Study on the insecticidal activity of entomopathogenic fungi for the control of the fruit fly (Anastrepha obliqua), the main pest in mango crop in Colombia.

The aim of this study was to evaluate and select entomopathogenic fungi that produces insecticidal compounds for the control of adults of Anastrepha obliqua Macquart (Diptera: tephritidae) that are the main pest of mango (Mangifera indica L. Bark) in Colombia. Nine entomopathogenic fungi isolates were evaluated, five belonging to the genus Metarhizium and four belonging to the genus Beauveria. One strain of the species Metarhizium robertsii with insecticidal activity was selected. By column fractionation, an active fraction was obtained, which caused mortalities higher than 90% after 48 h of exposure. Through HPLC it was determined that the active fraction is composed of more than 22 metabolites. Identification of the metabolites by UHPLC MS/MS revealed the presence of destruxin in E, D, A and B groups (destruxin E-diol, destruxin D, destruxin D1, destruxin D2, destruxin A2, destruxin A, destruxin A3, dihydrodestruxin A, desmB, destruxin B2, destruxin B and destruxin B1). The evaluation of the insecticidal capacity of the organic fractions obtained by HPLC indicated that the extract obtained from the isolate M. robertsii had a compound with high activity on adults of A. obliqua (destruxin A) causing massive mortality of up to 100%, after 48 h of the treatment administration. Furthermore, two other compounds with medium activity were found (destruxin A2 and destruxin B), showing mortalities between 60.0 and 81.3%, respectively. The extract of the isolate MT008 of M. robertsii showed higher insecticidal activity and a potential source for the control of A. obliqua.

Test-Retest repeatability of automated threshold audiometry in Nicaraguan schoolchildren.

OBJECTIVE: Automated threshold audiometry (ATA) could increase access to paediatric hearing assessment in low- and middle-income countries, but few studies have evaluated test-retest repeatability of ATA in children. This study aims to analyse test-retest repeatability of ATA and to identify factors that affect the reliability of this method. DESIGN: ATA was performed twice in a cohort of Nicaraguan schoolchildren. During testing, the proportion of responses occurring in the absence of a stimulus was measured by calculating a stimulus response false positive rate (SRFP). Absolute test-retest repeatability was determined between the two trials, as well as the impact of age, gender, ambient noise, head circumference, and SRFP on these results. STUDY SAMPLE: 807 children were randomly selected from 35 schools in northern Nicaragua. RESULTS: Across all frequencies, the absolute value of the difference between measurements was 5.5 ± 7.8 dB. 89.6% of test-retest differences were within 10 dB. Intra-class correlation coefficients between the two measurements showed that lower SRFP was associated with improved repeatability. No effect of age, gender, or ambient noise was found. CONCLUSIONS: ATA produced moderate test-retest repeatability in Nicaraguan schoolchildren. Participant testing behaviours, such as delayed or otherwise inappropriate response patterns, significantly impacts the repeatability of these measurements.

Epicardial adipose tissue thickness is related to early subclinical myocardial dysfunction, particularly in patients with type 2 diabetes mellitus: a case control study.

BACKGROUND: Cardiac myofibrillary dysfunction, which can be measure by echocardiographical strain value, represents an early subclinical manifestation of heart failure. Epicardial Adipose tissue (EAT) is related to low degree inflammation and oxidative damage in the adjacent tissue. AIM: To explore whether EAT affects early myocardial dysfunction, as assessed strain values. METHODS: Case-Control design. Patients lacking clinical significant heart failure, thyroid or renal disease or malignant abnormalities were included. Clinical-demographic and biochemical data were collected. EAT and myofibril deformation were measured by echocardiography. RESULTS: A total of 71 patients were analyzed, and further subdivided according to type 2 Diabetes Mellitus (t2DM). Higher strain value (higher than -22.4%cut-off value) was associated with male sex and higher anthropometric and metabolic risk measures; particularly those with t2DM. Higher EAT was also associated higher strain value (AUC = 0.92 ± 0.06, p = 0.004), and further correlation was evidenced (rho = 0.488, p < 0.001), with significant influence of t2DM. CONCLUSION: EAT was related to strain value, suggesting the influence of cardiac adipose tissue on the deformability of cardiac myofibril, with a more significant effect in the population with t2DM.

Diabetes Prevention Programs in Rural North America: a Systematic Scoping Review.

AIMS: The aims of this systematic scoping review were to characterize the extent to which diabetes prevention programs have focused on rural populations in North America and where possible, identify efficacious program components. METHODS: The review was guided by the PRISMA statement and five steps for scoping studies. Searches were conducted in August 2017 in Tucson, Arizona. Two teams of three independently screened full texts, excluding prior reviews, systematic reviews, and opinion pieces. Two authors abstracted data, which were reviewed by other team members. RESULTS: Of the 12,840 articles identified, 12 met all criteria. Nine studies were based in the USA and three were Canadian. Demographics reflected high enrollment of underrepresented minorities, adults, and females. Methodological rigor was low; most studies were single-arm interventions evaluated using pre-/post-measures. Weight was measured across all studies, although biological, behavioral, and psychosocial outcomes were inconsistently assessed. Eight studies reported significant changes in primary outcomes. Duration and intensity were variable; delivery was led by trained volunteers or health professionals. Seven studies reported recruitment, retention, and adherence data. CONCLUSIONS: Surprisingly, few rural diabetes prevention studies have been published. Published programs were notable for lack of youth and/or family involvement, integrated prevention and treatment programs, and heavy reliance on self-reported outcomes.

Janus kinase inhibitors modify the fatty acid profile of extracellular vesicles and modulate the immune response.

Background: Janus kinase inhibitors (jakinibs) are immunomodulators used for treating malignancies, autoimmune diseases, and immunodeficiencies. However, they induce adverse effects such as thrombosis, lymphocytosis, and neutropenia that could be mediated by extracellular vesicles (EVs). These particles are cell membrane-derived structures that transport cellular and environmental molecules and participate in intercellular communication. Jakinibs can modify the content of EVs and enable them to modulate the activity of different components of the immune response. Objective: to evaluate the interactions between immune system components of healthy individuals and EVs derived from monocytic and lymphoid lineage cells generated in the presence of baricitinib (BARI) and itacitinib (ITA) and their possible effects. Methods: EVs were isolated from monocytes (M) and lymphocytes (L) of healthy individuals, as well as from U937 (U) and Jurkat (J) cells exposed to non-cytotoxic concentrations of BARI, ITA, and dimethyl sulfoxide (DMSO; vehicle control). The binding to and engulfment of EVs by peripheral blood leukocytes of healthy individuals were analyzed by flow cytometry using CFSE-stained EVs and anti-CD45-PeCy7 mAb-labeled whole blood. The effect of EVs on respiratory burst, T-cell activation and proliferation, cytokine synthesis, and platelet aggregation was evaluated. Respiratory burst was assessed in PMA-stimulated neutrophils by the dihydrorhodamine (DHR) test and flow cytometry. T-cell activation and proliferation and cytokine production were assessed in CFSE-stained PBMC cultures stimulated with PHA; expression of the T-cell activation markers CD25 and CD69 and T-cell proliferation were analyzed by flow cytometry, and the cytokine levels were quantified in culture supernatants by Luminex assays. Platelet aggregation was analyzed in platelet-rich plasma (PRP) samples by light transmission aggregometry. The EVs' fatty acid (FA) profile was analyzed using methyl ester derivatization followed by gas chromatography. Results: ITA exposure during the generation of EVs modified the size of the EVs released; however, treatment with DMSO and BARI did not alter the size of EVs generated from U937 and Jurkat cells. Circulating neutrophils, lymphocytes, and monocytes showed a 2-fold greater tendency to internalize ITA-U-EVs than their respective DMSO control. The neutrophil respiratory burst was attenuated in greater extent by M-EVs than by L-EVs. Autologous ITA-M-EVs reduced T-cell proliferation by decreasing IL-2 levels and CD25 expression independently of CD69. A higher accumulation of pro-inflammatory cytokines was observed in PHA-stimulated PBMC cultures exposed to M-EVs than to L-EVs; this difference may be related to the higher myristate content of M-EVs. Platelet aggregation increased in the presence of ITA-L/M-EVs by a mechanism presumably dependent on the high arachidonic acid content of the vesicles. Conclusions: Cellular origin and jakinib exposure modify the FA profile of EVs, enabling them, in turn, to modulate neutrophil respiratory burst, T-cell proliferation, and platelet aggregation. The increased T-cell proliferation induced by BARI-L/M-EVs could explain the lymphocytosis observed in patients treated with BARI. The higher proportion of arachidonic acid in the FA content of ITA-L/M-EVs could be related to the thrombosis described in patients treated with ITA. EVs also induced a decrease in the respiratory burst of neutrophils.

Assessing health outcomes: a systematic review of electronic patient-reported outcomes in oncology.

PURPOSE: This study investigates the clinical impact of electronic patient-reported outcome (ePRO) monitoring apps/web interfaces, aimed at symptom-management, in cancer patients undergoing outpatient systemic antineoplastic treatment. Additionally, it explores the advantages offered by these applications, including their functionalities and healthcare team-initiated follow-up programmes. METHODS: A systematic literature review was conducted using a predefined search strategy in MEDLINE. Inclusion criteria encompassed primary studies assessing symptom burden through at-home ePRO surveys in adult cancer patients receiving outpatient systemic antineoplastic treatment, whenever health outcomes were evaluated. Exclusion criteria excluded telemedicine-based interventions other than ePRO questionnaires and non-primary articles or study protocols. To evaluate the potential bias in the included studies, an exhaustive quality assessment was conducted, as an additional inclusion filter. RESULTS: Among 246 identified articles, 227 were excluded for non-compliance with inclusion/exclusion criteria. Of the remaining 19 articles, only eight met the rigorous validity assessment and were included for detailed examination and data extraction, presented in attached tables. CONCLUSION: This review provides compelling evidence of ePRO monitoring's positive clinical impact across diverse cancer settings, encompassing various cancer types, including early and metastatic stages. These systems are crucial in enabling timely interventions and reducing communication barriers, among other functionalities. While areas for future ePRO innovation are identified, the primary limitation lies in comparing clinical outcomes of reviewed articles, due to scale variability and study population heterogeneity. To conclude, our results reaffirm the transformative potential of ePRO apps in oncology and their pivotal role in shaping the future of cancer care.

PLGA-LEC/F127 hybrid nanoparticles loaded with curcumin and their modulatory effect on monocytes.

Aim: To investigate the effect of surfactant type on curcumin-loaded (CUR) PLGA nanoparticles (NPs) to modulate monocyte functions. Materials & methods: The nanoprecipitation method was used, and PLGA NPs were designed using Pluronic F127 (F127) and/or lecithin (LEC) as surfactants. Results: The Z-average of the NPs was <200 nm, they had a spherical shape, Derjaguin-Muller-Toporov modulus >0.128 MPa, they were stable during storage at 4°C, ζ-potential ∼-40 mV, polydispersity index <0.26 and % EE of CUR >94%. PLGA-LEC/F127 NPs showed favorable physicochemical and nanomechanical properties. These NPs were bound and internalized mainly by monocytes, suppressed monocyte-induced reactive oxygen species production, and decreased the ability of monocytes to modulate T-cell proliferation. Conclusion: These results demonstrate the potential of these NPs for targeted therapy.

This study explores how different surfactants affect curcumin-loaded PLGA nanoparticles, a biodegradable polymer. The nanoparticles were designed using Pluronic F127 and/or lecithin as surfactants. They are less than 200 nm and spherical. They are stable when stored at 4 °C, with a surface charge of about -40 mV, and can encapsulate more than 94% of curcumin.The results of this study are promising, showing that PLGA nanoparticles using a mixture of lecithin and Pluronic F127 as surfactants have favorable properties toward monocyte adhesion. They are primarily taken up by monocytes, a type of white blood cell, and demonstrate a remarkable ability to reduce the production of reactive oxygen species, which can cause cell damage, as well as the ability of monocytes to stimulate the proliferation of T cells. This underscores the potential of these nanoparticles in targeted therapy, particularly in diseases where monocytes play a pivotal role, such as chronic inflammatory conditions.

Assessment of Central Auditory Processing in Children Using a Novel Tablet-Based Platform: Application for Low- and Middle-Income Countries.

OBJECTIVE: Evaluate whether a portable, tablet-based central auditory processing (CAP) test system using native language training videos and administered by minimally trained community health workers can produce CAP results comparable to previously published norms. Our secondary aim was to determine subject parameters that influence test results. STUDY DESIGN: Cross-sectional study. SETTING: Community-based settings in Chontales, Nicaragua, New Hampshire, and Florida. PATIENTS: English- and/or Spanish-speaking children and adolescents (n = 245; average age, 12.20 yr; range, 6-18 yr). MAIN OUTCOME MEASURES: Completion of the following tests with responses comparable to published norms: Pure-tone average (PTA), gap detection threshold (GDT), fixed-level frequency threshold, masking level difference (MLD), Hearing in Noise Test (HINT), Dichotic Digits Test (DDT), and Frequency Pattern Recognition (FPR) test. RESULTS: GDT, HINT, and DDT had comparable results to previously published normative values. MLD and FPR results differed compared with previously published normative values. Most CAP tests (MLD, GDT, HINT) results were independent of age and PTA (p = 0.1-0.9). However, DDT was associated with age and PTA (p < 0.0001). CONCLUSIONS: Pediatric CAP testing can be successfully completed in remote low- and middle- income country environments using a tablet-based platform without the presence of an audiologist. Performance on DDT improved with age but deteriorated with hearing loss. Further investigation is warranted to assess the variability of FPR.

Combination therapy of Epidermal Growth Factor and Growth Hormone-Releasing Hexapeptide in acute ischemic stroke: a phase I/II non-blinded, randomized clinical trial.

Objective: This study tested the hypothesis that a neuroprotective combined therapy based on epidermal growth factor (EGF) and growth hormone-releasing hexapeptide (GHRP6) could be safe for acute ischemic stroke patients, admitting up to 30% of serious adverse events (SAE) with proven causality. Methods: A multi-centric, randomized, open-label, controlled, phase I-II clinical trial with parallel groups was conducted (July 2017 to January 2018). Patients aged 18-80 years with a computed tomography-confirmed ischemic stroke and less than 12 h from the onset of symptoms were randomly assigned to the study groups I (75 µg rEGF + 3.5 mg GHRP6 i.v., n=10), II (75 µg rEGF + 5 mg GHRP6 i.v., n=10), or III (standard care control, n=16). Combined therapy was given BID for 7 days. The primary endpoint was safety over 6 months. Secondary endpoints included neurological (NIHSS) and functional [Barthel index and modified Rankin scale (mRS)] outcomes. Results: The study population had a mean age of 66 ± 11 years, with 21 men (58.3%), a baseline median NIHSS score of 9 (95% CI: 8-11), and a mean time to treatment of 7.3 ± 2.8 h. Analyses were conducted on an intention-to-treat basis. SAEs were reported in 9 of 16 (56.2%) patients in the control group, 3 of 10 (30%) patients in Group I (odds ratio (OR): 0.33; 95% CI: 0.06-1.78), and 2 of 10 (20%) patients in Group II (OR: 0.19; 95% CI: 0.03-1.22); only two events in one patient in Group I were attributed to the intervention treatment. Compliance with the study hypothesis was greater than 0.90 in each group. Patients treated with EGF + GHRP6 had a favorable neurological and functional evolution at both 90 and 180 days, as evidenced by the inferential analysis of NIHSS, Barthel, and mRS and by their moderate to strong effect size. At 6 months, proportion analysis evidenced a higher survival rate for patients treated with the combined therapy. Ancillary analysis including merged treated groups and utility-weighted mRS also showed a benefit of this combined therapy. Conclusion: EGF + GHRP6 therapy was safe. The functional benefits of treatment in this study supported a Phase III study. Clinical Trial Registration: RPCEC00000214 of the Cuban Public Registry of Clinical Trials, Unique identifier: IG/CIGB-845I/IC/1601.

Nanoparticles targeting monocytes and macrophages as diagnostic and therapeutic tools for autoimmune diseases.

Autoimmune diseases are chronic conditions that result from an inadequate immune response to self-antigens and affect many people worldwide. Their signs, symptoms, and clinical severity change throughout the course of the disease, therefore the diagnosis and treatment of autoimmune diseases are major challenges. Current diagnostic tools are often invasive and tend to identify the issue at advanced stages. Moreover, the available treatments for autoimmune diseases do not typically lead to complete remission and are associated with numerous side effects upon long-term usage. A promising strategy is the use of nanoparticles that can be used as contrast agents in diagnostic imaging techniques to detect specific cells present at the inflammatory infiltrates in tissues that are not easily accessible by biopsy. In addition, NPs can be designed to deliver drugs to a cell population or tissue. Considering the significant role played by monocytes in the development of chronic inflammatory conditions and their emergence as a target for extracorporeal monitoring and precise interventions, this review focuses on recent advancements in nanoparticle-based strategies for diagnosing and treating autoimmune diseases, with a particular emphasis on targeting monocyte populations.

B cell-targeted polylactic acid nanoparticles as platform for encapsulating jakinibs: potential therapeutic strategy for systemic lupus erythematosus.

Background: B cells are pivotal in systemic lupus erythematosus and autoimmune disease pathogenesis. Materials & methods: To address this, Nile Red-labeled polylactic acid nanoparticles (NR-PLA NPs) loaded with the JAK inhibitor baricitinib (BARI), specifically targeting JAK1 and JAK2 in B cells, were developed. Results: Physicochemical characterization confirmed NP stability over 30 days. NR-PLA NPs were selectively bound and internalized by CD19+ B cells, sparing other leukocytes. In contrast to NR-PLA NPs, BARI-NR-PLA NPs significantly dampened B-cell activation, proliferation and plasma cell differentiation in healthy controls. They also inhibited key cytokine production. These effects often surpassed those of equimolar-free BARI. Conclusion: This study underscores the potential of PLA NPs to regulate autoreactive B cells, offering a novel therapeutic avenue for autoimmune diseases.

In this study, a new approach to treating autoimmune diseases, particularly systemic lupus erythematosus, was investigated by focusing on a type of immune cell called B cells. Special nanoparticles (NPs) labeled with Nile Red (NR) and made from polylactic acid (PLA) were created. These NPs were loaded with a drug called baricitinib (BARI), which targets specific proteins (JAK1 and JAK2) in B cells. This was done to determine if these NPs could help control the behavior of B cells, which are important in autoimmune diseases. First, these NPs remained stable for a long time (30 days). The NR-labeled PLA NPs (NR-PLA NPs) were also good at attaching to and entering a specific type of B cell called CD19⁺ B cells while leaving other types of immune cells alone. The use of NR-PLA NPs loaded with BARI produced exciting results. These NPs were better at reducing the activity, growth and transformation of B cells into plasma cells compared with the drug BARI by itself. They also stopped the production of certain immune system signals called cytokines, which are usually overactive in autoimmune diseases. This work suggests that PLA NPs could be a promising way to control overactive B cells that contribute to autoimmune diseases like systemic lupus erythematosus. This could open a new and exciting path for developing treatments for these conditions.

HIV Antiretroviral Medication Neuropenetrance and Neurocognitive Outcomes in HIV+ Adults: A Review of the Literature Examining the Central Nervous System Penetration Effectiveness Score.

This literature review summarizes the existing research examining the CNS penetration effectiveness (CPE) score and neurocognitive outcomes (i.e., neuropsychological assessment and neurocognitive screening) in HIV+ individuals. Despite the effectiveness of Combined Antiretroviral Therapy (CART) in reducing mortality and morbidity in HIV and controlling viral replication, HIV often persists in the Central Nervous System (CNS), and rates of neurocognitive impairment remain higher than predicted in the post-CART era. The CPE score was developed to rank antiretroviral regimens on their ability to penetrate the CNS and potency in inhibiting the virus, and it has been examined in relation to neurocognitive functioning for over a decade. Based on the results of 23 studies, we conclude that CPE is not as strongly associated with neurocognitive outcomes as initially hypothesized, although higher CPE ARV regimens may be associated with modest, improved outcomes in global neurocognitive functioning, and to a lesser extent attention/working memory and learning/memory. Conclusions, however, are limited by the heterogeneity in study design and methods, and the lack of a more recent CPE metric update. It is recommended that future research in this area employ comprehensive, standardized neuropsychological test batteries and examine domain-level performance, and use the newer 2010 CPE metric, although an updated CPE ranking is urgently needed.

School Hearing Screening With a Portable, Tablet-Based, Noise-Attenuating Audiometric Headset in Rural Nicaragua.

OBJECTIVE: To investigate the utility and effectiveness of a noise-attenuating, tablet-based mobile health system combined with asynchronous telehealth evaluations for screening rural Nicaraguan schoolchildren for hearing loss. STUDY DESIGN: Prospective population-based survey. SETTING: Rural Nicaraguan communities. PATIENTS: There were 3,398 school children 7 to 9 years of age. INTERVENTIONS: Diagnostic automated and manual audiometry, detailed asynchronous telehealth evaluations. MAIN OUTCOME MEASURES: Referral rates, ambient noise levels, and audiometric results as well as hearing loss prevalence, types, and risk factors. RESULTS: Despite high ambient noise levels during screening (46.7 dBA), no effect of noise on referral rates on automated audiometry or confirmatory manual audiometry in those who failed automated testing was seen. The overall audiometric referral rate was 2.6%. Idiopathic sensorineural hearing loss (SNHL) and cerumen impaction were the most common types of hearing loss in this population with an estimated prevalence of hearing loss (all types) of 18.3 per 1,000 children. SNHL was associated with both drug exposure during pregnancy (p = 0.04) and pesticide exposure in the home (p = 0.03). CONCLUSION: Hearing screening using a tablet-based, noise-attenuating wireless headset audiometer is feasible and effective in rural low-resource environments with moderately elevated ambient noise levels. The referral rate with noise-attenuating headsets was much lower than that previous reports on this population. In addition, manual audiometry resulted in much lower referral rates than automated audiometry. The confirmed hearing loss rate in this study is comparable to reports from other low-income countries that use some form of noise attenuation during screening. Pesticide exposure and drug exposure during pregnancy are potential causes of SNHL in this population.

Community health workers and mHealth systems for hearing screening in rural Nicaraguan schoolchildren.

Background: We aimed to investigate the effectiveness of using minimally trained community health workers (CHW) to screen schoolchildren in rural Nicaragua for hearing loss using a tablet-based audiometric system integrated with asynchronous telehealth evaluations and mobile health (mHealth) appointment reminders. Methods: A population-based survey was conducted using community health workers (CHWs) to perform tablet-based audiometry, asynchronous telehealth evaluations, and mHealth reminders to screen 3398 school children (7-9 years of age) in 92 rural Nicaraguan communities. The accuracy of screening, test duration, testing efficiency, telehealth data validity, and compliance with recommended clinic visits were analyzed. Results: Minimally trained CHWs successfully screened children within remote rural schools with automated audiometry (test duration = 5.8 minutes) followed by manual audiometry if needed (test duration = 4.3 minutes) with an estimated manual audiometry validity of 98.5% based on a review of convergence patterns. For children who were referred based on audiometry, the otoscopy and tympanometry obtained during telehealth evaluations were high quality (as reviewed by 3 experts) in 44.6% and 80.1% of ears, respectively. A combination of automated short message service (SMS) text messages and voice reminders resulted in a follow-up compliance of 75.2%. No families responded to SMS messages alone. Conclusions: Tablet-based hearing screening administered by minimally trained CHWs is feasible and effective in low- and middle-income countries. Manual audiometry was as efficient as automated audiometry in this setting. The physical exam tasks of otoscopy and tympanometry require additional training. Mobile phone messages improve compliance for confirmatory audiometry, but the utility of SMS messaging alone is unclear in this population.

Induction of NF-κB inflammatory pathway in monocytes by microparticles from patients with systemic lupus erythematosus.

BACKGROUND: Elevated levels of circulating microparticles (MPs) and molecules of the complement system have been reported in patients with systemic lupus erythematosus (SLE). Moreover, microparticles isolated from patients with SLE (SLE-MPs) contain higher levels of damage-associated molecular patterns (DAMPs) than MPs from healthy controls (CMPs). We hypothesize that the uptake of MPs by monocytes could contribute to the chronic inflammatory processes observed in patients with SLE. Therefore, the aim of this study was to evaluate the expression of activation markers, production of proinflammatory mediators, and activation of the NF-κB signaling pathway in monocytes treated with CMPs and SLE-MPs. METHODOLOGY: Monocytes isolated from healthy individuals were pretreated or not with pyrrolidine dithiocarbamate (PDTC) and cultured with CMPs and SLE-MPs. The cell surface expression of CD69 and HLA-DR were evaluated by flow cytometry; cytokine and eicosanoid levels were quantified in culture supernatants by Cytokine Bead Array and ELISA, respectively; and the NF-κB activation was evaluated by Western blot and epifluorescence microscopy. RESULTS: The cell surface expression of HLA-DR and CD69, and the supernatant levels of IL-6, IL-1ß, PGE2, and LTB4 were higher in cultures of monocytes treated with SLE-MPs than CMPs. These responses were blocked in the presence of PDTC, a pharmacological inhibitor of the NF-κB pathway, with concomitant reduction of IκBα and cytoplasmic p65, and increased nuclear translocation of p65. CONCLUSIONS: The present findings indicate that significant uptake of SLE-MPs by monocytes results in activation, production of inflammatory mediators, and triggering of the NF-κB signaling pathway.

Disparities in Electronically Monitored Antiretroviral Adherence and Differential Adherence Predictors in Latinx and Non-Latinx White Persons Living with HIV.

Antiretroviral therapy (ART) adherence is vital for optimal HIV treatment. However, there is limited ART adherence research on the US Latinx population, who are at increased risk for HIV infection and worse HIV health outcomes. This study examined electronically measured ART adherence (Medication Event Monitoring System) and its association with demographic, clinical, neurocognitive, and sociocultural variables in Latinx and non-Latinx white (NLW) persons living with HIV [PLWH (N = 128)]. Latinx participants demonstrated worse adherence than NLW participants (p = 0.04). Linear regressions revealed different predictors of adherence. Among Latinx participants, recent cocaine use, stress, and, unexpectedly, higher US acculturation predicted worse adherence (ps < 0.05). Among NLW participants, recent cocaine use predicted worse adherence (p < 0.05). Intergroup comparisons within the Latinx group were not conducted due to subsample size. Thus, ethnicity, sociocultural variables, and cocaine use are important considerations for ART adherence, and poor ART adherence may be one pathway explaining worse outcomes in Latinx PLWH. Culturally tailored adherence interventions incorporating substance use treatment, acculturation, and stress management are warranted to improve health outcomes.

Anti-EGF antibodies as surrogate biomarkers of clinical efficacy in stage IIIB/IV non-small-cell lung cancer patients treated with an optimized CIMAvax-EGF vaccination schedule.

We previously reported that CIMAvax-EGF vaccine is safe, immunogenic and efficacious to treat advanced non-small-cell lung cancer (NSCLC) patients. A phase III trial was designed using an optimized immunization schedule. It included higher antigen dose and injections at multiple sites. Immune response and circulating biomarkers were studied in a subset of patients. EGF-specific antibody titers, IgG subclasses, peptide immunodominance and circulating biomarkers were assessed by ELISA. In vitro EGF-neutralization capacity of immune sera and EGF-IgG binding kinetics was evaluated by Western Blot and Surface Plasmon Resonance (SPR) technology, respectively. We show that CIMAvax-EGF elicited mainly IgG3/IgG4 antibodies at titers exceeding 1:4000 in 80% of vaccinated patients after 3 months of treatment. The EGF-specific humoral response was directed against the central region of the EGF molecule. For the first time, the kinetic constants of EGF-specific antibodies were measured evidencing affinity maturation of antibody repertoire up to month 12 of vaccination. Notably, the capacity of post-immune sera to inhibit EGFR phosphorylation significantly increased during the course of the immunization scheme and was related to clinical outcome (P = .013, log-rank test). Basal concentrations of EGF and TGFα in the serum were affected by EGF-based immunization. In conclusion, the CIMAvax-EGF vaccine induces an EGF-specific protective humoral response in a high percent of NSCLC vaccinated patients, the quantity and quality of which were associated with clinical benefit (clinical trial registration number: RPCEC00000161, http://registroclinico.sld.cu/). Abbreviations: EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; Ab: antibody; AR: amphiregulin; NSCLC: non-small-cell lung cancer; rhEGF: recombinant human epidermal growth factor; BSC: best supportive care; TGFα: tumor growth factor alpha; IL-8: interleukin 8; MAb: monoclonal antibody; SPR: surface plasmon resonance.

The SLC16A11 risk haplotype is associated with decreased insulin action, higher transaminases and large-size adipocytes.

Objective A haplotype at chromosome 17p13 that reduces expression and function of the solute carrier transporter SLC16A11 is associated with increased risk for type 2 diabetes in Mexicans. We aim to investigate the detailed metabolic profile of SLC16A11 risk haplotype carriers to identify potential physiological mechanisms explaining the increased type 2 diabetes risk. Design Cross-sectional study. Methods We evaluated carriers (n = 72) and non-carriers (n = 75) of the SLC16A11 risk haplotype, with or without type 2 diabetes. An independent sample of 1069 subjects was used to replicate biochemical findings. The evaluation included euglycemic-hyperinsulinemic clamp, frequently sampled intravenous glucose tolerance test (FSIVGTT), dual-energy X-ray absorptiometry (DXA), MRI and spectroscopy and subcutaneous abdominal adipose tissue biopsies. Results Fat-free mass (FFM)-adjusted M value was lower in carriers of the SLC16A11 risk haplotype after adjusting for age and type 2 diabetes status (ß = -0.164, P = 0.04). Subjects with type 2 diabetes and the risk haplotype demonstrated an increase of 8.76 U/L in alanine aminotransferase (ALT) (P = 0.02) and of 7.34 U/L in gamma-glutamyltransferase (GGT) (P = 0.05) compared with non-carriers and after adjusting for gender, age and ancestry. Among women with the risk haplotype and normal BMI, the adipocyte size was higher (P < 0.001). Conclusions Individuals carrying the SLC16A11 risk haplotype exhibited decreased insulin action. Higher serum ALT and GGT levels were found in carriers with type 2 diabetes, and larger adipocytes in subcutaneous fat in the size distribution in carrier women with normal weight.

Damage-associated molecular patterns and their role as initiators of inflammatory and auto-immune signals in systemic lupus erythematosus.

Damage-associated molecular patterns (DAMPs) are endogenous molecules that are released into the extracellular space under conditions of activation, cellular stress, or tissue damage. These molecules are recognized by pattern-recognition receptors (PRRs) and can induce inflammation and immune responses in the absence of infection. An increasing number of DAMPs have been linked to the pathogenesis of many auto-immune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriatic arthritis, and systemic sclerosis (SSc); as they promote the maturation/activation of different immune cells and pro-inflammatory cytokines production associated with these diseases. Several studies suggest that the loss of tolerance to self-antigens in these diseases could be due to continuous exposure to DAMPs. Thus, understanding the mechanisms of sterile inflammation triggered by DAMPs is important to elucidate novel therapeutic strategies for the treatment of various auto-immune diseases through inhibition or modulation the expression of these molecules. To this end, this review describes different DAMPs, their molecular characteristics, their modifications, and the receptors through which they activate an immune response while considering their role in the pathogenesis of various auto-immune diseases.

Otoacoustic Emissions in Rural Nicaragua: Cost Analysis and Implications for Newborn Hearing Screening.

Objective (1) Determine the incidence and risk factors for congenital hearing loss. (2) Perform cost analysis of screening programs. Study Design Proportionally distributed cross-sectional survey. Setting Jinotega, Nicaragua. Subjects and Methods Otoacoustic emissions (OAEs) were used to screen 640 infants <6 months of age from neonatal intensive care unit, institutional, and home birth settings. Data on 15 risk factors were analyzed. Cost of 4 implementation strategies was studied: universal screening, screening at the regional health center (RHC), targeted screening, and screening at the RHC plus targeted screening. Cost-effectiveness analysis over 10 years was based on disability-adjusted life year estimates, with the World Health Organization standard of cost-effectiveness ratio (CER) / gross domestic product (GDP) <3, with GDP set at $4884.15. Results Thirty-eight infants failed the initial OAE (5.94%). In terms of births, 325 (50.8%) were in the RHC, 69 (10.8%) in the neonatal intensive care unit, and 29 (4.5%) at home. Family history and birth defect were significant in univariate analysis; birth defect was significant in multivariate analysis. Cost-effectiveness analysis demonstrated that OAE screening is cost-effective without treatment (CER/GDP = 0.06-2.00) and with treatment (CER/GDP = 0.58-2.52). Conclusions Our rate of OAE failures was comparable to those of developed countries and lower than hearing loss rates noted among Nicaraguan schoolchildren, suggesting acquired or progressive etiology in the latter. Birth defects and familial hearing loss correlated with OAE failure. OAE screening of infants is feasible and cost-effective in rural Nicaragua, although highly influenced by estimated hearing loss severity in identified infants and the high travel costs incurred in a targeted screening strategy.