Human-animal interactions and machine-animal interactions in animals under human care: A summary of stakeholder and researcher perceptions and future directions.

Animals under human care are exposed to a potentially large range of both familiar and unfamiliar humans. Human-animal interactions vary across settings, and individuals, with the nature of the interaction being affected by a suite of different intrinsic and extrinsic factors. These interactions can be described as positive, negative or neutral. Across some industries, there has been a move towards the development of technologies to support or replace human interactions with animals. Whilst this has many benefits, there can also be challenges associated with increased technology use. A day-long Animal Welfare Research Network workshop was hosted at Harper Adams University, UK, with the aim of bringing together stakeholders and researchers (n = 38) from the companion, farm and zoo animal fields, to discuss benefits, challenges and limitations of human-animal interactions and machine-animal interactions for animals under human care and create a list of future research priorities. The workshop consisted of four talks from experts within these areas, followed by break-out room discussions. This work is the outcome of that workshop. The key recommendations are that approaches to advancing the scientific discipline of machine-animal interactions in animals under human care should focus on: (1) interdisciplinary collaboration; (2) development of validated methods; (3) incorporation of an animal-centred perspective; (4) a focus on promotion of positive animal welfare states (not just avoidance of negative states); and (5) an exploration of ways that machines can support a reduction in the exposure of animals to negative human-animal interactions to reduce negative, and increase positive, experiences for animals.

Learning curve of laparoscopic inguinal hernia repair: systematic review, meta-analysis, and meta-regression.

BACKGROUND: Laparoscopic inguinal hernia repair has a long learning curve. It can be a technically challenging procedure and initially presents an unfamiliar view of inguinal anatomy. The aim of this review was to evaluate published literature relating to the learning curve of laparoscopic inguinal hernia repair and identify the number of cases required for proficiency. The secondary aim was to compare outcomes between surgeons before and after this learning curve threshold had been attained. METHODS: A systematic literature search was conducted in databases of PubMed, Medline, Embase, Web of Science, and Cochrane Library, to identify studies that evaluated the learning curve of laparoscopic inguinal hernia repair. A meta-regression analysis was undertaken to identify the number of cases to achieve surgical proficiency, and a meta-analysis was performed to compare outcomes between cases that were undertaken during a surgeon's learning phase and experienced phase of the curve. RESULTS: Twenty-two studies were included in this review, with 19 studies included in the meta-regression analysis, and 11 studies included in the meta-analysis. Mixed-effects Poisson regression demonstrated that there was a non-linear trend in the number of cases required to achieve surgical proficiency, with a 2.7% year-on-year decrease. The predicted number of cases to achieve surgical proficiency in 2020 was 32.5 (p < 0.01). The meta-analysis determined that surgeons in their learning phase may experience a higher rate of conversions to open (OR 4.43, 95% CI 1.65, 11.88), postoperative complications (OR 1.61, 95% CI 1.07, 2.42), and recurrences (OR 1.32, 95% CI 0.40, 4.30). CONCLUSION: Laparoscopic inguinal hernia repair has a well-defined learning curve. While learning surgeons demonstrated reasonable outcomes, supervision during this period may be appropriate given the increased risk of conversion to open surgery. These data may benefit learning surgeons in the skill development of minimally invasive inguinal hernia repairs.

Survivorship, complications and patient-reported outcomes in calcar-guided short-stem THA: prospective mid-term multicenter data of the first 879 hips.

INTRODUCTION: Short stems are a bone and soft-tissue preserving alternative to conventional stems. The aim of this multicenter study is to present the mid-term outcomes of a calcar-guided short stem. MATERIALS AND METHODS: This is a prospective case series of the first 879 total hip arthroplasties performed on 782 patients across 5 centers using identical calcar-guided short stems. In a mid-term follow-up (6 years), rates and reasons for complications and revisions were documented. The Harris Hip Score (HHS) was obtained; patients reported pain and satisfaction using a visual analog scale. RESULTS: A total of 43 patients died in the study cohort for non-related reasons; 26 patients (3.0%) required at least 1 revision after the index procedure. The survival rate for endpoint stem revision at mid-term was 98.4%. The main reasons for stem revision were aseptic loosening and early periprosthetic fractures. Sex had no influence on stem survival. Older patients or those with a high body mass index showed increased risk for stem revision during follow-up. Dorr type A morphology revealed a significantly lower risk of stem revision than Dorr type B or C (p = 0.0465). The HHS, satisfaction, and load pain at mid-term were 96.5 (SD 8.0), 9.7 (SD 0.9), and 0.5 (SD 1.9), respectively. CONCLUSIONS: This short stem produced highly satisfactory outcomes at mid-term, with 98.4% implant survival for any cause of stem revision and low complication rates. Long-term results are required to further evaluate these promising mid-term results.

Successful use of azithromycin for Escherichia coli-associated renal allograft malakoplakia: a report of two cases.

Malakoplakia is a chronic granulomatous disease associated with incomplete clearance of bacterial pathogens. A multimodal approach to therapy includes antimicrobials with intracellular activity, reduction in immunosuppression, and debulking of lesions. Azithromycin has an intracellular mechanism of action and enhanced Gram-negative activity compared to other macrolides. Despite some in vitro data to support its use, there are no clinical breakpoints or epidemiological cut-off values for most Enterobacterales from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) or the Clinical and Laboratory Standards Institute (CLSI). We present two cases, previously unreported, of Escherichia coli associated renal allograft malakoplakia successfully treated with azithromycin.

Long-Term Functional Patency and Cost-Effectiveness of Arteriovenous Fistula Creation under Regional Anesthesia: a Randomized Controlled Trial.

BACKGROUND: Regional anesthesia improves short-term blood flow through arteriovenous fistulas (AVFs). We previously demonstrated that, compared with local anesthesia, regional anesthesia improves primary AVF patency at 3 months. METHODS: To study the effects of regional versus local anesthesia on longer-term AVF patency, we performed an observer-blinded randomized controlled trial at three university hospitals in Glasgow, United Kingdom. We randomly assigned 126 patients undergoing primary radiocephalic or brachiocephalic AVF creation to receive regional anesthesia (brachial plexus block; 0.5% L-bupivacaine and 1.5% lidocaine with epinephrine) or local anesthesia (0.5% L-bupivacaine and 1% lidocaine). This report includes findings on primary, functional, and secondary patency at 12 months; reinterventions; and additional access procedures (primary outcome measures were previously reported). We analyzed data by intention to treat, and also performed cost-effectiveness analyses. RESULTS: At 12 months, we found higher primary patency among patients receiving regional versus local anesthesia (50 of 63 [79%] versus 37 of 63 [59%] patients; odds ratio [OR], 2.7; 95% confidence interval [95% CI], 1.6 to 3.8; P=0.02) as well as higher functional patency (43 of 63 [68%] versus 31 of 63 [49%] patients; OR, 2.1; 95% CI, 1.5 to 2.7; P=0.008). In 12 months, 21 revisional procedures, 53 new AVFs, and 50 temporary dialysis catheters were required. Regional anesthesia resulted in net savings of £195.10 (US$237.36) per patient at 1 year, and an incremental cost-effectiveness ratio of approximately £12,900 (US$15,694.20) per quality-adjusted life years over a 5-year time horizon. Results were robust after extensive sensitivity and scenario analyses. CONCLUSIONS: Compared with local anesthesia, regional anesthesia significantly improved both primary and functional AVF patency at 1 year and is cost-effective. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Local Anaesthesia versus Regional Block for Arteriovenous Fistulae, NCT01706354.

Pathophysiology of the right ventricle and of the pulmonary circulation in pulmonary hypertension: an update.

The function of the right ventricle determines the fate of patients with pulmonary hypertension. Since right heart failure is the consequence of increased afterload, a full physiological description of the cardiopulmonary unit consisting of both the right ventricle and pulmonary vascular system is required to interpret clinical data correctly. Here, we provide such a description of the unit and its components, including the functional interactions between the right ventricle and its load. This physiological description is used to provide a framework for the interpretation of right heart catheterisation data as well as imaging data of the right ventricle obtained by echocardiography or magnetic resonance imaging. Finally, an update is provided on the latest insights in the pathobiology of right ventricular failure, including key pathways of molecular adaptation of the pressure overloaded right ventricle. Based on these outcomes, future directions for research are proposed.

Effect of regional versus local anaesthesia on outcome after arteriovenous fistula creation: a randomised controlled trial.

BACKGROUND: Arteriovenous fistulae are the optimum form of vascular access in end-stage renal failure. However, they have a high early failure rate. Regional compared with local anaesthesia results in greater vasodilatation and increases short-term blood flow. This study investigated whether regional compared with local anaesthesia improved medium-term arteriovenous fistula patency. METHODS: This observer-blinded, randomised controlled trial was done at three university hospitals in Glasgow, UK. Adults undergoing primary radiocephalic or brachiocephalic arteriovenous fistula creation were randomly assigned (1:1; in blocks of eight) using a computer-generated allocation system to receive either local anaesthesia (0·5% L-bupivacaine and 1% lidocaine injected subcutaneously) or regional (brachial plexus block [BPB]) anaesthesia (0·5% L-bupivacaine and 1·5% lidocaine with epinephrine). Patients were excluded if they were coagulopathic, had no suitable vessels, or had a previous failed ipsilateral fistula. The primary endpoint was arteriovenous fistula patency at 3 months. We analysed the data on an intention-to-treat basis. This study was registered with ClinicalTrials.gov (NCT01706354) and is complete. FINDINGS: Between Feb 6, 2013, and Dec 4, 2015, 163 patients were assessed for eligibility and 126 patients were randomly assigned to local anaesthesia (n=63) or BPB (n=63). All patients completed follow-up on an intention-to-treat basis. Primary patency at 3 months was higher in the BPB group than the local anaesthesia group (53 [84%] of 63 patients vs 39 [62%] of 63; odds ratio [OR] 3·3 [95% CI 1·4-7·6], p=0·005) and was greater in radiocephalic fistulae (20 [77%] of 26 patients vs 12 [48%] of 25; OR 3·6 [1·4-3·6], p=0·03). There were no significant adverse events related to the procedure. INTERPRETATION: Compared with local anaesthesia, BPB significantly improved 3 month primary patency rates for arteriovenous fistulae. FUNDING: Regional Anaesthesia UK, Darlinda's Charity for Renal Research.

Interoperator and intraoperator variability of whole blood coagulation assays: a comparison of thromboelastography and rotational thromboelastometry.

OBJECTIVES: Near-patient viscoelastic tests have proved useful in decreasing blood and blood product use in cardiac surgery. Two different analyzers are available, TEG and ROTEM. Many different individuals operate these devices, which raises concern that this factor may significantly affect results. The present study sought to objectively assess variability in results between operators. DESIGN: Prospective study. SETTING: Regional cardiac center. PARTICIPANTS: Adult patients undergoing elective cardiac surgery. INTERVENTIONS: Thirty-six mL of blood were taken from each of 21 patients. TEG kaolin and functional fibrinogen (FF) analyses and the equivalent ROTEM INTEM S and FIBTEM S analyses were performed. Six operators performed one of each test per patient to assess interoperator variability. One further operator performed 6 of each test per patient to assess intraoperator variability. MEASUREMENTS AND MAIN RESULTS: All routine measurement parameters were noted and the coefficient of variation (CV) calculated, analyzing comparable parameters. All inter-operator CVs were significantly lower for ROTEM analyses compared with TEG. CV for INTEM S CT/ kaolin r time was 4.7 versus 16.3 and MCF/MA was 2.6 versus 4.3 (p < 0.01). Similarly, FIBTEM S MCF/ FF MA was 8.3 versus 12.2. All intraoperator CVs were significantly lower for ROTEM analyses compared with TEG (p<0.01). CV for INTEM S CT/kaolin r time was 3.1 versus 9.8 and MCF/ MA was 1.6 versus 4. Similarly, FIBTEM S MCF/ MA was 6.9 versus 12.1. CONCLUSIONS: This series of results suggested ROTEM analyses are more reproducible than TEG and, consequently, that ROTEM may be better suited for use in a multiuser environment.

Molecular glues and induced proximity: An evolution of tools and discovery.

Small molecule molecular glues can nucleate protein complexes and rewire interactomes. Molecular glues are widely used as probes for understanding functional proximity at a systems level, and the potential to instigate event-driven pharmacology has motivated their application as therapeutics. Despite advantages such as cell permeability and the potential for low off-target activity, glues are still rare when compared to canonical inhibitors in therapeutic development. Their often simple structure and specific ability to reshape protein-protein interactions pose several challenges for widespread, designer applications. Molecular glue discovery and design campaigns can find inspiration from the fields of synthetic biology and biophysics to mine chemical libraries for glue-like molecules.

From bench to bedside: 64Cu/177Lu 1C1m-Fc anti TEM-1: mice-to-human dosimetry extrapolations for future theranostic applications.

The development of diagnostic and therapeutic radiopharmaceuticals is an hot topic in nuclear medicine. Several radiolabeled antibodies are under development necessitating both biokinetic and dosimetry extrapolations for effective human translation. The validation of different animal-to-human dosimetry extrapolation methods still is an open issue. This study reports the mice-to-human dosimetry extrapolation of 64Cu/177Lu 1C1m-Fc anti-TEM-1 for theranostic application in soft-tissue sarcomas. We adopt four methods; direct mice-to-human extrapolation (M1); dosimetry extrapolation considering a relative mass scaling factor (M2), application of a metabolic scaling factor (M3) and combination of M2 and M3 (M4). Predicted in-human dosimetry for the [64Cu]Cu-1C1m-Fc resulted in an effective dose of 0.05 mSv/MBq. Absorbed dose (AD) extrapolation for the [177Lu]Lu-1C1m-Fc indicated that the AD of 2 Gy and 4 Gy to the red-marrow and total-body can be reached with 5-10 GBq and 25-30 GBq of therapeutic activity administration respectively depending on applied dosimetry method. Dosimetry extrapolation methods provided significantly different absorbed doses in organs. Dosimetry properties for the [64Cu]Cu-1C1m-Fc are suitable for a diagnostic in-human use. The therapeutic application of [177Lu]Lu-1C1m-Fc presents challenges and would benefit from further assessments in animals' models such as dogs before moving into the clinic.

The pathophysiology and clinical presentation of cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is defined as the deposition of amyloid ß peptide within leptomeningial and cortical vessels, likely reflecting an imbalance between Aß production and clearance. Amyloid buildup triggers a series of destructive alterations in the cerebral vascular architecture, leading to a spectrum of neurological events including lobar intracerebral hemorrhage, brain ischemia and cognitive decline. Although traditionally diagnosed pathologically, neuroimaging has taken a central role in defining CAA. This review will discuss the pathological, clinical and radiological aspects of CAA.

Outcome of modified Kidner procedure with subtalar arthroereisis for painful accessory navicular associated with planovalgus deformity.

BACKGROUND: Type II accessory naviculars are frequently associated with planovalgus deformity. Operative treatment for patients recalcitrant to nonoperative treatment involves resection, with or without takedown, and reattachment of the tibialis posterior tendon as described by Kidner. This does not address the planovalgus deformity. The authors hypothesized that adding a subtalar arthroereisis to the Kidner procedure would lead to improvement of pain and function and correction of the deformity. METHODS: Institutional Review Board-approved, prospectively collected data were reviewed for 20 patients (23 feet), who underwent a combined modified Kidner and subtalar arthroereisis for painful type II accessory navicular with planovalgus deformity recalcitrant to nonoperative treatment. The average age at the time of surgery was 18 years. Patients were evaluated preoperatively and at final follow-up clinically, radiographically, and via the visual analog pain scale (VAPS), the American Orthopaedic Foot and Ankle Society (AOFAS) ankle hindfoot score, and a satisfaction rating. Mean follow-up was 53.9 months. RESULTS: The mean AOFAS scores improved from 53 preoperatively to 95 at final follow-up and the mean VAPS score decreased from 7.4 preoperatively to 1.7 at final follow-up. Radiographically, the average Meary's angle improved from 18.5° apex plantar preoperatively to 3° apex plantar on weight-bearing lateral radiographs, and the average talar head uncoverage percentage on weight-bearing anteroposterior radiographs improved from 24% preoperatively to 3%. Nineteen of 20 patients reported good or excellent results. Three patients required implant removal because of pain; no recurrence of planovalgus deformity occurred after implant removal. No patients developed subtalar arthritis. CONCLUSION: The modified Kidner procedure combined with a subtalar arthroereisis resulted in significant pain and functional improvement. The deformity correction obtained at surgery was maintained even if the arthroereisis plug was removed. The extra-articular plug did not lead to subtalar arthritis.

Assessing the Accuracy of Leg Mounted Sensors for Recording Dairy Cow Behavioural Activity at Pasture, in Cubicle Housing and a Straw Yard.

The accuracy of CowAlert IceQube sensors (IceRobotics Ltd., Edinburgh, UK) for recording lying duration, standing and lying transitions and number of steps when dairy cows where at pasture, in cubicle housing and in a straw yard, was investigated. Holstein Friesian cows at Harper Adams University, UK were fitted with IceQube sensors; one on the back left (BL) leg and one on the front left (FL) leg. Cows at pasture (n = 48), in cubicle housing (n = 46) and in a straw yard (n = 45) were visually observed. Data were analysed in two stages: (1) an initial exploratory phase determined the correlation level between sensor measurements andvisual observations. Subsequently, (2) a mixed effects modelling framework was used to check whether sensors provide significantly different measures of cow's activities compared to the observations. Results indicate that lying and standing times are similar between the observed and recorded times, in all three locations. In terms of sensor placement, significant differences were found between the number of steps recorded between BL and FL on straw and pasture, but all other activities were similar, in each location. The accuracy of CowAlert IceQube sensors on the BL leg gives them the potential to be used as lifelong sensors.

Risk of intracranial haemorrhage and ischaemic stroke after convexity subarachnoid haemorrhage in cerebral amyloid angiopathy: international individual patient data pooled analysis.

OBJECTIVE: To investigate the frequency, time-course and predictors of intracerebral haemorrhage (ICH), recurrent convexity subarachnoid haemorrhage (cSAH), and ischemic stroke after cSAH associated with cerebral amyloid angiopathy (CAA). METHODS: We performed a systematic review and international individual patient-data pooled analysis in patients with cSAH associated with probable or possible CAA diagnosed on baseline MRI using the modified Boston criteria. We used Cox proportional hazards models with a frailty term to account for between-cohort differences. RESULTS: We included 190 patients (mean age 74.5 years; 45.3% female) from 13 centers with 385 patient-years of follow-up (median 1.4 years). The risks of each outcome (per patient-year) were: ICH 13.2% (95% CI 9.9-17.4); recurrent cSAH 11.1% (95% CI 7.9-15.2); combined ICH, cSAH, or both 21.4% (95% CI 16.7-26.9), ischemic stroke 5.1% (95% CI 3.1-8) and death 8.3% (95% CI 5.6-11.8). In multivariable models, there is evidence that patients with probable CAA (compared to possible CAA) had a higher risk of ICH (HR 8.45, 95% CI 1.13-75.5, p = 0.02) and cSAH (HR 3.66, 95% CI 0.84-15.9, p = 0.08) but not ischemic stroke (HR 0.56, 95% CI 0.17-1.82, p = 0.33) or mortality (HR 0.54, 95% CI 0.16-1.78, p = 0.31). CONCLUSIONS: Patients with cSAH associated with probable or possible CAA have high risk of future ICH and recurrent cSAH. Convexity SAH associated with probable (vs possible) CAA is associated with increased risk of ICH, and cSAH but not ischemic stroke. Our data provide precise risk estimates for key vascular events after cSAH associated with CAA which can inform management decisions.

Mobile technology and delegated work in specialist community services: the EnComPaSS Integration project.

OBJECTIVES: The current UK healthcare workforce crisis is particularly severe in community services. A key limitation with traditional service-delivery models is the reliance on practitioners with levels of training and experience to enable them to operate independently. This paper describes a real-world evaluation of the implementation of digital health technology designed to provide remote, real-time support and task delegation in community palliative care services. It explores the ability of technology to support sustainable community workforce models and reports on key indicators of quality and efficiency. METHODS: The study was a mixed-methods, theory-driven evaluation, incorporating interviews, observations and analysis of routine data. The focus of this paper is the reporting of findings from pre-post implementation comparison and interrupted time series analysis. Data include community hospice service visits, hospital use by hospice patients and patient reported experiences. RESULTS: The digital health intervention allowed the service to include a more junior workforce (p<0.001, Cramer's V=0.241), requiring fewer joint visits (p<0.001, Cramer's V=0.087). No negative changes in hospitalisation were observed and patient reported experiences improved (p=0.023). Changes in hospital non-emergency bed days were inconclusive. However, emergency department admissions reduced significantly (-76.9 /month at 17 months, p=0.001). The cost per hour for visits reduced from £16.71 to £16.23 and annual savings of £135 153 are estimated for reduced emergency admissions. CONCLUSIONS: The evaluation demonstrates the value of digital innovation to support programmes of service redesign and begin to address the healthcare workforce crisis, while having a positive economic effect and indicating an improvement to patient experiences.

Impact of DOTA Conjugation on Pharmacokinetics and Immunoreactivity of [177Lu]Lu-1C1m-Fc, an Anti TEM-1 Fusion Protein Antibody in a TEM-1 Positive Tumor Mouse Model.

1C1m-Fc, an anti-tumor endothelial marker 1 (TEM-1) scFv-Fc fusion protein antibody, was previously successfully radiolabeled with 177Lu. TEM-1 specific tumor uptake was observed together with a non-saturation dependent liver uptake that could be related to the number of dodecane tetraacetic acid (DOTA) chelator per 1C1m-Fc. The objective of this study was to verify this hypothesis and to find the best DOTA per 1C1m-Fc ratio for theranostic applications. 1C1m-Fc was conjugated with six concentrations of DOTA. High-pressure liquid chromatography, mass spectrometry, immunoreactivity assessment, and biodistribution studies in mice bearing TEM-1 positive tumors were performed. A multi-compartment pharmacokinetic model was used to fit the data and a global pharmacokinetic model was developed to illustrate the effect of liver capture and immunoreactivity loss. Organ absorbed doses in mice were calculated from biodistribution results. A loss of immunoreactivity was observed with the highest DOTA per 1C1m-Fc ratio. Except for the spleen and bone, an increase of DOTA per 1C1m-Fc ratio resulted in an increase of liver uptake and absorbed dose and a decrease of uptake in tumor and other tissues. Pharmacokinetic models correlated these results. The number of DOTA per antibody played a determining role in tumor targeting. One DOTA per 1C1m-Fc gave the best pharmacokinetic behavior for a future translation of [177Lu]Lu-1C1m-Fc in patients.

Copper-64-Labeled 1C1m-Fc, a New Tool for TEM-1 PET Imaging and Prediction of Lutetium-177-Labeled 1C1m-Fc Therapy Efficacy and Safety.

1C1m-Fc, a promising anti-TEM-1 DOTA conjugate, was labeled with 64Cu to target cancer cells for PET imaging and predicting the efficacy and safety of a previously studied [177Lu]Lu-1C1m-Fc companion therapy. DOTA-conjugated 1C1m-Fc was characterized by mass spectrometry, thin layer chromatography and immunoreactivity assessment. PET/CT and biodistribution studies were performed in human neuroblastoma xenografted mice. Absorbed doses were assessed from biodistribution results and extrapolated to 177Lu based on the [64Cu]Cu-1C1m-Fc data. The immunoreactivity was ≥ 70% after 48 h of incubation in serum, and the specificity of [64Cu]Cu-1C1m-Fc for the target was validated. High-resolution PET/CT images were obtained, with the best tumor-to-organ ratios reached at 24 or 48 h and correlated with results of the biodistribution study. Healthy organs receiving the highest doses were the liver, the kidneys and the uterus. [64Cu]Cu-1C1m-Fc could be of interest to give an indication of 177Lu dosimetry for parenchymal organs. In the uterus and the tumor, characterized by specific TEM-1 expression, the 177Lu-extrapolated absorbed doses are overestimated because of the lack of later measurement time points. Nevertheless, 1C1m-Fc radiolabeled with 64Cu for imaging would appear as an interesting radionuclide companion for therapeutic application with [177Lu]Lu-1C1m-Fc.