Serum Neurofilaments in Motor Neuron Disease and Their Utility in Differentiating ALS, PMA and PLS.

Neurofilament levels are elevated in many neurodegenerative diseases and have shown promise as diagnostic and prognostic biomarkers in Amyotrophic Lateral Sclerosis (ALS), the most common form of Motor Neuron Disease (MND). This study assesses serum neurofilament light (NFL) and neurofilament heavy (NFH) chain concentrations in patients with ALS, other variants of motor neuron disease such as Progressive Muscular Atrophy (PMA) and Primary Lateral Sclerosis (PLS), and a range of other neurological diseases. It aims to evaluate the use of NFL and NFH to differentiate these conditions and for the prognosis of MND disease progression. NFL and NFH levels were quantified using electrochemiluminescence immunoassays (ECLIA). Both were elevated in 47 patients with MND compared to 34 patients with other neurological diseases and 33 healthy controls. NFL was able to differentiate patients with MND from the other groups with a Receiver Operating Characteristic (ROC) curve area under the curve (AUC) of 0.90 (p < 0.001). NFL correlated with the rate of disease progression in MND (rho 0.758, p < 0.001) and with the ALS Functional Rating Scale (rho -0.335, p = 0.021). NFL levels were higher in patients with ALS compared to both PMA (p = 0.032) and PLS (p = 0.012) and were able to distinguish ALS from both PMA and PLS with a ROC curve AUC of 0.767 (p = 0.005). These findings support the use of serum NFL to help diagnose and differentiate types of MND, in addition to providing prognostic information to patients and their families.

A Neurology Advanced Referral Management System (NARMS) Reduces Face-to-Face Consultations By Over Sixty Percent.

Background: The COVID-19 pandemic has made neurology clinic waiting times longer. To prevent a build-up of patients waiting, we introduced a neurology advanced referral management system (NARMS) to deal with new referrals from GPs, using advice, investigations, or the telephone, as alternatives to face-to-face (FF) assessment. Methods: For six months, electronic referrals from GPs were triaged to the above categories. We recorded the numbers in each category, patient satisfaction, inter-consultant triage variation, re-referrals, and calculated CO2 emissions. Results: There were 573 referrals. Triage destinations were advice 33%, investigations 27%, telephone 17%, and FF 33%. Of patients referred for MRI, 95% were happy not to be seen if their investigation was normal. Less-experienced consultants triaged 20% and 30% respectively, to advice or investigations, compared with 40% by a triage-experienced neurologist. Four percent were re-referred. Numbers on the waiting list did not increase. CO2 emissions were reduced by 50%. Discussion: Two thirds of neurological referrals from GPs did not need to be seen FF and 50% were dealt with without the neurologist meeting the patient. Carbon emission was halved. This system should be employed more, with FF examination reserved for those patients who need a neurological examination for diagnosis and management.

Risdiplam for the treatment of adults with spinal muscular atrophy: Experience of the Northern Ireland neuromuscular service.

INTRODUCTION/AIMS: Risdiplam is the newest available treatment for patients with spinal muscular atrophy (SMA). There is little information on its use in adults. We present the clinical experience of adults with SMA treated with risdiplam through the Early Access to Medicines Scheme (EAMS) in Northern Ireland. METHODS: All adults with Type 2 SMA attending the regional neuromuscular clinic were offered risdiplam treatment. Patients had assessments of respiratory function, the Epworth Sleepiness Scale (ESS), Quality of Life Measure for People with Slowly Progressive and Genetic Neuromuscular Disease (QOLM), and Egen Klassifikation 2 (EK2) every 3 mo and the Revised Upper Limb Module for SMA (RULM) at baseline and 6 mo. All assessments other than the RULM were carried out virtually. RESULTS: Six of seven patients who were offered risdiplam consented to treatment through the EAMS (five female, one male, mean age 33.7 y). It was generally well tolerated other than skin photosensitivity in all patients. All patients remained on therapy at 9 mo. All reported meaningful improvements in overall strength, sense of wellbeing, and speech quality. There was no change in respiratory function, daytime hypersomnolence, or upper limb function (all p > .05). There was improvement in the QOLM (p = .027) and EK2 (p = .009). DISCUSSION: Our study raises hopes that risdiplam may be efficacious in adults; however, more systematic studies in larger cohorts are needed before drawing any definitive conclusions. This study also demonstrated the feasibility of virtual assessments.

The Role of Sphingomyelin and Ceramide in Motor Neuron Diseases.

Amyotrophic Lateral Sclerosis (ALS), Spinal Bulbar Muscular Atrophy (SBMA), and Spinal Muscular Atrophy (SMA) are motor neuron diseases (MNDs) characterised by progressive motor neuron degeneration, weakness and muscular atrophy. Lipid dysregulation is well recognised in each of these conditions and occurs prior to neurodegeneration. Several lipid markers have been shown to predict prognosis in ALS. Sphingolipids are complex lipids enriched in the central nervous system and are integral to key cellular functions including membrane stability and signalling pathways, as well as being mediators of neuroinflammation and neurodegeneration. This review highlights the metabolism of sphingomyelin (SM), the most abundant sphingolipid, and of its metabolite ceramide, and its role in the pathophysiology of neurodegeneration, focusing on MNDs. We also review published lipidomic studies in MNDs. In the 13 studies of patients with ALS, 12 demonstrated upregulation of multiple SM species and 6 demonstrated upregulation of ceramides. SM species also correlated with markers of clinical progression in five of six studies. These data highlight the potential use of SM and ceramide as biomarkers in ALS. Finally, we review potential therapeutic strategies for targeting sphingolipid metabolism in neurodegeneration.

Real-World Data on Access to Standards of Care for People With Spinal Muscular Atrophy in the UK.

Spinal Muscular Atrophy (SMA) is characterized by muscle atrophy and weakness and has an incidence of 1:11. 000 live births which projects an estimated population in the UK of 650-1,300 affected patients. Standards of Care (SoC) were updated in 2017 and they have been widely adopted as a reference for implementation of care in SMA across the globe. The effectiveness of implementation and adherence to these standards across different countries is unclear. The aim of this study is to describe the experience of individuals with SMA regarding their care in the UK. An online anonymised survey was sent out via patient organizations, the UK SMA Patient Registry, professional networks, and social media to reach across the UK. The survey captured demographic profile, professionals involved in a patient's care, Interventions and access to mobility aids and home adaptations. Participants responded about their access to services and to rate how important each professional and intervention was for their health and wellbeing. One hundred and twenty-eight responses were collected with a median age of 34 years (1-81). Seventy-three percent of participants were adults and 60% men. Overall good access to neurologist (>90%) but limited to nurse specialist (48%) and physiotherapist (57%). Good access to respiratory support was reported but limited for interventions for positioning and bracing and exercise. This survey highlights that access to certain professionals for people with SMA is limited in the UK. Striking differences were noted between pediatric and adult populations. Limited access to care were regularly reported, with half of the study population consistently not accessing full multidisciplinary care. Access to interventions for contracture management were recorded to have significant limitations. Mobility aids and home adaptations are widely available and were also reported as the most valued interventions. Access to nutritional support or speech and language therapy appears only to be available for a small proportion of the participants. Access to respiratory care was good especially in severe forms of SMA. We found pockets of good practice in the UK that align with the SoC. However, access is not equal for adults and children and access to certain professionals is significantly limited.

Recently Graduated Medical Students Lack Exposure to and Comfort with Chronic Liver Diseases.

BACKGROUND: The prevalence of chronic liver disease (CLD) is rising, but it remains unclear if medical school curricula are emphasizing CLD to reflect its growing epidemiology. AIMS: To assess comfort levels and knowledge of CLD among recently graduated medical students METHODS: An anonymous survey was distributed to incoming categorical Internal Medicine (IM) interns at a single academic institution during a 2-year period. The survey consisted of 38 Likert-like questions evaluating comfort levels and self-assessed knowledge for several general medicine and liver diseases, as well as 12 multiple-choice questions to objectively test knowledge. Wilcoxon ranked sum and Fisher's exact test were then used. RESULTS: There was a 100% (n = 65) completion rate. Only 14 (22%) of those surveyed reported exposure to a hepatology rotation in medical school. Highest mean comfort levels (1 = not at all comfortable, 5 = very comfortable) were for managing congestive heart failure (3.59) and chronic obstructive pulmonary disease (3.77). Mean comfort levels for various liver diseases were significantly lower (2.22-3.03, all p < 0.01). Mean self-rated knowledge (1 = no knowledge, 5 = strong knowledge) was also low (2.14-3.13). Although 98% agreed that hepatology is critical to IM training, only 42% agreed that their hepatology education during medical school was adequate. CONCLUSIONS: Recently graduated medical students are less comfortable managing liver diseases compared to other general medical conditions. Only a minority report satisfaction with hepatology education during medical school. These findings suggest that medical curricula need to be modified to better emphasize CLD.

Genetic defects are common in myopathies with tubular aggregates.

OBJECTIVE: A group of genes have been reported to be associated with myopathies with tubular aggregates (TAs). Many cases with TAs still lack of genetic clarification. This study aims to explore the genetic background of cases with TAs in order to improve our knowledge of the pathogenesis of these rare pathological structures. METHODS: Thirty-three patients including two family members with biopsy confirmed TAs were collected. Whole-exome sequencing was performed on 31 unrelated index patients and a candidate gene search strategy was conducted. The identified variants were confirmed by Sanger sequencing. The wild-type and the mutant p.Ala11Thr of ALG14 were transfected into human embryonic kidney 293 cells (HEK293), and western blot analysis was performed to quantify protein expression levels. RESULTS: Eleven index cases (33%) were found to have pathogenic variant or likely pathogenic variants in STIM1, ORAI1, PGAM2, SCN4A, CASQ1 and ALG14. Among them, the c.764A>T (p.Glu255Val) in STIM1 and the c.1333G>C (p.Val445Leu) in SCN4A were novel. Western blot analysis showed that the expression of ALG14 protein was severely reduced in the mutant ALG14 HEK293 cells (p.Ala11Thr) compared with wild type. The ALG14 variants might be associated with TAs in patients with complex multisystem disorders. INTERPRETATION: This study expands the phenotypic and genotypic spectrums of myopathies with TAs. Our findings further confirm previous hypothesis that genes related with calcium signalling pathway and N-linked glycosylation pathway are the main genetic causes of myopathies with TAs.

Mandatory Hepatology Education for Internal Medicine Residents: Long-Term Effects and Implications for Workforce Needs.

We previously created a mandatory, inpatient, hepatology resident curriculum that immediately improved comfort, knowledge, and career interest in chronic liver disease (CLD). The durability of these effects needs to be known to use this intervention to address the hepatologist shortage. Thus, we aimed to assess this curriculum's long-term outcomes on internal medicine (IM) residents' CLD comfort, knowledge, and career interest. From 2015 to 2019 at a single institution, one IM resident was always assigned to the rotation. Similar anonymous assessments were administered to incoming postgraduate year (PGY)-1 residents and graduating PGY-3 residents, including a historic control cohort that graduated in June 2015. At residency completion, the intervention cohort (n = 61) had significantly higher comfort (1, not at all comfortable/strongly disagree; 5, very comfortable/strongly agree) with both hepatology (e.g., hepatitis C, 2.5 vs. 3.3, P < 0.001) and common IM topics (e.g., heart failure, 3.6 vs. 4.8, P < 0.001) but not specialty topics lacking curricula (e.g., inflammatory bowel disease, 2.8 vs. 2.7, P = 0.54). Compared to the historic cohort (n = 27), the intervention cohort was more comfortable in several CLD topics (e.g., cirrhosis, 3.2 vs. 3.8; P = 0.005) and answered more questions correctly (65% vs. 55%; P = 0.04), but career interest was unchanged (1.9 vs. 1.8; P = 0.45). Many residents (33%) would consider a hepatology career if training were separated from gastroenterology. Conclusion: With the completion of a mandatory hepatology curriculum, residents' CLD comfort and knowledge durably improved and exceeded that of historic counterparts. Initial career interest was not sustained, perhaps due to prerequisite gastroenterology training. These findings suggest IM educational initiatives may better address hepatology workforce needs by generating comanagers than by recruiting trainees.

Standardized residency training in China: the new internal medicine curriculum.

China formally established a system of national standardized medical residency training in 2014, which affects the health of its 1.4 billion people. Accompanying this system were new guidelines and standards for internal medicine residency training. However, the majority of the standards focused on process measurements, such as minimum case requirements of diseases and procedural skills, rather than describing broader physician competencies in the domains of professionalism, patient care, communication, teamwork, quality improvement, and scholarship. While China has taken a large step forward with standardization of certain aspects of internal medicine residency training, the next step should focus on outcome measures and creating a system that is competency-based.

Problematic communications during 2016 fellowship recruitment in internal medicine.

Some internal medicine residency program directors have expressed concerns that their third-year residents may have been subjected to inappropriate communication during the 2016 fellowship recruitment season. The authors sought to study applicants' interpersonal communication experiences with fellowship programs. Many respondents indicated that they had been asked questions that would constitute violations of the National Residency Matching Program (NRMP) Communications Code of Conduct agreement, including how they plan to rank specific programs. Moreover, female respondents were more likely to have been asked questions during interview experiences about other programs to which they applied, and about their family plans. Post-interview communication policies were not made clear to most applicants. These results suggest ongoing challenges for the internal medicine community to improve communication with applicants and uniform compliance with the NRMP communications code of conduct during the fellowship recruitment process.

Pentraxin 3 deletion aggravates allergic inflammation through a TH17-dominant phenotype and enhanced CD4 T-cell survival.

BACKGROUND: Pentraxin 3 (PTX3) is a multifunctional molecule that plays a nonredundant role at the crossroads between pathogen clearance, innate immune system, matrix deposition, female fertility, and vascular biology. It is produced at sites of infection and inflammation by both structural and inflammatory cells. However, its role in allergen-induced inflammation remains to be tested. OBJECTIVE: We sought to determine the effect of Ptx3 deletion on ovalbumin (OVA)-induced allergic inflammation in a murine model of asthma. METHODS: Bronchoalveolar lavage fluid was collected from patients with severe asthma and healthy subjects, and the level of PTX3 was determined by using ELISA. Ptx3+/+ and Ptx3-/- mice were sensitized and challenged with OVA and bronchoalveolar lavage fluid, and the lungs were collected for assessing inflammation. Lung tissue inflammation and mucus production were assessed by means of flow cytometry and hematoxylin and eosin and periodic acid-Schiff staining, respectively. flexiVent was used to determine airway resistance to methacholine in these mice. RESULTS: Here we report that mice with severe asthma and OVA-sensitized/challenged mice had increased PTX3 levels in the lungs compared with healthy control mice. Mice lacking PTX3 have exaggerated neutrophilic/eosinophilic lung inflammation, mucus production, and airway hyperresponsiveness in an experimental model of OVA-induced asthma. Furthermore, OVA-exposed lung Ptx3-/- CD4 T cells exhibit an increased production of IL-17A, an effect that is accompanied by an increased signal transducer and activator of transcription 3 phosphorylation, reduced IL-2 production, and enhanced activation and survival. Also, we observed an increase in numbers of IL-6- and IL-23-producing dendritic cells in OVA-exposed Ptx3-/- mice compared with those in wild-type control mice. CONCLUSION: Altogether, PTX3 deficiency results in augmented airway hyperresponsiveness, mucus production, and IL-17A-dominant pulmonary inflammation, suggesting a regulatory role of PTX3 in the development of allergic inflammation.

Internal Medicine Residents' Retention of Knowledge and Skills in Bedside Ultrasound.

BACKGROUND: The long-term retention of knowledge and skills in bedside ultrasound by internal medicine residents after ultrasound training is not well understood. OBJECTIVE: We sought to determine whether knowledge and skills acquired from focused training in bedside ultrasound are retained over time, and whether retention is related to independent practice. METHODS: We conducted a prospective observational trial of 101 internal medicine residents at an academic medical center who participated in a bedside ultrasound workshop followed by 12 months of independent practice. Performance was measured on image-based knowledge and skills assessment using direct observation, both before the workshop and 12 months later. Individual usage data were obtained along with a survey on attitudes toward bedside ultrasound. RESULTS: Participants' mean knowledge assessment score increased from a baseline of 63.7% to 84.5% immediately after training (P < .001). At 12 months, mean knowledge score fell to 73.0%, significantly different from both prior assessments (P < .001). Despite knowledge decline, the mean skills assessment score improved from a baseline of 30.5% to 50.4% at 12 months (P < .001). Residents reporting more ultrasound use (> 25 examinations) had higher scores in baseline knowledge and skills assessments than those with lower usage (< 25 examinations). Change in knowledge and image acquisition skills between assessments was equal in both subgroups. CONCLUSIONS: Residents' knowledge of ultrasound improved after brief training but decayed over time, whereas skills showed marginal improvement over the study, with minimal support. Growth and retention of ultrasound abilities were not impacted by usage rates.

Novel educational interventions in residency increase knowledge of chronic liver disease and career interest in hepatology.

There is an increasing burden of chronic liver disease (CLD) in the United States but a significant shortage of hepatologists. Thus, it is necessary to develop new recruitment strategies to the field of hepatology as well as ensure that non-gastroenterology-trained physicians are able to capably assist in the care of CLD. We established a novel, nonelective, inpatient hepatology rotation that uses required modules in the American Association for the Study of Liver Diseases Curriculum and Training-First Hepatitis B and C curriculums as well as in LiverLearning. A paper-based anonymous assessment was distributed to the inaugural 25 postgraduate years 2 and 3 internal medicine residents before and after the 2-week rotation over the course of 1 year. Both the prerotation and postrotation assessments included validated multiple-choice questions and Likert-type questions, which evaluated self-perceived knowledge and comfort with managing CLD. The mean comfort level (1 = not at all comfortable/strongly disagree, 5 = very comfortable/strongly agree) of managing several common liver diseases increased significantly after completion of the rotation (i.e., cirrhosis 2.8 versus 3.8, P < 0.001; hepatitis B 2.4 versus 3.4, P = 0.001; hepatitis C 2.6 versus 3.7, P = 0.002; nonalcoholic steatohepatitis 3.0 versus 4.0, P < 0.001; liver transplant care 2.1 versus 3.4, P < 0.001). There was also a significantly increased interest in hepatology as a career (2.6 versus 3.0, P = 0.03). Finally, the mean percentage of multiple-choice questions answered correctly on the pretest was 62% and posttest was 77% (P = 0.02). CONCLUSION: Our novel curriculum and nonelective hepatology rotation has effectively demonstrated improvement in internal medicine residents' comfort with and knowledge of CLD, and increased career interest in hepatology was also observed after completion of the curriculum, which suggests that more exposure to CLD could positively impact recruitment to the workforce; larger, multicenter studies are needed to validate these results. (Hepatology 2016;64:2210-2218).

Piloting a Structured Practice Audit to Assess ACGME Milestones in Written Handoff Communication in Internal Medicine.

BACKGROUND: Written communication skills are integral to patient care handoffs. Residency programs require feasible assessment tools that provide timely formative and summative feedback, ideally linked to the Accreditation Council for Graduate Medical Education Milestones. OBJECTIVE: We describe the use of 1 such tool-UPDATED-to assess written handoff communication skills in internal medicine interns. METHODS: During 2012-2013, the authors piloted a structured practice audit at 1 academic institution to audit written sign-outs completed by 45 interns, using the UPDATED tool, which scores 7 aspects of sign-out communication linked to milestones. Intern sign-outs were audited by trained faculty members throughout the year. Results were incorporated into intern performance reviews and Clinical Competency Committees. RESULTS: A total of 136 sign-outs were audited (averaging 3.1 audits per intern). In the first trimester, 14 interns (31%) had satisfactory audit results. Five interns (11%) had critical deficiencies and received immediate feedback, and the remaining 26 (58%) were assigned future audits due to missing audits or unsatisfactory scores. In the second trimester, 21 interns (68%) had satisfactory results, 1 had critical deficiencies, and 9 (29%) required future audits. Nine of the 10 remaining interns in the final trimester had satisfactory audits. Faculty time was estimated at 10 to 15 minutes per sign-out audited. CONCLUSIONS: The UPDATED audit is a milestone-based tool that can be used to assess written sign-out communication skills in internal medicine residency programs. Future work is planned to adapt the tool for use by senior supervisory residents to appraise sign-outs in real time.