all, primiparous, and multiparous). During this same time period, formulated diets for dry and lactating cows, including ingredients and nutrient composition, and AMS milking data were collected. Data from the AMS were used to determine milking behaviors and milk production of each herd during the first 45 DIM. Multivariable regression models were used to associate herd-level housing, feeding management practices, and formulated nutrient composition with first test milk BHB concentrations and within-herd HKL levels separately for primiparous and multiparous cows. The within-herd HKL prevalence for all cows was 21.8%, with primiparous cows having a lower mean prevalence (12.2 ± 9.2%) than multiparous cows (26.6 ± 11.3%). Milk BHB concentration (0.095 ± 0.018 mmol/L) and HKL prevalence for primiparous cows were positively associated with formulated prepartum DMI and forage content of the dry cow diet; however, they were negatively associated with formulated postpartum DMI, the major ingredient in the concentrate supplemented through the AMS, and the partially mixed ration to AMS concentrate ratio. Multiparous cows' milk BHB concentration (0.12 ± 0.023 mmol/L) and HKL prevalence were positively associated with the length of the previous lactation, milk BHB at dry-off, prepartum diet nonfiber carbohydrate content, and the major forage fed on farm, while tending to be negatively associated with feed bunk space during lactation. This study is the first to determine the farm-level risk factors associated with herd-level prevalence of HKL in AMS dairy herds. The results may help to optimize management and guide diet formulation and thus promote the reduction of HKL prevalence.

As our planet warms, Arctic sea ice coverage continues to decline, resulting in complex feedbacks with the climate system. The core objective of NASA's Salinity and Stratification at the Sea Ice Edge (SASSIE) mission is to understand how ocean salinity and near-surface stratification affect upper-ocean heat content and thus sea ice freeze and melt. SASSIE specifically focuses on the formation of Arctic Sea ice in autumn. The SASSIE field campaign in 2022 collected detailed observations of upper-ocean properties and meteorology near the sea ice edge in the Beaufort Sea using ship-based and piloted and drifting assets. The observations collected during SASSIE include vertical profiles of stratification up to the sea surface, air–sea fluxes, and ancillary measurements that are being used to better understand the role of salinity in coupled Arctic air–sea–ice processes. This publication provides a detailed overview of the activities during the 2022 SASSIE campaign and presents the publicly available datasets generated by this mission (available at https://podaac.jpl.nasa.gov/SASSIE, last access: 29 May 2024; DOIs for individual datasets in the “Data availability” section), introducing an accompanying repository that highlights the numerical routines used to generate the figures shown in this work.

ABSTRACT: The objective of this study was to examine the influence of different environmental factors on ATP luminometry measurements of feeding equipment and to investigate associations with health of preweaning calves and the levels of ATP identified through luminometry. On 50 commercial dairy farms in Quebec, Canada, ATP luminometry measurements (in relative light units, RLU) were obtained using the direct swabbing technique with Hygiena UltraSnap swabs and a liquid rinsing technique with the same swab for automatic milk feeders (AMF), bottles, buckets, esophageal tube feeders (ET), milk replacer, nipples, and water. During this visit, environmental factors (including temperature, air draft, humidity, ammonia, and bacterial count) were collected, and a clinical examination (including respiratory score and fecal score) was performed for all preweaning calves present at the farm. This process was repeated 4 times in a year, leading to collection of luminometer results, environmental parameters, and overall health of calves for each season per farm. Overall, a difference in luminometer results was seen between the different periods sampled for all feeding equipment (except the ET), milk replacer, and water, showing higher RLU values in spring and summer and lower values in autumn and winter. When comparing RLU measurements with environmental factors, only a low to negligible correlation could be found. When feeding equipment was classified as not contaminated or contaminated based on previously described cutoff values, a good agreement within a farm for the different seasons was noticed only for nipples (Gwet's agreement AC1 = 0.64), with a poor to moderate agreement for other feeding equipment. Regarding the different models of nipples, Peach Teat nipples showed higher RLU values compared with Merrick's nipples. An association was seen between the proportion of preweaning calves suffering from diarrhea on the farm and the contamination of AMF based on ATP luminometry (logistic regression estimate = 0.52). For other feeding equipment, milk replacer, and water, no significant associations were found. This study showed that ATP luminometry measurements of feeding equipment from preweaning calves are susceptible to seasonality and type of nipple. Thus, these factors should be taken into consideration when interpreting results. Additionally, an association could be made between diarrhea in preweaning calves and the contamination of AMF based on ATP luminometry, showing the potential clinical importance of this on-farm hygiene assessment tool.

During 2020–2022, players and staff in the English Premier League in the United Kingdom were tested regularly for SARS-CoV-2 with the aim of creating a biosecure bubble for each team. We found that prevalence and reinfection estimates were consistent with those from other studies and with community infection trends.

Abstract Background The ultimate aim of medical education is to produce successful practitioners, which is a goal that educators, students and stakeholders support. These groups consider success to comprise optimum patient care with consequently positive career progression. Accordingly, identification of the common educational features of such high-achieving doctors will facilitate the generation of clinical excellence amongst future medical trainees. In our study we source data from British clinical merit award schemes and subsequently identify the medical school origins of anaesthetists who have achieved at least national distinction. Methods Britain operates Distinction Award/Clinical Excellence Award schemes which honour National Health Service doctors in Scotland, Wales and England who are identified as high achievers. This quantitative observational study used these awards as an outcome measure in an analysis of the 2019–20 dataset of all 901 national award-winning doctors. Where appropriate, Pearson's Chi-Square test was applied. Results The top five medical schools (London university medical schools, Edinburgh, Dundee, Aberdeen and Glasgow) were responsible for 56.4% of the anaesthetist award-winners, despite the dataset representing 85 medical schools. 93.6% of the anaesthetist merit award-winners were from European medical schools. 8.06% of the anaesthetist award-winners were international medical graduates compared with 11.5% non-anaesthetist award-winners being international medical graduates. Conclusions The majority of anaesthetists who were national merit award-winners originated from only five, apparently overrepresented, UK university medical schools. In contrast, there was a greater diversity of medical school origins among the lower grade national award-winners; tier 3 award-winners represented 20 different medical schools from three continents. As well as ranking educationally successful university medical schools, this study assists UK and international students, by providing a roadmap for rational decision making when selecting anaesthetist and non-anaesthetist medical education pathways that are more likely to fulfil their career ambitions.

Abstract Wheat is an important source of minerals for human nutrition and increasing grain mineral content can contribute to reducing mineral deficiencies. Here, we identify QTLs for mineral micronutrients in grain of wheat by determining the contents of six minerals in a total of eleven sample sets of three biparental populations from crosses between A.E. Watkins landraces and cv. Paragon. Twenty-three of the QTLs are mapped in two or more sample sets, with LOD scores above five in at least one set with the increasing alleles for sixteen of the QTLs being present in the landraces and seven in Paragon. Of these QTLs, the number for each mineral varies between three and five and they are located on 14 of the 21 chromosomes, with clusters on chromosomes 5A (four), 6A (three), and 7A (three). The gene content within 5 megabases of DNA on either side of the marker for the QTL with the highest LOD score is determined and the gene responsible for the strongest QTL (chromosome 5A for Ca) identified as an ATPase transporter gene (TraesCS5A02G543300) using mutagenesis. The identification of these QTLs, together with associated SNP markers and candidate genes, will facilitate the improvement of grain nutritional quality.

Abstract Background Healthy siblings of children with life-limiting conditions often experience emotional and behavioural struggles over the course of the ill child’s condition(s). Resources to support these siblings are limited due to a lack of understanding about their needs. Therefore, this study was designed to characterize the emotional and behavioural trajectories among siblings of children with progressive, life-limiting genetic, metabolic, or neurological conditions over a 12-month observation period. Methods Seventy siblings were recruited from a large-survey based study (Charting the Territory) that examined the bio-psychosocial health outcomes of parents and siblings. Linear mixed effect models were used to assess the association between siblings’ emotions and behaviour trajectories and selected demographic variables. Siblings’ emotions and behaviour were measured with Child Behaviour Checklist (CBCL). Results Siblings’ mean age was 11.2 years at baseline and Internalizing, Externalizing, and Total Behaviour Problems mean scores were within normal ranges across time. However, 7–25% of siblings had scores within the clinical range. Brothers had higher levels of Internalizing Problems than sisters, whereas sisters had higher levels of Externalizing Problems than brothers. When treatment was first sought for the ill child less than a year prior to study participation, siblings had higher levels of Internalizing and Externalizing Problems compared with siblings who participated more than one year after treatment was sought. Conclusion Healthy siblings experience emotional and behavioural problems early in the child’s disease trajectory. Although these problems improve with time, our findings show that brothers and sisters experience different types of challenges. Therefore, timely support for siblings is important as they navigate through the uncertainties and challenges.

Abstract Understanding the longevity of Mars’s dynamo is key to interpreting the planet’s atmospheric loss history and the properties of its deep interior. Satellite data showing magnetic lows above many large impact basins formed 4.1-3.7 billion years ago (Ga) have been interpreted as evidence that Mars’s dynamo terminated before 4.1 Ga—at least 0.4 Gy before intense late Noachian/early Hesperian hydrological activity. However, evidence for a longer-lived, reversing dynamo from young volcanics and the Martian meteorite ALH 84001 supports an alternative interpretation of Mars’s apparently demagnetized basins. To understand how a reversing dynamo would affect basin fields, here we model the cooling and magnetization of 200-2200 km diameter impact basins under a range of Earth-like reversal frequencies. We find that magnetic reversals efficiently reduce field strengths above large basins. In particular, if the magnetic properties of the Martian mantle are similar to most Martian meteorites and late remagnetization of the near surface is widespread, >90% of large ( > 800 km diameter) basins would appear demagnetized at spacecraft altitudes. This ultimately implies that Mars’s apparently demagnetized basins do not require an early dynamo cessation. A long-lived and reversing dynamo, unlike alternative scenarios, satisfies all available constraints on Mars’s magnetic history.

Abstract Background Digital technologies, such as wearable devices and smartphone applications (apps), can enable the decentralisation of clinical trials by measuring endpoints in people’s chosen locations rather than in traditional clinical settings. Digital endpoints can allow high-frequency and sensitive measurements of health outcomes compared to visit-based endpoints which provide an episodic snapshot of a person’s health. However, there are underexplored challenges in this emerging space that require interdisciplinary and cross-sector collaboration. A multi-stakeholder Knowledge Exchange event was organised to facilitate conversations across silos within this research ecosystem. Methods A survey was sent to an initial list of stakeholders to identify potential discussion topics. Additional stakeholders were identified through iterative discussions on perspectives that needed representation. Co-design meetings with attendees were held to discuss the scope, format and ethos of the event. The event itself featured a cross-disciplinary selection of talks, a panel discussion, small-group discussions facilitated via a rolling seating plan and audience participation via Slido. A transcript was generated from the day, which, together with the output from Slido, provided a record of the day’s discussions. Finally, meetings were held following the event to identify the key challenges for digital endpoints which emerged and reflections and recommendations for dissemination. Results Several challenges for digital endpoints were identified in the following areas: patient adherence and acceptability; algorithms and software for devices; design, analysis and conduct of clinical trials with digital endpoints; the environmental impact of digital endpoints; and the need for ongoing ethical support. Learnings taken for next generation events include the need to include additional stakeholder perspectives, such as those of funders and regulators, and the need for additional resources and facilitation to allow patient and public contributors to engage meaningfully during the event. Conclusions The event emphasised the importance of consortium building and highlighted the critical role that collaborative, multi-disciplinary, and cross-sector efforts play in driving innovation in research design and strategic partnership building moving forward. This necessitates enhanced recognition by funders to support multi-stakeholder projects with patient involvement, standardised terminology, and the utilisation of open-source software.

Abstract Background The ultimate aim of medical education is to produce successful practitioners, which is a goal that educators, students and stakeholders support. These groups consider success to comprise optimum patient care with consequently positive career progression. Accordingly, identification of the common educational features of such high-achieving doctors will facilitate the generation of clinical excellence amongst future medical trainees. In our study we source data from British clinical merit award schemes and subsequently identify the medical school origins of pathologists who have achieved at least national distinction. Methods Britain operates Distinction Award/Clinical Excellence Award schemes which honour National Health Service doctors in Scotland, Wales and England who are identified as high achievers. This quantitative observational study used these awards as an outcome measure in an analysis of the 2019-20 dataset of all 901 national award-winning doctors. Where appropriate, Pearson’s Chi-Square test was applied. Results The top five medical schools (London university medical schools, Aberdeen, Edinburgh, Oxford and Cambridge) were responsible for 60.4% of the pathologist award-winners, despite the dataset representing 85 medical schools. 96.4% of the pathologist merit award-winners were from European medical schools. 9.0% of the pathologist award-winners were international medical graduates in comparison with 11.4% of all 901 award-winners being international medical graduates. Conclusions The majority of pathologists who were national merit award-winners originated from only five, apparently overrepresented, UK university medical schools. In contrast, there was a greater diversity in medical school origin among the lower grade national award-winners; the largest number of international medical graduates were in these tier 3 awards (13.9%). As well as ranking educationally successful university medical schools, this study assists UK and international students, by providing a roadmap for rational decision making when selecting pathologist and non-pathologist medical education pathways that are more likely to fulfil their career ambitions.

Abstract The interleukin (IL)-23 pathway is a pathogenic driver in psoriasis, psoriatic arthritis, and inflammatory bowel disease. Currently, no oral therapeutics selectively target this pathway. JNJ-77242113 is a peptide targeting the IL-23 receptor with high affinity (KD: 7.1 pM). In human cells, JNJ-77242113 potently and selectively inhibited proximal IL-23 signaling (IC50: 5.6 pM) without impacting IL-12 signaling. JNJ-77242113 inhibited IL-23–induced interferon (IFN)γ production in NK cells, and in blood from healthy donors and psoriasis patients (IC50: 18.4, 11 and 9 pM, respectively). In a rat trinitrobenzene sulfonic acid-induced colitis model, oral JNJ-77242113 attenuated disease parameters at doses ≥ 0.3 mg/kg/day. Pharmacologic activity beyond the gastrointestinal tract was also demonstrated. In blood from rats receiving oral JNJ-77242113, dose-dependent inhibition of ex vivo IL-23–stimulated IL-17A production was observed. In an IL-23–induced rat skin inflammation model, JNJ-77242113 inhibited IL-23–induced skin thickening and IL-17A, -17F and -22 gene induction. Oral dosing of JNJ-77242113 in healthy human volunteers inhibited ex vivo IL-23–stimulated IFNγ production in whole blood. Thus, JNJ-77242113 provided selective, systemic IL-23 pathway inhibition in preclinical models which translated to pharmacodynamic activity in healthy human volunteers, supporting the potential for JNJ-77242113 as a selective oral therapy for IL-23–driven immune-mediated diseases.

Abstract The purpose of this study is to examine the effect of early incomplete follow-up on overall survival among stage I lung cancer patients. Patients with clinical stage I lung cancer at our institution between 2007 and 2016 were identified (N = 1111). Exclusions included

Abstract Malawi experienced its deadliest Vibrio cholerae (Vc) outbreak following devastating cyclones, with >58,000 cases and >1700 deaths reported between March 2022 and May 2023. Here, we use population genomics to investigate the attributes and origin of the Malawi 2022–2023 Vc outbreak isolates. Our results demonstrate the predominance of ST69 clone, also known as the seventh cholera pandemic El Tor (7PET) lineage, expressing O1 Ogawa (~ 80%) serotype followed by Inaba (~ 16%) and sporadic non-O1/non-7PET serogroups (~ 4%). Phylogenetic reconstruction revealed that the Malawi outbreak strains correspond to a recent importation from Asia into Africa (sublineage AFR15). These isolates harboured known antimicrobial resistance and virulence elements, notably the ICEGEN/ICEVchHai1/ICEVchind5 SXT/R391-like integrative conjugative elements and a CTXφ prophage with the ctxB7 genotype compared to historical Malawian Vc isolates. These data suggest that the devastating cyclones coupled with the recent importation of 7PET serogroup O1 strains, may explain the magnitude of the 2022–2023 cholera outbreak in Malawi.

Abstract The Scanning Habitable Environments with Raman and Luminescence for Organics and Chemicals (SHERLOC) instrument onboard the Mars 2020 Perseverance rover detected so far some of the most intense fluorescence signals in association with sulfates analyzing abraded patches of rocks at Jezero crater, Mars. To assess the plausibility of an organic origin of these signals, it is key to understand if organics can survive exposure to ambient Martian UV after exposure by the Perseverance abrasion tool and prior to analysis by SHERLOC. In this work, we investigated the stability of organo-sulfate assemblages under Martian-like UV irradiation and we observed that the spectroscopic features of phthalic and mellitic acid embedded into hydrated magnesium sulfate do not change for UV exposures corresponding to at least 48 Martian sols and, thus, should still be detectable in fluorescence when the SHERLOC analysis takes place, thanks to the photoprotective properties of magnesium sulfate. In addition, different photoproduct bands diagnostic of the parent carboxylic acid molecules could be observed. The photoprotective behavior of hydrated magnesium sulfate corroborates the hypothesis that sulfates might have played a key role in the preservation of organics on Mars, and that the fluorescence signals detected by SHERLOC in association with sulfates could potentially arise from organic compounds.

ABSTRACT: The objective of this study was to investigate the effects of feeding surplus dairy calves a milk replacer (MR) or one of 2 different oral rehydration solutions (ORS) during a midtransportation rest period on metabolic and clinical health indicators, growth, and behavioral outcomes after arrival at a calf-raising facility. Surplus dairy calves (n = 128) were transported in 4 cohorts from February to July 2022 for 12 h to a holding facility, rested for 8 h, then transported for an additional 6 h to a calf-raising facility. Upon arrival at the holding facility, calves were randomly assigned to 1 of 3 treatments: MR (n = 43), a high-sodium ORS developed for diarrhea (ORS-D; n = 43), or a high-potassium ORS developed for transportation (ORS-T; n = 42). The exact age of calves at transportation was unknown; however, all calves were less than 14 d of age. Calf BW at enrollment was 43.9 ± 5.9 kg, 43.7 ± 6.5 kg, and 45.0 ± 4.5 kg for calves fed MR, ORS-D, and ORS-T, respectively. Calves were fed 2.0 L of their treatment twice, once upon arrival and once before leaving the holding facility. At unloading and reloading at the holding facility, calves were weighed and blood samples were obtained. Calves were also health scored at unloading at the holding facility. After arrival at the calf-raising facility, calves were weighed, health scored, and blood samples were taken. Blood samples were collected at 24 and 48 h and BW was recorded at 24 h, 48 h, 72 h, 5 d, 7 d, 14 d, and at 8 wk after arrival at the calf-raising facility. Calves were also health scored daily for 14 d; health scoring included fecal consistency scoring and evaluating the presence or absence of respiratory disease. Lying time, lying bouts, and activity index were measured during transportation and from 3 d relative to transportation using accelerometers. At arrival to the calf-raiser, calves fed ORS-D had higher concentrations of nonesterified fatty acids (NEFA) and BHB than calves fed MR. Furthermore, calves fed ORS-T had higher concentrations of BHB at arrival to the calf raiser compared with calves fed MR. In the 14 d after arrival at the calf-raiser, there was evidence that calves fed ORS-T had a higher proportion of days with diarrhea and respiratory disease compared with those fed MR. During transportation, calves fed ORS-T had a lower activity index than calves fed MR, suggesting that ORS-T calves had lower overall activity. In addition, on the day of transportation (d 0), ORS-T and ORS-D calves had a lower activity index than calves fed MR. There were no treatment effects on growth outcomes. The results of this study suggest that feeding MR rather than an ORS during a midtransportation rest period could minimize fat mobilization and can potentially improve diarrhea and respiratory disease but does not affect growth outcomes after arrival at calf-raisers.

ABSTRACT: The objective of this study was to describe the nutritional strategies used on Canadian dairy farms with automated milking systems (AMS), both at the feed bunk and the concentrate offered at the AMS, as well as to determine what dietary components and nutrients, as formulated, were associated with milk production and milking behaviors on those farms. Formulated diets (including ingredients and nutrient content) and AMS data were collected from April 1, 2019, until September 30, 2020, on 160 AMS farms (eastern Canada [East] = 8, Ontario [ON] = 76, Quebec [QC] = 22, and western Canada [West] = 54). Both partial mixed ration (PMR) and AMS concentrate samples were collected from May 1 to September 30, 2019, on 169 farms (East = 12, ON = 63, QC = 42, West = 52). We collected AMS milking data for 154 herds. For each farm (n = 161), milk recording data were collected and summarized by farm to calculate average milk yield and components. Multivariable regression models were used to associate herd-level formulated nutrient composition and feeding management practices with milk production and milking behavior. Milk yield (mean ± SD = 37.0 ± 0.3 kg/d) was positively associated with the PMR ether extract (EE) concentration (+0.97 kg/d per percentage point [p.p.] increase) and with farms that fed barley silage as their major forage source (n = 16; +2.18 kg/d) as compared with haylage (n = 42), whereas farms that fed corn silage (n = 96; +1.23 kg/d) tended to produce more milk than farms that fed haylage. Greater milk fat content (4.09 ± 0.28%) was associated with a greater PMR-to-AMS concentrate ratio (+0.02 p.p. per unit increase) and total diet net energy for lactation (+0.046 p.p. per 0.1 Mcal/kg increase), but a lesser percentage of NFC of the PMR (−0.016 p.p. per p.p. increase of NFC percentage). Milk protein content (3.38 ± 0.14%) was positively associated with the forage percentage of the PMR (+0.003 p.p. per p.p. increase of forage percentage) and the total diet starch percentage (+0.009 p.p. per p.p. increase of starch percentage), but was negatively associated with farms feeding corn silage (−0.1 p.p. compared with haylage) as their major forage. Greater milking frequency (2.77 ± 0.40 milkings/d) was observed on farms with free-flow cow traffic systems (+0.62 milkings/d) and was positively associated with feed push-up frequency (+0.013 milkings/d per additional feed push-up), but negatively associated with PMR NFC content and forage percentage of the total ration (−0.017 milkings/d per p.p. increase of forage percentage). Lastly, greater milking refusal frequency (1.49 ± 0.82 refusals/d) was observed on farms with free-flow cow traffic systems (+0.84 refusals/d) and farms feeding barley silage (+0.58 refusals/d) than with guided flow and farms feeding either corn silage or haylage, respectively. These data give insight into the ingredients, nutrient formulations and type of diets fed on AMS dairy farms across Canada and the association of those factors with milk production and milking behaviors.

Start-up packages are a tool for successful transition to an academic career. This institutional case study examined the faculty experience with start-up packages at one public university in the Southeastern United States including gender differences, content, negotiation, and perceived outcomes. A mixed method research design was utilized to answer the study research questions. Data were gathered through an online survey with quantitative and qualitative questions. Data from 121 participants were analyzed using descriptive statistics, chi‐squared test, and thematic analysis. Most start-up package agreements included moving expenses, personal computer and software, and start-up funds. On the other hand, child daycare, guaranteed junior sabbatical, and salary advancement were the most missing benefits in the agreements. Male faculty were able to obtain, significantly more often than female faculty, a specific number of years for secure funding, laboratory space, and student or postdoc funding in their agreements. Faculty were not well prepared for the negotiation process, and they were not aware what exactly they needed to establish a successful research program. Universities should focus more on the influence of start-up packages on faculty careers because perceived unfair treatment during the negotiation process or during administration can influence faculty performance and their turnover intentions.

Abstract Background Tubular biomarkers, which reflect tubular dysfunction or injury, are associated with incident chronic kidney disease and kidney function decline. Several tubular biomarkers have also been implicated in the progression of autosomal dominant polycystic kidney disease (ADPKD). We evaluated changes in multiple tubular biomarkers in four groups of patients with ADPKD who participated in one of two clinical trials (metformin therapy and diet-induced weight loss), based on evidence suggesting that such interventions could reduce tubule injury. Methods 66 participants (26 M/40 F) with ADPKD and an estimated glomerular filtration rate (eGFR) ≥ 30 ml/min/1.73m2 who participated in either a metformin clinical trial (n = 22 metformin; n = 23 placebo) or dietary weight loss study (n = 10 daily caloric restriction [DCR]; n = 11 intermittent fasting [IMF]) were included in assessments of urinary tubular biomarkers (kidney injury molecule-1 [KIM-1], fatty-acid binding protein [FABP], interleukin-18 [IL-18], monocyte chemoattractant protein-1 [MCP-1], neutrophil gelatinase-associated lipocalin [NGAL], clusterin, and human cartilage glycoprotein-40 [YKL-40]; normalized to urine creatinine), at baseline and 12 months. The association of baseline tubular biomarkers with both baseline and change in height-adjusted total kidney volume (HtTKV; percent change from baseline to 12 months) and estimated glomerular filtration rate (eGFR; absolute change at 12 months vs. baseline), with covariate adjustment, was also assessed using multiple linear regression. Results Mean ± s.d. age was 48 ± 8 years, eGFR was 71 ± 16 ml/min/1.73m2, and baseline BMI was 30.5 ± 5.9 kg/m2. None of the tubular biomarkers changed with any intervention as compared to placebo. Additionally, baseline tubular biomarkers were not associated with either baseline or change in eGFR or HtTKV over 12 months, after adjustments for demographics, group assignment, and clinical characteristics. Conclusions Tubular biomarkers did not change with dietary-induced weight loss or metformin, nor did they associate with kidney disease progression, in this cohort of patients with ADPKD.

Abstract Missions into Deep Space are planned this decade. Yet the health consequences of exposure to microgravity and galactic cosmic radiation (GCR) over years-long missions on indispensable visceral organs such as the kidney are largely unexplored. We performed biomolecular (epigenomic, transcriptomic, proteomic, epiproteomic, metabolomic, metagenomic), clinical chemistry (electrolytes, endocrinology, biochemistry) and morphometry (histology, 3D imaging, miRNA-ISH, tissue weights) analyses using samples and datasets available from 11 spaceflight-exposed mouse and 5 human, 1 simulated microgravity rat and 4 simulated GCR-exposed mouse missions. We found that spaceflight induces: 1) renal transporter dephosphorylation which may indicate astronauts’ increased risk of nephrolithiasis is in part a primary renal phenomenon rather than solely a secondary consequence of bone loss; 2) remodelling of the nephron that results in expansion of distal convoluted tubule size but loss of overall tubule density; 3) renal damage and dysfunction when exposed to a Mars roundtrip dose-equivalent of simulated GCR.

Abstract Background As Holstein calves are susceptible to gastrointestinal disorders during the first week of life, understanding how intestinal immune function develops in neonatal calves is important to promote better intestinal health. Feeding probiotics in early life may contribute to host intestinal health by facilitating beneficial bacteria colonization and developing intestinal immune function. The objective of this study was to characterize the impact of early life yeast supplementation and growth on colon mucosa-attached bacteria and host immune function. Results Twenty Holstein bull calves received no supplementation (CON) or Saccharomyces cerevisiae boulardii (SCB) from birth to 5 d of life. Colon tissue biopsies were taken within 2 h of life (D0) before the first colostrum feeding and 3 h after the morning feeding at d 5 of age (D5) to analyze mucosa-attached bacteria and colon transcriptome. Metagenome sequencing showed that there was no difference in α and β diversity of mucosa-attached bacteria between day and treatment, but bacteria related to diarrhea were more abundant in the colon mucosa on D0 compared to D5. In addition, qPCR indicated that the absolute abundance of Escherichia coli (E. coli) decreased in the colon mucosa on D5 compared to D0; however, that of Bifidobacterium, Lactobacillus, and Faecalibacterium prausnitzii, which could competitively exclude E. coli, increased in the colon mucosa on D5 compared to D0. RNA-sequencing showed that there were no differentially expressed genes between CON and SCB, but suggested that pathways related to viral infection such as “Interferon Signaling” were activated in the colon mucosa of D5 compared to D0. Conclusions Growth affected mucosa-attached bacteria and host immune function in the colon mucosa during the first 5 d of life in dairy calves independently of SCB supplementation. During early life, opportunistic pathogens may decrease due to intestinal environmental changes by beneficial bacteria and/or host immune function. Predicted activation of immune function-related pathways may be the result of host immune function development or suggest other antigens in the intestine during early life. Further studies focusing on the other antigens and host immune function in the colon mucosa are required to better understand intestinal immune function development.

Near-term iterative ecological forecasting has great potential for providing new insights into our ability to predict multiple ecological variables. However, true, out-of-sample probabilistic forecasts remain rare, and variability in forecast performance has largely been unexamined in process-based forecasts which predict multiple ecosystem variables. To explore how forecast performance varies for water temperature and dissolved oxygen, two freshwater variables important for lake ecosystem functioning, we produced probabilistic forecasts at multiple depths over two open-water seasons in Lake Sunapee, NH, USA. Our forecasting system, FLARE (Forecasting Lake And Reservoir Ecosystems), uses a 1-D coupled hydrodynamic-biogeochemical process model, which we assessed relative to both climatology and persistence null models to quantify how much information process-based FLARE forecasts provide over null models across varying environmental conditions. We found that FLARE water temperature forecasts were always more skillful than FLARE oxygen forecasts. Specifically, temperature forecasts outperformed both null models up to 11 days into the future, as compared to only two days for oxygen. Across different years, we observed variable forecast skill, with performance generally decreasing with depth for both variables. Overall, all temperature forecasts and surface oxygen, but not deep oxygen, forecasts were more skillful than at least one null model >80 % of the forecasted period, indicating that our process-based model was able to reproduce the dynamics of these two variables with greater reliability than the null models. However, process-based oxygen forecasts from deeper waters were less skillful than both null models during a majority of the forecasted period, which suggests that deep-water oxygen dynamics are dominated by autocorrelation and seasonal change, which are inherently captured by the null forecasts. Our results highlight that forecast performance varies among lake water quality metrics and that process-based forecasts can provide important information in conjunction with null models in varying environmental conditions. Altogether, these process-based forecasts can be used to develop quantitative tools which inform our understanding of future ecosystem change.

Background: The tendons within the soleus muscle are commonly utilized to delineate location of injury for soleus muscle strains. Strains within the soleus frequently involve the myotendinous (MTJ) or myofascial (MFJ) junctions, although spatial relationship between these tendinous structures are not well understood. This study aimed to structurally identify the MTJs and MFJs within the soleus as a starting point to understanding the distribution of connective tissue for further anatomical classification. Methods: Forty (n = 40) soleus muscles, representing left and right sides from twenty (n = 20) formalin-embalmed cadavers (average age 78 years old; 10 males, 10 females) were dissected in-situ to analyze the distribution and orientation of the MTJs and MFJs within classified morphological variants. Muscles were cut in cross-section at three measured locations, proximal, middle, and distal, which allowed for analyzation of tendons through the course of the muscle. Additionally, anterior surfaces of morphological variants were visualized and reconstructed in three dimensions using a handheld blue light 3D scanner. Results: The study revealed five morphological variants. Bipennate-Midline (n = 25), Bipennate-Medial Deviation (n = 6), Bipennate-Lateral Deviation (n = 3), Unipennate (n = 3), and Hypopennate (n = 3). Muscles included an anterior aponeurosis that was split into medial and lateral components, with each side made up of interconnections between the MTJ and MJF. The average width of the medial aponeurosis was greatest in the middle location, while the average lateral aponeurotic width decreased from proximal to distal. Regression analysis at the middle location revealed that 65 % of the change in width of the medial aponeuroses is due to the width of the medial MFJ. Conclusions: Proximal-to-distal interconnections between the lateral and medial anterior aponeuroses and their corresponding MTJs and MFJs likely play a role in soleus injury patterns, especially in morphological variants. Awareness of anatomical variations in the location and orientation of these tendinous relationships is crucial for understanding lesions on diagnostic imaging.

Abstract A comprehensive design methodology for the realization of ultra‐wideband and highly miniaturized capacitively loaded Marchand baluns (MBs), suitable for integration into balanced antenna systems is presented. A design technique to maximize the fractional bandwidth (FBW) for a given manufacturing process is demonstrated for the first time. Furthermore, a novel MB integration scheme using broadside‐coupled lines and 3D vertically integrated capacitors in a two‐material inkjet printing process is uniquely proposed. The concept has been experimentally validated within the S and C bands. It exhibits a footprint of 0.128 × 0.098 λg2, centre frequency of 4.4 GHz, and FBW of 121%. Its power loss, phase imbalance and amplitude imbalance were measured between 0.8 and 2.2 dB, 3 ± 2°, and 0.4 ± 0.4 dB, respectively.

An increase in the risk of developing uterine serous carcinoma (USC) has been observed among BRCA1 and BRCA2 germline pathogenic variant carriers in the published literature. However, routine germline genetic testing is not currently incorporated into USC management guidelines. The primary objective of this study is to define the incidence of germline pathogenic variants identified through genetic counseling referrals for USC patients at our institution. A retrospective cohort study was performed of patients diagnosed with USC at a single institution over a seven-year interval. A total of 91 patients with uterine serous carcinoma were identified. Almost half of the patients were referred to genetic counseling, and just over half of referred patients (24/43, 56%) ultimately underwent germline genetic testing. Pathogenic variants were noted in 12.5% (3/24) of the patients who were tested. Pathogenic mutations were found in BRCA1, BRCA2, and MSH6. Variants of unknown significance (VUS) were seen in 16.6% (4/24) of patients. Based on our findings, we recommend integration of germline testing into the standard management of patients with USC.

Summary: Background: We aimed to study the clinical characteristics, myocardial injury, and longitudinal outcomes of COVID-19 vaccine-associated myocarditis (C-VAM). Methods: In this longitudinal retrospective observational cohort multicenter study across 38 hospitals in the United States, 333 patients with C-VAM were compared with 100 patients with multisystem inflammatory syndrome in children (MIS-C). We included patients ≤30 years of age with a clinical diagnosis of acute myocarditis after COVID-19 vaccination based on clinical presentation, abnormal biomarkers and/or cardiovascular imaging findings. Demographics, past medical history, hospital course, biochemistry results, cardiovascular imaging, and follow-up information from April 2021 to November 2022 were collected. The primary outcome was presence of myocardial injury as evidenced by late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging. Findings: Patients with C-VAM were predominantly white (67%) adolescent males (91%, 15.7 ± 2.8 years). Their initial clinical course was more likely to be mild (80% vs. 23%, p 15 years, OR 2.74 [95% CI: 1.28, 5.83, p = 0.009]) and when C-VAM occurred after the first or second dose as compared to the third dose of mRNA vaccine. Mid-term clinical outcomes of C-VAM at a median follow-up of 178 days (IQR 114–285 days) were reassuring. No cardiac deaths or heart transplantations were reported until the time of submission of this report. LGE persisted in 60% of the patients at follow up. Interpretation: Myocardial injury at initial presentation and its persistence at follow up, despite a mild initial course and favorable mid-term clinical outcome, warrants continued clinical surveillance and long-term studies in affected patients with C-VAM. Funding: The U.S. Food and Drug Administration.

Purpose: Patients with primary sinonasal and cutaneous head and neck (H&N) malignancies often receive meaningful radiation dose to their hippocampi, but this not a classic avoidance structure in radiation planning. We aimed to characterize the feasibility and tradeoffs of hippocampal-sparing radiation therapy (HSRT) for patients with primary sinonasal and cutaneous H&N malignancies. Methods and Materials: We retrospectively selected patients who were treated definitively for primary sinonasal or cutaneous malignancies of the H&N at an academic medical center. All received (chemo)radiation alone or adjuvantly and substantial radiation dose to 1 or both hippocampi. We created new HSRT plans for each patient with intensity modulated radiation therapy using the original target and organ-at-risk (OAR) volumes. Hippocampi were contoured based on Radiation Therapy Oncology Group guidelines and reviewed by a neuroradiologist. Absolute and relative differences in radiation dose to the hippocampi, planning target volumes (PTVs), and OARs were recorded and compared. Results: There were 18 sinonasal and 12 cutaneous H&N primary tumors (30 patients in total). Median prescription dose was 6600 cGy (range, 5000-7440 cGy), and 14 of the 30 patients received 120 cGy/fraction twice daily, 13 of the 30 patients received 200 cGy/fraction once daily, whereas others received 180-275 cGy/fraction once daily. The relative decrease in ipsilateral hippocampal Dmax and D100% using HSRT was 44% (median, 2009 cGy from 3586 cGy) and 65% (median 434 cGy from 1257 cGy), respectively. There were no statistically significant or clinically meaningful differences in PTV V100%, PTV D1%, or radiation dose to other OARs between HSRT and non-HSRT plans. Conclusions: HSRT is feasible and results in meaningful dose reduction to the hippocampi without reducing PTV coverage or increasing dose to other OARs. We suggest target hippocampal constraints of Dmax < 1600 cGy and D100% < 500 cGy when feasible (without compromising PTV coverage or impacting other critical OARs). The clinical significance of HSRT in patients with primary H&N tumors should be investigated prospectively.

Background: Transforming growth factor β-activated protein kinase-1 (TAK1) plays an important role in MAPK and NFκB pathways and has been associated with colorectal cancer. The aim of this study was to determine how cytoplasmic and juxtanuclear punctate staining of TAK1 relates to immune checkpoint expression and cancer specific survival in colorectal cancer. Methods: Protein expression was assessed by immunohistochemistry on tissue microarrays from primary curative colorectal cancer resected specimens. Expression levels of cytoplasmic TAK1 by QuPath digital quantification and punctate TAK1 staining was scored using a manual point scoring technique and correlated with clinicopathological features, immune checkpoint expression and cancer-specific survival. Bulk RNA sequencing was performed in specimens to determine mutational profiles and differentially expressed genes. Results: A cohort of 875 patients who had undergone colorectal cancer resection were assessed for TAK1 expression. Higher levels of cytoplasmic TAK1 expression correlated with elevated PD1 and PD-L1 expression (p < 0.010). High punctate TAK1 expression was more commonly identified in poorly differentiated colorectal cancers (p = 0.036), had dysregulated mutational and transcriptional profiles with decreased insulin-like growth factor 2(IGF2) expression (p < 0.010), and independently predicted poor cancer-specific survival (HR 2.690, 95% CI 1.419–5.100, p = 0.002). The association of punctate TAK1 expression and recurrence remained after subgroup analysis for microsatellite-stable colorectal cancer (p = 0.028). Discussion: Punctate TAK1 expression is associated with worse cancer specific survival. TAK1 signalling may be an important pathway to investigate underlying mechanisms for recurrence in microsatellite-stable colorectal cancer.

Sapphire is a technologically highly relevant material, but it poses many challenges when performing epitaxial thin-film deposition. We have identified and applied the conditions for adsorption-controlled homoepitaxial growth of c-plane sapphire. The films thus grown are atomically smooth, have a controlled termination, and are of outstanding crystallinity. Their chemical purity exceeds that of the substrates. The films exhibit exceptional optical properties, such as a single-crystal-like bandgap and a low density of F+ centers.

Abstract Studies of lake ice phenology have historically relied on limited in situ data. Relatively few observations exist for ice out and fewer still for ice in, both of which are necessary to determine the temporal extent of ice cover. Satellite data provide an opportunity to better document patterns of ice phenology across landscapes and relate them to the climatological drivers behind changing ice phenology. We developed a model, the Cumulative Sum Method (CSM), that uses daytime and nighttime surface temperature observations from the Moderate Resolution Imaging Spectroradiometer (MODIS) sensor on board the Earth‐observing Aqua satellite to approximate ice in (the onset of ice cover) and ice out from training datasets of 13 and 58 Maine lakes, respectively, during the 2002/2003 through 2017/2018 ice seasons. Ice in was signaled by reaching a threshold of cumulative negative degrees following the first day of the season below 0°C. Ice out was signaled by reaching a threshold of cumulative positive degrees following the first day of the year above 0°C. The comparison of observed and remotely sensed ice‐in dates showed relative agreement with a correlation coefficient of 0.71 and a mean absolute error (MAE) of 9.8 days. Ice‐out approximations had a correlation coefficient of 0.67 and an MAE of 8.8 days. Lakes smaller in surface area and nearer the Atlantic coast had the greatest error in approximation. Application of the CSM to 20 additional lakes in Maine produced a comparable ice‐out MAE of 8.9 days. Ice‐out model performance was weaker for the warmest years; there was a larger MAE of 12.0 days when the model was applied to the years 2019–2023 for the original 58 lakes. The development of this model, which utilizes daily satellite data, demonstrates the promise of remote sensing for quantifying ice phenology over short, temporal scales, and wider geographic regions than can be observed in situ, and allows exploration of the influence of surface temperature patterns on the process and timing of ice in and ice out.

Introduction In late 2020, the COVID-19 vaccine acceptance rates of Chinese people living in the UK were estimated between 52% and 57%, significantly lower than that of the general population (76%). This disparity formed a primary motivation for this study which explored Chinese communities’ overall understanding of and attitude towards the COVID-19 vaccines, the sources of information about the vaccines and levels of (dis)trust in these sources.Methods 29 focus groups with 154 participants from UK-based Chinese communities of varied sociodemographic backgrounds were conducted between March and November 2021. Focus group data were coded with NVivo and analysed using thematic analysis.Results Participants generally had a good understanding of the health benefits of the vaccines, however, many still had concerns about vaccine safety and efficacy. They accessed COVID-19 vaccine information from a multitude of sources and had diverse information needs which to a large extent shaped their knowledge of and attitude towards the vaccines. Participants generally had good digital access and some have developed good digital literacy enabling discernment of mis/disinformation. The ways in which they accessed and engaged with various types of information sources were differentiated by diversities in country/regions of origin, years of residence and main language/dialects spoken. They also demonstrated varying degrees of trust about the communication around vaccines depending on the perceived expertise of the authority, their character and the perceived accuracy and transparency of the information.Conclusion The UK government and health authorities need to understand Chinese communities’ diverse information needs and cultural practices to form culturally and linguistically appropriate COVID-19 vaccine communication strategies to develop trust, targeting not the entire community but subgroups within the community via credible media sources and community networks.

Detection and analysis of spontaneous synaptic events is an extremely common task in many neuroscience research labs. Various algorithms and tools have been developed over the years to improve the sensitivity of detecting synaptic events. However, the final stages of most procedures for detecting synaptic events still involve the manual selection of candidate events. This step in the analysis is laborious and requires care and attention to maintain consistency of event selection across the whole dataset. Manual selection can introduce bias and subjective selection criteria that cannot be shared with other labs in reporting methods. To address this, we have created Eventer, a standalone application for the detection of spontaneous synaptic events acquired by electrophysiology or imaging. This open-source application uses the freely available MATLAB Runtime and is deployed on Mac, Windows, and Linux systems. The principle of the Eventer application is to learn the user's “expert” strategy for classifying a set of detected event candidates from a small subset of the data and then automatically apply the same criterion to the remaining dataset. Eventer first uses a suitable model template to pull out event candidates using fast Fourier transform (FFT)-based deconvolution with a low threshold. Random forests are then created and trained to associate various features of the events with manual labeling. The stored model file can be reloaded and used to analyse large datasets with greater consistency. The availability of the source code and its user interface provide a framework with the scope to further tune the existing Random Forest implementation, or add additional, artificial intelligence classification methods. The Eventer website (https://eventerneuro.netlify.app/) includes a repository where researchers can upload and share their machine learning model files and thereby provide greater opportunities for enhancing reproducibility when analyzing datasets of spontaneous synaptic activity. In summary, Eventer, and the associated repository, could allow researchers studying synaptic transmission to increase throughput of their data analysis and address the increasing concerns of reproducibility in neuroscience research.

BackgroundCommon Variable Immunodeficiency Disorders (CVID) encompass a spectrum of immunodeficiency characterised by recurrent infections and diverse non-infectious complications (NICs). This study aimed to describe the clinical features and variation in NICs in CVID with and without interstitial lung disease (ILD) from a large UK national registry population.MethodsRetrospective, cross-sectional data from a UK multicentre database (previously known as UKPIN), categorising patients into those with CVID-ILD and those with NICs related to CVID but without pulmonary involvement (CVID-EP; EP= extra-pulmonary involvement only).Results129 patients were included. Chronic lung diseases, especially CVID-ILD, are prominent complications in complex CVID, occurring in 62% of the cohort. Bronchiectasis was common (64% of the cohort) and associated with greater pulmonary function impairment in patients with CVID-ILD compared to those without bronchiectasis. Lymphadenopathy and the absence of gastrointestinal diseases were significant predictors of ILD in complex CVID. Although the presence of liver disease did not differ significantly between the groups, nearly half of the CVID-ILD patients were found to have liver disease. Patients with CVID-ILD were more likely to receive immunosuppressive treatments such as rituximab and mycophenolate mofetil than the CVID-EP group, indicating greater need for treatment and risk of complications.ConclusionThis study highlights the significant burden of CVID-ILD within the CVID population with NICs only. The lungs emerged as the most frequently affected organ, with ILD and bronchiectasis both highly prevalent. These findings emphasise the necessity of a comprehensive and multidisciplinary approach in managing CVID patients, considering their susceptibility to various comorbidities and complications.

Previous research has identified a replicable role for the posterior parietal cortex (PPC) in risk behaviors, but it is unclear whether this relationship is causal. Here, we used a targeted neuromodulation protocol leveraging a single-session of 10-Hz rTMS to the PPC versus a control region in the visual cortex (V5), as well as two active comparison regions [superior frontal gyrus (SFG), dorsolateral prefrontal cortex (DLPFC)] (within-person, randomized order), to examine within-session changes in a comprehensive measure of self-reported risk-taking propensity (the Domain-Specific Risk-Taking or DOSPERT scale). Individuals with tobacco use disorder were selected as sample participants who present with clinically relevant risk-taking propensity (N = 50; 14 women, mean [SE] age=33.1 [1.04] years). Results indicated that stimulating the PPC (versus V5) resulted in trend-level reductions in self-reported risk-taking propensity (region-by-time interaction, P = 0.065). A similar pattern emerged comparing PPC stimulation to effects of stimulating either the DLPFC (P = 0.080) or SFG (P = 0.032). PPC-related reductions in risk-taking propensity were domain general and potentially driven by changes in risk perception rather than perceptions of expected benefits of risk-taking. These findings support a possible causal role of the PPC in risk behaviors that warrants further consideration for therapeutic indications in conditions like tobacco use disorder.

Abstract Background Musculoskeletal injuries are a common occurrence in sport. The goal of sport injury epidemiology is to study these injuries at a population level to inform their prevention and treatment. Main body This review provides an overview of musculoskeletal sport injuries and the musculoskeletal system from a biological and epidemiologic perspective, including injury mechanism, categorizations and types of sport injuries, healing, and subsequent injuries. It is meant to provide a concise introductory substantive background of musculoskeletal sport injuries for epidemiologists who may not have formal training in the underlying anatomy and pathophysiology. Conclusion An understanding of sport injuries is important for researchers in sport injury epidemiology when determining how to best define and assess their research questions and measures.

Abstract All-inorganic lead halide perovskites (LHPs) and their use in optoelectronic devices have been widely explored because they are more thermally stable than their hybrid organic‒inorganic counterparts. However, the active perovskite phases of some inorganic LHPs are metastable at room temperature due to the critical structural tolerance factor. For example, black phase CsPbI3 is easily transformed back to the nonperovskite yellow phase at ambient temperature. Much attention has been paid to improving the phase stabilities of inorganic LHPs, especially those with high solar cell efficiencies. Herein, we discussed the origin of phase stability for CsPbI3 and the strategies used to stabilize the cubic (α) phase. We also assessed the CsPbI3 black β/γ phases that are relatively stable at nearly room temperature. Furthermore, we determined the relationship between phase stabilization and defect passivation and reviewed the growing trend in solar cell efficiency based on black phase CsPbI3. Finally, we provide perspectives for future research related to the quest for optimum device efficiency and green energy.

ABSTRACT: Milk replacers (MR) for calves contain alternative fat sources as substitute for milk fat. This substitution leads to differences in fat properties, such as the fatty acid profile and the triglyceride structure. This study evaluated how fat composition in MR affects gastrointestinal health, blood redox parameters, and postprandial metabolism in calves fed twice daily. Forty-five individually housed male Holstein-Friesian calves (2.3 ± 0.85 d of age) were assigned to 1 of 15 blocks based on the age and the day of arrival. Within each block, calves were randomly assigned to 1 of 3 experimental diets and received their respective diet from arrival until 35 d after arrival. The 3 experimental diets (n = 15 per treatment group) consisted of an MR with a blend of vegetable fats containing rapeseed and coconut (VG), an MR with only animal fats from lard and dairy cream (AN), and an MR containing a mixture of animal and vegetable fats including lard and coconut (MX). The fatty acid profile of each MR was formulated to resemble that of bovine milk fat while using only 2 fat sources. All MR were isoenergetic, with 30% fat (% DM), 24% crude protein, and 36% lactose. Chopped straw and water were available ad libitum from arrival onward but no starter feed was provided. Daily milk allowances were 6.0 L from d 1 to 5, 7.0 L from d 6 to 9, and 8.0 L from d 10 to 35, divided into 2 equal meals and prepared at 135 g/L (13.5% solids). Fecal appearance was scored daily; calves were weighed and blood was drawn on arrival and weekly thereafter. Urine and feces were collected over a 24-h period at wk 3 and 5 to determine apparent total-tract digestibility and assess gastrointestinal permeability using indigestible markers. Postprandial metabolism was evaluated at wk 4 by sequential blood sampling over 7.5 h, and the abomasal emptying rate was determined by acetaminophen appearance in blood. Fat composition in MR did not affect growth, MR intake, gastrointestinal permeability, nor nutrient digestibility. The percentage of calves with abnormal fecal scores was lower at wk 2 after arrival in calves fed VG than MX, whereas AN did not differ from the other treatments. Calves fed AN and MX had higher thiobarbituric acid reactive substances measured in serum than VG, whereas plasma ferric-reducing ability was greater in calves fed MX than VG. Postprandial acetaminophen concentrations did not differ across treatment groups, but the area under the curve was smaller in calves fed VG than in the other 2 treatments, which is indicative of a slower abomasal emptying. Postprandial serum triglyceride concentration was greater in calves fed AN than VG, whereas MX did not differ from the other treatments. Based on these outcomes, all 3 fat blends can be considered suitable for inclusion in MR for calves.

ABSTRACT: Fat composition in milk replacers (MR) for calves differs from bovine milk fat in multiple ways. The aim of the study was to investigate the impact of different approaches of formulating fat in MR on growth, ad libitum intakes of MR and solid feeds, as well as blood metabolites in dairy calves. Upon 24 to 96 h after birth, 63 calves were acquired from dairy farms and incorporated into the study. Calves were blocked based on arrival day and randomly assigned within each block to one of 3 treatments differing in MR fat composition (n = 21 per group): VG was based on vegetable fats including 80% rapeseed and 20% coconut fats; AN was formulated with animal fats including 65% lard and 35% dairy cream; and MX with a mixture of 80% lard and 20% coconut fats. All 3 MR contained 30% fat, 24% crude protein, and 36% lactose and were formulated to have a fatty acid profile resembling that of milk fat. From arrival onward (3.1 ± 0.84 d of age; means ± standard deviation), calves were group housed and were offered an ad libitum supply of MR at 135 g/L (13.5% solids). Weaning was gradual and induced between wk 7 and 10, after which calves were fed only solid feeds. Starter feed, chopped straw, and water were offered ad libitum throughout the study. Calves were weighed, and blood was collected weekly until d 84 after arrival. Preweaning average daily gain was greater in calves fed AN (915 g/d) than other treatments (783 g/d), whereas no differences were detected in the weaning and postweaning phases. Preweaning MR intake was greater in calves fed AN than MX from wk 2 to 6 and was also higher in calves fed AN than VG in wk 5 and 6. Consistently, the number of rewarded visits during the ad libitum phase was greater in calves fed AN than MX, whereas VG showed no differences. This led to a higher preweaning total metabolizable energy intake in calves fed AN than in calves fed VG and MX. Serum cholesterol was higher, and serum albumin was lower in calves fed VG than other treatments. The proportion of high-density lipoprotein cholesterol in total plasma cholesterol was lower and that of low-density lipoprotein (LDL) cholesterol was higher in calves fed VG compared with other treatments. Overall, the fatty acid profile of plasma largely mirrored the MR fat composition during the preweaning period. Feeding AN enhanced MR intake and improved preweaning growth compared with other treatments. Feeding VG resulted in a marked increase in plasma cholesterol, particularly in the form of LDL cholesterol, which could be linked to an excessive intake of polyunsaturated fatty acids. These findings underscore the importance of formulating the fat content of MR to be similar to bovine milk fat.

ABSTRACT: The preweaning period for a dairy calf is characterized by high morbidity and mortality rates, leading to financial losses for producers. Identifying strategies to improve the health and welfare of calves while reducing antimicrobial use continues to be crucial to the success of the dairy industry. The objective of this study was to determine the effects of feeding colostrum replacer (CR) to dairy heifer calves beyond d 1 of life on growth, serum IgG, the incidence of diarrhea and bovine respiratory disease (BRD), and the risk of mortality in the preweaning period. At birth, Holstein heifer calves (n = 200; 50/treatment) weighing 40.7 ± 0.35 kg (mean ± SE) were fed 3.2 L of CR (205 g IgG/feeding) at 0 h and 12 h of life. Calves were then randomly assigned to 1 of 4 treatments: 450 g of milk replacer (MR) from d 2 to 14 (control, CON), 380 g of CR + 225 g of MR from d 2 to 3, then 450 g of MR from d 4 to 14 (transition, TRAN), 45 g of CR + 450 g of MR from d 2 to 14 (extended, EXT); or 380 g of CR + 225 g of MR from d 2 to 3, then 45 g of CR + 450 g of MR from d 4 to 14 (transition + extended, TRAN+EXT). Each treatment was reconstituted to 3 L and fed twice daily. All CR treatments were fed using bovine-derived CR containing 27% IgG. From d 15 to 41, all calves were fed 600 g of MR reconstituted to 4 L twice daily. Body weight was recorded at birth and every 7 d until study completion on d 49. Blood samples were taken daily until d 7 to evaluate serum IgG and then every 7 d until d 49. A health assessment was performed daily to evaluate calves for BRD and diarrhea. Data were analyzed using mixed linear regression, mixed logistic regression, and survival analysis models in SAS 9.4. Serum IgG concentrations were not affected by treatment for the study period. The EXT and TRAN+EXT groups had greater average daily gain (ADG) from d 7 to 14 (0.14 kg/d) and the TRAN group had greater ADG from d 14 to 21 (0.11 kg/d), compared with CON. There was no association of treatment with the odds or the duration of a diarrhea bout. However, provision of CR to the TRAN and EXT calves was associated with a reduced hazard of diarrhea compared with CON calves. Furthermore, TRAN and EXT calves have a lower hazard of mortality compared with CON calves, with TRAN and EXT calves had a 2.8- and 3.8-times lower hazard of mortality, respectively. Our findings suggest that the supplementation of CR to dairy calves positively affects ADG, and reduces the hazard of diarrhea and mortality during the preweaning period. Future research should look to further refine the supplementation strategy of CR to calves and explore the mechanism of action.

Abstract This research aimed to determine whether accomplished surfers could accurately perceive how changes to surfboard fin design affected their surfing performance. Four different surfboard fins, including conventional, single-grooved, and double-grooved fins, were developed using computer-aided design combined with additive manufacturing (3D printing). We systematically installed these 3D-printed fins into instrumented surfboards, which six accomplished surfers rode on waves in the ocean in a random order while blinded to the fin condition. We quantified the surfers’ wave-riding performance during each surfing bout using a sport-specific tracking device embedded in each instrumented surfboard. After each fin condition, the surfers rated their perceptions of the Drive, Feel, Hold, Speed, Stiffness, and Turnability they experienced while performing turns using a visual analogue scale. Relationships between the surfer’s perceptions of the fins and their surfing performance data collected from the tracking devices were then examined. The results revealed that participants preferred the single-grooved fins for Speed and Feel, followed by double-grooved fins, commercially available fins, and conventional fins without grooves. Crucially, the surfers’ perceptions of their performance matched the objective data from the embedded sensors. Our findings demonstrate that accomplished surfers can perceive how changes to surfboard fins influence their surfing performance.

Background: Clinical trials on the use of viscosupplementation with hyaluronic acid (HA) in patients with knee osteoarthritis (KOA) are inconsistent, making it challenging to determine its value in clinical practice. One issue is the availability of various HA products on the market; differences in their chemical features can impact patient outcomes. Herein, we assess the efficacy and safety of three once-weekly intra-articular (IA) injections of Hylan G-F 20, a high-molecular-weight and highly crosslinked HA product, in patients with KOA. We hypothesized that Hylan G-F 20 would provide significant pain relief with no increased safety risk compared with IA saline (placebo). Methods: This was a 26-week, patient-blinded and evaluator-blinded, single-centre, randomized placebocontrolled trial. Men or women ≥18 years of age with Larsen grade II or III KOA were included. Patients received IA injections of either Hylan G-F 20 or placebo once a week for 3 weeks. The primary endpoints were the week 12 and 26 visits. Primary efficacy outcomes included visual analogue scale (VAS) pain scores, patient activity level and an overall assessment of clinical condition. Secondary outcomes included adverse events (AEs) that emerged during treatment. The primary analysis included the intention-to-treat population. An alpha level of 0.05 was used in the statistical analysis. Results: Thirty patients were included in the intentionto- treat population (15 per group). All efficacy outcomes were statistically significant in favour of Hylan G-F 20, except night pain and inactivity stiffness, for both patientassessed (all p=0.0001 at week 12) and evaluator-assessed (all p=0.0001 at week 12 and p=0.0004–0.0180 at week 26) measurements. There was also a greater proportion of symptom-free patients and those with a >50% improvement in their VAS scores, except night pain, in the Hylan G-F 20 group (p=0.001–0.003 in patient-assessed scores and p

Abstract We present an overview of the Conference on Transformative Opportunities for Modeling in Neurorehabilitation held in March 2023. It was supported by the Disability and Rehabilitation Engineering (DARE) program from the National Science Foundation’s Engineering Biology and Health Cluster. The conference brought together experts and trainees from around the world to discuss critical questions, challenges, and opportunities at the intersection of computational modeling and neurorehabilitation to understand, optimize, and improve clinical translation of neurorehabilitation. We organized the conference around four key, relevant, and promising Focus Areas for modeling: Adaptation & Plasticity, Personalization, Human-Device Interactions, and Modeling ‘In-the-Wild’. We identified four common threads across the Focus Areas that, if addressed, can catalyze progress in the short, medium, and long terms. These were: (i) the need to capture and curate appropriate and useful data necessary to develop, validate, and deploy useful computational models (ii) the need to create multi-scale models that span the personalization spectrum from individuals to populations, and from cellular to behavioral levels (iii) the need for algorithms that extract as much information from available data, while requiring as little data as possible from each client (iv) the insistence on leveraging readily available sensors and data systems to push model-driven treatments from the lab, and into the clinic, home, workplace, and community. The conference archive can be found at (dare2023.usc.edu). These topics are also extended by three perspective papers prepared by trainees and junior faculty, clinician researchers, and federal funding agency representatives who attended the conference.

ABSTRACT: The gastrointestinal microbial consortium in dairy cattle is critical to determining the energetic status of the dairy cow from birth through her final lactation. The ruminant's microbial community can degrade a wide variety of feedstuffs, which can affect growth, as well as production rate and efficiency on the farm, but can also affect food safety, animal health, and environmental impacts of dairy production. Gut microbial diversity and density are powerful tools that can be harnessed to benefit both producers and consumers. The incentives in the United States to develop Alternatives to Antibiotics for use in food-animal production have been largely driven by the Veterinary Feed Directive and have led to an increased use of probiotic approaches to alter the gastrointestinal microbial community composition, resulting in improved heifer growth, milk production and efficiency, and animal health. However, the efficacy of direct-fed microbials or probiotics in dairy cattle has been highly variable due to specific microbial ecological factors within the host gut and its native microflora. Interactions (both synergistic and antagonistic) between the microbial ecosystem and the host animal physiology (including epithelial cells, immune system, hormones, enzyme activities, and epigenetics) are critical to understanding why some probiotics work but others do not. Increasing availability of next-generation sequencing approaches provides novel insights into how probiotic approaches change the microbial community composition in the gut that can potentially affect animal health (e.g., diarrhea or scours, gut integrity, foodborne pathogens), as well as animal performance (e.g., growth, reproduction, productivity) and fermentation parameters (e.g., pH, short-chain fatty acids, methane production, and microbial profiles) of cattle. However, it remains clear that all direct-fed microbials are not created equal and their efficacy remains highly variable and dependent on stage of production and farm environment. Collectively, data have demonstrated that probiotic effects are not limited to the simple mechanisms that have been traditionally hypothesized, but instead are part of a complex cascade of microbial ecological and host animal physiological effects that ultimately impact dairy production and profitability.

ABSTRACT: This graduate student literature review provides an examination of the ontological adaptations of the calf's immune system and how the intestinal microbiota influences calf immune function in health and disease. Within dairy rearing systems, various nutritional and management factors have emerged as critical determinants of development influencing multiple physiological axes in the calf. Furthermore, we discuss how multiple pre- and postnatal maternal factors influence the trajectory of immune development in favor of establishing regulatory networks to successfully cope with the new environment, while providing early immune protection via immune passive transfer from colostrum. Additionally, our review provides insights into the current understanding of how the intestinal microbiota contributes to the development of the intestinal and systemic immune system in calves. Lastly, we address potential concerns related to the use of prophylactic antimicrobials and waste milk, specifically examining their adverse effects on intestinal health and metabolic function. By examining these factors, we aim to better understand the intricate relationship between current management practices and their long-term effect on animal health.