Early administration of canine parvovirus monoclonal antibody prevented mortality after experimental challenge.

OBJECTIVE: To evaluate the effectiveness of canine parvovirus monoclonal antibody (CPMA) as a treatment against canine parvovirus (CPV-2)-induced mortality and to support USDA product licensure. ANIMALS: 28 purpose-bred Beagle dogs aged 8 weeks were randomized to the treated (n = 21) or control (7) group. METHODS: Dogs were challenged intranasally with 104.2 TCID50 virulent CPV-2b on Day 0 and monitored for 14 days for fecal viral shed and clinical disease. All dogs began shedding CPV-2 on Day 4 and were treated intravenously with a single dose of either CPMA (0.2 mL/kg) or saline (equal volume). No additional treatments were given to either group. Feces and sera were collected for quantitative analysis of fecal viral shed (hemagglutination) and antibody responses (hemagglutination inhibition and dot-blot ELISA), respectively. Dogs were monitored twice daily for parameters including lymphopenia, fever, vomiting, abnormal feces, inappetence, and lethargy. Humane endpoints triggered euthanasia by a veterinarian masked to treatment groups. The primary outcome variable was prevention of mortality as compared to controls. RESULTS: Mortality was prevented in all CPMA-treated dogs compared to 57% mortality in the control group (P = .0017, Fisher exact test). Canine parvovirus monoclonal antibody-treated dogs also experienced less severe and/or shorter durations of diarrhea, fever, vomiting, CPV-2 shedding in feces, and lymphopenia. Both groups showed similar immunoglobulin M responses as measured by semiquantitative analysis. CLINICAL RELEVANCE: Intravenous administration of CPMA can effectively improve clinical outcome when administered early in CPV-2 disease. Canine parvovirus monoclonal antibody treatment after proven infection does not interfere with adaptive immunity.

A point-of-care dot blot ELISA assay for detection of protective antibody against canine adenovirus, canine parvovirus, and canine distemper virus is diagnostically accurate.

OBJECTIVE: To determine diagnostic accuracy of a point-of-care antibody-screening test by determining sensitivity, specificity, and overall accuracy when compared to reference standard tests for antibody against core vaccine viruses canine adenovirus (CAV), canine parvovirus (CPV), and canine distemper virus (CDV). A further aim was to provide the practitioner with information to guide selection of vaccinal antibody testing methods. SAMPLES: Canine sera from across North America were submitted to a fee-for-service titer-testing laboratory. Samples came from healthy pet dogs with known core vaccination history (n = 431) as well as unvaccinated dogs held in isolation (132). This study examined a total of 563 samples for CDV/CPV and 183 for CAV. PROCEDURES: Serum virus neutralization assays determined antibody titers for CDV and CAV. Hemagglutination inhibition assay determined antibody titers against CPV. All sera were also tested by point-of-care dot blot ELISA (index test). RESULTS: For all 3 viral antigens, the index test provided sensitivity ranging from 96.03% to 96.75% and specificity ranging from 87.50% to 94.33%. Overall accuracy ranged from 93.43% to 95.91%. CLINICAL RELEVANCE: The index test correlates well with reference standard tests and is a reliable, rapid screening test for detection of protective vaccinal antibody against CAV, CDV, and CPV in healthy dogs over 20 weeks of age. An accurate assessment of immunity allows clinicians to administer core vaccines appropriately as needed, avoiding unnecessary risk of adverse vaccine events.

Production, safety and efficacy of iPSC-derived mesenchymal stromal cells in acute steroid-resistant graft versus host disease: a phase I, multicenter, open-label, dose-escalation study.

The therapeutic potential of donor-derived mesenchymal stromal cells (MSCs) has been investigated in diverse diseases1, including steroid-resistant acute graft versus host disease (SR-aGvHD)2. However, conventional manufacturing approaches are hampered by challenges with scalability and interdonor variability, and clinical trials have shown inconsistent outcomes3,4. Induced pluripotent stem cells (iPSCs) have the potential to overcome these challenges, due to their capacity for multilineage differentiation and indefinite proliferation5,6. Nonetheless, human clinical trials of iPSC-derived cells have not previously been completed. CYP-001 (iPSC-derived MSCs) is produced using an optimized, good manufacturing practice (GMP)-compliant manufacturing process. We conducted a phase 1, open-label clinical trial (no. NCT02923375) in subjects with SR-aGvHD. Sixteen subjects were screened and sequentially assigned to cohort A or cohort B (n = 8 per group). One subject in cohort B withdrew before receiving CYP-001 and was excluded from analysis. All other subjects received intravenous infusions of CYP-001 on days 0 and 7, at a dose level of either 1 × 106 cells per kg body weight, to a maximum of 1 × 108 cells per infusion (cohort A), or 2 × 106 cells per kg body weight, to a maximum dose of 2 × 108 cells per infusion (cohort B). The primary objective was to assess the safety and tolerability of CYP-001, while the secondary objectives were to evaluate efficacy based on the proportion of participants who showed a complete response (CR), overall response (OR) and overall survival (OS) by days 28/100. CYP-001 was safe and well tolerated. No serious adverse events were assessed as related to CYP-001. OR, CR and OS rates by day 100 were 86.7, 53.3 and 86.7%, respectively. The therapeutic application of iPSC-derived MSCs may now be explored in diverse inflammatory and immune-mediated diseases.

Duration of immunity after rabies vaccination in dogs: The Rabies Challenge Fund research study.

A prospective study of 65 research beagles kept in a rabies-free environment was undertaken to determine the duration of immunity after they received licensed rabies vaccines. The eventual goal was to extend mandated rabies booster intervals to 5 or 7 years and help reduce the risk of vaccine-associated adverse events. Three groups of dogs were vaccinated with 1 of 2 commercial rabies vaccines or saline at 12 and 15 weeks of age. Beginning 5 years 5 months later, vaccinated and unvaccinated dogs were challenged with virulent rabies virus and observed for 90 days over a series of 3 trials. Humoral and cellular immune responses were examined by serology and flow cytometry. Brain tissue from all challenged dogs was tested for rabies virus. Challenge trial 1 was confounded due to insufficiently virulent virus. In trials 2 and 3 virulent challenge provided 100% mortality in controls. Vaccinate survival was 80% (4/5) after 6 years 7 months, 50% (6/12) after 7 years 1 month, and 20% (1/5) after 8years 0 months. Antibody responses 12 days post-challenge correlated strongly with survival. In a separate non-challenge trial, administration of either a recombinant or a killed rabies vaccine demonstrated memory antibody responses 6 years 1 month after initial vaccination compared with unvaccinated controls. Our data demonstrated that i) duration of immunity to rabies in vaccinated dogs extends beyond 3 years; ii) immunologic memory exists even in vaccinated dogs with serum antibody titer < 0.1 IU/mL; and iii) non-adjuvanted recombinant rabies vaccine induces excellent antibody responses in previously vaccinated dogs 14 days after administration.

Une étude prospective sur 65 chiens beagle de recherche gardés dans un environnement exempt de rage fut entreprise afin de déterminer la durée de l'immunité après qu'ils reçurent un vaccin homologué contre la rage. Le but éventuel était d'allonger l'intervalle requis du rappel du vaccin contre la rage à 5 ou 7 ans et aider à réduire le risque associé aux réactions adverses au vaccin. Trois groupes de chiens furent vaccinés avec un des deux vaccins commerciaux contre la rage ou de la saline à 12 et 15 semaines d'âge. Débutant 5 ans et 5 mois plus tard, les chiens vaccinés et non-vaccinés furent soumis à une infection défi avec un virus de la rage virulent et observés pendant 90 jours lors d'une série de trois essais. Les réponses immunitaires humorale et cellulaire furent examinées par sérologie et cytométrie de flux. Du tissu cérébral de tous les chiens infectés fut testé pour la présence du virus rabique. L'essai 1 était décevant étant donné la quantité insuffisante de virus virulent. Lors des essais 2 et 3, l'infection défi a entrainé 100 % de mortalité chez les témoins. Le taux de survie des animaux vaccinés était de 80 % (4/5) après 6 ans et 7 mois, 50 % (6/12) après 7 ans et 1 mois et 20 % (1/5) après 8 ans 0 mois. La réponse en anticorps 12 jours post-infection corrélait fortement avec la survie. Dans un essai séparé sans infection défi, l'administration de soit un vaccin recombinant ou un vaccin tué a mis en évidence une réponse anamnestique en anticorps 6 ans et 1 mois après la vaccination initiale comparativement aux témoins non-vaccinés. Nos résultats démontrent que (1) la durée de l'immunité contre la rage chez les chiens vaccinés va au-delà de 3 ans, (2) une mémoire immunologique existe même chez les chiens vaccinés avec des titres d'anticorps sériques < 0,1 IU/mL, et (3) un vaccin antirabique recombinant sans adjuvant induit d'excellentes réponses en anticorps chez des chiens préalablement vaccinés 14 jours après son administration.(Traduit par Docteur Serge Messier).

Cholestatic Liver Injury: Care of Patients With Primary Biliary Cholangitis or Primary Sclerosing Cholangitis.

The most common causes of chronic cholestatic liver disease are primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Both disease processes are characterized by a destruction of intrahepatic and/or extrahepatic biliary ducts. The etiology is not entirely clear; however, there is an underlying autoimmune component contributing to both disease processes. Although PBC and PSC are often diagnosed and managed in the outpatient setting, in some instances, a patient may have jaundice, fatigue, and pruritus requiring evaluation and determination of the cholestatic cause. Patients with PSC should be monitored for evidence of cholangiocarcinoma, colon cancer, and gallbladder polyps as they are at an increased risk of malignant neoplasms. Liver transplant has the potential for improving quality of life, although disease recurrence is a risk.

DOING THEIR HOMEWORK.

One health care network is proving the value of community health workers to reach patients at home. The effort improves population health, identifies patients who are at risk of illness and averts preventable hospitalizations.

Clinical Integration Managing across the care continuum.

In the changing world of health care, the traditional boundaries are vanishing and hospitals and others must integrate care within their own organizations, as well as externally, across the care continuum. Here are three approaches to accomplishing just that.