Novant Health

Treon et al provide early clinical data supporting a theoretical rationale for continuing ibrutinib in patients receiving the drug during COVID-19 illness.

BACKGROUND: In the Carotid Revascularization Endarterectomy versus Stenting Trial, we found no significant difference between the stenting group and the endarterectomy group with respect to the primary composite end point of stroke, myocardial infarction, or death during the periprocedural period or any subsequent ipsilateral stroke during 4 years of follow-up. We now extend the results to 10 years. METHODS: Among patients with carotid-artery stenosis who had been randomly assigned to stenting or endarterectomy, we evaluated outcomes every 6 months for up to 10 years at 117 centers. In addition to assessing the primary composite end point, we assessed the primary end point for the long-term extension study, which was ipsilateral stroke after the periprocedural period. RESULTS: Among 2502 patients, there was no significant difference in the rate of the primary composite end point between the stenting group (11.8%; 95% confidence interval [CI], 9.1 to 14.8) and the endarterectomy group (9.9%; 95% CI, 7.9 to 12.2) over 10 years of follow-up (hazard ratio, 1.10; 95% CI, 0.83 to 1.44). With respect to the primary long-term end point, postprocedural ipsilateral stroke over the 10-year follow-up occurred in 6.9% (95% CI, 4.4 to 9.7) of the patients in the stenting group and in 5.6% (95% CI, 3.7 to 7.6) of those in the endarterectomy group; the rates did not differ significantly between the groups (hazard ratio, 0.99; 95% CI, 0.64 to 1.52). No significant between-group differences with respect to either end point were detected when symptomatic patients and asymptomatic patients were analyzed separately. CONCLUSIONS: Over 10 years of follow-up, we did not find a significant difference between patients who underwent stenting and those who underwent endarterectomy with respect to the risk of periprocedural stroke, myocardial infarction, or death and subsequent ipsilateral stroke. The rate of postprocedural ipsilateral stroke also did not differ between groups. (Funded by the National Institutes of Health and Abbott Vascular Solutions; CREST ClinicalTrials.gov number, NCT00004732.).

OBJECTIVE: To evaluate the literature and identify important aspects of insulin therapy that facilitate safe and effective infusion therapy for a defined glycemic end point. METHODS: Where available, the literature was evaluated using Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology to assess the impact of insulin infusions on outcome for general intensive care unit patients and those in specific subsets of neurologic injury, traumatic injury, and cardiovascular surgery. Elements that contribute to safe and effective insulin infusion therapy were determined through literature review and expert opinion. The majority of the literature supporting the use of insulin infusion therapy for critically ill patients lacks adequate strength to support more than weak recommendations, termed suggestions, such that the difference between desirable and undesirable effect of a given intervention is not always clear. RECOMMENDATIONS: The article is focused on a suggested glycemic control end point such that a blood glucose ≥ 150 mg/dL triggers interventions to maintain blood glucose below that level and absolutely <180 mg/dL. There is a slight reduction in mortality with this treatment end point for general intensive care unit patients and reductions in morbidity for perioperative patients, postoperative cardiac surgery patients, post-traumatic injury patients, and neurologic injury patients. We suggest that the insulin regimen and monitoring system be designed to avoid and detect hypoglycemia (blood glucose ≤ 70 mg/dL) and to minimize glycemic variability.Important processes of care for insulin therapy include use of a reliable insulin infusion protocol, frequent blood glucose monitoring, and avoidance of finger-stick glucose testing through the use of arterial or venous glucose samples. The essential components of an insulin infusion system include use of a validated insulin titration program, availability of appropriate staffing resources, accurate monitoring technology, and standardized approaches to infusion preparation, provision of consistent carbohydrate calories and nutritional support, and dextrose replacement for hypoglycemia prevention and treatment. Quality improvement of glycemic management programs should include analysis of hypoglycemia rates, run charts of glucose values <150 and 180 mg/dL. The literature is inadequate to support recommendations regarding glycemic control in pediatric patients. CONCLUSIONS: While the benefits of tight glycemic control have not been definitive, there are patients who will receive insulin infusion therapy, and the suggestions in this article provide the structure for safe and effective use of this therapy.

BACKGROUND: Older patients who are hospitalized for acute decompensated heart failure have high rates of physical frailty, poor quality of life, delayed recovery, and frequent rehospitalizations. Interventions to address physical frailty in this population are not well established. METHODS: We conducted a multicenter, randomized, controlled trial to evaluate a transitional, tailored, progressive rehabilitation intervention that included four physical-function domains (strength, balance, mobility, and endurance). The intervention was initiated during, or early after, hospitalization for heart failure and was continued after discharge for 36 outpatient sessions. The primary outcome was the score on the Short Physical Performance Battery (total scores range from 0 to 12, with lower scores indicating more severe physical dysfunction) at 3 months. The secondary outcome was the 6-month rate of rehospitalization for any cause. RESULTS: A total of 349 patients underwent randomization; 175 were assigned to the rehabilitation intervention and 174 to usual care (control). At baseline, patients in each group had markedly impaired physical function, and 97% were frail or prefrail; the mean number of coexisting conditions was five in each group. Patient retention in the intervention group was 82%, and adherence to the intervention sessions was 67%. After adjustment for baseline Short Physical Performance Battery score and other baseline characteristics, the least-squares mean (±SE) score on the Short Physical Performance Battery at 3 months was 8.3±0.2 in the intervention group and 6.9±0.2 in the control group (mean between-group difference, 1.5; 95% confidence interval [CI], 0.9 to 2.0; P<0.001). At 6 months, the rates of rehospitalization for any cause were 1.18 in the intervention group and 1.28 in the control group (rate ratio, 0.93; 95% CI, 0.66 to 1.19). There were 21 deaths (15 from cardiovascular causes) in the intervention group and 16 deaths (8 from cardiovascular causes) in the control group. The rates of death from any cause were 0.13 and 0.10, respectively (rate ratio, 1.17; 95% CI, 0.61 to 2.27). CONCLUSIONS: In a diverse population of older patients who were hospitalized for acute decompensated heart failure, an early, transitional, tailored, progressive rehabilitation intervention that included multiple physical-function domains resulted in greater improvement in physical function than usual care. (Funded by the National Institutes of Health and others; REHAB-HF ClinicalTrials.gov number, NCT02196038.).

OBJECTIVE: To update the 2002 version of "Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient." DESIGN: A Task Force comprising 17 members of the Society of Critical Medicine with particular expertise in the use of neuromuscular-blocking agents; a Grading of Recommendations Assessment, Development, and Evaluation expert; and a medical writer met via teleconference and three face-to-face meetings and communicated via e-mail to examine the evidence and develop these practice guidelines. Annually, all members completed conflict of interest statements; no conflicts were identified. This activity was funded by the Society for Critical Care Medicine, and no industry support was provided. METHODS: Using the Grading of Recommendations Assessment, Development, and Evaluation system, the Grading of Recommendations Assessment, Development, and Evaluation expert on the Task Force created profiles for the evidence related to six of the 21 questions and assigned quality-of-evidence scores to these and the additional 15 questions for which insufficient evidence was available to create a profile. Task Force members reviewed this material and all available evidence and provided recommendations, suggestions, or good practice statements for these 21 questions. RESULTS: The Task Force developed a single strong recommendation: we recommend scheduled eye care that includes lubricating drops or gel and eyelid closure for patients receiving continuous infusions of neuromuscular-blocking agents. The Task Force developed 10 weak recommendations. 1) We suggest that a neuromuscular-blocking agent be administered by continuous intravenous infusion early in the course of acute respiratory distress syndrome for patients with a PaO2/FIO2 less than 150. 2) We suggest against the routine administration of an neuromuscular-blocking agents to mechanically ventilated patients with status asthmaticus. 3) We suggest a trial of a neuromuscular-blocking agents in life-threatening situations associated with profound hypoxemia, respiratory acidosis, or hemodynamic compromise. 4) We suggest that neuromuscular-blocking agents may be used to manage overt shivering in therapeutic hypothermia. 5) We suggest that peripheral nerve stimulation with train-of-four monitoring may be a useful tool for monitoring the depth of neuromuscular blockade but only if it is incorporated into a more inclusive assessment of the patient that includes clinical assessment. 6) We suggest against the use of peripheral nerve stimulation with train of four alone for monitoring the depth of neuromuscular blockade in patients receiving continuous infusion of neuromuscular-blocking agents. 7) We suggest that patients receiving a continuous infusion of neuromuscular-blocking agent receive a structured physiotherapy regimen. 8) We suggest that clinicians target a blood glucose level of less than 180 mg/dL in patients receiving neuromuscular-blocking agents. 9) We suggest that clinicians not use actual body weight and instead use a consistent weight (ideal body weight or adjusted body weight) when calculating neuromuscular-blocking agents doses for obese patients. 10) We suggest that neuromuscular-blocking agents be discontinued at the end of life or when life support is withdrawn. In situations in which evidence was lacking or insufficient and the study results were equivocal or optimal clinical practice varies, the Task Force made no recommendations for nine of the topics. 1) We make no recommendation as to whether neuromuscular blockade is beneficial or harmful when used in patients with acute brain injury and raised intracranial pressure. 2) We make no recommendation on the routine use of neuromuscular-blocking agents for patients undergoing therapeutic hypothermia following cardiac arrest. 3) We make no recommendation on the use of peripheral nerve stimulation to monitor degree of block in patients undergoing therapeutic hypothermia. 4) We make no recommendation on the use of neuromuscular blockade to improve the accuracy of intravascular-volume assessment in mechanically ventilated patients. 5) We make no recommendation concerning the use of electroencephalogram-derived parameters as a measure of sedation during continuous administration of neuromuscular-blocking agents. 6) We make no recommendation regarding nutritional requirements specific to patients receiving infusions of neuromuscular-blocking agents. 7) We make no recommendation concerning the use of one measure of consistent weight over another when calculating neuromuscular-blocking agent doses in obese patients. 8) We make no recommendation on the use of neuromuscular-blocking agents in pregnant patients. 9) We make no recommendation on which muscle group should be monitored in patients with myasthenia gravis receiving neuromuscular-blocking agents. Finally, in situations in which evidence was lacking or insufficient but expert consensus was unanimous, the Task Force developed six good practice statements. 1) If peripheral nerve stimulation is used, optimal clinical practice suggests that it should be done in conjunction with assessment of other clinical findings (e.g., triggering of the ventilator and degree of shivering) to assess the degree of neuromuscular blockade in patients undergoing therapeutic hypothermia. 2) Optimal clinical practice suggests that a protocol should include guidance on neuromuscular-blocking agent administration in patients undergoing therapeutic hypothermia. 3) Optimal clinical practice suggests that analgesic and sedative drugs should be used prior to and during neuromuscular blockade, with the goal of achieving deep sedation. 4) Optimal clinical practice suggests that clinicians at the bedside implement measure to attenuate the risk of unintended extubation in patients receiving neuromuscular-blocking agents. 5) Optimal clinical practice suggests that a reduced dose of an neuromuscular-blocking agent be used for patients with myasthenia gravis and that the dose should be based on peripheral nerve stimulation with train-of-four monitoring. 6) Optimal clinical practice suggests that neuromuscular-blocking agents be discontinued prior to the clinical determination of brain death.

PURPOSE: To update the ASCO guideline (2018) on the practical assessment and management of age-associated vulnerabilities in older patients undergoing systemic cancer therapy. METHODS: An Expert Panel conducted a systematic review to identify relevant randomized clinical trials (RCTs), systematic reviews, and meta-analyses from January 2016 to December 2022. RESULTS: A total of 26 publications met eligibility criteria and form the evidentiary basis for the update. RECOMMENDATIONS: The Expert Panel reiterates its overarching recommendation from the prior guideline that geriatric assessment (GA), including all essential domains, should be used to identify vulnerabilities or impairments that are not routinely captured in oncology assessments for all patients over 65 years old with cancer. Based on recently published RCTs demonstrating significantly improved clinical outcomes, all older adults with cancer (65+ years old) receiving systemic therapy with GA-identified deficits should have GA-guided management (GAM) included in their care plan. GAM includes using GA findings to inform cancer treatment decision-making as well as to address impairments through appropriate interventions, counseling, and/or referrals. A GA should include high priority aging-related domains known to be associated with outcomes in older adults with cancer: physical and cognitive function, emotional health, comorbid conditions, polypharmacy, nutrition, and social support. Clinical adaptation of the GA based on patient population, resources, and time is appropriate.The Panel recommends the Practical Geriatric Assessment as one option for this purpose (https://old-prod.asco.org/sites/new-www.asco.org/files/content-files/practice-patients/documents/2023-PGA-Final.pdf; https://youtu.be/jnaQIjOz2Dw; https://youtu.be/nZXtwaGh0Z0).Additional information is available at www.asco.org/supportive-care-guidelines.

Importance: Older patients with cancer and their caregivers worry about the effects of cancer treatment on aging-related domains (eg, function and cognition). Quality conversations with oncologists about aging-related concerns could improve patient-centered outcomes. A geriatric assessment (GA) can capture evidence-based aging-related conditions associated with poor clinical outcomes (eg, toxic effects) for older patients with cancer. Objective: To determine whether providing a GA summary and GA-guided recommendations to oncologists can improve communication about aging-related concerns. Design, Setting, and Participants: This cluster-randomized clinical trial enrolled 541 participants from 31 community oncology practices within the University of Rochester National Cancer Institute Community Oncology Research Program from October 29, 2014, to April 28, 2017. Patients were aged 70 years or older with an advanced solid malignant tumor or lymphoma who had at least 1 impaired GA domain; patients chose 1 caregiver to participate. The primary outcome was assessed on an intent-to-treat basis. Interventions: Oncology practices were randomized to receive either a tailored GA summary with recommendations for each enrolled patient (intervention) or alerts only for patients meeting criteria for depression or cognitive impairment (usual care). Main Outcomes and Measures: The predetermined primary outcome was patient satisfaction with communication about aging-related concerns (modified Health Care Climate Questionnaire [score range, 0-28; higher scores indicate greater satisfaction]), measured after the first oncology visit after the GA. Secondary outcomes included the number of aging-related concerns discussed during the visit (from content analysis of audiorecordings), quality of life (measured with the Functional Assessment of Cancer Therapy scale for patients and the 12-Item Short Form Health Survey for caregivers), and caregiver satisfaction with communication about aging-related patient concerns. Results: A total of 541 eligible patients (264 women, 276 men, and 1 patient did not provide data; mean [SD] age, 76.6 [5.2] years) and 414 caregivers (310 women, 101 men, and 3 caregivers did not provide data; mean age, 66.5 [12.5] years) were enrolled. Patients in the intervention group were more satisfied after the visit with communication about aging-related concerns (difference in mean score, 1.09 points; 95% CI, 0.05-2.13 points; P = .04); satisfaction with communication about aging-related concerns remained higher in the intervention group over 6 months (difference in mean score, 1.10; 95% CI, 0.04-2.16; P = .04). There were more aging-related conversations in the intervention group's visits (difference, 3.59; 95% CI, 2.22-4.95; P < .001). Caregivers in the intervention group were more satisfied with communication after the visit (difference, 1.05; 95% CI, 0.12-1.98; P = .03). Quality of life outcomes did not differ between groups. Conclusions and Relevance: Including GA in oncology clinical visits for older adults with advanced cancer improves patient-centered and caregiver-centered communication about aging-related concerns. Trial Registration: ClinicalTrials.gov identifier: NCT02107443.

PURPOSE Resistance to immune checkpoint inhibition (ICI) in advanced non–small-cell lung cancer (NSCLC) represents a major unmet need. Combining ICI with vascular endothelial growth factor (VEGF)/VEGF receptor inhibition has yielded promising results in multiple tumor types. METHODS In this randomized phase II Lung-MAP nonmatch substudy (S1800A), patients ineligible for a biomarker-matched substudy with NSCLC previously treated with ICI and platinum-based chemotherapy and progressive disease at least 84 days after initiation of ICI were randomly assigned to receive ramucirumab plus pembrolizumab (RP) or investigator's choice standard of care (SOC: docetaxel/ramucirumab, docetaxel, gemcitabine, and pemetrexed). With a goal of 130 eligible patients, the primary objective was to compare overall survival (OS) using a one-sided 10% level using the better of a standard log-rank (SLR) and weighted log-rank (WLR; G[rho = 0, gamma = 1]) test. Secondary end points included objective response, duration of response, investigator-assessed progression-free survival, and toxicity. RESULTS Of 166 patients enrolled, 136 were eligible (69 RP; 67 SOC). OS was significantly improved with RP (hazard ratio [80% CI]: 0.69 [0.51 to 0.92]; SLR one-sided P = .05; WLR one-sided P = .15). The median (80% CI) OS was 14.5 (13.9 to 16.1) months for RP and 11.6 (9.9 to 13.0) months for SOC. OS benefit for RP was seen in most subgroups. Investigator-assessed progression-free survival (hazard ratio [80% CI]: 0.86 [0.66 to 1.14]; one-sided SLR, P = .25 and .14 for WLR) and response rates (22% RP v 28% SOC, one-sided P = .19) were similar between arms. Grade ≥ 3 treatment-related adverse events occurred in 42% of patients in the RP group and 60% on SOC. CONCLUSION This randomized phase II trial demonstrated significantly improved OS with RP compared with SOC in patients with advanced NSCLC previously treated with ICI and chemotherapy. The safety was consistent with known toxicities of both drugs. These data warrant further evaluation.

Intestinal nematodes affecting dogs, i.e. roundworms, hookworms and whipworms, have a relevant health-risk impact for animals and, for most of them, for human beings. Both dogs and humans are typically infected by ingesting infective stages, (i.e. larvated eggs or larvae) present in the environment. The existence of a high rate of soil and grass contamination with infective parasitic elements has been demonstrated worldwide in leisure, recreational, public and urban areas, i.e. parks, green areas, bicycle paths, city squares, playgrounds, sandpits, beaches. This review discusses the epidemiological and sanitary importance of faecal pollution with canine intestinal parasites in urban environments and the integrated approaches useful to minimize the risk of infection in different settings.

Bruton tyrosine kinase (BTK) inhibitors have improved chronic lymphocytic leukemia (CLL) outcomes and offer a chemotherapy-free option [ 1 ]. The BTK inhibitor ibrutinib, alone or with a CD20 antibody, demonstrated better efficacy versus chemoimmunotherapy in treatment-naïve (TN) CLL [ 2 , 3 , 4 ]. However, cardiovascular toxicity is a concern with continuous ibrutinib use [ 5 , 6 ]. Acalabrutinib is a next-generation, selective BTK inhibitor approved for CLL/small lymphocytic leukemia (SLL). Acalabrutinib, alone or with obinutuzumab, showed favorable efficacy in clinical trials [ 7 , 8 ]. ELEVATE-TN demonstrated superior efficacy for acalabrutinib-obinutuzumab versus obinutuzumab-chlorambucil with acceptable tolerability in TN CLL [ 9 ]. We report 4-year follow-up results from ELEVATE-TN. ELEVATE-TN is a phase 3, randomized, multicenter, open-label study (NCT02475681) that enrolled patients aged ≥65 years, or 18–65 years with comorbidities (Cumulative Illness Rating Scale-Geriatric score >6, creatinine clearance 30–69 mL/min by Cockcroft-Gault), who had TN CLL or SLL requiring treatment, Eastern Cooperative Oncology Group performance status score of ≤2, and adequate hematologic, hepatic, and renal function [ 9 ]. Patients were randomized (1:1:1) to acalabrutinib 100 mg twice daily (until disease progression or unacceptable toxicity) with or without obinutuzumab (fixed-duration, up to 6 cycles) or obinutuzumab plus chlorambucil (up to 6 cycles). Crossover to acalabrutinib monotherapy was permitted in patients who progressed on obinutuzumab-chlorambucil. The primary study endpoint was independent review committee (IRC)-assessed progression-free survival (PFS). After primary analysis, PFS was investigator-assessed. Key secondary/exploratory endpoints were investigator-assessed PFS, investigator-assessed overall response rate (ORR), overall survival (OS), undetectable minimal residual disease (uMRD) rate, and safety. The study was not powered to compare acalabrutinib versus acalabrutinib-obinutuzumab. Informed consent was obtained from all patients before enrollment. Study details were previously published [ 9 ]. In total, 535 patients were randomized (acalabrutinib-obinutuzumab, n = 179; acalabrutinib, n = 179; obinutuzumab-chlorambucil, n = 177). Median age was 70 years (range, 41.0–91.0); 14% had del(17)(p13.1) and/or mutated TP53 and 63% had unmutated immunoglobulin heavy chain variable (IGHV) gene (Supplementary Table 1 ). At a median follow-up of 46.9 months (range, 0.0–59.4), treatment was ongoing in 74.9% ( n = 134) and 69.3% ( n = 124) of patients in the acalabrutinib-obinutuzumab and acalabrutinib monotherapy arms, respectively (Supplementary Table 2 ). Sixty-nine patients (39.0%) in the obinutuzumab-chlorambucil arm had crossed over to acalabrutinib. Overall, 25.1% of acalabrutinib-obinutuzumab patients and 30.7% of acalabrutinib patients discontinued treatment; 22.6% of obinutuzumab-chlorambucil patients did not complete therapy. The most common reason for treatment discontinuation (acalabrutinib-obinutuzumab, acalabrutinib, and obinutuzumab-chlorambucil) was adverse events (AEs; 12.8%, 12.3%, and 14.7%, respectively). Median investigator-assessed PFS was not reached (acalabrutinib-containing arms) versus 27.8 months for obinutuzumab-chlorambucil (both P < 0.0001; Fig. 1A ). In a post hoc analysis, prolonged PFS also was observed with acalabrutinib-obinutuzumab versus acalabrutinib ( P = 0.0296; Fig. 1A ); however, the study was not sufficiently powered for this comparison. The PFS benefit of acalabrutinib-containing regimens was consistent in high-risk genomic subgroups. In patients with del(17)(p13.1) and/or mutated TP53 , median PFS was not reached (acalabrutinib-containing arms) versus 17.5 months for obinutuzumab-chlorambucil (both P < 0.0001; Fig. 1B ); similar results were seen in patients with only del(17)(p13.1) (Supplementary Fig. 1 ). In patients with unmutated IGHV, median PFS was not reached (acalabrutinib-containing arms) versus 22.2 months for obinutuzumab-chlorambucil (both P < 0.0001); median PFS was not reached in any treatment arm in patients with mutated IGHV (Fig. 1C ). Estimated 48-month PFS rates overall were 87.0% for acalabrutinib-obinutuzumab, 77.9% for acalabrutinib, and 25.1% for obinutuzumab-chlorambucil. In the acalabrutinib-obinutuzumab and acalabrutinib monotherapy arms, 48-month PFS rates were 74.8% and 76.2%, respectively, for patients with del(17)(p13.1) and/or mutated TP53 , and 85.7% and 77.1% for patients with unmutated IGHV. Fig. 1: Investigator-assessed progression-free survival (A) overall, (B) by del(17)(p13.1) and/or mutated TP53 status, and (C) by IGHV mutation status. a Hazard ratio was based on stratified Cox-Proportional-Hazards model; b P value was based on stratified log-rank test; c Hazard ratio was based on unstratified Cox-Proportional-Hazards model. d P value was based on unstratified log-rank test. A acalabrutinib, CI confidence interval, Clb chlorambucil, HR hazard ratio, IGHV immunoglobulin heavy chain variable region, m TP53 mutated TP53 , NR not reached, O obinutuzumab, PFS progression-free survival, w/o without. Full size image Median OS was not reached in any treatment arm. Fewer deaths occurred in patients receiving acalabrutinib-obinutuzumab versus obinutuzumab-chlorambucil, but the difference was not statistically significant (HR: 0.50; 95% CI, 0.25, 1.02; P = 0.0604; Supplementary Fig. 2 ). While the OS HR for acalabrutinib-obinutuzumab versus acalabrutinib in a post hoc analysis was noteworthy (HR: 0.53; 95% CI, 0.26, 1.06), the difference between the two acalabrutinib-containing arms was not statistically significant ( P = 0.0836). Estimated 48-month OS rates were 92.9% for acalabrutinib-obinutuzumab, 87.6% for acalabrutinib, and 88.0% for obinutuzumab-chlorambucil. The ORR was significantly higher with acalabrutinib-obinutuzumab (96.1% [ n = 172/179]; 95% CI, 92.1, 98.1) versus obinutuzumab-chlorambucil (82.5% [ n = 146/177]; 95% CI, 76.2, 87.4; P < 0.0001; Supplementary Fig. 3A ). The ORR with acalabrutinib (89.9% [ n = 161/179]; 95% CI, 84.7, 93.5) also was significantly higher versus obinutuzumab-chlorambucil ( P = 0.035). The complete response (CR) rate, including CR with incomplete hematologic recovery (CRi), was higher with acalabrutinib-obinutuzumab (30.7% [ n = 55/179]) versus obinutuzumab-chlorambucil (13.0% [ n = 23/177]) and versus acalabrutinib (post hoc; 11.2% [n = 20/179]). Comparing the acalabrutinib-obinutuzumab and acalabrutinib monotherapy arms, CR + CRi rates were 32.0% and 13.0%, respectively, for patients with del(17)(p13.1) and/or mutated TP53 , and 28.2% and 12.6% for patients with unmutated IGHV. Sustained uMRD rates based on the last two MRD assessments are shown in Supplementary Fig. 3B . Median treatment exposure was 46.6 months for acalabrutinib-obinutuzumab and 45.7 months for acalabrutinib monotherapy (Table 1 ); no new safety signals were observed. The most common any-grade AEs (≥30%) were diarrhea, headache, and neutropenia for acalabrutinib-obinutuzumab; diarrhea and headache for acalabrutinib monotherapy; and neutropenia, infusion-related reaction, and nausea for obinutuzumab-chlorambucil (Table 1 ). AEs occurring more frequently in the acalabrutinib-containing arms included headache, diarrhea, fatigue, arthralgia, cough, and upper respiratory tract infection. Headaches, while common, were typically low grade; none led to treatment discontinuation. Among patients receiving acalabrutinib-obinutuzumab, neutropenia, fatigue, and arthralgia were more frequent relative to acalabrutinib alone. The obinutuzumab-chlorambucil arm had more frequent neutropenia, nausea, and infusion-related reactions relative to both acalabrutinib-containing arms, though differences in AE reporting could be due to the longer treatment exposure in the acalabrutinib-containing arms versus the comparator arm. In the acalabrutinib-containing arms, most of the common AEs decreased in incidence over time, and most events occurred more predominantly during the first year of treatment (Supplementary Table 3 ). Incidence and time to onset of AEs leading to discontinuation of acalabrutinib-containing treatment are described in Supplementary Table 4 . Table 1 Common adverse events (AEs) and selected AEs of interest. Full size table Events of clinical interest (ECIs), including cardiovascular events, were similar in both acalabrutinib arms (Table 1 ). In addition, the cumulative incidences of atrial fibrillation and hypertension over time were low and similar across treatment groups (Supplementary Fig. 4 ). With a median follow-up of 46.9 months, the efficacy and safety of acalabrutinib plus obinutuzumab and acalabrutinib monotherapy were maintained with low rates of treatment discontinuation. Median PFS was not reached for either acalabrutinib-containing arm, and PFS continued to be significantly longer for both acalabrutinib-containing arms versus obinutuzumab-chlorambucil. Consistent with the primary report [ 9 ], the acalabrutinib-containing arms continued to demonstrate significantly greater PFS benefits versus obinutuzumab-chlorambucil in high-risk genomic subgroups, including del(17)(p13.1) and/or mutated TP53 and unmutated IGHV, with longer-term treatment. Of note, the estimated PFS rate at 48 months trended in favor of the acalabrutinib combination versus acalabrutinib monotherapy, consistent with findings from preclinical studies demonstrating that, in contrast to ibrutinib, acalabrutinib does not interfere with the anti-tumor immune-mediated mechanisms of anti-CD20 monoclonal antibodies [ 10 , 11 ]. In the acalabrutinib-containing arms, the CR/CRi rate increased from the primary analysis at 28.3 months (acalabrutinib-obinutuzumab: 24.0%; acalabrutinib: 7.8% [ 9 ]) to the current report at a follow-up of 4 years (30.7% and 11.2%, respectively). In high-risk subgroups, CR/CRi rates were numerically higher with the acalabrutinib combination versus monotherapy; however, the study was not powered for this comparison. Further research is needed to assess the efficacy benefits of acalabrutinib-obinutuzumab combination therapy. With longer-term follow-up, the tolerability profile of the acalabrutinib-containing arms was consistent with that of the primary analysis. Incidences of the most common AEs, such as headache, diarrhea, neutropenia, and fatigue, were generally unchanged or saw a slight increase from the primary analysis [ 9 ]. Though cross-trial comparisons are limited, the efficacy results from this study are aligned with those from the iLLUMINATE study of ibrutinib-obinutuzumab in a similar patient population at a median follow-up of 31.3 months [ 4 ]. In that study, median PFS (assessed by IRC) was not reached; the estimated 30-month PFS rate was 79% with ibrutinib-obinutuzumab. Atrial fibrillation and hypertension rates with ibrutinib-obinutuzumab (12 and 17%, respectively) in iLLUMINATE [ 4 ] were higher than the atrial fibrillation/flutter and hypertension rates reported with acalabrutinib-obinutuzumab in the present study (4 and 8%). Discontinuation due to AEs was similar with ibrutinib-obinutuzumab (16%) in the iLLUMINATE study and with acalabrutinib-obinutuzumab in the present study (13%). By comparison, a head-to-head study of acalabrutinib versus ibrutinib (ELEVATE-RR; NCT02477696) at a median follow-up of 40.9 months demonstrated non-inferiority for PFS (primary endpoint) and a statistically significantly lower incidence of atrial fibrillation/flutter with acalabrutinib versus ibrutinib (9% vs 16%, respectively) in patients with previously treated CLL [ 12 ]. In ELEVATE-RR, hypertension incidence was also statistically higher with ibrutinib versus acalabrutinib (23% vs 9%). Based on these updated results, ELEVATE-TN shows continued efficacy at 4 years and a significant PFS benefit in the acalabrutinib-containing arms regardless of high-risk status. PFS benefit is seen particularly with acalabrutinib-obinutuzumab, although this combination resulted in a higher incidence of AEs compared with acalabrutinib monotherapy. No new safety signals were observed with acalabrutinib-containing treatment with longer-term follow-up. The safety of acalabrutinib-containing treatment was consistent with the primary analysis [ 9 ], with a low incidence of ECIs, particularly cardiovascular AEs (atrial fibrillation/flutter and hypertension) and low rates of treatment discontinuation despite longer treatment exposure. Findings illustrate the flexibility to tailor acalabrutinib treatment as monotherapy or combination treatment and support acalabrutinib as a combination partner with obinutuzumab in the first-line CLL setting.

OBJECTIVE: To determine clinical features and outcome in dogs and cats with obsessive-compulsive disorder (OCD). DESIGN: Retrospective study. ANIMALS: 103 dogs and 23 cats. PROCEDURES: Records of patients with OCD were analyzed for clinical features, medication used, extent of behavior modification, and outcome. RESULTS: Most dogs affected with OCD had been obtained from breeders. Male dogs significantly outnumbered females (2:1). Female cats outnumbered male cats by 2:1 in a small sample. Most affected dogs lived in households with 2 or more humans and other dogs or cats, and had some formal training. Client compliance with behavior modification was high. A combination of behavior modification and medication resulted in a large decrease in intensity and frequency of OCD in most animals. Clomipramine was significantly more efficacious for treatment in dogs than was amitriptyline. Only 1 dog and 1 cat were euthanatized because of OCD during the study. CONCLUSIONS AND CLINICAL RELEVANCE: OCD in dogs does not appear to be associated with lack of training, lack of household stimulation, or social confinement. In cats, OCD may be associated with environmental and social stress. Obsessive-compulsive disorder appears at the time of social maturity and may have sporadic and heritable forms. With appropriate treatment (consistent behavior modification and treatment with clomipramine), frequency and intensity of clinical signs in most dogs and cats may decrease by > 50%. Success appears to depend on client understanding and compliance and the reasonable expectation that OCD cannot be cured, but can be well controlled.

Fragile X syndrome generally arises as a consequence of a large expansion of a CGG trinucleotide repeat element that is located in the GC-rich promoter region of the fragile X mental retardation gene (FMR1). In the conventional model for fragile X, clinical involvement arises as a consequence of silencing of the FMR1 gene, with the attendant loss of FMR1 protein (FMRP). However, it has recently been demonstrated that most males with large premutation alleles (100-200 repeats), or with unmethylated full mutation alleles, have FMR1 mRNA levels that are higher than normal, despite reduced levels of FMRP. In the current work, we extend and confirm these observations using quantitative (fluorescent) reverse transcription polymerase chain reaction on larger sample populations, establishing that even for smaller premutation alleles (55-100 repeats) the mRNA levels are significantly elevated (mean 2.1-fold elevation; P = 3.9 x 10(-3)), relative to normal controls. Thus, an abnormal molecular phenotype is established close to the upper end of the normal range. We also demonstrate that the levels of FMR1 mRNA are elevated in females with premutation alleles; however, the mRNA levels are more varied than in the males, and are attenuated in a manner that is consistent with the fraction of normal alleles that are active in any given individual. Finally, we demonstrate that in lymphoblastoid cells derived from a patient with a severe form of fragile X caused by a point mutation in the second KH domain of the gene, but with a normal CGG element (25 repeats), the FMR1 mRNA level is normal. Thus, although models in which FMRP level (or level of function) modulates transcriptional activity remain viable, other explanations for the elevated message levels, including direct (cis) effects of the CGG element on transcription, must also be considered.

PURPOSE: Accurate risk assessment is essential for the success of population screening programs in breast cancer. Models with high sensitivity and specificity would enable programs to target more elaborate screening efforts to high-risk populations, while minimizing overtreatment for the rest. Artificial intelligence (AI)-based risk models have demonstrated a significant advance over risk models used today in clinical practice. However, the responsible deployment of novel AI requires careful validation across diverse populations. To this end, we validate our AI-based model, Mirai, across globally diverse screening populations. METHODS: We collected screening mammograms and pathology-confirmed breast cancer outcomes from Massachusetts General Hospital, USA; Novant, USA; Emory, USA; Maccabi-Assuta, Israel; Karolinska, Sweden; Chang Gung Memorial Hospital, Taiwan; and Barretos, Brazil. We evaluated Uno's concordance index for Mirai in predicting risk of breast cancer at one to five years from the mammogram. RESULTS: A total of 128,793 mammograms from 62,185 patients were collected across the seven sites, of which 3,815 were followed by a cancer diagnosis within 5 years. Mirai obtained concordance indices of 0.75 (95% CI, 0.72 to 0.78), 0.75 (95% CI, 0.70 to 0.80), 0.77 (95% CI, 0.75 to 0.79), 0.77 (95% CI, 0.73 to 0.81), 0.81 (95% CI, 0.79 to 0.82), 0.79 (95% CI, 0.76 to 0.83), and 0.84 (95% CI, 0.81 to 0.88) at Massachusetts General Hospital, Novant, Emory, Maccabi-Assuta, Karolinska, Chang Gung Memorial Hospital, and Barretos, respectively. CONCLUSION: Mirai, a mammography-based risk model, maintained its accuracy across globally diverse test sets from seven hospitals across five countries. This is the broadest validation to date of an AI-based breast cancer model and suggests that the technology can offer broad and equitable improvements in care.

BACKGROUND: The role that dietary interventions can play in multiple sclerosis (MS) management is of huge interest amongst patients and researchers but data evaluating this is limited. Possible effects of a very-low-fat, plant-based dietary intervention on MS related progression and disease activity as measured by brain imaging and MS related symptoms have not been evaluated in a randomized-controlled trial. Despite use of disease modifying therapies (DMT), poor quality of life (QOL) in MS patients can be a significant problem with fatigue being one of the common disabling symptoms. Effective treatment options for fatigue remain limited. Emerging evidence suggests diet and vascular risk factors including obesity and hyperlipidemia may influence MS disease progression and improve QOL. OBJECTIVES: To evaluate adherence, safety and effects of a very-low-fat, plant-based diet (Diet) on brain MRI, clinical [MS relapses and disability, body mass index (BMI)] and metabolic (blood lipids and insulin) outcomes, QOL [Short Form-36 (SF-36)], and fatigue [Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS)], in relapsing-remitting MS (RRMS). METHODS: This was a randomized-controlled, assessor-blinded, one-year long study with 61 participants assigned to either Diet (N=32) or wait-listed (Control, N=29) group. RESULTS: The mean age (years) [Control-40.9±8.48; Diet-40.8±8.86] and the mean disease duration (years) [Control -5.3±3.86; Diet-5.33±3.63] were comparable between the two groups. There was a slight difference between the two study groups in the baseline mean expanded disability status scale (EDSS) score [Control-2.22±0.90; Diet-2.72±1.05]. Eight subjects withdrew (Diet, N=6; Control, N=2). Adherence to the study diet based on monthly Food Frequency Questionnaire (FFQ) was excellent with the diet group showing significant difference in the total fat caloric intake compared to the control group [total fat intake/total calories averaged ~15% (Diet) versus ~40% (Control)]. The two groups showed no differences in brain MRI outcomes, number of MS relapses or disability at 12 months. The diet group showed improvements at six months in low-density lipoprotein cholesterol (Δ=-11.99mg/dL; p=0.031), total cholesterol (Δ=-13.18mg/dL; p=0.027) and insulin (Δ=-2.82mg/dL; p=0.0067), mean monthly reductions in BMI (Rate=-1.125kg/m2 per month; p<0.001) and fatigue [FSS (Rate=-0.0639 points/month; p=0.0010); MFIS (Rate=-0.233 points/month; p=0.0011)] during the 12-month period. CONCLUSIONS: While a very-low fat, plant-based diet was well adhered to and tolerated, it resulted in no significant improvement on brain MRI, relapse rate or disability as assessed by EDSS scores in subjects with RRMS over one year. The diet group however showed significant improvements in measures of fatigue, BMI and metabolic biomarkers. The study was powered to detect only very large effects on MRI activity so smaller but clinically meaningful effects cannot be excluded. The diet intervention resulted in a beneficial effect on the self-reported outcome of fatigue but these results should be interpreted cautiously as a wait-list control group may not completely control for a placebo effect and there was a baseline imbalance on fatigue scores between the groups. If maintained, the improved lipid profile and BMI could yield long-term vascular health benefits. Longer studies with larger sample sizes are needed to better understand the long-term health benefits of this diet.

BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (S-ICD) was developed to reduce short- and long-term complications associated with transvenous ICD leads. Early multicenter studies included younger patients with less left ventricular systolic dysfunction and fewer comorbidities than cohorts with traditional ICD. OBJECTIVE: The purpose of this study was to characterize patient selection and the acute performance of the S-ICD in a contemporary real-world setting. METHODS: The S-ICD Post-Approval Study is a prospective registry involving 86 US centers. Patients were enrolled if they met criteria for S-ICD implantation, passed an electrocardiogram screening test, and had a life expectancy of >1 year. Analyses of descriptive statistics, Kaplan-Meier time to event, and multivariate logistic regression were performed. RESULTS: The study includes 1637 patients who underwent S-ICD implantation. The cohort included 68.6% (1123/1637) male patients, and 13.4% (220/1636) were receiving dialysis for end-stage renal disease. The mean age was 52 ± 15 years, with a mean left ventricular ejection fraction of 32.0% ± 14.6%. Electrocardiogram screening was successful for at least 1, 2, or 3 vectors in 100%, 93.8%, and 51.4% of patients, respectively. Medical imaging (65.1%, 1065/1636) and general anesthesia (64.1%, 1048/16) were used in a majority of patients, and 52.2% (855/1637) were implanted with the 2-incision technique. Induced ventricular tachycardia/ventricular tachycardia was successfully converted in 98.7% (1394/1412) of patients. The 30-day complication-free rate was 96.2%. Predictors of complications included diabetes, younger age, and higher body mass index. CONCLUSION: Contemporary US patients with S-ICD have more comorbidities than do previous cohorts with S-ICD, but they are younger with more end-stage renal disease than do patients with transvenous ICD. Implantation success is high, and short-term complication rates are acceptable.

Background: This phase II study was designed to determine the efficacy of the mammalian target of rapamycin (mTOR) inhibitor everolimus administered daily with conventional radiation therapy and chemotherapy in patients with newly diagnosed glioblastoma. Methods: Patients were randomized to radiation therapy with concurrent and adjuvant temozolomide with or without daily everolimus (10 mg). The primary endpoint was progression-free survival (PFS) and the secondary endpoints were overall survival (OS) and treatment-related toxicities. Results: A total of 171 patients were randomized and deemed eligible for this study. Patients randomized to receive everolimus experienced a significant increase in both grade 4 toxicities, including lymphopenia and thrombocytopenia, and treatment-related deaths. There was no significant difference in PFS between patients randomized to everolimus compared with control (median PFS time: 8.2 vs 10.2 mo, respectively; P = 0.79). OS for patients randomized to receive everolimus was inferior to that for control patients (median survival time: 16.5 vs 21.2 mo, respectively; P = 0.008). A similar trend was observed in both O6-methylguanine-DNA-methyltransferase promoter hypermethylated and unmethylated tumors. Conclusion: Combining everolimus with conventional chemoradiation leads to increased treatment-related toxicities and does not improve PFS in patients with newly diagnosed glioblastoma. Although the median survival time in patients receiving everolimus was comparable to contemporary studies, it was inferior to the control in this randomized study.

Importance: Patients with malignant mesothelioma whose disease has progressed after platinum and pemetrexed treatment have limited options. Anti-programmed cell death 1 (PD-1) antibodies have antitumor activity in this disease, but little is known about the activity of anti-programmed cell death ligand 1 (PD-L1) antibodies in patients with mesothelioma. Objective: To assess the efficacy and safety of avelumab in a cohort of patients with previously treated mesothelioma. Design, Setting, and Participants: Phase 1b open-label study (JAVELIN Solid Tumor) in patients with unresectable mesothelioma that progressed after platinum and pemetrexed treatment, enrolled at 25 sites in 3 countries between September 9, 2014, and July 22, 2015. Interventions: Participants received avelumab, 10 mg/kg, every 2 weeks until disease progression, unacceptable toxic effects, or withdrawal from the study. Main Outcomes and Measures: Prespecified end points included confirmed best overall response based on Response Evaluation Criteria In Solid Tumors, version 1.1; duration of response; progression-free survival (PFS); overall survival (OS); PD-L1 expression-based analyses; and safety. Results: Of 53 patients treated with avelumab, the median age was 67 (range, 32-84) years; 32 (60%) were male. As of December 31, 2016, median follow-up was 24.8 (range, 16.8-27.8) months. Twenty patients (38%) had 3 or more previous lines of therapy (median, 2; range, 1-8). The confirmed objective response rate (ORR) was 9% (5 patients; 95% CI, 3.1%-20.7%), with complete response in 1 patient and partial response in 4 patients. Responses were durable (median, 15.2 months; 95% CI, 11.1 to not estimable months) and occurred in patients with PD-L1-positive tumors (3 of 16; ORR, 19%; 95% CI, 4.0%-45.6%) and PD-L1-negative tumors (2 of 27; ORR, 7%; 95% CI, 0.9%-24.3%) based on a 5% or greater PD-L1 cutoff. Disease control rate was 58% (31 patients). Median PFS was 4.1 (95% CI, 1.4-6.2) months, and the 12-month PFS rate was 17.4% (95% CI, 7.7%-30.4%). Median OS was 10.7 (95% CI, 6.4-20.2) months, and the median 12-month OS rate was 43.8% (95% CI, 29.8%-57.0%). Five patients (9%) had a grade 3 or 4 treatment-related adverse event, and 3 (6%) had a grade 3 or 4 immune-related, treatment-related adverse event. There were no treatment-related deaths. Conclusions and Relevance: Avelumab showed durable antitumor activity and disease control with an acceptable safety profile in a heavily pretreated cohort of patients with mesothelioma. Trial Registration: ClinicalTrials.gov identifier: NCT01772004.

OBJECTIVE: To assess the efficacy of etodolac in improving hind limb function in dogs with osteoarthritis of the hip joint. DESIGN: Prospective study. ANIMALS: 100 client-owned dogs with clinical signs of osteoarthritis of the hip joint. PROCEDURE: Baseline ground reaction forces and subjective assessment scores were collected twice at a 7- to 10-day interval. After meeting entrance criteria, dogs were randomly assigned to the following 3 treatment groups: control group (0 mg of etodolac), low-dosage group (135 mg of etodolac), or high-dosage group (450 mg of etodolac). Dogs were treated once daily for 8 days, and gait analysis was repeated on day 8. RESULTS: On day 8 of treatment, vertical impulse and vertical peak force values for low- and high-dosage groups were significantly greater than baseline values within each group. On day 8, vertical impulse values from the high-dosage group were significantly greater than values from the low-dosage group. Vertical peak forces for the low- and high-dosage groups were significantly greater at 8 days than that of the control group. Analysis of the effect of evaluation center (site) on treatment outcome did not reveal a significant effect. CLINICAL IMPLICATIONS: Etodolac administration for 8 days improved ground reaction forces in dogs with osteoarthritis of the hip joint. Improvement in force transmission was dosage dependent for the primary outcome measurement (vertical impulse). Results of the study indicate that etodolac is well tolerated by dogs, with minimal adverse effects during an 8-day treatment period.

An unmet need exists for patients with relapsed/refractory (R/R) follicular lymphoma (FL) and high-risk disease features, such as progression of disease within 24 months (POD24) from first-line immunochemotherapy or disease refractory to both CD20-targeting agent and alkylator (double refractory), due to no established standard of care and poor outcomes. Chimeric antigen receptor (CAR) T cell therapy is an option in R/R FL after two or more lines of prior systemic therapy, but there is no consensus on its optimal timing in the disease course of FL, and there are no data in second-line (2L) treatment of patients with high-risk features. Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, 4-1BB CAR T cell product. The phase 2 TRANSCEND FL study evaluated liso-cel in patients with R/R FL, including 2L patients who all had POD24 from diagnosis after treatment with anti-CD20 antibody and alkylator ≤6 months of FL diagnosis and/or met modified Groupe d'Etude des Lymphomes Folliculaires criteria. Primary/key secondary endpoints were independent review committee-assessed overall response rate (ORR)/complete response (CR) rate. At data cutoff, 130 patients had received liso-cel (median follow-up, 18.9 months). Primary/key secondary endpoints were met. In third-line or later FL (n = 101), ORR was 97% (95% confidence interval (CI): 91.6‒99.4), and CR rate was 94% (95% CI: 87.5‒97.8). In 2L FL (n = 23), ORR was 96% (95% CI: 78.1‒99.9); all responders achieved CR. Cytokine release syndrome occurred in 58% of patients (grade ≥3, 1%); neurological events occurred in 15% of patients (grade ≥3, 2%). Liso-cel demonstrated efficacy and safety in patients with R/R FL, including high-risk 2L FL. ClinicalTrials.gov identifier: NCT04245839 .

AIM: The Creighton Competency Evaluation Instrument (CCEI) was modified from an existing instrument, the Creighton Simulation Evaluation Instrument, for use in the National Council of States Boards of Nursing National Simulation Study (NCSBN NSS). BACKGROUND: The CCEI was developed for the NCSBN NSS for use as the evaluation instrument for both simulation and traditional clinical experiences in associate and baccalaureate nursing programs. METHOD: Five nursing programs assisted with reliability and validity testing of the CCEI. Using a standardized validation questionnaire, faculty rated the CCEI on its ability to accurately measure student performance and clinical competency. Videos scripted at three levels of performance were used to test reliability. RESULTS: Content validity ranged from 3.78 to 3.89 on a four-point Likert-like scale. Cronbach's alpha was > .90 when used to score three different levels of simulation performance. CONCLUSION: The CCEI is useful for evaluating both the simulation and traditional clinical environments.