The sensory shark: high-quality morphological, genomic and transcriptomic data for the small-spotted catshark Scyliorhinus canicula reveal the molecular bases of sensory organ evolution in jawed vertebrates.

Cartilaginous fishes (chimaeras and elasmobranchs -sharks, skates and rays) hold a key phylogenetic position to explore the origin and diversifications of jawed vertebrates. Here, we report and integrate reference genomic, transcriptomic and morphological data in the small-spotted catshark Scyliorhinus canicula to shed light on the evolution of sensory organs. We first characterise general aspects of the catshark genome, confirming the high conservation of genome organisation across cartilaginous fishes, and investigate population genomic signatures. Taking advantage of a dense sampling of transcriptomic data, we also identify gene signatures for all major organs, including chondrichthyan specializations, and evaluate expression diversifications between paralogs within major gene families involved in sensory functions. Finally, we combine these data with 3D synchrotron imaging and in situ gene expression analyses to explore chondrichthyan-specific traits and more general evolutionary trends of sensory systems. This approach brings to light, among others, novel markers of the ampullae of Lorenzini electro-sensory cells, a duplication hotspot for crystallin genes conserved in jawed vertebrates, and a new metazoan clade of the Transient-receptor potential (TRP) family. These resources and results, obtained in an experimentally tractable chondrichthyan model, open new avenues to integrate multiomics analyses for the study of elasmobranchs and jawed vertebrates.

Wearable sensor and smartphone assisted vestibular physical therapy for multiple sclerosis: usability and outcomes.

Introduction: Vertigo, dizziness, gaze instability and disequilibrium are highly prevalent in people with MS (PwMS) and head movement induced dizziness is commonly reported. Vestibular physical therapy (VPT) is a specialised, non-invasive and effective therapy for these problems but usually involves travel for the person to a specialist center with both personal and carbon costs. The use of wearable sensors to track head movement and smartphone applications to deliver and track programs has potential to improve VPT in MS. Methods: This study investigated the usability and effects of a commercially available digital VPT system (wearable head sensor, smartphone app and clinician software) to deliver VPT to PwMS. A pre/post treatment design was employed and the primary outcome was the System Usability Scale (SUS). Other patient reported outcomes were the Service User Acceptability Questionnaire (SUTAQ), the Patient Enablement Instrument (PEI) and the Dizziness Handicap Inventory (DHI). Physical outcomes measurements included Mini-BESTest (MB), Modified Dynamic Gait Index (mDGI), Gait Speed (GS), Dynamic Visual Acuity (DVA) and head kinematics and symptoms during exercise. Results: Sixteen PwMS (14 female), mean age 44(±14) years were recruited to the study and twelve completed VPT. Mean adherence to exercise, measured digitally was 60% (±18.4). SUS scores were high at 81 (±14) and SUTAQ scores also demonstrated high levels of satisfaction and acceptability of the system. Statistically significant improvements in MB (mean change 2.25; p = 0.004), mDGI (median change 1.00; p = 0.008), DVA (median change -1.00; p = 0.004) were found. Head frequencies significantly improved with concurrent decreased intensity of dizziness during head movements (mean change across 4 gaze stabilization exercises was 23 beats per minute; p < 0.05). Non-significant improvements were seen in DHI (p = 0.07) and GS (p = 0.15). 64.5% of follow up visits were conducted remotely (video or phone), facilitated by the system. Discussion: This study had two main outcomes and benefits for PwMS. Firstly, we showed that the system used was both acceptable and could be used by PwMS. Secondly, we demonstrated an improvement in a range of dizziness, balance and gait metrics with remotely delivered care. This system has the potential to positively impact on MS physiotherapy service provision with the potential to deliver effective remote care.

Perception of cure in prostate cancer: human-led and artificial intelligence-assisted landscape review and linguistic analysis of literature, social media and policy documents.

BACKGROUND: Understanding stakeholders' perception of cure in prostate cancer (PC) is essential to preparing for effective communication about emerging treatments with curative intent. This study used artificial intelligence (AI) for landscape review and linguistic analysis of definition, context and value of cure among stakeholders in PC. MATERIALS AND METHODS: Subject-matter experts (SMEs) selected cure-related key words using Elicit, a semantic literature search engine, and extracted hits containing the key words from Medline, Sermo and Overton, representing academic researchers, health care providers (HCPs) and policymakers, respectively. NetBase Quid, a social media analytics and natural language processing tool, was used to carry out key word searches in social media (representing the general public). NetBase Quid analysed linguistics of key word-specific hit sets for key word count, geolocation and sentiments. SMEs qualitatively summarised key word-specific insights. Contextual terms frequently occurring with key words were identified and quantified. RESULTS: SMEs identified seven key words applicable to PC (number of acquired hits) across four platforms: Cure (12429), Survivor (6063), Remission (1904), Survivorship (1179), Curative intent (432), No evidence of disease (381) and Complete remission (83). Most commonly used key words were Cure by the general public and HCPs (11815 and 224 hits), Survivorship by academic researchers and Survivor by policymakers (378 hits each). All stakeholders discussed Cure and cure-related key words primarily in early-stage PC and associated them with positive sentiments. All stakeholders defined cure differently but communicated about it in relation to disease measurements (e.g. prostate-specific antigen) or surgery. Stakeholders preferred different terms when discussing cure in PC: Cure (academic researchers), Cure rates (HCPs), Potential cure and Survivor/Survivorship (policymakers) and Cure and Survivor (general public). CONCLUSION: This human-led, AI-assisted large-scale qualitative language-based research revealed that cure was commonly discussed by academic researchers, HCPs, policymakers and the general public, especially in early-stage PC. Stakeholders defined and contextualised cure in their communications differently and associated it with positive value.

The association between selective dry cow therapy, milking routine and dry cow management practices with somatic cell count in early lactation cows from 21 commercial grazing dairy herds.

This observational study aimed to explore the association of farmer-driven selective dry cow therapy (DCT), milking routine and dry cow management practices with somatic cell count (SCC) in early lactation cows from 21 commercial dairy herds. Milking routine practices evaluated referred to cow preparation for milking, in-lactation mastitis management and recording. Dry cow management practices related to dry cow environment and cleaning, dry-off procedure, milk cessation strategy and calving environment. Data from 2,016 multiparous cows in 21 commercial spring-calving grazing dairy herds were available for the study. Herd owners self-reported DCT (the assignment and administration of DCT was at the discretion of the herd owners with no involvement from the research team), management practices during milking and the dry period. Cow-level last test-day SCC records in 2020 [range = 105 to 285 d in milk (DIM)] and first test-day records in 2021 (range = 5 to 60 DIM) were obtained from milk recording databases. Quarter-level milk sampling was carried out on all cows in late lactation of 2020 (range = 240 to 261 DIM) for bacterial culturing. Bacteriological results were used to define cows with intramammary infection (IMI) when ≥ 1 quarter sample resulted in bacterial growth and there were no contaminated samples from that cow. Mixed model analyses were used to evaluate the association of selective DCT, milking routine and dry cow management practices with cows' first test-day log 10 SCC (logSCC) in 2021. At dry-off in 2020, 47.6% of the cows were administered an internal teat sealant alone (ITS) while 52.4% were administered an antibiotic plus an internal teat sealant (AB+ITS). The mean herd-level percentage of cows with IMI was 19.7% (range = 9.8% to 39.5%); Staphylococcus aureus accounted for the majority of cow-level IMI (89.9%, 357/397). Between herds, the proportion of cows administered ITS ranged from 17.7% (14/79; in a herd with an IMI prevalence of 10.1%) to 86.8% (66/76; in a herd with an IMI prevalence of 27.6%). In total, 11.8% (105/889) and 29.8% (292/980) of cows that were administered ITS or AB+ITS had an IMI in late lactation 2020, respectively. The mean untransformed SCC at the last test-day in 2020 of cows administered ITS and AB+ITS was 55,000 and 197,200 cells/mL, respectively. The statistical analysis showed a significant interaction between selective DCT and milk yield at last test-day in 2020; cows with a milk yield of 15 kg and administered ITS had a 0.1 higher (untransformed SCC of 19,000 cells/mL higher) first test-day logSCC compared with cows administered AB+ITS. Additionally, greater parity, IMI in late lactation, higher log SCC at the last test-day in 2020 and longer dry periods were associated with higher logSCC at the first test-day in 2021. The current study identified cow- and herd-level management practices that could aid dairy farmers in improving the outcome of selective DCT and decrease early lactation SCC.

Deep, rapid, and durable prostate-specific antigen decline with apalutamide plus androgen deprivation therapy is associated with longer survival and improved clinical outcomes in TITAN patients with metastatic castration-sensitive prostate cancer.

BACKGROUND: The first interim analysis of the phase III, randomized, double-blind, placebo-controlled, multinational TITAN study demonstrated improved overall survival (OS) and radiographic progression-free survival (rPFS) with apalutamide added to ongoing androgen deprivation therapy (ADT) in patients with metastatic castration-sensitive prostate cancer. The final analysis confirmed improvement in OS and other long-term outcomes. We evaluated prostate-specific antigen (PSA) kinetics and the association between PSA decline and outcomes in patients with metastatic castration-sensitive prostate cancer from TITAN. PATIENTS AND METHODS: Patients received apalutamide (240 mg/day) or placebo plus ADT (1 : 1). This post hoc exploratory analysis evaluated PSA kinetics and decline in relation to rPFS (22.7 months' follow-up) and OS, time to PSA progression, and time to castration resistance (44.0 months' follow-up) in patients with or without confirmed PSA decline using a landmark analysis, the Kaplan-Meier method, and Cox proportional hazards model. RESULTS: One thousand and fifty-two patients (apalutamide, 525; placebo, 527) were enrolled. Best confirmed PSA declines (≥50% or ≥90% from baseline or to ≤0.2 ng/ml) were achieved at any time during the study in 90%, 73%, and 68% of apalutamide-treated versus 55%, 29%, and 32% of placebo-treated patients, respectively. By 3 months of apalutamide treatment, best deep PSA decline of ≥90% or to ≤0.2 ng/ml occurred in 59% and 51% of apalutamide- and in 13% and 18% of placebo-treated patients, respectively. Achievement of deep PSA decline at landmark 3 months of apalutamide treatment was associated with longer OS [hazard ratio (HR) 0.35; 95% confidence interval (CI) 0.25-0.48), rPFS (HR 0.44; 95% CI 0.30-0.65), time to PSA progression (HR 0.31; 95% CI 0.22-0.44), and time to castration resistance (HR 0.38; 95% CI 0.27-0.52) compared with no decline (P < 0.0001 for all). Similar results were observed at landmark 6 and 12 months of apalutamide treatment. CONCLUSIONS: Apalutamide plus ADT demonstrated a robust (rapid, deep, and durable) PSA decline that was associated with improved clinical outcomes, including long-term survival.

Recommendations for breast cancer education for African American women below screening age.

Although statistically unlikely, early-onset breast cancer tends to be more aggressive and leads to greater mortality than breast cancer among women of screening age. Young African American women are disproportionately impacted by early-onset breast cancer compared to women of other races. Given the racial disparities and because young women are typically not the primary audience for breast cancer educational messaging, there is a need to identify recommendations for age-appropriate breast cancer education for African American women below mammogram eligibility. Through N = 30 key informant interviews with young African American breast cancer survivors, family members of young survivors, community organization leaders and healthcare providers, we identified breast cancer educational message content and communication channels relevant for these women. Participants recommended that message content should emphasize the need to address family cancer history and self-advocacy in healthcare encounters in addition to concerns about loss of womanhood, financial costs and opportunity costs associated with preventive healthcare visits. Breast cancer messages for this audience should consider the influences of earlier life stage, culture and race. Recommended communication channels highlighted use of social media and videos. Findings will inform future age-appropriate educational messaging aimed at eliminating early-onset breast cancer disparities disproportionately impacting young African American women.

Review: Trends for meat, milk and egg consumption for the next decades and the role played by livestock systems in the global production of proteins.

Meeting the food demands of a growing global population within planetary boundaries is a challenge. Sustainably producing animal-sourced foods while supplying sufficient protein to meet the requirements of a healthy diet is a particular challenge. This paper informs the development of pathways to sustainable animal production by examining trends in animal-sourced foods since 2000, including the significance of animal- relative to plant-protein sources. Drawing on three distinct scenarios defined by the Food and Agriculture Organization (FAO), (i.e. Business As Usual (BAU), a continuation of historical trends of food preferences including initiatives to address Sustainable Development Goal targets; Stratified Societies (SSs), leaving challenges unattended; and Towards Sustainability (TS); a more equitable global society and more sustainable food system due to effective polices), future demand for animal-sourced foods is projected. Analysis is based on FAO Food Balance Sheet data (2000-2017) and projected national protein demand per capita (2012-2050). Analysis is disaggregated to five global regions defined by the World Health Organization. It finds that patterns of past demand for animal-sourced foods vary by food (e.g. red vs white meat) and region. However, the European region consistently has the highest levels of consumption of animal-sourced foods, while the South-East Asian and African regions have the lowest. The ratio of animal to plant-sourced protein varies across regions, ranging from 0.29 in Africa to 1.08 in Europe in 2017. Over time, the ratio is relatively stable or moderately increasing, driven by rising incomes in low- or middle-income countries. Under the future scenarios, all World Health Organization regions show a marked increase in demand for animal-sourced protein across BAU and SS. The TS scenario, however, projects notable declines in consumption across Europe and the Americas when compared to the 2012 BAU baseline, with a decline in milk also in the Western Pacific. In contrast, meat and milk consumption in Africa and South-East Asia is projected to increase, reflecting their far lower starting consumption levels. The analysis and subsequent discussion highlight the importance of having regional-specific strategies to deal with the challenge of sustainable livestock production and consumption, with a requirement to consider the impact of actions in one region on others. Clearly, the challenge is not merely one for science and technology but one based on wider aspects of the food system and its diverse stakeholders.

A catalog of associations between rare coding variants and COVID-19 outcomes.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease-19 (COVID-19), a respiratory illness that can result in hospitalization or death. We investigated associations between rare genetic variants and seven COVID-19 outcomes in 543,213 individuals, including 8,248 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome-wide or when specifically focusing on (i) 14 interferon pathway genes in which rare deleterious variants have been reported in severe COVID-19 patients; (ii) 167 genes located in COVID-19 GWAS risk loci; or (iii) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, with results publicly browsable at https://rgc-covid19.regeneron.com.

Genome-wide analysis in 756,646 individuals provides first genetic evidence that ACE2 expression influences COVID-19 risk and yields genetic risk scores predictive of severe disease.

SARS-CoV-2 enters host cells by binding angiotensin-converting enzyme 2 (ACE2). Through a genome-wide association study, we show that a rare variant (MAF = 0.3%, odds ratio 0.60, P=4.5×10-13) that down-regulates ACE2 expression reduces risk of COVID-19 disease, providing human genetics support for the hypothesis that ACE2 levels influence COVID-19 risk. Further, we show that common genetic variants define a risk score that predicts severe disease among COVID-19 cases.

Reconnaissance of tumor immune microenvironment spatial heterogeneity in metastatic renal cell carcinoma and correlation with immunotherapy response.

A clearer understanding of the tumor immune microenvironment (TIME) in metastatic clear cell renal cell carcinoma (ccRCC) may help to inform precision treatment strategies. We sought to identify clinically meaningful TIME signatures in ccRCC. We studied tumors from 39 patients with metastatic ccRCC using quantitative multiplexed immunofluorescence and relevant immune marker panels. Cell densities were analyzed in three regions of interest (ROIs): tumor core, tumor-stroma interface and stroma. Patients were stratified into low- and high-marker density groups using median values as thresholds. Log-rank and Cox regression analyses while controlling for clinical variables were used to compare survival outcomes to patterns of immune cell distributions. There were significant associations with increased macrophage (CD68+ CD163+ CD206+ ) density and poor outcomes across multiple ROIs in primary and metastatic tumors. In primary tumors, T-bet+ T helper type 1 (Th1) cell density was highest at the tumor-stromal interface (P = 0·0021), and increased co-expression of CD3 and T-bet was associated with improved overall survival (P = 0·015) and survival after immunotherapy (P = 0·014). In metastatic tumor samples, decreased forkhead box protein 3 (FoxP3)+ T regulatory cell density correlated with improved survival after immunotherapy (P = 0·016). Increased macrophage markers and decreased Th1 T cell markers within the TIME correlated with poor overall survival and treatment outcomes. Immune markers such as FoxP3 showed consistent levels across the TIME, whereas others, such as T-bet, demonstrated significant variance across the distinct ROIs. These findings suggest that TIME profiling outside the tumor core may identify clinically relevant associations for patients with metastatic ccRCC.

Purified ß-glucans from the Shiitake mushroom ameliorates antibiotic-resistant Klebsiella pneumoniae-induced pulmonary sepsis.

Bacterial infection remains the main cause of acute respiratory distress syndrome and is a leading cause of death and disability in critically ill patients. Here we report on the use of purified ß-glucan (lentinan) extracts from Lentinus edodes (Shiitake) mushroom that can reduce infection by a multidrug-resistant clinical isolate of Klebsiella pneumoniae in a rodent pneumonia model, likely through immunomodulation. Adult male Sprague-Dawley rats were subjected to intra-tracheal administration of K. pneumoniae to induce pulmonary sepsis and randomized to three groups; vehicle control (Vehicle, n = 12), commercial lentinan (CL, n = 8) or in-house extracted lentinan (IHL, n = 8) were administered intravenously 1 h postinfection. Physiological parameters and blood gas analysis were measured, bacterial counts from bronchoalveolar-lavage (BAL) were determined, along with differential staining of white cells and measurement of protein concentration in BAL 48 h after pneumonia induction. Use of IHL extract significantly decreased BAL CFU counts. Both CL and IHL extractions reduced protein concentration in BAL. Use of IHL resulted in an improvement in physiological parameters compared to controls and CL. In conclusion, administration of lentinan to treat sepsis-induced lung injury appears safe and effective and may exert its effects in an immunomodulatory manner.

Randomised controlled trial of an intervention to improve parental knowledge and management practices of fever.

BACKGROUND: We know that parents require resources which can assist them to improve fever knowledge and management practices. The purpose of this study, using an RCT, was to examine the effectiveness of an information leaflet at increasing parental knowledge of fever, specifically temperature definition. METHODS: A prospective, multi-centre, randomised, two-parallel arm, controlled trial with blinded outcome ascertainment was conducted. Parents presenting at purposively selected healthcare facilities who had a child aged ≤5 years of age were invited to participate. An information leaflet for use in the trial was designed based on previous studies with parents. Parents in the intervention arm read an information leaflet on fever and management of fever in children, completed a short questionnaire at Time 1 (T1) and again 2 weeks after randomisation at Time 2 (T2). Parents in the control arm did not receive the fever information leaflet but completed the same questionnaire as the intervention arm at T1 and againat T2. The primary outcome was the correct definition of fever (higher than ≥38 °C). RESULTS: A total of 100 parents participated in the study at T1. A greater proportion of the intervention group (76%) than the control group (28%) selected the correct temperature (≥38 °C) at T1. 76% of the intervention arm correctly identified "higher than ≥38°C" as the temperature at which a fever is said to be present compared to 28% of the control arm. After 2 weeks, there was an increase of 6% of parents in the intervention arm (increase to 82.4%) who gave the correct temperature compared to just a 2.8% increase in the control arm (increase to 30.8%). Univariate logistic regression showed that parents in the intervention arm were significantly more likely to give the correct answer at both time-points (T1: OR 8.1; CI 95% 3.3-19.9: p < 0.01; T2: OR 10.5; CI 95% 3.4-32.0: p < 0.01). CONCLUSIONS: Our RCT of this simple educational intervention has been shown to improve parental understanding of fever knowledge and correct management strategies. Education interventions providing simple, clear information is a key step to decreasing parental mismanagement of fever and febrile illness in children. TRIAL REGISTRATION: ClinicalTrials.gov NCT02903342, September 16, 2016, Retrospectively registered.

Distance as a Barrier to Melanoma Care

Aim Our aim was to review cases of melanoma diagnosed histologically in UHK in 2016 and to compare them to cases of melanoma nationally and in Kerry. Methods For each patient we recorded age, Breslow depth, and shortest distance to travel by car and travelling time (without traffic) to the South Infirmary Victoria University Hospital (SIVUH) from their primary residence (calculated using Google maps™ (2018)). Results 20 cases of invasive melanoma were diagnosed in UHK in 2016. Of the 20 cases, 9 (45%) presented at a very advanced stage with a Breslow depth of greater than 4mm. A further 7 (35%) cases had a depth of 1.5-4mm. These patients with invasive melanoma had a mean age of 72.5 (±15). The mean shortest distance to travel from the patient's primary residence to the SIVUH was 114.8km (±15.5) taking an average of 102 minutes (±14.6) by car. Conclusion Cases of melanoma diagnosed locally in UHK presented at an advanced stage compared to the national average. We suspect that the long distances to travel to the SIVUH pigmented lesion clinic is a barrier for these patients.

A Comparison of Summer and Winter Emergency Hospitalisations in Ireland

There is increasing demand on the Irish health service, particularly in winter months. This study described and compared acute hospitals admissions across summer and winter periods from 2015 to 2018. The analysis used Hospital In-Patient Enquiry data accessed through the National Quality Assurance Information System ­ NQAIS Clinical. There were 84 additional emergency hospitalisations in winter per week compared with summer (1.2% increase). Across diagnostic categories, emergency hospitalisations reduced in winter, except respiratory conditions which increased by 379 per week representing a 40.5% increase. The profile of emergency respiratory admissions were similar in summer and winter in terms of age, length of stay, day of week and medical card status. Length of stay was approximately one day longer for weekend admissions in both seasons. This research highlights the importance of taking a whole-population approach to winter resilience planning, focussing on prevention and optimal management of respiratory conditions.

The effects of different sampling techniques on peripheral post mortem tryptase levels: a recommended sampling method.

Different sampling techniques can impact on post mortem tryptase levels. A previous study demonstrated significantly lower femoral post mortem total tryptase levels in samples collected via transcutaneous aspiration compared with directly sampling during internal examination. However, an outlier with high tryptase level was noted in one transcutaneous aspiration sample. This 6-month prospective study compared total post mortem tryptase levels between 21 paired aspirated venous and arterial femoral blood samples, and 19 paired aspirated and cutdown femoral venous blood samples in non-anaphylactic deaths only. No statistical differences were demonstrated between the different sampling methods. However, four outlier cases with higher tryptase levels in aspirated arterial and femoral cutdown samples compared with aspirated venous femoral samples were noted. The reasons for the outliers may be due to the bloods collected from these two methods being contaminated by central arterial and venous blood with high tryptase levels respectively. None of the aspirated venous femoral post mortem tryptase levels were above recognized post mortem tryptase cutoff to diagnose anaphylaxis. This study recommends aspirating blood samples from a clamped femoral/external iliac vein for post mortem tryptase analysis should be defined as the gold standard. Further study using the recommended sampling method on post mortem tryptase levels in non-anaphylactic and anaphylactic cases is warranted.