Electrophysiological measures can help understand brain function both in healthy individuals and in the context of a disease. Given the amount of information that can be extracted from these measures ...and their frequent use, it is essential to know more about their inherent reliability.
To understand the reliability of electrophysiology measures in healthy individuals. We hypothesized that measures of threshold and latency would be the most reliable and least susceptible to methodological differences between study sites.
Somatosensory evoked potentials from 112 control participants; long-latency reflexes, transcranial magnetic stimulation with resting and active motor thresholds, motor evoked potential latencies, input/output curves, and short-latency sensory afferent inhibition and facilitation from 84 controls were collected at 3 visits over 24 months at 4 Track-On HD study sites. Reliability was assessed using intra-class correlation coefficients for absolute agreement, and the effects of reliability on statistical power are demonstrated for different sample sizes and study designs.
Measures quantifying latencies, thresholds, and evoked responses at high stimulator intensities had the highest reliability, and required the smallest sample sizes to adequately power a study. Very few between-site differences were detected.
Reliability and susceptibility to between-site differences should be evaluated for electrophysiological measures before including them in study designs. Levels of reliability vary substantially across electrophysiological measures, though there are few between-site differences. To address this, reliability should be used in conjunction with theoretical calculations to inform sample size and ensure studies are adequately powered to detect true change in measures of interest.
•Levels of reliability varied substantially between electrophysiological measures.•Latencies, thresholds, and SEPs at high intensities had the highest reliability.•Measures of amplitude rather than area were more reliable.•Few between-site differences suggest usefulness of measures in multi-centre trials.•Reliability and hypothetical statistical power calculations can inform study design.
Between August 1990 and August 1995, 231 patients (median age 51, 53% Durie-Salmon stage III, median serum beta-2-microglobulin 3.1 g/L, median C-reactive protein 4 g/L) with symptomatic multiple ...myeloma were enrolled in a program that used a series of induction regimens and two cycles of high-dose therapy ("Total Therapy"). Remission induction utilized non-cross-resistant regimens (vincristine-doxorubicin-dexamethasone VAD, high-dose cyclophosphamide and granulocyte-macrophage colony-stimulating factor with peripheral blood stem cell collection, and etoposide-dexamethasone-cytarabine-cisplatin). The first high-dose treatment comprised melphalan 200 mg/m2 and was repeated if complete (CR) or partial (PR) remission was maintained after the first transplant; in case of less than PR, total body irradiation or cyclophosphamide was added. Interferon--2b maintenance was used after the second autotransplant. Fourteen patients with HLA-compatible donors underwent an allograft as their second high-dose therapy cycle. Eighty-eight percent completed induction therapy whereas first and second transplants were performed in 84% and 71% (the majority within 8 and 15 months, respectively). Eight patients (3%) died of toxicity during induction, and 2 (1%) and 6 (4%) during the two transplants. True CR and at least a PR (PR plus CR) were obtained in 5% (34%) after VAD, 15% (65%) at the end of induction, and 26% (75%) after the first and 41% (83%) after the second transplants (intent-to-treat). Median overall (OS) and event-free (EFS) survival durations were 68 and 43 months, respectively. Actuarial 5-year OS and EFS rates were 58% and 42%, respectively. The median time to disease progression or relapse was 52 months. Among the 94 patients achieving CR, the median CR duration was 50 months. On multivariate analysis, superior EFS and OS were observed in the absence of unfavorable karyotypes (11q breakpoint abnormalities, -13 or 13-q) and with low beta-2-microglobulin at diagnosis. CR duration was significantly longer with early onset of CR and favorable karyotypes. Time-dependent covariate analysis suggested that timely application of a second transplant extended both EFS and OS significantly, independent of cytogenetics and beta-2-microglobulin. Total Therapy represents a comprehensive treatment approach for newly diagnosed myeloma patients, using multi-regimen induction and tandem transplantation followed by interferon maintenance. As a result, the proportion of patients attaining CR increased progressively with continuing therapy. This observation is particularly important because CR is a sine qua non for long-term disease control and, eventually, cure.
Genotoxicity evaluation of medical devices: A regulatory perspective Kumaravel, Tirukalikundram S.; Sathya, Tiruvathipuram N.; Balaje, Ramalingam ...
Mutation research. Reviews in mutation research,
January-June 2022, 2022 Jan-Jun, 2022-01-00, 20220101, Letnik:
789
Journal Article
Recenzirano
Odprti dostop
This review critically evaluates our current regulatory understanding of genotoxicity testing and risk assessment of medical devices. Genotoxicity risk assessment of these devices begins with the ...evaluation of materials of construction, manufacturing additives and all residual materials for potential to induce DNA damage. This is followed by extractable and/or leachable (E&L) studies to understand the worst case and/or clinical exposures, coupled with risk assessment of extractables or leachables. The TTC (Threshold of Toxicological Concern) approach is used to define acceptable levels of genotoxic chemicals, when identified. Where appropriate, in silico predictions may be used to evaluate the genotoxic potentials of identifiable chemicals with limited toxicological data and above the levels defined by TTC. Devices that could not be supported by E&L studies are evaluated by in vitro genotoxicity studies conducted in accordance with ISO10993-3 and 33. Certain endpoints such as ‘site of contact genotoxicity’ that are specific for certain classes of medical devices are currently not addressed in the current standards. The review also illustrates the potential uses of recent advances to achieve the goal of robust genotoxicity assessment of medical devices which are being increasingly used for health benefits. The review also highlights the gaps for genotoxicity risk assessment of medical devices and suggests possible approaches to address them taking into consideration the recent advances in genotoxicity testing including their potential uses in biocompatibility assessment.
Although important predictors of survival in myeloma patients have been identified, it is well recognized that better prognostic factors for this disease are needed. Because cytogenetics play a ...dominant role in the outcome of patients with acute leukemia, their prognostic value was evaluated in a large group of newly diagnosed and previously treated myeloma patients receiving autotransplants.
A total of 427 either newly diagnosed (26%) or previously treated patients (74%) received tandem transplants, supported by mobilized peripheral-blood stem cells. Numerous variables, including cytogenetics, were analyzed for their impact on complete remission, event-free survival (EFS), and overall survival (OS).
Abnormal karyotypes were detected in 37% of our patients and were very complex, irrespective of the duration of standard therapy before the first autotransplant. In addition to previously recognized unfavorable implications of partial or complete deletion of chromosome 13 and 11q abnormalities, we now observed that the presence of any translocation likewise portended poor outcome (unfavorable karyotypes). On multivariate analysis, the absence of an unfavorable karyotype was the most favorable variable for both EFS (P = .0001) and OS (P = .0001). Other favorable factors were duration of standard therapy and a low beta-2 microglobulin (B2M) level before the first autotransplant. A risk-based classification system was developed according to the number of these favorable variables present, showing highly significant differences in event-free and overall survival.
Cytogenetics play a dominant role in myeloma and were independent of previously recognized important prognostic factors, such as B2M and duration of prior standard therapy.
Of 496 consecutive patients with multiple myeloma (MM) enrolled in clinical trials of tandem transplants with peripheral blood stem cells support, 470 (95%) completed the first autotransplant with ...melphalan 200 mg/m2 (MEL 200) and 363 (73%) completed the second transplant with either MEL 200 (40%), MEL 140 mg/m2 (MEL 140) with total-body irradiation (17%), or a combination of alkylating agents (16%), depending on the response status prior to the second transplant; 31 patients up to age 60 years received an allograft as the second transplant. The median interval from first to second transplant was 5 months. Treatment-related mortality during the first year after transplantation was 7%, and complete remission (CR) was obtained in 36%; the median durations of event-free survival (EFS) and overall survival (OS) after transplant were 26 and 41 months, respectively. Low β2-microglobulin (B2M c2.5 mg/L) and C-reactive protein (CRP c0.4 mg/dL) were the most significant standard parameters associated with both prolonged EFS and OS. Median OS exceeded 5.5 years in the one third of patients with both low B2M and CRP. When cytogenetics were included in the analysis, the presence of 11q abnormalities and/or complete or partial deletion of chromosome 13 (“unfavorable karyotype”) became a dominant negative feature for both EFS and OS. In addition to these pretransplant parameters, attainment of CR and application of two transplants within 6 months both significantly extended EFS and OS. The group of patients (7%) with high B2M and CRP with either IgA isotype or unfavorable karyotype had the worst prognosis (EFS, c10 months; median OS, c12 months) and will require novel therapy. We conclude that tandem transplants are feasible in the majority of patients up to age 70 years, effecting CR in one third of all patients. Median OS was greater than 5.5 years, regardless of pretransplant features, if the first transplant was applied within 12 months of initial treatment and the second transplant no more than 6 months later.
Objectives
To identify prevalence of pulmonary tuberculosis (TB) in severely malnourished children admitted to nutritional rehabilitation centers.
Methods
A multicenter cross-sectional study ...involving 41 nutrition rehabilitation centres (NRCs) across India was carried out to document prevalence of pulmonary tuberculosis in acute severe malnourished children admitted in NRCs. After training of the NRC staff to follow algorithm provided by national tuberculosis elimination program, children admitted to NRCs were screened for pulmonary tuberculosis.
Results
A total of 4356 children were enrolled across all the sites. Gastric aspirate for Cartridge based nucleic acid amplification test (CBNAAT), tuberculin skin test (TST) and X-ray film of chest were done in more than 99% of enrolled subjects. A total of 189 children (4.3%) had pulmonary tuberculosis. Eighty-seven (1.99%) were microbiologically confirmed by positive CBNAAT. On multivariate analysis, only significant association was with history of contact with TB patient in family.
Conclusions
The present results suggest that a significant proportion (>4%) of children admitted in NRCs suffer from pulmonary tuberculosis. It is feasible to improve diagnosis of tuberculosis as a whole and microbiologically confirmed TB.
To compare, in the setting of tandem autotransplantations for multiple myeloma (MM), two established methods of peripheral-blood stem-cell (PBSC) procurement with chemotherapy or hematopoietic growth ...factor alone.
Between June 1994 and July 1995, 44 patients with MM were randomized to PBSC mobilization with either granulocyte colony-stimulating factor (G-CSF) 16 microg/kg (group 1; n = 22) or high-dose cyclophosphamide (HDCTX) 6 g/m2 plus G-CSF 5 microg/kg (group 2; n = 22). All 44 patients received melphalan 200 mg/m2 with their first autograft and 32 patients proceeded to a second transplantation.
Group 2 required a significantly longer time interval for completion of PBSC collection than group 1 (median, 22 v 8 days; P = .0001), greater frequency of hospitalization (100% v 32%; P = .0001), and increased transfusion of platelets (86% v 18%; P = .0001) and packed RBCs (86% v 55%; P = .02). Likewise, the incidence of fever and pneumonia/sepsis were higher in group 2 (P = .02 and P = .04, respectively). Surprisingly, despite greater CD34 cell quantities infused in group 2, median recovery times of granulocytes (both > 500/microL and 2,500/microL) and platelets (both > 50,000/microL and > 100,000/microL) were similar (all P > .7). Posttransplant toxicities were also similar.
Compared with HDCTX plus G-CSF, high-dose G-CSF alone is associated with lower morbidity, shorter duration of PBSC mobilization, and comparable hematopoietic recovery after transplantation, which should result in significant cost reduction. Considering the relatively limited antitumor activity of HDCTX (10% with > or = 50% tumor cytoreduction), PBSC mobilization with HDCTX should be limited to selected patients with persistent MM despite induction chemotherapy.
Multiple myeloma (MM) typically afflicts elderly patients with a median age of 65 years. However, while recently shown to provide superior outcome to standard treatment, high-dose therapy (HDT) has ...usually been limited to patients up to 65 years. Among 550 patients with MM and a minimum follow-up of 18 months, 49 aged ≥65 years were identified (median age, 67; range, 65 to 76 years). Their outcome was compared with 49 younger pair mates (median, 52; range, 37 to 64 years) selected among the remaining 501 younger patients (<65 years) matched for five previously recognized critical prognostic factors (cytogenetics, β2-microglobulin, C-reactive protein, albumin, creatinine). Nearly one half had been treated for more than 1 year with standard therapy and about one third had refractory MM. All patients received high-dose melphalan-based therapy; 76% of the younger and 65% of the older group completed a second transplant (P = .3). Sufficient peripheral blood stem cells to support two HDT cycles (CD34 > 5 × 106/kg) were available in 83% of younger and 73% of older patients (P = .2). After HDT, hematopoietic recovery to critical levels of granulocytes (>500/μL) and of platelets (>50,000/μL) proceeded at comparable rates among younger and older subjects with both first and second HDT. The frequency of extramedullary toxicities was comparable. Treatment-related mortality with the first HDT cycle was 2% in younger and 8% among older subjects, whereas no mortality was encountered with the second transplant procedure. Comparing younger/older subjects, median durations of event-free and overall survival were 2.8/1.5 years (P = .2) and 4.8/3.3 years (P = .4). Multivariate analysis showed pretransplant cytogenetics and β2-microglobulin levels as critical prognostic features for both event-free and overall survival, whereas age was insignificant for both endpoints (P = .2/.8). Thus, age is not a biologically adverse parameter for patients with MM receiving high-dose melphalan-based therapy with peripheral blood stem cell support and, hence, should not constitute an exclusion criterion for participation in what appears to be superior therapy for symptomatic MM.
The authors examined false recognition of semantic
associates in patients with probable Alzheimer's disease (AD), older
adults, and young adults using a paradigm that provided rates of
false ...recognition after single and multiple exposures to word lists.
Using corrected false recognition scores to control for unrelated
false alarms, the authors found that (a) the level of false
recognition after a single list exposure was lower in AD patients
than in controls; (b) across 5 trials, false recognition increased
in AD patients, decreased in young adults, and showed a fluctuating
pattern in older adults; and (c) all groups showed an increase in
true recognition over the 5 trials. Analyses suggested that AD
patients built up semantic gist across trials, whereas both control
groups were able to use increased item-specific recollection and
more conservative response criteria to suppress gist-based false
alarms.
Anti‐myeloma activity of pamidronate in vivo Dhodapkar, Madhav V.; Singh, Joginder; Mehta, Jayesh ...
British journal of haematology,
November 1998, Letnik:
103, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Two patients with progressive myeloma were treated with pamidronate disodium every 2‐4 weeks. Pamidronate therapy resulted in a significant reduction of marrow plasmacytosis and plasma cell labelling ...index (PCLI), together with durable (20 months) stabilization of immunoglobulin (Ig) levels and an increase in bone mineral density in the first patient and >50% reduction in Ig levels and bone marrow plasmacytosis in the second. This, to our knowledge, is the first report of an anti‐myeloma effect of bisphosphonates in humans and provides evidence that a therapeutic intervention largely directed at the myeloma microenvironment may alter the natural history of the disease.
PDF
