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While randomized controlled trials (RCTs) are the gold standard for comparative effectiveness research, they are unable to provide the answers to all pertinent clinical and research questions. Real world evidence (RWE), that is, clinical evidence obtained outside RCTs and often through routine clinical practice, offers the potential to conduct observational studies that accelerate advances in care, improve outcomes for patients, and provide important insights that can answer important questions. Once appropriate information technology is available, real world data can be cost-effective to generate. RWE serves a vital role in the evaluation of treatment strategies for which there are no RCTs and for describing patterns of care. RWE also serves as an important adjunct to RCTs and can be used to determine if benefits seen in RCTs extend to clinical practice, provide insight into the findings of RCTs, generate hypotheses for future RCTs, and inform the design of future RCTs. These potential benefits must be balanced against some of the important limitations of RWE, including variable data quality, lack of granularity for important clinical variables, and the potential for bias and confounding. By using appropriate analytic techniques and study design, these limitations can be minimized but not eliminated. Going forward, RWE studies may be enhanced by using rigorous data quality standards, incorporating randomization, developing more prospective registries, and better leveraging data from electronic health records., (© 2020 John Wiley & Sons Ltd.)

Introduction: Health systems are seeking innovative solutions to improve specialty care access. Electronic consultations (eConsults) allow specialists to provide formal clinical recommendations to primary care providers (PCPs) based on patient chart review, without a face-to-face visit., Methods: We implemented a nephrology eConsult pilot program within a large, academic primary care practice to facilitate timely communication between nephrologists and PCPs. We used primary care referral data to compare wait times and completion rates between traditional referrals and eConsults. We surveyed PCPs to assess satisfaction with the program., Results: For traditional nephrology referrals placed during the study period (July 2016-March 2017), there was a 51-day median appointment wait time and a 40.9% referral completion rate. For eConsults, there was a median nephrologist response time of one day and a 100% completion rate; 67.5% of eConsults did not require a subsequent face-to-face specialty appointment. For eConsults that were converted to an in-person visit, the median wait time and completion rate were 40 days and 73.1%, respectively. Compared to traditional referrals placed during the study period, eConsults converted to in-person visits were more likely to be completed ( p = 0.001). Survey responses revealed that PCPs were highly satisfied with the program and consider the quick turnaround time as the greatest benefit., Discussion: Our eConsult pilot program reduced nephrology wait times and significantly increased referral completion rates. In large integrated health systems, eConsults have considerable potential to improve access to specialty care, reduce unnecessary appointments, and optimize the patient population being seen by specialists.

Purpose: Ideally, a referral from a primary care physician (PCP) to a specialist results in a completed specialty appointment with results available to the PCP. This is defined as "closing the referral loop." As health systems grow more complex, regulatory bodies increase vigilance, and reimbursement shifts towards value, closing the referral loop becomes a patient safety, regulatory, and financial imperative., Objective/design: To assess the ability of a large health system to close the referral loop, we used electronic medical record (EMR)-generated data to analyze referrals from a large primary care network to 20 high-volume specialties between July 1, 2015 and June 30, 2016., Main Measures: The primary metric was documented specialist appointment completion rate. Explanatory analyses included documented appointment scheduling rate, individual clinic differences, appointment wait times, and geographic distance to appointments., Key Results: Of the 103,737 analyzed referral scheduling attempts, only 36,072 (34.8%) resulted in documented complete appointments. Low documented appointment scheduling rates (38.9% of scheduling attempts lacked appointment dates), individual clinic differences in closing the referral loop, and significant differences in wait times and distances to specialists between complete and incomplete appointments drove this gap. Other notable findings include high variation in wait times among specialties and correlation between high wait times and low documented appointment completion rates., Conclusions: The rate of closing the referral loop in this health system is low. Low appointment scheduling rates, individual clinic differences, and patient access issues of wait times and geographic proximity explain much of the gap. This problem is likely common among large health systems with complex provider networks and referral scheduling. Strategies that improve scheduling, decrease variation among clinics, and improve patient access will likely improve rates of closing the referral loop. More research is necessary to determine the impact of these changes and other potential driving factors.

The tumor suppressor gene TP53 is the most frequently mutated gene in human cancer, and the germline TP53 R337H mutation is the most common mutation reported to date. However, this mutation is associated with a lower cumulative lifetime cancer risk than other mutations in the p53 DNA-binding domain. A detailed statistical analysis of 171,500 DNA tests in Brazilian neonates found that 0.27% of the general population is positive for this mutation, and some of the estimated 200,000 Brazilian R337H carriers in southern and southeastern Brazil have already developed cancer. The present study was designed to estimate R337H prevalence in neighboring Paraguay. To address this question, 10,000 dried blood samples stored in Guthrie cards since 2008 were randomly selected from the Paraguayan municipalities located at the border with Brazil. These samples were tested for R337H mutation using the PCR-restriction fragment length polymorphism assay. This germline mutation was detected in five samples (5/10,000), indicating that the total number of R337H carriers in Paraguay may be as high as 3500. Previous studies have shown that other countries (i.e., Portugal, Spain, and Germany) presented one family with this mutation, leading us to conclude that, besides Brazil and Paraguay, other countries may have multiple families carrying this mutation, which is an inherited syndrome that is difficult to control., (Copyright © 2015. Published by Elsevier Ltd.)

The presence of oligoclonal bands of IgG (OCB) in cerebrospinal fluid (CSF) is used to establish a diagnosis of multiple sclerosis (MS), but their specificity has remained an enigma since its first description over forty years ago. We now report that the use of lipid arrays identifies heteromeric complexes of myelin derived lipids as a prominent target for this intrathecal B cell response., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Deficits in motor functioning, including walking, and in cognitive functions, including attention, are known to be prevalent in multiple sclerosis (MS), though little attention has been paid to how impairments in these areas of functioning interact., Objectives: This study investigated the effects of performing a concurrent cognitive task when walking in people with MS. Level of task demand was manipulated to investigate whether this affected level of dual-task decrement., Method: Eighteen participants with MS and 18 healthy controls took part. Participants completed walking and cognitive tasks under single- and dual-task conditions., Results: Compared to healthy controls, MS participants showed greater decrements in performance under dual-task conditions in cognitive task performance, walking speed and swing time variability. In the MS group, the degree of decrement under dual-task conditions was related to levels of fatigue, a measure of general cognitive functioning and self-reported everyday cognitive errors, but not to measures of disease severity or duration., Conclusions: Difficulty with walking and talking in MS may be a result of a divided attention deficit or of overloading of the working memory system, and further investigation is needed. We suggest that difficulty with walking and talking in MS may lead to practical problems in everyday life, including potentially increasing the risk of falls. Clinical tools to assess cognitive-motor dual-tasking ability are needed.

Background: The association between Guillain-Barre syndrome (GBS) and malignancy is uncommon and has not been previously reported in gynecological cancers., Case: Our case documents this syndrome occurring in a patient shortly after completion of adjuvant chemo-radiotherapy for endometrial carcinoma. We review the current literature and discuss potential pathogenic mechanisms of this likely paraneoplastic association., Conclusion: GBS in cancer patients is a potentially life-threatening condition and should be differentiated from simple chemotherapy toxicity, particularly as effective treatment is available.

The clinical and laboratory phenotype of a paraproteinaemic neuropathy syndrome termed chronic sensory ataxic neuropathy with anti-disialosyl IgM antibodies is described in a series of 18 cases. Previous single case reports have outlined some features of this syndrome. All 18 cases were defined by the presence of serum IgM antibodies which react principally with NeuAc (alpha2-8)NeuAc(alpha2-3)Gal-configured disialosyl epitopes common to many gangliosides including GDlb, GD3, GTlb and GQlb. In 17 out of 18 cases, the serum contained benign IgM paraproteins, and in four of these cases at least two IgM paraproteins were present. The IgM antibodies were also cold agglutinins in 50% of cases. The clinical picture comprised a chronic neuropathy with marked sensory ataxia and areflexia, and with relatively preserved motor function in the limbs. In addition, 16 out of 18 cases had motor weakness affecting oculomotor and bulbar muscles as fixed or as relapsing-remitting features. When present in their entirety, these clinical features have been described previously under the acronym CANOMAD: chronic ataxic neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins and disialosyl antibodies. This distribution of clinical features is reminiscent of Miller Fisher syndrome, in which acute-phase anti-disialylated ganglioside IgG antibodies are found. Clinical electrophysiology and nerve biopsy show both demyelinating and axonal features. A partial response to intravenous immunoglobulin and other treatments is reported in some cases.

A 26-year-old man with a history of an embryonal rhabdomyosarcoma arising from the urachus and a large, right-sided, epidermal nevus presented with a rapidly evolving tetraparesis. Investigations confirmed an intramedullary hemorrhage of the cervical spinal cord and an extensive arteriovenous malformation (AVM). An association between his nevus, rhabdomyosarcoma, and spinal AVM is hypothesized.

The role of antiglycolipid antibodies in peripheral neuropathy continues to be defined in terms of clinical-serological associations and innovative experimental work establishing the role of these antibodies in pathogenesis. The present review focuses on the major developments in this field over the past 12 months.

The neurophysiological effects of nine neuropathy-associated human anti-ganglioside antisera, three monoclonal antibodies to ganglioside GM1 (GM1) and of the cholera toxin B subunit (a GM1 ligand) were studied on mouse sciatic nerve in vitro. GM1 antisera and monoclonal antibodies from patients with chronic motor neuropathies and Guillain-Barre syndrome, and GQ1b/ disialosyl antisera and monoclonal antibodies from patients with chronic ataxic neuropathies and Miller Fisher syndrome were studied. In vitro recording, for up to 6 h, of compound nerve action potentials, latencies, rise times and stimulus thresholds from isolated desheathed sciatic nerve was performed in the presence of antiganglioside antibodies and fresh human serum as an additional source of complement. No changes were observed over this time course, with 4-6 h values for all electrophysiological parameters being within 15% of the starting values for both normal and antibody containing sera and for the cholera toxin B subunit. Parallel experiments on identically prepared desheathed nerves performed with 0.5 nM saxitoxin led to complete conduction block within 10 min of application. Under identical conditions to those used for electrophysiological recordings, quantitative immunohistological evaluation revealed a significant increase in IgM (immunoglobulin M) deposition at nodes of Ranvier from 5.3+/-3.1% to 28.7+/-8.4% (mean+/-SEM) of desheathed nerves exposed to three normal and three antibody containing sera, respectively (P < 0.03). Complement activation was seen at 100% of normal and 79% of disease-associated IgM positive nodes of Ranvier. These data indicate that anti-ganglioside antibodies can diffuse into a desheathed nerve, bind to nodes of Ranvier and fix complement in vitro without resulting in any overt physiological deterioration of the nerve over 4-6 h. This suggests that the node of Ranvier is relatively resistant to acute antiganglioside antibody mediated injury over this time scale and that anti-ganglioside antibodies and the cholera toxin B subunit are unlikely to have major direct pharmacological effects on nodal function, at least in comparison with the effect of saxitoxin. This in vitro sciatic nerve model appears of limited use for analysing electrophysiologically the effects of anti-ganglioside antibodies on nerve function, possibly because its short-term viability and isolation from circulating systemic factors do not permit the evolution of an inflammatory lesion of sufficient magnitude to induce overt electrophysiological abnormalities. In vivo models may be more suitable for identifying the effects of these antibodies on nerve conduction.

Anti-GM1 and anti-GQ1b ganglioside antibodies are found in association with acute and chronic peripheral neuropathies, including Guillain-Barré syndrome. They are believed to arise as a result of molecular mimicry with immunogenic microbial polysaccharides. Although anti-ganglioside antibodies are suspected to play a causal role in neuropathy pathogenesis, the details of this have yet to be proven. The approach in this laboratory to solving this issue has been to generate anti-GM1 and anti-GQ1b monoclonal antibodies from peripheral blood lymphocytes of affected patients and to study their immunolocalization in peripheral nerve and their electrophysiologic effects in animal models in which peripheral nerve sites are exposed to anti-ganglioside antibodies. These data show that anti-ganglioside antibody-reactive epitopes are widely distributed in peripheral nerve and can cause electrophysiologic abnormalities in a variety of model systems; thus, these data support the view that anti-ganglioside antibody-reactive epitopes may directly contribute to neuropathy pathogenesis.

Autoimmune ataxic neuropathies are a subset of the sensory ataxic neuropathies which are characterized by ataxia as the dominant presenting feature. The major known causes of autoimmune ataxic neuropathies include sensory variants of the Guillain-Barré syndrome, including Miller-Fisher syndrome, subsets of immunoglobulin M paraproteinaemic neuropathy, paraneoplastic neuropathy and the neuropathy associated with Sjögren's syndrome. Identified antigens as targets for autoantibodies include gangliosides, myelin associated glycoprotein, Hu antigen and extractable nuclear antigens. Some recent studies support the pathogenic role of anti-GD1b ganglioside antibody in autoimmune ataxic neuropathies. The major site of pathology in autoimmune ataxic neuropathies is the dorsal root ganglion, but dorsal roots and peripheral nerve myelin and axons may also be affected.

Multifocal motor neuropathy (MMN) is typically associated with distal upper limb weakness and wasting. However, proximal muscle bulk, particularly of biceps brachii, may be well preserved even in the presence of severe proximal weakness. Here we report 3 patients with MMN who had true muscle hypertrophy of severely weakened biceps muscles and positive motor symptoms including cramp and fasciculations in these muscles. Electromyographic studies demonstrated markedly impaired recruitment in the affected muscles and continuous motor unit activity comprising multiple fasciculation potentials at a frequency of up to 30 per minute. We propose that this continuous motor unit activity may have contributed to the hypertrophy in these muscles.

Three patients with acute oropharyngeal palsy had high titre anti-GQ1b and anti-GT1a IgG antibodies. No patients had ophthalmoplegia or ptosis. In all patients limb ataxia or areflexia were present without notable limb weakness. These patients describe an oropharyngeal variant of Guillain-Barré syndrome in terms of anti-GQ1b antibody reactivity and show that high titre anti-GQ1b antibodies, serologically indistinguishable from those found in Miller Fisher syndrome, can occur in a clinical setting without ophthalmoplegia. The anti-GQ1b and anti-GT1a antibody assays may be helpful tests when considering the differential diagnosis of acute oropharyngeal palsy.