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BackgroundDefining the transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive multiple sclerosis (SPMS) can be challenging and delayed. A digital tool (MSProDiscuss) was developed to facilitate physician-patient discussion in evaluating early, subtle signs of multiple sclerosis (MS) disease progression representing this transition. ObjectiveThis study aimed to determine cut-off values and corresponding sensitivity and specificity for predefined scoring algorithms, with or without including Expanded Disability Status Scale (EDSS) scores, to differentiate between RRMS and SPMS patients and to evaluate psychometric properties. MethodsExperienced neurologists completed the tool for patients with confirmed RRMS or SPMS and those suspected to be transitioning to SPMS. In addition to age and EDSS score, each patient’s current disease status (disease activity, symptoms, and its impacts on daily life) was collected while completing the draft tool. Receiver operating characteristic (ROC) curves determined optimal cut-off values (sensitivity and specificity) for the classification of RRMS and SPMS. ResultsTwenty neurologists completed the draft tool for 198 patients. Mean scores for patients with RRMS (n=89), transitioning to SPMS (n=47), and SPMS (n=62) were 38.1 (SD 12.5), 55.2 (SD 11.1), and 69.6 (SD 12.0), respectively (P

BackgroundMagnetic resonance imaging (MRI) measurements of gray matter (GM) atrophy and magnetization transfer ratio (MTR; correlate of myelination) may provide better insights than conventional MRI regarding brain tissue integrity/myelination in multiple sclerosis (MS).ObjectiveTo examine the effect of siponimod in the EXPAND trial on whole-brain and GM atrophy, newly formed normalized magnetization transfer ratio (nMTR) lesions, and nMTR-assessed integrity of normal-appearing brain tissue (NABT), cortical GM (cGM), and normal-appearing white matter (NAWM).MethodsPatients with secondary progressive multiple sclerosis (SPMS) received siponimod (2 mg/day; n =1037) or placebo (n = 523). Endpoints included percentage change from baseline to months 12/24 in whole-brain, cGM, and thalamic volumes; change in nMTR from baseline to months 12/24 in NABT, cGM, and NAWM; MTR recovery in newly formed lesions.ResultsCompared with placebo, siponimod significantly reduced progression of whole-brain and GM atrophy over 12/24 months, and was associated with improvements in brain tissue integrity/myelination within newly formed nMTR lesions and across NABT, cGM, and NAWM over 24 months. Effects were consistent across age, disease duration, inflammatory activity subgroups, and disease severity.ConclusionSiponimod reduced brain tissue damage in patients with SPMS as evidenced by objective measures of brain tissue integrity/myelination. This is consistent with central nervous system (CNS) effects observed in preclinical models. ClinicalTrials.gov number: NCT01665144.

BackgroundSiponimod is a sphingosine 1-phosphate receptor modulator approved for active secondary progressive multiple sclerosis (aSPMS) in most countries; however, phase 3 EXPAND study data are from an SPMS population with/without disease activity. A need exists to characterize efficacy/safety of siponimod in aSPMS.MethodsPost hoc analysis of participants with aSPMS (≥ 1 relapse in 2 years before study and/or ≥ 1 T1 gadolinium-enhancing [Gd +] magnetic resonance imaging [MRI] lesions at baseline) receiving oral siponimod (2 mg/day) or placebo for up to 3 years in EXPAND.Endpoints3-month/6-month confirmed disability progression (3mCDP/6mCDP); 3-month confirmed ≥ 20% worsening in Timed 25-Foot Walk (T25FW); 6-month confirmed improvement/worsening in Symbol Digit Modalities Test (SDMT) scores (≥ 4-point change); T2 lesion volume (T2LV) change from baseline; number of T1 Gd + lesions baseline-month 24; number of new/enlarging (N/E) T2 lesions over all visits.ResultsData from 779 participants with aSPMS were analysed. Siponimod reduced risk of 3mCDP/6mCDP vs placebo (by 31%/37%, respectively; p

Background and objectivesTo describe the characteristics of patients with MS reporting cryptococcal meningitis (CM) while treated with fingolimod.MethodsThe Novartis safety database was searched for cases with CM between January 26, 2006, and February 28, 2020. The reporting rate of CM was estimated based on the case reports received and exposure to fingolimod in the postmarketing setting during the relevant period.ResultsA total of 60 case reports of CM were identified, mostly from the United States. The median age was 48 years, and 51.8% were women. Most of the patients had recovered or were recovering at the time of final report. A fatal outcome occurred in 13 cases. During the study period, the rate of CM in patients with MS receiving fingolimod was estimated to be 8 per 100,000 patient-years (95% CI: 6.0; 10.0). The incidence of CM seemed to increase with duration of treatment; however, this relationship remains uncertain due to wide CIs and missing data.DiscussionThe causal relationship between fingolimod treatment and CM is not yet fully understood. The CM mortality rate in fingolimod-treated patients is similar to that reported in HIV-negative patients. Vigilance for signs and symptoms of CM in patients receiving fingolimod, particularly the new onset of headaches and altered mental status, is essential. Early diagnosis and treatment are critical to reducing CM-associated mortality.

A descriptive analysis of COVID-19 infection in patients with multiple sclerosis (MS) receiving fingolimod or siponimod. We reviewed the cases of COVID-19 from postmarketing or ongoing clinical trials reported to Novartis through December 27, 2020. As of December 27, 2020, 283 cases had been reported in fingolimod-treated patients. The mean age was 44 years (from n = 224; range 11-69 years), and 190 were women. Of 161 cases with available information, 138 were asymptomatic (6), mild (100), or moderate (32); 50 cases required hospitalization. At the last follow-up, 140 patients were reported as recovered/recovering, condition was unchanged in 22, and deteriorated in 3 patients; 4 patients had a fatal outcome. Information was not available for 114 patients. Of the 54 cases of COVID-19 reported in siponimod-treated patients, 45 were from the postmarketing setting and 9 from an ongoing open-label clinical trial. The mean age was 54 years (from n = 45; range 31-70), and 30 were women. Of 28 cases with available information, 24 were asymptomatic (2), mild (17), or moderate (5); 9 cases required hospitalization. At the last follow-up, 27 patients were reported as recovered/recovering, condition remained unchanged for 1, and 3 patients had a fatal outcome. Information was not available for 23 patients. Based on a review of available information, the risk of more severe COVID-19 in patients receiving fingolimod or siponimod seems to be similar to that reported in the general population and the MS population with COVID-19. However, limitations of spontaneous reporting, especially missing data, should be considered in the interpretation of these observations.

Background: Patient-reported outcomes (PROs) are widely measured in multiple sclerosis (MS) studies. However, the quality of instrument development processes varies, raising concerns about the meaningfulness of associated data. Objectives: To review the development of selected PROs commonly used in MS studies, including definitions of the concepts measured, use of conceptual frameworks, and degree of input from people living with MS (PlwMS). To gain insights and recommendations from PlwMS on their experience with these PROs. Methods: We assessed 6 PROs (FSIQ-RMS, modified-FIS, MSQoL-54, Leeds 8-item MSQoL, MSIS-29 and EQ-5D) for alignment with regulatory and scientific requirements on PRO structure/development. PlwMS evaluated the degree to which the PROs reflect disease aspects they perceive important. Results: Definitions, clarifications and conceptualisations of the measurement variables were often lacking. PlwMS were variably involved in PRO development. Ethnic diversity was rarely documented. PlwMS identified individualisation, ease of understanding, time burden, and mode of administration as factors affecting PRO usability. Conclusions: To date, the PRO development process has consistently lacked clear definitions of concepts of interest, use of conceptual frameworks and patient involvement, thereby compromising the validity of data they generate. PRO instrument development must be conducted more robustly to maximise the value of pivotal clinical trials. [ABSTRACT FROM AUTHOR]

This paper presents a novel pipeline for adding 3D geometry information to conventional green screen assets in virtual broadcast studios. Today's green screen studios are limited to 2D object interaction. Information about depth is not available, and hence the 3D relation to nonvirtual objects is unknown. We overcome this situation by using an integrated RGB+depth camera and a specialized processing pipeline, which delivers an additional synchronized depth channel in realtime. This technology enables interaction of virtual and real objects, including shadow casting and occluding virtual objects. We implemented and tested several of these effects within a professional virtual studio renderer. [ABSTRACT FROM AUTHOR]

We investigated the efficacy and safety of empagliflozin over 24 weeks in Asian patients with type 2 diabetes ( T2DM) using pooled data from four phase III trials. In these trials, patients were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg or placebo as monotherapy or add-on to metformin, metformin plus sulphonylurea or pioglitazone ± metformin. In total, 1326 patients from Asia received ≥1 dose of study drug. At week 24, adjusted mean differences versus placebo in change from baseline in glycated haemoglobin ( HbA1c) were −0.66% [95% confidence interval ( CI) −0.76, −0.56] and −0.73% (95% CI −0.83, −0.64) and in weight were −1.6 kg (95% CI −1.9, −1.3) and −1.8 kg (95% CI −2.1, −1.5) with empagliflozin 10 and 25 mg, respectively (all p < 0.001). Empagliflozin significantly reduced systolic and diastolic blood pressure. The proportion of patients reporting ≥1 adverse event was similar across treatment groups, but events consistent with genital infection were more common in patients treated with empagliflozin 10 mg (3.4%) or 25 mg (2.3%) than placebo (0.9%). Thus in Asian patients with T2DM, empagliflozin reduced HbA1c, weight and blood pressure, and was well tolerated. [ABSTRACT FROM AUTHOR]

Background: This study evaluated the effect of empagliflozin on postprandial glucose (PPG) and 24-hour glucose variability in Japanese patients with type 2 diabetes mellitus (T2DM). Methods: Patients (N = 60; baseline mean [SD] HbA1c 7.91 [0.80]%; body mass index 24.3 [3.2] kg/m²) were randomized to receive empagliflozin 10 mg (n = 20), empagliflozin 25 mg (n = 19) or placebo (n = 21) once daily as monotherapy for 28 days. A meal tolerance test and continuous glucose monitoring (CGM) for 24 hours were performed at baseline and on days 1 and 28. The primary endpoint was change from baseline in area under the glucose concentration-time curve 3 hours after breakfast (AUC1-4hfor PPG) at day 28. Results: Adjusted mean (95%) differences versus placebo in changes from baseline in AUC1-4h for PPG at day 1 were -97.1 (-126.5, -67.8) mg·h/dl with empagliflozin 10 mg and -91.6 (-120.4, -62.8) mg·h/dl with empagliflozin 25 mg (both p < 0.001 versus placebo) and at day 28 were -85.5 (-126.0, -45.0) mg · h/dl with empagliflozin 10 mg and -104.9 (-144.8, -65.0) mg·h/dl with empagliflozin 25 mg (both p < 0.001 versus placebo). Adjusted mean (95% CI) differences versus placebo in change from baseline in 24-hour mean glucose (CGM) at day 1 were -20.8 (-27.0, -14.7) mg/dl with empagliflozin 10 mg and -23.9 (-30.0, -17.9) mg/dl with empagliflozin 25 mg (both p < 0.001 versus placebo) and at day 28 were -24.5 (-35.4, -13.6) mg/dl with empagliflozin 10 mg and -31.7 (-42.5,-20.9) mg/dl with empagliflozin 25 mg (both p < 0.001 versus placebo). Changes from baseline in mean amplitude of glucose excursions (MAGE; CGM) were not significantly different with either empagliflozin dose versus placebo at either timepoint. Curves of mean glucose (CGM) did not change between baseline and day 1 or 28 with placebo, but shifted downward with empagliflozin. Percentage of time with glucose =70 to <180 mg/dl increased from 52.0% at baseline to 77.0% at day 28 with empagliflozin 10 mg and from 55.0% to 81.1% with empagliflozin 25 mg, without increasing time spent with hypoglycemia. Conclusion: Empagliflozin for 28 days reduced PPG from the first day and improved daily blood glucose control in Japanese patients with T2DM. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. Data now indicate that proinsulin C-peptide exerts important physiological effects and shows the characteristics of an endogenous peptide hormone. This study aimed to investigate the influence of C-peptide and fragments thereof on erythrocyte deformability and to elucidate the relevant signal transduction pathway. Methods. Blood samples from 23 patients with type 1 diabetes and 15 matched healthy controls were incubated with 6.6 nM of either human C-peptide, C-terminal hexapeptide, C-terminal pentapeptide, a middle fragment comprising residues 11-19 of C-peptide, or randomly scrambled Cpeptide. Furthermore, red blood cells from 7 patients were incubated with C-peptide, penta- and hexapeptides with/without addition of ouabain, EDTA, or pertussis toxin. Erythrocyte deformability was measured using a laser diffractoscope in the shear stress range 0.3-60 Pa. Results. Erythrocyte deformability was impaired by 18-25% in type 1 diabetic patients compared to-matched controls in the physiological shear stress range 0.6-12 Pa (P < .01-.001). C-peptide, penta- and hexapeptide all significantly improved the impaired erythrocyte deformability of type 1 diabetic patients, while the middle fragment and scrambled C-peptide had no detectable effect. Treatment of erythrocytes with ouabain or EDTA completely abolished the C-peptide, penta-and hexapeptide effects. Pertussis toxin in itself significantly increased erythrocyte deformability. Conclusion/interpretation. C-peptide and its C-terminal fragments are equally effective in improving erythrocyte deformability in type 1 diabetes. The C-terminal residues of C-peptide are causally involved in this effect. The signal transduction pathway is Ca2+-dependent and involves activation of red blood cell Na+,K+-ATPase. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. Data now indicate that proinsulin C-peptide exerts important physiological effects and shows the characteristics of an endogenous peptide hormone. This study aimed to investigate the influence of C-peptide and fragments thereof on erythrocyte deformability and to elucidate the relevant signal transduction pathway. Methods. Blood samples from 23 patients with type 1 diabetes and 15 matched healthy controls were incubated with 6.6 nM of either human C-peptide, C-terminal hexapeptide, C-terminal pentapeptide, a middle fragment comprising residues 11-19 of C-peptide, or randomly scrambled C-peptide. Furthermore, red blood cells from 7 patients were incubated with C-peptide, penta- and hexapeptides with/without addition of ouabain, EDTA, or pertussis toxin. Erythrocyte deformability was measured using a laser diffractoscope in the shear stress range 0.3-60 Pa. Results. Erythrocyte deformability was impaired by 18-25% in type 1 diabetic patients compared to matched controls in the physiological shear stress range 0.6-12 Pa (P < .01-.001). C-peptide, penta- and hexapeptide all significantly improved the impaired erythrocyte deformability of type 1 diabetic patients, while the middle fragment and scrambled C-peptide had no detectable effect. Treatment of erythrocytes with ouabain or EDTA completely abolished the C-peptide, penta and hexapeptide effects. Pertussis toxin in itself significantly increased erythrocyte deformability. Conclusion/interpretation. C-peptide and its C-terminal fragments are equally effective in improving erythrocyte deformability in type 1 diabetes. The C-terminal residues of C-peptide are causally involved in this effect. The signal transduction pathway is Ca2+ dependent and involves activation of red blood cell Na+K+-ATPase. [ABSTRACT FROM AUTHOR]

Background: MSProDiscuss is a validated physician-completed tool based on a set of weighted questions that include information on multiple sclerosis (MS) relapses, symptoms, and impacts experienced by the patient within the past 6 months. The tool's traffic light system-linked output is meant as an aid for discussing the signs of MS disease progression. The tool is available online at www.msprodiscuss.com. Objectives: To report physician findings on usability and usefulness testing of the MSProDiscuss tool while discussing disease progression with patients in the real-world setting. Methods: An online qualitative survey was undertaken in 34 countries. Health care practitioners (HCPs) completed individual questionnaires (i) after using MSProDiscuss during face-to-face patient consultations and a final questionnaire (f) to capture the overall experience on the tool. The HCPs also provided general feedback and recommendations for improving the tool. Results: In total, 301 HCPs (including 23 MS nurses and 6 neurology nurse practitioners) tested the tool in 6974 patients with MS. The time taken to complete MSProDiscuss during a regular consultation was 1-4 minutes in 97% (i) to 98% (f) of the time. In 94% (i) to 97% (f ) of cases, HCPs agreed that patients were able to comprehend the questions from the tool. HCPs were willing to use the tool again in the same patient 91% (i) of the time. MSProDiscuss was useful in discussing MS symptoms and its impact on daily activities (88% i / 92% f) and cognitive function (79% both i and f) and in discussing progression in general (88% i / 90% f). While completing the final questionnaire, 95% of HCPs agreed that the questions were similar to those asked in regular consultation. MSProDiscuss was also found helpful for understanding the impact of MS symptoms on daily activities (91%) and cognitive function (80%). Overall, 92% of the HCPs would recommend MSProDiscuss to a colleague. Regarding integration of MSProDiscuss into their clinical practice, 92% of HCPs think that it is feasible and 86% are willing to integrate. Key recommendations were to allow for longitudinal follow-up, expand on cognitive assessments, and provide a patient-completed version; these are considered in the updated version of MSPro- Discuss. Conclusions: The findings from this real-world study suggest that MSProDiscuss is a usable and useful tool to facilitate physician-patient discussion on disease progression in daily clinical practice by capturing structured disease history. [ABSTRACT FROM AUTHOR]

Background: A digital tool, Multiple Sclerosis Progression Discussion Tool (MSProDiscuss), was developed to facilitate discussions between health care professionals (HCPs) and patients in evaluating early, subtle signs of multiple sclerosis (MS) disease progression.Objective: The aim of this study is to report the findings on the usability and usefulness of MSProDiscuss in a real-world clinical setting.Methods: In this cross-sectional, web-based survey, HCPs across 34 countries completed an initial individual questionnaire (comprising 7 questions on comprehensibility, usability, and usefulness after using MSProDiscuss during each patient consultation) and a final questionnaire (comprising 13 questions on comprehensibility, usability, usefulness, and integration and adoption into clinical practice to capture the HCPs' overall experience of using the tool). The responses were provided on a 5-point Likert scale. All analyses were descriptive, and no statistical comparisons were made.Results: In total, 301 HCPs tested the tool in 6974 people with MS, of whom 77% (5370/6974) had relapsing-remitting MS, including those suspected to be transitioning to secondary progressive MS. The time taken to complete MSProDiscuss was reported to be in the range of 1 to 4 minutes in 97.3% (6786/6974; initial) to 98.2% (269/274; final) of the cases. In 93.54% (6524/6974; initial) to 97.1% (266/274; final) of the cases, the HCPs agreed (4 or 5 on the Likert scale) that patients were able to comprehend the questions in the tool. The HCPs were willing to use the tool again in the same patient, 90.47% (6310/6974; initial) of the cases. The HCPs reported MSProDiscuss to be useful in discussing MS symptoms and their impact on daily activities (6121/6974, 87.76% initial and 252/274, 92% final) and cognitive function (5482/6974, 78.61% initial and 271/274, 79.2% final), as well as in discussing progression in general (6102/6974, 87.49% initial and 246/274, 89.8% final). While completing the final questionnaire, 94.9% (260/274) of the HCPs agreed that the questions were similar to those asked in regular consultation, and the tool helped to better understand the impact of MS symptoms on daily activities (249/274, 90.9%) and cognitive function (220/274, 80.3%). Overall, 92% (252/274) of the HCPs reported that they would recommend MSProDiscuss to a colleague, and 85.8% (235/274) were willing to integrate it into their clinical practice.Conclusions: MSProDiscuss is a usable and useful tool to facilitate a physician-patient discussion on MS disease progression in daily clinical practice. Most of the HCPs agreed that the tool is easy to use and were willing to integrate MSProDiscuss into their daily clinical practice. [ABSTRACT FROM AUTHOR]

Background: The alternative complement pathway plays a key role in the pathogenesis of IgA nephropathy. Iptacopan specifically binds to factor B and inhibits the alternative pathway., Methods: In this phase 3, double-blind, randomized, placebo-controlled trial, we enrolled adults with biopsy-confirmed IgA nephropathy and proteinuria with a 24-hour urinary protein-to-creatinine ratio of 1 or higher (with protein and creatinine both measured in grams) despite optimized supportive therapy. Patients were randomly assigned, in a 1:1 ratio, to receive oral iptacopan (200 mg) or placebo twice daily for 24 months while continuing to receive supportive therapy. The primary objective of this prespecified interim analysis was to assess the efficacy of iptacopan as compared with that of placebo in reducing proteinuria at month 9; the primary end point was the change from baseline in the 24-hour urinary protein-to-creatinine ratio at month 9. The proportion of patients who had a 24-hour urinary protein-to-creatinine ratio of less than 1 at month 9 without receiving rescue or alternative medication or undergoing kidney-replacement therapy (dialysis or transplantation) was a secondary end point. Safety was also assessed. The effect of iptacopan on kidney function will be assessed at the end of the 2-year double-blind treatment period., Results: The main trial population included 222 patients in the iptacopan group and 221 in the placebo group. The interim efficacy analysis included the first 250 patients who underwent randomization in the main trial population (125 patients in each group) and who remained in the trial until month 9 or discontinued the trial by month 9. Safety was assessed in all the patients in the main trial population. At month 9, the adjusted geometric mean 24-hour urinary protein-to-creatinine ratio was 38.3% (95% confidence interval, 26.0 to 48.6; two-sided P<0.001) lower with iptacopan than with placebo. The reduction in proteinuria was supported by consistent results in secondary end point analyses. There were no unexpected safety findings with iptacopan. The incidence of adverse events that occurred during the treatment period was similar in the two groups; most events were mild to moderate in severity and reversible. No increased risk of infection was observed., Conclusions: Among patients with IgA nephropathy, treatment with iptacopan resulted in a significant and clinically meaningful reduction in proteinuria as compared with placebo. (Funded by Novartis; APPLAUSE-IgAN ClinicalTrials.gov number, NCT04578834.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: To assign a course of secondary progressive multiple sclerosis (MS) (SPMS) may be difficult and the proportion of persons with SPMS varies between reports. An objective method for disease course classification may give a better estimation of the relative proportions of relapsing-remitting MS (RRMS) and SPMS and may identify situations where SPMS is under reported., Materials and Methods: Data were obtained for 61,900 MS patients from MS registries in the Czech Republic, Denmark, Germany, Sweden, and the United Kingdom (UK), including date of birth, sex, SP conversion year, visits with an Expanded Disability Status Scale (EDSS) score, MS onset and diagnosis date, relapses, and disease-modifying treatment (DMT) use. We included RRMS or SPMS patients with at least one visit between January 2017 and December 2019 if ≥ 18 years of age. We applied three objective methods: A set of SPMS clinical trial inclusion criteria ("EXPAND criteria") modified for a real-world evidence setting, a modified version of the MSBase algorithm, and a decision tree-based algorithm recently published., Results: The clinically assigned proportion of SPMS varied from 8.7% (Czechia) to 34.3% (UK). Objective classifiers estimated the proportion of SPMS from 15.1% (Germany by the EXPAND criteria) to 58.0% (UK by the decision tree method). Due to different requirements of number of EDSS scores, classifiers varied in the proportion they were able to classify; from 18% (UK by the MSBase algorithm) to 100% (the decision tree algorithm for all registries). Objectively classified SPMS patients were older, converted to SPMS later, had higher EDSS at index date and higher EDSS at conversion. More objectively classified SPMS were on DMTs compared to the clinically assigned., Conclusion: SPMS appears to be systematically underdiagnosed in MS registries. Reclassified patients were more commonly on DMTs., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Lars Forsberg has nothing to disclose. Tim Spelman has received compensation for serving on the scientific advisory board for Biogen and speaker honoraria from Novartis. Pernilla Klyve has nothing to disclose. Ali Manouchehrinia is supported by the Margaretha af Ugglas Foundation. Ryan Ramanujam has nothing to disclose. Elena Mouresan has nothing to disclose. Jiri Drahota has nothing to disclose. Dana Horakova was supported by the Czech Ministry of Education (project Cooperatio LF1, research area Neuroscience). She also received compensation for travel, speaker honoraria, and consultant fees from Biogen Idec, Novartis, Merck, Sanofi, Roche, and Teva, as well as support for research activities from Biogen Idec. Hanna Joensen has received honoraria for an advisory board from Biogen. Luigi Pontieri has nothing to disclose. Melinda Magyari has served on the scientific advisory board, served as a consultant for, received support for congress participation, and received speaker honoraria from Biogen, Sanofi, Roche, Novartis, Merck, Abbvie, and Alexion. The Danish MR Registry received research support from Biogen, Genzyme, Roche, Merck, and Novartis. David Ellenberger has nothing to disclose. Alexander Stahmann has no personal pecuniary interests to disclose, other than being the lead of the German MS Registry, which receives funding from a range of public and corporate sponsors, recently including The German Innovation Fund (G-BA), The German MS Trust, German MS Society, Biogen, Celgene (Bristol-Myers Squibb), Merck, Novartis, Roche, and Sanofi. None resulted in a conflict of interest. Jeff Rodgers has nothing to disclose. The UK MS Register is funded by the MS Society. James Witts has nothing to disclose. The UK MS Register is funded by the MS Society. Rod Middleton has nothing to disclose. The UK MS Register is funded by the MS Society. Richard Nicholas has received support from advisory boards from Roche and Biogen. He has grant support from the UK MS Society and Berkeley Foundation and is a vice chair of a NICE HTA committee. Vladimir Bezlyak is an employee of Novartis Pharma AG. Nicholas Adlard is an employee of Novartis Pharma AG. Thomas Hach is an employee of Novartis Pharma AG. Carol Lines is an employee of Novartis Pharma AG. Sandra Vukusic has received grants, personal fees, unrestricted research grants, and nonfinancial support from Biogen, BMS-Celgene, Genzyme, Janssen, Merck Serono, Novartis, Roche, Sanofi, and Teva. Merja Soilu-Hanninen has received congress fee covering and lecture and consultation fees by Biogen, Celgene, Merck, Novartis, Roche, Sanofi, and Teva. Anneke van der Walt served on advisory boards and receives unrestricted research grants from Novartis, Biogen, Merck, Alexion, NervGen, and Roche. She has received speaker's honoraria and travel support from Novartis, Roche, Biogen, and Merck. She receives grant support from the National Health and Medical Research Council of Australia and MS Research Australia. Helmut Butzkueven's institution (Monash University) has received compensation for his services on scientific advisory boards and as a speaker from Biogen, Novartis, Roche, Merck, and UCB. He serves on steering committees for trials conducted by Biogen, Merck, and Novartis, and his institution has received research support from Roche, Merck, Novartis, and Biogen. Pietro Iaffaldano has received advisory board membership, speaker honoraria, and travel support from Almirall, Bayer Shering, Biogen, Genzyme, Merck, Novartis, Sanofi, Roche, Teva, and their local affiliates. Maria Trojano received advisory board membership, speaker honoraria, travel support and research grant from Almirall, Bayer Shering, Biogen, Genzyme, Merck, Novartis, Sanofi, Roche, Teva, and their local affiliates. Anna Glaser has received research support from Novartis. Jan Hillert has received honoraria for serving on advisory boards for Biogen, Celgene, Sanofi-Genzyme, Merck KGaA, Novartis, and Sandoz and speaker's fees from Biogen, Novartis, Merck KGaA, Teva, and Sanofi-Genzyme. He has served as PI for projects or received unrestricted research support from Biogen, Celgene, Merck KGaA, Novartis, Roche, and Sanofi-Genzyme. His MS research was funded by the Swedish Research Council and the Swedish Brain foundation., (© The Author(s), 2023.)

Many challenges exist in the precise diagnosis and clinical management of secondary progressive multiple sclerosis (SPMS) because of the lack of definitive clinical, imaging, immunologic, or pathologic criteria that demarcate the transition from relapsing-remitting MS to SPMS. This review provides an overview of the diagnostic criteria/definition and the heterogeneity associated with different SPMS patient populations; it also emphasizes the importance of available prospective/retrospective tools to identify patients with SPMS earlier in the disease course so that approved disease-modifying therapies and nonpharmacological strategies will translate into better outcomes. Delivery of such interventions necessitates an evolving patient-clinician dialog within the context of a multidisciplinary team., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Objectives: A descriptive analysis of COVID-19 infection in patients with multiple sclerosis (MS) receiving fingolimod or siponimod., Methods: We reviewed the cases of COVID-19 from postmarketing or ongoing clinical trials reported to Novartis through December 27, 2020., Results: As of December 27, 2020, 283 cases had been reported in fingolimod-treated patients. The mean age was 44 years (from n = 224; range 11-69 years), and 190 were women. Of 161 cases with available information, 138 were asymptomatic (6), mild (100), or moderate (32); 50 cases required hospitalization. At the last follow-up, 140 patients were reported as recovered/recovering, condition was unchanged in 22, and deteriorated in 3 patients; 4 patients had a fatal outcome. Information was not available for 114 patients. Of the 54 cases of COVID-19 reported in siponimod-treated patients, 45 were from the postmarketing setting and 9 from an ongoing open-label clinical trial. The mean age was 54 years (from n = 45; range 31-70), and 30 were women. Of 28 cases with available information, 24 were asymptomatic (2), mild (17), or moderate (5); 9 cases required hospitalization. At the last follow-up, 27 patients were reported as recovered/recovering, condition remained unchanged for 1, and 3 patients had a fatal outcome. Information was not available for 23 patients., Discussion: Based on a review of available information, the risk of more severe COVID-19 in patients receiving fingolimod or siponimod seems to be similar to that reported in the general population and the MS population with COVID-19. However, limitations of spontaneous reporting, especially missing data, should be considered in the interpretation of these observations., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Aims: To analyse the effect of baseline glycated haemoglobin (HbA 1c ) on the reduction in HbA 1c with empagliflozin compared with sitagliptin or glimepiride in patients with type 2 diabetes., Materials and Methods: Using regression analyses of individual patient data from two Phase III studies, we compared the change in HbA 1c according to a unit change in baseline HbA 1c (the slope) with empagliflozin 10 mg or 25 mg vs sitagliptin (monotherapy) after 24 weeks, and with empagliflozin 25 mg vs glimepiride (as add-on to metformin) after 52 weeks., Results: Steeper slopes of HbA1c decline were observed with empagliflozin 10 or 25 mg vs sitagliptin monotherapy at week 24. Regression analysis showed slopes of -0.59 (95% CI -0.70, -0.47), -0.49 (95% CI -0.62, -0.37) and -0.29 (95% CI -0.42, -0.15) for empagliflozin 10 mg, empagliflozin 25 mg and sitagliptin, respectively ( P  < .001 and P  < .05 for empagliflozin 10 mg and empagliflozin 25 mg, respectively, vs sitagliptin). Similarly, a steeper slope of HbA 1c decline was observed with empagliflozin 25 mg vs glimepiride as add-on to metformin at week 52. Regression analysis showed slopes of - 0.52 (95% CI -0.59, -0.44) and -0.32 (95% CI -0.39, -0.25) for empagliflozin 25 mg and glimepiride, respectively ( P  < .001 for empagliflozin 25 mg vs glimepiride)., Conclusions: Incremental reductions in HbA 1c with increasing baseline HbA 1c are greater with empagliflozin compared with sitagliptin or glimepiride in patients with type 2 diabetes.

C-Peptide is produced in beta-cells in the pancreas, and secreted into the blood stream in equimolar amounts with insulin. For a long time, C-peptide was considered as an important component in the biosynthesis of insulin, but otherwise believed to possess minimal biological activity. In the recent years, numerous studies demonstrated that lacking C-peptide in type 1 diabetic patients might exert an important role in the development of microvascular complications such as nephropathy or neuropathy. There is increasing evidence that the biological effects of C-peptide are, at least in part, mediated through the modulation of endothelial function and microvascular blood flow. In several tissues, an increase in microvascular and nutritional blood flow could be observed during substitution of physiological amounts of C-peptide. Recent studies confirmed that C-peptide stimulates endothelial NO release by the activation of Ca2+ calmodulin-regulated endothelial NO synthase. A restoration of Na+/K+-ATPase activity during C-peptide supplementation could be observed in erythrocytes and renal tubular cells. The improvement of erythrocyte Na+/K+-ATPase is associated with an increase in erythrocyte deformability, and improved rheological properties. In this article, we consider the role of C-peptide in the context of endothelial function and microvascular blood flow as pathophysiologic components in the development of microvascular complications in patients with diabetes mellitus and loss of beta-cell function.