Antibody Response to Symptomatic Infection With SARS-CoV-2 Omicron Variant Viruses, December 2021-June 2022.

We describe humoral immune responses in 105 ambulatory patients with laboratory-confirmed SARS-CoV-2 Omicron variant infection. In dried blood spot (DBS) collected within 5 days of illness onset and during convalescence, we measured binding antibody (bAb) against ancestral spike protein receptor binding domain (RBD) and nucleocapsid (N) protein using a commercial multiplex bead assay. Geometric mean bAb concentrations against RBD increased by a factor of 2.5 from 1258 to 3189 units/mL and by a factor of 47 against N protein from 5.5 to 259 units/mL between acute illness and convalescence; lower concentrations were associated with greater geometric mean ratios. Paired DBS specimens may be used to evaluate humoral response to SARS-CoV-2 infection.

Late-Season Influenza Vaccine Effectiveness Against Medically Attended Outpatient Illness, United States, December 2022-April 2023.

BACKGROUND: The 2022-23 US influenza season peaked early in fall 2022. METHODS: Late-season influenza vaccine effectiveness (VE) against outpatient, laboratory-confirmed influenza was calculated among participants of the US Influenza VE Network using a test-negative design. RESULTS: Of 2561 participants enrolled from December 12, 2022 to April 30, 2023, 91 laboratory-confirmed influenza cases primarily had A(H1N1)pdm09 (6B.1A.5a.2a.1) or A(H3N2) (3C.2a1b.2a.2b). Overall, VE was 30% (95% confidence interval -9%, 54%); low late-season activity precluded estimation for most subgroups. CONCLUSIONS: 2022-23 late-season outpatient influenza VE was not statistically significant. Genomic characterization may improve the identification of influenza viruses that circulate postinfluenza peak.

Effectiveness of Updated 2023-2024 (Monovalent XBB.1.5) COVID-19 Vaccination Against SARS-CoV-2 Omicron XBB and BA.2.86/JN.1 Lineage Hospitalization and a Comparison of Clinical Severity - IVY Network, 26 Hospitals, October 18, 2023-March 9, 2024.

Background: Assessing COVID-19 vaccine effectiveness (VE) and severity of SARS-CoV-2 variants can inform public health risk assessments and decisions about vaccine composition. BA.2.86 and its descendants, including JN.1 (referred to collectively as "JN lineages"), emerged in late 2023 and exhibited substantial genomic divergence from co-circulating XBB lineages. Methods: We analyzed patients hospitalized with COVID-19-like illness at 26 hospitals in 20 U.S. states admitted October 18, 2023-March 9, 2024. Using a test-negative, case-control design, we estimated the effectiveness of an updated 2023-2024 (Monovalent XBB.1.5) COVID-19 vaccine dose against sequence-confirmed XBB and JN lineage hospitalization using logistic regression. Odds of severe outcomes, including intensive care unit (ICU) admission and invasive mechanical ventilation (IMV) or death, were compared for JN versus XBB lineage hospitalizations using logistic regression. Results: 585 case-patients with XBB lineages, 397 case-patients with JN lineages, and 4,580 control-patients were included. VE in the first 7-89 days after receipt of an updated dose was 54.2% (95% CI = 36.1%-67.1%) against XBB lineage hospitalization and 32.7% (95% CI = 1.9%-53.8%) against JN lineage hospitalization. Odds of ICU admission (adjusted odds ratio [aOR] 0.80; 95% CI = 0.46-1.38) and IMV or death (aOR 0.69; 95% CI = 0.34-1.40) were not significantly different among JN compared to XBB lineage hospitalizations. Conclusions: Updated 2023-2024 COVID-19 vaccination provided protection against both XBB and JN lineage hospitalization, but protection against the latter may be attenuated by immune escape. Clinical severity of JN lineage hospitalizations was not higher relative to XBB lineage hospitalizations.

Knowledge, attitudes, and practices associated with influenza vaccine uptake among healthcare personnel in Israel during three influenza seasons, 2016-2019.

INTRODUCTION: Despite a longstanding Israel Ministry of Health recommendation that all healthcare personnel (HCP) receive a seasonal influenza vaccine, vaccine uptake among HCP remains below the country's target of 60% coverage. To understand factors related to vaccine hesitancy, we used data from a prospective three-year (2016-2019) influenza vaccine effectiveness study among Israeli HCP to examine knowledge, attitudes, and practices (KAP) about influenza vaccination and their association with vaccine uptake. METHODS: At the start of each influenza season, all participating HCP completed a questionnaire that included questions about socio-demographic and occupational characteristics, health status, and KAP related to seasonal influenza vaccination. We extracted vaccination history from electronic medical records and employee vaccination registries. We used logistic regression models to identify demographic and occupational factors, and KAP about influenza vaccination, associated with receipt of vaccination. RESULT: A total of 2,126 HCP were enrolled and had available data on vaccination history. Their median age was 42 years [IQR 35-52], and 73 % self-identified as female. Influenza vaccine uptake in 2016, 2017 and 2018 was 46 %, 48 % and 47 %, respectively. Overall, 36 % of HCP had received an influenza vaccine in ≥ 4 of the eight years prior. HCP aged 35-49 years were less likely to receive influenza vaccine compared to HCP aged ≥ 50 years (OR: 0.81 [95 % CI: 0.67-0.98]). Nurses and allied personnel were less likely to receive influenza vaccine compared to physicians (OR: 0.63 [95 % CI: 0.50-0.78] and OR: 0.53 [95 % CI: 0.40-0.70], respectively). The emotional benefit of vaccination (e.g., anticipating regret if not vaccinated) and the perception of vaccine safety were factors associated with vaccine uptake (OR: 7.60 [95 % CI: 6.27-9.22] and OR: 3.43 [95 % CI:2.91-4.03], respectively). CONCLUSION: Among HCP at two hospitals in Israel, less than half received an annual influenza vaccine. Older HCP, physicians, and those who reported the emotional benefit of vaccination or agreed that influenza vaccines are safe were more likely to be vaccinated. Future influenza vaccination campaigns could focus on these demographic groups and tailor messages emphasizing the emotional benefits of vaccination and vaccine safety to increase seasonal influenza vaccine uptake among HCP in Israel.

Evaluation of pharmacokinetics of metoclopramide administered via subcutaneous bolus and intravenous constant rate infusion to adult horses.

OBJECTIVE: To determine the pharmacokinetics (PK) of metoclopramide administered via intravenous continuous rate infusion (IV CRI) and subcutaneous (SC) bolus and evaluate for gastrointestinal motility and adverse side effects. STUDY DESIGN: Experimental study; randomized, crossover design. ANIMALS: Six healthy adult horses. METHODS: Each horse received metoclopramide via IV CRI (0.04 mg/kg/h for 24 h) and SC bolus (0.08 mg/kg once), with ≥1 week washout period between. Plasma was analyzed by UPLC-MS/MS. Compartmental modeling was used to determine PK parameters for each treatment; nonparametric superposition was used to simulate multiple SC bolus regimens. Gastrointestinal motility and evidence of adverse effects were monitored. RESULTS: Tmax (h) for SC bolus was 0.583 ± 0.204 versus 17.3 ± 6.41 for IV CRI, while Cmax (ng/mL) was 27.7 ± 6.38 versus 43.6 ± 9.97, respectively. AUC (h × ng/mL) was calculated as 902 ± 189 for 24 h IV CRI versus 244 ± 37.4 simulated for 0.08 mg/kg SC bolus every 8 h. Simulations revealed similar exposure between groups with administration of 0.96 mg/kg/day SC bolus, divided into three, four, or six doses. SC bolus bioavailability was estimated as 110 ± 11.5%. No clear trends in motility alteration were identified. No adverse effects were noted. CONCLUSION: Repeated SC boluses of metoclopramide at 0.08 mg/kg would result in lower total drug exposure and Tmax than IV CRI administration but would be highly bioavailable. CLINICAL SIGNIFICANCE: Higher and/or more frequent SC bolus doses are needed to achieve a similar AUC to IV CRI. No adverse effects were noted; however, evaluation of alternative dosing strategies is warranted.

Widefield in vivo imaging system with two fluorescence and two reflectance channels, a single sCMOS detector, and shielded illumination.

Significance: Widefield microscopy of the entire dorsal part of mouse cerebral cortex enables large-scale ("mesoscopic") imaging of different aspects of neuronal activity with spectrally compatible fluorescent indicators as well as hemodynamics via oxy- and deoxyhemoglobin absorption. Versatile and cost-effective imaging systems are needed for large-scale, color-multiplexed imaging of multiple fluorescent and intrinsic contrasts. Aim: We aim to develop a system for mesoscopic imaging of two fluorescent and two reflectance channels. Approach: Excitation of red and green fluorescence is achieved through epi-illumination. Hemoglobin absorption imaging is achieved using 525- and 625-nm light-emitting diodes positioned around the objective lens. An aluminum hemisphere placed between objective and cranial window provides diffuse illumination of the brain. Signals are recorded sequentially by a single sCMOS detector. Results: We demonstrate the performance of our imaging system by recording large-scale spontaneous and stimulus-evoked neuronal, cholinergic, and hemodynamic activity in awake, head-fixed mice with a curved "crystal skull" window expressing the red calcium indicator jRGECO1a and the green acetylcholine sensor GRAB ACh 3.0 . Shielding of illumination light through the aluminum hemisphere enables concurrent recording of pupil diameter changes. Conclusions: Our widefield microscope design with a single camera can be used to acquire multiple aspects of brain physiology and is compatible with behavioral readouts of pupil diameter.

Epidemiology of RSV in Adults and Children with Medically-Attended Acute Respiratory Illness over Three Seasons.

BACKGROUND: Data on the true prevalence of RSV among medically-attended acute respiratory illnesses (MAARI) has been limited by the lack of regular clinical testing of mild to moderate illnesses. Here we present a prospective evaluation of the epidemiology of RSV-associated MAARI across age groups and multimorbidity status over three seasons, which is informative in light of the recommendations for shared decision-making for vaccination in older adults. METHODS: Ambulatory patients ≥6 months of age meeting a common MAARI case definition were prospectively enrolled in the Michigan Ford Influenza Vaccine Effectiveness (MFIVE) study, a subsite of the US Influenza Vaccine Effectiveness Network. All participants were tested by nasal-throat swab for RSV and influenza, including subtype, independently from clinician-directed testing. Participant illness characteristics and calculated Multimorbidity-Weighted Index (MWI) were collected by in-person survey and electronic medical record review. RESULTS: Over three surveillance seasons (fall 2017 to spring 2020), 9.9% (n=441) of 4,442 participants had RSV detected. RSV-associated MAARI was more prevalent than influenza for participants 6 months-4 years of age. Adults with RSV-MAARI had higher median MWI scores overall compared to influenza-MAARI and controls with neither virus (1.62, 0.40, and 0.64, respectively). CONCLUSIONS: RSV is a significant, underrecognized cause of MAARI in both children and adults presenting for ambulatory care. Multimorbidity is an important contributor to RSV-associated MAARI in outpatient adults, providing information to support shared clinical decision-making for vaccination.

Electroconvulsive therapy in a tertiary Australian mental health facility between 2009 and 2020.

BACKGROUND: Despite electroconvulsive therapy being one of the most effective treatments in psychiatry, few studies report trends in the provision of electroconvulsive therapy over time. This study aims to investigate the use of electroconvulsive therapy between 2009 and 2020 in an Australian public tertiary mental health facility, and to describe the electroconvulsive therapy patient population and change in courses of treatment. METHODS: Routinely collected data for 677 patients who received 1669 electroconvulsive therapy courses of treatment at an Australian public tertiary mental health facility between 2009 and 2020 were examined. RESULTS: The provision of acute electroconvulsive therapy was stable across the study period; however, the number of maintenance electroconvulsive therapy courses commenced declined over the study. Schizophrenia was the most common indication for index treatment (37.4%). The majority of patients (85.7%) received acute electroconvulsive therapy only. Voluntary provision of electroconvulsive therapy declined over the study period, reducing from 44.9% in 2009 to 16.3% in 2020. CONCLUSION: Over the study period, there was a significant reduction in the number of maintenance electroconvulsive therapy courses commenced, and a large increase in involuntary treatment. The provision of electroconvulsive therapy was more likely to occur in males with a diagnosis of schizophrenia. Further studies are needed to generate a greater understanding of the factors influencing the provision of electroconvulsive therapy within differing geographical, social and healthcare landscapes.

Reduced effectiveness of repeat influenza vaccination: distinguishing among within-season waning, recent clinical infection, and subclinical infection.

Studies have reported that prior-season influenza vaccination is associated with higher risk of clinical influenza infection among vaccinees. This effect might arise from incomplete consideration of within-season waning and recent infection. Using data from the US Flu Vaccine Effectiveness (VE) Network (2011-2012 to 2018-2019 seasons), we found that repeat vaccinees were vaccinated earlier in a season by one week. After accounting for waning VE, repeat vaccinees were still more likely to test positive for A(H3N2) (OR=1.11, 95%CI:1.02-1.21) but not for influenza B or A(H1N1). We found that clinical infection influenced individuals' decision to vaccinate in the following season while protecting against clinical infection of the same (sub)type. However, adjusting for recent clinical infections did not strongly influence the estimated effect of prior-season vaccination. In contrast, we found that adjusting for subclinical infection could theoretically attenuate this effect. Additional investigation is needed to determine the impact of subclinical infections on VE.

Unraveling the CLCC1 interactome: Impact of the Asp25Glu variant and its interaction with SigmaR1 at the Mitochondrial-Associated ER Membrane (MAM).

The endoplasmic reticulum (ER) plays an indispensable role in cellular processes, including maintenance of calcium homeostasis, and protein folding, synthesized and processing. Disruptions in these processes leading to ER stress and the accumulation of misfolded proteins can instigate the unfolded protein response (UPR), culminating in either restoration of balanced proteostasis or apoptosis. A key player in this intricate balance is CLCC1, an ER-resident chloride channel, whose essential role extends to retinal development, regulation of ER stress, and UPR. The importance of CLCC1 is further underscored by its interaction with proteins localized to mitochondria-associated endoplasmic reticulum membranes (MAMs), where it participates in UPR induction by MAM proteins. In previous research, we identified a p.(Asp25Glu) pathogenic CLCC1 variant associated with retinitis pigmentosa (RP) (CLCC1 hg38 NC_000001.11; NM_001048210.3, c.75C > A; UniprotKB Q96S66). In attempt to decipher the impact of this variant function, we leveraged liquid chromatography-mass spectrometry (LC-MS) to identify likely CLCC1-interacting proteins. We discovered that the CLCC1 interactome is substantially composed of proteins that localize to ER compartments and that the Asp25Glu variant results in noticeable loss and gain of specific protein interactors. Intriguingly, the analysis suggests that the CLCC1Asp25Glu mutant protein exhibits a propensity for increased interactions with cytoplasmic proteins compared to its wild-type counterpart. To corroborate our LC-MS data, we further scrutinized two novel CLCC1 interactors, Calnexin and SigmaR1, chaperone proteins that localize to the ER and MAMs. Through microscopy, we demonstrate that CLCC1 co-localizes with both proteins, thereby validating our initial findings. Moreover, our results reveal that CLCC1 co-localizes with SigmaR1 not merely at the ER, but also at MAMs. These findings reinforce the notion of CLCC1 interacting with MAM proteins at the ER-mitochondria interface, setting the stage for further exploration into how these interactions impact ER or mitochondria function and lead to retinal degenerative disease when impaired.

Volatile drug use and overdose during the first year of the COVID-19 pandemic in the United States.

BACKGROUND: Overdose deaths in the United States rose substantially during the COVID-19 pandemic. Disruptions to the drug supply and service provision introduced significant instability into the lives of people who use drugs (PWUD), including volatility in their drug use behaviors. METHODS: Using data from a multistate survey of PWUD, we examined sociodemographic and drug use correlates of volatile drug use during COVID-19 using multivariable linear regression. In a multivariable logistic regression model, we assessed the association between volatile drug use and past month overdose adjusting for sociodemographic and other drug use characteristics. RESULTS: Among participants, 52% were male, 50% were white, 29% had less than a high school education, and 25% were experiencing homelessness. Indicators of volatile drug use were prevalent: 53% wanted to use more drugs; 45% used more drugs; 43% reported different triggers for drug use, and 23% used drugs that they did not typically use. 14% experienced a past-month overdose. In adjusted models, hunger (ß=0.47, 95% CI: 0.21-0.72), transactional sex (ß=0.50, 95% CI: 0.06-0.94), and the number of drugs used (ß=0.16, 95% CI: 0.07-0.26) were associated with increased volatile drug use. Volatile drug use was associated with increased overdose risk (aOR=1.42, 95% CI: 1.17-1.71) in the adjusted model. CONCLUSIONS: Volatile drug use during the COVID-19 pandemic was common, appeared to be driven by structural vulnerability, and was associated with increased overdose risk. Addressing volatile drug use through interventions that ensure structural stability for PWUD and a safer drug supply is essential for mitigating the ongoing overdose crisis.

Post-recovery health domain scores among outpatients by SARS-CoV-2 testing status during the pre-Delta period.

BACKGROUND: Symptoms of COVID-19 including fatigue and dyspnea, may persist for weeks to months after SARS-CoV-2 infection. This study compared self-reported disability among SARS-CoV-2-positive and negative persons with mild to moderate COVID-19-like illness who presented for outpatient care before widespread COVID-19 vaccination. METHODS: Unvaccinated adults with COVID-19-like illness enrolled within 10 days of illness onset at three US Flu Vaccine Effectiveness Network sites were tested for SARS-CoV-2 by molecular assay. Enrollees completed an enrollment questionnaire and two follow-up surveys (7-24 days and 2-7 months after illness onset) online or by phone to assess illness characteristics and health status. The second follow-up survey included questions measuring global health, physical function, fatigue, and dyspnea. Scores in the four domains were compared by participants' SARS-CoV-2 test results in univariate analysis and multivariable Gamma regression. RESULTS: During September 22, 2020 - February 13, 2021, 2712 eligible adults were enrolled, 1541 completed the first follow-up survey, and 650 completed the second follow-up survey. SARS-CoV-2-positive participants were more likely to report fever at acute illness but were otherwise comparable to SARS-CoV-2-negative participants. At first follow-up, SARS-CoV-2-positive participants were less likely to have reported fully or mostly recovered from their illness compared to SARS-CoV-2-negative participants. At second follow-up, no differences by SARS-CoV-2 test results were detected in the four domains in the multivariable model. CONCLUSION: Self-reported disability was similar among outpatient SARS-CoV-2-positive and -negative adults 2-7 months after illness onset.

Crop and landscape heterogeneity increase biodiversity in agricultural landscapes: A global review and meta-analysis.

Agricultural intensification not only increases food production but also drives widespread biodiversity decline. Increasing landscape heterogeneity has been suggested to increase biodiversity across habitats, while increasing crop heterogeneity may support biodiversity within agroecosystems. These spatial heterogeneity effects can be partitioned into compositional (land-cover type diversity) and configurational heterogeneity (land-cover type arrangement), measured either for the crop mosaic or across the landscape for both crops and semi-natural habitats. However, studies have reported mixed responses of biodiversity to increases in these heterogeneity components across taxa and contexts. Our meta-analysis covering 6397 fields across 122 studies conducted in Asia, Europe, North and South America reveals consistently positive effects of crop and landscape heterogeneity, as well as compositional and configurational heterogeneity for plant, invertebrate, vertebrate, pollinator and predator biodiversity. Vertebrates and plants benefit more from landscape heterogeneity, while invertebrates derive similar benefits from both crop and landscape heterogeneity. Pollinators benefit more from configurational heterogeneity, but predators favour compositional heterogeneity. These positive effects are consistent for invertebrates and vertebrates in both tropical/subtropical and temperate agroecosystems, and in annual and perennial cropping systems, and at small to large spatial scales. Our results suggest that promoting increased landscape heterogeneity by diversifying crops and semi-natural habitats, as suggested in the current UN Decade on Ecosystem Restoration, is key for restoring biodiversity in agricultural landscapes.

Interim Estimates of 2023-24 Seasonal Influenza Vaccine Effectiveness - United States.

In the United States, annual influenza vaccination is recommended for all persons aged ≥6 months. Using data from four vaccine effectiveness (VE) networks during the 2023-24 influenza season, interim influenza VE was estimated among patients aged ≥6 months with acute respiratory illness-associated medical encounters using a test-negative case-control study design. Among children and adolescents aged 6 months-17 years, VE against influenza-associated outpatient visits ranged from 59% to 67% and against influenza-associated hospitalization ranged from 52% to 61%. Among adults aged ≥18 years, VE against influenza-associated outpatient visits ranged from 33% to 49% and against hospitalization from 41% to 44%. VE against influenza A ranged from 46% to 59% for children and adolescents and from 27% to 46% for adults across settings. VE against influenza B ranged from 64% to 89% for pediatric patients in outpatient settings and from 60% to 78% for all adults across settings. These findings demonstrate that the 2023-24 seasonal influenza vaccine is effective at reducing the risk for medically attended influenza virus infection. CDC recommends that all persons aged ≥6 months who have not yet been vaccinated this season get vaccinated while influenza circulates locally.

Interim Effectiveness of Updated 2023-2024 (Monovalent XBB.1.5) COVID-19 Vaccines Against COVID-19-Associated Emergency Department and Urgent Care Encounters and Hospitalization Among Immunocompetent Adults Aged ≥18 Years - VISION and IVY Networks, September 2023-January 2024.

In September 2023, CDC's Advisory Committee on Immunization Practices recommended updated 2023-2024 (monovalent XBB.1.5) COVID-19 vaccination for all persons aged ≥6 months to prevent COVID-19, including severe disease. However, few estimates of updated vaccine effectiveness (VE) against medically attended illness are available. This analysis evaluated VE of an updated COVID-19 vaccine dose against COVID-19-associated emergency department (ED) or urgent care (UC) encounters and hospitalization among immunocompetent adults aged ≥18 years during September 2023-January 2024 using a test-negative, case-control design with data from two CDC VE networks. VE against COVID-19-associated ED/UC encounters was 51% (95% CI = 47%-54%) during the first 7-59 days after an updated dose and 39% (95% CI = 33%-45%) during the 60-119 days after an updated dose. VE estimates against COVID-19-associated hospitalization from two CDC VE networks were 52% (95% CI = 47%-57%) and 43% (95% CI = 27%-56%), with a median interval from updated dose of 42 and 47 days, respectively. Updated COVID-19 vaccine provided increased protection against COVID-19-associated ED/UC encounters and hospitalization among immunocompetent adults. These results support CDC recommendations for updated 2023-2024 COVID-19 vaccination. All persons aged ≥6 months should receive updated 2023-2024 COVID-19 vaccine.

Effect of Evobrutinib on Slowly Expanding Lesion Volume in Relapsing Multiple Sclerosis: A Post Hoc Analysis of a Phase 2 Trial.

BACKGROUND AND OBJECTIVES: Chronic active lesions (CALs) are demyelinated multiple sclerosis (MS) lesions with ongoing microglia/macrophage activity, resulting in irreversible neuronal damage and axonal loss. Evobrutinib is a highly selective, covalent, CNS-penetrant, Bruton tyrosine kinase inhibitor. This post hoc analysis evaluated the effect of evobrutinib on slowly expanding lesion (SEL) volume, an MRI marker of CALs, assessed baseline-week 48 in a phase 2, double-blind, randomized trial (NCT02975349) in relapsing MS (RMS). METHODS: In the 48-week, double-blind trial, adult patients received evobrutinib (25 mg once daily [QD], 75 mg QD, or 75 mg twice daily [BID]), placebo (switched to evobrutinib 25 mg QD after week 24), or open-label dimethyl fumarate (DMF) 240 mg BID. SELs were defined as slowly and consistently radially expanding areas of preexisting T2 lesions of ≥10 contiguous voxels (∼30 mm3) over time. SELs were identified by MRI and assessed by the Jacobian determinant of the nonlinear deformation from baseline to week 48. SEL volume analysis, stratified by baseline T2 lesion volume tertiles, was based on week 48/end-of-treatment status (completers/non-completers). Treatment effect was analyzed using the stratified Hodges-Lehmann estimate of shift in distribution and stratified Wilcoxon rank-sum test. Comparisons of evobrutinib and DMF vs placebo/evobrutinib 25 mg QD were made. Subgroup analyses used pooled treatment groups (evobrutinib high dose [75 mg QD/BID] vs low dose [placebo/evobrutinib 25 mg QD]). RESULTS: The SEL analysis set included 223 patients (mean [SD] age: 42.4 [10.7] years; 69.3% female; 87.4% relapsing/remitting MS). Mean (SD) SEL volume was 2,099 (2,981.0) mm3 with evobrutinib 75 mg BID vs 2,681 (3,624.2) mm3 with placebo/evobrutinib 25 mg QD. Median number of SELs/patient ranged from 7 to 11 across treatments. SEL volume decreased with increasing evobrutinib dose vs placebo/evobrutinib 25 mg QD, and no difference with DMF vs placebo/evobrutinib 25 mg QD was noted. SEL volume significantly decreased with evobrutinib 75 mg BID vs placebo/evobrutinib 25 mg QD (-474.5 mm3 [-1,098.0 to -3.0], p = 0.047) and vs DMF (-711.6 [-1,290.0 to -149.0], p = 0.011). SEL volume was significantly reduced for evobrutinib high vs low dose within baseline Expanded Disability Status Scale ≥3.5 and longer disease duration (≥8.5 years) subgroups. DISCUSSION: Evobrutinib reduced SEL volume in a dose-dependent manner in RMS, with a significant reduction with evobrutinib 75 mg BID. This is evident that evobrutinib affects brain lesions associated with chronic inflammation and tissue loss. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov number: NCT02975349. Submitted to ClinicalTrials.gov on November 29, 2016. First patient enrolled: March 7, 2017. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that evobrutinib reduces the volume of SELs assessed on MRI comparing baseline with week 48, in patients with RMS.

Reflective Engagement With a Digital Physical Activity Intervention Among People Living With and Beyond Breast Cancer: Mixed Methods Study.

BACKGROUND: People living with and beyond breast cancer can face internal barriers to physical activity (eg, fatigue and pain). Digital interventions that promote psychological acceptance and motivation may help this population navigate these barriers. The degree to which individuals (1) adhere to intervention protocols and (2) reflect on and internalize intervention content may predict intervention efficacy. OBJECTIVE: The objective of this study was to characterize the nature of reflective processes brought about by an 8-week acceptance- and mindfulness-based physical activity intervention for insufficiently active survivors of breast cancer (n=75). Furthermore, we explored the potential utility of a metric of reflective processes for predicting study outcomes. METHODS: Of the intervention's 8 weekly modules, 7 (88%) included an item that asked participants to reflect on what they found to be most useful. Two coders conducted directed content analysis on participants' written responses. They assessed each comment's depth of reflection using an existing framework (ranging from 0 to 4, with 0=simple description and 4=fundamental change with consideration of social and ethical issues). The coders identified themes within the various levels of reflection. We fit multiple linear regression models to evaluate whether participants' (1) intervention adherence (ie, number of modules completed) and (2) the mean level of the depth of reflection predicted study outcomes. RESULTS: Participants were aged on average 57.2 (SD 11.2) years, mostly non-Hispanic White (58/75, 77%), and mostly overweight or obese (54/75, 72%). Of the 407 responses to the item prompting personal reflection, 70 (17.2%) were rated as reflection level 0 (ie, description), 247 (60.7%) were level 1 (ie, reflective description), 74 (18.2%) were level 2 (ie, dialogic reflection), 14 (3.4%) were level 3 (ie, transformative reflection), and 2 (0.5%) were level 4 (ie, critical reflection). Lower levels of reflection were characterized by the acquisition of knowledge or expressing intentions. Higher levels were characterized by personal insight, commentary on behavior change processes, and a change of perspective. Intervention adherence was associated with increases in self-reported weekly bouts of muscle-strengthening exercise (B=0.26, SE 0.12, 95% CI 0.02-0.50) and decreases in sleep disturbance (B=-1.04, SE 0.50, 95% CI -0.06 to -2.02). The mean level of reflection was associated with increases in psychological acceptance (B=3.42, SE 1.70, 95% CI 0.09-6.75) and motivation for physical activity (ie, integrated regulation: B=0.55, SE 0.25, 95% CI 0.06-1.04). CONCLUSIONS: We identified a useful method for understanding the reflective processes that can occur during digital behavior change interventions serving people living with and beyond breast cancer. Intervention adherence and the depth of reflection each predicted changes in study outcomes. Deeper reflection on intervention content was associated with beneficial changes in the determinants of sustained behavior change. More research is needed to investigate the relations among digital behavior change intervention use, psychological processes, and intervention efficacy.