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The synucleinopathies Parkinson disease (PD), multiple system atrophy (MSA), and the Lewy body form of pure autonomic failure (PAF) entail intra‐cytoplasmic deposition of the protein alpha‐synuclein and pathogenic catecholaminergic neurodegeneration. Cerebrospinal fluid (CSF) levels of catecholamines and their metabolites are thought to provide a “neurochemical window” on central catecholaminergic innervation and can identify specific intra‐neuronal dysfunctions in synucleinopathies. We asked whether there are CSF concentration gradients for catechols such as 3,4‐dihydroxyphenylacetic acid (DOPAC), the main neuronal metabolite of dopamine, and if so whether the gradients influence neurochemical differences among synucleinopathies. In a retrospective cohort study, we reviewed data about concentrations of catechols in the first, sixth, and twelfth 1‐mL aliquots from 33 PD, 28 MSA, and 15 PAF patients and 41 controls. There were concentration gradients for DOPAC, dopamine, norepinephrine, and 3,4‐dihydroxyphenylglycol (the main neuronal metabolite of norepinephrine) and gradients in the opposite direction for 5‐S‐cysteinyldopa and 5‐S‐cysteinyldopamine. In all 3 aliquots, CSF DOPAC was low in PD and MSA compared with controls (p < 0.0001 each) and normal in PAF. Synucleinopathies differ in CSF catechols regardless of concentration gradients. Concentration gradients for 5‐S‐cysteinyl derivatives in opposite directions from the parent catechols may provide biomarkers of spontaneous oxidation in the CSF space. [ABSTRACT FROM AUTHOR]

Following on from the COVID-19 pandemic is another worldwide public health challenge that is referred to variously as long COVID, post-COVID syndrome or post-acute sequelae of SARS-CoV-2 infection (PASC). PASC comes in many forms and affects all body organs. This heterogeneous presentation suggests involvement of the autonomic nervous system (ANS), which has numerous roles in the maintenance of homeostasis and coordination of responses to various stressors. Thus far, studies of ANS dysregulation in people with PASC have been largely observational and descriptive, based on symptom inventories or objective but indirect measures of cardiovascular function, and have paid little attention to the adrenomedullary, hormonal and enteric nervous components of the ANS. Such investigations do not consider the syndromic nature of autonomic dysfunction. This Review provides an update on the literature relating to ANS abnormalities in people with post-COVID syndrome and presents a theoretical perspective on how the ANS might participate in common features of PASC. Autonomic nervous system dysregulation contributes to the chronic, debilitating disorders referred to as 'long COVID' or post-acute sequelae of SARS-CoV-2 infection (PASC). Here, Goldstein describes a multisystem, multidisciplinary approach to understanding PASC-induced alterations in feedback-regulated, plastic networks that determine homeostasis and allostasis. Key points: The diverse nature of post-COVID syndrome suggests involvement of the autonomic nervous system (ANS), which plays numerous roles in homeostasis and coordinates responses to essentially all stressors. The ANS concept was promulgated before the discoveries of neuroendocrine systems, immune and inflammatory systems, and the central autonomic network; the extended autonomic system theory is a necessary update. Publications on post-COVID dysautonomias have not considered the syndromic nature of autonomic dysfunctions. Such studies have been largely observational and descriptive, based on symptom inventories or objective but indirect cardiovascular measures; the hormonal and enteric components of the ANS have generally been ignored. Understanding of multisystem disorders of regulation, such as post-COVID syndrome, requires a shift towards consideration of the feedback-regulated, plastic networks that, via the extended autonomic system, determine homeostasis and allostasis. [ABSTRACT FROM AUTHOR]

BACKGROUND. In Lewy body diseases (LBDs) Parkinson disease (PD), and dementia with Lewy bodies (DLB), by the time parkinsonism or cognitive dysfunction manifests clinically, substantial neurodegeneration has already occurred. Biomarkers are needed to identify central LBDs in a preclinical phase, when neurorescue strategies might forestall symptomatic disease. This phase may involve catecholamine deficiency in the autonomic nervous system. We analyzed data from the prospective, observational, long-term PDRisk study to assess the predictive value of low versus normal cardiac 18F-dopamine positron emission tomography (PET), an index of myocardial content of the sympathetic neurotransmitter norepinephrine, in at-risk individuals. METHODS. Participants self-reported risk factor information (genetics, olfactory dysfunction, dream enactment behavior, and orthostatic intolerance or hypotension) at a protocol-specific website. Thirty-four with 3 or more confirmed risk factors underwent serial cardiac 18F-dopamine PET at 1.5-year intervals for up to 7.5 years or until PD was diagnosed. RESULTS. Nine participants had low initial myocardial 18F-dopamine-derived radioactivity (<6,000 nCi-kg/cc-mCi) and 25 had normal radioactivity. At 7 years of follow-up, 8 of 9 with low initial radioactivity and 1 of 11 with normal radioactivity were diagnosed with a central LBD (LBD+) (P = 0.0009 by Fisher's exact test). Conversely, all 9 LBD+ participants had low 18F-dopamine-derived radioactivity before or at the time of diagnosis of a central LBD, whereas among 25 participants without a central LBD only 1 (4%) had persistently low radioactivity (P < 0.0001 by Fisher's exact test). CONCLUSION. Cardiac 18F-dopamine PET highly efficiently distinguishes at-risk individuals who are diagnosed subsequently with a central LBD from those who are not. [ABSTRACT FROM AUTHOR]

Dysautonomias are conditions in which altered functions of one or more components of the autonomic nervous system (ANS) adversely affect health. This essay is about how elucidating mechanisms of dysautonomias may rationalize personalized treatments. Emphasized here are two relatively new ideas—the "extended" autonomic system (EAS) and the "homeostat" theory as applied to the pathophysiology and potential treatments of dysautonomias. The recently promulgated concept of the EAS updates Langley's ANS to include neuroendocrine, immune/inflammatory, and central components. The homeostat theory builds on Cannon's theory of homeostasis by proposing the existence of comparators (e.g., a thermostat, glucostat, carbistat, barostat) that receive information about regulated variables (e.g., core temperature, blood glucose, blood gases, delivery of blood to the brain). Homeostats sense discrepancies between the information and response algorithms. The presentation links the EAS with the homeostat theory to understand pathophysiological mechanisms of dysautonomias. Feed-forward anticipatory processes shift input–output curves and maintain plateau levels of regulated variables within different bounds of values—"allostasis". Sustained allostatic processes increase long-term wear-and-tear on effectors and organs—allostatic load. They decreaseing thresholds for destabilizing and potentially fatal positive feedback loops. The homeostat theory enables mathematical models that define stress, allostasis, and allostatic load. The present discussion applies the EAS and homeostat concepts to specific examples of pediatric, adolescent/adult, and geriatric dysautonomias—familial dysautonomia, chronic orthostatic intolerance, and Lewy body diseases. Computer modeling has the potential to take into account the complexity and dynamics of allostatic processes and may yield testable predictions about individualized treatments and outcomes. [ABSTRACT FROM AUTHOR]

Freeze tolerant animals survive the winter by tolerating the freezing and thawing of up to 70% of body water and the respective cessation and resumption of essential functions including circulation and respiration during each freeze‐thaw cycle. Cope's gray treefrog Dryophytes chrysoscelis is a freeze tolerant anuran that uses a system of cryoprotectants to prevent intracellular freezing and mitigate osmotic stress during freezing and thawing episodes. Morphological features were documented in D. chrysoscelis using a repeated freeze‐thaw protocol. Dorsal skin in frozen frogs was distinctly blue and green before reverting to brown during thawing. The dorsal color change in frozen frogs does not function similarly to other known color change events in amphibians. The return to brown skin color in thawing animals coincides with recovery of vital functions in freeze tolerant frogs, suggesting that dorsal color change is an indicator of postfreeze recovery in D. chrysoscelis. We also provide evidence of "freeze resistance" in D. chrysoscelis. Two individuals did not freeze following three successive bouts of ice inoculation at −2.5°C and maintained brown dorsal color despite ice crystallization on the dorsum and contact with frozen substrate. Both frogs had similar plasma osmolality, circulating cryoprotectants, and incidence of cryoinjury compared to frogs that were frozen and thawed once or three times. Freeze resistance may be explained by physical changes in the skin including lipid accumulation and dehydration. This integrative study presents novel attributes of organismal freeze tolerance in D. chrysoscelis. Research highlights: Dynamic blue and green dorsal coloration was observed in frozen and thawing frogs.Two frogs "resisted" freezing following ice inoculation at −2.5°C.These observations may represent novel attributes of freeze tolerance in Dryophytes chrysoscelis. [ABSTRACT FROM AUTHOR]

We describe a patient with neurogenic orthostatic hypotension (nOH) after brainstem neurosurgery in whom baroreflex-cardiovagal function was normal despite baroreflex-sympathoneural failure. We also cite other conditions entailing differential alterations in the two efferent limbs of the baroreflex. Any condition involving nOH from selective loss of sympathetic noradrenergic innervation, interference with sympathetic pre-ganglionic transmission in the thoracolumbar spinal cord, sympathectomies, or attenuated intra-neuronal synthesis, storage, or release of norepinephrine would be expected to manifest with selective baroreflex-sympathoneural dysfunction. We advise caution in relying on indices of baroreflex-cardiovagal function for diagnosing nOH, since normal values for these indices do not exclude nOH. [ABSTRACT FROM AUTHOR]

Purpose: In central Lewy body diseases (LBDs) such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB), by the time parkinsonism or cognitive dysfunction becomes manifest, substantial central neurodegeneration has already occurred. Cardiovascular autonomic biomarkers might detect preclinical central LBDs in at-risk individuals, enabling possibly effective disease-modifying treatment. Methods: In the prospective, longitudinal PDRisk study, 59 participants provided information about family history of PD, olfactory dysfunction, dream enactment behavior, and orthostatic intolerance or hypotension at a protocol-specific website and were screened as outpatients. Thirty-four had three or more confirmed risk factors and were followed until PD was diagnosed or up to 7.5 years. Dependent measures included assessments of baroreflex-sympathoneural function, via the blood pressure recovery time (PRT) after release of the Valsalva maneuver and baroreflex areas; and baroreflex-cardiovagal function, via heart rate variability in the time and frequency domains and Valsalva baroslopes. Data were compared from groups with or without a subsequent diagnosis of a central LBD (LBD+, N = 9; LBD−, N = 25) and PDRisk participants with fewer than three confirmed risk factors (PDRisk−, N = 25). Results: The LBD+ group had larger orthostatic falls in systolic blood pressure than did the LBD− and PDRisk− groups (p < 0.0001 each). The LBD+ group had increased PRTs (p = 0.0114 versus LBD−, p = 0.0094 versus PDRisk−) and baroreflex areas after the Valsalva maneuver (p = 0.0225 versus LBD−, p = 0.0028 versus PDRisk−), whereas the groups did not differ in indices of baroreflex-cardiovagal function. Conclusion: Orthostatic hypotension and baroreflex-sympathoneural dysfunction characterize at-risk individuals who go on to be diagnosed with a central LBD during longitudinal follow-up. [ABSTRACT FROM AUTHOR]

Background: Medicare-subsidised Team Care Arrangements (TCAs) support Australian general practitioners to implement shared care between collaborating health professionals for patients with chronic medical conditions and complex needs. We assessed the prevalence of TCAs, factors associated with TCA uptake and visits to TCA-subsidised allied health practitioners, for adults newly diagnosed with cancer in New South Wales, Australia. Methods: We carried out a retrospective individual patient data linkage study with 13 951 45 and Up Study participants diagnosed with incident cancer during 2006–16. We used a proportional hazards model to estimate the factors associated with receipt of a TCA after cancer diagnosis. Results: In total, 6630 patients had a TCA plan initiated (47.5%). A TCA was more likely for patients aged ≥65 years, those with higher service utilisation 4–15 months prior to cancer diagnosis, a higher number of comorbidities, lower self-rated overall health status, living in areas of greater socio-economic disadvantage, lower educational attainment and those with no private health insurance. A total of 4084 (61.6%) patients with a TCA had at least one TCA-subsidised allied health visit within 24 months of the TCA. Conclusions: TCAs appear to be well targeted at cancer patients with chronic health conditions and lower socioeconomic status. Nevertheless, not all patients with a TCA subsequently attended a TCA-subsidised allied healthcare professional. This suggests either a misunderstanding of the plan, the receipt of allied health via other public schemes, a low prioritisation of the plan compared to other health care, or suboptimal availability of these services. Medicare-subsidised Team Care Arrangements (TCAs), designed to coordinate care for people with long-term chronic or terminal conditions requiring treatment from a multidisciplinary team, have not been evaluated for adults newly diagnosed with cancer. Of those, 47.5% have a TCA initiated, but not all take up community-based TCA-subsidised allied health care. Prior poor health and lower socioeconomic status made TCAs more likely. TCAs appear well aligned with need. Apparent incomplete uptake of TCA-subsidised allied health services suggests suboptimal utilisation of this plan. Investigation of the healthcare trajectories of specific patient subgroups may help identify barriers. [ABSTRACT FROM AUTHOR]

Aim: There are many barriers to physical activity among cancer survivors. Survivors treated with neurotoxic chemotherapy may develop chemotherapy‐induced peripheral neuropathy (CIPN) and experience additional barriers related to sensorimotor and mobility deficits. This study examined physical activity behaviors, including physical activity predictors, among cancer survivors treated with neurotoxic chemotherapies. Methods: A cross‐sectional study of 252 participants, 3–24 months after neurotoxic chemotherapy, was undertaken. Physical activity was self‐reported (IPAQ). CIPN was self‐reported (FACT/GOG‐Ntx‐13), clinically graded (NCI‐CTCAE), and objectively measured using neurological grading scales and neurophysiological techniques (tibial and sural nerve conduction studies). Balance (Swaymeter) and fine motor skills (grooved pegboard) were assessed. Regression models were used to identify clinical, demographic and CIPN predictors of walking and moderate–vigorous physical activity. Results: Forty‐four percent of participants did not meet recommended physical activity guidelines (≥150 min/week). Sixty‐six percent presented with CIPN. Nineteen percent of participants with CIPN reported that symptoms interfered with their ability to be physically active. A lower proportion of survivors aged ≥60, with grade ≥1 CIPN or BMI ≥30, reported meeting physical activity guidelines (all p <.05). Regression models identified older age, higher BMI, and patient‐reported CIPN associated with lower walking, while higher BMI and females were associated with lower moderate–vigorous physical activity. Neurologically assessed CIPN did not associate with walking or moderate–vigorous physical activity. Conclusion: Cancer survivors exposed to neurotoxic chemotherapy have low physical activity levels. Further work should examine the factors causing physical activity limitations in this cohort and designing interventions to improve physical function and quality of life in survivors. [ABSTRACT FROM AUTHOR]

Purpose: Drug development strategies for genetic diseases depend critically on accurate knowledge of how pathogenic variants cause disease. For some well‐studied genes, the direct effects of pathogenic variants are well documented as loss‐of‐function, gain‐of‐function or hypermorphic, or a combination of the two. For many genes, however, even the direction of effect of variants remains unclear. Classification of Mendelian disease genes in terms of whether pathogenic variants are loss‐ or gain‐of‐function would directly inform drug development strategies. Methods: We leveraged the recent dramatic increase in reported pathogenic variants to provide a novel approach to inferring the direction of effect of pathogenic variants. Specifically, we quantify the ratio of reported pathogenic variants that are missense compared to loss‐of‐function. Results: We first show that for many genes that cause dominant Mendelian disease, the ratio of reported pathogenic missense variants is diagnostic of whether the gene causes disease through loss‐ or gain‐of‐function, or a combination. Second, we identify a set of genes that appear to cause disease largely or entirely through gain‐of‐function or hypermorphic pathogenic variants. Conclusions: We suggest a set of 16 genes suitable for drug developmental efforts utilizing direct inhibition. [ABSTRACT FROM AUTHOR]

Background: Genetic risk factors for chemotherapy-induced peripheral neuropathy (CIPN), a major dose-limiting side-effect of paclitaxel, are not well understood. Methods: We performed a genome-wide association study (GWAS) in 183 paclitaxel-treated patients to identify genetic loci associated with CIPN assessed via comprehensive neuropathy phenotyping tools (patient-reported, clinical and neurological grading scales). Bioinformatic analyses including pathway enrichment and polygenic risk score analysis were used to identify mechanistic pathways of interest. Results: In total, 77% of the cohort were classified with CIPN (n = 139), with moderate/severe neuropathy in 36%. GWAS was undertaken separately for the three measures of CIPN. GWAS of patient-reported CIPN identified 4 chromosomal regions that exceeded genome-wide significance (rs9846958, chromosome 3; rs117158921, chromosome 18; rs4560447, chromosome 4; rs200091415, chromosome 10). rs4560447 is located within a protein-coding gene, LIMCH1, associated with actin and neural development and expressed in the dorsal root ganglia (DRG). There were additional risk loci that exceeded the statistical threshold for suggestive genome-wide association (P < 1 × 10–5) for all measures. A polygenic risk score calculated from the top 46 ranked SNPs was highly correlated with patient-reported CIPN (r2 = 0.53; P = 1.54 × 10–35). Overlap analysis was performed to identify 3338 genes which were in common between the patient-reported CIPN, neurological grading scale and clinical grading scale GWAS. The common gene set was subsequently analysed for enrichment of gene ontology (GO) and Reactome pathways, identifying a number of pathways, including the axon development pathway (GO:0061564; P = 1.78 × 10–6) and neuronal system (R-HSA-112316; adjusted P = 3.33 × 10–7). Conclusions: Our findings highlight the potential role of axon development and regeneration pathways in paclitaxel-induced CIPN. [ABSTRACT FROM AUTHOR]

Purpose: 18F-Dopamine positron emission tomography is a validated method for identifying cardiac noradrenergic deficiency, a characteristic feature of Lewy body forms of neurogenic orthostatic hypotension; however, 18F-dopamine is a research drug. Brain 18F-DOPA positron emission tomography is FDA-approved. Since 18F-DOPA is converted to 18F-dopamine in the heart, 18F-DOPA might be useful for cardiac sympathetic neuroimaging. We compared 18F-DOPA with 18F-dopamine in patients who either had or did not have low 18F-dopamine-derived radioactivity. Methods: Brain and cardiac 18F-DOPA scanning and cardiac 18F-dopamine scanning were done on separate days in patient groups with neurogenic orthostatic hypotension or Parkinsonism or control subjects across a range of values for 18F-dopamine-derived radioactivity. The lower limit of normal for myocardial 18F-dopamine-derived radioactivity was 6000 Bq-kg/cc-MBq. We also examined inter-relationships among cardiac 18F-DOPA-derived radioactivity, cardiac 18F-dopamine-derived radioactivity, putamen/occipital cortex ratios of 18F-DOPA-derived radioactivity, and Unified Parkinson Disease Rating Scale scores in patients with or without Parkinsonism. For putamen/occipital cortex ratios, the cutoff value was 2.70. Results: Twelve subjects had severely decreased and eight normal cardiac 18F-dopamine-derived radioactivity. Cardiac 18F-DOPA-derived radioactivity did not distinguish the two groups and was unrelated to 18F-dopamine-derived radioactivity. Left ventricular myocardial 18F-DOPA-derived radioactivity was poorly resolved from that in the chamber. Putamen/occipital cortex ratios of 18F-DOPA-derived radioactivity were negatively correlated with Unified Parkinson Disease Rating Scale scores (− 0.67, p = 0.0015). Conclusions: 18F-DOPA does not seem to be a valid cardiac sympathetic neuroimaging agent, although brain 18F-DOPA scanning provides a biomarker of Parkinsonism. [ABSTRACT FROM AUTHOR]

Background: Cancer patients treated with neurotoxic chemotherapy are at risk of developing neurological symptoms that can impact functional capacity and quality of life. However, there are no standardised pathways to assess and manage chemotherapy-induced peripheral neurotoxicity (CIPN). This study aimed to determine consensus on statements regarding a CIPN assessment and management clinical pathway. Methods: A CIPN clinical pathway (CIPN-path) was developed and reviewed by an expert multi-disciplinary panel and consumers. Agreement with 18 statements regarding four content themes (pretreatment review, screening and assessment, management and referral, and CIPN-path feasibility) were assessed by 70 Australian respondents (68 health professionals, 2 consumers), using a 2-stage Delphi survey process to reach consensus. Respondents rated statements using a 5-point Likert scale to determine the level of agreement, with consensus defined as ≥ 80% of respondents agreeing with each statement. Results: The consensus was reached for 14 of 18 items after stage 1 and all items after stage 2. Feedback was obtained for all items to refine the CIPN-path. There was an agreement on important characteristics of the CIPN-path, including pretreatment screening, regular patient-reported assessment, and a stepped-care approach to investigating and managing symptom burden. There was a lack of agreement on who should oversee CIPN assessment, which may differ according to the structure and resources of each site. Conclusions: There was an overall agreement concerning the CIPN-path to assess and manage CIPN, which may be adapted accordingly to the resources of each clinic. The CIPN-path may assist teams across different health services in identifying CIPN symptoms, aiding decision-making, and reducing morbidity from CIPN. [ABSTRACT FROM AUTHOR]

This scientific commentary discusses a study on the autonomic involvement in dementia with Lewy bodies (DLB). The study used a PET radiotracer to visualize cholinergic deficiency in the brain and periphery of DLB patients. The authors found that DLB patients had decreased cholinergic activity in the pancreas and colon, suggesting lesions in the parasympathetic component of the autonomic nervous system. However, the study did not examine sympathetic noradrenergic function or assess other regions relevant to autonomic functions. Further research is needed to understand the relationship between cholinergic deficiency and other autonomic abnormalities in DLB. [Extracted from the article]

Anatomic co-registration of SP 123 sp I-MIBG SPECT images and low-dose chest computed tomography (CT) enabled the examination of regional SP 123 sp I-MIBG-derived radioactivity within the left-ventricular myocardium. SPECT imaging PET scanning offers several advantages over SPECT scanning. Abnormal cardiac sympathetic neuroimaging is more consistently found in PD + OH than in PD without OH, by both SP 123 sp I-MIBG SPECT scanning [[5]] and SP 18 sp F-DA PET scanning [[6]]. Keywords: MIBG; SPECT; PET; Fluorodopamine; Parkinson disease; Multiple system atrophy EN MIBG SPECT PET Fluorodopamine Parkinson disease Multiple system atrophy 95 98 4 05/05/22 20220401 NES 220401 Introduction Neuroimaging evidence indicating cardiac sympathetic denervation in the Lewy body (LB) synucleinopathy Parkinson disease (PD) and generally intact innervation in the non-LB synucleinopathy multiple system atrophy (MSA) was first reported using SP 18 sp F-dopamine ( SP 18 sp F-DA) positron emission tomography (PET) imaging [[1]]. [Extracted from the article]

The goal of this work is to build up the capability of quasi-particle simulation (QuiPS), a novel flow solver, such that it can adequately model the rarefied portion of an atmospheric reentry trajectory. Direct simulation Monte Carlo (DSMC) is the conventional solver for such conditions, but struggles to resolve transient flows, trace species, and high-level internal energy states due to stochastic noise. Quasi-particle simulation (QuiPS) is a novel Boltzmann solver that describes a system with a discretized, truncated velocity distribution function. The resulting fixed-velocity, variable weight quasi-particles enable smooth variation of macroscopic properties. The distribution function description enables the use of a variance-reduced collision model, greatly minimizing expense near equilibrium. This work presents the addition of a neutral air chemistry model to QuiPS and some demonstrative 0D simulations. The explicit representation of internal distributions in QuiPS reveals some of the flaws in existing physics models. Variance reduction, a key feature of QuiPS, can greatly reduce expense of multi-dimensional calculations, but is only cheaper when the gas composition is near chemical equilibrium. [ABSTRACT FROM AUTHOR]

Pure autonomic failure (PAF) is a rare disease in which chronic neurogenic orthostatic hypotension (nOH) dominates the clinical picture. Longitudinal studies have reported that PAF can phenoconvert to a central synucleinopathy with motor or cognitive involvement—i.e., to Parkinson disease (PD), dementia with Lewy bodies (DLB), or multiple system atrophy (MSA). These studies have classified patients clinically as having PAF based on nOH without an identified secondary cause or clinical evidence of motor or cognitive impairment due to central neurodegeneration. This approach lumps together two nOH syndromes that are pathologically and neurochemically distinct. One is characterized by intraneuronal cytoplasmic alpha-synuclein aggregates (i.e., Lewy bodies) and degeneration of postganglionic sympathetic neurons, as in PD and DLB; the other is not, as in MSA. Clinical and postmortem data show that the form of PAF that involves sympathetic intraneuronal synucleinopathy and noradrenergic deficiency can phenoconvert to PD or DLB—but not to MSA. Conversely, PAF without these features leaves open the possibility of premotor MSA. [ABSTRACT FROM AUTHOR]

Background: After hospitalization for acute myocardial infarction (AMI), older adults may be at increased risk for falls due to deconditioning, new medications, and worsening health status. Our primary objective was to identify risk factors for falls after AMI hospitalization among adults over age 75. Methods: We used data from the Comprehensive Evaluation of Risk Factors in Older Patients with AMI (SILVER‐AMI) study, a prospective cohort study of 3041 adults age 75 and older hospitalized with AMI at 94 community and academic medical centers across the United States. In‐person interviews and physical assessments, as well as medical record review, were performed to collect demographic, clinical, functional, and psychosocial data. Falls were self‐reported in telephone interviews and medically serious falls (those associated with emergency department use or hospitalization) were determined by medical record adjudication. Backward selection was used to identify predictors of fall risk in logistic regression analysis. Results: A total of 554 (21.6%) participants reported a fall and 191 (6.4%) had a medically serious fall within 6 months of discharge. Factors independently associated with self‐reported falls included impaired mobility, prior fall history, longer hospital stay, visual impairment, and weak grip. Factors independently associated with medically serious falls included older age, polypharmacy, impaired functional mobility, prior fall history, and living alone. Conclusions: Among older patients hospitalized for AMI, falls are common in the 6 months following discharge and associated with demographic, functional, and clinical factors that are readily identifiable. Fall risk should be considered in post‐AMI clinical decision‐making and interventions to prevent falls should be evaluated. [ABSTRACT FROM AUTHOR]

Immune cell infiltration has been implicated in neurotoxic chemotherapy for cancer treatment. However, our understanding of immune processes is still incomplete and current methods of observing immune cells are time consuming or invasive. Corneal dendritic cells are potent antigen-presenting cells and can be imaged with in-vivo corneal confocal microscopy. Corneal dendritic cell densities and nerve parameters in patients treated with neurotoxic chemotherapy were investigated. Patients treated for cancer with oxaliplatin (n = 39) or paclitaxel (n = 48), 3 to 24 months prior to assessment were recruited along with 40 healthy controls. Immature (ImDC), mature (MDC) and total dendritic cell densities (TotalDC), and corneal nerve parameters were analyzed from in-vivo corneal confocal microscopy images. ImDC was increased in the oxaliplatin group (Median, Md = 22.7 cells/mm2) compared to healthy controls (Md = 10.1 cells/mm2, p = 0.001), but not in the paclitaxel group (Md = 10.6 cells/mm2). ImDC was also associated with higher oxaliplatin cumulative dose (r = 0.33, p = 0.04) and treatment cycles (r = 0.40, p = 0.01). There was no significant difference in MDC between the three groups (p > 0.05). Corneal nerve parameters were reduced in both oxaliplatin and paclitaxel groups compared to healthy controls (p < 0.05). There is evidence of elevation of corneal ImDC in oxaliplatin-treated patients. Further investigation is required to explore this potential link through longitudinal studies and animal or laboratory-based immunohistochemical research. [ABSTRACT FROM AUTHOR]

Background: Cytoplasmic inclusions of α‐synuclein (α‐syn) in brainstem neurons are characteristic of idiopathic Parkinson's disease (PD). PD also entails α‐syn buildup in sympathetic nerves. Among genetic forms of PD, the relative extents of sympathetic intraneuronal accumulation of α‐syn have not been reported. Objective: This cross‐sectional observational study compared magnitudes of intraneuronal deposition of α‐syn in common and rare genetic forms of PD. Methods: α‐Syn deposition was quantified by the α‐syn‐tyrosine hydroxylase colocalization index in C2 cervical skin biopsies from 65 subjects. These included 30 subjects with pathogenic mutations in SNCA (n = 3), PRKN [biallelic (n = 7) and monoallelic (n = 3)], LRRK2 (n = 7), GBA (n = 7), or PARK7/DJ1 [biallelic (n = 1) and monoallelic (n = 2)]. Twenty‐five of the mutation carriers had PD and five did not. Data were also analyzed from 19 patients with idiopathic PD and 16 control participants. Results: α‐Syn deposition varied as a function of genotype (F = 16.7, P < 0.0001). It was above the control range in 100% of subjects with SNCA mutations, 100% with LRRK2 mutations, 95% with idiopathic PD, 83% with GBA mutations, and 0% with biallelic PRKN mutations. α‐Syn deposition in the biallelic PRKN group was significantly higher than in the control group. In addition, patients with biallelic PRKN mutations had higher α‐syn deposition than their unaffected siblings. Conclusions: Individuals with SNCA, DJ‐1, LRRK2, or GBA mutations have substantial intraneuronal α‐syn deposition in sympathetic noradrenergic nerves in skin biopsies, whereas those with biallelic PRKN mutations do not. Biallelic PRKN patients may have mildly increased α‐syn deposition compared with control subjects. © 2021 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

We present a general, theoretical model describing the three-dimensional elastic behavior of point contacts. We provide a prescription for employing the model in a variety of physical systems and describe in detail how the model enables the use of lower-dimensional dynamic models while including approximate three-dimensional behavior of elastic point contacts. We conduct a series of experiments to validate the model for extensional and cantilever oscillators, and find good agreement between our measurements and the predictions of the model. We observe that the phenomenological effects of elastic point contacts can be significant and believe that our model will be useful to a broad range of research and engineering disciplines. [ABSTRACT FROM AUTHOR]

The synucleinopathies Parkinson's disease (PD), multiple system atrophy (MSA), and pure autonomic failure (PAF) are characterized by intra-cytoplasmic deposition of the protein alpha-synuclein and by catecholamine depletion. PAF, which manifests with neurogenic orthostatic hypotension (nOH) and no motor signs of central neurodegeneration, can evolve into PD+nOH. The cerebrospinal fluid (CSF) levels of catecholamine metabolites may indicate central catecholamine deficiency in these synucleinopathies, but the literature is inconsistent and incomplete. In this retrospective cohort study we reviewed data about CSF catecholamines, the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the norepinephrine metabolites 3,4-dihydroxyphenylglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG). The compounds were measured in 36 patients with PD, 37 patients with MSA, and 19 patients with PAF and in 38 controls. Compared to the control group, the PD, MSA, and PAF groups had decreased CSF MHPG (p < .0001 each by Dunnett's post hoc test), D HPG (p = .004; p < .0001; p < .0001) and norepinephrine (p = .017; p = .0003; p = .044). CSF HVA and DOPAC were decreased in PD (p < .0001 each) and MSA (p < .0001 each) but not in PAF. The three synucleinopathies therefore have in common in vivo evidence of central noradrenergic deficiency but differ in the extents of central dopaminergic deficiency--prominent in PD and MSA, less apparent in PAF. Data from putamen 18F-DOPA and cardiac 18F-dopamine neuroimaging in the same patients, post-mortem tissue catecholamines in largely separate cohorts, and review of the neuropathology literature fit with these distinctions. The results suggest a 'norepinephrine first' ascending pathogenetic sequence in synucleinopathies, with degeneration of pontine locus ceruleus noradrenergic neurons preceding the loss of midbrain substantia nigra dopaminergic neurons. [ABSTRACT FROM AUTHOR]

The synucleinopathies Parkinson's disease (PD), multiple system atrophy (MSA), and pure autonomic failure (PAF) are characterized by intra‐cytoplasmic deposition of the protein alpha‐synuclein and by catecholamine depletion. PAF, which manifests with neurogenic orthostatic hypotension (nOH) and no motor signs of central neurodegeneration, can evolve into PD+nOH. The cerebrospinal fluid (CSF) levels of catecholamine metabolites may indicate central catecholamine deficiency in these synucleinopathies, but the literature is inconsistent and incomplete. In this retrospective cohort study we reviewed data about CSF catecholamines, the dopamine metabolites 3,4‐dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the norepinephrine metabolites 3,4‐dihydroxyphenylglycol (DHPG) and 3‐methoxy‐4‐hydroxyphenylglycol (MHPG). The compounds were measured in 36 patients with PD, 37 patients with MSA, and 19 patients with PAF and in 38 controls. Compared to the control group, the PD, MSA, and PAF groups had decreased CSF MHPG (p <.0001 each by Dunnett's post hoc test), DHPG (p =.004; p <.0001; p <.0001) and norepinephrine (p =.017; p =.0003; p =.044). CSF HVA and DOPAC were decreased in PD (p <.0001 each) and MSA (p <.0001 each) but not in PAF. The three synucleinopathies therefore have in common in vivo evidence of central noradrenergic deficiency but differ in the extents of central dopaminergic deficiency—prominent in PD and MSA, less apparent in PAF. Data from putamen 18F‐DOPA and cardiac 18F‐dopamine neuroimaging in the same patients, post‐mortem tissue catecholamines in largely separate cohorts, and review of the neuropathology literature fit with these distinctions. The results suggest a 'norepinephrine first' ascending pathogenetic sequence in synucleinopathies, with degeneration of pontine locus ceruleus noradrenergic neurons preceding the loss of midbrain substantia nigra dopaminergic neurons. [ABSTRACT FROM AUTHOR]

Bubble trajectories in the presence of a decaying Lamb–Oseen vortex are calculated using a modified Maxey–Riley equation. Some bubbles are shown to get trapped within the vortex in quasi-equilibrium states. All the trapped bubbles exit the vortex at a time that is only a function of the Galilei number and the vortex Reynolds number. The set of initial bubble locations that lead to entrapment is numerically determined to show the capturing potential of a single vortex. The results provide insight into the likelihood of bubble entrapment within vortical structures in turbulent flows. [ABSTRACT FROM AUTHOR]

We present a novel analytical treatment of nearfield elasticity effects in mechanical resonator systems, which shows that local strain fields near a point contact can be accounted for by introducing a spring-like contact impedance at appropriate interfaces. We demonstrate via experiment that such effects can cause significant shifts in resonant frequency, and predict that the local displacements give rise to an additional dissipation mechanism which can be significant. The mathematical expressions we obtain are simple enough as to be easily included in traditional engineering models that are typically used to approximate the results one would obtain via true three-dimensional elasticity theory calculations. The effects we describe are scale invariant; we briefly discuss potentially relevant biological, nanomechanical, and large-scale systems. [ABSTRACT FROM AUTHOR]

Ocular surface dysfunction is common in patients receiving anti-cancer drug treatment. The effects of paclitaxel, a neurotoxic chemotherapeutic drug, on ocular surface discomfort associated with dry eye disease was investigated. Patients with cancer who had completed paclitaxel treatment between 3 and 24 months prior to assessment (n = 29) and age- and sex-matched healthy control subjects (n = 29) were recruited and assessed with the Ocular Surface Disease Index (OSDI) to measure ocular surface discomfort. In-vivo corneal confocal microscopy was used to evaluate corneal nerve parameters in the right eye. Peripheral neurotoxicity was assessed using patient-reported outcomes and clinical grading scales. The paclitaxel group had significantly worse OSDI total scores compared with controls (Median, Md = 19.3 and Md = 0, p = 0.007, respectively). Corneal nerve fiber and inferior whorl lengths were reduced in the paclitaxel group compared with controls (14.2 ± 4.0 and 14.4 ± 4.0 mm/mm2 vs. 16.4 ± 4.0 and 16.9 ± 4.9 mm/mm2, respectively, p = 0.04). When analyzed by presence of peripheral neuropathy, paclitaxel-treated patients with neuropathy showed worse OSDI total scores compared to those without peripheral neuropathy post-treatment (p = 0.001) and healthy controls (p < 0.001). More severe ocular discomfort and worse visual function was associated with greater peripheral neurotoxicity symptoms (r = 0.60, p = 0.001) and neuropathy severity (r = 0.49, p = 0.008), respectively. Patients who have been treated with paclitaxel have a higher risk of ocular surface discomfort associated with dry eye disease, particularly those with peripheral neuropathy. Future longitudinal studies should investigate the clinical impact of corneal nerve reduction in dry eye disease. [ABSTRACT FROM AUTHOR]

Passive agents in ancient Greek exhibit a well-known alternation between dative case and prepositional phrase. It has long been recognized that grammatical aspect plays a crucial role in this alternation: dative agents preponderate among aspectually perfect predicates, prepositional phrase agents elsewhere. Although the importance of grammatical aspect is undeniable, it is not the only factor that determines the realization of passive agents. The identification of other factors has proven challenging, however, not least because previous researchers have lacked methods for assessing the relative importance of the determinants that influence the realization of agent phrases. In this paper, I use Bayesian mixed-effects logistic regression to provide a multifactorial account of differential agent marking in Herodotus, according to which the realization of passive agent phrases is conditioned by the relationship between semantic role and referential prominence (Haspelmath 2021). Dative agents are favored in clauses where semantic role and referential prominence are aligned (i.e., the agent is referentially prominent or the patient is referentially non-prominent). By contrast, prepositional phrase agents are more likely when semantic role and referential prominence are at odds (i.e., the patient is referentially prominent or the agent is referentially non-prominent). [ABSTRACT FROM AUTHOR]

Profound depletion of the catecholamines dopamine (DA) and norepinephrine in the brain, heart, or both characterizes Lewy body diseases such as Parkinson disease, dementia with Lewy bodies, and pure autonomic failure. Although one might presume that catecholamine deficiency in these disorders results directly and solely from loss of catecholaminergic neurons, there is increasing evidence that functional abnormalities in extant residual neurons contribute to the neurotransmitter deficiencies—the "sick-but-not-dead" phenomenon. This brief review highlights two such functional abnormalities—decreased vesicular sequestration of cytoplasmic catecholamines and decreased catecholamine biosynthesis. Another abnormality, decreased activity of aldehyde dehydrogenase, may have pathogenetic significance and contribute indirectly to the loss of catecholamine stores via interactions between the autotoxic catecholaldehyde 3,4-dihydroxyphenylacetaldehyde and the protein alpha-synuclein, which is a major component of Lewy bodies. Theoretically, chronically repeated stress responses could accelerate these abnormalities, via increased exocytosis and neuronal reuptake, which indirectly shifts tissue catecholamines from vesicular stores into the cytoplasm, and via increased tyrosine hydroxylation, which augments intra-cytoplasmic DA production. The discovery of specific paths mediating the sick-but-not-dead phenomenon offers novel targets for multi-pronged therapeutic approaches. [ABSTRACT FROM AUTHOR]

Objective: Pure autonomic failure (PAF) is a rare disease characterized by neurogenic orthostatic hypotension (nOH), absence of signs of central neurodegeneration, and profound deficiency of the sympathetic neurotransmitter norepinephrine. Reports have disagreed about mechanisms of the noradrenergic lesion. Neuropathological studies have highlighted denervation, while functional studies have emphasized deficient vesicular sequestration of cytoplasmic catecholamines in extant neurons. We examined both aspects by a combined positron emission tomographic (PET) neuroimaging approach using 11C‐methylreboxetine (11C‐MRB), a selective ligand for the cell membrane norepinephrine transporter, to quantify interventricular septal myocardial noradrenergic innervation and using 18F‐dopamine (18F‐DA) to assess intraneuronal vesicular storage in the same subjects. Methods: Seven comprehensively tested PAF patients and 11 controls underwent 11C‐MRB PET scanning for 45 minutes (dynamic 5X1', 3X5', 1X10', static 15 minutes) and 18F‐DA scanning for 30 minutes (same dynamic imaging sequence) after 3‐minute infusions of the tracers on separate days. Results: In the PAF group septal 11C‐MRB‐derived radioactivity in the static frame was decreased by 26.7% from control (p = 0.012). After adjustment for nonspecific binding of 11C‐MRB, the PAF group had a 41.1% mean decrease in myocardial 11C‐MRB‐derived radioactivity (p = 0.015). The PAF patients had five times faster postinfusion loss of 18F‐DA‐derived radioactivity (70 ± 3% vs. 14 ± 8% by 30 minutes, p < 0.0001). At all time points after infusion of 18F‐DA and 11C‐MRB mean 18F/11C ratios in septal myocardium were lower in the PAF than control group. Interpretation: PAF entails moderately decreased cardiac sympathetic innervation and a substantial vesicular storage defect in residual nerves. [ABSTRACT FROM AUTHOR]

The catecholamines dopamine and norepinephrine are key central neurotransmitters that participate in many neurobehavioral processes and disease states. Norepinephrine is also the main neurotransmitter mediating regulation of the circulation by the sympathetic nervous system. Several neurodegenerative disorders feature catecholamine deficiency. The most common is Parkinson's disease (PD), in which putamen dopamine content is drastically reduced. PD also entails severely decreased myocardial norepinephrine content, a feature that characterizes two other Lewy body diseases—pure autonomic failure and dementia with Lewy bodies. It is widely presumed that tissue catecholamine depletion in these conditions results directly from loss of catecholaminergic neurons; however, as highlighted in this review, there are also important functional abnormalities in extant residual catecholaminergic neurons. We refer to this as the "sick-but-not-dead" phenomenon. The malfunctions include diminished dopamine biosynthesis via tyrosine hydroxylase (TH) and L-aromatic-amino-acid decarboxylase (LAAAD), inefficient vesicular sequestration of cytoplasmic catecholamines, and attenuated neuronal reuptake via cell membrane catecholamine transporters. A unifying explanation for catecholaminergic neurodegeneration is autotoxicity exerted by 3,4-dihydroxyphenylacetaldehyde (DOPAL), an obligate intermediate in cytoplasmic dopamine metabolism. In PD, putamen DOPAL is built up with respect to dopamine, associated with a vesicular storage defect and decreased aldehyde dehydrogenase activity. Probably via spontaneous oxidation, DOPAL potently oligomerizes and forms quinone-protein adducts with ("quinonizes") α-synuclein (AS), a major constituent in Lewy bodies, and DOPAL-induced AS oligomers impede vesicular storage. DOPAL also quinonizes numerous intracellular proteins and inhibits enzymatic activities of TH and LAAAD. Treatments targeting DOPAL formation and oxidation therefore might rescue sick-but-not-dead catecholaminergic neurons in Lewy body diseases. [ABSTRACT FROM AUTHOR]

With the COVID-19 pandemic, there has been significant changes and challenges in the management of oncology patients. One of the major strategies to reduce transmission of the virus between patients and healthcare workers is deferral of follow-up visits. However, deferral may not be possible in total laryngectomy patients. Urgent procedures may be necessary to prevent complications related to ill-fitting tracheoesophageal puncture (TEP) voice prostheses, such as aspiration or loss of voicing. In this paper, we describe the Princess Margaret Cancer Center's approach to managing this unique patient population. [ABSTRACT FROM AUTHOR]

The pandemic viral illness COVID-19 is especially life-threatening in the elderly and in those with any of a variety of chronic medical conditions. This essay explores the possibility that the heightened risk may involve activation of the "extended autonomic system" (EAS). Traditionally, the autonomic nervous system has been viewed as consisting of the sympathetic nervous system, the parasympathetic nervous system, and the enteric nervous system. Over the past century, however, neuroendocrine and neuroimmune systems have come to the fore, justifying expansion of the meaning of "autonomic." Additional facets include the sympathetic adrenergic system, for which adrenaline is the key effector; the hypothalamic-pituitary-adrenocortical axis; arginine vasopressin (synonymous with anti-diuretic hormone); the renin-angiotensin-aldosterone system, with angiotensin II and aldosterone the main effectors; and cholinergic anti-inflammatory and sympathetic inflammasomal pathways. A hierarchical brain network—the "central autonomic network"—regulates these systems; embedded within it are components of the Chrousos/Gold "stress system." Acute, coordinated alterations in homeostatic settings (allostasis) can be crucial for surviving stressors such as traumatic hemorrhage, asphyxiation, and sepsis, which throughout human evolution have threatened homeostasis; however, intense or long-term EAS activation may cause harm. While required for appropriate responses in emergencies, EAS activation in the setting of chronically decreased homeostatic efficiencies (dyshomeostasis) may reduce thresholds for induction of destabilizing, lethal vicious cycles. Testable hypotheses derived from these concepts are that biomarkers of EAS activation correlate with clinical and pathophysiologic data and predict outcome in COVID-19 and that treatments targeting specific abnormalities identified in individual patients may be beneficial. [ABSTRACT FROM AUTHOR]

Monoamine oxidase (MAO) plays a central role in the metabolism of the neurotransmitters dopamine, norepinephrine, and serotonin. This brief review focuses on 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is the immediate product of MAO acting on cytoplasmic dopamine. DOPAL is toxic; however, normally DOPAL is converted via aldehyde dehydrogenase (ALDH) to 3,4-dihydroxyphenylacetic acid (DOPAC), which rapidly exits the neurons. In addition to vesicular uptake of dopamine via the vesicular monoamine transporter (VMAT), the two-enzyme sequence of MAO and ALDH keeps cytoplasmic dopamine levels low. Dopamine oxidizes readily to form toxic products that could threaten neuronal homeostasis. The catecholaldehyde hypothesis posits that diseases featuring catecholaminergic neurodegeneration result from harmful interactions between DOPAL and the protein alpha-synuclein, a major component of Lewy bodies in diseases such as Parkinson disease, dementia with Lewy bodies, and pure autonomic failure. DOPAL potently oligomerizes alpha-synuclein, and alpha-synuclein oligomers impede vesicular functions, shifting the fate of cytoplasmic dopamine toward MAO-catalyzed formation of DOPAL—a vicious cycle. When MAO deaminates dopamine to form DOPAL, hydrogen peroxide is generated; and DOPAL, hydrogen peroxide, and divalent metal cations react to form hydroxyl radicals, which peroxidate lipid membranes. Lipid peroxidation products in turn inhibit ALDH, causing DOPAL to accumulate—another vicious cycle. MAO inhibition decreases DOPAL formation but concurrently increases the spontaneous oxidation of dopamine, potentially trading off one form of toxicity for another. These considerations rationalize a neuroprotection strategy based on concurrent treatment with an MAO inhibitor and an anti-oxidant. [ABSTRACT FROM AUTHOR]

Background: An elevated neutrophil-lymphocyte ratio (NLR) is associated with poor prognosis in advanced renal cell carcinoma (RCC). We examined whether the addition of NLR improves the risk reclassification of advanced RCC using current prognostic tools from the Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). Methods: Using randomised data from the COMPARZ trial of first-line pazopanib vs. sunitinib in advanced RCC, we constructed multivariable models containing MSKCC and IMDC predictor variables with and without NLR. We evaluated model discrimination using the concordance index (C-index). We computed net reclassification improvement to quantify patient reclassification into low/intermediate/poor risk groups with the addition of NLR. Results: Of 1102 patients, NLR ≥ 5 (16%) was associated with shorter survival adjusting for MSKCC variables (adjusted HR 1.89, p <.001). Adding NLR to MSKCC variables increased the C-index by 0.01. Among patients who died before 24 months (N = 415), adding NLR reclassified 8% and 2% to a higher and lower risk category, respectively. Among those alive at 24 months (N = 636), adding NLR reclassified 4% and 1% to a higher and lower risk category, respectively. This finding translates to a net benefit of eight additional patients who die within 24 months correctly identified as poor risk per 1000 patients tested. We obtained similar results when evaluating NLR with IMDC variables. Conclusions: NLR does not substantially improve risk reclassification over pre-existing prognostic tools. MSKCC and IMDC classifications remain the standard for guiding risk-directed therapy and trial stratification of patients with advanced RCC. [ABSTRACT FROM AUTHOR]

Context: Efficient and accurate clinical screening for treatment-related toxicities is a critical component of optimal patient management. A number of alternate screening tools for chemotherapy-induced peripheral neuropathy (CIPN) have been proposed in response to demonstrated limitations with standard clinical screening, although their relative diagnostic value is unclear.Objectives: The aim of this study is to evaluate the relative construct validity and discriminant properties of available CIPN screening tools.Methods: Patients treated with known potentially neurotoxic therapies underwent CIPN evaluation at one or multiple timepoints (N = 316 patients; age = 56 ± 13 years). At each testing session (N = 644 testing sessions), patients were evaluated using screening tools and comprehensive CIPN assessments. Comprehensive assessments were clinician-rated (Total Neuropathy Score, reduced) or patient-reported outcome (PRO; Functional Assessment of Cancer Therapy-Gynecologic Oncology Group/Neurotoxicity questionnaire). Similarly, screening tools were clinician-rated (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE]) or PRO (Patient Neurotoxicity Questionnaire, PRO-CTCAE).Results: Analyses revealed moderate-to-high correlations between screening tools and comprehensive assessments (0.55 ≤ rho ≤ 0.75; P < 0.001) and similar discriminant properties across screening tools (P > 0.01). Screening tool grading corresponding to clinically significant (grade 2/3) vs. low-grade (grade 0/1) CIPN would correspond to greater ratings of CIPN severity by more comprehensive assessments in a predicted 77%-91% of cases (c-statistic = 0.77-0.91; P < 0.01).Conclusions: PRO screening tools provide adequate CIPN screening while avoiding potential biases demonstrated to limit currently used clinician-rated screening tools. Addition of a brief objective test did not add value to PRO screening. Up to 23% of patients would be misidentified through screening, providing quantitative evidence of the limitations of available screening tools. More extensive CIPN evaluations are critical in patients at risk of serious neurotoxicity. [ABSTRACT FROM AUTHOR]

Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) affects up to 40% of cancer survivors and is associated with functional deficits and an increased falls incidence. There are presently no strongly recommended treatment strategies for CIPN. The aim of this study was to evaluate the impact of a multimodal exercise intervention on CIPN symptoms and related functional deficits, as well as neurophysiologic parameters.Methods: All outcomes were assessed before and after an 8-week exercise intervention (3-weekly sessions) and preceding 8-week control period at baseline, pre-exercise and post-exercise. Outcome measures were objective and patient-reported CIPN, standing and dynamic balance, mobility, quality of life, and sensory and motor nerve excitability and conduction studies.Results: Twenty-nine cancer survivors (8 male, 21 female; mean age 61.6 ± 11.8 years) with CIPN symptoms affecting function completed all assessments. Objective and patient-reported CIPN, dynamic balance, standing balance in eyes open conditions, mobility and quality of life were improved from pre- to post-exercise (4.0 < F < 10.2; p < .05), with no changes over the control period (p > .21). No changes were observed in sensory or motor neurophysiologic parameters (p > .23).Conclusions: This study provides encouraging evidence of the rehabilitative potential of multimodal exercise for persisting CIPN in a post-treatment cohort. Large randomised controlled trials are justified to confirm observed benefits and determine the mechanisms and clinical significance. [ABSTRACT FROM AUTHOR]

Active surveillance (AS) in the management of small, low risk papillary thyroid cancer (PTC) as an alternative option to thyroidectomy, is an area of active research. A national Canadian study is proposed to evaluate the long-term outcomes of patients with small, low risk PTC who choose AS or surgery. This letter describes the proceedings of a national investigator meeting to plan the study. [ABSTRACT FROM AUTHOR]

Synucleinopathies include Parkinson disease (PD), dementia with Lewy bodies (DLB), pure autonomic failure (PAF), and multiple system atrophy (MSA). Keywords: Supine hypertension; Atomoxetine; Ampreloxetine; Lightheadedness; Multiple system atrophy; Parkinson disease EN Supine hypertension Atomoxetine Ampreloxetine Lightheadedness Multiple system atrophy Parkinson disease 351 353 3 06/09/21 20210601 NES 210601 Neurogenic orthostatic hypotension (nOH) is a not infrequent consequence of neurodegenerative disorders and can result in impaired mobility, falls and associated fractures, decreased quality of life, hospitalizations, and increased mortality. [Extracted from the article]

In the article by Norcliffe-Kaufmann I et al i .,[1] 'Fear conditioning as a pathogenic mechanism in the postural tachycardia syndrome', this reader sees over- or mis-interpretation of findings and possible investigator bias, as follows. Post-COVID-19 tachycardia syndrome: A distinct phenotype of post-acute COVID-19 syndrome. [Extracted from the article]

Io is a highly volcanic satellite of Jupiter. Its giant plumes rise hundreds of kilometers, creating large targets for incoming ions as Jupiter's plasma torus overtakes Io in its orbit. Neutral material from Io's sublimation atmosphere and volcanic plumes supplies the plasma torus, but the details of the interaction between neutral gas at Io and ions in the torus are not well understood. This paper suggests a process by which plume material is energized and ionized so as to supply the torus. We present three-dimensional direct simulation Monte Carlo simulations of giant plumes being bombarded by S+ and O+ ions which are moved based on precomputed electric and magnetic fields. The dependence of the plume/plasma interaction on the plume's location on Io is investigated. The plume/plasma interaction is seen to be asymmetric even for a plume at the subplasma point because of the electric field that arises in an Io-fixed reference frame. Plasma is found to inflate and heat plume canopies and to give rise to a large, diffuse neutral cloud over the plume's entire hemisphere. We also find that plasma can explain the thickness of red deposition rings observed on Io. [ABSTRACT FROM AUTHOR]

The article explains how the Joint Ownership Entity of New York City (JOE NYC) program is helping and empowering some of New York City's leading organizations to leverage their local expertise and group capacity to compete in the market to create more affordable housing. Topics discussed include the evolution of Community Development Corporations, the CDC 4G Initiative and how JOE NYC works.

Medicine has long sought to match diagnostic and treatment approaches to the particular needs and risks of individual patients. The decreasing cost and increasing ease of genetic sequencing have propelled the rise of precision medicine. Precision medicine aims to use genetic and other information to provide care tailored to the individual patient, with the goal of improving clinical outcomes and minimizing unnecessary diagnostic and therapeutic interventions. Although developments in genetic sequencing have the potential to transform clinical care, there are important limitations, including uncertainty in the clinical interpretation of many genetic variants and concerns about privacy, discrimination, and cost. To help clinicians understand the basics of genetic sequencing and how to apply it in clinical practice, Annals of Internal Medicine is launching a new "Precision Medicine" series. This introduction provides a general overview of clinical sequencing, with a focus on germline variation. Subsequent articles will use a case-based format to provide concise summaries of specific clinical precision medicine scenarios that are relevant to the practice of internal medicine. These cases will highlight specific clinical indications; interpretation of genetic test results; and ethical, legal, cost, and privacy issues related to genetic testing. The goal is to provide practical information on the appropriate application and interpretation of genomics in routine clinical practice. [ABSTRACT FROM AUTHOR]

Summary: Objective: The Epilepsy Genetics Initiative (EGI) was formed in 2014 to create a centrally managed database of clinically generated exome sequence data. EGI performs systematic research‐based reanalysis to identify new molecular diagnoses that were not possible at the time of initial sequencing and to aid in novel gene discovery. Herein we report on the efficacy of this approach 3 years after inception. Methods: One hundred sixty‐six individuals with epilepsy who underwent diagnostic whole exome sequencing (WES) were enrolled, including 139 who had not received a genetic diagnosis. Sequence data were transferred to the EGI and periodically reevaluated on a research basis. Results: Eight new diagnoses were made as a result of updated annotations or the discovery of novel epilepsy genes after the initial diagnostic analysis was performed. In five additional cases, we provided new evidence to support or contradict the likelihood of variant pathogenicity reported by the laboratory. One novel epilepsy gene was discovered through dual interrogation of research and clinically generated WES. Significance: EGI's diagnosis rate of 5.8% represents a considerable increase in diagnostic yield and demonstrates the value of periodic reinterrogation of whole exome data. The initiative's contributions to gene discovery underscore the importance of data sharing and the value of collaborative enterprises. [ABSTRACT FROM AUTHOR]

This perspective piece on head-up tilt table testing is part of a series on autonomic function testing. The tilt table can be a useful diagnostic test, but methodologies vary, and the results are sometimes misinterpreted. The intent here is not to review comprehensively the utility of various tilt table testing protocols but to convey a number of general points that may give perspective and have practical clinical value, based on an understanding of autonomic physiology and our long clinical and research experience in the evaluation of autonomic disorders. The goals of tilt table testing are to assess orthostatic hypotension (OH), chronic orthostatic intolerance (COI), and unexplained syncope. The testing is useful for distinguishing neurogenic from non-neurogenic OH, identifying failure of the sympathetic noradrenergic system in autonomic neuropathies and ganglionopathies, and assessing baroreflex-sympathoneural function in α-synucleinopathies. For COI, the testing can provide objective data related to the patient's symptoms, diagnose postural tachycardia syndrome (POTS), and distinguish POTS from other causes of tachycardia. Provocative tilt table testing can help understand bases for recurrent transient loss of consciousness in patients with syncope, distinguish neurally mediated syncope from psychogenic pseudosyncope, and separate syncope-related convulsion from epileptic seizures. For each of these purposes, the goals, formats, endpoints, and clinical utility are different. As for any autonomic test, tilt table findings must be interpreted in the context of the patient's clinical presentation. [ABSTRACT FROM AUTHOR]

Homeostasis is a founding principle of integrative physiology. In current systems biology, however, homeostasis seems almost invisible. Is homeostasis a key goal driving body processes, or is it an emergent mechanistic fact? In this perspective piece, I propose that the integrative physiological and systems biological viewpoints about homeostasis reflect different epistemologies, different philosophies of knowledge. Integrative physiology is concept driven. It attempts to explain biological phenomena by continuous formation of theories that experimentation or observation can test. In integrative physiology, "function" refers to goals or purposes. Systems biology is data driven. It explains biological phenomena in terms of "omics"-i.e., genomics, gene expression, epigenomics, proteomics, and metabolomics- it depicts the data in computer models of complex cascades or networks, and it makes predictions from the models. In systems biology, "function" refers more to mechanisms than to goals. The integrative physiologist emphasizes homeostasis of internal variables such as PCO2 and blood pressure. The systems biologist views these emphases as teleological and unparsimonious in that the "regulated variable" (e.g., arterial PCO2 and blood pressure) and the "regulator" (e.g., the "carbistat" and "barostat") are unobservable constructs. The integrative physiologist views systems biological explanations as not really explanations but descriptions that cannot account for phenomena we humans believe exist, although they cannot be observed directly, such as feelings and, ultimately, the conscious mind. This essay reviews the history of the two epistemologies, emphasizing autonomic neuroscience. I predict rapprochement of integrative physiology with systems biology. The resolution will avoid teleological purposiveness, transcend pure mechanism, and incorporate adaptiveness in evolution, i.e., "Darwinian medicine." [ABSTRACT FROM AUTHOR]

This paper explores the mechanisms underlying roughness induced transition (RIT) caused by discrete roughness elements (DREs) using immersed boundary direct numerical simulations. We show via favorable comparison between RIT in Blasius boundary layers and equivalent Couette flows that linear instability of the boundary layer profile does not play a significant role for the DREs considered (k < 0.6δ*, where k is the height of the DRE) and that k+ = uτk/ν is the dominant parameter (for a given shape of the DRE) which strongly affects the transition location. For a suitable range of k+, the flow evolution can be separated into four distinct stages: (i) generation of vortical disturbances at the roughness, (ii) a steady and spatial amplification of a three dimensional disturbance, (iii) the emergence and amplification of unsteady disturbances, and (iv) the emergence of chaotic behavior leading to a "turbulent wedge" (with a relatively high mean wall shear stress). Each of these stages is studied in detail. A mechanistic understanding of RIT is suggested which includes a new and fundamental understanding of the final stage. Novel results include the description of a mutual stretching mechanism leading to the near wall amplification of streamwise vorticity at the onset of stage IV, complementary interpretations of the lift up and the "modal instability" using a control volume formulation for different components of the enstrophy, and a demonstration of a passive RIT mitigation strategy using an "anti-roughness" element (i.e., a second downstream roughness element), which exploits this understanding of RIT mechanisms from the vorticity-based analysis. [ABSTRACT FROM AUTHOR]

Highlights • This review provides an update about cardiac denervation in Lewy body diseases. • There is decreased storage of catecholamines in the residual terminals. • The catecholaldehyde hypothesis: DOPAL contributes catecholamine neuronal death. • Decreasing DOPAL production and oxidation might slow the neurodegeneration. • Tracking cardiac sympathetic innervation could be used in a clinical trial. Abstract This review provides an update about cardiac sympathetic denervation in Lewy body diseases. The family of Lewy body diseases includes Parkinson's disease (PD), pure autonomic failure (PAF), and dementia with Lewy bodies (DLB). All three feature intra-neuronal cytoplasmic deposits of the protein, alpha-synuclein. Multiple system atrophy (MSA), the parkinsonian form of which can be difficult to distinguish from PD with orthostatic hypotension, involves glial cytoplasmic inclusions that contain alpha-synuclein. By now there is compelling neuroimaging, neuropathologic, and neurochemical evidence for cardiac sympathetic denervation in Lewy body diseases. In addition to denervation, there is decreased storage of catecholamines in the residual terminals. The degeneration develops in a centripetal, retrograde, "dying back" sequence. Across synucleinopathies the putamen and cardiac catecholaminergic lesions seem to occur independently of each other, whereas non-motor aspects of PD (e.g., anosmia, dementia, REM behavior disorder, OH) are associated with each other and with cardiac sympathetic denervation. Cardiac sympathetic denervation can be caused by synucleinopathy in inherited PD. According to the catecholaldehyde hypothesis, 3,4-dihydroxyphenylacetaldehyde (DOPAL), an intermediary metabolite of dopamine, causes or contributes to the death of catecholamine neurons, especially by interacting with proteins such as alpha-synuclein. DOPAL oxidizes spontaneously to DOPAL-quinone, which probably converts alpha-synuclein to its toxic oligomeric form. Decreasing DOPAL production and oxidation might slow the neurodegenerative process. Tracking cardiac sympathetic innervation over time could be the basis for a proof of principle experimental therapeutics trial targeting DOPAL. [ABSTRACT FROM AUTHOR]

Sympathetic neuroimaging is based on the injection of compounds that either radiolabel sites of the cell membrane norepinephrine transporter (NET) or that are taken up into sympathetic nerves via the NET and radiolabel intra-neuronal catecholamine storage sites. Detection of the radioactivity is by planar or tomographic radionuclide imaging. The heart stands out among body organs in terms of the intensity of radiolabeling of sympathetic nerves, and virtually all of sympathetic neuroimaging focuses on the left ventricular myocardium. The most common cardiac sympathetic neuroimaging method worldwide is 123I-metaiodobenzylguanidine (123I-MIBG) scanning. 123I-MIBG scanning is used routinely in Europe and East Asia in the diagnostic evaluation of neurogenic orthostatic hypotension (nOH), to distinguish Lewy body diseases (e.g., Parkinson disease with orthostatic hypotension (OH), pure autonomic failure) from non-Lewy body diseases (e.g., multiple system atrophy) and to distinguish dementia with Lewy bodies from Alzheimer’s disease. In the USA, 123I-MIBG scanning has been approved by the Food and Drug Administration for the evaluation of pheochromocytoma and some forms of heart failure—but not for the above-mentioned differential diagnoses. Positron emission tomographic methods based on imaging agents such as 18F-dopamine are categorized as research tools, despite more than a quarter century of clinical experience with these modalities. Considering that 123I-MIBG scanning is available at most academic medical centers in the USA, cardiac sympathetic neuroimaging by this methodology merits consideration as an autonomic test, especially in patients with nOH. [ABSTRACT FROM AUTHOR]