BACKGROUND: Cladribine is an oral disease-modifying drug approved for the treatment of highly active relapsing multiple sclerosis (MS). The recommended number of treatment courses is two, with the courses given 1 year apart (i.e., in year 1 and year 2), followed by 2 years without treatment. Pivotal clinical trials showed that, compared with placebo, cladribine significantly reduced relapse rates, risk of disability progression and magnetic resonance imaging measures of disease activity for up to 4 years in treatment-naïve or -experienced adults with relapsing-remitting MS (RRMS). The management of patients and requirement for retreatment with cladribine beyond year 4 is unclear.
METHODS: We describe the treatment history and outcomes of three people with MS retreated with cladribine, given as a third course 5 years after treatment initiation. We also include a review of evidence on retreatment with cladribine from year 3 onwards and a discussion of patient selection criteria for retreatment.
RESULTS: The cases included a 53-year-old female patient with RRMS, a 43-year-old female patient with RRMS, and a 42-year-old male patient with RRMS. Six months after the third course of cladribine, all three patients were relapse-free and stable on magnetic resonance imaging, with no evidence of disease activity. At 11-12 months follow-up, all patients had clinical and radiological stability (i.e., no evidence of disease activity).
CONCLUSIONS: Continuation of oral cladribine treatment may be considered for people with MS beyond year 5 following completion of the initial two courses. Our real-world experience is ongoing and additional data are required to obtain insight into patient phenotypes which predict response to cladribine treatment.

OBJECTIVE: Uncertainty regarding the long-term relative effectiveness is an important factor in health technology assessment (HTA) of medicines. This study investigated how different HTA bodies address this uncertainty in their assessments.
METHODS: A total of 49 HTA reports from 6 national HTA bodies, assessing 9 medicines for spinal muscular atrophy, cystic fibrosis, and hypercholesterolemia, were included. In these reports, 81 relative effectiveness assessments and 45 cost-effectiveness assessments were performed on an indication level. We collected information on included trials, assessment outcomes, uncertainty regarding the long-term effectiveness, proposed managed entry agreements, and reassessments.
RESULTS: Uncertainty regarding the long-term effectiveness was an important consideration in almost all cost-effectiveness assessments (91%) and three-quarters of relative effectiveness assessments (74%), despite differences in methodologies among HTA bodies. There were considerable differences in the amount and type of long-term effectiveness data included by HTA bodies due to timing and inclusion criteria. In total 23 managed entry agreements were proposed of which 14 were linked to uncertainty regarding the long-term effectiveness. In addition, 13 reassessments were performed of which 4 led to an increase in patient access because of more available long-term effectiveness data.
CONCLUSIONS: Uncertainty regarding the long-term effectiveness is an important challenge for HTA bodies. There are large differences in the acceptance of evidence among HTA bodies, which leads to heterogeneity in the inclusion of available long-term effectiveness data for decision making. In cases with large uncertainty regarding the long-term effectiveness, outcome-based agreements and reassessments are used by HTA bodies, but differently between HTA bodies and indications.

OBJECTIVE: To compare the long-term effectiveness of self-compassion therapy (SCT) combined with core stability exercise (CSE) versus CSE alone in managing nonspecific chronic low back pain (NCLBP).
METHODS: The combined group received SCT and CSE, while the exercise group only received CSE. Treatment was administered once weekly for four weeks, followed by one year of follow-up. The primary outcomes were changes in functional limitations (measured by Roland and Morris Disability Questionnaire scores[RMDQ]) and self-reported back pain (measured by the Numeric Pain Rating Scale[NRS]) at 52 weeks, with assessments also conducted at 2, 4, and 16 weeks.
RESULTS: 52 (83.9%) completed the follow-up assessments and were included in the analysis (42 women [80.8%]; mean [SD] age,35.3 [10.0] years). In the combined group, the baseline mean (SD) RMDQ score was 9.3 (4.1),5.7 (5.8) at 2 weeks, 3.8 (3.4) at 4 weeks, 3.8 (3.7) at 16 weeks, and 2.4 (2.7) at 52 weeks. For the exercise group, the RMDQ scores were 8.2 (3.3) at baseline, 6.2 (4.2) at 2 weeks, 5.5 (4.7) at 4 weeks, 4.4 (4.5) at 16 weeks, and 5.2 (5.6) at 52 weeks. The estimated mean difference between the groups at 52 weeks was -3.356 points (95% CI, -5.835 to -0.878; P = 0.009), favoring the combined group. NRS scores showed similar changes.
CONCLUSIONS: The addition of self-compassion therapy enhances the long-term efficacy of core stability training for NCLBP (Preregistered at chictr.org.cn:ChiCTR2100042810).

Few studies have reported the differential outcomes of Small Incision Lenticule Extraction (SMILE) on myopic astigmatism. Given this, we examined the effectiveness of SMILE for up to one year, comparing with-the-rule (WTR), against-the-rule (ATR), and oblique astigmatism, conducting a retrospective review of patients who underwent correction of myopic astigmatism using the 500-kHz VisuMax femtosecond laser (Carl Zeiss Meditec) at two refractive clinics in Poland between 2016-2017. Patients were aged ≥21 with stable refractive errors between -0.5 and -10.0 diopter (D) with astigmatism up to 5D. The mean age of the 209 patients (355 eyes) available was 32 years; 58.4% were female. Of these, 247 had WTR, 62 oblique, and 46 ATR astigmatism. The mean pre-operative spherical equivalent (SE) was -5.4 ± 2.57D and the cylinder -1.7 ± 1.0D. The mean SE for WTR reduced from -5.60 ± 2.37D to -0.31 ± 0.67D at 2 months and -0.38 ± 0.70D at 12 months; the mean cylinder improved from -1.90 ± 1.10D to -0.31 ± 0.39D and -0.36 ± 0.43D, respectively. Eyes with oblique astigmatism also improved from a mean SE of -5.8 ± 3.4 D to -0.82 ± 1.50D and -0.69 ± 1.15D and a cylinder of -1.4 ± 0.73D to -0.17 ± 0.33D at 2 months and -0.1 ± 0.32D at 12. For ATR, the mean SE improved from -4.0 ± 1.8D to -0.08 ± 0.22D and -0.04 ± 0.12D; and the mean cylinder from -1.25 ± 0.53 to -0.02 ± 0.09D -0.08 ± 0.21D at 2 and 12 months, respectively. There were statistically significant improvements in SE, manifest sphere and cylinder refraction, and UDVA and CDVA scores for each cylinder type at 2 months with ATR cylinders having better outcomes. Although missing data limited interpretation at one year, differences were maintained. The magnitude of error calculations suggests that WTR was more prone to under-correction, particularly for high astigmatism (>1.5D). SMILE for myopic astigmatism reliably corrects SE, irrespective of the subtype of astigmatism.

Maintenance doses for allergen immunotherapy (AIT) have been recommended for at least 3 years but little data on long-term efficacy is available depending on AIT duration. To show sustained efficacy 10 years after completion of treatment with depigmented-polymerized house dust mite (dpg-pol HDM) allergen extract in adults with asthma and/or rhinoconjunctivitis.
Patients included in a double-blind placebo-controlled AIT study with dpg-pol HDM allergen extract were reviewed at completion of the perennial treatment and 10-year follow-up (10y-FU). Change in symptom and rescue medication score was the primary objective. Visual analog scale (VAS), asthma control test (ACT), and degree of disease control were the secondary objectives. A comparative analysis between patients who underwent AIT treatment for <3 years and ≥3 years was performed.
Data from 31 patients (mean age 38 years) were available at 10y-FU. All had asthma and 29 had rhinoconjunctivitis at baseline. Twenty-three patients were treated ≥3 years and 8 for <3 years. Seventeen (55%) patients were asymptomatic at completion of AIT, with significant differences for nasal, conjunctival, and bronchial symptoms (p < .0001) compared with baseline only in those patients treated ≥3 years. Nine (52.9%) patients remained completely asymptomatic at 10y-FU, all were treated for ≥3 years. Moreover, significant reduction in the number of patients with rhinitis (p = .0117), conjunctivitis (p < .0001), and bronchial (p = .0005) symptoms was observed at 10y-FU compared with baseline only in the ≥3 years treated. Ten (32.3%) patients did not require any rescue medication at 10y-FU, all had been treated for ≥3 years. ACT at 10y-FU showed a good control of asthma (median 23.5; 95% IC[22.0, 25.0]). No significant differences were observed between VAS at end of treatment compared with VAS at 10y-FU.
Sustained clinical efficacy is achieved 10 years after completion of depigmented-polymerized HDM, however, these findings were observed only if patients are treated for at least 3 years.

Stabilization/solidification is the most frequently used method for treating soils contaminated by heavy metals; however, degradation of the treatment will occur under freeze-thaw (F-T) cycles. In this paper, a low-carbon emission by-product, ground granulated blast furnace slag (GGBS), was adopted as a binder to treat Cr(VI)-contaminated soil after alkali excitation. Built on the usage scenarios of subgrade materials, the impact of F-T cycles and initial water content on the geoenvironmental properties of the treated soils, including leaching toxicity, unconfined compressive strength (UCS), pH, Eh, and permeability, were discussed. To investigate the mechanisms of the changing properties, this study analyzed the chemical morphology of Cr, the micromorphology of the reaction products, and the pore characteristics. The results demonstrated that negative impact of F-T cycles on treatment effectiveness was low at the optimal water content. After 28 F-T cycles, the Cr(VI) component increased by 6.4 %, and the leached Cr concentration showed a significant increase, especially for specimens with low water content. A new solid phase with mixed valence Mn(III/IV), mainly composed of birnessite and manganite, was observed via microscopic analysis. During the first 3 F-T cycles, the content of hydration gel increased by 0.18 %, and the cumulative pore volume decreased such that the UCS increased by an average of 1.2 MPa. This study demonstrated that a few F-T cycles would result in a secondary alkali-activated GGBS reaction, enhancing the treatment effect. However, additional F-T cycles would create an oxidizing environment under which the initially precipitated Cr(III) would react with manganese oxide, resulting in more Cr(VI) released. The degree of reoxidation was closely related to the initial water content of the solidified soil.

BACKGROUND: Currently, self-locking stand-alone cages (SSC) are commonly applied in anterior cervical discectomy and fusion (ACDF), as are cage-plate constructs (CPC). However, it remains controversial concerning the long-term effectiveness of both apparatuses. Our purpose is to compare long-term effectiveness of SSC with CPC in monosegmental ACDF.
METHODS: Four electronic databases were queried to identify studies comparing SSC versus CPC in monosegmental ACDF. The meta-analysis was carried out with the use of the Stata MP 17.0 software package.
RESULTS: Ten trials with 979 patients were included. Compared to CPC, SSC significantly reduced operative time, intraoperative blood loss, duration of hospitalisation, cervical Cobb angle at final follow-up, 1-month postoperative dysphagia rate, and incidence of adjacent segment degeneration (ASD) at final follow-up. No significant difference was found regarding 1-month postoperative cervical Cobb angle, JOA scores, NDI scores, fusion rate and cage subsidence rate at final follow-up.
CONCLUSIONS: Both devices achieved similar long-term effectiveness in monosegmental ACDF regarding JOA scores, NDI scores, fusion rate and cage subsidence rate. SSC had significant advantages over CPC in reducing surgical duration, intraoperative bleeding, duration of hospitalisation, as well as rates of dysphagia and ASD after surgery. Therefore, SSC is a better option than CPC in monosegmental ACDF. However, SSC is inferior to CPC in maintaining cervical curvature at long-term follow-up. Whether radiological changes affect clinical symptoms needs confirmation in trials with longer follow-up.

The long-term effectiveness of heavy metal immobilization is always a concern. This study proposes a completely novel approach to enhance the stability of heavy metals by combined biochar and microbial induced carbonate precipitation (MICP) technology, to create a \"surface barrier\" of CaCO3 layer on biochar after lead (Pb2+) immobilization. Aqueous sorption studies and chemical and micro-structure tests were used to verify the feasibility. Rice straw biochar (RSB700) was produced at 700 °C, which shows high immobilization capacity of Pb2+ (maximum of 118 mg g-1). But the stable fraction only accounts for 4.8% of the total immobilized Pb2+ on biochar. After MICP treatment, the stable fraction of Pb2+ significantly increased to a maximum of 92.5%. Microstructural tests confirm the formation of CaCO3 layer on biochar. The CaCO3 species are predominantly calcite and vaterite. Higher Ca2+ and urea concentrations in cementation solution resulted in higher CaCO3 yield but lower Ca2+ utilization efficiency. The main mechanism of the \"surface barrier\" to enhance Pb2+ stability on biochar was likely the encapsulation effect: it physically blocked the contact between acids and Pb2+ on biochar, and chemically buffer the acidic attack from the environment. The performance of the \"surface barrier\" depends on both the yield of CaCO3 and their distribution uniformity on biochar\'s surface. This study shed lights on the potential application of the \"surface barrier\" strategy combining biochar and MICP technologies for enhanced heavy metal immobilization.

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Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation. In clinical studies, dupilumab reduced the risk of severe asthma exacerbations, and improved forced expiratory volume in 1 s and quality of life in patients with uncontrolled moderate-to-severe asthma.
The objectives of RAPID (NCT04287621) are to characterize patients with asthma initiating dupilumab in routine clinical practice and to collect information on long-term effectiveness and safety in these patients.
RAPID is a global, prospective, observational registry that will enroll approximately 1000 patients (aged ≥ 12 years) with asthma from 150 sites globally. Dupilumab treatment will be initiated in routine clinical practice according to country-specific prescribing information, per physician discretion as part of routine care. Patients will be followed prospectively for up to 3 years, with postbaseline assessments at months 1 and 3, and every 3 months thereafter.
Baseline data collected will include patient demographics, disease characteristics, and medication history. Patient adherence and persistence will be recorded alongside health-care resource utilization, and effectiveness of dupilumab will be assessed (clinician assessment) as per standard of care. Quality of life, asthma control, type 2 inflammatory comorbidities, work productivity, and physical activity limitation will be assessed. Incidence and severity of adverse events will be recorded.
RAPID is the first global registry to characterize patients beginning dupilumab treatment for asthma in clinical practice and will expand on prior clinical studies by providing real-world data.
ClinicalTrials.gov identifier NCT04287621.