Differential Effects of Fingolimod and Natalizumab on B Cell Repertoires in Multiple Sclerosis Patients

Natalizumab and fingolimod are effective multiple sclerosis (MS) therapies that disrupt lymphocyte migration but have differential effects on B cell maturation and trafficking. We investigated their effects on peripheral blood (PB) and cerebrospinal fluid (CSF) B cell repertoires using next-generation deep sequencing. Paired CSF and PB B cell subsets (naïve, CD27⁺ memory, and CD27⁻IgD⁻ double-negative B cells and plasmablasts) were collected by applying flow cytometry at baseline and after 6 months of treatment and their respective heavy-chain variable region repertoires assessed by Illumina MiSeq. Treatment with fingolimod contracted, whereas natalizumab expanded circulating PB B cells. CSF B cell numbers remained stable following fingolimod treatment but decreased with natalizumab therapy. Clonal overlap between CSF and PB B cells was reduced with natalizumab treatment but remained stable with fingolimod therapy. Lineage analyses of pre- and posttreatment CSF B cell repertoires revealed large, clonally expanded B cell clusters in natalizumab-treated MS patients but no intrathecal clonal expansion following fingolimod therapy. Our findings suggest that natalizumab diminishes the exchange of peripheral and intrathecal B cells without impacting intrathecal clonal expansion. In contrast, fingolimod treatment fails to alter blood–brain barrier B cell exchange but diminishes intrathecal clonal expansion. Sphingosine-1 phosphate receptor inhibition may alter intrathecal B cell biology in MS.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-020-00975-7.Key Words: Natalizumab, fingolimod, cerebrospinal fluid, B cell migration, B cell maturation, mass sequencing.     

The Economic Impact of Providing Evidence-Based Pediatric Mental Health Literacy Training to Primary Care Physicians

ObjectiveThis paper presents a review of the current state of child and adolescent mental health literacy and provides current evidence of the economic impact of a pediatric mental health literacy (MHL) training program. MethodsEmploying a case-series-comparison design, physician referrals to urgent and specialized mental health services were linked with patient-specific information comparing referrals from MHL participants and non-participating physicians. The economic impact analysis was based on changes in the admitted referral frequency and lengths of stay for the MHL group, compared to themselves pretraining, and over the same time period compared to non-participating physicians. ResultsAverage scheduled ambulatory admission rates per physician remained constant for trained and untrained pre-post groups. Average scheduled ambulatory admission wait time and length of stay reduced significantly post-training for MHL-trained physicians compared to pre-training and untrained physicians. In addition to reductions in length of stay, the total bed costs saving for emergency/inpatients admission deferrals was $2,932,112 or about $20,000 per MHL-trained physician. ConclusionThe estimated economic impact of the MHL training shows a substantial return on investment and supports wider implementation. The MHL training program should be a key feature of mental health reform strategies, as well as continuing and undergraduate medical education.     

The effect of anaesthesia and surgery for benign disease of the upper urinary tract on circulating leucocyte subpopulations identified with monoclonal antibodies

Summary Circulating lymphocyte subpopulations were monitored, using monoclonal antibodies and flow cytometry, in six patients undergoing surgery for benign disease of the upper urinary tract. A significant decrease in the total number of circulating lymphocytes was observed. This could be attributed to a significant decrease of T cells of both major subsets — the so-called T helper (Th) and T suppressor/cytotoxic (Ts) subpopulations. When the results of the T cell subsets were expressed as a ratio (leu-3a⁺/leu2a⁺, T helper/suppressor) no significant change was noted. In contrast neither B cells nor natural killer (NK) and antibody dependent killer (K) cells were significantly affected. This selective loss of T cells from the circulation may be relevant to post operative infection and should be considered in the course of immunological monitoring.Supported by the Cancer Research Campaign     

Neuropsychological impairment in bipolar disorder: the relationship with glucocorticoid receptor function

OBJECTIVE: Basal levels of glucocorticoids, such as cortisol, are generally unaltered in bipolar disorder. However, neuroendocrine tests of glucocorticoid receptor (GR) function such as the dexamethasone suppression test (DST) are frequently abnormal. Neuropsychological impairment is well documented in healthy volunteers after administration of glucocorticoids and in patients with bipolar affective disorder. This suggests a potential link between neuropsychological and hypothalamic-pituitary-adrenal axis function. We examined the hypothesis that neuropsychological impairment in bipolar disorder is associated with abnormal GR function. METHODS: Seventeen euthymic bipolar patients and 16 controls completed tests of verbal declarative and working memory (WM) tests and the DST. The correlation between neuroendocrine and neuropsychological function was examined. RESULTS: Bipolar patients made significantly more errors of omission and commission on the WM paradigm and demonstrated impaired verbal recognition memory. Patients' post-dexamethasone cortisol correlated with WM commission errors (r(s) = 0.64, p = 0.0006). No such relationship was evident in controls. CONCLUSION: Deficits in declarative memory and WM are evident in patients with bipolar disorder. The deficit in retrieval accuracy from WM appears to be correlated with abnormal GR function.     

Preliminary evidence of disease response to the pan deacetylase inhibitor panobinostat (LBH589) in refractory Hodgkin Lymphoma

There are few treatment options for patients with Hodgkin Lymphoma (HL) who relapse after conventional therapies. Panobinostat is an orally available pan deacetylase inhibitor with evidence of activity in myeloid malignancies and cutaneous T cell lymphoma. Thirteen HL patients were treated with escalating doses of this novel agent in a phase IA/II multicentre study. A computed tomography partial response was achieved in 5/13(38%), and a metabolic response by ¹⁸F-fluoro-2-deoxy- d - glucose positron emission tomography scanning in 7/12 (58%) evaluable patients. This report describes the preliminary evidence of anti-tumour activity seen in the early phase of this study, which recently closed to accrual.     

Reviewing deaths in the emergency department: Deaths in the department or deaths within 48 h

Objectives: To investigate an ED death audit process that included deaths occurring within 48 h of admission in addition to deaths in the ED. Methods: The study was a review of a prospective audit process undertaken in routine clinical practice that included auditing deaths in the ED and deaths of admitted patients within 48 h of ED presentation. Data were extracted from the audit database and included demography, clinical information and medical recommendations. The hospital incident investigation and monitoring system (IIMS) was searched for major incident reports involving death. The main outcome was the number of medical record audits from each group reported to the clinical governance unit for review, and whether the 48 h audit identified relevant cases to the ED in addition to those identified in the ED audit alone. Secondary outcomes were the number of audits resulting in other actions: ED policy review, education, case discussion or review with the inpatient team. Results: Over a 2 year period, 303 deaths were reviewed, including 75 deaths in the ED and 228 deaths within 48 h. The ED auditor recommended no further action in 66/75 (88%) ED deaths and 195/228 (86%) 48 h deaths. A major hospital review was recommended in 4/75 (5%) ED deaths and 11/228 (5%) 48 h deaths, with only 3 and 7 of these, respectively, having been detected by the hospital's IIMS. The audit identified 10 of 13 deaths notified to the IIMS and the remaining 3 did not involve error relevant to the ED. Internal review was recommended in one ED death and eight 48 h deaths. Conclusions: The present study demonstrates that auditing both ED deaths and 48 h deaths identifies additional issues relevant to the ED compared with auditing ED deaths alone or relying on standard hospital incident reporting.