Biocidal Efficacies of Contact Lens Disinfecting Solutions Against International Organization for Standardization (ISO) Compendial Organisms.

Purpose: This study was conducted to evaluate and compare the in vitro disinfection efficacies of six commercial lens cleaning and disinfecting products for planned replacement soft contact lenses. Methods: Disinfection efficacies of five multi-purpose solutions (MPSs) and one hydrogen peroxide solution (HPS) as control were evaluated in the presence of organic soil according to the International Organization for Standardization (ISO, Geneva, Switzerland) ISO 14729 stand-alone test protocol. The five specified compendial organisms, three bacteria (Staphylococcus aureus, Pseudomonas aeruginosa, and Serratia marcescens) and two fungi (Candida albicans and Fusarium solani) were incubated with each solution under standard conditions, after which microbes were recovered and quantified. Results: Each of the solutions evaluated met or exceeded the standard's primary criteria (3-log reduction of bacteria and 1-log reduction of fungi) after incubation for the manufacturer-recommended soaking time, except for COMPLETE MPS, which achieved only 0.4 ± 0.1 average log reduction for C. albicans. However, differences in efficacy between the solutions were noted. Average log reduction across all microbes for Biotrue Hydration Plus (4.6 ± 0.1) was comparable to that for CLEAR CARE PLUS HPS (4.3 ± 0.1) and greater than those for OPTI-FREE puremoist (3.6 ± 0.1), OPTI-FREE Replenish (4.0 ± 0.2), ACUVUE RevitaLens (3.9 ± 0.03), and COMPLETE MPS (3.6 ± 0.1). Biotrue Hydration Plus was especially effective at reducing the population of C. albicans (4.2 ± 0.7-log reduction). Conclusion: Products marketed for planned replacement soft CL disinfection generally meet the ISO 14729 standard's primary criteria for reducing populations of compendial organisms, with larger differences between solutions noted with C. albicans.

A phase 1/2 clinical trial of invariant natural killer T cell therapy in moderate-severe acute respiratory distress syndrome.

Invariant natural killer T (iNKT) cells, a unique T cell population, lend themselves for use as adoptive therapy due to diverse roles in orchestrating immune responses. Originally developed for use in cancer, agenT-797 is a donor-unrestricted allogeneic ex vivo expanded iNKT cell therapy. We conducted an open-label study in virally induced acute respiratory distress syndrome (ARDS) caused by the severe acute respiratory syndrome-2 virus (trial registration NCT04582201). Here we show that agenT-797 rescues exhausted T cells and rapidly activates both innate and adaptive immunity. In 21 ventilated patients including 5 individuals receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO), there are no dose-limiting toxicities. We observe an anti-inflammatory systemic cytokine response and infused iNKT cells are persistent during follow-up, inducing only transient donor-specific antibodies. Clinical signals of associated survival and prevention of secondary infections are evident. Cellular therapy using off-the-shelf iNKT cells is safe, can be rapidly scaled and is associated with an anti-inflammatory response. The safety and therapeutic potential of iNKT cells across diseases including infections and cancer, warrants randomized-controlled trials.

Overcoming resistance to programmed cell death protein 1 (PD-1) blockade with allogeneic invariant natural killer T-cells (iNKT).

Gastric cancer is the 5th most common malignancy worldwide with only 36% of patients with metastatic disease surviving beyond 5 years. Despite therapeutic improvements with the advent of immune checkpoint inhibitors, most patients with gastric cancer develop disease progression related to tumor resistance. Novel immunotherapeutic approaches, including invariant natural killer (iNKT) cells, are in clinical development and represent potential therapeutic options to overcome resistance. AgenT-797 is an allogeneic human unmodified iNKT derived from healthy donors. Activation of iNKT cells by tumor lipid antigens can trigger direct cytotoxicity and promote indirect anti-tumor immune responses such as recruitment and activation of T cells, NK cells, and dendritic cells through secretion of cytokines and IFNγ. We describe immune modulation leading to durable tumor response in a patient with microsatellite instability-high (MSI-H) advanced gastric adenocarcinoma treated with agent-797 after progression on standard chemotherapy and anti-PD-1 therapy.

Molecular mechanism of phosphopeptide neoantigen immunogenicity.

Altered protein phosphorylation in cancer cells often leads to surface presentation of phosphopeptide neoantigens. However, their role in cancer immunogenicity remains unclear. Here we describe a mechanism by which an HLA-B*0702-specific acute myeloid leukemia phosphoneoantigen, pMLL747-755 (EPR(pS)PSHSM), is recognized by a cognate T cell receptor named TCR27, a candidate for cancer immunotherapy. We show that the replacement of phosphoserine P4 with serine or phosphomimetics does not affect pMHC conformation or peptide-MHC affinity but abrogates TCR27-dependent T cell activation and weakens binding between TCR27 and pMHC. Here we describe the crystal structures for TCR27 and cognate pMHC, map of the interface produced by nuclear magnetic resonance, and a ternary complex generated using information-driven protein docking. Our data show that non-covalent interactions between the epitope phosphate group and TCR27 are crucial for TCR specificity. This study supports development of new treatment options for cancer patients through target expansion and TCR optimization.

Screening and Brief Intervention With Low-Income Youth in Community-Based Settings.

PURPOSE: We described screening, brief intervention, and referral to treatment (SBIRT) results and assessed whether SBIRT is associated with positive changes in substance use, risky use, and educational/employment outcomes for youth in community-based settings that are not healthcare focused. METHODS: YouthBuild USA serves youth of ages 16-24 who are neither in school nor employed. In an SBIRT intervention, youth completed substance use surveys and Alcohol Use Disorders Identification Test and Drug Abuse Screening Test screenings at entry and program completion. Staff reported on services provided in response to screening scores. Regression models compared changes in youth screening results and substance use from intake to follow-up and, with aggregate program-level data, youth outcomes across programs with and without the SBIRT intervention. RESULTS: Youth significantly reduced Alcohol Use Disorders Identification Test (3.1 vs. 2.3, p < .001) and Drug Abuse Screening Test (1.9 vs. 1.4, p < .001) scores, positive screens (64% vs. 54%, p < .001), and need for referrals to treatment (48% vs. 37%, p < .001), indicating less risky substance use, although self-reports of substance use in the past 30 days did not decrease. Proportionately more youth in SBIRT programs attained a high school diploma or equivalent (49% vs. 42%, p = .01) and were still in educational/job placements 3 months after program completion (67% vs. 59%, p = .02), compared to youth in non-SBIRT programs. DISCUSSION: These findings suggest that community-based SBIRT is associated with positive outcomes-both reduced risky substance use and improved education and employment-that relate to longer-term positive development for youth. SBIRT appears to be an evidence-based approach to intervene and help youth.

Virtual Community Engagement Studio (V-CES): Engaging Mothers With Mental Health and Substance Use Conditions in Research.

Active engagement of community stakeholders is increasingly encouraged in behavioral health research, often described as a co-production approach. Community stakeholders (e.g., patients, providers, policy makers, advocates) play a leading role together with research investigators in conducting the various phases of research, including conceptualization, design, implementation, and the interpretation and dissemination of findings. The concept of co-production has promising benefits for both the target population and the research outcomes, such as producing person-centered interventions with greater acceptability and usability potential. However, it is often the case that neither researchers nor community members are trained or skilled in co-production methods. The field of behavioral health research lacks tools and methods to guide and promote the engagement of diverse stakeholders in the research process. The purpose of this methods paper is to describe the Virtual Community Engagement Studio (V-CES) as a new method for engaging vulnerable populations like mothers with mental health and substance use conditions in research. We piloted the method in collaboration with the Maternal Mental Health Research Collaborative (MMHRC), focusing on one of the most vulnerable, under-researched populations, mothers coping with mental health and/or substance abuse disorders. Our pilot included mothers and providers who work with them as Community Experts to inform all phases of research design and implementation, and the interpretation and application of findings. The aim of this article is to describe the V-CES as a powerful tool that supports the engagement of mothers with mental health and/or substance use disorders and other community stakeholders in research, to provide examples of its use, and to make recommendations for future use, based on lessons learned. The V-CES toolkit is available for use with this target population as well as others.

Correction to: Angiosarcoma patients treated with immune checkpoint inhibitors: a case series of seven patients from a single institution.

Following publication of the original article [1], the authors have reported that the following sentence "While of the same IgG1 class as ipilimumab, preclinical data suggests this molecule may have enhanced activity against T regulatory cells".

Angiosarcoma patients treated with immune checkpoint inhibitors: a case series of seven patients from a single institution.

BACKGROUND: Angiosarcoma is an uncommon endothelial malignancy and a highly aggressive soft tissue sarcoma. Due to its infiltrative nature, successful management of localized angiosarcoma is often challenging. Systemic chemotherapy is used in the metastatic setting and occasionally in patients with high-risk localized disease in neoadjuvant or adjuvant settings. However, responses tend to be short-lived and most patients succumb to metastatic disease. Novel therapies are needed for patients with angiosarcomas. METHODS: We performed a retrospective analysis of patients with locally advanced or metastatic angiosarcoma, who were treated with checkpoint inhibitors at our institution. We collected their clinical information and outcome measurements. In one patient with achieved complete response, we analyzed circulating and infiltrating T cells within peripheral blood and tumor tissue. RESULTS: We have treated seven angiosarcoma (AS) patients with checkpoint inhibitors either in the context of clinical trials or off label [Pembrolizumab + Axitinib (NCT02636725; n = 1), AGEN1884, a CTLA-4 inhibitor (NCT02694822; n = 2), Pembrolizumab (n = 4)]. Five patients had cutaneous angiosarcoma, one primary breast angiosarcoma and one radiation-associated breast angiosarcoma. At 12 weeks, 5/7 patients (71%) had partial response of their lesions either on imaging and/or clinical exam and two (29%) had progressive disease. 6/7 patients are alive to date and, thus far, 3/7 patients (43%) have progressed (median 3.4 months)- one achieved partial response after pembrolizumab was switched to ongoing Nivolumab/Ipilimumab, one died of progressive disease at 31 weeks (primary breast angiosarcoma) and one was placed on pazopanib. One patient had a complete response (CR) following extended treatment with monotherapy AGEN1884. No patient experienced any ≥ grade 2 toxicities. CONCLUSIONS: This case series underscores the value of targeted immunotherapy in treating angiosarcoma. It also identifies genetic heterogeneity of cutaneous angiosarcomas and discusses specific genetic findings that may explain reported benefits from immunotherapy.

Mutation-Derived Neoantigens for Cancer Immunotherapy.

Mutation-derived neoantigens distinguish tumor from normal cells. T cells can sense the HLA-presented mutations, recognize tumor cells as non-self and destroy them. Therapeutically, immunotherapy antibodies can increase the virulence of the immune system by increasing T-cell cytotoxicity targeted toward neoantigens. Neoantigen vaccines act through antigen-presenting cells, such as dendritic cells, to activate patient-endogenous T cells that recognize vaccine-encoded mutations. Infusion of mutation-targeting T cells by adoptive cell therapy (ACT) directly increases the number and frequency of cytotoxic T cells recognizing and killing tumor cells. At the same time, publicly-funded consortia have profiled tumor genomes across many indications, identifying mutations in each tumor. For example, we find basal and HER2 positive tumors contain more mutated proteins and more TP53 mutations than luminal A/B breast tumors. HPV negative tumors have more mutated proteins than HPV positive head and neck tumors and in agreement with the hypothesis that HPV activity interferes with p53 activity, only 14% of the HPV positive mutations have TP53 mutations vs. 86% of the HPV negative tumors. Lung adenocarcinomas in smokers have over four times more mutated proteins relative to those in never smokers (median 248 vs. 61, respectively). With an eye toward immunotherapy applications, we review the spectrum of mutations in multiple indications, show variations in indication sub-types, and examine intra- and inter-indication prevalence of re-occurring mutation neoantigens that could be used for warehouse vaccines and ACT.

Selective FcγR Co-engagement on APCs Modulates the Activity of Therapeutic Antibodies Targeting T Cell Antigens.

The co-engagement of fragment crystallizable (Fc) gamma receptors (FcγRs) with the Fc region of recombinant immunoglobulin monoclonal antibodies (mAbs) and its contribution to therapeutic activity has been extensively studied. For example, Fc-FcγR interactions have been shown to be important for mAb-directed effector cell activities, as well as mAb-dependent forward signaling into target cells via receptor clustering. Here we identify a function of mAbs targeting T cell-expressed antigens that involves FcγR co-engagement on antigen-presenting cells (APCs). In the case of mAbs targeting CTLA-4 and TIGIT, the interaction with FcγR on APCs enhanced antigen-specific T cell responses and tumoricidal activity. This mechanism extended to an anti-CD45RB mAb, which led to FcγR-dependent regulatory T cell expansion in mice.

Toxicological and pharmacological assessment of AGEN1884, a novel human IgG1 anti-CTLA-4 antibody.

CTLA-4 and CD28 exemplify a co-inhibitory and co-stimulatory signaling axis that dynamically sculpts the interaction of antigen-specific T cells with antigen-presenting cells. Anti-CTLA-4 antibodies enhance tumor-specific immunity through a variety of mechanisms including: blockade of CD80 or CD86 binding to CTLA-4, repressing regulatory T cell function and selective elimination of intratumoral regulatory T cells via an Fcγ receptor-dependent mechanism. AGEN1884 is a novel IgG1 antibody targeting CTLA-4. It potently enhanced antigen-specific T cell responsiveness that could be potentiated in combination with other immunomodulatory antibodies. AGEN1884 was well-tolerated in non-human primates and enhanced vaccine-mediated antigen-specific immunity. AGEN1884 combined effectively with PD-1 blockade to elicit a T cell proliferative response in the periphery. Interestingly, an IgG2 variant of AGEN1884 revealed distinct functional differences that may have implications for optimal dosing regimens in patients. Taken together, the pharmacological properties of AGEN1884 support its clinical investigation as a single therapeutic and combination agent.

Vitamin D is associated with cognitive function in elders receiving home health services.

BACKGROUND: The objective of this study was to examine the association between 25-hydroxyvitamin D, 25(OH)D, and cognitive function. METHODS: A cross-sectional investigation of 25(OH)D and cognition was completed in 377 black and 703 non-black (mainly Caucasian) elders (65-99 years) participating in the nutrition and memory in elders study. Participants underwent a comprehensive neuropsychological battery, and 25(OH)D concentrations were obtained. RESULTS: More than 65% of elders had suboptimal 25(OH)D concentrations (< or =20 ng/mL or < or =50 nmol/L). Approximately 18% were deficient in 25(OH)D (<10 ng/mL or <25 nmol/L). After adjusting for age, sex, race, body mass index, education, center, kidney function, seasonality, physical activity, and alcohol use, 25(OH)D was associated with better performance on trails A (beta = -0.49, p < .03), trails B (beta = -0.73, p < .02), digit symbol (beta = 0.19, p < .001), matrix reasoning (beta = 0.04, p < .02), and block design (beta = 0.07, p < .04) tests. Associations remained after adjustment for homocysteine, apoE4 allele, plasma B vitamins, and multivitamin use (y/n). 25(OH)D concentrations >20 ng/mL were associated with better performance on tests of executive function, including trails A (80.5 vs 95, p < .05), trails B (205s vs 226s, p < .05), matrix reasoning (7.8 vs 7.0, p = .03), and digit symbol (31.5 vs 37, p < .01). There were no associations between 25(OH)D and memory tests. Factor analysis yielded factors for memory, executive function, and attention/processing speed. After adjustment, 25(OH)D was associated with the executive function (beta = 0.01, p < 0.01) and attention/processing speed factors (beta = 0.01, p = .03), but not the memory factor (beta = -0.001, p = 0.65). CONCLUSIONS: 25(OH)D was positively associated with cognitive performance, particularly with measures of executive function in this elderly population.

Vitamin D and neurocognitive dysfunction: preventing "D"ecline?

A preponderance of evidence supports a role for vitamin D beyond the classical function in mineral homeostasis. Epidemiologic investigations have revealed a beneficial role of vitamin D in muscle function, cardiovascular health, diabetes, and cancer prevention. More recently, studies have suggested a potential beneficial role of vitamin D in cognitive function. Vitamin D exhibits functional attributes that may prove neuroprotective through antioxidative mechanisms, neuronal calcium regulation, immunomodulation, enhanced nerve conduction and detoxification mechanisms. Compelling evidence supports a beneficial role for the active form of vitamin D in the developing brain as well as in adult brain function. The vitamin D receptor and biosynthetic and degradative pathways for the hydroxylation of vitamin D have been found in the rodent brain; more recently these findings have been confirmed in humans. The vitamin D receptor and catalytic enzymes are colocalized in the areas of the brain involved in complex planning, processing, and the formation of new memories. These findings potentially implicate vitamin D in neurocognitive function.

The homocysteine hypothesis of depression.

High levels of homocysteine are associated with cerebrovascular disease, monoamine neurotransmitters, and depression of mood. A plausible hypothesis for these associations is that high homocysteine levels cause cerebral vascular disease and neurotransmitter deficiency, which cause depression of mood. The homocysteine depression hypothesis, if true, would mandate inclusions of imaging studies for cerebrovascular disease and measures of homocysteine, folate, and B12 and B6 vitamins in the clinical evaluation of older depressed patients. Longitudinal studies and clinical trials should be designed to challenge the hypothesis.

Poor iron status is more prevalent in Hispanic than in non-Hispanic white older adults in Massachusetts.

Iron status and dietary correlates of iron status have not been well described in Hispanic older adults of Caribbean origin. The aim of this study was to evaluate iron status and describe dietary components and correlates of iron status in Hispanic older adults and in a neighborhood-based comparison group of non-Hispanic white older adults. Six hundred four Hispanic and non-Hispanic white adults (59-91 y of age) from the Massachusetts Hispanic Elders Study were included in the analysis. We examined physiological markers of iron status as well as dietary factors in relation to iron status. Dietary intake was assessed by FFQ. Our results revealed that Hispanics had significantly lower geometric mean serum ferritin (74.1 microg/L vs. 100 microg/L; P<0.001), lower hemoglobin concentrations (137+/-13 vs. 140+/-12 g/L; P<0.01), higher prevalence of anemia (11.5 vs. 7.3%; P<0.05), and suboptimal hemoglobin concentrations (<125 g/L) for this age group (21.4 vs. 13.3%; P<0.05). Iron deficiency anemia was higher (7.2% vs. 2.3%; P<0.05) in Hispanic women. Hispanics had lower mean intakes of total iron, vitamin C, supplemental vitamin C, and total calcium than did non-Hispanic whites. After adjusting for age, sex, BMI, alcohol use, smoking, total energy intake, inflammation, diabetes, and liver disease, intake of heme iron from red meat was positively associated and dietary calcium was negatively associated with serum ferritin. This population of Hispanic older adults was significantly more likely than their non-Hispanic white neighbors to suffer from anemia and poor iron status, particularly among women. Cultural variation in dietary patterns may influence iron availability and body iron stores and contribute to an increased risk for iron deficiency anemia among some Hispanic older adults.

The Nutrition, Aging, and Memory in Elders (NAME) study: design and methods for a study of micronutrients and cognitive function in a homebound elderly population.

BACKGROUND: Micronutrient status can affect cognitive function in the elderly; however, there is much to learn about the precise effects. Understanding mediating factors by which micronutrient status affects cognitive function would contribute to elders' quality of life and their ability to remain in the home. OBJECTIVES: The Nutrition, Aging, and Memory in Elders (NAME) Study is designed to advance the current level of knowledge by investigating potential mediating factors by which micronutrient status contributes to cognitive impairment and central nervous system abnormalities in the elderly. NAME targets homebound elders because they are understudied and particularly at risk for poor nutritional status. METHODS: Subjects are community-based elders aged 60 and older, recruited through area Aging Services Access Points. The NAME core data include demographics; neuropsychological testing and activities of daily living measures; food frequency, health and behavioral questionnaires; anthropometrics; gene status; plasma micronutrients, homocysteine, and other blood determinants. A neurological examination, psychiatric examination, and brain MRI and volumetric measurements are obtained from a sub-sample. RESULTS: Preliminary data from first 300 subjects are reported. These data show that the NAME protocol is feasible and that the enrolled subjects are racially diverse, at-risk, and had similar basic demographics to the population from which they were drawn. CONCLUSION: The goal of the NAME study is to evaluate novel relationships between nutritional factors and cognitive impairment. These data may provide important information on potential new therapeutic strategies and supplementation standards for the elderly to maintain cognitive function and potentially reduce the public health costs of dementia.

Executive dysfunction in homebound older people with diabetes mellitus.

OBJECTIVES: To describe patterns of cognitive deficits and activities of daily living (ADLs) in older people with diabetes mellitus. DESIGN: Cross-sectional, population-based study. SETTING: Three homecare agency areas in Boston, Massachusetts. PARTICIPANTS: Two hundred ninety-one homebound people aged 60 and older; 40% with diabetes mellitus. MEASUREMENTS: Demographic data; evidence of diabetes mellitus and other diseases; Mini-Mental State Examination and tests of memory and executive function; ADLs. RESULTS: Executive and visuospatial functions were more impaired in individuals with diabetes mellitus than in those without, as assessed using Block Design (mean score+/-standard deviation 17.1+/-8.6 vs 20.5+/-9.6, P=.003) and Trails B (median seconds to accomplish the task: 255 vs 201, P=.03). For memory, word retention score was lower in those with diabetes mellitus than without (39.1+/-28.9 vs 48.0+/-29.7, P=.01), but the other memory tests did not show a difference between these two subgroups. More individuals with diabetes mellitus suffered from depressive symptoms than those without (55% vs 42%, P=.03). The ADL scores of those with diabetes mellitus were higher than those without. CONCLUSION: The pattern of cognitive deficits in people with diabetes mellitus suggests frontal-subcortical dysfunction, as seen in microvascular disease of the brain. The impairment in ADLs may be associated with this executive dysfunction, which cerebral microvascular disease in diabetes mellitus may cause.