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This critical review summarizes the advancement of exosome based vaccine development and delivery, and this comprehensive review can be used as a valuable reference for the broader delivery science community.NF-κB essential modulator (NEMO, IKK-γ) deficiency is a rare combined immunodeficiency caused by mutations in the IKBKG gene. Conventionally, patients are afflicted with life threatening recurrent microbial infections. Paradoxically, the spectrum of clinical manifestations includes severe inflammatory disorders. The mechanisms leading to autoinflammation in NEMO deficiency are currently unknown. Herein, we sought to investigate the underlying mechanisms of clinical autoinflammatory manifestations in a 12-years old male NEMO deficiency (EDA-ID, OMIM #300,291) patient by comparing the immune profile of the patient before and after hematopoietic stem cell transplantation (HSCT). Response to NF-kB activators were measured by cytokine ELISA. Neutrophil and low-density granulocyte (LDG) populations were analyzed by flow cytometry. Peripheral blood mononuclear cells (PBMC) transcriptome before and after HSCT and transcriptome of sorted normal-density neutrophils and LDGs were determined using the NanoString nCounter gene expression panels. ISG15 expression and protein ISGylation was based on Immunoblotting. Consistent with the immune deficiency, PBMCs of the patient were unresponsive to toll-like and T cell receptor-activators. Paradoxically, LDGs comprised 35% of patient PBMCs and elevated expression of genes such as MMP9, LTF, and LCN2 in the granulocytic lineage, high levels of IP-10 in the patient's plasma, spontaneous ISG15 expression and protein ISGylation indicative of a spontaneous type I interferon (IFN) signature were observed, all of which normalized after HSCT. Collectively, our results suggest that type I IFN signature observed in the patient, dysregulated LDGs and spontaneously activated neutrophils, potentially contribute to tissue damage in NEMO deficiency.To analyze the prognostic value of left ventricular global longitudinal strain (LV-GLS) and other echocardiographic parameters to predict adverse outcomes in chronic Chagas cardiomyopathy (CCM). Prospective cohort study conducted in 177 consecutive patients with different CCM stages. Transthoracic echocardiography measurements were obtained following the American Society of Echocardiography recommendations. By speckle-tracking echocardiography, LV-GLS was obtained from the apical three-chamber, apical two-chamber, and apical four-chamber views. The primary composite outcome (CO) was all-cause mortality, cardiac transplantation, and a left ventricular assist device implantation. After a median follow-up of 42.3 months (Q1 = 38.6; Q3 = 52.1), the CO incidence was 22.6% (95% CI 16.7-29.5%, n = 40). The median LV-GLS value was - 13.6% (Q1 = - 18.6%; Q3 = - 8.5%). LVEF, LV-GLS, and E/e' ratio with cut-off points of 40%, - 9, and 8.1, respectively, were the best independent CO predictors. We combined these three echocardiographic markers and evaluated the risk of CO according to the number of altered parameters, finding a significant increase in the risk across the groups. While in the group of patients in which all these three parameters were normal, only 3.2% had the CO; those with all three abnormal parameters had an incidence of 60%. We observed a potential incremental prognostic value of LV-GLS in the multivariate model of LVEF and E/e' ratio, as the AUC increased slightly from 0.76 to 0.79, nevertheless, this difference was not statistically significant (p = 0.066). LV-GLS is an important predictor of adverse cardiovascular events in CCM, providing a potential incremental prognostic value to LVEF and E/e' ratio when analyzed using optimal cut-off points, highlighting the potential utility of multimodal echocardiographic tools for predicting adverse outcomes in CCM.Previous morphological and histological data are supplemented with molecular and ultrastructural data for a Henneguya sp. isolated from farm-raised channel catfish Ictalurus punctatus in Mississippi, USA. Myxospores were cryptic, encapsulated within a thin layer of epithelium in the gill lamellae with spore measurements consistent with the original description of Henneguya postexilis Minchew, 1977. Myxospores were 42.7-49.1 µm in total length with spore bodies 12.1-17.2 × 3.6-4.8 × 2.9-3 µm. Polar capsules were of unequal length, with the longer capsule being 4.4-6.7 × 1.1-1.6 µm and the shorter capsule being 4.4-6.4 × 1.1-1.6 µm. Polar tubules had 6-8 turns. Caudal processes were 25.7-38.1 µm in length. see more Spores were encapsulated in a thin layer of epithelium in the gill lamellae. Molecular data from the most commonly used markers for myxozoan identification and phylogeny, partial 18S small subunit ribosomal gene (SSU), partial 28S large subunit ribosomal gene (LSU), and elongation factor 2 (EF2) were generated for H. postexilis. Additionally, novel data for LSU and EF2 were generated for archived myxozoan specimens from farm-raised catfish (H. mississippiensis, H. ictaluri, H. exilis, H. adiposa, H. sutherlandi, H. bulbosus, Unicauda fimbrethilae), as well as archived specimens from wild fish (H. laseeae [from Pylodictis olivaris], Hennegoides flockae [from Aphredoderus sayanus], Myxobolus cloutmani [from Cycleptus elongatus]. These include the first EF2 sequence data for the genera Hennegoides and Unicauda. Phylogenetic analyses using these data placed H. postexilis in well supported clades with other ictalurid-infecting Henneguya species. Phylogenetic signal assessments on these analyses suggest that while SSU provided the greatest phylogenetic signal, LSU yielded comparable signal, supporting previous work implying this region may be underutilised in reconstructing myxobolid phylogenies.Dissolution profile comparison among different formulations plays a critical role during new drug as well as generic product development. In the generic product development, dissolution profile comparison is a mandate for biowaivers (BCS-based, for lower strengths and IVIVC-based biowaivers) and also from quality control perspective. Even though traditionally similarity factor or f2 is used as a metric for dissolution profile comparison, it comes with multiple limitations and requirements (e.g., number of time points and variability). To overcome this, regulatory agencies suggested model-independent (e.g., MSD) and model-dependent (e.g., zero order, Weibull) dissolution profile comparison methods. Although most of regulatory guidance documents mention about such approaches, their usage in reality is limited probably due to lack of clear, detailed, and step-wise procedure. In this context, the present article describes simplistic yet detailed procedures of dissolution profile comparison with case studies covering generic product development scenario's from a regulatory perspective. Detailed review of regulatory guidances from various agencies was made along with examples of such approaches in regulatory submissions. Data from three formulations-Formulations A, B, and C-were utilized to perform dissolution profile comparison using MSD, zero-order, and Weibull release profile-based comparisons. Dissolution profile comparisons were made using all of these three approaches complying with regulatory requirements. These examples demonstrated value and utility of these approaches and the simplified and detailed procedure explained in this manuscript can be adapted for generic product applications.
The U.S. foreign-born population is rapidly increasing, and cancer incidence/mortality rates have been shown to differ by nativity status. Our study aimed to characterize differences in gastric cancer presentation and survival among Hispanic patients in Texas by nativity status.
We conducted a retrospective review of the Texas Cancer Registry to identify Hispanic patients diagnosed with gastric adenocarcinoma between 2004 and 2017. Existing indices applied to 2010 census tract-level data were utilized to measure neighborhood socioeconomic status (nSES) and Hispanic enclaves. Nativity status was imputed for patients with missing data. Multivariable Cox proportional hazard models were fit for overall survival adjusted for age, insurance status, diagnosis year, tumor location, stage, grade, reporting source, nativity status, nSES, and Hispanic enclave.
Our study cohort consisted of 6186 patients and 39% were foreign-born. A greater proportion of foreign-born patients were diagnosed at < 45years old (16%ve improved survival after adjusting for socioeconomic, neighborhood, and clinical factors. Further studies are needed to identify specific causal mechanisms driving the observed survival difference by nativity status.In 2019, the West Virginia Bureau for Public Health (WV BPH), Cabell-Huntington Health Department (CHHD), and CDC collaborated to respond to an HIV outbreak among people who inject drugs (PWID). CDC, WV BPH, and CHHD formed a cross-agency communications team to establish situational awareness, identify knowledge gaps, and establish key audiences for messages, including the general population, PWID, and clinical and social service providers. The team disseminated up-to-date information about the outbreak, and prioritized messages addressing stigma related to drug use, syringe services programs, and HIV. Messages were continually updated to address the evolving situation and to resonate with local values. Messages were disseminated via advertisements, local news media, and directly to PWID, people experiencing homelessness, and providers. The response supplemented CHHD's assets, including strong relationships and community knowledge, with staff capacity and expertise from state and federal agencies. This collaborative approach is a useful model to address communication needs.The papers in this Special Supplement provide insight into current research on and partnerships needed to address HIV-related stigma and better characterize the negative effects of HIV-related stigma on populations disproportionately affected by HIV in the United States. The findings may be used to inform evidence-based strategies and ideally additional interventional research with the goal of reducing stigma, new HIV infections, and improved health for persons with HIV.
Optimal timing for anticoagulation resumption after polypectomy is unclear. We explored the association between timing of anticoagulation resumption and occurrence of delayed post-polypectomy bleeding (PPB) and thromboembolic (TE) events.
We performed a post-hoc analysis of patients in an earlier study whose anticoagulants were interrupted for polypectomy. We compared rates of clinically important delayed PPB and TE events in relationship to timing of anticoagulant resumption. Late resumption was defined as > 2days after polypectomy.
Among 437 patients, 351 had early and 86 late resumption. Compared to early resumers, late resumers had greater polypectomy complexity. PPB rate was higher (but not significantly) in the late versus early resumers (2.3% vs. 0.9%, 1.47% greater, 95% CI [-2.58 to 5.52], p = 0.26). TE events were more frequent in late versus early resumers [0% vs. 1.2% at 30days, 0% vs. 2.3%, 95% CI 0.3-8, (p = 0.04) at 90days]. On multivariate analysis, timing of restarting anticoagulation was not a significant predictor of PPB (OR 0.
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