Clofazimine-induced cutaneous hyperpigmentation as a source of stigma in the treatment of leprosy: A cross-sectional study.

OBJECTIVES: Cutaneous hyperpigmentation is one of the main adverse effects encountered in patients undergoing leprosy treatment with multidrug therapy (WHO-MDT). This adverse effect has been described as intolerable and capable of contributing to social stigma. The objectives of this study were to quantify the variation in skin colour induced by clofazimine during and after treatment and to assess the related stigma. METHODS: This observational cross-sectional study objectively measured skin colour in 51 patients by reading the individual typology angle (ITA°) with a spectrophotometer, followed by the application of the Stigma Scale of the Explanatory Model Interview Catalogue (EMIC). RESULTS: Skin hyperpigmentation was observed in 100% of the individuals. They showed more negative ITA° values in lesion areas than non-lesion areas, particularly in sun-exposed regions. Clofazimine-induced cutaneous hyperpigmentation was not homogeneous and seemed to follow the lesion locations. The mean EMIC score was 18.8 points. CONCLUSION: All patients presented skin hyperpigmentation caused by clofazimine, detectable through spectrophotometry. Hyperpigmentation strongly impacted the social domain, indicating the intersectionality of disease and skin colour stigma, contributing to the social isolation of these patients. Health authorities should consider the negative impact of clofazimine on treatment adherence.

Interactive euthanasia training program for the dairy industry: Implementation and perceived respondent knowledge change.

This study described the development of an interactive euthanasia training program and its potential to improve dairy workers' perceived euthanasia decision-making skills and awareness of timely euthanasia by using a survey instrument before and after the program. Training material encompassed euthanasia information over 2 production stages (calves and cows or heifers) and material was delivered on-farm in a case-scenario format (14 cases). During a 3-mo period, 30 different dairy farms were visited and 81 participants were enrolled in this study. Each participant was required to complete a survey pretraining, to complete the case studies from the production stage in which their job responsibility was more closely aligned with (estimated completion time of 1 h), and to complete a survey post-training. Surveys contained 8 statements regarding participants' perceived knowledge of euthanasia practices. The questions were answered on a 5-point scale: (1) strongly disagree, (2) disagree, (3) neither agree nor disagree, (4) agree, or (5) strongly agree. Multivariable mixed-effects logistic regression models were created for each question to investigate the effect of age, sex, dairy experience, farm size, role at the farm, race, previous experience with euthanasia, veterinarian degree, and production stage in the score change, defined by the presence or absence of an increase in the 5-point scale score. Upon completion of the training, respondents were more confident in identifying compromised animals (score change = 0.35), determining when an animal should be euthanized (score change = 0.64), and understanding the importance of timely euthanasia (score change = 0.26). Age and euthanasia experience were significantly associated with the respondents' perceived knowledge; suggesting that younger, less-experienced caretakers on-farm should be prioritized to receive training. The proposed interactive case-based euthanasia training program has proven to be valuable to dairy participants and veterinarians as it provides a means to improve dairy welfare.

Dairy workers' attitudes toward dairy cattle euthanasia.

Implementing timely and humane euthanasia in dairy farms remains a critical concern. One of the possible barriers for the implementation of timely euthanasia on-farm is dairy workers' attitudes toward the act. The objectives of this study were to investigate dairy workers' attitudes toward dairy cattle euthanasia and their association to individuals' demographic characteristics. A total of 81 workers from 30 dairy farms (ranging in size from less than 500 to more than 3,000 cows) participated in the survey and most participants were caretakers (n = 45; 55.6%) or farm managers (n = 16; 19.8%), with an average work experience of 14.8 years. Dairy workers' attitudes toward dairy cattle (empathy affect, empathy attribution, and negative attitudes about cattle), working environment (relying on others, perceived time constraints) and euthanasia decision-making (feeling comfortable with euthanasia, feeling confident, seeking knowledge, using different sources to obtain advice, having negative attitudes about euthanasia, having insufficient knowledge, having trouble deciding when to euthanize and avoiding if possible) were identified and used for cluster analyses. Cluster analyses identified 3 distinct clusters: (1) confident but uncomfortable with euthanasia (n = 40); (2) confident and comfortable with euthanasia (n = 32); and (3) unconfident, lacking knowledge and detached from cattle (n = 9). Dairy workers' demographic characteristics (age, sex, race and ethnicity, dairy experience, role on-farm, farm size, and previous euthanasia experience) were used as predictors for the risk factor analyses. The risk analysis demonstrated that there were no predictors for cluster 1, but White workers (P = 0.04) and caretakers that had previous euthanasia experience tended to be more likely to be members of cluster 2 (P = 0.07) whereas respondents that worked in farms with 501-1,000 cows were more likely to be grouped in cluster 3. This study provides vital information about variability in dairy workers' attitudes toward dairy euthanasia as well as its association with race and ethnicity, farm size, and previous euthanasia experience. This information can be used to implement appropriate training and euthanasia protocols to increase both human and dairy cattle welfare on-farm.

Can dogs help chickens? Pet owners' willingness to pay for animal welfare-friendly pet food in the United States.

Consumer concern about farmed animal welfare is growing but does not always translate into real-world purchasing behaviour of welfare-friendly animal products for human consumption. Possible reasons for this include unfamiliarity with farming practices and economic sensitivity. In contrast, the number and role of pets in the United States have grown measurably, and spending on pets is strong. The pet food market has many opportunity niches as pet owners navigate strong marketing trends and nutrition philosophies. We hypothesised that pet owners in the US would be willing to pay a premium for pet food containing welfare-friendly animal ingredients. Eight hundred and thirty-eight pet owners completed an online survey asking questions that measured their knowledge of and interest in farm animal welfare, and their willingness-to-pay for pet food labelled as farm animal welfare-friendly. Respondents overall displayed relatively low knowledge about farm animal welfare, but poor self-assessment of their own knowledge. They displayed interest in farm animal welfare and an overall positive mean willingness-to-pay (WTP) for welfare-friendly pet food. Younger respondents, women and cat owners displayed a higher WTP than older respondents, men and dog owners. Income level was not correlated to WTP. Creating pet food products that contain animal ingredients produced using welfare-friendly practices may enhance farm animal welfare via two primary avenues: by providing a sustainable and value-added outlet for the by-products of welfare-friendly human food products, and by providing an educational opportunity about farm animal production via pet food packaging and other advertising.

Creatine supplementation impairs airway inflammation in an experimental model of asthma involving P2 × 7 receptor.

Creatine (Cr) is a substrate for adenosine triphosphate synthesis, and it is the most used dietary supplement among professional and recreative athletes and sportsmen. Creatine supplementation may increase allergic airway response, but the cellular and molecular mechanisms are unknown. We used murine model of OVA-induced chronic asthma and showed that Cr supplementation increased total proteins, ATP level, lymphocytes, macrophages, and IL-5 levels in BALF, as well as IL-5 in the supernatant of re-stimulated mediastinal lymph nodes. IL-5 and IL-13 expression by epithelial cells and by peribronchial leukocytes were increased by Cr. Cr augmented the expression of P2 × 7 receptor by peribronchial leukocytes and by epithelial cells, and increased the accumulation of eosinophils in peribronchial space and of collagen fibers in airway wall. In human cells, while Cr induced a release of ATP, IL-6, and IL-8 from BEAS-2B cells, whole blood cells, such as eosinophils, and CD4+ T cells, P2 × 7 receptor inhibitor (A740003) reduced such effects, as denoted by reduced levels of ATP, IL-6, and IL-8. Therefore, Cr supplementation worsened asthma pathology due to activation of airway epithelial cells and peribronchial leukocytes, involving purinergic signaling.

Pharmacokinetics of transdermal flunixin in sows.

The objective of this study was to describe the pharmacokinetics (PK) of flunixin in 12 nonlactating sows following transdermal (TD) flunixin (3.33 mg/kg) and intravenous (IV; 2.20 mg/kg) flunixin meglumine (FM) administration using a crossover design with a 10-day washout period. Blood samples were collected postadministration from sows receiving IV FM (3, 6, 10, 20, 40 min and 1, 3, 6, 12, 16, 24, 36, and 48 hr) and from sows receiving TD flunixin (10, 20, 40 min and 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, and 72 hr). Liquid chromatography and mass spectrometry were used to determine plasma flunixin concentrations, and noncompartmental methods were used for PK analysis. The geometric mean ± SD area under the plasma concentration-time curve (AUC) following IV injection was 26,820.59 ± 9,033.88 and 511.83 ± 213.98 hr ng/ml for TD route. Mean initial plasma concentration (C0 ) was 26,279.70 ± 3,610.00 ng/ml, and peak concentration (Cmax ) was 14.61 ± 7.85 ng/ml for IV and TD administration, respectively. The percent mean bioavailability of TD flunixin was 1.55 ± 1.00. Our results demonstrate that topical administration is not an efficient route for delivering flunixin in mature sows.

Basophil-lineage commitment in acute promyelocytic leukemia predicts for severe bleeding after starting therapy.

Severe hemorrhagic events occur in a significant fraction of acute promyelocytic leukemia patients, either at presentation and/or early after starting therapy, leading to treatment failure and early deaths. However, identification of independent predictors for high-risk of severe bleeding at diagnosis, remains a challenge. Here, we investigated the immunophenotype of bone marrow leukemic cells from 109 newly diagnosed acute promyelocytic leukemia patients, particularly focusing on the identification of basophil-related features, and their potential association with severe bleeding episodes and patient overall survival.From all phenotypes investigated on leukemic cells, expression of the CD203c and/or CD22 basophil-associated markers showed the strongest association with the occurrence and severity of bleeding (p ≤ 0.007); moreover, aberrant expression of CD7, coexpression of CD34+/CD7+ and lack of CD71 was also more frequently found among patients with (mild and severe) bleeding at baseline and/or after starting treatment (p ≤ 0.009). Multivariate analysis showed that CD203c expression (hazard ratio: 26.4; p = 0.003) and older age (hazard ratio: 5.4; p = 0.03) were the best independent predictors for cumulative incidence of severe bleeding after starting therapy. In addition, CD203c expression on leukemic cells (hazard ratio: 4.4; p = 0.01), low fibrinogen levels (hazard ratio: 8.8; p = 0.001), older age (hazard ratio: 9.0; p = 0.002), and high leukocyte count (hazard ratio: 5.6; p = 0.02) were the most informative independent predictors for overall survival.In summary, our results show that the presence of basophil-associated phenotypic characteristics on leukemic cells from acute promyelocytic leukemia patients at diagnosis is a powerful independent predictor for severe bleeding and overall survival, which might contribute in the future to (early) risk-adapted therapy decisions.

Teaching Tip: The Development of an Interactive Computer-Based Training Program for Timely and Humane On-Farm Pig Euthanasia.

With extensive knowledge and training in the prevention, management, and treatment of disease conditions in animals, veterinarians play a critical role in ensuring good welfare on swine farms by training caretakers on the importance of timely euthanasia. To assist veterinarians and other industry professionals in training new and seasoned caretakers, an interactive computer-based training program was created. It consists of three modules, each containing five case studies, which cover three distinct production stages (breeding stock, piglets, and wean to grower-finisher pigs). Case study development was derived from five specific euthanasia criteria defined in the 2015 Common Swine Industry Audit, a nationally recognized auditing program used in the US. Case studies provide information regarding treatment history, clinical signs, and condition severity of the pig and prompt learners to make management decisions regarding pig treatment and care. Once a decision is made, feedback is provided so learners understand the appropriateness of their decision compared to current industry guidelines. In addition to training farm personnel, this program may also be a valuable resource if incorporated into veterinary, graduate, and continuing education curricula. This innovative tool represents the first interactive euthanasia-specific training program in the US swine industry and offers the potential to improve timely and humane on-farm pig euthanasia.

The N-glycosylation of immunoglobulin G as a novel biomarker of Parkinson's disease.

The use of the emerging "omics" technologies for large scale population screening is promising in terms of predictive, preventive and personalized medicine. For Parkinson's disease, it is essential that an accurate diagnosis is obtained and disease progression can be monitored. Immunoglobulin G (IgG) has the ability to exert both anti-inflammatory and pro-inflammatory effects, and the N-glycosylation of the fragment crystallizable portion of IgG is involved in this process. This study aimed to determine whether the IgG glycome could be a candidate biomarker for Parkinson's disease. Ninety-four community-based individuals with Parkinson's disease and a sex-, age- and ethnically-matched cohort of 102 individuals with mixed phenotypes, representative of a "normally" aged Caucasian controls, were investigated. Plasma IgG glycans were analyzed by ultra-performance liquid chromatography. Overall, seven glycan peaks and 11 derived traits had statistically significant differences (P < 8.06 × 10-4) between Parkinson's disease cases and healthy controls. Out of the seven significantly different glycan peaks, four were selected by Akaike's Information Criterion to be included in the logistic regression model, with a sensitivity of 87.2% and a specificity of 92.2%. The study suggested that there may be a reduced capacity for the IgG to inhibit Fcγ-RIIIa binding, which would allow an increased ability for the IgG to cause antibody-dependent cell cytotoxicity and a possible state of low-grade inflammation in individuals with Parkinson's disease.

A novel corporate-community partnership model provides safe housing for pets of domestic violence victims.

OBJECTIVE: To document and evaluate a novel partnership model of a safekeeping program for pets owned by domestic violence victims between May 1, 2021, and June 1, 2023. ANIMALS: 19 animals referred to the program. METHODS: Procedures for identification, intake, medical and behavioral needs, and shelter of pets belonging to domestic violence victims were established and cases reviewed over the program's initial 2 years. RESULTS: 13 dogs and 6 cats belonging to 13 owners were referred to the program. Seven dogs and 1 cat were placed into foster housing. Most pets were intact. One pet had medical concerns at intake (cardiac disease and seizures). Five pets were returned to their owners after an average stay of 5.3 weeks. Two pets were rehomed to new owners. CLINICAL RELEVANCE: Veterinarians are likely to encounter pets affected by domestic violence and may be mandatory reporters in some states. This paper will aid veterinarians and community partners to understand the challenges and pet types they are likely to encounter and how best to assist.

Presence of Extended-Spectrum Beta-Lactamase-Producing Escherichia coli in Food-Producing and Companion Animals and Wildlife on Small-Holder Farms of Floreana Island, Galápagos Islands.

Background: Antimicrobial resistance (AR) has led to increasing human and animal morbidity and mortality and negative consequences for the environment. AR among Escherichia coli (EC) is on the rise, with serious concerns about extended-spectrum ß-lactamase-producing E. coli (ESBL-EC). In the Galápagos Islands, where antimicrobials are available without a prescription, growing demands for food production can drive antimicrobial use. Food producing animals are at the interface of wildlife and environmental health on the smallest human-inhabited Galápagos Island, Floreana. We sought to determine if ESBL-EC were present in Floreana Island farm animal species and nearby wildlife and the relatedness of ESBL-EC isolates identified. Materials and Methods: During July 4-5, 2022, we visited 8 multispecies farms, representing 75% of food-producing animal production on Floreana, and collected 227 fecal samples from farm animals and wildlife. Each sample was plated on MacConkey agar supplemented with cefotaxime (4 µg/mL). Results: ESBL-EC was isolated from 20 (9%) fecal samples collected from pigs (N = 10), chickens (N = 6), wildlife (N = 3), and dog (N = 1). All ESBL-EC isolates were from samples taken at three (38%) of the eight farms. Fifteen (75%) of the ESBL-EC isolates were from a single farm. All ESBL-EC isolates were multidrug resistant. The most prevalent ESBL genes belonged to the blaCTX-M group. Among the typeable isolates from the farm with the largest proportion of ESBL-EC isolates (N = 14), we observed nine unique pulsed-field gel electrophoresis (PFGE) patterns, with identical patterns present across pig and chicken isolates. PFGE patterns in the three farms with ESBL-EC isolates were different. Conclusions: These results lend support for future routine AR monitoring activities at the livestock-wildlife interface in Galápagos to characterize potential interspecies transmission of AR bacteria and AR genes in this unique protected ecosystem, and the related human, animal, and environmental health impacts, and to formulate interventions to reduce AR spread in this setting.

Real-time and video-recorded pain assessment in beef cattle: clinical application and reliability in young, adult bulls undergoing surgical castration.

Bovine pain assessment relies on validated behavioral scales related to normal and pain-related behaviors. This study investigated the reliability and applicability of real-time and video-recorded pain assessment, and their agreement, in young, adult bulls undergoing surgical castration. Ten Nelore and nine Angus bulls underwent general anesthesia and surgical castration. Three-minute real-time observations and simultaneous videos were recorded at - 48 h (M0), before sedation, under fasting (M1), after surgery, 3 h after sternal recumbency (M2), after rescue analgesia (M3) and at 24 h (M4). Animals received morphine (after M2), dipyrone (after M3), and flunixin meglumine after surgical castration (M4). Two trained evaluators assessed real-time (n = 95) and video-recorded time-points (n = 95) using the Unesp-Botucatu Cattle Pain Scale (UCAPS). Both assessment methods inferred 'very good' reliability (≥ 0.81) with minimal bias, however, video-recorded assessment (4.33 ± 2.84) demonstrated slightly higher scores compared to real-time (3.08 ± 2.84). The results from this study suggest that UCAPS can be used in real-time or video-recorded to assess pain and guide analgesic therapy in cattle.

Efficacy of a novel cervical dislocation tool for humane euthanasia of broilers and broiler breeders.

Euthanasia is an essential task performed daily on commercial poultry farms around the world to safeguard animal welfare. Manual cervical dislocation (MCD) is the most common euthanasia method but can be challenging to perform given the physical strength required to implement this technique. Therefore, the objective of this study was to evaluate the efficacy of a novel cervical dislocation tool (NCDT) compared to MCD. A total of 60 Ross 308 chickens (6-wk old) and 60 Ross 706 parent stock breeders (21-wk old) were enrolled in the study. Birds were sexed, blocked by body weight, and allocated to 1 of 2 treatments: 1) MCD and 2) NCDT. Immediately following euthanasia application, insensibility, and death were monitored. Once death was confirmed, gross evaluation, radiograph, and macroscopic/microscopic scoring were performed. Both euthanasia methods were 100% effective in achieving insensibility followed by cardiac and respiratory arrest in both age groups. In 6-wk-old broilers, there were no differences in insensibility measures or location and severity of the dislocation site by treatment. The NCDT treatment group showed an increased frequency of fractures located at the tooth-like process that projects from the cranial aspect of the centrum of the axis (dens) but had no impact on bird insensibility. For parent stock, differences in nictitating membrane reflex (NMR) and laceration scores for birds euthanized with NCDT were found and likely associated with additional force exerted with the tool. The NCDT is a promising replacement for MCD and future work should address the development of free and accessible training materials for on-farm use.

Pharmacokinetics of flunixin meglumine in mature swine after intravenous, intramuscular and oral administration.

BACKGROUND: The purpose of this study was to determine intravenous (IV), intramuscular (IM) and oral (PO) FM PK in mature swine. Appropriate pain management for lameness in swine is a critical control point for veterinarians and producers, but science-based guidance on optimal housing, management and treatment of lameness is deficient. Six mature swine (121-168 kg) were administered an IV, IM, or PO dose of flunixin meglumine at a target dose of 2.2 mg/kg in a cross-over design with a 10 day washout period between treatments. Plasma samples collected up to 48 hours post-administration were analyzed by high pressure liquid chromatography and mass spectrometry (HPLC-MS) followed by non-compartmental pharmacokinetic analysis. RESULTS: No adverse effects were observed with flunixin meglumine administration for all routes. Flunixin meglumine was administered at an actual mean dose of 2.21 mg/kg (range: 2.05-2.48 mg/kg) IV, IM and PO. A mean peak plasma concentration (CMAX) for IM and PO administration was 3748 ng/ml (range: 2749-6004 ng/ml) and 946 ng/ml (range: 554-1593 ng/ml), respectively. TMAX was recorded at 1.00 hour (range: 0.50-2.00 hours) and 0.61 hours (range: 0.17-2.00 hours) after PO and IM administration. Half-life (T ½ λz) for IV, IM and PO administration was 6.29 hours (range: 4.84-8.34 hours), 7.49 hours (range: 5.55-12.98 hours) and 7.08 hours (range: 5.29-9.15 hours) respectively. In comparison, bioavailability (F) for PO administration was 22% (range: 11-44%) compared to IM F at 76% (range: 54-92%). CONCLUSIONS: The results of the present study suggest that FM oral administration is not the most effective administration route for mature swine when compared to IV and IM. Lower F and Cmax of PO-FM in comparison to IM-FM suggest that PO-FM is less likely to be an effective therapeutic administration route.

Assessing Livestock Production Practices on Small-Scale Multi-Species Farms Located on Floreana Island, Galápagos Islands.

Globally to date, established international standards for animal welfare, a priority of sustainable agriculture, have primarily focused on large-scale producers. However, across Latin America, including in Ecuador's Galápagos Islands, smallholder farms play a critical role in food safety and security. We assessed five basic animal welfare measures (feed and water access, shelter availability and housing systems, animal health management, animal behavior, and timely euthanasia) for poultry, pigs, and cattle on Floreana Island, Galápagos. Utilizing assessment standards from multiple US sources and international standards, we developed a questionnaire and used it to conduct in-depth interviews during 4-5 July 2022 with eight participating producers, representing 75% of animal agriculture on Floreana. While we identified opportunities to enhance competencies in animal health management and timely euthanasia, farms performed well in the other assessed measures. Future work should promote knowledge transfer and in-country capacity building in farm biosecurity, access to veterinary care, antimicrobial resistance surveillance, and euthanasia methods. Efforts to positively impact smallholder farm livelihoods in Galápagos-one of the most biodiverse and protected ecosystems on the planet-will sustainably support human health through the interconnected realms of animal health and welfare, wildlife and environmental health, and food safety and security.

Efficacy of inguinal buffered lidocaine and intranasal flunixin meglumine on mitigating physiological and behavioral responses to pain in castrated piglets.

Managing castration pain on US sow farms is hindered by the lack of Food and Drug Administration (FDA) approved products for mitigating pain. Previous work assessing flunixin meglumine (FM) efficacy in mitigating castration pain has shown the drug to be effective in pigs, meanwhile, results from previous work evaluating lidocaine efficacy are contradictory. Therefore, the objectives of this study were to determine the efficacy of inguinal buffered lidocaine (BL) and FM in mitigating castration pain in piglets. This study was divided into Part I (physiological response) and Part II (behavioral response). For part I piglets were randomly assigned to the following treatments: T1: (C) Castration plus physiological saline; T2: (S) Sham plus physiological saline; T3: (CL) Castration plus BL; T4: (SL) Sham plus BL; T5: (CF) Castration plus FM; T6: (SF) Sham plus FM; T7: (CLF) Castration plus BL and FM; T8: (SLF) Sham plus BL and FM. Blood was collected 24 h prior to castration, 1 h, and 24 h post castration for cortisol quantification. For Part II another cohort of piglets was enrolled and randomly assign to the following treatments: T1: (C) Castration plus physiological saline and T7: (CLF) Castration plus BL and FM. Behavior scoring was obtained in real-time by observing each piglet for 4-min continuously using Unesp-Botucatu pig acute pain scale (UPAPS) at the following timepoints: 1 h before castration (-1 h), immediately post-castration (0 h), and 3 h post-castration (+3 h). Average cortisol concentrations did not differ at -24 h (P > 0.05) or at 24 h post-castration (P > 0.05) between treatments. At 1 h post-castration, castrated piglets (C and CL) demonstrated greater cortisol concentrations (P < 0.05). Castrated piglets in the CF and CLF group had lower cortisol concentrations compared to C and CL-treated pigs (P < 0.05). For behavioral response, there were no differences between treatments on total UPAPS scores (C and CLF, P > 0.05). Intranasal FM was able to effectively reduce the physiological piglet's response immediately post-castration. Inguinal buffered lidocaine had no effect on the either physiological or behavioral response to pain. Long-term research should focus on refining injection techniques for inguinal BL and consider administration frequency and dosing of intranasal FM to control pain for a longer period post-castration.

Effects of assessment method (real-time versus video-recorded) on a validated pain-altered behavior scale used in castrated piglets.

We aimed to compare two assessment methodologies (real-time vs. video-recorded) using the Unesp-Botucatu Pig Composite Acute Pain Scale (UPAPS) in piglets before and after castration. Twenty-nine male piglets were castrated. Four observers scored the UPAPS over three perioperative timepoints of castration following two assessment methodologies. In real-time assessments, the observers were in-person observing the piglets in front of the pen. After two weeks, the observers did video-recorded assessments randomizing piglets and timepoints. Modeling was conducted to compare the UPAPS and each pain-altered behavior between methodologies. Intraclass correlation coefficient (ICC), Bland-Altman, and Lin's concordance correlation coefficient (CCC) were conducted to investigate agreement between methodologies. UPAPS was statistically equivalent between methodologies (P = 0.4371). The ICC for each method was very good (0.85 to 0.91). The agreement of the UPAPS assessed between methodologies had minimal bias (- 0.04), no proportion bias, and 53% of the assessments presented a perfect agreement. However, CCC of the UPAPS was moderate (0.65), and only one pain-altered behavior ("presents difficulty in overcoming obstacles or other animals") occurred more in real-time assessments (P = 0.0444). In conclusion, piglet pain assessment by UPAPS can be conducted in real-time based on a suitable agreement between the real-time and video-recorded assessment methods.

Simplified assessment of castration-induced pain in pigs using lower complexity algorithms.

Pigs are raised on a global scale for commercial or research purposes and often experience pain as a by product of management practices and procedures performed. Therefore, ensuring pain can be effectively identified and monitored in these settings is critical to ensure appropriate pig welfare. The Unesp-Botucatu Pig Composite Acute Pain Scale (UPAPS) was validated to diagnose pain in pre-weaned and weaned pigs using a combination of six behavioral items. To date, statistical weighting of supervised and unsupervised algorithms was not compared in ranking pain-altered behaviors in swine has not been performed. Therefore, the aim of this study was to verify if supervised and unsupervised algorithms with different levels of complexity can improve UPAPS pain diagnosis in pigs undergoing castration. The predictive capacity of the algorithms was evaluated by the area under the curve (AUC). Lower complexity algorithms containing fewer pain-altered behaviors had similar AUC (90.1-90.6) than algorithms containing five (89.18-91.24) and UPAPS (90.58). In conclusion, utilizing a short version of the UPAPS did not influence the predictive capacity of the scale, and therefore it may be easier to apply and be implemented consistently to monitor pain in commercial and experimental settings.

Gene therapy rescues cone function in congenital achromatopsia.

The successful restoration of visual function with recombinant adeno-associated virus (rAAV)-mediated gene replacement therapy in animals and humans with an inherited disease of the retinal pigment epithelium has ushered in a new era of retinal therapeutics. For many retinal disorders, however, targeting of therapeutic vectors to mutant rods and/or cones will be required. In this study, the primary cone photoreceptor disorder achromatopsia served as the ideal translational model to develop gene therapy directed to cone photoreceptors. We demonstrate that rAAV-mediated gene replacement therapy with different forms of the human red cone opsin promoter led to the restoration of cone function and day vision in two canine models of CNGB3 achromatopsia, a neuronal channelopathy that is the most common form of achromatopsia in man. The robustness and stability of the observed treatment effect was mutation independent, but promoter and age dependent. Subretinal administration of rAAV5-hCNGB3 with a long version of the red cone opsin promoter in younger animals led to a stable therapeutic effect for at least 33 months. Our results hold promise for future clinical trials of cone-directed gene therapy in achromatopsia and other cone-specific disorders.

Efficacy and Safety of Immunotherapy for Cervical Cancer-A Systematic Review of Clinical Trials.

PURPOSE: To systematically review the current body of evidence on the efficacy and safety of immunotherapy for cervical cancer (CC). MATERIAL AND METHODS: Medline, the Cochrane Central Register of Controlled Trials and Web of Science were searched for prospective trials assessing immunotherapy in CC patients in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Full-text articles in English and German reporting outcomes of survival, response rates or safety were eligible. RESULTS: Of 4655 screened studies, 51 were included (immune checkpoint inhibitors (ICI) n=20; therapeutic vaccines n = 25; adoptive cell transfer therapy n=9). Of these, one qualified as a phase III randomized controlled trial and demonstrated increased overall survival following treatment with pembrolizumab, chemotherapy and bevacizumab. A minority of studies included a control group (n = 7) or more than 50 patients (n = 15). Overall, response rates were low to moderate. No response to ICIs was seen in PD-L1 negative patients. However, few remarkable results were achieved in heavily pretreated patients. There were no safety concerns in any of the included studies. CONCLUSION: Strong evidence on the efficacy of strategies to treat recurrent or metastatic cervical cancer is currently limited to pembrolizumab in combination with chemotherapy and bevacizumab, which substantiates an urgent need for large confirmatory trials on alternative immunotherapies. Overall, there is sound evidence on the safety of immunotherapy in CC.