Ultrasonographic liver nodules are more often benign lesions in dogs with hemoperitoneum secondary to splenic tumor rupture.

OBJECTIVE: To evaluate the reliability of preoperative abdominal ultrasonography as a staging tool for dogs with hemoperitoneum due to presumed splenic tumor rupture, focusing on the detection of metastatic lesions in the liver. ANIMALS: 99 dogs from 20 emergency and specialty hospitals across the US. METHODS: Dogs with nontraumatic hemoperitoneum secondary to splenic tumor rupture were included. A post hoc analysis was conducted on data from a nationwide prospective trial investigating novel treatments for canine hemangiosarcoma. The accuracy of preoperative staging was assessed by comparing ultrasonographic findings with intraoperative observations and histologic findings. RESULTS: On preoperative ultrasonography, there was a 20% incidence of liver lesions identified, with no association to liver lesions seen during operation. Notably, 22% of liver lesions observed during operation were missed on preoperative ultrasonography. The presence of liver lesions on preoperative ultrasonography was associated with a higher likelihood of a benign splenic tumor diagnosis. There was no association between the identification of liver lesions on preoperative ultrasonography and the presence of metastatic disease on liver biopsy, with a sensitivity and specificity of 19% and 82%, respectively. Additionally, ultrasound had low sensitivity in detecting intra-abdominal lesions beyond the liver and spleen, with 82% of these lesions missed preoperatively. CLINICAL RELEVANCE: This study challenges conventional perceptions around the approach to staging in dogs with hemoperitoneum. These findings advocate for a reevaluation of the staging approach, with more comprehensive modalities like whole-body CT or MRI potentially being more warranted.

In-vitro exposure of feline red blood cells to rattlesnake venom causes echinocytosis.

The objective of this study was to investigate in-vitro exposure of healthy feline red blood cells to venom of four species of rattlesnakes and to evaluate the presence and type of echinocytes that form. Blood from 10 healthy felines was collected and within 30 min exposed to four species of rattlesnake venom. Cytologic evaluation for echinocytes was performed at 0-, 15-, and 30-min post-exposure to each of the species' venom. There was significant formation of echinocytes in a time dependent manner with in-vitro exposure of red blood cells to rattlesnake venom. Cytologic evaluation of blood smears at 15 and 30 min showed a progressive increase in echinocyte numbers over time, with a significantly higher number of echinocytes formed at both timepoints compared to the 0-min timepoint. Furthermore, the morphology of the echinocytes differed based on the length of time exposed to the venom, with type I echinocytes being significantly present early on post-exposure (0 and 15 min) and type III echinocytes being most prevalent later post-exposure (15 and 30 min). There was not a significant difference in the formation of echinocytes between the rattlesnake species. This study demonstrates that there is a time dependent formation of echinocytes in feline blood post-exposure to four species of rattlesnake venom in the in-vitro setting. Cytologic evaluation of blood smears in cats with suspected rattlesnake envenomation to evaluate for echinocyte populations may use to provide support for the diagnosis and to direct the timely administration of appropriate treatments.

Can deep learning classify cerebral ultrasound images for the detection of brain injury in very preterm infants?

OBJECTIVES: Cerebral ultrasound (CUS) is the main imaging screening tool in preterm infants. The aim of this work is to develop deep learning (DL) models that classify normal vs abnormal CUS to serve as a computer-aided detection tool providing timely interpretation of the scans. METHODS: A population-based cohort of very preterm infants (220-306 weeks) born between 2004 and 2016 in Nova Scotia, Canada. A set of nine sequential CUS images per infant was retrieved at three specific coronal landmarks at three pre-identified times (first, sixth weeks, and term age). A radiologist manually labeled each image as normal or abnormal. The dataset was split into training/development/test subsets (80:10:10). Different convolutional neural networks were tested, with filtering of the most uncertain prediction. The model's performance was assessed using precision/recall and the receiver operating area under the curve. RESULTS: Sequential CUS retrieved for 538/665 babies (81% of the cohort). Four thousand one hundred eighty images were used to develop and test the model. The model performance was only discrete at the beginning but, through different machine learning strategies was boosted to good levels averaging 0.86 ROC AUC (95% CI: 0.82, 0.90) and 0.87 PR AUC (95% CI: 0.84, 0.90) (model uncertainty estimation filters using normalized entropy threshold = 0.5). CONCLUSION: This study offers proof of the feasibility of applying DL to CUS. This basic diagnostic model showed good discriminative ability to classify normal versus abnormal CUS. This serves as a CAD and a framework for constructing a prognostic model. CLINICAL RELEVANCE STATEMENT: This DL model can serve as a computer-aided detection tool to classify CUS of very preterm babies as either normal or abnormal. This model will also be used as a framework to develop a prognostic model. KEY POINTS: Binary computer-aided detection models of CUS are applicable for classifying ultrasound images in very preterm babies. This model acts as a step towards developing a model for predicting neurodevelopmental outcomes in very preterm babies. This model serves as a tool for interpretation of CUS in this patient population with a heightened risk of brain injury.

Serial Range of Motion and Grip Strength Measurements, Patient-Reported Outcomes, and Radiographic Thresholds Associated With Less Satisfactory Outcomes After Low-Energy Distal Radius Fracture in Women Aged 50 Years and Older.

PURPOSE: To document the change of clinical (wrist motion and grip strength) measurements and Patient-Rated Wrist Evaluation (PRWE) scores at 9 weeks and 3, 6, and 12 months after distal radius fracture (DRF) in women 50 years and older with exclusively isolated, displaced, and low-energy DRFs treated by either closed and/or open reduction and to relate these outcomes to their radiographic results. METHODS: In this retrospective single-institution cohort study, patients' post-DRF clinical measurements and PRWE scores were prospectively collected from December 2007 through September 2018 and stratified according to their final radiographic values of volar/dorsal tilt, ulnar variance, and radial inclination. RESULTS: Of the 1,319 women identified, 1,126 (85%) were treated nonsurgically, and 193 (15%) were treated operatively. At 12 months, patients averaged restoration (ratio of injured and uninjured sides' values) of 96% pronation, 95% extension, 91% supination, 81% flexion, and 80% (77% nondominant, 85% dominant) grip strength. The mean PRWE score was 39.5 at week 9 and 14.4 at 12 months with 54% of patients scoring <10 and 13% scoring zero. The mean volar/dorsal tilt, ulnar variance, and radial inclination values in those treated nonsurgically were 1.4° dorsal, +3.9 mm, and 18.0°, respectively. Analogous values in patients treated surgically were 6° volar, +2.6 mm, and 22°, respectively. Volar tilt ≥25°, dorsal tilt >10°, ulnar variance >+7.5 mm, and radial inclination ≤13° were thresholds beyond which motion and grip strength were reduced and/or PRWE scores increased. In general, older patients experienced more residual deformity and were less likely to have undergone surgery. CONCLUSIONS: Generally, outcomes were satisfactory for patients with radiographic results within identified thresholds for acceptable fracture reduction. Outcomes were significantly less favorable for patients with radiographic results beyond these thresholds; for these patients, early surgical intervention should be considered. Low-energy DRFs should prompt bone density investigation. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic 2b.

Highly Sensitive and Selective Detection of L-Tryptophan by ECL Using Boron-Doped Diamond Electrodes.

L-tryptophan is an amino acid that is essential to the metabolism of humans. Therefore, there is a high interest for its detection in biological fluids including blood, urine, and saliva for medical studies, but also in food products. Towards this goal, we report on a new electrochemiluminescence (ECL) method for L-tryptophan detection involving the in situ production of hydrogen peroxide at the surface of boron-doped diamond (BDD) electrodes. We demonstrate that the ECL response efficiency is directly related to H2O2 production at the electrode surface and propose a mechanism for the ECL emission of L-tryptophan. After optimizing the analytical conditions, we show that the ECL response to L-tryptophan is directly linear with concentration in the range of 0.005 to 1 µM. We achieved a limit of detection of 0.4 nM and limit of quantification of 1.4 nM in phosphate buffer saline (PBS, pH 7.4). Good selectivity against other indolic compounds (serotonin, 3-methylindole, tryptamine, indole) potentially found in biological fluids was observed, thus making this approach highly promising for quantifying L-tryptophan in a broad range of aqueous matrices of interest.

Corrigendum to "Uptake of community pharmacist prescribing over a three-year period" [Exploratory Research in Clinical and Social Pharmacy, Volume 9, March 2023, 100221].

[This corrects the article DOI: 10.1016/j.rcsop.2023.100221.].

High concordance of blood glucose measurement in cats between a beta prototype glucometer device and a reference laboratory standard in a clinical setting.

OBJECTIVE: The objective of this study was to evaluate the accuracy of a beta prototype version of a new portable blood glucose meter in feline patients. ANIMALS: 60 client-owned cats. METHODS: In this prospective study, 3-mL blood samples were collected from each cat and analyzed in triplicate using a beta prototype device (AlphaTRAK 3 [AT3]) and by a reference lab standard immediately after collection. Accuracy of the AT3 device was determined in accordance with the International Organization of Standardization (ISO) 15197:2013 criteria, including Bland-Altman plotting and consensus error grid analysis. A Passing-Bablok regression analysis was also performed. RESULTS: 96% of feline measurements fell within the ISO accuracy threshold, and 100% of measurements fell within zones A and B of the consensus error grid, meeting the ISO accuracy requirements. There was no significant bias in the data according to the Bland-Altman analysis. Within the full range of glucose concentrations (20 to 750 mg/dL) the correlation coefficient between the AT3 and the reference lab standard was 0.99. There was no significant constant or proportional bias present in the data. CLINICAL RELEVANCE: The AT3 device met the ISO requirements and is accurate for measurement of blood glucose concentrations in cats.

An early clinical phenotype of necrotizing meningoencephalitis in the Pug reveals similarities to multiple sclerosis in humans.

Necrotizing meningoencephalitis (NME) is a fatal neuroinflammatory disease that previously carried a uniformly grave prognosis. Our recent identification of a novel early form of NME in Pugs suggests that disease onset and progression are likely more insidious than previously recognized and provides new hope that early therapeutic intervention may halt disease progression and ultimately prevent or cure NME. This novel perspective also sheds new light on the clinical similarities to multiple sclerosis (MS) in humans and provides a rationale for cross-species translation. The history of recent scientific discoveries in NME and new parallels between MS and NME will be reviewed.

Retrospective evaluation of the impact of hypoxemia during thoracic surgery in dogs on outcome: a multicenter analysis of 94 cases.

OBJECTIVE: To investigate the statistical association of severe intraoperative hypoxemia in thoracic surgery with mortality, postoperative hospitalization times and cost of care. STUDY DESIGN: Retrospective study. ANIMALS: Dogs that underwent thoracic surgery in three veterinary hospitals between October 1, 2018 and October 1, 2020. METHODS: Anesthesia and hospitalization records from 112 dogs were reviewed and 94 cases met inclusion criteria. Recorded data included signalment, disease etiology, pulmonary or extrapulmonary nature of disease, surgical procedure performed, episodes of severe intraoperative hypoxemia defined as a pulse oximetry reading (SpO2) <90% of 5 minutes or longer duration, survival to discharge, time from extubation to hospital discharge and total invoice cost for clinical visit. Dogs were divided into two groups, those that experienced severe hypoxemia (group A) and those in which SpO2 reading <90% was not observed throughout the procedure (group B). RESULTS: Group A had a greater risk of mortality (odds ratio 10.6, 95% confidence interval 1.9-106.7; p = 0.002), prolonged hospitalization (median 62 hours versus 46 hours; p = 0.035) and more expensive cost of care (median US$10,287 versus $8506; p = 0.056) than group B. No significant difference was found for the type of surgical procedure or pulmonary versus extrapulmonary nature of disease. CONCLUSIONS AND CLINICAL RELEVANCE: Severe intraoperative hypoxemia was statistically associated with an increased risk of mortality and longer postoperative hospitalization times. Although not achieving statistical significance, there was a trend toward increased costs to the client for animals with intraoperative hypoxemia.

Outcomes of surgical treatment with patterns of bacterial culture and antimicrobial susceptibility testing in cases of cervical abscessation in dogs: 82 cases (2018-2021).

OBJECTIVE: The objective of this study was to summarize the presentation, diagnosis, and outcome for dogs surgically treated for chronic cervical abscessation following suspected or reported cervical or oropharyngeal trauma, as well as to report on culture results and antimicrobial susceptibility patterns. RESULTS: Eighty-two dogs were identified by retrospective review. Successful surgical outcome was achieved in 92.7% of dogs. Abscess recurrence was confirmed or suspected in 6/82 (7.3%) cases, and surgical intervention for abscess recurrence was performed in 4/82 (4.9%) cases. Foreign material was identified at surgery in 5/82 (6%) cases. Incisional healing complications were noted in 9/82 (10.9%) cases and required additional surgery in 5/82 (6%) cases. Twenty-three (28%) dogs had negative culture results. The results of antimicrobial sensitivity testing led to a change in antimicrobial treatment in only 9% of cases.Surgically treated cervical abscessation carries a good prognosis with a low incidence of recurrence in this cohort (in contrast to previous reports), despite low frequency of foreign body removal or identification of the underlying cause of the abscess. Excision of chronic inflammatory tissue may not be necessary for a successful outcome, contrary to previous recommendations. Multi-pathogen infections and anaerobic infections are commonly encountered.

Trajectories of the socioeconomic gradient of mental health: Results from the CLSA COVID-19 Questionnaire Study.

As the coronavirus disease (COVID-19) pandemic prolongs, documenting trajectories of the socioeconomic gradient of mental health is important. We describe changes in the prevalence and absolute and relative income-related inequalities of mental health between April and December 2020 in Canada. We used data from the Canadian Longitudinal Study on Aging (CLSA) COVID-19 Questionnaire Study and the pre-pandemic CLSA Follow-up 1. We estimated the prevalence proportion, the concentration index (relative inequality), and the generalized concentration index (absolute inequality) for anxiety and self-reported feeling generally unwell at multiple points in April-December 2020, overall, by sex and age group, by region, and among those who reported poor or fair overall health and mental health pre-pandemic. Overall, the prevalence of anxiety remained unchanged (22.45 to 22.10%, p = 0.231), but self-reported feeling generally unwell decreased (9.83 to 5.94%, p = 0.004). Relative and absolute income-related inequalities were unchanged for both anxiety and self-reported feeling generally unwell, with exceptions of an increased concentration of self-reported feeling generally unwell among the poor, measured by the concentration index, overall (-0.054 to -0.115, p = 0.004) and in Ontario (-0.035 to -0.123, p = 0.047) and British Columbia (-0.055 to -0.141, p = 0.044). The COVID-19 pandemic appeared to neither exacerbate nor ameliorate existing income-related inequalities in mental health among older adults in Canada between April and December 2020. Continued monitoring of inequalities is necessary.

Associations of abdominal discomfort and length of clinical signs with surgical procedure in 181 cases of canine small intestinal foreign body obstruction.

BACKGROUND: Gastrointestinal foreign bodies are a common indication for abdominal exploratory surgery. OBJECTIVES: The objective of this study was to evaluate the relationship of pre-operative abdominal discomfort and duration of clinical signs with surgical resolution of canine small intestinal foreign body obstructions (SIFBO). METHODS: We performed a retrospective study of 181 canine abdominal exploratory surgeries for confirmed SIFBO at two referral hospitals. Animals were categorized into five surgical groups (gastrotomy after manipulation into the stomach, enterotomy, resection-and-anastomosis [R&A], manipulated into colon, already in colon) and further grouped by whether entry into the gastrointestinal tract (GIT) was required. RESULTS: Abdominal discomfort was noted in 107/181 cases (59.1%), but no significant differences in abdominal discomfort rates were present among the surgical groups or between GIT entry and no entry groups. Clinical sign duration was associated with surgical procedure; median durations were R&A = 3 days (range, 1-9), enterotomy = 2 days (range, 1-14), gastrotomy = 2 days (range, 1-6), already in colon = 1.5 days (range, 1-2), and manipulated into colon = 1 day (range, 1-7). In a pairwise comparison, differences in the duration of clinical signs were found for obstructions manipulated into the colon versus R&A, gastrotomy versus R&A, and in colon versus R&A. When patients were grouped according to GIT entry, cases with entry had a longer duration of clinical signs (median = 2 days [range, 1-14] versus 1 day [range, 1-7], respectively). CONCLUSIONS: Abdominal discomfort was not associated with surgical complexity; however, the duration of clinical signs was associated with surgical complexity, with longer duration being associated with entry into the GIT and R&A. Despite statistical significance, the maximum difference of 2 days between surgical groups is unlikely to be clinically relevant.

Uptake of community pharmacist prescribing over a three-year period.

Objectives: Pharmacists in Nova Scotia have had legislated authority to prescribe since 2011. This study aimed to describe the prescribing activities of pharmacists and the characteristics of patients who used pharmacist prescribing services. Methods: Using provincial health administrative databases we identified all community pharmacists who prescribed during the study period (October 2016 to March 2020) and correspondingly patients who had medications prescribed by a pharmacist during this period. Differences in, and predictors of the quantity of pharmacist prescribing over three fiscal years (April 2017 to March 2020) were described. Pharmacist prescribing activity was compared across the fiscal years of the study period with One-way Analysis of Variance. Negative binomial regression examined patient factors associated with use of pharmacist prescribing services. Analysis was carried out using SAS ENTERPRISE GUIDE v.8.2 (SAS Institute Cary, NC, USA). Key findings: A total of 1182 pharmacist prescribers were identified, who on average prescribed 24.6, 26.3, and 32.5 (p < 0.001) times per month in fiscal years 2018, 2019, 2020, respectively. The patient cohort contained 372,203 Nova Scotians over the 3-year period. For approved common and minor ailment prescribing in Nova Scotia, gastroesophageal reflux disease, vaccines (non-travel), contraceptive management, herpes zoster treatment, and allergic rhinitis had the highest number of prescriptions over the study period. Patient factors most strongly related to receiving more prescribing services by a pharmacist included receiving income assistance without copay (Incidence rate ratio (IRR) = 1.70), having >2 comorbidities (IRR = 1.51), male sex (IRR = 1.03), and greater age (IRR = 1.01). Those from an urban area (IRR = 0.92) or having a higher income (IRR = 0.95) received fewer pharmacist prescribing services (all p < 0.0001). Conclusions: Pharmacist prescribing increased over the 3-year period. Patients who were older and those with multiple comorbidities used pharmacist prescribing services most often. Prescribing activities represent an increasingly utilized role for pharmacists in primary care.

Patterns of Antipsychotic Dispensation to Long-Term Care Residents.

OBJECTIVES: To describe dispensing patterns of antipsychotic medications to long-term care (LTC) residents and assess factors associated with continuation of an antipsychotic after a fall-related hospitalization. DESIGN: A retrospective cohort study. SETTING AND PARTICIPANTS: Nova Scotia Seniors Pharmacare Program (NSSPP) beneficiaries age 66 years and older who resided in LTC and received at least 1 dispensation of an antipsychotic within the study period of April 1, 2009, to March 31, 2017. METHODS: Linkage of administrative claims data from the NSSPP and the Canadian Institute of Health Information Discharge Abstract Database identified LTC residents with an antipsychotic dispensation and from the subgroup of those dispensed antipsychotic medications who experienced a fall-related hospitalization. Antipsychotic dispensing patterns were reported with counts and means. Predictors of continuation of an antipsychotic after a fall-related hospitalization (sex, length of stay, days supplied, age, year of admission, rural/urban) were reported and analyzed with multiple logistic regression. RESULTS: There were 19,164 unique NSSPP beneficiaries who were dispensed at least 1 prescription for an antipsychotic medication. Of those who received at least 1 antipsychotic dispensation 90% (n = 17,201) resided in LTC. A mean of 40% (n = 2637) of LTC residents received at least 1 antipsychotic dispensation in each year. Risperidone and quetiapine were dispensed most frequently. Of the 544 beneficiaries residing in LTC who survived a fall-related hospitalization, 439 (80.7%) continued an antipsychotic after hospital discharge. Female sex [OR 1.7, 95% CI (1.013‒2.943)], age 66‒69 [OR 4.587, 95% CI (1.4‒20.8)], 75-79 [OR 2.8, 95% CI (1.3‒6.3)], and 80‒84 years [OR 3.1, 95% CI (1.6‒6.4)] (compared with age 90+ years) were associated with increased risk of antipsychotic continuation. CONCLUSIONS AND IMPLICATIONS: With 90% of antipsychotic dispensations in Nova Scotia being to LTC residents and 40% of LTC residents being dispensed antipsychotics in any year there is a need to address this level of antipsychotic dispensation to older adults.

Comparison of the pharmacokinetics of continuous and intermittent infusions of ampicillin-sulbactam in dogs with septic peritonitis.

OBJECTIVE: To evaluate the time-course of ampicillin-sulbactam and percentage of time that its concentration is above a given MIC (T% > MIC) in dogs with septic peritonitis when delivered as either a continuous infusion (CI) or intermittent infusion (II). ANIMALS: 11 dogs with septic peritonitis. PROCEDURES: Dogs were randomized to receive ampicillin-sulbactam as either CI or II. Continuous infusions were delivered as a 50 mg/kg bolus IV followed by a rate of 0.1 mg/kg/min. Intermittent infusions were administered as 50 mg/kg IV q8h. Serum ampicillin-sulbactam concentrations were measured at hours 0, 1, 6, and every 12 hours after until patients were transitioned to an oral antimicrobial equivalent. All other care was at the discretion of the attending clinician. Statistical analysis was used to determine each patient's percentage of time T% > MIC for 4 MIC breakpoints (0.25, 1.25, 8, and 16 µg/mL). RESULTS: No dogs experienced adverse events related to ampicillin-sulbactam administration. Both CI and II maintained a T% > MIC of 100% of MIC 0.25 µg/mL and MIC 1.25 µg/mL. The CI group maintained a higher T% > MIC for MIC 8 µg/mL and MIC 16 µg/mL; however, these differences did not reach statistical significance (P = .15 and P = .12, respectively). CLINICAL RELEVANCE: This study could not demonstrate that ampicillin-sulbactam CI maintains a greater T% > MIC in dogs with septic peritonitis than II; however, marginal differences were noted at higher antimicrobial breakpoints. While these data support the use of antimicrobial CI in septic and critically ill patients, additional prospective trials are needed to fully define the optimal doses and the associated clinical responses.

Has medical assistance in dying changed end-of-life care in the ICU? A qualitative survey of Canadian intensivists.

PURPOSE: Since 2016, Canada has permitted medical assistance in dying (MAID). Our aims were to understand how Canadian intensivists view MAID and the impact of MAID on end-of-life care in the ICU. MATERIAL AND METHODS: This was a descriptive qualitative study of responses from a 41-item questionnaire. We recruited intensivists and trainees from 11 pediatric ICU programs and 14 adult ICU programs across Canada between December 2019 and May 2020. Two qualitative researchers inductively coded responses and then conducted preliminary thematic analysis. Themes were subsequently refined through group discussion. RESULTS: We obtained 150 complete questionnaires (33% response rate), of which 50% were adult practitioners and 50% pediatric. We identified six main themes including: intensivists have a wide range of opinions on MAID; MAID has not changed ICU practice; and moral distress has a diverse impact on practice. Physicians also discussed the role of provider intent and the importance of treating withdrawal of life-sustaining treatments (WLST) as a process to protect patients, families, and providers. CONCLUSIONS: Canadian intensivists hold a wide range of opinions on MAID, but most agree it has not changed ICU practice. Importantly, intensivists also hold differing views on the relevance of physician intent in medical ethics.

Genomic landscapes of canine splenic angiosarcoma (hemangiosarcoma) contain extensive heterogeneity within and between patients.

Cancer genomic heterogeneity presents significant challenges for understanding oncogenic processes and for cancer's clinical management. Variation in driver mutation frequency between patients with the same tumor type as well as within an individual patients' cancer can shape the use of mutations as diagnostic, prognostic, and predictive biomarkers. We have characterized genomic heterogeneity between and within canine splenic hemangiosarcoma (HSA), a common naturally occurring cancer in pet dogs that is similar to human angiosarcoma (AS). HSA is a clinically, physiologically, and genomically complex canine cancer that may serve as a valuable model for understanding the origin and clinical impact of cancer heterogeneity. We conducted a prospective collection of 52 splenic masses from 43 dogs (27 HSA, 15 benign masses, and 1 stromal sarcoma) presenting for emergency care with hemoperitoneum secondary to a ruptured splenic mass. Multi-platform genomic analysis included matched tumor/normal targeted sequencing panel and exome sequencing. We found candidate somatic cancer driver mutations in 14/27 (52%) HSAs. Among recurrent candidate driver mutations, TP53 was most commonly mutated (30%) followed by PIK3CA (15%), AKT1 (11%), and CDKN2AIP (11%). We also identified significant intratumoral genomic heterogeneity, consistent with a branched evolution model, through multi-region exome sequencing of three distinct tumor regions from selected primary splenic tumors. These data provide new perspectives on the genomic landscape of this veterinary cancer and suggest a cross-species value for using HSA in pet dogs as a naturally occurring model of intratumoral heterogeneity.

Pharmacokinetic Exposures Associated With Oral Administration of Sorafenib in Dogs With Spontaneous Tumors.

Sorafenib is a multi-kinase small molecule inhibitor that targets serine/threonine and tyrosine kinases including the RAF kinase family, VEGFR-2, and PDGFR. The aim of this study was to evaluate the systemic pharmacokinetics of a previously defined tolerable oral dose of sorafenib in tumor-bearing dogs. Six client-owned dogs with a cytologic or histologic diagnosis of cancer were enrolled in this open-label, tolerability study. Dogs were administered sorafenib at an intended dose of 3 mg/kg and serum samples were obtained for analysis of sorafenib serum concentrations at 0, 1, 2, 6, 12, 24, 48, 72, 96, and 168 h post-drug administration. Median time to peak serum sorafenib concentration occurred at 4 h (range 2-12 h) resulting in an average serum concentration of 54.9 ± 33.5 ng/mL (118.2 ± 72.1 nM). Mean sorafenib levels declined by over 70% relative to peak serum concentrations by 24 h in all dogs, suggesting the value of at least twice daily administration. Doses of 3 mg/kg were well-tolerated and no patients in the study experienced adverse events that were attributable to sorafenib. Future trials in dogs with cancer are recommended at this dosing schedule to assess the effect of sorafenib administration on anti-tumor efficacy signals and relevant pharmacodynamic target modulation in vivo.

Simultaneous monitoring of HIV viral load and screening of SARS-CoV-2 employing a low-cost RT-qPCR test workflow.

The COVID-19 pandemic interrupted routine care for individuals living with HIV, putting them at risk of virologic failure and HIV-associated illness. Often this population is at high risk for exposure to SARS-CoV-2 infection, and once infected, for severe disease. Therefore, close monitoring of HIV plasma viral load (VL) and screening for SARS-CoV-2 infection are needed. We developed a non-proprietary method to isolate RNA from plasma, nasal secretions (NS), or both. The extracted RNA is then submitted to RT-qPCR to estimate the VL and classify HIV/SARS-CoV-2 status (i.e., HIV virologic failure or suppressed; SARS-CoV-2 as positive, presumptive positive, negative, or indeterminate). In contrived samples, the in-house RNA extraction workflow achieved a detection limit of 200-copies per mL for HIV RNA in plasma and 100-copies per mL for SARS-CoV-2 RNA in NS. Similar detection limits were observed for HIV and SARS-CoV-2 in pooled plasma/NS contrived samples. When comparing in-house with standard extraction methods, we found high agreement (>0.91) between input and measured RNA copies for HIV LTR in contrived plasma; SARS-CoV-2 N1/N2 in contrived NS; and LTR, N1, and N2 in pooled plasma/NS samples. We further evaluated this workflow on 133 clinical specimens: 40 plasma specimens (30 HIV-positive), 67 NS specimens (31 SARS-CoV-2-positive), and 26 combined plasma/NS specimens (26 HIV-positive with 10 SARS-CoV-2-positive), and compared the results obtained using the in-house RNA extraction to those using a commercial kit (standard extraction method). The in-house extraction and standard extraction of clinical specimens were positively correlated: plasma HIV VL (R2 of 0.81) and NS SARS-CoV-2 VL (R2 of 0.95 and 0.99 for N1 and N2 genes, respectively); and pooled plasma/NS HIV VL (R2 of 0.71) and SARS-CoV-2 VL (R2 of 1 both for N1 and N2 genes). Our low-cost molecular test workflow ($1.85 per pooled sample extraction) for HIV RNA and SARS-CoV-2 RNA could serve as an alternative to current standard assays ($12 per pooled sample extraction) for laboratories in low-resource settings.

A potential early clinical phenotype of necrotizing meningoencephalitis in genetically at-risk pug dogs.

BACKGROUND: Necrotizing meningoencephalitis (NME) in the pug dogs is a fatal neuroinflammatory disease associated with rapid progression and poor response to conventional immunosuppressive therapy. Diagnosis is typically made after severe neurological abnormalities have manifested. HYPOTHESIS/OBJECTIVE: Pug dogs at genetic risk for NME might manifest neurological abnormalities before developing pathognomonic clinical signs of NME. ANIMALS: Thirty-six pug dogs less than 4 years of age asymptomatic for NME. METHODS: Prospective observational cohort study with germline genome-wide genotyping. Neurological examinations were performed 4 weeks apart to document reproducible findings of central nervous system disease. Magnetic resonance imaging, cerebrospinal fluid analysis, and testing for infectious diseases were performed in all pugs with reproducible abnormalities detected on neurological examination. RESULTS: The overall risk allele frequency in this cohort was 40%; 5 (14%) dogs were high risk, 19 (53%) dogs were medium risk, and 12 (33%) dogs were low genetic risk for NME. Reproducible abnormalities detected on neurological examination were identified in 8/24 (33%) genetically at-risk dogs and 0/12 (0%) low risk dogs. Clinical abnormalities included multifocal spinal pain in 8/8, reduced menace response in 5/8, and lateralizing postural reaction deficits in 5/8 pugs. There was a strong association between genotype risk and the presence of this clinical phenotype (P = .03). CONCLUSIONS AND CLINICAL IMPORTANCE: Our findings suggest the presence of a novel early clinical phenotype of NME in apparently asymptomatic genetically at-risk pugs which might be used to plan early diagnostic and therapeutic clinical trials.