Anti-drug Antibody Magnitude and Clinical Relevance Using Signal to Noise (S/N): Bococizumab Case Study.

Historically, the biopharmaceutical industry has used titer to characterize the magnitude of an anti-drug antibody (ADA) response. While reporting levels of antibodies in terms of titer is generally understood and accepted by regulatory and medical communities, titer values are inherently variable given the multiple serial dilutions and reporting a value either directly before or interpolated at the assay cut point on the lower plateau of the assay curve range. Using S/N is an appealing alternative approach to titer as it simplifies analysis with less dilutions, significantly reducing testing, time, and resources and provides a more precise value potentially differentiating low-level ADA responses. Current bridging electrochemiluminescence (ECL) ADA assays using Meso Scale Discovery (MSD) platform are also significantly more sensitive and drug tolerant with wider assay ranges compared to historic ELISA platforms; therefore, ADA response based on S/N may help differentiate and identify those ADA samples that are more likely to be clinically relevant. Bococizumab is a humanized monoclonal antibody targeting proprotein convertase subtilisin-kexin type 9 (PCSK9), which reduces plasma levels of low-density lipoprotein (LDL) cholesterol. Bococizumab was discontinued during Phase 3 clinical development based in part on the high rate of ADA and wide variation in LDL cholesterol responses among patients. The impact of anti-bococizumab antibodies on pharmacokinetic (PK) and pharmacodynamic (PD) endpoints was originally assessed using titer. Retrospective analysis of anti-bococizumab ADA responses using S/N ratios illustrates that S/N is an acceptable alternative to titer for characterizing the magnitude of ADA response and interpretation of clinically relevant ADA.

Computed tomography angiography aids in predicting resectability of isolated liver tumors in dogs.

OBJECTIVE: To assess the accuracy of CT angiography (CTA) in predicting resectability, degree of surgical difficulty, and individual factors that may impact resectability of isolated hepatic masses in dogs. ANIMALS: Prospective study of 20 dogs with 21 isolated hepatic masses. PROCEDURES: All CTAs and surgeries were performed between June 16, 2013, and November 30, 2016, at The Animal Medical Center in New York. Preoperative CTA images were evaluated by a board-certified surgeon (n = 2). A preoperative assessment was completed, documenting several predetermined factors aimed at predicting resectability of each mass and the degree of surgical difficulty. Resectability was divided into gross resectability and complete histologic excision. Following surgery, the surgeon completed a postoperative assessment documenting the intraoperative findings. Independently, a blinded board-certified radiologist analyzed the images and completed an identical preoperative assessment. RESULTS: The radiologist was more accurate in lesion localization compared to the surgeon (P = .023). Seventeen (17/21) masses were grossly resectable in surgery. Two additional (2/21) masses that were deemed grossly resectable were incompletely excised on histopathologic analysis. Both the surgeon and radiologist were accurate in their prediction of gross resectability and complete excision. Major vascular involvement, multilobar involvement, and right-sided laterality negatively affected resectability. The surgeon was significantly more accurate in predicting the degree of surgical difficulty (κ = 0.50) when compared to the radiologist (κ = 0.38). CLINICAL RELEVANCE: Preoperative CTA of isolated hepatic masses is useful in prediction of surgical difficulty and resectability, as well as identifying several factors that impact resectability.

Comparing two durations of medically tailored meals posthospitalization: A randomized clinical trial.

BACKGROUND: Medically tailored meals (MTM) may be beneficial to patients after hospital discharge. OBJECTIVE: To determine if 2 versus 4 weeks of MTM posthospitalization will improve patient outcomes. DESIGN: Randomized unblinded trial. SETTINGS AND PARTICIPANTS: Six hundred and fifty patients pending hospital discharge with at least one chronic condition. INTERVENTION: One MTM a day for 2 versus 4 weeks. MAIN OUTCOME AND MEASURES: The primary outcome was a change from baseline to 60 days in the Hospital Anxiety Depression Scale (HADS). Secondary outcomes measured change in the Katz activities of daily living (ADLs), DETERMINE nutritional risk, and all-cause emergency department (ED) visits and rehospitalizations. RESULTS: From baseline to 60 days the HADS anxiety subscale changed 5.4-4.9 in the 2-week group (p = .03) and 5.4-5.3 in the 4-week group (p = .49); the difference in change between groups 0.4 (p = .25). HADS changed 5.4-4.8 in the 2-week group (p = .005) and 5.3-5.1 in the 4-week group (p = .34); the difference in change between groups 0.4 (p = .18). ADL score changed from 5.3 to 5.6 in the 2-week group (p ≤ .0001) and 5.2-5.5 in the 4-week group (p ≤ .0001); the difference in change between groups -0.01 (p = .90). The DETERMINE changed in the 2-week group from 7.2 to 6.4 (p = .0006) and from 7 to 6.7 in the 4-week group (p = .19); the difference in change between groups 0.5 (p = .13). There was no difference in ED visits and rehospitalizations between groups or time to rehospitalization. CONCLUSIONS: Different durations of short-term MTM did not affect patient-centered or utilization outcomes.

Association of an Advance Care Planning Video and Communication Intervention With Documentation of Advance Care Planning Among Older Adults: A Nonrandomized Controlled Trial.

Importance: COVID-19 has disproportionately killed older adults and racial and ethnic minority individuals, raising questions about the relevance of advance care planning (ACP) in this population. Video decision aids and communication skills training offer scalable delivery models. Objective: To assess whether ACP video decision aids and a clinician communication intervention improved the rate of ACP documentation during an evolving pandemic, with a focus on African American and Hispanic patients. Design, Setting, and Participants: The Advance Care Planning: Communicating With Outpatients for Vital Informed Decisions trial was a pre-post, open-cohort nonrandomized controlled trial that compared ACP documentation across the baseline pre-COVID-19 period (September 15, 2019, to March 14, 2020), the COVID-19 wave 1 period (March 15, 2020, to September 14, 2020), and an intervention period (December 15, 2020, to June 14, 2021) at a New York metropolitan area ambulatory network of 22 clinics. All patients 65 years or older who had at least 1 clinic or telehealth visit during any of the 3 study periods were included. Main Outcomes and Measures: The primary outcome was ACP documentation. Results: A total of 14 107 patients (mean [SD] age, 81.0 [8.4] years; 8856 [62.8%] female; and 2248 [15.9%] African American or Hispanic) interacted with clinicians during the pre-COVID-19 period; 12 806 (mean [SD] age, 81.2 [8.5] years; 8047 [62.8%] female; and 1992 [15.6%] African American or Hispanic), during wave 1; and 15 106 (mean [SD] 80.9 [8.3] years; 9543 [63.2%] female; and 2535 [16.8%] African American or Hispanic), during the intervention period. Clinicians documented ACP in 3587 patients (23.8%) during the intervention period compared with 2525 (17.9%) during the pre-COVID-19 period (rate difference [RD], 5.8%; 95% CI, 0.9%-7.9%; P = .01) and 1598 (12.5%) during wave 1 (RD, 11.3%; 95% CI, 6.3%-12.1%; P < .001). Advance care planning was documented in 447 African American patients (30.0%) during the intervention period compared with 233 (18.1%) during the pre-COVID-19 period (RD, 11.9%; 95% CI, 4.1%-15.9%; P < .001) and 130 (11.0%) during wave 1 (RD, 19.1%; 95% CI, 11.7%-21.2%; P < .001). Advance care planning was documented for 222 Hispanic patients (21.2%) during the intervention period compared with 127 (13.2%) during the pre-COVID-19 period (RD, 8.0%; 95% CI, 2.1%-10.9%; P = .004) and 82 (10.2%) during wave 1 (RD, 11.1%; 95% CI, 5.5%-14.5%; P < .001). Conclusions and Relevance: This intervention, implemented during the evolving COVID-19 pandemic, was associated with higher rates of ACP documentation, especially for African American and Hispanic patients. Trial Registration: ClinicalTrials.gov Identifier: NCT04660422.

Current Concepts in Urinary Surgery.

Management of canine and feline ureteral obstructions and urinary incontinence can be both controversial and frustrating. There has been a movement toward minimally invasive procedures, which in certain cases, can be used to both confirm the diagnosis as well as treat the condition. This chapter focuses on the advancements in urologic surgery associated with ureteral obstruction and urinary incontinence with primary focus on ureteral stenting, subcutaneous ureteral bypass systems, transurethral bulking agents, and hydraulic occluders.

Hepatitis a Vaccine Promotion Using Facebook Ads to Reach At-Risk Groups.

PURPOSE: To evaluate using Facebook ads to promote hepatitis A vaccination to at-risk groups. DESIGN: This descriptive research study used Facebook ads and posts to deliver a social media health campaign. SETTING: The social networking site Facebook was used to target audiences in the United States. SUBJECTS: Adults in the United States with Facebook accounts were the general audience with at-risk audiences having interests or profile attributes in either LGBTQ or food service groups. MEASURES: Facebook Ads Manager was used to determine impressions, engagement rates, link clicks, and cost per result of the ads. These metrics were measured to examine the use of Facebook ads and targeting audiences. ANALYSIS: Quantitative data were analyzed using descriptive statistics, and the Pearson correlation coefficient analysis was used to determine if the amount spent on each ad had any correlation with reach, results, cost per result, or impressions. RESULTS: The campaign resulted in a reach of 53 422 users, 70 542 impressions, 457 unique link clicks (483 link clicks), an average cost per results of $0.92 USD, and the total amount spent of $445.68 USD. The amount spent was positively correlated with reach (r = .969), results (r = .994), cost per result (r = .841), and impressions (r =.957). CONCLUSION: The social media health campaign was effective in reaching an audience about hepatitis A vaccination. Using interest groups was not more cost-effective than a using a general audience for link clicks.

Dominant outflow vein occlusion in the management of naturally occurring peripheral arteriovenous anomalies in cats and dogs.

Two dogs and 1 cat were referred to a tertiary veterinary center for the consultation and treatment of limb edema, variable dermal sanguineous crusting lesions, and intermittent lameness. A peripheral arteriovenous anomaly (PAA) was diagnosed via computed tomographic angiography (CTA) in each case. Arteriography enabled further evaluation of the PAA with confirmation of a dominant outflow vein. Dominant outflow vein occlusion was achieved by direct ligation in 1 dog and retrograde transvenous glue embolization in the cat and other dog. Repeat arteriography demonstrated resolution of arteriovenous shunting. Presenting clinical signs resolved in all animals. The previously identified aberrant vessels in 1 dog were not identified after CTA 40 days postoperatively. No postoperative complications or recurrence was identified in any case during the 6- to 55-month follow-up period.

Comprehensive Reentry Policy for Student Registered Nurse Anesthetists With Substance Use Disorder.

Substance use disorder (SUD) is a common problem in anesthesia. Although there are SUD policies in place for practicing anesthetists, there were no known studies before this inquiry discussing reentry policies specific to the student registered nurse anesthetist (SRNA). The purpose of this research was to describe key stakeholders' knowledge and perspectives surrounding policies for reentry into academic programs in Illinois for SRNAs with SUD and to create a comprehensive structured policy template for SRNAs with SUD. The theoretical framework for this research was based on the Biopsychosocial Theory. Between November 2017 and January 2018, qualitative interviews, using a semistructured interview guide, were conducted with anesthesiologists and Certified Registered Nurse Anesthetists (CRNAs) from throughout Illinois (n = 4). The interviews were audiorecorded, transcribed, and analyzed using thematic analysis. All participants stated that they did not have a policy in place to address SRNAs with SUD, yet 50% (2/4) reported knowing a student who had experienced SUD. Institutions that educate and use SRNA services should have a comprehensive reentry policy in place, which includes an option for SRNAs recovering from SUD to reenter their educational program. A policy template is provided for use by academic anesthesia programs.

The association between sugar-sweetened beverage availability in school vending machines and school staff sugar-sweetened beverage consumption.

Reducing sugar-sweetened beverage (SSB) consumption is a leading strategy to help combat high rates of adult obesity and overweight. Regulating SSB sales in schools has reduced access among youth. However, current federal school nutrition standards are focused on student rather than staff environments (i.e. school staff lounges). This study examines the association between the availability of SSBs in school vending machines and school staff SSB consumption. The study sample included 51 public schools in California, Oregon, Washington, Maryland, and Washington DC participating in an evaluation of Kaiser Permanente's Thriving Schools initiative in school year 2017-18. Data collection included: 1) observations of school cafeterias, staff lounges, stores and outdoor snack areas for the presence of, and content in, vending machines, and 2) an online survey of school staff about their SSB consumption. Fifty-nine percent (n = 1586) of staff responded to the survey; 1229 (77% of respondents) reported on SSB consumption. Thirty percent of schools had staff lounges with SSB vending machines and 34% of staff reported drinking ≥1 SSBs/day. On average, the probability of consuming ≥1 SSBs/day was 6.6% greater in staff in schools with SSBs available in staff lounge vending machines (95% CI: 0.11%, 13.12%). Staff in schools with SSB vending machines in staff lounges were more likely to report consuming ≥1 SSBs per day compared to staff without SSB vending in staff lounges. Examining the impact of extending SSB regulations to the entire school environment on school staff SSB consumption is an important next step.

Retrospective multicentric study comparing durations of surgery and anesthesia and likelihoods of short- and long-term complications between cats positioned in sternal or dorsal recumbency for perineal urethrostomy.

OBJECTIVE: To compare the durations of surgery and anesthesia and the likelihoods of short- and long-term postoperative complications between cats positioned in sternal recumbency versus dorsal recumbency for perineal urethrostomy (PU). ANIMALS: 247 client-owned cats that underwent PU between January 2004 and December 2015 at 6 veterinary teaching hospitals and 1 private veterinary referral hospital. PROCEDURES: Medical records were reviewed, and signalment, presenting complaints, previous history of urethral obstruction or PU, diet fed, medications administered, indication for PU, durations of surgery and anesthesia for PU, suture type and size, suture pattern for skin closure, and short- and long-term postoperative complications were recorded. Univariable and multivariable analyses were performed to identify differences in durations of surgery and anesthesia and the likelihoods of short- and long-term complications between cats positioned in sternal recumbency and those positioned in dorsal recumbency. RESULTS: Patient position was not associated with durations of surgery and anesthesia for PU, even if a concurrent cystotomy was necessary or the patient required repositioning from sternal to dorsal recumbency. Likewise, patient position was not associated with the likelihood of short- and long-term complications. CONCLUSIONS AND CLINICAL RELEVANCE: The observed lack of differences in outcomes between sternal and dorsal recumbency suggested that logistic considerations and personal preference can continue to guide veterinarians when positioning cats for PU.

Prospective Evaluation of Feline Sourced Platelet-Rich Plasma Using Centrifuge-Based Systems.

Objective: To evaluate the hematologic components of platelet-rich plasma (PRP) generated using feline blood with two commercially available centrifuge-based systems,. Materials and methods: Twenty healthy adult cats were enrolled in this prospective study from November 2018 to January 2019. Feline blood samples were obtained for analysis of whole blood (WB) cellular components and preparation of PRP product. PRP was prepared using two commercial systems and complete blood count (CBC) testing was performed on both WB and PRP samples. The cellular composition of the PRP product was compared to the WB sample for each patient. Results: Both systems showed significant decrease of median RBC concentration in PRP products compared to WB samples (P = 0.002 for both systems). System 1 significantly decreased median WBC concentration (P = 0.002). System 2 decreased WBC concentration, though statistical significance was not reached (P = 0.63). Median platelet concentration was decreased by 3% using System 1, and increased by 187% using System 2. Platelet aggregation presented a challenge with 8/20 (40%) of samples demonstrating platelet aggregation. Clinical relevance: Commercial systems available for generation of PRP may be useful for creating a feline sourced product and in this study showed promise in decreasing RBC and WBC concentration. Neither system tested achieved 2-5 times platelet concentration from baseline. Platelet aggregation presented a significant obstacle to reliable generation of PRP products using feline blood. This treatment modality may be particularly beneficial for feline patients with osteoarthritis and soft tissue injuries, though first characterizing the PRP product made using feline blood is critical to validate its use in further clinical studies.

Assessing the Potential Risk of Cross-Reactivity Between Anti-Bococizumab Antibodies and Other Anti-PCSK9 Monoclonal Antibodies.

BACKGROUND: Anti-drug antibodies (ADAs) to bococizumab were detected in > 40% of subjects in the SPIRE lipid-lowering trials. The risk of cross-reactivity between anti-bococizumab antibodies and other approved anti-proprotein convertase subtilisin/kexin type-9 (PCSK9) monoclonal antibodies (mAbs) was investigated using a single-assay approach. METHODS: Bococizumab immunogenicity was assessed in SPIRE-HR, a 52-week study. The highest ADA titer sample from each ADA-positive subject (n = 155) was tested in vitro for cross-reactivity to alirocumab and evolocumab using a novel ADA assay approach. Additional specificity tiers within the bococizumab ADA assay against each drug were validated using recombinant PCSK9 as a surrogate cross-reactive positive control. If the highest ADA titer sample showed cross-reactivity, additional samples from that subject were analyzed. Cross-reactivity was determined by the ability of alirocumab or evolocumab to inhibit the sample signal greater than or equal to the cross-reactivity cut-points. RESULTS: ADAs were detected in 44.0% (155/352) of bococizumab-treated subjects, and 27.0% also developed neutralizing antibodies (NAbs). Median ADA and NAb titers ranged from 276 to 526 and 8 to 12 over the course of the study, respectively. From 155 ADA-positive subjects tested for cross-reactivity, one (0.6%) subject showed weak cross-reactivity to both alirocumab and evolocumab. This cross-reactivity signal was transient (from Days 337 to 373) and undetectable at the last ADA-positive timepoint (Day 407). CONCLUSION: A novel, single-assay approach was validated to assess the potential cross-reactivity of anti-bococizumab antibodies to alirocumab and evolocumab. In subjects who developed ADAs to bococizumab, the likelihood of clinically relevant cross-reactivity to marketed anti-PCSK9 mAbs is remote, based on the low frequency of cross-reactivity observed, which was weak in signal inhibition and transient in nature. CLINICAL TRIAL REGISTRATION: The SPIRE-HR study is registered on ClinicalTrials.gov under the identifier NCT01968954.

Comparison of Initial and Postlavage Bacterial Culture Results of Septic Peritonitis in Dogs and Cats.

Septic peritonitis is a common, life-threatening condition encountered in dogs and cats. Efficacy of peritoneal lavage has not been proven in veterinary studies. Our objective was to evaluate differences in bacterial identity and susceptibility in samples obtained pre- and postlavage in animals who underwent laparotomy for treatment of septic peritonitis and to assess the effect of empirical antimicrobial selection on survival. Culture samples were collected from the peritoneal surface pre- and postlavage from dogs and cats treated surgically for septic peritonitis. Culture results were compared for each patient with regard to bacterial isolates and bacterial susceptibility profiles. Survival to discharge was evaluated. Microbial growth occurred in at least one culture in 88.6% of patients. There was no significant difference in bacterial isolates or susceptibility profiles pre- versus postlavage. Positive culture pre- or postlavage and appropriate antimicrobial selection did not significantly affect survival. For individual animals, culture results differed between pre- and postlavage samples, although no definitive effect of peritoneal lavage was seen for the population as a whole. Antimicrobials most commonly effective against isolates were Cefotaxime, Ceftazidime, and Imipenem. If prompt surgical source control is employed, antibiotic choice may not affect clinical outcome.

Dose as a Tool for Planning and Implementing Community-Based Health Strategies.

A major challenge in community-based health promotion is implementing strategies that could realistically improve health at the population level. Population dose methodology was developed to help understand the combined impact of multiple strategies on population-level health behaviors. This paper describes one potential use of dose: as a tool for working collaboratively with communities to increase impact when planning and implementing community-level initiatives. Findings are presented from interviews conducted with 11 coordinators who used dose for planning and implementing local efforts with community coalitions. During early-stage planning, dose was used as a tool for strategic planning, and as a framework to build consensus among coalition partners. During implementation, a dose lens was used to revise strategies to increase their reach (the number of people exposed to the intervention) or strength (the relative change in behavior for each exposed person) to create population-level impact. A case study is presented, illustrating how some community coalitions and evaluators currently integrate dose into the planning and implementation of place-based healthy eating and active living strategies. Finally, a planning checklist was developed for program coordinators and evaluators. SUPPLEMENT INFORMATION: This article is part of a supplement entitled Building Thriving Communities Through Comprehensive Community Health Initiatives, which is sponsored by Kaiser Permanente, Community Health.

Using Population Dose to Evaluate Community-level Health Initiatives.

Successful community-level health initiatives require implementing an effective portfolio of strategies and understanding their impact on population health. These factors are complicated by the heterogeneity of overlapping multicomponent strategies and availability of population-level data that align with the initiatives. To address these complexities, the population dose methodology was developed for planning and evaluating multicomponent community initiatives. Building on the population dose methodology previously developed, this paper operationalizes dose estimates of one initiative targeting youth physical activity as part of the Kaiser Permanente Community Health Initiative, a multicomponent community-level obesity prevention initiative. The technical details needed to operationalize the population dose method are explained, and the use of population dose as an interim proxy for population-level survey data is introduced. The alignment of the estimated impact from strategy-level data analysis using the dose methodology and the data from the population-level survey suggest that dose is useful for conducting real-time evaluation of multiple heterogeneous strategies, and as a viable proxy for existing population-level surveys when robust strategy-level evaluation data are collected. SUPPLEMENT INFORMATION: This article is part of a supplement entitled Building Thriving Communities Through Comprehensive Community Health Initiatives, which is sponsored by Kaiser Permanente, Community Health.

A Community-Level Initiative to Prevent Obesity: Results From Kaiser Permanente's Healthy Eating Active Living Zones Initiative in California.

INTRODUCTION: A growing number of health systems are leading health promotion efforts in their wider communities. What impact are these efforts having on health behaviors and ultimately health status? This paper presents evaluation results from the place-based Kaiser Permanente Healthy Eating Active Living Zones obesity prevention initiative, implemented in 2011-2015 in 12 low-income communities in Kaiser Permanente's Northern and Southern California Regions. METHODS: The Healthy Eating Active Living Zones design targeted places and people through policy, environmental, and programmatic strategies. Each Healthy Eating Active Living Zone is a small, low-income community of 10,000 to 20,000 residents with high obesity rates and other health disparities. Community coalitions planned and implemented strategies in each community. A population-dose approach and pre and post surveys were used to assess impact of policy, program, and environmental change strategies; the analysis was conducted in 2016. Population dose is the product of reach (number of people affected by a strategy divided by target population size) and strength (the effect size or relative change in behavior for each person exposed to the strategy). RESULTS: More than 230 community change strategies were implemented over 3 years, encompassing policy, environmental, and programmatic changes as well as efforts to build community capacity to sustain strategies and make changes in the future. Positive population-level results were seen for higher-dose strategies, particularly those targeting youth physical activity. Higher-dose strategies were more likely to be found in communities with the longest duration of investment. CONCLUSIONS: These results demonstrate that strong (high-dose), community-based obesity prevention strategies can lead to improved health behaviors, particularly among youth in school settings. SUPPLEMENT INFORMATION: This article is part of a supplement entitled Building Thriving Communities Through Comprehensive Community Health Initiatives, which is sponsored by Kaiser Permanente, Community Health.

Multiple-dose ponezumab for mild-to-moderate Alzheimer's disease: Safety and efficacy.

INTRODUCTION: Multiple intravenous doses of ponezumab, an anti-amyloid antibody, were evaluated in subjects with mild-to-moderate Alzheimer's disease (AD). METHODS: In part A, 77 subjects were randomized to ponezumab 0.1, 0.5, or 1 mg/kg (75 treated) and 26 to placebo (24 treated). In part B, 63 subjects were randomized and treated with ponezumab 3 or 8.5 mg/kg and 32 with placebo. Subjects received 10 infusions over 18 months and were followed for 6 months thereafter. RESULTS: Ponezumab was generally safe and well tolerated. Most common adverse events were fall (16.7% ponezumab, 21.4% placebo), headache (13.8%, 21.4%), and cerebral microhemorrhage (13.8%, 19.6%). Plasma ponezumab increased dose-dependently with limited accumulation. Cerebrospinal fluid penetration was low. Plasma Aß1-x and Aß1-40 showed robust increases, but cerebrospinal fluid biomarkers showed no dose response. Ponezumab had no effects on cognitive/functional outcomes or brain volume. CONCLUSIONS: Multiple-dose ponezumab was generally safe, but not efficacious, in mild-to-moderate AD.

Ponezumab in mild-to-moderate Alzheimer's disease: Randomized phase II PET-PIB study.

INTRODUCTION: The safety, pharmacokinetics, and effect on peripheral and central amyloid ß (Aß) of multiple doses of ponezumab, an anti-Aß monoclonal antibody, were characterized in subjects with mild-to-moderate Alzheimer's disease treated for 1 year. METHODS: Subjects were aged ≥50 years with Mini-Mental State Examination scores 16 to 26. Cohort Q was randomized to ponezumab 10 mg/kg (n = 12) or placebo (n = 6) quarterly. Cohort M was randomized to a loading dose of ponezumab 10 mg/kg or placebo, followed by monthly ponezumab 7.5 mg/kg (n = 12) or placebo (n = 6), respectively. RESULTS: Ponezumab was generally well tolerated. Plasma concentrations increased dose dependently, but cerebrospinal fluid (CSF) penetration was low. Plasma Aß increased dose dependently with ponezumab, but CSF biomarkers, brain amyloid burden, cognition, and function were not affected. CONCLUSIONS: Both ponezumab dosing schedules were generally safe and well tolerated but did not alter CSF biomarkers, brain amyloid burden, or clinical outcomes.

Splenomegaly in small-breed dogs: 45 cases(2005-2011).

OBJECTIVE To assess causes of splenomegaly and postsurgical outcomes in small-breed (ie, < 16-kg [< 35.2-lb]) dogs that underwent splenectomy and evaluate associations among malignant disease, hemoperitoneum, and survival time in these patients. DESIGN Retrospective case series. ANIMALS 45 client-owned dogs. PROCEDURES Medical records of 2 veterinary facilities were reviewed to identify small-breed dogs that underwent splenectomy and had a histologic diagnosis recorded. Data analyzed included signalment, diagnosis, presence or absence of hemoperitoneum, and survival time. RESULTS 21 dogs had malignant neoplasia and 24 had benign splenic diseases. Hemangiosarcoma was the most common malignancy (14/21 [67%] dogs) and lymphoid nodular hyperplasia, hematoma, or extramedullary hematopoiesis (alone or in combination) was most commonly diagnosed in dogs with benign disease (17/24 [71%]). Wheaton Terriers were significantly more likely to have malignant splenic disease than were dogs of other breeds. Malignant splenic disease and the presence of hemoperitoneum had significant negative associations with survival time. Malignant disease was not significantly associated with the presence of hemoperitoneum. CONCLUSIONS AND CLINICAL RELEVANCE Causes for splenomegaly and survival times were similar to those previously reported for populations that primarily included large-breed dogs. There were approximately equal numbers of benign and malignant causes for splenomegaly in this population. Results suggested that Wheaton Terriers with splenomegaly had a higher likelihood of malignant neoplasia than other breeds and that hemoperitoneum may not be a significant predictor of malignancy in small-breed dogs. However, further research including a larger number of dogs is needed to confirm these findings. (J Am Vet Med Assoc 2017;250:1148-1154).