Feasibility and Safety of a Combined Metabolic Strategy in Glioblastoma Multiforme: A Prospective Case Series.

Background: Glioblastoma multiforme (GBM) may be susceptible to metabolic strategies such as fasting and ketogenic diets, which lower blood glucose and elevate ketones. Combining these two strategies may be an ideal approach for sustaining a potentially therapeutic glucose ketone index (GKI). In this prospective case series, we observed whether a combined metabolic strategy was feasible, safe, and capable of sustaining a GKI <6 in patients with GBM. Methods: We provided recommendations and guidelines to 10 GBM patients at various stages of tumour progression and treatment that enabled them to complete a 5-7-day fast every 1-2 months combined with a modified ketogenic diet during the intervening weeks. Patients monitored their blood glucose and ketone levels and body weight. Adverse effects were assessed. Results: Patients completed a mean of 161 ± 74 days of the combined metabolic strategy, with 34 ± 18 (21%) days of prolonged fasting (mean fast duration: 6.0 ± 1.4 days) and 127 ± 59 (79%) days on the ketogenic diet. The mean GKI for all 10 patients was 3.22 (1.28 during the fasts, 5.10 during the ketogenic diet). Body weight decreased by 8.4 ± 6.9 kg (11.2% decrease in baseline weight). The most common adverse effects attributed to the fasts and ketogenic diet were fatigue, irritability, and feeling lightheaded. The metabolic strategy did not interfere with standard oncological treatments. Conclusion: This is the first study to observe the feasibility and safety of repeated, prolonged fasting combined with a modified ketogenic diet in patients with GBM. Using minimal support, patients maintained the combined metabolic strategy for 5-6 months while sustaining a potentially therapeutic mean GKI of 3.22. Weight loss was considerable. Adverse effects attributed to the metabolic strategy were mild, and it did not interfere with standard oncological treatments. Study Registration: This study is registered on the Australia New Zealand Clinical Trials Registry, number ACTRN12620001310954. The study was registered on 4 December 2020.

Sociodemographic disparities in non-diabetic hyperglycaemia and the transition to type 2 diabetes: evidence from the English Longitudinal Study of Ageing.

AIM: To explore whether there are social inequalities in non-diabetic hyperglycaemia (NDH) and in transitions to type 2 diabetes mellitus and NDH low-risk status in England. METHODS: Some 9143 men and women aged over 50 years were analysed from waves 2, 4, 6 and 8 (2004-2016) of the English Longitudinal Study of Ageing (ELSA). Participants were categorized as: NDH 'low-risk' [HbA1c < 42 mmol/mol (< 6.0%)], NDH [HbA1c 42-47 mmol/mol (6.0-6.4%)] and type 2 diabetes [HbA1c > 47 mmol/mol (> 6.4%)]. Logistic regression models estimated the association between sociodemographic characteristics and NDH, and the transitions from NDH to diagnosed or undiagnosed type 2 diabetes and low-risk status in future waves. RESULTS: NDH was more prevalent in older participants, those reporting a disability, those living in deprived areas and in more disadvantaged social classes. Older participants with NDH were less likely to progress to undiagnosed type 2 diabetes [odds ratio (OR) 0.27, 95% confidence interval (CI) 0.08, 0.96]. NDH individuals with limiting long-standing illness (OR 1.72, 95% CI 1.16, 2.53), who were economically inactive (OR 1.60, 95% CI 1.02, 2.51) or from disadvantaged social classes (OR 1.63, 95% CI 1.02, 2.61) were more likely to progress to type 2 diabetes. Socially disadvantaged individuals were less likely (OR 0.64, 95% CI 0.41, 0.98) to progress to NDH low-risk status. CONCLUSIONS: There were socio-economic differences in NDH prevalence, transition to type 2 diabetes and transition to NDH low-risk status. Disparities in transitions included the greater likelihood of disadvantaged social groups with NDH developing type 2 diabetes and greater likelihood of advantaged social groups with NDH becoming low-risk. These socio-economic differences should be taken into account when targeting prevention initiatives.

An introduction to the methods of decision-analytic modelling used in economic evaluations for Dermatologists.

Economic evaluations are used to identify which health treatments or preventions offer the most effective use of resources, or value for money. This is achieved by identifying, measuring and valuing the inputs and outcomes of alternative interventions. These evaluations are often conducted alongside clinical trials; however, these trials may end before the outcomes of economic interest have been observed and measured. An alternative to within trial economic evaluation is to use decision modelling, which can model the cost-effectiveness of interventions over an extended time period. This paper aims to provide an overview for clinicians of the different modelling techniques used within health economic evaluations and to introduce methods for critical appraisal. The most common modelling approaches, and their associated strengths and weaknesses, were discussed. Alongside this, practical examples specific to dermatology were given. These examples include studies where the model chosen or the methods used may not have been the most appropriate. Methods for critical appraisal were also highlighted. Common modelling approaches include Decision Trees, Markov Cohort, extensions to the Markov model (Monte Carlo Simulation) and Discrete Event Simulation models. Items of the Philips Checklist were discussed in the context of performing critical appraisal. Health economic decision models are multi-faceted and can often be complex. Full critical appraisal requires clinicians' unique knowledge, which is complementary to the knowledge of health economists.

Understanding economic evidence for the prevention and treatment of atopic eczema.

BACKGROUND: Atopic eczema is an inflammatory skin condition, with a similar impact on health-related quality of life as other chronic diseases. Increasing pressures on resources within the National Health Service increase the importance of having good economic evidence to inform their allocation. OBJECTIVES: To educate dermatologists about economic methods with reference to currently available economic evidence on eczema. METHODS: The role of different types of economic evidence is illustrated by evidence found in a systematic literature search conducted across 12 online databases up to 22 May 2017. Primary empirical studies either reporting the results of a cost-of-illness study or evaluating the cost, utility or full economic evaluation of interventions for preventing or treating eczema were included. Two reviewers independently assessed studies for eligibility and performed data abstraction, with disagreements resolved by a third reviewer. Evidence tables of results were produced for narrative discussion. The reporting quality of economic evaluations was assessed. RESULTS: Seventy-eight studies (described in 80 papers) were deemed eligible. Thirty-three (42%) were judged to be economic evaluations, 12 (15%) cost analyses, six (8%) utility analyses, 26 (33%) cost-of-illness studies and one a feasibility study (1%). The calcineurin inhibitors tacrolimus and pimecrolimus, as well as barrier creams, had the most economic evidence available. Partially hydrolysed infant formula was the most commonly evaluated prevention. CONCLUSIONS: The current level of economic evidence for interventions aimed at preventing and treating eczema is limited compared with that available for clinical outcomes, suggesting that greater collaboration between clinicians and economists might be beneficial.

The use of interferon beta in relapsing-remitting multiple sclerosis.

The use of interferon beta-1a to treat multiple sclerosis in a child of 7 years of age is discussed. To date, there is only one other published report of the use of interferon beta in a child as young as this. One year after commencing treatment she had shown significant clinical improvement, with a marked reduction in number of relapses. In her second year of treatment she suffered a major relapse from which she slowly recovered.

1,4-Disubstituted imidazoles are potential antibacterial agents functioning as inhibitors of enoyl acyl carrier protein reductase (FabI).

1,4-Disubstituted imidazole inhibitors of Staphylococcus aureus and Escherichia coli enoyl acyl carrier protein reductase (FabI) have been identified. Crystal structure data shows the inhibitor 1 bound in the enzyme active site of E. coli FabI.

Reducing the risk of major elective surgery: randomised controlled trial of preoperative optimisation of oxygen delivery.

OBJECTIVES: To determine whether preoperative optimisation of oxygen delivery improves outcome after major elective surgery, and to determine whether the inotropes, adrenaline and dopexamine, used to enhance oxygen delivery influence outcome. DESIGN: Randomised controlled trial with double blinding between inotrope groups. SETTING: York District Hospital, England. SUBJECTS: 138 patients undergoing major elective surgery who were at risk of developing postoperative complications either because of the surgery or the presence of coexistent medical conditions. INTERVENTIONS: Patients were randomised into three groups. Two groups received invasive haemodynamic monitoring, fluid, and either adrenaline or dopexamine to increase oxygen delivery. Inotropic support was continued during surgery and for at least 12 hours afterwards. The third group (control) received routine perioperative care. MAIN OUTCOME MEASURES: Hospital mortality and morbidity. RESULTS: Overall, 3/92 (3%) preoptimised patients died compared with 8/46 controls (17%) (P=0.007). There were no differences in mortality between the treatment groups, but 14/46 (30%) patients in the dopexamine group developed complications compared with 24/46 (52%) patients in the adrenaline group (difference 22%, 95% confidence interval 2% to 41%) and 28 patients (61%) in the control group (31%, 11% to 50%). The use of dopexamine was associated with a decreased length of stay in hospital. CONCLUSION: Routine preoperative optimisation of patients undergoing major elective surgery would be a significant and cost effective improvement in perioperative care.

Freedom to enjoy learning in the 21st century: developing an active learning culture in nursing.

In 1994, the Wolfson School of Health Sciences was created in Thames Valley University, UK. This paper discusses an active learning approach being implemented throughout the university, and gives an outline of its application within nursing education. Practising as a confident, competent, reflective practitioner in the profession of nursing cannot automatically commence on the day of registration. Rather, the philosophical underpinnings necessary should be fostered throughout the initial nursing education curricula. In a political climate where there is a strong emphasis on efficiency, nurse teachers need to reconsider how the acquisition of nursing knowledge is facilitated. A description of how an active learning approach is being further developed in the nursing skills laboratory and the physiology laboratory is given. An outline identifies how these facilities may help students of nursing to gain knowledge and skills in relation to respiration. The authors recognize that while laboratories have been used widely in general education, their use has been limited in nursing education, particularly in the UK. Informal feedback from students implies that not only do they enjoy learning in these facilities, but also motivation towards learning is raised, an important element in the learning process. It is suggested that this will result ultimately in increased nursing competence. The authors acknowledge that these are preliminary informal findings and that formal investigation is required.

Health promotion and social support for community-based clients with chronic mental illness.

The purpose of this study was to determine the health promotion practices and life styles of 35 chronically mentally ill clients who resided in four group homes in a medium-sized southern community. Supervision in these homes ranged from full supervision to none. The Pender Health Promotion and Lifestyle Instrument (HPLP), the Duke-University of North Carolina Functional Support Questionnaire, and the Hollingshead Four Factor Index of Social Status were used. The Pender instrument had internal consistency scores that ranged from .92 for health promotion and lifestyle scale to .70 for the stress management subscale. Several findings emerged. The total scores were low for this sample on the HPLP and the six subscales: nutrition, exercise, health responsibility, stress management, internal support, and self-actualization. There were strong positive correlations between social interaction and age, father's education, and HPLP.

Overwhelming pulmonary blastomycosis associated with the adult respiratory distress syndrome.

BACKGROUND AND METHODS: Few cases of overwhelming pulmonary blastomycosis associated with the adult respiratory distress syndrome have been reported. We describe 10 patients with this condition who were treated at one center in Wisconsin. RESULTS: All 10 patients presented with fever, cough, and dyspnea; radiographic evidence of diffuse pulmonary infiltrates; and marked impairment of oxygenation. The mean alveolar-arterial oxygen gradient was 616 mm Hg. Six of the patients had no underlying disease associated with altered immunity, and two had no recent exposure to environmental reservoirs of Blastomyces dermatitidis. In all 10 patients, large numbers of broad-based budding yeasts were seen on microscopical examination of tracheal secretions. All patients were treated with intravenous amphotericin B (0.7 to 1.0 mg per kilogram per day). Of the five survivors, four received full doses of amphotericin B in the first 24 hours, and four required mechanical ventilatory support for 7 to 151 days. Long-term follow-up of three survivors showed good recovery of pulmonary function. CONCLUSIONS: Overwhelming infection with B. dermatitidis can cause diffuse pneumonitis and the adult respiratory distress syndrome, even in immunocompetent hosts. With prompt diagnosis by microscopical examination of tracheal secretions, intensive therapy with amphotericin B, and ventilatory support, good recovery of pulmonary function is possible.

Continuing education in state hospitals using external consultants.

A continuing education project for registered nurses in a state psychiatric hospital was implemented collaboratively by a nurse administrator and two nurse consultants. This program sought to enhance the nurses' knowledge of psychiatric-mental health nursing practice and prepare them to take the American Nurses Association certification examination for psychiatric-mental health nursing. The project was based on the premise that the nursing departments that offer educational services for their nurses foster professional competency and maintain current standards of nursing care. Twenty-one registered nurses volunteered for and completed the 16-week program. Improvements in their knowledge base were evidenced by mean test scores. A t-test analysis indicated a significant difference. The pretest mean score was 70.2%, the posttest mean score 79.4%. Mean scores varied with the education level of the nurses.

Treatment of murine candidosis and cryptococcosis with a unilamellar liposomal amphotericin B formulation (AmBisome).

This investigation examined the therapeutic efficacy of AmBisome, a unilamellar (55-75 nm) liposome amphotericin B preparation with a murine LD50 by the intravenous route of greater than 175 mg/kg amphotericin B. Both fungal burden and survival were used to evaluate the drug's efficacy against murine candidosis and cryptococcosis. Single and multiple dose intravenous treatment with AmBisome (2.5, 5.0 and 10.0 mg/kg) reduced the colony forming units/mg kidney in candida-infected mice by 99% and improved survival by at least 40% relative to untreated control mice. Repeated intravenous dosing of candida-infected mice with equivalent amounts (0.75 mg/kg) of conventional amphotericin B (Fungizone) or AmBisome showed comparable reduction of yeasts in the kidneys. When mice were infected systemically with Cryptococcus neoformans, all but one of the 30 mice given AmBisome (5.0, 7.5 or 10.0 mg/kg) survived until the experiment was terminated 35 days after infection. Liver and spleen cultures from AmBisome-treated mice were negative for fungal growth. All the mice given conventional amphotericin B intraperitoneally at 4.5 mg/kg survived and cleared the infection from the livers although some of the mice had infected spleens. The percentage of cultured brains free of cryptococcus was 89% following treatment with 10.0 mg/kg AmBisome, and 80% with 4.5 mg/kg conventional drug. These preclinical studies of systemic candidosis and cryptococcosis demonstrate comparable efficacy of AmBisome and conventional amphotericin B at low doses and improved efficacy with AmBisome at doses higher than can be safely administered of the conventional drug.

Comparative safety, tolerance, and pharmacokinetics of amphotericin B lipid complex and amphotericin B desoxycholate in healthy male volunteers.

Amphotericin B lipid complex (ABLC), a lipid complex formulation of amphotericin B, and amphotericin B desoxycholate (AB) were compared for safety, tolerance, and pharmacokinetics in two groups of eight healthy male volunteers. After a 1-mg test dose, study drug was infused at 0.1, 0.25, and 0.5 mg/kg; the 0.5-mg/kg dose was not given to subjects receiving AB. ABLC caused few acute adverse effects except for mild somnolence (drowsiness) in six volunteers. In addition, three of eight ABLC recipient had asymptomatic, transient serum transaminase elevations that resolved spontaneously. The AB recipients experienced more acute side effects, but only one had a mild shaking chill: three of eight also experienced sleepiness. No significant changes in vital signs, electrocardiogram, oximetry, pulmonary function, or clinical status were observed in either group. Due to its increased estimate volume of distribution and estimated clearance. ABLC yielded decreased amphotericin B levels and area under the serum concentration versus time curve relative to AB.

In vitro tumor necrosis factor induction assay for analysis of febrile toxicity associated with amphotericin B preparations.

Amphotericin B can stimulate macrophages to produce tumor necrosis factor alpha (TNF alpha), one of the inflammatory mediators that may be responsible for the febrile toxicity associated with drug administration. The purpose of this study was to compare the in vitro TNF-inducing activity of one recalled lot of an amphotericin B preparation which was associated with more frequent febrile reactions in patients with a preparation not associated with a greater incidence of febrile reaction. We found that the former preparation induced significantly more TNF than the latter preparation, and the in vitro data correlated with the results of rabbit pyrogen testing. The in vitro TNF induction assay may serve as a screening tool for the selection of the least pyrogenic lots of amphotericin B preparation.

Decision making and work loads as predictors of student nurses' health status.

This study was conceived as a means of exploring the factors that could contribute to student nurses' burnout with their educational programs. Current literature mainly addresses this process in terms of the experience of registered nurses. This descriptive study sought to determine the relationships between nursing students' latitude in academic decision making and school work load demands and their effects on the students' health status. Thirty-four female, second-quarter senior nursing students completed a written tool, adapted from one developed by Karasek. Data analysis revealed that for this study, alterations in the nursing students' health status could be predicted from the independent variables, latitude in academic decision making, and school work load demand.

The use of ketoconazole in the treatment of blastomycosis.

We retrospectively reviewed our experience using ketoconazole in the therapy of blastomycosis. Over the course of 30 months, blastomycosis was diagnosed in 11 patients. Their clinical presentations ranged from the asymptomatic pulmonary nodule to the adult respiratory distress syndrome. Six of 8 patients treated with ketoconazole completed a 6-month course of 400 mg daily. Seventeen to 40 months after completion of therapy, the patients who had completed 6 months of therapy were well. Ketoconazole should play a major role in the therapy of blastomycosis because of its efficacy and because its administrative costs are lower than those of amphotericin B. It can be recommended for patients who have been symptomatic for longer than 3 wk and are not improving and for those who undergo resection of an asymptomatic pulmonary nodule. Amphotericin B remains the drug of choice in patients with life-threatening illness who require ventilatory assistance, have developed renal failure, or have central nervous system involvement. Severely immunocompromised patients with disseminated disease should also be treated with amphotericin B. Patients treated with ketoconazole should have close medical follow-up.