Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration.

Metabolites in the kynurenine pathway, generated by tryptophan degradation, are thought to play an important role in neurodegenerative disorders, including Alzheimer's and Huntington's diseases. In these disorders, glutamate receptor-mediated excitotoxicity and free radical formation have been correlated with decreased levels of the neuroprotective metabolite kynurenic acid. Here, we describe the synthesis and characterization of JM6, a small-molecule prodrug inhibitor of kynurenine 3-monooxygenase (KMO). Chronic oral administration of JM6 inhibits KMO in the blood, increasing kynurenic acid levels and reducing extracellular glutamate in the brain. In a transgenic mouse model of Alzheimer's disease, JM6 prevents spatial memory deficits, anxiety-related behavior, and synaptic loss. JM6 also extends life span, prevents synaptic loss, and decreases microglial activation in a mouse model of Huntington's disease. These findings support a critical link between tryptophan metabolism in the blood and neurodegeneration, and they provide a foundation for treatment of neurodegenerative diseases.

Publisher Correction: The effect of large-scale anti-contagion policies on the COVID-19 pandemic.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The effect of large-scale anti-contagion policies on the COVID-19 pandemic.

Governments around the world are responding to the coronavirus disease 2019 (COVID-19) pandemic1, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with unprecedented policies designed to slow the growth rate of infections. Many policies, such as closing schools and restricting populations to their homes, impose large and visible costs on society; however, their benefits cannot be directly observed and are currently understood only through process-based simulations2-4. Here we compile data on 1,700 local, regional and national non-pharmaceutical interventions that were deployed in the ongoing pandemic across localities in China, South Korea, Italy, Iran, France and the United States. We then apply reduced-form econometric methods, commonly used to measure the effect of policies on economic growth5,6, to empirically evaluate the effect that these anti-contagion policies have had on the growth rate of infections. In the absence of policy actions, we estimate that early infections of COVID-19 exhibit exponential growth rates of approximately 38% per day. We find that anti-contagion policies have significantly and substantially slowed this growth. Some policies have different effects on different populations, but we obtain consistent evidence that the policy packages that were deployed to reduce the rate of transmission achieved large, beneficial and measurable health outcomes. We estimate that across these 6 countries, interventions prevented or delayed on the order of 61 million confirmed cases, corresponding to averting approximately 495 million total infections. These findings may help to inform decisions regarding whether or when these policies should be deployed, intensified or lifted, and they can support policy-making in the more than 180 other countries in which COVID-19 has been reported7.

Insights into ALD and AUD diagnosis and prognosis: Exploring AI and multimodal data streams.

The rapid evolution of artificial intelligence and the widespread embrace of digital technologies have ushered in a new era of clinical research and practice in hepatology. Although its potential is far from realization, these significant strides have generated new opportunities to address existing gaps in the delivery of care for patients with liver disease. In this review, we discuss how artificial intelligence and opportunities for multimodal data integration can improve the diagnosis, prognosis, and management of alcohol-associated liver disease. An emphasis is made on how these approaches will also benefit the detection and management of alcohol use disorder. Our discussion encompasses challenges and limitations, concluding with a glimpse into the promising future of these advancements.

Priming chondrocytes during expansion alters cell behavior and improves matrix production in 3D culture.

OBJECTIVE: Cartilage tissue engineering strategies that use autologous chondrocytes require in vitro expansion of cells to obtain enough cells to produce functional engineered tissue. However, chondrocytes dedifferentiate during expansion culture, limiting their ability to produce chondrogenic tissue and their utility for cell-based cartilage repair strategies. The current study identified conditions that favor cartilage production and the mechanobiological mechanisms responsible for these benefits. DESIGN: Chondrocytes were isolated from juvenile bovine knee joints and cultured with (primed) or without (unprimed) a growth factor cocktail. Gene expression, cell morphology, cell adhesion, cytoskeletal protein distribution, and cell mechanics were assessed. Following passage 5, cells were embedded into agarose hydrogels to evaluate functional properties of engineered cartilage. RESULTS: Priming cells during expansion culture altered cell phenotype and chondrogenic tissue production. Unbiased ribonucleic acid-sequencing analysis suggested, and experimental studies confirmed, that growth factor priming delays dedifferentiation associated changes in cell adhesion and cytoskeletal organization. Priming also overrode mechanobiological pathways to prevent chondrocytes from remodeling their cytoskeleton to accommodate the stiff, monolayer microenvironment. Passage 1 primed cells deformed less and had lower yes associated protein 1 activity than unprimed cells. Differences in cell adhesion, morphology, and cell mechanics between primed and unprimed cells were mitigated by passage 5. CONCLUSIONS: Priming suppresses mechanobiologic cytoskeletal remodeling to prevent chondrocyte dedifferentiation, resulting in more cartilage-like tissue-engineered constructs.

Congenital Eyelid Imbrication and Floppy Eyelid Syndromes Complicated by Eversion due to Prostaglandin E Infusion in a Patient With Trisomy 21 and Tetralogy of Fallot.

Congenital eyelid imbrication syndrome is a rare eyelid finding where a long upper lid overlaps the lower lid when the eyes are closed. To date, congenital eyelid imbrication syndrome has been described in the literature less than 10 times. We present a case of congenital eyelid imbrication syndrome in a patient with trisomy 21 and tetralogy of Fallot on a prostaglandin E infusion to maintain a patent ductus arteriosus prior to definitive heart surgery. While on the infusion, the patient developed peripheral edema and flushing due to vasodilation. This coincided with eyelid swelling, conjunctival chemosis, and eversion of the eyelids. Upon cessation of the prostaglandin E1 infusion, his eyelid eversion resolved.

The digital transformation of hepatology: The patient is logged in.

The rise in innovative digital health technologies has led a paradigm shift in health care toward personalized, patient-centric medicine that is reaching beyond traditional brick-and-mortar facilities into patients' homes and everyday lives. Digital solutions can monitor and detect early changes in physiological data, predict disease progression and health-related outcomes based on individual risk factors, and manage disease intervention with a range of accessible telemedicine and mobile health options. In this review, we discuss the unique transformation underway in the care of patients with liver disease, specifically examining the digital transformation of diagnostics, prediction and clinical decision-making, and management. Additionally, we discuss the general considerations needed to confirm validity and oversight of new technologies, usability and acceptability of digital solutions, and equity and inclusivity of vulnerable populations.

Formation of multicellular colonies by choanoflagellates increases susceptibility to capture by amoeboid predators.

Many heterotrophic microbial eukaryotes are size-selective feeders. Some microorganisms increase their size by forming multicellular colonies. We used choanoflagellates, Salpingoeca helianthica, which can be unicellular or form multicellular colonies, to study the effects of multicellularity on vulnerability to predation by the raptorial protozoan predator, Amoeba proteus, which captures prey with pseudopodia. Videomicrography used to measure the behavior of interacting S. helianthica and A. proteus revealed that large choanoflagellate colonies were more susceptible to capture than were small colonies or single cells. Swimming colonies produced larger flow fields than did swimming unicellular choanoflagellates, and the distance of S. helianthica from A. proteus when pseudopod formation started was greater for colonies than for single cells. Prey size did not affect the number of pseudopodia formed and the time between their formation, pulsatile kinematics and speed of extension by pseudopodia, or percent of prey lost by the predator. S. helianthica did not change swimming speed or execute escape maneuvers in response to being pursued by pseudopodia, so size-selective feeding by A. proteus was due to predator behavior rather than prey escape. Our results do not support the theory that the selective advantage of becoming multicellular by choanoflagellate-like ancestors of animals was reduced susceptibility to protozoan predation.

Eye-related quality of life and activities of daily living in pediatric retinoblastoma patients: A single-center, non-controlled, cross-sectional analysis.

INTRODUCTION: Childhood retinoblastoma (RB) survivors are known to experience long-term morbidity; however, eye-related quality of life (QoL), which may significantly impact activities of daily living (ADL), has not been extensively studied in this population. The purpose of this cross-sectional study was to assess QoL and ADL morbidity among school-age RB survivors. METHODS: The Pediatric Eye Questionnaire (PedEyeQ) and Roll Evaluation Activities of Life (REAL) were administered to childhood RB survivors between ages 5 and 17 followed at St. Louis Children's Hospital. Visual outcomes and demographic predictors of ADL and QoL were examined. RESULTS: Total 23 patients (mean age 9.6 years) consented for participation in this study. All children experienced at least one domain on the PedEyeQ ≤ 80%. Subjects and parents marked functional vision to be the most impacted domain with a median score of 82.5 and 83.4, respectively. Only 10.5% of participants scored above 75% on the ADL percentile rank. On multivariable analysis, decreased visual acuity (VA) was associated with worse "Child Functional" (odds ratio [OR] -59.2, p = .004) and "Parent Worry Function" (OR -66.5, p = .03) metrics. Decreased contrast sensitivity was associated with worse "Parent Impact" (OR 21.0, p = .02) and "Parent Worry Function" (OR 3.70, p = .04) metrics. Longer saccade horizontal latency was associated with a worse "Parent Worry Function" metric (OR 43.0, p = .009). On multivariable analysis, no variable was significantly associated with ADL. CONCLUSION: RB survivors have impaired QoL and ADL. Screening for such difficulties should strongly be considered for all RB patients. Additional studies may help predict morbidity based on visual metrics and demographic data.

Neonatal Intensive Care Unit Network Neurobehavioral Scale Profiles in Full-Term Infants: Associations with Maternal Adversity, Medical Risk, and Neonatal Outcomes.

OBJECTIVES: To examine healthy, full-term neonatal behavior using the Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS) in relation to measures of maternal adversity, maternal medical risk, and infant brain volumes. STUDY DESIGN: This was a prospective, longitudinal, observational cohort study of pregnant mothers followed from the first trimester and their healthy, full-term infants. Infants underwent an NNNS assessment and high-quality magnetic resonance imaging 2-5 weeks after birth. A latent profile analysis of NNNS scores categorized infants into neurobehavioral profiles. Univariate and multivariate analyses compared differences in maternal factors (social advantage, psychosocial stress, and medical risk) and neonatal characteristics between profiles. RESULTS: The latent profile analysis of NNNS summary scales of 296 infants generated 3 profiles: regulated (46.6%), hypotonic (16.6%), and fussy (36.8%). Infants with a hypotonic profile were more likely to be male (χ2 = 8.601; P = .014). Fussy infants had smaller head circumferences (F = 3.871; P = .022) and smaller total brain (F = 3.522; P = .031) and cerebral white matter (F = 3.986; P = .020) volumes compared with infants with a hypotonic profile. There were no differences between profiles in prenatal maternal health, social advantage, or psychosocial stress. CONCLUSIONS: Three distinct neurobehavioral profiles were identified in healthy, full-term infants with hypotonic and fussy neurobehavioral features related to neonatal brain volumes and head circumference, but not prenatal exposure to socioeconomic or psychosocial adversity. Follow-up beyond the neonatal period will determine if identified profiles at birth are associated with subsequent clinical or developmental outcomes.

Acute on Chronic Liver Failure From Nonalcoholic Fatty Liver Disease: A Growing and Aging Cohort With Rising Mortality.

BACKGROUND AND AIMS: We assessed the burden of nonalcoholic fatty liver disease (NAFLD)-related acute on chronic liver failure (ACLF) among transplant candidates in the United States, along with waitlist outcomes for this population. APPROACH AND RESULTS: We analyzed the United Network for Organ Sharing registry from 2005 to 2017. Patients with ACLF were identified using the European Association for the Study of the Liver/Chronic Liver Failure criteria and categorized into NAFLD, alcohol-associated liver disease (ALD), and hepatitis C virus (HCV) infection. We used linear regression and Chow's test to determine significance in trends and evaluated waitlist outcomes using Fine and Gray's competing risks regression and Cox proportional hazards regression. Between 2005 and 2017, waitlist registrants for NAFLD-ACLF rose by 331.6% from 134 to 574 candidates (P < 0.001), representing the largest percentage increase in the study population. ALD-ACLF also increased by 206.3% (348-1,066 registrants; P < 0.001), whereas HCV-ACLF declined by 45.2% (P < 0.001). As of 2017, the NAFLD-ACLF population consisted primarily of persons aged ≥60 years (54.1%), and linear regression demonstrated a significant rise in the proportion of patients aged ≥65 in this group (ß = 0.90; P = 0.011). Since 2014, NAFLD-ACLF grade 1 was associated with a greater risk of waitlist mortality relative to ALD-ACLF (subhazard ratio [SHR] = 1.24; 95% confidence interval [CI], 1.05-1.44) and HCV-ACLF (SHR = 1.35; 95% CI, 1.08-1.71), among patients aged ≥60 years. Mortality was similar among the three groups for patients with ACLF grade 2 or 3. CONCLUSIONS: NAFLD is the fastest rising etiology of cirrhosis associated with ACLF among patients listed in the United States. As the NAFLD population continues to grow and age, patients with NAFLD-ACLF will likely have the highest risk of waitlist mortality.

Dynamics of cellular immune responses in recipients of renal allografts positive for hepatitis B surface antigen.

BACKGROUND/PURPOSE: Hepatitis B surface antigen (HBsAg)-positive renal transplantation recipients must take lifelong immunosuppressants and nucleotide analogues (NAs). We investigated the cellular immune responses of HBsAg-positive renal transplantation recipients taking immunosuppressants and NAs. METHODS: Blood samples were collected from HBsAg-positive individuals with end-stage renal disease on the transplant waiting list (Group 1) and renal transplantation recipients taking immunosuppressants and NAs (Group 2) or immunosuppressants without NAs (Group 3). Hepatitis B virus (HBV)-specific pentamers were used to quantify circulating HBV-specific CD8+ T cells. RESULTS: Groups 2 and 3 had higher cellular immune responses, as indicated by significantly lower regulatory T (Treg)/CD8+ T cell ratios than Group 1. With undetectable viral loads under both immunosuppressant and NAs, the CD8+ T cell and HBV-specific CD8+ T cell frequencies were similar in Group 2 and Group 1. Patients in Group 3 did not use NAs and had an elevated viral load and higher HBV-specific CD8+ T cell and IFN-γ-producing HBV-specific CD8+ T cell frequencies, but lower a frequency of programmed death-1 (PD-1)+ HBV-specific CD8+ T cells than the other groups. Increased viral replication in Group 3 resulted in significantly higher CD8+ T cell and IFN-γ-producing CD8+ T cell frequencies than Group 1. CONCLUSION: Immunosuppressant therapy increases viral replication in HBsAg-positive renal transplant recipients due to disabling or dysregulation of virus-specific CD8+ T cells. The higher cellular immune responses due to lower Treg/CD8+ T cell ratios in HBsAg-positive renal transplant recipients may be one of the reasons to induce liver pathology because of uncontrolled viral replication.

Trem2 Deletion Reduces Late-Stage Amyloid Plaque Accumulation, Elevates the Aß42:Aß40 Ratio, and Exacerbates Axonal Dystrophy and Dendritic Spine Loss in the PS2APP Alzheimer's Mouse Model.

TREM2 is an Alzheimer's disease (AD) risk gene expressed in microglia. To study the role of Trem2 in a mouse model of ß-amyloidosis, we compared PS2APP transgenic mice versus PS2APP mice lacking Trem2 (PS2APP;Trem2ko) at ages ranging from 4 to 22 months. Microgliosis was impaired in PS2APP;Trem2ko mice, with Trem2-deficient microglia showing compromised expression of proliferation/Wnt-related genes and marked accumulation of ApoE. Plaque abundance was elevated in PS2APP;Trem2ko females at 6-7 months; but by 12 or 19-22 months of age, it was notably diminished in female and male PS2APP;Trem2ko mice, respectively. Across all ages, plaque morphology was more diffuse in PS2APP;Trem2ko brains, and the Aß42:Aß40 ratio was elevated. The amount of soluble, fibrillar Aß oligomers also increased in PS2APP;Trem2ko hippocampi. Associated with these changes, axonal dystrophy was exacerbated from 6 to 7 months onward in PS2APP;Trem2ko mice, notwithstanding the reduced plaque load at later ages. PS2APP;Trem2ko mice also exhibited more dendritic spine loss around plaque and more neurofilament light chain in CSF. Thus, aggravated neuritic dystrophy is a more consistent outcome of Trem2 deficiency than amyloid plaque load, suggesting that the microglial packing of Aß into dense plaque is an important neuroprotective activity.SIGNIFICANCE STATEMENT Genetic studies indicate that TREM2 gene mutations confer increased Alzheimer's disease (AD) risk. We studied the effects of Trem2 deletion in the PS2APP mouse AD model, in which overproduction of Aß peptide leads to amyloid plaque formation and associated neuritic dystrophy. Interestingly, neuritic dystrophies were intensified in the brains of Trem2-deficient mice, despite these mice displaying reduced plaque accumulation at later ages (12-22 months). Microglial clustering around plaques was impaired, plaques were more diffuse, and the Aß42:Aß40 ratio and amount of soluble, fibrillar Aß oligomers were elevated in Trem2-deficient brains. These results suggest that the Trem2-dependent compaction of Aß into dense plaques is a protective microglial activity, limiting the exposure of neurons to toxic Aß species.

Identification of biochemically neutral positions in liver pyruvate kinase.

Understanding how each residue position contributes to protein function has been a long-standing goal in protein science. Substitution studies have historically focused on conserved protein positions. However, substitutions of nonconserved positions can also modify function. Indeed, we recently identified nonconserved positions that have large substitution effects in human liver pyruvate kinase (hLPYK), including altered allosteric coupling. To facilitate a comparison of which characteristics determine when a nonconserved position does vs does not contribute to function, the goal of the current work was to identify neutral positions in hLPYK. However, existing hLPYK data showed that three features commonly associated with neutral positions-high sequence entropy, high surface exposure, and alanine scanning-lacked the sensitivity needed to guide experimental studies. We used multiple evolutionary patterns identified in a sequence alignment of the PYK family to identify which positions were least patterned, reasoning that these were most likely to be neutral. Nine positions were tested with a total of 117 amino acid substitutions. Although exploring all potential functions is not feasible for any protein, five parameters associated with substrate/effector affinities and allosteric coupling were measured for hLPYK variants. For each position, the aggregate functional outcomes of all variants were used to quantify a "neutrality" score. Three positions showed perfect neutral scores for all five parameters. Furthermore, the nine positions showed larger neutral scores than 17 positions located near allosteric binding sites. Thus, our strategy successfully enriched the dataset for positions with neutral and modest substitutions.

Role of membrane-tension gated Ca2+ flux in cell mechanosensation.

Eukaryotic cells are sensitive to mechanical forces they experience from the environment. The process of mechanosensation is complex, and involves elements such as the cytoskeleton and active contraction from myosin motors. Ultimately, mechanosensation is connected to changes in gene expression in the cell, known as mechanotransduction. While the involvement of the cytoskeleton in mechanosensation is known, the processes upstream of cytoskeletal changes are unclear. In this paper, by using a microfluidic device that mechanically compresses live cells, we demonstrate that Ca2+ currents and membrane tension-sensitive ion channels directly signal to the Rho GTPase and myosin contraction. In response to membrane tension changes, cells actively regulate cortical myosin contraction to balance external forces. The process is captured by a mechanochemical model where membrane tension, myosin contraction and the osmotic pressure difference between the cytoplasm and extracellular environment are connected by mechanical force balance. Finally, to complete the picture of mechanotransduction, we find that the tension-sensitive transcription factor YAP family of proteins translocate from the nucleus to the cytoplasm in response to mechanical compression.

Factors Associated with Survival of Patients With Severe Acute-On-Chronic Liver Failure Before and After Liver Transplantation.

BACKGROUND & AIMS: Liver transplantation for patients with acute-on-chronic liver failure (ACLF) with 3 or more failing organs (ACLF-3) is controversial. We compared liver waitlist mortality or removal according to model for end-stage liver disease (MELD) score vs ACLF category. We also studied factors associated with reduced odds of survival for 1 year after liver transplantation in patients with ACLF-3. METHODS: We analyzed data from the United Network for Organ Sharing (UNOS) from 2005 through 2016. We identified patients who were on the waitlist (100,594) and those who received liver transplants (50,552). Patients with ACLF were identified based on the European Association for the Study of the Liver-chronic liver failure criteria. Outcomes were evaluated with competing risks regression, Kaplan-Meier analysis, and Cox proportional hazards regression. RESULTS: Patients with ACLF-3 were more likely to die or be removed from the waitlist, regardless of MELD-sodium (MELD-Na) score, compared with the other ACLF groups; the proportion was greatest for patients with an ACLF-3 score and MELD-Na score below 25 (43.8% at 28 days). Mechanical ventilation at liver transplantation (hazard ratio [HR] 1.49; 95% confidence interval [CI] 1.22-1.84), donor risk index above 1.7 (HR 1.22; 95% CI 1.09-1.35), and liver transplantation within 30 days of listing (HR 0.89; 95% CI 0.81-0.98) were independently associated with survival for 1 year after liver transplantation CONCLUSIONS: In an analysis of data from the UNOS registry, we found high mortality among patients with ACLF-3 on the liver transplant waitlist, even among those with lower MELD-Na scores. So, certain patients with ACLF-3 have poor outcomes regardless of MELD-Na score. Liver transplantation increases odds of survival for these patients, particularly if performed within 30 days of placement on the waitlist. Mechanical ventilation at liver transplantation and use of marginal organs were associated with increased risk of death.

Imatinib as a potentially effective therapeutic alternative in corticosteroid-resistant eosinophilic fasciitis.

Eosinophilic fasciitis (EF) is a rare condition in children that is typically treated with systemic corticosteroids. We present the case of a 9-year-old boy with biopsy-proven EF, refractory to systemic corticosteroids and methotrexate. The tyrosine kinase inhibitor imatinib was added as adjuvant therapy, leading to improvement in joint function and skin laxity. Our case is the first to suggest the anti-fibrotic properties of imatinib may benefit EF patients.

Impact of Prior Bariatric Surgery on Perioperative Liver Transplant Outcomes.

Bariatric surgery (BS) is effective in treating morbid obesity, but the impact of prior BS on candidacy for liver transplantation (LT) is unclear. We examined 78 patients with cirrhosis with prior BS compared with a concurrent cohort of 156 patients matched by age, Model for End-Stage Liver Disease score, and underlying liver disease. We compared rates of transplant denial after evaluation, delisting on the waiting list, and survival after LT. The median time from BS to LT evaluation was 7 years. Roux-en-Y gastric bypass was the most common BS procedure performed (63% of cohort). Nonalcoholic fatty liver disease was the leading etiology for liver cirrhosis (47%). Delisting/death on the waiting list was higher among patients with BS (33.3% versus 10.1%; P = 0.002), and the transplantation rate was lower (48.9% versus 65.2%; P = 0.03). Intention-to-treat (ITT) survival from listing to 1 year after LT was lower in the BS cohort versus concurrent cohort (1-year survival, 84% versus 90%; P = 0.05). On adjusted analysis, a history of BS was associated with an increased risk of death on the waiting list (hazard ratio [HR], 5.7; 95% confidence interval [CI], 2.2-15.1), but this impact was attenuated (HR, 4.9; 95% CI, 1.8-13.4) by the presence of malnutrition. When limited to matched controls by sex, mortality attributed to BS was no longer significant for females (P = 0.37) but was significant for males (P = 0.046). Sarcopenia, as captured by skeletal muscle index, was calculated in a subset of patients (n = 49). The total skeletal surface area was lower in the BS group (127 [105-141] cm2 versus 153 [131-191] cm2 ; P = 0.005). Rates of sarcopenia were higher among patients delisted after listing (71.4% versus 16.7%; P = 0.04). In conclusion, a history of BS was associated with higher rates of delisting on the waiting list as well as lower survival from the time of listing on ITT analysis. Presence of malnutrition and sarcopenia among patients with BS may contribute to worse outcomes.

Correlation of ultrasound cross-sectional area of the median nerve, nerve conduction studies and 2-point discrimination.

INTRODUCTION: The purpose of this study was to determine the correlation between a measure of physical performance, a measure of physiology and a measure of anatomy in the setting of carpal tunnel syndrome (CTS). METHODS: A retrospective review of 215 consecutive patients with suspected CTS was conducted. All patients were evaluated with static 2-point discrimination (2PD), ultrasound (US) measurement of the median nerve cross-sectional area (CSA), and nerve conduction studies (NCS). Correlations between 2PD and US and NCS parameters were calculated. The ability of US/NCS to predict 2PD was evaluated. RESULTS: Analysis failed to prove a statistically significant correlation between 2PD and median nerve CSA. A weak correlation was detected between 2PD and NCS parameters. When 2PD was used as a reference standard, NCS parameters combined had the greatest sensitivity, followed by US. CONCLUSIONS: Currently used diagnostic tests (NCS and US) correlate poorly with 2PD. Muscle Nerve 000: 000-000, 2018 Muscle Nerve 59:236-239, 2019.