A Novel CARMIL2 Immunodeficiency Identified in a Subset of Cavalier King Charles Spaniels with Pneumocystis and Bordetella Pneumonia.

Pet dogs are a valuable natural animal model for studying relationships between primary immunodeficiencies and susceptibility to Pneumocystis and other opportunistic respiratory pathogens. Certain breeds, such as the Cavalier King Charles Spaniel, are over-represented for Pneumocystis pneumonia (PCP), suggesting the presence of a primary immunodeficiency in the breed. Here, we report the discovery of a CARMIL2 nonsense variant in three Cavalier King Charles Spaniel dogs with either PCP (n = 2) or refractory Bordetella pneumonia (n = 1). CARMIL2 encodes a protein that plays critical roles in T-cell activation and other aspects of immune function. Deleterious CARMIL2 variants have recently been reported in human patients with PCP and other recurrent pneumonias. In addition to opportunistic respiratory infection, the affected dogs also exhibited other clinical manifestations of CARMIL2 deficiencies that have been reported in humans, including early-onset gastrointestinal disease, allergic skin disease, mucocutaneous lesions, abscesses, autoimmune disorders, and gastrointestinal parasitism. This discovery highlights the potential utility of a natural canine model in identifying and studying primary immunodeficiencies in patients affected by PCP.

Diagnostic Utility of Parent Ratings on the Behavior Assessment System for Children-Third Edition in Children who are Deaf and Hard of Hearing and Diagnosed with Autism Spectrum Disorder.

Between 1 to 2 of every 1,000 children are born deaf or hard of hearing (DHH) and, of those, 30-50% have additional disabilities, including Autism Spectrum Disorder (ASD). Most measures assessing ASD characteristics rely on some degree of behavioral response to sound (e.g., responding to name, listening response), and may not be appropriate for use with children who are DHH. Further, ASD specific measures do not provide information on a child's functional abilities across developmental domains. We conducted a cross-sectional analysis comparing mean T-scores on a standardized multidimensional measure, the Behavior Assessment System for Children, Third Edition, Parent Rating Scale (BASC-3 PRS), across three groups matched for age and sex: children who are DHH and diagnosed with ASD (DHH + ASD; n = 16); children who are DHH without ASD (DHH-ASD; n = 16); and children who are typically hearing with ASD (H + ASD; n = 16). Analyses revealed statistically significant differences across scales of Attention Problems, Atypicality, Withdrawal, Behavioral Symptoms Index, Social Skills, Leadership, Functional Communication, Activities of Daily Living, Adaptive Skills, Autism Probability Indices, and Developmental Social Disorders. Pairwise comparisons showed DHH + ASD and H + ASD mean T-scores were statistically similar and distinct from DHH-ASD mean T-scores on all these scales except for Withdrawal, Leadership, Functional Communication, and Activities of Daily Living, where pairwise comparisons varied. The findings add to the literature on ASD and DHH children and call for further exploration of the BASC-3 as a tool for both evaluation of ASD and the development of individualized treatment plans in this unique population.

Concurrent and prospective associations of inflammatory signaling, specific depressive symptoms, and substance use in adolescence.

Substance use and depression frequently co-occur. Adolescence appears to be a vulnerable developmental period for increases in both substance use and depressive symptoms, often attributed to rapid maturation of reward and motivation systems. Another contributing factor could be inflammatory signaling, which has been associated with both substance use disorder and depression. Prior research indicates that an increase in inflammatory activity can cause physical and emotional malaise, which resembles depression, and the anhedonia and somatic symptoms could lead to substance use. This perspective that substance use is a type of self-medication in response to anhedonia and subjective experiencing of increased inflammatory physiology has not been investigated previously. To test these associations, we used path analysis to examine concurrent and prospective associations between three pro-inflammatory markers, specific depressive symptoms, and substance use frequency in a diverse sample of older adolescents. Participants completed repeated self-report measures of specific depressive symptoms (i.e., dysphoria, anhedonia, somatic concerns, negative cognitions, and functional difficulties) and substance use frequency. Blood was collected to quantify circulating levels of interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP). This analysis showed an indirect effect of IL-6 and TNF-α levels on future substance use, but only via functional difficulties. Substance use also predicted future functional difficulties. Only anhedonia directly predicted future substance use frequency. These findings help to more precisely identify pathways through which inflammatory physiology and specific depressive symptoms synergistically confer risk for substance use.

Negative Inferential Style Mediates the Association between Racial Identity and Depressive Symptoms among African American Adolescents.

Negative inferential style is a cognitive vulnerability for depression. Yet, few studies have explored how this risk factor intersects with culturally-specific protective factors, such as racial identity, in a unified cognitive risk-cultural asset model in youth of color. The current study addressed this gap by exploring the interplay between negative inferential style, racial identity, and depressive symptoms in an urban African-American adolescent community sample (N = 233; 51.9% female). Cross-lagged panel analyses estimated concurrent and prospective relationships between study variables. Racial identity dimensions of regard, but not centrality, were significant predictors of inferential style, and buffered against the development of depressive symptoms via the development of a less negative inferential style. Implications for the study of racial identity and cognition, and treatment of African-American adolescents are discussed.

Heterobilharzia americana infection in dogs: A retrospective study of 60 cases (2010-2019).

BACKGROUND: The trematode Heterobilharzia americana (HA) causes granulomatous gastrointestinal and hepatic disease in dogs. Before 2008, diagnosis relied on saline fecal sedimentation or histopathology, and earlier reports primarily described dogs with advanced disease or cases diagnosed incidentally at necropsy. The advent of a fecal PCR test has facilitated the diagnosis of HA and provided insights into manifestations and response to treatment. OBJECTIVES: Describe the clinical findings, response to treatment, and outcome for dogs infected with HA. ANIMALS: Sixty dogs diagnosed with HA between 2010 and 2019. METHODS: Retrospective study. Medical records were searched for dogs diagnosed with HA by fecal PCR testing, identification of ova in feces, or histopathology. RESULTS: Mean age was 7.5 (±4.1) years and weight was 23.2 (±10.18) kg. Clinical signs included diarrhea (55.8%), vomiting (46.2%), and weight loss with or without anorexia (15.4%). Laboratory abnormalities included hyperglobulinemia (42.6%) and increased liver enzyme activities (30%). More than 40% of dogs had an eosinophil count >500/µL. Hypercalcemia attributable to HA was identified in only 4 dogs. Pinpoint hyperechoic foci were noted in intestines, liver, or mesenteric lymph nodes during transabdominal ultrasonography in 64.4% of dogs. Survival data was available for 34 dogs, of which 73.5% (25) were alive 6 months after diagnosis. CONCLUSIONS AND CLINICAL IMPORTANCE: Hyperglobulinemia, high eosinophil count, and ultrasonographic evidence of visceral mineralization were suggestive of infection. Hypercalcemia was uncommon. Combination treatment with praziquantel and fenbendazole was variably effective, and 17.6% of treated dogs with known outcome died as a result of HA infection.

Factors associated with clinical interpretation of tracheal wash fluid from dogs with respiratory disease: 281 cases (2012-2017).

BACKGROUND: Clinicians face several dilemmas regarding tracheal washes (TWs) for the diagnosis of respiratory disease, including method and prediction of bacterial growth from cytology results. OBJECTIVE: To compare cytology and culture of endotracheal and transtracheal washes and identify factors associated with discordancy and bacterial growth. ANIMALS: Two hundred forty-five dogs with respiratory disease. METHODS: Retrospective study. Tracheal wash submissions were included if cellularity was sufficient for cytologic interpretation and aerobic cultures were performed. Collection technique, cytology, bacterial growth, and antibiotic history were analyzed. RESULTS: Fewer transtracheal specimens (9/144, 6.3%) were excluded for hypocellularity than endotracheal (28/174, 16.1%); otherwise, results were similar and were combined. Of 281 specimens with cellularity sufficient for interpretation, 97 (34.5%) had bacteria on cytology and 191 (68.0%) had bacterial growth. Cytology positive/culture negative discordancy was uncommon (8/97, 8%). Cytology negative/culture positive discordancy was frequent (102/184, 55.4%), but occurred less often (28/184, 14.2%) when only 1+ growth or greater was considered positive. Oropharyngeal contamination was associated with bacterial growth, but not discordancy. No association was found between antibiotic administration and bacterial growth. CONCLUSIONS AND CLINICAL IMPORTANCE: Endotracheal wash fluid, in particular, should be screened for gross mucus or turbidity to maximize the likelihood of an adequate specimen. Otherwise, endotracheal and transtracheal specimens were similar. Presence of bacteria on cytology was a good predictor of any growth, while their absence was a good predictor of the absence of growth of 1+ or more. Recent antibiotic usage should not discourage TW culture if there is compelling reason to avoid delay.

Pubertal Synchrony and Depressive Symptoms: Differences by Race and Sex.

Individual differences in the timing and tempo of pubertal development have been shown to be related to depressive symptoms during adolescence, particularly among girls. Another measure of variability in pubertal development is pubertal synchrony, the degree to which the development of pubertal indicators (e.g., breast growth and ancillary hair growth) are synchronized within the individual. Pubertal synchrony also has been hypothesized to be related to depressive symptoms, but, to date, only one study has tested this hypothesis. However, it remains unclear whether pubertal synchrony confers risk for depressive symptoms more proximally in time or differentially among boys or non-White youth. The current study examined the relation between pubertal synchrony and depressive symptoms concurrently and six months later as a function of race and sex in a community sample of 215 youth (53% female, 44.7% African American; mean age = 12.90 years (SD = 0.86)). Girls with asynchronous development at Time 1 reported significantly higher depressive symptoms at Time 2 than girls with synchronous development and boys with asynchronous development. In addition, boys with asynchronous development at Time 1 had lower depressive symptoms at Time 2 than boys with synchronous development. Race did not moderate pubertal synchrony-depression relations. These results suggest that pubertal asynchrony is a risk factor for girls, but a protective factor for boys, and lend support for pubertal synchrony as a potential contributor to the gender gap in depression that emerges during adolescence.

Prevalence and impact of cholecystitis on outcome in dogs with gallbladder mucocele.

BACKGROUND: Gallbladder mucocele is a potentially life-threatening extrahepatic biliary disease in dogs. The primary aims of this study were to evaluate the prevalence of cholecystitis in dogs with gross and histopathologically confirmed gallbladder mucocele and to investigate if there is an association between cholecystitis, including its subtypes (eg, acute, acute on chronic, with necrosis, chronic), and survival. Our secondary objective was to evaluate if there is an association between cholecystitis and intraoperative bacteriological culture positivity. KEY FINDINGS: Two hundred nineteen dogs with gallbladder mucocele were included in this multi-institutional retrospective study, of which 63 (28.8%) dogs had histopathological evidence of cholecystitis. The most common forms of cholecystitis were acute on chronic (n = 22/63, 34.9%) and with necrosis (n = 20, 31.7%). Thirty-one (14.1%) dogs had growth of at least 1 bacterial isolate; however, 88.7% had antimicrobials administered within the 48 hours before surgery or intraoperatively. There was not an association between cholecystitis or its subtypes and survival. Furthermore, there was not an association between cholecystitis and intraoperative bacteriological culture positivity. A total of 38 (17.4%) dogs either died or were euthanized during hospitalization. SIGNIFICANCE: Cholecystitis is a common comorbidity in dogs with gallbladder mucocele but was not associated with decreased survival.

Dynamic changes of the respiratory microbiota and its relationship to fecal and blood microbiota in healthy young cats.

Advances in the field of metagenomics using culture-independent methods of microbial identification have allowed characterization of rich and diverse communities of bacteria in the lungs of healthy humans, mice, dogs, sheep and pigs. These data challenge the long held belief that the lungs are sterile and microbial colonization is synonymous with pathology. Studies in humans and animals demonstrate differences in the composition of airway microbiota in health versus disease suggesting respiratory dysbiosis occurs. Using 16S rRNA amplicon sequencing of DNA extracted from rectal and oropharyngeal (OP) swabs, bronchoalveolar lavage fluid (BALF), and blood, our objective was to characterize the fecal, OP, blood, and lower airway microbiota over time in healthy cats. This work in healthy cats, a species in which a respiratory microbiota has not yet been characterized, sets the stage for future studies in feline asthma in which cats serve as a comparative and translational model for humans. Fecal, OP and BALF samples were collected from six healthy research cats at day 0, week 2, and week 10; blood was collected at week 10. DNA was extracted, amplified via PCR, and sequenced using the Illumina MiSeq platform. Representative operational taxonomic units (OTUs) were identified and microbial richness and diversity were assessed. Principal component analysis (PCA) was used to visualize relatedness of samples and PERMANOVA was used to test for significant differences in microbial community composition. Fecal and OP swabs provided abundant DNA yielding a mean±SEM of 65,653±6,145 and 20,6323±4,360 sequences per sample, respectively while BALF and blood samples had lower coverage (1,489±430 and 269±18 sequences per sample, respectively). Oropharyngeal and fecal swabs were significantly richer than BALF (mean number OTUs 93, 88 and 36, respectively; p < 0.001) with no significant difference (p = 0.180) in richness between time points. PCA revealed site-specific microbial communities in the feces, and upper and lower airways. In comparison, blood had an apparent compositional similarity with BALF with regard to a few dominant taxa, but shared more OTUs with feces. Samples clustered more by time than by individual, with OP swabs having subjectively greater variation than other samples. In summary, healthy cats have a rich and distinct lower airway microbiome with dynamic bacterial populations. The microbiome is likely to be altered by factors such as age, environmental influences, and disease states. Further data are necessary to determine how the distinct feline microbiomes from the upper and lower airways, feces and blood are established and evolve. These data are relevant for comparisons between healthy cats and cats with respiratory disease.

Effects of positive end-expiratory pressure and 30% inspired oxygen on pulmonary mechanics and atelectasis in cats undergoing non-bronchoscopic bronchoalveolar lavage.

Objectives The objective of this study was to determine if modification of inspired oxygen concentration or positive end-expiratory pressure (PEEP) would alter bronchoalveolar lavage (BAL)-induced changes in pulmonary mechanics or atelectasis, as measured using ventilator-acquired pulmonary mechanics and thoracic CT. Methods Six experimentally asthmatic cats underwent anesthesia and non-bronchoscopic BAL, each under four randomized treatment conditions: 100% oxygen, zero PEEP; 30% oxygen, zero PEEP; 100% oxygen, PEEP 2 cmH2O; and 30% oxygen, PEEP 2 cmH2O. Pulse oximetry was used to estimate oxygen saturation (SpO2). Ventilator-acquired pulmonary mechanics and thoracic CT scans were collected prior to BAL and at 1, 5 and 15 mins post-BAL. Results While receiving 100% oxygen, no cat had SpO2 <91%. Some cats receiving 30% oxygen had decreased saturation immediately post-BAL (mean ± SD 70.8 ± 31%), but 6/8 of these had SpO2 >90% by 1 min later. There was a significant increase in airway resistance and a decrease in lung compliance following BAL, but there was no significant difference between treatment groups. Cats receiving no PEEP and 30% oxygen conserved better aeration of the lung parenchyma in BAL-sampled areas than those receiving no PEEP and 100% oxygen. Conclusions and relevance Alterations in pulmonary mechanics or atelectasis may not be reflected by SpO2 following BAL. The use of 30% inspired oxygen concentration failed to show any significant improvement in pulmonary mechanics but did diminish atelectasis. In some cats, it was also associated with desaturation of hemoglobin. The use of PEEP in this study did not show any effect on our outcome parameters. Further studies using higher PEEP (5-10 cmH2O) and intermediate inspired oxygen concentration (40-60%) are warranted to determine if they would confer clinical benefit in cats undergoing diagnostic BAL.

Chronic neurokinin-1 receptor antagonism fails to ameliorate clinical signs, airway hyper-responsiveness or airway eosinophilia in an experimental model of feline asthma.

OBJECTIVES: Feline allergic asthma is a common chronic lower airway disease characterized by clinical signs attributed to eosinophilic inflammation, airway hyper-responsiveness (AHR) and airway remodeling. Tachykinins released from sensory nerves and immune cells bind neurokinin-1 (NK-1) receptors in the lung. The resultant neurogenic airway inflammation has been implicated in asthma pathogenesis. In mouse models and spontaneous human asthma, NK receptor antagonists reduce bronchospasm and inflammation. We hypothesized that chronic administration of maropitant, an NK-1 receptor antagonist, would decrease clinical signs of asthma, AHR and eosinophilic inflammation in experimentally asthmatic cats. METHODS: Cats (n = 6) induced to have asthma using Bermuda grass allergen (BGA) were enrolled in a randomized, prospective, placebo-controlled crossover design study. Cats received either oral maropitant (2 mg/kg) or placebo q48h for 4 weeks; following a 2 week washout, cats were crossed-over to the alternate treatment. Study endpoints included subjective clinical scoring systems after BGA challenge, ventilator-acquired pulmonary mechanics to assess AHR after bronchoprovocation with methacholine, and collection of bronchoalveolar lavage fluid to quantify airway eosinophilia. Statistical analysis was performed using a Mann-Whitney rank sum test with P <0.05 considered significant. RESULTS: Administration of maropitant for 1 month in experimentally asthmatic cats produced no significant difference in clinical scoring scheme (P = 0.589 and P = 1.0), AHR (P = 0.818) or airway eosinophilia (P = 0.669) compared with placebo. CONCLUSIONS AND RELEVANCE: Chronic administration of maropitant was ineffective at blunting clinical signs, AHR and airway eosinophilia in experimental feline asthma and thus cannot be recommended as a novel treatment for this disorder.