The role of low-carbohydrate diets in the intensive care unit.

Low-carbohydrate, high-fat (LCHF) nutrition therapy is characterized by carbohydrates comprising <26% of the daily caloric intake and a higher proportion of fat. LCHF therapies reduce exogenous glucose load, improve glycemic control, decrease inflammation, and improve clinical outcomes such as respiratory function. Given the altered metabolism in critically ill patients, LCHF nutrition therapy may be especially beneficial as it enables the conservation of protein and glucose for metabolic roles beyond energy use. In critical illness, LCHF diets have the potential to reduce hyperglycemia, improve ventilation, decrease hospital length of stay and reduce hospital costs. The purpose of this commentary piece is to describe LCHF nutrition therapy, summarize its impact on health outcomes, and discuss its role in the intensive care unit (ICU). Additional research on the effects of LCHF nutrition therapy on critically ill patients is warranted, including a focus on COVID-19.

Selective inhibition of TGFß1 activation overcomes primary resistance to checkpoint blockade therapy by altering tumor immune landscape.

Despite breakthroughs achieved with cancer checkpoint blockade therapy (CBT), many patients do not respond to anti-programmed cell death-1 (PD-1) due to primary or acquired resistance. Human tumor profiling and preclinical studies in tumor models have recently uncovered transforming growth factor-ß (TGFß) signaling activity as a potential point of intervention to overcome primary resistance to CBT. However, the development of therapies targeting TGFß signaling has been hindered by dose-limiting cardiotoxicities, possibly due to nonselective inhibition of multiple TGFß isoforms. Analysis of mRNA expression data from The Cancer Genome Atlas revealed that TGFΒ1 is the most prevalent TGFß isoform expressed in many types of human tumors, suggesting that TGFß1 may be a key contributor to primary CBT resistance. To test whether selective TGFß1 inhibition is sufficient to overcome CBT resistance, we generated a high-affinity, fully human antibody, SRK-181, that selectively binds to latent TGFß1 and inhibits its activation. Coadministration of SRK-181-mIgG1 and an anti-PD-1 antibody in mice harboring syngeneic tumors refractory to anti-PD-1 treatment induced profound antitumor responses and survival benefit. Specific targeting of TGFß1 was also effective in tumors expressing more than one TGFß isoform. Combined SRK-181-mIgG1 and anti-PD-1 treatment resulted in increased intratumoral CD8+ T cells and decreased immunosuppressive myeloid cells. No cardiac valvulopathy was observed in a 4-week rat toxicology study with SRK-181, suggesting that selectively blocking TGFß1 activation may avoid dose-limiting toxicities previously observed with pan-TGFß inhibitors. These results establish a rationale for exploring selective TGFß1 inhibition to overcome primary resistance to CBT.

Recombinant factor VIII Fc fusion protein drives regulatory macrophage polarization.

The main complication of replacement therapy with factor in hemophilia A (HemA) is the formation of inhibitors (neutralizing anti-factor VIII [FVIII] antibodies) in ∼30% of severe HemA patients. Because these inhibitors render replacement FVIII treatment essentially ineffective, preventing or eliminating them is of top priority in disease management. The extended half-life recombinant FVIII Fc fusion protein (rFVIIIFc) is an approved therapy for HemA patients. In addition, it has been reported that rFVIIIFc may induce tolerance to FVIII more readily than FVIII alone in HemA patients that have developed inhibitors. Given that the immunoglobulin G1 Fc region has the potential to interact with immune cells expressing Fc receptors (FcRs) and thereby affect the immune response to rFVIII, we investigated how human macrophages, expressing both FcRs and receptors reported to bind FVIII, respond to rFVIIIFc. We show herein that rFVIIIFc, but not rFVIII, uniquely skews macrophages toward an alternatively activated regulatory phenotype. rFVIIIFc initiates signaling events that result in morphological changes, as well as a specific gene expression and metabolic profile that is characteristic of the regulatory type Mox/M2-like macrophages. Further, these changes are dependent on rFVIIIFc-FcR interactions. Our findings elucidate mechanisms of potential immunomodulatory properties of rFVIIIFc.

Hearing Care Intervention for Persons with Dementia: A Pilot Study.

OBJECTIVE: Hearing loss is a commonly unmet need among adults with dementia that may exacerbate common dementia-related behavioral symptoms. Accessing traditional audiology services for hearing loss is a challenge because of high cost and time commitment. To improve accessibility and affordability of hearing treatment for persons with dementia, there is a need for unique service delivery models. The purpose of this study is to test a novel hearing intervention for persons with dementia and family caregivers delivered in outpatient settings. METHODS: The Memory-HEARS pilot study delivered a 2-hour in-person intervention in an outpatient setting. A trained interventionist provided hearing screening, communication strategies, and provision of and instruction using a simple over-the-counter amplification device. Caregivers (N = 20) responded to questionnaires related to depression, neuropsychiatric symptoms, and caregiver burden at baseline and 1-month postintervention. RESULTS: Overall, caregivers believed the intervention was beneficial, and most participants with dementia wore the amplification device daily. For the depression and neuropsychiatric outcome measures, participants with high symptom burden at baseline showed improvement at 1-month postintervention. The intervention had no effect on caregiver burden. Qualitative responses from caregivers described improved engagement for their loved ones, such as laughing more, telling more stories, asking more questions, and having more patience. CONCLUSION: The Memory-HEARS intervention is a low-cost, low-risk, nonpharmacologic approach to addressing hearing loss and behavioral symptoms in patients with dementia. Improved communication has the potential to reduce symptom burden and improve quality of life.

Age-related hearing loss in older adults with cognitive impairment.

BACKGROUND: Hearing loss can impair effective communication between caregivers and individuals with cognitive impairment. However, hearing loss is not often measured or addressed in care plans for these individuals. The aim of this study is to measure the prevalence of hearing loss and the utilization of hearing aids in a sample of individuals with cognitive impairment in a tertiary care memory clinic. METHODS: A retrospective review of 133 charts of individuals >50 years who underwent hearing assessment at a tertiary care memory clinic over a 12-month period (June 2014-June 2015) was undertaken. Using descriptive statistics, the prevalence of hearing loss was determined and associations with demographic variables, relevant medical history, cognitive status, and hearing aid utilization were investigated. RESULTS: Results indicate that hearing loss is highly prevalent among this sample of cognitively impaired older adults. Sixty percent of the sample had at least a mild hearing loss in the better hearing ear. Among variables examined, age, MMSE, and medical history of diabetes were strongly associated with hearing impairment. Hearing aid utilization increased in concordance with severity of hearing loss, from 9% to 54% of individuals with a mild or moderate/severe hearing loss, respectively. CONCLUSIONS: Hearing loss is highly prevalent among older adults with cognitive impairment. Despite high prevalence of hearing loss, hearing aid utilization remains low. Our study highlights the importance of hearing evaluation and rehabilitation as part of the cognitive assessment and care management plan in this vulnerable population.

Elucidating the interplay between IgG-Fc valency and FcγR activation for the design of immune complex inhibitors.

Autoantibody immune complex (IC) activation of Fcγ receptors (FcγRs) is a common pathogenic hallmark of multiple autoimmune diseases. Given that the IC structural features that elicit FcγR activation are poorly understood and the FcγR system is highly complex, few therapeutics can directly block these processes without inadvertently activating the FcγR system. To address these issues, the structure activity relationships of an engineered panel of multivalent Fc constructs were evaluated using sensitive FcγR binding and signaling cellular assays. These studies identified an Fc valency with avid binding to FcγRs but without activation of immune cell effector functions. These observations directed the design of a potent trivalent immunoglobulin G-Fc molecule that broadly inhibited IC-driven processes in a variety of immune cells expressing FcγRs. The Fc trimer, Fc3Y, was highly efficacious in three different animal models of autoimmune diseases. This recombinant molecule may represent an effective therapeutic candidate for FcγR-mediated autoimmune diseases.

Impaired gastrointestinal transit and its associated morbidity in the intensive care unit.

PURPOSE: To determine the proportion of critically ill adults developing impaired gastrointestinal transit (IGT) using a clinically pragmatic definition, its associated morbidity and risk factors. MATERIALS AND METHODS: Critically ill adult patients receiving enteral nutrition for ≥ 72 hours and mechanically ventilated for ≥ 48 hours were prospectively identified. IGT was defined as absence of a bowel movement for ≥ 3 days, treatment for constipation, and one of the following: (1) radiologic confirmed ileus, (2) feed intolerance, (3) abdominal distention, or (4) gastric decompression. RESULTS: One thousand patients were screened, and 248 were included for analysis. Fifty patients (20.1%; 95% confidence interval, 15.1-25.6%) developed IGT persisting for 6.5 ± 2.5 days. Patients with IGT had longer lengths of intensive care unit stay and were less likely to reach nutrition targets compared to patients without IGT or traditional definitions of constipation. Daily opioid use and pharmacological constipation prophylaxis were identified risk factors for IGT. CONCLUSION: Traditional definitions of constipation or ileus in intensive care unit patients are simplistic and lack clinical relevance. Pragmatically defined IGT is a common complication of critical illness and is associated with significant morbidity. Future interventional studies for IGT in critically ill adults should use a more clinically relevant definition and evaluate energy deficits and lengths of stay as clinically relevant outcomes.