Easing Suffering for ICU Patients and Their Families: Evidence and Opportunities for Primary and Specialty Palliative Care in the ICU.

Intensive care unit (ICU) admissions are often accompanied by many physical and existential pressure points that can be extraordinarily wearing on patients and their families and surrogate decision makers (SDMs). Multidisciplinary palliative support, including physicians, advanced practice nurses, nutritionists, chaplains and other team members, may alleviate many of these sources of potential suffering. However, the palliative needs of ICU patients undoubtedly exceed the bandwidth of current consultative specialty palliative medicine teams. Informed by standard-of-care palliative medicine domains, we review common ICU symptoms (pain, dyspnea and thirst) and their prevalence, sources and their treatment. We then identify palliative needs and impacts in the domains of communication, SDM support and transitions of care for patients and their families through their journey in the ICU, from discharge and recovery at home to chronic critical illness, post-ICU disability or death. Finally, we examine the evidence for strategies to incorporate specialty palliative medicine and palliative principles into ICU care for the improvement of patient- and family-centered care. While randomized controlled studies have failed to demonstrate measurable improvement in pre-determined outcomes for patient- and family-relevant outcomes, embracing the principles of palliative medicine and assuring their delivery in the ICU is likely to translate to overall improvement in humanistic, person-centered care that supports patients and their SDMs during and following critical illness.

Aging astrocytes metabolically support aging axon function by proficiently regulating astrocyte-neuron lactate shuttle.

The astrocyte-neuron lactate shuttle (ANLS) is an essential metabolic support system that uptakes glucose, stores it as glycogen in astrocytes, and provides glycogen-derived lactate for axonal function. Aging intrinsically increases the vulnerability of white matter (WM) to injury. Therefore, we investigated the regulation of this shuttle to understand vascular-glial metabolic coupling to support axonal function during aging in two different WM tracts. Aging astrocytes displayed larger cell bodies and thicker horizontal processes in contrast to thinner vertically oriented processes of young astrocytes. Aging axons recovered less following aglycemia in mouse optic nerves (MONs) compared to young axons, although providing lactate during aglycemia equally supported young and aging axonal function. Incubating MONs in high glucose to upregulate glycogen stores in astrocytes delayed loss of function during aglycemia and improved recovery in both young and aging axons. Providing lactate during recovery from aglycemia unmasked a metabolic switch from glucose to lactate in aging axons. Young and aging corpus callosum consisting of a mixture of myelinated and unmyelinated axons sustained their function fully when lactate was available during aglycemia and surprisingly showed a greater resilience to aglycemia compared to fully myelinated axons of optic nerve. We conclude that lactate is a universal substrate for axons independent of their myelination content and age.

Changes in Health-Related Quality of Life After Transient Ischemic Attack.

Importance: Numerous studies have found that patients diagnosed with TIA have decreased health-related quality of life, which has been interpreted as suggesting that patients with TIA have residual symptoms after the event. Studies assessing health status in the same patients before and after an event are lacking but may allow a direct determination of the association of TIA with postevent health status. Objective: To examine patient-reported health before transient ischemic attack (TIA) among individuals diagnosed with this event and evaluate change in patient-reported health after the event overall and by TIA characterization subgroups. Design, Setting, and Participants: This cohort study was conducted among 236 patients with a clinical diagnosis of TIA from October 2015 to December 2017 in a large US health system that collects a patient-reported outcome measure in ambulatory setting as part of routine care. Included patients had patient-reported global health scale assessments completed as part of routine care before and after a TIA event. Data were analyzed from March through July 2020. Main Outcomes and Measures: The main outcome was Patient-Reported Outcome Measurement Information System Global Health (PROMIS GH) scale score before and after TIA. A change of 5 or more points in this score is considered clinically relevant. The secondary outcomes included change in patient-reported global health by clinical impression of the probability of a TIA event, pattern of neurological deficits, and short-term risk of stroke, as assessed by the ABCD2 score. Results: Among 263 patients who experienced TIA, mean (SD) age was 67.9 (13.4) years and 138 (52.5%) were women. The median (interquartile range) time between patient-reported global health scores was 152 (94-284) days. Mean (SD) baseline patient-reported global physical health and mental health scale summary scores were 43.4 (8.2) and 47.7 (9.7), respectively, and were statistically significantly decreased compared with the general population mean (SD) scores of 50 (10; P < .001) for physical and mental health. The difference between physical health summary score among study participants and the general population was clinically relevant. Mean (SD) summary scores were not statistically significantly different after the event compared with before the event overall (physical health: 44.1 [8.2], for a mean [SE] improvement of 0.65 [0.38] points; P = .09; mental health: 47.4 [9.1], for a mean [SE] worsening of 0.25 [0.38] points; P = .51) or within subgroups. Conclusions and Relevance: These findings suggest that impaired health status among patients diagnosed with TIA reflect, at least in part, an impaired premorbid state of health. This study did not find that TIA events were associated with worsening of health status overall or within subgroups.

Bilateral Pulmonary Emboli and Deep Venous Thrombi in Association With Chronic Inflammatory Demyelinating Polyneuropathy.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune neurological disorder primarily affecting the peripheral nervous system. It is important to recognize because treatment with immunomodulators can improve symptoms. We present the case of a 61-year-old man who developed a saddle pulmonary embolus as well as right-sided deep venous thrombi following left knee arthroplasty. Two months later, he had persistent pre-syncopal symptoms with exertion and had developed paraesthesias in both feet. Invasive cardiopulmonary exercise testing revealed preload failure with no evidence of pulmonary hypertension. He was then referred to neurology where clinical history, physical examination, autonomic battery, and nerve biopsy were consistent with a diagnosis of CIDP with autonomic dysfunction. Extensive venous thromboembolism may be a unique presentation of CIDP. The mechanisms, which may lead to hypercoagulability in CIDP, include the presence of systemic inflammation and denervation of peripheral vasculature leading to stasis.

The role of genetic polymorphisms in executive functioning performance in temporal lobe epilepsy.

OBJECTIVE: To explore the role of several genetic polymorphisms (APOE ε4, BDNF Met, and COMT Val) in executive functioning performance in patients with pharmacoresistant temporal lobe epilepsy (TLE). METHODS: Ninety-three adults (51 female, mean age = 39 years) with TLE completed executive functioning measures as part of a comprehensive preoperative neuropsychological evaluation, including Trail Making Test (Part B), Wisconsin Card Sorting Test (Conceptual Level Responses and Perseverative Errors), Color Word Interference from the Delis Kaplan Executive Function System, and measures of phonemic and semantic verbal fluency. Genotyping of the APOE, BDNF, and COMT genes was conducted using DNA extracted from peripheral blood or brain tissue (from epilepsy surgery). RESULTS: After adjustment for general cognitive ability, COMT Val carriers showed poorer performance on semantic verbal fluency and color word interference than non-carriers, and BDNF Met carriers showed poorer performance on phonemic verbal fluency than those without a Met allele. SIGNIFICANCE: Results suggest that COMT and BDNF polymorphisms are associated with performance on several EF measures in patients with TLE, including tasks assessing verbal fluency and response inhibition and account for up to 16% of the variance in test performance. The APOE polymorphism was not significantly associated with any of the executive function measures analyzed.

Social Behaviors Associated With a Positive COVID-19 Test Result.

Objective To compare the social behaviors of individuals who were tested positive for COVID-19 relative to non-infected individuals.   Methods We sent COVID positive cases and age/gender-matched controls a survey regarding their social behaviors via MyChart (online patient portal). We called cases if they did not complete the electronic survey within two days. Data were collected from May to June 2020. Survey responses for cases without close contact and controls were compared using Pearson chi-square or Fisher's exact tests as appropriate.   Results A total of 339 participants completed the survey (113 cases, 226 controls); 45 (40%) cases had known contact with COVID-19. Cases were more likely to have recently traveled (4% vs. 0%, p = 0.01) or to work outside the home (40% vs. 25%, p = 0.02). There was no difference in the rates of attending private or public gatherings, mask/glove use, hand-washing, cleaning surfaces, and cleaning mail/groceries between cases and controls.   Conclusions Sixty percent of cases had no known contact with COVID-19, indicating ongoing community transmission and underlining the importance of contact tracing. The greater percentage of cases who work outside the home provides further evidence for social distancing and remote telework when possible.

Predicting mood decline following temporal lobe epilepsy surgery in adults.

OBJECTIVE: To develop a model to predict the probability of mood decline in adults following temporal lobe resection for the treatment of pharmacoresistant epilepsy. METHODS: Variable selection was performed on 492 patients from the Cleveland Clinic using best subsets regression. After completing variable selection, a subset of variables was requested from four epilepsy surgery centers across North America (n = 100). All data were combined to develop a final model to predict postoperative mood decline (N = 592). Internal validation with bootstrap resampling was performed. A clinically significant increase in depressive symptoms was defined as a 15% increase in Beck Depression Inventory-Second Edition score and a postoperative raw score > 11. RESULTS: Fourteen percent of patients in the Cleveland Clinic cohort and 22% of patients in the external cohort experienced clinically significant increases in depressive symptoms following surgery. The final prediction model included six predictor variables: psychiatric history, resection side, relationship status, verbal fluency score, age at preoperative testing, and presence/absence of malformation of cortical development on magnetic resonance imaging. The model had an optimism-adjusted c-statistic of .70 and good calibration, with slight probability overestimation in higher risk patients. SIGNIFICANCE: Clinicians can utilize our nomogram via a paper tool or online calculator to estimate the risk of postoperative mood decline for individual patients prior to temporal lobe epilepsy surgery.

Role of Brain Glycogen During Ischemia, Aging and Cell-to-Cell Interactions.

The astrocyte-neuron lactate transfer shuttle (ANLS) is one of the important metabolic systems that provides a physiological infrastructure for glia-neuronal interactions where specialized architectural organization supports the function. Perivascular astrocyte end-feet take up glucose via glucose transporter 1 to actively regulate glycogen stores, such that high ambient glucose upregulates glycogen and low levels of glucose deplete glycogen stores. A rapid breakdown of glycogen into lactate during increased neuronal activity or low glucose conditions becomes essential for maintaining axon function. However, it fails to benefit axon function during an ischemic episode in white matter (WM). Aging causes a remarkable change in astrocyte architecture characterized by thicker, larger processes oriented parallel to axons, as opposed to vertically-transposing processes. Subsequently, aging axons become more vulnerable to depleted glycogen, although aging axons can use lactate as efficiently as young axons. Lactate equally supports function during aglycemia in corpus callosum (CC), which consists of a mixture of myelinated and unmyelinated axons. Moreover, axon function in CC shows greater resilience to a lack of glucose compared to optic nerve, although both WM tracts show identical recovery after aglycemic injury. Interestingly, emerging evidence implies that a lactate transport system is not exclusive to astrocytes, as oligodendrocytes support the axons they myelinate, suggesting another metabolic coupling pathway in WM. Future studies are expected to unravel the details of oligodendrocyte-axon lactate metabolic coupling to establish that all WM components metabolically cooperate and that lactate may be the universal metabolite to sustain central nervous system function.

BDNF and COMT, but not APOE, alleles are associated with psychiatric symptoms in refractory epilepsy.

OBJECTIVE: The objective of this study was to determine whether three common genetic polymorphisms [apolipoprotein (APOE) ε4 (rs42938 and rs7412), brain derived neurotrophic factor (BDNF) Met (rs6265), and catechol-O-methyltransferase (COMT) Val (rs4680)] are associated with increased psychiatric symptomatology in individuals with pharmacoresistant epilepsy. METHODS: One hundred forty-eight adults (Mage = 38 years; 53% female) with refractory epilepsy completed self-report measures of mood, anxiety, and/or personality/psychopathology. Mann-Whitney U, t-tests, and Fisher's exact tests were used to determine if APOE4, BDNF Val66Met, or COMT Val158Met are associated with increased psychiatric symptomatology in people with epilepsy. RESULTS: As a group, BDNF Met carriers reported greater symptoms of depression on the Personality Assessment Inventory (PAI) than those without a Met allele (p = 0.004); COMT Val carriers reported greater symptoms on the PAI Schizophrenia (p = 0.007), Antisocial Features (p = 0.04), and Alcohol Problems (p = 0.03) scales than noncarriers. On the individual level, a significantly greater proportion of BDNF Met carriers demonstrated elevated PAI Depression scores compared to those without a Met allele (p = 0.046). There was also a larger proportion of COMT Val carriers with elevated PAI Anxiety scores as compared to those without a Val allele (p = 0.036). SIGNIFICANCE: This retrospective cross-sectional study provides preliminary evidence for a genetic basis of psychiatric comorbidities in epilepsy and suggests that BDNF and COMT may play an important role in the pathophysiology of mental health problems in this vulnerable population.

Suramin Inhibits Osteoarthritic Cartilage Degradation by Increasing Extracellular Levels of Chondroprotective Tissue Inhibitor of Metalloproteinases 3.

Osteoarthritis is a common degenerative joint disease for which no disease-modifying drugs are currently available. Attempts to treat the disease with small molecule inhibitors of the metalloproteinases that degrade the cartilage matrix have been hampered by a lack of specificity. We aimed to inhibit cartilage degradation by augmenting levels of the endogenous metalloproteinase inhibitor, tissue inhibitor of metalloproteinases (TIMP)-3, through blocking its interaction with the endocytic scavenger receptor, low-density lipoprotein receptor-related protein 1 (LRP1). We discovered that suramin (C51H40N6O23S6) bound to TIMP-3 with a KD value of 1.9 ± 0.2 nM and inhibited its endocytosis via LRP1, thus increasing extracellular levels of TIMP-3 and inhibiting cartilage degradation by the TIMP-3 target enzyme, adamalysin-like metalloproteinase with thrombospondin motifs 5. NF279 (8,8'-[carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)]bis-1,3,5-naphthalenetrisulfonic acid hexasodium salt), a structural analog of suramin, has an increased affinity for TIMP-3 and increased ability to inhibit TIMP-3 endocytosis and protect cartilage. Suramin is thus a promising scaffold for the development of novel therapeutics to increase TIMP-3 levels and inhibit cartilage degradation in osteoarthritis.

Engineered Tissue Inhibitor of Metalloproteinases-3 Variants Resistant to Endocytosis Have Prolonged Chondroprotective Activity.

Tissue inhibitor of metalloproteinases-3 (TIMP-3) is a central inhibitor of matrix-degrading and sheddase families of metalloproteinases. Extracellular levels of the inhibitor are regulated by the balance between its retention on the extracellular matrix and its endocytic clearance by the scavenger receptor low density lipoprotein receptor-related protein 1 (LRP1). Here, we used molecular modeling to predict TIMP-3 residues potentially involved in binding to LRP1 based on the proposed LRP1 binding motif of 2 lysine residues separated by about 21 Å and mutated the candidate lysine residues to alanine individually and in pairs. Of the 22 mutants generated, 13 displayed a reduced rate of uptake by HTB94 chondrosarcoma cells. The two mutants (TIMP-3 K26A/K45A and K42A/K110A) with lowest rates of uptake were further evaluated and found to display reduced binding to LRP1 and unaltered inhibitory activity against prototypic metalloproteinases. TIMP-3 K26A/K45A retained higher affinity for sulfated glycosaminoglycans than K42A/K110A and exhibited increased affinity for ADAMTS-5 in the presence of heparin. Both mutants inhibited metalloproteinase-mediated degradation of cartilage at lower concentrations and for longer than wild-type TIMP-3, indicating that their increased half-lives improved their ability to protect cartilage. These mutants may be useful in treating connective tissue diseases associated with increased metalloproteinase activity.

Crystal structure of the integral membrane diacylglycerol kinase.

Diacylglycerol kinase catalyses the ATP-dependent phosphorylation of diacylglycerol to phosphatidic acid for use in shuttling water-soluble components to membrane-derived oligosaccharide and lipopolysaccharide in the cell envelope of Gram-negative bacteria. For half a century, this 121-residue kinase has served as a model for investigating membrane protein enzymology, folding, assembly and stability. Here we present crystal structures for three functional forms of this unique and paradigmatic kinase, one of which is wild type. These reveal a homo-trimeric enzyme with three transmembrane helices and an amino-terminal amphiphilic helix per monomer. Bound lipid substrate and docked ATP identify the putative active site that is of the composite, shared site type. The crystal structures rationalize extensive biochemical and biophysical data on the enzyme. They are, however, at variance with a published solution NMR model in that domain swapping, a key feature of the solution form, is not observed in the crystal structures.