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  • The Role American Thoracic Society Healthcare Providers Have in Immunization

    Ortiz, Justin R; Hartert, Tina V (American Thoracic Society, 2021-02-19)
  • Persistent Disparity: Socioeconomic Deprivation and Cancer Outcomes in Patients Treated in Clinical Trials

    Unger, Joseph M; Moseley, Anna B; Cheung, Christabel K; Osarogiagbon, Raymond U; Symington, Banu; Ramsey, Scott D; Hershman, Dawn L (American Society of Clinical Oncology, 2021-03-17)
    PURPOSE: Patients with cancer living in socioeconomically disadvantaged areas have worse cancer outcomes. The association between socioeconomic deprivation and outcomes among patients with cancer participating in clinical trials has not been systematically examined. METHODS: We examined survival outcomes for patients enrolled in phase III and large phase II clinical trials for major cancers conducted by the SWOG Cancer Research Network from 1985 to 2012. Socioeconomic deprivation was measured using trial participants' residential zip codes linked to the Area Deprivation Index (ADI). Five-year overall survival, progression-free survival, and cancer-specific survival were examined using Cox regression frailty models, adjusting for age, sex, and race, and separately for insurance status, prognostic risk, and rural or urban residency. RESULTS: We examined 41,109 patients from 55 trials comprising 24 cancer histology and stage-specific cohorts. Compared with trial participants in the most affluent areas (ADI, 0%-20%), trial participants from areas with the highest socioeconomic deprivation (ADI, 80%-100%) had worse overall (hazard ratio [HR] = 1.28, 95% CI, 1.20 to 1.37, P < .001), progression-free (HR = 1.20, 95% CI, 1.13 to 1.28, P < .001), and cancer-specific survival (HR = 1.27, 95% CI, 1.18 to 1.37, P < .001). The results were similar after adjusting for insurance status, prognostic risk, and rural or urban residency. There was a continuous increase in risk of all outcomes as the ADI quintile increased. CONCLUSION: In patients with cancer with access to protocol-directed care in clinical trials, high area-level socioeconomic deprivation was associated with worse survival. Future research should examine whether the etiology of this residual disparity is related to reduced access to supportive care or postprotocol therapy and/or to differences in health status not reflected by protocol selection criteria.
  • Nivolumab Exposure-Response Analysis for Adjuvant Treatment of Melanoma Supporting a Change in Posology

    Sanghavi, Kinjal; Vuppala, Pradeep; Ivaturi, Vijay; Hamuro, Lora; Roy, Amit; Suryawanshi, Satyendra (Wiley-Blackwell, 2021-05-06)
    Nivolumab monotherapy is approved as adjuvant treatment for melanoma, based on results from the pivotal CheckMate 238 trial. We present a model-based benefit-risk assessment of nivolumab in adjuvant melanoma supporting a posology change from a weight-based to a less frequent, flat-dosing regimen. The exposure-response (E-R) relationship for efficacy was evaluated using recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) endpoints from the CheckMate 238 trial. The E-R for safety was evaluated using data from 14 studies across a broad range of doses in several tumor types, using grade 3+ adverse events (AEs) and grade 2+ immune-mediated AEs (IMAEs) endpoints. Nivolumab trough exposures were not significant predictors of RFS or DMFS. Covariates significantly associated with increased risk of disease recurrence or death were PD-L1 (< 5% cutoff), lower baseline lactate dehydrogenase, and higher age. Covariates associated with increased risk of distant metastasis or death were PD-L1 (< 5% cutoff) and higher age. Higher nivolumab Cmax1 (maximum concentration after first dose) was significantly associated with grade 2+ IMAEs, but not grade 3+ AEs. The risk of grade 3+ AEs was significantly lower in adjuvant versus advanced melanoma. PS > 0 was associated with higher incidences of grade 2+ IMAEs and grade 3+ AEs. Female patients had significantly higher incidence of grade 2+ IMAEs than male patients. Nivolumab monotherapy in adjuvant melanoma demonstrated a relatively flat E-R relationship over the range of exposures produced by 3 mg/kg every 2 weeks and predicted a comparable benefit-risk profile to flat-dosing regimens.
  • Rising Black voices in urology - the next generation.

    Achua, Justin K; Bilbrew, Jordan; Cooley, Keiko; Herbert, Amber; Matthew-Onabanjo, Asia N; Moghalu, Odinachi; Myrie, Akya; Odeluga, Nkiruka; Owens-Walton, Jeunice; Rieland, Arriana; et al. (Springer Nature, 2021-05-04)
    In 2020, Nature Reviews Urology made a pledge to actively work towards improving diversity in our field. As we head into 2021, Black urologists make up only 2% of the US workforce in urology; this lack of representation is detrimental to the field as a whole and to the patients it serves. In this Viewpoint, which follows on from our previous article ‘Supporting Black voices in urology’, 12 medical students who have chosen to enter the field recount their experiences, describing their reasons for entering urology and why they chose particular programmes. As well as illustrating the importance of mentorship and representation, they also offer ideas on how urology programmes can better appeal to Black students, in order to encourage and support under-represented minorities into our specialty in the future.
  • Nourin-Dependent miR-137 and miR-106b: Novel Biomarkers for Early Diagnosis of Myocardial Ischemia in Coronary Artery Disease Patients

    Elgebaly, Salwa A; Christenson, Robert H; Kandil, Hossam; Ibrahim, Mohsen; Rizk, Hussien; El-Khazragy, Nashwa; Rashed, Laila; Yacoub, Beshoy; Eldeeb, Heba; Ali, Mahmoud M; et al. (MDPI AG, 2021-04-14)
    Although cardiovascular imaging techniques are widely used to diagnose myocardial ischemia in patients with suspected stable coronary artery disease (CAD), they have limitations related to lack of specificity, sensitivity and "late" diagnosis. Additionally, the absence of a simple laboratory test that can detect myocardial ischemia in CAD patients, has led to many patients being first diagnosed at the time of the development of myocardial infarction. Nourin is an early blood-based biomarker rapidly released within five minutes by "reversible" ischemic myocardium before progressing to necrosis. Recently, we demonstrated that the Nourin-dependent miR-137 (marker of cell damage) and miR-106b-5p (marker of inflammation) can diagnose myocardial ischemia in patients with unstable angina (UA) and also stratify severity of ischemia, with higher expression in acute ST-segment elevation myocardial infarction (STEMI) patients compared to UA patients. Minimal baseline-gene expression levels of Nourin miRNAs were detected in healthy subjects.
  • Choose your path: Divergent basolateral amygdala efferents differentially mediate incentive motivation, flexibility and decision-making

    Keefer, Sara E; Gyawali, Utsav; Calu, Donna J (Elsevier B.V., 2021-04-19)
    To survive in a complex environment, individuals form associations between environmental stimuli and rewards to organize and optimize reward seeking behaviors. The basolateral amygdala (BLA) uses these learned associations to inform decision-making processes. In this review, we describe functional projections between BLA and its cortical and striatal targets that promote learning and motivational processes central to decision-making. Specifically, we compare and contrast divergent projections from the BLA to the orbitofrontal (OFC) and to the nucleus accumbens (NAc) and examine the roles of these pathways in associative learning, value-guided decision-making, choice behaviors, as well as cue and context-driven drug seeking. Finally, we consider how these projections are involved in disorders of motivation, with a focus on Substance Use Disorder.
  • Exploring the Collateral Damage of the COVID-19 Pandemic on Stroke Care: A Statewide Analysis

    Balucani, Clotilde; Carhuapoma, J Ricardo; Canner, Joseph K; Faigle, Roland; Johnson, Brenda; Aycock, Anna; Phipps, Michael S; Schrier, Chad; Yarbrough, Karen; Toral, Linda; et al. (Lippincott Williams and Wilkins, 2021-03-11)
    Background and Purpose: During the coronavirus disease 2019 (COVID-19) pandemic, the various emergency measures implemented to contain the spread of the virus and to overcome the volume of affected patients presenting to hospitals may have had unintended consequences. Several studies reported a decrease in the number of stroke admissions. There are no data on the impact of the COVID-19 pandemic on stroke admissions and stroke care in Maryland. Methods: A retrospective analysis of quality improvement data reported by stroke centers in the State of Maryland. The number of admissions for stroke, overall and by stroke subtype, between March 1 and September 30, 2020 (pandemic) were compared with the same time period in 2019 (prepandemic). Median last known well to hospital arrival time, the number of intravenous thrombolysis and thrombectomy were also compared. Results: During the initial 7 months of the pandemic, there were 6529 total admissions for stroke and transient ischemic attack, monthly mean 938 (95% CI, 837.1-1038.9) versus prepandemic 8003, monthly mean 1156.3 (CI, 1121.3-1191.2), P<0.001. A significant decrease was observed in intravenous thrombolysis treatments, pandemic 617, monthly mean 88.1 (80.7-95.6) versus prepandemic 805, monthly mean 115 (CI, 104.3-125.6), P<0.001; there was no significant decrease for thrombectomies. The pandemic decreased the probability of admissions for stroke and transient ischemic attack by 19%, for acute ischemic stroke by 20%, for the number of intravenous thrombolysis performed by 23%. There was no difference in the number of admissions for subarachnoid hemorrhage, pandemic 199, monthly mean 28.4 (CI, 22.5-34.3) versus prepandemic 217, monthly mean 31 (CI, 23.9-38.1), respectively, P=0.507. Conclusions: Our findings suggest that the COVID-19 pandemic adversely affected the acute care of unrelated cerebrovascular emergencies.
  • Removing Barriers: A Confidential Opt-Out Mental Health Pilot Program for Internal Medicine Interns

    Major, Ajay; Williams, John G; McGuire, W Cameron; Floyd, Eleanor; Chacko, Karen (Lippincott Williams and Wilkins, 2021-02-02)
    Problem There are significant barriers for resident physicians seeking mental health care, including lack of time, cost, and concerns about confidentiality. The authors sought to improve access to mental health resources by addressing these barriers through the development of a confidential opt-out mental health pilot program for interns and to assess the feasibility, acceptability, and resident satisfaction with the program. Approach All internal medicine and internal medicine-pediatrics interns in the 2017-2018 residency class at the University of Colorado were enrolled in the confidential opt-out mental health program. Each intern was provided with an additional half-day off during their continuity clinic week, during which a mental health screening appointment at the campus health center with an in-network mental health provider was scheduled. All costs were covered by the residency program. An anonymous follow-up survey was sent to all interns to assess participation in the program and its perceived impact on their wellness. Outcomes Appointments were made for 80 interns: 23 (29%) attended the appointment, 45 (56%) opted out in advance, and 12 (15%) were no-shows. The total cost of the program was $940 or $11.75 per intern. Of the 41 interns who responded to the survey, 35 (85%) agreed the program should continue next year. The majority of interns felt the program positively affected their wellness regardless of whether they attended the appointment. Of the 16 interns who attended the appointment and completed the survey, 4 (25%) reported receiving additional mental health referrals or follow-up appointments. Next Steps This confidential opt-out mental health pilot program for interns was feasible, relatively low cost and simple to implement, and had positive impacts on self-reported wellness. Further study of interventions that remove barriers to accessing mental health care for residents is urgently needed.
  • Bilateral Retinal Vasculitis as the First Presentation of Systemic Lupus Erythematosus

    Alhassan, Eaman; Gendelman, Hannah K; Sabha, Marwa M; Hawkins-Holt, Melissa; Siaton, Bernadette C (International Scientific Information, Inc., 2021-04-06)
    Objective: Background: Case Report: Conclusions: Unusual clinical course Systemic lupus erythematosus (SLE) can involve any part of the eye. Keratoconjunctivitis sicca (dry eye) is the most common ocular manifestation, followed by scleritis, episcleritis, and retinitis. Retinal disease affects around 10% of patients with SLE. Mild retinopathy may be asymptomatic. However, severe cases can cause visual loss requiring urgent ophthalmic evaluation. We present a case of bilateral retinal vasculitis as the presenting manifestation of SLE. A 14-year-old girl with a history of schizophrenia presented to the emergency department (ED) with generalized weakness. Four days before her presentation, she developed itching in her eyes and frontal headaches. In the ED, she reported blurry vision in her left eye only and diffuse arthralgia. The ophthalmic evaluation showed bilateral reduced visual acuity, worse in the left eye. Both eyes had diffuse hemorrhages, white retinal lesions, and blurred optic disc margins. She was diagnosed with panuveitis and retinal vasculitis. The patient was then found to have SLE, diagnosed by the presence of arthralgias, panuveitis, severe bilateral retinal vasculitis, positive ANA and anti-dsDNA, and normocytic anemia. The patient received intravenous methylprednisolone with subsequent oral prednisone upon discharge, hydroxychloroquine, and azathioprine. One year after her presentation, she had significant visual improvement and no other system involvement. Retinal vasculitis, as the presenting symptom of SLE, has been overlooked in large studies. However, the number of case reports documenting this as a presenting symptom, often with minimal or no organ involvement, suggests that upon diagnosis, patients might benefit from a skilled ophthalmic evaluation. © Am J Case Rep, 2021.
  • Article hsp60 quantification in human gastric mucosa shows differences between pathologies with various degrees of proliferation and malignancy grade

    Pitruzzella, Alessandro; Burgio, Stefano; Lo Presti, Pietro; Ingrao, Sabrina; Fucarino, Alberto; Bucchieri, Fabio; Cabibi, Daniela; Cappello, Francesco; Conway de Macario, Everly; Macario, Alberto J.L.; et al. (MDPI AG, 2021-04-16)
    Background: Stomach diseases are an important sector of gastroenterology, including proliferative benign; premalignant; and malignant pathologies of the gastric mucosa, such as gastritis, hyperplastic polyps, metaplasia, dysplasia, and adenocarcinoma. There are data showing quantitative changes in chaperone system (CS) components in inflammatory pathologies and tumorigenesis, but their roles are poorly understood, and information pertaining to the stomach is scarce. Here, we report our findings on one CS component, the chaperone Hsp60, which we studied first considering its essential functions inside and outside mitochondria. Methods: We performed immunohistochemical experiments for Hsp60 in different samples of gastric mucosa. Results: The data obtained by quantitative analysis showed that the average percentages of Hsp60 were of 32.8 in normal mucosa; 33.5 in mild-to-moderate gastritis; 51.8 in severe gastritis; 58.5 in hyperplastic polyps; 67.0 in intestinal metaplasia; 89.4 in gastric dysplasia; and 92.5 in adenocarcinomas. Noteworthy were: (i) the difference between dysplasia and adenocarcinoma with the other pathologies; (ii) the progressive increase in Hsp60 from gastritis to hyperplastic polyp, gastric dysplasia, and gastric carcinoma; and (iii) the correlation of Hsp60 levels with histological patterns of cell proliferation and, especially, with tissue malignancy grades. Conclusions: This trend likely reflects the mounting need for cells for Hsp60 as they progress toward malignancy and is a useful indicator in differential diagnosis, as well as the call for research on the mechanisms underpinning the increase in Hsp60 and its possible roles in carcinogenesis. © 2021 by the authors.
  • Sustained antibacterial effect and wear behavior of quaternary ammonium contact‐killing dental polymers after one‐year of hydrolytic degradation

    Balhaddad, Abdulrahman A.; Mokeem, Lamia S.; Weir, Michael D.; Xu, Huakun; Melo, Mary Anne S. (MDPI AG, 2021-04-20)
    This study intended to investigate the long‐term antibacterial effect, mechanical perfor-mance, and surface topography of new anticaries dental composites. While most artificial aging studies of dental resins lasted for 30–90 days, this study prolonged the water‐aging to one year to be more clinically relevant. The base resin was loaded with dimethylaminohexadecyl methacrylate (DMAHDM) at 3 or 5 wt.% and nano‐sized amorphous calcium phosphate (NACP) at 20 wt.%. Composites were subjected to one‐year water storage and wear. Following water aging, samples were evaluated for flexural strength, elastic modulus, and microbiological assays. Biofilm plate counting method, metabolic assay, colorimetric quantification of lactic acid, and Baclight bacterial viability assay were measured after one year. Topography changes (ΔRa, ΔRq, ΔRv, ΔRt) were ex-amined after wear and observed by scanning electron microscopy. Biofilm assays and topography changes data were analyzed via one‐way ANOVA and Tukey’s tests. Mechanical properties and normalized data were verified using a t‐test. The flexural strength values for the formulations that contained 5% DMAHDM‐20% NACP, 3% DMAHDM, and 5% DMAHDM were reduced signifi-cantly (p < 0.05) in relation to the baseline but the values were still above the ISO standards. No significant differences were observed between the groups concerning the topography changes, ex-cept for the ΔRt, where there was a significant increase in the 5% DMAHDM‐20% NACP group. All the groups demonstrated robust biofilm‐inhibition, with slightly reduced antibacterial properties following water aging. The aged samples reduced the total microorganisms, total streptococci, and mutans streptococci by 1.5 to 3‐log, compared to the experimental control. The new formulations containing DMAHDM and NACP were able to sustain the antibacterial performance after one‐year of aging. Mechanical properties and surface topography were slightly affected over time. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
  • Opioid and benzodiazepine dispensing and co-dispensing patterns among commercially insured pregnant women in the United States, 2007-2015

    Qato, Danya M; Gandhi, Aakash Bipin (Springer Nature, 2021-05-03)
    Background: Little is known about benzodiazepine and opioid-benzodiazepine co-dispensing patterns among pregnant women. Understanding these patterns is necessary to mitigate high-risk medication use during pregnancy. Our objective in this analysis was to evaluate opioid and benzodiazepine dispensing and co-dispensing patterns among commercially insured pregnant women in the United States. Methods: This retrospective study used a 10% random sample of commercially insured enrollees from the IQVIA™ Adjudicated Health Plan Claims Data from 2007 to 2015. The study included women (12-55 years of age) with completed pregnancies who had continuous medical and prescription drug coverage from 3 months prior to the date of conception through 3 months post-delivery. We estimated the prevalence of opioid and benzodiazepine dispensing and co-dispensing before, during, and after pregnancy, and evaluated trends in dispensing patterns across the study period (2007-2015) using Cochrane-Armitage tests. Chi-square tests were used to examine differences in demographic and clinical characteristics by dispensing and co-dispensing patterns. Among women that received an opioid or benzodiazepine during pregnancy, logistic regression models were used to quantify the association between sample characteristics and dispensing patterns (co-dispensing vs single dispensing). Results: Of 168,025 pregnant women that met our inclusion criteria, 10.1% received at least one opioid and 2.0% received at least one benzodiazepine during pregnancy, while 0.5% were co-dispensed these drugs. During the study period (2007 vs 2015), prevalence of opioid dispensing during pregnancy decreased from 11.2 to 8.6% (p < 0.01); while benzodiazepine dispensing increased from 1.3 to 2.9% (p < 0.01), and the prevalence of co-dispensing, while low and stable, increased slightly from 0.39 to 0.44% (p < 0.01). Older age, a higher comorbidity burden, pain diagnosis, anxiety diagnosis, and alcohol, tobacco, and drug use disorders, were all associated with an increased odds of co-dispensing during pregnancy. Conclusions: This study provides evidence that while opioid dispensing during pregnancy has decreased in the past decade, benzodiazepine dispensing has increased. The prevalence of opioid-benzodiazepine co-dispensing was rare and remained fairly stable during our study period. Those co-dispensed both drugs had a higher prevalence of adverse birth outcomes. Further research to establish the potentially causal relationship between opioid and benzodiazepine co-dispensing and adverse birth outcomes should be undertaken.
  • Characterization of the Plasma Lipidome in Dairy Cattle Transitioning from Gestation to Lactation: Identifying Novel Biomarkers of Metabolic Impairment

    Rico, Jorge Eduardo; Saed Samii, Sina; Zang, Yu; Deme, Pragney; Haughey, Norman J; Grilli, Ester; McFadden, Joseph W (MDPI AG, 2021-04-30)
    The discovery of novel biomarkers for peripartal diseases in dairy cows can improve our understanding of normal and dysfunctional metabolism, and lead to nutritional interventions that improve health and milk production. Our objectives were to characterize the plasma lipidome and identify metabolites associated with common markers of metabolic disease in peripartal dairy cattle. Multiparous Holstein cows (n = 27) were enrolled 30 d prior to expected parturition. Blood and liver samples were routinely collected through to d 14 postpartum. Untargeted lipidomics was performed using quadrupole time-of-flight mass spectrometry. Based on postpartum measures, cows were categorized into low or high total fatty acid area under the curve (total FAAUC; d 1-14 postpartum; 4915 ± 1369 vs. 12,501 ± 2761 (μmol/L × 14 d); n = 18), β-hydroxybutyrate AUC (BHBAAUC; d 1-14 postpartum; 4583 ± 459 vs. 7901 ± 1206 (μmol/L × 14 d); n = 18), or liver lipid content (d 5 and 14 postpartum; 5 ± 1 vs. 12 ± 2% of wet weight; n = 18). Cows displayed decreases in plasma triacylglycerols and monoalkyl-diacylglycerols, and the majority of phospholipids reached a nadir at parturition. Phosphatidylcholines (PC) 32:3, 35:5, and 37:5 were specific for high total FAAUC, PC 31:3, 32:3, 35:5, and 37:5 were specific for high BHBAAUC, and PC 31:2, 31:3, and 32:3 were specific for high liver lipid content. PC 32:3 was specific for elevated total FA, BHBA, and liver lipid content. Lipidomics revealed a dynamic peripartal lipidome remodeling, and lipid markers associated with elevated total FA, BHBA, and liver lipid content. The effectiveness of nutrition to impact these lipid biomarkers for preventing excess lipolysis and fatty liver warrants evaluation.
  • Arthritis

    Grainger, Andrew J.; Resnik, Charles S. (Springer International Publishing, 2021-04-13)
  • The importance of genomic analysis in cracking the coronavirus pandemic

    Zella, Davide; Giovanetti, Marta; Cella, Eleonora; Borsetti, Alessandra; Ciotti, Marco; Ceccarelli, Giancarlo; D'Ettorre, Gabriella; Pezzuto, Aldo; Tambone, Vittoradolfo; Campanozzi, Laura; et al. (Taylor and Francis Inc., 2021-04-28)
    Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has pushed the scientific community to undertake intense research efforts. Understanding SARS-CoV-2 biology is necessary to discover therapeutic or preventive strategies capable of containing the pandemic. Knowledge of the structural characteristics of the virus genome and proteins is essential to find targets for therapies and immunological interventions.Areas covered: This review covers different areas of expertise, genomic analysis of circulating strains, structural biology, viral mutations, molecular diagnostics, disease, and vaccines. In particular, the review is focused on the molecular approaches and modern clinical strategies used in these fields.Expert opinion: Molecular approaches to SARS-CoV-2 pandemic have been critical to shorten time for new diagnostic, therapeutic and prevention strategies. In this perspective, the entire scientific community is moving in the same direction. Vaccines, together with the development of new drugs to treat the disease, represent the most important strategy to protect human from viral disease and prevent further spread. In this regard, new molecular technologies have been successfully implemented. The use of a novel strategy of communication is suggested for a better diffusion to the broader public of new data and results.
  • Parameters of biliary hydrodynamic injection during endoscopic retrograde cholangio-pancreatography in pigs for applications in gene delivery

    Huang, Yuting; Kruse, Robert L; Ding, Hui; Itani, Mohamad I; Morrison, Jonathan; Wang, Zack Z; Selaru, Florin M; Kumbhari, Vivek (Public Library of Science, 2021-04-28)
    The biliary system is routinely accessed for clinical purposes via endoscopic retrograde cholangiopancreatography (ERCP). We previously pioneered ERCP-mediated hydrodynamic injection in large animal models as an innovative gene delivery approach for monogenic liver diseases. However, the procedure poses potential safety concerns related mainly to liver or biliary tree injury. Here, we sought to further define biliary hydrodynamic injection parameters that are well-tolerated in a human-sized animal model. ERCP was performed in pigs, and hydrodynamic injection carried out using a novel protocol to reduce duct wall stress. Each pig was subjected to multiple repeated injections to expedite testing and judge tolerability. Different injection parameters (volume, flow rate) and injection port diameters were tested. Vital signs were monitored throughout the procedure, and liver enzyme panels were collected pre- and post-procedure. Pigs tolerated repeated biliary hydrodynamic injections with only occasional, mild, isolated elevation in aspartate aminotransferase (AST), which returned to normal levels within one day post-injection. All other liver tests remained unchanged. No upper limit of volume tolerance was reached, which suggests the biliary tree can readily transmit fluid into the vascular space. Flow rates up to 10 mL/sec were also tolerated with minimal disturbance to vital signs and no anatomic rupture of bile ducts. Measured intrabiliary pressure was up to 150 mmHg, and fluid-filled vesicles were induced in liver histology at high flow rates, mimicking the changes in histology observed in mouse liver after hydrodynamic tail vein injection. Overall, our investigations in a human-sized pig liver using standard clinical equipment suggest that ERCP-guided hydrodynamic injection will be safely tolerated in patients. Future investigations will interrogate if higher flow rates and pressure mediate higher DNA delivery efficiencies.
  • A novel small molecule LLL12B inhibits STAT3 signaling and sensitizes ovarian cancer cell to paclitaxel and cisplatin

    Zhang, Ruijie; Yang, Xiaozhi; Roque, Dana M; Li, Chenglong; Lin, Jiayuh (Public Library of Science, 2021-04-28)
    Ovarian cancer is the fifth most common cause of cancer deaths among American women. Platinum and taxane combination chemotherapy represents the first-line approach for ovarian cancer, but treatment success is often limited by chemoresistance. Therefore, it is necessary to find new drugs to sensitize ovarian cancer cells to chemotherapy. Persistent activation of Signal Transducer and Activator of Transcription 3 (STAT3) signaling plays an important role in oncogenesis. Using a novel approach called advanced multiple ligand simultaneous docking (AMLSD), we developed a novel nonpeptide small molecule, LLL12B, which targets the STAT3 pathway. In this study, LLL12B inhibited STAT3 phosphorylation (tyrosine 705) and the expression of its downstream targets, which are associated with cancer cell proliferation and survival. We showed that LLL12B also inhibits cell viability, migration, and proliferation in human ovarian cancer cells. LLL12B combined with either paclitaxel or with cisplatin demonstrated synergistic inhibitory effects relative to monotherapy in inhibiting cell viability and LLL12B-paclitaxel or LLL12B-cisplatin combination exhibited greater inhibitory effects than cisplatin-paclitaxel combination in ovarian cancer cells. Furthermore, LLL12B-paclitaxel or LLL12B-cisplatin combination showed more significant in inhibiting cell migration and growth than monotherapy in ovarian cancer cells. In summary, our results support the novel small molecule LLL12B as a potent STAT3 inhibitor in human ovarian cancer cells and suggest that LLL12B in combination with the current front-line chemotherapeutic drugs cisplatin and paclitaxel may represent a promising approach for ovarian cancer therapy.
  • Molecular Characterisation of Cryptosporidium spp. in Mozambican Children Younger than 5 Years Enrolled in a Matched Case-Control Study on the Aetiology of Diarrhoeal Disease

    Messa, Augusto; Köster, Pamela C; Garrine, Marcelino; Nhampossa, Tacilta; Massora, Sérgio; Cossa, Anélsio; Bassat, Quique; Kotloff, Karen; Levine, Myron M; Alonso, Pedro L; et al. (MDPI AG, 2021-04-09)
    Cryptosporidium is a leading cause of childhood diarrhoea and associated physical and cognitive impairment in low-resource settings. Cryptosporidium-positive faecal samples (n = 190) from children aged ≤ 5 years enrolled in the Global Enteric Multicenter Study (GEMS) in Mozambique detected by ELISA (11.5%, 430/3754) were successfully PCR-amplified and sequenced at the gp60 or ssu rRNA loci for species determination and genotyping. Three Cryptosporidium species including C. hominis (72.6%, 138/190), C. parvum (22.6%, 43/190), and C. meleagridis (4.2%, 8/190) were detected. Children ≤ 23 months were more exposed to Cryptosporidium spp. infections than older children. Both C. hominis and C. parvum were more prevalent among children with diarrhoeal disease compared to those children without it (47.6% vs. 33.3%, p = 0.007 and 23.7% vs. 11.8%, p = 0.014, respectively). A high intra-species genetic variability was observed within C. hominis (subtype families Ia, Ib, Id, Ie, and If) and C. parvum (subtype families IIb, IIc, IIe, and IIi) but not within C. meleagridis (subtype family IIIb). No association between Cryptosporidium species/genotypes and child's age was demonstrated. The predominance of C. hominis and C. parvum IIc suggests that most of the Cryptosporidium infections were anthroponotically transmitted, although zoonotic transmission events also occurred at an unknown rate. The role of livestock, poultry, and other domestic animal species as sources of environmental contamination and human cryptosporidiosis should be investigated in further molecular epidemiological studies in Mozambique.
  • Early Life Stress and Risks for Opioid Misuse: Review of Data Supporting Neurobiological Underpinnings

    Oswald, Lynn M; Dunn, Kelly E; Seminowicz, David A; Storr, Carla L (MDPI AG, 2021-04-19)
    A robust body of research has shown that traumatic experiences occurring during critical developmental periods of childhood when neuronal plasticity is high increase risks for a spectrum of physical and mental health problems in adulthood, including substance use disorders. However, until recently, relatively few studies had specifically examined the relationships between early life stress (ELS) and opioid use disorder (OUD). Associations with opioid use initiation, injection drug use, overdose, and poor treatment outcome have now been demonstrated. In rodents, ELS has also been shown to increase the euphoric and decrease antinociceptive effects of opioids, but little is known about these processes in humans or about the neurobiological mechanisms that may underlie these relationships. This review aims to establish a theoretical model that highlights the mechanisms by which ELS may alter opioid sensitivity, thereby contributing to future risks for OUD. Alterations induced by ELS in mesocorticolimbic brain circuits, and endogenous opioid and dopamine neurotransmitter systems are described. The limited but provocative evidence linking these alterations with opioid sensitivity and risks for OUD is presented. Overall, the findings suggest that better understanding of these mechanisms holds promise for reducing vulnerability, improving prevention strategies, and prescribing guidelines for high-risk individuals.
  • Synthesis and Antibacterial Activity of New Azole, Diazole and Triazole Derivatives Based on -Aminobenzoic Acid

    Sapijanskaitė-Banevič, Birutė; Palskys, Vykintas; Vaickelionienė, Rita; Šiugždaitė, Jūratė; Kavaliauskas, Povilas; Grybaitė, Birutė; Mickevičius, Vytautas (MDPI AG, 2021-04-29)
    The p-aminobenzoic acid was applied for the synthesis of substituted 1-phenyl-5-oxopyrrolidine derivatives containing benzimidazole, azole, oxadiazole, triazole, dihydrazone, and dithiosemicarbazide moieties in the structure. All the obtained compounds were evaluated for their in vitro antimicrobial activity against Staphylococcus aureus, Bacillus cereus, Listeria monocytogenes, Salmonella enteritidis, Escherichia coli, and Pseudomonas aeruginosa by using MIC and MBC assays. This study showed a good bactericidal activity of γ-amino acid and benzimidazoles derivatives. The antimicrobial activity of the most promising compounds was higher than ampicillin. Furthermore, two benzimidazoles demonstrated good antimicrobial activity against L. monocytogenes (MIC 15.62 µg/mL) that was four times more potent than ampicillin (MIC 65 µg/mL). Further studies are needed to better understand the mechanism of the antimicrobial activity as well as to generate antimicrobial compounds based on the 1-phenyl-5-oxopyrrolidine scaffold.

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