Conditioned taste avoidance and conditioned place preference induced by the third-generation synthetic cathinone eutylone in female sprague-dawley rats.

Recently, use of the synthetic cathinone (aka "bath salt") eutylone has risen in the United States and globally. Due to its novelty in drug markets, its affective properties remain largely uninvestigated. In this context, drugs of abuse have both rewarding and aversive effects and understanding these effects, their relative balance, and factors that impact each are important to understanding the likelihood of drug use and abuse. This investigation attempted to characterize eutylone's rewarding and aversive effects in a combined conditioned taste avoidance/place preference assay. Female Sprague-Dawley rats were given 20-min access to saccharin, injected with one of five doses of eutylone (0, 3, 10, 18, 32 mg/kg; intraperitoneally; IP), and placed on one side of a place conditioning apparatus. On the following day, subjects were given 20-min access to water, injected IP with vehicle, and placed on the other side of the apparatus. After five conditioning cycles, place preference and saccharin avoidance were assessed. Eutylone induced significant taste avoidance but did not significantly increase time spent on the drug-paired side (relative to controls). Excluding animals with high initial side preference, however, eutylone induced a preference at all doses with the high dose group displaying higher preference than controls. There was no significant correlation between eutylone's aversive and rewarding effects. These data indicate that eutylone (like other synthetic cathinones) induces both rewarding and aversive effects and highlight the need to assess the impact of various factors on its affective properties (and their balance) and on their use and abuse. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Long-term Outcomes of a 1-year Hypertension Quality Improvement Initiative in a Large Health System.

BACKGROUND: Understanding whether practices retain outcomes attained during a quality improvement (QI) initiative can inform resource allocation. OBJECTIVE: We report blood pressure (BP) control and medication intensification in the 3 years after a 2016 QI initiative ended. RESEARCH DESIGN: Retrospective cohort. SUBJECTS: Adults with a diagnosis of hypertension who had a primary care visit in a large-integrated health system between 2015 and 2019. MEASURES: We report BP control (<140/90 mm Hg) at the last reading of each year. We used a multilevel regression to identify the adjusted propensity to receive medication intensification among patients with an elevated BP in the first half of the year. To examine variation, we identified the average predicted probability of control for each practice. Finally, we grouped practices by the proportion of their patients whose BP was controlled in 2016: lowest performing (<75%), middle (≥75%-<85%), and highest performing (≥85%). RESULTS: The dataset contained 184,981 patients. From 2015 to 2019, the percentage of patients in control increased from 74% to 82%. In 2015, 38% of patients with elevated BP received medication intensification. This increased to 44% in 2016 and 50% in 2019. Practices varied in average BP control (from 62% to 91% in 2016 and 68% to 90% in 2019). All but one practice had a substantial increase from 2015 to 2016. Most maintained the gains through 2019. Higher-performing practices were more likely to intensify medications than lower-performing practices. CONCLUSIONS: Most practices maintained gains 3 years after the QI program ended. Low-performing practices should be the focus of QI programs.

Effect of Curcuma longa extract on serum inflammatory markers and MRI-based synovitis in knee osteoarthritis: secondary analyses from the CurKOA randomised trial.

BACKGROUND: Curcuma longa (CL) extract is modestly effective for relieving knee symptoms in knee osteoarthritis (OA) patients; however, its mechanism of action is unclear. PURPOSE: We aimed to determine the effects of CL treatment on serum inflammatory markers over 12 weeks and to explore its potential effects on synovitis assessed by contrast-enhanced magnetic resonance imaging (CE-MRI) of the knee. METHODS: Secondary analyses were conducted on the CL for knee OA (CurKOA) trial, which compared CL (n = 36) and placebo (n = 34) over 12 weeks for the treatment of knee OA. Systemic inflammatory markers (TNFα, IL6, and hsCRP) and a cartilage extracellular matrix degradative enzyme (MMP-3) were measured. A subgroup of participants (CL, n = 7; placebo, n = 5) underwent CE-MRI at baseline and a 12-week follow-up. RESULTS: Over 12 weeks, there were no between-group differences in change in hsCRP, IL-6, and TNFα levels. MMP-3 levels decreased in both CL (-1.31 ng/ml [95%CI: -1.89 to -0.73]) and placebo (-2.34 ng/ml [95%CI: -2.95 to -1.73]) groups, with the placebo group having a slightly greater decrease (1.03 ng/ml [95%CI: 0.19 to 1.88]). Most (10 of 12) sub-study participants had normal synovial thickness scores at baseline. One participant had mild synovitis in each of the placebo and CL groups. Synovitis status was stable for all except two participants, one each in the CL and placebo group, whose synovitis score increased. CONCLUSION: This is the first study that explored the effect of CL treatment on local and systemic inflammation using biochemical markers and CE-MRI outcomes on knee OA patients. Secondary analyses from this pilot study suggest that CL is unlikely to have clinically significant effects on systemic (inflammatory and cartilage) or local synovitis (CE-MRI) biomarkers compared to placebo. The mechanism of action for CL effect on pain remains unclear.

Co-producing nurse education with academics, students, service users and carers: lessons from the pandemic.

This article presents a holistic view of re-designing learner-centred nursing curricula in a post-coronavirus pandemic digital educational system while maintaining authentic service user and carer involvement. Higher education is facing turbulent times through ever-increasing recruitment targets and financial demands. This is coupled with increased requirements from health professional bodies to involve students and service users and carers in co-creating curricula. Reflecting on the authors' collective experiences pre-COVID-19, during COVID-19 and looking to the future, they present a service user-and-student-led proposal for the future of digitally enabled nursing education that involves people with lived experience in an authentic way.

Oil biodegradation in permeable marine sediments: Effects of benthic pore-water advection and solute exchange.

Oil spills have been recognized as among the worst kinds of environmental disasters, causing severe coastal ecological and economic damages. Although benthic flow and solute fluxes are known to have strong impacts on fate and transport of oil deposited within marine sediments, their endogenous mechanisms still remain to be uncovered. In this paper, simulations of flow and solute transport processes along with hydrocarbon biodegradation were conducted in a cylindrical benthic chamber system to investigate influences of benthic hydrodynamics on oil biodegradation in permeable marine sediments. Results show that ripple-flow interactions create subsurface recirculation cells whereby seawater infiltrates into the benthic sediments at ripple troughs while groundwater discharges near the crests. It results in a spatially varied oil biodegradation rate in marine sediments. Significant oil biodegradation occurs near sediment ripple troughs due to direct oxygen recharge, while biodegradation of oil deposited uphill becomes slow due to limited oxygen replenishment. Oil biodegradation decreases subsurface oxygen content, and consequently impedes discharge of oxygen from benthic sediments. Our results reveal a dynamic interaction between oil biodegradation and benthic flow and solute transport processes, which has strong implications for predicting oil persistence and biodegradation within marine sediments and its associated impacts on benthic biogeochemical processes.

Acute effects of prior dietary fat ingestion on postprandial metabolic responses to protein and carbohydrate co-ingestion in overweight and obese men: A randomised crossover trial.

BACKGROUND: Obesity and insulin resistance are associated with an impaired sensitivity to anabolic stimuli such as dietary protein (anabolic resistance). Omega-3 polyunsaturated fatty acids (n-3 PUFA) may be protective against the deleterious effects of saturated fatty acids (SFA) on insulin resistance. However, the contribution of excess fat consumption to anabolic and insulin resistance and the interaction between SFA and n-3 PUFA is not well studied. AIM: The primary aim of this study was to investigate the effects of an oral fat pre-load, with or without the partial substitution of SFA with fish oil (FO)-derived n-3 PUFA, on indices of insulin and anabolic sensitivity in response to subsequent dietary protein and carbohydrate (dextrose) co-ingestion. METHODS: Eight middle-aged males with overweight or obesity (52.8 ± 2.0 yr, BMI 31.8 ± 1.4 kg·m-2) ingested either an SFA, or isoenergetic SFA and FO emulsion (FO), or water/control (Con), 4 h prior to a bolus of milk protein and dextrose. RESULTS: Lipid ingestion (in particular FO) impaired the early postprandial uptake of branched chain amino acids (BCAA) into the skeletal muscle in response to protein and dextrose, and attenuated the peak glycaemic response, but was not accompanied by differences in whole body (Matsuda Index: Con: 4.66 ± 0.89, SFA: 5.10 ± 0.94 and FO: 4.07 ± 0.59) or peripheral (forearm glucose netAUC: Con: 521.7 ± 101.7; SFA: 470.2 ± 125.5 and FO: 495.3 ± 101.6 µmol·min-1·100 g lean mass·min [t = 240-420 min]) insulin sensitivity between visits. Postprandial whole body fat oxidation was affected by visit (P = 0.024) with elevated rates in SFA and FO, relative to Con (1.85 ± 0.55; 2.19 ± 0.21 and 0.65 ± 0.35 kJ·h-1·kg-1 lean body mass, respectively), however muscle uptake of free fatty acids (FFA) was unaffected. CONCLUSION: Oral lipid preloads, consisting of SFA and FO, impair the early postprandial BCAA uptake into skeletal muscle, which occurs independent of changes in insulin sensitivity. CLINICAL TRIAL REGISTRY NUMBER: ClinicalTrials.gov Identifier NCT03146286.

Lead poisoning among asymptomatic individuals with a long-term history of opiate use in Golestan Cohort Study.

BACKGROUND: Recent reports of lead poisoning suggest that people who use opium may be exposed to high amounts of lead. Here, we investigate the association between opium use and blood lead levels (BLL) in a population-based cohort study. METHODS: In 2017, we studied a random sample of 410 people who currently (both within the past year and the past month) used opium and 104 who did not from participants of the Golestan Cohort Study in northeast Iran. Participants were stratified by sex and tobacco use history, completed a comprehensive opiate and tobacco use questionnaire and provided blood. BLL was measured by Lead Care® II Blood Lead Test Kit, validated by inductively coupled plasma triple quadrupole mass spectrometry. BLL was categorized as "<5 µg/dL", "elevated" (5-10 µg/dL), "high" (10-50 µg/dL), and "very high" (above 50 µg/dL). To assess the association between BLL categories and opiate use, route of consumption and weekly use, we used ordered logistic regression models, and report OR (odds ratio) and 95% CI (confidence interval) adjusted for age, sex, place of residence, education, occupation, household fuel type, and tobacco use. RESULTS: In the cohort, participants used only raw (teriak) or refined (shireh) opium, which were smoked (45%, n = 184), taken orally (46%, n = 189), or both (9%, n = 37), for a mean duration of 24.2 (standard deviation: 11.6) years. The median BLL was significantly higher in people who currently used opium (11.4 µg/dL; IQR: 5.2-23.4) compared with those who did not (2.3 µg/dL; IQR: 2.3-4.2), and the highest median BLL was seen in oral use (21.7 µg/dL; IQR: 12.1-34.1). The BLL was <5 µg/dL among 79.8% of people with no opiate use, compared with only 22.7% in those using opium. BLL was elevated in 21.7%, high in 50.5% and very high in 5.1% of people using opium. About 95% of those with oral (180/189) or dual use (35/37) and 55% (102/184) of those who smoked opium had levels of blood lead above 5 µg/dL. The OR for the association between any opium use and each unit of increase in BLL category was 10.5 (95%CI: 5.8-19.1), and oral use of opium was a very strong predictor of increasing BLL category (OR=74.1; 95%CI: 35.1-156.3). This odds ratio was 38.8 (95%CI: 15.9-95.1) for dual use and 4.9 (95%CI: 2.6-9.1) for opium smoking. There was an independent dose-response association between average weekly dose and BLL among people using opium, overall and when stratified by route of use. CONCLUSION: Our results indicate that regular use of lead-adulterated opium can expose individuals to high levels of lead, which may contribute to mortality and cancer risks associated with long-term opium use.

Do clinical trials change practice? A longitudinal, international assessment of colorectal cancer prescribing practices.

INTRODUCTION: Over half of the 1.5 million individuals globally who are diagnosed with colorectal cancer (CRC) present with stage II-III disease. Understanding clinician attitudes towards treatment for this group is paramount to contextualise real-world outcomes and plan future trials. The aim of this study was to assess clinician awareness of trials assessing the optimal duration of CRC adjuvant therapy, their attitudes towards shorter treatment and their self-reported practice. METHODS: A survey was developed using OnlineSurveys® and distributed to clinicians in April 2019, with a follow-up survey disseminated to a subset of respondents in August 2020. Microsoft Excel® and Stata® were used for analysis. RESULTS: 265 clinicians replied to the first survey, with the majority aware of findings from the International Duration Evaluation of Adjuvant Therapy collaboration and contributory trials. Practice change was greatest for patients under 70 with low-risk stage III CRC, with most uncertainty around using 3-months of doublet chemotherapy for high-risk stage II disease. In August 2020, clinicians (n = 106) were more likely to use 3-months of FOLFOX for low-risk stage III disease and 3-months of CAPOX for stage II disease compared to April 2019. There was no indication that the COVID-19 pandemic had enduring changes on treatment decisions beyond those made in response to trial evidence. DISCUSSION: Clinicians use a risk-stratified approach to treat CRC the adjuvant setting. Lower utilisation of doublet chemotherapy for older and stage II patients has affected the extent of trial implementation. Active dialogue regarding how trial results apply to these groups may improve consensus.

Exploring Large Community- and Clinically-Generated Datasets to Understand Resilience Before and During the COVID-19 Pandemic.

PURPOSE: To explore resilience in the context of whole-person health and the social determinants of health at the individual and community levels using large, standardized nursing datasets. DESIGN: A retrospective, observational, correlational study of existing deidentified Health Insurance Portability and Accountability Act (HIPAA)-compliant data using the Omaha System and its equivalent, Simplified Omaha System Terms. METHODS: We used three samples to explore for patterns of resilience: pre-COVID-19 community-generated data (N = 383), pre-COVID-19 clinical documentation data (N = 50,509), and during-COVID-19 community-generated data (N = 102). Community participants used the My Strengths + My Health (MSMH) app to generate the two community datasets. The clinical data were obtained from the Omaha System Data Collaborative. We operationalized resilience as Omaha System Status scores of 4 (minimal signs or symptoms) or 5 (no signs or symptoms) as a discrete strengths measure for each of 42 Omaha System problem concepts. We used visualization techniques and standard descriptive and inferential statistics for analysis. FINDINGS: It was feasible to examine resilience, operationalized as strengths by problem concept, within existing Omaha System or Simplified Omaha System Terms (MSMH) data. We identified several patterns indicating strengths and resilience that were consistent with literature related to community connectedness for community participants, and sleep for individuals in the clinical data. CONCLUSIONS: When used consistently, the Omaha System within MSMH enabled robust data collection for a comprehensive, holistic assessment, resulting in better whole-person data including strengths, and enabled us to discover a potentially useful approach for defining resilience in new ways using standardized nursing data. CLINICAL RELEVANCE: The notion that how we assess individuals and communities (i.e., the completeness of our assessments in relation to whole-person health) determines what we can know about resilience is seemingly in opposition to the critical need to decrease documentation burden, despite the potential to shift from a problem deficit-based assessment to one of strengths and resilience. However, a patient-facing comprehensive assessment that includes resilience and the social determinants of health can provide a transformative, whole-person platform for strengths-based care and population management.

Blind and partially sighted physiotherapy in the United Kingdom. A century of development, success and challenge. Will it still belong?

Background:In 2019 the Association of Visually Impaired Chartered Physiotherapists, originally the Association of Blind Certificated Masseurs, celebrated the centenary of its formation and becoming the first ever Specific Interest Group admitted to the Incorporated Society of Trained Masseuses which, later in the 20th century, became the Chartered Society of Physiotherapy. These landmarks motivated the author to research for this chronological, descriptive, narrative review of the history of blind physiotherapy and its contribution to physiotherapy in the United Kingdom. Purpose:The early training and practice of massage by blind practitioners, the organizational milestones in mainstream and blind physiotherapy and the inter-relationship between the two is considered. Key developments, challenges, innovations and opportunities throughout the history are reviewed including the impact of World War 1 and contribution of blind physiotherapy to the profession. Conclusion:Significant changes in physiotherapy educational and training arrangements for blind students and changes in physiotherapy practice generally over the last four decades engender serious questions about whether blind physiotherapy will still "belong", despite the increasing aspiration within society toward acceptance of diversity and inclusion. The author challenges the profession about whether it will facilitate blind physiotherapy to continue making its valuable contribution and be included. Will it still "belong?"

Effectiveness of Curcuma longa Extract for the Treatment of Symptoms and Effusion-Synovitis of Knee Osteoarthritis : A Randomized Trial.

BACKGROUND: Current pharmacologic therapies for patients with osteoarthritis are suboptimal. OBJECTIVE: To determine the efficacy of Curcuma longa extract (CL) for reducing knee symptoms and effusion-synovitis in patients with symptomatic knee osteoarthritis and knee effusion-synovitis. DESIGN: Randomized, double-blind, placebo-controlled trial. (Australian New Zealand Clinical Trials Registry: ACTRN12618000080224). SETTING: Single-center study with patients from southern Tasmania, Australia. PARTICIPANTS: 70 participants with symptomatic knee osteoarthritis and ultrasonography-defined effusion-synovitis. INTERVENTION: 2 capsules of CL (n = 36) or matched placebo (n = 34) per day for 12 weeks. MEASUREMENTS: The 2 primary outcomes were changes in knee pain on a visual analogue scale (VAS) and effusion-synovitis volume on magnetic resonance imaging (MRI). The key secondary outcomes were change in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and cartilage composition values. Outcomes were assessed over 12 weeks. RESULTS: CL improved VAS pain compared with placebo by -9.1 mm (95% CI, -17.8 to -0.4 mm [P = 0.039]) but did not change effusion-synovitis volume (3.2 mL [CI, -0.3 to 6.8 mL]). CL also improved WOMAC knee pain (-47.2 mm [CI, -81.2 to -13.2 mm]; P = 0.006) but not lateral femoral cartilage T2 relaxation time (-0.4 ms [CI, -1.1 to 0.3 ms]). The incidence of adverse events was similar in the CL (n = 14 [39%]) and placebo (n = 18 [53%]) groups (P = 0.16); 2 events in the CL group and 5 in the placebo group may have been treatment related. LIMITATION: Modest sample size and short duration. CONCLUSION: CL was more effective than placebo for knee pain but did not affect knee effusion-synovitis or cartilage composition. Multicenter trials with larger sample sizes are needed to assess the clinical significance of these findings. PRIMARY FUNDING SOURCE: University of Tasmania and Natural Remedies Private Limited.

Contribution of Monocarboxylate Transporter 6 to the Pharmacokinetics and Pharmacodynamics of Bumetanide in Mice.

Bumetanide, a sulfamyl loop diuretic, is used for the treatment of edema in association with congestive heart failure. Being a polar, anionic compound at physiologic pH, bumetanide uptake and efflux into different tissues is largely transporter-mediated. Of note, organic anion transporters (SLC22A) have been extensively studied in terms of their importance in transporting bumetanide to its primary site of action in the kidney. The contribution of one of the less-studied bumetanide transporters, monocarboxylate transporter 6 (MCT6; SLC16A5), to bumetanide pharmacokinetics (PK) and pharmacodynamics (PD) has yet to be characterized. The affinity of bumetanide for murine Mct6 was evaluated using Mct6-transfected Xenopus laevis oocytes. Furthermore, bumetanide was intravenously and orally administered to wild-type mice (Mct6+/+) and homozygous Mct6 knockout mice (Mct6-/-) to elucidate the contribution of Mct6 to bumetanide PK/PD in vivo. We demonstrated that murine Mct6 transports bumetanide at a similar affinity compared with human MCT6 (78 and 84 µM, respectively, at pH 7.4). After bumetanide administration, there were no significant differences in plasma PK. Additionally, diuresis was significantly decreased by ∼55% after intravenous bumetanide administration in Mct6-/- mice. Kidney cortex concentrations of bumetanide were decreased, suggesting decreased Mct6-mediated bumetanide transport to its site of action in the kidney. Overall, these results suggest that Mct6 does not play a major role in the plasma PK of bumetanide in mice; however, it significantly contributes to bumetanide's pharmacodynamics due to changes in kidney concentrations. SIGNIFICANCE STATEMENT: Previous evidence suggested that MCT6 transports bumetanide in vitro; however, no studies to date have evaluated the in vivo contribution of this transporter. In vitro studies indicated that mouse and human MCT6 transport bumetanide with similar affinities. Using Mct6 knockout mice, we demonstrated that murine Mct6 does not play a major role in the plasma pharmacokinetics of bumetanide; however, the pharmacodynamic effect of diuresis was attenuated in the knockout mice, likely because of the decreased bumetanide concentrations in the kidney.

The Role of Regional Collaboratives in Quality Improvement: Time to Organize, and How?

Over the last 12 years, surgeon representatives from the 33 participating hospitals of the Michigan Society of Thoracic and Cardiovascular Surgeons Quality Collaborative (MSTCVS-QC), along with data specialists, surgical and quality improvement (QI) teams, have met at least 4 times a year to improve health-care quality and outcomes of cardiac and general thoracic surgery patients. The MSTCVS-QC nature of interactive learning has allowed all members to examine current data from each site in an unblinded manner for benchmarking, learn from their findings, institute clinically meaningful changes in survival and health-related quality of life, and carefully follow the effects. These meetings have resulted in agreement on various interventions to improve patient selection, periprocedural strategies, and adherence with evidence-based directed medication regimens, Factors contributing to the quality movement across hospitals include statewide-recognized clinicians who are eager to involve themselves in QI initiatives, dedicated health-care professionals at the hospital level, trusting environments in which failure is only a temporary step on the way toward achieving QI goals, real-time analytics of accurate data, and payers who strongly support QI efforts designed to improve outcomes.

Third-wave therapies and adults with intellectual disabilities: A systematic review.

BACKGROUND: Third-wave therapies appear to produce positive outcomes for people without intellectual disabilities. This systematic review aimed to establish which third-wave therapies have been adapted for adults with intellectual disabilities and whether they produced positive outcomes. METHOD: Four databases were searched systematically (PsycINFO, Web of Science, MEDLINE and PubMed), yielding 1,395 results. Twenty studies (N = 109) met the present review's inclusion/exclusion criteria. RESULTS: Included studies used mindfulness-based approaches, dialectical behaviour therapy, compassion focused therapy and acceptance and commitment therapy. Due to considerable heterogeneity in the designs and outcome measures used, a meta-analysis was not possible. CONCLUSIONS: Evidence indicated that third-wave therapies improved mental health symptoms for some and improved challenging/offending behaviour, smoking and mindfulness/acceptance skills for most. These findings must be interpreted with caution due to the low methodological quality of included studies. Future research should build on the current evidence base, using scientifically rigorous designs and standardized measures.

Assessing the stability of Cd, Mn, Pb, Se, and total Hg in whole human blood by ICP-DRC-MS as a function of temperature and time.

BACKGROUND: Comprehensive information on the effect of time and temperature storage on the measurement of elements in human, whole blood (WB) by inductively coupled plasma-dynamic reaction cell-mass spectrometry (ICP-DRC-MS) is lacking, particularly for Mn and Se. METHODS: Human WB was spiked at 3 concentration levels, dispensed, and then stored at 5 different temperatures: -70 °C, -20 °C, 4 °C, 23 °C, and 37 °C. At 3 and 5 weeks, and at 2, 4, 6, 8, 10, 12, 36 months, samples were analyzed for Pb, Cd, Mn, Se and total Hg, using ICP-DRC-MS. We used a multiple linear regression model including time and temperature as covariates to fit the data with the measurement value as the outcome. We used an equivalence test using ratios to determine if results from the test storage conditions, warmer temperature and longer time, were comparable to the reference storage condition of 3 weeks storage time at -70 °C. RESULTS: Model estimates for all elements in human WB samples stored in polypropylene cryovials at -70 °C were equivalent to estimates from samples stored at 37 °C for up to 2 months, 23 °C up to 10 months, and -20 °C and 4 °C for up to 36 months. Model estimates for samples stored for 3 weeks at -70 °C were equivalent to estimates from samples stored for 2 months at -20 °C, 4 °C, 23 °C and 37 °C; 10 months at -20 °C, 4 °C, and 23 °C; and 36 months at -20 °C and 4 °C. This equivalence was true for all elements and pools except for the low concentration blood pool for Cd. CONCLUSIONS: Storage temperatures of -20 °C and 4 °C are equivalent to -70 °C for stability of Cd, Mn, Pb, Se, and Hg in human whole blood for at least 36 months when blood is stored in sealed polypropylene vials. Increasing the sample storage temperature from -70 °C to -20 °C or 4 °C can lead to large energy savings. The best analytical results are obtained when storage time at higher temperature conditions (e.g. 23 °C and 37 °C) is minimized because recovery of Se and Hg is reduced. Blood samples stored in polypropylene cryovials also lose volume over time and develop clots at higher temperature conditions (e.g., 23 °C and 37 °C), making them unacceptable for elemental testing after 10 months and 2 months, respectively.

Sorafenib dose escalation in treatment-naïve patients with metastatic renal cell carcinoma: a non-randomised, open-label, Phase 2b study.

OBJECTIVE: To assess the efficacy and safety of sorafenib dose escalation in metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Intra-patient dose escalation may enhance the clinical benefit of targeted anticancer agents in metastatic disease. In this non-randomised, open-label, Phase 2b study, treatment-naïve patients with mRCC were initially treated with the standard oral sorafenib dose [400 mg twice daily (BID)]. Two dose escalations were planned, each 200 mg BID after 28 days at the prior level. Dose reductions, interruptions, or delayed escalations were used to manage adverse events (AEs). The primary endpoint was objective response rate (ORR) in the modified intent-to-treat (mITT) population, which comprised patients with ≥6 months of treatment including ≥4 months of therapy at their highest tolerated dose. Secondary endpoints included progression-free survival (PFS) and safety. RESULTS: In all, 83 patients received sorafenib. The dose received for the longest duration was 400, 600, and 800 mg BID in 48.2%, 15.7%, and 24.1% of patients, respectively. The ORR was 44.4% [n = 8/18; 95% confidence interval (CI) 21.5-69.2] and 17.9% (n = 12/67; 95% CI 9.6-29.2) in the mITT and ITT populations, respectively. The median (95% CI) PFS was 7.4 (6.0-11.7) months (ITT). The most common AEs of any grade were hand-foot skin reaction (66.3%) and diarrhoea (63.9%). CONCLUSION: Sorafenib demonstrated clinical benefit in treatment-naïve patients with mRCC. However, relatively few patients could sustain doses of >400 mg BID. There was evidence that, where tolerated, escalation from the standard sorafenib dose may have enhanced clinical benefit. However, this study does not support dose escalation for most patients with treatment-naïve mRCC. Alternative protocols for sorafenib dose escalation could be explored.

Analysis of whole human blood for Pb, Cd, Hg, Se, and Mn by ICP-DRC-MS for biomonitoring and acute exposures.

We improved our inductively coupled plasma mass spectrometry (ICP-MS) whole blood method [1] for determination of lead (Pb), cadmium (Cd), and mercury (Hg) by including manganese (Mn) and selenium (Se), and expanding the calibration range of all analytes. The method is validated on a PerkinElmer (PE) ELAN® DRC II ICP-MS (ICP-DRC-MS) and uses the Dynamic Reaction Cell (DRC) technology to attenuate interfering background ion signals via ion-molecule reactions. Methane gas (CH4) eliminates background signal from 40Ar2+ to permit determination of 80Se+, and oxygen gas (O2) eliminates several polyatomic interferences (e.g. 40Ar15N+, 54Fe1H+) on 55Mn+. Hg sensitivity in DRC mode is a factor of two higher than vented mode when measured under the same DRC conditions as Mn due to collisional focusing of the ion beam. To compensate for the expanded method's longer analysis time (due to DRC mode pause delays), we implemented an SC4-FAST autosampler (ESI Scientific, Omaha, NE), which vacuum loads the sample onto a loop, to keep the sample-to-sample measurement time to less than 5min, allowing for preparation and analysis of 60 samples in an 8-h work shift. The longer analysis time also resulted in faster breakdown of the hydrocarbon oil in the interface roughing pump. The replacement of the standard roughing pump with a pump using a fluorinated lubricant, Fomblin®, extended the time between pump maintenance. We optimized the diluent and rinse solution components to reduce carryover from high concentration samples and prevent the formation of precipitates. We performed a robust calculation to determine the following limits of detection (LOD) in whole blood: 0.07µgdL-1 for Pb, 0.10µgL-1 for Cd, 0.28µgL-1 for Hg, 0.99µgL-1 for Mn, and 24.5µgL-1 for Se.

Can a mindfulness-informed intervention reduce aggressive behaviour in people with intellectual disabilities? Protocol for a feasibility study.

BACKGROUND: Approximately 10-20 % of adults with intellectual disabilities engage in challenging behaviours such as aggression, destructiveness, and self-injury, which are often accompanied by feelings of anger. The inability to manage anger can reduce quality of life. For example, aggression is a strong predictor of out-of-area placements and is a risk variable for abuse. Recent research suggests that mindfulness-based therapies (specifically, Singh's Soles of the Feet meditation) can help people with intellectual disabilities manage angry emotions, with resultant reductions in challenging behaviour. However, previous research has been single-case design studies, and no group studies have been published with people with intellectual disabilities and aggressive behaviour. METHODS/DESIGN: For this feasibility study, a UK protocol will be developed for use by health professionals within National Health Service (NHS) Intellectual Disability (ID) teams, based upon Singh's Soles of the Feet manual. Twenty adults with intellectual disabilities and identified problems with anger control will be recruited and six sessions will be delivered by a trained ID clinician. The study will monitor participant's aggressive behaviour, health-related quality of life, anxiety, depression, and use of support services (medication, hospital appointments etc.). These will be measured at three time points: (1) Baseline (within 2 weeks prior to the first session of the intervention), (2) 2 months post-baseline, and (3) 6 months post-baseline. Qualitative interviews will be conducted with participants, their carers, and the therapists who delivered the intervention. In order to help design an economic evaluation alongside a future full trial, we will cost the intervention and test the acceptability and validity of health economics measures to record resource use and health-related quality of life outcomes. DISCUSSION: The data from this study will inform the feasibility of the project protocol and intervention, which will help develop future research and to determine whether a larger, randomised controlled trial with concurrent economic evaluation is feasible. TRIAL REGISTRATION: UKCERN: 16743.

Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints.

Despite compelling antitumour activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in lung cancer, resistance to these therapies has increasingly been observed. In this study, to elucidate mechanisms of adaptive resistance, we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. In tumours progressing following response to anti-PD-1 therapy, we observe upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade. Two patients who developed adaptive resistance to anti-PD-1 treatment also show a similar TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. These data suggest that upregulation of TIM-3 and other immune checkpoints may be targetable biomarkers associated with adaptive resistance to PD-1 blockade.

Managing Neuropathic Pain.

Neuropathic pain (NP) arises from injuries or diseases affecting the somatosensory component of the nervous system at any level of the peripheral or central nervous system. NP is diagnosed based on common neurologic signs and symptoms. NP is best treated with a combination of multiple therapeutic approaches, and treatments include conservative, complementary, medical, interventional, and surgical treatment modalities. Goals of treatment are the same as in pain management and include improvement in pain control and in coping skills as well as restoration of functional status. Most patients with NP benefit most from an individualized, multimodal approach that emphasizes both pain and function.