Therapy discontinuation in inflammatory bowel disease,particularly involving immunomodulators,biologics,and small molecules,remains a controversial and evolving topic.This letter reflects on developments following the...Therapy discontinuation in inflammatory bowel disease,particularly involving immunomodulators,biologics,and small molecules,remains a controversial and evolving topic.This letter reflects on developments following the publication by Meštrovićet al,emphasizing the complex balance between risks of relapse,antidrug antibody formation,and potential complications of long-term immunosuppression.Recent evidence underscores high relapse rates following withdrawal-especially of anti-tumor necrosis factor agents-and highlights the lack of robust data for newer biologics.Updated guidelines from European Crohn’s and Colitis Organization,British Society of Gastroenterology,and American College of Gastroenterology all support cautious and individualized approaches,with strict criteria and close follow-up,particularly in Crohn’s disease.For ulcerative colitis,therapeutic cycling remains insufficiently addressed.We proposed a flowchart to support clinical decision-making and stress the importance of shared decisionmaking in the era of personalized medicine since,despite new drug classes and evolving strategies,the therapeutic ceiling in inflammatory bowel disease has yet to be fully overcome.展开更多
Objective:To evaluate the performance of orthokeratology(ortho-k)lens reordering using software-designed system,so as to determine the feasibility of ortho-k lens reordering without discontinuing lens wear.Methods:Thi...Objective:To evaluate the performance of orthokeratology(ortho-k)lens reordering using software-designed system,so as to determine the feasibility of ortho-k lens reordering without discontinuing lens wear.Methods:This study is a retrospective analysis of data of ortho-k lens wearers who had a history of short-term discontinuation of lens wear.A total of 94 individuals aged over 8 years with spherical equivalent refraction ranging from-0.50 to-6.50 diopters were included.The corneal topography data at baseline(before ortho-k)and after lens wear discontinuation(cessation of ortho-k treatment)were imported separately into the lens-design software,along with corresponding refraction data.Subsequently,corneal and lens parameters were generated and compared.Intraclass correlation coefficients(ICC)were calculated,and Bland and Altman analyses were conducted.Results:All 94 children were involved in the retrospective analysis.Compared with baseline data,there was a high level of consistency between Rwo(without discontinuation)and Rwith(with discontinuation),with an ICC of 0.96(P<0.001).Furthermore,the comparison of lens parameters generated by the Easyfit software between baseline and after short-term discontinuation showed a high degree of consistency,with all of the ICC values exceeding 0.90.Similar results were obtained using the WAVE software,as both ICC values and Bland-Altman plots demonstrated a high level of consistency in lens parameters between two conditions(nearly all data points fell within the 95%LoAs).Conclusions:It is feasible to directly reorder new ortho-k lenses using software fitting approaches.However,further investigations are necessary to validate their practicability in a clinical setting.展开更多
The discontinuation of denosumab[antibody targeting receptor activator of nuclear factor kappa B ligand(RANKL)]therapy may increase the risk of multiple vertebral fractures;however,the underlying pathophysiology is la...The discontinuation of denosumab[antibody targeting receptor activator of nuclear factor kappa B ligand(RANKL)]therapy may increase the risk of multiple vertebral fractures;however,the underlying pathophysiology is largely unknown.In patients who underwent discontinuation after multiple injections of denosumab,the levels of tartrate-resistant acid phosphatase 5b increased compared to pretreatment levels,indicating a phenomenon known as“overshoot.”The rate of decrease in bone mineral density during the withdrawal period was higher than the rate of decrease associated with aging,suggesting that the physiological bone metabolism had broken down.Overshoot and significant bone loss were also observed in mice receiving continuous administration of anti-RANKL antibody after treatment was interrupted,resembling the original pathology.In mice long out of overshoot,bone resorption recovered,but osteoblast numbers and bone formation remained markedly reduced.The bone marrow exhibited a significant reduction in stem cell(SC)antigen 1-and platelet-derived growth factor receptor alpha-expressing osteoblast progenitors(PαS cells)and alkaline phosphatase-positive early osteoblasts.Just before the overshoot phase,the osteoclast precursor cell population expands and RANKL-bearing extracellular vesicles(EVs)became abundant in the serum,leading to robust osteoclastogenesis after cessation of anti-RANKL treatment.Thus,accelerated bone resorption due to the accumulation of RANKLbearing EVs and long-term suppression of bone formation uncoupled from bone resorption leads to the severe bone loss characteristic of denosumab discontinuation.展开更多
AIM To characterize the prescribing patterns for hydrocortisone for patients with septic shock and perform an exploratory analysis in order to identify the variables associated with better outcomes.METHODS This prospe...AIM To characterize the prescribing patterns for hydrocortisone for patients with septic shock and perform an exploratory analysis in order to identify the variables associated with better outcomes.METHODS This prospective cohort study included 59 patients with septic shock who received stress-dose hydrocortisone.It was performed at 2 critical care units in academic hospitals from June 1st,2015,to July 31 st,2016.Demographic data,comorbidities,medical management details,adverse effects related to corticosteroids,and outcomes were collected after the critical care physician indicated initiation of hydrocortisone.Univariate comparison between continuous and bolus administration of hydrocortisone was performed,including multivariate analysis,as well as Kaplan-Meier analysis to compare the proportion of shock reversal at 7 d after presentation.Receiver operating characteristic(ROC)curves determined the best cut-off criteria for initiation of hydrocortisone associated with the highest probability of shock reversal.We addressed the effects of the taper strategy for discontinuation of hydrocortisone,noting risk of shock relapse and adverse effects.RESULTS All-cause 30-d mortality was 42%.Hydrocortisone was administered as a continuous infusion in 54.2%of patients;time to reversal of shock was 49 h longer in patients who were given a bolus administration[59 h(range,47.5-90.5)vs 108 h(range,63.2-189);P=0.001].The maximal dose of norepinephrine after initiation of hydrocortisone was lower in patients on continuous infusion[0.19μg/kg per minute(range,0.11-0.28μg)]compared with patients who were given bolus[0.34μg/kg per minute(range,0.16-0.49);P=0.004].Kaplan-Meier analysis revealed a higher proportion of shock reversal at 7 d in patients with continuous infusion compared to those given bolus(83%vs 63%;P=0.004).There was a good correlation between time to initiation of hydrocortisone and time to reversal of shock(r=0.80;P<0.0001);ROC curve analysis revealed that the best criteria for prediction of shock reversal was a time to initiation of hydrocortisone of≤13 h after administration of norepinephrine,with an area under the curve of 0.81(P<0.001).The maximal dose of norepinephrine at initiation of hydrocortisone with the highest association with shock reversal was≤0.28μg/kg per minute,with an area under the curve of 0.75(P=0.0002).On a logistic regression model,hydrocortisone taper was not associated with a lower risk of shock relapse(RR=1.29;P=0.17)but was related to a higher probability of hyperglycemia[odds ratio(OR),5.3;P=0.04]and hypokalemia(OR=10.6;P=0.01).CONCLUSION Continuous infusion of hydrocortisone could hasten the resolution of septic shock compared to bolus administration.Earlier initiation corresponds with a higher probability of shock reversal.Tapering strategy is unnecessary.展开更多
Aim: To investigate the reasons for discontinuations of sildenafil after the successful restoration of erectile function. Methods: One hundred fifty six patients, whose scores of erectile function domain of the 15-ite...Aim: To investigate the reasons for discontinuations of sildenafil after the successful restoration of erectile function. Methods: One hundred fifty six patients, whose scores of erectile function domain of the 15-item International Index of Erectile Function (IIEF) increased to 26 or more after sildenafil medication, were included in this study. Six-months after the first sildenafil prescription, compliance to medication and the reason for discontinuity were reviewed by chart or surveyed by telephone. Results: Fifty-four (34.6%) of the 156 successfully treated patients discontinued sildenafil medication. The r easons for discontinuance were shortcomings in the partners' or patients' emotional readiness for the restoration of sexual life after long-term abstinence (37.0%), fear of possible side effects (18.5 %), recovery of spontaneous erection (14.8 %), postponement of ED treatment because of co morbid disease treatment (11.1%), unwillingness to accept drug-dependent erection (7.4%), high drug cost (3.7%), unacceptability of planned sexual activity (3.7%) and lack of sexual interesi (3.7%). Conclusion: The reasons for discontinuing sildenafil medication were primarily emotional or relationship-oriented, which indicates that simple recovery of a rigid erection is insufficient to restore sexual activity. More education about the effects of drug and the counseling of both partners is recommended to promote the successful recovery of sexual activity.展开更多
The timely introduction and adjustment of the appropriate drug in accordance with previously well-defined treatment goals is the foundation of the approach in the treatment of inflammatory bowel disease(IBD).The thera...The timely introduction and adjustment of the appropriate drug in accordance with previously well-defined treatment goals is the foundation of the approach in the treatment of inflammatory bowel disease(IBD).The therapeutic approach is still evolving in terms of the mechanism of action but also in terms of the possibility of maintaining remission.In patients with achieved long-term remission,the question of de-escalation or discontinuation of therapy arises,considering the possible side effects and economic burden of long-term therapy.For each of the drugs used in IBD(5-aminosalycaltes,immunomodulators,biological drugs,small molecules)there is a risk of relapse.Furthermore,studies show that more than 50%of patients who discontinue therapy will relapse.Based on the findings of large studies and meta-analysis,relapse of disease can be expected in about half of the patients after therapy withdrawal,in case of monotherapy with aminosalicylates,immunomodulators or biological therapy.However,longer relapse-free periods are recorded with withdrawal of medication in patients who had previously been on combination therapies immunomodulators and anti-tumor necrosis factor.It needs to be stressed that randomised clinical trials regarding withdrawal from medications are still lacking.Before making a decision on discontinuation of therapy,it is important to distinguish potential candidates and predictive factors for the possibility of disease relapse.Fecal calprotectin level has currently been identified as the strongest predictive factor for relapse.Several other predictive factors have also been identified,such as:High Crohn's disease activity index or Harvey Bradshaw index,younger age(<40 years),longer disease duration(>40 years),smoking,young age of disease onset,steroid use 6-12 months before cessation.An important factor in the decision to withdraw medication is the success of re-treatment with the same or other drugs.The decision to discontinue therapy must be based on individual approach,taking into account the severity,extension,and duration of the disease,the possibility of side adverse effects,the risk of relapse,and patient’s preferences.展开更多
Discontinuation of antipsychotic therapy has been a significant clinical issue among patients with schizophrenia, since the patients who discontinued antipsychotic treatment showed worse clinical and functional outcom...Discontinuation of antipsychotic therapy has been a significant clinical issue among patients with schizophrenia, since the patients who discontinued antipsychotic treatment showed worse clinical and functional outcomes, and higher risks of relapse of schizophrenia symptoms and hospitalization. We conducted a post-hoc analysis of a post-marketing research with a 12-month follow-up period to identify the predictors for discontinuation of antipsychotic monotherapy in Japan. This is a prospective, naturalistic multicenter observational study, designed to evaluate the discontinuation rates of olanzapine monotherapy and non-olanzapine antipsychotic monotherapy in Japanese adult patients with acute schizophrenia. Patients were treatment-naive, or had switched from other antipsychotics or from poly-pharmacotherapy to oral antipsychotic monotherapy. We analyzed the correlation of discontinuation of antipsychotic monotherapy with baseline characteristics of patients. A total of 1089 patients (578 patients treated with olanzapine and 511 with non-olanzapine antipsychotics) were eligible for analysis. By the end of the 12-month study period, 614 patients (56.4%) discontinued antipsychotic therapy. Multivariate logistic regression analyses indicated significantly lower discontinuation rates in all patients treated with antipsychotics: older age (Odds ratio [OR], 0.871;95% confidence interval [CI], 0.797 to 0.953;p = 0.003), outpatient status (OR, 0.508;95% CI, 0.383 to 0.675;p < 0.001), prior use of antipsychotics (OR, 0.693;95% CI, 0.516 to 0.930;p = 0.015), and olanzapine group showed lower discontinuation rate than that of non-olanzapine group (OR, 1.416;95% CI, 1.086 to 1.846;p = 0.010). The present study indicated that the outpatient status, older age, and prior use of antipsychotics have better adherence to antipsychotic treatment. In addition to these factors, use of anti-parkinson agents showed lower discontinuation rates in the olanzapine monotherapy group.展开更多
Clinical trials have demonstrated that some patients with chronic myeloid leukemia(CML)treated for several years with tyrosine kinase inhibitors(TKIs)who have maintained a molecular response can successfully discontin...Clinical trials have demonstrated that some patients with chronic myeloid leukemia(CML)treated for several years with tyrosine kinase inhibitors(TKIs)who have maintained a molecular response can successfully discontinue treatment without relapsing.Treatment free remission(TFR)can be reached by approximately 50%of patients who discontinue.Despite having similar levels of deep molecular response and an identical duration of treatment,the factors that influence the successful discontinuation of CML patients remain to be determined.In this review we will explore the factors identified to date that can help predict whether a patient will successfully achieve TFR.We will also discuss the need for the identification of predictive biomarkers associated with a high probability of achieving TFR for the future personalized identification of patients who are suitable for the discontinuation of TKI treatment.展开更多
Once a patient has initiated an antiepileptic drug (AED) and achieved a sustained period of seizure freedom, the decision to discontinue AED should be balanced against continuation of AED therapy indefinitely. Studies...Once a patient has initiated an antiepileptic drug (AED) and achieved a sustained period of seizure freedom, the decision to discontinue AED should be balanced against continuation of AED therapy indefinitely. Studies show that the rate of seizure recurrence after AED withdrawal is about two to three times the rate in patients who continue AEDs. However, there are many benefits to AED withdrawal that should be evaluated on an individualized basis. AED discontinuation may be considered in patients whose seizures have been completely controlled for a prolonged period. There are several factors that would increase risk of recurrences which will be reviewed and discussed. As a consequence, the decision to withdraw or withhold treatment must be still individualized. In any patient, the decision to discontinue treatment should also take into effect the social aspects like driving license, job and leisure activities as well as emotional and personal factors and patients with adverse effects or drug interactions. Patients will ultimately have to decide themselves whether they wish to discontinue drug treatment.展开更多
Hepatic encephalopathy(HE)is one of the main complications of cirrhosis,characterized by a wide spectrum of neuropsychiatric alterations that lead to an increase in mortality,morbidity and recurrent hospitalizations.D...Hepatic encephalopathy(HE)is one of the main complications of cirrhosis,characterized by a wide spectrum of neuropsychiatric alterations that lead to an increase in mortality,morbidity and recurrent hospitalizations.Due to the central role in HE pathogenesis of ammonia and other neurotoxins primarily produced by the gut microbiota,the main therapeutic approaches for the treatment of HE are based on the modulation of the gut microbiota.Rifaximin is a non-absorbable broad-spectrum antibiotic,that is effective against ammonia-producing grampositive,gram-negative,and anaerobic species,approved for the treatment of HE in secondary prophylaxis.The chronic administration of rifaximin in this setting is associated with a lower risk of HE recurrence and mortality,while the role of rifaximin for the treatment of an overt-HE episode in inpatients is still unclear.Limited data exist about the coadministration of rifaximin and broad-spectrum antibiotics commonly used to treat concomitant infections,as patients receiving or recently treated with antibiotics were frequently excluded from clinical trials.In this editorial we comment on the article by Ward et al published in the recent issue of the World Journal of Hepatology.It is a single center,retrospective,quasiexperimental,pharmacist-driven protocol,with the aim to evaluate the feasibility and safety of rifaximin discontinuation in critically ill patients with HE and chronic liver disease receiving broad-spectrum antibiotic therapies in intensive care units.The study revealed no differences between the protocol and control group in terms of primary outcome(days alive and free of delirium and coma to day 14)and secondary outcomes which include:Intensive care mortality,intensive care length of stay,intravenous vasopressor requirement changes and adverse effects rate.Therefore,rifaximin discontinuation during broad-spectrum antibiotic therapy does not appear to negatively impact the clinical status of critically ill liver patients,with a similar safety profile and significant cost savings,as compared to the coadministration of rifaximin and broad-spectrum antibiotics.In agreement with Ward et al,a recently published double-blind,randomized controlled trial provided additional evidence to support the feasibility of withholding rifaximin during broad-spectrum antibiotic therapy in critically ill cirrhotic patients.However,given the limitations of these studies,further multicentric and prospective clinical trials,enrolling a larger sample of non-critically ill patients,are needed to better establish the role of rifaximin in this setting.展开更多
Purpose: The aim was to study discontinuation of statin treatment, especially with respect to clinical characteristics and adverse effect measured by clinical laboratory tests indicating muscle damage (plasma creatine...Purpose: The aim was to study discontinuation of statin treatment, especially with respect to clinical characteristics and adverse effect measured by clinical laboratory tests indicating muscle damage (plasma creatine kinase, CK) and liver AEs (plasma alanine aminotransferase, ALAT). Methods: The initial study population included 60,488 individuals who had purchased first time statin prescription in Helsinki-Uusimaa region between 01-01-2007 and 31-12-2009. The follow-up started when first statin prescription was purchased and ended 31-12-2009 or death, which ever occurred first. From this population 54,172 individuals were defined to eligible to study population of this study. Clinical laboratory measurements were obtained from Helsinki-Uusimaa University Hospital (HUSLAB) that which provides the laboratory tests for the Helsinki-Uusimaa region serving about a population of 1.5 million. Results: In this fairly large real-life study the occurrence of ALAT-AE and mild CK-elevations after initiation of first statin treatments were relatively low. Increasing age and the presence of co-morbidities increased the risk of these AEs. Further, the ALAT-AEs implied increased risk of discontinuation of treatment. Diabetic patients discontinued treatment more often than non-diabetics, whereas the presence of other chronic conditions implied higher persistence of statin treatment. Conclusions: It is essential that those who would benefit from statin therapy actually are treated and by far in most patients treatment seems to be safe and well tolerated. For those who cannot tolerate statins new therapeutic options are needed.展开更多
A 54-year-old man diagnosed with metastatic melanoma of the right inguinal node with occult primary developed liver and bone metastases. The combination of dabrafenib plus trametinib was initiated, and a complete resp...A 54-year-old man diagnosed with metastatic melanoma of the right inguinal node with occult primary developed liver and bone metastases. The combination of dabrafenib plus trametinib was initiated, and a complete response (CR) was achieved 24 months after starting treatment. One month later, the target therapy was discontinued at the patient’s decision, and he has remained free from progression for 21 months since discontinuation. To the extent of our knowledge, real-world data in Asian melanoma concerning the discontinuation of dabrafenib plus trametinib after achieving CR have not been published;therefore, our case is a meaningful one for considering to cease target drugs and to rescue their financial toxicity.展开更多
Background: Discontinuation remains a legitimate threat to the long-term success of antiretroviral therapy (ART) scale-up in Zimbabwe. Furthermore, the characteristics associated with ART discontinuation and trends ar...Background: Discontinuation remains a legitimate threat to the long-term success of antiretroviral therapy (ART) scale-up in Zimbabwe. Furthermore, the characteristics associated with ART discontinuation and trends are poorly understood in developing countries like Zimbabwe. We analysed the HIV/AIDS data to describe the characteristics associated with ART discontinuation and the trends from 2015 to 2019. Methods: We conducted an analytical cross- sectional study using secondary data from Electronic Patient Management System (ePMS) in Kadoma City. We interviewed eighteen health care workers to find the reasons for ART discontinuation. Data were analysed using Microsoft Office Excel 2016 and Epi info 7 version 7.2.2.6. Microsoft office excel was used to generate linear graphs to demonstrate the trends in ART discontinuation in Kadoma City in 2015-2019. Epi info 7 was used to generate frequencies, means, prevalence odds ratios p-values, and 95% confidence intervals (CI) and significance testing. Backward stepwise logistic regression analysis was done to determine the independent factors associated with discontinuation. Results: A total number of 2833 patients were enrolled on ART from 2015 to 2019. One hundred and seventy-three 173/2833 (6.1%) discontinued ART, 415/2833 (14.7%) transferred out, 69/2833 (2.4%) died and 2176/2833 (76.8%) were retained on ART. Out of those who discontinued ART, sixty-five percent (112/173) were females. Approximately two-thirds had immunological failure 110/173 (64%). The trend in ART discontinuation decreased over the years but was not statistically significant (R<sup>2</sup> = 0.57, p > 0.05). ART discontinuation was independently associated with being Conclusion: We concluded that the characteristics associated with ART discontinuation were having never attended school, being less than forty years of age and having immunological failure. The reasons why patients discontinue ART were health state not improving, participating in artisanal mining activities, change in marital status, medical side effects of ART, living far from health facilities, and relocating to neighbouring countries. We recommended continuous provision of health education, enhanced adherence counselling sessions to those with unsuppressed viral loads and investigating the cause of virologic failure.展开更多
Objective To evaluate the dynamic changes of glucocorticoid(GC)dose and the feasibility of GC discontinuation in rheumatoid arthritis(RA)patients under the background of Chinese medicine(CM).Methods This multicenter r...Objective To evaluate the dynamic changes of glucocorticoid(GC)dose and the feasibility of GC discontinuation in rheumatoid arthritis(RA)patients under the background of Chinese medicine(CM).Methods This multicenter retrospective cohort study included 1,196 RA patients enrolled in the China Rheumatoid Arthritis Registry of Patients with Chinese Medicine(CERTAIN)from September 1,2019 to December 4,2023,who initiated GC therapy.Participants were divided into the Western medicine(WM)and integrative medicine(IM,combination of CM and WM)groups based on medication regimen.Follow-up was performed at least every 3 months to assess dynamic changes in GC dose.Changes in GC dose were analyzed by generalized estimator equation,the probability of GC discontinuation was assessed using Kaplan-Meier curve,and predictors of GC discontinuation were analyzed by Cox regression.Patients with<12 months of follow-up were excluded for the sensitivity analysis.Results Among 1,196 patients(85.4%female;median age 56.4 years),880(73.6%)received IM.Over a median 12-month follow-up,34.3%(410 cases)discontinued GC,with significantly higher rates in the IM group(40.8%vs.16.1%in WM;P<0.05).GC dose declined progressively,with IM patients demonstrating faster reductions(median 3.75 mg vs.5.00 mg in WM at 12 months;P<0.05).Multivariate Cox analysis identified age<60 years[P<0.001,hazard ratios(HR)=2.142,95%confidence interval(CI):1.523–3.012],IM therapy(P=0.001,HR=2.175,95%CI:1.369–3.456),baseline GC dose⩽7.5 mg(P=0.003,HR=1.637,95%CI:1.177–2.275),and absence of non-steroidal anti-inflammatory drugs use(P=0.001,HR=2.546,95%CI:1.432–4.527)as significant predictors of GC discontinuation.Sensitivity analysis(545 cases)confirmed these findings.Conclusions RA patients receiving CM face difficulties in following guideline-recommended GC discontinuation protocols.IM can promote GC discontinuation and is a promising strategy to reduce GC dependency in RA management.(Trial registration:ClinicalTrials.gov,No.NCT05219214)展开更多
In this paper,we propose a systematic approach for accelerating finite element-type methods by machine learning for the numerical solution of partial differential equations(PDEs).The main idea is to use a neural netwo...In this paper,we propose a systematic approach for accelerating finite element-type methods by machine learning for the numerical solution of partial differential equations(PDEs).The main idea is to use a neural network to learn the solution map of the PDEs and to do so in an element-wise fashion.This map takes input of the element geometry and the PDE’s parameters on that element,and gives output of two operators:(1)the in2out operator for inter-element communication,and(2)the in2sol operator(Green’s function)for element-wise solution recovery.A significant advantage of this approach is that,once trained,this network can be used for the numerical solution of the PDE for any domain geometry and any parameter distribution without retraining.Also,the training is significantly simpler since it is done on the element level instead on the entire domain.We call this approach element learning.This method is closely related to hybridizable discontinuous Galerkin(HDG)methods in the sense that the local solvers of HDG are replaced by machine learning approaches.Numerical tests are presented for an example PDE,the radiative transfer or radiation transport equation,in a variety of scenarios with idealized or realistic cloud fields,with smooth or sharp gradient in the cloud boundary transition.Under a fixed accuracy level of 10^(−3) in the relative L^(2) error,and polynomial degree p=6 in each element,we observe an approximately 5 to 10 times speed-up by element learning compared to a classical finite element-type method.展开更多
This paper investigates the following mixed local and nonlocal elliptic problem fea-turing concave-convex nonlinearities and a discontinuous right-hand side:{L(u)=H(u−μ)|u|^(p−2)u+λ|u|^(q−2)u,x∈Ω,u≥0,x∈Ω,u=0,x...This paper investigates the following mixed local and nonlocal elliptic problem fea-turing concave-convex nonlinearities and a discontinuous right-hand side:{L(u)=H(u−μ)|u|^(p−2)u+λ|u|^(q−2)u,x∈Ω,u≥0,x∈Ω,u=0,x∈R^(N)\Ω,where Ω ⊂R^(N)(N>2)is a bounded domain,μ≥0 and λ>0 are real parameters,H denotes the Heaviside function(H(t)=0 for t<0,H(t)=1 for t>0),and the mixed local and nolocal operator is defined as L(u)=−Δu+(−Δ)^(s)u with(−Δ)^(s) being the restricted fractional Laplace(0<s<1).The exponents satisfy 1<q<2<p.By employing a novel non-smooth variational principle,we establish the existence of an M-solution for this problem and identify a range for the exponent p.展开更多
Discontinuities in rock masses critically impact the stability and safety of underground engineering.Mainstream discontinuities identificationmethods,which rely on normal vector estimation and clustering algorithms,su...Discontinuities in rock masses critically impact the stability and safety of underground engineering.Mainstream discontinuities identificationmethods,which rely on normal vector estimation and clustering algorithms,suffer from accuracy degradation,omission of critical discontinuities when orientation density is unevenly distributed,and need manual intervention.To overcome these limitations,this paper introduces a novel discontinuities identificationmethod based on geometric feature analysis of rock mass.By analyzing spatial distribution variability of point cloud and integrating an adaptive region growing algorithm,the method accurately detects independent discontinuities under complex geological conditions.Given that rock mass orientations typically follow a Fisher distribution,an adaptive hierarchical clustering algorithm based on statistical analysis is employed to automatically determine the optimal number of structural sets,eliminating the need for preset clusters or thresholds inherent in traditional methods.The proposed approach effectively handles diverse rock mass shapes and sizes,leveraging both local and global geometric features to minimize noise interference.Experimental validation on three real-world rock mass models,alongside comparisons with three conventional directional clustering algorithms,demonstrates superior accuracy and robustness in identifying optimal discontinuity sets.The proposed method offers a reliable and efficienttool for discontinuities detection and grouping in underground engineering,significantlyenhancing design and construction outcomes.展开更多
The identification of rock mass hazard sources is fundamental for preventing rockfall and landslide disasters in mountainous regions,with rock mass structural characteristics playing a vital role in hazard assessment....The identification of rock mass hazard sources is fundamental for preventing rockfall and landslide disasters in mountainous regions,with rock mass structural characteristics playing a vital role in hazard assessment.In this study,terrestrial laser scanning(TLS)and unmanned aerial vehicle(UAV)technologies were integrated to enhance the evaluation methodology for rock mass hazard sources,focusing on the Sichuan Yanjiang Expressway project in China.The findings demonstrate that TLS-UAV technology enhanced both spatial coverage and data density in slope modeling.Through integrated algorithmic analysis,rock discontinuities within heterogeneous datasets were systematically identified,enabling quantitative extraction and statistical analysis of key geometric parameters,including orientation,trace length,spacing,and roughness.Furthermore,quantitative models were developed for cohesion,friction angle and the morphology parameter M of in situ discontinuities,respectively,facilitating efficient mechanical parameter acquisition.A novel rock mass hazard index(RHI)was developed incorporating discontinuity geometric rating(DGR),discontinuity mechanical rating(DMR),and slope mass rating(SMR).Field validation confirmed the methodology's effectiveness in evaluating risk levels and spatial heterogeneity of rock mass hazard sources,revealing the contribution of different discontinuity sets to the rock mass hazard and identifying the primary discontinuity sets controlling instability mechanisms.This study is of great significance for evaluating discontinuity-controlled rock mass hazard sources and preventing rockfall disasters.展开更多
Automatic identificationof discontinuities is a key focus in rock slope research.Conventional methods typically target small areas,which limits efficiencyand applicability for complex discontinuities in large-scale ro...Automatic identificationof discontinuities is a key focus in rock slope research.Conventional methods typically target small areas,which limits efficiencyand applicability for complex discontinuities in large-scale rock slopes.This study uses multi-angle unmanned aerial vehicle(UAV)nap-of-the-object photogrammetry to construct a high-definitionthree-dimensional(3D)point cloud model of the slope.The edge-firstconnection algorithm identifiesall edge points of discontinuities in the point cloud and completes recognition through simple connection analysis.This method avoids the complex calculations required for sequentially identifying discontinuity edges in conventional methods and achieves significantacceleration through algorithm optimization and parallel computation support.Based on this algorithm,the RockDiscontinuity Identification(RD ID)software is developed and applied to identify numerous highly disordered discontinuities on the Xulong slope in the Jinsha River suture zone.Processing tens of millions of point clouds within approximately 2 h demonstrates exceptional computational efficiency.The automatic algorithm accurately identifiesnearly 80%of planar discontinuities,with orientations and trace lengths closely matching manual results,highlighting its potential for large-scale rock outcrop applications.Comparisons with region growing algorithms further emphasize its effectiveness and accuracy.However,the algorithm struggles to identify linear discontinuities,which are a major source of error.Additionally,high roughness and smooth edges of discontinuities affect recognition accuracy,indicating areas for further improvement.展开更多
Background:Severe functional impairment is often considered a contraindication to intravesical therapy for nonmuscle-invasive bladder cancer(NMIBC).A tailored intravesical bacillus Calmette-Guérin(BCG)procedure w...Background:Severe functional impairment is often considered a contraindication to intravesical therapy for nonmuscle-invasive bladder cancer(NMIBC).A tailored intravesical bacillus Calmette-Guérin(BCG)procedure was evaluated in high-risk(HR)-NMIBC patients with severe functional impairment.Materials and methods:Patients with a Katz Index score of 2 or less and an initial diagnosis of HR-NMIBC with atraumatic insertion of a Foley-type indwelling catheter,bladder emptying,and BCG instillation were prospectively treated;after 2 hours,the bladder was emptied and the catheter was removed(group A).After propensity score matching,52 patients in group A were compared with that of 52 consecutive patients in group B using a retrospective database,with similar baseline/oncological characteristics and treated with standard intermittent catheterization.Moreover,groups A and B were compared with that of 130 consecutive patients(group C)retrospectively evaluated,with similar oncological characteristics but with a Katz Index score of 3 or greater and treated with standard intermittent catheterization.Results:The discontinuation rates were 11.5%,35%,and 9%in groups A,B,and C,respectively(A vs.B,log-rank score 42.52[po<0.05];B vs.C,107.6[p<0.05];A vs.C,3.45[p>0.05]).The overall adverse event rates were 38.5%,57.7%,and 39.2%,respectively(A vs.B,p=0.04;B vs.C,0.03;A vs.C,0.92).The rates of severe adverse events were 1.9%,1.9%,and 1.5%,respectively,without statistically significant differences.The cumulative HR disease-free survival rates were 63.4%,48%,and 69.2%,respectively(A vs.B,log-rank score 154.9[p<0.05];B vs.C,415[p<0.05];A vs.C,244[p<0.05]).Conclusions:A tailored intravesical instillation procedure may reduce BCG discontinuation and adverse effects.展开更多
文摘Therapy discontinuation in inflammatory bowel disease,particularly involving immunomodulators,biologics,and small molecules,remains a controversial and evolving topic.This letter reflects on developments following the publication by Meštrovićet al,emphasizing the complex balance between risks of relapse,antidrug antibody formation,and potential complications of long-term immunosuppression.Recent evidence underscores high relapse rates following withdrawal-especially of anti-tumor necrosis factor agents-and highlights the lack of robust data for newer biologics.Updated guidelines from European Crohn’s and Colitis Organization,British Society of Gastroenterology,and American College of Gastroenterology all support cautious and individualized approaches,with strict criteria and close follow-up,particularly in Crohn’s disease.For ulcerative colitis,therapeutic cycling remains insufficiently addressed.We proposed a flowchart to support clinical decision-making and stress the importance of shared decisionmaking in the era of personalized medicine since,despite new drug classes and evolving strategies,the therapeutic ceiling in inflammatory bowel disease has yet to be fully overcome.
基金supported by the National Natural Science Foundation of China(82371089).
文摘Objective:To evaluate the performance of orthokeratology(ortho-k)lens reordering using software-designed system,so as to determine the feasibility of ortho-k lens reordering without discontinuing lens wear.Methods:This study is a retrospective analysis of data of ortho-k lens wearers who had a history of short-term discontinuation of lens wear.A total of 94 individuals aged over 8 years with spherical equivalent refraction ranging from-0.50 to-6.50 diopters were included.The corneal topography data at baseline(before ortho-k)and after lens wear discontinuation(cessation of ortho-k treatment)were imported separately into the lens-design software,along with corresponding refraction data.Subsequently,corneal and lens parameters were generated and compared.Intraclass correlation coefficients(ICC)were calculated,and Bland and Altman analyses were conducted.Results:All 94 children were involved in the retrospective analysis.Compared with baseline data,there was a high level of consistency between Rwo(without discontinuation)and Rwith(with discontinuation),with an ICC of 0.96(P<0.001).Furthermore,the comparison of lens parameters generated by the Easyfit software between baseline and after short-term discontinuation showed a high degree of consistency,with all of the ICC values exceeding 0.90.Similar results were obtained using the WAVE software,as both ICC values and Bland-Altman plots demonstrated a high level of consistency in lens parameters between two conditions(nearly all data points fell within the 95%LoAs).Conclusions:It is feasible to directly reorder new ortho-k lenses using software fitting approaches.However,further investigations are necessary to validate their practicability in a clinical setting.
文摘The discontinuation of denosumab[antibody targeting receptor activator of nuclear factor kappa B ligand(RANKL)]therapy may increase the risk of multiple vertebral fractures;however,the underlying pathophysiology is largely unknown.In patients who underwent discontinuation after multiple injections of denosumab,the levels of tartrate-resistant acid phosphatase 5b increased compared to pretreatment levels,indicating a phenomenon known as“overshoot.”The rate of decrease in bone mineral density during the withdrawal period was higher than the rate of decrease associated with aging,suggesting that the physiological bone metabolism had broken down.Overshoot and significant bone loss were also observed in mice receiving continuous administration of anti-RANKL antibody after treatment was interrupted,resembling the original pathology.In mice long out of overshoot,bone resorption recovered,but osteoblast numbers and bone formation remained markedly reduced.The bone marrow exhibited a significant reduction in stem cell(SC)antigen 1-and platelet-derived growth factor receptor alpha-expressing osteoblast progenitors(PαS cells)and alkaline phosphatase-positive early osteoblasts.Just before the overshoot phase,the osteoclast precursor cell population expands and RANKL-bearing extracellular vesicles(EVs)became abundant in the serum,leading to robust osteoclastogenesis after cessation of anti-RANKL treatment.Thus,accelerated bone resorption due to the accumulation of RANKLbearing EVs and long-term suppression of bone formation uncoupled from bone resorption leads to the severe bone loss characteristic of denosumab discontinuation.
文摘AIM To characterize the prescribing patterns for hydrocortisone for patients with septic shock and perform an exploratory analysis in order to identify the variables associated with better outcomes.METHODS This prospective cohort study included 59 patients with septic shock who received stress-dose hydrocortisone.It was performed at 2 critical care units in academic hospitals from June 1st,2015,to July 31 st,2016.Demographic data,comorbidities,medical management details,adverse effects related to corticosteroids,and outcomes were collected after the critical care physician indicated initiation of hydrocortisone.Univariate comparison between continuous and bolus administration of hydrocortisone was performed,including multivariate analysis,as well as Kaplan-Meier analysis to compare the proportion of shock reversal at 7 d after presentation.Receiver operating characteristic(ROC)curves determined the best cut-off criteria for initiation of hydrocortisone associated with the highest probability of shock reversal.We addressed the effects of the taper strategy for discontinuation of hydrocortisone,noting risk of shock relapse and adverse effects.RESULTS All-cause 30-d mortality was 42%.Hydrocortisone was administered as a continuous infusion in 54.2%of patients;time to reversal of shock was 49 h longer in patients who were given a bolus administration[59 h(range,47.5-90.5)vs 108 h(range,63.2-189);P=0.001].The maximal dose of norepinephrine after initiation of hydrocortisone was lower in patients on continuous infusion[0.19μg/kg per minute(range,0.11-0.28μg)]compared with patients who were given bolus[0.34μg/kg per minute(range,0.16-0.49);P=0.004].Kaplan-Meier analysis revealed a higher proportion of shock reversal at 7 d in patients with continuous infusion compared to those given bolus(83%vs 63%;P=0.004).There was a good correlation between time to initiation of hydrocortisone and time to reversal of shock(r=0.80;P<0.0001);ROC curve analysis revealed that the best criteria for prediction of shock reversal was a time to initiation of hydrocortisone of≤13 h after administration of norepinephrine,with an area under the curve of 0.81(P<0.001).The maximal dose of norepinephrine at initiation of hydrocortisone with the highest association with shock reversal was≤0.28μg/kg per minute,with an area under the curve of 0.75(P=0.0002).On a logistic regression model,hydrocortisone taper was not associated with a lower risk of shock relapse(RR=1.29;P=0.17)but was related to a higher probability of hyperglycemia[odds ratio(OR),5.3;P=0.04]and hypokalemia(OR=10.6;P=0.01).CONCLUSION Continuous infusion of hydrocortisone could hasten the resolution of septic shock compared to bolus administration.Earlier initiation corresponds with a higher probability of shock reversal.Tapering strategy is unnecessary.
文摘Aim: To investigate the reasons for discontinuations of sildenafil after the successful restoration of erectile function. Methods: One hundred fifty six patients, whose scores of erectile function domain of the 15-item International Index of Erectile Function (IIEF) increased to 26 or more after sildenafil medication, were included in this study. Six-months after the first sildenafil prescription, compliance to medication and the reason for discontinuity were reviewed by chart or surveyed by telephone. Results: Fifty-four (34.6%) of the 156 successfully treated patients discontinued sildenafil medication. The r easons for discontinuance were shortcomings in the partners' or patients' emotional readiness for the restoration of sexual life after long-term abstinence (37.0%), fear of possible side effects (18.5 %), recovery of spontaneous erection (14.8 %), postponement of ED treatment because of co morbid disease treatment (11.1%), unwillingness to accept drug-dependent erection (7.4%), high drug cost (3.7%), unacceptability of planned sexual activity (3.7%) and lack of sexual interesi (3.7%). Conclusion: The reasons for discontinuing sildenafil medication were primarily emotional or relationship-oriented, which indicates that simple recovery of a rigid erection is insufficient to restore sexual activity. More education about the effects of drug and the counseling of both partners is recommended to promote the successful recovery of sexual activity.
文摘The timely introduction and adjustment of the appropriate drug in accordance with previously well-defined treatment goals is the foundation of the approach in the treatment of inflammatory bowel disease(IBD).The therapeutic approach is still evolving in terms of the mechanism of action but also in terms of the possibility of maintaining remission.In patients with achieved long-term remission,the question of de-escalation or discontinuation of therapy arises,considering the possible side effects and economic burden of long-term therapy.For each of the drugs used in IBD(5-aminosalycaltes,immunomodulators,biological drugs,small molecules)there is a risk of relapse.Furthermore,studies show that more than 50%of patients who discontinue therapy will relapse.Based on the findings of large studies and meta-analysis,relapse of disease can be expected in about half of the patients after therapy withdrawal,in case of monotherapy with aminosalicylates,immunomodulators or biological therapy.However,longer relapse-free periods are recorded with withdrawal of medication in patients who had previously been on combination therapies immunomodulators and anti-tumor necrosis factor.It needs to be stressed that randomised clinical trials regarding withdrawal from medications are still lacking.Before making a decision on discontinuation of therapy,it is important to distinguish potential candidates and predictive factors for the possibility of disease relapse.Fecal calprotectin level has currently been identified as the strongest predictive factor for relapse.Several other predictive factors have also been identified,such as:High Crohn's disease activity index or Harvey Bradshaw index,younger age(<40 years),longer disease duration(>40 years),smoking,young age of disease onset,steroid use 6-12 months before cessation.An important factor in the decision to withdraw medication is the success of re-treatment with the same or other drugs.The decision to discontinue therapy must be based on individual approach,taking into account the severity,extension,and duration of the disease,the possibility of side adverse effects,the risk of relapse,and patient’s preferences.
文摘Discontinuation of antipsychotic therapy has been a significant clinical issue among patients with schizophrenia, since the patients who discontinued antipsychotic treatment showed worse clinical and functional outcomes, and higher risks of relapse of schizophrenia symptoms and hospitalization. We conducted a post-hoc analysis of a post-marketing research with a 12-month follow-up period to identify the predictors for discontinuation of antipsychotic monotherapy in Japan. This is a prospective, naturalistic multicenter observational study, designed to evaluate the discontinuation rates of olanzapine monotherapy and non-olanzapine antipsychotic monotherapy in Japanese adult patients with acute schizophrenia. Patients were treatment-naive, or had switched from other antipsychotics or from poly-pharmacotherapy to oral antipsychotic monotherapy. We analyzed the correlation of discontinuation of antipsychotic monotherapy with baseline characteristics of patients. A total of 1089 patients (578 patients treated with olanzapine and 511 with non-olanzapine antipsychotics) were eligible for analysis. By the end of the 12-month study period, 614 patients (56.4%) discontinued antipsychotic therapy. Multivariate logistic regression analyses indicated significantly lower discontinuation rates in all patients treated with antipsychotics: older age (Odds ratio [OR], 0.871;95% confidence interval [CI], 0.797 to 0.953;p = 0.003), outpatient status (OR, 0.508;95% CI, 0.383 to 0.675;p < 0.001), prior use of antipsychotics (OR, 0.693;95% CI, 0.516 to 0.930;p = 0.015), and olanzapine group showed lower discontinuation rate than that of non-olanzapine group (OR, 1.416;95% CI, 1.086 to 1.846;p = 0.010). The present study indicated that the outpatient status, older age, and prior use of antipsychotics have better adherence to antipsychotic treatment. In addition to these factors, use of anti-parkinson agents showed lower discontinuation rates in the olanzapine monotherapy group.
文摘Clinical trials have demonstrated that some patients with chronic myeloid leukemia(CML)treated for several years with tyrosine kinase inhibitors(TKIs)who have maintained a molecular response can successfully discontinue treatment without relapsing.Treatment free remission(TFR)can be reached by approximately 50%of patients who discontinue.Despite having similar levels of deep molecular response and an identical duration of treatment,the factors that influence the successful discontinuation of CML patients remain to be determined.In this review we will explore the factors identified to date that can help predict whether a patient will successfully achieve TFR.We will also discuss the need for the identification of predictive biomarkers associated with a high probability of achieving TFR for the future personalized identification of patients who are suitable for the discontinuation of TKI treatment.
文摘Once a patient has initiated an antiepileptic drug (AED) and achieved a sustained period of seizure freedom, the decision to discontinue AED should be balanced against continuation of AED therapy indefinitely. Studies show that the rate of seizure recurrence after AED withdrawal is about two to three times the rate in patients who continue AEDs. However, there are many benefits to AED withdrawal that should be evaluated on an individualized basis. AED discontinuation may be considered in patients whose seizures have been completely controlled for a prolonged period. There are several factors that would increase risk of recurrences which will be reviewed and discussed. As a consequence, the decision to withdraw or withhold treatment must be still individualized. In any patient, the decision to discontinue treatment should also take into effect the social aspects like driving license, job and leisure activities as well as emotional and personal factors and patients with adverse effects or drug interactions. Patients will ultimately have to decide themselves whether they wish to discontinue drug treatment.
文摘Hepatic encephalopathy(HE)is one of the main complications of cirrhosis,characterized by a wide spectrum of neuropsychiatric alterations that lead to an increase in mortality,morbidity and recurrent hospitalizations.Due to the central role in HE pathogenesis of ammonia and other neurotoxins primarily produced by the gut microbiota,the main therapeutic approaches for the treatment of HE are based on the modulation of the gut microbiota.Rifaximin is a non-absorbable broad-spectrum antibiotic,that is effective against ammonia-producing grampositive,gram-negative,and anaerobic species,approved for the treatment of HE in secondary prophylaxis.The chronic administration of rifaximin in this setting is associated with a lower risk of HE recurrence and mortality,while the role of rifaximin for the treatment of an overt-HE episode in inpatients is still unclear.Limited data exist about the coadministration of rifaximin and broad-spectrum antibiotics commonly used to treat concomitant infections,as patients receiving or recently treated with antibiotics were frequently excluded from clinical trials.In this editorial we comment on the article by Ward et al published in the recent issue of the World Journal of Hepatology.It is a single center,retrospective,quasiexperimental,pharmacist-driven protocol,with the aim to evaluate the feasibility and safety of rifaximin discontinuation in critically ill patients with HE and chronic liver disease receiving broad-spectrum antibiotic therapies in intensive care units.The study revealed no differences between the protocol and control group in terms of primary outcome(days alive and free of delirium and coma to day 14)and secondary outcomes which include:Intensive care mortality,intensive care length of stay,intravenous vasopressor requirement changes and adverse effects rate.Therefore,rifaximin discontinuation during broad-spectrum antibiotic therapy does not appear to negatively impact the clinical status of critically ill liver patients,with a similar safety profile and significant cost savings,as compared to the coadministration of rifaximin and broad-spectrum antibiotics.In agreement with Ward et al,a recently published double-blind,randomized controlled trial provided additional evidence to support the feasibility of withholding rifaximin during broad-spectrum antibiotic therapy in critically ill cirrhotic patients.However,given the limitations of these studies,further multicentric and prospective clinical trials,enrolling a larger sample of non-critically ill patients,are needed to better establish the role of rifaximin in this setting.
文摘Purpose: The aim was to study discontinuation of statin treatment, especially with respect to clinical characteristics and adverse effect measured by clinical laboratory tests indicating muscle damage (plasma creatine kinase, CK) and liver AEs (plasma alanine aminotransferase, ALAT). Methods: The initial study population included 60,488 individuals who had purchased first time statin prescription in Helsinki-Uusimaa region between 01-01-2007 and 31-12-2009. The follow-up started when first statin prescription was purchased and ended 31-12-2009 or death, which ever occurred first. From this population 54,172 individuals were defined to eligible to study population of this study. Clinical laboratory measurements were obtained from Helsinki-Uusimaa University Hospital (HUSLAB) that which provides the laboratory tests for the Helsinki-Uusimaa region serving about a population of 1.5 million. Results: In this fairly large real-life study the occurrence of ALAT-AE and mild CK-elevations after initiation of first statin treatments were relatively low. Increasing age and the presence of co-morbidities increased the risk of these AEs. Further, the ALAT-AEs implied increased risk of discontinuation of treatment. Diabetic patients discontinued treatment more often than non-diabetics, whereas the presence of other chronic conditions implied higher persistence of statin treatment. Conclusions: It is essential that those who would benefit from statin therapy actually are treated and by far in most patients treatment seems to be safe and well tolerated. For those who cannot tolerate statins new therapeutic options are needed.
文摘A 54-year-old man diagnosed with metastatic melanoma of the right inguinal node with occult primary developed liver and bone metastases. The combination of dabrafenib plus trametinib was initiated, and a complete response (CR) was achieved 24 months after starting treatment. One month later, the target therapy was discontinued at the patient’s decision, and he has remained free from progression for 21 months since discontinuation. To the extent of our knowledge, real-world data in Asian melanoma concerning the discontinuation of dabrafenib plus trametinib after achieving CR have not been published;therefore, our case is a meaningful one for considering to cease target drugs and to rescue their financial toxicity.
文摘Background: Discontinuation remains a legitimate threat to the long-term success of antiretroviral therapy (ART) scale-up in Zimbabwe. Furthermore, the characteristics associated with ART discontinuation and trends are poorly understood in developing countries like Zimbabwe. We analysed the HIV/AIDS data to describe the characteristics associated with ART discontinuation and the trends from 2015 to 2019. Methods: We conducted an analytical cross- sectional study using secondary data from Electronic Patient Management System (ePMS) in Kadoma City. We interviewed eighteen health care workers to find the reasons for ART discontinuation. Data were analysed using Microsoft Office Excel 2016 and Epi info 7 version 7.2.2.6. Microsoft office excel was used to generate linear graphs to demonstrate the trends in ART discontinuation in Kadoma City in 2015-2019. Epi info 7 was used to generate frequencies, means, prevalence odds ratios p-values, and 95% confidence intervals (CI) and significance testing. Backward stepwise logistic regression analysis was done to determine the independent factors associated with discontinuation. Results: A total number of 2833 patients were enrolled on ART from 2015 to 2019. One hundred and seventy-three 173/2833 (6.1%) discontinued ART, 415/2833 (14.7%) transferred out, 69/2833 (2.4%) died and 2176/2833 (76.8%) were retained on ART. Out of those who discontinued ART, sixty-five percent (112/173) were females. Approximately two-thirds had immunological failure 110/173 (64%). The trend in ART discontinuation decreased over the years but was not statistically significant (R<sup>2</sup> = 0.57, p > 0.05). ART discontinuation was independently associated with being Conclusion: We concluded that the characteristics associated with ART discontinuation were having never attended school, being less than forty years of age and having immunological failure. The reasons why patients discontinue ART were health state not improving, participating in artisanal mining activities, change in marital status, medical side effects of ART, living far from health facilities, and relocating to neighbouring countries. We recommended continuous provision of health education, enhanced adherence counselling sessions to those with unsuppressed viral loads and investigating the cause of virologic failure.
基金Supported by the National Natural Science Foundation of China Key Program(No.82230121)the High Level Chinese Medical Hospital Promotion Project(No.HLCMHPP2023087)。
文摘Objective To evaluate the dynamic changes of glucocorticoid(GC)dose and the feasibility of GC discontinuation in rheumatoid arthritis(RA)patients under the background of Chinese medicine(CM).Methods This multicenter retrospective cohort study included 1,196 RA patients enrolled in the China Rheumatoid Arthritis Registry of Patients with Chinese Medicine(CERTAIN)from September 1,2019 to December 4,2023,who initiated GC therapy.Participants were divided into the Western medicine(WM)and integrative medicine(IM,combination of CM and WM)groups based on medication regimen.Follow-up was performed at least every 3 months to assess dynamic changes in GC dose.Changes in GC dose were analyzed by generalized estimator equation,the probability of GC discontinuation was assessed using Kaplan-Meier curve,and predictors of GC discontinuation were analyzed by Cox regression.Patients with<12 months of follow-up were excluded for the sensitivity analysis.Results Among 1,196 patients(85.4%female;median age 56.4 years),880(73.6%)received IM.Over a median 12-month follow-up,34.3%(410 cases)discontinued GC,with significantly higher rates in the IM group(40.8%vs.16.1%in WM;P<0.05).GC dose declined progressively,with IM patients demonstrating faster reductions(median 3.75 mg vs.5.00 mg in WM at 12 months;P<0.05).Multivariate Cox analysis identified age<60 years[P<0.001,hazard ratios(HR)=2.142,95%confidence interval(CI):1.523–3.012],IM therapy(P=0.001,HR=2.175,95%CI:1.369–3.456),baseline GC dose⩽7.5 mg(P=0.003,HR=1.637,95%CI:1.177–2.275),and absence of non-steroidal anti-inflammatory drugs use(P=0.001,HR=2.546,95%CI:1.432–4.527)as significant predictors of GC discontinuation.Sensitivity analysis(545 cases)confirmed these findings.Conclusions RA patients receiving CM face difficulties in following guideline-recommended GC discontinuation protocols.IM can promote GC discontinuation and is a promising strategy to reduce GC dependency in RA management.(Trial registration:ClinicalTrials.gov,No.NCT05219214)
基金partially supported by the NSF(Grant No.DMS 2324368)by the Office of the Vice Chancellor for Research and Graduate Education at the University of Wisconsin-Madison with funding from the Wisconsin Alumni Research Foundation.
文摘In this paper,we propose a systematic approach for accelerating finite element-type methods by machine learning for the numerical solution of partial differential equations(PDEs).The main idea is to use a neural network to learn the solution map of the PDEs and to do so in an element-wise fashion.This map takes input of the element geometry and the PDE’s parameters on that element,and gives output of two operators:(1)the in2out operator for inter-element communication,and(2)the in2sol operator(Green’s function)for element-wise solution recovery.A significant advantage of this approach is that,once trained,this network can be used for the numerical solution of the PDE for any domain geometry and any parameter distribution without retraining.Also,the training is significantly simpler since it is done on the element level instead on the entire domain.We call this approach element learning.This method is closely related to hybridizable discontinuous Galerkin(HDG)methods in the sense that the local solvers of HDG are replaced by machine learning approaches.Numerical tests are presented for an example PDE,the radiative transfer or radiation transport equation,in a variety of scenarios with idealized or realistic cloud fields,with smooth or sharp gradient in the cloud boundary transition.Under a fixed accuracy level of 10^(−3) in the relative L^(2) error,and polynomial degree p=6 in each element,we observe an approximately 5 to 10 times speed-up by element learning compared to a classical finite element-type method.
基金Supported by the National Natural Science Foundation of China(Grant No.12361026)the Discipline Construction Fund Project of Northwest Minzu University.
文摘This paper investigates the following mixed local and nonlocal elliptic problem fea-turing concave-convex nonlinearities and a discontinuous right-hand side:{L(u)=H(u−μ)|u|^(p−2)u+λ|u|^(q−2)u,x∈Ω,u≥0,x∈Ω,u=0,x∈R^(N)\Ω,where Ω ⊂R^(N)(N>2)is a bounded domain,μ≥0 and λ>0 are real parameters,H denotes the Heaviside function(H(t)=0 for t<0,H(t)=1 for t>0),and the mixed local and nolocal operator is defined as L(u)=−Δu+(−Δ)^(s)u with(−Δ)^(s) being the restricted fractional Laplace(0<s<1).The exponents satisfy 1<q<2<p.By employing a novel non-smooth variational principle,we establish the existence of an M-solution for this problem and identify a range for the exponent p.
基金the National Key Research and Development Program of China(Grant No.2023YFC3009400).
文摘Discontinuities in rock masses critically impact the stability and safety of underground engineering.Mainstream discontinuities identificationmethods,which rely on normal vector estimation and clustering algorithms,suffer from accuracy degradation,omission of critical discontinuities when orientation density is unevenly distributed,and need manual intervention.To overcome these limitations,this paper introduces a novel discontinuities identificationmethod based on geometric feature analysis of rock mass.By analyzing spatial distribution variability of point cloud and integrating an adaptive region growing algorithm,the method accurately detects independent discontinuities under complex geological conditions.Given that rock mass orientations typically follow a Fisher distribution,an adaptive hierarchical clustering algorithm based on statistical analysis is employed to automatically determine the optimal number of structural sets,eliminating the need for preset clusters or thresholds inherent in traditional methods.The proposed approach effectively handles diverse rock mass shapes and sizes,leveraging both local and global geometric features to minimize noise interference.Experimental validation on three real-world rock mass models,alongside comparisons with three conventional directional clustering algorithms,demonstrates superior accuracy and robustness in identifying optimal discontinuity sets.The proposed method offers a reliable and efficienttool for discontinuities detection and grouping in underground engineering,significantlyenhancing design and construction outcomes.
基金support from the National Natural Science Foundation of China(Grant Nos.42177142 and 52378477)the Key Research and Development Program of Shaanxi(Grant No.2023-YBSF-486).
文摘The identification of rock mass hazard sources is fundamental for preventing rockfall and landslide disasters in mountainous regions,with rock mass structural characteristics playing a vital role in hazard assessment.In this study,terrestrial laser scanning(TLS)and unmanned aerial vehicle(UAV)technologies were integrated to enhance the evaluation methodology for rock mass hazard sources,focusing on the Sichuan Yanjiang Expressway project in China.The findings demonstrate that TLS-UAV technology enhanced both spatial coverage and data density in slope modeling.Through integrated algorithmic analysis,rock discontinuities within heterogeneous datasets were systematically identified,enabling quantitative extraction and statistical analysis of key geometric parameters,including orientation,trace length,spacing,and roughness.Furthermore,quantitative models were developed for cohesion,friction angle and the morphology parameter M of in situ discontinuities,respectively,facilitating efficient mechanical parameter acquisition.A novel rock mass hazard index(RHI)was developed incorporating discontinuity geometric rating(DGR),discontinuity mechanical rating(DMR),and slope mass rating(SMR).Field validation confirmed the methodology's effectiveness in evaluating risk levels and spatial heterogeneity of rock mass hazard sources,revealing the contribution of different discontinuity sets to the rock mass hazard and identifying the primary discontinuity sets controlling instability mechanisms.This study is of great significance for evaluating discontinuity-controlled rock mass hazard sources and preventing rockfall disasters.
基金supported by the National Key R&D Program of China(Grant No.2022YFC3080200)the China Postdoctoral Science Foundation(Grant No.2023M731264)the Science and Technology Development Plan Project of Jilin Province,China(Grant No.20250602007RC).
文摘Automatic identificationof discontinuities is a key focus in rock slope research.Conventional methods typically target small areas,which limits efficiencyand applicability for complex discontinuities in large-scale rock slopes.This study uses multi-angle unmanned aerial vehicle(UAV)nap-of-the-object photogrammetry to construct a high-definitionthree-dimensional(3D)point cloud model of the slope.The edge-firstconnection algorithm identifiesall edge points of discontinuities in the point cloud and completes recognition through simple connection analysis.This method avoids the complex calculations required for sequentially identifying discontinuity edges in conventional methods and achieves significantacceleration through algorithm optimization and parallel computation support.Based on this algorithm,the RockDiscontinuity Identification(RD ID)software is developed and applied to identify numerous highly disordered discontinuities on the Xulong slope in the Jinsha River suture zone.Processing tens of millions of point clouds within approximately 2 h demonstrates exceptional computational efficiency.The automatic algorithm accurately identifiesnearly 80%of planar discontinuities,with orientations and trace lengths closely matching manual results,highlighting its potential for large-scale rock outcrop applications.Comparisons with region growing algorithms further emphasize its effectiveness and accuracy.However,the algorithm struggles to identify linear discontinuities,which are a major source of error.Additionally,high roughness and smooth edges of discontinuities affect recognition accuracy,indicating areas for further improvement.
文摘Background:Severe functional impairment is often considered a contraindication to intravesical therapy for nonmuscle-invasive bladder cancer(NMIBC).A tailored intravesical bacillus Calmette-Guérin(BCG)procedure was evaluated in high-risk(HR)-NMIBC patients with severe functional impairment.Materials and methods:Patients with a Katz Index score of 2 or less and an initial diagnosis of HR-NMIBC with atraumatic insertion of a Foley-type indwelling catheter,bladder emptying,and BCG instillation were prospectively treated;after 2 hours,the bladder was emptied and the catheter was removed(group A).After propensity score matching,52 patients in group A were compared with that of 52 consecutive patients in group B using a retrospective database,with similar baseline/oncological characteristics and treated with standard intermittent catheterization.Moreover,groups A and B were compared with that of 130 consecutive patients(group C)retrospectively evaluated,with similar oncological characteristics but with a Katz Index score of 3 or greater and treated with standard intermittent catheterization.Results:The discontinuation rates were 11.5%,35%,and 9%in groups A,B,and C,respectively(A vs.B,log-rank score 42.52[po<0.05];B vs.C,107.6[p<0.05];A vs.C,3.45[p>0.05]).The overall adverse event rates were 38.5%,57.7%,and 39.2%,respectively(A vs.B,p=0.04;B vs.C,0.03;A vs.C,0.92).The rates of severe adverse events were 1.9%,1.9%,and 1.5%,respectively,without statistically significant differences.The cumulative HR disease-free survival rates were 63.4%,48%,and 69.2%,respectively(A vs.B,log-rank score 154.9[p<0.05];B vs.C,415[p<0.05];A vs.C,244[p<0.05]).Conclusions:A tailored intravesical instillation procedure may reduce BCG discontinuation and adverse effects.
