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On December 16, 2020, the FDA granted regular approval to margetuximab-cmkb (MARGENZA), in combination with chemotherapy, for the treatment of adult patients with HER2-positive (HER2+) metastatic breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. Approval was based on data from SOPHIA, a multicenter, randomized, open-label, active controlled study comparing margetuximab with trastuzumab, in combination with chemotherapy. The primary efficacy endpoint was progression-free survival (PFS) by blinded independent central review. SOPHIA demonstrated a 0.9-month difference in median PFS between the two treatment arms [5.8 vs. 4.9 months, respectively; stratified HR, 0.76 (95% confidence interval: 0.59–0.98; P = 0.0334)]. Overall survival (OS) was immature at the data cut-off date of September 10, 2019. Infusion-related reactions (IRR) are an important safety signal associated with margetuximab plus chemotherapy. In SOPHIA, 13% of patients treated with margetuximab plus chemotherapy reported IRRs, of which 1.5% were grade 3. The most commonly reported adverse drug reactions (>10%) with margetuximab in combination with chemotherapy were fatigue/asthenia, nausea, diarrhea, vomiting, constipation, headache, pyrexia, alopecia, abdominal pain, peripheral neuropathy, arthralgia/myalgia, cough, decreased appetite, dyspnea, IRR, palmar-plantar erythrodysesthesia, and extremity pain. Overall, the favorable risk-benefit profile for margetuximab when added to chemotherapy supported its approval for the intended indication.

BACKGROUND Physical therapy and hip arthroscopy are two viable treatment options for patients with nonarthritic hip pain (NAHP); however, patients may experience considerable decisional conflict when making a treatment decision. Interdisciplinary evaluation with a physical therapist and surgeon may better inform the decision-making process and reduce decisional conflict. OBJECTIVE To identify the extent to which an interdisciplinary evaluation between a surgeon, physical therapist, and patient influences treatment plans and decisional conflict of persons with NAHP. DESIGN Randomized controlled trial. SETTING Hip preservation clinic. PARTICIPANTS Adults with primary NAHP. INTERVENTIONS Participants were randomized to receive a standard (surgeon) or interdisciplinary (surgeon+physical therapist) evaluation. Surgeon evaluations included patient interview, strength and range-of-motion examination, palpation, gross motor observation, and special testing. Interdisciplinary evaluations started with the surgeon evaluation, then a physical therapist evaluated movement impairments during sitting, sit-to-stand, standing, single-leg stance, single-leg squat, and walking. All evaluations concluded with treatment planning with the respective provider(s). OUTCOME MEASURES Treatment plan and decisional conflict were collected pre- and postevaluation. Inclusion of physical therapy in participants' postevaluation treatment plans and postevaluation decisional conflict were compared between groups using chi-square tests and Mann-Whitney U tests, respectively. RESULTS Seventy-eight participants (39 in each group) met all eligibility criteria and were included in all analyses. Sixty-six percent of participants who received an interdisciplinary evaluation included physical therapy in their postevaluation treatment plan, compared to 48% of participants who received a standard evaluation (p = .10). Participants who received an interdisciplinary evaluation reported 6.3 points lower decisional conflict regarding their postevaluation plan (100-point scale; p = .04). The interdisciplinary and standard groups reduced decisional conflict on average 24.8 ± 18.9 and 23.6 ± 14.6 points, respectively. CONCLUSIONS Adding a physical therapist to a surgical clinic increased interest in physical therapy treatment, but this increase was not statistically significant. The interdisciplinary group displayed lower postevaluation decisional conflict; however, both groups displayed similar reductions in decisional conflict from pre- to postevaluation. This study also demonstrated the feasibility of an interdisciplinary evaluation in a hip preservation clinic.

Objective Synthesize available evidence that have examined the relationship between physical therapy (PT) and opioid-use. Literature survey Data sources including Google scholar, Embase, PubMed, Cochrane Library, and CINAHL were searched for English articles up to 10-24-2019 using terms ("physical therapy"[Title/Abstract] OR physiotherapy[Title/Abstract] OR rehabilitation[Title/Abstract]) AND (opiate*[Title/Abstract] OR opioid*[Title/Abstract]). Methodology Included studies evaluated a PT intervention and reported an opioid-use outcome. Data were extracted to describe the PT intervention, patient sample, opioid-use measurement, and results of any time or group comparisons. Study quality was evaluated with Joanna Briggs checklists based on study design. Synthesis Thirty studies were included that evaluated PT in at least one of these seven categories: interdisciplinary program (n = 8), modalities (n = 3), treatment (n = 3), utilization (n = 2), content (n = 3), timing (n = 13), and location (n = 2). Mixed results were reported for reduced opioid-use after interdisciplinary care and after PT modalities. Utilizing PT was associated with lower odds (ranging from 0.2-0.8) to use opioid medication for persons with low back pain (LBP) and injured workers; however, guideline-adherent care did not further reduce opioid-use for persons with LBP. Early PT utilization after index visit for spine or joint pain and after orthopaedic surgery was also associated with lower odds to use opioid medications (ranging from 0.27-0.93). Emergency department PT care was not associated with fewer opioid prescriptions than standard emergency department care. PT in a rehabilitation center after total knee replacement was not associated with lower opioid use than inpatient PT. Conclusions The relationship between timing of PT and opioid use was evaluated in 13 of 30 studies for a variety of patient populations. Eight of these 13 studies reported a relationship between early PT and reduced subsequent opioid use, making the largest sample of studies in this scoping review with supporting evidence. There is limited and inconclusive evidence to establish whether the content and/or location of PT interventions improves outcomes due to heterogeneity between studies. This article is protected by copyright. All rights reserved.

Like most events that have taken place since March of last year, the Sundance Film Festival—normally hosted in the cozy ski town of Park City, Utah—was held virtually in 2021. But what it lacked in celebrity sightings and snowy ambiance was more than made up for in the festival's assortment of provocative and timely offerings—from gripping accounts of the COVID-19 pandemic and California's wildfire crisis to mind-bending meditations on the limits of perception and the nature of reality. Read on to see what our reviewers thought of nine of the films that featured strong science and technology themes.

Polytrauma clinical triad (PCT) is the comorbid occurrence of traumatic brain injury (TBI), posttraumatic stress disorder (PTSD), and pain after trauma. No clinical practice guidelines for postacute care of patients with PCT currently exist; instead, clinical practice guidelines have been published for the three conditions (TBI, PTSD, and pain) as distinct clinical entities. Using multiple, individual practice guidelines for a patient with PCT may lead to unintended prescription of multiple and potentially adversely interacting medications (ie, polypharmacy). Polypharmacy, especially that which includes central nervous system-acting medications, may lead to overdose, suicidality, and chronic symptomatology. Current individual guidelines for each condition of PCT do not address how to coordinate care for the polytraumatic diagnosis. The purpose of this Practice Management piece is to describe the unintended consequences of polypharmacy in patients with PCT and to discuss mitigation approaches including rational prescribing, nonpharmacologic alternatives, and interdisciplinary coordination.

Repeated bolus injections are associated with higher costs and poor compliance and can hinder the implementation of global immunization campaigns. Here, we report the development and preclinical testing of patches of transdermal core-shell microneedles-which were fabricated by the micromoulding and alignment of vaccine cores and shells made from poly(lactic-co-glycolic acid) with varying degradability kinetics-for the preprogrammed burst release of vaccine payloads over a period of a few days to more than a month from a single administration. In rats, microneedles loaded with a clinically available vaccine (Prevnar-13) against the bacterium Streptococcus pneumoniae induced immune responses that were similar to immune responses observed after multiple subcutaneous bolus injections, and led to immune protection against a lethal bacterial dose. Microneedle patches delivering preprogrammed doses may offer an alternative strategy to prophylactic and therapeutic protocols that require multiple injections.

BACKGROUND Outcomes for operative and nonoperative management of femoroacetabular impingement syndrome (FAIS) are variable. Understanding factors that inform patients' treatment decisions may optimize their outcomes. OBJECTIVE To identify factors that predict which patients with FAIS proceed to surgery within 90 days of their initial evaluation by an orthopedic surgeon. The study explored potential predictors of surgical intervention, including demographic factors, activity level, symptom duration, previous treatment, hip function, pain, presence of labral tear, and patient interest in surgical and physical therapy (PT) treatment. DESIGN Prospective cohort. SETTING Single-site academic medical center. PATIENTS Seventy-seven individuals with FAIS. INTERVENTION After evaluation in a hip preservation clinic, participants reported activity level, symptom duration, treatment history, hip function [Hip Outcome Score Activities of Daily Living(HOS-ADL)], pain severity and location, and treatment interests. These variables were evaluated based on univariate analysis for entry into a multiple binomial logistic regression to identify predictors of surgery within 90 days. Adjusted marginal prevalence ratios and 95% confidence interval estimates (PR [95% CI]) were reported (P ≤ .05). MAIN OUTCOME MEASURE(S) Ninety-day treatment (surgery or not). RESULTS Participants indicated initial interest in surgery (n = 27), PT (n = 22), both (n = 18), or neither (n = 10). Those only interested in PT had lower prevalence of diagnosed labral tear (P

Background Physical therapy and surgery are viable treatment options for nonarthritic hip disease (NAHD). Interdisciplinary collaboration can help patients make informed treatment decisions. Understanding how each provider can contribute is a critical first step in developing collaborative evaluation efforts. Objective The objective of this study was to describe the current evaluation of NAHD by both physical therapists and physicians, and evaluate national use of expert-recommended evaluation guidelines. Design A national survey study distributed in the United States was implemented to accomplish the objective. Methods A survey was distributed to 25,027 potential physical therapist and physician respondents. Respondents detailed their evaluation content for patients with NAHD across the following domains: patient-reported outcomes, patient history, special tests, movement assessment, clinical tests, and imaging. Respondents ranked importance of each domain using a 5-point Likert scale (not important, slightly important, important, very important, or extremely important). Odds ratios (ORs [95% CIs]) were calculated to identify the odds that physical therapists, compared with physicians, would report each evaluation domain as at least very important. Fisher exact tests were performed to identify statistically significant ORs. Results Nine hundred and fourteen participants (3.6%) completed the survey. Physical therapists were more likely to indicate movement assessment (OR: 4.23 [2.99–6.02]) and patient-reported outcomes (OR: 2.56 [1.67–3.99]) as at least very important for determining a diagnosis and plan of care. Physical therapists had lower odds of rating imaging (OR: 0.09 [0.06–0.14]) and special tests (OR: 0.72 [0.53–0.98]) as at least very important compared with physicians. Limitations This survey study did not include many orthopedic surgeons and thus, primarily represents evaluation practices of physical therapists and nonsurgical physicians. Conclusions Physical therapists were more likely to consider movement assessment very important for the evaluation of patients with NAHD, whereas physicians were more likely to consider imaging and special testing very important.

Objective The purpose of the study was to synthesize studies of movement patterns and their association with hip pain, function/activity, and morphology in individuals with femoroacetabular impingement syndrome (FAIS). Methods PubMed, SPORTDiscus, CINAHL, Embase, and Scopus databases were searched using predefined terms. Two authors independently reviewed abstracts and full texts. Studies were included if they enrolled individuals with FAIS, reported kinematic or kinetic data during movement tasks, and tested the data’s associations with hip pain, function/activity, or morphology. Exclusion criteria were studies that did not evaluate associations between movement patters and pain, function/activity, or hip morphology. Additionally, studies with hip conditions other than FAIS, case reports, conference proceedings, review articles, and non-English studies were excluded. Descriptive consolidation and qualitative synthesis were performed for the included studies. Results Of the 1155 potential studies, 5 studies met all eligibility criteria. Movement patterns were evaluated during walking (n = 4) and squatting (n = 1). Studies reported multiple associations between variables of interest. Statistically significant associations were identified between movement patterns and hip pain (n = 2), function/activity (n = 2), or morphology (n = 3). Significant associations included increased hip flexion moment impulse during walking was associated with worse pain, increased hip flexion moment during walking was associated with worse hip function, decreased hip external rotation during gait and hip internal rotation during squat were associated with larger cam deformity, and increased hip flexion moment impulse during walking was also associated with more severe acetabular cartilage abnormalities. Conclusions Very little current evidence has evaluated the associations between altered movement patterns and hip pain, function/activity, or morphology in individuals with FAIS, and only low-intensity tasks have been tested. These studies found some preliminary associations between altered hip biomechanics and higher hip pain, worse hip function, and specific measures of hip morphology in individuals with FAIS. Impact This review is a first step in gaining a better understanding of movement patterns and their associations with hip pain, function/activity, and morphology, which could ultimately assist with the development of movement retraining interventions and potentially improve rehabilitation outcomes for those with FAIS.

To identify patient- and physical therapist-level predictors for therapeutic alliance at the end of an episode of physical therapy for knee or low back pain (LBP).Secondary analysis of observational cohort.Outpatient physical therapy clinics.Patients receiving physical therapy for knee (n=189) or LBP (n=252) and physical therapists (n=19). Candidate predictor variables included demographics, patient clinical characteristics, and physical therapist attitudes and beliefs (Pain Attitudes and Beliefs Scale for Physical Therapists) and confidence in providing patient-centered care (Self-Efficacy in Patient-Centeredness Questionnaire).Not applicable.Patient-reported therapeutic alliance was measured using the 12-item Work Alliance Inventory-Short Revised (WAI-SR).Final linear mixed models indicated different patient- and physical therapist-level factor contributions in predicting final WAI-SR scores across cohorts with knee and LBP. Female sex was a consistent patient-level predictor for both knee (estimated β=1.57, P.05) and LBP (β=1.42, P.05), with age (β=-0.07, P.01) and baseline function (β=0.06, P.01) contributing to cohorts with knee and LBP, respectively. Physical therapist-level predictors included female sex (β=6.04, P.05), Pain Attitudes and Beliefs Scale for Physiotherapists behavioral (β=0.65, P.01), and Self-Efficacy in Patient-Centeredness Questionnaire (SEPCQ) Exploring Patient Perspective (β=-0.75, P.01) subscale scores for LBP, with SEPCQ Sharing Information and Power subscale scores (β=0.56, P.05) contributing to both cohorts with knee (β=0.56, P.05) and LBP (β=0.74, P.01). Random effects for patients nested within physical therapists were observed for both cohorts.These findings provide preliminary evidence for inconsistent relationships among patient- and physical therapist-level factors and therapeutic alliance across cohorts with knee and LBP.

Previous research has shown that acute competition training stress negatively affects neuromuscular function which can perpetuate a predisposition to injury. This study's aim was to investigate the effect of accumulated competition training stress effect on neuromuscular function and incidence of increased injury risk in uninjured female D1 soccer players. Neuromuscular function was evaluated in fifteen female division I soccer athletes who played >85% of competitive season competitions who were tested for mobility/stability, leg length symmetry, and vertical power at three different points across the competitive season (pre, mid, and post time blocks). Leg length symmetry was measured from the anterior superior iliac spine to the lateral malleolus prior to Y-balance testing. The Y-balance testing measures unilateral anterior, posteromedial, and posterolateral reach achieved in single leg stance using metrics that include L/R normalized composite reach (NCOMP), L/R normalized antiorior reach (NANT), and L/R NCOMP/NANT segmental differences across time. Injury risk was evaluated using validated objective criteria that included: (NCOMP total reach *3), (NANT reach distance 4.0. Maximal vertical power (MVP) was measured via vertical jump. Multiple repeated measures ANOVAs evaluated NCOMP, NANT, MVP, and leg length symmetry across time with LSD post hoc testing when relevant (X ± SD). A significant main effect was found [F(1, 14) = 62.92, p < 0.001; η2 =0.82] with training stress and neuromuscular function without affecting maximal vertical power. Eighty percent of subject's bilateral NCOMP scores fell below the YBT reach standard at midseason (ES = 0.95, p = 0.02) while all subjects NANT reach distance remained below the reach threshold (ES = 0.74, p = 0.003) indicating a 6.5× and 2.5× greater injury risk, respectively. Competition stress affected neuromuscular function without affecting maximal power, which negatively impacted stability and increased injury risk.

BACKGROUND Low back pain (LBP) has been associated with worse hip function for persons with femoroacetabular impingement syndrome (FAIS). Reports are limited to surgical populations and based on the presence or absence of LBP, regardless of pain severity. OBJECTIVES To report the prevalence of clinically significant LBP for persons with FAIS; compare demographics, pain, and function between those with and without clinically significant LBP; and evaluate relationships between hip function and both LBP-related disability and LBP severity. We hypothesized that participants with LBP would be older, have higher body mass index (BMI), and report worse groin pain, longer symptom duration, and worse hip function. We hypothesized that worse LBP-related disability and LBP severity would be related to worse hip function. DESIGN Observational cross-sectional study. SETTING Hip preservation clinic. PARTICIPANTS 158 persons with FAIS. INTERVENTIONS n/a MAIN OUTCOME MEASURE(S): Visual analog pain scales (VAS 0-100) were used to categorize participants with (≥30) and without (

Publications reporting discrete choice experiments of healthcare interventions rarely discuss whether patient and public involvement (PPI) activities have been conducted. This paper presents examples from the existing literature and a detailed case study from the National Institute for Health Research-funded PATHWAY programme that comprehensively included PPI activities at multiple stages of preference research. Reflecting on these examples, as well as the wider PPI literature, we describe the different stages at which it is possible to effectively incorporate PPI across preference research, including the design, recruitment and dissemination of projects. Benefits of PPI activities include gaining practical insights from a wider perspective, which can positively impact experiment design as well as survey materials. Further benefits included advice around recruitment and reaching a greater audience with dissemination activities, amongst others. There are challenges associated with PPI activities; examples include time, cost and outlining expectations. Overall, although we acknowledge practical difficulties associated with PPI, this work highlights that it is possible for preference researchers to implement PPI across preference research. Further research systematically comparing methods related to PPI in preference research and their associated impact on the methods and results of studies would strengthen the literature. Electronic supplementary material The online version of this article (10.1007/s40271-020-00439-2) contains supplementary material, which is available to authorized users.

(1) To determine the prevalence of depression in patients undergoing hip arthroscopy for the treatment of femoroacetabular impingement (FAI) syndrome and (2) to determine whether depression has a statistically significant and clinically relevant effect on preoperative and postoperative patient-reported outcome scores.Consecutive subjects undergoing hip arthroscopy for FAI syndrome were retrospectively reviewed. The Beck Depression Inventory-II (BDI-II), Hip Outcome Score (HOS), and 33-item International Hip Outcome Tool (iHOT-33) were administered preoperatively and postoperatively. Clinically relevant differences were defined by the minimal clinically important difference, substantial clinical benefit, and patient acceptable symptom state. Comparisons between preoperative and postoperative scores were completed. The Spearman correlation coefficient (r) was used to determine the degree of correlation between the BDI-II score, HOS, and iHOT-33 score preoperatively and postoperatively.We analyzed 77 patients (72.7% female patients; mean age, 35.2 ± 12.5 years). Depressive symptoms were reported as minimal (75.3%), mild (11.7%), moderate (6.5%), or severe (6.5%). Patients with minimal or mild depression had a superior HOS Activities of Daily Living (Δ17.3 preoperatively [P.001] and Δ37.8 postoperatively [P.001]), HOS Sport-Specific Subscore (Δ12.8 preoperatively [P = .002] and Δ52.1 postoperatively [P.0001]), and iHOT-33 score (Δ15.4 preoperatively [P.0001] and Δ51.3 postoperatively [P.0001]) compared with patients with moderate or severe depression. There was a weak to moderate negative correlation between the BDI-II score and iHOT-33 score (r = -0.4614, P.0001 preoperatively; r = -0.327, P.0001 at 1 year), HOS Activities of Daily Living (r = -0.531, P.0001 preoperatively), and HOS Sport-Specific Subscore (r = -0.379, P.0017 at 1 year).Most patients undergoing hip arthroscopy for FAI have minimal depressive symptoms with the overall prevalence higher than the general population. Patients with minimal or mild depressive symptoms have statistically and clinically better preoperative and postoperative patient-reported outcomes, are more likely to obtain substantial clinical benefit from surgery, and are more likely to reach a patient acceptable symptom state after surgery than patients with moderate to severe depressive symptoms.Level III, case-control study.

Postoperative gait mechanics in persons with femoroacetabular impingement syndrome (FAIS) remain understudied as a treatment outcome despite observed, yet inconclusive, preoperative gait abnormalities. Females with FAIS demonstrate worse preoperative patient-reported hip function and altered hip mechanics when compared with males; it is unknown whether these sex differences persist postarthroscopy. The purpose of this study was to compare sex-specific gait kinematics between persons at least 1 year postarthroscopy for FAIS and healthy comparisons. General linear models with estimating equations were used to evaluate the effect of (a) limb and sex within each group, and (b) limb and group within each sex for peak sagittal and frontal plane trunk, pelvis, and hip kinematics during stance phase of gait. Analyses were covaried by gait speed. Seventeen females and eight males an average 2.5 years postarthroscopy (1.1-7.2 year) for FAIS were compared with healthy females (n = 7) and males (n = 5). Females in the FAIS group presented with an average of 4.6° more anterior pelvic tilt, and 4.8° less hip extension compared with healthy females (P ≤ .03) and 8.6° less trunk flexion, 4.8° more anterior pelvic tilt, 3.1° more pelvic drop, and 7.5° more hip flexion than males with FAIS (P ≤ .03). Males in the FAIS group presented with 2.9° less pelvic drop, and 3.2° less hip adduction than healthy males. Preoperative gait mechanics were not collected and thus changes in mechanics could not be evaluated. This study is significant to clinicians who treat patients postarthroscopy to consider sex-specific gait impairments.

BACKGROUND: Non-arthritic hip disease (NAHD) is a clinical condition often accompanied by painful movement. Current literature is lacking regarding how movement abnormalities are evaluated and treated in this population, which may be key to identifying which patients may respond to non-operative versus operative treatment. Combining the expertise of a hip arthroscopist and physical therapist may better inform treatment decisions for persons with NAHD. The primary objective of this study is to identify the extent to which an interdisciplinary evaluation between a physical therapist and surgeon influences treatment decisions of persons presenting to a hip preservation clinic. RATIONALE FOR STUDY DESIGN: A prospective, randomized controlled trial provides the ability to identify cause and effect of this new evaluation type. METHODS: Ninety-six adults with unilateral, NAHD presenting to a hip preservation clinic for initial evaluation will be randomized to receive either a standard evaluation with a surgeon or an interdisciplinary evaluation by a physical therapist and surgeon. Regardless of group, the surgeon conducts a standard-care examination. For participants in the interdisciplinary group, the physical therapist conducts an assessment of 6 postures and movements to identify asymmetrical, abnormal, or painful strategies. Treatment selection(s) and decisional conflict will be compared between groups after the evaluations. DISCUSSION: Persons with NAHD may experience considerable decisional conflict because of prolonged duration of symptoms and minimal evidence to compare operative and non-operative treatment for this population. The findings of this study have the potential to improve patient experience and produce more informed and supported treatment decisions for persons considering surgical treatment for NAHD.

Repeated bolus injections are associated with higher costs and poor compliance and can hinder the implementation of global immunization campaigns. Here, we report the development and preclinical testing of patches of transdermal core-shell microneedles-which were fabricated by the micromoulding and alignment of vaccine cores and shells made from poly(lactic-co-glycolic acid) with varying degradability kinetics-for the preprogrammed burst release of vaccine payloads over a period of a few days to more than a month from a single administration. In rats, microneedles loaded with a clinically available vaccine (Prevnar-13) against the bacterium Streptococcus pneumoniae induced immune responses that were similar to immune responses observed after multiple subcutaneous bolus injections, and led to immune protection against a lethal bacterial dose. Microneedle patches delivering preprogrammed doses may offer an alternative strategy to prophylactic and therapeutic protocols that require multiple injections.

TIR domain containing proteins are important immune associated proteins shared among Toll-like and interleukin-1/18 receptor family members. In a recent discovery select bacterial, plant and human TIR proteins exhibit enzymatic activity in binding and processing nicotinamide adenine dinucleotide (NAD+). Based on their abilities to facilitate signaling across biology, we hypothesize that TIR proteins represent unique therapeutic targets for modulating infection, inflammation and disease. Our previous structural studies of bacterial-host TIR proteins B. melitensis (TcpB) and uropathogenic E. coli CFT073 (TcpC) with human host TIRAP and MyD88 characterized peptides that negatively regulate signaling and infection. From these studies we identified interactions that are at or near reported biological TIR protein interfaces. In particular, we identified a functionally important motif found conserved on the C helix of most bacterial, human host and NAD+ consuming TIR proteins. As proof of concept for select targeting of TIR proteins and this region in particular we have used the TLR4 antagonist, TAK-242, which selectively binds within this motif. Treatment with TAK-242 or TLR4-C747S blocks LPS signaling. Additionally, TAK-242 protected mice from lethal influenza challenge similar to an extracellular TLR4 antagonist, Eritoran. Bioinformatic analysis of the region targeted by TAK242 show that it is located within the WxxxE structural motif identified to be important for protecting against microtubule destabilization and includes a catalytically essential glutamic acid (E) residue conserved among nearly all NAD+ consuming TIR proteins. These studies provide a framework for future studies targeting TIR protein function.

BackgroundElectronic administrative data exist in several domains which, if linked, are potentially useful for research. However, benefits from data linkage should be considered alongside risks such as the threat to privacy. Avon Longitudinal Study of Parents and Children (ALSPAC) is a birth cohort study. The Project to Enhance ALSPAC through Record Linkage (PEARL) was established to enrich the ALSPAC resource through linkage between ALSPAC participants and routine sources of health and social data. Qualitative research was incorporated in the PEARL study to examine participants’ views about data linkage and inform approaches to information. This paper focusses on issues of consent. MethodsDigitally recorded interviews were conducted with 55 participants aged 17-19 years. Terms and processes relating to consent, anonymization and data linkage were explained to interviewees. Scenarios were used to prompt consideration of linking different sources of data, and whether consent should be requested. Interview recordings were fully transcribed. Thematic analysis was undertaken using the Framework approach. ResultsParticipant views on data linkage appeared to be most influenced by: considerations around the social sensitivity of the research question, and; the possibility of tangible health benefits in the public interest. Some participants appeared unsure about the effectiveness of anonymization, or did not always view effective anonymization as making consent unnecessary. This was related to notions of ownership of personal information and etiquette around asking permission for secondary use. Despite different consent procedures being explained, participants tended to equate consent with ‘opt-in’ consent through which participants are ‘asked’ if their data can be used for a specific study. Participants raising similar concerns came to differing conclusions about whether consent was needed. Views changed when presented with different scenarios, and were sometimes inconsistent. ConclusionsFindings from this study question the validity of ‘informed consent’ as a cornerstone of good governance, and the extent to which potential research participants understand different types of consent and what they are consenting, or not consenting, to. Pragmatic, imaginative and flexible approaches are needed if research using data linkage is to successfully realise its potential for public good without undermining public trust in the research process.

Single-peaked preferences are important throughout social choice theory. In this article, we consider single-peaked preferences over multidimensional binary alternative spaces—that is, alternative spaces of the form {0,1}n for some integer n≥2. We show that preferences that are single-peaked with respect to a normalized separable base order are nonseparable except in the most trivial cases. We establish that two distinct base orders can induce the same single-peaked preference order if any only if they differ by a transposition of their two central elements. We then use this result to enumerate single-peaked binary preference orders over a separable base order.

A recurring single amino acid somatic mutation associated with human diffuse large B cell lymphomas (DLBCLs), correlates with tumor cell proliferation and survival involving spontaneous and sustained activation of MyD88-dependent NF-κB and Janus Kinase (JAK) signaling pathways. MyD88 acts as a central signaling adapter for mediating innate and cytokine driven inflammation for the Interleukin-1 (IL-1R) and Toll-like receptors (TLRs). Computer aided molecular modeling of MyD88 and in silico screening have identified and functionally characterized MyD88 specific small molecule compounds shown to protect against Staphylococcal enterotoxin B (SEB) induced death in animal models. We hypothesize that MyD88 specific small molecule compounds may also be useful in treating DLBCLs bearing the oncogenic mutation MYD88L265P. Using in vitro and in vivo studies we evaluate MyD88 specific small molecule compounds for the ability to inhibit tumor cell proliferation and signaling in human patient cancer cells OCI Ly3 bearing the oncogenic mutation MYD88 L265P and OCI Ly19 DLBCLs. Previously we identified differences in the ability of MyD88 small molecule compounds to inhibit cell proliferation in activated human B cell lymphoma cells bearing the MyD88 L265P mutation. We now correlate these differences with a reduction of MyD88 interaction with IRAK in small molecule treated OCI-Ly3 cells bearing the MYD88 L265P mutation in comparison to OCI-Ly19 (wt-MyD88) and treated controls, as measured by CoIP. We continue to characterize MyD88 specific small molecule compounds that target MyD88 dimerization for their ability to reduce MyD88 containing signaling complexes in DLBCLs bearing MYD88 L265P mutation.

Background Avon Longitudinal Study of Parents and Children (ALSPAC) is a birth cohort study within which the Project to Enhance ALSPAC through Record Linkage (PEARL) was established to enrich the ALSPAC resource through linkage between ALSPAC participants and routine sources of health and social data. PEARL incorporated qualitative research to seek the views of young people about data linkage, including their opinions about appropriate safeguards and research governance. In this paper we focus on views expressed about the purpose and composition of research ethics committees. Methods Digitally recorded interviews were conducted with 48 participants aged 17–19 years. Participants were asked about whether medical research should be monitored and controlled, their knowledge of research ethics committees, who should sit on these committees and what their role should be. Interview recordings were fully transcribed and anonymised. Thematic analysis was undertaken, assisted by the Framework approach to data management. Results The majority of interviewees had little or no specific knowledge of ethics committees. Once given basic information about research ethics committees, only three respondents suggested there was no need for such bodies to scrutinise research. The key tasks of ethics committees were identified as monitoring the research process and protecting research participants. The difficulty of balancing the potential to inhibit research against the need to protect research participants was acknowledged. The importance of relevant research and professional expertise was identified but it was also considered important to represent wider public opinion, and to counter the bias potentially associated with self-selection possibly through a selection process similar to ‘jury duty’. Conclusions There is a need for more education and public awareness about the role and composition of research ethics committees. Despite an initial lack of knowledge, interviewees were able to contribute their ideas and balance the rights of individuals with the wider benefits from research. The suggestion that public opinion should be represented through random selection similar to jury duty may be worth pursuing in the light of the need to ensure diversity of opinion and establish trust amongst the general public about the use of ‘big data’ for the wider public good.

This study examined the impact of an afterschool program on resilience in youth at an elementary school in Central NY. The goals of the program were to: (a) increase resiliency among participants, and (b) reduce the occurrence of aggressive behaviors (i.e., bullying) in 5th and 6th graders. Of the 79 students who completed the survey, 19 participants were able to be matched with pre- and posttests. In the study, 13 as participants in the afterschool program, and six as non-participants. Results of paired samples t-tests indicated that those who participated in the afterschool program showed a significant increase (p= 0.05) in resiliency scores. The program also had a positive impact on decreasing discipline-related referrals.

The purpose of this study was to adapt and experimentally test the effectiveness of a research-based, employment-focused group counseling intervention (OPTIONS). OPTIONS was designed to increase male inmates’ exploration and identification of employment interests and options, identification and development of employment-search skills, and knowledge of vocational options, goal planning, and identification and use of contextual supports. A randomized block design and measurements at pretest, posttest, and 1-month follow-up were used to examine the effects of OPTIONS. Participants included 77 ( n = 38 treatment, n = 39 control) adult male inmates. Results indicated that OPTIONS participants had higher career search self-efficacy, problem solving, and hopefulness scores at posttest and follow-up than did treatment-as-usual control group participants.

This brief report provides a concise overview of decades of research into what really makes a difference in treatment outcomes for the most common psychiatrics disorders. The evidence points to the conclusion that the relationship with the clinician accounts for much more of the variance in treatment outcomes than the treatment methods themselves. The discussion of research and statistical methodology are relevant to investigations of treatments for speech and language disorders.

Background Electronic administrative data exist in several domains which, if linked, are potentially useful for research. However, benefits from data linkage should be considered alongside risks such as the threat to privacy. Avon Longitudinal Study of Parents and Children (ALSPAC) is a birth cohort study. The Project to Enhance ALSPAC through Record Linkage (PEARL) was established to enrich the ALSPAC resource through linkage between ALSPAC participants and routine sources of health and social data. Qualitative research was incorporated in the PEARL study to examine participants’ views about data linkage and inform approaches to information sharing. This paper focusses on issues of consent. Methods Digitally recorded interviews were conducted with 55 participants aged 17–19 years. Terms and processes relating to consent, anonymization and data linkage were explained to interviewees. Scenarios were used to prompt consideration of linking different sources of data, and whether consent should be requested. Interview recordings were fully transcribed. Thematic analysis was undertaken using the Framework approach. Results Participant views on data linkage appeared to be most influenced by: considerations around the social sensitivity of the research question, and; the possibility of tangible health benefits in the public interest. Some participants appeared unsure about the effectiveness of anonymization, or did not always view effective anonymization as making consent unnecessary. This was related to notions of ownership of personal information and etiquette around asking permission for secondary use. Despite different consent procedures being explained, participants tended to equate consent with ‘opt-in’ consent through which participants are ‘asked’ if their data can be used for a specific study. Participants raising similar concerns came to differing conclusions about whether consent was needed. Views changed when presented with different scenarios, and were sometimes inconsistent. Conclusions Findings from this study question the validity of ‘informed consent’ as a cornerstone of good governance, and the extent to which potential research participants understand different types of consent and what they are consenting, or not consenting, to. Pragmatic, imaginative and flexible approaches are needed if research using data linkage is to successfully realise its potential for public good without undermining public trust in the research process.

The purpose of this study was to ascertain whether a measurable difference existed in normative scores for the American Shoulder and Elbow Surgeons (ASES) questionnaire between subjects who had an active workers' compensation claim (WC) with no known shoulder injury and subjects without a compensation claim (non-WC). Subjects with non-shoulder-related orthopaedic injuries were recruited from a suburban orthopaedic sports medicine clinic and an urban occupational medicine clinic. They were asked to complete a composite questionnaire that consisted of demographic information and the ASES questionnaire. There were no significant differences in the ASES scores between subject groups. There were significant differences between subject groups with regard to work hours (P = .0001), work demands (P = .0001), and tobacco use (P = .0001). Subject group was also significantly associated with education level (P = .0001), marital status (P = .0001), work demands (P = .0001), gender (P = .0001), and sports participation (P = .0314). The ASES score was significantly affected by marital status (P = .0476), sports participation (P = .0008), and age (P = .0129).

Pseudowollastonite ceramic (psW) is a bioactive ceramic that binds to bone when implanted in vivo and may be useful for the treatment of skeletal defects. However, there have been no studies that examined the interaction between psW and osteoblastic cells in vitro. This study investigated the suitability of psW as a substratum for cell attachment and the ability of the material to effect osteoblasts at a distance from the material surface. Fetal rat calvarial cells were plated onto the ceramic and examined by scanning electron microscopy. The findings reported show that cells attached and proliferated on the surface to the ceramic. Attachment by cells to the material can be enhanced by preincubation of psW in serum or media containing fibronectin. The adhesion of cells can be inhibited by addition of GRGDS peptides suggesting that adhesion to psW is mediated by integrin binding to adsorbed proteins. To study the effects of psW at a distance, cells were cultured in the presence but not in direct contact with the material. Subsequent changes in proliferation, alkaline phosphatase expression, and bone nodule formation were assessed. Cells grown in wells containing psW demonstrated an increase in both the rate and total numbers of bone nodules formed, although there were no differences in proliferation or alkaline phosphatase expression. Overall, these results suggest that psW is biocompatible and osteoconductive.

Background Attrition is an important problem in cohort studies. Tracing cohort members who have moved or otherwise lost contact with the study is vital. There is some debate about the acceptability and relative effectiveness of opt-in versus opt-out methods of contacting cohort members to re-engage them in this context. We conducted a randomised controlled trial to compare the two approaches in terms of effectiveness (tracing to confirm address and consenting to continue in the study), cost-effectiveness and acceptability. Methods Participants in this trial were individuals (young people and mothers) recruited to the Avon Longitudinal Study of Parents and Children (ALSPAC), who had not engaged with the study in the previous 5 years and for whom mail had been returned from their last known address. The sampling frame was restricted to those for whom database searching led to a potential new address being found in the Bristol area. 300 participants were randomly selected and assigned using stratified randomisation to the opt-in or opt-out arm. A tailored letter was sent to the potential new address, either asking participants to opt in to a home visit, or giving them the option to opt out of a home visit. Fieldworkers from Ipsos MORI conducted home visits to confirm address details. Results The proportion who were traced was higher in the opt-out arm (77/150 = 51 %) than the opt-in arm (6/150 = 4 %), as was the proportion who consented to continue in ALSPAC (46/150 = 31 % v 4/150 = 3 %). The mean cost per participant was £8.14 in the opt-in arm and £71.93 in the opt-out arm. There was no evidence of a difference in acceptability between the opt-in and opt-out approaches. Conclusion Since the opt-in approach yielded very low response rates, and there were no differences in terms of acceptability, we conclude that the opt-out approach is the most effective method of tracing disengaged study members. The gains made in contacting participants must be weighed against the increase in cost using this methodology. Electronic supplementary material The online version of this article (doi:10.1186/s12874-015-0041-y) contains supplementary material, which is available to authorized users.

Disability is as much a factor in interactional dynamics as ethnicity, age, gender or sexuality, and therefore its impact on the processes around qualitative research warrants much more systematic attention. Disabled researchers are not confined to disability studies research, although most accounts of the impact of disability on the research process have, thus far, been undertaken within this field. This paper moves beyond this narrow focus to consider the impact of disabled identities and the embodied experiences of impairment on studies involving, primarily, non-disabled people. By reflecting on our experiences as visibly disabled researchers, we highlight some of the practical, ethical and conceptual dilemmas we encountered. Impairments may assist rapport building with participants, but also introduce complex dilemmas concerning whether, when and how to disclose them, and the consequences of doing so. We highlight the centrality of the visibility of the disabled body in mediating these dilemmas, and its part in constraining our responses to them. While we value our commitment to positive readings of disability, we demonstrate that disabled researchers nevertheless undertake research in contexts where disability is assigned meanings disabled people may not share. We argue that all researchers should attend to their own ‘body signifiers’ (whether in relation to ethnicity, wealth, gender, age etc.) and embodied experiences of research processes, as these are integral to research outcomes, the ethics of research, and are a means by which to address power differentials between researcher and participant. This paper addresses a gap in the literature, using our experiences of research to highlight the negotiations and dilemmas faced by visibly disabled researchers. Negotiations of identity prompted by the disabled body in the research process require consideration and should not be ignored.\ud \ud

The absolute stereostructures of the hallucinogenic diterpenes salvinorin A and B have been unambiguously determined by the use of the non-empirical exciton chirality circular dichroism method on their 1α,2α-diol dibenzoate derivative.

In the construction of thin film interference filters, It is necessary to have materials with various indices of refraction. Thorium fluoride (ThF4) is an excellent material for use from the near ultraviolet to the far infrared spectral range. It has a low index of refraction, moderate stress in thin film form (20kpsi)(1), and it is environmentally very robust. The primary disadvantage of using ThF4 is its radioactivity.

Smyth discusses the recent report from the Academy of Medical Sciences on research regulation.1 2 The expert group’s reliance on anonymity to protect participants in research was based on assumptions about key NHS patient data systems that may no longer be justified in an era of ubiquitous data generation and sharing. The report also pays insufficient attention to patient autonomy. Patients are not currently being adequately informed about possible secondary uses of their medical …

Les alcoxy-2 et epoxy-2,3 cyclohexanones traitees par le triphenyl ethylidene phosphorane conduisent aux ethylidenecyclohexanes (Z) de facon stereoselective

The application of 1,3-diyl trapping reactions to the synthesis of commonly used prostanoid precursors is described.