A sequential, multiple assignment randomized trial comparing web-based education to mobile video interpreter access for improving provider interpreter use in primary care clinics: the mVOCAL hybrid type 3 study protocol.

BACKGROUND: Individuals who use a language other than English for medical care are at risk for disparities related to healthcare safety, patient-centered care, and quality. Professional interpreter use decreases these disparities but remains underutilized, despite widespread access and legal mandates. In this study, we compare two discrete implementation strategies for improving interpreter use: (1) enhanced education targeting intrapersonal barriers to use delivered in a scalable format (interactive web-based educational modules) and (2) a strategy targeting system barriers to use in which mobile video interpreting is enabled on providers' own mobile devices. METHODS: We will conduct a type 3 hybrid implementation-effectiveness study in 3-5 primary care organizations, using a sequential multiple assignment randomized trial (SMART) design. Our primary implementation outcome is interpreter use, calculated by matching clinic visits to interpreter invoices. Our secondary effectiveness outcome is patient comprehension, determined by comparing patient-reported to provider-documented visit diagnosis. Enrolled providers (n = 55) will be randomized to mobile video interpreting or educational modules, plus standard interpreter access. After 9 months, providers with high interpreter use will continue as assigned; those with lower use will be randomized to continue as before or add the alternative strategy. After another 9 months, both strategies will be available to enrolled providers for 9 more months. Providers will complete 2 surveys (beginning and end) and 3 in-depth interviews (beginning, middle, and end) to understand barriers to interpreter use, based on the Theoretical Domains Framework. Patients who use a language other than English will be surveyed (n = 648) and interviewed (n = 75) following visits with enrolled providers to understand their experiences with communication. Visits will be video recorded (n = 100) to assess fidelity to assigned strategies. We will explore strategy mechanism activation to refine causal pathway models using a quantitative plus qualitative approach. We will also determine the incremental cost-effectiveness of each implementation strategy from a healthcare organization perspective, using administrative and provider survey data. DISCUSSION: Determining how these two scalable strategies, alone and in sequence, perform for improving interpreter use, the mechanisms by which they do so, and at what cost, will provide critical insights for addressing a persistent cause of healthcare disparities. TRIAL REGISTRATION: NCT05591586.

Stratification of biological therapies by pathobiology in biologic-naive patients with rheumatoid arthritis (STRAP and STRAP-EU): two parallel, open-label, biopsy-driven, randomised trials.

BACKGROUND: Despite highly effective targeted therapies for rheumatoid arthritis, about 40% of patients respond poorly, and predictive biomarkers for treatment choices are lacking. We did a biopsy-driven trial to compare the response to rituximab, etanercept, and tocilizumab in biologic-naive patients with rheumatoid arthritis stratified for synovial B cell status. METHODS: STRAP and STRAP-EU were two parallel, open-label, biopsy-driven, stratified, randomised, phase 3 trials done across 26 university centres in the UK and Europe. Biologic-naive patients aged 18 years or older with rheumatoid arthritis based on American College of Rheumatology (ACR)-European League Against Rheumatism classification criteria and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs) were included. Following ultrasound-guided synovial biopsy, patients were classified as B cell poor or B cell rich according to synovial B cell signatures and randomly assigned (1:1:1) to intravenous rituximab (1000 mg at week 0 and week 2), subcutaneous tocilizumab (162 mg per week), or subcutaneous etanercept (50 mg per week). The primary outcome was the 16-week ACR20 response in the B cell-poor, intention-to-treat population (defined as all randomly assigned patients), with data pooled from the two trials, comparing etanercept and tocilizumab (grouped) versus rituximab. Safety was assessed in all patients who received at least one dose of study drug. These trials are registered with the EU Clinical Trials Register, 2014-003529-16 (STRAP) and 2017-004079-30 (STRAP-EU). FINDINGS: Between June 8, 2015, and July 4, 2019, 226 patients were randomly assigned to etanercept (n=73), tocilizumab (n=74), and rituximab (n=79). Three patients (one in each group) were excluded after randomisation because they received parenteral steroids in the 4 weeks before recruitment. 168 (75%) of 223 patients in the intention-to-treat population were women and 170 (76%) were White. In the B cell-poor population, ACR20 response at 16 weeks (primary endpoint) showed no significant differences between etanercept and tocilizumab grouped together and rituximab (46 [60%] of 77 patients vs 26 [59%] of 44; odds ratio 1·02 [95% CI 0·47-2·17], p=0·97). No differences were observed for adverse events, including serious adverse events, which occurred in six (6%) of 102 patients in the rituximab group, nine (6%) of 108 patients in the etanercept group, and three (4%) of 73 patients in the tocilizumab group (p=0·53). INTERPRETATION: In this biologic-naive population of patients with rheumatoid arthrtitis, the dichotomic classification into synovial B cell poor versus rich did not predict treatment response to B cell depletion with rituximab compared with alternative treatment strategies. However, the lack of response to rituximab in patients with a pauci-immune pathotype and the higher risk of structural damage progression in B cell-rich patients treated with rituximab warrant further investigations into the ability of synovial tissue analyses to inform disease pathogenesis and treatment response. FUNDING: UK Medical Research Council and Versus Arthritis.

Fidelity evaluation of the dialogue around respiratory illness treatment (DART) program communication training.

OBJECTIVE: To evaluate receipt fidelity of communication training content included in a multifaceted intervention known to reduce antibiotic over-prescribing for pediatric acute respiratory tract infections (ARTIs), by examining the degree to which clinicians implemented the intended communication behavior changes. METHODS: Parents were surveyed regarding clinician communication behaviors immediately after attending 1026 visits by children 6 months to < 11 years old diagnosed with ARTIs by 53 clinicians in 18 pediatric practices. Communication outcomes analyzed were whether clinicians: (A) provided both a combined (negative + positive) treatment recommendation and a contingency plan (full implementation); (B) provided either a combined treatment recommendation or a contingency plan (partial implementation); or (C) provided neither (no implementation). We used mixed effects multinomial logistic regression to determine whether these 3 communication outcomes changed between baseline and the time periods following each of 3 training modules. RESULTS: After completing the communication training, the adjusted probability of clinicians fully implementing the intended communication behavior changes increased by an absolute 8.1% compared to baseline (95% Confidence Interval [CI]: 2.4%, 13.8%, p = .005). CONCLUSIONS: Our findings support the receipt fidelity of the intervention's communication training content. PRACTICAL IMPLICATIONS: Clinicians can be trained to implement communication behaviors that may aid in reducing antibiotic over-prescribing for ARTIs.

First-In-Human Phase I Study of a Next-Generation, Oral, TGFß Receptor 1 Inhibitor, LY3200882, in Patients with Advanced Cancer.

PURPOSE: A novel, selective, next-generation transforming growth factor beta (TGFß) receptor type-1 small molecule inhibitor, LY3200882, demonstrated promising preclinical data. This first-in-human trial evaluated safety, tolerability, recommended phase II dose (RP2D), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of LY3200882 as monotherapy or with other anticancer agents in patients with advanced cancer. PATIENTS AND METHODS: This phase I multicenter study of oral LY3200882 (NCT02937272) comprised dose escalation, monotherapy expansion in grade 4 glioma, and combination therapy in solid tumors (LY3200882 and PD-L1 inhibitor LY3300054), pancreatic cancer (LY3200882, gemcitabine, and nab-paclitaxel), and head and neck squamous cell cancer (LY3200882, cisplatin, and radiation). RESULTS: Overall, 139 patients with advanced cancer were treated. The majority (93.5%) of patients experienced ≥1 treatment-emergent adverse events (TEAE), with 39.6% LY3200882-related. Grade 3 LY3200882-related toxicities were only observed in combination therapy arms. One patient in the pancreatic cancer arm experienced cardiovascular toxicity. The LY3200882 monotherapy RP2Ds were established in two schedules: 50 mg twice a day 2-weeks-on/2-weeks-off and 35 mg twice a day 3-weeks-on/1-week-off. Four patients with grade 4 glioma had durable Revised Assessment in Neuro Oncology (RANO) partial responses (PR) with LY3200882 monotherapy (n = 3) or LY3200882-LY3300054 combination therapy (n = 1). In treatment-naïve patients with advanced pancreatic cancer, 6 of 12 patients achieved Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 PR and 3 of 12 patients demonstrated stable disease, for an overall 75% disease-control rate with the combination of LY3200882, gemcitabine, and nab-paclitaxel. CONCLUSIONS: LY3200882 as monotherapy and combination therapy was safe and well tolerated with preliminary antitumor activity observed in pancreatic cancer. Further studies to evaluate the efficacy of LY3200882 with gemcitabine and nab-paclitaxel in advanced pancreatic cancer are warranted.

Reducing Antibiotic Prescribing in Primary Care for Respiratory Illness.

BACKGROUND: One-third of outpatient antibiotic prescriptions for pediatric acute respiratory tract infections (ARTIs) are inappropriate. We evaluated a distance learning program's effectiveness for reducing outpatient antibiotic prescribing for ARTI visits. METHODS: In this stepped-wedge clinical trial run from November 2015 to June 2018, we randomly assigned 19 pediatric practices belonging to the Pediatric Research in Office Settings Network or the NorthShore University HealthSystem to 4 wedges. Visits for acute otitis media, bronchitis, pharyngitis, sinusitis, and upper respiratory infection for children 6 months to <11 years old without recent antibiotic use were included. Clinicians received the intervention as 3 program modules containing online tutorials and webinars on evidence-based communication strategies and antibioti c prescribing, booster video vignettes, and individualized antibiotic prescribing feedback reports over 11 months. The primary outcome was overall antibiotic prescribing rates for all ARTI visits. Mixed-effects logistic regression compared prescribing rates during each program module and a postintervention period to a baseline control period. Odds ratios were converted to adjusted rate ratios (aRRs) for interpretability. RESULTS: Among 72 723 ARTI visits by 29 762 patients, intention-to-treat analyses revealed a 7% decrease in the probability of antibiotic prescribing for ARTI overall between the baseline and postintervention periods (aRR 0.93; 95% confidence interval [CI], 0.90-0.96). Second-line antibiotic prescribing decreased for streptococcal pharyngitis (aRR 0.66; 95% CI, 0.50-0.87) and sinusitis (aRR 0.59; 95% CI, 0.44-0.77) but not for acute otitis media (aRR 0.93; 95% CI, 0.83-1.03). Any antibiotic prescribing decreased for viral ARTIs (aRR 0.60; 95% CI, 0.51-0.70). CONCLUSIONS: This program reduced antibiotic prescribing during outpatient ARTI visits; broader dissemination may be beneficial.

Understanding your own and other's minds: the relationship to eating disorder related symptoms.

A study using a cross-sectional survey design examined whether eating disorder (ED) related symptoms are associated with understanding one's own and others' minds. A non-clinical sample of 145 women completed self-report questionnaires and recorded their emotional, cognitive and behavioural responses to descriptions of scenarios (vignettes). Responses to scenarios were made from the perspective of self, an attachment figure and a same sex acquaintance. Data were analysed using multiple regression statistics with ED related symptoms as the dependent variable. High levels of ED related symptoms were associated with 'concretised' understanding of own emotions (i.e. a greater number of food related responses), but sophisticated understanding of same sex acquaintance's emotions. They were associated with fewer positive thoughts for self, fewer negative emotions about their own behaviour, and more food responses for same sex acquaintance's behaviour. Similarities and differences were observed in the different perspectives. Limitations are discussed. Implications for further research related to this topic and relevant to EDs are briefly summarised.

The relationship between body weight (body mass index) and attachment history in young women.

OBJECTIVE: This study investigated whether attachment history predicts unique variance in body mass index in young women. METHOD: A cross-sectional design was employed. One hundred and forty five women completed self report measures of attachment history and psychological symptoms. RESULTS: The findings indicated that negative parental discipline predicted significant variance in body mass index when common variance associated with demographic and psychological symptom measures was taken into account. CONCLUSIONS: It is concluded that attachment history may contribute to overweight and obesity and may be an important factor to consider in the prevention and treatment of overweight in women.

Confirmation of the association of the C4B null allelle in autism.

The objective of this study was to examine and attempt to confirm our previous findings of an increased frequency of the C4B null allele (C4BQ0) in subjects with autism. Newly identified subjects from Utah and Oregon were studied. Families evaluated included 85 who had a child with autism and 69 control families. Of the subjects with autism studied, 42.4% carried at least one C4BQ0, compared with 14.5% of the control subjects (p = 0.00013), with a relative risk of 4.33. Over half of the C4B null alleles in the subjects with autism involved C4A duplications. A marked increase in the ancestral haplotype 44.1 that lacks a C4B gene and has 2 C4A genes was also observed. The results of this study suggest that the human leukocyte antigen class III C4BQ0 significantly increases the risk for autism.

Dissimilatory iron(III) reduction by Rhodobacter capsulatus.

The photosynthetic proteobacterium Rhodobacter capsulatus was shown to be capable of dissimilatory Fe(III) reduction. Activity was expressed during anaerobic phototrophic and microaerobic growth with malate as the carbon source, but not during equivalent aerobic growth. A variety of Fe(III) complexes were demonstrated to act as substrates for intact cells and membrane fractions of strain N22DNAR+ using a ferrozine assay for Fe(II) formation. Rates of reduction appeared to be influenced by the reduction potentials of the Fe(III) complexes. However, Fe(III) complexed by citrate, which is readily reduced by Shewanella putrefaciens, was a poor substrate for dissimilation by R. capsulatus. The Fe(III)-reducing activity of R. capsulatus was located solely in the membrane fraction. The reduction of Fe(III) complexes by intact cells was inhibited by 2-heptyl-4-hydroxyquinoline-N-oxide (HQNO), suggesting the involvement of ubiquinol: cytochrome c oxidoreductases in the electron transport chain. Lack of sensitivity to myxothiazol plus data from mutant strains implies that the cytochrome bc 1 complex and cytochrome c 2 are not obligatory for dissimilation of Fe(III)(maltol)3. Alternative pathways of electron transfer to Fe(III) must hence operate in R. capsulatus. Using strain N22DNAR+, the reduction rate of Fe(III) complexed by nitrilotriacetic acid (NTA) was elevated compared to that of Fe(III)(maltol)3, and moreover was sensitive to myxothiazol. However, these differences were not observed in the absence of the electron donor malate. The governing factor for the reduction rate of Fe(III)(maltol)3 thus appears to be the limited Fe(III)-reducing activity, whilst the reduction rate of Fe(III) complexed by NTA is controlled by the flux of electrons through the respiratory chain. The use of mutant strains confirmed that the role of the cytochrome bc 1 complex in Fe(III) reduction becomes apparent only with the superior substrate. The energy-conserving nature of Fe(III) reduction by R. capsulatus was demonstrated by electrochromic measurements, with the endogenous carotenoid pigments being employed as indicators of membrane potential generation in intact cells. Using Fe(III)EDTA as electron acceptor, periods of membrane potential generation were directly proportional to the quantity of complex added, and were extended in the presence of HQNO. Fe(III)-dependent carotenoid bandshifts were abolished by addition of the protonophoric uncoupler carbonyl cyanide p-trifluoromethoxy-phenylhydrazone.