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Since the last case of indigenous rubella virus (RuV) was detected in 2009 in the Region of the Americas, sporadic rubella and congenital rubella cases have been confirmed, and subsequently, a low number of associated sequences have been reported. Fifty-one sequences of wild-type RuV, representing four genotypes (1E, 1G, 1J, and 2B), were reported from five countries, with confirmed sources of exposure for 46 cases. Phylogenetic analysis revealed the diversity of these viruses, showing no associations with sustained endemic transmission from previously endemic strains. Notably, 13 sequences were associated with travel from countries where no genetic information of wild-type viruses was available. In addition to sequences from postnatal and congenital infections, 23 sequences were collected from patients with diseases associated with RuV persistent infection. These findings highlight the Region's success in maintaining rubella elimination, emphasize its valuable contribution to global RuV molecular epidemiology, and address potential challenges in progressing toward the goal of rubella eradication., Competing Interests: Conflicts of interest. None reported.

Objectives: To examine if point-of-care urine tenofovir testing-informed counseling could be used to improve virologic suppression (VS) among participants with virologic failure (VF) after ≥1 prior round of enhanced adherence counseling (EAC)., Methods: Participants were enrolled from 42 clinics across Namibia. At each monthly medication pick-up, participants completed the point-of-care urine test and received EAC informed by this testing (EAC+). If VS was not achieved after 3 months of EAC+, up to 3 additional rounds of EAC+ were provided, with resistance testing at month (M)9., Results: Of 310 potentially-eligible participants across 42 clinics in Namibia, we enrolled 211 participants with VF (median age 33 years, 61% female); 195 reached M3 defined as receiving EAC+ and follow-up viral load testing; 169 achieved VS within M3 (87%, p<0 . 001) and 97% by M9 (181/186) compared to 40% (22/55) prior to the intervention (p<0.001). Resistance testing was performed in five remaining participants with VF at M9, of whom 1/5 (20%) developed dolutegravir resistance., Conclusions: The urine tenofovir assay when incorporated into adherence counseling has potential to be a cost-effective intervention among participants failing tenofovir-based regimens, increasing VS to 97% in those failing TLD. Encouraging results of this pre-post intervention will be rigorously tested in a randomized trial., Competing Interests: Declaration of competing interest The authors report no conflicts of interest, (Copyright © 2024. Published by Elsevier Ltd.)

On April 24, 2023, the American Samoa Department of Health (ASDoH) declared a public health emergency amid concern about a possible measles outbreak given low 2-dose vaccination coverage at the time. ASDoH had received two positive measles immunoglobulin (Ig) M test results after Flag Day festivities 1 week earlier from vaccinated children. ASDoH performed active case finding, took actions to mitigate transmission, and requested technical assistance from CDC. ASDoH implemented a vaccination campaign to improve suboptimal coverage. Confirmatory molecular testing of specimens from these initial persons under investigation (PUIs) was not possible, but subsequent testing of specimens from additional PUIs by Hawaii State Laboratories Division and CDC ruled out measles. In settings with low measles prevalence, measles antibody testing results have low positive predictive value and can lead to difficulties with interpreting results. Testing for additional pathogens revealed a variety of viruses known to cause common childhood viral exanthems. Both molecular and serologic testing should be performed for all suspected measles cases. To decrease the probability of false-positive IgM results, testing should be reserved for cases that meet the Council of State and Territorial Epidemiologists measles case definition, especially those in persons with no evidence of immunity and with a history of recent international travel. In addition, maintaining high measles vaccination coverage can prevent future outbreaks., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Annette Fa’alevao Ilimaleota reports travel support from the Pacific Island Health Officers Association and the World Health Organization and an uncompensated leadership role in the U.S.-Affiliated Pacific Islands Serology Technicians Program Collaboration and Service Integration as the Coordinator for American Samoa. No other potential conflicts of interest were disclosed.

The association between granulomas and vaccine-derived rubella virus (VDRV) in people with primary immunodeficiencies has raised concerns about the ability of immunoglobulin preparations to neutralize VDRVs. We investigated the capacity of immunoglobulin to neutralize rubella vaccine virus and 4 VDRV strains. As expected, the rubella vaccine virus itself was potently neutralized by immunoglobulin preparations, but the VDRV isolates from patients after intrahost evolution, 2-6 times less so. Diagnosis of immune deficiencies before possible live-virus vaccination is thus of critical importance, while immunoglobulin replacement therapy can be expected to provide protection from rubella virus infection., Competing Interests: Potential conflicts of interest. C. L., M. R. F., M. K., and T. R. K. are employees of Takeda Manufacturing Austria AG, Vienna, Austria. M. R. F., M. K. and T. R. K. have Takeda stock interest. Other authors: No reported conflicts. 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., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

With 762 laboratories, the Global Measles and Rubella Laboratory Network (GMRLN) is the largest laboratory network coordinated by the World Health Organization (WHO). Like the Global Polio Laboratory Network, the GMRLN has multiple tiers, including global specialized laboratories, regional reference laboratories, national laboratories, and, in some countries, subnational laboratories. Regional networks are supervised by regional laboratory coordinators reporting to a global coordinator at WHO headquarters. Laboratories in the GMRLN have strong links to national disease control and vaccination programs. The GMRLN's goal is to support member states in obtaining timely, complete, and reliable laboratory-based surveillance data for measles and rubella as part of the strategy for achieving measles and rubella elimination. Surveillance data are reported to the national program and are included in annual reports on the status of measles and rubella elimination to national verification committees for review by regional verification commissions. Quality within the GMRLN is ensured by monitoring performance through external quality assurance programs, confirmatory and quality control testing, accreditation, and coordination of corrective action and training where needed. The overall performance of the laboratories has remained high over the years despite many challenges, particularly the COVID-19 pandemic. The GMRLN is well-positioned to support high-quality laboratory-based surveillance for measles and rubella and to transition to supporting laboratory testing for other pathogens, including vaccine-preventable diseases.

More than 100 laboratories in the World Health Organization Global Measles and Rubella Laboratory Network (GMRLN) perform nucleic acid-based methods for case confirmation of measles or rubella infections and/or strain surveillance (genotyping). The quality of laboratory data is critical to ensure that diagnostic results and country reports to regional verification committees are based on accurate data. A molecular External Quality Assurance (mEQA) program was initiated by the US-CDC in 2014 to evaluate the performance of laboratories in the network. The inclusion of testing for measles and rubella viruses, with a focus on detection and genotyping, plus the diversity of assays and platforms employed required a flexible and comprehensive proficiency testing program. A stepwise introduction of new evaluation criteria gradually increased the stringency of the proficiency testing program, while giving laboratories time to implement the required changes. The mEQA program plays an important role in many processes in the GMRLN, including informing plans for the training of laboratory staff, access to reagents, and the submission of sequence data to global databases. The EQA program for Local Public Health Institutes in Japan is described as an example for national mEQA programs. As more laboratories initiate molecular testing, the mEQA will need to continue to expand and to adapt to the changing landscape for molecular testing.

Measles and rubella are vaccine-preventable viral diseases and can be prevented by safe, highly effective vaccination with measles- and rubella-containing vaccines. Given the myriad causes of febrile exanthems, laboratory surveillance for both measles and rubella is important to document the incidence of these diseases and to track the progress and maintenance of elimination in near- and post-elimination settings. Diagnostic challenges can hinder effective surveillance and classification challenges can hinder efforts to demonstrate achievement or maintenance of elimination. In this report, we review diagnostic and classification challenges for measles and rubella in near- and post-elimination settings.

The optical atomic clock based on the 5S 1/2  → 5D 5/2 two-photon transition in rubidium is a candidate for a next generation, manufacturable, portable clock that fits in a small size, weight, and power (SWaP) envelope. Here, we report the first two-photon rubidium clock stabilized by detecting 776 nm fluorescence. We also demonstrate the use of a multi-pixel photon counter as a low voltage substitute to a photomultiplier tube in the feedback loop to the clock laser.

Given the demanding nature of its mission, the collective units of the Army, not just individual Soldiers, need to be able to withstand and adapt to a wide range of challenges. Therefore, it is important to be able to effectively assess resilience at the team-level and to understand the factors that can enable or diminish it. This article describes the development of a construct valid and psychometrically-sound measure of team resilience - the Team Resilience Scale (TRS). A theoretical framework of team resilience and related constructs is introduced. We then summarize the procedures for developing the TRS and related constructs, providing evidence of the content validity of the TRS. Finally, we assess the psychometric soundness and construct validity of the TRS in two Army field studies. Our analyses support the convergent validity of items and indicate that the measure can be used to examine three first-order dimensions of resilience (i.e., physical, affective, and cognitive) or as a single overall resilience composite. Results show the TRS was positively related to team performance in both samples and it co-varied with stressors and team actions. Practical recommendations for use of the measure and suggestions for future research are offered.

The purpose of this study was to compare the survival, recurrence, and complication rates in patients with pancreatic ductal adenocarcinoma (PDAC) who underwent robotic pancreaticoduodenectomy (RPD) or open pancreaticoduodenectomy (OPD) and who received adjuvant therapy. The study was a single-center retrospective analysis of consecutive PDAC patients who underwent RPD/OPD. Patient characteristics, tumor findings, neoadjuvant therapy, adjuvant therapies, overall survival (OS) and recurrence-free survival (RFS) were compared between the OPD and RPD cohorts. Cox proportional hazard regression with and without propensity score matching was used to establish the association between predictors and outcomes. One hundred PDAC patients underwent OPD (n = 36) or RPD (n = 64) from 2013 to 2019. Cox proportional hazard models showed that baseline bilirubin (HR 1.6, p = 0.0006) and operative characteristics such as the number of positive lymph nodes (HR 1.1, p = 0.002), lymph node ratio (HR 1.6, p = 0.001), tumor grade (HR 1.7, p = 0.02), and TNM classification (HR 2.3, p = 0.01) were associated with OS. The independent predictors post-intervention associated with mortality were adjuvant therapy (HR 0.4, p = 0.0003), ISGPS complications (HR 2.8, p = 0.02), and 90-day readmission (HR 2, p = 0.004). After adjustment for these predictors, adjuvant therapy, baseline bilirubin, lymph node ratio, and tumor grade remained the main predictors of mortality. Baseline bilirubin, adjuvant therapy, lymph node ratio, and tumor grade were the main determinants of mortality after OPD or RPD. There was no significant difference in OS and RFS after RPD or OPD in PC patients who received adjuvant therapy., (© 2022. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Undergraduate student engagement in research increases retention and degree completion, especially for students who are underrepresented in science. Several approaches have been adopted to increase research opportunities including curriculum based undergraduate research opportunities (CUREs), in which research is embedded into course content. Here we report on efforts to tackle a different challenge: providing research opportunities to students engaged in remote learning or who are learning at satellite campuses or community colleges with limited research infrastructure. In our project we engaged students learning remotely or at regional centers to map gene expression in the mouse brain. In this project we mapped expression of the Down syndrome cell adhesion molecule like 1 (Dscaml1) gene in mouse brain using a LacZ expression reporter line. Identifying where Dscaml1 is expressed in the brain is an important next step in determining if its roles in development and function in the retina are conserved in the rest of the brain. Students working remotely reconstruct brain montages and annotated Dscaml1 expression in the brain of mice carrying one or two copies of the gene trap. We built on these findings by further characterizing Dscaml1 expression in inhibitory neurons of the visual pathway. These results build on and extend previous findings and demonstrate the utility of including distance learners in an active research group for both the student learners and the research team. We conclude with best practices we have developed based on this and other distance learner focused projects., (© 2022 Wiley-VCH GmbH.)

The US President's Emergency Plan for AIDS Relief (PEPFAR) supports molecular HIV and tuberculosis diagnostic networks and information management systems in low- and middle-income countries. We describe how national programs leveraged these PEPFAR-supported laboratory resources for SARS-CoV-2 testing during the COVID-19 pandemic. We sent a spreadsheet template consisting of 46 indicators for assessing the use of PEPFAR-supported diagnostic networks for COVID-19 pandemic response activities during April 1, 2020, to March 31, 2021, to 27 PEPFAR-supported countries or regions. A total of 109 PEPFAR-supported centralized HIV viral load and early infant diagnosis laboratories and 138 decentralized HIV and TB sites reported performing SARS-CoV-2 testing in 16 countries. Together, these sites contributed to >3.4 million SARS-CoV-2 tests during the 1-year period. Our findings illustrate that PEPFAR-supported diagnostic networks provided a wide range of resources to respond to emergency COVID-19 diagnostic testing in 16 low- and middle-income countries.

Antibody-drug conjugate (ADC) research has typically focused on the release of highly potent cytotoxic agents to achieve antitumor efficacy. However, recently approved ADCs trastuzumab deruxtecan and sacituzumab govitecan release lower-potency topoisomerase inhibitors. This has prompted interest in ADCs that release lower-potency cytotoxic drugs to potentially enhance therapeutic index and reduce unwanted toxicity. Pyrrolobenzodiazepine (PBD) dimer ADCs have been widely investigated in human clinical trials, which have focused on high-potency PBDs. In this study, we evaluated five ADCs that release the low-potency PBD dimer SG3650. The relatively low clogD for this agent facilitated higher drug-to-antibody ratio (DAR) conjugation without the need for antibody engineering or functionalization of the drug. The rank order of potency for DAR 2 site-specific ADCs (conjugated at the C239i position) matched the order for the corresponding free drugs in vitro. Despite free drug SG3650 being inactive in vivo, the DAR 2 ADCs derived from the corresponding drug-linker SG3584 showed antitumor efficacy in solid (anti-HER2) and hematologic (anti-CD22) xenograft models. Antitumor activity could be enhanced by conjugating SG3584 to trastuzumab at higher DARs of 4 and 8 and by adjusting dosing and schedule. Higher-DAR conjugates were stable and displayed good rat pharmacokinetic profiles as measured by ELISA and LC/MS-MS. A single intravenous dose of isotype control SG3584 DAR 2 ADC resulted in no mortality in rats or monkeys at doses of up to 25 and 30 mg/kg, respectively. These findings suggest that further investigations of low-potency PBD dimers in ADCs that target hematologic and solid tumors are warranted., (©2022 American Association for Cancer Research.)

Introduction: Delayed HIV diagnosis in HIV-exposed infants (HEIs) results in missed opportunities for early antiretroviral therapy (ART), causing significant morbidity and mortality. Early infant diagnosis (EID) depends on the availability of accessible and reliable testing services. We explored the acceptability, appropriateness, and feasibility of deploying a targeted community-based point-of-care (POC) EID testing model (i.e., "community POC model") to reach high-risk mother-infant pairs (MIPs) in Lusaka, Zambia., Methods: We conducted in-depth interviews with a purposive sample of health care workers, study staff, and caregivers in high-risk MIPs at 6 health facilities included in a larger implementation research study evaluating the community POC model. We defined "high-risk MIPs" as mothers who did not receive antenatal testing or an attended delivery or infants who missed EID testing milestones. Interviews were audio-recorded, translated, and transcribed verbatim in English. Content and thematic analysis were done using NVivo 10 software., Results: Health care workers (n=20) and study staff (n=12) who implemented the community POC model noted that the portability and on-screen prompts of the POC platform made it mobile and easy to use, but maintenance and supply chain management were key to field operations. Respondents also felt that the community POC model reached more infants who had never had EID testing, allowing them to find infants with HIV infection and immediately initiate them on ART. Caregivers (n=22) found the community POC model acceptable, provided that privacy could be ensured because the service was convenient and delivered close to home., Conclusion: We demonstrate the acceptability, appropriateness, and feasibility of implementing the community POC model in Zambia, while identifying potential challenges related to client privacy and platform field operations. The community POC model may represent a promising strategy to further facilitate active HIV case finding and linkage to ART for children with undiagnosed HIV infection in the community., (© Tembo et al.)

Optical clocks are emerging as next-generation timekeeping devices with technological and scientific use cases. Simplified atomic sources such as vapor cells may offer a straightforward path to field use, but suffer from long-term frequency drifts and environmental sensitivities. Here, we measure a laboratory optical clock based on warm rubidium atoms and find low levels of drift on the month-long timescale. We observe and quantify helium contamination inside the glass vapor cell by gradually removing the helium via a vacuum apparatus. We quantify a drift rate of 4×10-15/day, a 10 day Allan deviation less than 5×10-15, and an absolute frequency of the Rb-87 two-photon clock transition of 385,284,566,371,190(1970) Hz. These results support the premise that optical vapor cell clocks will be able to meet future technology needs in navigation and communications as sensors of time and frequency.

Background Context: Osseointegration is a pivotal process in achieving a rigid fusion and ultimately a successful clinical outcome following interbody fusion surgery. Advancements in 3D printing technology permit commonly used titanium interbody spacers to be designed with unique architectures, such as a highly interconnected and specific porous structure that mimics the architecture of trabecular bone. Interbody implants with a microscale surface roughness and biomimetic porosity may improve bony ongrowth and ingrowth compared to traditional materials., Purpose: The purpose of this study was to compare the osseointegration of lumbar interbody fusion devices composed of surgical-grade polyetheretherketone (PEEK), titanium-alloy (TAV), and 3D-printed porous, biomimetic TAV (3DP) using an in vivo ovine model., Study Design: In Vivo Preclinical Animal Study METHODS: Eighteen sheep underwent two-level lateral lumbar interbody fusion randomized with either 3DP, PEEK, or TAV interbody spacers (n=6 levels for each spacer per time point). Postoperative time points were 6 and 12 weeks. Microcomputed tomography and histomorphometry were used to quantify bone volume (BV) within the spacers (ingrowth) and the surface bone apposition ratio (BAR) (ongrowth), respectively., Results: The 3DP-treatment group demonstrated significantly higher BV than the PEEK and TAV groups at 6 weeks (77.3±44.1 mm 3 , 116.9±43.0 mm 3 , and 108.7±15.2 mm 3 , respectively) (p<.05). At 12 weeks, there were no BV differences between groups (p>.05). BV increased in all groups from the 6- to 12-week time points (p<.05). At both time points, the 3DP-treated group (6w: 23.6±10.9%; 12w: 36.5±10.9%) had significantly greater BAR than the PEEK (6w: 8.6±2.1%; 12w: 14.0±5.0%) and TAV (6w: 6.0±5.7%; 12w: 4.1±3.3%) groups (p<.05)., Conclusions: 3DP interbody spacers facilitated greater total bony ingrowth at 6 weeks, and greater bony ongrowth postoperatively at both 6 and 12 weeks, in comparison to solid PEEK and TAV implants., Clinical Significance: Based on these findings, the 3DP spacers may be a reasonable alternative to traditional PEEK and TAV spacers in various clinical applications of interbody fusion., (Copyright © 2021. Published by Elsevier Inc.)

Delivering peptides into cells could open up possibilities for targeting intracellular proteins. Although fatty acylation of peptide therapeutics improves their systemic half-life, it remains unclear how it influences their cellular uptake. Here, we demonstrate that a fatty acylated peptide exhibits enhanced cellular internalization and cytosolic distribution compared to the un-acylated version. By using a cystine-knot peptide as a model system, we report an efficient strategy for site-specific conjugation of fatty acids. Peptides modified with fatty acids of different chain lengths entered cells through clathrin-mediated and macropinocytosis pathways. The cellular uptake was mediated by the length of the hydrocarbon chain, with myristic acid conjugates displaying the highest distribution across the cytoplasm including the cytosol, and endomembranes of the ER, Golgi and mitochondria. Our studies demonstrate how fatty acylation improves the cellular uptake of peptides, and lay the groundwork for future development of bioactive peptides with enhanced intracellular distribution., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Objectives: Multiple clinical trials have established a role for adjuvant chemotherapy for patients with pancreatic ductal adenocarcinoma. Adjuvant FOLFIRINOX increases survival as compared with gemcitabine but with increased toxicity. FOLFOX+nab-paclitaxel (FOLFOX-A) was developed by the Brown University Oncology Research Group (BrUOG) as an alternative to FOLFIRINOX. This phase II trial explored the feasibility and toxicity of adjuvant FOLFOX-A in patients who have completed resection for pancreatic ductal adenocarcinoma., Patients and Methods: Patients with resected pancreatic ductal adenocarcinoma were eligible. The primary objective was to determine the feasibility of adjuvant FOLFOX-A. Patients experiencing grade 2 neuropathy received a 20% reduction of oxaliplatin. Secondary end points were disease-free survival, and overall survival., Results: Between June 2014 and October 2018, 25 patients were enrolled following surgical resection. The median number of cycles completed was 9.5. Median disease-free survival was 19.7 months (95% confidence interval, 10.3 to not reached) and median overall survival was 53.5 months (95% confidence interval, 24.2 to not reached). The most common treatment-related grade 3 or greater adverse events were fatigue (58%), nausea (13%), and neutropenia (26%). Fourteen patients had grade 2 neuropathy (58%) and 1 patient (4%) had grade 3 neuropathy. Only 2 patients (8%) had grade 3 diarrhea., Conclusions: Adjuvant FOLFOX-A is a feasible multi-agent adjuvant treatment regimen and, with further validation, could be an alternative to FOLFIRINOX., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

A primary component of exercise, mechanical signals, when applied in the form of low intensity vibration (LIV), increases mesenchymal stem cell (MSC) osteogenesis and proliferation. While it is generally accepted that exercise effectively combats the deleterious effects of aging in the musculoskeletal system, how long-term exercise affects stem cell aging, which is typified by reduced proliferative and differentiative capacity, is not well explored. As a first step in understanding the effect of long-term application of mechanical signals on stem cell function, we investigated the effect of LIV during in vitro expansion of MSCs. Primary MSCs were subjected to either a control or to a twice-daily LIV regimen for up to sixty cell passages (P60) under in vitro cell expansion conditions. LIV effects were assessed at both early passage (EP) and late passage (LP). At the end of the experiment, P60 cultures exposed to LIV maintained a 28% increase of cell doubling and a 39% reduction in senescence-associated β-galactosidase activity (p < 0.01) but no changes in telomere lengths and p16 INK4a levels were observed. Prolonged culture-associated decreases in osteogenic and adipogenic capacity were partially protected by LIV in both EP and LP groups (p < 0.05). Mass spectroscopy of late passage MSC indicated a synergistic decrease of actin and microtubule cytoskeleton-associated proteins in both control and LIV groups while LIV induced a recovery of proteins associated with oxidative reductase activity. In summary, our findings show that the application of long-term mechanical challenge (+LIV) during in vitro expansion of MSCs for sixty passages significantly alters MSC proliferation, differentiation and structure. This suggests LIV as a potential tool to investigate the role of physical activity during aging.

Game theory examines strategic decision-making in situations of conflict, cooperation, and coordination. It has become an established tool in economics, psychology and political science, and more recently has been applied to disease control. Used to examine vaccination uptake in human medicine, game theory shows that when vaccination is voluntary some individuals will choose to "free-ride" on the protection provided by others, resulting in insufficient coverage for control of a vaccine-preventable disease. Here, we use game theory to examine farmer uptake of a new diagnostic ELISA test for sheep scab-a highly infectious disease with an estimated cost exceeding £8M per year to the UK industry. The stochastic game models decisions made by neighboring farmers when deciding whether to adopt the newly available test, which can detect subclinical infestation. A key element of the stochastic game framework is that it allows multiple states. Depending on infestation status and test adoption decisions in the previous year, a farm may be at high, medium or low risk of infestation this year-a status which influences the decision the farmer makes and the farmer payoffs. Ultimately, each farmer's decision depends on the costs of using the diagnostic test vs. the benefits of enhanced disease control, which may only accrue in the longer term. The extent to which a farmer values short-term over long-term benefits reflects external factors such as inflation or individual characteristics such as patience. Our results show that when using realistic parameters and with a test cost around 50% more than the current clinical diagnosis, the test will be adopted in the high-risk state, but not in the low-risk state. For the medium risk state, test adoption will depend on whether the farmer takes a long-term or short-term view. We show that these outcomes are relatively robust to change in test costs and, moreover, that whilst the farmers adopting the test would not expect to see large gains in profitability, substantial reduction in sheep scab (and associated welfare implications) could be achieved in a cost-neutral way to the industry., (Copyright © 2020 Mohr, Beard, Nisbet, Burgess, Reeve, Denwood, Porphyre, Zadoks and Matthews.)

Absorptive- and receptor-mediated transcytosis (AMT/RMT) are widely studied strategies to deliver therapeutics across the blood-brain barrier (BBB). However, an improved understanding of the mechanism surrounding trafficking is required that could promote delivery. Accordingly, we designed a flexible platform that merged AMT and RMT motifs on a single scaffold to probe various parameters (ligand, affinity, valency, position) in a screening campaign. During this process we adapted an in vitro BBB model to reliably rank transcytosis of the vehicle library. Our results demonstrate heightened uptake and trafficking for the shuttles, with a structure-activity relationship for transcytosis emerging. Notably, due to their small size, the majority of shuttles demonstrated increased permeation compared to transferrin, with the highest performing shuttle affording a 4.9-fold increase. Consequently, we have identified novel peptide conjugates that have the capacity to act as promising brain shuttles., (This journal is © The Royal Society of Chemistry 2019.)

Mesenchymal stem cells (MSC) rely on their ability to integrate physical and spatial signals at load bearing sites to replace and renew musculoskeletal tissues. Designed to mimic unloading experienced during spaceflight, preclinical unloading and simulated microgravity models show that alteration of gravitational loading limits proliferative activity of stem cells. Emerging evidence indicates that this loss of proliferation may be linked to loss of cellular cytoskeleton and contractility. Low intensity vibration (LIV) is an exercise mimetic that promotes proliferation and differentiation of MSCs by enhancing cell structure. Here, we asked whether application of LIV could restore the reduced proliferative capacity seen in MSCs that are subjected to simulated microgravity. We found that simulated microgravity (sMG) decreased cell proliferation and simultaneously compromised cell structure. These changes included increased nuclear height, disorganized apical F-actin structure, reduced expression, and protein levels of nuclear lamina elements LaminA/C LaminB1 as well as linker of nucleoskeleton and cytoskeleton (LINC) complex elements Sun-2 and Nesprin-2. Application of LIV restored cell proliferation and nuclear proteins LaminA/C and Sun-2. An intact LINC function was required for LIV effect; disabling LINC functionality via co-depletion of Sun-1, and Sun-2 prevented rescue of cell proliferation by LIV. Our findings show that sMG alters nuclear structure and leads to decreased cell proliferation, but does not diminish LINC complex mediated mechanosensitivity, suggesting LIV as a potential candidate to combat sMG-induced proliferation loss., Competing Interests: The authors declare no competing interests.

Background: The main objective of this study was to determine the frequency and patterns of HIV drug resistance-associated mutations among children under 18 months of age born to HIV-1-positive mothers enrolled in the prevention of mother-to-child transmission services in Haiti., Methods: Between January 1, 2013 and December 31, 2014, HIV-positive remnant dried blood spots collected from children under 18 months of age for Early Infant Diagnosis at the National Public Health Laboratory were used for HIV-1 genotyping. HIV drug resistance mutations were analyzed using the Stanford Drug Resistance HIVdb program., Results: Of the 3555 dried blood spots collected for Early Infant Diagnosis, 360 (10.1%) were HIV-positive and 355 were available for genotyping. Of these, 304 (85.6%) were successfully genotyped and 217 (71.4%) had ≥1 drug resistance mutation. Mutations conferring resistance to nucleoside reverse transcriptase inhibitor (NRTIs) and non-NRTIs were present in 40.5% (123) and 69.1% (210), respectively. The most frequent mutations were K103N/S (48.0%), M184V (37.5%), G190A/S (15.1%), and Y181C/G/V (14.1%). Predicted drug resistance analysis revealed that 68.8% of the children had high-level resistance to non-NRTIs and 11.5% had intermediate to high-level resistance to abacavir., Conclusions: This study showed high rates of resistance to NRTIs and non-NRTIs among newly HIV-diagnosed children in Haiti, suggesting that in the era of "Option B+" (initiation of lifelong combination antiretroviral therapy to pregnant women with HIV), the majority of children who acquire HIV infection through mother-to-child transmission of HIV have resistant HIV. These results have led the National HIV Program to revise the pediatric guidelines to include protease inhibitors in first-line regimens for all HIV-positive newborns.

Objective: Operating room simulation exercises have been well established as an effective means of improving confidence, task engagement, and learning retention among surgical residents. We have established a cost-effective model and scoring system assessing resident skills to tie secure surgical knots with minimal tension., Design: A circular grid divided into 18 segments was placed underlying an aluminum can. Trainees tie 20 surgical square knots scored for time and total knot length. Movement of the can outside the grid served as a scoring penalty. Recorded were time, length of the 20 knots, and number of segments exposed at exercise end. A score was developed to identify a progression of skills with PGY level. All outcomes were compared between classes using ANOVA., Setting: Brown University/Rhode Island Hospital Department of Surgery., Participants: Surgical residents (PGY1-PGY5) and participating attending surgeons employed by Rhode Island Hospital., Results: Knot length and exposed segments showed trends of improved scores with ascending PGY level. Only average time attained statistical significance. Overall scores improved with PGY level: Composite scores significantly improved when comparing PGY1 to PGY3, PGY5, and Attending surgeons (p = 0.016, 0.011, and 0.011, respectively). Time significantly improved when comparing PGY1 to PGY3 and Attending surgeons (77vs. 50 and 47 seconds, p = 0.019 and 0.022 respectively). Composite scores were not significantly different above PGY3., Conclusions: A low fidelity, high impact knot tying model has been developed to assess the ability to securely tie surgical knots while minimizing tension, with linear increases in scores that appear to plateau at the PGY3 level., (Published by Elsevier Inc.)

Despite some clinical success with antibody-drug conjugates (ADCs) in patients with solid tumors and hematological malignancies, improvements in ADC design are still desirable due to the narrow therapeutic window of these compounds. Tumor-targeting antibody fragments have distinct advantages over monoclonal antibodies, including more rapid tumor accumulation and enhanced penetration, but are subject to rapid clearance. Half-life extension technologies such as PEGylation and albumin-binding domains (ABDs) have been widely used to improve the pharmacokinetics of many different types of biologics. PEGylation improves pharmacokinetics by increasing hydrodynamic size to reduce renal clearance, whereas ABDs extend half-life via FcRn-mediated recycling. In this study, we used an anti-oncofetal antigen 5T4 diabody conjugated with a highly potent cytotoxic pyrrolobenzodiazepine (PBD) warhead to assess and compare the effects of PEGylation and albumin binding on the in vivo efficacy of antibody fragment drug conjugates. Conjugation of 2× PEG20K to a diabody improved half-life from 40 min to 33 h, and an ABD-diabody fusion protein exhibited a half-life of 45 h in mice. In a xenograft model of breast cancer MDA-MB-436, the ABD-diabody-PBD showed greater tumor growth suppression and better tolerability than either PEG-diabody-PBD or diabody-PBD. These results suggest that the mechanism of half-life extension is an important consideration for designing cytotoxic antitumor agents.

Background: Zoonotic diseases account for a substantial portion of infectious disease outbreaks and burden on public health programs to maintain surveillance and preventative measures. Taking advantage of new modeling approaches and data sources have become necessary in an interconnected global community. To facilitate data collection, analysis, and decision-making, the number of spatial decision support systems reported in the last 10 years has increased. This systematic review aims to describe characteristics of spatial decision support systems developed to assist public health officials in the management of zoonotic disease outbreaks., Methods: A systematic search of the Google Scholar database was undertaken for published articles written between 2008 and 2018, with no language restriction. A manual search of titles and abstracts using Boolean logic and keyword search terms was undertaken using predefined inclusion and exclusion criteria. Data extraction included items such as spatial database management, visualizations, and report generation., Results: For this review we screened 34 full text articles. Design and reporting quality were assessed, resulting in a final set of 12 articles which were evaluated on proposed interventions and identifying characteristics were described. Multisource data integration, and user centered design were inconsistently applied, though indicated diverse utilization of modeling techniques., Conclusions: The characteristics, data sources, development and modeling techniques implemented in the design of recent SDSS that target zoonotic disease outbreak were described. There are still many challenges to address during the design process to effectively utilize the value of emerging data sources and modeling methods. In the future, development should adhere to comparable standards for functionality and system development such as user input for system requirements, and flexible interfaces to visualize data that exist on different scales. PROSPERO registration number: CRD42018110466.

Magnesium's complete in vivo degradation is appealing for medical implant applications. Rapid corrosion and hydrogen bubble generation along with inflammatory host tissue response have limited its clinical use. Here we electropolymerized a poly (3,4-ethylenedioxythiophene) (PEDOT) and graphene oxide (GO) film directly on Mg surface. GO acted as nano-drug carrier to carry anti-inflammatory drug dexamethasone (Dex). PEDOT/GO/Dex coatings improved Mg corrosion resistance and decreased the rate of hydrogen production. Dex could be released driven by the electrical current generated from Mg corrosion. The anti-inflammatory activity of the released Dex was confirmed in microglia cultures. This PEDOT/GO/Dex film displayed the ability to both control Mg corrosion and act as an on demand release coating that delivers Dex at the corrosion site to minimize detrimental effects of corrosion byproducts. Such multi-functional smart coating will improve the clinical use of Mg implants. Furthermore, the PEDOT/GO/Drug/Mg system may be developed into self-powered implantable drug delivery devices., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Surveillance of HIV drug resistance (HIVDR) is crucial to ensuring the continued success of antiretroviral therapy (ART) programs. With the concern of reduced genotyping sensitivity of HIV on dried blood spots (DBS), DBS for HIVDR surveillance have been limited to ART-naïve populations. To investigate if DBS under certain conditions may also be a feasible sample type for HIVDR testing in ART patients, we piloted nationwide surveys for HIVDR among ART patients using DBS in two African countries with rapid scale-up of ART., Methods: EDTA-venous blood was collected to prepare DBS from adult and pediatric ART patients receiving treatment during the previous 12-36 months. DBS were stored at ambient temperature for two weeks and then at -80°C until shipment at ambient temperature to the WHO-designated Specialized HIVDR Laboratory at CDC in Atlanta. Viral load (VL) was determined using NucliSENS EasyQ® HIV-1 v2.0 kits; HIVDR genotyping was performed using the ATCC HIV-1 Drug Resistance Genotyping kits., Results: DBS were collected from 1,368 and 1,202 ART patients; 244 and 255 these specimens had VL ≥1,000 copies/mL in Kenya and Tanzania, respectively. The overall genotyping rate of those DBS with VL ≥1,000 copies/mL was 93.0% (95% CI: 89.1%-95.6%) in Kenya and 91.8% (87.7%-94.6%) in Tanzania. The turnaround times for the HIVDR surveys from the time of collecting DBS to completing laboratory testing were 6.5 months and 9.3 months for the Kenya and Tanzania surveys, respectively., Conclusions: The study demonstrates a favorable outcome of using DBS for nationwide surveillance of HIVDR in ART patients. Our results confirm that DBS collected and stored at ambient temperature for two weeks, and shipped with routine courier services are a reliable sample type for large-scale surveillance of acquired HIVDR., Competing Interests: Chunfu Yang, Nicolas Wagar and Joshua DeVos are the inventors in U.S. patent application PCT/US2012/045523. This does not alter the authors’ adherence to all the journal’s policies on sharing data and materials.

A novel Al18F labelled peptide tracer for PET imaging of oxytocin receptor has been accessed through a high radiochemical yield approach. This tracer showed comparable affinity and higher selectivity and stability compared to oxytocin, and was used to demonstrate direct nose-to-brain uptake following intranasal administration, a common yet controversial delivery route for oxytocin-based therapeutics.

Oxytocin (OT) is an exciting potential therapeutic agent, but it is highly sensitive to modification and suffers extensive degradation at elevated temperature and in vivo. Here we report studies towards OT analogs with favorable selectivity, affinity and potency towards the oxytocin receptor (OTR), in addition to improving stability of the peptide by bridging the disulfide region with substituted dibromo-xylene analogs. We found a sensitive structure-activity relationship in which meta-cyclized analogs (dOT meta ) gave highest affinity (50 nM K i ), selectivity (34-fold), and agonist potency (34 nM EC 50 , 87-fold selectivity) towards OTR. Surprisingly, ortho-cyclized analogs demonstrated OTR and vasopressin V 1a receptor subtype affinity (220 nM and 69 nM, respectively) and pharmacological activity (294 nM and 35 nM, respectively). V 1a binding and selectivity for ortho-cyclized peptides could be improved 6-fold by substituting a neutral residue at position 8 with a basic amino acid, providing potent antagonists (14 nM IC 50 ) that displayed no activation of the OTR. Furthermore, xylene-bridged analogs demonstrated increased stability compared to OT at elevated temperature, demonstrating promising therapeutic potential for these analogs which warrants further study., (Copyright © 2018. Published by Elsevier Ltd.)

Intermediate level radioactive waste (ILW) generally contains a heterogeneous range of organic and inorganic materials, of which some are encapsulated in cement. Of particular concern are cellulosic waste items, which will chemically degrade under the conditions predicted during waste disposal, forming significant quantities of isosaccharinic acid (ISA), a strongly chelating ligand. ISA therefore has the potential to increase the mobility of a wide range of radionuclides via complex formation, including Ni-63 and Ni-59. Although ISA is known to be metabolized by anaerobic microorganisms, the biodegradation of metal-ISA complexes remains unexplored. This study investigates the fate of a Ni-ISA complex in Fe(III)-reducing enrichment cultures at neutral pH, representative of a microbial community in the subsurface. After initial sorption of Ni onto Fe(III)oxyhydroxides, microbial ISA biodegradation resulted in >90% removal of the remaining Ni from solution when present at 0.1 mM, whereas higher concentrations of Ni proved toxic. The microbial consortium associated with ISA degradation was dominated by close relatives to Clostridia and Geobacter species. Nickel was preferentially immobilized with trace amounts of biogenic amorphous iron sulfides. This study highlights the potential for microbial activity to help remove chelating agents and radionuclides from the groundwater in the subsurface geosphere surrounding a geodisposal facility.

Researchers have focused on preadolescents' appraisals, coping, and adjustment in the context of postdivorce interparental conflict, but have yet to assess their goals in these events. Fifty 9- to 12-year-old (52% female) preadolescents were interviewed to assess their goals for the coping strategies that they reported using in response to interparental conflict at home. The patterns observed were consistent with goal-oriented research in the peer conflict literature. Preadolescents reported goal orientations that matched (i.e., were functionally similar to) their respective behaviorally-based coping strategies, multiple goals for the same type of coping strategy, and multiple coping strategies for the same goal orientation. Relative to other coping strategies, preadolescents were more likely to choose a matching coping strategy to obtain social support, maintain self-boundary, and distraction goals. Relative to other goals, preadolescents' matching goal-strategy pairs occurred more frequently than nonmatching pairs, but these pairings accounted for about only one-third of the goals reported for a given strategy. Emotional regulation goal orientations more often than any other goal, which highlighted their importance in preadolescents coping with parental conflict. Finally, preadolescents' coping efforts were chosen for objectives beyond traditional category systems of coping, such as the personal characteristics of family members and others, helping others, and threats to self and others. Thus, the assessment of preadolescents' goals may improve our understanding of the motivations underlying their appraisals and coping strategies as they seek to adapt to interparental conflict environments.

Globally pharmacists are becoming increasingly involved in veterinary medicine; however, little is known about the level of interest for pharmacists playing a larger role in animal treatment in New Zealand. A key stakeholder in any progression of pharmacists becoming more involved in the practice of veterinary pharmacy is the veterinary profession. The aim of this study was to investigate views of veterinarians and veterinary students on the role of pharmacists supporting veterinarians with advice on animal medicines. Open interviews were conducted with veterinarians in Dunedin, New Zealand. Veterinary students at Massey University completed an online survey. Most veterinarians do not have regular communication with pharmacists regarding animal care, but believe it may be beneficial. In order to support veterinarians, pharmacists would need further education in veterinary medicine. Veterinary students believe there is opportunity for collaboration between professions provided that pharmacists have a better working knowledge of animal treatment. Most of the veterinary students surveyed perceive a gap in their knowledge concerning animal medicines, specifically pharmacology and compounding. While there is support for pharmacists contributing to veterinary medicine, particularly in the area of pharmaceutics, this is currently limited in New Zealand due to a lack of specialized education opportunities., Competing Interests: The authors declare no conflict of interest.

The Soladey™ toothbrush has a moisture-permeable titanium dioxide (TiO2) resin core in the replacement brush end of a handle activated by light conversion power cells. Purported to have an antibacterial effect and remove more plaque than an ordinary toothbrush, this study was undertaken to establish output measurements of the dry and wet TiO₂ core of the toothbrush during typical illumination of the handle, then quantify lipid peroxidation in three distinct lipid-containing solutions, and bactericidal effects in a live bacterial suspension grown from suctioned oral secretions., Methods: Within a range of illumination of the power cells in the handle, corresponding flow of electrons emitted from dry and wetted TiO2 cores was measured. The claim that an antibacterial effect can be attributed to generation of reactive oxygen-mediated lipid peroxidation of cell membranes was tested by exposing three lipid substrates to the light-activated ionic toothbrush tips for incremental periods of time. Products of lipid peroxidation were quantified using 3 commercially available assays, and bactericidal effects were assessed by scoring colony-forming units., Results: Illumination of the handle generated quantifiable increases in electrons flowing from the wetted TiO₂ core. Immersion of the TiO₂ core end of illuminated toothbrush handles into lipid substrates showed linear effects of incremental exposure times on products of lipid peroxidation, but no evidence of a bactericidal effect occurring within 15 minutes., Conclusions: This validates capacity of the wetted current- activated TiO₂ core to generate time-dependent lipid peroxides, particularly in the sonicated matrix containing disrupted cell membranes. Finding no time-dependent reduction in colony- forming units and less lipid peroxidation in a suspension of intact cells casts doubt that the ionic toothbrush has an immediate antibacterial effect while brushing teeth. If a toothbrush with a TiO₂ core is self-disinfecting between uses, bactericidal effects requiring longer periods of exposure might still confer a hygienic advantage.

The recent Ebola virus outbreak in West Africa clearly demonstrated the critical role of laboratory systems and networks in responding to epidemics. Because of the huge challenges in establishing functional laboratories at all tiers of health systems in developing countries, strengthening specimen referral networks is critical. In this review article, we propose a platform strategy for developing specimen referral networks based on 2 models: centralized and decentralized laboratory specimen referral networks. These models have been shown to be effective in patient management in programs in resource-limited settings. Both models lead to reduced turnaround time and retain flexibility for integrating different specimen types. In Haiti, decentralized specimen referral systems resulted in a 182% increase in patients enrolling in human immunodeficiency virus treatment programs within 6 months. In Uganda, cost savings of up to 62% were observed with a centralized model. A platform strategy will create a network effect that will benefit multiple disease programs., (Published by Oxford University Press for the Infectious Diseases Society of America 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Early diagnosis of HIV infection in infants and children remains a challenge in resource-limited settings, with approximately half of all HIV-exposed infants receiving virological testing for HIV by the recommended age of 2 months in 2015. To reduce morbidity and mortality among HIV-infected children and close the treatment gap for HIV-infected children, there is an urgent need to evaluate existing programmatic and laboratory practices for early infant diagnosis and introduce strategies to improve identification of HIV-exposed infants and ensure access to systematic, early HIV testing, with early linkage to treatment for HIV-infected infants. This article describes progress made in follow-up of HIV-exposed infants since 2006, including remaining unmet laboratory and programmatic needs, and recommends strategies for improvement, especially those related to the implementation of point-of-care technology for early infant diagnosis.

Pediatric human immunodeficiency virus (HIV) infection remains an important public health issue in resource-limited settings. In 2015, 1.4 million children aged <15 years were estimated to be living with HIV (including 170,000 infants born in 2015), with the vast majority living in sub-Saharan Africa (1). In 2014, 150,000 children died from HIV-related causes worldwide (2). Access to timely HIV diagnosis and treatment for HIV-infected infants reduces HIV-associated mortality, which is approximately 50% by age 2 years without treatment (3). Since 2011, the annual number of HIV-infected children has declined by 50%. Despite this gain, in 2014, only 42% of HIV-exposed infants received a diagnostic test for HIV (2), and in 2015, only 51% of children living with HIV received antiretroviral therapy (1). Access to services for early infant diagnosis of HIV (which includes access to testing for HIV-exposed infants and clinical diagnosis of HIV-infected infants) is critical for reducing HIV-associated mortality in children aged <15 years. Using data collected from seven countries supported by the U.S. President's Emergency Plan for AIDS Relief (PEPFAR), progress in the provision of HIV testing services for early infant diagnosis was assessed. During 2011-2015, the total number of HIV diagnostic tests performed among HIV-exposed infants within 6 weeks after birth (tests for early infant diagnosis of HIV), as recommended by the World Health Organization (WHO) increased in all seven countries (Cote d'Ivoire, the Democratic Republic of the Congo, Haiti, Malawi, South Africa, Uganda, and Zambia); however, in 2015, the rate of testing for early infant diagnosis among HIV-exposed infants was <50% in five countries. HIV positivity among those tested declined in all seven countries, with three countries (Cote d'Ivoire, the Democratic Republic of the Congo, and Uganda) reporting >50% decline. The most common challenges for access to testing for early infant diagnosis included difficulties in specimen transport, long turnaround time between specimen collection and receipt of results, and limitations in supply chain management. Further reductions in HIV mortality in children can be achieved through continued expansion and improvement of services for early infant diagnosis in PEPFAR-supported countries, including initiatives targeted to reach HIV-exposed infants, ensure access to programs for early infant diagnosis of HIV, and facilitate prompt linkage to treatment for children diagnosed with HIV infection.

Objective: The metadata reflecting the location of the infected host (LOIH) of virus sequences in GenBank often lacks specificity. This work seeks to enhance this metadata by extracting more specific geographic information from related full-text articles and mapping them to their latitude/longitudes using knowledge derived from external geographical databases., Materials and Methods: We developed a rule-based information extraction framework for linking GenBank records to the latitude/longitudes of the LOIH. Our system first extracts existing geospatial metadata from GenBank records and attempts to improve it by seeking additional, relevant geographic information from text and tables in related full-text PubMed Central articles. The final extracted locations of the records, based on data assimilated from these sources, are then disambiguated and mapped to their respective geo-coordinates. We evaluated our approach on a manually annotated dataset comprising of 5728 GenBank records for the influenza A virus., Results: We found the precision, recall, and f-measure of our system for linking GenBank records to the latitude/longitudes of their LOIH to be 0.832, 0.967, and 0.894, respectively., Discussion: Our system had a high level of accuracy for linking GenBank records to the geo-coordinates of the LOIH. However, it can be further improved by expanding our database of geospatial data, incorporating spell correction, and enhancing the rules used for extraction., Conclusion: Our system performs reasonably well for linking GenBank records for the influenza A virus to the geo-coordinates of their LOIH based on record metadata and information extracted from related full-text articles., (© The Author 2016. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: IL-1β is a cytokine involved in mediating epithelial barrier dysfunction in the gut. It is known that IL-1β mediates activation of non-muscle myosin light chain kinase in epithelial cells, but the precise mechanism by which epithelial barrier dysfunction is induced by IL-1β is not understood., Methods and Results: Using a Caco2 cell model, we show that the expression of the tight junction protein, claudin-3, is transcriptionally downregulated by IL-1β treatment. In addition, after assessing protein and mRNA expression, and protein localization, we show that inhibition of nmMLCK rescues IL-1β-mediated decrease in claudin-3 expression as well as junction protein redistribution. Using chromatin immunoprecipitation assays, we also show that β-catenin targeting of the claudin-3 promoter occurs as a consequence of IL-1β-mediated epithelial barrier dysfunction, and inhibition of nmMLCK interferes with this interaction., Conclusions: Taken together, these data represent the first line of evidence demonstrating nmMLCK regulation of claudin-3 expression in response to IL-1β-treated epithelial cells.

The annual influenza vaccine is one of the most common public health interventions and is universally recommended for all individuals older than six months. Vaccine composition depends on viruses circulating over the past flu season and are estimated to be the most prevalent and representative strains in the current season. Here, we use clinical data outfitted with viral genetics to characterize confirmed influenza cases from the past two flu seasons and genetically compare them to the strains that they were vaccinated against that year. We show that case similarities to vaccine strains differ by geographic region and that the vaccines appear to have different levels of effectiveness by region. This study demonstrates the value of merging viral genetics with clinical data. Further research is needed to formally evaluate whether this improves biosurveillance efforts and enhances efficacy of influenza vaccines.

Unlabelled: Diseases caused by zoonotic viruses (viruses transmittable between humans and animals) are a major threat to public health throughout the world. By studying virus migration and mutation patterns, the field of phylogeography provides a valuable tool for improving their surveillance. A key component in phylogeographic analysis of zoonotic viruses involves identifying the specific locations of relevant viral sequences. This is usually accomplished by querying public databases such as GenBank and examining the geospatial metadata in the record. When sufficient detail is not available, a logical next step is for the researcher to conduct a manual survey of the corresponding published articles., Motivation: In this article, we present a system for detection and disambiguation of locations (toponym resolution) in full-text articles to automate the retrieval of sufficient metadata. Our system has been tested on a manually annotated corpus of journal articles related to phylogeography using integrated heuristics for location disambiguation including a distance heuristic, a population heuristic and a novel heuristic utilizing knowledge obtained from GenBank metadata (i.e. a 'metadata heuristic')., Results: For detecting and disambiguating locations, our system performed best using the metadata heuristic (0.54 Precision, 0.89 Recall and 0.68 F-score). Precision reaches 0.88 when examining only the disambiguation of location names. Our error analysis showed that a noticeable increase in the accuracy of toponym resolution is possible by improving the geospatial location detection. By improving these fundamental automated tasks, our system can be a useful resource to phylogeographers that rely on geospatial metadata of GenBank sequences. ., (© The Author 2015. Published by Oxford University Press.)

A key event in the progression of systemic inflammation resulting from severe trauma or shock involves microvascular hyperpermeability, which leads to excessive plasma fluid and proteins accumulating in extravascular space resulting in tissue edema. The precise molecular mechanism of the hyperpermeability response is not completely understood. Protein tyrosine kinase 6 (PTK6, also known as breast tumor kinase BRK) is a non-receptor tyrosine kinase related to Src-family proteins. Although it has also been shown that PTK6 participates in regulating epithelial barrier function, the role of PTK6 in endothelial barrier function has not been reported. In this study, we hypothesized that PTK6 is (1) expressed in vascular endothelial cells, and (2) contributes to vascular endothelial hyperpermeability in response to TNFα. Results showed that PTK6 was detected in mouse endothelial cells at the level of protein and mRNA. In addition, PTK6 knockdown attenuated TNFα induced decrease in endothelial barrier function as measured by electric cell-substrate impedance sensing (ECIS) and in vitro transwell albumin-flux assays. Furthermore, we showed that TNFα treatment of endothelial cells increased active PTK6 association with p120-catenin at endothelial cell-cell junctions. Further analysis using immunocytochemistry and immunoprecipitation demonstrated that PTK6 knockdown attenuated TNFα induced VE-cadherin internalization as well as promoting its association with p120-catenin. Our study demonstrates a novel role of PTK6 in mediating endothelial barrier dysfunction., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Emerging and re-emerging infectious diseases of zoonotic origin like highly pathogenic avian influenza pose a significant threat to human and animal health due to their elevated transmissibility. Identifying the drivers of such viruses is challenging, and estimation of spatial diffusion is complicated by the fact that the variability of viral spread from locations could be caused by a complex array of unknown factors. Several techniques exist to help identify these drivers, including bioinformatics, phylogeography, and spatial epidemiology, but these methods are generally evaluated separately and do not consider the complementary nature of each other. Here, we studied an approach that integrates these techniques and identifies the most important drivers of viral spread by focusing on H5N1 influenza A virus in Egypt because of its recent emergence as an epicenter for the disease. We used a Bayesian phylogeographic generalized linear model (GLM) to reconstruct spatiotemporal patterns of viral diffusion while simultaneously assessing the impact of factors contributing to transmission. We also calculated the cross-species transmission rates among hosts in order to identify the species driving transmission. The densities of both human and avian species were supported contributors, along with latitude, longitude, elevation, and several meteorological variables. Also supported was the presence of a genetic motif found near the hemagglutinin cleavage site. Various genetic, geographic, demographic, and environmental predictors each play a role in H1N1 diffusion. Further development and expansion of phylogeographic GLMs such as this will enable health agencies to identify variables that can curb virus diffusion and reduce morbidity and mortality.

As more HIV-infected people gain access to antiretroviral therapy (ART), monitoring HIV drug resistance (HIVDR) becomes essential to combat both acquired and transmitted HIVDR. Studies have demonstrated dried blood spots (DBS) are a suitable alternative in HIVDR monitoring using DBS collected on Whatman 903 (W-903). In this study, we sought to evaluate two other commercially available filter papers, Ahlstrom 226 (A-226) and Munktell TFN (M-TFN), for HIVDR genotyping following ambient temperature storage. DBS were prepared from remnant blood specimens collected from 334 ART patients and stored at ambient temperature for a median time of 30 days. HIV-1 viral load was determined using NucliSENS EasyQ® HIV-1 v2.0 RUO test kits prior to genotyping of the protease and reverse transcriptase regions of the HIV-1 pol gene using an in-house assay. Among the DBS tested, 26 specimens had a viral load ≥ 1000 copies/mL in all three types of filter paper and were included in the genotyping analysis. Genotyping efficiencies were similar between DBS collected on W-903 (92.3%), A-226 (88.5%), and M-TFN (92.3%) filter papers (P = 1.00). We identified 50 DR-associated mutations in DBS collected on W-903, 33 in DBS collected on A-226, and 48 in DBS collected on M-TFN, resulting in mutation detection sensitivities of 66.0% for A-226 and 88.0% for M-TFN when compared to W-903. Our data indicate that differences among filter papers may exist at this storage condition and warrant further studies evaluating filter paper type for HIVDR monitoring.

Zoonotic viruses represent emerging or re-emerging pathogens that pose significant public health threats throughout the world. It is therefore crucial to advance current surveillance mechanisms for these viruses through outlets such as phylogeography. Despite the abundance of zoonotic viral sequence data in publicly available databases such as GenBank, phylogeographic analysis of these viruses is often limited by the lack of adequate geographic metadata. However, many GenBank records include references to articles with more detailed information and automated systems may help extract this information efficiently and effectively. In this paper, we describe our efforts to determine the proportion of GenBank records with "insufficient" geographic metadata for seven well-studied viruses. We also evaluate the performance of four different Named Entity Recognition (NER) systems for automatically extracting related entities using a manually created gold-standard.