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This study aimed at assessing the long-term effects of intranasal insulin (INI) on cognition and gait in older people with and without type 2 diabetes mellitus (T2DM).Phase 2 randomized, double-blinded trial consisted of 24 week treatment with 40 IU of INI (NovolinDM-INI had faster NW (~ 7 cm/s; p = 0.025) and DTW on-treatment (p = 0.007; p = 0.812 adjusted for baseline difference) than DM-Placebo. Control-INI had better executive functioning on-treatment (p = 0.008) and post-treatment (p = 0.007) and verbal memory post-treatment (p = 0.004) than Control-Placebo. DM-INI increased cerebral blood flow in medio-prefrontal cortex (p 0.001) on MRI. Better vasoreactivity was associated with faster DTW (p 0.008). In DM-INI, plasma insulin (p = 0.006) and HOMA-IR (p 0.013) decreased post-treatment. Overall INI effect demonstrated faster walking (p = 0.002) and better executive function (p = 0.002) and verbal memory (p = 0.02) (combined DM-INI and Control-INI cohort, hemoglobin A1c-adjusted). INI was not associated with serious adverse events, hypoglycemic episodes, or weight gain.There is evidence for positive INI effects on cognition and gait. INI-treated T2DM participants walked faster, showed increased cerebral blood flow and decreased plasma insulin, while controls improved executive functioning and verbal memory. The MemAID trial provides proof-of-concept for preliminary safety and efficacy and supports future evaluation of INI role to treat T2DM and age-related functional decline.

The aim of this work is to highlight challenges, if there are any, in decarbonising national power system in Republic of Slovenia. National electricity grid was hourly simulated using EnergyPlan ? Advanced energy system analysis computer model in circumstances where distributed power sources capacity exceeds peak system demand. The goal was to estimate the influence of 4400 MW distributed power production to the power grid with peak demand of up to 3000 MW, respecting the fact that distributed power sources partly meet demand in summer sunlight time, however modestly meets demand in winter time. Electricity demand in summer and winter time are of the same magnitude of order. Modest system capacity for electricity storage were respected and influence to cross border transmission demand was estimated. Chalenges related to grid stability were shown and how nuclear can improve grid stability is presented.

Background KLS-1 is zinc (Zn) aspartate enriched with isotope

Multiple system atrophy (MSA) is a fatal neurodegenerative disease of unknown etiology characterized by widespread aggregation of the protein alpha-synuclein in neurons and glia. Its orphan status, biological relationship to Parkinson’s disease (PD), and rapid progression have sparked interest in drug development. One significant obstacle to therapeutics is disease heterogeneity. Here, we share our process of developing a clinical trial-ready cohort of MSA patients (69 patients in 2 years) within an outpatient clinical setting, and recruiting 20 of these patients into a longitudinal “n-of-few” clinical trial paradigm. First, we deeply phenotype our patients with clinical scales (UMSARS, BARS, MoCA, NMSS, and UPSIT) and tests designed to establish early differential diagnosis (including volumetric MRI, FDG-PET, MIBG scan, polysomnography, genetic testing, autonomic function tests, skin biopsy) or disease activity (PBR06-TSPO). Second, we longitudinally collect biospecimens (blood, CSF, stool) and clinical, biometric, and imaging data to generate antecedent disease-progression scores. Third, in our Mass General Brigham SCiN study (stemcellsinneurodegeneration), we generate induced pluripotent stem cell (iPSC) models from our patients, matched to biospecimens, including postmortem brain. We present 38 iPSC lines derived from MSA patients and relevant disease controls (spinocerebellar ataxia and PD, including alpha-synuclein triplication cases), 22 matched to whole-genome sequenced postmortem brain. iPSC models may facilitate matching patients to appropriate therapies, particularly in heterogeneous diseases for which patient-specific biology may elude animal models. We anticipate that deeply phenotyped and genotyped patient cohorts matched to cellular models will increase the likelihood of success in clinical trials for MSA.

Effective recruitment and retention strategies are essential in clinical trials.The MemAID trial consisted of 12 visits during 24 weeks of intranasal insulin or placebo treatment and 24 weeks of post-treatment follow-up in older people with and without diabetes. Enhanced retention strategies were implemented mid study to address high drop-out rate. Baseline variables used in Cox regression models to identify dropout risk factors were: demographics and social characteristics, functional measures, metabolic and cardiovascular parameters, and medications.244 participants were randomized; 13 (5.3%) were discontinued due to adverse events. From the remaining 231 randomized participants, 65 (28.1%) dropped out, and 166 (71.9%) did not. The Non-retention group included 95 participants not exposed to retention strategies, of which 43 (45.2%) dropped out. The Retention group included 136 participants exposed to enhanced retention strategies, of which 22 (16.2%) dropped out. Dropout risk factors included being unmarried, a longer diabetes duration, using oral antidiabetics as compared to not using, worse executive function and chronic pain. After adjusting for exposure to retention strategies, worse baseline executive function composite score (p = 0.001) and chronic pain diagnosis (p = 0.032) were independently associated with a greater risk of dropping out. The probability of dropping out decreased with longer exposure to retention strategies and the dropout rate per month decreased from 4.1% to 1.8% (p = 0.04) on retention strategies.Baseline characteristics allow prediction of dropping out from a clinical trial in older participants. Retention strategies has been effective at minimizing the impact of dropout-related risk factors.Clinical trials.gov NCT2415556 3/23/2015 (www.gov).

SUMMARY This review recapitulates the head-up tilt test, which is commonly used for evaluation of orthostatic syndromes and dysautonomia. Tilt test evaluates autonomic system responses to orthostatic stress. Established tilt testing includes monitoring of heart rate and blood pressure; adding capnography and cerebral blood flow monitoring expands its diagnostic yield and allows assessing cerebral blood flow regulation. Common syndromes detectable by the tilt test are neurally mediated syncope (vasodepressor, cardiovagal, or mixed), orthostatic hypotension, postural orthostatic tachycardia syndrome, hypocapnic cerebral hypoperfusion, and orthostatic cerebral hypoperfusion syndrome. This review describes relevant physiology, tilt test protocols, diagnostic criteria for orthostatic syndromes, grading test results, diagnostic accuracy, limitations of the tilt test, and safety considerations.

Objective: To model the probability of improvement on gait and cognition among patients who received intranasal insulin (INI) Methods: 223 patients (1diabetes, 117 controls) randomized into 4 arms: 55 diabetes placebo, 51 diabetes INI, 59 control placebo, 58 control INI, 1women, 66±9 years of age. INI treatment lasted 24 weeks with 40 IU of INI (Novolin® R, off-label use) or placebo (sterile saline) . normal walk speed (NW) , dual task walk speed (DT) , executive function (EF) , verbal memory (VB) . Improvement due was defined to be better performance at end of treatment compared to baseline. Eleven of 20 baseline predictors were selected in a multivariable generalized linear model with logit link and binomial error to predict the probability of improvement among the 1patients who received INI. Results: 58% of the INI patients improved on NW, 62% improved on DT, 69% EF, and 47% VB. The predictors for the final model included 6 baseline demographic variables (age, number of years of diabetes, number of years in school, Wechsler Adult Reading test, global depression score, and waist circumference; and 5 metabolism-related variables of hemoglobinA1c, fasting plasma glucose, total cholesterol, microalbumin in urine, and microalbumin to creatinine ratio. Conclusion: Modeling technique also allows us to compute the estimated probability of improvement for any individual patients, thus, enabling us to understand better the particular demographic and metabolic profiles that best predict who among those receiving INI could benefit the most from the treatment. Funded by NIH-NIDDK (1R01DK103902) , FDA (IND#107690) , Novo Nordisk, Inc. (ISS-001063) , Medtronic Inc. (NERP15-0310) and registered on www.clinicaltrials.gov (NCT02415556.) Disclosure L.H.Ngo: None. V.Novak: None. P.Novak: Stock/Shareholder; Moderna, Inc., Novavax, Pfizer Inc., Prothena. C.Mantzoros: Advisory Panel; Novo Nordisk. W.Dai: None. V.Lioutas: None. Funding Funded by NIH-NIDDK (1R01DK103902) , FDA (IND#107690) , Novo Nordisk, Inc. (ISS-001063) , Medtronic Inc. (NERP15-0310)

The efficiency of an electrochemical power source, to a great degree, depends on the internal resistance of the system. This internal resistance includes interface resistance between current collector and active electrode mass, solid electrolyte and electrode, and other systems. The developed method and device enable non-destructive, non-contact evaluation of the interface resistance. Results enable the prediction and optimization of electrochemical power sources properties, especially their power.

Quantitative grading of testing has research and clinical relevance. QASAT (quantitative scale for grading of cardiovascular reflex tests, transcranial Doppler, sudomotor testing, and small fiber densities from skin biopsies) is an objective instrument for grading dysautonomia, related small fiber neuropathy and cerebral blood flow. QASAT uses established autonomic tests (deep breathing, Valsalva maneuver, tilt test, sudomotor test) and skin biopsies for assessment of small fibers. Calculations of scores are complex. This paper presents a qpack-an open source software package that implements QASAT in a Python programming language. The qpack automatically generates reproducible scores of each test and reduces calculation errors. Datasets for verifying the correct qpack implementation are provided. The goal of qpack is to facilitate availability, reproducibility, and quality of autonomic studies and skin biopsies for assessment of small fibers. Qpack is easy to use with standard Python distributions, can be incorporated into routine clinical or research autonomic testing and it is freely available.

The purpose of this study was to describe cerebrovascular, neuropathic, and autonomic features of post-acute sequelae of coronavirus disease 2019 ((COVID-19) PASC).This retrospective study evaluated consecutive patients with chronic fatigue, brain fog, and orthostatic intolerance consistent with PASC. Controls included patients with postural tachycardia syndrome (POTS) and healthy participants. Analyzed data included surveys and autonomic (Valsalva maneuver, deep breathing, sudomotor, and tilt tests), cerebrovascular (cerebral blood flow velocity [CBFv] monitoring in middle cerebral artery), respiratory (capnography monitoring), and neuropathic (skin biopsies for assessment of small fiber neuropathy) testing and inflammatory/autoimmune markers.Nine patients with PASC were evaluated 0.8 ± 0.3 years after a mild COVID-19 infection, and were treated as home observations. Autonomic, pain, brain fog, fatigue, and dyspnea surveys were abnormal in PASC and POTS (n = 10), compared with controls (n = 15). Tilt table test reproduced the majority of PASC symptoms. Orthostatic CBFv declined in PASC (-20.0 ± 13.4%) and POTS (-20.3 ± 15.1%), compared with controls (-3.0 ± 7.5%, p = 0.001) and was independent of end-tidal carbon dioxide in PASC, but caused by hyperventilation in POTS. Reduced orthostatic CBFv in PASC included both subjects without (n = 6) and with (n = 3) orthostatic tachycardia. Dysautonomia was frequent (100% in both PASC and POTS) but was milder in PASC (p = 0.002). PASC and POTS cohorts diverged in frequency of small fiber neuropathy (89% vs 60%) but not in inflammatory markers (67% vs 70%). Supine and orthostatic hypocapnia was observed in PASC.PASC following mild COVID-19 infection is associated with multisystem involvement including: (1) cerebrovascular dysregulation with persistent cerebral arteriolar vasoconstriction; (2) small fiber neuropathy and related dysautonomia; (3) respiratory dysregulation; and (4) chronic inflammation. ANN NEUROL 2022;91:367-379.

Autonomic complaints are frequently encountered in clinical practice. They can be due to primary autonomic disorders or secondary to other medical conditions. Primary autonomic disorders can be categorized as orthostatic intolerance syndromes and small fiber neuropathies; the latter are associated with autonomic failure, pain, or their combinations. The review outlines orthostatic intolerance syndromes (neurally mediated syncope, orthostatic hypotension, postural tachycardia syndrome, inappropriate sinus tachycardia, orthostatic cerebral hypoperfusion syndrome, and hypocapnic cerebral hypoperfusion) and small fiber neuropathies (sensory/autonomic/mixed, acute/subacute/chronic, idiopathic/secondary, inflammatory and noninflammatory). Several specific autonomic syndromes (diabetic neuropathy, primary hyperhidrosis, paroxysmal sympathetic hyperactivity, autonomic dysreflexia), neurogenic bladder, and gastrointestinal motility disorders are discussed as well.

Mast cell disorders including hereditary alpha tryptasemia (HαT) and idiopathic mast cell activation syndrome (MCAS) can be associated with neurologic symptoms such as orthostatic intolerance, pain, and cognitive impairment. The origin of these symptoms is not well understood.To characterize neurologic findings in patients with HαT and MCAS through objective measurements.Patients with a confirmed diagnosis of HαT or MCAS with neurologic symptoms were referred for standardized autonomic testing encompassing Valsalva maneuver, deep breathing, sudomotor and tilt tests with cerebral blood flow velocity (CBFv) determination, and skin biopsies for small fiber neuropathy (SFN).There were 15 patients with HαT (age 44.4 ± 15.9 years), 16 with MCAS (34.4 ± 15.5), and 14 matched controls who were evaluated. Baseline serum tryptase level was increased in patients with HαT when compared with patients with MCAS (14.3 ± 2.5 ng/mL vs 3.8 ± 1.8; P.001) and neurologic symptoms were similar between the 2 groups. When compared with controls, orthostatic CBFv was reduced in HαT (-24.2 ± 14.3%; P.001) and MCAS (-20.8 ± 5.5%; P.001). Reduced nerve fibers consistent with SFN were found in 80% of patients with HαT and 81% of those with MCAS. Mild-to-moderate dysautonomia was detected in all patients with HαT and MCAS when results of sympathetic, parasympathetic, and sudomotor tests were combined.We provide evidence of reduced orthostatic CBFv and SFN associated with mild-to-moderate autonomic dysfunction in patients with HαT and MCAS. Our findings suggest that comprehensive autonomic testing may be helpful to explain neurologic symptoms and guide treatment in patients with HαT and MCAS.

Type 2 diabetes mellitus (T2DM) increases the risk of dementia. Intranasal insulin (INI) has emerged as treatment for T2DM-related cognitive impairment. This randomized, doubled blind trial consisted of 24-week treatment with 40 IU of intranasal insulin (Novolin® R) or placebo (sterile saline) once daily and 24-week follow-up period. T2DM and control participants > 50 years old and able to walk for 6 minutes, were enrolled. The primary outcomes were INI effect on cognition and normal and dual task walking. A total of 244 participants (122 women; 65.8 ± 9.1 years old) were randomized in the four groups (57 DM-INI, 58 DM-Placebo, 65 Control-INI, 64 Control-Placebo). Of 223 at baseline, 174 completed treatment (84 DM [70% of planned enrollment] and 90 controls [100%]), and 156 (69 DM) completed the follow-up. In T2DM, INI did not improve cognitive outcomes or depression as compared to placebo. In controls, INI improved verbal learning during on-treatment (p=0.03) and post-treatment (p=0.03) periods (Mixed Models). DM-INI group had faster normal walking at baseline and on-treatment (p Disclosure V. Novak: Advisory Panel; Spouse/Partner; Endonovo Therapeutics, Inc., Consultant; Spouse/Partner; Dysimmune Foundtation, Other Relationship; Spouse/Partner; Oxford University Press. L. Aponte becerra: None. L. H. Ngo: Consultant; Self; Five Islands Consulting, Other Relationship; Self; Radiological Society of America. C. Mantzoros: Advisory Panel; Self; Amgen Inc., GENFIT, Intercept Pharmaceuticals, Inc., Novo Nordisk, Regeneron Pharmaceuticals Inc. P. Novak: Other Relationship; Self; Dysimmune Foundation, Endonovo Therapeutics, Oxford Press. R. Mcglinchey: None. W. Dai: None. V. Lioutas: Consultant; Self; QMetis. S. Buss: Consultant; Self; Kinto Care. C. B. Fortier: None. F. Khan: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK103902); U.S. Food and Drug Administration (IND107690); Novo Nordisk (ISS-001063), Medtronic (NERP15-0310); World Health Organization (UTN-U111-1175-1588)

Effective recruitment and retention strategies in clinical trials are essential to achieve the enrollment goals. We aimed to identify baseline characteristics predicting dropouts and analyze the effect of retention strategies within the MemAID elderly cohort. The trial consisted of 12 visits during 24 weeks of INI/placebo treatment and 24 weeks of follow-up. Retention strategies were implemented 2 years after the beginning of the study and included incentives (meals, stipend, transportation), revised eligibility criteria, and flexibility in scheduling. A total of 244 participants (122 female; 65.8 ± 9.1 years old, 115 diabetes (DM)) were randomized, and completed baseline (223), treatment (174), and follow-up (156). After randomization, 65 participants (27%, 30 DM [46%]) dropped out. Dropouts occurred earlier in the study (19.6% cumulative failure at 100 days) as compared to later (25.3% cumulative failure at 300 days). Cox models showed no risk of dropout with DM diagnosis, but increased risk (p Disclosure F. Khan: None. D. F. Isaza-pierotti: None. P. Novak: Other Relationship; Self; Dysimmune Foundation, Endonovo Therapeutics, Oxford Press. C. Mantzoros: Advisory Panel; Self; Amgen Inc., GENFIT, Intercept Pharmaceuticals, Inc., Novo Nordisk, Regeneron Pharmaceuticals Inc. L. H. Ngo: Consultant; Self; Five Islands Consulting, Other Relationship; Self; Radiological Society of America. V. Novak: Advisory Panel; Spouse/Partner; Endonovo Therapeutics, Inc., Consultant; Spouse/Partner; Dysimmune Foundtation, Other Relationship; Spouse/Partner; Oxford University Press. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK103902); U.S. Food and Drug Administration (IND107690); Novo Nordisk (ISS-001063), Medtronic (NERP15-0310); World Health Organization (UTN-U111-1175-1588)

INI has emerged as a potential treatment for T2DM-related functional decline and is safe in adults without T2DM. However, INI safety in T2DM-IDDM is unknown. We aimed to demonstrate safety of long-term INI use in T2DM-IDDM MemAID participants. We screened 86 participants with T2DM-IDDM, 14 were randomized (9 INI/5 Placebo), 9 started treatment (5 INI [60±14 years, 2 Female]; 4 Placebo [68±2 years, 1 Female]). Of those, 2-INI and 3-Placebo participants completed 24 weeks of treatment and 24 weeks of follow-up. Participants underwent one week of continuous glucose monitoring (CGM)(Medtronic IPro2) at baseline and after INI (Novolin® R ) or placebo initiation. HbA1c, fasting plasma and capillary glucose, and insulin were measured throughout the study. Insulin levels were unchanged across the study. In 2 INI-treated participants, HbA1c, fasting plasma and capillary glucose declined from baseline, but the average values were similar during treatment and follow up, and comparable to 3 placebo-treated participants. Both INI-treated participants had adjustments of IDDM regimens. Capillary glucose did not decline 2 hours after INI administration, and there were no interactions between INI and subcutaneous insulin. There were no INI-related serious adverse events. Of 13 hypoglycemia (HG) episodes across the study, 2 asymptomatic level-1 HG (15.4%) occurred in INI group and 7 (53.8%) in placebo group. There were 2 asymptomatic level-2 HG (15.4%) in both INI and placebo groups. INI therapy was not associated with serious adverse events or HG in older participants with T2DM-IDDM. This study may pave the way towards future larger studies evaluating the safety of concomitant administration of INI and subcutaneous insulin (NCT02415556). Disclosure L. Aponte becerra: None. B. Galindo mendez: None. F. Khan: None. C. Mantzoros: Advisory Panel; Self; Amgen Inc., GENFIT, Intercept Pharmaceuticals, Inc., Novo Nordisk, Regeneron Pharmaceuticals Inc. P. Novak: Other Relationship; Self; Dysimmune Foundation, Endonovo Therapeutics, Oxford Press. V. Lioutas: Consultant; Self; QMetis. L. H. Ngo: Consultant; Self; Five Islands Consulting, Other Relationship; Self; Radiological Society of America. Memaid investigators (j. trevino): n/a. V. Novak: Advisory Panel; Spouse/Partner; Endonovo Therapeutics, Inc., Consultant; Spouse/Partner; Dysimmune Foundtation, Other Relationship; Spouse/Partner; Oxford University Press. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK103902); U.S. Food and Drug Administration (IND107690); Novo Nordisk (ISS-001063), Medtronic (NERP15-0310); World Health Organization (UTN-U111-1175-1588)

SUMMARY The autonomic nervous system is a complex neural network that controls several organ systems. Its assessment includes a detailed history of autonomic functions, clinical examination, and autonomic tests. Most widely used is a battery of tests that assess cardiovascular reflex autonomic and sudomotor tests, which include deep breathing (assesses parasympathetic function), Valsalva maneuver, tilt test (both assess parasympathetic and adrenergic functions), and sudomotor testing for the evaluation of postganglionic sudomotor fibers. These basic tests represent a foundation of autonomic testing. Nevertheless, the autonomic nervous system also controls organ systems not directly assessed by basic tests. This review describes a number of auxiliary autonomic tests that can be used in addition to basic autonomic tests or can be used independently to explore particular autonomic functions or to answer a specific clinical question. The auxiliary tests described in this review evaluate cardiovascular, thermoregulatory, gastrointestinal, genitourinary, eye, and exocrine functions. These tests are cold pressor test, sustained handgrip maneuver, reverse tilt test, venoarteriolar reflex, laser Doppler flare imaging, microneurography, neck suction, lower body negative pressure, venous occlusion plethysmography, pharmacologic assessment of postganglionic sympathetic outflow, plasma norepinephrine, sympathetic skin response, video cinefluoroscopic swallowing test, esophageal manometry test, small bowel manometry test, wireless motility capsule test, urodynamic studies, penile plethysmography, intracavernosal papaverine injection, infrared video pupillography, corneal confocal microscopy, pupillary response to dilute pilocarpine and hydroxyamphetamine, Schirmer test, tear osmolarity test, and salivary secretion test. The protocol of each test is described in detail. This review can be used as a quick reference for the auxiliary autonomic tests.

Mast cells (MCs) are important in intestinal homeostasis and pathogen defense but are also implicated in many of the clinical manifestations in disorders such as irritable bowel syndrome. The utility of specifically staining for MCs in order to quantify and phenotype them in intestinal biopsies in patients with gastrointestinal (GI) symptoms is controversial and is not a widely adopted practice. Whether or not intestinal MCs are increased or have a unique phenotype in individuals with hereditary alpha-tryptasemia (HαT), who have extra copies of the mast cell tryptase gene TPSAB1 and typically elevated baseline serum tryptase levels >8ng/mL is not known. We examined the duodenal biopsies of 17 patients with HαT and compared them to 15 patients with mast cell activation syndrome who had baseline serum tryptases

Background Hereditary alpha-tryptasemia (HαT) is an autosomal dominant genetic trait characterized by multiple copies of the alpha-tryptase gene at the TPSAB1 locus. Previously described symptomatology involves multiple organ systems and anaphylaxis. The spectrum of mast cell activation symptoms is unknown, as is its association with specific genotypes. Objective To describe clinical, laboratory, and genetic characteristics of patients referred for the evaluation of mast cell activation–related symptoms and genotype-confirmed HαT. Methods We retrospectively describe clinical characteristics, baseline tryptase, and tryptase genotype in 101 patients. Patients were referred for mast cell activation–related symptoms and underwent genotyping to confirm diagnosis of HαT. Results Of 101 patients, 80% were female with average tryptase of 17.2 ng/mL. Tryptase was less than 11.4 ng/mL in 8.9% and greater than 20 ng/mL in 22.3% (range 6.2-51.3 ng/mL). KIT D816V mutation was negative in all subjects tested. 2α:3β was the most common genotype but did not correlate with tryptase levels. Unprovoked anaphylaxis was noted in 57% of the subjects with heterogeneous genotypes. Most common symptoms include gastrointestinal, cutaneous, psychiatric, pulmonary, cardiovascular, and neurologic. A total of 85% of patients were taking H1- or H2-antihistamines with partial symptom relief. Omalizumab was effective at suppressing anaphylaxis or urticaria in 94% of the patients. Conclusion HαT encompasses a broad range of baseline tryptase and should be considered in patients with symptoms of mast cell activation and tryptase levels greater than 6.2 ng/mL. Patients may present with complex symptomatology including cutaneous, gastrointestinal, neurologic, and psychiatric symptoms and anaphylaxis, some of which respond to omalizumab.

ObjectiveTo evaluate the safety and efficacy of l-serine in humans with hereditary sensory autonomic neuropathy type I (HSAN1).MethodsIn this randomized, placebo-controlled, parallel-group trial with open-label extension, patients aged 18–70 years with symptomatic HSAN1 were randomized to l-serine (400 mg/kg/day) or placebo for 1 year. All participants received l-serine during the second year. The primary outcome measure was the Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNS). Secondary outcomes included plasma sphingolipid levels, epidermal nerve fiber density, electrophysiologic measurements, patient-reported measures, and adverse events.ResultsBetween August 2013 and April 2014, we enrolled and randomized 18 participants, 16 of whom completed the study. After 1 year, the l-serine group experienced improvement in CMTNS relative to the placebo group (−1.5 units, 95% CI −2.8 to −0.1, p = 0.03), with evidence of continued improvement in the second year of treatment (−0.77, 95% CI −1.67 to 0.13, p = 0.09). Concomitantly, deoxysphinganine levels dropped in l-serine-treated but not placebo-treated participants (59% decrease vs 11% increase; p < 0.001). There were no serious adverse effects related to l-serine.ConclusionHigh-dose oral l-serine supplementation appears safe in patients with HSAN1 and is potentially effective at slowing disease progression.Clinicaltrials.gov identifierNCT01733407.Classification of evidenceThis study provides Class I evidence that high-dose oral l-serine supplementation significantly slows disease progression in patients with HSAN1.

Currently available techniques for the evaluation of small fiber neuropathy and related sudomotor function remain suboptimal. Electrochemical skin conductance (ESC) has recently been introduced as a simple noninvasive and fast method for the detection of sudomotor dysfunction. The purpose of this review is to synthesize and appraise research using ESC measurements for sudomotor evaluation in adults. Electronic databases including MEDLINE and Google Scholar were searched (up to March 13, 2017). The search strategy included the following terms: "electrochemical skin conductance,” “Sudoscan,” and “EZSCAN.” Evidence was graded according to defined quality indicators including (1) level of evidence; (2) use of established tests as reference tests (e.g., quantitative sudomotor axon test [QSART], sympathetic skin responses [SSR], thermoregulatory sweat test [TST], and skin biopsies to assess sudomotor and epidermal small fibers); (3) use of consecutive/non-consecutive subjects; and (4) study design (prospective/retrospective). A total of 24 studies met the inclusion criteria. These were classified into preclinical, normative, comparative/diagnostic, or interventional. ESC measurement properties, diagnostic accuracy, and similarities to and differences from established tests were examined. ESC measurements expand the arsenal of available tests for the evaluation of sudomotor dysfunction. The advantages and disadvantages of ESC versus established tests for evaluating sudomotor/small fiber function reviewed herein should be used as evidence to inform future guidelines on the assessment of sudomotor function.

We present the redesign of the Slovenian avalanche bulletin, published regularly during the winter season to warn against avalanche danger and to provide specific information for advanced users. The former version included an estimation of danger on a scale from one to five with supporting text for the whole country, while the new one offers an additional graphical description, specified for several geographical regions. The paper highlights the importance of usability testing with users to understand how they think about avalanches (problem first vs location first), what information they use to decide etc. Among the key findings is the fact that the word “danger” should be emphasized in all aspects of communication of avalanche conditions, starting with the name of the bulletin.

Background Type 2 diabetes mellitus (T2DM) accelerates brain aging and increases the risk for dementia. Insulin is a key neurotrophic factor in the brain, where it modulates energy metabolism, neurovascular coupling, and regeneration. Impaired insulin-mediated brain signaling and central insulin resistance may contribute to cognitive and functional decline in T2DM. Intranasal insulin (INI) has emerged as a potential therapy for treating T2DM-related cognitive impairment. Methods/design Ongoing from 2015, a prospective, two-center, randomized, double-blind, placebo-controlled trial of 210 subjects (120 T2DM and 90 non-diabetic older adults) randomized into four treatment arms (60 T2DM-INI, 60 T2DM-Placebo, 45 Control-INI, and 45 Control-Placebo) evaluating the long-term effects of daily intranasal administration of 40 International Units (IU) of human insulin, as compared to placebo (sterile saline) over 24 weeks and 24 weeks of post-treatment follow-up. Study outcomes are: 1) long-term INI effects on cognition, daily functionality, and gait speed; 2) identifying a clinically relevant phenotype that predicts response to INI therapy; 3) long-term safety. Conclusion This study addresses an important knowledge gap about the long-term effects of intranasal insulin on memory and cognition in older people with T2DM and non-diabetic controls, and may provide a novel therapeutic target for prevention and treatment of cognitive and functional decline and dementia. Trial Registration NCT02415556

The tilt provoked most of the patient’s symptoms, including dizziness, nausea and loss of consciousness, which was consistent with postural tachycardia syndrome and neurally mediated syncope of mixed type.

The tilt test provoked this patient’s typical waxing and waning spells associated with palpitations and dizziness. Testing showed mild adrenergic dysfunction of unclear clinical significance and small fiber neuropathy. Anxiety can mimic and exaggerate symptoms of orthostatic intolerance.

Small fiber neuropathy, mixed, length-dependent can be autoimmune even if no antineuronal antibodies can be found. Yet the seronegative small fiber neuropathy may still respond to therapy with immune globulins.

This patient has a history of Lyme disease with persistent cognitive and sensory symptoms, and he may have posttreatment Lyme disease syndrome (PLDS). The autonomic testing showed small fiber neuropathy and cerebral autoregulatory failure.

Autonomic testing revealed length-dependent small fiber neuropathy affecting sensory fibers. Repeated titer of acetylcholine ganglionic antibody was negative, but repeated epidermal nerve fiber density testing showed progressive deterioration. Symptoms improved with intravenous immune globulin therapy.

Dizziness can be associated with cerebral autoregulatory failure and hypovolemia, which can be detected by pulse pressure collapse during the Valsalva maneuver.

Small fiber neuropathy is associated with adrenergic failure. Anxiety is common and occasionally can be identified as a transient elevation of heart rate, blood pressure, and cerebral blood flow velocity.

In this patient, autonomic tests were positive for small fiber neuropathy, mixed, length-dependent. Clinical workup was positive for ganglionic acetylcholine receptor antibody. Patient subsequently improved with immunotherapy with intravenous immunoglobulins.