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Gut inflammatory diseases cause microbial dysbiosis. Human immunodeficiency virus-1 (HIV) infection disrupts intestinal integrity, subverts repair/renewal pathways, impairs mucosal immunity and propels microbial dysbiosis. However, microbial metabolic mechanisms driving repair mechanisms in virally inflamed gut are not well understood. We investigated the capability and mechanisms of gut microbes to restore epithelial barriers and mucosal immunity in virally inflamed gut by using a multipronged approach: an in vivo simian immunodeficiency virus (SIV)-infected nonhuman primate model of HIV/AIDS, ex vivo HIV-exposed human colorectal explants and primary human intestinal epithelial cells. SIV infection reprogrammed tryptophan (TRP) metabolism, increasing kynurenine catabolite levels that are associated with mucosal barrier disruption and immune suppression. Administration of Lactiplantibacillus plantarum or Bifidobacterium longum subsp. infantis into the SIV-inflamed gut lumen in vivo resulted in rapid reprogramming of microbial TRP metabolism towards indole-3-lactic acid (ILA) production. This shift accelerated epithelial repair and enhanced anti-viral defenses through induction of IL-22 signaling in mucosal T cells and aryl hydrocarbon receptor activation. Additionally, ILA treatment of human colorectal tissue explants ex vivo inhibited HIV replication by reducing mucosal inflammatory cytokine production and cell activation. Our findings underscore the therapeutic potential of microbial metabolic reprogramming of TRP-to-ILA and mechanisms in mitigating viral pathogenic effects and bolstering mucosal defenses for HIV eradication., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier Inc.)

Objectives: To describe the symptoms, duration, severity, and microbiology of lower respiratory tract infection (LRTI) in outpatients., Methods: Prospective cohort study of adults in US primary or urgent care with a chief complaint of cough and symptoms consistent with LRTI. Baseline data included demographics, signs, symptoms, and PCR for 46 viruses and bacteria. The severity of symptoms reported for ≤28 days follow-up via diary and text message. The Bronchitis severity score assessed severity at baseline; overall severity was defined as the area under the symptom severity curve., Results: Of 718 patients with complete baseline data, 618 had valid PCR results, and 443 were followed until symptoms resolved. Of those with valid PCR, 100 (16.2%) had 1+ viruses detected, 211 (34.1%) had 1+ bacteria, and 168 (27.2%) had both. Symptoms more likely with viral or mixed infection included feverishness (36.7-38.4% vs. 18.5%), chills or sweats (36.0-38.1% vs. 17.9%), being generally unwell (78.2-81.3% vs. 64.9%), and myalgias (42.7-48.2% vs. 28.6%). Coloured sputum (42.9% vs. 23.2-29.5%) was more common with a bacterial infection. The mean duration of cough was 14.7 days with viruses (95% CI: 13.2-16.2), 17.3 with bacteria (95% CI: 15.9-18.6), 16.9 with mixed infection (95% CI: 15.2-18.6), and 18.4 with no detection (95% CI: 16.1-20.8). Overall severity of cough was lower for viral infections (20.9 points, 95% CI: 18.6-23.3) than for other groups (range 24.2-26.3). The most common potential bacterial pathogens were Haemophilus influenza (28.0%), Moraxella catarrhalis (16.2%), and Streptococcus pneumoniae (10.2%), whereas the most common viral pathogens were rhinovirus (17.3%), influenza (12.8%), SARS-CoV-2 (11.5%), and seasonal coronaviruses (8.1%)., Discussion: The mean duration of cough was 16.4 days. Consistent with European studies, the type of infection or potential pathogen was not an important predictor of the duration or severity of LRTI., (Copyright © 2024 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Subjective cognitive concerns (SCC) are common even in cognitively normal older adults who lack objectively-detectable deficits on standard neuropsychological evaluation. The clinical relevance of these concerns, particularly considering the nature of concerns (e.g., memory versus non-memory), remains unclear. Thus, we examined whether baseline memory and non-memory SCC relate to longitudinal change in brain volume and neuropsychological test performance in 476 functionally-intact, objectively unimpaired older adults (M age = 72y, 56 % female, follow-up time = 1 - 9 years). Mixed-effects models revealed that both higher baseline memory and non-memory SCC predicted greater atrophy in total gray matter and dorsolateral prefrontal cortex atrophy over time, while only memory SCC predicted steeper medial temporal lobe atrophy. Regarding neuropsychological performance, higher non-memory SCC predicted decline in processing speed performance, while memory SCC did not predict neuropsychological trajectories. SCC are a risk factor for more adverse brain and cognitive aging trajectories, even in functionally-intact, seemingly cognitively normal older adults., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: This study reports the detailed management and outcomes of women treated with Primary Endocrine Therapy (PET) in a large prospective UK cohort of older women (≥70) with breast cancer., Methods: This was an unplanned secondary analysis of a prospective, multicentre, observational study (The Age Gap study). Data were collected at baseline and regular intervals on patient, tumour and treatment characteristics with tumour RECIST response category recorded. Direct study follow-up was 24 months with longer-term survival data obtained from the UK cancer registry., Results: The Age Gap study recruited 3316 women across 56 breast units. Primary endocrine therapy (PET) was initiated for 505/3316 (15 %) women; median age was 84 (IQR 79-88) with median follow-up 41.9 months (IQR 27-60). Death occurred in 205/505(40.6 %) patients, 160/205; 78 % non- Breast Cancer related, 45/205; 21.9 % Breast Cancer related. Multivariate analysis identified older age (HR-1.055(95 % Confidence Interval: 1.029-1.084); P < 0.001) and higher Charlson Index (HR-1.166 (1.086-1.252); P < 0.001) as risk factors for all-cause mortality, but conversion to surgery (HR-0.372(0.152-0.914); P = 0.031) was protective. Grade 3 cancer (G1 vs G3 HR-0.28 (0.094-0.829); P = 0.022 & G2 vs G3 HR-0.469 (0.226-0.973); P = 0.042), axillary positivity (axilla positivity HR-2.548 (1.321-4.816); P = 0.005) and change of endocrine therapy (HR-3.010 (1.532-5.913); P = 0.001) were associated with worse breast cancer specific survival (BCSS). RECIST category was not significantly associated with either overall survival or BCSS (P > 0.05)., Conclusion: Early disease response and change of endocrine therapy are not significantly associated with overall survival, conversion to surgery is linked to improved outcome. Prognosis is largely determined by age and comorbidity in older women treated with PET., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Key Words: Breast cancer, mastectomy, breast conserving surgery, post-mastectomy reconstruction, older women, quality of life., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier Ltd.)

Objectives: Federal initiatives have been successful in reducing antipsychotic exposure in nursing home residents with dementia. We assessed if these initiatives were implemented equally across racial and ethnic minority groups., Design: Retrospective, cross-sectional trends study., Setting and Participants: National long-stay nursing home residents with dementia from 2011 to 2017., Methods: We examined trends in psychotropic drug class exposures from the Minimum Data Set assessments for non-Hispanic Black (NHB), Hispanic, and non-Hispanic White (NHW) residents using interrupted time-series analyses with age-sex standardized quarterly outcomes and time points to denote the National Partnership (2012) and Five Star Rating changes (2015)., Results: Initially, antipsychotic (33.0%) and sedative (6.8%) exposure was highest for Hispanic residents; antidepressant (59.8%) and anxiolytic (23.4%) exposure was highest for NHW residents; NHB residents had the lowest use of each. Antipsychotic use dropped at the time of the Partnership (β = -0.8807, P = .0023) and the slope declined further after the Partnership (β = -0.6611, P < .0001) for NHW. In comparison to NHW, the level and slope changes for NHB and Hispanics were not significantly different. The Five Star Rating change did not impact the level of antipsychotic use (β = 0.027, P = .9467), but the slope changed to indicate a slowed rate of decline (β = 0.1317, P = .4075) for NHW. As to the other psychotropic drug classes, there were few significant differences between trends seen in the racial and ethnic subgroups. The following exceptions were noted: antidepressant use decreased at a faster rate for NHB residents post-Partnership (β = -0.1485, P = .0371), and after the Five Star Rating change, NHB residents (β = -0.0428, P = .0312) and Hispanic residents (β = -0.0834, P < .0001) saw antidepressant use decrease faster than NHW. Sedative use in slope post-Partnership period (β = -0.086, P = .0275) and post-Five Star Rating (β = -0.0775, P < .0001) declined faster among Hispanic residents., Conclusions and Implications: We found little evidence of clinically meaningful differences in changes to 4 classes of psychotropic medication use among racial and ethnic minority nursing home residents with dementia following 2 major federal initiatives., (Copyright © 2023 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

In 2005, the city and state of New York launched New York/New York III (NY/NY III), a permanent supportive housing program for individuals experiencing homelessness or at risk of homelessness with complex medical and behavioral health issues. This review paper summarizes a decade of findings (2007-2017) from the NY/NY III evaluation team, to analyze this program's impact on various housing and health outcomes. The evaluation team linked NY/NY III eligible persons with administrative data from two years pre- and two years post-eligibility and compared housing and health outcomes between placed and unplaced groups using propensity score analysis. Placement into NY/NY III housing was associated with improved physical and mental health outcomes, increased housing stability, and statistically significant cost savings per person after one year of placement. The evaluation team recommends that municipalities invest in supportive housing as a means for mitigating homelessness and improving health outcomes in this vulnerable population., Competing Interests: Conflict of interest None declared., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Bleeding and thrombosis are major clinical problems with high morbidity and mortality. Treatment modalities for these diseases have improved in recent years, but there are many clinical questions remaining and a need to advance diagnosis, management, and therapeutic options. Basic research plays a fundamental role in understanding normal and disease processes, yet this sector has observed a steady decline in funding prospects thereby hindering support for studies of mechanisms of disease and therapeutic development opportunities. With the financial constraints faced by basic scientists, the ISTH organized a basic science task force (BSTF), comprising Scientific and Standardization Committee subcommittee chairs and co-chairs, to identify research opportunities for basic science in hemostasis and thrombosis. The goal of the BSTF was to develop a set of recommended priorities to build support in the thrombosis and hemostasis community and to inform ISTH basic science programs and policy making. The BSTF identified three principal opportunity areas that were of significant overarching relevance: mechanisms causing bleeding, innate immunity and thrombosis, and venous thrombosis. Within these, five fundamental research areas were highlighted: blood rheology, platelet biogenesis, cellular contributions to thrombosis and hemostasis, structure-function protein analyses, and visualization of hemostasis. This position paper discusses the importance and relevance of these opportunities and research areas, and the rationale for their inclusion. These findings have implications for the future of fundamental research in thrombosis and hemostasis to make transformative scientific discoveries and tackle key clinical questions. This will permit better understanding, prevention, diagnosis, and treatment of hemostatic and thrombotic conditions., (© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

The endometrial scratch procedure is an IVF 'add-on' sometimes provided prior to the first IVF cycle. A 2019 systematic review concluded that there was insufficient evidence to show whether endometrial scratch has a significant effect on pregnancy outcomes (including live birth rate, LBR) when undertaken prior to the first IVF cycle. Further evidence was published following this review, including the Endometrial Scratch Trial (ISRCTN23800982). The objective of the current review was to synthesize and critically appraise the evidence for the clinical effectiveness and safety of the endometrial scratch procedure in women undergoing their first IVF cycle. Databases searched include MEDLINE, Embase, CINAHL and ClinicalTrials.gov. Eligible randomized controlled trials included women undergoing IVF for the first time that reported the effectiveness and/or safety of the endometrial scratch procedure; 12 studies were included. Meta-analysis showed no evidence of a significant effect of the endometrial scratch on LBR (10 trials, odds ratio [OR] 1.17, 95% confidence interval [CI] 0.76-1.79) or other pregnancy outcomes. This review confirms that there is a lack of evidence that endometrial scratch improves pregnancy outcomes, including LBR, for women undergoing their first IVF cycle. Clinicians are recommended not to perform this procedure in individuals undergoing their first cycle of IVF., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Long-term services and supports (LTSS), including care received at home and in residential settings such as nursing homes, are highly racially segregated; Black, Indigenous, and persons of color (BIPOC) users have less access to quality care and report poorer quality of life compared to their White counterparts. Systemic racism lies at the root of these disparities, manifesting via racially segregated care, low Medicaid reimbursement, and lack of livable wages for staff, along with other policies and processes that exacerbate disparities. We reviewed Medicaid reimbursement, pay-for-performance, public reporting of quality of care, and culture change in nursing homes and integrated home- and community-based service (HCBS) programs as possible mechanisms for addressing racial and ethnic disparities. We developed a set of recommendations for LTSS based on existing evidence, including (1) increase Medicaid and Medicare reimbursement rates, especially for providers serving high proportions of Medicaid-eligible and BIPOC older adults; (2) reconsider the design of pay-for-performance programs as they relate to providers who serve underserved groups; (3) include culturally sensitive measures, such as quality of life, in public reporting of quality of care, and develop and report health equity measures in outcomes of care for BIPOC individuals; (4) implement culture change so services are more person-centered and homelike, alongside improvements in staff wages and benefits in high-proportion BIPOC nursing homes; (5) expand access to Medicaid-waivered HCBS services; (6) adopt culturally appropriate HCBS practices, with special attention to family caregivers; (7) and increase promotion of integrated HCBS programs that can be targeted to BIPOC consumers, and implement models that value community health workers. Multipronged solutions may help diminish the role of systemic racism in existing racial disparities in LTSS, and these recommendations provide steps for action that are needed to reimagine how long-term care is delivered, especially for BIPOC populations., (Copyright © 2021 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Weight-bearing (WB) status following a fracture or surgical fixation is an important determinant of the mechanical environment for healing. In order for healthcare professionals to communicate and understand the extent of bearing weight through a limb, clear terminology must be used. There is widespread variation in the usage and definitions of WB terminology in the literature and clinical practice. This study sought to define the understanding and extent of variation across the United Kingdom., Methods: A nationwide online survey of UK-based Trauma & Orthopaedic (T&O) multidisciplinary healthcare professionals was conducted. Participants answered seven questions assessing their usage and understanding of various WB terminology., Results: A total of 707 responses were received: 48% by doctors, 32% by physiotherapists, 13% by occupational therapists and 7% from other healthcare professionals. In terms of understanding of WB terminology with respect to percentage body weight (BW), 89% of respondents interpret 'full WB' as 100% BW, 97% interpret 'non WB' as 0% BW, 80% interpret 'partial WB' as 50% BW, and 89% interpret 'touch/toe-touch WB' as 10% or 20% BW. There were statistically significant differences between the responses of doctors and therapists for these four terms, with doctors tending to give higher %BW values. 'Protected WB' and 'WB as tolerated' had less consensus and more variability in responses. The majority (68%) of respondents do not usually quantify terminology such as 'partial WB' with a value, and 94% agreed that standardisation of WB terminology would improve communication amongst professionals., Conclusion: This study provides evidence of the substantial variation in the understanding of WB terminology amongst healthcare professionals, which likely results in ambiguous rehabilitation advice. Existing literature has shown that patients struggle to comply with terms such as 'partial weight-bearing'. We recommend consensus within the T&O multidisciplinary community to standardise and define common weight-bearing terminology., Competing Interests: Declaration of Competing Interest None (all authors)., (Copyright © 2021. Published by Elsevier Ltd.)

Introduction: Recruitment and retention are two of the most important factors in successfully running clinical trials. Many trials encounter problems with both, causing delays or preventing study progress. These issues are greater in older adults and patients with cancer., Materials and Methods: We assessed recruitment and retention in a large, multicentre, observational breast cancer study in older female patients (>70 years, N = 3440). Data collected by the Age Gap study were used to assess rates of, and reasons for, patients not being recruited or retained. Statistical analysis assessed the impact of age as a predictor of recruitment and retention., Results: Between February 2013 and June 2018, 6876 patients were screened and 3456 were consented across 56 United Kingdom (UK) breast units. Reasons for non-recruitment included ineligibility, clinician issues, staffing resource issues, patients' lack of interest or time and trial burden. In comparison with the age demographics of patients with breast cancer in the UK, women aged 70-75 years were over-represented compared to older age groups. Logistic regression demonstrated that older age significantly reduced the odds of consent (OR = 0.96, CI: 0.938-0.982; p < 0.001). Multivariate analysis showed that age (p < 0.001), markers of poor functional ability (Eastern Cooperative Oncology Group Performance Status (p = 0.011)) and instrumental activities of daily living (p = 0.026) were significant predictors of withdrawal., Discussion: This study has demonstrated that selection and attrition bias for age are apparent despite a range of 'age friendly' study design measures. Exploration of the underlying reasons for this and development of measures to address this should be the focus of further research., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest. Jenna Morgan, Stephen Walters and Thompson Robinson are all funded or part funded by the NIHR., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: The presence of dementia co-existing with a diagnosis of breast cancer may render management more challenging and have a substantial impact on oncological outcomes. The aim of this study was to examine the treatment and outcomes of older women with co-existing cognitive impairment and primary breast cancer., Materials and Methods: A prospective, multicentre UK cohort study of women aged 70 years or over with primary operable breast cancer. Patients with and without cognitive impairment were compared to assess differences in treatment and survival outcomes., Results: In total, 3416 women were recruited between 2013 and 2018. Of these, 478 (14%) had a diagnosis of dementia or cognitive impairment, subcategorised as mild, moderate and severely impaired. Up to 85% of women with normal cognition underwent surgery compared to 74%, 61% and 40% with mild, moderate, and severe impairment (p = 0.001). Among women at higher risk of recurrence, the uptake of chemotherapy was 25% for cognitively normal women compared to 20%, 22% and 12% for mild, moderate and severe impairment groups (p = 0.222). Radiotherapy use was similar in the subgroups. Although patients with cognitive impairment had shorter overall survival (HR: 2.10, 95% CI: 1.77-2.50, p < 0.001), there were no statistically significant differences in breast cancer specific or progression-free survival., Conclusion: Cognitive impairment appears to play a significant part in deciding how to treat older women with breast cancer. Standard treatment may be over-treatment for some women with severe dementia and careful consideration must be given to a more tailored approach in these women., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest. Professors Thompson Robinson and Stephen Walters are National Institute for Health Research (NIHR) Senior Investigators and Jenna Morgan is a NIHR Clinical Lecturer., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Research suggests that the built environment is associated with drug use. However, there is limited scholarship focusing on specific features of the built environment that influence drug use behaviors, experiences, and patterns and how risk factors for drug use are placed in distinctive urban and rural settings. Applying Neely and Samura's conceptual theory that describes space as contested, fluid and historical, interactional and relational, and defined by inequality and difference, we assessed data from semi-structured qualitative interviews conducted between 2019 and 2020 with consumers at syringe exchange programs (SEPs) in an urban location (New York City) and a rural location (southern Illinois). We aimed to contextualize how drug use manifests in each space. In total, 65 individuals, including 59 people who use drugs (PWUD) and six professionals who worked with PWUD, were interviewed. Findings illustrate that, in both the urban and rural setting, the built environment regulates the drug use milieu by mediating social reproduction, namely the degree of agency PWUD exert to acquire and use drugs where they desire. Processes of "stigma zoning," defined as socio-spatial policing of boundaries of behavior deemed undesirable or deviant, impacted PWUD's socio-geographic mobility, social conditions, and resource access, and modulated PWUD's broader capacity and self-efficacy. Similar patterns of drug use, according to social and economic inequities chiefly related to housing instability, were further observed in both settings., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background and Purpose: Pain and disability may persist following lumbar spine surgery and patients may subsequently seek providers trained in manipulative and manual therapy (MMT). This systematic review investigates the effectiveness of MMT after lumbar surgery through identifying, summarizing, assessing quality, and grading the strength of available evidence. Secondarily, we synthesized the impact on medication utilization, and reports on adverse events., Methods: Databases and grey literature were searched from inception through August 2020. Article extraction consisted of principal findings, pain and function/disability, medication consumption, and adverse events., Results: Literature search yielded 2025 articles,117 full-text articles were screened and 51 citations met inclusion criteria., Conclusion: There is moderate evidence to recommend neural mobilization and myofascial release after lumbar fusion, but inconclusive evidence to recommend for or against most manual therapies after most surgical interventions. The literature is primarily limited to low-level studies. More high-quality studies are needed to make recommendations., (Published by Elsevier Ltd.)

Clinical research in venous thromboembolism (VTE) is hindered by variability in the collection and reporting of data and outcomes. A consistent data language facilitates efficiencies, leads to higher quality data, and permits between-study comparisons and evidence synthesis. The International Society on Thrombosis and Haemostasis (ISTH) launched an international task force of more than 50 researchers to develop common data elements for clinical research in venous thromboembolism. The project was organized in seven working groups, each focusing on a topic area: General Core Data Elements; Anticoagulation and Other Therapies; Chronic VTE and Functional Outcomes; Diagnosis of VTE; Malignancy; Perioperative; and Predictors of VTE. The groups met via teleconference to collaboratively identify key data elements and develop definitions and data standards that were structured in a project-specific taxonomy. A Steering Committee met by teleconference and in-person to determine the overall scope of the project and resolve questions arising from the working groups. ISTH held an open public comment period to enable broader stakeholder involvement and feedback. The common data elements were then refined by the working groups to create a set of 512 unique data elements that are publicly available at http://isth.breakthrough.healthcare. The ISTH VTE Common Data Elements are intended to be a living project with ongoing curation, future expansion, and adaptation to meet the needs of the thrombosis and hemostasis research community., (© 2020 International Society on Thrombosis and Haemostasis.)

Background: Increasing diagnosis of cancer when the disease is still at early stages is a priority of cancer policy internationally. In England, reducing geographical inequalities in early diagnosis is also a key objective. Stage at diagnosis is not recorded for many patients, which may bias assessments of progress. We evaluate temporal and geographical changes in stage at diagnosis during 2008-2013 for colorectal, non-small cell lung, and ovarian cancers, using multiple imputation to minimise bias from missing data., Methods: Population-based data from cancer registrations, routes to diagnosis, secondary care, and clinical audits were individually linked. Patient characteristics and recorded stage were summarised. Stage was imputed where missing using auxiliary information (including patient's survival time). Logistic regression was used to estimate temporal and geographical changes in early diagnosis adjusted for case mix using a multilevel model., Results: We analysed 196,511 colorectal, 180,048 non-small cell lung, and 29,076 ovarian cancer patients. We estimate that there were very large increases in the percentage of patients diagnosed at stages I or II between 2008-09 and 2012-13: from 32% to 44% for colorectal cancer, 19% to 25% for non-small cell lung cancer, and 28% to 31% for ovarian cancer. Geographical inequalities reduced for colorectal and ovarian cancer., Interpretation: Multiple imputation is an optimal approach to reduce bias from missing data, but residual bias may be present in these estimates. Increases in early-stage diagnosis coincided with increased diagnosis through the "two week wait" pathway and colorectal screening. Epidemiological analyses from 2013 are needed to evaluate continued progress., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Age-related cognitive decline is a public health problem but highly diverse and difficult to predict. We captured nonoverlapping cognitive phenotypes in high-functioning adults and identified baseline factors differentiating trajectories. Three hundred fourteen functionally normal adults (M = 69 y) completed 2+ visits. Participants with sample-based longitudinal slopes in memory or processing speed less than -1 SD were classified as "declining" on that measure; 29 and 50 individuals had slopes less than -1 SD on processing speed or memory, respectively; 2.5% met criteria for both, who were excluded. At baseline, speed decliners demonstrated greater age, inflammation, and cognitive complaints compared with speed-stable adults; memory decliners were more likely to be male and had lower depressive symptoms, gray matter volumes, and white matter hyperintensities compared with memory-stable adults. Baseline speed, TNFα, and cognitive complaints accurately classified 96.3% of future speed decliners; baseline memory, sex, precuneal volume, and white matter hyperintensities accurately classified 88.5% of future memory decliners. There are discrete cognitive aging phenotypes reflecting nonoverlapping vulnerabilities in high-functioning adults. Early markers can predict cognition even within the "normal" spectrum and underscore therapeutic targets., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: A key component of recent English cancer policy is the monitoring of trends in early diagnosis of cancer. Early diagnosis can be defined by the disease stage at diagnosis or by other indicators derived from electronic health records. We evaluate the association between different early diagnosis indicators and survival, and discuss the implementation of the indicators in surveillance of early diagnosis., Methods: We searched the PubMed database and grey literature to identify early diagnosis indicators and evaluate their association with survival. We analysed cancer registrations for 355,502 cancer patients diagnosed in England during the period 2009-2013, and quantified the association between each early diagnosis indicator and 30-day mortality and five-year net survival., Results: Each incremental difference in stage (I-IV) predicts lower 5-year survival, so prognostic information is lost in comparisons which use binary stage indicators. Patients without a recorded stage have high risk of death shortly following diagnosis and lower 5-year survival. Emergency presentation is independently associated with lower five-year survival. Shorter intervals between first symptoms and diagnosis are not consistently associated with improved survival, potentially due to confounding from tumour characteristics., Interpretation: Contrary to current practice, we recommend that all the stage information should be used in surveillance. Patients missing stage should also be included to minimise bias. Combined data on stage and emergency presentation could be used to create summary prognostic measures. More work is needed to create statistics based on the diagnostic interval that will be useful for surveillance., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Primary endocrine therapy (PET) is used variably in the UK as an alternative to surgery for older women with operable breast cancer. Guidelines state that only patients with "significant comorbidity" or "reduced life expectancy" should be treated this way and age should not be a factor., Methods: A Discrete Choice Experiment (DCE) was used to determine the impact of key variables (patient age, comorbidity, cognition, functional status, cancer stage, cancer biology) on healthcare professionals' (HCP) treatment preferences for operable breast cancer among older women. Multinomial logistic regression was used to identify associations., Results: 40% (258/641) of questionnaires were returned. Five variables (age, co-morbidity, cognition, functional status and cancer size) independently demonstrated a significant association with treatment preference (p < 0.05). Functional status was omitted from the multivariable model due to collinearity, with all other variables correlating with a preference for operative treatment over no preference (p < 0.05). Only co-morbidity, cognition and cancer size correlated with a preference for PET over no preference (p < 0.05)., Conclusion: The majority of respondents selected treatment in accordance with current guidelines, however in some scenarios, opinion was divided, and age did appear to be an independent factor that HCPs considered when making a treatment decision in this population., (Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Objective: To evaluate a modified extended Timed Up and Go (extended-TUG) assessment against a panel of validated clinical assessments, as an indicator of Parkinson's disease (PD) severity and cognitive impairment., Methods: Eighty-seven participants with idiopathic PD were sequentially recruited from a Movement Disorders Clinic. An extended-TUG assessment was employed which required participants to stand from a seated position, walk in a straight line for 7m, turn 180° and then return to the start, in a seated position. The extended-TUG assessment duration was correlated to a panel of clinical assessments, including the Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Quality of Life (PDQ-39), Scales for Outcomes in Parkinson's Disease (SCOPA-Cog), revised Addenbrooke's Cognitive Index (ACE-R) and Barratt's Impulsivity Scale 11 (BIS-11)., Results: Extended-TUG time was significantly correlated to MDS-UPDRS III score and to SCOPA-Cog, ACE-R (p<0.001) and PDQ-39 scores (p<0.01). Generalized linear models determined the extended-TUG to be a sole variable in predicting ACE-R or SCOPA-Cog scores. Patients in the fastest extended-TUG tertile were predicted to perform 8.3 and 13.4 points better in the SCOPA-Cog and ACE-R assessments, respectively, than the slowest group. Patients who exceeded the dementia cut-off scores with these instruments exhibited significantly longer extended-TUG times., Conclusions: Extended-TUG performance appears to be a useful indicator of cognition as well as motor function and quality of life in PD, and warrants further evaluation as a first line assessment tool to monitor disease severity and response to treatment. Poor extended-TUG performance may identify patients without overt cognitive impairment form whom cognitive assessment is needed., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To evaluate the relationship between the volume of abdominal aortic aneurysm (AAA) procedures undertaken and the primary outcome of mortality in Europe. Previous systematic reviews of this relationship are outdated and are overwhelmingly based on US data., Data Sources: Comprehensive searching within MEDLINE and other bibliographic databases supplemented by citation searching and hand-searching of journals was undertaken to identify studies that reported the effect of hospital or clinician volume on any reported outcomes in adult, European populations, undergoing AAA repair and published in the last 10 years., Methods: Two reviewers conducted study selection with independent, duplicate data extraction and quality assessment. A planned meta-analysis was not conducted because of the high risk of bias, the likelihood of individual study subjects being included in more than one study and diversity in the clinical populations studied and methods used., Results: Sixteen studies (n = 237,074 participants) from the UK (n = 11 studies), Germany (n = 3 studies), Norway (n = 1 study), and one from the UK and Sweden were included. Data in the included studies came from administrative databases and clinical registries incorporating a variety of clinical and procedural groups; the study quality was limited by the use of observational study designs. Overall, the evidence favoured the existence of an inverse volume outcome relationship between hospital volume and mortality. Insufficient evidence was available to reach conclusions on the relationship between clinician volume and outcome and between hospital or clinician volume and secondary outcomes including complications and length of hospital stay., Conclusions: The evidence from this review suggests a relationship between the hospital volume of AAA procedures conducted and short-term mortality; however, as volume typically represents a complex amalgamation of factors further research will be useful to identify the core characteristics of volume that influence improved outcomes., (Copyright © 2016 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.)

HIV targets the gut mucosa early in infection, causing immune and epithelial barrier dysfunction and disease progression. However, gut mucosal sensing and innate immune signaling through mucosal pattern recognition receptors (PRRs) during HIV infection and disease progression are not well defined. Using the simian immunodeficiency virus (SIV)-infected rhesus macaque model of AIDS, we found a robust increase in PRRs and inflammatory cytokine gene expression during the acute SIV infection in both peripheral blood and gut mucosa, coinciding with viral replication. PRR expression remained elevated in peripheral blood following the transition to chronic SIV infection. In contrast, massive dampening of PRR expression was detected in the gut mucosa, despite the presence of detectable viral loads. Exceptionally, expression of Toll-like receptor 4 (TLR4) and TLR8 was downmodulated and diverged from expression patterns for most other TLRs in the gut. Decreased mucosal PRR expression was associated with increased abundance of several pathogenic bacterial taxa, including Pasteurellaceae members, Aggregatibacter and Actinobacillus, and Mycoplasmataceae family. Early antiretroviral therapy led to viral suppression but only partial maintenance of gut PRRs and cytokine gene expression. In summary, SIV infection dampens mucosal innate immunity through PRR dysregulation and may promote immune activation, gut microbiota changes, and ineffective viral clearance.

Objectives: To test the hypothesis that the percentage of patients screened that randomize differs between prevention and therapy trials., Study Design and Setting: Rapid review of randomized controlled trials (RCTs) identified through published systematic reviews in August 2013. Individually randomized, parallel group controlled RCTs were eligible if they evaluated metformin monotherapy or exercise for the prevention or treatment of type 2 diabetes. Numbers of patients screened and randomized were extracted by a single reviewer. Percentages were calculated for each study for those randomized: as a function of those approached, screened, and eligible. Percentages (95% confidence intervals) from each individual study were weighted according to the denominator and pooled rates calculated. Statistical heterogeneity was assessed using I(2)., Results: The percentage of those screened who subsequently randomized was 6.2% (6.0%, 6.4%; 3 studies, I(2) = 100.0%) for metformin prevention trials; 50.7% (49.9%, 51.4%; 21 studies, I(2) = 99.6%) for metformin treatment trials; 4.8% (4.7%, 4.8%; 14 studies, I(2) = 99.9%) for exercise prevention trials; and 43.3% (42.6%, 43.9%; 28 studies, I(2) = 99.8%) for exercise treatment trials., Conclusion: This study provides qualified support for the hypothesis that prevention trials recruit a smaller proportion of those screened than treatment trials. Statistical heterogeneity associated with pooled estimates and other study limitations is discussed., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The Centre for Public Health (CPH), at the United Kingdom's National Institute for Health and Care Excellence (NICE) is responsible for producing national guidance relating to the promotion of good health and the prevention and treatment of disease. Given the challenges of developing guidance in this area, choosing the most appropriate topics for further study is of fundamental importance. This paper explores the current prioritisation process and describes how the Analytic Hierarchy Process (AHP), a multi criteria decision analysis (MCDA) technique, might be used to do so., Study Design: A proposed approach is outlined, which was tested in a proof of concept pilot. This consisted of eight participants with experience of related NICE committees building scores for each topic together in a 'decision conference' setting., Methods: Criteria were identified and subsequently weighted to indicate the relative importance of each. Participants then collaboratively estimated the performance of each topic on each criterion., Results: Total scores for each topic were calculated, which could be ranked and used as the basis for better informed discussion for prioritising topics to recommend to the Minister for future guidance. Sensitivity analyses of the dataset found it to be robust., Conclusions: Choosing the right topics for guidance at the earliest possible time is of fundamental importance to public health guidance, and judgement is likely to play an important part in doing so. MCDA techniques offer a potentially useful approach to structuring the problem in a rational and transparent way. NICE should consider carefully whether such an approach might be worth pursuing in the future.

Tendinopathy is a term used to describe a painful tendon disorder but despite being a well-recognised clinical presentation, a definitive understanding of the pathoaetiology of rotator cuff tendinopathy remains elusive. Current explanatory models, which relate to peripherally driven nocioceptive mechanisms secondary to structural abnormality, or failed healing, appear inadequate on their own in the context of current literature. In light of these limitations this paper presents an extension to current models that incorporates the integral role of the central nervous system in the pain experience. The role of the central nervous system (CNS) is described and justified along with a potential rationale to explain the favourable response to loaded therapeutic exercises demonstrated by previous studies. This additional consideration has the potential to offer a useful way to explain pain to patients, for clinicians to prescribe appropriate therapeutic management strategies and for researchers to advance knowledge in relation to this clinically challenging problem., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Sporadic inclusion body myositis (sIBM) usually occurs as an isolated condition, but it may occur in association with another autoimmune disorder such as Sjögren's syndrome. We reviewed sIBM cases with Sjögren's syndrome (sIBM/SS) from the Perth Inflammatory Myopathies Database to determine whether they are distinguishable from other sIBM cases. Six such cases were identified, representing 12% of all sIBM cases. Muscle biopsies confirmed the presence of an inflammatory myopathy with rimmed vacuoles and the characteristic muscle fibre inclusions of sIBM. Five of the six were females, contrasting with a 2:1 male preponderance in the rest of the sIBM cohort. The mean age-at-onset and the pattern of muscle weakness were similar in the two groups. Four out of five sIBM/SS patients treated with immune therapies had improvement in muscle strength lasting for 6-24 months, whereas only 27% of other sIBM patients improved. All 6 patients with sIBM/SS carried the HLA-DRB1*0301 allele, or its equivalent HLA-DR3 serological specificity, compared with 83% of other sIBM cases and all carried some or all of the major markers of the 8.1 MHC ancestral haplotype which is also associated with Sjögren's syndrome. Patients with sIBM/SS represent a subgroup of sIBM cases who are more likely to be female and carriers of HLA-DR3 and the 8.1 MHC ancestral haplotype, and are more likely to respond to treatment. The association of sIBM and Sjögren's syndrome is likely to be due to a common genetic predisposition linked to the MHC and supports the notion that sIBM has an autoimmune basis., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Purpose: To examine cross-sectional and longitudinal associations between socioeconomic status (SES), gender, sports participation and moderate-to-vigorous physical activity (MVPA) in adolescents., Methods: Project EAT (Eating Among Teens), a population-based longitudinal study followed a socioeconomically and ethnically diverse sample of 1709 adolescents in 1998-1999 (Time 1) and 2003-2004 (Time 2). Mixed model regression analyses were used to examine longitudinal trends in MVPA as a function of SES and previous sports involvement., Results: For both genders, participation in organized sports and weekly hours of MVPA were positively associated with SES. On average, MVPA decreased between high school and young adulthood for both genders. Adolescents who participated in sports during high school showed a steeper decline in weekly hours of MVPA than their non-sports-participating counterparts. SES had a significant moderating effect on the change in MVPA over time for boys who participated in organized sports, with low SES boys showing a steeper decline in MVPA between time periods than higher SES boys. Although on average, a statistically significant difference in MVPA between previous sports participants and nonparticipants remained at Time 2, for all SES groups and both genders, the gap between hours of MVPA was either overcome or significantly narrowed by young adulthood., Conclusions: Increased dependence on organized sports for MVPA may be insufficient to meet the needs of youth following high school, especially for low SES youth. Designing physical activity promotions that reach and address the unique needs of lower SES youth and families is a public health priority.

Porcine liver proteome iTRAQ analysis enabled the confident identification of 880 proteins with a rate of false positive identifications of less than 5%. Proteins involved in energy metabolism, catabolism, protein biosynthesis, electron transport, and other oxidoreductase reactions were highly enriched confirming the central role of liver as the major chemical and energy factory. Comparative analysis with human and mouse liver proteomes demonstrated that 80% of proteins were common to all three liver proteomes. In addition, it was also demonstrated that both sex of the animal and introduction of a novel phytase transgene into the genome each affected around 5% of total liver proteome. After controlling the false discovery rate (FDR

Misuse of opioids is associated with abnormalities of pituitary function. Patients with chronic pain frequently complain of fatigue and undergo endocrine testing. To test whether oral opioid treatment causes abnormal pituitary function we prospectively assessed pituitary function in 37 patients with chronic pain who were receiving either oral opioid analgesia or non-opioid analgesia. Oral opioid treatment was not associated with abnormal pituitary function although a few patients had abnormal results mainly related to obesity. Our results suggest that patients with chronic pain who have abnormal endocrine results should have a complete assessment, since abnormal test results cannot be attributed to their analgesia.

Previously, we demonstrated that combination CTLA4-Fc and anti-CD40L mAb treatment results in tolerance to concordant, cellular islet xenografts. The aim of this study was to determine its effectiveness in a model of fetal pig pancreas (FPP) xenotransplantation. Survival of FPP fragment grafts were compared to the survival of rat islet or cardiac xenografts following short term CTLA4-Fc and anti-CD40L mAb treatment. Rat islet and FPP fragment grafts survived long-term. However, rat cardiac grafts were rejected by 52-91 days. Both rat islet and FPP grafts showed similar histology with intact islet structures and adjacent 'nests' of lymphocytes. Concordant vascularised rat hearts showed extensive polymorphonuclear infiltrate, concentric vasculitis and a perivascular infiltrate predominantly of CD8+ T cells. This suggests that this therapy is effective for prolonging islet xenografts and demonstrates that the cellular mechanism of rejection for vascularised and non-vascularised xenografts are different.

In response to the introduction of ethnic monitoring within the U.K. hospital inpatient data set, this study investigates the variations in secondary healthcare utilization by Black and minority ethnic communities whose cause of admission is related to asthma. The study examines all residents of the West Midlands: over 5 million people, of whom 8.5% are from Black and minority ethnic groups. A retrospective study of 15,921 asthma-related hospital admissions, from 1 April 1995 to 31 March 1996, was carried out. Age-standardized admission rates were higher in all Black and minority ethnic groups studied than in the White group. There were elevated rates in Black children aged 5-14 years, and particular differences were observed for Indian and Bangladeshi men and women aged 65 years or over. Emergency admissions to hospital for asthma were strongly associated with patients' socioeconomic background but this was largely observed for Black and minority ethnic groups that also generally experience high levels of deprivation. The findings support previous studies which suggest that hospital utilization rates for asthma among people from Black and minority ethnic groups are high compared with the White group, despite little evidence in measured prevalence. This study suggests that ethnic background is more important in asthma admissions than deprivation, which raises serious concerns on the appropriateness and quality of asthma care for these patient groups within our society. Future studies need to examine pathways to care, that is the health-seeking behaviour of Black and minority ethnic groups, the type of treatment received at the primary care level and referral patterns to secondary care.

Background: Although previous studies have shown that psychological disturbances are frequently associated with the irritable bowel syndrome (IBS), the relation was not necessarily cause and effect. The development of chronic bowel symptoms resembling IBS after an episode of acute gastroenteritis has allowed us to examine prospectively the role of psychological factors., Methods: 75 patients with acute gastroenteritis completed a series of psychometric tests soon after admission to hospital. Of these, 22 had persistent symptoms compatible with IBS after the acute illness, and in 20 of these the symptoms were still present at six months., Findings: At the time of their initial illness, patients who subsequently developed IBS symptoms had higher scores for anxiety, depression, somatisation, and neurotic trait than those who returned to normal bowel function. The psychometric scores had not changed when remeasured three months after the acute illness. Lactose malabsorption was not an important factor., Interpretation: These results support the hypothesis that psychological factors are important in IBS.

The effects of KN-62, a specific inhibitor of Ca2+/calmodulin-dependent protein kinase II (CamPKII), on insulin secretion and protein phosphorylation were studied in rat pancreatic islets and RINm5F cells. KN-62 was found to dose-dependently inhibit autophosphorylation of CamPKII in subcellular preparations of RINm5F cells (K0.5 = 3.1 +/- 0.3 microM), but had no effect on protein kinase C or myosin light chain kinase activity. KN-62, but not the inactive analogue KN-04, dose-dependently inhibited glucose-induced insulin release (K0.5 = 1.5 +/- 0.5 microM) in a manner similar to the inhibition of CamPKII autophosphorylation. KN-62 (10 microM) inhibited carbachol (in the presence of 8 mM glucose) and potassium-stimulated insulin secretion from islets by 53% and 59%, respectively. These results support a role of CamPKII in glucose-sensitive insulin secretion.

Methods for the determination of diphenoxylate hydrochloride and atropine sulfate combinations in solutions and powdered tablet composites are presented. A semiautomated assay for diphenoxylate hydrochloride in individual tablets (content uniformity) also is presented. The USP XIX assays for these products are cumbersome and, in the case of solutions, inaccurate due to spectral interferences; the proposed methods offer substantial improvements in sensitivity, specificity, and speed. Results obtained by the USP and proposed methods are compared for several lots of commercial products. The accuracy and precision of the proposed methods are shown by standard recovery studies.

The influence of pH on the hydrolysis of diethylpropion hydrochloride was investigated. Hydrolytic decomposition of the drug in solution at 45 degrees occurred at a very slow and constant rate at pH 3.5 and below but increased rapidly as the pH was raised above 3.5. Results of stability studies performed on six commercial tablet products from five manufacturers showed a similar relationship between the decomposition rate and the formulation pH. A reaction pathway based on the formation of an enamine structure is proposed for the pH-dependent hydrolysis. A high-performance liquid chromatographic assay for the drug is presented, which also separates and detects the hydrolysis product 1-phenyl-1,2-propanedione and the compound assumed to be the enol tautomer of this product.

High-performance liquid chromatographic (HPLC) separations of eighteen phenylurea pesticides were investigated using both reversed-phase and normal-phase systems. A photoconductivity detector, which responds selectively to ionic products formed via postcolumn UV irradiation of photolabile analytes, was connected in tandem with a UV detector permitting serial dual detection of these compounds. The photoconductivity detector responded selectively to the thirteen halogen and sulfur containing compounds whereas the UV detector responses were of the same order of magnitude for all eighteen compounds at 250 nm. The HPLC-UV-photoconductivity detection system was successfully applied to the determination of chloroxuron in strawberries at the official tolerance level of 0.5 ppm. The tandem detectors combined with a choice of columns and chromatographic modes offers enhanced selectivity for the HPLC analysis of these pesticides as trace contaminants in complex samples.

The applicability of the Tracor Model 965 photoconductivity detector to the determination of a variety of pesticide chemicals, particularly polar and/or thermally labile compounds which are troublesome in gas chromatographic analysis, has been investigated. The effects of various operating parameters (e.g., mobile phase composition, flow-rate and irradiation wavelength) on signal-to-noise output for selected compounds have been evaluated. A comparison of photoconductivity responses with those obtained from a UV detector connected in tandem was made for selected reference standards and food sample extracts. The photoconductivity detector was found to be suitable for the determination of pesticide residues at sub-parts-per-million levels. The linearity and reproducibility of response are adequate for practical quantitative applications.

In order to investigate the subcellular distribution of unoccupied 1,25-dihydroxyvitamin D3 receptors, highly purified cytoplasts and nucleoplasts were prepared from two kidney cell lines (PK1 and MDBK). This was accomplished utilizing the technique of enucleation by cytochalasin B and density gradient centrifugation. Unoccupied 1,25-dihydroxyvitamin D3 receptors were found in both the nuclear and cytosolic compartments, with approximately 70% of the receptors localized in the cytoplasm. When cells were pretreated with 1,25-[3H]dihydroxyvitamin D, prior to enucleation, it was found that 90% of the receptor-hormone complex was associated with nucleoplasts, thus demonstrating that cytochalasin B treatment does not alter the high-affinity association of the receptor-hormone complex with the nucleus. The ratio of unoccupied receptor/protein was found to be the same in whole cells, cytoplasts, and nucleoplasts for both cell types. The ratio of unoccupied receptor/DNA was highest in cytoplasts and lowest in nucleoplasts. Taken together, these data indicate that the unoccupied 1,25-dihydroxyvitamin D receptor is generally associated with cell proteins and not specifically associated with cell DNA. We therefore propose, at least for these cells, that the unoccupied 1,25-dihydroxyvitamin D receptor exists in equilibrium between the nuclear and cytosolic compartments of the whole cell, and receptor-hormone binding shifts this equilibrium to favor nuclear localization.

A rapid assay was developed for diethylpropion hydrochloride tablets using high-performance liquid chromatography (HPLC) with UV detection. This technique provided separation of the drug from other UV-absorbing components present as the result of decomposition. A major decomposition product detected by HPLC in extracts of tablets and of the cotton filler from a tablet bottle was collected from the column effluents. This product was subsequently identified as 1-phenyl-1,2-propanedione, a highly volatile compound. A second decomposition product, isolated from decomposed drug by distillation from alkaline solution, was identified as diethylamine, apparently present as the hydrochloride salt, GLC, UV, IR, NMR, and mass spectrometry were used to confirm the identity of the decomposition products. HPLC assay results compared favorably with results of the NF assay; the latter procedure separated the drug from 1-phenyl-1,2-propanedione via liquid-liquid extraction.