Novel small molecules inhibit proteotoxicity and inflammation: Mechanistic and therapeutic implications for Alzheimer's Disease, healthspan and lifespan- Aging as a consequence of glycolysis.

Inflammation drives many age-related, especially neurological, diseases, and likely mediates age-related proteotoxicity. For example, dementia due to Alzheimer's Disease (AD), cerebral vascular disease, many other neurodegenerative conditions is increasingly among the most devastating burdens on the American (and world) health system and threatens to bankrupt the American health system as the population ages unless effective treatments are developed. Dementia due to either AD or cerebral vascular disease, and plausibly many other neurodegenerative and even psychiatric conditions, is driven by increased age-related inflammation, which in turn appears to mediate Abeta and related proteotoxic processes. The functional significance of inflammation during aging is also supported by the fact that Humira, which is simply an antibody to the pro-inflammatory cytokine TNF-a, is the best-selling drug in the world by revenue. These observations led us to develop parallel high-throughput screens to discover small molecules which inhibit age-related Abeta proteotoxicity in a C. elegans model of AD AND LPS-induced microglial TNF-a. In the initial screen of 2560 compounds (Microsource Spectrum library) to delay Abeta proteotoxicity, the most protective compounds were, in order, phenylbutyrate, methicillin, and quetiapine, which belong to drug classes (HDAC inhibitors, beta lactam antibiotics, and tricyclic antipsychotics, respectably) already robustly implicated as promising to protect in neurodegenerative diseases, especially AD. RNAi and chemical screens indicated that the protective effects of HDAC inhibitors to reduce Abeta proteotoxicity are mediated by inhibition of HDAC2, also implicated in human AD, dependent on the HAT Creb binding protein (Cbp), which is also required for the protective effects of both dietary restriction and the daf-2 mutation (inactivation of IGF-1 signaling) during aging. In addition to methicillin, several other beta lactam antibiotics also delayed Abeta proteotoxicity and reduced microglial TNF-a. In addition to quetiapine, several other tricyclic antipsychotic drugs also delayed age-related Abeta proteotoxicity and increased microglial TNF-a, leading to the synthesis of a novel congener, GM310, which delays Abeta as well as Huntingtin proteotoxicity, inhibits LPS-induced mouse and human microglial and monocyte TNF-a, is highly concentrated in brain after oral delivery with no apparent toxicity, increases lifespan, and produces molecular responses highly similar to those produced by dietary restriction, including induction of Cbp inhibition of inhibitors of Cbp, and genes promoting a shift away from glycolysis and toward metabolism of alternate (e.g., lipid) substrates. GM310, as well as FDA-approved tricyclic congeners, prevented functional impairments and associated increase in TNF-a in a mouse model of stroke. Robust reduction of glycolysis by GM310 was functionally corroborated by flux analysis, and the glycolytic inhibitor 2-DG inhibited microglial TNF-a and other markers of inflammation, delayed Abeta proteotoxicity, and increased lifespan. These results support the value of phenotypic screens to discover drugs to treat age-related, especially neurological and even psychiatric diseases, including AD and stroke, and to clarify novel mechanisms driving neurodegeneration (e.g., increased microglial glycolysis drives neuroinflammation and subsequent neurotoxicity) suggesting novel treatments (selective inhibitors of microglial glycolysis).

Combined Presentation of Acute Confusion and Severe Pancytopenia in Vitamin B12 Deficiency.

Vitamin B12 deficiency is more prevalent in the elderly and can develop as a result of malnutrition, malabsorption, chronic alcoholism, and chronic use of common medications (e.g. metformin, PPI, methotrexate) along with other causes. A wide spectrum of hematological and neuropsychiatric manifestations exist with the most common being Megaloblastic anemia and subacute combined degeneration, respectively. The mechanisms leading to the manifestations specific to these two organ systems are thought to be different. The severity of neuropsychiatric presentation is reported to be inversely proportional to that of hematological presentation, thus making it uncommon for both to be readily apparent simultaneously. Regardless of the severity of the clinical presentation, a good response to vitamin B12 replacement therapy is reported despite the lack of guidelines regarding dosing, frequency, or duration of treatment needed to note improvement in manifestations. The aim of this report is to increase the provider's knowledge that a severe combined hematological and neuropsychiatry manifestation can co-exist and report the management used for recovery.

Statin-Induced Anti-3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase (Anti-HMGCR) Myopathy.

Statins are known to pharmacologically target 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). Several subtypes of anti-HMGCR autoimmune myopathies have been reported as a result of statin use. Although these types vary widely, a severe and rare form of statin-induced myopathy is immune-mediated necrotizing myopathy (IMNM), resulting in severe muscle injury that does not respond to statin cessation and is associated with poor outcomes. Diagnosis is confirmed through biopsy confirming the necrosis of biopsy fibers, in addition to elevated anti-HMGCR serum levels. Management lacks proper guidelines, however, immunosuppressive therapy has been proposed as a possible intervention. The aim of this report is to increase providers' knowledge of the presentation and possible treatment of statin-induced immune-mediated necrotizing myopathy.

Optimizing Discharge Summaries: A Multispecialty, Multicenter Survey of Primary Care Clinicians.

BACKGROUND: Patient care in the United States has become increasingly more fragmented, and the discharge summary serves as a critical tool for transmitting information on a patient's hospital admission to the primary care clinician. Some guidelines regarding how to write discharge summaries exist, but few are focused on prioritizing content that is most important to optimize a patient's transition of care. METHODS: We conducted a national survey across various medical primary care specialties, including trainees and advanced practice providers, to understand the priorities of primary care clinicians. We distributed the survey to 2184 clinicians affiliated with 8 large academic institutions. Our response rate was 21%. RESULTS: Hospital course, discharge diagnoses, medication reconciliation, and follow-up sections were ranked as the most important categories with a 95.5% concordance rate among surveyed institutions. The least important sections were contact numbers for inpatient clinicians, ancillary services, weight-bearing status, and wound care. Similar themes were also identified via consensus review of the free-texted comments, adding that discharge summary style was also important. Other identified barriers to high-quality transition of care are both the limited time primary care clinicians can spend reviewing discharge summaries and lack of adequate communication between hospitalists and the outpatient clinician. CONCLUSIONS: High-yield content should be presented at the beginning of the discharge summary and conveyed in a brief, succinct manner to ensure maximal utility of the document as a transition of care tool.

Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study.

BACKGROUND: A subset of patients with COVID-19 develops a hyperinflammatory syndrome that has similarities with other hyperinflammatory disorders. However, clinical criteria specifically to define COVID-19-associated hyperinflammatory syndrome (cHIS) have not been established. We aimed to develop and validate diagnostic criteria for cHIS in a cohort of inpatients with COVID-19. METHODS: We searched for clinical research articles published between Jan 1, 1990, and Aug 20, 2020, on features and diagnostic criteria for secondary haemophagocytic lymphohistiocytosis, macrophage activation syndrome, macrophage activation-like syndrome of sepsis, cytokine release syndrome, and COVID-19. We compared published clinical data for COVID-19 with clinical features of other hyperinflammatory or cytokine storm syndromes. Based on a framework of conserved clinical characteristics, we developed a six-criterion additive scale for cHIS: fever, macrophage activation (hyperferritinaemia), haematological dysfunction (neutrophil to lymphocyte ratio), hepatic injury (lactate dehydrogenase or asparate aminotransferase), coagulopathy (D-dimer), and cytokinaemia (C-reactive protein, interleukin-6, or triglycerides). We then validated the association of the cHIS scale with in-hospital mortality and need for mechanical ventilation in consecutive patients in the Intermountain Prospective Observational COVID-19 (IPOC) registry who were admitted to hospital with PCR-confirmed COVID-19. We used a multistate model to estimate the temporal implications of cHIS. FINDINGS: We included 299 patients admitted to hospital with COVID-19 between March 13 and May 5, 2020, in analyses. Unadjusted discrimination of the maximum daily cHIS score was 0·81 (95% CI 0·74-0·88) for in-hospital mortality and 0·92 (0·88-0·96) for mechanical ventilation; these results remained significant in multivariable analysis (odds ratio 1·6 [95% CI 1·2-2·1], p=0·0020, for mortality and 4·3 [3·0-6·0], p<0·0001, for mechanical ventilation). 161 (54%) of 299 patients met two or more cHIS criteria during their hospital admission; these patients had higher risk of mortality than patients with a score of less than 2 (24 [15%] of 138 vs one [1%] of 161) and for mechanical ventilation (73 [45%] vs three [2%]). In the multistate model, using daily cHIS score as a time-dependent variable, the cHIS hazard ratio for worsening from low to moderate oxygen requirement was 1·4 (95% CI 1·2-1·6), from moderate oxygen to high-flow oxygen 2·2 (1·1-4·4), and to mechanical ventilation 4·0 (1·9-8·2). INTERPRETATION: We proposed and validated criteria for hyperinflammation in COVID-19. This hyperinflammatory state, cHIS, is commonly associated with progression to mechanical ventilation and death. External validation is needed. The cHIS scale might be helpful in defining target populations for trials and immunomodulatory therapies. FUNDING: Intermountain Research and Medical Foundation.

Measuring nonequilibrium vesicle dynamics in neurons under tension.

Vesicle transport in neurons is a highly complex nonequilibrium process. Their subcellular environment is undergoing constant fluctuations from thermal energy and molecular motors. Vesicle transport is an interplay between random motion (passive) and directed motion (active) driven by molecular motors along cytoskeletal filaments. It has been shown that growth, guidance, and vesicle dynamics of neurons is affected by mechanical tension. Here we present a method to analyze vesicle transport via a temporal Mean Square Displacement (tMSD) analysis while applying mechanical strain to neurons. The tMSD analysis allows characterization of active and passive vesicle motion as well as many other parameters including: power law scaling, velocity, direction, and flux. Our results suggest: (1) The tMSD analysis is able to capture vesicle motion alternating between passive and active states, and indicates that vesicle motion in Aplysia neurons is primarily passive (exhibiting active motion for ~8% of the time). (2) Under mechanical stretch (increased neurite tension), active transport of vesicles increases to ~13%, while vesicle velocity remains unchanged. (3) Upon unstretching (decreased tension), the level of active transport returns to normal but vesicle velocity decreases. These results suggest that vesicle transport in neurons is highly sensitive to mechanical stimulation. Our method allows precise characterization of vesicle dynamics in response to applied mechanical strain.

Using support vector machines to optimally classify rotator cuff strength data and quantify post-operative strength in rotator cuff tear patients.

Shoulder strength data are important for post-operative assessment of shoulder function and have been used in diagnosis of rotator cuff pathology. Support vector machines (SVM) employ complex analysis techniques to solve classification and regression problems. A SVM, a machine learning technique, can be used for analysis and classification of shoulder strength data. The goals of this study were to determine the diagnostic competency of SVM based on shoulder strength data and to apply SVM analysis in efforts to derive a single representative shoulder strength score. Data were taken from fourteen isometric shoulder strength measurements of each shoulder (involved and uninvolved) in 45 rotator cuff tear patients. SVM diagnostic proficiency was found to be comparable to reported ultrasound values. Improvement of shoulder function was accurately represented by a single score in pairwise comparison of the pre-operative and the 12 month post-operative group (P < 0.004). Thus, the SVM-based score may be a promising metric for summarizing rotator cuff strength data.