Treatment switching is a common challenge and opportunity in real-world clinical practice. Increasing diversity in disease-modifying treatments (DMTs) has generated interest in the identification of ...reliable and robust predictors of treatment switching across different countries, DMTs, and time periods.
The objective of this retrospective, observational study was to identify independent predictors of treatment switching in a population of relapsing-remitting MS (RRMS) patients in the Big Multiple Sclerosis Data Network of national clinical registries, including the Italian MS registry, the OFSEP of France, the Danish MS registry, the Swedish national MS registry, and the international MSBase Registry.
In this cohort study, we merged information on 269,822 treatment episodes in 110,326 patients from 1997 to 2018 from five clinical registries. Patients were included in the final pooled analysis set if they had initiated at least one DMT during the relapsing-remitting MS (RRMS) stage. Patients not diagnosed with RRMS or RRMS patients not initiating DMT therapy during the RRMS phase were excluded from the analysis. The primary study outcome was treatment switching. A multilevel mixed-effects shared frailty time-to-event model was used to identify independent predictors of treatment switching. The contributing MS registry was included in the pooled analysis as a random effect.
Every one-point increase in the Expanded Disability Status Scale (EDSS) score at treatment start was associated with 1.08 times the rate of subsequent switching, adjusting for age, sex, and calendar year (adjusted hazard ratio aHR 1.08; 95% CI 1.07-1.08). Women were associated with 1.11 times the rate of switching relative to men (95% CI 1.08-1.14), whilst older age was also associated with an increased rate of treatment switching. DMTs started between 2007 and 2012 were associated with 2.48 times the rate of switching relative to DMTs that began between 1996 and 2006 (aHR 2.48; 95% CI 2.48-2.56). DMTs started from 2013 onwards were more likely to switch relative to the earlier treatment epoch (aHR 8.09; 95% CI 7.79-8.41; reference = 1996-2006).
Switching between DMTs is associated with female sex, age, and disability at baseline and has increased in frequency considerably in recent years as more treatment options have become available. Consideration of a patient's individual risk and tolerance profile needs to be taken into account when selecting the most appropriate switch therapy from an expanding array of treatment choices.
Tyrosine kinase inhibitors (TKIs) have increased survival dramatically for patients with chronic myeloid leukemia (CML), but continuous administration of these drugs may elicit long-term toxicity.
To ...investigate the incidence of vascular events in patients with CML treated with first- and second-generation TKIs.
Retrospective cohort study using nationwide population-based registries.
Sweden.
All patients diagnosed with chronic-phase CML in Sweden from 2002 to 2012 and treated with a TKI, and 5 age- and sex-matched control individuals per patient.
Relative risks, expressed as incidence rate ratios comparing patients with control individuals, were calculated. Events per 1000 person-years were assessed in interdrug comparisons.
896 patients, 94.4% with documented TKI treatment, were followed for a median of 4.2 years. There were 54 arterial and 20 venous events in the CML cohort, corresponding to relative risks of 1.5 (95% CI, 1.1 to 2.1) and 2.0 (CI, 1.2 to 3.3), respectively. The event rate for myocardial infarction was higher in patients treated with nilotinib or dasatinib (29 and 19 per 1000 person-years, respectively) than in those receiving imatinib (8 per 1000 person-years), although data are limited and the CIs were wide and overlapped. Among 31 patients treated with a TKI who had myocardial infarction, 26 (84%) had at least 1 major cardiac risk factor diagnosed before the event occurred.
Patients may have been exposed to multiple TKIs. Data on second- and third-generation TKIs were limited.
An increased risk for arterial and venous vascular events was seen in patients with CML treated with a TKI. Further study is needed to determine whether the risk for myocardial infarction increases with second-generation drugs.
No external funding.
A side-by-side comparison of updated guidelines regarding contrast medium-induced acute kidney injury (CI-AKI) from the Swedish Society of Uroradiology (SSUR) and the European Society of Urogenital ...Radiology (ESUR) is presented. The major discrepancies include a higher glomerular filtration rate (GFR) threshold as a risk factor for CI-AKI and for discontinuation of metformin by SSUR, i.e., < 45 ml/min versus < 30 ml/min/1.73 m
2
by ESUR, when intravenous or intra-arterial contrast media (CM) with second-pass renal exposure is administered. SSUR also continues to recommend consideration of traditional non-renal risk factors such as diabetes and congestive heart failure, while ESUR considers these factors as non-specific for CI-AKI and does not recommend any consideration. Contrary to ESUR, SSUR also recommends discontinuation of NSAID and nephrotoxic medication if possible. Insufficient evidence at the present time motivates the more cautionary attitude taken by SSUR. Furthermore, SSUR expresses GFR thresholds in absolute values in ml/min as recommended by the National Kidney Foundation for drugs excreted by glomerular filtration, while ESUR uses the relative GFR normalised to body surface area in ml/min/1.73 m
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. CM dose/GFR ratio thresholds established for coronary angiography/interventions are also applied as recommendations for CM-enhanced CT by SSUR, since SSUR regards coronary procedures as a second-pass renal exposure of CM with no obvious difference in the incidence of AKI compared with IV CM administration. Finally, SSUR recommends reducing the gram-iodine dose/GFR ratio from < 1.0 in patients not at risk to < 0.5 in patients at risk of CI-AKI, while ESUR has no such recommendation.
Key Points
• The more cautionary attitude taken by SSUR compared with that of ESUR is motivated by insufficient evidence regarding risk for contrast medium-induced acute kidney injuries (CI-AKI).
• SSUR recommends that absolute and not relative GFR should be used when dosing drugs eliminated by the kidneys such as contrast media.
• According to SSUR the gram-iodine dose/GFR ratio should be < 0.5 in patients at risk of CI-AKI, while ESUR has no such recommendation.
The first ATLAS result on a search for a high mass top pair resonance at the LHC in the subset of events where both W bosons from the top decays decay to either a final state electron or muon is ...presented. The analysis is performed on 1.04 fb−1 of pp collisions at √s = 7 TeV. Numerous models predict the production of new massive particles that decay preferentially to a top-anti-top pair, including Randall-Sundrum models where the observation of a Kaluza-Klein excitation of the gluon may be the first indication of the existence of an extra spatial dimension. In the analysis presented, a simple observable, sensitive to resonance mass, is formed by summing the missing transverse energy, and the transverse momenta of the selected jets and the two candidate leptons. A deviation from the Standard Model prediction for this observable is searched for using Bayesian statistical methods that compare the yields, and shapes, of the Standard Model background and signal predictions for KK-gluons with masses between 500 and 1600 GeV. No excess over the Standard Model is observed and 95% C.L. upper limits are set on the production cross-section times branching ratio to top quarks for KK-gluon-like resonances. The results of the analysis exclude Randall-Sundrum KK-gluons with masses less than 840 GeV.
OBJECTIVE:To determine if blood neurofilament light chain (NfL) protein can discriminate between Parkinson disease (PD) and atypical parkinsonian disorders (APD) with equally high diagnostic accuracy ...as CSF NfL, and can therefore improve the diagnostic workup of parkinsonian disorders.
METHODS:The study included 3 independent prospective cohortsthe Lund (n = 278) and London (n = 117) cohorts, comprising healthy controls and patients with PD, progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), as well as an early disease cohort (n = 109) of patients with PD, PSP, MSA, or CBS with disease duration ≤3 years. Blood NfL concentration was measured using an ultrasensitive single molecule array (Simoa) method, and the diagnostic accuracy to distinguish PD from APD was investigated.
RESULTS:We found strong correlations between blood and CSF concentrations of NfL (ρ ≥ 0.73–0.84, p ≤ 0.001). Blood NfL was increased in patients with MSA, PSP, and CBS (i.e., all APD groups) when compared to patients with PD as well as healthy controls in all cohorts (p < 0.001). Furthermore, in the Lund cohort, blood NfL could accurately distinguish PD from APD (area under the curve AUC 0.91) with similar results in both the London cohort (AUC 0.85) and the early disease cohort (AUC 0.81).
CONCLUSIONS:Quantification of blood NfL concentration can be used to distinguish PD from APD. Blood-based NfL might consequently be included in the diagnostic workup of patients with parkinsonian symptoms in both primary care and specialized clinics.
CLASSIFICATION OF EVIDENCE:This study provides Class III evidence that blood NfL levels discriminate between PD and APD.
The first ATLAS result on a search for a high mass top pair resonance at the LHC in the subset of events where both W bosons from the top decays decay to either a final state electron or muon is ...presented. The analysis is performed on 1.04 fb−1 of pp collisions at √s = 7 TeV. Numerous models predict the production of new massive particles that decay preferentially to a top-anti-top pair, including Randall-Sundrum models where the observation of a Kaluza-Klein excitation of the gluon may be the first indication of the existence of an extra spatial dimension. In the analysis presented, a simple observable, sensitive to resonance mass, is formed by summing the missing transverse energy, and the transverse momenta of the selected jets and the two candidate leptons. A deviation from the Standard Model prediction for this observable is searched for using Bayesian statistical methods that compare the yields, and shapes, of the Standard Model background and signal predictions for KK-gluons with masses between 500 and 1600 GeV. No excess over the Standard Model is observed and 95% C.L. upper limits are set on the production cross-section times branching ratio to top quarks for KK-gluon-like resonances. The results of the analysis exclude Randall-Sundrum KK-gluons with masses less than 840 GeV.
Patients with Alzheimer's disease can present with different clinical phenotypes. Individuals with late-onset Alzheimer's disease (>65 years) typically present with medial temporal lobe ...neurodegeneration and predominantly amnestic symptomatology, while patients with early-onset Alzheimer's disease (<65 years) exhibit greater neocortical involvement associated with a clinical presentation including dyspraxia, executive dysfunction, or visuospatial impairment. We recruited 20 patients with early-onset Alzheimer's disease, 21 with late-onset Alzheimer's disease, three with prodromal early-onset Alzheimer's disease and 13 with prodromal late-onset Alzheimer's disease, as well as 30 cognitively healthy elderly controls, that had undergone 18F-AV-1451 tau positron emission tomography and structural magnetic resonance imaging to explore whether early- and late-onset Alzheimer's disease exhibit differential regional tau pathology and atrophy patterns. Strong associations of lower age at symptom onset with higher 18F-AV-1451 uptake were observed in several neocortical regions, while higher age did not yield positive associations in neither patient group. Comparing patients with early-onset Alzheimer's disease with controls resulted in significantly higher 18F-AV-1451 retention throughout the neocortex, while comparing healthy controls with late-onset Alzheimer's disease patients yielded a distinct pattern of higher 18F-AV-1451 retention, predominantly confined to temporal lobe regions. When compared against each other, the early-onset Alzheimer's disease group exhibited greater uptake than the late-onset group in prefrontal and premotor, as well as in inferior parietal cortex. These preliminary findings indicate that age may constitute an important contributor to Alzheimer's disease heterogeneity highlighting the potential of tau positron emission tomography to capture phenotypic variation across patients with Alzheimer's disease.
Allogeneic stem cell transplantation (alloSCT) reduces relapse rates in acute leukemia, but outcome is hampered by toxicity. Population-based data avoid patient selection and may therefore substitute ...for lack of randomized trials.
We evaluated alloSCT rates within the Swedish Acute Leukemia Registry, including 3899 adult patients diagnosed from 1997 through 2006 with a coverage of 98% and a median follow-up of 6.2 years.
AlloSCT rates and survival decreased rapidly with age >55 years. The 8-year overall survival (OS) was 65% in patients <30 years and 38% in patients <60 years and was similar for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Among 1073 patients <60 years, alloSCT was performed in 42% and 49% of patients with AML and ALL, respectively. Two-thirds of the alloSCTs were performed in first complete remission, and half used unrelated donors, the same in AML and ALL. Regional differences in management and outcome were found: 60% of AML patients <40 years received alloSCT in all parts of Sweden, but two-thirds of AML patients 40-59 years had alloSCT in one region compared with one-third in other regions (P<.001), with improved 8-year OS among all AML patients in this age cohort (51% vs 30%; P = .005).
More Swedish AML patients received alloSCT, and long-term survival was better than in recently published large international studies, despite our lack of selection bias. There was no correlation between alloSCT rate and survival in ALL. In adult AML patients <60 years of age, a high alloSCT rate was associated with better long-term survival, but there was no such correlation in ALL.
Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk factors for PASC and their biological associations are poorly resolved. We executed a deep ...multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2–3 months later), integrated with clinical data and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific auto-antibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes, exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time, leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.
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•Longitudinal multi-omics associate PASC with auto-antibodies, viremia, and comorbidities•Reactivation of latent viruses during initial infection may contribute to PASC•Subclinical auto-antibodies negatively correlate with anti-SARS-CoV-2 antibodies•Gastrointestinal PASC uniquely present with post-acute expansion of cytotoxic T cells
By correlating patient symptoms with in-depth profiling of blood cells and plasma components throughout COVID-19 infection, this study identifies factors that may predict sustained disease.
Objective To investigate the long term effects of continuous subcutaneous insulin infusion (insulin pump therapy) on cardiovascular diseases and mortality in people with type 1 diabetes.Design ...Observational study.Setting Swedish National Diabetes Register, Sweden 2005-12.Participants 18 168 people with type 1 diabetes, 2441 using insulin pump therapy and 15 727 using multiple daily insulin injections.Main outcome measures Cox regression analysis was used to estimate hazard ratios for the outcomes, with stratification of propensity scores including clinical characteristics, risk factors for cardiovascular disease, treatments, and previous diseases.Results Follow-up was for a mean of 6.8 years until December 2012, with 114 135 person years. With multiple daily injections as reference, the adjusted hazard ratios for insulin pump treatment were significantly lower: 0.55 (95% confidence interval 0.36 to 0.83) for fatal coronary heart disease, 0.58 (0.40 to 0.85) for fatal cardiovascular disease (coronary heart disease or stroke), and 0.73 (0.58 to 0.92) for all cause mortality. Hazard ratios were lower, but not significantly so, for fatal or non-fatal coronary heart disease and fatal or non-fatal cardiovascular disease. Unadjusted absolute differences were 3.0 events of fatal coronary heart disease per 1000 person years; corresponding figures were 3.3 for fatal cardiovascular disease and 5.7 for all cause mortality. When lower body mass index and previous cardiovascular diseases were excluded, results of subgroup analyses were similar to the results from complete data. A sensitivity analysis of unmeasured confounders in all individuals showed that an unmeasured confounders with hazard ratio of 1.3 would have to be present in >80% of the individuals treated with multiple daily injections versus not presence in those treated with pump therapy to invalidate the significantly lower hazard ratios for fatal cardiovascular disease. Data on patient education and frequency of blood glucose monitoring were missing, which might have influenced the observed association.Conclusion Among people with type 1 diabetes use of insulin pump therapy is associated with lower cardiovascular mortality than treatment with multiple daily insulin injections.
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