Pitfalls in Diagnosing Hypoglycemia Due to Exogenous Insulin: Validation and Utility of an Insulin Analog Assay

ObjectiveTo overcome the limitations of commercially available insulin immunoassays which have variable detection of analog insulin and can lead to clinically discordant results and misdiagnosis in the workup of factitious hypoglycemia.Patients and MethodsWe performed analytical validation of a liquid chromatography high resolution accurate mass (LC-HRAM) immunoassay to detect insulin analogs. We completed clinical assessment using a large cohort of human serum samples from 78 unique individuals, and subsequently used the assay in the evaluation of eight individuals with high diagnostic suspicion for factitious hypoglycemia.ResultsThe performance characteristics show that the LC-HRAM immunoassay can be applied to detect five commonly used synthetic insulin analogs (lispro, glulisine, aspart, glargine metabolite, and detemir) in human serum. Our clinical cases show that this assay could be used in the diagnosis of factitious hypoglycemia by identifying the analog insulin(s) in question.ConclusionThe LC-HRAM immunoassay reported here overcomes a gap in our diagnostic pathway for hypoglycemia. The results obtained from our studies suggest that this method is appropriate for use in clinical laboratories when factitious hypoglycemia is considered as a differential diagnosis.     

Reproducibility and Convergent Validity of the Sitting-Rising Test in People With Multiple Sclerosis

ObjectiveTo evaluate the test-retest reproducibility and convergent validity of the sitting-rising test (SRT) in people with multiple sclerosis (PwMS).DesignObservational study comprising a test-retest design.SettingMultiple Sclerosis Center, Rehabilitation Hospital at Sheba Medical Center, Tel-Hashomer, Israel.ParticipantsA total of 50 PwMS (32 women, 18 men, N=50), mean age 44.8±7.6 years and mean disease duration of 13.8±8.5 years since diagnosis, were enrolled in the study. The median Expanded Disability Status Scale score was 4.5, indicating a mild-moderate neurologic disability.InterventionsNot applicable.Main Outcome MeasuresSRT, posturography measures, 10-repetion sit-to-stand test (10STS), timed Up and Go (TUG) test, hand grip strength, strength of hip flexion/extension/abduction, knee flexion/extension, and Fall Status Questionnaire.ResultsThe intraclass correlation coefficient value for the intrarater test-retest reproducibility (7- to 10-day interval between tests) of the SRT test, was 0.931 (95% confidence interval, 0.796-0.977). Strong correlations were found between the SRT, TUG test (ρ=−0.709), and 10STS (ρ=−0.719), and moderate correlations were found between the SRT and postural control measures (ρ∼0.4). Moderate correlations were found between the SRT and the hip and knee strength (combined) of the weaker limb (ρ=0.344). No differences were found in the SRT score between fallers and nonfallers.ConclusionsThe current study supports the convergent validity and test-retest reproducibility of the SRT in PwMS.     

Renal Neoplasia in Tuberous Sclerosis: A Study of 41 Patients

ObjectiveTo study the clinical features and identify unique renal neoplasia subtypes and their prognostic implications in individuals with tuberous sclerosis complex (TSC).Patients and MethodsThe Mayo Clinic nephrectomy registry included 37 patients with TSC diagnosed between 1970 and 2018. Four additional patients were identified from the pathology consultation and autopsy files. All available renal tumors were further characterized using immunohistochemistry and fluorescence in situ hybridization. Clinicopathologic features and follow-up were obtained from the medical record. The American Association for Cancer Research Project GENIE registry was accessed using cBioPortal for molecular profiling of angiomyolipoma (AML).ResultsA total of 276 renal tumors from 41 patients were analyzed. Renal tumors were classified into 9 distinct morphological subtypes, with AML predominating (238 [86%]). Interestingly, all these tumors acted in a benign fashion except one renal cell carcinoma with clear cells and fibromyomatous stroma and one epithelioid AML that metastasized. Molecular profiling studies revealed that epithelioid AMLs were enriched for alterations of TP53, RB1, and ATRX. Eight patients died of direct complications of TSC, including 3 of end-stage renal disease. To date, none have died of a renal epithelial neoplasm.ConclusionThe identification of unique renal neoplasia subtypes may provide important clues to establish a diagnosis of TSC, and in the somatic setting, this finding has important implications for accurate prognostication. These tumors tend to be indolent, and only 2 of 276 tumors in our study exhibited metastatic behavior. Our results support multidisciplinary management with a focus on preservation of renal function.     

Clinical Determinants of Fitness to Drive in Persons With Multiple Sclerosis: Systematic Review

ObjectiveTo critically appraise the evidence for the clinical determinants of fitness to drive in adults with multiple sclerosis (MS).Data SourcesThe research librarian and lead author searched 7 databases for driving simulator and on-road studies for adults with MS published in the English language from 1991 to 2018.Study SelectionThree reviewers independently screened titles, abstracts, and full-texts for studies with: cohort, case-control, or cross-sectional designs; participants, 18 years or older, with relapsing or progressive MS; visual, cognitive, or motor clinical assessments as predictors; and driving performance through simulator or fitness to drive through on-road assessment as outcomes.Data ExtractionUsing the 2017 American Academy of Neurology guidelines, reviewers independently classified each study from class I to class IV, or highest to lowest amount of rigor. For each clinical assessment, reviewers independently rated the level of confidence for predicting driving performance or fitness to drive from level A, highly probable; B, probable; C, possible; to level U, insufficient conclusions.Data SynthesisThrough qualitative synthesis, 2 class III and 4 class IV driving simulator studies employed 24 clinical assessments with level C (n=4) or level U (n=20) confidence for predicting driving performance. Six class II and 3 class IV on-road studies employed 35 clinical assessments with level B (n=9), level C (n=22), or level U (n=4) confidence for predicting fitness to drive.ConclusionsThis systematic review identified mostly insufficient conclusions for predicting driving performance in driving simulator studies, and possible conclusions for predicting fitness to drive in on-road studies. The best available evidence suggests that the Stroke Driver Screening Assessment and Useful Field of View test probably predict fitness to drive in adults with MS (level B). Class I studies that compare predictors of fitness to drive with large prospective samples of adults with and without MS are necessary for highly probable conclusions.     

Reliability and Validity of the Lower Extremity Motor Activity Log for Measuring Real-World Leg Use in Adults With Multiple Sclerosis

ObjectivesTo determine the test-retest reliability and validity of the Lower Extremity Motor Activity Log (LE-MAL) for assessing LE use in the community in adults with multiple sclerosis (MS).DesignProspective analysis of measures conducted by trained examiners.SettingParticipants were evaluated by telephone on several measures of LE use.ParticipantsAdults with MS (N=43).InterventionsNot applicable.Main Outcome MeasuresThe LE-MAL has 3 subscales (Assistance, Functional Performance, and Confidence). It was administered twice, at least 2 weeks apart. The Multiple Sclerosis Walking Scale (MSWS-12), Patient Determined Disease Steps (PDDS), and Mobility Scale were only administered during the first call.ResultsThe test-retest reliability of the composite and the 3 subscale LE-MAL scores were high (intraclass correlation, >0.94). The composite and subscale LE-MAL scores were strongly correlated with the MSWS-12, PDDS, and Mobility Scale scores (r=–0.56 to –0.77; P<.001).ConclusionThis initial study suggests that the LE-MAL reliably and validly measures LE use in the community in adults with MS.     

Influence of Multiple Sclerosis on Spatiotemporal Gait Parameters: A Systematic Review and Meta-Regression

ObjectiveTo quantify the effect of multiple sclerosis (MS) on spatiotemporal gait characteristics accounting for disability severity and fall classification.Data SourcesMEDLINE (1946-August 2018), Allied and Complementary Medicine Database (1985-2018 August), and PsycINFO (1806-August 2018) were searched for terms on MS and gait.Study SelectionDual independent screening was conducted to identify observational, cross-sectional studies that compared adults with MS grouped according to Expanded Disability Status Scale (EDSS) level or fall history, reported on spatiotemporal gait characteristics, and were published in English. The search retrieved 5891 results, of which 12 studies satisfied the inclusion criteria.Data ExtractionTwo authors worked independently to extract and verify data on publication details, study methodology, participant characteristics, gait outcomes, conclusions, and limitations. Risk of bias was assessed using the QualSyst critical appraisal tool. A random-effects meta-regression and meta-analysis were conducted on pooled data.Data SynthesisAll studies received quality ratings of very good to excellent and collectively examined 1513 individuals with MS. With every 1-point increase in EDSS, significant changes (P<.05) were observed in gait speed (−0.12 m/s; 95% confidence interval (CI), 0.08-0.15), step length (−0.04 m; 95% CI, 0.03-0.05), step time (+0.04 seconds; 95% CI, 0.02-0.06), step time variability (+0.009 seconds; 95% CI, 0.003-0.016), stride time (+0.08 seconds; 95% CI, 0.03-0.12), cadence (−4.4 steps per minute; 95% CI, 2.3-6.4), stance phase duration (+0.8% gait cycle; 95% CI, 0.1-1.5), and double support time (+3.5% gait cycle; 95% CI, 1.5-5.4). Recent fallers exhibited an 18% (95% CI, 13%-23%) reduction in gait speed compared with nonfallers (P<.001).ConclusionsThis review provides the most accurate reference values to-date that can be used to assess the effectiveness of MS gait training programs and therapeutic techniques for individuals who differ on disability severity and fall classification. Some gait adaptations could be part of adopting a more cautious gait strategy and should be factored into the design of future interventions.     

Cutoff Score of the Lower-Extremity Motor Subscale of Fugl-Meyer Assessment in Chronic Stroke Survivors: A Cross-Sectional Study

ObjectiveTo derive an optimal cutoff score for the lower-extremity motor subscale of the Fugl-Meyer Assessment (FMA) to differentiate stroke survivors with high mobility function from those with low mobility function using a data-driven approach.DesignCross-sectional study.SettingUniversity-based clinical research laboratory.ParticipantsChronic stroke survivors (N=80) recruited from local self-help groups.InterventionsNot applicable.Main Outcome MeasuresLower-extremity motor subscale of Fugl-Meyer Assessment (FMA-LE), Berg Balance Scale, 5 times sit-to-stand test, comfortable walking speed, 6-minute walk test, and timed Up and Go test.ResultsK-mean clustering analysis classified 42 stroke survivors in the high mobility function group. The receiver operating characteristic curve showed that FMA-LE can differentiate stroke survivors based on their mobility level (area under the curve, 0.85). An FMA-LE score of 21 of 34 was the best cutoff score (sensitivity, 0.87; specificity: 0.81).ConclusionsAn FMA-LE score of 21 or higher could indicate a high level of mobility function in chronic stroke survivors.     

Effects of Virtual Reality vs Conventional Balance Training on Balance and Falls in People With Multiple Sclerosis: A Randomized Controlled Trial

ObjectiveTo assess the efficacy of virtual reality (VR)-based vs conventional balance training on the improvement of balance and reduction of falls in people with multiple sclerosis (PwMS).DesignSingle-blinded, randomized, controlled trial.SettingMusculoskeletal Rehabilitation Research Center, Ahvaz Jundishapur University of Medical Sciences.ParticipantsPwMS (N=39), randomized into VR (n=19) and control (n=20) groups.InterventionThe VR group performed exergames using Kinect, while the control group accomplished conventional balance exercises. Both groups received 18 training sessions for 6 weeks.Main Outcome MeasuresLimits of stability, timed Up and Go (TUG) test, and 10-m walk tests with and without cognitive task and their dual-task costs (DTCs), Berg Balance Scale, Multiple Sclerosis Walking Scale-12, Fall Efficacy Scale-International, Activities-specific Balance Confidence Scale, and fall history were obtained pre- and post intervention and after a 3-month follow-up.ResultsAt both post intervention and follow-up, TUG^cognitive and DTCs on the TUG were significantly lower and the 10-m walk^cognitive was significantly higher in the VR group. At follow-up, reaction time and the number of falls demonstrated significant differences favoring the VR group, whereas the directional control revealed significant difference in favor of the control group (P<.05). The other outcomes showed no statistically significant difference at post intervention or follow-up.ConclusionsBoth the VR-based and conventional balance exercises improved balance and mobility in PwMS, while each acted better in improving certain aspects. VR-based training was more efficacious in enhancing cognitive-motor function and reducing falls, whereas conventional exercises led to better directional control. Further studies are needed to confirm the effectiveness of recruiting VR-based exercises in clinical settings.     

Employment and Job Benefits Among Those With Spinal Cord Dysfunction: A Comparison of People With Spinal Cord Injury and Multiple Sclerosis

Objective(1) Identify the proportion of participants with spinal cord dysfunction (SCD) reporting each of 10 job benefits and compare the proportions between participants with spinal cord injury (SCI) and multiple sclerosis (MS); and (2) examine if diagnostic criteria, demographics, education level, and functional limitations are associated with the number of job benefits received.DesignEconometric modeling of cross-sectional data using a 2-step data analytic model of employment and job benefits.SettingMedical university in the southeastern United States.ParticipantsParticipants (N=2624) were identified from the southeastern United States. After eliminating those age 65 and older, there were 2624 adult participants with SCD; 1234 had MS and 1390 had SCI.InterventionsNot applicable.Main Outcome MeasuresCurrent employment status; number of benefits received and specific benefits received.ResultsA greater proportion of participants with MS received benefits, with significant differences observed on all but 1 type of benefit. Among those who were employed, a greater number of benefits was associated with having MS, greater education, younger age, married or in an unmarried couple, and not having functional restrictions with cognition, doing errands, or shopping alone in the community, and walking.ConclusionsEmployed participants with MS were more likely to receive job benefits, indicative of a higher quality of employment, compared to participants with SCI. Employment without benefits is a form of underemployment that disproportionately affects individuals with many of the same characteristics that initially lead to disparities in probability of gainful employment.     

Effects of Robotic Exoskeleton-Aided Gait Training in the Strength,Body Balance,and Walking Speed in Individuals With Multiple Sclerosis: A Single-Group Preliminary Study

ObjectiveTo assess effects of 15 exoskeleton-assisted gait training sessions, reflected by the muscle strength of the lower limbs and by walking speed immediately after the training sessions and at the 6-week follow-up.DesignSingle-group longitudinal preliminary study.SettingIndividuals with multiple sclerosis (MS) at a hospital neurology ward.ParticipantsParticipants (N=14) included women and men aged from 36-61 years, with Expanded Disability Status Scale scores from 5.0-6.5.InterventionsExoskeleton-assisted walk training.Main Outcome MeasuresPrimary outcomes included dynamometric knee extensor and flexor strength (Biodex Pro4), postural balance, and center of pressure displacements (Zebris FMD-S). Secondary outcomes included walking speed measured with the timed 25-foot walk test and fatigue (Fatigue Severity Scale). Assessments were performed 4 times, that is, prior to the start of the program (T0), at the end of the physiotherapy without an exoskeleton (T1), at the end of the exoskeleton-assisted training (T2), and at 6-week follow-up (T3).ResultsAt the end of exoskeleton-assisted gait training there was a statistically significant improvement in peak torque of knee extensor muscles compared with the period of exercise without an exoskeleton. No statistically significant change was identified in the value of peak torque of knee flexors at T1. Likewise, the assessment at T2 showed the change in peak torque of knee flexors was not significant. The participants presented significantly faster walking speed after exoskeleton-assisted gait training compared with T0 and T1. No improvement was found in body balance. The subjects reported lower fatigue after exoskeleton-assisted gait training; however, the differences between the assessments at T1 and T0 as well as at T2 and T1 were statistically insignificant.ConclusionsIndividuals with MS and severe gait impairment participating in exoskeleton-assisted gait training achieved significant improvement in lower-limb muscle strength and increase in walking speed, yet the effect was not long-lasting.     

Development and Validation of a Multivariable Risk Prediction Model for COVID-19 Mortality in the Southern United States

ObjectiveTo evaluate clinical characteristics of patients admitted to the hospital with coronavirus disease 2019 (COVID-19) in Southern United States and development as well as validation of a mortality risk prediction model.Patients and MethodsSouthern Louisiana was an early hotspot during the pandemic, which provided a large collection of clinical data on inpatients with COVID-19. We designed a risk stratification model to assess the mortality risk for patients admitted to the hospital with COVID-19. Data from 1673 consecutive patients diagnosed with COVID-19 infection and hospitalized between March 1, 2020, and April 30, 2020, was used to create an 11-factor mortality risk model based on baseline comorbidity, organ injury, and laboratory results. The risk model was validated using a subsequent cohort of 2067 consecutive hospitalized patients admitted between June 1, 2020, and December 31, 2020.ResultsThe resultant model has an area under the curve of 0.783 (95% CI, 0.76 to 0.81), with an optimal sensitivity of 0.74 and specificity of 0.69 for predicting mortality. Validation of this model in a subsequent cohort of 2067 consecutively hospitalized patients yielded comparable prognostic performance.ConclusionWe have developed an easy-to-use, robust model for systematically evaluating patients presenting to acute care settings with COVID-19 infection.     

Randomized Controlled Trial of a Telephone-Delivered Physical Activity and Fatigue Self-management Interventions in Adults With Multiple Sclerosis

ObjectiveTo compare the effectiveness of telephone-delivered interventions on fatigue, physical activity, and quality of life outcomes in adults with multiple sclerosis (MS).DesignA single-blinded, randomized controlled trial. Participants were randomized to contact-control intervention (CC), physical activity–only intervention (PA-only), and physical activity plus fatigue self-management intervention (FM+). Outcomes were measured at baseline (2wk prerandomization), posttest (14wk postrandomization), and follow-up (26wk postrandomization).SettingTelephone-delivered in Midwest and Northeast regions of the United States.ParticipantsInactive adults with MS (N=208) and moderate-to-severe fatigue.InterventionsThree or 6 group teleconferences followed by 4 individually tailored phone calls delivered during 12 weeks. An occupational therapist and research assistant delivered the teleconferences and tailored phone calls, respectively.Main Outcome MeasuresPrimary outcomes were self-report fatigue and physical activity measured with the Fatigue Impact Scale and Godin Leisure-Time Exercise Questionnaire, respectively. Secondary outcomes included quality of life measured with the Multiple Sclerosis Impact Scale and moderate-to-vigorous exercise and step count measured with an accelerometer.ResultsLinear mixed effects models showed FM+ significantly improved self-reported fatigue (β=−11.08; P=.03) and physical activity (β=0.54; P=.01) compared with CC at posttest. However, FM+ had nonsignificant differences compared with PA-only on self-report fatigue (β=−1.08, P=.84) and physical activity (β=0.09; P=.68) at posttest. PA–only had significant improvements compared with CC on moderate-to-vigorous exercise (β=0.38; P=.02) at posttest and step count at posttest (β=1.30; P<.01) and follow-up (β=1.31; P=.01) measured with an accelerometer. FM+ and PA-only had nonsignificant differences compared with CC on quality of life.ConclusionsGroup teleconferences followed by tailored phone calls have a small yet statistically significant effect in promoting physical activity and reducing fatigue impact in people with MS.     

Is Fatigue Associated With Aerobic Capacity and Muscle Strength in People With Multiple Sclerosis: A Systematic Review and Meta-analysis

ObjectiveTo determine the relationship between self-reported fatigue and aerobic capacity and muscle strength in people with multiple sclerosis (MS).Data SourcesFour databases (Cumulative Index to Nursing and Allied Health, MEDLINE, ProQuest, and Web of Science Core Collections) were searched up to October 2018.Study SelectionCross-sectional or longitudinal studies that reported the association between self-reported fatigue and aerobic capacity or objectively measured muscle strength in people with MS were included.Data ExtractionStudy details, participant demographics, outcome measurement protocols, and the correlation coefficient derived from the association between fatigue and aerobic capacity or muscle strength at baseline was extracted, and methodological quality of included studies was assessed using the Joanna Briggs Institute Appraisal Checklist for Analytical Cross-sectional Studies.Data SynthesisTen studies were identified, of which 5 examined the association between fatigue and aerobic capacity and 7 examined the association between fatigue and muscle strength. Meta-analysis of the extracted correlation coefficients was performed using the Hedges-Olkin method, and pooled correlation coefficients demonstrated a moderate negative association between fatigue and aerobic capacity (r=−0.471; 95% CI, −0.644 to −0.251; P<.001) and a weak negative association between fatigue and muscle strength (r=−0.224; 95% CI, −0.399 to −0.032; P=.022).ConclusionsThe results of this meta-analysis suggest that higher levels of aerobic capacity are associated with lower fatigue. Therefore, this finding highlights the potential role of aerobic exercise interventions in managing fatigue. Conversely, the relationship between fatigue and muscle strength was weak and inconsistent, and further studies are required to examine the association between these variables.     

Comparison Between Common Performance-Based Tests and Self-Reports of Physical Function in People With Multiple Sclerosis: Does Sex or Gender Matter?

ObjectiveTo estimate the extent to which sex or gender differences affect the relations between tests of physical performance and self-reports about function in everyday life activities. Ecological validity is an important psychometric property when choosing tests of physical function, because they need to relate to everyday function. In multiple sclerosis (MS), the EQUI scale, modified Canadian Aerobic Fitness Test, grip strength, vertical jump, push-up, partial curl-up, gait speed (comfortable or fast), 6-minute walk test, and 9-hole peg test are commonly used but the extent to which they relate to everyday function is understudied and the extent to which ecological validity of these tests differ between women and men is unknown.DesignA cross-sectional analysis was conducted on a random sample of men and women recruited for a study on the life effect of MS. Correlations between pairs of performance outcome (PerfO) and self-reported outcome (SRO) items pairs of variables with theoretical coherence were calculated and gender effects identified using linear regression.SettingParticipants were recruited from MS clinic at Montreal Neurological Hospital.ParticipantsThe sample (N=188) consisted of 140 women and 48 men with MS.InterventionsNot applicable.ResultsThe mean age ± SD of the participants was 43±10. Sixty PerfO and SRO items yielded 165 theoretically linked pairs separately for women and men. Of these 330 possible pairs, 77 pairs (23%) had correlations ≥0.8, showing strong support for the link between performance tests and everyday function; 203 pairs provided moderate support (r≥0.5). Thirty-one pairs had a statistically significant interaction with gender with men having higher correlations than women (n=27/31).ConclusionThe results support the ecological validity for physical performance tests, particularly balance tests and particularly for men. The observation that many indicators of everyday function derived from SROs were related to physical performance supports the routine use of SROs in clinical practice to guide therapy to meet the needs of clients with MS.     

Clinical,Experimental, and Computational Validation of a New Doppler-Based Index for Coarctation Severity Assessment

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Dosage and Effectiveness of Aerobic Training on Cardiorespiratory Fitness,Functional Capacity,Balance, and Fatigue in People With Multiple Sclerosis: A Systematic Review and Meta-Analysis

ObjectivesTo evaluate the benefits of aerobic training (AT) programs on cardiorespiratory fitness, functional capacity, balance, and fatigue in individuals with multiple sclerosis (MS) and to identify the optimal dosage of AT programs for individuals with MS via a systematic review with meta-analysis.Data sourcesTwo electronic databases were searched until March 2020 (PubMed-Medline and Web of Science).Study SelectionStudies examining the effect of AT program on cardiorespiratory fitness, functional capacity, balance, and fatigue were included.Data ExtractionAfter applying the inclusion and exclusion criteria, we included 43 studies. A total sample of 1070 individuals with MS (AT group, n=680; control group, n=390) were analyzed.Data SynthesisThe AT group demonstrated a significant increase in cardiorespiratory fitness (standardized mean difference [SMD], 0.29; P=.002), functional capacity (timed Up and Go Test: SMD, –1.14; P<.001; gait speed: SMD, –1.19; P<.001; walking endurance: SMD, 0.46; P<.001), and balance (SMD, 3.49; P<.001) after training. Fatigue perception also decreased (SMD, –0.45; P<.001). However, no significant differences were observed when compared with the control group in either cardiorespiratory fitness (SMD, 0.14; P=.19) or fatigue perception. Nevertheless, we observed significant differences between the AT and control groups in balance (P=.02), gait speed (P=.02), and walking endurance (P=.03), favoring the participants who performed AT. Regarding the subgroup analysis, no significant differences were observed between subgroups in any of the variables studied except for gait speed, for which a greater increase in posttraining was observed when the AT program applied the continuous method (χ²=7.75; P=.005) and the exercises were performed by walking (χ²=9.36; P=.002).ConclusionsAerobic training improves gait speed, walking endurance, and balance. Cardiorespiratory fitness and fatigue perception also improved after AT, but we found no differences with the control group. In addition, subgroup analysis suggested that training using continuous and walking methods could optimize gait speed.