Using self-reports of pain and other variables to distinguish between older women with back pain due to vertebral fractures and those with back pain due to degenerative changes

SUMMARY: Women with back pain and vertebral fractures describe different pain experiences than women without vertebral fractures, particularly a shorter duration of back pain, crushing pain and pain that improves on lying down. This suggests a questionnaire could be developed to identify older women who may have osteoporotic vertebral fractures. INTRODUCTION: Approximately 12 % of postmenopausal women have vertebral fractures (VFs), but less than a third come to clinical attention. Distinguishing back pain likely to relate to VF from other types of back pain may ensure appropriate diagnostic radiographs, leading to treatment initiation. This study investigated whether characteristics of back pain in women with VF are different from those in women with no VFs. METHODS: A case control study was undertaken with women aged ≥60 years who had undergone thoracic spinal radiograph in the previous 3 months. Cases were defined as those with VFs identified using the algorithm-based qualitative (ABQ) method. Six hundred eighty-three potential participants were approached. Data were collected by self-completed questionnaire including the McGill Pain Questionnaire. Chi-squared tests assessed univariable associations; logistic regression identified independent predictors of VFs. Receiver operating characteristic (ROC) curves were used to evaluate the ability of the combined independent predictors to differentiate between women with and without VFs via area under the curve (AUC) statistics. RESULTS: One hundred ninety-seven women participated: 64 cases and 133 controls. Radiographs of controls were more likely to show moderate/severe degenerative change than cases (54.1 vs 29.7 %, P = 0.011). Independent predictors of VF were older age, history of previous fracture, shorter duration of back pain, pain described as crushing, pain improving on lying down and pain not spreading down the legs. AUC for combination of these factors was 0.85 (95 % CI 0.79 to 0.92). CONCLUSION: We present the first evidence that back pain experienced by women with osteoporotic VF is different to back pain related solely to degenerative change

Changing practice: the possibilities and limits for reshaping social work practice

Since 2010 the United Kingdom has witnessed a number of initiatives that shift away from reliance on performance management to improve social work with children and families, towards a renewed interest in practice models. This study reports on the evaluation of a local government programme in England to introduce and embed systemic family practice through the roll out of intensive training to social workers and frontline managers. It was anticipated through the programme that child protection social workers would undertake more direct work with families and build more positive relationships, resulting in a fall in the number of child protection plans and children experiencing repeat periods of care. The evaluation adopted a mixed method approach encompassing an online survey of social workers, interviews with team managers and family members, a case audit and statistical analysis of local level metrics. It found limited employment of systemic family practice or improvement due to the programme. Adopting the 7 S framework, this study examines the barriers to and facilitators of successful change and identifies generic considerations for change programmes in child protection social work

The STAR care pathway for patients with pain at 3 months after total knee replacement:a multicentre, pragmatic randomised controlled trial

BACKGROUND: Approximately 20% of people experience chronic pain after total knee replacement, but effective treatments are not available. We aimed to evaluate the clinical effectiveness and cost-effectiveness of a new care pathway for chronic pain after total knee replacement. METHODS: We did an unmasked, parallel group, pragmatic, superiority, randomised, controlled trial at eight UK National Health Service (NHS) hospitals. People with chronic pain at 3 months after total knee replacement surgery were randomly assigned (2:1) to the Support and Treatment After Replacement (STAR) care pathway plus usual care, or to usual care alone. The STAR intervention aimed to identify underlying causes of chronic pain and enable onward referrals for targeted treatment through a 3-month post-surgery assessment with an extended scope practitioner and telephone follow-up over 12 months. Co-primary outcomes were self-reported pain severity and pain interference in the replaced knee, assessed with the Brief Pain Inventory (BPI) pain severity and interference scales at 12 months (scored 0–10, best to worst) and analysed on an as-randomised basis. Resource use, collected from electronic hospital records and participants, was valued with UK reference costs. Quality-adjusted life-years (QALYs) were calculated from EQ-5D-5L responses. This trial is registered with ISRCTN, ISRCTN92545361. FINDINGS: Between Sept 6, 2016, and May 31, 2019, 363 participants were randomly assigned to receive the intervention plus usual care (n=242) or to receive usual care alone (n=121). Participants had a median age of 67 years (IQR 61 to 73), 217 (60%) of 363 were female, and 335 (92%) were White. 313 (86%) patients provided follow-up data at 12 months after randomisation (213 assigned to the intervention plus usual care and 100 assigned to usual care alone). At 12 months, the mean between-group difference in the BPI severity score was −0·65 (95% CI −1·17 to −0·13; p=0·014) and the mean between-group difference in the BPI interference score was −0·68 (−1·29 to −0·08; p=0·026), both favouring the intervention. From an NHS and personal social services perspective, the intervention was cost-effective (greater improvement with lower cost), with an incremental net monetary benefit of £1256 (95% CI 164 to 2348) at £20 000 per QALY threshold. One adverse reaction of participant distress was reported in the intervention group. INTERPRETATION: STAR is a clinically effective and cost-effective intervention to improve pain outcomes over 1 year for people with chronic pain at 3 months after total knee replacement surgery. FUNDING: National Institute for Health Research

Plcg2M28L Interacts With High Fat/High Sugar Diet to Accelerate Alzheimer\u27s Disease-Relevant Phenotypes in Mice.

Obesity is recognized as a significant risk factor for Alzheimer\u27s disease (AD). Studies have supported the notion that obesity accelerates AD-related pathophysiology in mouse models of AD. The majority of studies, to date, have focused on the use of early-onset AD models. Here, we evaluate the impact of genetic risk factors on late-onset AD (LOAD) in mice fed with a high fat/high sugar diet (HFD). We focused on three mouse models created through the IU/JAX/PITT MODEL-AD Center. These included a combined risk model wit

A highly compact packaging concept for ultrasound transducer arrays embedded in neurosurgical needles

State-of-the-art neurosurgery intervention relies heavily on information from tissue imaging taken at a pre-operative stage. However, the data retrieved prior to performing an opening in the patient’s skull may present inconsistencies with respect to the tissue position observed by the surgeon during intervention, due to both the pulsing vasculature and possible displacements of the brain. The consequent uncertainty of the actual tissue position during the insertion of surgical tools has resulted in great interest in real-time guidance techniques. Ultrasound guidance during neurosurgery is a promising method for imaging the tissue while inserting surgical tools, as it may provide high resolution images. Microfabrication techniques have enabled the miniaturisation of ultrasound arrays to fit needle gauges below 2 mm inner diameter. However, the integration of array transducers in surgical needles requires the development of advanced interconnection techniques that can provide an interface between the microscale array elements and the macroscale connectors to the driving electronics. This paper presents progress towards a novel packaging scheme that uses a thin flexible printed circuit board (PCB) wound inside a surgical needle. The flexible PCB is connected to a probe at the tip of the needle by means of magnetically aligned anisotropic conductive paste. This bonding technology offers higher compactness compared to conventional wire bonding, as the individual electrical connections are isolated from one another within the volume of the paste line, and applies a reduced thermal load compared to thermo-compression or eutectic packaging techniques. The reduction in the volume required for the interconnection allows for denser wiring of ultrasound probes within interventional tools. This allows the integration of arrays with higher element counts in confined packages, potentially enabling multi-modality imaging with Raman, OCT, and impediography. Promising experimental results and a prototype needle assembly are presented to demonstrate the viability of the proposed packaging scheme. The progress reported in this work are steps towards the production of fully-functional imaging-enabled needles that can be used as surgical guidance tools

Prophylactic evaluation of verubecestat on disease- and symptom-modifying effects in 5XFAD mice.

Introduction: Alzheimer\u27s disease (AD) is the most common form of dementia. Beta-secretase (BACE) inhibitors have been proposed as potential therapeutic interventions; however, initiating treatment once disease has significantly progressed has failed to effectively stop or treat disease. Whether BACE inhibition may have efficacy when administered prophylactically in the early stages of AD has been under-investigated. The present studies aimed to evaluate prophylactic treatment of the BACE inhibitor verubecestat in an AD mouse model using the National Institute on Aging (NIA) resources of the Model Organism Development for Late-Onset Alzheimer\u27s Disease (MODEL-AD) Preclinical Testing Core (PTC) Drug Screening Pipeline. Methods: 5XFAD mice were administered verubecestat ad libitum in chow from 3 to 6 months of age, prior to the onset of significant disease pathology. Following treatment (6 months of age), in vivo imaging was conducted with 18F-florbetapir (AV-45/Amyvid) (18F-AV45) and 18-FDG (fluorodeoxyglucose)-PET (positron emission tomography)/MRI (magnetic resonance imaging), brain and plasma amyloid beta (Aβ) were measured, and the clinical and behavioral characteristics of the mice were assessed and correlated with the pharmacokinetic data. Results: Prophylactic verubecestat treatment resulted in dose- and region-dependent attenuations of 18F-AV45 uptake in male and female 5XFAD mice. Plasma Aβ40 and Aβ42 were also dose-dependently attenuated with treatment. Across the dose range evaluated, side effects including coat color changes and motor alterations were reported, in the absence of cognitive improvement or changes in 18F-FDG uptake. Discussion: Prophylactic treatment with verubecestat resulted in attenuated amyloid plaque deposition when treatment was initiated prior to significant pathology in 5XFAD mice. At the same dose range effective at attenuating Aβ levels, verubecestat produced side effects in the absence of improvements in cognitive function. Taken together these data demonstrate the rigorous translational approaches of the MODEL-AD PTC for interrogating potential therapeutics and provide insight into the limitations of verubecestat as a prophylactic intervention for early-stage AD

Comprehensive Screening of Eight Known Causative Genes in Congenital Hypothyroidism With Gland-in-Situ.

CONTEXT: Lower TSH screening cutoffs have doubled the ascertainment of congenital hypothyroidism (CH), particularly cases with a eutopically located gland-in-situ (GIS). Although mutations in known dyshormonogenesis genes or TSHR underlie some cases of CH with GIS, systematic screening of these eight genes has not previously been undertaken. OBJECTIVE: Our objective was to evaluate the contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD, and TSHR) in CH cases with GIS. Patients, Design, and Setting: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico. PATIENTS, DESIGN, AND SETTING: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico. RESULTS: Twenty-nine cases harbored likely disease-causing mutations. Monogenic defects (19 cases) most commonly involved TG (12), TPO (four), DUOX2 (two), and TSHR (one). Ten cases harbored triallelic (digenic) mutations: TG and TPO (one); SLC26A4 and TPO (three), and DUOX2 and TG (six cases). Novel variants overall included 15 TG, six TPO, and three DUOX2 mutations. Genetic basis was not ascertained in 20 patients, including 14 familial cases. CONCLUSIONS: The etiology of CH with GIS remains elusive, with only 59% attributable to mutations in TSHR or known dyshormonogenesis-associated genes in a cohort enriched for familial cases. Biallelic TG or TPO mutations most commonly underlie severe CH. Triallelic defects are frequent, mandating future segregation studies in larger kindreds to assess their contribution to variable phenotype. A high proportion (∼41%) of unsolved or ambiguous cases suggests novel genetic etiologies that remain to be elucidated.This study made use of data generated by the UK10K Project and we acknowledge the contribution of the UK10K Consortium. This work was supported by Wellcome Trust Grants 100585/Z/12/Z (to N.S.), and 095564/Z/11/Z (to V.K.C.) and the National Institute for Health Research Cambridge Biomedical Research Center (to V.K.C., N.S.). E.G.S and C.A.A. are supported by the Wellcome Trust (098051). Funding for the UK10K Project was provided by the Wellcome Trust under award WT091310

MAVS-Mediated Apoptosis and Its Inhibition by Viral Proteins

BACKGROUND: Host responses to viral infection include both immune activation and programmed cell death. The mitochondrial antiviral signaling adaptor, MAVS (IPS-1, VISA or Cardif) is critical for host defenses to viral infection by inducing type-1 interferons (IFN-I), however its role in virus-induced apoptotic responses has not been elucidated. PRINCIPAL FINDINGS: We show that MAVS causes apoptosis independent of its function in initiating IFN-I production. MAVS-induced cell death requires mitochondrial localization, is caspase dependent, and displays hallmarks of apoptosis. Furthermore, MAVS(-/-) fibroblasts are resistant to Sendai virus-induced apoptosis. A functional screen identifies the hepatitis C virus NS3/4A and the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) nonstructural protein (NSP15) as inhibitors of MAVS-induced apoptosis, possibly as a method of immune evasion. SIGNIFICANCE: This study describes a novel role for MAVS in controlling viral infections through the induction of apoptosis, and identifies viral proteins which inhibit this host response

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy