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There is a critical need to increase Latino participation in research on Alzheimer's disease and related disorders (ADRD). Applying principles of community-based participatory research, we convened a community advisory board (CAB) to identify barriers and recommend strategies to increase participation of older Latinos in a longitudinal observational research study of ADRD at the Shiley-Marcos Alzheimer's Disease Research Center. Six major barriers were identified and programmatic changes to overcome them were implemented. Changes resulted in a nearly three-fold increase in the number of Latino individuals recruited, with the proportion of all newly recruited participants who were Latino increasing from 12.2% to 57.4%. Newer Latino recruits were more representative of the elderly Latino population in San Diego County than those recruited pre-CAB and remained highly agreeable to blood draw and neuroimaging, though less so to lumbar puncture and autopsy. Results demonstrate the value of CAB involvement in enhancing diversity in ADRD research., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: David P. Salmon is a paid consultant for Biogen and Aptinyx. Douglas Galasko is a paid consultant for Eisai, Biogen, Roche Diagnostics, GE Healthcare, and Fujirebio, Inc., and is on the Data and Safety Monitoring Board (DSMB) for Artery Therapeutics. James B. Brewer reports equity interest in Cortechs.ai, Enkephalos, Impact Biomedicines, ACLIP, and Human Longevity, Inc. All other authors have declared no conflicts of interest.

Moringa oleifera (MO) is a native tree of Asia and is cultivated in some areas of Mexico as part of traditional horticulture. The aim of the present study was to compare the efficacy of MO infusion vs. MO ethanolic extract for the simultaneous treatment of nonalcoholic fatty liver (NAFLD), hyperlipidemia, and hyperglycemia in a murine model fed with a high-fat diet (HFD). BALB/c mice were fed a balanced diet (healthy control) or an HFD for 6 months. With this, the NAFLD model was established before starting a therapeutic intervention with MO for two months. The phytochemical analysis by nuclear magnetic resonance in 1 H and 13 C experiments showed signals for pyrrole alkaloids and triterpenes as the main constituents of the extract and infusion preparation. A significant reduction of SGPT, SGOT, lipids, urea, and glucose in blood among NAFLD groups treated with MO (infusion or extract) was found, when compared to the NAFLD-placebo group. Steatosis and liver inflammation were found to be decreased in the MO groups, as infusion or ethanolic extract. Infusion produced a better therapeutic effect than the extract in all parameters, except glycemic control, where the extract was better. As an additional finding, it is noteworthy that treatment with MO, particularly through infusion, resulted in improved motor activity. Moreover, a reduction in anxiety-like behavior was observed exclusively with the administration of infusion. These observations provide valuable insights into the potential broader effects of Moringa oleifera beyond the primary aim of the study., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2024 Salma I. Cortes-Alvarez et al.)

Purpose: To review the available evidence on the different retinal and visual prostheses for patients with retinitis pigmentosa and new implants for other indications including dry age-related macular degeneration., Methods: The PubMed, GoogleScholar, ScienceDirect, and ClinicalTrials databases were the main resources used to conduct the medical literature search. An extensive search was performed to identify relevant articles concerning the worldwide advances in retinal prosthesis, clinical trials, status of devices and potential future directions up to December 2022., Results: Thirteen devices were found to be current and were ordered by stimulation location. Six have active clinical trials. Four have been discontinued, including the Alpha IMS, Alpha AMS, IRIS II, and ARGUS II which had FDA and CE mark approval. Future directions will be presented in the review., Conclusion: This review provides an update of retinal prosthetic devices, both current and discontinued. While some devices have achieved visual perception in animals and/or humans, the main issues impeding the commercialization of these devices include: increased length of time to observe outcomes, difficulties in finding validated meaures for use in studies, unknown long-term effects, lack of funding, and a low amount of patients simultaneously diagnosed with RP lacking other comorbid conditions. The ARGUS II did get FDA and CE mark approval so it was deemed safe and also effective. However, the company became more focused on a visual cortical implant. Future efforts are headed towards more biocompatible, safe, and efficacious devices., (© 2023. The Author(s).)

Background: Monoclonal antibody (palivizumab), intravenous immune globulin (IGIV), or respiratory syncytial virus (RSV)-polyclonal-hyperimmune-globulin (RSV-IG as Respigam®, RI-001, RI-002) are used with ribavirin in RSV-infected immunocompromised patients, with debated efficacy. Palivizumab-resistance (PR) can arise during treatment of persistent infections in this population. RSV-IG may confer benefit in PR-RSV infection., Methods: RSV-IG [RI-001] was provided for an immunocompromised infant with RSV-pneumonitis refractory to ribavirin and palivizumab. RSV-neutralizing antibody, respiratory RSV load (qPCR), and F-gene-sequence-detection of PR was determined. Prophylactic RSV-IG [RI-002] or palivizumab was administered in a cotton-rat model infected with wild-type and PR-RSV. Lung RSV load and neutralizing antibody were measured., Results: As protective RI-001-neutralizing antibody titers waned in the infant, a subpopulation of PR-escape mutants were detected with a fatal RSV-burden in the lungs. In PR-RSV-infected cotton rats, prophylactic RI-002 reduced RSV-load in the lungs (2.45 vs 0.28 log 10  PFU/g lung-tissue reduction, respectively, p < 0.05) and provided protective RSV-neutralizing antibody., Conclusions: RSV-IG and ribavirin use in immunocompromised patients requires further study., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Invasive pulmonary aspergillosis (IPA) is uncommon in immunocompetent patients, but rare cases have been described after nonfatal drowning, particularly in contaminated water sources. Given subacute disease manifestations, diagnostic difficulties and the rapidly progressive nature of this organism, its mortality rate approaches 50%. Clinicians must rely on nonculture-based biomarkers and imaging to inform early diagnosis. There are currently no recommendations regarding diagnostics or empiric therapy for mold infections in near-drowning patients. We report a fatal case of IPA in a 4-year-old male following submersion in a manure pond. Early serum biomarkers and empiric voriconazole should be strongly considered in all patients after near-drowning in contaminated water sources.

For inoperable esophageal adenocarcinoma (EAC), identifying patients likely to benefit from recently approved immunochemotherapy (ICI+CTX) treatments remains a key challenge. We address this using a uniquely designed window-of-opportunity trial (LUD2015-005), in which 35 inoperable EAC patients received first-line immune checkpoint inhibitors for four weeks (ICI-4W), followed by ICI+CTX. Comprehensive biomarker profiling, including generation of a 65,000-cell single-cell RNA-sequencing atlas of esophageal cancer, as well as multi-timepoint transcriptomic profiling of EAC during ICI-4W, reveals a novel T cell inflammation signature (INCITE) whose upregulation correlates with ICI-induced tumor shrinkage. Deconvolution of pre-treatment gastro-esophageal cancer transcriptomes using our single-cell atlas identifies high tumor monocyte content (TMC) as an unexpected ICI+CTX-specific predictor of greater overall survival (OS) in LUD2015-005 patients and of ICI response in prevalent gastric cancer subtypes from independent cohorts. Tumor mutational burden is an additional independent and additive predictor of LUD2015-005 OS. TMC can improve patient selection for emerging ICI+CTX therapies in gastro-esophageal cancer., Competing Interests: Declaration of interests S.L.: consulting fees, honoraria, travel/accommodation or research funding (Sanofi, GLG Consulting, Rejuversen, Eisai, Prosigna, Roche, Pfizer, Novartis, Shionogi, Synthon, CRUK, Boehringer Ingelheim, Piqur Therapeutics, AstraZeneca, Carrick Therapeutics, Merck KGaA) and previous employment by Pfizer. A.R.: stock ownership (Amgen, Immunogen). I.K: honoraria, travel/accommodation (BMS , Delcath Inc, Immunocore, Pierre Fabre, Genentech, Merck Serono, Takeda Pharmaceuticals Int.). B.J.V.D.E.: consulting and ownership interests (iTeos Therapeutics, Oncorus, Amgen, Vaccitech). M.R.M.: grants or personal fees (AstraZeneca, Roche, G.S.K., Novartis, Immunocore, BMS, Pfizer, Merck/MSD, Regeneron, BiolineRx, Replimune, Kineta, Silicon Therapeutics and GRAIL). T.M.C.: founder, employee, and shareholder (Cleancard). X.L.: consulting (SimCell). A provisional patent related to applications of the INCITE signature has been filed. No other authors declare competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Mefenamic acid is a non‑steroidal anti‑inflammatory drug exhibiting a wide range of anti‑inflammatory, antipyretic, analgesic and probable antiviral activities. The present study evaluated the efficacy of treatment with mefenamic acid combined with standard medical care vs. standard medical care plus a placebo in ambulatory patients with coronavirus disease 2019 (COVID‑19; nasal/oropharyngeal swabs reverse transcription‑PCR test results positive for severe acute respiratory syndrome coronavirus 2). The present study is a phase II prospective, two‑arm, parallel‑group, randomized, double‑blind placebo‑controlled clinical trial which analyzed 36 patients. Two aspects were evaluated during the 14‑day follow‑up period: i) The time for reaching a patient acceptable symptom state (PASS), and ii) the last day of each COVID‑19 symptom presentation. Adverse effects were evaluated. The clinical severity for all the patients in the study was mild (88.9%) and moderate (11.1%). The control (placebo) group achieved PASS on day 8.0±1.3, compared with day 4.4±0.8 in the mefenamic acid group (P=0.020, Kaplan‑Meier analyses using log‑rank tests). Patients that received mefenamic acid plus standard medical care had a ~16‑fold higher probability of achieving PASS on day 8 (adjusted RR, 15.57; 95% CI, 1.22‑198.71; P=0.035), compared with the placebo plus standard medical care group. All symptoms lasted for fewer days in the mefenamic acid group, compared with the placebo group; however, only the symptoms of headache (P=0.008), retro‑orbital eye pain (P=0.049), and sore throat (P=0.029) exhibited statistically significant differences. The experimental treatment produced no severe adverse effects. On the whole, the present study demonstrates that the administration of mefenamic acid markedly reduced the symptomatology and time to reach PASS in ambulatory patients with COVID‑19. Due to its probable antiviral effects and potent anti‑inflammatory mechanisms, mefenamic acid may prove to be useful in the treatment of COVID‑19, in combination with other drugs, including the new antivirals (remdesivir, molnupiravir, or favipiravir). However, future studies are also required to confirm these findings.

Purpose: Germline heterozygous mutations of GATA2 underlie a variety of hematological and clinical phenotypes. The genetic, immunological, and clinical features of GATA2-deficient patients with mycobacterial diseases in the familial context remain largely unknown., Methods: We enrolled 15 GATA2 index cases referred for mycobacterial disease. We describe their genetic and clinical features including their relatives., Results: We identified 12 heterozygous GATA2 mutations, two of which had not been reported. Eight of these mutations were loss-of-function, and four were hypomorphic. None was dominant-negative in vitro, and the GATA2 locus was found to be subject to purifying selection, strongly suggesting a mechanism of haploinsufficiency. Three relatives of index cases had mycobacterial disease and were also heterozygous, resulting in 18 patients in total. Mycobacterial infection was the first clinical manifestation in 11 patients, at a mean age of 22.5 years (range: 12 to 42 years). Most patients also suffered from other infections, monocytopenia, or myelodysplasia. Strikingly, the clinical penetrance was incomplete (32.9% by age 40 years), as 16 heterozygous relatives aged between 6 and 78 years, including 4 older than 60 years, were completely asymptomatic., Conclusion: Clinical penetrance for mycobacterial disease was found to be similar to other GATA2 deficiency-related manifestations. These observations suggest that other mechanisms contribute to the phenotypic expression of GATA2 deficiency. A diagnosis of autosomal dominant GATA2 deficiency should be considered in patients with mycobacterial infections and/or other GATA2 deficiency-related phenotypes at any age in life. Moreover, all direct relatives should be genotyped at the GATA2 locus.

Purpose: Preclinical data suggest that radiotherapy (RT) is beneficial in combination with immune checkpoint blockade. Clinical trials have explored RT with single-agent immune checkpoint blockade, but no trials have reported RT with the combination of nivolumab and ipilimumab., Patients and Methods: We conducted a phase 1 study of patients with stage IV melanoma receiving nivolumab and ipilimumab with two different dose-fractionation schemes of RT. Patients had at least one melanoma metastasis that would benefit from palliative RT and one metastasis that would not be irradiated. Nivolumab 1 mg/kg + ipilimumab 3 mg/kg and extracranial RT with a dose of 30 Gy in 10 fractions was administered in Cohort A, and then 27 Gy in 3 fractions was administered in Cohort B. The primary outcome was safety., Results: Twenty patients were treated (10 in each cohort). The rates of treatment-related grade 3-4 adverse events in Cohort A and B were 40% and 30%, respectively. There were no grade ≥3 adverse events attributed to RT. Patients responded to treatment outside of the irradiated volume (Cohort A 5/10; Cohort B 1/9). No evaluable patients had progression of irradiated metastases. Immunologic changes were seen in the peripheral blood with increases in T-cell receptor diversity in some responding patients., Conclusions: RT with nivolumab and ipilimumab was safe compared with historical data of nivolumab and ipilimumab alone. Immunologic effects were observed in the peripheral blood. Randomized studies are ongoing to assess whether RT increases the efficacy of nivolumab and ipilimumab., (©2020 American Association for Cancer Research.)

Objectives: Vancomycin weight-based dosing regimens often fail to achieve therapeutic trough serum concentration in children ≤12 years of age and rigorous studies evaluating efficacy and safety of body surface area (BSA)-based dosing regimens have not been performed. We compared vancomycin trough serum concentrations in pediatric patients receiving a weight- or BSA-based dosing regimen., Methods: This was a single-center, retrospective study evaluating pediatric patients, ages 1 to 12 years, who received vancomycin from September 2012 to October 2015. Patients received a minimum of 3 consecutive doses at the same scheduled interval within a dosing regimen prior to a measured vancomycin serum trough concentration. The primary outcome was percentage of initial vancomycin trough concentrations ≥10 mg/L. The secondary outcomes were percentage of supratherapeutic, therapeutic, and subtherapeutic vancomycin serum concentration for all patients, including a subset of overweight and obese patients, and number of nephrotoxic occurrences., Results: BSA-based dosing regimens resulted in 50% of the initial vancomycin trough concentrations ≥ 10 mg/L compared with 17% for the weight-based dosing regimens (p < 0.0001). No statistically significant differences were noted between the 2 dosing regimens for supratherapeutic, therapeutic, or subtherapeutic trough concentrations for all patients, and for the subset of overweight and obese patients. Nephrotoxic occurrences were noted in 7% of the weight-based dosing regimens compared with none in the BSA-based dosing regimens., Conclusions: A BSA-based vancomycin dosing regimen resulted in significantly more initial vancomycin trough concentrations ≥10 mg/L and trended towards higher initial vancomycin trough concentrations without observable nephrotoxicity., Competing Interests: Disclosure The authors declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. Beth Sawrey and Mary Subramanian have full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Background: Herpes Simplex Virus encephalitis (HSVE) is a devastating disease of all ages. Rigorous studies correlating viral load with neuroradiological and clinical severity have not been performed, particularly in neonates. Understanding these relationships may improve therapies., Objectives: To correlate molecularly quantified HSV in cerebrospinal fluid (CSF) and disease severity., Study Design: HSV loads (VL) were evaluated by real-time PCR from the CSF of 33 patients (20 neonates, 5 children, 8 adults) with HSVE. We studied relationships between CSF VL and structural and volumetric brain abnormalities (MRI); hospital morbidity; and discharge and long-term (>3 month) clinical outcomes., Results: Initial CSF VL did not differ in neonates vs non-neonates (median 4.6 vs 5.1 log10 copies/mL, p = 0.75). Initial CSF VL was higher in neonates with HSV-2 vs HSV-1 (median 4.8 vs 3.2 log10 copies/mL, respectively, p = 0.02). Persistently detectable DNA in CSF despite acyclovir trended towards higher odds of unfavorable outcome at discharge for neonates [0.87 (CI 0.75-1), p = 0.07]. Initial VL correlated with higher CSF protein concentrations for the cohort and for neonates (p = 0.03 and 0.01, respectively), but not with lesion volume or subarachnoid exposure of involved brain (p all >0.05), hospital morbidity (p all >0.05), nor with higher odds of unfavorable discharge or long-term outcomes for the cohort [OR = 0.9(CI 0.5-1.6), p = 0.72; OR = 1.0(CI 0.5-1.8), p = 0.9] or for neonates [OR = 1.3(CI 0.5-3.3), p = 0.57; OR = 2.3(CI 0.7-8), p = 0.2]., Conclusions: Initial HSV VL did not predict neuroradiological or clinical outcomes in patients with HSVE, suggesting host inflammatory factors contribute to disease in treated patients with good viral clearance., (Copyright © 2018 Elsevier B.V. All rights reserved.)