The Morphology of the Dorsal Part of the First Rib in Neurogenic Thoracic Outlet Syndrome Patients: A Retrospective Clinical Study.

BACKGROUND: The recurrence or persistence of symptoms after thoracic outlet decompression (TOD) in patients with neurogenic thoracic outlet syndrome (NTOS) is not uncommon. Some authors have shown significantly better clinical outcomes in patients who underwent TOD with exarticulation of the first rib compared to a group who underwent TOD with preservation of the dorsal portion of the first rib. Several other case series have shown significant improvement after redo surgery with removal of the dorsal first rib remnant. This indicates the importance of the dorsal part of the first rib in NTOS. However, radical exarticulation may not always be necessary. In this study, we tried to answer the question of whether there is a morphological difference in the dorsal part of the first rib in NTOS patients that might help in the diagnosis and treatment of NTOS. METHODS: We used the CT data of 21 NTOS patients who underwent TOD surgery and measured the dorsal part of the first rib, then compared them with a quota sample. RESULTS: We found no difference in the dorsal part of the first rib between NTOS patients and the quota sample in our data. CONCLUSIONS: As there was no detectable difference, we were not able to use these data to help decide whether exarticulation is necessary in achieving adequate symptom relief. Therefore, we advocate exarticulation of the first rib when TOD is indicated.

High temperature gamma radiation-induced chromium redox chemistry via in situ spectroscopic measurements.

Chromium ions can make their way into the primary coolant of nuclear power reactors from the corrosion of stainless-steel reactor components, decreasing the material's corrosion resistance and resulting in increased transport of further corrosion products. Despite these potential effects, the radiation-induced redox speciation of chromium ions in aqueous solution is not well understood, especially at the elevated temperatures experienced by reactor coolants. In the present work, we report new experimental results demonstrating that in aerated aqueous solution, the radiolytic oxidation of Cr(III) to Cr(VI) occurs at pH 4, while the reduction of Cr(VI) to Cr(III) occurs at pH 2. The oxidation of Cr(III) is primarily attributed to the reaction of the hydroxyl radical (˙OH) with the Cr(OH)2+ species, while the reduction of Cr(VI) is attributed to reactions involving the hydrated electron (eaq-) and hydrogen atom (H˙). Additionally, the steady-state equilibrium yield of Cr(VI) from the gamma irradiation of pH 4 Cr(III) solutions decreased with increasing temperature (over a range of 37-195 °C). This observation indicates that the activation energy of the Cr(VI) reduction reactions is higher than that for the Cr(III) oxidation reactions, such that it becomes relatively more favorable at higher temperatures. Overall, these data are important for the development of complementary multiscale models for the prediction of metal ion speciation in high temperature radiation environments.

The impact of cigarette smoking on cognitive processing speed and brain atrophy in multiple sclerosis.

BACKGROUND: Smoking is associated with an increased risk of multiple sclerosis (MS) and disability worsening. The relationship between smoking, cognitive processing speed, and brain atrophy remains uncertain. OBJECTIVE: To quantify the impact of smoking on processing speed and brain volume in MS and to explore the longitudinal relationship between smoking and changes in processing speed. METHODS: A retrospective study of MS patients who completed the processing speed test (PST) between September 2015 and March 2020. Demographics, disease characteristics, smoking history, and quantitative magnetic resonance imaging (MRI) were collected. Cross-sectional associations between smoking, PST performance, whole-brain fraction (WBF), gray matter fraction (GMF), and thalamic fraction (TF) were assessed using multivariable linear regression. The longitudinal relationship between smoking and PST performance was assessed by linear mixed modeling. RESULTS: The analysis included 5536 subjects of whom 1314 had quantitative MRI within 90 days of PST assessment. Current smokers had lower PST scores than never smokers at baseline, and this difference persisted over time. Smoking was associated with reduced GMF but not with WBF or TF. CONCLUSION: Smoking has an adverse relationship with cognition and GMF. Although causality is not demonstrated, these observations support the importance of smoking cessation counseling in MS management.

Long-term safety and efficacy of dimethyl fumarate for up to 13 years in patients with relapsing-remitting multiple sclerosis: Final ENDORSE study results.

BACKGROUND: Dimethyl fumarate (DMF) demonstrated favorable benefit-risk in relapsing-remitting multiple sclerosis (RRMS) patients in phase-III DEFINE and CONFIRM trials, and ENDORSE extension. OBJECTIVE: The main aim of this study is assessing DMF safety/efficacy up to 13 years in ENDORSE. METHODS: Randomized patients received DMF 240 mg twice daily or placebo (PBO; Years 0-2), then DMF (Years 3-10; continuous DMF/DMF or PBO/DMF); maximum follow-up (combined studies), 13 years. RESULTS: By January 2020, 1736 patients enrolled/dosed in ENDORSE (median follow-up 8.76 years (ENDORSE range: 0.04-10.98) in DEFINE/CONFIRM and ENDORSE); 52% treated in ENDORSE for ⩾6 years. Overall, 551 (32%) patients experienced serious adverse events (mostly multiple sclerosis (MS) relapse or fall; one progressive multifocal leukoencephalopathy); 243 (14%) discontinued treatment due to adverse events (4% gastrointestinal (GI) disorders). Rare opportunistic infections, malignancies, and serious herpes zoster occurred, irrespective of lymphocyte count. For DMF/DMF (n = 501), overall annualized relapse rate (ARR) remained low (0.143 (95% confidence interval (CI), 0.120-0.169)), while for PBO/DMF (n = 249), ARR decreased after initiating DMF and remained low throughout (ARR 0-2 years, 0.330 (95% CI, 0.266-0.408); overall ARR (ENDORSE, 0.151 (95% CI, 0.118-0.194)). Over 10 years, 72% DMF/DMF and 73% PBO/DMF had no 24-week confirmed disability worsening. CONCLUSION: Sustained DMF safety/efficacy was observed in patients followed up to 13 years, supporting DMF's positive benefit/risk profile for long-term RRMS treatment.

Patient Perceptions of FDA Approval: Gaps in Education or Variation in Values?

OBJECTIVE: To assess perceptions and opinions about the Food and Drug Administration (FDA) approval process for disease-modifying therapies (DMT) in people living with multiple sclerosis (MS). METHODS: People living with MS were invited to complete a web-based survey of their perceptions of the FDA role and process for approval of MS medications. The survey asked about the role of the FDA, factors involved in the approval process, which voices should represent those with MS in deliberations about drug approval, and the level of comfort with uncertain safety of newly approved therapies. RESULTS: Three thousand thirty-three respondents met inclusion criteria for data analysis. Most respondents seemed to understand the role of the FDA, although only half understood a fundamental FDA role: balancing the risks and benefits when considering drug approval. Significant differences were observed in many areas between those who have and have not tried DMTs. Comfort with uncertainty was associated with several factors relating to side effects and benefits believed important for the FDA to consider. Most respondents reported that people who participated in the medication's clinical trial were particularly able to represent people living with MS. CONCLUSION: Perceptions regarding the FDA and views of who should represent people living with MS varied between those who have and have not tried DMT. There is variability in personal values that should be recognized and taken into account when considering regulatory responsibilities. Interventions are needed to address educational gaps regarding the mission and trustworthiness of the FDA as an oversight body.

Shared Pathogenetic Features Between Common Variable Immunodeficiency and Sjögren's Syndrome: Clues for a Personalized Medicine.

Common variable immunodeficiency disorders (CVID) are a group of rare diseases of the immune system and the most common symptomatic primary antibody deficiency in adults. The "variable" aspect of CVID refers to the approximately half of the patients who develop non-infective complications, mainly autoimmune features, in particular organ specific autoimmune diseases including thyroiditis, and cytopenias. Among these associated conditions, the incidence of lymphoma, including mucosal associated lymphoid tissue (MALT) type, is increased. Although these associated autoimmune disorders in CVID are generally attributed to Systemic Lupus Erythematosus (SLE), we propose that Sjogren's syndrome (SS) is perhaps a better candidate for the associated disease. SS is an autoimmune disorder characterized by the lymphocytic infiltrates of lacrimal and salivary glands, leading to dryness of the eyes and mouth. Thus, it is a lymphocyte aggressive disorder, in contrast to SLE where pathology is generally attributed to auto-antibody and complement activation. Although systemic lupus erythematosus (SLE) shares these features with SS, a much higher frequency of MALT lymphoma distinguishes SS from SLE. Also, the higher frequency of germ line encoded paraproteins such as the monoclonal rheumatoid factor found in SS patients would be more consistent with the failure of B-cell VDJ switching found in CVID; and in contrast to the hypermutation that characterizes SLE autoantibodies. Thus, we suggest that SS may fit as a better "autoimmune" association with CVID. Examining the common underlying biologic mechanisms that promote lymphoid infiltration by dysregulated lymphocytes and lymphoma in CVID may provide new avenues for treatment in both the diseases. Since the diagnosis of SLE or rheumatoid arthritis is usually based on specific autoantibodies, the associated autoimmune features of CVID patients may not be recognized in the absence of autoantibodies.

Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis in the Active-Comparator Phase 3 OPTIMUM Study: A Randomized Clinical Trial.

Importance: To our knowledge, the Oral Ponesimod Versus Teriflunomide In Relapsing Multiple Sclerosis (OPTIMUM) trial is the first phase 3 study comparing 2 oral disease-modifying therapies for relapsing multiple sclerosis (RMS). Objective: To compare the efficacy of ponesimod, a selective sphingosine-1-phosphate receptor 1 (S1P1) modulator with teriflunomide, a pyrimidine synthesis inhibitor, approved for the treatment of patients with RMS. Design, Setting, and Participants: This multicenter, double-blind, active-comparator, superiority randomized clinical trial enrolled patients from April 27, 2015, to May 16, 2019, who were aged 18 to 55 years and had been diagnosed with multiple sclerosis per 2010 McDonald criteria, with a relapsing course from the onset, Expanded Disability Status Scale (EDSS) scores of 0 to 5.5, and recent clinical or magnetic resonance imaging disease activity. Interventions: Patients were randomized (1:1) to 20 mg of ponesimod or 14 mg of teriflunomide once daily and the placebo for 108 weeks, with a 14-day gradual up-titration of ponesimod starting at 2 mg to mitigate first-dose cardiac effects of S1P1 modulators and a follow-up period of 30 days. Main Outcomes and Measures: The primary end point was the annualized relapse rate. The secondary end points were the changes in symptom domain of Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) at week 108, the number of combined unique active lesions per year on magnetic resonance imaging, and time to 12-week and 24-week confirmed disability accumulation. Safety and tolerability were assessed. Exploratory end points included the percentage change in brain volume and no evidence of disease activity (NEDA-3 and NEDA-4) status. Results: For 1133 patients (567 receiving ponesimod and 566 receiving teriflunomide; median [range], 37.0 [18-55] years; 735 women [64.9%]), the relative rate reduction for ponesimod vs teriflunomide in the annualized relapse rate was 30.5% (0.202 vs 0.290; P < .001); the mean difference in FSIQ-RMS, -3.57 (-0.01 vs 3.56; P < .001); the relative risk reduction in combined unique active lesions per year, 56% (1.405 vs 3.164; P < .001); and the reduction in time to 12-week and 24-week confirmed disability accumulation risk estimates, 17% (10.1% vs 12.4%; P = .29) and 16% (8.1% vs 9.9; P = .37), respectively. Brain volume loss at week 108 was lower by 0.34% (-0.91% vs -1.25%; P < .001); the odds ratio for NEDA-3 achievement was 1.70 (25.0% vs 16.4%; P < .001). Incidence of treatment-emergent adverse events (502 of 565 [88.8%] vs 499 of 566 [88.2%]) and serious treatment-emergent adverse events (49 [8.7%] vs 46 [8.1%]) was similar for both groups. Treatment discontinuations because of adverse events was more common in the ponesimod group (49 of 565 [8.7%] vs 34 of 566 [6.0%]). Conclusions and Relevance: In this study, ponesimod was superior to teriflunomide on annualized relapse rate reduction, fatigue, magnetic resonance imaging activity, brain volume loss, and no evidence of disease activity status, but not confirmed disability accumulation. The safety profile was in line with the previous safety observations with ponesimod and the known profile of other S1P receptor modulators. Trial Registration: ClinicalTrials.gov Identifier: NCT02425644.

Juxtacortical susceptibility changes in progressive multifocal leukoencephalopathy at the gray-white matter junction correlates with iron-enriched macrophages.

OBJECTIVE: Describe magnetic resonance imaging (MRI) susceptibility changes in progressive multifocal leukoencephalopathy (PML) and identify neuropathological correlates. METHODS: PML cases and matched controls with primary central nervous system lymphoma (PCNSL) were retrospectively identified. MRI brain at 3 T and 7 T were reviewed. MRI-pathology correlations in fixed brain autopsy tissue were conducted in three subjects with confirmed PML. RESULTS: With PML (n = 26 total, n = 5 multiple sclerosis natalizumab-associated), juxtacortical changes on susceptibility-weighted imaging (SWI) or gradient echo (GRE) sequences were noted in 3/3 cases on 7 T MRI and 14/22 cases (63.6%) on 1.5 T or 8/22 (36.4%) 3 T MRI. Similar findings were only noted in 3/25 (12.0%) of PCNSL patients (odds ratio (OR) 12.83, 95% confidence interval (CI), 2.9-56.7, p < 0.001) on 1.5 or 3 T MRI. On susceptibility sequences available prior to diagnosis of PML, 7 (87.5%) had changes present on average 2.7 ± 1.8 months (mean ± SD) prior to diagnosis. Postmortem 7 T MRI showed SWI changes corresponded to areas of increased iron density along the gray-white matter (GM-WM) junction predominantly in macrophages. CONCLUSION: Susceptibility changes in PML along the GM-WM junction can precede noticeable fluid-attenuated inversion recovery (FLAIR) changes and correlates with iron accumulation in macrophages.

A Survey of Cannabis Use in a Large US-Based Cohort of People with Multiple Sclerosis.

BACKGROUND: As cannabis products become increasingly accessible across the United States, it is important to understand the contemporary use of cannabis for managing multiple sclerosis (MS) symptoms. METHODS: We invited participants with MS from the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry (aged 18 years or older) to complete a supplemental survey on cannabis use between March and April 2020. Participants reported cannabis use, treated symptoms, patterns, preferences, methods of use, and the factors limiting use. Findings are reported using descriptive statistics. RESULTS: Of the 6934 participants invited, 3249 responded. Of the respondents, 31% reported having ever used cannabis to treat MS symptoms, with 20% currently using cannabis. The remaining 69% had never used cannabis for MS symptoms, for reasons including not enough data about efficacy (40%) and safety (27%), and concerns about legality (25%) and cost (18%). The most common symptoms current users were attempting to treat were spasticity (80%), pain (69%), and sleep problems (61%). Ever users (vs never users) were more likely to be younger, be non-White, have lower education, reside in the Northeast and West, be unemployed, be younger at symptom onset, be currently smoking, and have higher levels of disability and MS-related symptoms (all P < .001). CONCLUSIONS: Despite concerns about insufficient safety and efficacy data, legality, and cost, almost one-third of NARCOMS Registry respondents report having tried nonprescription cannabis products in an attempt to alleviate their symptoms. Given the lack of efficacy and safety data on such products, future research in this area is warranted.

Cryopreservation of hematopoietic cells using a pre-constituted, protein-free cryopreservative solution with 5% dimethyl sulfoxide.

BACKGROUND AIMS: Adequate cryopreservation techniques are critical to ensure optimal recovery of functional progenitor cells in hematopoietic cell (HC) transplantation, minimize risk of contamination and prevent infusion-related adverse events (irAEs). In this article, we provide graft function and infusion safety results observed by decreasing the concentration of dimethyl sulfoxide (DMSO) in cryopreservative media and by minimizing processor-dependent formulation. METHODS: Ten HC products, collected after standard mobilization of multiple myeloma patients, were cryopreserved with PRIME-XV FreezIS (FreezIS) and compared with products previously cryopreserved with media formulated in-house to achieve a final DMSO concentration of 10% (Std10) and 5% (Std5). At infusion, HCs were analyzed for recovery of CD34+ cells and viability; irAEs and time to engraftment of neutrophils and platelets were also monitored. RESULTS: Median CD34+ cell recovery for HC cryopreserved with Std10, Std5 and FreezIS was 38%, 78% and 68%, respectively (P = 0.0002). There were less frequent irAEs with Std5 and FreezIS (10%) compared with Std10 (80%) (P ≤ 0.0001). Median time to neutrophil engraftment was comparable (11 days) for all three groups, while platelet engraftment occurred at a median of 20, 19 and 17 days, respectively (p-values not significant). CONCLUSIONS: FreezIS, a Good Manufacturing Practice-grade, pre-constituted cryopreservative with low DMSO content, maintains functional viability of the HC product while reducing the incidence of irAEs compared with 10% DMSO solutions. The pre-constituted nature of this agent also decreases processor-dependent handling, hence decreasing the risk of variability and infection.

Fentanyl self-administration impacts brain immune responses in male Sprague-Dawley rats.

Opioid use disorder (OUD) affects over two million in the United States and is an increasing public health crisis. The abuse of fentanyl and the emergence of potent fentanyl derivatives increases the risk for the user to succumb to overdose, but also to develop OUD. While intense attention is currently focused on understanding the complexity of behaviors and neural functions that contribute to OUD, much remains to be discovered concerning the interactions of opioid intake with the immune response in the central nervous system (CNS). In the present studies, we tested the hypothesis that short-term abstinence from fentanyl self-administration associates with altered expression of innate immune markers. Male Sprague-Dawley rats were trained to self-administer fentanyl (0.0032 mg/kg/infusion) to stability followed by 24 h of abstinence. Several innate immune markers, as well as opioid receptors (ORs) and intracellular pattern recognition receptors (PRRs), were interrogated within nodes of the neurocircuitry involved in OUD processes, including the prefrontal cortex (PFC), nucleus accumbens (NAc), caudate putamen (CPu), hippocampus (HIP) and midbrain (MB). In the present study, few immune targets were impacted in the PFC and MB during short-term abstinence from fentanyl (relative to saline) self-administration. However, increased expression of cytokines [e.g., interleukin (IL)1ß, IL5], chemokines [e.g., C-C motif chemokine 20 (MIP3α)], tumor necrosis factor α (TNFα) and interferon (IFN) proteins (e.g., IFNß and IFNγ)] was seen in the NAc, while decreased expression of cytokines (e.g., several ILs), chemokines [e.g., granulocyte-macrophage colony-stimulating factor (GMCSF), monocyte chemoattractant protein (MCP) MCP1, MIP3α], the chemokine ligand 5 (RANTES) and interferons (e.g., IFNß and IFNγ) in the HIP. Positive correlations were observed between cumulative fentanyl intake and expression of IL1ß and IL6 in the NAc, and significant negative correlations with fentanyl intake and IFN ß, IL2, IL5, IL12p70 and IL17 in the HIP. Few changes in OR expression was observed during early abstinence from fentanyl self-administration. Excitingly, the expression of the PRR, stimulator of interferon genes (STING) negatively correlated with cumulative fentanyl intake and significantly correlated to specific cytokines, chemokines and interferon proteins in the HIP. Although the CPu appears relatively invulnerable to changes in innate immune markers, the highest correlations between cumulative fentanyl intake with MAVS and/or STING was measured in the CPu. Our findings provide the first evidence of CNS innate immune responses and implicate STING as novel mechanistic targets of immunomodulation during short-term abstinence from fentanyl self-administration.

A survey of risk tolerance to multiple sclerosis therapies.

OBJECTIVE: To determine tolerance to various risk scenarios associated with current multiple sclerosis (MS) therapies. METHODS: People with MS from the North American Research Committee on Multiple Sclerosis Registry's online cohort and the National Multiple Sclerosis Society were invited to complete a questionnaire on tolerance to real-world risks associated with a hypothetical therapy. Multiple risks levels were presented, including skin rash, infection, kidney injury, thyroid injury, liver injury, and progressive multifocal leukoencephalopathy (PML). RESULTS: Both PML and kidney injury had the lowest risk tolerance (RT) at 1:1,000,000, and thyroid and infection risks had the highest tolerance at 1:1,000. Men, younger individuals, and participants with greater disability reported a higher tolerance to all risk scenarios. Those who were currently taking an MS therapy reported higher tolerance than those not taking any therapy. Participants taking infusion therapies reported high tolerance to all risks, and those taking injectables reported a lower tolerance. CONCLUSION: People with MS displayed a wide range of RT for MS therapies. Our study identified sex, age, disability, and current disease-modifying therapy use to be associated with RT.

Impact of lenalidomide on collected hematopoietic myeloid and erythroid progenitors: peripheral stem cell collection may not be affected.

Lenalidomide (LEN) is commonly used as part of induction therapy in transplant-eligible patients with multiple myeloma. However, LEN use is associated with increased chance of peripheral blood stem cell (PBSC) collection failure. This has led to early collection in patients receiving induction with LEN-containing regimens, and the use of mobilization agents such as plerixafor. Despite potential significant clinical implications, the impact of LEN on autograft composition is unclear. We examined the effect of LEN exposure on hematopoietic progenitors in collected grafts of 94 patients who underwent autologous stem cell transplantation (HSCT) at our institution. LEN exposure resulted in lower myeloid and erythroid progenitors in collected grafts, but this effect was not seen in patients who received plerixafor-based mobilization. Exposure to LEN did not affect PBSC collection, possibly due to high plerixafor use in our cohort (70%). LEN changes the composition of PBSC grafts; the clinical implication of this finding is unknown.

Effect of dimethyl fumarate on lymphocytes in RRMS: Implications for clinical practice.

OBJECTIVE: To assess functional changes in lymphocyte repertoire and subsequent clinical implications during delayed-release dimethyl fumarate (DMF) treatment in patients with multiple sclerosis. METHODS: Using peripheral blood from several clinical trials of DMF, immune cell subsets were quantified using flow cytometry. For some patients, lymphocyte counts were assessed after DMF discontinuation. Incidence of adverse events, including serious and opportunistic infections, was assessed. RESULTS: In DMF-treated patients, absolute lymphocyte counts (ALCs) demonstrated a pattern of decline followed by stabilization, which also was reflected in the global reduction in numbers of circulating functional lymphocyte subsets. The relative frequencies of circulating memory T- and B-cell populations declined and naive cells increased. No increased incidence of serious infection or malignancy was observed for patients treated with DMF, even when stratified by ALC or T-cell subset frequencies. For patients who discontinued DMF due to lymphopenia, ALCs increased after DMF discontinuation; recovery time varied by ALC level at discontinuation. T-cell subsets closely correlated with ALCs in both longitudinal and cross-sectional analyses. CONCLUSIONS: DMF shifted the immunophenotype of circulating lymphocyte subsets. ALCs were closely correlated with CD4+ and CD8+ T-cell counts, indicating that lymphocyte subset monitoring is not required for safety vigilance. No increased risk of serious infection was observed in patients with low T-cell subset counts. Monitoring ALC remains the most effective way of identifying patients at risk of subsequently developing prolonged moderate to severe lymphopenia, a risk factor for progressive multifocal leukoencephalopathy in DMF-treated patients. TRIAL REGISTRATION NUMBERS: EUDRA CT 2015-001973-42, NCT00168701, NCT00420212, NCT00451451, and NCT00835770.

Assessment of Trauma Symptoms in Toddlers and Preschoolers Living in Poverty.

A first-line screening instrument, the Preschool Inventory of Trauma Symptoms (PITS), was developed to assess trauma symptoms with a diverse sample of 150 toddlers and preschoolers (M = 2.49 years; SD = 1.12). Items reflected the current trauma literature, assessment measures, and diagnostic criteria for very young children. A principal component analysis produced a 34-item, four-factor model: Arousal and Hyper-Reactivity, Fearful Attachment, Intrusion and Re-Experiencing, and Avoidance and Negative Cognition and Mood. One validity scale, Response Style, was also developed. All scales significantly correlated (r = .45 to .81; p < .01) with preestablished trauma measures and demonstrated adequate internal consistency (α = .68 - .87). A receiver operating characteristics curve analysis identified a cut-score with good discrimination ability (.88), sensitivity (.81), and specificity (.81). In a preliminary pilot study, PITS also was found to be sensitive to trauma symptom change following participation in an evidence-based trauma informed treatment program. A copy of the PITS is included in the Appendix for free use by qualified professionals.

Joint longitudinal and time-to-event models for multilevel hierarchical data.

Joint modelling of longitudinal and time-to-event data has received much attention recently. Increasingly, extensions to standard joint modelling approaches are being proposed to handle complex data structures commonly encountered in applied research. In this paper, we propose a joint model for hierarchical longitudinal and time-to-event data. Our motivating application explores the association between tumor burden and progression-free survival in non-small cell lung cancer patients. We define tumor burden as a function of the sizes of target lesions clustered within a patient. Since a patient may have more than one lesion, and each lesion is tracked over time, the data have a three-level hierarchical structure: repeated measurements taken at time points (level 1) clustered within lesions (level 2) within patients (level 3). We jointly model the lesion-specific longitudinal trajectories and patient-specific risk of death or disease progression by specifying novel association structures that combine information across lower level clusters (e.g. lesions) into patient-level summaries (e.g. tumor burden). We provide user-friendly software for fitting the model under a Bayesian framework. Lastly, we discuss alternative situations in which additional clustering factor(s) occur at a level higher in the hierarchy than the patient-level, since this has implications for the model formulation.

Therapeutic Advances and Challenges in the Treatment of Progressive Multiple Sclerosis.

Despite the fact that majority of patients with multiple sclerosis (MS) have relapsing-remitting disease, many transition to secondary progressive disease (SPMS) over time. This transition is thought to be related to neurodegenerative processes increasingly predominating over inflammatory processes as the driving forces of disability. However, some patients initially present with primary progressive disease (PPMS) that is characterized by a gradual accumulation of neurological symptoms and subsequent disability accumulation. The treatment of both PPMS and SPMS, collectively referred to as progressive MS, has proven quite challenging due to the multifactorial and poorly understood pathophysiology of multiple sclerosis in general, specifically that of progressive disease. The purpose of this article is to discuss important clinical and pathophysiologic differences between relapsing and progressive forms of MS, review previous notable trials of drugs in progressive MS, examine current literature regarding recent and promising progressive MS treatments, and discuss future considerations for progressive MS therapeutics and management. Specifically, the current evidence regarding treatment of progressive MS with ocrelizumab, simvastatin, ibudilast, alpha-lipoic acid, high-dose biotin, siponimod, and cell-based therapies are discussed.

Feasibility of mesenchymal stem cell culture expansion for a phase I clinical trial in multiple sclerosis.

BACKGROUND: Multiple sclerosis is an inflammatory, neurodegenerative disease of the central nervous system for which therapeutic mesenchymal stem cell transplantation is under study. Published experience of culture-expanding multiple sclerosis patients' mesenchymal stem cells for clinical trials is limited. OBJECTIVE: To determine the feasibility of culture-expanding multiple sclerosis patients' mesenchymal stem cells for clinical use. METHODS: In a phase I trial, autologous, bone marrow-derived mesenchymal stem cells were isolated from 25 trial participants with multiple sclerosis and eight matched controls, and culture-expanded to a target single dose of 1-2 × 106 cells/kg. Viability, cell product identity and sterility were assessed prior to infusion. Cytogenetic stability was assessed by single nucleotide polymorphism analysis of mesenchymal stem cells from 18 multiple sclerosis patients and five controls. RESULTS: One patient failed screening. Mesenchymal stem cell culture expansion was successful for 24 of 25 multiple sclerosis patients and six of eight controls. The target dose was achieved in 16-62 days, requiring two to three cell passages. Growth rate and culture success did not correlate with demographic or multiple sclerosis disease characteristics. Cytogenetic studies identified changes on one chromosome of one control (4.3%) after extended time in culture. CONCLUSION: Culture expansion of mesenchymal stem cells from multiple sclerosis patients as donors is feasible. However, culture time should be minimized for cell products designated for therapeutic administration.

A survey of dietary characteristics in a large population of people with multiple sclerosis.

INTRODUCTION: Dietary approaches to management of MS has been proposed for several decades, yet very little is known concerning dietary composition or adherence to specialized diets in people with multiple sclerosis (MS). METHODS: We conducted a survey of participants in the North American Research Committee on MS (NARCOMS) registry assessing diet composition and the prevalence of 19 different diets. We characterized prevalence of different diets and compared diet composition with estimated intakes from the National Health and Nutrition Examination Survey (NHANES) survey respondents and across demographics and MS clinical characteristics. RESULTS: Among the 7639 (68%) responders, 6990 provided sufficient information on diet to be included in the analysis. Compared to NHANES participants, responders tended to have comparable intakes of fruit, vegetables and legumes (mean [SD] 2.5 [1.0] servings/day) and whole grains (0.9 [1.3] servings/day) and consume less added sugar (NARCOMS: 9.7 [6.0] vs. NHANES: 18.5[13.5] tsp/day; P < 0.001) and more red meat (NARCOMS: 0.50 [0.47] vs. NHANES: 0.35 [0.97] servings/day; P < 0.001). Of the 3120 (45%) participants who reported any history of following a specific diet, commonly-followed diets were: low-sugar (n = 642), low-carbohydrate (n = 508) and low-calorie (n = 475). Those with no history of following any specific diet were more likely to have progressive MS, be more obese, have worse overall diet quality, not participate in physical activity and smoke (all P < 0.001). CONCLUSIONS: In this large survey, we found that diet composition in MS patients may vary by demographic and disease characteristics.