Recent Submissions

  • Generation of MuRF-GFP transgenic zebrafish models for investigating murf gene expression and protein localization in Smyd1b and Hsp90α1 knockdown embryos.

    Li, Baojun; Li, Siping; He, Qiuxia; Du, Shaojun (Elsevier Inc., 2019-10-24)
    Muscle-specific RING-finger proteins (MuRFs) are E3 ubiquitin ligases that play important roles in protein quality control in skeletal and cardiac muscles. Here we characterized murf gene expression and protein localization in zebrafish embryos. We found that the zebrafish genome contains six murf genes, including murf1a, murf1b, murf2a, murf2b, murf3 and a murf2-like gene that are specifically expressed in skeletal and cardiac muscles of zebrafish embryos. To analyze the subcellular localization, we generated transgenic zebrafish models expressing MurF1a-GFP or MuRF2a-GFP fusion proteins. MuRF1a-GFP and MuRF2a-GFP showed distinct patterns of subcellular localization. MuRF1a-GFP displayed a striated pattern of localization in myofibers, whereas MuRF2a-GFP mainly exhibited a random pattern of punctate distribution. The MuRF1a-GFP signal appeared as small dots aligned along the M-lines of the sarcomeres in skeletal myofibers. To determine whether knockdown of smyd1b or hsp90α1 that increased myosin protein degradation could alter murf gene expression or MuRF protein localization, we knocked down smyd1b or hsp90α1 in wild type, Tg(ef1a:MurF1a-GFP) and Tg(ef1a:MuRF2a-GFP) transgenic zebrafish embryos. Knockdown of smyd1b or hsp90α1 had no effect on murf gene expression. However, the sarcomeric distribution of MuRF1a-GFP was abolished in the knockdown embryos. This was accompanied by an increased random punctate distribution of MuRF1a-GFP in muscle cells of zebrafish embryos. Collectively, these studies demonstrate that MuRFs are specifically expressed in developing muscles of zebrafish embryos. The M-line localization MuRF1a is altered by sarcomere disruption in smyd1b or hsp90α1 knockdown embryos.
  • Polytropic Influence of rs2295490 Genetic Polymorphism on Response to Antihypertensive Agents in Patients With Essential Hypertension.

    Zhou, Jiecan; He, Fazhong; Sun, Bao; Liu, Rong; Gao, Yongchao; Ren, Huan; Shu, Yan; Chen, Xiaoping; Liu, Zhaoqian; Zhou, Honghao; et al. (Frontiers Media S.A., 2019-03-27)
    Tribbles homolog 3 (TRIB3) mediating signaling pathways are closely related to blood pressure regulation. Our previous findings suggested a greater benefit on vascular outcomes in patients carrying TRIB3 (251, A > G, rs2295490) G allele with good glucose and blood pressure control. And TRIB3 (rs2295490) AG/GG genotypes were found to reduce primary vascular events in type 2 diabetic patients who received intensive glucose treatment as compared to those receiving standard glucose treatment. However, the effect of TRIB3 genetic variation on antihypertensives was not clear in essential hypertension patients. A total of 368 patients treated with conventional dosage of antihypertensives (6 groups, grouped by atenolol/bisoprolol, celiprolol, doxazosin, azelnidipine/nitrendipine, imidapril, and candesartan/irbesartan) were enrolled in our study. Genetic variations were successfully identified by sanger sequencing. A linear mixed model analysis was performed to evaluate blood pressures among TRIB3 (251, A > G) genotypes and adjusted for baseline age, gender, body mass index, systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol and other biochemical factors appropriately. Our data suggested that TRIB3 (251, A > G) AA genotype carriers showed better antihypertensive effect than the AG/GG genotype carriers [P = 0.014 for DBP and P = 0.042 for mean arterial pressure (MAP)], with a maximal reduction of DBP by 4.2 mmHg and MAP by 3.56 mmHg after azelnidipine or nitrendipine treatment at the 4th week. Similar tendency of DBP-change and MAP-change was found for imidapril (ACEI) treatment, in which marginally significances were achieved (P = 0.073 and 0.075, respectively). Against that, we found that TRIB3 (251, A > G) AG/GG genotype carriers benefited from antihypertensive therapy of ARBs with a larger DBP-change during the period of observation (P = 0.036). Additionally, stratified analysis revealed an obvious difference of the maximal blood pressure change (13 mmHg for the MAP between male and female patients with AA genotype who took ARBs). Although no significant difference in antihypertensive effect between TRIB3 (251, A > G) genotypes in patients treated with α, β-ADRs was observed, we found significant difference in age-, sex-dependent manner related to α, β-ADRs. In conclusion, our data supported that TRIB3 (251, A > G) genetic polymorphism may serve as a useful biomarker in the treatment of hypertension.
  • Current Psychotropic Medication Use and Contributing Factors Among Nursing Home Residents With Cognitive Impairment

    Resnick, Barbara; Kolanowski, Ann; Van Haitsma, Kimberly; Galik, Elizabeth; Boltz, Marie; Ellis, Jeanette; Behrens, Liza; Eshraghi, Karen; Zhu, Shijun (SAGE Publications Inc., 2019-04-03)
    This study described current use and predictors of psychotropics among residents with moderate to severe cognitive impairment. This was a secondary data analysis using baseline data from the first 341 residents in an ongoing trial. Predictive measures included age, gender, race, depressive symptoms, agitation, resistiveness to care, depression, cognition, pain, comorbidities, facility factors, and state. Overall 63% (n = 211) received at least one psychotropic medication, 16% (n = 52) an anti-seizure medication, 23% (n = 77) an anxiolytic, 30% (n = 99) an antidepressant, 2% (n = 8) a sedative hypnotic, 28% (n = 93) an antipsychotic medication, and 9% (n = 29) an opioid. Testing of models explained 9% to 15% of psychotropic medication use. There were high rates of psychotropic medication use and a limited association between demographic factors, behavioral symptoms, and psychotropic medication use. Continued research is needed to explore the impact of deprescribing, person-centered behavioral interventions, and beliefs of providers on psychotropic medication use.
  • The Prevalence of Bacterial Infection in Patients Undergoing Elective ACDF for Degenerative Cervical Spine Conditions: A Prospective Cohort Study With Contaminant Control

    Bivona, Louis J; Camacho, Jael E; Usmani, Farooq; Nash, Alysa; Bruckner, Jacob J; Hughes, Meghan; Bhandutia, Amit K; Koh, Eugene Y; Banagan, Kelley E; Gelb, Daniel E; et al. (SAGE Publications Inc., 2019-11-19)
    Ninety-six patients were enrolled, 41.7% were males with an average age of 54 ± 11 years and a body mass index of 29.7 ± 5.9 kg/m2. Seventeen patients (17.7%) were considered true positives, having a negative control and positive disc culture. Otherwise, no significant differences in culture positivity was found between groups of patients. However, our results show that patients were more likely to have both control and disc negative than being a true positive (odds ratio = 6.2, 95% confidence interval = 2.5-14.6). Propionibacterium acnes was the most commonly identified bacteria. Two patients with disc positive cultures returned to the operating room secondary to pseudarthrosis; however, age, body mass index, prior spine surgery or injection, postoperative infection, and reoperations were not associated with culture results.
  • Mobile Support for Older Adults and Their Caregivers: Dyad Usability Study.

    Quinn, Charlene C; Staub, Sheila; Barr, Erik; Gruber-Baldini, Ann (JMIR Publications, 2019-05-23)
    Background: Evaluation of digital health applications to support older adults' independence and family caregiving is needed. Digital health is increasingly providing opportunities for older adults and their family caregivers to educate, engage, and share health information across digital platforms. Few apps have documented evidence of usability by older adults and their caregivers. Objective: The objective of this study was to determine the usability of a mobile app in a community-based older adult population aged ≥65 years. The app was designed to improve engagement of the patient-informal caregiver team. Methods: This observational usability study was conducted in participants' homes and independent living facilities in Baltimore, Maryland. Community-dwelling older adults aged ≥65 years and their caregivers enrolled as a dyad (n=24, 12 dyads). The usability evaluation was a mobile and Web-based app that allowed older adult users to record social and health information and share this information with their caregivers. The older adult-caregiver dyad downloaded the app to a smart phone or accessed the Web version, participated in training and onboarding, and used the app for a 1-month period. Participants responded to weekly surveys sent by app push notifications and to the usability and satisfaction surveys at the end of the study. Participant satisfaction and usability were assessed using the Modified Mobile Application Rating Scale (M-MARS) and the System Usability Scale (SUS). Results: The final sample comprised 16 people (8 dyads). Responses to the M-MARS were comparable between older adults and caregiver respondents in terms of engagement and functionality. Caregivers rated aesthetics slightly higher (mean 3.7) than older adult participants did (mean 3.3). Although most responses to the SUS were around the mean (2.3-3.4), older adults and their caregivers differed with regard to integration of app features (mean 3.7 vs 2.8) and the need to learn more before using the app (mean 2.3 vs 3.1). Conclusions: Technology ownership and use among older adults and caregivers was high. Usability and engagement of the mobile app was average. Additional training is recommended for older adults and their caregivers, including that on targeted behaviors for digital health record keeping.
  • Phosphorylation of TRPV1 S801 Contributes to Modality-Specific Hyperalgesia in Mice

    Joseph, J.; Wang, S.; Kim, M.; Ro, J.; Chung, M.-K. (Society for Neuroscience, 2019)
    Transient receptor potential vanilloid subtype 1 (TRPV1) is a nonselective cationic channel activated by painful stimuli such as capsaicin and noxious heat, and enriched in sensory neurons of the pain pathway. During inflammation, chemical mediators activate protein kinases (such as PKC) that phosphorylate TRPV1 and thereby enhance its function, with consequent increases in nociceptor sensitization. However, the causal relationships between TRPV1 phosphorylation and pathological pain remain unexplored. To directly investigate the roles of one specific TRPV1 phosphorylation event in vivo, we genetically altered a major PKC phosphorylation site, mouse TRPV1 S801, to alanine. The TRPV1 expression pattern in sensory neurons of S801A knock-in (KI) mice was comparable to that in WT controls. However, sensitization of capsaicin-mediated currents after the activation of PKC was substantially impaired in sensory neurons from KI mice. Thermal hyperalgesia induced by PMA or burn injury in KI was identical to WT. Inflammatory thermal hyperalgesia was only marginally attenuated in KI mice. In contrast, PMA-evoked nocifensive responses and sensitization of capsaicin responses were significantly attenuated in the hindpaws of KI mice. Ongoing pain from inflamed masseter muscle was also reduced in KI mice, and was further inhibited by the TRPV1 antagonist AMG9810. These results suggest that PKC-mediated phosphorylation of TRPV1 S801 contributes to inflammation-mediated sensitization of TRPV1 to ligand, but not heat, in vivo Further, this suggests that interference with TRPV1 S801 phosphorylation might represent one potential way to attenuate inflammatory pain, yet spare basal sensitivity and produce fewer side effects than more general TRPV1 inhibition.SIGNIFICANCE STATEMENT Transient receptor potential vanilloid subtype 1 (TRPV1) has been considered a potential target for pain intervention. Global inhibitors of TRPV1 function, however, produce side effects which could compromise their clinical utility. By precisely removing a unique PKC phosphorylation site (TRPV1 S801) in mice through CRISPR/Cas9 editing, we provide in vivo evidence for a highly specific inhibition that leaves basal TRPV1 function intact, yet alleviates some forms of hyperalgesia. These findings support inhibition of TRPV1 S801 phosphorylation as a potential intervention for pain management. Copyright 2019 the authors.
  • Ventilator-Associated Pneumonia: Diagnostic Test Stewardship and Relevance of Culturing Practices

    O'Hara, L.M.; Kenaa, B.; Richert, M.E.; Claeys, K.C.; Shipper, A.; Sullivan, K.V.; Schrank, G.M.; Morgan, D.J.; Shanholtz, C.; Leekha, S. (Springer, 2019)
    Purpose of Review: Ventilator-associated pneumonia (VAP) is one of the most common infections in the ICU. Prompt diagnosis is vital as mortality increases with delayed antibiotic therapy. However, accurate diagnosis is challenging due to non-specific clinical features in a complicated patient cohort. Microbiological culture data remains a crucial aspect in confirming diagnosis. Recent Findings: Literature data comparing the benefit of invasive respiratory sampling to non-invasive is inconclusive. Differences in culturing practices translate in overidentification of organisms of unclear significance. Positive culture data in a low pre-test probability does not differentiate between true infection and colonization resulting in overtreatment. Furthermore, there are also opportunities for modifying the reporting of respiratory tract cultures that can better guide antimicrobial therapy. Summary: Under the umbrella of antimicrobial stewardship, diagnostic stewardship can be incorporated to create a systematic approach that would target culturing practices to match the right pre-test probability. Ideal outcome will be targeting cultures to the right patient population and minimizing unnecessary treatment.
  • Chronic oxidative stress and comorbidities in the HIV-1 transgenic rat

    Benedetti, F.; Curreli, S.; Zella, D.; Bryant, J. (Cambridge University Press, 2019)
  • Influence of the Maryland All-Payer Model on Primary Total Knee Arthroplasties

    Delanois, R.E.; Pollak, A.N.; Davila Castrodad, I.M.; Mohamed, M.S. (Lippincott Williams and Wilkins, 2019)
    Background: In 2014, Maryland received a waiver for the Global Budget Revenue (GBR) program. We evaluated GBR’s impact on patient and hospital trends for total knee arthroplasty (TKA) in Maryland compared with the U.S. Specifically, we examined (1) patient characteristics, (2) inpatient course, and (3) costs and charges associated with TKAs from 2014 through 2016. Methods: A comparative analysis of TKA-treated patients in the Maryland State Inpatient Database (n = 36,985) versus those in the National Inpatient Sample (n = 2,117,191) was performed. Patient characteristics included race, Charlson Comorbidity Index (CCI), morbid obesity, patient income status, and primary payer. Inpatient course included length of hospital stay (LOS), discharge disposition, and complications. Results: In the Maryland TKA cohort, the proportion of minorities increased from 2014 to 2016 while the proportion of whites decreased (p = 0.001). The proportion of patients with a CCI of ≥3 decreased (p = 0.014), that of low-income patients increased (p < 0.001), and that of patients covered by Medicare or Medicaid increased (p < 0.001). In the U.S. TKA cohort, the proportion of blacks increased (p < 0.001), that of patients with a CCI score of ≥3 decreased (p < 0.001), and the proportions of low-income patients (p < 0.001) and those covered by Medicare or Medicaid increased (p < 0.001). In both Maryland and the U.S., the LOS (p < 0.001) and complication rate (p < 0.001) decreased while home-routine discharges increased (p < 0.001). Costs and charges decreased in Maryland (p < 0.001 for both) whereas charges in the U.S. increased (p < 0.001) and costs decreased (p < 0.001). Conclusions: While the U.S. health reform and GBR achieved similar patient and hospital-specific outcomes and broader inclusion of minority patients, Maryland experienced decreased hospital charges while hospital charges increased in the U.S. Copyright 2019 The Authors
  • Cardiovascular risks impact human brain Nacetylaspartate in regionally specific patterns

    Chiappelli, J.; Rowland, L.M.; Wijtenburg, S.A.; Chen, H.; Maudsley, A.A.; Sheriff, S.; Chen, S.; Savransky, A.; Marshall, W.; Ryan, M.C.; et al. (National Academy of Sciences, 2019)
    Cardiovascular risk factors such as dyslipidemia and hypertension increase the risk for white matter pathology and cognitive decline. We hypothesize that white matter levels of N-acetylaspartate (NAA), a chemical involved in the metabolic pathway for myelin lipid synthesis, could serve as a biomarker that tracks the influence of cardiovascular risk factors on white matter prior to emergence of clinical changes. To test this, we measured levels of NAA across white matter and gray matter in the brain using echo planar spectroscopic imaging (EPSI) in 163 individuals and examined the relationship of regional NAA levels and cardiovascular risk factors as indexed by the Framingham Cardiovascular Risk Score (FCVRS). NAA was strongly and negatively correlated with FCVRS across the brain, but, after accounting for age and sex, the association was found primarily in white matter regions, with additional effects found in the thalamus, hippocampus, and cingulate gyrus. FCVRS was also negatively correlated with creatine levels, again primarily in white matter. The results suggest that cardiovascular risks are related to neurochemistry with a predominantly white matter pattern and some subcortical and cortical gray matter involvement. NAA mapping of the brain may provide early surveillance for the potential subclinical impact of cardiovascular and metabolic risk factors on the brain.
  • Male With Anterior Left Knee Pain

    Dubbs, S.B.; Richardson, A.C.; Blosser, K.M.; Tewelde, S.Z. (Elsevier, 2019)
  • Fixation using alternative implants for the treatment of hip fractures (FAITH-2): Design and rationale for a pilot multi-centre 2 x 2 factorial randomized controlled trial in young femoral neck fracture patients

    Slobogean, G.P.; Sprague, S.; Bzovsky, S. (BioMed Central Ltd., 2019)
    Background: Femoral neck fractures in patients . 60 years of age are often very different injuries compared to low-energy, hip fractures in elderly patients and are difficult to manage because of inherent problems associated with high-energy trauma mechanisms and increased functional demands for recovery. Internal fixation, with multiple cancellous screws or a sliding hip screw (SHS), is the most common treatment for this injury in young patients. However, there is no clinical consensus regarding which surgical technique is optimal. Additionally, there is compelling rationale to use vitamin D supplementation to nutritionally optimize bone healing in young patients. This pilot trial will determine feasibility and provide preliminary clinical data for a larger definitive trial. Methods: We will conduct a multicenter, concealed randomized controlled pilot study, using a 2 ~ 2 factorial design in 60 patients aged 18.60 years with a femoral neck fracture. Eligible patients will be randomized in equal proportions to one of four groups: 1) SHS and vitamin D supplementation (4000 international units (IU) daily dose) for 6 months, 2) cancellous screws and vitamin D supplementation (4000 IU daily dose) for 6 months, 3) SHS and placebo, and 4) cancellous screws and placebo. Participants will be followed for 12 months post-fracture. Feasibility outcomes include initiation of clinical sites, recruitment, follow-up, data quality, and protocol adherence. Clinical outcomes, for both the pilot and planned definitive trials, include a composite of patient-important outcomes (re-operation, femoral head osteonecrosis, severe femoral neck malunion, and nonunion), health-related quality of life and patient-reported function, fracture healing complications, and radiographic fracture healing. A priori success criteria have been established. If the pilot study is deemed successful, study participants will be included in the definitive trial and clinical outcomes for the pilot will not be analyzed. If the pilot study is not deemed successful, clinical outcome data will be analyzed. Discussion: Results of this study will inform the feasibility of a definitive trial. If clinical outcome data are analyzed, they will be disseminated through a publication and presentations. Trial registration: The FAITH-2 trial, described as a definitive trial, was registered at ClinicalTrials.gov (NCT01908751) prior to enrollment of the first participant. Copyright The Author(s).
  • Effect of fish oil supplement administration method on tolerability and adherence: A randomized pilot clinical trial

    Malinowski, S.S.; Barber, K.E.; Kishk, O.A. (BioMed Central Ltd., 2019)
    Objectives: Anecdotally, several strategies have been suggested in order to improve tolerability of fish oil supplements, but there is little evidence supporting any of these strategies. The aim of this study was to determine if there is a difference among four methods of oral administration of fish oil supplementation in terms of tolerability and adherence. Methods: A randomized, prospective, open-label, four-arm pilot study was conducted on 60 healthy adult subjects randomized to different fish oil supplement administration methods with (1) milk, (2) food, (3) an empty stomach, and (4) frozen capsules prior to ingestion. Each subject was instructed to take two capsules three times daily for 30 consecutive days. Adherence was assessed by pill counts. Adverse effects were assessed by survey and patient exit interview. Results: No apparent differences were demonstrated among the four administration groups in terms of adherence, reasons for non-adherence, or self-reported adverse effects. Conclusions: Method of administration did not affect rates of adherence or incidence of adverse effects in a small cohort of healthy adults taking fish oil supplement capsules for 30 days. Trial registration: ClinicalTrials.gov NCT01471366. Registered November 16, 2011. Copyright The Author(s).
  • 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).
  • 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).
  • 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).
  • 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.
  • 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.
  • 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.

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