The future of viral hepatitis testing: innovations in testing technologies and approaches.

A large burden of undiagnosed hepatitis virus cases remains globally. Despite the 257 million people living with chronic hepatitis B virus infection, and 71 million with chronic viraemic HCV infection, most people with hepatitis remain unaware of their infection. Advances in rapid detection technology have created new opportunities for enhancing access to testing and care, as well as monitoring of treatment. This article examines a range of other technological innovations that can be leveraged to provide more affordable and simplified approaches to testing for HBV and HCV infection and monitoring of treatment response. These include improved access to testing through alternative sampling methods (use of dried blood spots, oral fluids, self-testing) and combination rapid diagnostic tests for detection of HIV, HBV and HCV infection; more affordable options for confirmation of virological infection (HBV DNA and HCV RNA) such as point-of-care molecular assays, HCV core antigen and multi-disease polyvalent molecular platforms that make use of existing centralised laboratory based or decentralised TB and HIV instrumentation for viral hepatitis testing; and finally health system improvements such as integration of laboratory services for procurement and sample transportation and enhanced data connectivity to support quality assurance and supply chain management

Development of mobile laboratory for viral hemorrhagic fever detection in Africa

Background In order to enable local response to viral haemorrhagic fever outbreaks a mobile laboratory transportable on commercial flights was developed. Methodology The development progressed from use of mobile real time RT-PCR to mobile Recombinase Polymerase Amplification (RT-RPA). The various stages of the mobile laboratory development are described. Results A brief overview of its deployments, which culminated in the first on site detection of Ebola virus disease (EVD) in March 2014 and a successful use in a campaign to roll back EVD cases in Conakry in the West-Africa Ebola virus outbreak are described. Conclusion The developed mobile laboratory successfully enabled local teams to perform rapid viral haemorrhagic fever disgnostics

Prevention of Mother-to-Child Transmission of HIV-1 in Lesotho

The number of new pediatric HIV-1 infections is reducing globally as services for the prevention of mother-to-child transmission of HIV-1 (PMTCT) are being scaled up. Lesotho has one of the highest HIV burdens globally with an estimated HIV prevalence of 25.7% in antenatal care (ANC). In 2013, the Ministry of Health of Lesotho adopted lifelong antiretroviral therapy (ART) for all HIV-positive pregnant and breastfeeding women, regardless of clinical or immunologic status (Option B+). Although this is expected to decrease mother-to-child transmission (MTCT) in general, program effectiveness data are only starting to emerge. In this thesis, I present results of three studies: conventional early infant diagnosis (EID) turnaround time (TAT); six-week PMTCT outcomes for HIV-exposed and HIV-unexposed infants in the era of lifelong ART, and 18-24-month HIV-free survival measured through community survey. The overall aim of the study was to assess the effectiveness of the PMTCT program by determining birth outcomes and HIV-free survival of a prospective cohort of HIV-exposed infants compared to HIV-unexposed infants. In addition, we assess HIV-free survival among HIV-exposed children identified in the community who were born 18-24 months prior to study initiation. This was built on a baseline evaluation where we described turnaround time for EID when conventional EID was used. Methods: The baseline study was a retrospective cohort where data were abstracted from routine clinical records in health facility. The prospective observational cohort study included HIV-positive and HIV-negative women attending ANC and their infants up to 24 months postpartum; enrolled in the study June 2014 – February 2016. Study visits for HIV-positive mothers were three-monthly until 24 months after delivery, while HIV-negative mothers had study visits every three to six months after delivery. Demographic, social, and medical data were collected from participants during clinic visits through interviews and extraction of medical record information. For the community cross-sectional study, we captured the mortality and HIV infection outcomes of HIV-exposed children who were born after the introduction of Option B+. For all studies, quantitative data analysis was performed using Stata. Categorical variables were summarized using frequencies and percentages of participants, while continuous variables were summarized using means and standard deviations or medians and interquartile ranges, as appropriate. Maternal baseline characteristics were stratified by HIV status. For the baseline study, turnaround time geometric means (with 95% CI) were calculated and compared using linear mixed models. For the prospective cohort study, we compared birth outcomes between HEIs and HIV-unexposed infants (HUIs). Categorical variables were compared using Chi-square tests and continuous variables using t-tests or Wilcoxon rank-sum tests, as appropriate. HIV-free survival was estimated as the proportion of children alive and HIV-negative among HEI. For the community cross-sectional survey, the difference in survival between subgroups was determined using the log-rank test. Results: Concerning the baseline study, of the total of 1,187 infants reviewed, the turnaround time was 61.7 days (95% CI: 55.3-68.7). The longest turnaround time was time of results from central laboratory to district hospital, 23.3 days (95% CI: 18.7-29.0). Mean times from specimen transfer to the central laboratory and for result transfer from central laboratory to district hospital were significantly shorter in the Lowlands Region (0.9 and 16.2 days, respectively), compared to Highlands Region (6.0 [p = 0.030] and 34.3 days [p = 0.0099]. Results of the cohort study showed that prematurity was more frequent among HEI, 7.8% vs. 3.6%, although there was no difference in rates of congenital anomalies between HEI (1.0%) and HUI (0.6%). For HEI, cumulative HIV-1 transmission was 0.9% (N = 4/431) (95% CI: 0.25–2.36) at birth and 1.0% (N = 6/583) (95% CI: 0.38–2.23) at six weeks. Among liveborn infants, six-week HIV-free survival for HEI was 95.6% (95% CI: 93.7–97.1). For the cross-sectional community survey, the MTCT rate was 5.7% [95% CI: 4.0-8.0] and the reported mortality rate was 2.6% [95% CI: 1.6-4.2] among HIV-exposed children compared to 1.4% (95% CI: 0.9 – 2.3) among HIV-unexposed children. The estimated HIV-free survival was 91.8% [95% CI: 89.2-93.8] among HEI. Disclosure of mother’s HIV status (aOR = 4.9; 95% CI: 1.3-18.2) and initiation of cotrimoxazole prophylaxis in the child (aOR = 3.9; 95% CI: 1.2-12.6) were independently associated with increased HIV-free survival while child growth problems (aOR = 0.2; 95% CI: 0.09 – 0.5) were independently associated with reduced HIV-free survival. Conclusion: The turnaround study showed that average EID turnaround time was two months; the longest period of delay was transfer of results from central laboratory to district hospital. Meanwhile the prospective cohort study showed that implementation of universal maternal ART lowers MTCT at six weeks of age with no differences in congenital anomalies or early mortality between HEIs and HUIs. Of note, HEIs were reported to have high rates of prematurity. From the community cross-sectional survey, despite scale up of lifelong ART among pregnant and breastfeeding women, HIV has a significant effect on survival among HIV-exposed children compared to unexposed children.Doktorgradsavhandlin

IGNITE4 : Results of a phase 3, randomized, multicenter, prospective trial of eravacycline vs meropenem in the treatment of complicated intraabdominal infections

Funding Information: Financial support. This work was supported by Tetraphase Pharmaceuticals Inc. Funding Information: Potential conflicts of interest. J. S. S. has received support from Tetraphase Pharmaceuticals Inc. during the production of this manuscript and has served as a consultant to Merck, Pfizer, GlaxoSmithKline, and Melinta outside of the submitted work. A. S received support from Tetraphase Pharmaceuticals Inc. during the production of this manuscript. J. G. received research funding from Tetraphase Pharmaceuticals Inc. for his role as principal investigator of this study. K. L. and L. T. are employed by Tetraphase Pharmaceuticals Inc. D. E. reports grants from Tetraphase Pharmaceuticals Inc. during the conduct of the study and grants from Merck outside of the submitted work. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Publisher Copyright: © 2018 The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.Background: Increasing antimicrobial resistance among pathogens that cause complicated intraabdominal infections (cIAIs) supports the development of new antimicrobials. Eravacycline, a novel member of the fluorocycline family, is active against multidrug-resistant bacteria including extended-spectrum β-lactamase (ESBL) and carbapenem-resistant Enterobacteriaceae. Methods: IGNITE4 was a prospective, randomized, double-blind trial. Hospitalized patients with cIAI received either eravacycline 1 mg/kg every 12 hours or meropenem 1 g every 8 hours intravenously for 4-14 days. The primary objective was to demonstrate statistical noninferiority (NI) in clinical cure rates at the test-of-cure visit (25-31 days from start of therapy) in the microbiological intent-to-treat population using a NI margin of 12.5%. Microbiological outcomes and safety were also evaluated. Results: Eravacycline was noninferior to meropenem in the primary endpoint (177/195 [90.8%] vs 187/205 [91.2%]; difference, -0.5%; 95% confidence interval [CI], -6.3 to 5.3), exceeding the prespecified margin. Secondary endpoints included clinical cure rates in the modified ITT population (231/250 [92.4%] vs 228/249 [91.6%]; difference, 0.8; 95% CI, -4.1, 5.8) and the clinically evaluable population (218/225 [96.9%] vs 222/231 [96.1%]; (difference, 0.8; 95% CI -2.9, 4.5). In patients with ESBL-producing Enterobacteriaceae, clinical cure rates were 87.5% (14/16) and 84.6% (11/13) in the eravacycline and meropenem groups, respectively. Eravacycline had relatively low rates of adverse events for a drug of this class, with less than 5%, 4%, and 3% of patients experiencing nausea, vomiting, and diarrhea, respectively. Conclusions: Treatment with eravacycline was noninferior to meropenem in adult patients with cIAI, including infections caused by resistant pathogens. Clinical Trials Registration: NCT01844856.publishersversionPeer reviewe

Product Development of a Neurovascular Embolization Device

Stroke is the number one cause of adult disability in the United States and the third leading cause of death in the United States, Europe, and China.12 It is estimated 5% to 15% of all strokes are caused by ruptured intracranial aneurysms.3 In 2010, the National Stroke Association estimated the direct and indirect cost of strokes was $73.3 billion. The most common method for treating intracranial aneurysms is with platinum coils that are deployed to pack the aneurysm and block blood flow and prevent rupture. However, coil compaction and re-bleeding are two limitations with the coils because they have limited space filling capacity. Dr. Duncan Maitland has proposed a neurovascular embolization device (NED) be made out of shape memory polymer foam (SMP). The SMP device can be compressed down into a compact size for delivery via a catheter. Once in place, the device can be stimulated to regain its primary shape and expand up to 70x for superior occlusion of aneurysms. Design research is necessary to generate performance specifications for the NED that can assess the quality of prototypes. Customer needs are generated from interviews, activity diagrams, and market research. Functional models define the function and various sub-functions of the NED. Benchmarking highlights technology trends. A House of Quality matrix maps the customer needs to the engineering requirements. A failure modes and effects analysis emphasizes possible design deficiencies as a way of mitigating future risk. Performance specifications for the SMP foam are defined and can be used to establish a quality control program. Purification methods are suggested for the chemicals used in the synthesis of the SMP foam. Purification of the chemicals can reduce potential biocompatibility issues

Designing a state-of-the-science, accredited, commercially-successful biorepository utilizing ISO:9001(2008) quality management system requirements to construct the framework

The research community relies upon biorepositories’ ability to prepare for the scientific advancement that can precipitate the discoveries of the future. Furthermore, as the complexities, financial pressure, and quality issues biorepositories face continue to unfold, it is imperative to explore unmet needs researchers may have for biorepository services as well as evaluate the commercial potential, funding, and competitiveness of a new biorepository. With the goal of contributing to medical and scientific research and the biorepository field, this paper utilizes principles from ISO 9001:2008 “Quality management systems- Requirements” to outline and explore the challenges in establishing a state-of-the-science, accredited, commercial BSL-2 biorepository in order to support academic, clinical, and translational research. In addition, this paper provides detailed quality assurance strategies to meet investigator’s needs, ensure high quality, fit-for-purpose biospecimens, and, most importantly, protect and preserve the biospecimens entrusted to its care