Magnetic Amplification at Yb3+ "Designer Defects" in the van der Waals Ferromagnet CrI3.

The two-dimensional (2D) van der Waals ferromagnet CrI3 has been doped with the magnetic optical impurity Yb3+ to yield materials that display sharp multiline Yb3+ photoluminescence (PL) controlled by the magnetism of CrI3. Magneto-PL shows that Yb3+ magnetization is pinned to the magnetization of CrI3. An effective internal field of ∼10 T at Yb3+ is estimated, attributed to strong in-plane Yb3+-Cr3+ superexchange coupling. The anomalously low energy of Yb3+ PL in CrI3 reflects relatively high Yb3+-I- covalency, contributing to Yb3+-Cr3+ superexchange coupling. The Yb3+ PL energy and line width both reveal the effects of spontaneous zero-field CrI3 magnetic ordering within 2D layers below TC, despite the absence of net magnetization in multilayer samples. These results illustrate the use of optical impurities as "designer defects" to introduce unique functionality to 2D magnets.

Luminescence and Covalency in Ytterbium-Doped CrX3 (X = Cl, Br, I) van der Waals Compounds.

The layered 2D van der Waals ferromagnets CrX3 (X = Cl, Br, I) show broad d-d photoluminescence (PL). Here we report preparation, structural characterization, and spectroscopic studies of all three CrX3 compounds doped with the optical impurity, Yb3+. EXAFS measurements show very similar Cr K-edge and Yb L-edge data for each doped compound, and good fits of the latter are obtained for structures having Yb3+ occupying substitutional octahedral sites. Yb-X bond lengths are systematically ∼0.25 Å larger than their Cr-X counterparts. 4 K PL measurements show efficient sensitization of Yb3+ luminescence upon photoexcitation into lattice absorption bands [Cr3+ d-d and ligand-to-metal charge-transfer (LMCT)] for all three compounds, converting their nondescript broadband d-d PL into sharp f-f emission. The PL of CrCl3:Yb3+ and CrBr3:Yb3+ occurs at energies typical for [YbX6]3- with these halides, with PL decay times of 0.5-1.0 ms at 4 K, but CrI3:Yb3+ displays anomalously low-energy Yb3+ emission and an unusually short PL decay time of only 8 µs at 4 K. Data analysis and angular overlap model (AOM) calculations show that Yb3+ in CrI3:Yb3+ has a lower spin-orbit splitting energy than reported for any other Yb3+ in any other compound. We attribute these observations to exceptionally high covalency of the Yb3+ f orbitals in CrI3:Yb3+ stemming primarily from the shallow valence-shell ionization potentials of the iodide anions.

An Experimental and Computational Approach to Development of Mixing Processes for Miscible Liquids in Unbaffled Tanks.

PURPOSE: Mixing of liquids is a critical unit operation in the biopharmaceutical drug product manufacturing. It commonly consists of mixing miscible liquids to dilute bulk drug substance (DS) or pool multiple lots of drug substance. In the past, at-scale mixing studies have been conducted to determine the mixing parameters, namely mixing speed, and mixing time. At-scale studies have historically been utilized to overcome the challenges associated with geometric dissimilarity of mixing systems found when scaling up. In addition, such studies are quite costly, as they often use actual DS to overcome a lack of representativeness associated with simple salt trace models often employed. As a result, there is a significant need for alternative cost-effective methods that can predict mixing parameters with close agreement to actual experiments and operations. METHOD: At-scale mixing experiments were conducted using full-sized tanks and surrogate solutions. Several computational fluid dynamic (CFD) simulation methods were conducted and compared with the experiments to determine the most reliable computational techniques. RESULTS: The experiments demonstrate that surrogate solutions can be used reliably to determine mixing parameters in at-scale studies instead of the valuable drug products. Studying different CFD methods also showed that transient simulations that use a large eddy simulation (LES) viscous model and a sliding mesh can correctly predict the mixing parameters. CONCLUSION: Results of this study establish a practical and reliable methodology to perform mixing studies for miscible liquids with different kinematic viscosities. The methods discussed herein greatly reduce the routine mixing study costs in the biopharmaceutical industry and increase efficiency and accuracy of the results, allowing proactive scale-up of mixing operations.

Efficient in vitro digestion of lipids and proteins in bovine milk fat globule membrane ingredient (MFGMi) and whey-casein infant formula with added MFGMi.

The relative immaturity of the infant digestive system has the potential to affect the bioavailability of dietary lipids, proteins, and their digested products. We performed a lipidomic analysis of a commercial bovine milk fat globule membrane ingredient (MFGMi) and determined the profile of lipids and proteins in the bioaccessible fraction after in vitro digestion of both the ingredient and whey-casein-based infant formula without and with MFGMi. Test materials were digested using a static 2-phase in vitro model, with conditions simulating those in the infant gut. The extent of digestion and the bioaccessibility of various classes of neutral and polar lipids were monitored by measuring a wide targeted lipid profile using direct infusion-mass spectrometry. Digestion of abundant proteins in the ingredient and whey-casein infant formula containing the ingredient was determined by denaturing PAGE with imaging of Coomassie Brilliant Blue stained bands. Cholesterol esters, diacylglycerides, triacylglycerides, phosphatidylcholines, and phosphatidylethanolamines in MFGMi were hydrolyzed readily during in vitro digestion, which resulted in marked increases in the amounts of free fatty acids and lyso-phospholipids in the bioaccessible fraction. In contrast, sphingomyelins, ceramides, and gangliosides were largely resistant to simulated digestion. Proteins in MFGMi and the infant formulas also were hydrolyzed efficiently. The results suggest that neutral lipids, cholesterol esters, phospholipids, and proteins in MFGMi are digested efficiently during conditions that simulate the prandial lumen of the stomach and small intestine of infants. Also, supplementation of whey-casein-based infant formula with MFGMi did not appear to alter the profiles of lipids and proteins in the bioaccessible fraction after digestion.

Highly luminescent and catalytically active suprastructures of magic-sized semiconductor nanoclusters.

Metal chalcogenide magic-sized nanoclusters have shown intriguing photophysical and chemical properties, yet ambient instability has hampered their extensive applications. Here we explore the periodic assembly of these nanoscale building blocks through organic linkers to overcome such limitations and further boost their properties. We designed a diamine-based heat-up self-assembly process to assemble Mn2+:(CdSe)13 and Mn2+:(ZnSe)13 magic-sized nanoclusters into three- and two-dimensional suprastructures, respectively, obtaining enhanced stability and solid-state photoluminescence quantum yields (from <1% for monoamine-based systems to ~72% for diamine-based suprastructures). We also exploited the atomic-level miscibility of Cd and Zn to synthesize Mn2+:(Cd1-xZnxSe)13 alloy suprastructures with tunable metal synergy: Mn2+:(Cd0.5Zn0.5Se)13 suprastructures demonstrated high catalytic activity (turnover number, 17,964 per cluster in 6 h; turnover frequency, 2,994 per cluster per hour) for converting CO2 to organic cyclic carbonates under mild reaction conditions. The enhanced stability, photoluminescence and catalytic activity through combined cluster-assembly and metal synergy advance the usability of inorganic semiconductor nanoclusters.

Acceptance of oclacitinib maleate (Apoquel®) chewable tablets in client-owned dogs with allergic and atopic dermatitis.

BACKGROUND: The oral acceptance of oclacitinib maleate (Apoquel®) chewable tablets administered twice daily for 7 days at the labeled dose range of 0.4-0.6 mg/kg was evaluated in 121 dogs treated at ten general practice veterinary clinics in the United States. RESULTS: Dogs that were enrolled in the study were client-owned, ranged from 1 to 14 years of age, weighed 3.7 to 60.7 kg, and required twice daily treatment with Apoquel for allergic or atopic dermatitis for 7 days. One hundred and twenty-one (121) dogs with 1673 total dose administrations successfully completed the study and were included in the data summary. Out of a total number of 1673 administrations, 1533 (91.6%) were accepted voluntarily within 5 min, 134 (8%) were consumed with assistance (with food treats or by pilling) outside of the 5 min offering time and 6 (0.4%) doses were not consumed. The per dose percent acceptance rate for the 14 offered doses showed minimal variation ranging from 89.9 to 93.3%. CONCLUSIONS: Client-owned dogs from the general veterinary patient population that required treatment with oclacitinib found the chewable tablets to be very palatable and no aversion occurred with repeated dosing. Oclacitinib chewable tablets were well tolerated and are a palatable alternative to the film-coated tablet.

Physiotherapists Both Reproduce and Resist Biomedical Dominance when Working With People With Low Back Pain: A Qualitative Study Towards New Praxis.

Despite recommendations to incorporate physical and psychosocial factors when providing care for people with back pain, research suggests that physiotherapists continue to focus on biological aspects. This study investigated how interpersonal and institutional norms influence this continued enactment of the biological aspects of management. We used theoretically-driven analysis, drawing from Foucauldian notions of power, to analyse 28 ethnographic observations of consultations and seven group discussions with physiotherapists. Analysis suggested that physiotherapy training established expectations of what a physiotherapist 'should' focus on, and institutional circumstances strongly drew the attention of physiotherapists towards biological aspects. Resistance to these forces was possible when, for example, physiotherapists reflected upon their practice, used silences and pauses during consultations, and actively collaborated with patients. These circumstances facilitated use of non-biomedical management approaches. Findings may assist physiotherapists to rework the enduring normative focus on biomedical aspects of care when providing care for patients with back pain.

Improving Timeliness of ß-Agonist and Corticosteroid Administration in Patients With Acute Wheezing.

OBJECTIVE: Timely delivery of ß-agonists and steroids to patients with acute recurrent wheezing is a key component of the National Heart, Lung, and Blood Institute recommended emergency department (ED) asthma care. We conducted an ED improvement initiative to standardize asthma care and improve time to treatments. METHODS: Our multidisciplinary team identified key contributing factors to timeliness, developed key driver diagrams, implemented and refined a management pathway, designed and executed rapid cycle improvements, and implemented interventions. A time series design was used to analyze outcomes with baseline data and continuous monitoring during active intervention steps. The primary outcomes analyzed were the times to first ß-agonist and steroid administration. Secondary outcomes included admission rate, ED length of stay, and ED revisits. RESULTS: Assignment of the Pediatric Asthma Score, our initial pathway step, occurred in most patients within the first several months. Time to first ß-agonist administration decreased from the baseline mean of 76 minutes to 27 minutes. Time to steroid administration decreased from the baseline mean of 108 minutes to 49 minutes. Mean monthly admission rate remained at 22% with no special cause variation identified. The ED revisit rate was not negatively impacted and, in most months, was 0%. CONCLUSIONS: By standardizing asthma care in our ED and redesigning care delivery processes, care variation decreased and significant improvements in timeliness of ß-agonist and steroid administration occurred.

Functionally Distinct Bacterial Cytochrome c Peroxidases Proceed through a Common (Electro)catalytic Intermediate.

The diheme cytochrome c peroxidase from Shewanella oneidensis (So CcP) requires a single electron reduction to convert the oxidized, as-isolated enzyme to an active conformation. We employ protein film voltammetry to investigate the mechanism of hydrogen peroxide turnover by So CcP. When the enzyme is poised in the active state by incubation with sodium l-ascorbate, the graphite electrode specifically captures a highly active state that turns over peroxide in a high potential regime. This is the first example of an on-pathway catalytic intermediate observed for a bacterial diheme cytochrome c peroxidase that requires reductive activation, consistent with the observed voltammetric response from the diheme cytochrome c peroxidase from Nitrosomonas europaea (Ne), which is constitutively active and does not require the same one electron activation. Mutational analysis at the active site of So CcP confirms that the rate-limiting step involves a proton-coupled single electron reduction of a high valent iron species centered on the low-potential heme, consistent with the same mutation in Ne CcP. The pH dependence of catalysis for wild-type So CcP suggests that reduction shifts the pK(a)'s of at least two amino acids. Mutation of His81 in "loop 1", a surface exposed loop thought to shift conformation during the reductive activation process, eliminated one of the pH dependent features, confirming that the loop 1 shifts, changing the environment of His81 during the rate-limiting step. The observed catalytic intermediate has the same electron stoichiometry and similar pH dependence to that previously reported for Ne CcP, which is constitutively active and therefore hypothesized to follow a different catalytic mechanism. The prominent similarities between the rate-limiting steps of differing mechanistic classes of bCcPs suggest unexpected similarities in the intermediates formed.

A blinded, randomized, placebo-controlled trial of the safety of lokivetmab (ZTS-00103289), a caninized anti-canine IL-31 monoclonal antibody in client-owned dogs with atopic dermatitis.

BACKGROUND: Lokivetmab (ZTS-00103289) is a caninized anti-canine IL-31 monoclonal antibody that has demonstrated efficacy in reducing pruritus associated with atopic dermatitis (AD) in dogs in field trials. HYPOTHESIS/OBJECTIVES: This study evaluated the safety of lokivetmab in a randomized, double blind, placebo-controlled trial in client owned dogs with AD with minimal restrictions on concomitant medications and co-morbidities. ANIMALS: Clinicians at 14 veterinary clinics enrolled client owned dogs (n = 245) with chronic AD. METHODS: Dogs were randomized at a 2:1 ratio to receive either lokivetmab (1.0-3.3 mg/kg) or placebo administered subcutaneously on days 0 and 28. Clinicians examined dogs, and collected blood and urine for assessment of clinical pathology and immunogenicity (days 0, 28 and 42). RESULTS: There were no immediate hypersensitivity reactions (e.g. wheals, vomiting). Discomfort at administration occurred in 5.1% of dogs and was similar in frequency and severity between lokivetmab- and placebo-treated groups. Pruritus was reported as an adverse event during the study less frequently in the lokivetmab-treated group (4.9% and 19.3%, respectively); otherwise, adverse events occurred at a similar frequency between treatment groups. There were no clinically important differences between groups in clinical pathology results. Treatment-induced immunogenicity was found in 2.5% of lokivetmab treated dogs. A wide variety of concomitant medications were used with no clinically apparent adverse interactions. CONCLUSIONS AND CLINICAL IMPORTANCE: Among a diverse population of 162 client owned dogs with a clinical diagnosis of AD, treatment with two monthly doses of lokivetmab was safe, based on observed adverse events and clinical pathology results over a 42 day period.

A blinded, randomized, placebo-controlled, dose determination trial of lokivetmab (ZTS-00103289), a caninized, anti-canine IL-31 monoclonal antibody in client owned dogs with atopic dermatitis.

BACKGROUND: Pruritus is the hallmark clinical sign of atopic dermatitis (AD) in dogs. Lokivetmab, a caninized anti-canine IL-31 monoclonal antibody, reduced pruritus and associated inflammatory skin lesions in a proof-of-concept study in dogs with AD. HYPOTHESIS/OBJECTIVES: The objective was to describe lokivetmab dose response in a randomized, double blind, placebo-controlled trial. ANIMALS: Clinicians at 15 referral clinics enrolled 211 client owned dogs with a history of chronic AD. METHODS: Dogs were randomized to treatment with lokivetmab (0.125, 0.5 or 2.0 mg/kg) or placebo administered subcutaneously once on Day 0. Dog owners assessed visual analog scale (VAS) scores of pruritus on days 0, 1, 2, 3, 7, 14, 21, 28, 35, 42, 49 and 56. Clinicians assessed Canine AD Extent and Severity Index (CADESI-03) scores on days 0, 7, 14, 28, 42 and 56. RESULTS: Treatment with lokivetmab (2 mg/kg) resulted in a greater percentage reduction from baseline in owner assessed pruritus (days 1-49) and clinician assessed CADESI-03 scores (days 7-56) compared to placebo (P < 0.05); differences were achieved in lower dose groups but at later time points and for shorter duration for both owner assessed pruritus (0.5 mg/kg, days 2-35; 0.125 mg/kg, days 7-21) and clinician assessed CADESI-03 scores (0.5 mg/kg and 0.125 mg/kg, Day 14). CONCLUSIONS AND CLINICAL IMPORTANCE: Lokivetmab (0.5, 2.0 mg/kg) reduced pruritus compared to placebo for at least 1 month. Level and duration of response increased with increasing dose. Further studies are needed to better understand variability in individual responses across a broader population of dogs with AD.

Large Outbreak of Botulism Associated with a Church Potluck Meal--Ohio, 2015.

On April 21, 2015, the Fairfield Medical Center (FMC) and Fairfield Department of Health contacted the Ohio Department of Health (ODH) about a patient suspected of having botulism in Fairfield County, Ohio. Botulism is a severe, potentially fatal neuroparalytic illness.* A single case is a public health emergency, because it can signal an outbreak. Within 2 hours of health department notification, four more patients with similar clinical features arrived at FMC's emergency department. Later that afternoon, one patient died of respiratory failure shortly after arriving at the emergency department. All affected persons had eaten at the same widely attended church potluck meal on April 19. CDC's Strategic National Stockpile sent 50 doses of botulinum antitoxin to Ohio. FMC, the Fairfield Department of Health, ODH, and CDC rapidly responded to confirm the diagnosis, identify and treat additional patients, and determine the source.

Methionine ligand lability of homologous monoheme cytochromes c.

Direct electrochemical analysis of adsorbed bacterial monoheme cytochromes c has revealed a phenomenological loss of the axial methionine when examined using pyrolytic "edge-plane" graphite (EPG) electrodes. While prior findings have reported that the Met-loss state may be quantitatively understood using the cytochrome c from Hydrogenobacter thermophilus as a model system, here we demonstrate that the formation of the Met-loss state upon EPG electrodes can be observed for a range of cytochrome orthologs. Through an electrochemical comparison of the wild-type proteins from organisms of varying growth temperature optima, we establish that Met-ligand losses at graphite surfaces have similar energetics to the "foldons" for known protein folding pathways. Furthermore, a downward shift in reduction potential to approximately -100 mV vs standard hydrogen electrode was observed, similar to that of the alkaline transition found in mitochondrial cytochromes c. Pourbaix diagrams for the Met-loss forms of each cytochrome, considered here in comparison to mutants where the Met-ligand has been substituted to His or Ala, suggest that the nature of the Met-loss state is distinct from either a His-/aquo- or a bis-His-ligated heme center, yet more closely matches the pKa values found for bis-His-ligated hemes., We find the propensity for adoption of the Met-loss state in bacterial monoheme cytochromes c scales with their overall thermal stability, though not with the specific stability of the Fe-Met bond.

Outbreaks associated with cantaloupe, watermelon, and honeydew in the United States, 1973-2011.

Fresh fruits and vegetables are an important part of a healthy diet. Melons have been associated with enteric infections. We reviewed outbreaks reported to the Centers for Disease Control and Prevention's Foodborne Disease Outbreak Surveillance System during 1973-2011 in which the implicated food was a single melon type. We also reviewed published literature and records obtained from investigating agencies. During 1973-2011, 34 outbreaks caused by a single melon type were reported, resulting in 3602 illnesses, 322 hospitalizations, 46 deaths, and 3 fetal losses. Cantaloupes accounted for 19 outbreaks (56%), followed by watermelons (13, 38%) and honeydew (2, 6%). Melon-associated outbreaks increased from 0.5 outbreaks per year during 1973-1991 to 1.3 during 1992-2011. Salmonella was the most common etiology reported (19, 56%), followed by norovirus (5, 15%). Among 13 outbreaks with information available, melons imported from Mexico and Central America were implicated in 9 outbreaks (69%) and domestically grown melons were implicated in 4 outbreaks (31%). The point of contamination was known for 20 outbreaks; contamination occurred most commonly during growth, harvesting, processing, or packaging (13, 65%). Preventive measures focused on reducing bacterial contamination of melons both domestically and internationally could decrease the number and severity of melon-associated outbreaks.

Fostering equitable change in health services: Using critical reflexivity to challenge dominant discourses in low back pain care in Australia.

OBJECTIVES: Justice and equity-focused practices in health services play a critical but overlooked role in low back pain (LBP) care. Critical reflexivity - the ability to examine and challenge power relations, and broader social issues embedded in everyday life - can be a useful tool to foster practices that are more socially just. No research has yet explored this approach in back pain health services. This study sought to understand how clinicians construct LBP in relation to broader socio-cultural-political aspects of care and explore if those constructions changed when clinicians engaged with critically reflexive dialogues with researchers. METHODS: Using critical discourse analysis methods, this qualitative study explored institutionalised patterns of knowledge in the construction of LBP care. We conducted 22 critically reflexive dialogues with 29 clinicians from two health services in Australia - a private physiotherapy clinic and a public multidisciplinary pain clinic. RESULTS: Our analyses suggested that clinicians and services often constructed LBP care at an individual level. This dominant individualistic discourse constrained consideration of justice-oriented practices in the care of people with LBP. Through dialogues, discursive constructions of LBP care expanded to incorporate systems and health service workplace practices. This expansion fostered more equitable clinical and service practices - such as assisting patients to navigate health care systems, considering patients' socioeconomic circumstances when developing treatment plans, encouraging staff discussion of possible systemic changes to enhance justice, and fostering a more inclusive workplace culture. Although such expansions faced challenges, incorporating broader discourses enabled recommendations to address LBP care inequities. CONCLUSIONS: Critical reflexivity can be a tool to foster greater social justice within health services. By expanding constructions of LBP care beyond individuals, critical reflexive dialogues can foster discussion and actions towards more equitable workplace cultures, services and systems.

'Engaging on a slightly more human level': A qualitative study exploring the care of individuals with back pain in a multidisciplinary pain clinic.

Chronic low back pain is characterised by multiple and overlapping biological, psychological, social and broader dimensions, affecting individuals' lives. Multidisciplinary pain services have been considered optimal settings to account for the multidimensionality of chronic low back pain but have largely focused on cognitive and behavioural aspects of individuals' pain. Social dimensions are usually underexplored, considered outside or beyond healthcare professionals' scope of practice. Employing Actor Network Theorist Mol's concept multiplicity, our aim in this paper is to explore how a pain service's practices bring to the fore the social dimensions of individuals living with low back pain. Drawing on 32 ethnographic observations and four group exchanges with the service's clinicians, findings suggest that practices produced multiple enactments of an individual with low back pain. Although individuals' social context was present and manifested during consultations at the pain service (first enactment: 'the person'), it was often disconnected from care and overlooked in 'treatment/management' (second enactment: 'the patient'). In contrast, certain practices at the pain service not only provided acknowledgement of, but actions towards enhancing, individuals' social contexts by adapting rules and habits, providing assistance outside the service and shifting power relations during consultations (third enactment: 'the patient-person'). We therefore argue that different practices enact different versions of an individual with low back pain in pain services, and that engagement with individuals' social contexts can be part of a service's agenda.

Foodborne disease outbreaks caused by Bacillus cereus, Clostridium perfringens, and Staphylococcus aureus--United States, 1998-2008.

From 1998 to 2008, 1229 foodborne outbreaks caused by Bacillus cereus, Clostridium perfringens, and Staphylococcus aureus were reported in the United States; 39% were reported with a confirmed etiology. Vomiting was commonly reported in B. cereus (median, 75% of cases) and S. aureus outbreaks (median, 87%), but rarely in C. perfringens outbreaks (median, 9%). Meat or poultry dishes were commonly implicated in C. perfringens (63%) and S. aureus (55%) outbreaks, and rice dishes were commonly implicated in B. cereus outbreaks (50%). Errors in food processing and preparation were commonly reported (93%), regardless of etiology; contamination by a food worker was only common in S. aureus outbreaks (55%). Public health interventions should focus on these commonly reported errors to reduce the occurrence of outbreaks caused by B. cereus, C. perfringens, and S. aureus in the United States.

Outbreak-associated Salmonella enterica serotypes and food Commodities, United States, 1998-2008.

Salmonella enterica infections are transmitted not only by animal-derived foods but also by vegetables, fruits, and other plant products. To clarify links between Salmonella serotypes and specific foods, we examined the diversity and predominance of food commodities implicated in outbreaks of salmonellosis during 1998-2008. More than 80% of outbreaks caused by serotypes Enteritidis, Heidelberg, and Hadar were attributed to eggs or poultry, whereas >50% of outbreaks caused by serotypes Javiana, Litchfield, Mbandaka, Muenchen, Poona, and Senftenberg were attributed to plant commodities. Serotypes Typhimurium and Newport were associated with a wide variety of food commodities. Knowledge about these associations can help guide outbreak investigations and control measures.

Risk factors for venous thromboembolism in patients with chronic liver disease.

BACKGROUND: Pharmacologic prophylaxis for venous thromboembolism (VTE) in patients with chronic liver disease (CLD) presents a unique challenge because of coagulopathies associated with the disease. When evaluating whether these patients require VTE prophylaxis upon hospitalization, it would be advantageous if risk factors for the development of VTE in this population were known. OBJECTIVE: To evaluate risk factors associated with the development of VTE in patients with CLD. METHODS: A retrospective case-control study was conducted. Patients admitted to the University of Kentucky Chandler Hospital from October 2006 to July 2010 with a diagnosis of CLD and VTE were matched in a 1:3 fashion with CLD patients without VTE. The primary objective was to determine whether there were significant differences in laboratory values between the 2 groups. RESULTS: During this time, 27 patients with CLD (1.0%) were diagnosed with VTE. These patients had significantly lower median aspartate aminotransferase (AST) (47 vs 70 U/L, p = 0.04), alanine transaminase (ALT) (24.5 vs 36 U/L, p = 0.02), albumin (2.1 vs 2.4 g/dL, p = 0.02) and hematocrit (Hct) (28.3% vs 32%, p = 0.03) values compared to the control patients. Patients with albumin lower than 1.9 g/dL had a 5.1 times greater risk of VTE compared to patients with albumin of 2.8 g/dL and higher (OR 5.14, 95% CI 1.05-25.2). CONCLUSIONS: Patients with CLD who developed VTE had significantly lower AST, ALT, albumin, and Hct compared to those of control patients. Studies are necessary to further examine the significance of this finding.

A blinded, randomized, placebo-controlled trial of the efficacy and safety of the Janus kinase inhibitor oclacitinib (Apoquel®) in client-owned dogs with atopic dermatitis.

BACKGROUND: Pruritus is the hallmark clinical sign of atopic dermatitis (AD) in dogs. Preliminary study results suggest that oclacitinib, a selective Janus kinase inhibitor, could reduce pruritus and associated inflammatory skin lesions in dogs with AD. HYPOTHESIS/OBJECTIVES: The objective was to evaluate efficacy and safety of oclacitinib (Apoquel®) for the control of AD in a randomized, double-blind, placebo-controlled trial. ANIMALS: Clinicians at 18 specialty clinics enrolled client-owned dogs (n = 299) with a history of chronic AD. METHODS: Dogs were randomized to receive either oclacitinib (0.4-0.6 mg/kg twice daily for 14 days and then once daily for up to 112 days) or an excipient-matched placebo. Owners assessed visual analog scale (VAS) scores of pruritus on days 0, 1, 2, 7, 14, 28, 56, 84 and 112. Clinicians assessed Canine AD Extent and Severity Index (CADESI-02) scores on days 0, 14, 28, 56, 84 and 112. RESULTS: On days 1, 2, 7, 14 and 28, oclacitinib-treated dogs had a 29.5, 42.3, 61.5, 66.7 and 47.4% reduction from baseline in owner-assessed pruritus scores, respectively, compared with a 6.5, 9.1, 6.5, 3.9 and 10.4% reduction in placebo-treated dogs. On days 14 and 28, dermatologists recorded a 48.4% reduction in CADESI-02 scores in oclacitinib-treated dogs compared with a 1.7% reduction and a 3.6% increase in placebo-treated dogs. After day 28, >86% of all placebo-treated dogs had moved to an open-label study, making between-group comparisons biased. Differences were significant at all time points assessed (P < 0.0001). CONCLUSIONS AND CLINICAL IMPORTANCE: Oclacitinib provided rapid, effective and safe control of AD, with substantial improvement in VAS and CADESI-02 scores.