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Eligible relatives are given rights and powers in the compulsory treatment of people with mental health problems in several international jurisdictions, including within England and Wales. However, little attention has been given to whether relatives feel legally literate or competent to fulfil such roles. This article examines this issue through focussing on the experiences of Nearest Relatives, who are given rights and powers during Mental Health Act 1983 (MHA) assessments for compulsory admission in England and Wales. Interviews with nineteen Nearest Relatives in England were conducted and were thematically analysed. Three themes were identified. First, NRs spoke about their awareness and knowledge of the role. They predominantly reported negative experiences in which they received no or little information. They also reported that professionals assumed they possessed legal knowledge, and their legal knowledge was largely self-taught. Secondly, NRs reported uncertainty about their own rights and powers, noting the role lacked status or informational or emotional support. Third, NRs highlighted areas for legal reform, stating that the NR role was important, but required specialist support systems for NRs. The findings of this study indicate greater attention needs to be given by law and policy makers to support relatives' understanding of their rights and powers under the MHA, if the NR role is to be effective in helping to safeguard patient rights under the European Convention on Human Rights. These include the right in Article 5 not to be arbitrarily deprived of one's liberty and the right to a private and family life in Article 8. Legislators also need to take account of these factors when considering proposals to reform mental health law in England and Wales., Competing Interests: Declaration of competing interest ‘I was going into it blind’: Nearest relatives, legal literacy and the Mental Health Act 1983. I confirm there are no declarations of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: A well-established definition of obstruction in the setting of congenital hydronephrosis is lacking. Multiple imaging modalities and radiographic characteristics or parameters have been described to help confirm the diagnosis of ureteropelvic junction obstruction (UPJO). We sought to evaluate the change in anterior-posterior renal pelvic diameter (APRPD) following furosemide administration in patients with unilateral hydronephrosis and confirmed UPJO on functional magnetic resonance urography (fMRU) who underwent pyeloplasty., Materials and Methods: There were 49 patients who met inclusion criteria (11 females, 38 males; average age 2.2 years, SD 3.4 years) from February 2006 to September 2020, diagnosed with unilateral hydronephrosis (SFU Grade 3-4) who underwent fMRU prior to pyeloplasty for confirmed UPJO. 29 of the included patients also underwent a post-pyeloplasty fMRU. A weight-adjusted dose of 1 mg/kg of furosemide (max 20 mg/kg) was administered intravenously. Two board-certified pediatric radiologists measured the APRPD of the obstructed and non-dilated kidneys prior to pyeloplasty and APRPD of the hydronephrotic kidneys on the post-pyeloplasty follow up fMRUs. Measurements were performed on images prior to and approximately 30 min following furosemide injection., Results: The average APRPD before furosemide injection in the obstructed kidney prior to pyeloplasty was 26.3 mm (SD 9.0 mm) compared to the non-dilated (not obstructed) kidney measurement of 5.1 mm (SD 3.6 mm) (p < 0.001). Following administration of furosemide, the average APRPD was 31.4 mm (SD 8.8 mm) in the obstructed kidney, and 7.8 mm (SD 4.1 mm) in the non-dilated kidney (p < 0.001). After pyeloplasty, the pre-furosemide APRPD measurement was 17.8 mm (SD 11 mm), which was significantly less compared to the pre-pyeloplasty APRPD (p < 0.001). The post-pyeloplasty, post-furosemide APRPD measurement was 25.8 mm (SD 12 mm), also significantly less compared to the pre-pyeloplasty measurement (p = 0.02). The changes in APRPD in the obstructed kidney prior to pyeloplasty was 5.1 mm (SD 3.5 mm) and after pyeloplasty was 8 mm (SD 4.6 mm) (p = 0.002). Change in APRPD in the non-dilated kidney was 2.7 mm (SD 2.3 mm). Percent APRPD change in the obstructed kidney was 22.9% (SD 18.5%), which was significantly less than 33.3% (SD 22.1%) in the post-pyeloplasty kidney (p = 0.028) and 82.8% (SD 87.9%) in the non-dilated kidney (p < 0.001)., Conclusions: A relatively smaller change in APRPD on fMRU following administration of furosemide in the setting of UPJO may serve as another predictive characteristic of obstructed kidneys., Competing Interests: Conflict of interest Dr. Kirsch is a consultant for Palette Life Sciences, a speaker for Intuitive Surgical, and is the Co-founder and CEO of Global Continence, Inc. Dr. Linam, Dr. Janssen, Dr. Cho, and Ms. Stone have no disclosures., (Copyright © 2023 Journal of Pediatric Urology Company. All rights reserved.)

Background: A number of patients post-coronavirus disease-19 (COVID-19) report cognitive impairment (CI), even months after acute infection. We aimed to assess if COVID-19 is associated with increased incidence of CI in comparison to controls., Methods: We analyzed data from the Mount Sinai Health System Post-COVID-19 Registry in New York City, a prospective cohort of patients post-COVID-19 ≥18 years of age and non-infected controls. CI was defined by scores ≥ 1.0 standard deviation below population norms, and was assessed using well-validated measures of attention, working memory, processing speed, executive functioning/cognitive flexibility, language, learning, and memory. Logistic regression models assessed odds for CI in each domain in patients post-COVID-19 vs. controls after adjusting for potential confounders. In exploratory analyses, we assessed odds for CI by site of acute COVID-19 care as a proxy for disease severity., Findings: 417 patients post-COVID-19 and 151 controls (mean age 49 years, 63% female, 21% Black, 17% Latinx) were included. In adjusted analyses, patients were significantly more likely than controls to have CI in executive functioning (odds ratio [OR]: 2.19; 95% confidence interval [CI]: 1.03 to 4.67), particularly those treated in outpatient (OR: 2.22; 95% CI: 1.02 to 4.82) and inpatient hospital (OR: 3.59; 95% CI: 1.27 to 10.16) settings. There were no significant associations between CI in other domains and history of COVID-19 or site of acute care., Interpretation: Patients post-COVID-19 have greater odds of executive dysfunction, suggesting that focused cognitive screening may be prudent, even in those with mild to moderate disease. Studies should explore the pathophysiology and potential treatments for CI in this population., Funding: This work was funded by the Icahn School of Medicine at Mount Sinai., 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 © 2023 Elsevier Inc. All rights reserved.)

Introduction: Non-small-cell lung cancer (NSCLC) is a leading cause of death for people living with HIV (PWH). Nevertheless, there are no clinical trial data regarding the management of early-stage lung cancer in PWH. Using data from large HIV and cancer cohorts we parameterized a simulation model to compare treatments for stage I NSCLC according to patient characteristics., Materials and Methods: To parameterize the model we analyzed PWH and NSCLC patient outcomes and quality of life data from several large cohort studies. Comparative effectiveness of 4 stage I NSCLC treatments (lobectomy, segmentectomy, wedge resection, and stereotactic body radiotherapy) was estimated using evidence synthesis methods. We then simulated trials comparing treatments according to quality adjusted life year (QALY) gains by age, tumor size and histology, HIV disease characteristics and major comorbidities., Results: Lobectomy and segmentectomy yielded the greatest QALY gains among all simulated age, tumor size and comorbidity groups. Optimal treatment strategies differed by patient sex, age, and HIV disease status; wedge resection was among the optimal strategies for women aged 80 to 84 years with tumors 0 to 2 cm in size. Stereotactic body radiotherapy was included in some optimal strategies for patients aged 80 to 84 years with multimorbidity and in sensitivity analyses was a non-inferior option for many older patients or those with poor HIV disease control., Conclusion: In simulated comparative trials of treatments for stage I NSCLC in PWH, extensive surgical resection was often associated with the greatest projected QALY gains although less aggressive strategies were predicted to be non-inferior in some older, comorbid patient groups., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Bald eagles often scavenge hunting remains embedded with lead bullet fragments, which debilitate and kill many eagles. Measuring blood lead concentrations (BLC) in free-flying bald eagles and those received by rehabilitators allows researchers to both actively and opportunistically monitor exposure. From 2012 to 2022, we captured 62 free-flying bald eagles and measured their BLC following the big-game hunting season in Montana, USA, which occurs from late October through late November. Between 2011 and 2022, we also measured the BLC of 165 bald eagles received by Montana's four raptor rehabilitation centers. Most of the free-flying bald eagles (89 %) had BLC above background (≥10 μg/dL), and BLC of juveniles tended to be lower as winter progressed (ρ = -0.482, P = 0.017). Bald eagles received by rehabilitators had an almost identical prevalence of BLC above background (90 %) over that same timeframe (n = 48). However, those eagles in rehabilitation were more likely to have BLC exceeding the clinical threshold (≥ 60 μg/dL), which we observed only from November through May. Between June and October, 45 % of bald eagles in rehabilitation had sub-clinical BLC (10-59 μg/dL), suggesting that many eagles may live with BLC chronically above background concentrations. Hunters may help lower BLC in bald eagles by switching to lead-free bullets. Those mitigation efforts could be evaluated through a continued monitoring of BLC in both free-flying bald eagles and those received by rehabilitators., Competing Interests: Declaration of competing interest Michael McTee is the author of Wilted Wings: A Hunter's Fight for Eagles. All remaining 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 © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Older men with prostate cancer are commonly affected by reductions in lean mass and physical function following androgen deprivation therapy (ADT). Resistance-based exercise programs are critical to counteract the musculoskeletal toxicities derived from prostate cancer treatment and aging. However, there is significant variability in the effects of exercise interventions. Examining demographic and clinical moderators of exercise effects in this patient group can assist in identifying which subgroups of patients benefit most. Therefore, we examined the effects and moderators of resistance-based exercise programs on sarcopenia-related outcomes that included lean mass, skeletal muscle index, physical function, and muscle strength in older men with prostate cancer., Materials and Methods: Data were retrieved from the Predicting OptimaL cAncer RehabIlitation and Supportive care (POLARIS) consortium. For the present study, we included data from trials that examined the effects of supervised resistance-based exercise interventions on lean mass outcomes, muscle strength, and physical function in patients with prostate cancer previously or currently treated with ADT. Linear mixed models were undertaken to analyse the effects of resistance-based exercise programs considering the clustering of patients within studies. Effects were evaluated by regressing the study group on the post-intervention value of the outcome adjusted for the baseline value, while potential moderators were examined by adding the moderator and its interaction term into the regression model., Results: A total of 560 patients with prostate cancer (age: 69.5 ± 7.8 yrs.; body mass index: 28.6 ± 4.0 kg.m -2 ) previously or currently treated with ADT were included. Resistance-based exercise programs resulted in significant effects on whole-body and appendicular lean mass and the skeletal muscle index (P < 0.05), with improvements observed across different characteristics. Improvements were also observed in 400-m walk and 6-m backwards tandem walk (P < 0.05), with patients presenting with lower baseline levels deriving greater exercise effects on 400-m walk (-19.4 s, 95% confidence interval [CI]: -36.6 to -2.3) and 6-m backwards tandem walk tests (-3.0 s, 95% CI: -5.7 to -0.3). For relative muscle strength, significant exercise effects were observed, with greater effects in younger patients (0.35 kg.kg -1 , 95% CI: 0.22 to 0.48)., Discussion: Resistance-based exercise programs effectively improve well-known markers of sarcopenia in men with prostate cancer, with specific subgroups of patients, such as those younger and presenting with lower baseline levels of physical function, deriving greater effects on muscle strength and physical function, respectively., Competing Interests: Declaration of Competing Interest None to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Sleep is fragmented by brief arousals, and excessive arousal burden has been linked to increased cardiovascular (CV) risk, but mechanisms are poorly understood., Research Question: Do arousals trigger cardiac ventricular repolarization lability that may predispose people to long-term cardiovascular mortality?, Study Design and Methods: This study analyzed 407,541 arousals in the overnight polysomnograms of 2,558 older men in the Osteoporotic Fractures in Men sleep study. QT and RR intervals were measured beat-to-beat starting 15 s prior to arousal onset until 15 s past onset. Ventricular repolarization lability was quantified by using the QT variability index (QTVi)., Results: During 10.1 ± 2.5 years of follow-up, 1,000 men died of any cause, including 348 CV deaths. During arousals, QT and RR variability increased on average by 5 and 55 ms, respectively, resulting in a paradoxical transient decrease in QTVi from 0.07 ± 1.68 to -1.00 ± 1.68. Multivariable Cox proportional hazards analysis adjusted for age, BMI, cardiovascular and respiratory risk factors, sleep-disordered breathing and arousal, diabetes, and Parkinson disease indicated that excessive QTVi during arousal was independently associated with all-cause and CV mortality (all-cause hazard ratio, 1.20 [95% CI, 1.04-1.38; P = .012]; CV hazard ratio, 1.29 [95% CI, 1.01 -1.65; P = .043])., Interpretation: Arousals affect ventricular repolarization. A disproportionate increase in QT variability during arousal is associated with an increased all-cause and CV mortality and may reflect ventricular repolarization maladaptation to the arousal stimulus. Whether arousal-related QTVi can be used for more tailored risk stratification warrants further study, including evaluating whether arousal suppression attenuates ventricular repolarization lability and reduces subsequent mortality., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT00070681; URL: www., Clinicaltrials: gov., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Nutrition and physical activity are associated with prostate cancer recurrence and mortality. Few randomized controlled trials (RCT) have examined the effects of long-term exercise and diet changes on prostate cancer clinical, biological, and patient-reported outcomes., Methods: Prostate 8-II is a 4-arm RCT among 200 men with prostate cancer who chose radical prostatectomy (RP) as their primary treatment. Men are enrolled prior to RP and randomized to exercise-only, diet-only, exercise + diet, or usual care (50/arm). Participants begin their assigned intervention 0-5 weeks prior to RP and continue for 24-months following surgery. The 3 active intervention arms receive access to a web-portal and text messages, coaching calls, and other intervention resources (e.g., heart rate sensor and resistance bands and/or recipe booklet). Weekly exercise goals for the exercise intervention groups are 150 min moderate or 75 min vigorous aerobic exercise, 2 strength sessions, and 2 flexibility sessions. Diet intervention groups work with a dietitian to customize their goals (e.g., increase cruciferous vegetables, cooked tomatoes, healthy fats, fish; limit processed meats, whole milk). The primary endpoint is biochemical recurrence. Secondary endpoints include change in tumor biomarkers from biopsy to RP as well as patient-reported outcomes (e.g., quality-of-life), blood and urine biomarkers, and anthropometry at 0, 6, 12, and 24 months., Conclusion: This 4-arm RCT will examine the impact of change in exercise and diet (alone or in combination) on prostate cancer recurrence, biology, and quality-of-life., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S.A.K is a consultant and board member for Fellow Health Inc., unrelated to the current study. A.L. is the founder of Sportzpeak, Inc., unrelated to the current study., (Copyright © 2023. Published by Elsevier Inc.)

Study Objective: To determine the diagnostic accuracy of specialist-performed transvaginal ultrasound (TVUS) and pelvic magnetic resonance imaging (MRI) modalities in predicting depth of deep infiltrating endometriosis (DIE) of the rectosigmoid by comparison with histologic specimens obtained at surgery., Design: A retrospective analysis, which met the Standards for Reporting of Diagnostic Accuracy Studies (2015) guidelines for a diagnostic accuracy study., Setting: Tertiary teaching hospital., Patients: A total of 194 cases who underwent preoperative discussion at the gynecologic endosurgery unit multidisciplinary meeting between January 2012 and December 2019 were eligible for inclusion., Interventions: Retrospective assessment of the accuracy of TVUS and MRI in predicting histologic depth of rectosigmoid DIE after operative management., Measurements and Main Results: Al total of 135 surgeries were performed for DIE; 20 underwent a rectal shave, 14 had a disc/wedge resection, 38 an anterior/segmental resection, and 63 had no rectosigmoid surgery. Of the 52 patients with full-thickness rectal wall excision, all patients had at least one imaging modality available for review; 42 (81%) had both. At least one imaging modality was in agreement with histologic depth in 48 cases (92%) (sensitivity, 94%; specificity, 50%; positive predictive value [PPV], 97.9%; negative predictive value [NPV], 25.0%; area under the receiver operating curve, 0.720; 95% confidence interval, 0.229-1.000). When TVUS was assessed in isolation, the test remained sensitive for any rectal wall involvement (sensitivity, 93.6%; specificity, 50.0%; PPV, 97.8%; NPV, 25.0%; area under the receiver operating curve, 0.718; 95% confidence interval, 0.227-1.000). When only MRI was assessed, the test demonstrated both high sensitivity and specificity for rectal wall disease (sensitivity, 86.4%; specificity, 100%; PPV, 100%; NPV, 14.2)., Conclusion: Specialist-performed TVUS and MRI are accurate in predicting depth of disease in rectosigmoid endometriosis. These modalities were similar in their diagnostic performance at assessing depth of rectal wall involvement, and their use is justified in the preoperative planning of these gynecologic surgeries., (Copyright © 2022 AAGL. Published by Elsevier Inc. All rights reserved.)

Resilience of food systems is key to ensuring food security through crisis. The COVID-19 pandemic presents an unprecedented shock that reveals varying levels of resilience of increasingly interconnected food systems across the globe. We contribute to the ongoing debate about whether increased connectivity reduces or enhances resilience in the context of rural Pacific food systems, while examining how communities have adapted to the global shocks associated with the pandemic to ensure food security. We conducted 609 interviews across 199 coastal villages from May to October 2020 in Federated States of Micronesia, Fiji, Palau, Papua New Guinea, Solomon Islands, Tonga, and Tuvalu to understand community-level impacts and adaptations during the first 5-10 months of the COVID-19 crisis. We found that local food production practices and food sharing conferred resilience, and that imported foods could aid or inhibit resilience. Communities in countries more reliant on imports were almost twice as likely to report food insecurity compared to those least reliant. However, in places dealing with a concurrent cyclone, local food systems were impaired, and imported foods proved critical. Our findings suggest that policy in the Pacific should bolster sustainable local food production and practices. Pacific states should avoid becoming overly reliant on food imports, while having measures in place to support food security after disasters, supplementing locally produced and preserved foods with imported foods when necessary. Developing policies that promote resilient food systems can help prepare communities for future shocks, including those anticipated with climate change., (© 2022 Elsevier Ltd. All rights reserved.)

Background & Aims: Atherosclerosis and arteriosclerosis contribute to vascular aging and cardiovascular disease (CVD) risk. Both processes can be assessed simply in the lower-limbs and reflect systemic pathology. However, only atherosclerosis is routinely assessed, typically via ankle-brachial index (ABI). Arteriosclerosis can be assessed using femoral-ankle pulse wave velocity (faPWV), but no studies have identified whether ABI and faPWV similarly associate with overt CVD and risk factors, nor whether faPWV confers additional information. The aims of this study were to (i) compare associations of ABI and faPWV with traditional CVD risk factors, including age, sex, systolic blood pressure (SBP), high-density lipoprotein (HDL), total cholesterol (TC), smoking, and diabetes; and (ii) determine the independent and additive associations of ABI and faPWV with a composite measure of prevalent CVD., Methods: We evaluated ABI and faPWV in 4330 older-aged (75.3 ± 5.0 years) adults using an oscillometric screening device. Associations between ABI and faPWV with CVD risk factors and CVD were determined using mixed-model linear- and logistic-regression., Results: ABI and faPWV were associated with age, HDL, and smoking. ABI was associated with sex, TC, diabetes. faPWV was associated with SBP. Both ABI and faPWV were inversely associated with CVD. Low ABI (≤0.9 vs. >0.9) and low faPWV (≤9.94 vs. >9.94) increased the odds of CVD by 2.41-fold (95% CI:1.85,3.17) and 1.46-fold (95% CI:1.23,1.74), respectively. The inverse association between faPWV and CVD was independent of ABI and CVD risk factors., Conclusions: ABI and faPWV, measures of lower-limb atherosclerosis and arteriosclerosis, are independently associated with CVD risk factors and prevalent CVD. Assessment of faPWV may confer additional risk information beyond ABI., (Copyright © 2021. Published by Elsevier B.V.)

The combustion efficiency of simulated at-sea surface oil burns (in situ burns) was determined in a 63 m 3 tank while testing varied boom configurations and air-assist nozzles in the presence and absence of waves. Combustion efficiencies of Alaska North Slope oil based on unburned carbon in the plume emissions ranged from 85% to 93% while values based on oil mass loss ranged from 89% to 99%. A four-fold variation in PM 2.5 emission factors was observed from the test conditions. The most effective burns in terms of reduced emissions and post-burn residue concentration of total petroleum hydrocarbons were those that had high length to width boom ratios resulting in higher flame front surface area exposure to ambient air. The amount of oil mass lost was not related to any combustion efficiency parameters measured in the plume, representing a potential tradeoff between unburnt oil and air pollution., (Published by Elsevier Ltd.)

Charge variants of biological products, such as monoclonal antibodies (mAbs), often play an important role in stability and biological activity. Characterization of these charge variants is challenging, however, primarily due to the lack of both efficient and effective isolation methods. In this work, we present a novel use of an established, high productivity continuous chromatography method, known as multi-column counter-current solvent gradient purification (MCSGP), to create an enriched product that can be better utilized for analytical characterization. We demonstrate the principle of this separation method and compare it to traditional batch HPLC (high performance liquid chromatography) or FPLC (fast protein liquid chromatography) methods, using the isolation of charge variants of different mAbs as a case study. In a majority of cases, we are able to show that the MCSGP method is able to provide enhanced purity and quantity of samples when compared to traditional fractionation methods, using the same separation conditions. In one such case, a sample prepared by MCSGP methodology achieved 95% purity in 10 hours of processing time, while those prepared by FPLC and HPLC achieved purities of 78% and 87% in 48 and 300 hours of processing time, respectively. We further evaluate charge variant enrichment strategies using both salt and pH gradients on cation exchange chromatography (CEX) and anion exchange chromatography (AEX) resins, to provide more effective separation and less sample processing following enrichment. As a result, we find that we are able to utilize different gradients to change the enrichment capabilities of certain charged species. Lastly, we summarize the identified mAb charge variants used in this work, and highlight benefits to analytical characterization of charge variants enriched with the continuous chromatography method. The method adds a new option for charge variant enrichment and facilitates analytical characterization of charge variants., 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 © 2021 Elsevier B.V. All rights reserved.)

Objectives: Sedentary behavior is pervasive in the workplace and is harmful to health. Research on the effectiveness of comprehensive workplace interventions to reduce sedentary behavior and improve worker health and safety is crucial as sedentary jobs become more common., Methods: We developed a Total Worker Health intervention targeting sedentary behavior in call centers, and are evaluating intervention effectiveness in a randomized controlled trial. Four worksites will be randomly assigned to an intervention or control condition. The intervention condition includes the provision of active workstations along with programs and procedures at environmental, organizational, and individual levels. Control worksites will receive active workstations with no additional support, following common organizational practices., Results: Outcomes include objectively measured physical activity, biological markers of health, and self-report survey data at baseline, after the 6-month intervention or control period, and at a 12-month follow-up., Conclusions: The aims of the study are to determine whether a Total Worker Health intervention has stronger impacts on workplace sedentary behavior, uninterrupted bouts of sitting, and worker health and safety compared to a usual practice control condition. The study will inform future workplace sedentary behavior intervention and dissemination research, along with organizational best practices for reducing sedentary behavior in the workplace., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The coronavirus pandemic, referred to here as Covid-19, has brought into sharp focus the increasing divergence of devolved legislation and its implementation in the United Kingdom. One such instance is the emergency health and social care legislation and guidance introduced by the United Kingdom Central Government and the devolved Governments of Wales, Scotland and Northern Ireland in response to this pandemic. We provide a summary, comparison and discussion of these proposed and actual changes with a particular focus on the impact on adult social care and safeguarding of the rights of citizens. To begin, a summary and comparison of the relevant changes, or potential changes, to mental health, mental capacity and adult social care law across the four jurisdictions is provided. Next, we critique the suggested and actual changes and in so doing consider the immediate and longer term implications for adult social care, including mental health and mental capacity, at the time of publication.several core themes emerged: concerns around process and scrutiny; concerns about possible changes to the workforce and last, the possible threat on the ability to safeguard human rights. It has been shown that, ordinarily, legislative provisions across the jurisdictions of the UK are different, save for Wales (which shares most of its mental health law provisions with England). Such divergence is also mirrored in the way in which the suggested emergency changes could be implemented. Aside from this, there is also a wider concern about a lack of parity of esteem between social care and health care, a concern which is common to all. What is interesting is that the introduction of CVA 2020 forced a comparison to be made between the four UK nations which also shines a spotlight on how citizens can anticipate receipt of services., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

Objectives: Idiopathic intracranial hypertension (IIH) is strongly related to obesity. The relationship between intracranial pressure, body mass index (BMI), percentage body fat and distribution of body fat in non-IIH patients remains less clear. The aim of this study was to examine the relationship between intracranial pressure and body type in non-IIH patients., Patients and Methods: Lumbar puncture manometry was used to measure cerebrospinal fluid opening pressure (CSF OP ). BMI, in addition to neck, waist and hip circumferences were calculated. Air displacement plethysmography (BODPOD) was used to assess body composition., Results: Data was collected from 100 subjects. 11 subjects with conditions known to cause raised intracranial pressure were excluded from analysis. According to Pearson correlation factors displaying a significant relationship with CSF OP included: BMI (R = 0.635, p < 0.0001); waist circumference (R = 0.498, p < 0.0001), hip circumference (R = 0.513, p < 0.0001) and percentage body fat (R = 0.435, p < 0.001). Multivariate analysis indicated that BMI was the only independent factor which predicted CSF OP . Sub-analysis according to gender indicated that BMI was predictive in females and percentage body fat was predictive in males. We did not identify any differences in BMI, percentage body fat or distribution of body fat in 7 IIH patients and 7 wt-matched non-IIH patients., Conclusion: BMI and percentage body fat both positively correlated with CSF OP , but BMI was more predictive in women and percentage body fat was more predictive in men. We did not find a relationship between distribution of body fat and CSF OP ., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Context: Breast cancer morbidity and mortality disproportionately affect medically underserved women. Most studies of the experience of living with advanced breast cancer do not focus on this population. A deeper understanding of racial/ethnic minorities' and low-income patients' experiences is needed to reduce breast cancer health and health care disparities., Objectives: This qualitative, community-based participatory research study explores the lived experiences of medically underserved women with advanced breast cancer., Methods: We conducted in-depth, semistructured interviews with low-income patients from a community clinic and safety-net hospital, focusing on issues related to advanced breast cancer and end of life. Six team members independently coded transcripts, jointly reconciled coding differences, and identified key themes., Results: All 63 participants (83% response rate) had an income ≤200% of the federal poverty level; 68% identified as a racial/ethnic minority. Four predominant themes emerged: compounding of pre-existing financial distress, perceived bias/lack of confidence in medical care received, balancing personal needs with the needs of others, and enhanced engagement with sources of life meaning., Conclusion: Participants resiliently maintained engaged lives yet described extreme financial duress and perceived provider bias, which are known contributors to worse quality of life and health outcomes. Participants downplayed their desire to discuss dying to accommodate pressure to "stay positive" and to mitigate others' discomfort. Improving care for underserved women with advanced cancer will require addressing disparities from screening through hospice, developing personalized opportunities to discuss death and dying, and enhancing access to and affordability of medical and social support., (Published by Elsevier Inc.)

Competing Interests: Conflict-of-interest disclosure: The authors declare no competing financial interests.

Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8-negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from 10 countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases, and expert opinion. The anti-interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as second- and third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, #NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future.

Objective: To conduct a scoping literature review to identify practices or programs that promote AYA patient-centered communication., Methods: Between January and May of 2016, we applied standard scoping review methodology to systematically review articles. We considered peer-reviewed, English language articles written at any phase of intervention research. Both qualitative and quantitative studies were eligible, and no additional search restrictions were applied. We retained articles that included explicit or implicit outcomes for one of the six functions of patient-centered communication in cancer care. At least two independent reviewers assessed the articles., Results: We screened a total of 4072 titles and abstracts, retaining 27 for full-text review. Ultimately, eight titles met the review's inclusion criteria. We categorized each publication by the action or setting used to improve patient-centered communication, resulting in five categories. Most studies were not included because they did not include a patient-centered communication outcome., Conclusion: This area of research is still emerging, as indicated by the small number of eligible studies and predominance of qualitative, descriptive, pilot, and feasibility studies with small sample sizes., Practice Implications: Our results suggest a clear need to develop and evaluate interventions focused on improving patient-centered communication between AYA survivors and their healthcare providers., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Aims: Although it is well known that resistance training (RT) is beneficial for patients suffering from a variety of cardiovascular diseases, it remains underutilized as a rehabilitation tool as there is no reliable way to monitor the additional stress placed on the central organs. The current study aimed to determine between-day reliability of central haemodynamic indices using oscillometric pulse wave analysis (PWA) during progressive sub-maximal RT., Methods: Nineteen healthy young males were tested on 3 different mornings in a fasted state. Central hemodynamic variables including augmentation index (AIx), AIx normalized to a heart rate of 75 beats per minute (AIx@75), central systolic blood pressure (cSBP), forwards (Pf) and backwards (Pb) wave reflection were determined at rest, as well as during leg extension RT at 10, 15 and 20% of maximal volitional contraction (MVC), and following 1 min and 5 min passive recovery., Results: During RT at 10, 15 and 20% MVC, the intraclass correlation coefficient (ICC) values for AIx@75 (0.76-0.9), cSBP (0.74-0.78), Pf (0.75-0.82) and Pb (0.75-0.83) exceeded the criteria (0.75) for excellent reliability. During the 5 min recovery, the ICC values for AIx@75 (0.87-0.87), cSBP (0.69-0.7), Pf (0.63-0.67) and Pb (0.63-0.66) indicated good to excellent reliability., Conclusions: Clinically meaningful changes in central hemodynamic indices can be obtained during resistance training using oscillometric PWA devices. This technology holds potential for advancing resistance training prescription guidelines for patients with overt cardiovascular diseases., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The impact of marine ecotourism on reef predators is poorly understood and there is growing concern that overcrowding in Marine Protected Areas (MPAs) may disturb the species that these areas were established to protect. To improve our understanding of this issue, we used acoustic telemetry to examine the relationship between human activity at the Molokini Marine Life Conservation District (MLCD) and the habitat use of five reef-associated predators (Caranx melampygus, Caranx ignobilis, Triaenodon obesus, Carcharhinus amblyrhynchos, and Aprion virscens). During peak hours of human use, there was a negative relationship (R 2 =0.77, P<0.001) between the presence of bluefin trevally (Caranx melampygus) and vessels in subzone A. No other species showed strong evidence of this relationship. However, our results suggest that during this time, the natural ecosystem function that the reserve was established to protect may be compromised and overcrowding should be considered when managing MPAs., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: There is a growing interest in the intersection of heart failure (HF) and frailty; however, estimates of the prevalence of frailty in HF vary widely. The purpose of this paper was to quantitatively synthesize published literature on the prevalence of frailty in HF and to examine the relationship between study characteristics (i.e. age and functional class) and the prevalence of frailty in HF., Methods: The prevalence of frailty in HF, divided into Physical Frailty and Multidimensional Frailty measures, was synthesized across published studies using a random-effects meta-analysis of proportions approach. Meta-regression was performed to examine the influence of age and functional class (at the level of the study) on the prevalence of frailty., Results: A total of 26 studies involving 6896 patients with HF were included in this meta-analysis. Despite considerable differences across studies, the overall estimated prevalence of frailty in HF was 44.5% (95% confidence interval, 36.2%-52.8%; z=10.54; p<0.001). The prevalence was slightly lower among studies using Physical Frailty measures (42.9%, z=9.05; p<0.001) and slightly higher among studies using Multidimensional Frailty measures (47.4%, z=5.66; p<0.001). There were no significant relationships between study age or functional class and prevalence of frailty., Conclusions: Frailty affects almost half of patients with HF and is not necessarily a function of age or functional classification. Future work should focus on standardizing the measurement of frailty and on broadening the view of frailty beyond a strictly geriatric syndrome in HF., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Insufficient physical activity and unhealthy eating behaviors are major contributors to the obesity epidemic in the United States. Identifying health behaviors and disparities in underserved communities is needed to guide the development of targeted interventions. The Community Assessment for Public Health Emergency Response (CASPER) is a set of tools designed for public health emergencies, but the utility of CASPER in non-emergency settings has not been explored. The purpose of this study was to use CASPER to obtain information on household-based behaviors of and barriers to fruit/vegetable consumption and physical activity, and explore the utility of these methods for future health assessments. Cross-sectional survey data included households (n=100) in a low-income neighborhood. Half of adults did not meet recommendations for fruit/vegetable consumption and 20% reported no physical activity during the previous week. Cost was significantly associated with healthy eating and physical activity in our community. Four primary advantages of using CASPER methodology included a user-friendly CDC toolkit, yield of a representative community sample with a relatively low sample size, low-cost/low-tech requirements for implementation, and the strengthening of an academic-practice-community partnership. Our work demonstrates the utility of CASPER for assessing healthy living in a geographically-defined community where household health behaviors and barriers are unknown., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Knowledge of the complex kinematics of the native knee is a prerequisite for a successful reconstructive procedure. The aim of this study is to describe the primary and coupled motions of the native knee throughout the range of knee flexion, in response to applied varus and valgus loads., Methods: Twenty fresh-frozen cadaver knees were affixed to a six degree of freedom robotic arm with a universal force-moment sensor, and loaded with a 4Nm moment in varus and valgus at 0, 15, 30, 45, and 90° of knee flexion. The resulting tibiofemoral angulation, displacement, and rotation were recorded., Results: For each parameter investigated, the knee joint demonstrated more laxity at higher flexion angles. Varus angulation increased progressively from zero (2.0° varus) to 90 (5.2° varus) degrees of knee flexion (p<0.001). Valgus angulation also increased progressively, from zero (1.5° valgus) to 90 (3.9° valgus) degrees of knee flexion (p<0.001). At all flexion angles, the magnitude of tibiofemoral angle deviation was larger with varus than with valgus loading (p<0.05)., Conclusions: We conclude that the native knee exhibits small increases in coronal plane laxity as the flexion angle increases, and that the knee has generally more laxity under varus load than with valgus load throughout the Range of Motion (ROM). Larger differences in laxity of more than 2 to 3°, or peak laxity specifically during the range of mid-flexion, were not found in our cadaver model and are not likely to represent normal coronal plane kinematics., Level of Evidence: Level V, biomechanical cadaveric study., (Copyright © 2016 Elsevier B.V. All rights reserved.)

We investigated the association between serum level of oxidized low-density lipoprotein (oxLDL) and risk of cognitive impairment (dementia or mild cognitive impairment) among 572 nondemented community-dwelling women from a prospective cohort study of aging. After 5 years of follow-up, 228 (39.9%) developed cognitive impairment; and this did not differ by tertile of baseline oxLDL level (highest compared with lowest tertile 38.2% vs. 39.5%; odds ratio, 0.90; 95% confidence interval, 0.63-1.43). Multivariate adjustment produced similar results (odds ratio, 0.91; 95% confidence interval, 0.60-1.39). These findings suggest that increased levels of serum oxLDL are not associated with a greater risk of incident cognitive impairment in older women., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background and Aim: Recent research suggests that low vitamin D may be associated with cardiovascular disease (CVD)., Methods and Results: We prospectively evaluated the association of dietary plus supplemental vitamin D intake and serum 25(OH) vitamin D with CVD incidence in the Osteoporotic Fractures in Men (MrOS) Study. Vitamin D intake was measured using a food frequency questionnaire and self-reported supplemental intake in 3094 men (mean age 76.4 years). From a subset of this population, we measured 25(OH) vitamin D in 813 men. Median 25(OH) vitamin D was 25.3 ng/mL. During a median follow-up of 4.4 years, there were 472 CVD cases, including 371 from coronary heart disease (CHD) and 101 from cerebrovascular attack (CVA). In the 25(OH) vitamin D sub-cohort, there were 140 cases of CVD including 115 from CHD and 25 from CVA. We used a Cox proportional hazards regression to calculate hazard ratios (HR) for CVD by vitamin D quartile. After adjusting for age, season, and standard CVD risk factors, the lowest quartile of 25(OH) vitamin D (HR, 1.18; 95% CI, 0.69-2.03) and vitamin D intake (HR, 0.76; 95% CI, 0.56-1.04) were not significantly associated with CVD incidence, compared to the highest vitamin D quartiles. When 25(OH) vitamin D was further analyzed by sufficiency (≥30 ng/mL), insufficiency (≥15-29.9 ng/mL), and deficiency (<15 ng/mL), vitamin D deficiency was not significantly associated with CVD incidence compared to sufficiency (HR 1.34; 95% CI 0.65-2.77)., Conclusion: Vitamin D intake and serum 25(OH) vitamin D were not associated with CVD risk., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background Aims: Immunotherapy targeting MAGE-A3 in multiple myeloma (MM) could eradicate highly aggressive and proliferative clonal cell populations responsible for relapse. However, expression of many cancer-testis antigens, including MAGE-A3, can be heterogeneous, leading to the potential for tumor escape despite MAGE-A3-induced immunity. We hypothesized that a combination of the hypomethylating agent 5-azacitidine (5AC) and the histone deacetylase inhibitor (HDACi) MGCD0103 (MGC) could induce MAGE-A3 expression in MAGE-A3-negative MM, resulting in recognition and killing of MM cells by MAGE-A3-specific cytotoxic T lymphocytes (CTL)., Methods: Gene expression analyses of MAGE-A3 expression in primary MM patient samples at diagnosis and relapse were completed to identify populations that would benefit from MAGE-A3 immunotherapy. MM cell lines were treated with 5AC and MGC. Real-time polymerase chain reaction (PCR) and Western blotting were performed to assess MAGE-A3 RNA and protein levels, respectively. Chromium-release assays and interferon (IFN) secretion assays were employed to ascertain MAGE-A3 CTL specificity against treated targets., Results: Gene expression analysis revealed that MAGE-A3 is expressed in MM patients at diagnosis (25%) and at relapse (49%). We observed de novo expression of MAGE-A3 RNA and protein in MAGE-A3-negative cell lines treated with 5AC. MGC treatment alone did not induce expression but sequential 5AC/MGC treatment led to enhanced expression and augmented recognition by MAGE-A3-specific CTL, as assessed by (51)Cr-release assays (P = 0.047) and enzyme-linked immunosorbent assay (ELISA) for IFN-γ secretion (P = 0.004)., Conclusions: MAGE-A3 is an attractive target for immunotherapy of MM and epigenetic modulation by 5AC, and MGC can induce MAGE-A3 expression and facilitate killing by MAGE-A3-specific CTL.

Objectives: Few studies have examined the association between anxiety symptoms and objectively measured sleep quality in older adults. The authors determined this association in a large cohort of very old community-dwelling women., Design: Cross-sectional., Setting: Participants' homes, sites of the Study of Osteoporotic Fractures., Participants: Three thousand forty women (mean age: 83.6 years) enrolled in a prospective study of aging., Measurements: Participants completed the Goldberg Anxiety Scale (ANX), the 15-item Geriatric Depression Scale (GDS), and > or = 3 nights of actigraphy--a method of measuring sleep by recording wrist movement with a device called an actigraph. Elevated anxiety symptoms were defined as ANX > or = 6. Elevated depressive symptoms were defined as GDS > or = 6., Results: Participants' mean ANX score was 1.4 (standard deviation: 2.2); 9.2% (N = 280) had ANX > or = 6. Elevated anxiety symptoms were associated with greater odds of poor sleep efficiency (odds ratio [OR]: 1.73, 95% confidence interval [CI]: 1.34, 2.23) and time awake after sleep onset (OR: 1.64, 95% CI: 1.27, 2.11). Associations remained after adjustment for GDS > or = 6, antianxiety medications, and other potential confounders (sleep efficiency OR: 1.50, 95% CI: 1.15, 1.97; time awake after sleep onset OR: 1.33, 95% CI: 1.01, 1.75). Anxiety symptoms were not associated with other sleep parameters., Conclusion: Findings suggest that elevated anxiety symptoms are independently associated with poor objectively measured sleep efficiency and elevated sleep fragmentation in very old women, after accounting for significant depressive symptoms, medical comorbidities, and use of antianxiety medications.

To determine whether PAX-2 and PAX-8 are involved in Wilms tumor (WT) pathogenesis, we sought mutations in these two genes in 99 Wilms tumors of favorable histology. We screened the entire protein coding sequences as well as the intronic regions adjacent to exons, using denaturing HPLC followed by sequencing of samples displaying abnormal chromatograms. In PAX-2, a silent polymorphism was found within exon 2 and exon 8 in 1% and 21% of cases, respectively. Three apparently silent polymorphisms were also found in PAX-8, two in exon 5 (2 of 99 cases or 2%) and one in exon 6 (22 of 99 cases or 22%), all of which were located 3' to the exons. In conclusion, no evidence for disease causing mutation was found using this technique, and so the direct involvement of either of these two genes in WT is unlikely.

In this paper, we address the peak detection and alignment problem in the analysis of mass spectrometry data. To deal with the peak redundancy problem existing in the MALDI data acquired in the reflectron mode, we propose to use the amplitude modulation technique in peak detection. The alignment of two peak sets is formulated as a non-rigid registration problem and is solved using a robust point matching (RPM) approach. To align multiple peak sets, we first use a super set method to find a common peak set among all peak sets as a standard and then align all peak sets to the standard using the robust point matching approach in a sequential manner (i.e. We align only one peak set to the standard each time, thus reducing the multiple peak set alignment problem to a simpler two peak set alignment problem). Experimental results from a study of ovarian cancer data set show that the quantitative cross-correlation coefficients among technical replicates are increased after peak alignment. Additional comparisons also demonstrate that our method has a similar performance as the hierarchical clustering method, although the implementations of these methods are different.

Very little information is available to direct the prevention or management of osteoporosis in men. The Osteoporotic Fractures in Men (MrOS) Study is a prospective cohort study designed to examine the extent to which fracture risk is related to bone mass, bone geometry, lifestyle, anthropometric and neuromuscular measures, and fall propensity, as well as to determine how fractures affect quality of life in men. The study is also designed to understand how osteoporosis is related to prostate disease. At baseline, participants completed questionnaires regarding medical history, medications, physical activity, diet, alcohol intake, and cigarette smoking. Objective measures of anthropometric, neuromuscular, vision, strength, and cognitive variables were obtained. Skeletal assessments included DEXA, calcaneal ultrasound, and vertebral radiographs. Vertebral and proximal femoral QCT was performed on a subset (65%). Serum, urine, and DNA specimens were collected. After the baseline assessments, a questionnaire is mailed to participants every 4 months to ascertain incident falls, fractures, prostate cancer, and deaths. After an average of 4.5 years, participants are scheduled to return for a second comprehensive visit. Men were eligible if > or =65 years. 5995 men enrolled with a mean (+/-SD) age of 73.7 (+/-5.9) years, 11% of which were minorities. Most rated their health as good/excellent. Few were current smokers, although 59% had smoked previously, and 35% reported no alcohol intake, while 47% consumed at least 2 drinks per week. The mean (range) body mass index was 26.9 kg/m2 (17-56). A non-traumatic fracture after age 50 was reported by 17% of the cohort. The MrOS cohort should provide valuable information concerning the determinants of fracture in men and should help set the stage for the development of effective methods to identify those at risk.

A series of 11C-labeled analogs of the acetylcholinesterase (AChE) inhibitor pyridostigmine have been synthesized for evaluation as new potential positron emission tomography (PET) imaging agents for heart AChE. The appropriate precursors for radiolabeling were slightly modified from commercial reagents. The new tracers [11C]pyridostigmine (1), [11C]para-pyridostigmine (2) and [11C]ortho-pyridostigmine (3) were prepared by N-[11C]methylation of the precursors using [11C]methyl triflate. Pure target compounds were isolated by a solid-phase extraction (SPE) purification procedure with 60-85% radiochemical yields (decay corrected to end of bombardment), and a synthesis time of 10-15 min. The initial PET dynamic studies of compounds (1-3) in rat heart showed rapid heart uptake and blood pool clearance to give high quality heart images. These results suggest the new tracers delineate the heart very clearly and could be potential heart AChE imaging agents.

Purpose: To determine if age-related hearing loss may be related to bone health. Decreased vestibular function has been associated with hearing loss. We hypothesized that hearing loss would be related to an increased risk of falling and osteoporotic fracture in 6480 women aged 65 years or older enrolled in the Study of Osteoporotic Fractures. We further hypothesized that decreased bone mineral density would be associated with hearing loss., Methods: Hearing sensitivity was ascertained via screening audiometry, and was classified as normal, mild loss, or significant loss. Incident non-spine fractures and falls were ascertained every 4 months for an average 6.7 years and 3 years, respectively., Results: The age-adjusted annual fall rate did not differ significantly by hearing category, nor did the risk of incident fracture. Adjustment for confounding factors had no effect on our results. Age- and BMI-adjusted mean calcaneal bone mineral density (g/cm2) was 0.380 in the normal hearing group, 0.375 in the mild loss group, and 0.371 in the significant loss group (p = 0.02). There were no significant differences in total hip bone mineral density across hearing categories., Conclusions: Our results do not support the hypothesis that hearing loss is a risk factor for fracture or falls [corrected]

Objective: To determine the association between changes in visual acuity (VA) and frequent falls in older women., Design: Prospective cohort study., Participants: Two thousand two elderly community-residing women participating in the Study of Osteoporotic Fractures with measurements of VA at baseline and a follow-up examination 4 to 6 years later (mean of 5.6 years)., Methods: Binocular VA with habitual correction was measured under standard illumination using Bailey-Lovie charts at baseline and fourth examinations. Change in VA was stratified into 5 categories: no change or VA gain, loss of 1 to 5 letters, loss of 6 to 10 letters, loss of 11 to 15 letters, and loss of >15 letters. A separate analysis considered decline in VA as the loss of >or=10 letters (>or=2 lines) on the Bailey-Lovie acuity measure between baseline and follow-up examinations., Main Outcome Measures: Data on falls were obtained from postcards sent every 4 months after the follow-up examination. Frequent falling was defined as >or=2 falls during a 1-year period after the follow-up examination., Results: Compared with women with stable or improved VA, women with declining acuity had significantly greater odds of experiencing frequent falling during the subsequent year. Odds ratios after adjustment for baseline acuity and other confounders were 2.08 (95% confidence interval [CI]: 1.39-3.12) for loss of 1 to 5 letters, 1.85 (95% CI: 1.16-2.95) for loss of 6 to 10 letters, 2.51 (95% CI: 1.39-4.52) for loss of 11 to 15 letters, and 2.08 (95% CI: 1.01-4.30) for loss of >15 letters. In the analysis of visual decline defined as a loss of >or=10 letters, heightened risk of frequent falling was evident in each of 2 subgroups defined by splitting the sample on baseline VA, with borderline significant evidence of a more pronounced effect in those women with baseline VA of 20/40 or worse (P value for interaction, 0.083)., Conclusions: Loss of vision among elderly women increases the risk of frequent falls. Prevention or correction of visual loss may help reduce the number of future falls.

(S)-2-(4'-[11C]methoxybiphenyl-4-sulfonylamino)-3-methylbutyric acid ([11C]MSMA) and N-hydroxy-(R)-2-[[(4'-[11C]methoxyphenyl)sulfonyl]benzylamino]-3-methylbutanamide ([11C]CGS 25966), carbon-11 labeled matrix metalloproteinase (MMP) inhibitors, have been synthesized for evaluation as new potential positron emission tomography (PET) cancer biomarkers. [11C]MSMA was prepared by appropriate precursor (S)-2-(4'-hydroxybiphenyl-4-sulfonylamino)-3-methylbutyric acid tert-butyl ester, which was synthesized in eight steps from amino acid (L)-valine in 39.4% chemical yield. This precursor was labeled by [11C]methyl triflate through O-[11C]methylation method at the hydroxyl position of biphenol under basic conditions, followed by a quick acid hydrolysis and isolated by solid-phase extraction (SPE) purification to produce pure target compound [11C]MSMA in 35-55% radiochemical yield, based on 11CO2, decay corrected to end of bombardment (EOB), and 20-25 min synthesis time. [11C]CGS 25966 was prepared in our previous work starting from amino acid (D)-valine. The biodistribution of [11C]MSMA and [11C]CGS 25966 were determined at 45 min post iv injection in breast cancer animal models MCF-7's transfected with IL-1alpha implanted athymic mice and MDA-MB-435 implanted athymic mice. The results showed the uptakes of [11C]MSMA and [11C]CGS 25966 in these tumors were 0.95 and 0.42%dose/g in MCF-7's transfected with IL-1alpha implanted mice, 0.98 and 1.53%dose/g in MDA-MB-435 implanted mice, respectively; the ratios of tumor/muscle (T/M) and tumor/blood (T/B) were 1.21 and 1.09 (T/M, MCF-7's), 0.99 and 0.84 (T/B, MCF-7's), 1.38 and 1.27 (T/M, MDA-MB-435), 1.27 and 1.95 (T/B, MDA-MB-435), respectively. The micro-PET images of [11C]MSMA and [11C]CGS 25966 in both breast cancer athymic mice were acquired for 15 min from a MCF-7's transfected with IL-1alpha and/or MDA-MB-435 implanted mouse at 45 min post iv injection of 1 mCi of the tracer using a dedicated high resolution (<3 mm full-width at half-maximum) small FOV (field-of-view) PET imaging system, Indy-PET II scanner, developed in our laboratory, which showed both tumors were invisible with both tracers. The results were compared. From our results, we concluded that both [11C]MSMA and [11C]CGS 25966 might be unsuitable as PET tracers for cancer imaging.

(2R)-2-[[4-(6-fluorohex-1-ynyl)phenyl]sulfonylamino]-3-methylbutyric acid [(11)C]methyl ester ([(11)C]FMAME), a novel carbon-11 labeled matrix metalloproteinase (MMP) inhibitor, has been synthesized for evaluation as new potential positron emission tomography (PET) cancer biomarker. [(11)C]FMAME was prepared by appropriate precursor (2R)-2-[[4-(6-fluorohex-1-ynyl)phenyl]sulfonylamino]-3-methylbutyric acid (FMA), which was synthesized in six steps from (D)-valine in 71% chemical yield. This acid precursor was labeled by [(11)C]methyl triflate through O-[(11)C]methylation method under basic conditions and isolated by solid-phase extraction (SPE) purification to produce pure target compound in 40-55% radiochemical yield, based on (11)CO(2), decay corrected to end of bombardment, and 15-20 min synthesis time. The biodistribution of [(11)C]FMAME was determined at 30 min post IV injection in breast cancer animal models MCF-7 transfected with IL-1 alpha implanted athymic mice and MDA-MB-435 implanted athymic mice. The results showed the uptakes of [(11)C]FMAME in these tumors were 1.13% dose/g in MCF-7 transfected with IL-1 alpha implanted mice and 1.37% dose/g in MDA-MB-435 implanted mice, respectively; the ratios of tumor/muscle (T/M) and tumor/blood (T/B) were 1.05 +/- 0.29 (T/M, MCF-7's), 0.77 +/- 0.20 (T/B, MCF-7's) and 0.99 +/- 0.35 (T/M, MDA-MB-435), 1.44 +/- 0.69 (T/B, MDA-MB-435), respectively. Pretreatment of MCF-7 transfected with IL-1 alpha tumor-bearing mice with MMP inhibitor FMA had no effect on [(11)C]FMAME biodistribution. Likewise, pretreatment of MDA-MB-435 tumor-bearing mice with FMA also showed no effect on [(11)C]FMAME biodistribution. The micro-PET images were acquired for 15 min from a MCF-7 transfected with IL-1 alpha tumor-bearing mouse or a MDA-MB-435 tumor-bearing mouse at 30 min post IV injection of 1 mCi of [(11)C]FMAME using a dedicated high resolution (<3 mm full-width at half-maximum) PET imaging system (Indy-PET II scanner). The initial dynamic micro-PET images of [(11)C]FMAME in a MCF-7 transfected with IL-1 alpha tumor-bearing mouse during different time periods of 0-15, 15-30, 30-45 and 45-60 min were performed by Indy-PET II. The PET images clearly showed both tumors were visible with [(11)C]FMAME. These results suggest that the localization of [(11)C]FMAME in the tumor is mediated by non-specific processes, and the visualization of [(11)C]FMAME on the tumor using the Indy-PET II scanner is related to non-specific binding.

Novel radiolabeled O(6)-benzylguanine (O(6)-BG) derivatives, 2-amino-6-O-[(11)C]-[(methoxymethyl)benzyloxy]-9-methyl purines ([(11)C]p-O(6)-AMMP, 1a; [(11)C]m-O(6)-AMMP, 1b; [(11)C]o-O(6)-AMMP, 1c), 2-amino-6-O-benzyloxy-9-[(11)C]-[(methoxycarbonyl)methyl]purine ([(11)C]ABMMP, 2), and 2-amino-6-O-benzyloxy-9-[(11)C]-[(4'-methoxycarbonyl)benzyl]purine ([(11)C]ABMBP, 3), have been synthesized for evaluation as new potential positron emission tomography (PET) imaging agents for the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT) in breast cancer. The appropriate precursors for radiolabeling were obtained in two to three steps from starting material 2-amino-6-chloropurine with moderate to excellent chemical yields. Tracers were prepared by O-[(11)C]methylation of hydroxymethyl or acid precursors using [(11)C]methyl triflate. Pure target compounds were isolated by solid-phase extraction (SPE) purification procedure in 45-65% radiochemical yields (decay corrected to end of bombardment), and a synthesis time of 20-25 min. The activity of unlabeled standard samples of 1-3 was evaluated via an in vitro AGT oligonucleotide assay. Preliminary findings from biological assay indicate the synthesized analogs have similar strong inhibitory effectiveness on AGT in comparison with the parent compound O(6)-BG. The results warrant further evaluation of these radiotracers as new potential PET imaging agents for the DNA repair protein AGT in breast cancer in vivo.

[11C]Choline has been evaluated as a potential positron emission tomography (PET) marker for imaging of breast cancer. The biodistribution of [11C]choline was determined at 45 min post iv injection in MCF-7's transfected with IL-1alpha implanted athymic mice and MDA-MB-435 implanted athymic mice. The results showed the uptake of [11C]choline in these tumors was high, 2.0% dose/g in MCF-7's transfected with IL-1alpha implanted mice and 1.8% dose/g in MDA-MB-435 implanted mice; the ratios of tumor/muscle (T/M) and tumor/blood (T/B) were 1.7 (T/M, MCF-7's), 2.1 (T/M, MDA-MB-435) and 6.9 (T/B, MCF-7's), 12.5 (T/B, MDA-MB-435), respectively; the tumor/muscle ratios are moderate, and the tumor/blood ratios are high. The micro-PET imaging of [11C]choline in both breast cancer athymic mice was acquired for 15 min from a MCF-7's transfected with IL-1alpha and/or MDA-MB-435 implanted mouse at 45 min post iv injection of 1 mCi of the tracer using a dedicated high resolution (<3 mm full-width at half-maximum) small FOV (field-of-view) PET imaging system, Indy-PET II scanner, developed in our laboratory, which showed the uptake of [11C]choline in MCF-7's transfected with IL-1alpha tumor or MDA-MB-435 tumor implanted in a nude athymic mouse. These results suggest that [11C]choline may be a potential PET breast cancer imaging agent.

A series of [11C]methyl-halo-CGS 27023A analogs (2-F, 1a; 4-F, 1b; 2-Cl, 1c; 3-Cl, 1d; 4-Cl, 1e; 2-Br, 1f; 3-Br, 1g; 4-Br, 1h; 4-I, 1i), novel radiolabeled matrix metalloproteinase (MMP) inhibitors, have been synthesized for evaluation as new potential positron emission tomography (PET) breast cancer imaging agents. The precursors halo-CGS 27023A analogs (2-F, 6a; 4-F, 6b; 2-Cl, 6c; 3-Cl, 6d; 4-Cl, 6e; 2-Br, 6f; 3-Br, 6g; 4-Br, 6h; 4-I, 6i) for radiolabeling were obtained in four steps from starting material amino acid D-valine with moderate to excellent chemical yields. Precursors were labeled by [11C]methyl triflate through 11C-O-methylation method at the aminohydroxyl position under basic conditions and isolated by solid-phase extraction (SPE) purification to produce pure target compounds in 40-60% radiochemical yields (decay corrected to end of bombardment), in 20-25 min synthesis time.

Background: Several genes associated with sporadic Alzheimer's disease have been identified; however, approximately 50% of genetic factors remain unidentified. We investigated whether estrogen receptor 1 (ESR1) polymorphisms are associated with risk of developing cognitive impairment in older women., Methods: A total of 2625 women > or = 65 years of age completed a modified Mini-Mental Status Exam (mMMSE) at baseline and at 6-8 years of follow-up. We defined cognitive impairment as a mMMSE decline of > or = 3 points, follow-up score < or = 20, or a history of physician-diagnosed dementia. The ESR1 polymorphisms, PvuII (P or p) and XbaI (X or x), were coded so that the capital letter signifies the absence of the restriction site., Results: Women with a p allele had a greater age, education, and baseline-score adjusted decline in mMMSE (for PP, Pp, and pp, respectively:.6 +/-.1,.8 +/-.1, and.9 +/-.1 points, p for trend =.01); women with at least one x allele also had greater score decline (XX, Xx, and xx:.7 +/-.1,.7 +/-.1, and.9 +/-.1 points, p for trend =.02). Six percent (n = 166) of the women developed cognitive impairment. Compared to those who did not develop impairment, more women who developed cognitive impairment had a p allele (62% vs. 56%, p =.03; adjusted odds ration (OR) = 1.33; 95% confidence interval [CI], 1.03-1.72) or an x allele (70% vs. 64%, p =.03; adjusted OR = 1.38; 95% CI, 1.06-1.81). There was no interaction with current estrogen use, or with serum estradiol level and ESR1 polymorphisms (p >.10)., Conclusions: Estrogen receptor 1 polymorphisms are associated with risk of developing cognitive impairment. More research is needed to determine the mechanism whereby ESR1 polymorphisms or linked genes influence cognitive function in older women.

Background: Different sources of dietary protein may have different effects on bone metabolism. Animal foods provide predominantly acid precursors, whereas protein in vegetable foods is accompanied by base precursors not found in animal foods. Imbalance between dietary acid and base precursors leads to a chronic net dietary acid load that may have adverse consequences on bone., Objective: We wanted to test the hypothesis that a high dietary ratio of animal to vegetable foods, quantified by protein content, increases bone loss and the risk of fracture., Design: This was a prospective cohort study with a mean (+/-SD) of 7.0+/-1.5 y of follow-up of 1035 community-dwelling white women aged >65 y. Protein intake was measured by using a food-frequency questionnaire and bone mineral density was measured by dual-energy X-ray absorptiometry., Results: Bone mineral density was not significantly associated with the ratio of animal to vegetable protein intake. Women with a high ratio had a higher rate of bone loss at the femoral neck than did those with a low ratio (P = 0.02) and a greater risk of hip fracture (relative risk = 3.7, P = 0.04). These associations were unaffected by adjustment for age, weight, estrogen use, tobacco use, exercise, total calcium intake, and total protein intake., Conclusions: Elderly women with a high dietary ratio of animal to vegetable protein intake have more rapid femoral neck bone loss and a greater risk of hip fracture than do those with a low ratio. This suggests that an increase in vegetable protein intake and a decrease in animal protein intake may decrease bone loss and the risk of hip fracture. This possibility should be confirmed in other prospective studies and tested in a randomized trial.

Aims: To assess the prevalence of pacifier and digit sucking at 15 months of age and to investigate whether this habit adversely affects the health of 18 month old infants., Study Design: Data collected via self-completion questionnaires from mothers forming part of the prospective, population based Avon Longitudinal Study of Pregnancy and Childhood., Subjects and Methods: The mothers of 10006 infants gave information on their child's use of a pacifier and of digit sucking at 15 months of age and the presence of specific health symptoms at 18 months of age. Adjusted logistic regression was performed to identify any statistically significant associations between pacifier use, digit sucking or a combination of the two with possible infection., Results: 36.3% of infants sucked a pacifier, 21. 3% their thumb or finger and 2.7% sucked both at 15 months. Statistically significant differences were observed among various socio-demographic variables. Mothers were more likely to give their child a pacifier if they were younger, had lower levels of education, experienced greater financial difficulties or lived in council housing (compared to owned/mortgaged). The opposite was apparent for digit suckers. After allowing for these possible confounding factors, pacifier users had a higher incidence of earache and colic compared to children with no sucking habit, however digit suckers had a lower incidence of these symptoms. Children who sucked both were significantly more likely to have reported wheezing, earache, and poor health in the past month., Conclusions: Significantly different sociodemographic characteristics were observed with pacifier suckers compared to those who sucked their thumb or finger. It is almost impossible to attribute the direction of causality between infection and a sucking habit. Further and more detailed studies are needed before any recommendations can be made based on the statistically significant associations found as they are unlikely to be of major clinical significance.

Using electron microscopy, we investigated the effect of (i) a dilute surfactant and of water alone on the ultrastructure of stratum corneum lipids in pig skin exposed in vitro at 46 degrees C, and (ii) of water alone on human skin exposed in vivo at ambient temperature. For pig skin, the surfactant sodium dodecyl sulfate disrupts stratum corneum intercellular lamellar bilayers, leading to bilayer delamination and "roll-up" in a water milieu after 1 h, extensive bilayer disruption after 6 h, and nearly complete dissociation of corneocytes after 24 h. Corneodesmosomes show progressive degradation with exposure time. Water alone also disrupts the stratum corneum, but with a slower onset. Alterations in intercellular lamellar bilayers, but not intercellular lamellar bilayer roll-up, are detected after 2 h. Intercellular lamellar bilayer roll-up occurs after 6 h. Extensive dissociation of corneocytes occurs after 24 h of water exposure. Unlike sodium dodecyl sulfate, water exposure results in the formation of amorphous intercellular lipid. Corneodesmosome degradation parallels intercellular lamellar bilayer disruption; calcium appears to offer some protection. Similar disruption of intercellular lamellar bilayers occurs in human skin in vivo at ambient temperature. Our studies show that water can directly disrupt the barrier lipids and are consistent with surfactant-induced intercellular lamellar bilayer disruption being due at least in part to the deleterious action of water. Intercellular lamellar bilayer disruption by water would be expected to enhance permeability and susceptibility to irritants; accordingly, increased attention should be given to the potential dangers of prolonged water contact. For common in vitro procedures, such as skin permeation studies or isolation of stratum corneum sheets, exposure to water should also be minimized.