Epidemiological and clinicopathological findings of feline immunodeficiency virus and feline leukemia virus infections in domestic cats from the Brazilian semiarid region.

Feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV) are retroviruses of great importance for domestic cats with a worldwide distribution. A retrospective study was conducted to determine the epidemiological and clinicopathological aspects of the infection by FIV and FeLV in cats from the Brazilian semiarid region. Cats treated between 2011 and 2021 at the teaching veterinary hospital of the Federal Rural University of the Semi-Arid Region that were submitted to a point-of-care (POC) test to detect anti-FIV IgG antibodies and FeLV antigen were enrolled in the study. Overall, 454 cats were selected, of which 30.2% [95% CI = 26.0% - 34.3%] were FIV-positive, 1.1% [95% CI = 0.9% - 1.2%] were FeLV-positive, and 0.7% [95% CI = 0.1% - 1.3%] were coinfected by both retroviruses. No statistical association was found between the studied retroviruses (P = 0.144). Multivariable analysis detected significant associations between FIV infection and male sex [OR = 5.7, 95% CI = 3.0-10.7, P < 0.0001), age between 19 and 78 months [OR = 5.2, 95% CI = 2.2-12.1, P < 0.0001], age greater than 78 months [OR = 12.8, 95% CI = 5.1-31.9, P < 0.0001], crossbreed [OR = 4.1, 95% CI = 1.2-13.4, P = 0.021], the presence of oral disease [OR = 2.1, 95% CI = 1.3-3.4, P = 0.004], reduced red blood cell (RBC) count [OR = 3.7, 95% CI = 1.9-7.2, P < 0.0001], and an albumin:globulin (A:G) ratio lower than 0.6 [OR = 3.4, 95% CI = 1.6-7.1, P = 0.001]. No statistical analyses were performed for FeLV infection due to the low number of positive animals. In the quantitative analyses of hematological parameters, FIV-positive cats presented lower values for RBC, hemoglobin, hematocrit, lymphocytes, and platelets compared to the negative animals. In the biochemical profile, cats infected with FIV showed higher creatinine, urea, total protein, and globulin values, while lower values for albumin and A:G ratio were observed (P < 0.05). The findings of this study characterized the prevalence, clinicopathological findings, and risk factors associated with FIV and FeLV in cats from the Brazilian semiarid region. They may help support veterinary practitioners in diagnosing feline retroviruses. The FIV prevalence observed is among the highest reported in Brazil, demonstrating the need for prevention and control strategies for this retrovirus.

Distribution, seroprevalence and risk factors for bovine brucellosis in Brazil: Official data, systematic review and meta-analysis.

Bovine brucellosis is an endemic disease in Brazil, and evidence-based assessments of the available literature on its seroprevalence and risk factors are limited. The aim of this study was to systematically review and summarize studies related to seroprevalence and risk factors of bovine brucellosis in the entire Brazil, in addition to comparing published data with the most recent official reports. Articles available in scientific databases and published between October 2006 and October 2021 were evaluated. Forty-five publications were included in the meta-analysis on the seroprevalence of brucellosis and 29 publications in the review on risk factors. The largest number of publications was found for the State of Mato Grosso do Sul (n=4), and the highest and lowest seroprevalences were observed in Acre (11%; 95% CI: 8.0-14.0%) and in the Federal District (0.4%; 95% CI: 0.2-0.7%). The main risk factors were the purchase of animals for breeding, vaccination, the number of heifers (female ≥2 years), the presence of calving paddocks and the occurrence of abortions. The need for new official studies has been suggested to determine the true prevalence of bovine brucellosis in Brazil, supported by the National Program for the Control and Eradication of Animal Brucellosis and Tuberculosis.

Atezolizumab, vemurafenib, and cobimetinib in patients with melanoma with CNS metastases (TRICOTEL): a multicentre, open-label, single-arm, phase 2 study.

BACKGROUND: Targeted therapy and immunotherapy have shown intracranial activity in melanoma with CNS metastases, but there remains an unmet need, particularly for patients with symptomatic CNS metastases. We aimed to evaluate atezolizumab in combination with cobimetinib or vemurafenib plus cobimetinib in patients with melanoma with CNS metastases. METHODS: TRICOTEL was a multicentre, open-label, single-arm, phase 2 study done in two cohorts: a BRAFV600 wild-type cohort and a BRAFV600 mutation-positive cohort, recruited at 21 hospitals and oncology centres in Brazil, France, Germany, Hungary, Italy, Spain, and Switzerland. Eligible patients were aged 18 years or older with previously untreated metastatic melanoma, brain metastases of 5 mm or larger in at least one dimension, and an Eastern Cooperative Oncology Group performance status of 2 or less. Patients in the BRAFV600 wild-type cohort received intravenous atezolizumab (840 mg, days 1 and 15 of each 28-day cycle) plus oral cobimetinib (60 mg once daily, days 1-21). Patients in the BRAFV600 mutation-positive cohort received intravenous atezolizumab (840 mg, days 1 and 15 of each 28-day cycle) plus oral vemurafenib (720 mg twice daily) plus oral cobimetinib (60 mg once daily, days 1-21); atezolizumab was withheld in cycle 1. Treatment was continued until progression, toxicity, or death. The primary outcome was intracranial objective response rate confirmed by assessments at least 4 weeks apart, as assessed by independent review committee (IRC) using modified Response Evaluation Criteria in Solid Tumours version 1.1. Because of early closure of the BRAFV600 wild-type cohort, the primary endpoint of intracranial objective response rate by IRC assessment was not done in this cohort; intracranial objective response rate by investigator assessment was reported instead. Efficacy and safety were analysed in all patients who received at least one dose of study medication. This trial is closed to enrolment and is registered with ClinicalTrials.gov, NCT03625141. FINDINGS: Between Dec 13, 2018, and Dec 7, 2020, 65 patients were enrolled in the BRAFV600 mutation-positive cohort; the BRAFV600 wild-type cohort was closed early after enrolment of 15 patients. Median follow-up was 9·7 months (IQR 6·3-15·0) for the BRAFV600 mutation-positive cohort and 6·2 months (3·5-23·0) for the BRAFV600 wild-type cohort. Intracranial objective response rate was 42% (95% CI 29-54) by IRC assessment in the BRAFV600 mutation-positive cohort and 27% (95% CI 8-55) by investigator assessment in the BRAFV600 wild-type cohort. Treatment-related grade 3 or worse adverse events occurred in 41 (68%) of 60 patients who received atezolizumab plus vemurafenib plus cobimetinib in the BRAFV600 mutation-positive cohort, the most common of which were lipase increased (15 [25%] of 60 patients) and blood creatine phosphokinase increased (11 [18%]). Eight (53%) of 15 patients treated with atezolizumab plus cobimetinib in the BRAFV600 wild-type cohort had treatment-related grade 3 or worse adverse events, most commonly anaemia (two [13%]) and dermatitis acneiform (two [13%]). Treatment-related serious adverse events occurred in 14 (23%) of 60 patients who received triplet therapy in the BRAFV600 mutation-positive cohort and two (13%) of 15 in the BRAFV600 wild-type cohort. No treatment-related deaths occurred. INTERPRETATION: Atezolizumab plus vemurafenib and cobimetinib provided intracranial activity in patients with BRAFV600-mutated melanoma with CNS metastases. FUNDING: F Hoffmann-La Roche.

Strong Evidence of the Role of Donkeys in the Epidemiology of Leptospira spp. in Semiarid Conditions.

Donkeys (Equus asinus) are historically known for their close relationship to humanity, which raises the need to study zoonotic diseases that affect them. In this perspective, leptospirosis stands out as a disease with an economic and public health impact, and its occurrence is facilitated in times of higher rainfall indexes, especially in large urban centers. In view of the scarcity of information about leptospirosis in donkeys, the objective of this study was to detect the presence of Leptospira spp. and anti-leptospiral antibodies in donkeys rescued by a zoonosis center located in the Caatiga biome, Brazilian semiarid region. Overall, 30 donkeys of both sexes, aged between 4 months and 15 years, were used, from which 64 serum samples were collected and submitted to the microscopic agglutination test (MAT). In addition, 64 samples of urine, vaginal and preputial fluid, in duplicates, were subjected to the polymerase chain reaction (PCR) and microbiological. Sixteen (53.3%) animals tested positive in at least one diagnostic test, 12 (40%) of which were positive at MAT and seven (23.3%) in the molecular and bacteriological detection (urine, vaginal, and preputial fluid samples). This is the first report identifying donkeys infected with Leptospira spp. by molecular and bacteriological diagnosis in Brazil, and the first in the world to detect this agent in their genital fluids. The study also shows that donkeys are commonly exposed to leptospires in the Caatinga biome, and this constitutes a One Health-based concern, demonstrating the importance of broad studies where large numbers of humans and animals coexist when investigating zoonotic infections and when planning and implementing control measures for donkeys-associated leptospirosis.

Herd and animal level prevalences and risk factors for Neospora caninum infection in cattle in the state of Paraíba, northeastern Brazil.

Bovine neosporosis is a globally important disease, causing abortions and significant economic losses. In Brazil, studies on neosporosis in cattle are few and based on limited samples and/or from limited areas. We aimed to determine the herd and animal levels seroprevalence and associated factors for Neospora caninum infections in cattle from the state of Paraíba, Northeastern Brazil, using a planned sampling. Herds (n = 434) and cows aged ≥24 months (n = 1891) were randomly selected, and serum samples were tested with the immunofluorescence antibody test (IFAT) using as cut-off point the antibody titer 200. Herd-level and animal-level seroprevalences were 17.8% (95% CI = 14.3%-21.8%) and 18.1% (95% CI = 14.7%-22.1%), respectively. The factors associated with N. caninum infection were farm located in the Sertão mesoregion (Prevalence ratio [PR] = 2.37), mixed production (PR = 1.64), herd size of 34-111 animals (PR = 3.50) and herd size >111 animals (PR = 6.14). The results indicate high N. caninum circulation in the bovine population of the state of Paraíba, semiarid of Brazil, mainly in the Sertão mesoregion, where the highest apparent herd and animal-level prevalences of positive herds were identified. Control strategies should be adopted to mitigate the impact of disease on cattle production, as well as it's suggested the encouragement of conducting surveys in wildlife from Caatinga biome, mainly canids, to provide information on the importance of these animals on the epidemiology of bovine neosporosis.

Efficacy and Safety of Nivolumab Plus Ipilimumab vs Nivolumab Alone for Treatment of Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck: The Phase 2 CheckMate 714 Randomized Clinical Trial.

Importance: There remains an unmet need to improve clinical outcomes in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). Objective: To evaluate clinical benefit of first-line nivolumab plus ipilimumab vs nivolumab alone in patients with R/M SCCHN. Design, Setting, and Participants: The CheckMate 714, double-blind, phase 2 randomized clinical trial was conducted at 83 sites in 21 countries between October 20, 2016, and January 23, 2019. Eligible participants were aged 18 years or older and had platinum-refractory or platinum-eligible R/M SCCHN and no prior systemic therapy for R/M disease. Data were analyzed from October 20, 2016 (first patient, first visit), to March 8, 2019 (primary database lock), and April 6, 2020 (overall survival database lock). Interventions: Patients were randomized 2:1 to receive nivolumab (3 mg/kg intravenously [IV] every 2 weeks) plus ipilimumab (1 mg/kg IV every 6 weeks) or nivolumab (3 mg/kg IV every 2 weeks) plus placebo for up to 2 years or until disease progression, unacceptable toxic effects, or consent withdrawal. Main Outcomes and Measures: The primary end points were objective response rate (ORR) and duration of response between treatment arms by blinded independent central review in the population with platinum-refractory R/M SCCHN. Exploratory end points included safety. Results: Of 425 included patients, 241 (56.7%; median age, 59 [range, 24-82] years; 194 males [80.5%]) had platinum-refractory disease (nivolumab plus ipilimumab, n = 159; nivolumab, n = 82) and 184 (43.3%; median age, 62 [range, 33-88] years; 152 males [82.6%]) had platinum-eligible disease (nivolumab plus ipilimumab, n = 123; nivolumab, n = 61). At primary database lock, the ORR in the population with platinum-refractory disease was 13.2% (95% CI, 8.4%-19.5%) with nivolumab plus ipilimumab vs 18.3% (95% CI, 10.6%-28.4%) with nivolumab (odds ratio [OR], 0.68; 95.5% CI, 0.33-1.43; P = .29). Median duration of response for nivolumab plus ipilimumab was not reached (NR) (95% CI, 11.0 months to NR) vs 11.1 months (95% CI, 4.1 months to NR) for nivolumab. In the population with platinum-eligible disease, the ORR was 20.3% (95% CI, 13.6%-28.5%) with nivolumab plus ipilimumab vs 29.5% (95% CI, 18.5%-42.6%) with nivolumab. The rates of grade 3 or 4 treatment-related adverse events with nivolumab plus ipilimumab vs nivolumab were 15.8% (25 of 158) vs 14.6% (12 of 82) in the population with platinum-refractory disease and 24.6% (30 of 122) vs 13.1% (8 of 61) in the population with platinum-eligible disease. Conclusions and Relevance: The CheckMate 714 randomized clinical trial did not meet its primary end point of ORR benefit with first-line nivolumab plus ipilimumab vs nivolumab alone in platinum-refractory R/M SCCHN. Nivolumab plus ipilimumab was associated with an acceptable safety profile. Research to identify patient subpopulations in R/M SCCHN that would benefit from nivolumab plus ipilimumab over nivolumab monotherapy is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT02823574.

Clinical, histopathological, and molecular findings for Mycobacterium avium subspecies paratuberculosis (MAP) in dairy goats under semiarid conditions.

The objective of this study was to report the occurrence of Mycobacterium avium subspecies paratuberculosis (MAP) in dairy goats, via description of their clinical presentation, histopathological findings, and molecular identification of the infectious agent. Screening was performed using IS900 real-time PCR (qPCR) in milk samples from 179 properties in the semiarid of Northeast region of Brazil. Pooled milk samples from all lactating goats from processing plants were submitted to molecular diagnosis. One property had a positive result at qPCR. The production unit which had the positive sample for MAP was located, and an on-site visit to this property was performed to collect individual milk samples, seven of which tested MAP positive by IS900 qPCR. With permission from the owner, two goats (Animal 1 was positive and Animal 2 was negative on first qPCR for MAP) were acquired and euthanized. Animals 1 and 2 had milk and portions of the duodenum, ileum, colon, and mesenteric lymph nodes positive at qPCR for MAP. Animal 1 also had MAP DNA detected in part of the jejunum and cecum. In animal 2, the ileocecal valve tested positive. MAP was not detected in the blood or feces of either animal; however; it was confirmed for the association of clinical findings, histopathology, and qPCR. The gene IS900 from the positive samples were sequenced and showed a 99% similarity with MAP. The MAP was identified for the first time in the goat milk and tissues in the semiarid region of Northeast Brazil.

Factors associated with small ruminant lentivirus infection in goat herds from Pernambuco state, Northeast region of Brazil.

Serum samples (n = 1532) were collected between May 2011 to April 2012 from goats from 76 herds (49 from dairy farms and 27 herds for genetic improvement) from three geographical regions from the state of Pernambuco, Brazil: Zona da Mata, Agreste, and Sertão. Samples were processed using agar gel immunodiffusion test, with p28 CAEV antigen. The objective was to determine the risk factors for small ruminant lentivirus (SRLV) in dairy goats and goats with high genetic value. Overall, seroprevalence was 13.7% (210/1532) [95% CI: 12-15.4%] in animals and 67.1% (51/76) [95% CI: 56.5%- 77.7%] in herds. In dairy farms the seroprevalence was 73.5% (36/49) [95% CI: 61.1%- 85.8%], and in properties with animals of high genetic value it was 55.6% (15/27) [95% CI: 36.8%- 74.3%]. Robust Poisson regression analysis adjusted by the random effect of the herd showed that risk factors were: importing bucks from another Brazilian state (prevalence ratio [PR] = 4.73 [95% CI: 2.05; 10.88]), not isolating sick animals (PR = 3.27 [95% CI: 2.24; 4.76]), and participating in fairs/animal crowding (PR = 1.52 [95% CI: 1.09; 2.11]). Prevalence results show that SRLV is present in caprine herds in the state of Pernambuco and identified risk factors are strongly related to animal transit. Considering the epidemiological situation, the first step for mitigating the consequences of this disease would be controlling animal transit.

Epidemiology of Leptospira sp. Infection: Current Status, Insights and Future Prospects.

In recent decades, the scientific community has been faced with an increased risk of emerging or re-emerging zoonotic diseases, such as leptospirosis, mainly originating from anthropic actions [...].

Detection of human Mastadenovirus C in wild guinea pigs (Cavia aperea aperea) feces.

The Adenoviridae family is composed by a high diversity of viruses that are extremely resistant in environment and are frequently excreted in animal reservoir feces for long periods. The knowledge of adenovirus (AdV) diversity among wild species may be important for the understanding of the epidemiology of putative emerging diseases. Cavia aperea aperea, commonly known as wild guinea pigs, wild cavies, or preas, are small herbivorous rodents widely distributed throughout South America and classified in Caviidae family, as well as domestic guinea pigs and capybaras. In order to investigate their potential role as reservoir of zoonotic agents, the present study aimed to verify the presence of AdV in fecal samples of 14 preas from Northeast Brazil. When submitted to nested PCR, two out of 14 samples (14.28%) were positive for AdV and classified as human Mastadenovirus C (HAdV-C) using DNA sequencing and phylogenetic analysis. Wild guinea pigs are synanthropic rodents that live in close contact with humans. The investigation of viral agents in rodents is important due to their potential role as reservoirs of human and animal pathogens. Moreover, the present work presents the first known evidence of HAdV in wild guinea pig stool samples, which may represent both the impact of anthropogenic pollution to wild animals and an important knowledge in terms of human health.

Detection of Leptospira spp. in genitourinary tract of female goats managed in the brazilian semiarid.

Studies related to the prevalence of leptospirosis in the semiarid region showed that even during long periods of drought, the disease has a remarkable frequency in herds in the region. It is a neglected disease and the extent of its effects in the Brazilian semiarid region is not known. The dynamics of this agent is well studied in the urinary tract, however, there are not many studies regarding the genital tract in female goats. Observing this scenario, the present work aimed to diagnose Leptospira spp. in female goats kept in the Brazilian semiarid region by means of serological, molecular and isolation techniques. Blood samples, vaginal fluid, urine and fragments of organs from the genitourinary tract were collected from 40 goats destined for slaughter. Microscopic agglutination test (MAT) was used as a serological technique, with a battery of 24 serovars. The Polymerase Chain Reaction (PCR) of the vaginal fluid, urine and organ fragments was performed, as well as the bacterial growth of these same products in a selective medium. Isolation positive samples were subjected to PCR. It was observed that two (5%) animals were serologically positive for the Pyrogenes serogroup. A total of 29 (72.5%) animals were PCR positive, with DNA present in 51/160 (31.8%) samples from the genital tract and 34/120 (28.3%) from the urinary tract, with no statistical difference. For bacterial growth, 22/40 (55%) animals were positive for growth, with morphology being observed in 19/160 (11.8%) for the genital tract and 16/120 (13.3%) for the urinary tract, with no statistical difference. Two uterus samples showed 99% similarity with L. interrogans after sequencing. Thus, female goats kept under semiarid conditions were positive for Leptospira spp, with positive samples from both the urinary and genital tracts, which possible is an alternative way of adapting and maintaining the agent for severe and adverse conditions.

Atezolizumab, vemurafenib, and cobimetinib in patients with melanoma with CNS metastases (TRICOTEL): a multicentre, open-label, single-arm, phase 2 study.

BACKGROUND: Targeted therapy and immunotherapy have shown intracranial activity in melanoma with CNS metastases, but there remains an unmet need, particularly for patients with symptomatic CNS metastases. We aimed to evaluate atezolizumab in combination with cobimetinib or vemurafenib plus cobimetinib in patients with melanoma with CNS metastases. METHODS: TRICOTEL was a multicentre, open-label, single-arm, phase 2 study done in two cohorts: a BRAFV600 wild-type cohort and a BRAFV600 mutation-positive cohort, recruited at 21 hospitals and oncology centres in Brazil, France, Germany, Hungary, Italy, Spain, and Switzerland. Eligible patients were aged 18 years or older with previously untreated metastatic melanoma, CNS metastases of 5 mm or larger in at least one dimension, and an Eastern Cooperative Oncology Group performance status of 2 or less. Patients in the BRAFV600 wild-type cohort received intravenous atezolizumab (840 mg, days 1 and 15 of each 28-day cycle) plus oral cobimetinib (60 mg once daily, days 1-21). Patients in the BRAFV600 mutation-positive cohort received intravenous atezolizumab (840 mg, days 1 and 15 of each 28-day cycle) plus oral vemurafenib (720 mg twice daily) plus oral cobimetinib (60 mg once daily, days 1-21); atezolizumab was withheld in cycle 1. Treatment was continued until progression, toxicity, or death. The primary outcome was intracranial objective response rate confirmed by assessments at least 4 weeks apart, as assessed by independent review committee (IRC) using modified Response Evaluation Criteria in Solid Tumours version 1.1. Because of early closure of the BRAFV600 wild-type cohort, the primary endpoint of intracranial objective response rate by IRC assessment was not done in this cohort; intracranial objective response rate by investigator assessment was reported instead. Efficacy and safety were analysed in all patients who received at least one dose of study medication. This trial is closed to enrolment and is registered with ClinicalTrials.gov, NCT03625141. FINDINGS: Between Dec 13, 2018, and Dec 7, 2020, 65 patients were enrolled in the BRAFV600 mutation-positive cohort; the BRAFV600 wild-type cohort was closed early after enrolment of 15 patients. Median follow-up was 9·7 months (IQR 6·3-15·0) for the BRAFV600 mutation-positive cohort and 6·2 months (3·5-23·0) for the BRAFV600 wild-type cohort. Intracranial objective response rate was 42% (95% CI 29-54) by IRC assessment in the BRAFV600 mutation-positive cohort and 27% (95% CI 8-55) by investigator assessment in the BRAFV600 wild-type cohort. Treatment-related grade 3 or worse adverse events occurred in 41 (68%) of 60 patients who received atezolizumab plus vemurafenib plus cobimetinib in the BRAFV600 mutation-positive cohort, the most common of which were lipase increased (15 [25%] of 60 patients) and blood creatine phosphokinase increased (ten [17%]). Eight (53%) of 15 patients treated with atezolizumab plus cobimetinib in the BRAFV600 wild-type cohort had treatment-related grade 3 or worse adverse events, most commonly anaemia (two [13%]) and dermatitis acneiform (two [13%]). Treatment-related serious adverse events occurred in 14 (23%) of 60 patients in the BRAFV600 mutation-positive cohort and two (13%) of 15 in the BRAFV600 wild-type cohort. One death in the BRAFV600 mutation-positive cohort (limbic encephalitis) was considered to be related to atezolizumab treatment. INTERPRETATION: Adding atezolizumab to vemurafenib plus cobimetinib provided promising intracranial activity in patients with BRAFV600-mutated melanoma with CNS metastases. FUNDING: F Hoffmann-La Roche.

New insights on Leptospira sp. infection in ewes maintained in field semiarid conditions.

Leptospirosis is poorly studied in small ruminants raised in field semiarid conditions. In this study we compared serological, bacteriological and molecular diagnostic methods in ewes maintained in field Brazilian semiarid conditions. Blood, vaginal fluid and urine samples were collected from 60 Morada Nova ewes raised in a semi-intensive system in the Brazilian semiarid. Diagnostic tests performed were microscopic agglutination test (MAT), polymerase chain reaction (PCR) and bacterial isolation. Anti-Leptospira sp. antibodies were found in eight (13.33%) animals analyzed by MAT at reciprocal titer 25 (cut-off 25), while Leptospira sp. DNA was detected in urine or vaginal fluid of 56 animals (93.33%). There was growth of leptospires in 10 urine cultures and in 11 vaginal fluid cultures, however, two of urine (2/60-3.33%) and eight cultures of vaginal fluid (8/60-13.33%) were confirmed by PCR. Two samples of vaginal fluid (one of each animal) were submitted to sequencing demonstrating 99% similarity with L. santarosai and L. interrogans. The highest MAT sensitivities were obtained with reciprocal titer 25 (cut-off 25) compared to 50 and 100. The performance of different diagnostic techniques for leptospirosis in ewes raised in field semiarid conditions allowed a better evaluation of the herd, as well as made it possible to identify carrier animals. Genital route may be important for efficient transmission and without dependence on environmental factors in ewes from semiarid, as well as it's highlighted that titer 1:25 in serology was more efficient, indicating its use in ewes in field semiarid conditions.

Development of a core outcome set for basal cell carcinoma.

BACKGROUND: There is variation in the outcomes reported in clinical studies of basal cell carcinoma. This can prevent effective meta-analyses from answering important clinical questions. OBJECTIVE: To identify a recommended minimum set of core outcomes for basal cell carcinoma clinical trials. METHODS: Patient and professional Delphi process to cull a long list, culminating in a consensus meeting. To be provisionally accepted, outcomes needed to be deemed important (score, 7-9, with 9 being the maximum) by 70% of each stakeholder group. RESULTS: Two hundred thirty-five candidate outcomes identified via a systematic literature review and survey of key stakeholders were reduced to 74 that were rated by 100 health care professionals and patients in 2 Delphi rounds. Twenty-seven outcomes were provisionally accepted. The final core set of 5 agreed-upon outcomes after the consensus meeting included complete response; persistent or serious adverse events; recurrence-free survival; quality of life; and patient satisfaction, including cosmetic outcome. LIMITATIONS: English-speaking patients and professionals rated outcomes extracted from English language studies. CONCLUSION: A core outcome set for basal cell carcinoma has been developed. The use of relevant measures may improve the utility of clinical research and the quality of therapeutic guidance available to clinicians.

Global Prevalence of RNA-Positive Horses for Hepacivirus (EqHV): Systematic Review and Meta-Analysis.

Equine hepacivirus (EqHV) belongs to the Flaviviridae family, genus Hepacivirus and has the greatest genomic identity with the hepatitis C virus (HCV), one of the main causes of chronic liver disease in humans. Due to the limited applicability of studies of HCV in animal hosts, the interest in studies of characterization of viral homologues has been growing. For this reason, we performed a systematic review of the literature with meta-analysis of the prevalence of EqHV and genetic sequencing studies. Twenty-three studies from four different continents were analyzed. The OR meta-analysis (0.98; 95% CI = 0.69-1.39) showed no influence of sex (female or male) on the risk of infection. Variables associated with EqHV infection were indirectly related to animal management such as transport, reproductive practices, among others. The combined prevalence of positive animals was 7.88% (95% CI = 5.23-11.69%), with the highest proportions in Asia (16.13%; 95% CI = 7.79-30.43%), followed by South America (12.03%; 95% CI = 9.58-15.01%), Africa (8.69%; 95% CI = 6.71-11.20%), and Europe (3.63%; 95% CI = 2.10-6.22%). However, these results represent the regional stratification of the epidemiological studies for EqHV published to date and, therefore, cannot extrapolate to determine the continental prevalence of EqHV. It is therefore important to update the systematic review as further research becomes available.

Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer.

Standard first-line chemotherapy results in disease progression and death within one year in most patients with human epidermal growth factor receptor 2 (HER2)-negative gastro-oesophageal adenocarcinoma1-4. Nivolumab plus chemotherapy demonstrated superior overall survival versus chemotherapy at 12-month follow-up in gastric, gastro-oesophageal junction or oesophageal adenocarcinoma in the randomized, global CheckMate 649 phase 3 trial5 (programmed death ligand-1 (PD-L1) combined positive score ≥5 and all randomized patients). On the basis of these results, nivolumab plus chemotherapy is now approved as a first-line treatment for these patients in many countries6. Nivolumab and the cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor ipilimumab have distinct but complementary mechanisms of action that contribute to the restoration of anti-tumour T-cell function and induction of de novo anti-tumour T-cell responses, respectively7-11. Treatment combining 1 mg kg-1 nivolumab with 3 mg kg-1 ipilimumab demonstrated clinically meaningful anti-tumour activity with a manageable safety profile in heavily pre-treated patients with advanced gastro-oesophageal cancer12. Here we report both long-term follow-up results comparing nivolumab plus chemotherapy versus chemotherapy alone and the first results comparing nivolumab plus ipilimumab versus chemotherapy alone from CheckMate 649. After the 24.0-month minimum follow-up, nivolumab plus chemotherapy continued to demonstrate improvement in overall survival versus chemotherapy alone in patients with PD-L1 combined positive score ≥5 (hazard ratio 0.70; 95% confidence interval 0.61, 0.81) and all randomized patients (hazard ratio 0.79; 95% confidence interval 0.71, 0.88). Overall survival in patients with PD-L1 combined positive score ≥ 5 for nivolumab plus ipilimumab versus chemotherapy alone did not meet the prespecified boundary for significance. No new safety signals were identified. Our results support the continued use of nivolumab plus chemotherapy as standard first-line treatment for advanced gastro-oesophageal adenocarcinoma.

Intradermal comparative cervical tuberculin test in the diagnosis of caprine tuberculosis.

Tuberculosis remains one of the most important infectious diseases with well-known zoonotic nature that affect humans, wildlife, and domestic animals, including goats. Nonetheless, no intradermal tuberculin test has been standardized for caprine diagnosis of tuberculosis. The present study investigated the intradermal comparative cervical tuberculin test (ICCTT) in the diagnosis of tuberculosis among 60 goats from farms with history of tuberculosis. The cutoff applied to goats was based on a study where goats had been experimentally infected with Mycobacterium bovis and Mycobacterium avium. Clinical examination, bacteriological culture, and histopathological staining were assessed to the diagnosis. Isolates compatible with mycobacteria were subjected for molecular diagnosis based on gyrB-restriction fragment length polymorphism (RFLP) analysis and PCR restriction-enzyme analysis (PRA) of hsp65 gene by BstEII and HaeIII, namely PRA-hsp65 assay. From all goats, 60% (n = 36/60), 3.3% (n = 2/60), and 36.7% (n = 22/60) showed positive, inconclusive, and negative reactions, respectively. Out of 36 goats with ICCTT positive, 75% (n = 27/36) had isolation of mycobacteria and were detected M. bovis by gyrB-RFLP. Molecular diagnosis and histopathological findings compatible with tuberculosis showed 86.1% (n = 31/36) concordance with the ICCTT. When compared ICCTT with M. bovis isolation, gyrB-RFLP, and histopathology, the better arithmetic means of sensitivity and specificity were 2.5 mm for ICCTT compared with M. bovis isolation and gyrB-RFLP, and 4.55 mm when compared with histopathology. Both receiver operating characteristic (ROC) curves presented statistical significance (P < 0.001). The identification of other mycobacteria, e.g., M. kansasii, M. flavescens, M. avium, M. florentinum, M. lentiflavum, M. simiae, and Corynebacterium pseudotuberculosis, not influenced positive results in ICCTT. The concordance between bacteriological, histopathological, and molecular identification with ICCTT findings indicate that the tuberculin test may be used as a valuable tool for diagnosis of caprine tuberculosis and reinforce the importance of association of methods to diagnostic of the disease from animal origin.

Cross-sectional survey for sheep leptospirosis in the northeast region of Brazil.

Sheep farming has shown expressive growth, even in the Northeast region of Brazil, with rainfall below expectations in the last decade. This growth has been observed not only in the number of herds, but also in the number of properties involved in sheep farming. Although expressive, the production of small ruminants still presents low levels of performance, mainly due to the occurrence of diseases, which constitute an obstacle to this activity. The aim of this study was to determine the factors associated with the seroprevalence of leptospirosis in sheep in Northeastern Brazil. Blood samples were collected from 3438 sheep in 190 herds from 48 municipalities, belonging to the states of Ceará, Paraíba, Piauí, Rio Grande do Norte and Sergipe. Serological diagnosis was performed using the microscopic agglutination test (MAT). In 76.3 % (95 % CI = 69.79-81.81) of the herds there was at least one animal seropositive for at least one of the Leptospira spp. serogroups and 14.94 % (95 %CI = 13.8-16.18) of the animals were seropositive. The state of Paraíba had the highest herd (95.7 %) and animal (26.6 %) prevalences, followed by Ceará (93.9 % and 23.7 %, respectively). The most frequent serogroups were Autumnalis (18.68 %), Australis (17.9 %) and Pyrogenes (15.18 %). There was no association between the studied variables and the herd-level prevalence of leptospirosis. High herd and animal-level seroprevalences was found for sheep leptospirosis in the semiarid region of Northeastern Brazil, and there is a need to implement control and prevention measures, such as quarantine, serology, vaccination and adequate treatment, in addition to the introduction of proven healthy animals, mainly in the states of Paraíba and Ceará, aiming to reduce the prevalence of disease.

High herd-level seroprevalence and associated factors for bovine leukemia virus in the semi-arid Paraíba state, Northeast Region of Brazil.

Epidemiological surveys that investigate infectious diseases such as enzootic bovine leukosis (EBL) are important. Furthermore, estimating the prevalence of such infectious diseases and associated factors is key to assess the disease impact and design control programs. In this study, we identified a high herd-level seroprevalence of EBL in cattle from the semi-arid Paraíba state, Northeast Region of Brazil, using a planned cross-sectional survey. Herd-level and animal-level prevalence were estimated using a two-stage random sampling survey. In total, 2067 cows aged ≥24 months from 400 herds were sampled. An enzyme-linked immunosorbent assay was used to detect specific antibodies directed to the bovine leukosis virus gp51 antigen in both individual and pooled sera. The herd-level and animal-level prevalence was 23.4 % (95 % CI = 19.2-28.1 %) and 10.8 % (95 % CI = 7.5 %-15.3 %), respectively. There were no significant clusters of positive herds (within a radius of 2 km). The factors associated with herd-level prevalence were the exclusive use of hand milking (prevalence ratio [PR] = 1.88), herd size (PR = 1.005), artificial insemination (PR = 2.03), purchase of animals in the previous year (PR = 1.87), and peri-urban farms (PR = 2.09). Prevention measures should be applied at the herd-level, particularly for farms located in peri-urban areas, focusing on good hygiene in hand milking, robust practices and standards for artificial insemination, and serological testing of animals prior to purchase.

Antibody detection and molecular analysis for Mycobacterium avium subspecies paratuberculosis (MAP) in goat milk: Systematic review and meta-analysis.

Paratuberculosis is an incurable infectious disease that affects several species, including goat (Capra hircus). The etiologic agent is Mycobacterium avium subspecies paratuberculosis (MAP) that has tropism for the intestine, causing anorexia, progressive weight loss and death. In goats, the main transmission route is the ingestion of water and food contaminated by infected feces. Affected animals also eliminate the agent through milk, with a potential biological risk to public health. Thus, the aim of this study was to conduct a research of the literature available in electronic media for a systematic review, followed by a meta-analysis of the results found on prevalence and diagnostic tests adopted in the detection of MAP antibodies and DNA in goat milk. The following search parameters were used: "Mycobacterium avium subsp. paratuberculosis" AND (goat OR small ruminant) AND (milk OR pasteurized milk). Strictly obeying pre-established criteria, 437 articles were selected from the respective electronic databases of scientific content: ScienceDirect (285), PubMed (68), Web of Science (60) and Scopus (24), of which nine papers were elected to the construction of the systematic review and meta-analysis. The prevalence of MAP antibodies in milk detected by milk-ELISA ranged from 1.1 to 67.7% and the prevalence of MAP DNA in goat milk detected by MAP-specific polymerase chain reaction (PCR) ranged from 1.94 to 37.74%. A meta-analysis indicated a combined MAP infection prevalence of 8.24%, but with high heterogeneity among study findings (I2 = 98.7%). The identification of the MAP in goat milk implies the need for surveillance of the agent in order to prevent economic losses and impact on public health.