Selective anti-malarial minor groove binders

A set of 31 DNA minor groove binders (MGBs) with diverse structural features relating to both physical chemical properties and DNA binding sequence preference has been evaluated as potential drugs to treat Plasmodium falciparum infections using a chloroquine sensitive strain (3D7) and a chloroquine resistant strain (Dd2) in comparison with human embryonic kidney (HEK) cells as an indicator of mammalian cell toxicity. MGBs with an alkene link between the two N-terminal building blocks were demonstrated to be most active with IC50 values in the range 30–500 nM and therapeutic ratios in the range 10–>500. Many active compounds contained a C-alkylthiazole building block. Active compounds with log D7.4 values of approximately 3 or 7 were identified. Importantly the MGBs tested were essentially equally effective against both chloroquine sensitive and resistant strains. The results show that suitably designed MGBs have the potential for development into clinical candidates for antimalarial drugs effective against resistant strains of Plasmodia

Bioactivities of extracts, debromolaurinterol and fucosterol from macroalgae species

Parasitic diseases including malaria, and other numerous microbial infections and physiological diseases are threatening the global population. Tanzanian coast shores are endowed with a variety of macroalgae (seaweeds), hitherto unsystematically explored to establish their biomedical potentials. Thus, antiplasmodial activity using malarial imaging assay, antimicrobial activity using microplate dilution technique, antioxidant activity using DPPH radical scavenging method and cytotoxicity using brine shrimp test were carried out on crude extracts from the selected species of algae (Acanthophora spicifera, Cystoseira myrica, Cystoseira trinodis, Laurencia filiformis, Padina boryana, Sargassum oligocystum, Turbinaria crateriformis, Ulva fasciata and Ulva reticulata) occurring along the coast of Tanzania. The extracts showed antimicrobial activities with MIC ranging from 0.3- 5.0 µg/mL against Staphylococcus aureus, Streptococcus pyogenes, Pseudomonas aeruginosa, Escherichia coli, Candida albicans and Cryptococcus neoformans; DPPH radical scavenging activity at EC50 1.0- 100 µg/mL and cytotoxicity on brine shrimp larvae with LC50 value ranging from20 - 1000 µg/mL. The extracts from C. myrica and P. boryana inhibited growth of Plasmodium falciparum (3D7 strain) by 80 and 71%, respectively at 40 µg/mL while a sesquiterpene debromolaurinterol (1) which was chromatographically isolated from C. myrica exhibited antiplasmodial activity with IC50 20 µM whereas a sterol fucosterol (2) from P. boryana showed weak activity at 40 µM. Bioactivities portrayed by the investigated extracts indicate their ingredients as potential sources of bioactive agents that warrant further explorations.Keywords:     Macrolgae, antiplasmodial, antimicrobial, antioxidant, cytotoxicity, DPPH radical scavenging, debromolaurinterol and fucosterol

Web-based patient-reported outcome measures for personalized treatment and care (PROMPT-Care) : multicenter pragmatic nonrandomized trial

Background: Despite the acceptability and efficacy of e–patient-reported outcome (ePRO) systems, implementation in routine clinical care remains challenging. Objective: This pragmatic trial implemented the PROMPT-Care (Patient Reported Outcome Measures for Personalized Treatment and Care) web-based system into existing clinical workflows and evaluated its effectiveness among a diverse population of patients with cancer. Methods: Adult patients with solid tumors receiving active treatment or follow-up care in four cancer centers were enrolled. The PROMPT-Care intervention supported patient management through (1) monthly off-site electronic PRO physical symptom and psychosocial well-being assessments, (2) automated electronic clinical alerts notifying the care team of unresolved clinical issues following two consecutive assessments, and (3) tailored online patient self-management resources. Propensity score matching was used to match controls with intervention patients in a 4:1 ratio for patient age, sex, and treatment status. The primary outcome was a reduction in emergency department presentations. Secondary outcomes were time spent on chemotherapy and the number of allied health service referrals. Results: From April 2016 to October 2018, 328 patients from four public hospitals received the intervention. Matched controls (n=1312) comprised the general population of patients with cancer, seen at the participating hospitals during the study period. Emergency department visits were significantly reduced by 33% (P=.02) among patients receiving the intervention compared with patients in the matched controls. No significant associations were found in allied health referrals or time to end of chemotherapy. At baseline, the most common patient reported outcomes (above-threshold) were fatigue (39%), tiredness (38.4%), worry (32.9%), general wellbeing (32.9%), and sleep (24.1%), aligning with the most frequently accessed self-management domain pages of physical well-being (36%) and emotional well-being (23%). The majority of clinical feedback reports were reviewed by nursing staff (729/893, 82%), largely in response to the automated clinical alerts (n=877). Conclusions: Algorithm-supported web-based systems utilizing patient reported outcomes in clinical practice reduced emergency department presentations among a diverse population of patients with cancer. This study also highlighted the importance of (1) automated triggers for reviewing above-threshold results in patient reports, rather than passive manual review of patient records; (2) the instrumental role nurses play in managing alerts; and (3) providing patients with resources to support guided self-management, where appropriate. Together, these factors will inform the integration of web-based PRO systems into future models of routine cancer care

Direct to public peer support and e-therapy program versus information to aid self-management of depression and anxiety: protocol for a randomized controlled trial

Regardless of geography or income, effective help for depression and anxiety only reaches a small proportion of those who might benefit from it. The scale of the problem suggests a role for effective, safe, anonymised public health driven online services such as Big White Wall which offers immediate peer support at low cost. Objectives: Using RE-AIM methodology we will aim to determine the population reach, effectiveness, cost effectiveness, and barriers and drivers to implementation of Big White Wall (BWW) compared to online information compiled by the UK’s National Health Service (NHS Choices Moodzone) in people with probable mild to moderate depression and anxiety disorder. Method/Design: A pragmatic, parallel group, single blind RCT is being conducted using a fully automated trial website in which eligible participants are randomised to receive either 6 months access to BWW or signposted to the NHS Moodzone site. The recruitment of 2200 people to the study will be facilitated by a public health engagement campaign involving general marketing and social media, primary care clinical champions, healthcare staff, large employers and third sector groups. People will refer themselves to the study and will be eligible if they are over 16 years, have probable mild to moderate depression or anxiety disorders and have access to the internet. The primary outcome will be the Warwick-Edinburgh Mental Well-being Scale at six weeks. We will also explore the reach, maintenance, cost-effectiveness, barriers and drivers to implementation and possible mechanisms of actions using a range of qualitative and quantitative methods. Discussion: This will be the first fully digital trial of a direct to public on line peer support programme for common mental disorders. The potential advantages of adding this to current NHS mental health services and the challenges of designing a public health campaign and randomised controlled trial of two digital interventions using a fully automated digital enrolment and data collection process are considered for people with depression and anxiety

Repositioning: the fast track to new anti-malarial medicines?

Repositioning of existing drugs has been suggested as a fast track for developing new anti-malarial agents. The compound libraries of GlaxoSmithKline (GSK), Pfizer and AstraZeneca (AZ) comprising drugs that have undergone clinical studies in other therapeutic areas, but not achieved approval, and a set of US Food and Drug Administration (FDA)-approved drugs and other bio-actives were tested against Plasmodium falciparum blood stages. Repositioning of existing therapeutics in malaria is an attractive proposal. Compounds active in vitro at muM concentrations were identified. However, therapeutic concentrations may not be effectively achieved in mice or humans because of poor bio-availability and/or safety concerns. Stringent safety requirements for anti-malarial drugs, given their widespread use in children, make this a challenging area in which to reposition therapy.This work was supported by the Medicines Malaria Venture, St Jude Children's Research Hospital, GlaxoSmithKline Plc and Pfizer Inc

An evaluation of Minor Groove Binders as anti- Trypanosoma brucei brucei therapeutics

A series of 32 structurally diverse MGBs, derived from the natural product distamycin, was evaluated for activity against Trypanosoma brucei brucei. Four compounds have been found to possess significant activity, in the nanomolar range, and represent hits for further optimisation towards novel treatments for Human and Animal African Trypanosomiases. Moreover, SAR indicates that the head group linking moiety is a significant modulator of biological activit

Hips Can Lie: Impact of Excluding Isolated Hip Fractures on External Benchmarking of Trauma Center Performance

BACKGROUND: Trauma centers (TCs) vary in the inclusion of patients with isolated hip fractures (IHFs) in their registries. This inconsistent case ascertainment may have significant implications on the assessment of TC performance and external benchmarking efforts. METHODS: Data were derived from the National Trauma Data Bank (2007-8.1). We included patients (aged 16 years or older) with Injury Severity Score value ≥ 9 who were admitted to Level I and II TCs. To ensure data quality, we limited the study to TC that routinely reported comorbidities and Abbreviated Injury Scale codes. IHF were defined as patients, aged 65 years or older, injured as a result of falls, with Abbreviated Injury Scale codes for hip fracture and without other significant injuries. TCs were stratified according to their reported inclusion of IHF in their registry. Observed-to-expected mortality ratios were used to rank TC performance first with and then, without the inclusion of patients with IHF. RESULTS: In total, 91,152 patients in 132 TCs were identified; 5% (n = 4,448) were IHF. The proportion of IHF per TC varied significantly, ranging from 0% to 31%. When risk-adjusted mortality was evaluated, excluding patients with IHF had significant effects: 37% (n = 49) of TCs changed their performance rank by ≥ 3 (range, 1-25) and 12% of centers changed their performance quintile. The greatest change in rank performance was evident in centers that routinely include IHF in their registries. CONCLUSIONS: Given the fact that IHFs in the elderly significantly influence risk-adjusted outcomes and are variably reported by TCs, these patients should be excluded from subsequent benchmarking efforts

Genre, Methodology and Feminist Practice

The rainy season is not quite over although it has nearly spent itself. I drive leisurely along five miles of roller coaster highway, down and up, up and down again as I drink in the grandeur of the sunset. I come to the 'big hill', around and over which the road twines narrowly. From its summit I see at my left a deep purple canyon, green at the bottom with irrigated fields. At my right the sun is setting across a wide valley, the shadows replaced by roseate gold interrupted by the white resplendence of chalk cliffs. As if this were not sufficient, a light female rain like that which falls constantly over the home of the Corn gods, drops between me and the sun. I gasp in my inability to comprehend the sight fully as I turn my head forty-five degrees to behold a complete rainbow and behind it the thinnest slice of a new moon. (Gladys Reichard, 1934:122)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68113/2/10.1177_0308275X9301300405.pd