The protozoan parasite Trichomonas gallinae causes adult and nestling mortality in a declining population of European Turtle Doves, Streptopelia turtur

Studies incorporating the ecology of clinical and sub-clinical disease in wild populations of conservation concern are rare. Here we examine sub-clinical infection by Trichomonas gallinae in a declining population of free-living European Turtle Doves and suggest caseous lesions cause mortality in adults and nestlings through subsequent starvation and/or suffocation. We found a 100% infection rate by T. gallinae in adult and nestling Turtle Doves (n = 25) and observed clinical signs in three adults and four nestlings (28%). Adults with clinical signs displayed no differences in any skeletal measures of size but had a mean 3·7% reduction in wing length, with no overlap compared to those without clinical signs. We also identified T. gallinae as the suggested cause of mortality in one Red-legged Partridge although disease presentation was different. A minimum of four strains of T. gallinae, characterized at the ITS/5·8S/ITS2 ribosomal region, were isolated from Turtle Doves. However, all birds with clinical signs (Turtle Doves and the Red-legged Partridge) carried a single strain of T. gallinae, suggesting that parasite spill over between Columbidae and Galliformes is a possibility that should be further investigated. Overall, we highlight the importance of monitoring populations for sub-clinical infection rather than just clinical disease

Extraction of Stride Events From Gait Accelerometry During Treadmill Walking

Objective: evaluating stride events can be valuable for understanding the changes in walking due to aging and neurological diseases. However, creating the time series necessary for this analysis can be cumbersome. In particular, finding heel contact and toe-off events which define the gait cycles accurately are difficult. Method: we proposed a method to extract stride cycle events from tri-axial accelerometry signals. We validated our method via data collected from 14 healthy controls, 10 participants with Parkinson's disease, and 11 participants with peripheral neuropathy. All participants walked at self-selected comfortable and reduced speeds on a computer-controlled treadmill. Gait accelerometry signals were captured via a tri-axial accelerometer positioned over the L3 segment of the lumbar spine. Motion capture data were also collected and served as the comparison method. Results: our analysis of the accelerometry data showed that the proposed methodology was able to accurately extract heel and toe-contact events from both feet. We used t-tests, analysis of variance (ANOVA) and mixed models to summarize results and make comparisons. Mean gait cycle intervals were the same as those derived from motion capture, and cycle-to-cycle variability measures were within 1.5%. Subject group differences could be similarly identified using measures with the two methods. Conclusions: a simple tri-axial accelerometer accompanied by a signal processing algorithm can be used to capture stride events. Clinical impact: the proposed algorithm enables the assessment of stride events during treadmill walking, and is the first step toward the assessment of stride events using tri-axial accelerometers in real-life settings

Results from the first multicenter, open-label, phase IIIb study investigating the combination of pertuzumab with subcutaneous trastuzumab and a taxane in patients with HER2-positive metastatic breast cancer (SAPPHIRE)

Introduction: The primary objective of this study was to assess the safety and tolerability of combination pertuzumab, subcutaneous trastuzumab (Herceptin), and investigator's choice of taxane chemotherapy in previously untreated patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. Efficacy was a secondary objective. Patients and Methods: This study was an open-label, non-randomized study of patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who had no previous systemic non-hormonal anti-cancer therapy for metastatic disease. The primary endpoints included adverse events (AE), serious AEs, and cardiac AEs. Secondary endpoints included overall response rate, progression-free survival, and overall survival. Patients were treated with pertuzumab and subcutaneous trastuzumab in 3-weekly cycles with taxane chemotherapy until disease progression, unacceptable toxicity, or withdrawal of consent and followed for a minimum of 24 months from initiation of study treatment. Results: Fifty patients were enrolled and included in the analysis. All patients experienced at least 1 AE, with diarrhea, fatigue, peripheral neuropathy, alopecia, rash, and nausea the most common. Three patients experienced at least 1 grade 3 event of suspected cardiac origin (cardiac failure, cardiomyopathy, hypertension). Six patients withdrew from therapy owing to AEs (cardiac failure, drug hypersensitivity, decreased left ventricular ejection fraction, syncope, and bullous dermatitis). Taxane chemotherapy comprised nab-paclitaxel (74.0% of patients), docetaxel (28.0%), or paclitaxel (4.0%). The overall response rate was 73.3% (95% confidence interval, 58.1%-85.4%), the median progression-free survival was 17.0 months (95% confidence interval, 12.5-31.2 months), and the median overall survival was not reached. Conclusions: Subcutaneous trastuzumab in this combination has an acceptable safety and tolerability profile, including cardiac safety profile. Safety and efficacy appear similar to previous studies of intravenous trastuzumab in this combination. This open-label, non-randomized study examined the safety and tolerability of combination pertuzumab, subcutaneous trastuzumab (Herceptin), and taxane chemotherapy in previously untreated patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. Fifty patients were assessed. The overall response rate was 73.3% (95% confidence interval, 58.1%-85.4%), and the median progression-free survival was 17.0 months (95% confidence interval, 12.5-31.2 months). This combination has an acceptable safety and tolerability profile

Trichomonad parasite infection in four species of Columbidae in the UK

Trichomonas gallinae is an emerging pathogen in wild birds, linked to recent declines in finch (Fringillidae) populations across Europe. Globally, the main hosts for this parasite are species of Columbidae (doves and pigeons); here we carry out the first investigation into the presence and incidence of Trichomonas in four species of Columbidae in the UK, through live sampling of wild-caught birds and subsequent PCR. We report the first knownUKcases of Trichomonas infection in 86% of European Turtle Doves Streptopelia turtur sampled, along with 86% of Eurasian Collared Doves Streptopelia decaocto, 47% of Woodpigeons Columba palumbus and 40% of Stock Doves Columba oenas. Birds were more likely to be infected if the farm provided supplementary food for gamebirds. We found three strains of T. gallinae and one strain clustering within the Trichomonas tenax clade, not previously associated with avian hosts in the UK. One T. gallinae strain was identical at the ITS/5.8S/ITS2 ribosomal region to that responsible for the finch trichomonosis epizootic. We highlight the importance of increasing our knowledge of the diversity and ecological implications of Trichomonas parasites in order further to understand the sub-clinical impacts of parasite infection

Predicting Response to Intravesical Bacillus Calmette-Guérin in High-Risk Nonmuscle-Invasive Bladder Cancer Using an Artificial Intelligence-Powered Pathology Assay:Development and Validation in an International 12-Center Cohort

Purpose:There are few markers to identify those likely to recur or progress after treatment with intravesical bacillus Calmette-Guérin (BCG). We developed and validated artificial intelligence (AI)-based histologic assays that extract interpretable features from transurethral resection of bladder tumor digitized pathology images to predict risk of recurrence, progression, development of BCG-unresponsive disease, and cystectomy.Materials and Methods:Pre-BCG resection-derived whole-slide images and clinical data were obtained for high-risk nonmuscle-invasive bladder cancer cases treated with BCG from 12 centers and were analyzed through a segmentation and feature extraction pipeline. Features associated with clinical outcomes were defined and tested on independent development and validation cohorts. Cases were classified into high or low risk for recurrence, progression, BCG-unresponsive disease, and cystectomy.Results:Nine hundred forty-four cases (development: 303, validation: 641, median follow-up: 36 months) representative of the intended use population were included (high-grade Ta: 34.1%, high-grade T1: 54.8%; carcinoma in situ only: 11.1%, any carcinoma in situ: 31.4%). In the validation cohort, "high recurrence risk"cases had inferior high-grade recurrence-free survival vs "low recurrence risk"cases (HR, 2.08, P &lt;.0001). "High progression risk"patients had poorer progression-free survival (HR, 3.87, P &lt;.001) and higher risk of cystectomy (HR, 3.35, P &lt;.001) than "low progression risk"patients. Cases harboring the BCG-unresponsive disease signature had a shorter time to development of BCG-unresponsive disease than cases without the signature (HR, 2.31, P &lt;.0001). AI assays provided predictive information beyond clinicopathologic factors.Conclusions:We developed and validated AI-based histologic assays that identify high-risk nonmuscle-invasive bladder cancer cases at higher risk of recurrence, progression, BCG-unresponsive disease, and cystectomy, potentially aiding clinical decision making.</p

Thrombosis, Bleeding, and the Observational Effect of Early Therapeutic Anticoagulation on Survival in Critically Ill Patients With COVID-19

BACKGROUND: Hypercoagulability may be a key mechanism of death in patients with coronavirus disease 2019 (COVID-19). OBJECTIVE: To evaluate the incidence of venous thromboembolism (VTE) and major bleeding in critically ill patients with COVID-19 and examine the observational effect of early therapeutic anticoagulation on survival. DESIGN: In a multicenter cohort study of 3239 critically ill adults with COVID-19, the incidence of VTE and major bleeding within 14 days after intensive care unit (ICU) admission was evaluated. A target trial emulation in which patients were categorized according to receipt or no receipt of therapeutic anticoagulation in the first 2 days of ICU admission was done to examine the observational effect of early therapeutic anticoagulation on survival. A Cox model with inverse probability weighting to adjust for confounding was used. SETTING: 67 hospitals in the United States. PARTICIPANTS: Adults with COVID-19 admitted to a participating ICU. MEASUREMENTS: Time to death, censored at hospital discharge, or date of last follow-up. RESULTS: Among the 3239 patients included, the median age was 61 years (interquartile range, 53 to 71 years), and 2088 (64.5%) were men. A total of 204 patients (6.3%) developed VTE, and 90 patients (2.8%) developed a major bleeding event. Independent predictors of VTE were male sex and higher D-dimer level on ICU admission. Among the 2809 patients included in the target trial emulation, 384 (11.9%) received early therapeutic anticoagulation. In the primary analysis, during a median follow-up of 27 days, patients who received early therapeutic anticoagulation had a similar risk for death as those who did not (hazard ratio, 1.12 [95% CI, 0.92 to 1.35]). LIMITATION: Observational design. CONCLUSION: Among critically ill adults with COVID-19, early therapeutic anticoagulation did not affect survival in the target trial emulation. PRIMARY FUNDING SOURCE: None

Modifying Ligand-Induced and Constitutive Signaling of the Human 5-HT4 Receptor

G protein–coupled receptors (GPCRs) signal through a limited number of G-protein pathways and play crucial roles in many biological processes. Studies of their in vivo functions have been hampered by the molecular and functional diversity of GPCRs and the paucity of ligands with specific signaling effects. To better compare the effects of activating different G-protein signaling pathways through ligand-induced or constitutive signaling, we developed a new series of RASSLs (receptors activated solely by synthetic ligands) that activate different G-protein signaling pathways. These RASSLs are based on the human 5-HT4b receptor, a GPCR with high constitutive Gs signaling and strong ligand-induced G-protein activation of the Gs and Gs/q pathways. The first receptor in this series, 5-HT4-D100A or Rs1 (RASSL serotonin 1), is not activated by its endogenous agonist, serotonin, but is selectively activated by the small synthetic molecules GR113808, GR125487, and RO110-0235. All agonists potently induced Gs signaling, but only a few (e.g., zacopride) also induced signaling via the Gq pathway. Zacopride-induced Gq signaling was enhanced by replacing the C-terminus of Rs1 with the C-terminus of the human 5-HT2C receptor. Additional point mutations (D66A and D66N) blocked constitutive Gs signaling and lowered ligand-induced Gq signaling. Replacing the third intracellular loop of Rs1 with that of human 5-HT1A conferred ligand-mediated Gi signaling. This Gi-coupled RASSL, Rs1.3, exhibited no measurable signaling to the Gs or Gq pathway. These findings show that the signaling repertoire of Rs1 can be expanded and controlled by receptor engineering and drug selection

Patient preferences for the delivery of cardiac rehabilitation

Objective: To elicit patients' preferences for cardiac rehabilitation(CR). Methods: A Discrete Choice Experiment was used to quantify patients' preferences for the delivery of CR. This survey-based method elicited the relative importance of different characteristics of a program. Results: 200 in-patients eligible to attend CR completed the survey. Over half of the patients strongly preferred a centre-based compared to a home-based program. Many but not all preferred a program starting within two rather than six weeks of discharge and exercise delivered in a group rather than individual setting, with exercise via the internet using telehealth strongly disliked. Some respondents preferred lifestyle information delivered one-to-one by a health professional, and there was an overall preference against delivery by smart phone Apps. Some preferred a program out of rather than within working hours and a shorter program (four weeks compared to eight weeks). Conclusions: This study provides further insight into patient preferences for a CR program. Although the strongest preferences were for centre-based programs with healthcare professionals facilitating exercise classes and one-on-one education, it is important to offer flexible delivery as one approach will not suit everyone

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Thrombosis, Bleeding, and the Observational Effect of Early Therapeutic Anticoagulation on Survival in Critically Ill Patients With COVID-19

This article is made available for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.Background: Hypercoagulability may be a key mechanism of death in patients with coronavirus disease 2019 (COVID-19). Objective: To evaluate the incidence of venous thromboembolism (VTE) and major bleeding in critically ill patients with COVID-19 and examine the observational effect of early therapeutic anticoagulation on survival. Design: In a multicenter cohort study of 3239 critically ill adults with COVID-19, the incidence of VTE and major bleeding within 14 days after intensive care unit (ICU) admission was evaluated. A target trial emulation in which patients were categorized according to receipt or no receipt of therapeutic anticoagulation in the first 2 days of ICU admission was done to examine the observational effect of early therapeutic anticoagulation on survival. A Cox model with inverse probability weighting to adjust for confounding was used. Setting: 67 hospitals in the United States. Participants: Adults with COVID-19 admitted to a participating ICU. Measurements: Time to death, censored at hospital discharge, or date of last follow-up. Results: Among the 3239 patients included, the median age was 61 years (interquartile range, 53 to 71 years), and 2088 (64.5%) were men. A total of 204 patients (6.3%) developed VTE, and 90 patients (2.8%) developed a major bleeding event. Independent predictors of VTE were male sex and higher D-dimer level on ICU admission. Among the 2809 patients included in the target trial emulation, 384 (11.9%) received early therapeutic anticoagulation. In the primary analysis, during a median follow-up of 27 days, patients who received early therapeutic anticoagulation had a similar risk for death as those who did not (hazard ratio, 1.12 [95% CI, 0.92 to 1.35]). Limitation: Observational design. Conclusion: Among critically ill adults with COVID-19, early therapeutic anticoagulation did not affect survival in the target trial emulation