Quantifying uncertainty in intervention effectiveness with structured expert judgement : an application to obstetric fistula

To demonstrate a new application of structured expert judgement to assess the effectiveness of surgery to correct obstetric fistula in a low-income setting. Intervention effectiveness is a major input of evidence-informed priority setting in healthcare, but information on intervention effectiveness is generally lacking. This is particularly problematic in the context of poorly resourced healthcare settings where even efficacious interventions fail to translate into improvements in health. The few intervention effectiveness studies related to obstetric fistula treatment focus on the experience of single facilities and do not consider the impact of multiple factors that may affect health outcomes. We use the classical model of structured expert judgement, a method that has been used to quantify uncertainty in the areas of engineering and environmental risk assessment when data are unavailable. Under this method, experts quantify their uncertainty about rates of long-term disability in patients with fistula following treatment in different contexts, but the information content drawn from their responses is statistically conditioned on the accuracy and informativeness of their responses to a set of calibration questions. Through this method, we develop best estimates and uncertainty bounds for the rate of disability associated with each treatment scenario and setting. Eight experts in obstetric fistula repair in low and middle income countries. Estimates developed using performance weights were statistically superior to those involving a simple averaging of expert responses. The performance-weight decision maker's assessments are narrower for 9 of the 10 calibration questions and 21 of 23 variables of interest. We find that structured expert judgement is a viable approach to investigating the effectiveness of medical interventions where randomised controlled trials are not possible. Understanding the effectiveness of surgery performed at different types of facilities can guide programme planning to increase access to fistula treatment

Design and synthesis of diazine-based panobinostat analogues for HDAC8 inhibition

© 2020 Balasubramaniam et al. Guided by computational analysis, herein we report the design, synthesis and evaluation of four novel diazine-based histone deacetylase inhibitors (HDACis). The targets of interest (TOI) are analogues of panobinostat, one of the most potent and versatile HDACi reported. By simply replacing the phenyl core of panobinostat with that of a diazine derivative, docking studies against HDAC2 and HDAC8 revealed that the four analogues exhibit inhibition activities comparable to that of panobinostat. Multistep syntheses afforded the visualized targets TOI1, TOI2, TOI3-rev and TOI4 whose biological evaluation confirmed the strength of HDAC8 inhibition with TOI4 displaying the greatest efficacy at varying concentrations. The results of this study lay the foundation for future design strategies toward more potent HDACis for HDAC8 isozymes and further therapeutic applications for neuroblastoma

How Can the Health System Retain Women in HIV Treatment for a Lifetime? A Discrete Choice Experiment in Ethiopia and Mozambique

Introduction: Option B+, an approach that involves provision of antiretroviral therapy (ART) to all HIV-infected pregnant women for life, is the preferred strategy for prevention of mother to child transmission of HIV. Lifelong retention in care is essential to its success. We conducted a discrete choice experiment in Ethiopia and Mozambique to identify health system characteristics preferred by HIV-infected women to promote continuity of care. Methods: Women living with HIV and receiving care at hospitals in Oromia Region, Ethiopia and Zambézia Province, Mozambique were shown nine choice cards and asked to select one of two hypothetical health facilities, each with six varying characteristics related to the delivery of HIV services for long term treatment. Mixed logit models were used to estimate the influence of six health service attributes on choice of clinics. Results: 2,033 women participated in the study (response rate 97.8% in Ethiopia and 94.7% in Mozambique). Among the various attributes of structure and content of lifelong ART services, the most important attributes identified in both countries were respectful provider attitude and ability to obtain non-HIV health services during HIV-related visits. Availability of counseling support services was also a driver of choice. Facility type, i.e., hospital versus health center, was substantially less important. Conclusions: Efforts to enhance retention in HIV care and treatment for pregnant women should focus on promoting respectful care by providers and integrating access to non-HIV health services in the same visit, as well as continuing to strengthen counseling

May Measurement Month 2018: a pragmatic global screening campaign to raise awareness of blood pressure by the International Society of Hypertension

Aims Raised blood pressure (BP) is the biggest contributor to mortality and disease burden worldwide and fewer than half of those with hypertension are aware of it. May Measurement Month (MMM) is a global campaign set up in 2017, to raise awareness of high BP and as a pragmatic solution to a lack of formal screening worldwide. The 2018 campaign was expanded, aiming to include more participants and countries. Methods and results Eighty-nine countries participated in MMM 2018. Volunteers (≥18 years) were recruited through opportunistic sampling at a variety of screening sites. Each participant had three BP measurements and completed a questionnaire on demographic, lifestyle, and environmental factors. Hypertension was defined as a systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg, or taking antihypertensive medication. In total, 74.9% of screenees provided three BP readings. Multiple imputation using chained equations was used to impute missing readings. 1 504 963 individuals (mean age 45.3 years; 52.4% female) were screened. After multiple imputation, 502 079 (33.4%) individuals had hypertension, of whom 59.5% were aware of their diagnosis and 55.3% were taking antihypertensive medication. Of those on medication, 60.0% were controlled and of all hypertensives, 33.2% were controlled. We detected 224 285 individuals with untreated hypertension and 111 214 individuals with inadequately treated (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg) hypertension. Conclusion May Measurement Month expanded significantly compared with 2017, including more participants in more countries. The campaign identified over 335 000 adults with untreated or inadequately treated hypertension. In the absence of systematic screening programmes, MMM was effective at raising awareness at least among these individuals at risk

A Study To Regioselectively Access Fluorinated Triazoles And Isoxazoles

The objective of the thesis is to develop regioselective methods for mono-fluorination of disubstituted triazoles, both 1,4- and 1,5-regioisomer, and isoxazoles. These strategies focus on one-pot direct access to final mono-fluorinated triazoles and isoxazoles. Eventually, these fluorinated substrates will be screened against various biological targets. Similarly, the optimization study of a regioselective method to generate 5-fluoro-1,4-disubstituted triazole was conducted. This reaction also utilized 1,3-dipolar cycloaddition to synthesize fluorinated triazole. However, difluoroalkene was used as a synthetic equivalent of fluoroalkyne for this method. This resulted into the inversion of polarity affording a different regioisomer. Here, fluoronitroalkene was identified as a synthetic equivalent of fluoroalkyne, which undergoes 1,3-dipolar cycloaddition reaction to provide a direct regioselective access to 4-fluorotriazoles. The cycloaddition of fluoro-nitroalkenes with organic azides in the presence of trifluoroacetic acid generated 4-fluoro-1,5-disubstituted triazoles regioselectively. Fluorinated heterocycles have recently received a surge of interest in the field of medicinal chemistry. An incorporation of a fluorine atom into heterocyclic compounds can influence the overall dipole moment, pKa, and hydrogen bonding patterns. Currently, there is about twenty-five percent of fluorinated drugs in the market. Among these, fluorinated nitrogen heterocycles such as isoxazoles and triazoles, have been frequently found in medicinal agents. Both triazole and isoxazole rings have shown a wide range of biological activities as anti-cancer, anti-fungal, anti-viral, anti-bacterial, and anti-diabetic. Also, a silver(I)-catalyzed reaction was studied to synthesize 4-fluoro-3,5-disubstituted isoxazole. An on-going optimization of cyclization reaction of oxime in presence of an electrophilic fluorinating source to furnish fluorinated isoxazole is discussed in detail

Modification of Panobinostat to Increase its Therapeutic Potential to Cure Multiple Myeloma

Panobinostat is a potent histone deacetylase inhibitor that can impede function of a wide range of zinc-dependent histone deacetylases. Panobinostat is the first approved histone deacetylase inhibitor for the treatment of multiple myeloma, along with other drugs such as Velcade and Dexamethasone. Simplistically, it helps to shrink or eradicate tumor growth in multiple myeloma patients. However, the treatment has severe adverse effects due to its lack of selectivity. In collaboration with Dr. Shana Stoddard (Rhodes College, Memphis TN) and Fatima Rivas (St. Jude’s Research Hospital, Memphis TN), our research aims to design a more selective model of panobinostat that binds with the human histone deacetylase 8. Model compounds were examined and docking scores were computed based on protein X-ray crystal data. Herein, panobinostat derivatives having the highest docking score are presented with a synthetic scheme for the first target derivative. The synthesis and characterization by nuclear magnetic resonance (NMR) are described

Regioselective synthesis of 4-fluoro-1,5-substituted-1,2,3-triazoles from synthetic surrogates of 1-fluoroalkynes

Here, we show that 1-fluoronitroalkenes can serve as synthetic surrogates of 1-fluoroalkynes in [3+2] cycloaddition reactions with organic azides facilitated by a catalytic amount of trifloroacetic acid. This work provides the first regioselective method to access 4-fluoro-1,5-substituted-1,2,3-triazoles

Morpholine-mediated defluorinative cycloaddition of gem-difluoroalkenes and organic azides

Here, we report the first transition-metal free defluorinative cycloaddition of gem-difluoroalkenes with organic azides in morpholine as a solvent to construct fully decorated morpholine substituted-1,2,3-triazoles. Mechanistic studies revealed the formation of an addition-elimination intermediate containing a morpholine adduct of gem-difluoroalkenes prior to triazolization reaction via two plausible pathways. Attractive elements include regioselective and straightforward direct synthesis of fully substituted 1,2,3-triazoles, which are difficult to access, from readily available starting materials

Varicella pneumonia in an immunocompetent child: A case report

Varicella-zoster virus (VZV) is a type of herpes virus that causes varicella (primary infection) and herpes zoster/shingles (due to reactivation of latent infection). Usually a benign and a self-limited illness, the illness sometimes can result in severe complications in both immunocompetent and immunocompromised persons. Varicella Pneumonia as a complication of herpes zoster is a rare event, with reports primarily concerning immunocompromised individuals. Here we report a 14-year-old female who developed a secondary bacterial infection of the skin lesions and varicella pneumonia associated with VZV infection. The patient presented with multiple painful vesicles that later turned into pustular lesions over the right cheek with erosions and hemorrhagic crusting. Swelling involving the right half of both upper and lower lips was present. She developed a fever, cough, and shortness of breath after two days of the presence of vesico-pustular lesions. A diagnosis of Pneumonia was made based on symptoms of fever and cough and findings on chest x-ray. This case highlights, though rare, varicella pneumonia has a high rate of respiratory failure, but early diagnosis with prompt administration of antiviral medications can improve outcomes