Designing Next-Generation Local Drug Delivery Vehicles for Glioblastoma Adjuvant Chemotherapy: Lessons from the Clinic.

To date, the clinical outcomes and survival rates for patients with glioblastoma (GB) remain poor. A promising approach to disease-modification involves local delivery of adjuvant chemotherapy into the resection cavity, thus circumventing the restrictions imposed by the blood-brain barrier. The clinical performance of the only FDA-approved local therapy for GB [carmustine (BCNU)-loaded polyanhydride wafers], however, has been disappointing. There is an unmet medical need in the local treatment of GB for drug delivery vehicles that provide sustained local release of small molecules and combination drugs over several months. Herein, key quantitative lessons from the use of local and systemic adjuvant chemotherapy for GB in the clinic are outlined, and it is discussed how these can inform the development of next-generation therapies. Several recent approaches are highlighted, and it is proposed that long-lasting soft materials can capture the value of stiff BCNU-loaded wafers while addressing a number of unmet medical needs. Finally, it is suggested that improved communication between materials scientists, biomedical scientists, and clinicians may facilitate translation of these materials into the clinic and ultimately lead to improved clinical outcomes.The Winston Churchill Foundation of the United State

Critical Review of Theoretical Models for Anomalous Effects (Cold Fusion) in Deuterated Metals

We briefly summarize the reported anomalous effects in deuterated metals at ambient temperature, commonly known as "Cold Fusion" (CF), with an emphasis on important experiments as well as the theoretical basis for the opposition to interpreting them as cold fusion. Then we critically examine more than 25 theoretical models for CF, including unusual nuclear and exotic chemical hypotheses. We conclude that they do not explain the data.Comment: 51 pages, 4 Figure

Study of mirtazapine for agitated behaviours in dementia (SYMBAD): a randomised, double-blind, placebo-controlled trial

BACKGROUND: Agitation is common in people with dementia and negatively affects the quality of life of both people with dementia and carers. Non-drug patient-centred care is the first-line treatment, but there is a need for other treatment when this care is not effective. Current evidence is sparse on safer and effective alternatives to antipsychotics. We assessed the efficacy and safety of mirtazapine, an antidepressant prescribed for agitation in dementia. METHODS: This parallel-group, double-blind, placebo-controlled trial-the Study of Mirtazapine for Agitated Behaviours in Dementia trial (SYMBAD)-was done in 26 UK centres. Participants had probable or possible Alzheimer's disease, agitation unresponsive to non-drug treatment, and a Cohen-Mansfield Agitation Inventory (CMAI) score of 45 or more. They were randomly assigned (1:1) to receive either mirtazapine (titrated to 45 mg) or placebo. The primary outcome was reduction in CMAI score at 12 weeks. This trial is registered with ClinicalTrials.gov, NCT03031184, and ISRCTN17411897. FINDINGS: Between Jan 26, 2017, and March 6, 2020, 204 participants were recruited and randomised. Mean CMAI scores at 12 weeks were not significantly different between participants receiving mirtazapine and participants receiving placebo (adjusted mean difference -1·74, 95% CI -7·17 to 3·69; p=0·53). The number of controls with adverse events (65 [64%] of 102 controls) was similar to that in the mirtazapine group (67 [66%] of 102 participants receiving mirtazapine). However, there were more deaths in the mirtazapine group (n=7) by week 16 than in the control group (n=1), with post-hoc analysis suggesting this difference was of marginal statistical significance (p=0·065). INTERPRETATION: This trial found no benefit of mirtazapine compared with placebo, and we observed a potentially higher mortality with use of mirtazapine. The data from this study do not support using mirtazapine as a treatment for agitation in dementia. FUNDING: UK National Institute for Health Research Health Technology Assessment Programme

Cost-effectiveness of mirtazapine for agitated behaviors in dementia: findings from a randomized controlled trial.

OBJECTIVES: To examine the costs and cost-effectiveness of mirtazapine compared to placebo over 12-week follow-up. DESIGN: Economic evaluation in a double-blind randomized controlled trial of mirtazapine vs. placebo. SETTING: Community settings and care homes in 26 UK centers. PARTICIPANTS: People with probable or possible Alzheimer's disease and agitation. MEASUREMENTS: Primary outcome included incremental cost of participants' health and social care per 6-point difference in CMAI score at 12 weeks. Secondary cost-utility analyses examined participants' and unpaid carers' gain in quality-adjusted life years (derived from EQ-5D-5L, DEMQOL-Proxy-U, and DEMQOL-U) from the health and social care and societal perspectives. RESULTS: One hundred and two participants were allocated to each group; 81 mirtazapine and 90 placebo participants completed a 12-week assessment (87 and 95, respectively, completed a 6-week assessment). Mirtazapine and placebo groups did not differ on mean CMAI scores or health and social care costs over the study period, before or after adjustment for center and living arrangement (independent living/care home). On the primary outcome, neither mirtazapine nor placebo could be considered a cost-effective strategy with a high level of confidence. Groups did not differ in terms of participant self- or proxy-rated or carer self-rated quality of life scores, health and social care or societal costs, before or after adjustment. CONCLUSIONS: On cost-effectiveness grounds, the use of mirtazapine cannot be recommended for agitated behaviors in people living with dementia. Effective and cost-effective medications for agitation in dementia remain to be identified in cases where non-pharmacological strategies for managing agitation have been unsuccessful

A pragmatic, multicentre, double-blind, placebo-controlled randomised trial to assess the safety, clinical and cost-effectiveness of mirtazapine and carbamazepine in people with Alzheimer’s disease and agitated behaviours: the HTA-SYMBAD trial

Background: Agitation is common and impacts negatively on people with dementia and carers. Non-drug patient-centred care is first-line treatment, but we need other treatment when this fails. Current evidence is sparse on safer and effective alternatives to antipsychotics. Objectives: To assess clinical and cost-effectiveness and safety of mirtazapine and carbamazepine in treating agitation in dementia. Design: Pragmatic, phase III, multicentre, double-blind, superiority, randomised, placebo-controlled trial of the clinical effectiveness of mirtazapine over 12 weeks (carbamazepine arm discontinued). Setting: Twenty-six UK secondary care centres. Participants: Eligibility: probable or possible Alzheimer’s disease, agitation unresponsive to non-drug treatment, Cohen-Mansfield Agitation Inventory score ≥ 45. Interventions: Mirtazapine (target 45 mg), carbamazepine (target 300 mg) and placebo. Outcome measures: Primary: Cohen-Mansfield Agitation Inventory score 12 weeks post randomisation. Main economic outcome evaluation: incremental cost per six-point difference in Cohen-Mansfield Agitation Inventory score at 12 weeks, from health and social care system perspective. Data from participants and informants at baseline, 6 and 12 weeks. Long-term follow-up Cohen-Mansfield Agitation Inventory data collected by telephone from informants at 6 and 12 months. Randomisation and blinding: Participants allocated 1: 1: 1 ratio (to discontinuation of the carbamazepine arm, 1: 1 thereafter) to receive placebo or carbamazepine or mirtazapine, with treatment as usual. Random allocation was block stratified by centre and residence type with random block lengths of three or six (after discontinuation of carbamazepine, two or four). Double-blind, with drug and placebo identically encapsulated. Referring clinicians, participants, trial management team and research workers who did assessments were masked to group allocation. Results: Two hundred and forty-four participants recruited and randomised (102 mirtazapine, 102 placebo, 40 carbamazepine). The carbamazepine arm was discontinued due to slow overall recruitment; carbamazepine/placebo analyses are therefore statistically underpowered and not detailed in the abstract. Mean difference placebo-mirtazapine (−1.74, 95% confidence interval −7.17 to 3.69; p = 0.53). Harms: The number of controls with adverse events (65/102, 64%) was similar to the mirtazapine group (67/102, 66%). However, there were more deaths in the mirtazapine group (n = 7) by week 16 than in the control group (n = 1). Post hoc analysis suggests this was of marginal statistical significance (p = 0.065); this difference did not persist at 6-and 12-month assessments. At 12 weeks, the costs of unpaid care by the dyadic carer were significantly higher in the mirtazapine than placebo group [difference: £1120 (95% confidence interval £56 to £2184)]. In the cost-effectiveness analyses, mean raw and adjusted outcome scores and costs of the complete cases samples showed no differences between groups. Limitations: Our study has four important potential limitations: (1) we dropped the proposed carbamazepine group; (2) the trial was not powered to investigate a mortality difference between the groups; (3) recruitment beyond February 2020, was constrained by the COVID-19 pandemic; and (4) generalisability is limited by recruitment of participants from old-age psychiatry services and care homes. Conclusions: The data suggest mirtazapine is not clinically or cost-effective (compared to placebo) for agitation in dementia. There is little reason to recommend mirtazapine for people with dementia with agitation. Future work: Effective and cost-effective management strategies for agitation in dementia are needed where non-pharmacological approaches are unsuccessful

Prevalence of Same-Sex Sexual Behavior and Associated Characteristics among Low-Income Urban Males in Peru

Peru has a concentrated HIV epidemic in which men who have sex with men are particularly vulnerable. We describe the lifetime prevalence of same-sex sexual contact and associated risk behaviors of men in Peru's general population, regardless of their sexual identity.A probability sample of males from low-income households in three Peruvian cities completed an epidemiologic survey addressing their sexual risk behavior, including sex with other men. Serum was tested for HSV-2, HIV, and syphilis. Urine was tested for chlamydia and gonorrhea. A total of 2,271 18-30 year old men and women were contacted, of whom 1,645 (72.4%) agreed to participate in the study. Among the sexually experienced men surveyed, 15.2% (85/558, 95% CI: 12.2%-18.2%) reported a history of sex with other men. Men ever reporting sex with men (MESM) had a lower educational level, had greater numbers of sex partners, and were more likely to engage in risk behaviors including unprotected sex with casual partners, paying for or providing compensated sex, and using illegal drugs. MESM were also more likely to have had previous STI symptoms or a prior STI diagnosis, and had a greater prevalence of HSV-2 seropositivity.Many low-income Peruvian men have engaged in same-sex sexual contact and maintain greater behavioral and biological risk factors for HIV/STI transmission than non-MESM. Improved surveillance strategies for HIV and STIs among MESM are necessary to better understand the epidemiology of HIV in Latin America and to prevent its further spread

Risk and clinical-outcome indicators of delirium in an emergency department intermediate care unit (EDIMCU) : an observational prospective study

We are thankful to the staff at the EDIMCU of Hospital de Braga.Background Identification of delirium in emergency departments (ED) is often underestimated; within EDs, studies on delirium assessment and relation with patient outcome in Intermediate Care Units (IMCU) appear missing in European hospital settings. Here we aimed to determine delirium prevalence in an EDIMCU (Hospital de Braga, Braga, Portugal) and assessed routine biochemical parameters that might be delirium indicators. Methods The study was prospective and observational. Sedation level was assessed via the Richmond Agitation-Sedation Scale and delirium status by the Confusion Assessment Method for the ICU. Information collected included age and gender, admission type, Charlson Comorbidity Index combined condition score (Charlson score), systemic inflammatory response syndrome criteria (SIRS), biochemical parameters (blood concentration of urea nitrogen, creatinine, hemoglobin, sodium and potassium, arterial blood gases, and other parameters as needed depending on clinical diagnosis) and EDIMCU length of stay (LOS). Statistical analyses were performed as appropriate to determine if baseline features differed between the ‘Delirium’ and ‘No Delirium’ groups. Multivariate logistic regression was performed to assess the effect of delirium on the 1-month outcome. Results Inclusion and exclusion criteria were met in 283 patients; 238 were evaluated at 1-month for outcome follow-up after EDIMCU discharge (“good” recovery without complications requiring hospitalization or institutionalization; “poor” institutionalization in permanent care-units/assisted-living or death). Delirium was diagnosed in 20.1% patients and was significantly associated with longer EDIMCU LOS. At admission, Delirium patients were significantly older and had significantly higher blood urea, creatinine and osmolarity levels and significantly lower hemoglobin levels, when compared with No Delirium patients. Delirium was an independent predictor of increased EDIMCU LOS (odds ratio 3.65, 95% CI 1.97-6.75) and poor outcome at 1-month after discharge (odds ratio 3.51, CI 1.84-6.70), adjusted for age, gender, admission type, presence of SIRS criteria, Charlson score and osmolarity at admission. Conclusions In an EDIMCU setting, delirium was associated with longer LOS and poor outcome at1-month post-discharge. Altogether, findings support the need for delirium screening and management in emergency settings.NCS is supported by the post-doctoral fellowship UMINHO/BPD/013/2011 by the European Commission (FP7) “SwitchBox” Project (Contract HEALTH-F2-2010-259772)