Recent Submissions

  • Insights into the Experience of Liver Transplant Recipients with Alcoholic Liver Disease: A Descriptive Qualitative Study

    Hochheimer, M.; Moreland, M.L.; Tuten, M.; Lamattina, J.; Connelly, M.; Sacco, P. (Wolters Kluwer Health, 2019)
    Background. Alcoholic liver disease (ALD) due to alcohol use disorder (AUD) is the primary cause of liver transplantation (LT) in the United States. Studies have found that LT recipients experience a range of physical and emotional difficulties posttransplantation including return to alcohol use, depression, and anxiety. The aim of this study is to better understand the experiences of LT recipients with ALD because they recovered posttransplant to inform the development of a patient-centered intervention to assist patients during recovery. Methods. Using qualitative methods, researchers conducted semi-structured interviews with 16 ALD LT recipients. The primary topics of the interview were physical recovery, mental health, substance use including alcohol and tobacco use, and financial experiences. Common patient themes were identified and coded. Results. Within the domain of physical health, patients stressed that undergoing LT was a near-death experience, they were helpless, changes in weight influenced their perception of their illness, and they have ongoing medical problems. In the domain of mental health, patients described cognitive impairments during their initial recovery, difficulty in processing the emotions of having a terminal condition, ongoing depression, anxiety, and irritability. The patients also described their perception of having AUD, the last time they used alcohol and their attitude to AUD treatment posttransplant. Patients also described their reliance on one member of their social support network for practical assistance during their recovery and identified one member of their medical team as being of particular importance in providing emotional as well as medical support during recovery. Conclusions. The patient's description of their lived experience during the months following transplant informed the development of a patient-centered intervention that colocates behavioral health components with medical treatment that helps broaden their social network while addressing topics that emerged from this study. Copyright 2019 The Author(s).
  • A new bioinformatic pipeline allows the design of small, targeted gene panels for efficient TMB estimation

    Manca, P.; Mallona, I.; Rolfo, C.D. (Elsevier Ltd, 2019)
    Background: The tumor mutation burden (TMB) is emerging as a prognostic and predictive marker for the response to immune checkpoint blockade (ICB) drugs. We aimed to develop a new method for the definition of gene panels that can precisely estimate the TMB with a considerably lower amount of genome. Methods: We developed a bioinformatic pipeline which allows the design of gene panels suited for TMB estimation. The method is particularly efficient in optimizing the balance between the precision of the TMB estimate and the length of the gene panel created. We tested in silico the efficiency of different panels obtained with our method in an independent cohort of patients with lung adenocarcinoma (LUAD). We also compared in the same cohort of patients the performance of our panels with the performance of existing gene panels. Results: We designed a 0.080 Megabases (Mb) long gene panel which estimated TMB in an independent LUAD cohort with an acceptable precision (adjusted R2=0.745; Spearman ρ = 0.827, Pearson ρ = 0.864). The panel showed 0.89 accuracy in the identification of TMB-high patients (25/28 patients, CI: 0.73 – 0.96). Every unitary increase of our TMB estimate was associated with lower risk of disease progression (univariate analysis: HR = 0.78; CI: 0.65-0.93; p = 0.006; multivariate analysis: HR = 0.8; CI: 0.63-1.01; p = 0.0621). Different existing panels of less than 1 Mb long showed a lower adjusted R2 when compared to our gene panel (Table). Two other commercial panels of 1.9 Mb and 1.1 Mb showed a similar adjusted R2 to panels of the same lengths built with our method; nevertheless, they showed a lower accuracy in TMB-high patients definition (ROC curves AUC of 0.862, 0.870, 0.946 and 0.967 were observed, respectively, for the commercial 1.9 Mb panel, the commercial 1.1 Mb panel, our 0.080 Mb panel and our 2.0 Mb panel).
  • Blood Pressure and Living Kidney Donors: A Clinical Perspective

    Rastogi, A.; Bromberg, J.S.; Weir, M.R. (Wolters Kluwer Health, 2019)
    Elevated blood pressure (BP), or "hypertension," has been one of the main exclusion criteria for living kidney donation, as it is a risk factor for renal and cardiovascular disease. The effect of elevated BP in living kidney donors is not well studied or understood. The most current living kidney donation guidelines state that donors with a BP >140/90 mm Hg with 1-2 antihypertensive medications or evidence of end-organ damage should be excluded from living kidney donation. Yet, the definitions of "hypertension" have changed with the release of the American Heart Association (AHA)/American College of Cardiology (ACC) clinical practice guidelines suggesting that 120-129 mm Hg is elevated BP and Stage 1 hypertension is 130 mm Hg. However, the kidney function (in terms of estimated GFR) of "hypertensive" living kidney donors does not fare significantly worse postdonation compared with that of "normotensive" donors. In addition, even though living kidney donation itself is not considered to be a risk factor for developing hypertension, there exist certain risk factors (African American or Hispanic descent, obesity, age) that may increase the risk of living kidney donors developing elevated BP postdonation. The choice of BP targets and medications needs to be carefully individualized. In general, a BP <130/80 mm Hg is needed, along with lifestyle modifications. Copyright 2019 The Author(s).
  • Intra-Abdominal Heterotopic Cardiac Xenotransplantation: Pearls and Pitfalls

    DiChiacchio, L.; Singh, A.K.; Shockcor, N.M.; Zhang, T.; Lewis, B.G.; Mohiuddin, M.M. (Frontiers Media S.A., 2019)
    Heterotopic cardiac xenotransplantation in the intra-abdominal position has been studied extensively in a pig-to-baboon model to define the optimal donor genetics and immunosuppressive regimen to prevent xenograft rejection. Extensive investigation using this model is a necessary stepping stone toward the development of a life-supporting animal model, with the ultimate goal of demonstrating suitability for clinical cardiac xenotransplantation trials. Aspects of surgical technique, pre- and post-operative care, graft monitoring, and minimization of infectious risk have all required refinement and optimization of heterotopic cardiac xenotransplantation over time. This review details non-immunologic obstacles relevant to this model described by our group and in the literature, as well as strategies that have been developed to address these specific challenges. Copyright 2019 The Authors.
  • Infrastructure and organization of adult intensive care units in resource-limited settings

    Papali, A.; Adhikari, N.K.J.; Diaz, J.V. (Springer International Publishing, 2019)
    In this chapter, we provide guidance on some basic structural requirements, focusing on organization, staffing, and infrastructure. We suggest a closed-format intensive care unit (ICU) with dedicated physicians and nurses, specifically trained in intensive care medicine whenever feasible. Regarding infrastructural components, a reliable electricity supply is essential, with adequate backup systems. Facilities for oxygen therapy are crucial, and the choice between oxygen concentrators, cylinders, and a centralized system depends on the setting. For use in mechanical ventilators, a centralized piped system is preferred. Facilities for proper hand hygiene are essential. Alcohol-based solutions are preferred, except in the context of Ebola virus disease (chloride-based solutions) and Clostridium difficile infection (soap and water). Availability of disposable gloves is important for self-protection; for invasive procedures masks, caps, sterile gowns, sterile drapes, and sterile gloves are recommended. Caring for patients with highly contagious infectious diseases requires access to personal protective equipment. Basic ICU equipment should include vital signs monitors and mechanical ventilators, which should also deliver noninvasive ventilator modes. We suggest that ICUs providing invasive ventilatory support have the ability to measure end-tidal carbon dioxide and if possible can perform blood gas analysis. We recommend availability of glucometers and capabilities for measuring blood lactate. We suggest implementation of bedside ultrasound as diagnostic tool. Finally, we recommend proper administration of patient data; suggest development of locally applicable bundles, protocols, and checklists for the management of sepsis; and implement systematic collection of quality and performance indicators to guide improvements in ICU performance.
  • Current challenges in the management of sepsis in icus in resource-poor settings and suggestions for the future

    Schultz, M.J.; Papali, A.; Dünser, M.W. (Springer International Publishing, 2019)
    Sepsis is a major cause of critical illness worldwide, especially in resource-poor settings. Intensive care units (ICUs) in low- and middle-income countries (LMICs) face many challenges that could affect patient outcome. The aim of this review is to describe differences between resource-poor and resource-rich settings regarding the epidemiology, pathophysiology, economics, and research aspects of sepsis. We restricted this manuscript to the ICU setting although we are aware that many sepsis patients in LMICs are treated outside an ICU. Although many bacterial pathogens causing sepsis in LMICs are similar to those in high-income countries, resistance patterns to antimicrobial drugs can be very different; in addition, causes of sepsis in LMICs often include tropical diseases in which direct damaging effects of pathogens and their products can be more important than the host response. There are differences in ICU capacities around the world; not surprisingly the lowest capacities are found in LMICs with important heterogeneity within individual LMICs. Although many aspects of sepsis management developed in resource-rich countries are applicable in LMICs, implementation requires strong consideration of cost implications and important differences in resources. Addressing both disease-specific and setting-specific factors is important to improve performance of ICUs in LMICs. Although critical care for sepsis is likely cost-effective in LMIC setting, more detailed evaluation at both a macro- and micro-economy level is necessary. Sepsis management in resource-limited settings is a largely unexplored frontier with important opportunities for research, training, and other initiatives for improvement.
  • Real-world experience with ceftazidime-avibactam for multidrug-resistant gram-negative bacterial infections

    Jorgensen, S.C.J.; Trinh, T.D.; Claeys, K.C. (Oxford University Press, 2019)
    Background. We conducted this study to describe the clinical characteristics, microbiology, and outcomes of patients treated with ceftazidime-avibactam (CZA) for a range of multidrug-resistant Gram-negative (MDR-GN) infections. Methods. This is a multicenter, retrospective cohort study conducted at 6 medical centers in the United States between 2015 and 2019. Adult patients who received CZA (?72 hours) were eligible. The primary outcome was clinical failure defined as a composite of 30-day all-cause mortality, 30-day microbiological failure, and/or failure to resolve or improve signs or symptoms of infection on CZA. Results. In total, data from 203 patients were evaluated. Carbapenem-resistant Enterobacteriaceae (CRE) and Pseudomonas spp were isolated from 117 (57.6%) and 63 (31.0%) culture specimens, respectively. The most common infection sources were respiratory (37.4%), urinary (19.7%), and intra-abdominal (18.7%). Blood cultures were positive in 22 (10.8%) patients. Clinical failure, 30-day mortality, and 30-day recurrence occurred in 59 (29.1%), 35 (17.2%), and 12 (5.9%) patients, respectively. On therapy, CZA resistance developed in 1 of 62 patients with repeat testing. Primary bacteremia or respiratory tract infection and higher SOFA score were positively associated with clinical failure (adjusted odds ratio [aOR] = 2.270, 95% confidence interval [CI] = 1.115-4.620 and aOR = 1.234, 95% CI = 1.118–1.362, respectively). Receipt of CZA within 48 hours of infection onset was protective (aOR, 0.409; 95% CI, 0.180-0.930). Seventeen (8.4%) patients experienced a potential drug-related adverse effect (10 acute kidney injury, 3 Clostridioides difficile infection, 2 rash, and 1 each gastrointestinal intolerance and neutropenia) Conclusions. Ceftazidime-avibactam is being used to treat a range of MDR-GN infections including Pseudomonas spp as well as CRE. Copyright The Author(s) 2019.
  • A single dose of modified vaccinia ankara expressing lassa virus-like particles protects mice from lethal intra-cerebral virus challenge

    Salvato, M.S.; Medina-Moreno, S.; Zapata, J.C.; Hsu, H.; Guzmán-Cardozo, C. (MDPI AG, 2019)
    Lassa fever surpasses Ebola, Marburg, and all other hemorrhagic fevers except Dengue in its public health impact. Caused by Lassa virus (LASV), the disease is a scourge on populations in endemic areas of West Africa, where reported incidence is higher. Here, we report construction, characterization, and preclinical efficacy of a novel recombinant vaccine candidate GEO-LM01. Constructed in the Modified Vaccinia Ankara (MVA) vector, GEO-LM01 expresses the glycoprotein precursor (GPC) and zinc-binding matrix protein (Z) from the prototype Josiah strain lineage IV. When expressed together, GP and Z form Virus-Like Particles (VLPs) in cell culture. Immunogenicity and efficacy of GEO-LM01 was tested in a mouse challenge model. A single intramuscular dose of GEO-LM01 protected 100% of CBA/J mice challenged with a lethal dose of ML29, a Mopeia/Lassa reassortant virus, delivered directly into the brain. In contrast, all control animals died within one week. The vaccine induced low levels of antibodies but Lassa-specific CD4+ and CD8+ T cell responses. This is the first report showing that a single dose of a replication-deficient MVA vector can confer full protection against a lethal challenge with ML29 virus. Copyright 2019 by the authors.
  • Late-onset renal hypertrophy and dysfunction in mice lacking CTRP1

    Rodriguez, S.; Little, H.C.; Woodward, O.M. (John Wiley and Sons Inc., 2019)
    Local and systemic factors that influence renal structure and function in aging are not well understood. The secretory protein C1q/TNF-related protein 1 (CTRP1) regulates systemic metabolism and cardiovascular function. We provide evidence here that CTRP1 also modulates renal physiology in an age- and sex-dependent manner. In mice lacking CTRP1, we observed significantly increased kidney weight and glomerular hypertrophy in aged male but not female or young mice. Although glomerular filtration rate, plasma renin and aldosterone levels, and renal response to water restriction did not differ between genotypes, CTRP1-deficient male mice had elevated blood pressure. Echocardiogram and pulse wave velocity measurements indicated normal heart function and vascular stiffness in CTRP1-deficient animals, and increased blood pressure was not due to greater salt retention. Paradoxically, CTRP1-deficient mice had elevated urinary sodium and potassium excretion, partially resulting from reduced expression of genes involved in renal sodium and potassium reabsorption. Despite renal hypertrophy, markers of inflammation, fibrosis, and oxidative stress were reduced in CTRP1-deficient mice. RNA sequencing revealed alterations and enrichments of genes in metabolic processes in CTRP1-deficient animals. These results highlight novel contributions of CTRP1 to aging-associated changes in renal physiology.
  • Benefit-risk assessment of nivolumab 240 mg flat dose relative to 3 mg/kg Q2W regimen in Japanese patients with advanced cancers

    Bei, D.; Osawa, M.; Gobburu, J. (Blackwell Publishing Ltd, 2019)
    Nivolumab 3 mg/kg every 2 weeks (Q2W) has been approved in Japan for various cancers; however, use of a flat dose is expected to simplify dosing and administration. A quantitative clinical pharmacology approach was used to assess the benefit-risk profile of nivolumab 240 mg Q2W relative to the approved dose of nivolumab 3 mg/kg Q2W in Japanese patients. Three exposure-response safety analyses were performed for adverse events that led to discontinuation/death, were grade 3 or higher, and were immune-mediated and grade 2 or higher for Japanese patients diagnosed with one of multiple tumor types. Exposure-response analyses of efficacy were evaluated for overall survival and objective response rate. Exposures of nivolumab 240 mg Q2W were 37% higher than those of nivolumab 3 mg/kg Q2W in Japanese patients across the tumor types analyzed. Predicted safety profiles at the two doses differed by less than 2% across tumor types for adverse events leading to discontinuation/death, adverse events of grade 3 or higher, or immune-mediated adverse events of grade 2 or higher. In addition, the predicted 1-year and 2-year overall survival rates, the mean overall survival and the objective response rates were comparable between the doses regardless of the tumor type analyzed. Overall, these results demonstrated that the benefit-risk of nivolumab 240 mg Q2W was comparable to that of the previously approved 3 mg/kg Q2W dosing regimen, and was the basis for the approval of the 240 mg Q2W as an alternative dosing regimen for treatment in Japanese patients across multiple tumor types. Copyright 2019 The Authors.
  • Mesencephalic Astrocyte-Derived Neurotrophic Factor Inhibits Liver Cancer Through Small Ubiquitin-Related Modifier (SUMO)ylation-Related Suppression of NF-κB/Snail Signaling Pathway and Epithelial-Mesenchymal Transition

    Liu, J.; Wu, Z.; Fang, S. (John Wiley and Sons Inc., 2019)
    Background and Aims: Endoplasmic reticulum (ER) stress is associated with liver inflammation and hepatocellular carcinoma (HCC). However, how ER stress links inflammation and HCC remains obscure. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an ER stress-inducible secretion protein that inhibits inflammation by interacting with the key subunit of nuclear factor kappa light chain enhancer of activated B cells (NF-κB) p65. We hypothesized that MANF may play a key role in linking ER stress and inflammation in HCC. Approach and Results: Here, we found that MANF mRNA and protein levels were lower in HCC tissues versus adjacent noncancer tissues. Patients with high levels of MANF had better relapse-free survival and overall survival rates than those with low levels. MANF levels were also associated with the status of liver cirrhosis, advanced tumor-node-metastasis (TNM) stage, and tumor size. In vitro experiments revealed that MANF suppressed the migration and invasion of hepatoma cells. Hepatocyte-specific deletion of MANF accelerated N-nitrosodiethylamine (DEN)-induced HCC by up-regulating Snail1+2 levels and promoting epithelial-mesenchymal transition (EMT). MANF appeared in the nuclei and was colocalized with p65 in HCC tissues and in tumor necrosis factor alpha (TNF-α)-treated hepatoma cells. The interaction of p65 and MANF was also confirmed by coimmunoprecipitation experiments. Consistently, knockdown of MANF up-regulated NF-κB downstream target genes TNF-α, interleukin (IL)-6 and IL-1α expression in vitro and in vivo. Finally, small ubiquitin-related modifier 1 (SUMO1) promoted MANF nuclear translocation and enhanced the interaction of MANF and p65. Mutation of p65 motifs for SUMOylation abolished the interaction of p65 and MANF. Conclusions: MANF plays an important role in linking ER stress and liver inflammation by inhibiting the NF-κB/Snail signal pathway in EMT and HCC progression. Therefore, MANF may be a cancer suppressor and a potential therapeutic target for HCC. Copyright 2019 The Authors.
  • Testosterone in Men With Chronic Hepatitis C Infection and After Hepatitis C Viral Clearance

    Chaudhury, C.S.; Mee, T.; Chairez, C.; McLaughlin, M.; Silk, R.; Gross, C.; Kattakuzhy, S.; Rosenthal, E.; Kottilil, S.; Hadigan, C. (Oxford University Press, 2019)
    BACKGROUND: Hepatitis C virus (HCV) and hepatic dysfunction are associated with low total and free testosterone (TT and FT) and high sex hormone-binding globulin (SHBG). However, little is known about changes in testosterone following successful HCV treatment. METHODS: We evaluated testosterone levels and the prevalence of low testosterone in a cohort of 327 men with chronic HCV infection (human immunodeficiency virus [HIV] coinfection = 150) and in a subset of 85 men with testosterone levels obtained pre-HCV treatment and after sustained virologic response (SVR). Median follow-up was 36 months. RESULTS: Participants with active HCV at baseline had higher TT (P < .0001) and SHBG (P < .0001) compared with participants who had achieved SVR, whereas FT did not differ. Low TT (<10.4 nmol/L) was more prevalent in participants with SVR compared with active HCV (P = .002); however, low FT (<0.1735 nmol/L) was common (50% active HCV, 43% SVR) and did not different between groups. For participants with longitudinal determinations, TT and SHBG decreased significantly (P < .0001) while FT remained unchanged post-SVR. Low FT persisted after SVR (pre-treatment 58%, post-SVR 54%, P = .72). HIV status and change in aspartate aminotrasferase-to-platelet ratio were significant independent predictors of change in FT following SVR. CONCLUSIONS: During active HCV infection, testosterone deficiency may be masked due to elevated SHBG. Despite improvements in SHBG following SVR, low FT was common and persisted after HCV clearance, indicating the need for enhanced awareness and screening using estimates of FT following successful treatment of chronic HCV. CLINICAL TRIALS REGISTRATION: NCT01350648.
  • Participation and consultation engagement strategies have complementary roles: A case study of patient and public involvement in clinical practice guideline development

    Armstrong, M.J.; Gronseth, G.S.; Mullins, C.D. (Blackwell Publishing Ltd, 2019)
    Background: Patient and public involvement (PPI) is recommended when developing high-quality clinical practice guidelines, but the effects of different PPI strategies are largely unstudied. Objective: To assess the impact of participation and consultation strategies on guideline question development. Design: Instrumental case study design. Setting and participants: This study used a clinical practice guideline in development by the American Academy of Neurology. A patient, two caregivers and a dementia advocate participated in the guideline development group alongside clinicians. The guideline protocol was posted for public consultation for 30 days. Interventions studied: Participation (patient representatives on the guideline development group) and consultation (public comment, survey) PPI strategies. Main outcome measures: Public comment responses and guideline development group meeting transcripts were analysed descriptively. Transcript quotes were compared to the conceptual model of PPI in guideline development. The effects of participation and consultation strategies within the guideline case were compared. Results: Participation strategies shaped discussions, set a patient-centred scope, highlighted personal aspects of disease, affected how professionals viewed PPI, identified issues overlooked by medical professionals, and contributed to selecting patient-relevant guideline populations and outcomes. Professionals responded to public comment more than patient representatives. Patient survey participants confirmed the priorities voiced by patient representatives on the guideline development group. Final guideline questions included populations and outcomes promoted by patient representatives despite negative feedback from professional public commenters. Discussion and conclusions: Participation and consultation PPI strategies have different advantages. Congruence between strategies increases the strength of the patient voice. Guideline developers should prioritize using both strategies for successful PPI. Copyright 2019 The Authors.
  • A Case of Complex and Abnormal Behaviors at Night: The Role of the Epilepsy Monitoring Unit in Diagnosis

    Diaz-Abad, M.; Sanchez A.M.; Kabir, A. (S. Karger AG, 2019)
    Complex nocturnal behaviors associated with sleep have many potential causes, including parasomnias and epilepsy. Although the type of event and description can frequently lead to a diagnosis, sometimes it is challenging clinically to determine the cause of the behaviors, requiring a more in-depth investigation. We report the case of a 29-year-old woman with a long history of complex abnormal behaviors and visual hallucinations at night. An extensive clinical evaluation failed to reveal a definitive cause of these episodes, prompting a 3-day epilepsy monitoring unit admission. During the stay, several events were captured on video electroencephalography, leading to a conclusive final diagnosis. This case highlights the challenging task of finding a definitive diagnosis in cases of complex nocturnal behaviors and the potential role of an admission to an epilepsy monitoring unit to help diagnose the cause of these behaviors. Copyright 2020 The Author(s).
  • A randomised single-centre trial of inhaled liposomal cyclosporine for bronchiolitis obliterans syndrome post-lung transplantation

    Iacono, A.; Wijesinha, M.; Murdock, N.; Timofte, I.; Griffith, B.; Terrin, M. (European Respiratory Society, 2019)
    Introduction: No proven treatments exist for bronchiolitis obliterans syndrome (BOS) following lung transplantation. Inhaled liposomal cyclosporine (L-CsA) may prevent BOS progression. Methods: A 48-week phase IIb randomised clinical trial was conducted in 21 lung transplant patients with BOS assigned to either L-CsA with standard-of-care (SOC) oral immunosuppression (L-CsA group) or SOC (SOC-alone group). Efficacy end-points were BOS progression-free survival (defined as absence of ⩾20% decline in forced expiratory volume in 1 s (FEV1) from randomisation, re-transplantation or death) and BOS grade change. Results: BOS progression-free survival was 82% for L-CsA versus 50% for SOC-alone (p=0.1) and BOS grade worsened in 18% for L-CsA versus 60% for SOC-alone (p=0.05). Mean changes in ΔFEV1 and forced vital capacity, respectively, stabilised with L-CsA: +0.005 (95% CI −0.004–+0.013) and −0.005 (95% CI −0.015–+0.006) L·month−1, but worsened with SOC-alone: −0.023 (95% CI −0.033–−0.013) and −0.026 (95% CI −0.039–−0.014) L·month−1 (p<0.0001 and p=0.009). Median survival (4.1 versus 2.9 years; p=0.03) and infection rate (45% versus 60%; p=0.7) improved with L-CsA versus SOC-alone; creatinine and tacrolimus levels were similar. Conclusions: L-CsA was well tolerated and stabilised lung function in lung transplant recipients affected by BOS without systemic toxicity, providing a basis for a global phase III trial using L-CsA.
  • Drug repurposing of bromodomain inhibitors as potential novel therapeutic leads for lymphatic filariasis guided by multispecies transcriptomics

    Chung, M.; Bromley, R.E.; Olley, D.; Kumar, N.; Sadzewicz, L.; Tallon, L.J.; Mahurkar, A.; Dunning Hotopp, J.C. (American Society for Microbiology, 2019)
    To better understand the transcriptomic interplay of organisms associated with lymphatic filariasis, we conducted multispecies transcriptome sequencing (RNA-Seq) on the filarial nematode Brugia malayi, its Wolbachia endosymbiont wBm, and its laboratory vector Aedes aegypti across the entire B. malayi life cycle. In wBm, transcription of the noncoding 6S RNA suggests that it may be a regulator of bacterial cell growth, as its transcript levels correlate with bacterial replication rates. For A. aegypti, the transcriptional response reflects the stress that B. malayi infection exerts on the mosquito with indicators of increased energy demand. In B. malayi, expression modules associated with adult female samples consistently contained an overrepresentation of genes involved in chromatin remodeling, such as the bromodomain-containing proteins. All bromodomain-containing proteins encoded by B. malayi were observed to be upregulated in the adult female, embryo, and microfilaria life stages, including 2 members of the bromodomain and extraterminal (BET) protein family. The BET inhibitor JQ1(+), originally developed as a cancer therapeutic, caused lethality of adult worms in vitro, suggesting that it may be a potential therapeutic that can be repurposed for treating lymphatic filariasis. IMPORTANCE The current treatment regimen for lymphatic filariasis is mostly microfilaricidal. In an effort to identify new drug candidates for lymphatic filariasis, we conducted a three-way transcriptomics/systems biology study of one of the causative agents of lymphatic filariasis, Brugia malayi, its Wolbachia endosymbiont wBm, and its vector host Aedes aegypti at 16 distinct B. malayi life stages. B. malayi upregulates the expression of bromodomain-containing proteins in the adult female, embryo, and microfilaria stages. In vitro, we find that the existing cancer therapeutic JQ1(+), which is a bromodomain and extraterminal protein inhibitor, has adulticidal activity in B. malayi. Copyright 2019 Chung et al.
  • Topical trabodenoson is neuroprotective in a rodent model of anterior ischemic optic neuropathy (Rnaion)

    Guo, Y.; Mehrabian, Z.; Johnson, M.A.; Bernstein, S.L. (Association for Research in Vision and Ophthalmology Inc., 2019)
    Purpose: Nonarteritic anterior ischemic optic neuropathy (NAION) is the leading cause of sudden optic nerve–related vision loss currently without effective treatment. We evaluated the neuroprotective potential of ocular (topical) delivery of trabodenoson, a selective A1 receptor mimetic, in a rodent model of NAION (rNAION). Methods: Daily topical delivery of 3% trabodenoson or vehicle administered in both eyes 3 days prior to rNAION induction and for 21 days post induction. Retinal appearance and optic nerve head (ONH) edema was evaluated using spectral-domain optical coherence tomography (SD-OCT). Retinal function was evaluated before and after induction by ganzfeld electroretinography (ERG). Brn3a(þ) retinal ganglion cells (RGCs) were quantified by stereology. Axonal ultrastructure was evaluated by electron microscopy. Results: Trabodenoson-treated eyes had significantly reduced optic nerve (ON) edema compared with vehicle-treated eyes (ANOVA, P, 0.05). Electrophysiologically, there was a nonsignificant trend toward b-wave and oscillatory potential (OP) preservation in the trabodenoson-treated eyes. RGC counts were higher in trabodenoson-treated eyes compared to vehicle (74% versus 47% of the contralateral eye; two-tailed t-test; P ¼ 0.01), as were ON axons. No overt morphologic differences in cell inflammation were observed between vehicle-and trabodenoson-treated ONHs, but trabodenoson-treated ONHs revealed increased expression of astrocyte-related neuroprotective responses. Conclusions: Trabodenoson preserves RGCs in the rodent NAION model. While previous clinical trials focused on trabodenoson’s ocular antihypertensive effect, our data suggest trabodenoson’s primary target may be both the retina and ONH. Selective adenosine A1 agonists may prove an appropriate neuroprotective adjunctive for ischemia-related ON diseases such as NAION and glaucoma. Translational Relevance: RGC and ON neuroprotection in ischemic neuropathies may be achievable by topical administration of A1 adenosine agonists rather than by simply relying on intraocular pressure reduction.
  • Blueprint for building a biorepository in a resource-limited setting that follows international best practices

    Abimiku, A.G.; Croxton, T.; Ozumba, P.J. (AOSIS OpenJournals Publishing AOSIS (Pty) Ltd, 2019)
    Background: Genetic diversity is abundant on the African continent. However, genomic research has been hampered by a lack of high quality and extensively annotated biospecimens and the necessary infrastructure to support such a technology-intensive effort. Objective: The Institute of Human Virology Nigeria (IHVN) partnered with the H3Africa Consortium and the Coriell Institute for Medical Research to build an internationally recognised biorepository for the receipt, processing, storage and distribution of biospecimens for biomedical research. Here, the authors describe the procedures, challenges and results encountered. Results: Key requirements for a high-quality biorepository were identified: (1) institutional support of infrastructure and services, (2) on-site trained staff with primary commitment to the biorepository, (3) reliance on best practices from globally recognised biorepository groups, (4) early implementation of a quality management system, (5) adoption of a laboratory information management system with demonstrated versatility in functions, (6) collaboration with external experts and sharing of experience through abstracts, newsletters, published manuscripts, and attendance at meetings and workshops, (7) strict adherence to local and national ethical standards and (8) a sustainability plan that is reviewed and updated annually. Conclusion: Utilising published best practices of globally recognised experts in the biorepository field as a benchmark, IHVN expanded and reorganised its existing laboratory facility and staff to take on this new purpose.
  • Emergency care research ethics in low-income and middle-income countries

    Millum, J.; Beecroft, B.; Hirshon, J.M. (BMJ Publishing Group, 2019)
    A large proportion of the total global burden of disease is caused by emergency medical conditions. Emergency care research is essential to improving emergency medicine but this research can raise some distinctive ethical challenges, especially with regard to (1) standard of care and risk-benefit assessment; (2) blurring of the roles of clinician and researcher; (3) enrolment of populations with intersecting vulnerabilities; (4) fair participant selection; (5) quality of consent; and (6) community engagement. Despite the importance of research to improve emergency care in low-income and middle-income countries (LMICs) and the widely acknowledged ethical challenges, very little has been written on the ethics of emergency care research in LMICs. This paper examines the ethical and regulatory challenges to conducting emergency care research with human participants in LMICs. We outline key challenges, present potential solutions or frameworks for addressing these challenges, and identify gaps. Despite the ethical and regulatory challenges, conducting high-quality, ethical emergency care research in LMICs is possible and it is essential for global health.
  • Comorbid diabetes results in immune dysregulation and enhanced disease severity following MERS-CoV infection

    Kulcsar, K.A.; Coleman, C.M.; Frieman, M.B. (American Society for Clinical Investigation, 2019)
    Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in 2012 in Saudi Arabia and has caused over 2400 cases and more than 800 deaths. Epidemiological studies identified diabetes as the primary comorbidity associated with severe or lethal MERS-CoV infection. Understanding how diabetes affects MERS is important because of the global burden of diabetes and pandemic potential of MERS-CoV. We used a model in which mice were made susceptible to MERS-CoV by expressing human DPP4, and type 2 diabetes was induced by administering a high-fat diet. Upon infection with MERS-CoV, diabetic mice had a prolonged phase of severe disease and delayed recovery that was independent of virus titers. Histological analysis revealed that diabetic mice had delayed inflammation, which was then prolonged through 21 days after infection. Diabetic mice had fewer inflammatory monocyte/macrophages and CD4+ T cells, which correlated with lower levels of Ccl2 and Cxcl10 expression. Diabetic mice also had lower levels of Tnfa, Il6, Il12b, and Arg1 expression and higher levels of Il17a expression. These data suggest that the increased disease severity observed in individuals with MERS and comorbid type 2 diabetes is likely due to a dysregulated immune response, which results in more severe and prolonged lung pathology.

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