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Abstract The harm-made mind phenomenon implies that witnessing intentional harm towards agents with ambiguous minds, such as robots, leads to augmented mind perception in these agents. We conducted two replications of previous work on this effect and extended it by testing if robots that detect and simulate emotions elicit a stronger harm-made mind effect than robots that do not. Additionally, we explored if someone is perceived as less prosocial when harming a robot compared to treating it kindly. The harm made mind-effect was replicated: participants attributed a higher capacity to experience pain to the robot when it was harmed, compared to when it was not harmed. We did not find evidence that this effect was influenced by the robot’s ability to detect and simulate emotions. There were significant but conflicting direct and indirect effects of harm on the perception of mind in the robot: while harm had a positive indirect effect on mind perception in the robot through the perceived capacity for pain, the direct effect of harm on mind perception was negative. This suggests that robots are both anthropomorphized and dehumanized when harmed intentionally. Additionally, the results showed that someone is perceived as less prosocial when harming a robot compared to treating it kindly.

Abstract The cardiac conduction system (CCS) is a network of specialized cardiomyocytes that coordinates electrical impulse generation and propagation for synchronized heart contractions. Although the components of the CCS, including the sinoatrial node, atrioventricular node, His bundle, bundle branches, and Purkinje fibers, were anatomically discovered more than 100 years ago, their molecular constituents and regulatory mechanisms remain incompletely understood. Here, we demonstrate the transcriptomic landscape of the postnatal mouse CCS at a single-cell resolution with spatial information. Integration of single-cell and spatial transcriptomics uncover region-specific markers and zonation patterns of expression. Network inference shows heterogeneous gene regulatory networks across the CCS. Notably, region-specific gene regulation is recapitulated in vitro using neonatal mouse atrial and ventricular myocytes overexpressing CCS-specific transcription factors, Tbx3 and/or Irx3. This finding is supported by ATAC-seq of different CCS regions, Tbx3 ChIP-seq, and Irx motifs. Overall, this study provides comprehensive molecular profiles of the postnatal CCS and elucidates gene regulatory mechanisms contributing to its heterogeneity.

Abstract Background The Mycobacterium avium complex (MAC) comprises the most frequent non-tuberculous mycobacteria (NTM) in Central Europe and currently includes twelve species. M. avium (MAV), M. intracellulare subsp. intracellulare (MINT), and M. intracellulare subsp. chimaera (MCH) are clinically most relevant. However, the population structure and genomic landscape of MAC linked with potential pathobiological differences remain little investigated. Methods Whole genome sequencing (WGS) was performed on a multi-national set of MAC isolates from Germany, France, and Switzerland. Phylogenetic analysis was conducted, as well as plasmids, resistance, and virulence genes predicted from WGS data. Data was set into a global context with publicly available sequences. Finally, detailed clinical characteristics were associated with genomic data in a subset of the cohort. Results Overall, 610 isolates from 465 patients were included. The majority could be assigned to MAV (n = 386), MCH (n = 111), and MINT (n = 77). We demonstrate clustering with less than 12 SNPs distance of isolates obtained from different patients in all major MAC species and the identification of trans-European or even trans-continental clusters when set into relation with 1307 public sequences. However, none of our MCH isolates clustered closely with the heater-cooler unit outbreak strain Zuerich-1. Known plasmids were detected in MAV (325/1076, 30.2%), MINT (62/327, 19.0%), and almost all MCH-isolates (457/463, 98.7%). Predicted resistance to aminoglycosides or macrolides was rare. Overall, there was no direct link between phylogenomic grouping and clinical manifestations, but MCH and MINT were rarely found in patients with extra-pulmonary disease (OR 0.12 95% CI 0.04–0.28, p

ABSTRACTIntroduction Influenza causes significant morbidity and mortality, but influenza vaccine uptake remains below most countries’ targets. Vaccine policy recommendations vary, as do procedures for reviewing and appraising the evidence.Areas Covered During a series of roundtable discussions, we reviewed procedures and methodologies used by health ministries in four European countries to inform vaccine recommendations. We review the type of evidence currently recommended by each health ministry and the range of approaches toward considering randomized controlled trials (RCTs) and real-world evidence (RWE) studies when setting influenza vaccine recommendations.Expert Opinion Influenza vaccine recommendations should be based on data from both RCTs and RWE studies of efficacy, effectiveness, and safety. Such data should be considered alongside health-economic, cost-effectiveness, and budgetary factors. Although RCT data are more robust and less prone to bias, well-designed RWE studies permit timely evaluation of vaccine benefits, effectiveness comparisons over multiple seasons in large populations, and detection of rare adverse events, under real-world conditions. Given the variability of vaccine effectiveness due to influenza virus mutations and increasing diversification of influenza vaccines, we argue that consideration of both RWE and RCT evidence is the best approach to more nuanced and timely updates of influenza vaccine recommendations.

Abstract Background Although inadequate sleep increases the risk of obesity in children, the mechanisms remain unclear. The aims of this study were to assess how sleep loss influenced dietary intake in children while accounting for corresponding changes in sedentary time and physical activity; and to investigate how changes in time use related to dietary intake. Methods A randomized crossover trial in 105 healthy children (8–12 years) with normal sleep (~ 8–11 h/night) compared sleep extension (asked to turn lights off one hour earlier than usual for one week) and sleep restriction (turn lights off one hour later) conditions, separated by a washout week. 24-h time-use behaviors (sleep, wake after sleep onset, physical activity, sedentary time) were assessed using waist-worn actigraphy and dietary intake using two multiple-pass diet recalls during each intervention week. Longitudinal compositional analysis was undertaken with mixed effects regression models using isometric log ratios of time use variables as exposures and dietary variables as outcomes, and participant as a random effect. Results Eighty three children (10.2 years, 53% female, 62% healthy weight) had 47.9 (SD 30.1) minutes less sleep during the restriction week but were also awake for 8.5 (21.4) minutes less at night. They spent this extra time awake in the day being more sedentary (+ 31 min) and more active (+ 21 min light physical activity, + 4 min MVPA). After adjusting for all changes in 24-h time use, losing 48 min of sleep was associated with consuming significantly more energy (262 kJ, 95% CI:55,470), all of which was from non-core foods (314 kJ; 43, 638). Increases in sedentary time were related to increased energy intake from non-core foods (177 kJ; 25, 329) whereas increases in MVPA were associated with higher intake from core foods (72 kJ; 7,136). Changes in diet were greater in female participants. Conclusion Loss of sleep was associated with increased energy intake, especially of non-core foods, independent of changes in sedentary time and physical activity. Interventions focusing on improving sleep may be beneficial for improving dietary intake and weight status in children. Trial Registration Australian New Zealand Clinical Trials Registry ANZCTR ACTRN12618001671257, Registered 10th Oct 2018, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=367587&isReview=true

Abstract Knowledge is limited as to how prior SARS-CoV-2 infection influences cellular and humoral immunity after booster-vaccination with bivalent BA.4/5-adapted mRNA-vaccines, and whether vaccine-induced immunity may indicate subsequent infection. In this observational study, individuals with prior infection (n = 64) showed higher vaccine-induced anti-spike IgG-antibodies and neutralizing titers, but the relative increase was significantly higher in non-infected individuals (n = 63). In general, both groups showed higher neutralizing activity towards the parental strain than towards Omicron-subvariants BA.1, BA.2 and BA.5. In contrast, CD4 or CD8 T cell levels towards spike from the parental strain and the Omicron-subvariants, and cytokine expression profiles were similar irrespective of prior infection. Breakthrough infections occurred more frequently among previously non-infected individuals, who had significantly lower vaccine-induced spike-specific neutralizing activity and CD4 T cell levels. In summary, we show that immunogenicity after BA.4/5-bivalent vaccination differs between individuals with and without prior infection. Moreover, our results may help to improve prediction of breakthrough infections.

Abstract Epilepsy imposes a substantial burden on the Democratic Republic of Congo (DRC). These challenges encompass the lack of comprehensive disease surveillance, an unresolved understanding of its pathophysiology, economic barriers limiting access to essential care, the absence of epilepsy surgical capabilities, and deeply ingrained societal stigmas. Notably, the national prevalence of epilepsy remains undetermined, with research primarily concentrating on infectious factors like Onchocerca volvulus, leaving other potential causes underexplored. Most patients lack insurance, incurring out‐of‐pocket expenses that often lead them to opt for traditional medicine rather than clinical care. Social stigma, perpetuated by common misconceptions, intensifies the social isolation experienced by individuals living with epilepsy. Additionally, surgical interventions are unavailable, and the accessibility of anti‐seizure medications and healthcare infrastructure remains inadequate. Effectively tackling these interrelated challenges requires a multifaceted approach, including conducting research into region‐specific factors contributing to epilepsy, increasing healthcare funding, subsidizing the costs of treatment, deploying mobile tools for extensive screening, launching awareness campaigns to dispel myths and reduce stigma, and promoting collaborations between traditional healers and medical practitioners to enhance local understanding and epilepsy management. Despite the difficulties, significant progress can be achieved through sustained and compassionate efforts to understand and eliminate the barriers faced by epilepsy patients in the region. This review outlines essential steps for alleviating the epilepsy burden in the DRC. Plain Language summary There are not enough resources to treat epilepsy in the DRC. PWEs struggle with stigma and the lack of money. Many of them still use traditional medicine for treatment and hold wrong beliefs about epilepsy. That is why there is a need for more resources to make the lives of PWEs better in the DRC.

BackgroundThe introduction of complementary foods during the first year of life influences the diversity of the gut microbiome. How this diversity affects immune development and health is unclear. ObjectiveThis study evaluates the effect of consuming kūmara or kūmara with added banana powder (resistant starch) compared to a reference control at 4 months post randomization on the prevalence of respiratory tract infections and the development of the gut microbiome. MethodsThis study is a double-blind, randomized controlled trial of mothers and their 6-month-old infants (up to n=300) who have not yet started solids. Infants are randomized into one of 3 groups: control arm (C), standard kūmara intervention (K), and a kūmara intervention with added banana powder product (K+) to be consumed daily for 4 months until the infant is approximately 10 months old. Infants are matched for sex using stratified randomization. Data are collected at baseline (prior to commencing solid food) and at 2 and 4 months after commencing solid food (at around 8 and 10 months of age). Data and samples collected at each timepoint include weight and length, intervention adherence (months 2 and 4), illness and medication history, dietary intake (months 2 and 4), sleep (diary and actigraphy), maternal dietary intake, breast milk, feces (baseline and 4 months), and blood samples (baseline and 4 months). ResultsThe trial was approved by the Health and Disability Ethics Committee of the Ministry of Health, New Zealand (reference 20/NTA/9). Recruitment and data collection did not commence until January 2022 due to the COVID-19 pandemic. Data collection and analyses are expected to conclude in January 2024 and early 2025, respectively. Results are to be published in 2024 and 2025. ConclusionsThe results of this study will help us understand how the introduction of a specific prebiotic complementary food affects the microbiota and relative abundances of the microbial species, the modulation of immune development, and infant health. It will contribute to the expanding body of research that aims to deepen our understanding of the connections between nutrition, gut microbiota, and early-life postnatal health. Trial RegistrationAustralian New Zealand Clinical Trials Registry ACTRN12620000026921; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378654 International Registered Report Identifier (IRRID)DERR1-10.2196/56772

Previously, a high prevalence of piroplasms has been reported from Florida pumas (Puma concolor coryi) from southern Florida. In the current study, we describe the biological characteristics of a novel Babesia species in Florida pumas. Ring-stage trophozoites were morphologically similar to trophozoites of numerous small babesids of felids including B. leo, B. felis, and Cytauxzoon felis. Parasitemias in Florida pumas were very low (

Background In 2020, almost 100 million people were blind or visually impaired from cataract. Cataract surgery is a cost-effective treatment for cataracts. In Nigeria, twice as many women are cataract blind as men. Cataract surgical rate (CSR, the number of cataract operations per million population per year in a defined geographical location) is an output indicator of cataract surgical services. The recommended target CSR for sub-Saharan Africa is 1000/year. The aim of this study was to assess the CSR in men and women in Imo state, Nigeria.Methods A retrospective review of cataract surgery undertaken in all eye health facilities in Imo State in 2019. Data collected included the type and location of facilities, patient demographics and the number and type of cataract operations performed in each facility. The CSR was calculated overall, in men and women, and in younger and older women.Results The CSR overall was 330/million and was slightly higher in women (347/million) than in men (315/million) (p

Abstract Latent associations between low serum amylase and reduced plasma insulin levels and increased adiposity have been described previously in a small study of asymptomatic middle‐aged humans. In the present study, we sought to determine the nature of such changes during the longitudinal progression from metabolically normal to overt type 2 diabetes mellitus (T2DM) in nonhuman primates (NHPs), a disease that appears to be the same in both pathophysiology and underlying mechanisms as that which most commonly develops in middle‐aged adult humans. Amylase and lipase levels were characterized in 157 unrelated adult rhesus monkeys (Macaca mulatta); 38% developed T2DM while under study. In all monkeys, multivariable linear regression analysis revealed that amylase could be negatively predicted by % body fat (β −0.29; p = 0.002), age (β −0.27; p = 0.005), and HbA1c (β −0.18; p = 0.037). Amylase levels were positively predicted by lipase levels (β = 0.19; p = −0.024) in all NHPs included in the study. Amylase was significantly lower in NHPs with metabolic syndrome (p

Abstract Linking clinical multi-omics with mechanistic studies may improve the understanding of rare cancers. We leverage two precision oncology programs to investigate rhabdomyosarcoma with FUS/EWSR1-TFCP2 fusions, an orphan malignancy without effective therapies. All tumors exhibit outlier ALK expression, partly accompanied by intragenic deletions and aberrant splicing resulting in ALK variants that are oncogenic and sensitive to ALK inhibitors. Additionally, recurrent CKDN2A/MTAP co-deletions provide a rationale for PRMT5-targeted therapies. Functional studies show that FUS-TFCP2 blocks myogenic differentiation, induces transcription of ALK and truncated TERT, and inhibits DNA repair. Unlike other fusion-driven sarcomas, TFCP2-rearranged tumors exhibit genomic instability and signs of defective homologous recombination. DNA methylation profiling demonstrates a close relationship with undifferentiated sarcomas. In two patients, sarcoma was preceded by benign lesions carrying FUS-TFCP2, indicating stepwise sarcomagenesis. This study illustrates the potential of linking precision oncology with preclinical research to gain insight into the classification, pathogenesis, and therapeutic vulnerabilities of rare cancers.

Abstract Background It is important that healthcare professionals recognise cognitive dysfunction in hospitalised older patients in order to address associated care needs, such as enhanced involvement of relatives and extra cognitive and functional support. However, studies analysing medical records suggest that healthcare professionals have low awareness of cognitive dysfunction in hospitalised older patients. In this study, we investigated the prevalence of cognitive dysfunction in hospitalised older patients, the percentage of patients in which cognitive dysfunction was recognised by healthcare professionals, and which variables were associated with recognition. Methods A multicentre, nationwide, cross-sectional observational study was conducted on a single day using a flash mob study design in thirteen university and general hospitals in the Netherlands. Cognitive function was assessed in hospitalised patients aged ≥ 65 years old, who were admitted to medical and surgical wards. A Mini-Cog score of

Abstract The tumour microenvironment is infiltrated by immunosuppressive cells, such as regulatory T cells (Tregs), which contribute to tumour escape and impede immunotherapy outcomes. Soluble fibrinogen-like protein 2 (sFGL2), a Treg effector protein, inhibits immune cell populations, via receptors FcγRIIB and FcγRIII, leading to downregulation of CD86 in antigen presenting cells and limiting T cell activation. Increased FGL2 expression is associated with tumour progression and poor survival in several different cancers, such as glioblastoma multiforme, lung, renal, liver, colorectal, and prostate cancer. Querying scRNA-seq human cancer data shows FGL2 is produced by cells in the tumour microenvironment (TME), particularly monocytes and macrophages as well as T cells and dendritic cells (DCs), while cancer cells have minimal expression of FGL2. We studied the role of FGL2 exclusively produced by cells in the TME, by leveraging Fgl2 knockout mice. We tested two murine models of cancer in which the role of FGL2 has not been previously studied: epithelial ovarian cancer and melanoma. We show that absence of FGL2 leads to a more activated TME, including activated DCs (CD86+, CD40+) and T cells (CD25+, TIGIT+), as well as demonstrating for the first time that the absence of FGL2 leads to more activated natural killer cells (DNAM-1+, NKG2D+) in the TME. Furthermore, the absence of FGL2 leads to prolonged survival in the B16F10 melanoma model, while the absence of FGL2 synergizes with oncolytic virus to prolong survival in the ID8-p53 −/− Brca2 −/− ovarian cancer model. In conclusion, targeting FGL2 is a promising cancer treatment strategy alone and in combination immunotherapies.

Periprosthetic joint infection (PJI) can present challenges in diagnosis and treatment, particularly in the setting of atypical causative organisms such as fungi and mycobacteria. Herein, we present a case and provide a review of the diagnosis and treatment of an unusual PJI caused by bacillus Calmette-Guérin, administered during the treatment of bladder cancer 3 years prior to total knee arthroplasty and subsequent PJI. Although the patient’s history of bladder cancer was known, neither his Bacillus Calmette-Guérin treatment nor its potential for distant site spread that could lead to PJI were appreciated, leading to a prolonged diagnostic evaluation and treatment course.

Gastrointestinal lymphoma is the most common form of lymphoma in domestic cats. Aggressive phenotypes are much less common but do bear and unfavorable prognosis. Immunophenotyping by flow cytometry (FCM) is not systematically performed in these patients, because of difficulties in the acquisition of suitable sample material from the gastrointestinal tract. A multimodal diagnostic approach is recommended to improve identification of subtypes targeting patient tailored therapeutic strategies. The aim of this prospective study was to present results of multicolor FCM immunophenotyping in surgically removed gastrointestinal mass and relate them with histopathology using the World Health Organization (WHO) classification and clonality PCR testing. Thirty-two patients were included. Eight cats (25%) had gastric, 23 (72%) had intestinal lymphoma and 1 (3%) had gastric/jejunal lymphoma. Intestinal lymphoma sites were represented by 18 small intestinal, 4 ileocaecal, 1 large intestinal. All gastric lymphomas were diffuse large B-cell lymphoma (DLBCL). Small intestinal lymphomas were 10 enteropathy associated T-cell lymphoma type I (EATL I), 2 enteropathy associated T-cell lymphoma type II (EATL II), 2 peripheral T-cell lymphoma (PTCL), 3 DLBCL and one DLBCL+EATL II. The most common small intestinal FCM T-cell phenotype was CD3+CD21− CD4−CD8−CD18+ CD5−CD79− in 7/10 EATL I and one EATL II. The most frequent FCM B-cell phenotype was CD3−CD21+ CD4−CD8−CD18+ CD5−CD79+ in 13/17 DLBCL and the DLBCL+EATL II. Clonality PCR results were positive in 87.5% (28/32) of all cases. No cross-lineage rearrangement was observed. IHC and FCM results agreed in 87.5% (28/32) of all cases. When all 3 methods were combined, consistent results were seen in 75% (24/32). This is the first demonstration of a multicolor FCM approach set in context to the gold standard histopathology and clonality testing results.

Abstract To better understand how vocalisations are used during interactions of multiple individuals, studies are increasingly deploying on‐board devices with a microphone on each animal. The resulting recordings are extremely challenging to analyse, since microphone clocks drift non‐linearly and record the vocalisations of non‐focal individuals as well as noise. Here we address this issue with callsync, an R package designed to align recordings, detect and assign vocalisations to the caller, trace the fundamental frequency, filter out noise and perform basic analysis on the resulting clips. We present a case study where the pipeline is used on a dataset of six captive cockatiels (Nymphicus hollandicus) wearing backpack microphones. Recordings initially had a drift of ~2 min, but were aligned to within ~2 s with our package. Using callsync, we detected and assigned 2101 calls across three multi‐hour recording sessions. Two had loud beep markers in the background designed to help the manual alignment process. One contained no obvious markers, in order to demonstrate that markers were not necessary to obtain optimal alignment. We then used a function that traces the fundamental frequency and applied spectrographic cross correlation to show a possible analytical pipeline where vocal similarity is visually assessed. The callsync package can be used to go from raw recordings to a clean dataset of features. The package is designed to be modular and allows users to replace functions as they wish. We also discuss the challenges that might be faced in each step and how the available literature can provide alternatives for each step.

Lymphoma is one of the most frequent hematopoietic tumors in dogs and shares similar features with human counterparts. MicroRNAs (miRNA, small non-coding RNAs) are pivotal in gene regulation fine tuning and cancer hallmarks are influenced by their aberrant expression. Consequently, miRNA biomarkers may assist predicting therapeutic response and clinical outcome by providing less-invasive novel diagnostics tools. The aim of this study was to detect dysregulated miRNAs in lymphomatous lymph node tissues in comparison to lymph node material or PBMCs from healthy control dogs. Potential significant differences in miRNA expression profiles between four lymphoma entities were evaluated. A customized PCR array was utilized to profile 89 canine target miRNAs. Quantification was performed using qPCR, relative expression was determined by the delta–delta Ct method, and p-values were calculated with student’s t-test. In the 14 diffuse large B-cell lymphoma (DLBCL) patients, 28 and 24 different miRNAs were significantly dysregulated compared to lymph node material or PBMCs. Sixteen miRNAs occurred in both control groups, with 12 miRNAs being down- and four miRNAs being upregulated. The six peripheral T-cell lymphoma (PTCL) samples showed 24 and 25 dysregulated miRNAs when compared to the healthy controls. A combined analysis of DLBCL and PTCL samples revealed seven shared and 19 differently expressed miRNAs. Potential biomarkers in T- and B-cell lymphoma could be the miRNA-17/92 cluster and miRNA-181-family together with miRNA-34a and miRNA-150. Diagnostic utility of potential biomarkers must be validated in larger, prospective cohorts of canine lymphoma cases and in higher numbers of physiological patient material.

Kidney transplantation is the best treatment for kidney failure in older patients. However, little is known regarding changes in health-related quality of life (HRQoL) from before to after transplantation and determinants of HRQoL in older kidney transplant recipients (KTR). We studied both, using data of older (≥65 years) patients waitlisted for kidney transplantation and older KTR 1 year after transplantation from the TransplantLines Biobank and Cohort Study. HRQoL was assessed using the SF-36 questionnaire. We included 145 older waitlisted patients (68% male, age 70 ± 4 years) and 115 older KTR at 1 year after transplantation (73% male, age 70 ± 4 years). Both mental (48.5 ± 8.4 versus 51.2 ± 7.7, p = 0.009) and physical (47.4 ± 8.5 versus 52.1 ± 7.2, p < 0.001) HRQoL were higher among included KTR, compared to the waitlisted patients. In paired analyses among 46 patients with HRQoL-data both before and after transplantation, there was a trend towards increased mental HRQoL (49.1 ± 8.4 to 51.6 ± 7.5, p = 0.054), and significantly increased physical HRQoL (48.1 ± 8.0 to 52.4 ± 6.7, p = 0.001) after transplantation. Among all assessed factors, the number of patient-reported immunosuppressive drug-related side effects was most strongly negatively associated with both mental and physical HRQoL. In conclusion, HRQoL is significantly higher among older KTR after kidney transplantation compared to older waitlisted patients.

Abstract Cancer cells often metastasize by undergoing an epithelial-mesenchymal transition (EMT). Although abundance of CD8+ T-cells in the tumor microenvironment correlates with improved survival, mesenchymal cancer cells acquire greater resistance to antitumor immunity in some cancers. We hypothesized the EMT modulates the immune response to ovarian cancer. Here we show that cancer cells from infiltrated/inflamed tumors possess more mesenchymal cells, than excluded and desert tumors. We also noted high expression of LGALS3 is associated with EMT in vivo, a finding validated with in vitro EMT models. Dissecting the cellular communications among populations in the tumor revealed that mesenchymal cancer cells in infiltrated tumors communicate through LGALS3 to LAG3 receptor expressed by CD8+ T cells. We found CD8+ T cells express high levels of LAG3, a marker of T cell exhaustion. The results indicate that EMT in ovarian cancer cells promotes interactions between cancer cells and T cells through the LGALS3 - LAG3 axis, which could increase T cell exhaustion in infiltrated tumors, dampening antitumor immunity.

Abstract Clinical trials are currently exploring combinations of PARP inhibitors and immunotherapies for the treatment of ovarian cancer, but their effects on the ovarian tumour microenvironment (TME) remain unclear. Here, we investigate how olaparib, PD-L1 monoclonal antibodies, and their combination can influence TME composition and survival of tumour-bearing mice. We further explored how BRCA deficiencies can influence the response to therapy. Olaparib and combination therapies similarly improved the median survival of Brca1- and Brca2-deficient tumour-bearing mice. Anti-PD-L1 monotherapy improved the survival of mice with Brca1-null tumours, but not Brca2-null tumours. A detailed analysis of the TME revealed that olaparib monotherapy resulted in a large number of immunosuppressive and immunomodulatory effects in the more inflamed Brca1-deficient TME but not Brca2-deficient tumours. Anti-PD-L1 treatment was mostly immunosuppressive, resulting in a systemic reduction of cytokines and a compensatory increase in PD-L1 expression. The results of the combination therapy generally resembled the effects of one or both of the monotherapies, along with unique changes observed in certain immune populations. In-silico analysis of RNA-seq data also revealed numerous differences between Brca-deficient tumour models, such as the expression of genes involved in inflammation, angiogenesis and PD-L1 expression. In summary, these findings shed light on the influence of novel therapeutics and BRCA mutations on the ovarian TME.

Abstract Ovarian cancers exhibit high rates of recurrence and poor treatment response. Preclinical models that recapitulate human disease are critical to develop new therapeutic approaches. Syngeneic mouse models allow for the generation of tumours comprising the full repertoire of non-malignant cell types but have expanded in number, varying in the cell type of origin, method for transformation, and ultimately, the properties of the tumours they produce. Here we have performed a comparative analysis of high-grade serous ovarian cancer models based on transcriptomic profiling of 22 cell line models, and intrabursal and intraperitoneal tumours from 12. Among cell lines, we identify distinct signalling activity, such as elevated inflammatory signalling in STOSE and OVE16 models, and MAPK/ERK signalling in ID8 and OVE4 models; metabolic differences, such as reduced glycolysis-associated expression in several engineered ID8 subclones; and relevant functional properties, including differences in EMT activation, PD-L1 and MHC class I expression, and predicted chemosensitivity. Among tumour samples, we observe increased variability and stromal content among intrabursal tumours. Finally, we predict differences in the microenvironment of ID8 models engineered with clinically relevant mutations. We anticipate that this work will serve as a valuable resource, providing new insight to help select models for specific experimental objectives.

Abstract Background Peripheral facial palsy (PFP) is a common neurologic symptom which can be triggered by pathogens, autoimmunity, trauma, tumors, cholesteatoma or further local conditions disturbing the peripheral section of the nerve. In general, its cause is often difficult to identify, remaining unknown in over two thirds of cases. As we have previously shown that the quantity and quality of pathogen-specific T cells change during active infections, we hypothesized that such changes may also help to identify the causative pathogen in PFPs of unknown origin. Methods In this observational study, pathogen-specific T cells were quantified in blood samples of 55 patients with PFP and 23 healthy controls after stimulation with antigens from varicella-zoster virus (VZV), herpes-simplex viruses (HSV) or borrelia. T cells were further characterized by expression of the inhibitory surface molecule CTLA-4, as well as markers for differentiation (CD27) and proliferation (Ki67). Pathogen-specific antibody responses were analyzed using ELISA. Results were compared with conventional diagnostics. Results Patients with PFP were more often HSV-seropositive than controls (p = 0.0003), whereas VZV- and borrelia-specific antibodies did not differ between groups. Although the quantity and general phenotypical characteristics of antigen-specific T cells did not differ either, expression of CTLA-4 and Ki67 was highly increased in VZV-specific T cells of 9 PFP patients, of which 5 showed typical signs of cutaneous zoster. In the remaining 4 patients, a causal relationship with VZV was possible but remained unclear by clinical standard diagnostics. A similar CTLA-4- and Ki67-expression profile of borrelia-specific T cells was also found in a patient with acute neuroborreliosis. Discussion In conclusion, the high prevalence of HSV-seropositivity among PFP-patients may indicate an underestimation of HSV-involvement in PFP, even though HSV-specific T cell characteristics seem insufficient to identify HSV as a causative agent. In contrast, striking alterations in VZV- and borrelia-specific T cell phenotype and function may allow identification of VZV- and borrelia-triggered PFPs. If confirmed in larger studies, antigen-specific immune-phenotyping may have the potential to improve specificity of the clinical diagnosis.

The aquaculture industry requires green solutions to solve several environmental challenges, including adequate wastewater remediation and natural drug applications to treat bacteria- and virus-related diseases. This study investigated the feasibility of cultivating the dinoflagellate Durusdinium glynnii in aquaculture wastewater from shrimp rearing in a synbiotic system (AWW-SS), with different dilutions of f/2 medium (FM). Interestingly, D. glynnii demonstrated enhanced growth in all AWW–SS treatments compared to the control (FM). The highest growth rates were achieved at AWW-SS:FM dilutions of 75:25 and 50:50. The removal of total nitrogen and total phosphorus reached 50.1 and 71.7%, respectively, of the crude AWW–SS. Biomass extracts of D. glynnii grown with AWW–SS were able to inhibit the growth of the bacteria Vibrio parahaemolyticus (inhibition zone of 10.0 ± 1.7 mm) and V. vulnificus (inhibition zone of 11.7 ± 1.5 mm). The presented results demonstrate that the dinoflagellate D. glynnii is a potential candidate for the development of circularity for sustainable aquaculture production, particularly by producing anti–Vibrio compounds at a near-zero cost.

Abstract Background Global migration has led to a sharp increase in the number of language‐discordant consultations (LDCs) in healthcare. Evidence on how healthcare providers (HCPs) meet migrant patients' needs while mitigating language barriers is lacking. Design Using purposive and snowball sampling, we recruited twenty‐seven Dutch HCPs (Mage = 45.07, SD = 11.46) and conducted semi‐structured interviews to collect qualitative, open‐ended data for identifying the communication strategies used with migrant patients in LDCs. We analysed the transcripts using deductive and inductive approaches (e.g., constant comparative method from Grounded Theory). Final pattern codes (i.e., key themes) were discussed among the research team until mutual agreement had been achieved. Results Five key themes emerged from the analyses: HCPs often ‘got‐by’ with (1) instrumental and (2) affective communication strategies used in language‐concordant consultations to start medical consultations. When some instrumental communication strategies were deemed ineffective (e.g., lingua franca, gesturing, etc.) to bridge language barriers, HCPs turned to (3) incorporating digital tools (e.g., Google Translate). When HCPs were unable to communicate with migrant patients at all, (4) informal, ad‐hoc and professional interpreters were involved. Finally, HCPs often (5) involved additional support to engage migrant patients to engage in treatment‐related behaviours. Discussion and Conclusions Our results highlight the importance of raising awareness among HCPs about using various combinations of different strategies. The development of a guideline indicating the optimal combination of communication strategies for different medical consultation goals may be useful in reshaping the current communication behaviour of HCPs in LDCs. Patient or Public Contribution HCPs were the study population involved in this qualitative study. Refugee health advisors, general practitioners and linguistic specialists (i.e., members of the Right2Health consortium) with experience with the Dutch healthcare system were involved throughout the development of this research. This includes a review of the research question, participant information sheet and interview topic guide as well as providing interpretations of the data and feedback to this manuscript.

IntroductionEpithelial ovarian cancer (OC) stands as one of the deadliest gynecologic malignancies, urgently necessitating novel therapeutic strategies. Approximately 60% of ovarian tumors exhibit reduced expression of major histocompatibility complex class I (MHC I), intensifying immune evasion mechanisms and rendering immunotherapies ineffective. NOD-like receptor CARD domain containing 5 (NLRC5) transcriptionally regulates MHC I genes and many antigen presentation machinery components. We therefore explored the therapeutic potential of NLRC5 in OC.MethodsWe generated OC cells overexpressing NLRC5 to rescue MHC I expression and antigen presentation and then assessed their capability to respond to PD-L1 blockade and an infected cell vaccine.ResultsAnalysis of microarray datasets revealed a correlation between elevated NLRC5 expression and extended survival in OC patients; however, NLRC5 was scarcely detected in the OC tumor microenvironment. OC cells overexpressing NLRC5 exhibited slower tumor growth and resulted in higher recruitment of leukocytes in the TME with lower CD4/CD8 T-cell ratios and increased activation of T cells. Immune cells from peripheral blood, spleen, and ascites from these mice displayed heightened activation and interferon-gamma production when exposed to autologous tumor-associated antigens. Finally, as a proof of concept, NLRC5 overexpression within an infected cell vaccine platform enhanced responses and prolonged survival in comparison with control groups when challenged with parental tumors.DiscussionThese findings provide a compelling rationale for utilizing NLRC5 overexpression in “cold” tumor models to enhance tumor susceptibility to T-cell recognition and elimination by boosting the presentation of endogenous tumor antigens. This approach holds promise for improving antitumoral immune responses in OC.

Abstract Background Hospital care organization, structured around medical specialties and focused on the separate treatment of individual organ systems, is challenged by the increasing prevalence of multimorbidity. To support the hospitals’ realization of multidisciplinary care, we hypothesized that using machine learning on clinical data helps to identify groups of medical specialties who are simultaneously involved in hospital care for patients with multimorbidity. Methods We conducted a cross-sectional study of patients in a Dutch general hospital and used a fuzzy c-means clustering algorithm for the analysis. We explored the patients’ membership degrees in each cluster to identify subgroups of medical specialties that provide care to the same patients with multimorbidity. We used retrospectively collected electronic health record data from 2017. We extracted data from 22,133 patients aged ≥18 years who had received outpatient clinical care for two or more chronic and/ or oncological diagnoses. Results We found six clusters of medical specialties and identified 22 subgroups. The clusters were labeled based on the specialties that most characterized them: 1. dermatology/ plastic surgery, 2. six specialties (gynecology/ rheumatology/ orthopedic surgery/ urology/ gastroenterology/ otorhinolaryngology), 3. pulmonology, 4. internal medicine/ cardiology/ geriatrics, 5. neurology/ physiatry (rehabilitation)/ anesthesiology, and 6. internal medicine. Most patients had a full or dominant membership to one of these clusters of medical specialties (11 subgroups), whereas fewer patients had a membership to two clusters. The prevalence of specific diagnosis groups, patient characteristics, and healthcare utilization differed between subgroups. Conclusion Our study shows that clusters and subgroups of medical specialties simultaneously involved in hospital care for patients with multimorbidity can be identified with fuzzy c-means cluster analysis using clinical data. Clusters and subgroups differed regarding the involved medical specialties, diagnoses, patient characteristics, and healthcare utilization. With this strategy, hospitals and medical specialists can further analyze which subgroups are target populations that might benefit from improved multidisciplinary collaboration.

Traumatic brain injury (TBI) is a leading cause of cognitive disability in adults, often characterized by marked deficits in episodic memory and executive function. Prior studies have found that direct electrical stimulation of the temporal cortex yielded improved memory in epilepsy patients, but it is not clear if these results generalize to patients with a specific history of TBI. Here we asked whether applying closed-loop, direct electrical stimulation to lateral temporal cortex could reliably improve memory in a TBI cohort. Among a larger group of patients undergoing neurosurgical evaluation for refractory epilepsy, we recruited a subset of patients with a history of moderate-to-severe TBI. By analyzing neural data from indwelling electrodes as patients studied and recalled lists of words, we trained personalized machine-learning classifiers to predict momentary fluctuations in mnemonic function in each patient. We subsequently used these classifiers to trigger high-frequency stimulation of the lateral temporal cortex (LTC) at moments when memory was predicted to fail. This strategy yielded a 19% boost in recall performance on stimulated as compared with non-stimulated lists (P = 0.012). These results provide a proof-of-concept for using closed-loop stimulation of the brain in treatment of TBI-related memory impairment.

We analyzed consecutive clinical cases of infections due to carbapenemase-producing gram-negative bacteria detected in war-wounded patients from Ukraine who were treated at one university medical center in southwest Germany between June and December 2022. The isolates of multiresistant gram-negative bacteria were subjected to a thorough microbiological characterization and whole genome sequencing (WGS). We identified five war-wounded Ukrainian patients who developed infections with New Delhi metallo-β-lactamase 1-positive Klebsiella pneumoniae. Two isolates also carried OXA-48 carbapenemases. The bacteria were resistant to novel antibiotics, such as ceftazidime/avibactam and cefiderocol. The used treatment strategies included combinations of ceftazidime/avibactam + aztreonam, colistin, or tigecycline. WGS suggested transmission during primary care in Ukraine. We conclude that there is an urgent need for thorough surveillance of multiresistant pathogens in patients from war zones.

Interdisciplinary communication and collaboration are crucial in the care of people with multiple long-term conditions (MLTCs) yet are often experienced as insufficient. Through the lens of complexity science, this study aims to explain how healthcare professionals (HCPs) adapt to emerging situations in the care of patients with MLTC by examining interdisciplinary communication and collaboration in the outpatient hospital setting. We used the constant comparative method to analyze transcribed data from seven focus groups with twenty-one HCPs to generate a constructivist grounded theory of ‘interdisciplinary communication and collaboration in the outpatient setting of the hospital for patients with multiple long-term conditions’. Our theory elucidates the various pathways of communication and collaboration. Why, when, and how team members choose to collaborate influences if and to what degree tailored care is achieved. There is great variability and unpredictability to this process due to internalized rules, such as beliefs on the appropriateness to deviate from guidelines, and the presence of an interprofessional identity. We identified organizational structures that influence the dynamics of the care team such as the availability of time and financial compensation for collaboration. As we strive for tailored care for patients with MLTC, our theory provides promising avenues for future endeavors.

In order to enhance interdisciplinary collaboration and promote better medication management, a partnered pharmacist medication charting (PPMC) model was piloted in the emergency department (ED) of an Australian referral hospital. The primary objective of this study was to evaluate the impact of PPMC on the timeliness of time-critical medicines (TCMs), completeness of medication orders, and assessment of venous thromboembolism (VTE) risk. This concurrent controlled retrospective pragmatic trial involved individuals aged 18 years and older presenting to the ED from 1 June 2020 to 17 May 2021. The study compared the PPMC approach (PPMC group) with traditional medical officer-led medication charting approaches in the ED, either an early best-possible medication history (BPMH) group or the usual care group. In the PPMC group, a BPMH was documented promptly soon after arrival in the ED, subsequent to which a collaborative discussion, co-planning, and co-charting of medications were undertaken by both a PPMC-credentialled pharmacist and a medical officer. In the early BPMH group, the BPMH was initially obtained in the ED before proceeding with the traditional approach of medication charting. Conversely, in the usual care group, the BPMH was obtained in the inpatient ward subsequent to the traditional approach of medication charting. Three outcome measures were assessed –the duration from ED presentation to the TCM’s first dose administration (e.g., anti-Parkinson’s drugs, hypoglycaemics and anti-coagulants), the completeness of medication orders, and the conduct of VTE risk assessments. The analysis included 321 TCMs, with 107 per group, and 1048 patients, with 230, 230, and 588 in the PPMC, early BPMH, and usual care groups, respectively. In the PPMC group, the median time from ED presentation to the TCM’s first dose administration was 8.8 h (interquartile range: 6.3 to 16.3), compared to 17.5 h (interquartile range: 7.8 to 22.9) in the early BPMH group and 15.1 h (interquartile range: 8.2 to 21.1) in the usual care group (p < 0.001). Additionally, PPMC was associated with a higher proportion of patients having complete medication orders and receiving VTE risk assessments in the ED (both p < 0.001). The implementation of the PPMC model not only expedited the administration of TCMs but also improved the completeness of medication orders and the conduct of VTE risk assessments in the ED.

Abstract Aim To describe nurses' roles, involvement, and topics in shared decision‐making with older patients with dementia in acute hospitals. Design An integrative review. Methods A systematic search was performed until April 2022 in PubMed, PsychInfo, CINAHL, and Cochrane, followed by a manual search on the reference lists of relevant systematic reviews. Studies were independently screened, appraised using the Joanna Briggs Institute (JBI) methodology, and extracted by two reviewers. Results Nine studies were included. Nurses were involved as treatment team members, intermediates, or patient supporters. Nurses' roles were most explicit in the preparatory phase of shared decision‐making. The step of ‘developing tailor‐made options’ was limitedly identified. ‘Deliberating and trying options to reach a decision’ were described from an outsider's perspective in which nurses attempted to influence the decision. In conclusion, nurses primarily have a role in decision‐making by supplementing patient information. Patient and Public Contribution No Patient or Public Contribution.

Introduction: Partnered pharmacist medication charting (PPMC), a process redesign hypothesised to improve medication safety and interdisciplinary collaboration, was trialed in a tertiary hospital’s emergency department (ED).Objective: To evaluate the health-related impact and economic benefit of PPMC.Methods: A pragmatic, controlled study compared PPMC to usual care in the ED. PPMC included a pharmacist-documented best-possible medication history (BPMH), followed by a clinical conversation between a pharmacist and a medical officer to jointly develop a treatment plan and chart medications. Usual care included medical officer-led traditional medication charting in the ED, without a pharmacist-obtained BPMH or clinical conversation. Outcome measures, assessed after propensity score matching, were length of hospital or ED stay, relative stay index (RSI), in-hospital mortality, 30-day hospital readmissions or ED revisits, and cost.Results: A total of 309 matched pairs were analysed. The median RSI was reduced by 15.4% with PPMC (p = 0.029). There were no significant differences between the groups in the median length of ED stay (8 vs. 10 h, p = 0.52), in-hospital mortality (1.3% vs. 1.3%, p > 0.99), 30-day readmission rates (21% vs. 17%; p = 0.35) and 30-day ED revisit rates (21% vs. 19%; p = 0.68). The hospital spent approximately $138.4 for the cost of PPMC care per patient to avert at least one medication error bearing high/extreme risk. PPMC saved approximately $1269 on the average cost of each admission.Conclusion: Implementing the ED-based PPMC model was associated with a significantly reduced RSI and admission costs, but did not affect clinical outcomes, noting that there was an additional focus on medication reconciliation in the usual care group relative to current practice at our study site.

Objectives: To explore travel burden in patients with multimorbidity and analyze patients with high travel burden, to stimulate actions towards adequate access and (remote) care coordination for these patients. Design: A retrospective, cross-sectional, explorative proof of concept study. Setting and Participants: Electronic health record data of all patients who visited our academic hospital in 2017 were used. Patients with a valid 4-digit postal code, aged ≥18 years, had >1 chronic or oncological condition and had >1 outpatient visits with >1 specialties were included. Methods: Travel burden (hours/year) was calculated as: travel time in hours × number of outpatient visit days per patient in one year × 2. Baseline variables were analyzed using univariate statistics. Patients were stratified into two groups by the median travel burden. The contribution of travel time (dichotomized) and the number of outpatient clinic visits days (dichotomized) to the travel burden was examined with binary logistic regression by adding these variables consecutively to a crude model with age, sex and number of diagnosis. National maps exploring the geographic variation of multimorbidity and travel burden were built. Furthermore, maps showing the distribution of socioeconomic status (SES) and proportion of older age (≥65 years) of the general population were built. Results: A total of 14 476 patients were included (54.4% female, mean age 57.3 years ([± standard deviation] = ± 16.6 years). Patients travelled an average of 0.42 (± 0.33) hours to the hospital per (one-way) visit with a median travel burden of 3.19 hours/year (interquartile range (IQR) 1.68 – 6.20). Care consumption variables, such as higher number of diagnosis and treating specialties in the outpatient clinic were more frequent in patients with higher travel burden. High travel time showed a higher Odds Ratio (OR = 578 (95% Confidence Interval (CI) = 353 – 947), p

Single-cell RNA sequencing (scRNA-seq) is the state-of-the-art approach to study transcriptomic signatures in individual cells in respiratory health and disease. However, classical scRNA-seq approaches provide no spatial information and are performed using either bronchoalveolar lavage fluid (BAL) or lung single cell suspensions to assess transcript levels in airway and tissue immune cells, respectively. Herein we describe a simple method to simultaneously characterize transcriptomic features of airway, lung parenchymal and intravascular immune cells based on differential in vivo labeling with barcoded antibodies. In addition to gaining basic spatial information, this approach allows for direct comparison of cells within different anatomical compartments. Furthermore, this method provides a time- and cost-effective alternative to classical scRNA-seq where lung and BAL samples are processed individually, reducing animal and reagent use. We demonstrate the feasibility of this approach in a preclinical mouse model of bacterial lung infection comparing airway, parenchymal and vasculature neutrophils early after infection.

Introduction: A process redesign, partnered pharmacist medication charting (PPMC), was recently piloted in the emergency department (ED) of a tertiary hospital. The PPMC model was intended to improve medication safety and interdisciplinary collaboration by having pharmacists work closely with medical officers to review and chart medications for patients. This study, therefore, aimed to evaluate the impact of PPMC on potentially inappropriate medication (PIM) use.Methods: A pragmatic concurrent controlled study compared a PPMC group to both early best-possible medication history (BPMH) and usual care groups. In the PPMC group, pharmacists initially documented the BPMH and collaborated with medical officers to co-develop treatment plans and chart medications in ED. The early BPMH group included early BPMH documentation by pharmacists, followed by traditional medication charting by medical officers in ED. The usual care group followed the traditional charting approach by medical officers, without a pharmacist-collected BPMH or collaborative discussion in ED. Included were older people (≥65 years) presenting to the ED with at least one regular medication with subsequent admission to an acute medical unit. PIM outcomes (use of at least one PIM, PIMs per patient and PIMs per medication prescribed) were assessed at ED presentation, ED departure and hospital discharge using Beers criteria.Results: Use of at least one PIM on ED departure was significantly lower for the PPMC group than for the comparison groups (χ2, p = 0.040). However, PIM outcomes at hospital discharge were not statistically different between groups. PIM outcomes on ED departure or hospital discharge did not differ from baseline within the comparison groups.Discussion: In conclusion, PIM use on leaving ED, but not at hospital discharge, was reduced with PPMC. Close interprofessional collaboration, as in ED, needs to continue on the wards.

Objective Atrial fibrillation (AF) is a condition that occurs in the presence of comorbidities. With the accumulation of comorbidities (multimorbidity), some combinations may more often occur together than others. Information on the impact of clustering of these on incident AF is sparse. We aimed to investigate clustering of cardiovascular and renal comorbidities and study the association between comorbidity clusters and incident AF.Methods We used the community-based Prevention of Renal and Vascular ENd-stage Disease (PREVEND) cohort in which 8592 individuals participated. Latent class analysis was performed to assess clustering of 10 cardiovascular and renal comorbidities.Results We excluded individuals with prior AF or missing ECG data, leaving 8265 individuals for analysis (mean age 48.9±12.6 years, 50.2% women). During 9.2±2.1 years of follow-up, 251 individuals (3.0%) developed AF. A model with three clusters was the optimal model, with one cluster being young (44.5±10.8 years) and healthy, carrying a low (1.0%) risk of incident AF; one cluster being older (63.0±8.4 years) and multimorbid, carrying a high (16.2%) risk of incident AF and a third middle-aged (57.0±11.3 years), obese and hypertensive cluster carrying an intermediate risk (5.9%) of incident AF. While the prevalence of the comorbidities differed between classes, no clear combination(s) of comorbidities was observed within the classes.Conclusions We identified three clusters of comorbidities in individuals in the community-based PREVEND cohort. The three clusters contained different amount of comorbidities carrying different risks of incident AF. However, there were no differences between the clusters regarding specific combination(s) of comorbidities.

Staphylococcus aureus is a common cause of hospital-acquired pneumonia associated with high mortality. Adequate clinical treatment is impeded by increasing occurrence of antibiotic resistances. Understanding the underlying mechanisms of its virulence during infections is a prerequisite to finding alternative treatments. Here, we demonstrated that an increased nuclease activity of a S. aureus isolate from a person with cystic fibrosis confers a growth advantage in a model of acute lung infection compared to the isogenic strain with low nuclease activity. Comparing these CF-isolates with a common MRSA-USA300 strain with similarly high nuclease activity but significantly elevated levels of Staphylococcal Protein A (SpA) revealed that infection with USA300 resulted in a significantly increased bacterial burden in a model of murine lung infection. Replenishment with the cell wall-bound SpA of S. aureus, which can also be secreted into the environment and binds to tumor necrosis factor receptor -1 (TNFR-1) to the CF-isolates abrogated these differences. In vitro experiments confirmed significant differences in spa-expression between USA300 compared to CF-isolates, thereby influencing TNFR-1 shedding, L-selectin shedding, and production of reactive oxygen species through activation of ADAM17.

Abstract Background Given the economic relevance of fertility and reproductive traits for the beef cattle industry, investigating their genetic background and developing effective breeding strategies are paramount. Considering their late and sex-dependent phenotypic expression, genomic information can contribute to speed up the rates of genetic progress per year. In this context, the main objectives of this study were to estimate variance components and genetic parameters, including heritability and genetic correlations, for fertility, female precocity, and semen production and quality (andrological attributes) traits in Nellore cattle incorporating genomic information. Results The heritability estimates of semen quality traits were low-to-moderate, while moderate-to-high estimates were observed for semen morphological traits. The heritability of semen defects ranged from low (0.04 for minor semen defects) to moderate (0.30 for total semen defects). For seminal aspect (SMN_ASPC) and bull reproductive fitness (BULL_FIT), low (0.19) and high (0.69) heritabilities were observed, respectively. The heritability estimates for female reproductive traits ranged from 0.16 to 0.39 for rebreeding of precocious females (REBA) and probability of pregnancy at 14 months (PP14), respectively. Semen quality traits were highly genetically correlated among themselves. Moderate-to-high genetic correlations were observed between the ability to remain productive in the herd until four years of age (stayability; STAY) and the other reproductive traits, indicating that selection for female reproductive performance will indirectly contribute to increasing fertility rates. High genetic correlations between BULL_FIT and female reproductive traits related to precocity (REBA and PP14) and STAY were observed. The genetic correlations between semen quality and spermatic morphology with female reproductive traits ranged from -0.22 (REBA and scrotal circumference) to 0.48 (REBA and sperm vigor). In addition, the genetic correlations between REBA with semen quality traits ranged from -0.23 to 0.48, and with the spermatic morphology traits it ranged from -0.22 to 0.19. Conclusions All male and female fertility and reproduction traits evaluated are heritable and can be improved through direct genetic or genomic selection. Selection for better sperm quality will positively influence the fertility and precocity of Nellore females. The findings of this study will serve as background information for designing breeding programs for genetically improving semen production and quality and reproductive performance in Nellore cattle.

Abstract Biologging devices are deployed on animals to collect ultra‐fine‐scale movement data that reveal subsecond patterns in locomotion or long‐term patterns in motion and space use. Often these two data types, although complementary, are rarely collected within the same study, given the limiting factors of memory space, power requirements and the need to retrieve stored data from animals. Biologging requires a revolutionary advancement in data networking to overcome these restrictions that constrain big data collection; for the continuous recording and remote download of fine‐scale movement and environmental data, from long‐term deployments and multiple individuals. Here, we adopt a strategy from the Internet of Things and develop the use of Wi‐Fi as a solution for big data biologging. Our ‘WildFi’ tag uses pre‐existing, or easy‐to‐set‐up, infrastructure in smartphones and Wi‐Fi gateways. We demonstrate the power of memory management and an embedded modular software architecture for functionality, including collective data retrieval at multiple gateways. We find that Wi‐Fi, together with smart embedded software, increases the retrieval efficiency of biologging data by orders of magnitude compared to other available systems: with a transmission speed of 230 kByte/s and range of ≤200 m that is 11 times faster than Bluetooth low energy and >3000 times faster than LoRaWAN. Case studies on a domestic dog (Canis lupus familiaris), aviary‐housed cockatiels (Nymphicus hollandicus) and free‐roaming pangolins (Smutsia temminckii) demonstrate the functionality of the WildFi tag for remote and robust autonomous Wi‐Fi data transmission under a range of conditions. Modularity in software and hardware allows for project‐specific tailoring beyond reconfiguring sampling parameters of a biologger, which we encourage with open‐source sharing of our architecture design. Enhanced communication between animal‐attached devices, Wi‐Fi infrastructure and smartphones, alongside smart and collaborative data retrieval, eases restrictions for big data collection in animal ecology.

Abstract The international precision oncology program INFORM enrolls relapsed/refractory pediatric cancer patients for comprehensive molecular analysis. We report a two-year pilot study implementing ex vivo drug sensitivity profiling (DSP) using a library of 75–78 clinically relevant drugs. We included 132 viable tumor samples from 35 pediatric oncology centers in seven countries. DSP was conducted on multicellular fresh tumor tissue spheroid cultures in 384-well plates with an overall mean processing time of three weeks. In 89 cases (67%), sufficient viable tissue was received; 69 (78%) passed internal quality controls. The DSP results matched the identified molecular targets, including BRAF, ALK, MET, and TP53 status. Drug vulnerabilities were identified in 80% of cases lacking actionable (very) high-evidence molecular events, adding value to the molecular data. Striking parallels between clinical courses and the DSP results were observed in selected patients. Overall, DSP in clinical real-time is feasible in international multicenter precision oncology programs.

Abstract Bioacoustic research spans a wide range of biological questions and applications, relying on identification of target species or smaller acoustic units, such as distinct call types. However, manually identifying the signal of interest is time-intensive, error-prone, and becomes unfeasible with large data volumes. Therefore, machine-driven algorithms are increasingly applied to various bioacoustic signal identification challenges. Nevertheless, biologists still have major difficulties trying to transfer existing animal- and/or scenario-related machine learning approaches to their specific animal datasets and scientific questions. This study presents an animal-independent, open-source deep learning framework, along with a detailed user guide. Three signal identification tasks, commonly encountered in bioacoustics research, were investigated: (1) target signal vs. background noise detection, (2) species classification, and (3) call type categorization. ANIMAL-SPOT successfully segmented human-annotated target signals in data volumes representing 10 distinct animal species and 1 additional genus, resulting in a mean test accuracy of 97.9%, together with an average area under the ROC curve (AUC) of 95.9%, when predicting on unseen recordings. Moreover, an average segmentation accuracy and F1-score of 95.4% was achieved on the publicly available BirdVox-Full-Night data corpus. In addition, multi-class species and call type classification resulted in 96.6% and 92.7% accuracy on unseen test data, as well as 95.2% and 88.4% regarding previous animal-specific machine-based detection excerpts. Furthermore, an Unweighted Average Recall (UAR) of 89.3% outperformed the multi-species classification baseline system of the ComParE 2021 Primate Sub-Challenge. Besides animal independence, ANIMAL-SPOT does not rely on expert knowledge or special computing resources, thereby making deep-learning-based bioacoustic signal identification accessible to a broad audience.

Abstract Objective The Mini-SIPS, a condensed version of the Structured Interview for Psychosis-Risk Syndromes (SIPS), is intended to efficiently identify for clinicians the minimum information needed to support a DSM-5 Attenuated Psychosis Syndrome (APS) diagnosis. Methods The instrument and the DSM-5 criteria are accessible through the online training program. Results Most individuals (67.5%) in the first 212 to complete the training program indicated an intended use of the Mini-SIPS exclusively for clinical purposes. Performance on the post-training quiz was excellent for those with and without prior training in structured diagnostic interviewing. Conclusion The Mini-SIPS, and accompanying training program, are offered as public-domain clinical resources to the mental health community.

ABSTRACT Osteoporosis, a disease classically attributed to postmenopausal women, is underappreciated, underdiagnosed, and undertreated in men. However, it is not uncommon for osteoporotic fractures to occur in men. About 40% of fractures occur in men with an incidence that has increased over the years. After a first fracture, the risk of a subsequent episode, as well as the risk of death, is higher in the male than in the female population. Despite these facts, only 10% of men with osteoporosis receive adequate treatment. Up to half of the cases of male osteoporosis have a secondary cause, the most common being hypogonadism, excessive alcohol consumption, and chronic use of glucocorticoids. The International Society for Clinical Densitometry (ISCD) recommends using the female database for the diagnosis of osteoporosis by DXA (T-score ≤ −2.5 in men over 50 years old). In addition, osteoporosis can also be diagnosed independently of the BMD if a fragility fracture is present, or if there is a high risk of fractures by FRAX. Treatment is similar to postmenopausal osteoporosis, because the data regarding changes in bone density track closely to those in women. Data concerning fracture risk reduction are not as certain because the clinical trials have included fewer subjects for shorter period of time. In men with symptomatic hypogonadism, testosterone replacement, if indicated, can improve BMD.

ABSTRACT Trabecular bone score (TBS) is an indirect and noninvasive measure of bone quality. A low TBS indicates degraded bone microarchitecture, predicts osteoporotic fracture, and is partially independent of clinical risk factors and bone mineral density (BMD). There is substantial evidence supporting the use of TBS to assess vertebral, hip, and major osteoporotic fracture risk in postmenopausal women, as well as to assess hip and major osteoporotic fracture risk in men aged > 50 years. TBS complements BMD information and can be used to adjust the FRAX (Fracture Risk Assessment) score to improve risk stratification. While TBS should not be used to monitor antiresorptive therapy, it may be potentially useful for monitoring anabolic therapy. There is also a growing body of evidence indicating that TBS is particularly useful as an adjunct to BMD for fracture risk assessment in conditions associated with increased fracture risk, such as type-2 diabetes, chronic corticosteroid excess, and other conditions wherein BMD readings are often misleading. The interference of abdominal soft tissue thickness (STT) on TBS should also be considered when interpreting these findings because image noise can impact TBS evaluation. A new TBS software version based on an algorithm that accounts for STT rather than BMI seems to correct this technical limitation and is under development. In this paper, we review the current state of TBS, its technical aspects, and its evolving role in the assessment and management of several clinical conditions.

ABSTRACT Hypoparathyroidism, despite the conventional therapy with calcium and active vitamin D, can lead to skeletal and nonskeletal abnormalities. Chronic hypoparathyroidism is associated with a significant reduction in bone remodeling, increases in areal and volumetric bone density, and improvement in trabecular microarchitecture and in trabecular bone score. Regardless of these advantages in bone mass and microarchitecture, recent data suggest an increased vertebral fracture risk in patients with nonsurgical hypoparathyroidism. Moreover, chronic hypoparathyroidism can lead to abnormalities in multiple organ systems, including the neurological, cardiovascular, renal, neuropsychiatric, ocular, and immune systems. Nephrocalcinosis, nephrolithiasis, and renal insufficiency, as well as decreased quality of life and cataracts, are common in patients with hypoparathyroidism. An increased incidence of hospitalization due to infections and a greater risk of cardiovascular diseases are observed in patients with hypoparathyroidism, particularly in those with nonsurgical disease. All these abnormalities may be because of the disease itself or complications of therapy. We herein reviewed the skeletal and nonskeletal consequences of hypoparathyroidism in patients conventionally managed with calcium and active vitamin D.

Abstract Background Capnocytophaga canimorsus, a Gram-negative rod, belongs to the Flavobacteriaceae family and colonizes the oropharynx of dogs and cats. Infections with C. canimorsus are rare and can induce a systemic infection with a severe course of the disease. So far, only five case reports of C. canimorsus infections associated with Waterhouse–Friderichsen Syndrome (WFS) have been reported with only two of the patients having a history of splenectomy. Case presentation Here, we report a fatal case of WFS due to C. canimorsus bacteremia and mycetal superinfection in a 61-year-old female asplenic patient. Despite extensive therapy including mechanical ventilation, antibiotic coverage with meropenem, systemic corticosteroids medication, vasopressor therapy, continuous renal replacement therapy, therapeutic plasma exchange, multiple transfusions of blood products and implantation of a veno-arterial extracorporeal membrane oxygenation the patient died 10 days after a dog bite. The autopsy showed bilateral hemorrhagic necrosis of the adrenal cortex and septic embolism to heart, kidneys, and liver. Diagnosis of C. canimorsus was prolonged due to the fastidious growth of the bacteria. Conclusions The occurrence of a severe sepsis after dog bite should always urge the attending physician to consider C. canimorsus as the disease-causing pathogen. A therapeutic regimen covering C. canimorsus such as aminopenicillins or carbapenems should be chosen. However, despite maximum therapy, the prognosis of C. canimorsus-induced septic shock remains very poor. Asplenic or otherwise immunocompromised patients are at higher risk for a severe course of disease and should avoid exposure to dogs and cats and consider antibiotic prophylaxis after animal bite.

Water is an essential element that sustains life on this planet, yet it is threatened by human activities. With little attention paid to the waterfall as a source of a domestic water supply and a tourist spot for recreation, this study was designed to investigate one of the waterfalls in Iligan City, Philippines: Dodiongan Falls. The location of the study is a neighborhood of the city garbage dumpsite that due to an uncontrollable situation, releases dark-colored secretion from the treatment box as has been verified by the residents in the area; this posed a threat to their food security and livelihood. Assessing the physicochemical parameters, heavy metal concentration and Escherichia coli counts is very crucial in interpreting its water quality. All parameters such as the pH, alkalinity, turbidity, lead (Pb), mercury (Hg), and the E. Coli test were done following the standard procedures. The results revealed that the pH, alkalinity, turbidity, total lead (less than 0.01 mg/L) and total mercury concentration (less than 0.001 mg/L) at the three sites were in conformity with the guidelines of the World Health Organization and Philippine national water quality standards. However, the E. Coli count has increased downstream from 220 to 1,600 MPN per 100 ml, which exceeded the standard limit. With these findings, it is paramount that the creation of a management plan be initiated as soon as possible by the different governmental agencies in order to bring back the life of Dodiongan Falls.