Lipid-Reduction Variability and Antidrug-Antibody Formation with Bococizumab.

BACKGROUND: Bococizumab, a humanized monoclonal antibody targeting proprotein convertase subtilisin-kexin type 9 (PCSK9), reduces levels of low-density lipoprotein (LDL) cholesterol. However, the variability and durability of this effect are uncertain. METHODS: We conducted six parallel, multinational lipid-lowering trials enrolling 4300 patients with hyperlipidemia who were randomly assigned to receive 150 mg of bococizumab or placebo subcutaneously every 2 weeks and who were followed for up to 12 months; 96% were receiving statin therapy at the time of enrollment. The patients were assessed for lipid changes over time, stratified according to the presence or absence of antidrug antibodies detected during the treatment period. RESULTS: At 12 weeks, patients who received bococizumab had a reduction of 54.2% in the LDL cholesterol level from baseline, as compared with an increase of 1.0% among those who received placebo (absolute between-group difference, -55.2 percentage points). Significant between-group differences were also observed in total cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) (P<0.001 for all comparisons). However, high-titer antidrug antibodies developed in a substantial proportion of the patients who received bococizumab, which markedly diminished the magnitude and durability of the reduction in LDL cholesterol levels. In addition, among patients with no antidrug antibodies, there was wide variability in the reduction in LDL cholesterol levels at both 12 weeks and 52 weeks. Major cardiovascular events occurred in 57 patients (2.5%) who received bococizumab and in 55 (2.7%) who received placebo (hazard ratio, 0.96; 95% confidence interval, 0.66 to 1.39; P=0.83). The most common adverse event among patients who received bococizumab was injection-site reaction (12.7 per 100 person-years). CONCLUSIONS: In six multinational trials evaluating bococizumab, antidrug antibodies developed in a large proportion of the patients and significantly attenuated the lowering of LDL cholesterol levels. Wide variation in the relative reduction in cholesterol levels was also observed among patients in whom antidrug antibodies did not develop. (Funded by Pfizer; SPIRE ClinicalTrials.gov numbers, NCT01968954 , NCT01968967 , NCT01968980 , NCT02100514 , NCT02135029 , and NCT02458287 .).

Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients.

BACKGROUND: Bococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and reduces levels of low-density lipoprotein (LDL) cholesterol. We sought to evaluate the efficacy of bococizumab in patients at high cardiovascular risk. METHODS: In two parallel, multinational trials with different entry criteria for LDL cholesterol levels, we randomly assigned the 27,438 patients in the combined trials to receive bococizumab (at a dose of 150 mg) subcutaneously every 2 weeks or placebo. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death; 93% of the patients were receiving statin therapy at baseline. The trials were stopped early after the sponsor elected to discontinue the development of bococizumab owing in part to the development of high rates of antidrug antibodies, as seen in data from other studies in the program. The median follow-up was 10 months. RESULTS: At 14 weeks, patients in the combined trials had a mean change from baseline in LDL cholesterol levels of -56.0% in the bococizumab group and +2.9% in the placebo group, for a between-group difference of -59.0 percentage points (P<0.001) and a median reduction from baseline of 64.2% (P<0.001). In the lower-risk, shorter-duration trial (in which the patients had a baseline LDL cholesterol level of ≥70 mg per deciliter [1.8 mmol per liter] and the median follow-up was 7 months), major cardiovascular events occurred in 173 patients each in the bococizumab group and the placebo group (hazard ratio, 0.99; 95% confidence interval [CI], 0.80 to 1.22; P=0.94). In the higher-risk, longer-duration trial (in which the patients had a baseline LDL cholesterol level of ≥100 mg per deciliter [2.6 mmol per liter] and the median follow-up was 12 months), major cardiovascular events occurred in 179 and 224 patients, respectively (hazard ratio, 0.79; 95% CI, 0.65 to 0.97; P=0.02). The hazard ratio for the primary end point in the combined trials was 0.88 (95% CI, 0.76 to 1.02; P=0.08). Injection-site reactions were more common in the bococizumab group than in the placebo group (10.4% vs. 1.3%, P<0.001). CONCLUSIONS: In two randomized trials comparing the PCSK9 inhibitor bococizumab with placebo, bococizumab had no benefit with respect to major adverse cardiovascular events in the trial involving lower-risk patients but did have a significant benefit in the trial involving higher-risk patients. (Funded by Pfizer; SPIRE-1 and SPIRE-2 ClinicalTrials.gov numbers, NCT01975376 and NCT01975389 .).

Evaluating bococizumab, a monoclonal antibody to PCSK9, on lipid levels and clinical events in broad patient groups with and without prior cardiovascular events: Rationale and design of the Studies of PCSK9 Inhibition and the Reduction of vascular Events (SPIRE) Lipid Lowering and SPIRE Cardiovascular Outcomes Trials.

BACKGROUND: Although statins significantly reduce vascular event rates, residual cholesterol risk remains high in many patient groups, including those with known vascular disease as well as in the setting of high-risk primary prevention. Bococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9), prolongs the half-life of hepatic low-density lipoprotein (LDL) receptors, and reduces circulating atherogenic cholesterol levels. DESIGN: The SPIRE program comprises 6 lipid-lowering studies and 2 cardiovascular outcomes trials, each comparing bococizumab (150 mg subcutaneously every 2 weeks) to matching placebo. The 6 SPIRE lipid-lowering studies include 3 parallel 12-month assessments of bococizumab on atherogenic lipids among statin-treated individuals at high residual risk (SPIRE-HR, SPIRE-LDL, SPIRE-LL), one 12-month study of bococizumab among individuals with familial hypercholesterolemia (SPIRE-FH), one 6-month study of bococizumab among those with statin intolerance (SPIRE-SI), and one 3-month study of bococizumab delivery using an auto-injector device (SPIRE-AI). The SPIRE-1 and SPIRE-2 event-driven cardiovascular outcome trials will assess the efficacy and safety of bococizumab in the prevention of incident vascular events in high-risk populations with and without clinically evident cardiovascular disease who have directly measured entry LDL cholesterol levels ≥70 mg/dL (SPIRE-1, n = 17,000) or ≥100 mg/dL (SPIRE-2, n = 11,000). SUMMARY: The SPIRE trials, inclusive of more than 30,000 participants worldwide, will ascertain the magnitude of reduction in atherogenic lipids that accrue with bococizumab and determine whether the addition of this PCSK9 inhibitor to standard treatment significantly reduces cardiovascular morbidity and mortality in high-risk patients, including those without a history of clinical cardiovascular events.

Using photovoice as a participatory evaluation tool in Kaiser Permanente's Community Health Initiative.

Photovoice is a community-based participatory research method that provides participants who traditionally have little voice in community policy decisions, with training in photography, ethics, critical dialogue, photo captioning, and policy advocacy. Photovoice has been used primarily as a needs assessment and advocacy tool and only rarely as a pre-/postintervention evaluation method. This article describes the use of Photovoice as a participatory evaluation method in the Community Health Initiative, a 6-year, multisite community-based obesity prevention initiative, sponsored by Kaiser Permanente. Fifty community participants (including six youth) from six Community Health Initiative communities used photos and captions to identify, from their perspective, the most significant accomplishments from the initiative at both baseline and follow-up. Accomplishments identified included increased access to fresh/healthy food in local neighborhoods; policy changes supporting a "healthy eating, active living" community; increased access to physical activity; changes to the built environment creating increased neighborhood walkability/safety; and leadership development.

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.

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.

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.

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.

The Kaiser Permanente Community Health Initiative: overview and evaluation design.

We provide an overview of the Kaiser Permanente Community Health Initiative--created in 2003 to promote obesity-prevention policy and environmental change in communities served by Kaiser Permanente-and describe the design for evaluating the initiative. The Initiative focuses on 3 ethnically diverse northern California communities that range in size from 37,000 to 52,000 residents. The evaluation assesses impact by measuring intermediate outcomes and conducting pre- and posttracking of population-level measures of physical activity, nutrition, and overweight.

Approaches to measuring the extent and impact of environmental change in three California community-level obesity prevention initiatives.

Despite growing support among public health researchers and practitioners for environmental approaches to obesity prevention, there is a lack of empirical evidence from intervention studies showing a favorable impact of either increased healthy food availability on healthy eating or changes in the built environment on physical activity. It is therefore critical that we carefully evaluate initiatives targeting the community environment to expand the evidence base for environmental interventions. We describe the approaches used to measure the extent and impact of environmental change in 3 community-level obesity-prevention initiatives in California. We focus on measuring changes in the community environment and assessing the impact of those changes on residents most directly exposed to the interventions.

Promoting policy and environmental change using photovoice in the Kaiser Permanente Community Health Initiative.

Creative ways must be found to engage both community residents and political leaders around policy and environmental solutions to public health issues. Photovoice is a community-based, participatory approach to documentary photography that provides people with training on photography, ethics, critical discussion, and policy advocacy. Photovoice projects have been implemented across the nation as part of Kaiser Permanente's Community Health Initiative-a community-based obesity prevention effort. This article focuses on the first Photovoice project implemented in three communities in Colorado. Photovoice themes related to healthy eating and active living include a lack of access to healthy food choices in stores and schools, unsafe street crossings and sidewalks, and the need to redevelop certain areas to encourage safe recreation. The involvement of policy leaders in the project combined with several dissemination activities has contributed to healthier food offerings in schools and neighborhoods and city planning efforts that emphasize walkability and access to healthy food, and park revitalization.

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.

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.

Intersession variability in single-breath diffusing capacity in diabetics without overt lung disease.

RATIONALE: American Thoracic Society guidelines state that a 10% or greater intersession change in diffusing capacity of the lung (DL(CO)) should be considered clinically significant. However, little is known about the short-term intersession variability in DL(CO) in untrained subjects or how variability is affected by rigorous external quality control. OBJECTIVES: To characterize the intersession variability of DL(CO) and the effect of different quality control methods in untrained individuals without significant lung disease. METHODS: Data were pooled from the comparator arms of 14 preregistration trials of inhaled insulin that included nonsmoking diabetic patients without significant lung disease. A total of 699 participants performed repeated DL(CO) measurements using a highly standardized technique. A total of 948 participants performed repeated measurements using routine clinical testing. MEASUREMENTS AND MAIN RESULTS: The mean intersession absolute change in DL(CO) using the highly standardized method was 1.45 ml/minute/mm Hg (5.64%) compared with 2.49 ml/minute/mm Hg (9.52%) in the routine testing group (P < 0.0001 for both absolute and percent difference). The variability in absolute intersession change in DL(CO) increased with increasing baseline DL(CO) values, whereas the absolute percentage of intersession change was stable across baseline values. Depending on the method, 15.5 to 35.5% of participants had an intersession change of 10% or greater. A 20% or greater threshold would reduce this percentage of patients to 1 to 10%. CONCLUSIONS: Intersession variability in DL(CO) measurement is dependent on the method of testing used and baseline DL(CO). Using a more liberal threshold to define meaningful intersession change may reduce the misclassification of normal variation as abnormal change.

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.