Search

BACKGROUND: Although targeted biological treatments have transformed the outlook for patients with rheumatoid arthritis, 40% of patients show poor clinical response, which is mechanistically still unexplained. Because more than 50% of patients with rheumatoid arthritis have low or absent CD20 B cells-the target for rituximab-in the main disease tissue (joint synovium), we hypothesised that, in these patients, the IL-6 receptor inhibitor tocilizumab would be more effective. The aim of this trial was to compare the effect of tocilizumab with rituximab in patients with rheumatoid arthritis who had an inadequate response to anti-tumour necrosis factor (TNF) stratified for synovial B-cell status. METHODS: This study was a 48-week, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial (rituximab vs tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis; R4RA) done in 19 centres across five European countries (the UK, Belgium, Italy, Portugal, and Spain). Patients aged 18 years or older who fulfilled the 2010 American College of Rheumatology and European League Against Rheumatism classification criteria for rheumatoid arthritis and were eligible for treatment with rituximab therapy according to UK National Institute for Health and Care Excellence guidelines were eligible for inclusion in the trial. To inform balanced stratification, following a baseline synovial biopsy, patients were classified histologically as B-cell poor or rich. Patients were then randomly assigned (1:1) centrally in block sizes of six and four to receive two 1000 mg rituximab infusions at an interval of 2 weeks (rituximab group) or 8 mg/kg tocilizumab infusions at 4-week intervals (tocilizumab group). To enhance the accuracy of the stratification of B-cell poor and B-cell rich patients, baseline synovial biopsies from all participants were subjected to RNA sequencing and reclassified by B-cell molecular signature. The study was powered to test the superiority of tocilizumab over rituximab in the B-cell poor population at 16 weeks. The primary endpoint was defined as a 50% improvement in Clinical Disease Activity Index (CDAI50%) from baseline. The trial is registered on the ISRCTN database, ISRCTN97443826, and EudraCT, 2012-002535-28. FINDINGS: Between Feb 28, 2013, and Jan 17, 2019, 164 patients were classified histologically and were randomly assigned to the rituximab group (83 [51%]) or the tocilizumab group (81 [49%]). In patients histologically classified as B-cell poor, there was no statistically significant difference in CDAI50% between the rituximab group (17 [45%] of 38 patients) and the tocilizumab group (23 [56%] of 41 patients; difference 11% [95% CI -11 to 33], p=0·31). However, in the synovial biopsies classified as B-cell poor with RNA sequencing the tocilizumab group had a significantly higher response rate compared with the rituximab group for CDAI50% (rituximab group 12 [36%] of 33 patients vs tocilizumab group 20 [63%] of 32 patients; difference 26% [2 to 50], p=0·035). Occurrence of adverse events (rituximab group 76 [70%] of 108 patients vs tocilizumab group 94 [80%] of 117 patients; difference 10% [-1 to 21) and serious adverse events (rituximab group 8 [7%] of 108 vs tocilizumab group 12 [10%] of 117; difference 3% [-5 to 10]) were not significantly different between treatment groups. INTERPRETATION: The results suggest that RNA sequencing-based stratification of rheumatoid arthritis synovial tissue showed stronger associations with clinical responses compared with histopathological classification. Additionally, for patients with low or absent B-cell lineage expression signature in synovial tissue tocilizumab is more effective than rituximab. Replication of the results and validation of the RNA sequencing-based classification in independent cohorts is required before making treatment recommendations for clinical practice. FUNDING: Efficacy and Mechanism Evaluation programme from the UK National Institute for Health Research. ispartof: LANCET vol:397 issue:10271 pages:305-317 ispartof: location:England status: published

OBJECTIVE. To evaluate communication training content fidelity included in a multifaceted intervention known to reduce antibiotic over-prescribing for pediatric acute respiratory illnesses (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 1,026 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 (positive + negative) 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=0.005). CONCLUSIONS. Our findings support the 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.

Effectiveness of health interventions can be substantially impaired by implementation failure. Context-driven implementation strategies are critical for successful implementation. However, there is no practical, evidence-based guidance on how to map the context in order to design context-driven strategies. Therefore, this practice paper describes the development and validation of a systematic context-mapping tool. The tool was cocreated with local end-users through a multistage approach. As proof of concept, the tool was used to map beliefs and behaviour related to chronic respiratory disease within the FRESH AIR project in Uganda, Kyrgyzstan, Vietnam and Greece. Feasibility and acceptability were evaluated using the modified Conceptual Framework for Implementation Fidelity. Effectiveness was assessed by the degree to which context-driven adjustments were made to implementation strategies of FRESH AIR health interventions. The resulting Setting-Exploration-Treasure-Trail-to-Inform-implementatioN-strateGies (SETTING-tool) consisted of six steps: (1) Coset study priorities with local stakeholders, (2) Combine a qualitative rapid assessment with a quantitative survey (a mixed-method design), (3) Use context-sensitive materials, (4) Collect data involving community researchers, (5) Analyse pragmatically and/or in-depth to ensure timely communication of findings and (6) Continuously disseminate findings to relevant stakeholders. Use of the tool proved highly feasible, acceptable and effective in each setting. To conclude, the SETTING-tool is validated to systematically map local contexts for (lung) health interventions in diverse low-resource settings. It can support policy-makers, non-governmental organisations and health workers in the design of context-driven implementation strategies. This can reduce the risk of implementation failure and the waste of resource potential. Ultimately, this could improve health outcomes.

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 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.

An online survey was conducted to assess professional views on social media use in clients with traumatic brain injury (TBI) and the prevalence of setting social media goals in neurorehabilitation. The majority of respondents had concerns over their clients’ social media use, however most did not set social media goals. Research is required to improve the processes of assessment, goal setting and rehabilitation in relation to clients’ social media use following brain injury.

Because mating entails both costs and potential benefits to both sexes, males and females should be under selection to make optimal choices from among available potential mates. For example, in some cases, individuals may benefit by using information on potential mates' previous sexual histories to make mate choices. In such cases, the form and direction of these benefits may vary both between the sexes and based on the sexual history of the choosing individuals themselves. We investigated the effects of recent previous sexual history on the mate choice and mating behavior of both males and females of the crayfish Orconectes limosus. In one experiment, we found that opposite-sex dyads comprising crayfish that had both mated 7–8 d previously with other conspecifics were significantly less likely to mate than dyads in which at least one crayfish was unmated. In a second experiment, we found that, when presented with a choice of tethered (but free to move) opposite-sex conspecifics, only virgin females discriminated between males based on sexual history, showing a preference for virgin males over recently mated males. Mated females, mated males, and virgin males showed no preferences based on the sexual histories of potential mates. We discuss the implications of these inferences in the context of what was previously known about mating behavior and potential sperm limitation in crustaceans and other taxa.

This study set out to investigate current practice and evaluate clinical psychologists’ views of copying letters to parents of child patients within the Oxford region.

We recently reported (Warren, Burger, Odell, Torres, & Warren, 1994) that a major subset of our autistic subjects has decreased plasma C4B levels resulting from inheritance of a null allele (no protein produced) of the C4B gene (Warren et al, 1991) located in the middle of the major histocompatibility complex (MHC) on chromosome 6. The C4B gene and the tightly linked structurally and functionally similar C4A gene encode products, designated as C4B and C4A proteins, that share several structural and functional characteristics identifying them as C4. However, they are distinct in other characteristics, most notably hemolytic activity; with C4B proteins having about four times more activity than C4A (Isenman & Young, 1986). The C4B null allele has been associated with increased viral and bacterial infections including bacterial meningitis (Rowe, McLean, Wood, Leggiardro, & Winkelstein, 1989), Streptococcus pneumoniae, Hemophilus influenzae, and Neisseria meningitidis (Bishof, Welch, & Beischel, 1990). The C4 genes along with other complement genes BF and C2 are located between the HLA-B region and HLA-DR region (Figure 1) of the MHC (Apler, Awdeh, & Yunis, 1989). Certain combinations of HLA-B, complement, and HLA-DR alleles associate together more often than would be expected from the relative distance between their respective loci and have been termed "extended MHC haplotypes" (Awdeh, Raum, Yunis, & Alper, 1983). The C4B null allele is recognized as part of one of these extended haplotypes designated [HLA-B44-SC30-DR4] in which the HLA-B allele is 44, the BF

We reported that the major histocompatibility complex (MHC) including the null allele of the C4B gene and the extended haplotype B44-C30-DR4 is associated with autism. We report now that the third hypervariable region (HVR-3) of certain DR beta 1 alleles have very strong association with autism. The HVR-3 of DR beta 1* 0401 or the shared HVR-3 alleles DR beta 1* 0404 and DR beta 1* 0404 and DR *0101, was expressed on extended haplotypes in 23 of 50 (46%) autistic subjects as compared to only 6 of 79 (7.5%) normal subjects. Another HVR-3 sequence, the DR beta 1* 0701 allele, was carried on extended haplotypes in 16 (32.0%) of the autistic subjects as compared to 8 (10.1%) of the normal subjects.

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.

The purpose of this study was to evaluate the psychometric properties of the Observer Alexithymia Scale (OAS; Haviland, Warren, & Riggs, 2000) in a clinical setting. Clinical and counseling psychologists used the OAS to rate outpatients (n = 192) with various Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 1994) diagnoses. Reliability and validity data are similar to the initial nonclinical data (n = 819): OAS scores are reliable (coefficient alpha = .90), and the five-factor structure--Distant, Uninsightful, Somatizing, Humorless, and Rigid--was confirmed. Moreover, the OAS does a relatively good job of differentiating clinical from nonclinical cases. The OAS is psychometrically sound, and it appears to be a useful tool for collecting and evaluating observer data on the clinically relevant, everyday expressions of alexithymia.

The authors developed a relatively brief observer alexithymia measure that can be used by patients’ acquaintances and relatives. Items corresponding to the defining features of alexithymia (California Q-Set Alexithymia Prototype) were written, and the new instrument's psychometric properties were evaluated in 3 lay-rater samples. The 33-item Observer Alexithymia Scale (OAS) is internally consistent (coefficient alphas = 0.88 and 0.89) and stable (2-week test-retest reliability = 0.87). Moreover, it has an interpretable five-factor structure (based on exploratory and confirmatory factor analyses): distant, uninsightful, somatizing, humorless, and rigid. The OAS is a reliable instrument with a stable factor structure and good conceptual coverage and thus, it appears to be a useful tool for collecting observer data on the clinically relevant expressions of alexithymia that receive minimal attention.

Objective: To determine complement C4 protein concentrations in the plasmas of autistic subjects and their family members. Design: Cross-sectional study. Setting: Center for Persons with Disabilities and the Department of Biology, Utah State University, Logan. Participants: Forty-two autistic subjects (34 males [81%] and eight females [19%]), 50 of their biologic parents, 21 siblings, and 105 normal subjects (56 females [53%] and 49 males [47%]; all white) living in northern Utah. Interventions: None. Methods: The enzyme-linked immunosorbent assay was used to determine C4 protein concentrations in autistic subjects. Main Results: Plasma concentration (median, 14.7 g/L of the C4B protein) in autistic patients was significantly ( P =.01) decreased compared with that of normal subjects (median, 22.4 g/L). The C4B concentrations in parents and siblings of autistic children were decreased, but not significantly. The C4A protein concentrations in the plasma of autistic subjects and their family members were normal. Conclusion: Decreased protein concentrations of C4B may be associated with autism. (Arch Pediatr Adolesc Med. 1994;148:180-183)

We previously reported that the complement C4B null allele appears to be associated with infantile autism. Since the C4B null allele is known to be part of the extended or ancestral haplotype [B44-SC30-Dr4], we investigated the incidence of [B44-Sc30-DR4] in 21 autistic children and their parents. This extended haplotype was increased by almost six-fold in the autistic subjects as compared with healthy controls. Moreover, the total number of extended haplotypes expressed on chromosomes of autistic subjects was significantly increased as compared with those expressed on chromosomes of healthy subjects. We conclude that a gene related to, or included in, the extended major histocompatibility complex may be associated with autism.

Maternal antibodies reactive with antigenic proteins expressed on the cell surface of paternal lymphocytes can be detected in couples with histories of more than one miscarriage or stillbirth. It is possible, but not proven, that these antibodies also react with tissues of the fetus and result in fetal death. Since many mothers of autistic children have a history of pregnancy disorder, antibodies were studied in 11 mothers of autistic children who were 6 years of age or younger. Six of the mothers had antibodies that reacted with lymphocytes of the autistic child. Five of these six mothers had a history of pregnancy disorder. Since antigens expressed on lymphocytes are found on cells of the central nervous system and, perhaps, other tissues of the developing embryo, it is suggested that aberrant maternal immunity may be associated with the development of some cases of infantile autism. J. Am. Acad. Child Adolesc. Psychiatry , 1990, 29, 6:873–877.

Jack was not a bad boy for a five year old, but he was a born nuisance. He never listened to adults, was even indifferent and certainly not interested in them. He was the center of commo tion in kindergarten, continually doing someone else's work, but too flighty to do his own. Discipline never established any pre dictable behavior. He accepted it for the time being, but never could remember the tasks he had to do and the limitations invol ved in doing them. His sister, who was in the first grade, was never any trouble. The mother even discussed the superiority of the sister with the teacher, in front of Jack, before his advent into kindergarten. She said, " Just you wait until you get Jack. " Before the first report card the father said, "Well, I suppose you'll bring home a terrible report card, unlike Judy. " Part ol Jack's reputation of being a bad boy had been acquired by his ina bility to play with other children in the neighborhood. How can we change Jack into a cooperative, understanding, pro ductive citizen in our society? This is the type of problem that faces anyone who deals in education today. A survey of today's curriculum in our schools shows a heavy loading of subject-matter materials and an emphasis on adult values which are not only not understood by the youngsters, but are enforces of negative methods; a study of home life shows con