Evaluation of Ethiopia's field epidemiology training program - frontline: perspectives of implementing partners.

BACKGROUND: Field Epidemiology Training Program (FETP) has been adopted as an epidemiology and response capacity building strategy worldwide. FETP-Frontline was introduced in Ethiopia in 2017 as a three-month in-service training. In this study, we evaluated implementing partners' perspectives with the aim of understanding program effectiveness and identifying challenges and recommendations for improvement. METHODS: A qualitative cross-sectional design was utilized to evaluate Ethiopia's FETP-Frontline. Using a descriptive phenomenological approach, qualitative data were collected from FETP-Frontline implementing partners, including regional, zonal, and district health offices across Ethiopia. We collected data through in-person key informant interviews, using semi-structured questionnaires. Thematic analysis was conducted, assisted with MAXQDA, while ensuring interrater reliability by using the consistent application of theme categorization. The major themes that emerged were program effectiveness, knowledge and skills differences between trained and untrained officers, program challenges, and recommended actions for improvement. Ethical approval was obtained from the Ethiopian Public Health Institute. Informed written consent was obtained from all participants, and confidentiality of the data was maintained throughout. RESULTS: A total of 41 interviews were conducted with key informants from FETP-Frontline implementing partners. The regional and zonal level experts and mentors had a Master of Public Health (MPH), whereas district health managers were Bachelor of Science (BSc) holders. Majority of the respondents reflected a positive perception towards FETP-Frontline. Regional and zonal officers as well as mentors mentioned that there were observable performance differences between trained and untrained district surveillance officers. They also identified various challenges including lack of resources for transportation, budget constraints for field projects, inadequate mentorship, high staff turnover, limited number of staff at the district level, lack of continued support from stakeholders, and the need for refresher training for FETP-Frontline graduates. CONCLUSIONS: Implementing partners reflected a positive perception towards FETP-Frontline in Ethiopia. In addition to scaling-up the program to reach all districts to achieve the International Health Regulation 2005 goals, the program also needs to consider addressing immediate challenges, primarily lack of resources and poor mentorship. Continued monitoring of the program, refresher training, and career path development could improve retention of the trained workforce.

Thermodynamic and kinetic analysis of human epidermal penetration of phenolic compounds: I. Stratum corneum solubility and partitioning.

Warming of the skin is now an accepted means of promoting skin permeation. Accordingly, the usually quite onerous thermodynamic studies on solute transport through the skin have practical applications. Phenolic compounds permeate through the skin by partitioning into and diffusing through the stratum corneum (SC) intercellular lipids, with their size being the main determinant of their maximal solute flux through skin. This paper sought to characterise the enthalpic and entropic changes associated with the solubility and equilibrium partitioning into the human SC of a series of phenols similar in size but with differing log P from aqueous vehicles. The solubilities of 9 phenolic compounds, covering a range of polarities, were determined in water and SC following 72 h at 4, 24, 32 and 37 °C which allowed the estimation of the SC-water partition coefficients. Van't Hoff plots were then used to estimate the enthalpies and entropies for the SC solubility, water solubility and SC partitioning of phenols. In addition, partition coefficients of 3 of the 9 phenols from mineral oil into hydrated and dehydrated SC were measured at the same temperatures. Van't Hoff plots were then used to estimate the enthalpies and entropies for the SC solubility, water solubility and SC partitioning of phenols from the oil. The SC solubility for the polar phenols increased more with temperature than the non-polar phenols, with the SC-water partition coefficients increasing with temperature for the polar phenols but decreasing with temperature for the non-polar phenols. Thermodynamic analyses suggest that, while enthalpy and entropy effects are involved in the SC partitioning of the non-polar solutes, the SC partitioning of the polar phenols were almost entirely entropy driven. The resultant thermodynamic parameters are consistent with the polar phenols being mainly associated with the SC polar head groups whereas the nonpolar phenols were more likely to be located in the interior interface SC lipid region adjacent to the polar head groups. Further, hydrating the SC led to an increase in the enthalpy of partitioning for both the polar and non-polar phenols studied. The estimated entropy of the partitioning for solutes from dehydrated SC suggests this is not only a hydrophobic effect in water but that the partitioning arises from the nature of phenolic compound - SC intercellular lipid interactions and SC intercellular lipid entropy. This partitioning process is dominated more by the extent of interaction between the SC and solute than the hydrophobic effect in water and is likely to be even greater above the SC lipid phase transition at around 36 °C for hydrated epidermal membranes.

A thermodynamic and kinetic analysis of human epidermal penetration of phenolic compounds: II. Maximum flux and solute diffusion through stratum corneum lipids.

Warming the skin is a key means of promoting solute permeation through the skin. Changes in solute permeation associated with variations in skin temperature also assist in understanding the mechanism by which solutes permeate the skin. However, few studies have considered the relative impact of temperature on the main determinants of the maximum flux for a solute across the skin, the solubility of a solute and its diffusivity in the stratum corneum. In this study, we quantified for the first time the thermodynamics associated with the maximum skin fluxes for a series of phenolic compounds of similar size but with varying lipophilicity (defined by the logarithms of their octanol/water partition coefficient, logP). These studies were undertaken using aqueous donor solutions (along with testosterone as a reference solute) across human epidermal membranes in vertical Franz diffusion cells at 4 °C, 24 °C and 37 °C with intermittent receptor sampling and volume replacement over 24 h. Kinetic and thermodynamic analyses included the estimation of the stratum corneum (SC) apparent SC diffusivity from the SC maximum fluxes and SC solubilities and the associated activation energies, enthalpies and entropies for diffusion. The key findings were that the differences in the maximum flux of phenolic compounds varying in lipophilicity mainly arose from differences in SC solubility at the various temperatures and that, at the highest temperature, SC permeability and SC diffusion were affected by SC lipid fluidisation and that variations in SC - water partitioning enthalpies explain some of the previously low activation energies for permeation of the more lipophilic phenols. Higher enthalpies for diffusion were seen for solutes with addition hydrogen bonding capacity and the highest negative entropy was observed with the more compact solutes. Various relationships between the derived thermodynamic parameters were explored and interpreted in a proposed model for solute partitioning into and permeation through the SC intercellular lipid lamellae.

Pitfalls in Cutaneous Melanoma Diagnosis and the Need for New Reliable Markers.

Cutaneous melanoma is one of the most aggressive forms of skin cancer, with the development of advanced stage disease resulting in a high rate of patient mortality. Accurate diagnosis of melanoma at an early stage is essential to improve patient outcomes, as this enables treatment before the cancer has metastasised. Histopathologic analysis is the current gold standard for melanoma diagnosis, but this can be subjective due to discordance in interpreting the morphological heterogeneity in melanoma and other skin lesions. Immunohistochemistry (IHC) is sometimes employed as an adjunct to conventional histology, but it remains occasionally difficult to distinguish some benign melanocytic lesions and melanoma. Importantly, the complex morphology and lack of specific biomarkers that identify key elements of melanoma pathogenesis can make an accurate confirmation of diagnosis challenging. We review the diagnostic constraints of melanoma heterogeneity and discuss issues with interpreting routine histology and problems with current melanoma markers. Innovative approaches are required to find effective biomarkers to enhance patient management.

Risk Factors for Ebola Virus Persistence in Semen of Survivors in Liberia.

BACKGROUND: Long-term persistence of Ebola virus (EBOV) in immunologically privileged sites has been implicated in recent outbreaks of Ebola virus disease (EVD) in Guinea and the Democratic Republic of Congo. This study was designed to understand how the acute course of EVD, convalescence, and host immune and genetic factors may play a role in prolonged viral persistence in semen. METHODS: A cohort of 131 male EVD survivors in Liberia were enrolled in a case-case study. "Early clearers" were defined as those with 2 consecutive negative EBOV semen test results by real-time reverse-transcription polymerase chain reaction (rRT-PCR) ≥2 weeks apart within 1 year after discharge from the Ebola treatment unit or acute EVD. "Late clearers" had detectable EBOV RNA by rRT-PCR >1 year after discharge from the Ebola treatment unit or acute EVD. Retrospective histories of their EVD clinical course were collected by questionnaire, followed by complete physical examinations and blood work. RESULTS: Compared with early clearers, late clearers were older (median, 42.5 years; P < .001) and experienced fewer severe clinical symptoms (median 2, P = .006). Late clearers had more lens opacifications (odds ratio, 3.9 [95% confidence interval, 1.1-13.3]; P = .03), after accounting for age, higher total serum immunoglobulin G3 (IgG3) titers (P = .005), and increased expression of the HLA-C*03:04 allele (0.14 [.02-.70]; P = .007). CONCLUSIONS: Older age, decreased illness severity, elevated total serum IgG3 and HLA-C*03:04 allele expression may be risk factors for the persistence of EBOV in the semen of EVD survivors. EBOV persistence in semen may also be associated with its persistence in other immunologically protected sites, such as the eye.

Bio-enabling strategies to mitigate the pharmaceutical food effect: A mini review.

The concomitant administration of oral drugs with food can result in significant changes in bioavailability, leading to variable pharmacokinetics and considerable clinical implications, such as over- or under-dosing. Consequently, there is increasing demand for bio-enabling formulation strategies to reduce variability in exposure between the fasted and fed state and/or mitigate the pharmaceutical food effect. The current review critically evaluates technologies that have been implemented to overcome the positive food effects of pharmaceutical drugs, including, lipid-based formulations, nanosized drug preparations, cyclodextrins, amorphisation and solid dispersions, prodrugs and salts. Additionally, improved insight into preclinical models for predicting the food effect is provided. Despite the wealth of research, this review demonstrates that application of optimal formulation strategies to mitigate the positive food effects and the evaluation in preclinical models is not a universal approach, and improved standardisation of models to predict the food effects would be desirable. Ultimately, the successful reformulation of specific drugs to eliminate the food effect provides a panoply of advantages for patients with regard to clinical efficacy and compliance.

Chitosan nanoparticles facilitate improved intestinal permeation and oral pharmacokinetics of the mast cell stabiliser cromoglycate.

Cromoglycate is a mast cell stabiliser typically administered via inhalation or intranasally for the treatment of allergy-based respiratory issues. Oral dosing of cromoglycate remains challenging due to its high solubility but low permeability across epithelial membranes in the gastrointestinal tract: effective formulation strategies are clearly needed. Here, we investigate and preclinically develop chitosan-cromoglycate complexes and associated nano/microparticle formulations with muco-adhesive and permeation enhancing capabilities to overcome the biopharmaceutical challenges for oral dosing.The synthesized complexes were optimized with respect to chitosan grade, particle size, and drug loading and demonstrated up to a 9.3-fold enhancement in permeability across a Caco-2 monolayer for chitosan-cromoglycate particles, compared to the pure drug. This increased intestinal permeability led to improved pharmacokinetic performance of cromoglycate, e.g. up to 1.82-fold increase in relative oral bioavailability when dosed to Sprague-Dawley rats in a fasted state. These findings confirm the potential for chitosan particles to serve as an effective oral delivery vehicle for cromoglycate, with additional formulation optimization presenting the opportunity to reduce dosing frequency for treatment of allergy-based respiratory ailments.

Simultaneous LC-MS/MS quantification of oxycodone, tramadol and fentanyl and their metabolites (noroxycodone, oxymorphone, O- desmethyltramadol, N- desmethyltramadol, and norfentanyl) in human plasma and whole blood collected via venepuncture and volumetric absorptive micro sampling.

INTRODUCTION: A range of opioids are commonly prescribed to manage chronic pain, but individual patient responses vary greatly, especially in older populations. One source of that variability are differences in absorption, metabolism and excretion, i.e. pharmacokinetics. Blood, plasma and serum concentrations of opioids allow that variability to be quantified and may be used to optimise opioid dosing. As an aid to that process, there is an unmet need to rapidly quantify several opioids and their metabolites in a single analytical method. AIMS: To develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous quantification of tramadol, oxycodone, fentanyl and their major metabolites in various human matrices. METHODS: Sample preparation involved adding three deuterated internal standards followed by protein precipitation with 100 % acetonitrile, evaporation and reconstitution. Separation of analytes via LC was achieved on a reversed phase column via binary gradient elution using 0.005 % formic acid in water and 100 % acetonitrile as mobile phases. Analytes were detected via MS/MS with multiple reaction monitoring (MRM). RESULTS: The method was accurate with the inter-day and intra-day accuracy of quality control samples (QCs) below 15 %. It was also precise with inter-day and intra-day coefficient of variation below 15 %. The lower limit of quantification (LLOQ) was 0.2 ng/mL for all analytes except tramadol and its metabolites, where the LLOQ was 10 ng/mL. Recovery was greater than 88 % for all analytes, except for O-desmethyltramadol (81 %). Analytes were stable over four freeze-thaw cycles, for 24 h on the bench top and for 24 h post-preparation. The inter- and intra-day variability of concentrations determined in blood and plasma were within 84-124%, whereas the inter- and intra-day variability for blood samples prepared using volumetric absorptive micro-sampling (VAMS) compared to those prepared from whole blood ranged between 83-122%. CONCLUSION: A LC-MS/MS method is described that is able to accurately and precisely quantify a number of commonly prescribed opioids and their major metabolites in plasma and whole blood, including whole blood collected using VAMS.

Efficacy and safety of statins in ethnic differences: a lesson for application in Indigenous Australian patient care.

Although statins are effective in treating high cholesterol, adverse effects do occur with their use. Efficacy and tolerability vary among statins in different ethnic groups. Indigenous Australians have a high risk for cardiovascular and kidney diseases. Prescribing statins to Indigenous Australians with multi-morbidity requires different strategies to increase efficacy and reduce their toxicity. Previous studies have reported that Indigenous Australians are more susceptible to severe statin-induced myopathies. However, there is a lack of evidence in the underlying genetic factors in this population. This review aims to identify: inter-ethnic differences in the efficacy and safety of statins; major contributing factors accounting for any identified differences; and provide an overview of statin-induced adverse effects in Indigenous Australians.

The Impact of Water Sanitation and Hygiene (WASH) Improvements on Hand Hygiene at Two Liberian Hospitals during the Recovery Phase of an Ebola Epidemic.

Fourteen years of civil war left Liberia with crumbling infrastructure and one of the weakest health systems in the world. The 2014-2015 Ebola virus disease (EVD) outbreak exposed the vulnerabilities of the Liberian health system. Findings from the EVD outbreak highlighted the lack of infection prevention and control (IPC) practices, exacerbated by a lack of essential services such as water, sanitation, and hygiene (WASH) in healthcare facilities. The objective of this intervention was to improve IPC practice through comprehensive WASH renovations conducted at two hospitals in Liberia, prioritized by the Ministry of Health (MOH). The completion of renovations was tracked along with the impact of improvements on hand hygiene (HH) practice audits of healthcare workers pre- and post-intervention. An occurrence of overall HH practice was defined as the healthcare worker practicing compliant HH before and after the care for a single patient encounter. Liberia Government Hospital Bomi (LGH Bomi) and St. Timothy Government Hospital (St. Timothy) achieved World Health Organization (WHO) minimum global standards for environmental health in healthcare facilities as well as Liberian national standards. Healthcare worker (HCW) overall hand hygiene compliance improved from 36% (2016) to 89% (2018) at LGH Bomi hospital and from 86% (2016) to 88% (2018) at St. Timothy hospital. Improved WASH services and IPC practices in resource-limited healthcare settings are possible if significant holistic WASH infrastructure investments are made in these settings.

Population pharmacokinetic model of subcutaneous fentanyl in older acute care patients.

PURPOSE: Subcutaneous fentanyl injection is commonly prescribed to manage acute pain in older patients; however, there is a gap in the literature describing the pharmacokinetic parameters for this route of administration in this population. The aim of this study was to develop and evaluate a population pharmacokinetic model for subcutaneous fentanyl injection in older patients. METHODS: Twenty-one patients who received subcutaneous fentanyl injections (50 to 75 µg) were recruited. Fentanyl concentrations were determined using a validated liquid chromatography/tandem mass spectrometry method. A population pharmacokinetic model was developed using non-linear mixed-effects modelling. A base model was selected based on the Akaike information criterion. Age, sex, body weight, number of previous fentanyl doses, number of prescribed medications, creatinine clearance, Charlson Comorbidity Index, Identification of Seniors at Risk score and concurrent use of CYP3A4 inhibitors were covariates considered for inclusion. A p value of < 0.05 was considered statistically significant for inclusion of covariates in the final model by stepwise addition. The simulation performance of the model was assessed by visual predictive check. RESULTS: A one-compartment, first-order absorption with lag time and linear elimination model was the best to fit to the fentanyl concentration data. The absorption rate constant was 0.136 h-1 (between subject variability (BSV), 46%), lag time 0.66 h (BSV 51%), apparent volume of distribution 6.28 L (BSV 30%), and apparent clearance 16.3 L.h-1 (BSV 54%). The Charlson Comorbidity Index was the only covariate included in the final model, where a higher value of the index increased fentanyl exposure and Cmax. CONCLUSION: This is the first report of subcutaneous fentanyl population pharmacokinetic model to evaluate fentanyl pharmacokinetic in older patients. The between subject variability in clearance and subcutaneous absorption rate was relatively high, and some patients recorded high fentanyl concentrations in the context of their titration to effect.

New physiological insights into the phenomena of deer antler: A unique model for skeletal tissue regeneration.

Generally, mammals are unable to regenerate complex tissues and organs however the deer antler provides a rare anomaly to this rule. This osseous cranial appendage which is located on the frontal bone of male deer is capable of stem cell-based organogenesis, annual casting, and cyclic de novo regeneration. A series of recent studies have classified this form of regeneration as epimorphic stem cell based. Antler renewal is initiated by the activation of neural crest derived pedicle periosteal cells (PPCs) found residing within the pedicle periosteum (PP), these PPCs have the potential to differentiate into multiple lineages. Other antler stem cells (ASCs) are the reserve mesenchymal cells (RMCs) located in the antlers tip, which develop into cartilage tissue. Antlerogenic periosteal cells (APCs) found within the antlerogenic periosteum (AP) form the tissues of both the pedicle and first set of antlers. Antler stem cells (ASCs) further appear to progress through various stages of activation, this coordinated transition is considered imperative for stem cell-based mammalian regeneration. The latest developments have shown that the rapid elongation of the main beam and antler branches are a controlled form of tumour growth, regulated by the tumour suppressing genes TP73 and ADAMTS18. Both osteoclastogenesis, as well as osteogenic and chondrogenic differentiation are also involved. While there remains much to uncover this review both summarises and comprehensively evaluates our existing knowledge of tissue regeneration in the deer antler. This will assist in achieving the goal of in vitro organ regeneration in humans by furthering the field of modern regenerative medicine. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: As a unique stem cell-based organ regeneration process in mammals, the deer antler represents a prime model system for investigating mechanisms of regeneration in mammalian tissues. Novel ASCs could provide cell-based therapies for regenerative medicine and bone remodelling for clinical application. A greater understanding of this process and a more in-depth defining of ASCs will potentiate improved clinical outcomes.

Protective Effect of Isothiocyanates from Cruciferous Vegetables on Breast Cancer: Epidemiological and Preclinical Perspectives.

BACKGROUND: The effect of cruciferous vegetable intake on breast cancer survival is controversial at present. Glucosinolates are the naturally occurring constituents found across the cruciferous vegetables. Isothiocyanates are produced from the hydrolysis of glucosinolates and this reaction is catalysed by the plant-derived enzyme myrosinase. The main Isothiocyanates (ITCs) from cruciferous vegetables are sulforaphane, benzyl ITC, and phenethyl ITC, which had been intensively investigated over the last decade for their anti-breast cancer effects. OBJECTIVE: The aim of this article is to systematically review the evidence from all types of studies, which examined the protective effect of cruciferous vegetables and/or their isothiocyanate constituents on breast cancer. METHODS: A systematic review was conducted in Pubmed, EMBASE, and the Cochrane Library from inception to 27 April 2020. Peer-reviewed studies of all types (in vitro studies, animal studies, and human studies) were selected. RESULTS: The systematic literature search identified 16 human studies, 4 animal studies, and 65 in vitro studies. The effect of cruciferous vegetables and/or their ITCs intake on breast cancer survival was found to be controversial and varied greatly across human studies. Most of these trials were observational studies conducted in specific regions, mainly in the US and China. Substantial evidence from in vitro and animal studies was obtained, which strongly supported the protective effect of sulforaphane and other ITCs against breast cancer. Evidence from in vitro studies showed that sulforaphane and other ITCs reduced cancer cell viability and proliferation via multiple mechanisms and pathways. Isothiocyanates inhibited cell cycle, angiogenesis and epithelial mesenchymal transition, as well as induced apoptosis and altered the expression of phase II carcinogen detoxifying enzymes. These are the essential pathways that promote the growth and metastasis of breast cancer. Noticeably, benzyl ITC showed a significant inhibitory effect on breast cancer stem cells, a new dimension of chemo-resistance in breast cancer treatment. Sulforaphane and other ITCs displayed anti-breast cancer effects at variable range of concentrations and benzyl isothiocyanate appeared to have a relatively lower inhibitory concentration IC50. The mechanisms underlying the cancer protective effect of sulforaphane and other ITCs have also been highlighted in this article. CONCLUSION: Current preclinical evidence strongly supports the role of sulforaphane and other ITCs as potential therapeutic agents for breast cancer, either as adjunct therapy or combined therapy with current anti-breast cancer drugs, with sulforaphane displaying the greatest potential.

Opioid prescribing and risk of drug-opioid interactions in older discharged patients with polypharmacy in Australia.

Background Opioids are commonly prescribed to managing chronic pain in older persons. However, these patients are often at risk of drug-opioid interactions due to polypharmacy. Objectives To identify the prevalence of opioid prescribing and drug-opioid interactions in poly-medicated older patients and factors associated with opioid prescribing. Setting Patients were included if they were admitted to the Royal Adelaide Hospital between September 2015 and August 2016, aged ≥ 75 years and took ≥ 5 medications at discharge. Methods After ethics approval, data of were retrospectively collected from case notes. The Charlson Comorbidity Index and Drug Burden Index were determined and opioids were classified as strong or weak. The association between opioid use and concurrent medications was computed using logistic regression and the results presented as odds ratios (OR) and 95% confidence intervals (95% CI), adjusted for age, sex, Charlson Comorbidity Index, number of prescribed medications and modified-Drug Burden Index. Main outcome measure Association between concurrent medications and opioid prescribing. Results 15,000 geriatric admissions were identified, of which 1192 were included. A total of 283 (23.7%) patients were prescribed opioids, with oxycodone accounting for 56% of these prescriptions. Opioid users were prescribed more medications (11.2 vs. 9.0, P < 0.001) and had higher Drug Burden Index (1.2 vs. 0.14, P < 0.001) compared to non-users. Opioid use was associated with concurrent prescription of antiepileptics (OR = 1.7, 95% CI 1.1-2.6), and negatively associated with Charlson Comorbidity Index (OR = 0.9, 95% CI 0.8-0.98) and concurrent use of antipsychotics (OR = 0.5, 95% CI 0.3-0.9) and beta blocking agents (OR = 0.4, 95% CI 0.3-0.6). Conclusions Strong opioids were prescribed more often than weak opioids and opioid users presented with characteristics and concurrent medications which increased the risk of opioid related adverse drug effects.

Characteristics of Ebola Virus Disease Survivor Blood and Semen in Liberia: Serology and Reverse Transcription Polymerase Chain Reaction (RT-PCR).

INTRODUCTION: Ebola virus (EBOV), species Zaire ebolavirus, may persist in the semen of male survivors of Ebola virus disease (EVD). We conducted a study of male survivors of the 2014-2016 EVD outbreak in Liberia and evaluated their immune responses to EBOV. We report here findings from the serologic testing of blood for EBOV-specific antibodies, molecular testing for EBOV in blood and semen, and serologic testing of peripheral blood mononuclear cells (PBMCs) in a subset of study participants. METHODS: We tested for EBOV RNA in blood by quantitative reverse transcription polymerase chain reaction (qRT-PCR), and for anti-EBOV-specific immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies by enzyme-linked immunosorbent assay (ELISA) for 126 study participants. We performed PBMC analysis on a subgroup of 26 IgG-negative participants. RESULTS: All 126 participants tested negative for EBOV RNA in blood by qRT-PCR. The blood of 26 participants tested negative for EBOV-specific IgG antibodies by ELISA. PBMCs were collected from 23/26 EBOV IgG-negative participants. Of these, 1/23 participants had PBMCs that produced anti-EBOV-specific IgG antibodies upon stimulation with EBOV-specific glycoprotein (GP) and nucleoprotein (NP) antigens. CONCLUSIONS: The blood of EVD survivors, collected when they did not have symptoms meeting the case definition for acute or relapsed EVD, is unlikely to pose a risk for EBOV transmission. We identified 1 IgM/IgG negative participant who had PBMCs that produced anti-EBOV-specific antibodies upon stimulation. Immunogenicity following acute EBOV infection may exist along a spectrum, and absence of antibody response should not be exclusionary in determining an individual's status as a survivor of EVD.

Drug-Eluting Biodegradable Implants for the Sustained Release of Bisphosphonates.

Despite being one of the first-line treatments for osteoporosis, the bisphosphonate drug class exhibits an extremely low oral bioavailability (<1%) due to poor absorption from the gastrointestinal tract. To overcome this, and to explore the potential for sustained drug release, bioerodible poly(lactic acid) (PLA) and poly(D,L-lactide-co-glycolide) (PLGA) implants loaded with the bisphosphonate alendronate sodium (ALN) were prepared via hot-melt extrusion. The rate of drug release in vitro was modulated by tailoring the ratio of lactide to glycolide in the polymer and by altering the ALN-loading of the implants. All investigated implants exhibited sustained ALN release in vitro between 25 to 130 days, where implants of greater glycolide composition and higher ALN-loadings released ALN more rapidly. All PLGA implants demonstrated a sigmoidal release profile, characterised by an initial surface dissolution phase, followed by a period of zero-order drug diffusion, then relaxation or erosion of the polymer chains that caused accelerated release over the subsequent days. Contrastingly, the PLA implants demonstrated a logarithmic release profile, characterised by a gradual decrease in ALN release over time.

Systems thinking for health emergencies: use of process mapping during outbreak response.

Process mapping is a systems thinking approach used to understand, analyse and optimise processes within complex systems. We aim to demonstrate how this methodology can be applied during disease outbreaks to strengthen response and health systems. Process mapping exercises were conducted during three unique emerging disease outbreak contexts with different: mode of transmission, size, and health system infrastructure. System functioning improved considerably in each country. In Sierra Leone, laboratory testing was accelerated from 6 days to within 24 hours. In the Democratic Republic of Congo, time to suspected case notification reduced from 7 to 3 days. In Nigeria, key data reached the national level in 48 hours instead of 5 days. Our research shows that despite the chaos and complexities associated with emerging pathogen outbreaks, the implementation of a process mapping exercise can address immediate response priorities while simultaneously strengthening components of a health system.

Copolymeric Micelles Overcome the Oral Delivery Challenges of Amphotericin B.

Classified as a Biopharmaceutical Classification System (BCS) class IV drug, amphotericin B (AmB) has low aqueous solubility and low permeability leading to low oral bioavailability. To improve these limitations, this study investigated the potential of AmB-loaded polymeric micelles (AmB-PM) to increase intestinal absorption. AmB-PM were prepared with polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus®) as a polymeric carrier and used a modified solvent diffusion and microfluidics (NanoAssemblr®) method. AmB-PM have a mean particle size of ~80 nm and are mono-disperse with a polydispersity index <0.2. The entrapment efficiency of AmB was up to 95% and achieved with a high drug loading up to ~20% (w/w) with a total amount of incorporated drug of 1.08 ± 0.01 mg/mL. Importantly, compared to free drug, AmB-PM protected AmB from degradation in an acidic (simulated gastric) environment. Viability studies in Caco-2 cells confirmed the safety/low toxicity of AmB-PM. In vitro cellular absorption studies confirmed that AmB-PM increased AmB uptake in Caco-2 cells 6-fold more than free AmB (i.e., 25% compared with 4% within 30 min). Furthermore, the permeability of AmB across Caco-2 monolayers was significantly faster (2-fold) and more pronounced for AmB-PM in comparison to free drug (3.5-fold increase). Thus, the developed AmB-PM show promise as a novel oral delivery system for AmB and justifies further investigation.

Prevalence and Factors Associated with Analgesic Prescribing in Poly-Medicated Elderly Patients.

BACKGROUND: Pain is common in older patients and management guidelines rarely consider the effect of multiple comorbidities and concurrent medications on analgesic selection. OBJECTIVES: The objectives of this study were to identify the prevalence and pattern of analgesic prescribing and associated factors in older patients with polypharmacy. METHODS: Older patients (aged ≥ 75 years) admitted to the Royal Adelaide Hospital between September 2015 and August 2016 and with polypharmacy were included and their comorbidities and medications prescribed at discharge were recorded. Drug Burden Index and Charlson Comorbidity Index were calculated. The number of medications that increased the risk of orthostatic hypotension were recorded. Logistic regression was used to compute the association between analgesic use and participant characteristics, and results were presented as odds ratios and 95% confidence intervals, adjusted for age, sex, Charlson Comorbidity Index, Drug Burden Index and orthostatic hypotension. RESULTS: Over 15,000 admissions were identified, of which 1192 patients were included, 824 (69%) of whom were prescribed an analgesic medication. Paracetamol (used by 89% of analgesic users), opioids (34%) and adjuvants (17%) were used more frequently than non-steroidal anti-inflammatory drugs (8%). Analgesic users had a higher Drug Burden Index, were prescribed more medications and were less likely to be male compared with non-users. Charlson Comorbidity Index across the cohort was high (7.3 ± 1.9) but there was no difference between analgesic users and non-users, but analgesic users were more likely to have a documented diagnosis of osteoarthritis, osteoporosis and falls. Opioid use was associated with the Drug Burden Index, while adjuvant use was associated with orthostatic hypotension. Opioid use was associated with having a diagnosis of osteoporosis and falls. CONCLUSIONS: In our cohort of poly-medicated elderly patients, prescription of analgesic medications was common, and these patients are likely to have an increased rate of adverse drug reactions and falls compared with those who were not prescribed analgesic medications.

Lassa virus circulating in Liberia: a retrospective genomic characterisation.

BACKGROUND: An alarming rise in reported Lassa fever cases continues in west Africa. Liberia has the largest reported per capita incidence of Lassa fever cases in the region, but genomic information on the circulating strains is scarce. The aim of this study was to substantially increase the available pool of data to help foster the generation of targeted diagnostics and therapeutics. METHODS: Clinical serum samples collected from 17 positive Lassa fever cases originating from Liberia (16 cases) and Guinea (one case) within the past decade were processed at the Liberian Institute for Biomedical Research using a targeted-enrichment sequencing approach, producing 17 near-complete genomes. An additional 17 Lassa virus sequences (two from Guinea, seven from Liberia, four from Nigeria, and four from Sierra Leone) were generated from viral stocks at the US Centers for Disease Control and Prevention (Atlanta, GA) from samples originating from the Mano River Union (Guinea, Liberia, and Sierra Leone) region and Nigeria. Sequences were compared with existing Lassa virus genomes and published Lassa virus assays. FINDINGS: The 23 new Liberian Lassa virus genomes grouped within two clades (IV.A and IV.B) and were genetically divergent from those circulating elsewhere in west Africa. A time-calibrated phylogeographic analysis incorporating the new genomes suggests Liberia was the entry point of Lassa virus into the Mano River Union region and estimates the introduction to have occurred between 300-350 years ago. A high level of diversity exists between the Liberian Lassa virus genomes. Nucleotide percent difference between Liberian Lassa virus genomes ranged up to 27% in the L segment and 18% in the S segment. The commonly used Lassa Josiah-MGB assay was up to 25% divergent across the target sites when aligned to the Liberian Lassa virus genomes. INTERPRETATION: The large amount of novel genomic diversity of Lassa virus observed in the Liberian cases emphasises the need to match deployed diagnostic capabilities with locally circulating strains and underscores the importance of evaluating cross-lineage protection in the development of vaccines and therapeutics. FUNDING: Defense Biological Product Assurance Office of the US Department of Defense and the Armed Forces Health Surveillance Branch and its Global Emerging Infections Surveillance and Response Section.