Predicting and managing primary and secondary non-response to rituximab using B-cell biomarkers in systemic lupus erythematosus.

OBJECTIVE: To assess factors associated with primary and secondary non-response to rituximab in systemic lupus erythematosus (SLE) and evaluate management of secondary non-depletion non-response (2NDNR). METHODS: 125 patients with SLE treated with rituximab over 12 years were studied prospectively. A major clinical response was defined as improvement of all active British Isles Lupus Assessment Group (BILAG)-2004 domains to grade C/better and no A/B flare. Partial responders were defined by one persistent BILAG B. B-cell subsets were measured using highly sensitive flow cytometry. Patients with 2NDNR, defined by infusion reaction and defective depletion, were treated with ocrelizumab or ofatumumab. RESULTS: 117 patients had evaluable data. In cycle 1 (C1), 96/117 (82%) achieved BILAG response (major=50%, partial=32%). In multivariable analysis, younger age (OR 0.97, 95% CI 0.94 to 1.00) and B-cell depletion at 6 weeks (OR 3.22, 95% CI 1.24 to 8.33) increased the odds of major response. Complete depletion was predicted by normal complement and lower pre-rituximab plasmablasts and was not associated with increased serious infection post-rituximab. Seventy-seven (with data on 72) C1 responders were retreated on clinical relapse. Of these, 61/72 (85%) responded in cycle 2 (C2). Of the 11 C2 non-responders, nine met 2NDNR criteria (incidence=12%) and tested positive for anti-rituximab antibodies. Lack of concomitant immunosuppressant and higher pre-rituximab plasmablasts predicted 2NDNR. Five were switched to ocrelizumab/ofatumumab, and all depleted and responded. CONCLUSION: Treatment with anti-CD20 agents can be guided by B-cell monitoring and should aim to achieve complete depletion. 2NDNR is associated with anti-rituximab antibodies, and switching to humanised agents restores depletion and response. In SLE, alternative anti-CD20 antibodies may be more consistently effective.

Diabetes is associated with posttranslational modifications in plasminogen resulting in reduced plasmin generation and enzyme-specific activity.

Diabetes is associated with hypofibrinolysis by mechanisms that are only partially understood. We investigated the effects of in vivo plasminogen glycation on fibrinolysis, plasmin generation, protein proteolytic activity, and plasminogen-fibrin interactions. Plasma was collected from healthy controls and individuals with type 1 diabetes before and after improving glycemia. Plasma-purified plasmin(ogen) functional activity was evaluated by chromogenic, turbidimetric, and plasmin conversion assays, with surface plasmon resonance employed for fibrin-plasminogen interactions. Plasminogen posttranslational modifications were quantified by mass spectrometry and glycation sites located by peptide mapping. Diabetes was associated with impaired plasma fibrin network lysis, which partly normalized upon improving glycaemia. Purified plasmin(ogen) from diabetic subjects had impaired fibrinolytic activity compared with controls (723 ± 16 and 317 ± 4 s, respectively; P < .01), mainly related to decreased fibrin-dependent plasmin generation and reduced protease activity (Kcat/KM 2.57 ± 1.02 × 10⁻³ and 5.67 ± 0.98 × 10⁻³ M⁻¹s⁻¹, respectively; P < .05). Nε-fructosyl-lysine residue on plasminogen was increased in diabetes compared with controls (6.26 ± 3.43 and 1.82 ± 0.95%mol, respectively; P < .01) with preferential glycation of lysines 107 and 557, sites involved in fibrin binding and plasmin(ogen) cleavage, respectively. Glycation of plasminogen in diabetes directly affects fibrinolysis by decreasing plasmin generation and reducing protein-specific activity, changes that are reversible with modest improvement in glycemic control.

A randomized controlled trial evaluating the erythropoiesis stimulating agent sparing potential of a vitamin E-bonded polysulfone dialysis membrane.

BACKGROUND: Vitamin E (VE) bonded polysulfone dialysis membranes have putative erythropoiesis stimulating agent (ESA)-sparing and anti-inflammatory properties based on data from a small number of studies. We sought to investigate this in a large, prospective 12-month randomized controlled trial. METHODS: Two-hundred and sixty prevalent haemodialysis (HD) patients were randomized to dialysis with VE-bonded polysulfone membranes or non-VE-bonded equivalents. All ESA-dosing was performed by means of a computer-based anaemia management decision support system. Monthly data were used to calculate the ESA resistance index (ERI) and blood tests were performed at baseline, 6 and 12 months for measurement of C-reactive protein (CRP) levels. RESULTS: Of the 260 patients, 123 were randomized to dialysis with the VE-membrane and 12-month data was available for 220 patients. At the study population level, no beneficial effect of the VE membranes on the ERI or CRP levels was observed. Post hoc analyses indicated that there was a significant fall in ERI for patients with the highest baseline ESA resistance dialysed with the VE (9.28 [7.70-12.5] versus 7.70 [5.34-12.7] IU/week/kg/g/dL Hb, P = 0.01) but not the control membranes (9.45 [7.62-12.3] versus 8.14 [4.44-15.6] IU/week/kg/g/dL Hb, P = 0.41); this was not attributable to changes in CRP levels. CONCLUSIONS: Wholesale switching of all chronic HD patients to dialysis with VE-bonded polysulfone membranes appears not to be associated with improvements in ESA-responsiveness or CRP. These membranes may have utility in patients with heightened ESA resistance.

Post-COVID Analysis of Which U.S. Medical Schools Produce the Most Neurosurgery Residents: 2021-2023 in Review.

OBJECTIVE: The process surrounding application to the national residency matching program changed drastically because of COVID. Virtual interviews, pre-interview Zoom socials, and limitations on sub-internships are major changes that applicants worldwide have had to overcome. The available literature does not reflect the impact of major changes to the interview process. Here, we examine the neurosurgery resident cohort from 2021-2023 to investigate differences between United States medical schools pre- and post-COVID. METHODS: A database was constructed reporting the number of students matched to neurosurgery for U.S. medical schools (M.D. and D.O.) from 2021-2023. Percentage of total graduates matched to neurosurgery was calculated and institutions were ranked by this metric. This rank was compared to a rank reported in 2021. Variables were compared across the pre- and post-COVID cohorts. RESULTS: Case Western, Johns Hopkins, Mayo Clinic, Vanderbilt, University of Illinois, and University of California San Francisco produced the most neurosurgical residents as a percentage of total graduates. There was a statistically significant difference in the post-COVID cohort between medical schools with a home program versus those without. For the top 20 ranked U.S. News and World Report medical schools, there was a statistically insignificant increase in the number of graduates matched to neurosurgery. CONCLUSIONS: With the data provided, there have not been many significant changes in which medical schools produce the most neurosurgery residents since COVID changes were implemented. The playing field has remained relatively stable in the setting of major changes.

Improving mental state in early imprisonment.

BACKGROUND: Pre-trial prisoners have high rates of mental disorder, but to date, little is known about mental state change or stability among them. AIM: The aim of this study was to describe mental state change over the first 4 weeks of imprisonment. METHODS: Two hundred and fifty-seven new pre-trial male prisoners consented to participate in a prospective interview study. Recruited men tended to be younger than non-recruited men, but otherwise similar. Mental state was assessed 1 and 4 weeks after reception, using the Comprehensive Psychopathological Rating Scale and two self-rating instruments [the 90-item symptom checklist (SCL-90); the Beck Depression Inventory]. RESULTS: After 4 weeks, 170 of the men were still in prison. In their demographics, previous offending, imprisonment, mental health histories or mental health ratings at initial interview, they did not differ from the 87 who were bailed, transferred, sentenced or had their case discontinued. The most sensitive of the rating schedules - the SCL-90 - identified only one new case among the 170 men, but the more illness-specific ratings suggested up to a 10% emergence of new cases by then. By contrast, while two-thirds of the men remained cases according to the SCL-90, about half of the men who had initial interview illness ratings were no longer 'cases'. DISCUSSION AND IMPLICATIONS FOR PRACTICE: Measured in terms of 'caseness', distress is likely to be apparent on reception into prison and relatively resistant to change compared with symptoms of mental disorder per se. One-off screening at reception could be misleading. A limitation of our study is that we could measure mental state only twice. A third measure would have clarified whether, in such circumstances, the trend towards improvement is sustained, but brevity of residence in any one prison at this stage tends to preclude this.

Complement and Cardiovascular Disease--The Missing Link in Haemodialysis Patients.

BACKGROUND: Patients on haemodialysis (HD) have high rates of cardiovascular (CV) disease and activation of the complement system. Despite evidence in non-renal patients that these may be linked, this association has received little attention in HD patients to date. In the setting of a randomised controlled trial we evaluated the relationships between baseline complement levels and subsequent CV events and mortality, in addition to the effects of HD with a vitamin E (VE)-coated dialysis membrane on circulating complement levels. METHODS: A total of 260 HD patients were randomised to dialysis with a VE-coated dialysis membrane or non-VE coated equivalent for 12 months. Blood samples were taken at baseline, 6 and 12 months for measurement of C3, factor D, factor H and SC5b-9 levels. Data were collected prospectively on deaths and CV events. RESULTS: Higher C3 levels at baseline were associated with subsequent CV events (hazard ratio 1.20 (1.01-1.42) per 0.1 mg/ml). Patients with intermediate SC5b-9 levels had significantly lower CV event rates and mortality than those with either high or low levels (p < 0.01). There were no effects of the VE-membranes on the complement components measured nor the clinical endpoints considered. CONCLUSIONS: The levels of C3 and SC5b-9 may have prognostic utility for predicting future CV events and/or mortality in HD patients - a relationship that requires further investigation. Dialysing prevalent HD patients with VE-bonded polysulfone membranes for a period of 12 months did not alter the circulating levels of the alternative complement pathway components considered here.

Transcranial magnetic stimulation for patients with depression.

Transcranial magnetic stimulation (TMS) is a relatively new technique which has been used to treat depression. It delivers magnetic radiation to the head using a hand-held coil. Some studies have indicated clinical remission of depressive symptomatology with use of TMS. Methodological limitations remain, however, and more studies are recommended to determine its efficacy.

Fibrinogen and fibrin clot structure in diabetes.

Diabetes is associated with an increased risk of developing cardiovascular disease, which is not fully accounted for by the accumulation of classic cardiovascular risk factors in patients. Recent evidence has demonstrated fibrinogen to be a powerful independent risk marker for cardiovascular disease in the general population, and it is also likely to contribute toward the increased atherosclerotic risk in diabetes. The etiology of hyperfibrinogenemia in diabetes is likely to be multifactorial, and at present the mechanisms involved have not been clarified. However, insulin, insulin resistance and inflammation are likely to be involved, especially in type 2 diabetes. The influence of diabetes in determining an individual's atherothrombotic risk is likely to extend beyond that of elevated fibrinogen levels, and may also act via changes in the structure and function of the fibrin clot that forms. Further research is needed to determine the mechanisms underlying these changes, which may lead to development of future interventions to reduce the excessive vascular risk associated with this disease.

Clinical presentation of postnatal and non-postnatal depressive episodes.

BACKGROUND: The relationship of postnatal (postpartum) depression (PND) to episodes of depression occurring at other times is not well understood. Despite a number of studies of clinical presentation, there is little consistency in the literature. We have undertaken within- and between-individual comparisons of the clinical presentation of postnatal (PN) and non-postnatal (NPN) depressive episodes in women with recurrent depression. METHOD: In a sample of well-characterized, parous women meeting DSM-IV and ICD-10 criteria for recurrent major depressive disorder, the clinical presentation of episodes of major depression with onset within 4 weeks of giving birth (PND group, n=50) were compared with (i) the non-postnatal episodes of women with PND, and (ii) episodes of major depression in parous women who had not experienced episodes of mood disorder in relation to childbirth (NPND group, n=132). In addition, the non-postnatal episodes of the PND group of women were compared with the depressive episodes of the NPND group. RESULTS: The small number of differences found between PN and NPN depressive episodes, such as reduced early morning wakening in postnatal episodes, are likely to be explicable by the context of having a new baby rather than by any difference in the nature of the underlying depression. CONCLUSIONS: The results do not point to substantial differences in clinical presentation between episodes of major depression occurring in relation to childbirth and at other times. Other avenues of research are therefore required to demonstrate a specific relationship between childbirth and depression.

Visual line bisection in sinistrals and dextrals as a function of hemispace, hand, and scan direction.

Visual line bisection was investigated in 26 sinistral and 24 dextral subjects as a function of hemispace, hand and scan direction. An ANOVA revealed significant main effects for hand preference, due to the mean bisection errors of dextral subjects being significantly leftward of those of sinistral subjects; for hand, due to the bisection errors of the left hand being significantly to the left of the right hand; and for scan, due to the bisection errors following a left scan being significantly to the left of a right scan. One significant interaction was found, that between hand and direction of scan, due to a significant difference between left and right hands following a scan from the left but not following a scan from the right. For dextral subjects the leftward bisection errors of the left and right hands following a scan from the left, but not for a scan from the right, differed significantly from the midpoint. For sinistral subjects the leftward bisection errors following a scan from the left and rightward bisection errors following a scan from the right differed significantly from the midpoint for the left hand but not for the right hand. No significant main effect or interactions for hemispace were found. This confirms that both sinistral and dextral subjects display pseudoneglect when using their preferred hand and scanning from the left. However, sinistrals, but not dextrals, will display reversed pseudoneglect when using their preferred hand and adopting a scan direction from the right. These results are discussed in terms of the interaction between three factors, whose influence can jointly and severally produce misbisections, hemispheric specialisation for visuospatial function, hemispheric activation for a manual response, and the allocation of visual attention.

Genetics of fibrin clot structure: a twin study.

Coronary artery thrombosis following plaque rupture is an important feature of myocardial infarction, and studies have highlighted the role of coagulation in this condition. Although genetic and environmental influences on the variance in coagulation protein concentrations have been reported, there are no data on the heritability of structure/function of the final phenotype of the coagulation cascade, the fibrin clot. To assess genetic and environmental contributions to fibrin structure, permeation and turbidity studies were performed in 137 twin pairs (66 monozygotic, 71 dizygotic). The environmental influence (e2) on pore size (Ks) (e2 = 0.61 [95% confidence interval (CI), 0.45-0.80]) and fiber size (e2 = 0.54 [95% CI, 0.39-0.73]) was greater than the heritability (h2 = 0.39 [95% CI, 0.20-0.55] and 0.46 [95% CI, 0.27-0.62], respectively). After correction for fibrinogen levels, the environmental effect persisted for Ks (e2 = 0.61), but genetic influence assumed a greater importance in determining fiber size (h2 = 0.73). Multivariate analysis revealed an overlap in the influence of genetic and environmental factors on fibrinogen levels, Ks, and fiber size. Factor XIII B subunit showed environmental and genetic correlation with fibrinogen and fiber size and a genetic correlation with Ks. The results indicate that genetic and environmental influences are important in determining fibrin clot structure/function.