Research evaluating the effectiveness of dementia interventions in low- and middle-income countries: A systematic mapping of 340 randomised controlled trials.

OBJECTIVES: More people with dementia live in low- and middle-income countries (LMICs) than in high-income countries, but best-practice care recommendations are often based on studies from high-income countries. We aimed to map the available evidence on dementia interventions in LMICs. METHODS: We systematically mapped available evidence on interventions that aimed to improve the lives of people with dementia or mild cognitive impairment (MCI) and/or their carers in LMICs (registered on PROSPERO: CRD42018106206). We included randomised controlled trials (RCTs) published between 2008 and 2018. We searched 11 electronic academic and grey literature databases (MEDLINE, EMBASE, PsycINFO, CINAHL Plus, Global Health, World Health Organization Global Index Medicus, Virtual Health Library, Cochrane CENTRAL, Social Care Online, BASE, MODEM Toolkit) and examined the number and characteristics of RCTs according to intervention type. We used the Cochrane risk of bias 2.0 tool to assess the risk of bias. RESULTS: We included 340 RCTs with 29,882 (median, 68) participants, published 2008-2018. Over two-thirds of the studies were conducted in China (n = 237, 69.7%). Ten LMICs accounted for 95.9% of included RCTs. The largest category of interventions was Traditional Chinese Medicine (n = 149, 43.8%), followed by Western medicine pharmaceuticals (n = 109, 32.1%), supplements (n = 43, 12.6%), and structured therapeutic psychosocial interventions (n = 37, 10.9%). Overall risk of bias was judged to be high for 201 RCTs (59.1%), moderate for 136 (40.0%), and low for 3 (0.9%). CONCLUSIONS: Evidence-generation on interventions for people with dementia or MCI and/or their carers in LMICs is concentrated in just a few countries, with no RCTs reported in the vast majority of LMICs. The body of evidence is skewed towards selected interventions and overall subject to high risk of bias. There is a need for a more coordinated approach to robust evidence-generation for LMICs.

Prescription and Usage Pattern of Topical Corticosteroids among Out-patient Attendees with Dermatophyte Infections and Its Analysis: A Cross-sectional, Survey-based Study.

BACKGROUND: There is scarce scientific data on topical corticosteroids (TCS) prescription by non-dermatologists including registered medical practitioners, ayurvedic, homeopathic practitioners, and over-the-counter (OTC) use of TCS-containing creams. OBJECTIVE: The main objective of this study is to analyze the prescription and usage pattern of topical steroids among out-patient attendees with dermatophyte infection. To study health-seeking behavior of patients with dermatophyte infections. MATERIAL AND METHODS: An open, cross-sectional, duration-based study of 3 months. Inclusion criteria: Patients with dermatophytosis having a history of topical steroid application; either prescribed or purchased OTC and used themselves. Exclusion criteria: Patients who were not willing to give informed consent. Patient's data like socio-demographic profile, duration, frequency, site of application, contents of the topical cream used, prescriber information, and patients' desire to continue the use of topical steroids were recorded. RESULTS: Total of 18.40% (n = 503) patients were already using cream-containing TCS at the time of presentation to the tertiary dermatology care center. The study shows that almost half of the patients (48.90%) were using unprescribed TCS. Registered medical practitioners were the most common source of TCS creams prescription (59.92%) in the prescribed group, while 26.07% patients were prescribed TCS by dermatologists. Clobetasol propionate (47.91%), was most common steroid agent used. CONCLUSION: Patients are able to get "prescription-only" drugs as OTC products. Such OTC use of TCS puts patients at risk of steroid modified dermatophytosis and topical steroid damaged skin. Even dermatologists may be culprit in creating menace of steroid abuse.

Advantages of crystallographic fragment screening: functional and mechanistic insights from a powerful platform for efficient drug discovery.

X-ray crystallography has been an under-appreciated screening tool for fragment-based drug discovery due to the perception of low throughput and technical difficulty. Investigators in industry and academia have overcome these challenges by taking advantage of key factors that contribute to a successful crystallographic screening campaign. Efficient cocktail design and soaking methodologies have evolved to maximize throughput while minimizing false positives/negatives. In addition, technical improvements at synchrotron beamlines have dramatically increased data collection rates thus enabling screening on a timescale comparable to other techniques. The combination of available resources and efficient experimental design has resulted in many successful crystallographic screening campaigns. The three-dimensional crystal structure of the bound fragment complexed to its target, a direct result of the screening effort, enables structure-based drug design while revealing insights regarding protein dynamics and function not readily obtained through other experimental approaches. Furthermore, this "chemical interrogation" of the target protein crystals can lead to the identification of useful reagents for improving diffraction resolution or compound solubility.

Crystallographic fragment screening and structure-based optimization yields a new class of influenza endonuclease inhibitors.

Seasonal and pandemic influenza viruses continue to be a leading global health concern. Emerging resistance to the current drugs and the variable efficacy of vaccines underscore the need for developing new flu drugs that will be broadly effective against wild-type and drug-resistant influenza strains. Here, we report the discovery and development of a class of inhibitors targeting the cap-snatching endonuclease activity of the viral polymerase. A high-resolution crystal form of pandemic 2009 H1N1 influenza polymerase acidic protein N-terminal endonuclease domain (PAN) was engineered and used for fragment screening leading to the identification of new chemical scaffolds binding to the PAN active site cleft. During the course of screening, binding of a third metal ion that is potentially relevant to endonuclease activity was detected in the active site cleft of PAN in the presence of a fragment. Using structure-based optimization, we developed a highly potent hydroxypyridinone series of compounds from a fragment hit that defines a new mode of chelation to the active site metal ions. A compound from the series demonstrating promising enzymatic inhibition in a fluorescence-based enzyme assay with an IC50 value of 11 nM was found to have an antiviral activity (EC50) of 11 µM against PR8 H1N1 influenza A in MDCK cells.