Now showing items 1-20 of 3178

    • Extended use or re-use of single-use surgical masks and filtering facepiece respirators during COVID-19: A rapid systematic review.

      Toomey, E; Conway, Y; Burton, C; Smith, S; Smalle, M; Chan, Xhs; Adisesh, A; Tanveer, S; Ross, L; Thomson, I; et al. (Cambridge University Press, 2020-10-08)
      Background: Shortages of personal protective equipment during the COVID-19 pandemic has led to the extended use or re-use of single-use respirators and surgical masks by frontline healthcare workers. The evidence base underpinning such practices warrants examination. Objectives: To synthesise current guidance and systematic review evidence on extended use, reuse, or reprocessing of single-use surgical masks or filtering facepiece respirators. Data sources: World Health Organization, European Centre for Disease Prevention and Control, the US Centers for Disease Control and Prevention, and Public Health England websites to identify guidance. Medline, Pubmed, Epistemonikos, Cochrane Database and preprint servers for systematic reviews. Methods: Two reviewers conducted screening and data extraction. Quality of included systematic reviews was appraised using AMSTAR-2. Findings were narratively synthesised. Results: Six guidance documents were identified. Levels of detail and consistency across documents varied. Four high-quality systematic reviews were included: three focused on reprocessing (decontamination) of N95 respirators, one on reprocessing of surgical masks. Vaporised hydrogen peroxide and ultraviolet germicidal irradiation were highlighted as the most promising reprocessing methods, but evidence on the relative efficacy and safety of different methods was limited. We found no well-established methods for reprocessing respirators at scale. Conclusions: There is limited evidence on the impact of extended use and re-use of surgical masks and respirators and gaps and inconsistencies exist in current guidance. Where extended use or reuse is being practiced, healthcare organisations should ensure that policies and systems are in place to ensure these practices are carried out safely and in line with available guidance.
    • Feasibility of removable balloon implant for simultaneous magnetic nanoparticle heating and HDR brachytherapy of brain tumor resection cavities.

      Stauffer, Paul R; Rodrigues, Dario B; Goldstein, Robert; Nguyen, Thinh; Yu, Yan; Wan, Shuying; Woodward, Richard; Gibbs, Michael; Vasilchenko, Ilya L; Osintsev, Alexey M; et al.
      Aim: Hyperthermia (HT) has been shown to improve clinical response to radiation therapy (RT) for cancer. Synergism is dramatically enhanced if HT and RT are combined simultaneously, but appropriate technology to apply treatments together does not exist. This study investigates the feasibility of delivering HT with RT to a 5-10mm annular rim of at-risk tissue around a tumor resection cavity using a temporary thermobrachytherapy (TBT) balloon implant. Methods: A balloon catheter was designed to deliver radiation from High Dose Rate (HDR) brachytherapy concurrent with HT delivered by filling the balloon with magnetic nanoparticles (MNP) and immersing it in a radiofrequency magnetic field. Temperature distributions in brain around the TBT balloon were simulated with temperature dependent brain blood perfusion using numerical modeling. A magnetic induction system was constructed and used to produce rapid heating (>0.2°C/s) of MNP-filled balloons in brain tissue-equivalent phantoms by absorbing 0.5 W/ml from a 5.7 kA/m field at 133 kHz. Results: Simulated treatment plans demonstrate the ability to heat at-risk tissue around a brain tumor resection cavity between 40-48°C for 2-5cm diameter balloons. Experimental thermal dosimetry verifies the expected rapid and spherically symmetric heating of brain phantom around the MNP-filled balloon at a magnetic field strength that has proven safe in previous clinical studies. Conclusions: These preclinical results demonstrate the feasibility of using a TBT balloon to deliver heat simultaneously with HDR brachytherapy to tumor bed around a brain tumor resection cavity, with significantly improved uniformity of heating over previous multi-catheter interstitial approaches. Considered along with results of previous clinical thermobrachytherapy trials, this new capability is expected to improve both survival and quality of life in patients with glioblastoma multiforme.
    • Delayed microglial depletion after spinal cord injury reduces chronic inflammation and neurodegeneration in the brain and improves neurological recovery in male mice.

      Li, Yun; Ritzel, Rodney M; Khan, Niaz; Cao, Tuoxin; He, Junyun; Lei, Zhuofan; Matyas, Jessica J; Sabirzhanov, Boris; Liu, Simon; Li, Hui; et al. (Ivyspring International Publisher, 2020-09-14)
      Neuropsychological deficits, including impairments in learning and memory, occur after spinal cord injury (SCI). In experimental SCI models, we and others have reported that such changes reflect sustained microglia activation in the brain that is associated with progressive neurodegeneration. In the present study, we examined the effect of pharmacological depletion of microglia on posttraumatic cognition, depressive-like behavior, and brain pathology after SCI in mice. Methods: Young adult male C57BL/6 mice were subjected to moderate/severe thoracic spinal cord contusion. Microglial depletion was induced with the colony-stimulating factor 1 receptor (CSF1R) antagonist PLX5622 administered starting either 3 weeks before injury or one day post-injury and continuing through 6 weeks after SCI. Neuroinflammation in the injured spinal cord and brain was assessed using flow cytometry and NanoString technology. Neurological function was evaluated using a battery of neurobehavioral tests including motor function, cognition, and depression. Lesion volume and neuronal counts were quantified by unbiased stereology. Results: Flow cytometry analysis demonstrated that PLX5622 pre-treatment significantly reduced the number of microglia, as well as infiltrating monocytes and neutrophils, and decreased reactive oxygen species production in these cells from injured spinal cord at 2-days post-injury. Post-injury PLX5622 treatment reduced both CD45int microglia and CD45hi myeloid counts at 7-days. Following six weeks of PLX5622 treatment, there were substantial changes in the spinal cord and brain transcriptomes, including those involved in neuroinflammation. These alterations were associated with improved neuronal survival in the brain and neurological recovery. Conclusion: These findings indicate that pharmacological microglia-deletion reduces neuroinflammation in the injured spinal cord and brain, improving recovery of cognition, depressive-like behavior, and motor function.
    • Gunshot wound to big red.

      Feliciano, David V (BMJ Publishing Group, 2020-08-13)
    • Brain Death Determination: An Interprofessional Simulation to Determine Brain Death and Communicate with Families Focused on Neurology Residents.

      Morris, Nicholas A; Zimmerman, Eli E; Pozner, Charles N; Henderson, Galen V; Milligan, Tracey A (Association of American Medical Colleges, 2020-09-25)
      Introduction: Significant variation exists in determining brain death despite an expectation of competence for all neurology residents. In addition, family discussions regarding brain death are challenging and may influence organ donation. Methods: We developed two simulations of increasing complexity for PGY 2 and PGY 3 neurology residents. High-fidelity mannequins were used to simulate patients; standardized actors portrayed family members. In the first simulation, residents determined brain death and shared this information with a grieving family. In the second simulation, residents determined brain death in a more complicated scenario, requiring ancillary testing and accurate result interpretation. Following the determination, residents met with a challenging family. The residents worked with an interdisciplinary team and responded to the family's emotions, used active listening skills, and supported the family through next steps. Results: Twelve residents completed the simulations. Prior to the simulation, three (25%) residents felt comfortable discussing a brain death diagnosis; following the simulation, eight (67%) residents felt comfortable/very comfortable discussing brain death. Prior to the simulation, eight (67%) residents stated they knew prerequisites for performing a brain death examination and seven (58%) agreed they knew indications for ancillary testing; these numbers increased to 100% following the simulation. The number of residents who felt comfortable performing the brain death exam increased from five (42%) to 10 (83%). Discussion: This simulation of determining brain death and leading difficult family meetings was well-received by neurology residents. Further work should focus on the effects of simulation-based education on practice variation and organ donation consent rates.
    • Immune Correlates of COVID-19 Control

      Poonia, Bhawna; Kottilil, Shyam (Frontiers Media S.A., 2020-09-29)
      COVID-19 caused by SARS CoV2 emerged in China at the end of 2019 and soon become a pandemic. Since the virus is novel, pre-existing CoV2-specific immunity is not expected to exist in humans, although studies have shown presence of CoV2 cross-reactive T cells in unexposed individuals. Lack of effective immunity in most individuals along with high infectiousness of the virus has resulted in massive global public health emergency. Intense efforts are on to study viral pathogenesis and immune response to help guide prophylactic and therapeutic interventions as well as epidemiological assessments like transmission modeling. To develop an effective vaccine or biologic therapeutic, it is critical to understand the immune correlates of COVID-19 control. At the same time, whether immunity in recovered individuals is effective for preventing re-infection will be important for informing interventions like social distancing. Key questions that are being investigated regarding immune response in COVID-19 which will help these efforts include, investigations of immune response that distinguishes patients with severe versus mild infection or those that recover relative to those that succumb, durability of immunity in recovered patients and relevance of developed immunity in a cured patient for protection against re-infection as well as value of convalescent plasma from recovered patients as a potential therapeutic modality. This is a broad and rapidly evolving area and multiple reports on status of innate and adaptive immunity against SARS-CoV2 are emerging on a daily basis. While many questions remain unanswered for now, the purpose of this focused review is to summarize the current understanding regarding immune correlates of COVID-19 severity and resolution in order to assist researchers in the field to pursue new directions in prevention and control. © Copyright © 2020 Poonia and Kottilil.
    • Novel Crown Cement Containing Antibacterial Monomer and Calcium Phosphate Nanoparticles.

      AlSahafi, Rashed; Balhaddad, Abdulrahman A; Mitwalli, Heba; Ibrahim, Maria Salem; Melo, Mary Anne S; Oates, Thomas W; Xu, Hockin H K; Weir, Michael D (MDPI AG, 2020-10-11)
      Oral biofilm accumulation at the tooth-restoration interface often leads to recurrent dental caries and restoration failure. The objectives of this study were to: (1) develop a novel bioactive crown cement containing dimethylaminohexadecyl methacrylate (DMAHDM) and nano-sized amorphous calcium phosphate (NACP), and (2) investigate the mechanical properties, anti-biofilm activity, and calcium (Ca2+) and phosphate (PO43-) ion release of the crown cement for the first time. The cement matrix consisted of pyromellitic glycerol dimethacrylate and ethoxylated bisphenol-A dimethacrylate monomers and was denoted PEHB resin matrix. The following cements were tested: (1) RelyX luting cement (commercial control); (2) 55% PEHB + 45% glass fillers (experimental control); (3) 55% PEHB + 20% glass + 25% NACP + 0% DMAHDM; (4) 52% PEHB + 20% glass + 25% NACP + 3% DMAHDM; (5) 51% PEHB + 20% glass + 25% NACP + 4% DMAHDM; (6) 50% PEHB + 20% glass + 25% NACP + 5% DMAHDM. Mechanical properties and ion release were measured. Streptococcusmutans (S. mutans) biofilms were grown on cements, and colony-forming units (CFUs) and other biofilm properties were measured. The novel bioactive cement demonstrated strong antibacterial properties and high levels of Ca2+ and PO43- ion release to remineralize tooth lesions. Adding NACP and DMAHDM into the cement did not adversely affect the mechanical properties and dentin bonding strength. In conclusion, the novel NACP + DMAHDM crown cement has excellent potential for restoration cementation to inhibit caries by suppressing oral biofilm growth and increasing remineralization via Ca2+ and PO43- ions. The NACP + DMAHDM composition may have wide applicability to other biomaterials to promote hard-tissue formation and combat bacterial infection.
    • Clinical Application of Oncolytic Viruses: A Systematic Review.

      Cook, Mary; Chauhan, Aman (MDPI AG, 2020-10-12)
      Leveraging the immune system to thwart cancer is not a novel strategy and has been explored via cancer vaccines and use of immunomodulators like interferons. However, it was not until the introduction of immune checkpoint inhibitors that we realized the true potential of immunotherapy in combating cancer. Oncolytic viruses are one such immunotherapeutic tool that is currently being explored in cancer therapeutics. We present the most comprehensive systematic review of all oncolytic viruses in Phase 1, 2, and 3 clinical trials published to date. We performed a systematic review of all published clinical trials indexed in PubMed that utilized oncolytic viruses. Trials were reviewed for type of oncolytic virus used, method of administration, study design, disease type, primary outcome, and relevant adverse effects. A total of 120 trials were found; 86 trials were available for our review. Included were 60 phase I trials, five phase I/II combination trials, 19 phase II trials, and two phase III clinical trials. Oncolytic viruses are feverously being evaluated in oncology with over 30 different types of oncolytic viruses being explored either as a single agent or in combination with other antitumor agents. To date, only one oncolytic virus therapy has received an FDA approval but advances in bioengineering techniques and our understanding of immunomodulation to heighten oncolytic virus replication and improve tumor kill raises optimism for its future drug development.
    • An integrated electrochemical microsystem for real-time treatment monitoring of clozapine in microliter volume samples from schizophrenia patients

      Shukla, Rajendra P.; Rapier, Crystal; Glassman, Matthew; Liu, Fang; Kelly, Deanna L.; Ben-Yoav, Hadar (Elsevier Ltd., 2020-11-01)
      This work presents the development of an electrochemical microsystem for antipsychotic clozapine treatment monitoring in schizophrenia patients. In our previous work, we demonstrated clozapine detection directly in spiked whole blood samples of a healthy volunteer using a chitosan–carbon nanotube-modified microelectrode with external counter and reference electrodes. Here we present the miniaturization of our previous clozapine sensing approach and its clinical validation in real samples obtained from 10 schizophrenia patients. We observed a sensitivity of 0.02 ± 2.3 × 10-4 mA/cm2µM and 0.003 ± 2.6 × 10-4 mA/cm2µM and a limit of detection of 0.08 ± 9.2 × 10-4 µM and 0.45 ± 0.04 µM using chitosan–carbon nanotube-modified microelectrodes in a 20 µL volume of spiked capillary plasma and capillary whole blood. Following a calibration curve, which was obtained from spiked samples of patients prior to clozapine therapy administration, clozapine capillary plasma and whole blood levels were recovered from patients’ samples after treatment with clozapine. The developed electrochemical microsystem allows clozapine analysis in a microliter volume of finger-pricked whole blood samples of schizophrenia patients without using any pretreatment steps. By further miniaturization and integration of this sensor into a point-of-care testing device, schizophrenia treatment management can be improved.
    • Pre-existing Helicobacter pylori serum IgG enhances the vibriocidal antibody response to CVD 103-HgR live oral cholera vaccine in Malian adults.

      Muhsen, Khitam; Sow, Samba O; Tapia, Milagritos D; Haidara, Fadima C; Reymann, Mardi; Asato, Valeria; Chen, Wilbur H; Pasetti, Marcela F; Levine, Myron M (Springer Nature, 2020-10-09)
      Accumulating evidence indicates that persistent Helicobacter pylori gastric infection influences immune responses to oral enteric vaccines. We studied the association between pre-existing H. pylori serum IgG and serum pepsinogens levels (PGs) as markers of gastric inflammation and the immune response to single-dose live oral cholera vaccine CVD 103-HgR in Malian adults. Baseline sera obtained during a phase 2 safety/immunogenicity clinical trial of cholera vaccine CVD 103-HgR among 93 healthy Malian adults were tested for H. pylori IgG antibodies and PGI and PGII levels using enzyme linked immunosorbent assays. Overall 74/93 (80%) vaccine recipients were H. pylori IgG seropositive at baseline. Vibriocidal antibody seroconversion (≥ fourfold increase 14 days following administration of CVD 103-HgR compared to baseline) among vaccine recipients was 56%. However, vibriocidal antibody seroconversion was markedly higher among H. pylori seropositives than seronegatives 64% vs. 26% (p = 0.004); adjusted relative risk: 2.20 (95% confidence intervals 1.00–4.80; p = 0.049). Among H. pylori seropositive vaccine recipients, there were no significant associations between PGI, PGII and PGI:PGII levels and vibriocidal seroconversion. The enhanced seroconversion to oral cholera vaccine CVD 103-HgR among H. pylori seropositive African adults provides further evidence of the immunomodulating impact of H. pylori on oral vaccine immunogenicity.
    • Social capital and cost-related medication nonadherence (CRN): A retrospective longitudinal cohort study using the Health and Retirement Study data, 2006–2016

      Majercak, Kayleigh R.; Magder, Laurence S.; Villalonga-Olives, Ester (Elsevier Ltd., 2020-12-01)
      Prescription drug spending and other financial factors (e.g., out-of-pocket costs) partially explain variation in cost-related medication nonadherence (CRN). Indicators of social capital such as neighborhood factors and social support may influence the health and well-being of older adults as they may rely on community resources and support from family and peers to manage conditions. Previous research on the relationship of social capital and CRN has limited evidence and contradictory findings. Hence, our objective is to assess the relationship of social capital indicators (neighborhood social cohesion, neighborhood physical disorder, positive social support, and negative social support) and CRN using a longitudinal design, 2006 to 2016, in a nationally representative sample of older adults in the United States (US). The Health and Retirement Study is a prospective panel study of US adults aged ≥ 50 years evaluated every two years. Data was pooled to create three waves and fitted using Generalized Estimating Equation modelling adjusting for both baseline and timevarying covariates (age, sex, education, race, total household income, and perceived health status). The three waves consisted of 11,791, 12,336, and 9,491 participants. Higher levels of neighborhood social cohesion and positive social support were related with lower CRN (OR 0.92, 95% CI 0.88-0.95 and OR 0.77, 95% CI 0.70-0.84, p<0.01). In contrast, higher levels of neighborhood physical disorder and negative social support were related to higher CRN (OR 1.07, 95% CI 1.03-1.11 and OR 1.46, 95% CI 1.32-1.62, p<0.01). Interventions targeting social capital are needed, reinforcing positive social support and neighborhood social cohesion and diminishing neighborhood physical disorder and negative social support for older adults.
    • Negative binomial mixed models for analyzing longitudinal CD4 count data.

      Yirga, Ashenafi A; Melesse, Sileshi F; Mwambi, Henry G; Ayele, Dawit G (Springer Nature, 2020-10-07)
      It is of great interest for a biomedical analyst or an investigator to correctly model the CD4 cell count or disease biomarkers of a patient in the presence of covariates or factors determining the disease progression over time. The Poisson mixed-effects models (PMM) can be an appropriate choice for repeated count data. However, this model is not realistic because of the restriction that the mean and variance are equal. Therefore, the PMM is replaced by the negative binomial mixed-effects model (NBMM). The later model effectively manages the over-dispersion of the longitudinal data. We evaluate and compare the proposed models and their application to the number of CD4 cells of HIV-Infected patients recruited in the CAPRISA 002 Acute Infection Study. The results display that the NBMM has appropriate properties and outperforms the PMM in terms of handling over-dispersion of the data. Multiple imputation techniques are also used to handle missing values in the dataset to get valid inferences for parameter estimates. In addition, the results imply that the effect of baseline BMI, HAART initiation, baseline viral load, and the number of sexual partners were significantly associated with the patient’s CD4 count in both fitted models. Comparison, discussion, and conclusion of the results of the fitted models complete the study.
    • The association between carbon dioxide, cerebral blood flow, and autoregulation in the premature infant

      Hoffman, Suma Bhat; Lakhani, Anisa; Viscardi, Rose Marie (Springer Nature, 2020-10-08)
      Objective: Evaluate the association between carbon dioxide (pCO2), cerebral blood flow (CBF), and cerebral autoregulation (CA) in preterm infants. Study design: Cerebral saturations (rScO2, surrogate for CBF using NIRS) and mean arterial blood pressure (MAP) monitored for 96 h in infants <29 weeks gestation. Relationship between rScO2, the rScO2-MAP correlation (CA analysis) and pCO2 category assessed by mixed effects modeling. Results: Median pCO2 differed by postnatal day (p < 0.0001)—pCO2 increased between day 1 and 2, and low variability seen on day 4. A 5% increase in rScO2 was noted when pCO2 was >55 mmHg on each postnatal day (p < 0.001). No association observed between the overall rScO2-MAP correlation and pCO2. On day 1 only, the correlation coefficient decreased from 0.26 to −0.09 as pCO2 category increased (p = 0.02). Conclusions: CBF increased above a pCO2 threshold of 55 mmHg, but overall, no association between pCO2 and CA was noted.
    • Comparison of outcomes of HCT in blast phase of BCR-ABL1- MPN with de novo AML and with AML following MDS

      Gupta, Vikas; Kim, Soyoung; Hu, Zhen-Huan; Liu, Ying; Aljurf, Mahmoud; Bacher, Ulrike; Beitinjaneh, Amer; Cahn, Jean-Yves; Cerny, Jan; Copelan, Edward; et al. (American Society of Hematology, 2020-10-13)
      Comparative outcomes of allogeneic hematopoietic cell transplantation (HCT) for BCR-ABL12 myeloproliferative neoplasms (MPNs) in blast phase (MPN-BP) vs de novo acute myeloid leukemia (AML), and AML with prior myelodysplastic syndromes (MDSs; post-MDS AML), are unknown. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we compared HCT outcomes in 177 MPN-BP patients with 4749 patients with de novo AML, and 1104 patients with post-MDS AML, using multivariate regression analysis in 2 separate comparisons. In a multivariate Cox model, no difference in overall survival (OS) or relapse was observed in patients with MPN-BP vs de novo AML with active leukemia at HCT. Patients with MPN-BP in remission had inferior OS in comparison with de novo AML in remission (hazard ratio [HR], 1.40 [95% confidence interval [CI], 1.12-1.76]) due to higher relapse rate (HR, 2.18 [95% CI, 1.69-2.80]). MPN-BP patients had inferior OS (HR, 1.19 [95% CI, 1.00-1.43]) and increased relapse (HR, 1.60 [95% CI, 1.31-1.96]) compared with post-MDS AML. Poor-risk cytogenetics were associated with increased relapse in both comparisons. Peripheral blood grafts were associated with decreased relapse in MPN-BP and post-MDS AML (HR, 0.70 [95% CI, 0.57-0.86]). Nonrelapse mortality (NRM) was similar between MPN-BP vs de novo AML, and MPN-BP vs post-MDS AML. Total-body irradiation-based myeloablative conditioning was associated with higher NRM in both comparisons. Survival of MPN-BP after HCT is inferior to de novo AML in remission and post-MDS AML due to increased relapse. Relapse-prevention strategies are required to optimize HCT outcomes in MPN-BP.
    • 1HN, 13C, and 15N resonance assignments of the Clostridioides difficile receptor binding domain 2 (CDTb, residues 757-876).

      Cook, Mary E; Varney, Kristen M; Godoy-Ruiz, Raquel; Weber, David J (Springer Science and Business Media B.V., 2020-10-09)
      Clostridioides difficile is a bacterial pathogen responsible for the majority of nosocomial infections in the developed world. C. difficile infection (CDI) is difficult to treat in many cases because hypervirulent strains have evolved that contain a third toxin, termed the C. difficile toxin (CDT), in addition to the two enterotoxins TcdA and TcdB. CDT is a binary toxin comprised of an enzymatic, ADP-ribosyltransferase (ART) toxin component, CDTa, and a pore-forming or delivery subunit, CDTb. In the absence of CDTa, CDTb assembles into two distinct di-heptameric states, a symmetric and an asymmetric form with both states having two surface-accessible host cell receptor-binding domains, termed RBD1 and RBD2. RBD1 has a unique amino acid sequence, when aligned to other well-studied binary toxins (i.e., anthrax), and it contains a novel Ca2+-binding site important for CDTb stability. The other receptor binding domain, RBD2, is critically important for CDT toxicity, and a domain such as this is missing altogether in other binary toxins and shows further that CDT is unique when compared to other binary toxins. In this study, the 1H, 13C, and 15N backbone and sidechain resonances of the 120 amino acid RBD2 domain of CDTb (residues 757-876) were assigned sequence-specifically and provide a framework for future NMR-based drug discovery studies directed towards targeting the most virulent strains of CDI.
    • The voltage-gated proton channel Hv1 plays a detrimental role in contusion spinal cord injury via extracellular acidosis-mediated neuroinflammation.

      Li, Yun; Ritzel, Rodney M; He, Junyun; Cao, Tuoxin; Sabirzhanov, Boris; Li, Hui; Liu, Simon; Wu, Long-Jun; Wu, Junfang (Academic Press Inc., 2020-10-08)
      Tissue acidosis is an important secondary injury process in the pathophysiology of traumatic spinal cord injury (SCI). To date, no studies have examined the role of proton extrusion as mechanism of pathological acidosis in SCI. In the present study, we hypothesized that the phagocyte-specific proton channel Hv1 mediates hydrogen proton extrusion after SCI, contributing to increased extracellular acidosis and poor long-term outcomes. Using a contusion model of SCI in adult female mice, we demonstrated that tissue pH levels are markedly lower during the first week after SCI. Acidosis was most evident at the injury site, but also extended into proximal regions of the cervical and lumbar cord. Tissue reactive oxygen species (ROS) levels and expression of Hv1 were significantly increased during the week of injury. Hv1 was exclusively expressed in microglia within the CNS, suggesting that microglia contribute to ROS production and proton extrusion during respiratory burst. Depletion of Hv1 significantly attenuated tissue acidosis, NADPH oxidase 2 (NOX2) expression, and ROS production at 3 d post-injury. Nanostring analysis revealed decreased gene expression of neuroinflammatory and cytokine signaling markers in Hv1 knockout (KO) mice. Furthermore, Hv1 deficiency reduced microglia proliferation, leukocyte infiltration, and phagocytic oxidative burst detected by flow cytometry. Importantly, Hv1 KO mice exhibited significantly improved locomotor function and reduced histopathology. Overall, these data suggest an important role for Hv1 in regulating tissue acidosis, NOX2-mediated ROS production, and functional outcome following SCI. Thus, the Hv1 proton channel represents a potential target that may lead to novel therapeutic strategies for SCI. © 2020 The Authors
    • Novel CaF2 nanocomposites with antibacterial function and fluoride and calcium ion release to inhibit oral biofilm and protect teeth

      Mitwalli, Heba; Balhaddad, Abdulrahman A.; AlSahafi, Rashed; Oates, Thomas W.; Melo, Mary Anne S.; Xu, Hockin H.K.; Weir, Michael D. (MDPI AG, 2020-09-01)
      (1) Background: The objective of this study was to develop a novel dental nanocomposite containing dimethylaminohexadecyl methacrylate (DMAHDM), 2-methacryloyloxyethyl phosphorylcholine (MPC), and nanoparticles of calcium fluoride (nCaF2) for preventing recurrent caries via antibacterial, protein repellent and fluoride releasing capabilities. (2) Methods: Composites were made by adding 3% MPC, 3% DMAHDM and 15% nCaF2 into bisphenol A glycidyl dimethacrylate (Bis-GMA) and triethylene glycol dimethacrylate (TEGDMA) (denoted BT). Calcium and fluoride ion releases were evaluated. Biofilms of human saliva were assessed. (3) Results: nCaF2+DMAHDM+MPC composite had the lowest biofilm colony forming units (CFU) and the greatest ion release; however, its mechanical properties were lower than commercial control composite (p < 0.05). nCaF2+DMAHDM composite had similarly potent biofilm reduction, with mechanical properties matching commercial control composite (p > 0.05). Fluoride and calcium ion releases from nCaF2+DMAHDM were much more than commercial composite. Biofilm CFU on composite was reduced by 4 logs (n = 9, p < 0.05). Biofilm metabolic activity and lactic acid were also substantially reduced by nCaF2+DMAHDM, compared to commercial control composite (p < 0.05). (4) Conclusions: The novel nanocomposite nCaF2+DMAHDM achieved strong antibacterial and ion release capabilities, without compromising the mechanical properties. This bioactive nanocomposite is promising to reduce biofilm acid production, inhibit recurrent caries, and increase restoration longevity. © 2020 by the authors.
    • Lymphocyte landscape after chronic hepatitis C virus (HCV) cure: The new normal

      Ghosh, Alip; Romani, Sara; Kottilil, Shyam; Poonia, Bhawna (MDPI AG, 2020-10-02)
      Chronic HCV (CHC) infection is the only chronic viral infection for which curative treatments have been discovered. These direct acting antiviral (DAA) agents target specific steps in the viral replication cycle with remarkable efficacy and result in sustained virologic response (SVR) or cure in high (>95%) proportions of patients. These treatments became available 6–7 years ago and it is estimated that their real impact on HCV related morbidity, including outcomes such as cirrhosis and hepatocellular carcinoma (HCC), will not be known for the next decade or so. The immune system of a chronically infected patient is severely dysregulated and questions remain regarding the immune system’s capacity in limiting liver pathology in a cured individual. Another important consequence of impaired immunity in patients cleared of HCV with DAA will be the inability to generate protective immunity against possible re-infection, necessitating retreatments or developing a prophylactic vaccine. Thus, the impact of viral clearance on restoring immune homeostasis is being investigated by many groups. Among the important questions that need to be answered are how much the immune system normalizes with cure, how long after viral clearance this recalibration occurs, what are the consequences of persisting immune defects for protection from re-infection in vulnerable populations, and does viral clearance reduce liver pathology and the risk of developing hepatocellular carcinoma in individuals cured with these agents. Here, we review the recent literature that describes the defects present in various lymphocyte populations in a CHC patient and their status after viral clearance using DAA treatments.
    • Opportunities and challenges to integrating mental health into HIV programs in a low- and middle-income country: insights from the Nigeria implementation science Alliance

      Ezeanolue, Echezona E; Iheanacho, Theddeus; Adedeji, Isaac A; Itanyi, Ijeoma Uchenna; Olakunde, Babayemi; Patel, Dina; Dakum, Patrick; Okonkwo, Prosper; Akinmurele, Timothy; Obiefune, Michael; et al. (2020-09-29)
      Background: In Nigeria, there is an estimated 1.9 million people living with HIV (PLHIV), 53% of whom utilize HIV care and services. With decreasing HIV-related deaths and increasing new infections, HIV with its associated comorbidities continue to be a key public health challenge in Nigeria. Untreated, comorbid mental disorders are a critical but potentially modifiable determinant of optimal HIV treatment outcomes. This study aimed to identify the challenges and opportunities related to integrating mental health care into existing HIV programs in Nigeria. Method: Attendees at the Nigeria Implementation Science Alliance (NISA)'s 2019 conference participated in nominal group technique (NGT) exercise informed by the "Exploration, Preparation, Implementation, and Sustainment (EPIS)"framework. The NGT process was conducted among the nominal groups in two major sessions of 30-min phases followed by a 30-min plenary session. Data analysis proceeded in four steps: transcription, collation, theming and content analysis. Results: The two major theoretical themes from the study were - opportunities and challenges of integrating mental health treatment into HIV services. Three sub-themes emerged on opportunities: building on health care facilities for HIV services (screening, counseling, task-sharing monitoring and evaluation frameworks), utilizing existing human resources or workforce in HIV programs (in-service training and including mental health in education curriculum) and the role of social and cultural structures (leveraging existing community, traditional and faith-based infrastructures). Four sub-themes emerged for challenges: double burden of stigma and the problems of early detection (HIV and mental health stigma, lack of awareness), existing policy gaps and structural challenges (fragmented health system), limited human resources for mental health care in Nigeria (knowledge gap and burnout) and dearth of data/evidence for planning and action (research gaps). Conclusions: Potential for integrating treatments for mental disorders into HIV programs and services exist in Nigeria. These include opportunities for clinicians' training and capacity building as well as community partnerships. Multiple barriers and challenges such as stigma, policy and research gaps would need to be addressed to leverage these opportunities. Our findings serve as a useful guide for government agencies, policy makers and research organizations to address co-morbid mental disorders among PLHIV in Nigeria. © 2020 The Author(s).
    • In Memory of Mark Shirtliff, PhD: Modern Concepts in Diagnosis, Treatment, Prevention, and Cost of Infection after Fracture Surgery

      O'Toole, Robert V.; Harro, Janette; Johnson, Aaron J.; O'Hara, Nathan N.; Natoli, Roman M.; Joshi, Manjari (Lippincott Williams and Wilkins, 2020-01-01)