Publications by authors named "Carolina Gutierrez"

109 Publications

Fecal microbiota transplantation in HIV: A pilot placebo-controlled study.

Nat Commun 2021 02 18;12(1):1139. Epub 2021 Feb 18.

Department of Infectious Diseases, Hospital Universitario Ramon y Cajal, and IRYCIS, Madrid, Spain.

Changes in the microbiota have been linked to persistent inflammation during treated HIV infection. In this pilot double-blind study, we study 30 HIV-infected subjects on antiretroviral therapy (ART) with a CD4/CD8 ratio < 1 randomized to either weekly fecal microbiota capsules or placebo for 8 weeks. Stool donors were rationally selected based on their microbiota signatures. We report that fecal microbiota transplantation (FMT) is safe, not related to severe adverse events, and attenuates HIV-associated dysbiosis. FMT elicits changes in gut microbiota structure, including significant increases in alpha diversity, and a mild and transient engraftment of donor's microbiota during the treatment period. The greater engraftment seems to be achieved by recent antibiotic use before FMT. The Lachnospiraceae and Ruminococcaceae families, which are typically depleted in people with HIV, are the taxa more robustly engrafted across time-points. In exploratory analyses, we describe a significant amelioration in the FMT group in intestinal fatty acid-binding protein (IFABP), a biomarker of intestinal damage that independently predicts mortality. Gut microbiota manipulation using a non-invasive and safe strategy of FMT delivery is feasible and deserves further investigation. Trial number: NCT03008941.
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http://dx.doi.org/10.1038/s41467-021-21472-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892558PMC
February 2021

Effect of the use of Galectin-9 and blockade of TIM-3 receptor in the latent cellular reservoir of HIV-1.

J Virol 2020 Dec 23. Epub 2020 Dec 23.

Department of Infectious Diseases, Hospital Ramón y Cajal, IRYCIS, Madrid, Spain.

Reactivation of latent HIV-1 is a necessary step for the purging of the viral reservoir, although it does not seem to be enough. The stimulation of HIV-1 specific cytotoxic T lymphocytes (CTL) may be just as essential for this purpose. In this study, we aimed to show the effect of galectin-9 (Gal-9), known to revert HIV-1 latency, in combination with the blockade of TIM-3, a natural receptor for Gal-9 and an exhaustion marker. We confirmed the ability of Gal-9 to reactivate latent HIV-1 in Jurkat-LAT-GFP cells, as well as in an IL-7-based cellular model. This reactivation was not mediated via the TIM-3 receptor, but rather by the recognition of the Gal-9 of a specific oligosaccharide pattern of resting memory CD4 T cells' surfaces. The potency of Gal-9 in inducing transcription of latent HIV-1 was equal to or greater than that of other latency-reversing agents (LRA). Furthermore, the combination of Gal-9 with other LRA did not show synergistic effects in the reactivation of the latent virus. To evaluate the impact of TIM-3 inhibition on the CTL-response, different co-culture experiments with CD4T, CD8 T, and NK cells were performed. Our data showed that blocking TIM-3 was associated with control of viral replication in both and models in cells from PLWH on antiretroviral therapy. A joint strategy of the use of Gal-9 to reactivate latent HIV-1 and the inhibition of TIM-3 to enhance the HIV-1 CTL specific-response was associated with control of the replication of the virus that was being reactivated, thus potentially contributing to the elimination of the viral reservoir. Our results place this strategy as a promising approach to be tested in future studies. Reactivation of latent-HIV-1 by Gal-9 and reinvigoration of CD8 T cells by TIM-3 blockade could be used separately or in combination.HIV-1 infection is a health problem of enormous importance that still causes significant mortality. Antiretroviral treatment (ART) has demonstrated efficacy in the control of HIV-1 replication, decreasing the morbidity and mortality of the infection, but it cannot eradicate the virus. In our work, we tested a protein, galectin-9 (Gal-9), an HIV-1 latency-reversing agent, using an in cellular model of latency and in cells from people living with HIV-1 (PLWH) on antiretroviral therapy. Our results confirmed the potential role of Gal-9 as a molecule with a potent HIV-1 reactivation capacity. More importantly, using a monoclonal antibody against T cell immunoglobulin and the mucin domain-containing molecule 3 (TIM-3) receptor we were able to enhance the HIV-1 cytotoxic T lymphocytes (CTL) specific response to eliminate the CD4 T cells in which the virus had been reactivated. When used together, i.e., Gal-9 and TIM-3 blockade, control of the replication of HIV-1 was observed, suggesting a decrease in the cellular reservoir.
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http://dx.doi.org/10.1128/JVI.02214-20DOI Listing
December 2020

Prolonged administration of maraviroc reactivates latent HIV in vivo but it does not prevent antiretroviral-free viral rebound.

Sci Rep 2020 12 18;10(1):22286. Epub 2020 Dec 18.

Servicio de Enfermedades Infecciosas, Instituto Ramón Y Cajal de Investigación Sanitaria (IRYCIS) - Hospital Universitario Ramón Y Cajal, Carretera de Colmenar, Km 9.100, 28034, Madrid, Spain.

Human immunodeficiency virus (HIV) remains incurable due to latent viral reservoirs established in non-activated CD4 T cells that cannot be eliminated via antiretroviral therapy. Current efforts to cure HIV are focused on identifying drugs that will induce viral gene expression in latently infected cells, commonly known as latency reversing agents (LRAs). Some drugs have been shown to reactivate latent HIV but do not cause a reduction in reservoir size. Therefore, finding new LRAs or new combinations or increasing the round of stimulations is needed to cure HIV. However, the effects of these drugs on viral rebound after prolonged treatment have not been evaluated. In a previous clinical trial, antiretroviral therapy intensification with maraviroc for 48 weeks caused an increase in residual viremia and episomal two LTR-DNA circles suggesting that maraviroc could reactivate latent HIV. We amended the initial clinical trial to explore additional virologic parameters in stored samples and to evaluate the time to viral rebound during analytical treatment interruption in three patients. Maraviroc induced an increase in cell-associated HIV RNA during the administration of the drug. However, there was a rapid rebound of viremia after antiretroviral therapy discontinuation. HIV-specific T cell response was slightly enhanced. These results show that maraviroc can reactivate latent HIV in vivo but further studies are required to efficiently reduce the reservoir size.
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http://dx.doi.org/10.1038/s41598-020-79002-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749169PMC
December 2020

Maraviroc reactivates HIV with potency similar to that of other latency reversing drugs without inducing toxicity in CD8 T cells.

Biochem Pharmacol 2020 12 23;182:114231. Epub 2020 Sep 23.

Servicio de Enfermedades Infecciosas, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) and Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain; Facultad de Medicina y Ciencias de la Salud, Universidad de Alcalá de Henares, 28871 Alcalá de Henares, Spain.

Human immunodeficiency virus (HIV) remains incurable due to latent reservoirs established in non-activated CD4 T cells. Current efforts to achieve a functional cure rely on immunomodulatory strategies focused on enhancing the functions of cytotoxic cells. Implementation of these actions requires a coordinated activation of the viral transcription in latently infected cells so that the reservoir became visible and accessible to cytotoxic cells. As no latency reversing agent (LRA) has been shown to be completely effective, new combinations are of increasing importance. Recent data have shown that maraviroc is a new LRA. In this work, we have explored how the combination of maraviroc with other LRAs influences on HIV reactivation using in vitro latency models as well as on the cell viability of CD8 T cells from ART-treated patients. Maraviroc reactivated HIV with a potency similar to other LRAs. Triple combinations resulted toxic and were rejected. No dual combination was synergistic. The combination with panobinostat or disulfiram maintained the effect of both drugs without inducing cell proliferation or toxicity. Maraviroc does not alter the viability of CD8 T cells isolated from patients under antiretroviral treatment. This finding enhances the properties of maraviroc as a LRA.
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http://dx.doi.org/10.1016/j.bcp.2020.114231DOI Listing
December 2020

Octreotide-related exocrine pancreatic insufficiency (EPI) in congenital hyperinsulinism.

J Pediatr Endocrinol Metab 2020 Jul;33(7):947-950

Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain.

Background Congenital hyperinsulinism (CH) is the most frequent cause of persistent hypoglycemia in the newborn. Octreotide, a long-acting somatostatin receptor analog (SSRA), is a second line treatment for diazoxide unresponsive CH patients. Although it has been found to be a safe and effective treatment, long-term benefits and side effects, have not been thoroughly evaluated. Case presentation Some authors have indicated that exocrine pancreatic insufficiency (EPI) is a common but under-recognized adverse reaction in adults treated with octreotide. However, no pediatric patient with SSRA-induced EPI has been reported to date. Here we report a case of an infant with diazoxide unresponsive, diffuse CH, caused by a heterozygous pathogenic paternally inherited mutation in the ABCC8 gene (NM_000352.4:c.357del), that developed exocrine pancreatic insufficiency and secondary vitamin K deficiency associated to chronic octreotide therapy. Conclusions We point out the atypical clinical onset with a cutaneous hemorrhagic syndrome, emphasizing the clinical relevance of this potential side effect.
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http://dx.doi.org/10.1515/jpem-2019-0565DOI Listing
July 2020

Blood Bacterial Profiles Associated With Human Immunodeficiency Virus Infection and Immune Recovery.

J Infect Dis 2021 Feb;223(3):471-481

Institute of Catalysis, Consejo Superior de Investigaciones Científicas, Madrid, Spain.

Human immunodeficiency virus (HIV) infection impairs mucosal immunity and leads to bacterial translocation, fueling chronic inflammation and disease progression. While this is well established, questions remain about the compositional profile of the translocated bacteria, and to what extent it is influenced by antiretroviral therapy (ART). Using 16S ribosomal DNA targeted sequencing and shotgun proteomics, we showed that HIV increases bacterial translocation from the gut to the blood. HIV increased alpha diversity in the blood, which was dominated by aerobic bacteria belonging to Micrococcaceae (Actinobacteria) and Pseudomonadaceae (Proteobacteria) families, and the number of circulating bacterial proteins was also increased. Forty-eight weeks of ART attenuated this phenomenon. We found that enrichment with Lactobacillales order, and depletion of Actinobacteria class and Moraxellaceae and Corynebacteriacae families, were significantly associated with greater immune recovery and correlated with several inflammatory markers. Our findings suggest that the molecular cross talk between the host and the translocated bacterial products could influence ART-mediated immune recovery.
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http://dx.doi.org/10.1093/infdis/jiaa379DOI Listing
February 2021

Randomized Trial of Combined Aerobic, Resistance, and Cognitive Training to Improve Recovery From Stroke: Feasibility and Safety.

J Am Heart Assoc 2020 05 12;9(10):e015377. Epub 2020 May 12.

Department of Neurology Miller School of Medicine University of Miami FL.

Background Physical exercise and cognitive training have been recommended to improve cognitive outcomes poststroke, but a multifaceted strategy including aerobic, resistance, and cognitive training to facilitate poststroke recovery has not been investigated. We aimed to assess the feasibility, adherence, and safety of a combined aerobic, resistance, and cognitive training intervention (CARET+CTI) after stroke. Methods and Results We prospectively randomized patients presenting with recent stroke to a comparison of a supervised 12-week CARET+CTI program and a control group receiving sham CARET+CTI. Participants were scheduled for 3 weekly CARET and CTI sessions. All participants underwent pre- and postintervention assessments of strength, endurance, and cognition. The primary outcomes were feasibility and adherence, defined as the ratio of scheduled and observed visits, and safety. We enrolled 131 participants, of whom 37 withdrew from the study. There were 17 (20%) withdrawals in the CARET+CTI and 20 (44%) in the control group. The observed-over-expected visit ratio was significantly higher in the intervention than in the control group (0.74±0.30 versus 0.54±0.38; =0.003). A total of 99 adverse events were reported by 59 participants, none of which were serious and related to the intervention. Greater gains in physical, cognitive, and mood outcomes were found in the CARET+CTI group than in the control group, but were not statistically significant after adjustments. Conclusions A CARET+CTI intervention, after stroke, is safe, feasible, and has satisfactory participant adherence over 12 weeks. REGISTRATION URL: https://www.clini​caltr​ials.gov. Unique identifier: NCT02272426.
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http://dx.doi.org/10.1161/JAHA.119.015377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660866PMC
May 2020

Comparative toxicity of larvicides and growth inhibitors on from select areas in Jamaica.

R Soc Open Sci 2020 Mar 18;7(3):192041. Epub 2020 Mar 18.

International Development Division (IDD), Abt Associates, Rockville, MD 20852, USA.

Insecticide resistance has become problematic in tropical and subtropical regions, where mosquitoes and -borne arboviral diseases thrive. With the recent occurrence of chikungunya and the Zika virus in Jamaica, the Ministry of Health and Wellness, Jamaica, partnered with the United States Agency for International Development to implement multiple intervention activities to reduce the populations in seven parishes across the island and to assess the susceptibility of collected samples to various concentrations of temephos, subsp. (Bti), diflubenzuron and methoprene. Of the insecticides tested, only temephos has been used in routine larviciding activities in the island. The results showed that only temephos at concentrations 0.625 ppm and Bti at concentrations 6-8 ppm were effective at causing 98-100% mortality of local at 24 h exposure. Surprisingly, the growth inhibitors diflubenzuron and methoprene had minimal effect at preventing adult emergence in larvae in the populations tested. The results demonstrate the need for insecticide resistance testing as a routine part of vector control monitoring activies in order to determine useful tools that may be incorporated to reduce the abundance of .
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http://dx.doi.org/10.1098/rsos.192041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137934PMC
March 2020

Longitudinal effects of a novel advanced pneumatic compression device on patient-reported outcomes in the management of cancer-related head and neck lymphedema: A preliminary report.

Head Neck 2020 08 18;42(8):1791-1799. Epub 2020 Mar 18.

Division of Head & Neck Surgical Oncology, Department of Otorhinolaryngology - Head & Neck Surgery Division of Medical Oncology, The University of Texas Health Science Center / McGovern Medical School, Houston, Texas.

Background: Head and neck cancer (HNC) survivors experience head and neck lymphedema (HNL), which requires treatment to prevent morbidity. We explore the self-reported outcomes and satisfaction of patients with HNC receiving treatment for HNL with an advanced pneumatic compression device (APCD).

Methods: HNC survivors (n = 205) prescribed with an at-home Flexitouch head and neck APCD completed pretreatment and posttreatment self-reported assessments addressing efficacy, function, and symptoms. Participant average age was 60 years with 74% male. Pre-post responses for ≥25 days of use were assessed via the non-parametric Wilcoxon Signed Rank test.

Results: Analysis revealed statistically significant improvement in all symptoms and all function items (P < 0.00001). Compliance with prescribed therapy (at least 30 minutes daily) was high with 71% of participants reporting daily use and 87% reporting overall satisfaction.

Conclusions: The reported improvements in function and symptoms, and high compliance rate, provide a rationale for a subsequent randomized controlled trial.
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http://dx.doi.org/10.1002/hed.26110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496342PMC
August 2020

FOXA1 upregulation promotes enhancer and transcriptional reprogramming in endocrine-resistant breast cancer.

Proc Natl Acad Sci U S A 2019 Dec 11. Epub 2019 Dec 11.

Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030;

Forkhead box A1 (FOXA1) is a pioneer factor that facilitates chromatin binding and function of lineage-specific and oncogenic transcription factors. Hyperactive FOXA1 signaling due to gene amplification or overexpression has been reported in estrogen receptor-positive (ER) endocrine-resistant metastatic breast cancer. However, the molecular mechanisms by which FOXA1 up-regulation promotes these processes and the key downstream targets of the FOXA1 oncogenic network remain elusive. Here, we demonstrate that FOXA1 overexpression in ER breast cancer cells drives genome-wide enhancer reprogramming to activate prometastatic transcriptional programs. Up-regulated FOXA1 employs superenhancers (SEs) to synchronize transcriptional reprogramming in endocrine-resistant breast cancer cells, reflecting an early embryonic development process. We identify the hypoxia-inducible transcription factor hypoxia-inducible factor-2α (HIF-2α) as the top high FOXA1-induced SE target, mediating the impact of high FOXA1 in activating prometastatic gene sets and pathways associated with poor clinical outcome. Using clinical ER/HER2 metastatic breast cancer datasets, we show that the aberrant FOXA1/HIF-2α transcriptional axis is largely nonconcurrent with the mutations, suggesting different mechanisms of endocrine resistance and treatment strategies. We further demonstrate the selective efficacy of an HIF-2α antagonist, currently in clinical trials for advanced kidney cancer and recurrent glioblastoma, in reducing the clonogenicity, migration, and invasion of endocrine-resistant breast cancer cells expressing high FOXA1. Our study has uncovered high FOXA1-induced enhancer reprogramming and HIF-2α-dependent transcriptional programs as vulnerable targets for treating endocrine-resistant and metastatic breast cancer.
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http://dx.doi.org/10.1073/pnas.1911584116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936436PMC
December 2019

TBCRC023: A Randomized Phase II Neoadjuvant Trial of Lapatinib Plus Trastuzumab Without Chemotherapy for 12 versus 24 Weeks in Patients with HER2-Positive Breast Cancer.

Clin Cancer Res 2020 02 29;26(4):821-827. Epub 2019 Oct 29.

Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.

Purpose: Prior neoadjuvant trials with 12 weeks of dual anti-HER2 therapy without chemotherapy demonstrated a meaningful pathologic complete response (pCR) in patients with HER2-positive breast cancer. In this trial, we sought to determine whether longer treatment would increase the rate of pCR.

Patients And Methods: TBCRC023 (NCT00999804) is a randomized phase II trial combining a Simon phase II design in the experimental arm with a pick-the-winner design, not powered for direct comparison. Women with HER2-positive breast tumors measuring ≥2 cm (median = 5 cm) were randomized in a 1:2 ratio to 12 versus 24 weeks of lapatinib and trastuzumab. Letrozole (along with ovarian suppression if premenopausal) was administered in patients whose tumors were also estrogen receptor (ER) positive. All evaluable patients were assessed for in-breast pCR.

Results: Ninety-seven patients were enrolled (33 in 12-week arm and 64 in 24-week arm), of whom 94 were evaluable. Median age was 51 years, and 55% were postmenopausal. Median tumor size was 5 cm, and 65% were ER-positive. The rate of pCR in the 24-week arm was 28% and numerically superior to the 12-week arm (12%). This was driven by increased pCR in the ER-positive subgroup (33% vs. 9%). Study treatment was well tolerated, with grade 1-2 diarrhea and acneiform rash being the most common toxicities.

Conclusions: Treatment with dual anti-HER2 therapy for 24 weeks led to a numeric increase in pCR rate in women with HER2-positive breast cancer, without using chemotherapy. If validated, this approach may help identify patients who may benefit from deescalation of therapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0851DOI Listing
February 2020

Evaluation of the Predictive Role of Tumor Immune Infiltrate in Patients with HER2-Positive Breast Cancer Treated with Neoadjuvant Anti-HER2 Therapy without Chemotherapy.

Clin Cancer Res 2020 02 25;26(3):738-745. Epub 2019 Oct 25.

Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.

Purpose: Tumor-infiltrating lymphocytes (TIL) are associated with benefit to trastuzumab and chemotherapy in patients with early-stage HER2 breast cancer. The predictive value of TILs, TIL subsets, and other immune cells in patients receiving chemotherapy-sparing lapatinib plus trastuzumab treatment is unclear. Hematoxylin and eosin-stained slides ( = 59) were used to score stromal (s-)TILs from pretreatment biopsies of patients enrolled in the neoadjuvant TBCRC006 trial of 12-week lapatinib plus trastuzumab therapy (plus endocrine therapy for ER tumors). A 60% threshold was used to define lymphocyte-predominant breast cancer (LPBC). Multiplexed immunofluorescence (m-IF) staining (CD4, CD8, CD20, CD68, and FoxP3) and multispectral imaging were performed to characterize immune infiltrates in single formalin-fixed paraffin-embedded slides ( = 33).

Results: The pathologic complete response (pCR) rate was numerically higher in patients with LPBC compared with patients with non-LPBC (50% vs. 19%, = 0.057). Unsupervised hierarchical clustering of the five immune markers identified two patient clusters with different responses to lapatinib plus trastuzumab treatment (pCR = 7% vs. 50%, for cluster 1 vs. 2 respectively; = 0.01). In multivariable analysis, cluster 2, characterized by high CD4, CD8, CD20 s-TILs, and high CD20 intratumoral TILs, was independently associated with a higher pCR rate ( = 0.03). Analysis of single immune subpopulations revealed a significant association of pCR with higher baseline infiltration by s-CD4, intratumoral (i-) CD4, and i-CD20 TILs.

Conclusions: LPBC was marginally associated with higher pCR rate than non-LPBC in patients with lapatinib plus trastuzumab treated HER2 breast cancer. Quantitative assessment of the immune infiltrate by m-IF is feasible and may help correlate individual immune cell subpopulations and immune cell profiles with treatment response.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002194PMC
February 2020

Race-Ethnic Disparities in 30-Day Readmission After Stroke Among Medicare Beneficiaries in the Florida Stroke Registry.

J Stroke Cerebrovasc Dis 2019 Dec 11;28(12):104399. Epub 2019 Oct 11.

Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida.

Objective: To examine racial/ethnic disparities in 30-day all-cause readmission after stroke.

Methods: Thirty-day all-cause readmission was compared by race/ethnicity among Medicare fee-for-service beneficiaries discharged for ischemic stroke from hospitals in the Florida Stroke Registry from 2010 to 2013. We fit a Cox proportional hazards model that censored for death and adjusted for age, sex, length of stay, discharge home, and comorbidities to assess racial/ethnic differences in readmission.

Results: Among 16,952 stroke patients (54% women, 75% white, 8% black, and 15% Hispanic), 30-day all-cause readmission was 15% (17.2% for blacks, 16.7% for Hispanics, 14.4% for whites, and 14.7% for others; P = .003). There was a median of 11 days between discharge and first readmission. In adjusted analyses, there was no significant difference in readmission for blacks (hazard ratio 1.15, 95% confidence interval 0.99-1.33), Hispanics (1.00, .90-1.13), and those of other race/ethnicity (.91, .71-1.16) compared with whites. Nearly 1 in 4 readmissions were attributable to acute cerebrovascular events: 16.6% ischemic stroke or transient ischemic attack, 1.5% hemorrhagic stroke, and 5.2% cerebral artery interventions. Interventions were more common among whites and those of other race than blacks and Hispanics (P = .029). Readmission due to pneumonia or urinary tract infection was 8.2%.

Conclusions: Readmissions attributable to acute cerebrovascular events were common and generally occurred within 2 weeks of hospital discharge. Racial/ethnic disparities were present in readmissions for arterial interventions. Our results underscore the importance of postdischarge transitional care and the need for better secondary prevention strategies after ischemic stroke, particularly among minority populations.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2019.104399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939298PMC
December 2019

Patterns and Outcomes of Endovascular Therapy in Mild Stroke.

Stroke 2019 08 15;50(8):2101-2107. Epub 2019 Jul 15.

From the Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, FL (N.A., D.R.Y., K.W., H.E.G., C.M.G., E.M.-L., S.K., C.D., S.A.O., T.R., R.L.S., J.G.R.).

Background and Purpose- We aimed to evaluate the current practice patterns, safety and outcomes of patients who receive endovascular therapy (EVT) having mild neurological symptoms. Methods- From Jan 2010 to Jan 2018, 127,794 ischemic stroke patients were enrolled in the Florida-Puerto Rico Stroke Registry. Patients presenting within 24 hours of symptoms who received EVT were classified into mild (National Institutes of Health Stroke Scale [NIHSS] ≤5) or moderate/severe (NIHSS>5) categories. Differences in clinical characteristics and outcomes were evaluated using multivariable logistic regression. Results- Among 4110 EVT patients (median age, 73 [interquartile range=20] years; 50% women), 446 (11%) had NIHSS ≤5. Compared with NIHSS >5, those with NIHSS ≤5 arrived later to the hospital (median, 138 versus 101 minutes), were less likely to receive intravenous alteplase (30% versus 43%), had a longer door-to-puncture time (median, 167 versus 115 minutes) and more likely treated in South Florida (64% versus 53%). In multivariable analysis younger age, private insurance (versus Medicare), history of hypertension, prior independent ambulation and hospital size were independent characteristics associated with NIHSS ≤5. Among EVT patients with NIHSS ≤5, 76% were discharged home/rehabilitation and 64% were able to ambulate independently at discharge as compared with 53% and 32% of patients with NIHSS >5. Symptomatic intracerebral hemorrhage occurred in 4% of mild stroke EVT patients and 6.4% in those with NIHSS >5. Conclusions- Despite lack of evidence-based recommendations, 11% of patients receiving EVT in clinical practice have mild neurological presentations. Individual, hospital and geographic disparities are observed among endovascularly treated patients based on the severity of clinical symptoms. Our data suggest safety and overall favorable outcomes for EVT patients with mild stroke.
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http://dx.doi.org/10.1161/STROKEAHA.118.023893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646058PMC
August 2019

Selective miRNA Modulation Fails to Activate HIV Replication in In Vitro Latency Models.

Mol Ther Nucleic Acids 2019 Sep 20;17:323-336. Epub 2019 Jun 20.

Servicio de Enfermedades Infecciosas, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) and Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain; Facultad de Medicina y Ciencias de la Salud, Universidad de Alcalá de Henares, 28871 Alcalá de Henares, Spain.

HIV remains incurable because of viral persistence in latent reservoirs that are inaccessible to antiretroviral therapy. A potential curative strategy is to reactivate viral gene expression in latently infected cells. However, no drug so far has proven to be successful in vivo in reducing the reservoir, and therefore new anti-latency compounds are needed. We explored the role of microRNAs (miRNAs) in latency maintenance and their modulation as a potential anti-latency strategy. Latency models based on treating resting CD4 T cells with chemokine (C-C motif) ligand 19 (CCL19) or interleukin-7 (IL7) before HIV infection and next-generation sequencing were used to identify the miRNAs involved in HIV latency. We detected four upregulated miRNAs (miRNA-98, miRNA-4516, miRNA-4488, and miRNA-7974). Individual or combined inhibition of these miRNAs was performed by transfection into cells latently infected with HIV. Viral replication, assessed 72 h after transfection, did not increase after miRNA modulation, despite miRNA inhibition and lack of toxicity. Furthermore, the combined modulation of five miRNAs previously associated with HIV latency was not effective in these models. Our results do not support the modulation of miRNAs as a useful strategy for the reversal of HIV latency. As shown with other drugs, the potential of miRNA modulation as an HIV reactivation strategy could be dependent on the latency model used.
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http://dx.doi.org/10.1016/j.omtn.2019.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614709PMC
September 2019

Neighbourhood greenness and depression among older adults.

Br J Psychiatry 2019 08 13;215(2):476-480. Epub 2019 Jun 13.

Research Associate Professor of Public Health Sciences,Miller School of Medicine,University of Miami,USA.

Background: Neighbourhood greenness or vegetative presence has been associated with indicators of health and well-being, but its relationship to depression in older adults has been less studied. Understanding the role of environmental factors in depression may inform and complement traditional depression interventions, including both prevention and treatment.AimsThis study examines the relationship between neighbourhood greenness and depression diagnoses among older adults in Miami-Dade County, Florida, USA.

Method: Analyses examined 249 405 beneficiaries enrolled in Medicare, a USA federal health insurance programme for older adults. Participants were 65 years and older, living in the same Miami location across 2 years (2010-2011). Multilevel analyses assessed the relationship between neighbourhood greenness, assessed by average block-level normalised difference vegetative index via satellite imagery, and depression diagnosis using USA Medicare claims data. Covariates were individual age, gender, race/ethnicity, number of comorbid health conditions and neighbourhood median household income.

Results: Over 9% of beneficiaries had a depression diagnosis. Higher levels of greenness were associated with lower odds of depression, even after adjusting for demographics and health comorbidities. When compared with individuals residing in the lowest tertile of greenness, individuals from the middle tertile (medium greenness) had 8% lower odds of depression (odds ratio 0.92; 95% CI 0.88, 0.96; P = 0.0004) and those from the high tertile (high greenness) had 16% lower odds of depression (odds ratio 0.84; 95% CI 0.79, 0.88; P < 0.0001).

Conclusions: Higher levels of greenness may reduce depression odds among older adults. Increasing greenery - even to moderate levels - may enhance individual-level approaches to promoting wellness.Declaration of interestNone.
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http://dx.doi.org/10.1192/bjp.2019.129DOI Listing
August 2019

Disparities and Temporal Trends in the Use of Anticoagulation in Patients With Ischemic Stroke and Atrial Fibrillation.

Stroke 2019 06 14;50(6):1452-1459. Epub 2019 May 14.

From the Department of Neurology (N.B.S., K.W., C.M.G., C.D., S.K., H.G., J.G.R., R.L.S., T.R.), University of Miami Miller School of Medicine, FL.

Background and Purpose- Ischemic stroke (IS) secondary to atrial fibrillation (AF) is largely preventable with the use of anticoagulation. We sought to identify race-ethnicity and sex disparities with the use of direct oral anticoagulants (DOACs), aspirin, and warfarin in IS patients with AF and to identify temporal trends in the utilization of these medications. Methods- The FLiPER-AF Stroke Study (Florida Puerto Rico Atrial Fibrillation) included 24 040 IS cases enrolled in the Florida-Puerto Rico Collaboration to Reduce Stroke Registry from 2010 to 2016. Multivariable logistic regression models were performed to evaluate the effect of race-ethnicity and sex on utilization of DOACs, aspirin, and warfarin for stroke prevention in AF after adjustment for sociodemographic, hospital, and clinical factors. Results- Among 24 040 IS cases, 54% were women and 10% black, 12% FL-Hispanics, 4% PR-Hispanic, and 74% whites. From 2010 to 2016, DOAC use increased from 0% to 36%, warfarin use decreased from 51% to 17%, and aspirin use remained relatively stable (42%-40%). After adjustment, blacks had higher odds of warfarin (odds ratio, 1.22; 95% CI, 1.07-1.40) prescription at discharge compared with whites. Men had higher rates of aspirin (42.1% versus 38.8%), warfarin (33.6% versus 28.9%), and DOAC (21.3% versus 19.3%) use compared with women. After adjustment, women had lower odds of being discharged on aspirin (odds ratio, 0.92; 95% CI, 0.86-0.98) or warfarin (odds ratio, 0.91; 95% CI, 0.84-0.99). There was no sex difference in use of DOACs. Conclusions- Our study confirmed the increasing use of DOACs, downtrending use of warfarin, whereas aspirin use remained similar over the years. There are sex and race-ethnicity disparities in anticoagulation use in IS patients with AF. It is critical to understand underlying drivers of these disparities to develop better practice strategies for stroke prevention in patients with AF. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT03627806.
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http://dx.doi.org/10.1161/STROKEAHA.118.023959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538423PMC
June 2019

HER2-Enriched Subtype and ERBB2 Expression in HER2-Positive Breast Cancer Treated with Dual HER2 Blockade.

J Natl Cancer Inst 2020 01;112(1):46-54

Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX.

Background: Identification of HER2-positive breast cancers with high anti-HER2 sensitivity could help de-escalate chemotherapy. Here, we tested a clinically applicable RNA-based assay that combines ERBB2 and the HER2-enriched (HER2-E) intrinsic subtype in HER2-positive disease treated with dual HER2-blockade without chemotherapy.

Methods: A research-based PAM50 assay was applied in 422 HER2-positive tumors from five II-III clinical trials (SOLTI-PAMELA, TBCRC023, TBCRC006, PER-ELISA, EGF104090). In SOLTI-PAMELA, TBCRC023, TBCRC006, and PER-ELISA, all patients had early disease and were treated with neoadjuvant lapatinib or pertuzumab plus trastuzumab for 12-24 weeks. Primary outcome was pathological complete response (pCR). In EGF104900, 296 women with advanced disease were randomized to receive either lapatinib alone or lapatinib plus trastuzumab. Progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) were evaluated.

Results: A total of 305 patients with early and 117 patients with advanced HER2-positive disease were analyzed. In early disease, HER2-E represented 83.8% and 44.7% of ERBB2-high and ERBB2-low tumors, respectively. Following lapatinib and trastuzumab, the HER2-E and ERBB2 (HER2-E/ERBB2)-high group showed a higher pCR rate compared to the rest (44.5%, 95% confidence interval [CI] = 35.4% to 53.9% vs 11.6%, 95% CI = 6.9% to 18.0%; adjusted odds ratio [OR] = 6.05, 95% CI = 3.10 to 11.80, P < .001). Similar findings were observed with neoadjuvant trastuzumab and pertuzumab (pCR rate of 66.7% in HER2-E/ERBB2-high, 95% CI = 22.3% to 95.7% vs 14.7% in others, 95% CI = 4.9% to 31.1%; adjusted OR = 11.60, 95% CI = 1.66 to 81.10, P = .01). In the advanced setting, the HER2-E/ERBB2-high group was independently associated with longer PFS (hazard ratio [HR] = 0.52, 95% CI = 0.35 to 0.79, P < .001); higher ORR (16.3%, 95% CI = 8.9% to 26.2% vs 3.7%, 95% CI = 0.8% to 10.3%, P = .02); and longer OS (HR = 0.66, 95% CI = 0.44 to 0.97, P = .01).

Conclusions: Combining HER2-E subtype and ERBB2 mRNA into a single assay identifies tumors with high responsiveness to HER2-targeted therapy. This biomarker could help de-escalate chemotherapy in approximately 40% of patients with HER2-positive breast cancer.
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http://dx.doi.org/10.1093/jnci/djz042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850037PMC
January 2020

Analytical validation of a standardised scoring protocol for Ki67 immunohistochemistry on breast cancer excision whole sections: an international multicentre collaboration.

Histopathology 2019 Aug 8;75(2):225-235. Epub 2019 Jul 8.

The Institute of Cancer Research, London, UK.

Aims: The nuclear proliferation marker Ki67 assayed by immunohistochemistry has multiple potential uses in breast cancer, but an unacceptable level of interlaboratory variability has hampered its clinical utility. The International Ki67 in Breast Cancer Working Group has undertaken a systematic programme to determine whether Ki67 measurement can be analytically validated and standardised among laboratories. This study addresses whether acceptable scoring reproducibility can be achieved on excision whole sections.

Methods And Results: Adjacent sections from 30 primary ER breast cancers were centrally stained for Ki67 and sections were circulated among 23 pathologists in 12 countries. All pathologists scored Ki67 by two methods: (i) global: four fields of 100 tumour cells each were selected to reflect observed heterogeneity in nuclear staining; (ii) hot-spot: the field with highest apparent Ki67 index was selected and up to 500 cells scored. The intraclass correlation coefficient (ICC) for the global method [confidence interval (CI) = 0.87; 95% CI = 0.799-0.93] marginally met the prespecified success criterion (lower 95% CI ≥ 0.8), while the ICC for the hot-spot method (0.83; 95% CI = 0.74-0.90) did not. Visually, interobserver concordance in location of selected hot-spots varies between cases. The median times for scoring were 9 and 6 min for global and hot-spot methods, respectively.

Conclusions: The global scoring method demonstrates adequate reproducibility to warrant next steps towards evaluation for technical and clinical validity in appropriate cohorts of cases. The time taken for scoring by either method is practical using counting software we are making publicly available. Establishment of external quality assessment schemes is likely to improve the reproducibility between laboratories further.
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http://dx.doi.org/10.1111/his.13880DOI Listing
August 2019

Analysis of the dysregulation between regulatory B and T cells (Breg and Treg) in human immunodeficiency virus (HIV)-infected patients.

PLoS One 2019 27;14(3):e0213744. Epub 2019 Mar 27.

Immuno-Regulation Laboratory, University General Hospital Gregorio Marañón, Health Research Institute Gregorio Marañón (IiSGM), Medicine and Experimental Surgery Building, Madrid, Spain.

This study examines the relationship between regulatory B (Breg) and T (Treg) compartments, which play crucial roles in the maintenance of immune homeostasis in the context of HIV. Using flow cytometry, the phenotypes of different Breg and Treg subsets from HIV-infected and healthy individuals were analyzed, along with the suppressive capacity of Breg. Peripheral blood samples of thirteen HIV+ treatment-naïve individuals, fourteen treated-HIV+ individuals with undetectable viral load and twelve healthy individuals were analyzed. The absolute counts of Breg and Treg subsets were decreased in HIV+ treatment-naïve individuals in comparison to treated-HIV+ and healthy individuals. Interestingly, correlations between Breg subsets (CD24hiCD27+ and PD-L1+ B cells) and IL-10-producing Breg observed in healthy individuals were lost in HIV+ treatment-naïve individuals. However, a correlation between frequencies of CD24hiCD38hi or TIM-1+-Breg subsets and Treg was observed in HIV+ treatment-naïve individuals and not in healthy individuals. Therefore, we hypothesized that various Breg subsets might have different functions during B and T-cell homeostasis during HIV-1 infection. In parallel, stimulated Breg from HIV-infected treatment-naïve individuals presented a decreased ability to suppress CD4+ T-cell proliferation in comparison to the stimulated Breg from treated-HIV+ or healthy individuals. We demonstrate a dysregulation between Breg and Treg subsets in HIV-infected individuals, which might participate in the hyper-activation and exhaustion of the immune system that occurs in such patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213744PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436717PMC
December 2019

Relationship of Neighborhood Greenness to Heart Disease in 249 405 US Medicare Beneficiaries.

J Am Heart Assoc 2019 03;8(6):e010258

1 University of Miami Miller School of Medicine Miami FL.

Background Nature exposures may be associated with reduced risk of heart disease. The present study examines the relationship between objective measures of neighborhood greenness (vegetative presence) and 4 heart disease diagnoses (acute myocardial infarction, ischemic heart disease, heart failure, and atrial fibrillation) in a population-based sample of Medicare beneficiaries. Methods and Results The sample included 249 405 Medicare beneficiaries aged 65 years and older whose location ( ZIP +4) in Miami-Dade County, Florida, did not change from 2010 to 2011. Analyses examined relationships between greenness, measured by mean block-level normalized difference vegetation index from satellite imagery, and 4 heart disease diagnoses. Hierarchical regression analyses, in a multilevel framework, assessed the relationship of greenness to each heart disease diagnosis, adjusting successively for individual sociodemographics, neighborhood income, and biological risk factors (diabetes mellitus, hypertension, and hyperlipidemia). Higher greenness was associated with reduced heart disease risk, adjusting for individual sociodemographics and neighborhood income. Compared with the lowest tertile of greenness, the highest tertile of greenness was associated with reduced odds of acute myocardial infarction by 25% (odds ratio, 0.75; 95% CI , 0.63-0.90), ischemic heart disease by 20% (odds ratio, 0.80; 95% CI , 0.77-0.83), heart failure by 16% (odds ratio, 0.84; 95% CI , 0.80-0.88), and atrial fibrillation by 6% (odds ratio, 0.94; 95% CI , 0.87-1.00). Associations were attenuated after adjusting for biological risk factors, suggesting that cardiometabolic risk factors may partly mediate the greenness to heart disease relationships. Conclusions Neighborhood greenness may be associated with reduced heart disease risk. Strategies to increase area greenness may be a future means of reducing heart disease at the population level.
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http://dx.doi.org/10.1161/JAHA.118.010258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475064PMC
March 2019

High CD8 T cell percentage and HCV replication control are common features in HIV-1 controllers and HTLV-2-co-infected patients with a history of injection drug use.

Virus Res 2019 04 15;264:40-44. Epub 2019 Feb 15.

Immunovirology Laboratory, Institute of Biomedicine of Seville (IBIS), Virgen del Rocío University Hospital, Avda. Manuel Siurot s/n, 41013 Seville, Spain. Electronic address:

HTLV-2/HIV-1-coinfected patients and HIV-infected patients with natural HIV-1 control show an immune capacity that allows some control of viral infections. These two groups of patients have showed an immune capacity that allows them to have some control over viral infections, very strong control of HIV-1 replication in the case of HIV-1 controllers. The purpose of this retrospective cross-sectional study was to compare viral and immunologic parameters between three cohorts of Caucasian adult HIV-1-infected patients, including HIV-1 controllers (29 patients), HTLV-2/HIV-1 chronic progressors (56 patients), and HIV-1 chronic progressors (101 patients), followed in two different tertiary University Hospitals in Spain. Demographic parameters, nadir CD4 T cell count, CD4 and CD8 T cell counts and percentage, anti-HCV antibodies, HCV RNA load, HCV genotype, HIV-1 RNA loads, and anti-HTLV-2 antibodies were analyzed. HIV-1 controllers and HTLV-2/HIV-1 chronic progressors were younger and with shorter time since HIV-1 diagnosis compared to HIV-1 chronic progressors. HIV-1 controllers and HTLV-2/HIV-1 chronic progressors had significantly higher CD8 T cell percentage (p = 0.002 and p = 0.016, respectively) and lower levels of HCV RNA loads (0.015 and 0.007, respectively) compared to that of HIV-1 chronic progressors. Multivariate analyses showed that gender and HTLV-2 infection were independently associated to HCV RNA load, while only HTLV-2 infection was independently associated to CD8 T cell percentage. The implication of HTLV-2 infection in the control of HIV-1 and HCV infections is worth being further analyze.
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http://dx.doi.org/10.1016/j.virusres.2019.02.007DOI Listing
April 2019

Head and Neck Lymphedema: Treatment Response to Single and Multiple Sessions of Advanced Pneumatic Compression Therapy.

Otolaryngol Head Neck Surg 2019 04 29;160(4):622-626. Epub 2019 Jan 29.

3 Center for Molecular Imaging, Brown Foundation Institute of Molecular Medicine at the University of Texas Head Science Center at Houston, Houston, Texas, USA.

Ten head and neck cancer survivors diagnosed with head and neck lymphedema (HNL) were imaged using near-infrared fluorescence lymphatic imaging (NIRFLI) prior to and immediately after an initial advance pneumatic compression device treatment and again after 2 weeks of daily at-home use. Images assessed the impact of pneumatic compression therapy on lymphatic drainage. Facial composite measurement scores assessed reduction/increase in external swelling, and survey results were obtained. After a single pneumatic compression treatment, NIRFLI showed enhanced lymphatic uptake and drainage in all subjects. After 2 weeks of daily treatment, areas of dermal backflow disappeared or were reduced in 6 of 8 subjects presenting with backflow. In general, reductions in facial composite measurement scores tracked with reductions in backflow and subject-reported improvements; however, studies are needed to determine whether longer treatment durations can be impactful and whether advanced pneumatic compression can be used to ameliorate backflow characteristic of HNL.
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http://dx.doi.org/10.1177/0194599818823180DOI Listing
April 2019

Disparities and Temporal Trends in Stroke Care Outcomes in Patients with Atrial Fibrillation: The FLiPER-AF Stroke Study.

Int J Cerebrovasc Dis Stroke 2019 22;2(1). Epub 2019 Jul 22.

Department of Neurology, University of Miami Miller School of Medicine, Florida, USA.

Background And Purpose: Atrial Fibrillation (AF) is the most common cardiac cause of ischemic stroke. However, the relation between AF and stroke care outcomes in diverse populations is understudied. We aimed to evaluate sex and race-ethnic disparities associated with AF in hospital stroke outcomes utilizing data from the FLorida PuErto Rico Atrial Fibrillation (FLiPER-AF) Stroke Study.

Methods: The study included 104,308 ischemic stroke cases with available information on AF status enrolled in a state-wide stroke registry from 2010 to 2016. Multivariable logistic regression models were performed to evaluate the association between AF and stroke outcomes and the modification effects on the associations by sex and by race-ethnicity, adjusted for socio-demographic status, vascular risk factors and stroke severity.

Results: AF was present in 23% of ischemic stroke cases. AF was associated with worse disability at discharge (OR=1.11, 95% CI, 1.04-1.18), less discharge to home (OR=0.89, 0.85-0.92), and longer length of hospital stay (LOS>6 days, OR=1.53, 1.46-1.60). Interaction analyses showed that the association between AF and less discharge to home was stronger in women than men (p for interaction <0.001), as well as in FL-whites than in FL-blacks, FL-Hispanics or PR-Hispanics (p for interaction=0.002). The association between AF and prolonged LOS was more prominent in PR-Hispanics than in FL-blacks, FL-Hispanics, or FL-whites (p for interaction <0.001). From 2010 to 2016, the effects of AF on hospital length of stay attenuated (p for interaction<0.001).

Conclusions: AF was associated with poor disability at discharge, less discharge to home, and prolonged hospital length of stay for acute stroke care. The effect of AF on length of stay attenuated over time. Sex and race-ethnic disparities were observed in the effect of AF on being less discharge to home and prolonged hospital stay. Further research is needed to identify and modify the biologic and systems of care contributors to these disparities.
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http://dx.doi.org/10.29011/2688-8734.100017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730022PMC
July 2019

Racial/Ethnic Disparities in Mortality Among Medicare Beneficiaries in the FL - PR CR eSD Study.

J Am Heart Assoc 2019 01;8(1):e009649

1 Department of Neurology University of Miami Miller School of Medicine Miami FL.

Background Racial/ethnic disparities in acute stroke care may impact stroke outcomes. We compared outcomes by race/ethnicity among elderly Medicare beneficiaries in hospitals participating in the FL-PR CReSD (Florida-Puerto Rico Collaboration to Reduce Stroke Disparities) registry with those in hospitals not participating in any quality improvement programs (non- QI ) in Florida and Puerto Rico (PR). Methods and Results The population included fee-for-service Medicare beneficiaries age 65+ in Florida and PR , discharged with primary diagnosis of ischemic stroke ( International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM], codes 433, 434, 436) in 2010-2013. We used mixed logistic models to assess racial/ethnic differences in outcomes (in-hospital, 30-day, and 1-year mortality, and 30-day readmission) for CR e SD and non- QI hospitals, adjusted for demographic and clinical characteristics. The study included 62 CR e SD hospitals (N=44 013, 84% white, 9% black, 4% Florida Hispanic, 1% PR Hispanic) and 113 non- QI hospitals (N=14 422, 78% white, 7% black, 5% Florida Hispanic, 8% PR Hispanic). For patients treated at CR e SD hospitals, there were no differences in risk-adjusted in-hospital mortality by race/ethnicity; blacks had lower 30-day mortality versus whites (odds ratio, 0.86; 95% confidence interval, 0.77-0.97), but higher 30-day readmission (hazard ratio, 1.09; 1.00-1.18) and 1-year mortality (odds ratio, 1.13; 1.04-1.23); Florida Hispanics had lower 30-day readmission (hazard ratio, 0.87; 0.78-0.98). PR Hispanic and black stroke patients treated at non- QI hospitals had higher risk-adjusted in-hospital, 30-day and 1-year mortality, but similar 30-day readmission versus whites treated in non- QI hospitals. Conclusions Disparities in outcomes were less common in CR e SD than non- QI hospitals, suggesting the benefits of quality improvement programs, particularly those focusing on racial/ethnic disparities.
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http://dx.doi.org/10.1161/JAHA.118.009649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405703PMC
January 2019

Need to Prioritize Education of the Public Regarding Stroke Symptoms and Faster Activation of the 9-1-1 System: Findings from the Florida-Puerto Rico CReSD Stroke Registry.

Prehosp Emerg Care 2019 Jul-Aug;23(4):439-446. Epub 2018 Oct 25.

Demographic differences (race/ethnicity/sex) in 9-1-1 emergency medical services (EMS) access and utilization have been reported for various time-dependent critical illnesses along with associated outcome disparities. However, data are lacking with respect to measuring the various components of time taken to reach definitive care facilities following the onset of acute stroke symptoms (i.e., stroke onset to 9-1-1 call, EMS response, time on-scene, transport interval) and particularly with respect to any differences across ethnicities and sex. Therefore, the specific aim of this study was to measure the various time intervals elapsing following the first symptom onset (FSO) from an acute stroke until stroke hospital arrival (SHA) and to delineate any race/ethnic/sex-related differences among any of those measurements. : The (FLPRSR) is an on-going, voluntary stroke registry of hospitals participating in the -Stroke initiative. The study population included patients treated at Florida hospitals participating in the FLPRSR between 2010 and 2014 who had called 9-1-1 and were managed and transported by EMS. In total, 10,481 patients (16% black, 8% Hispanic, 74% white) had complete data-sets that included birthdate/year, sex, ethnic background, date/hour/minute of FSO and date/hour/minute of EMS response, scene arrival, and SHA. Median time from FSO to SHA was 339 minutes (interquartile range [IQR] of 284-442), 301 of which constituted the time elapsed from FSO to the 9-1-1 call (IQR =249-392) versus only 10 from 9-1-1 call to EMS arrival (IQR =7-14), 14 on-scene (IQR =11-18) and 12 for transport to SHA (IQR =8-19). The FSO to 9-1-1 call interval, being by far the longest interval, was longest among whites and blacks (302 minutes for both) versus 291 for Hispanics (p = 0.01). However, this 11-minute difference was not deemed clinically-significant. There were neither significant sex-related differences nor any racial/ethnic/sex differences in the relatively short EMS-related intervals. Following acute stroke onset, time elapsed for EMS response and transport is relatively short compared to the lengthy intervals elapsing between symptom onset and 9-1-1 system activation, regardless of demographics. Exploration of innovative strategies to improve public education regarding stroke symptoms and immediate 9-1-1 system activation are strongly recommended.
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http://dx.doi.org/10.1080/10903127.2018.1525458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483889PMC
January 2020

CD72/CD100 and PD-1/PD-L1 markers are increased on T and B cells in HIV-1+ viremic individuals, and CD72/CD100 axis is correlated with T-cell exhaustion.

PLoS One 2018 30;13(8):e0203419. Epub 2018 Aug 30.

Immuno-Regulation Laboratory, Gregorio Marañón University General Hospital, Gregorio Marañón Health Research Institute (IiSGM), Madrid, Spain.

In our work, we analyzed the role of the CD100/CD72 and PD-1/PD-L1 axes in immune response dysfunction in human immunodeficiency virus (HIV)-1 infection in which high expressions of PD-1 and PD-L1 were associated with an immunosuppressive state via limitation of the HIV-1-specific T-cell responses. CD100 was demonstrated to play a relevant role in immune responses in various pathological processes and may be responsible for immune dysregulation during HIV-1 infection. We investigated the function of CD72/CD100, and PD-1/PDL-1 axes on T and B cells in HIV-infected individuals and in healthy individuals. We analyzed the frequencies and fluorescence intensities of these four markers on CD4+, CD8+ T and B cells. Marker expressions were increased during active HIV-1 infection. CD100 frequency on T cells was positively associated with the expression of PD-1 and PD-L1 on T cells from HIV-infected treatment-naïve individuals. In addition, the frequency of CD72-expressing T cells was associated with interferon gamma (IFN-γ) production in HIV-infected treatment-naïve individuals. Our data suggest that the CD72/CD100 and PD-1/PD-L1 axes may jointly participate in dysregulation of immunity during HIV-1 infection and could partially explain the immune systems' hyper-activation and exhaustion.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0203419PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117071PMC
February 2019

Sustainable production and use of cleaner fish for the biological control of sea lice: recent advances and current challenges.

Vet Rec 2018 Sep 30;183(12):383. Epub 2018 Jul 30.

Institute of Aquaculture, University of Stirling, Stirling, UK.

Currently, cleaner fish are one of the most widely used sea lice control strategies in Atlantic salmon aquaculture. Two species are currently being farmed in North Atlantic countries, ballan wrasse () and lumpfish (), and the sector in most countries is rapidly expanding towards self-sufficiency. The species are very different both in terms of their biology and life histories and, consequently, production and husbandry methods must be tailored to each species. There are numerous health challenges currently experienced in both species, with bacterial and parasitic diseases being the most prevalent, and cohabitation with salmon may increase the risk of disease. Good husbandry and routine health monitoring are essential, although treatment is often required when disease outbreaks occur. Ballan wrasse and lumpfish are both proven to be effective salmon delousers, although delousing efficacy can be variable in farmed fish; the provision of suitable habitat and acclimation to net-pen conditions may encourage natural behaviours, including delousing, and the use of operational welfare indicators can highlight potential welfare issues. Cleaner fish research is progressing rapidly, although much of the basic knowledge regarding the species' biology remains unknown. The simultaneous domestication of two new marine aquaculture species is a significant challenge demanding sustained effort and funding over a prolonged period of time. Research must focus on enhancing the robustness of the farmed stocks and increasing hatchery outputs to meet the urgent demands from the salmon sector and protect wild stocks from overfishing.
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http://dx.doi.org/10.1136/vr.104966DOI Listing
September 2018

Effects of Immunonutrition in Advanced Human Immunodeficiency Virus Disease: A Randomized Placebo-controlled Clinical Trial (Promaltia Study).

Clin Infect Dis 2019 01;68(1):120-130

HIV Unit, Hospital Clínico San Carlos, Madrid, Spain.

Background: While nutritional interventions with prebiotics and probiotics seem to exert immunological effects, their clinical implications in human immunodeficiency virus (HIV)-infected subjects initiating antiretroviral therapy (ART) at advanced HIV disease remain unclear.

Methods: This was a pilot multicenter randomized, placebo-controlled, double-blind study in which 78 HIV-infected, ART-naive subjects with <350 CD4 T cells/μL or AIDS were randomized to either daily PMT25341 (a mixture of synbiotics, omega-3/6 fatty acids and amino acids) or placebo for 48 weeks, each in combination with first-line ART. Primary endpoints were changes in CD4 T-cell counts and CD4/CD8 ratio from baseline to week 48 and safety. Secondary endpoints were changes in markers of T-cell activation, bacterial translocation, inflammation, and α and β microbiota diversity.

Results: Fifty-nine participants completed the follow-up with a mean CD4+ T-cell count of 221 ± 108 cells/μL and mean CD4/CD8 ratio of 0.26 ± 0.19. PMT25341 was well tolerated, without grade 3-4 adverse effects attributable to the intervention. While most of the assessed biomarkers improved during the follow-up in both arms, PMT25341-treated subjects did not experience any significant change, compared to placebo-treated subjects, in mean CD4+ T-cell count change (278 vs 250 cells/μL, P = .474) or CD4/CD8 ratio change (0.30 vs 0.32, P = .854). Similarly, we did not detect differences between treatment arms in secondary endpoints.

Conclusions: In HIV-infected patients initiating ART at advanced disease, the clear immunological benefits of ART were not enhanced by this nutritional intervention targeting the gut-associated lymphoid tissue and microbiota.

Clinical Trials Registration: NCT00870363.
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http://dx.doi.org/10.1093/cid/ciy414DOI Listing
January 2019

Change during psychotherapy: the perspective of children and adolescents who have been sexually abused.

Res Psychother 2018 Apr 12;21(1):288. Epub 2018 Apr 12.

Department of Psychology, University of Chile, Chile.

The aim of this research was to identify the meanings of psychotherapeutic change of children and adolescents who have suffered sexual abuse and were in psychotherapy. In order to do this, a qualitative study was carried out in which in-depth interviews complemented with drawings were conducted with 10 children and adolescents, aged between 6 and 16 years, who were taking part in psychotherapy due to sexual abuse. The interviews took place between 6 and 10 months after the start of the therapy and before it ended. Thematic narrative analysis was used for the interviews and visual narrative analysis for the drawings. The main findings showed that children and adolescents visualized psychotherapeutic change as a process in which gradual progress is made. The participants notice changes from an initial state of sadness and distress, mainly describing a positive shift in terms of emotional well-being. In addition, in this phase of the therapy only a few participants identified changes in their feelings regarding the abusive experience. The participants identified aspects of the therapy and supportive relationships with significant others as elements that foster these changes. In their view, hindering elements include changes of therapist, legal factors, and not being believed by their family. It is discussed the importance of knowing the children and adolescents' perspective regarding psychotherapeutic change while participating in therapy processes, using multiple methodologies, to generate interventions that suit the needs of this population and match the pace of children and adolescents' change.
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http://dx.doi.org/10.4081/ripppo.2018.288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451347PMC
April 2018