Different Durations Of Treatment Research Articles

Effect of Different Durations of Treatment With Antihypertensive Drugs With Anticholinergic Effects on the Risk of Dementia: A Target Trial Emulation Study.

Studying the effect of duration of treatment on prognostic outcomes using real-world data is challenging because only people who survive for a long time can receive a treatment for a long time. Specifying a target trial helps overcome such challenge. We aimed to estimate the effect of different durations of treatment with antihypertensive drugs with anticholinergic properties (AC AHT) on the risk of vascular dementia and Alzheimer's disease by emulating a target trial using the UK CPRD GOLD database (2001-2017). Comparing treatment for 3-6 years versus ≤3 years yielded null results for both types of dementia. Comparing a longer duration of treatment, >6 years versus ≤3 years, yielded a 10-year risk ratio of 0.69 (95% CI, 0.54-0.90) for vascular dementia and 0.91 (95% CI, 0.77-1.10) for Alzheimer's disease. For illustration, we performed an analysis that failed to emulate a target trial by assigning exposure categories using post-baseline information, obtaining implausible beneficial estimates. Our findings indicate a modest benefit of longer duration of treatment with AC AHT on vascular dementia and highlight the value of the target trial emulation to avoid selection bias in the evaluation of the effect of different durations of treatment.

Effects of tumor necrosis factor-alpha inhibitors on lipid profiles in patients with psoriasis: a systematic review and meta-analysis.

There is no consensus on the effect of tumor necrosis factor-alpha (TNF-alpha) inhibitors on lipid profiles in patients with psoriasis. This study aimed to investigate the effects of TNF-alpha inhibitors on lipid profiles (triglycerides, total cholesterol, low-density lipoprotein, or high-density lipoprotein) in patients with psoriasis. We searched PubMed, Embase, and Cochrane Library databases for articles published before October 17, 2023. Four TNF-alpha inhibitors (infliximab, etanercept, adalimumab, and certolizumab) were included in our study. (PROSPERO ID: CRD42023469703). A total of twenty trials were included. Overall results revealed that TNF-alpha inhibitors elevated high-density lipoprotein levels in patients with psoriasis (WMD = 2.31; 95% CI: 0.96, 3.67; P = 0.001), which was supported by the results of sensitivity analyses excluding the effect of lipid-lowering drugs. Subgroup analyses indicated that high-density lipoprotein levels were significantly increased in the less than or equal to 3 months group (WMD = 2.88; 95% CI: 1.37, 4.4; P < 0.001), the etanercept group (WMD = 3.4; 95% CI = 1.71, 5.09, P < 0.001), and the psoriasis group (WMD = 2.52; 95% CI = 0.57, 4.48, P = 0.011). Triglyceride levels were significantly increased in the 3 to 6-month group (WMD = 4.98; 95% CI = 1.97, 7.99, P = 0.001) and significantly decreased in the 6-month and older group (WMD = -19.84; 95% CI = -23.97, -15.7, P < 0.001). Additionally, Triglyceride levels were significantly increased in the psoriasis group (WMD = 5.22; 95% CI = 2.23, 8.21, P = 0.001). Our results revealed that TNF-alpha inhibitors might temporarily increase high-density lipoprotein levels in patients with psoriasis. However, changes in triglycerides were not consistent among the different durations of treatment, with significant increases after 3 to 6 months of treatment. Future prospective trials with long-term follow-up contribute to confirming and extending our findings. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023469703.

Establishment and Evaluation of a Mice Model of High-Altitude Cerebral Edema

To establish an animal model of high-altitude cerebral edema (HACE), to explore the altitude and oxygen partial pressure conditions that can lead to obvious clinical manifestations of HACE, and to lay the foundation for further research of the pathogenic mechanisms and intervention strategies of HACE. Male BALB/c mice of 8 weeks old were randomly assigned to Control and HACE groups. The Control group (n=10) was treated with normobaric and normoxic conditions, while the HACE groups were placed in hypobaric hypoxic (HH) chambers for the durations of 6 h, 12 h, 24 h, 48 h and 72 h, respectively, receiving treatments of simulated HH conditions at the altitudes of 4000 m (n=10 for each group receiving different durations of HH treatment), 5000 m (n=10 for each group receiving different durations of HH treatment), and 6000 m (n=10 for each group receiving different durations of HH treatment). HE staining was performed to observe the morphological changes of the brain tissue and the appropriate simulated altitude conditions were selected accordingly for the construction and evaluation of the best HACE model. The HACE model was evaluated in the following ways, the mouse brain was weighed and the cerebral edema was measured accordingly, Evans blue (EB) was injected to determine the permeability of the blood-brain barrier (BBB), and the cell apoptosis was determined by immunofluorescence staining. There were no deaths in the groups treated with the HH conditions of the altitudes of 4000 m and 5000 m, while the mortality in the 6000 m altitude treatment groups was 12.2%. HE staining showed no significant changes in brain morphology or structure in the group receiving HH treatment for the altitude of 4000 m. A small amount of brain cell edema was observed in the groups receiving 48 h and 72 h of HH treatment for the altitude of 5000 m. The groups receiving HH treatment for the altitude of 6000 m demonstrated the most prominent modeling effect. HE staining showed increased volume and swelling of brain cells in all the 6000 m groups, especially in the 24 h, 48 h and 72 h treatment groups. In all the 6000 m groups, cell arrangement disorder, gap enlargement, and nuclear contraction were observed. Evaluation of the modeling effect demonstrated that, in the HACE mice model constructed with the HH conditions for the altitude of 6000 m, cerebral edema and EB permeability increased after 12 h HH treatment and there was no obvious apoptosis in the modeling groups receiving different durations of treatment. The HACE model can be established effectively by simulating conditions at the altitude of 6000 m (the atmospheric pressure being 47.19 kPa and the oxygen partial pressure being 9.73 kPa) with a HH chamber.

The Effects of Polyphenols on Bone Metabolism in Postmenopausal Women: Systematic Review and Meta-Analysis of Randomized Control Trials.

Osteoporosis is a condition favored by the postmenopausal decline in estrogen levels and worsened by oxidative stress (OS). Polyphenols are natural compounds abundantly found in fruits and vegetables, and they exert antioxidant and hormonal effects that could be useful in osteoporosis prevention, as suggested by epidemiological studies showing a lower incidence of fractures in individuals consuming polyphenol-rich diets. The aim of our meta-analysis is to evaluate the effects of polyphenols on bone mineral density (BMD, primary endpoint) and bone turnover markers (BTMs, secondary endpoint) in postmenopausal women. Twenty-one randomized control trials (RCTs) were included in our analysis after in-depth search on PubMed, EMBASE, and Scopus databases. We found that supplementation with polyphenols for 3-36 months exerted no statically significant effects on BMD measured at lumbar spine (sMD: 0.21, 95% CI [-0.08 to 0.51], p = 0.16), femoral neck (sMD: 0.16, 95% CI [-0.23 to 0.55], p = 0.42), total hip (sMD: 0.05, 95% CI [-0.14 to 0.24], p = 0.61), and whole body (sMD: -0.12, 95% CI [-0.42 to 0.17], p = 0.41). Subgroup analysis based on treatment duration showed no statistical significance, but a significant effect on lumbar BMD emerged when studies with duration of 24 months or greater were analyzed separately. On the other hand, we found a significantly slight increase in bone-specific alkaline phosphatase (BALP) levels (sMD: 1.27, 95% CI [1.13 to 1.42], p < 0.0001) and a decrease in pyridinoline (PD) levels (sMD: -0.58, 95% CI [-0.77 to -0.39], p < 0.0001). High heterogeneity among studies and unclear risk of bias in one third of the included studies emerged. A subgroup analysis showed similar effects for different duration of treatment and models of dual-energy X-ray absorptiometry (DXA) scanner. More robust evidence is needed before recommending the prescription of polyphenols in clinical practice.

Systematic review and estimated cost-efficacy of biologics compared with narrowband ultraviolet B light for the treatment of moderate to severe psoriasis and atopic dermatitis.

Psoriasis and atopic dermatitis are chronic inflammatory skin conditions, each affecting about 2-3% of the United States adult population. Phototherapy, such as narrowband ultraviolet-B (NB-UVB) therapy have been employed for the treatment of both psoriasis and atopic dermatitis for decades. More recently, systemic biologics have been approved by the Food andDrug Administration (FDA), representing a great advancement in dermatology. No comprehensive study to date has compared the cost efficacy of phototherapy compared to FDA-approved biologics for the treatment of psoriasis and atopic dermatitis. We pursued a systematic review of the literature for studies assessing efficacy of NB-UVB or biologics with endpoints including the Psoriasis Area and Severity Index (PASI) and the Eczema Area and Severity Index (EASI). Thirty-four studies including 55 treatment regimens and 5,123 patients were included in the analysis. Phototherapy costs were estimated with Medicare fee schedules for phototherapy-related current procedural terminology code (CPT), and biologic costs were estimated with wholesale acquisition cost (WAC). Total costs to achieve PASI 75 or EASI 75 in each study were standardized to a single month, the "adjusted cost," and exploited to a year, the "effective yearly cost," allowing direct cost-efficacy comparison despite different durations of treatment described in studies. The psoriasis analysis found NB-UVB to be the most cost-effective therapy, with an adjusted monthly cost of $1714.00 per PASI 75. Infliximab was the least expensive biologic, with an adjusted monthly cost of $2076.00 to $2502.00 per PASI 75. For atopic dermatitis, no NB-UVB studies utilized EASI 75 as their outcome measure, hindering the ability to directly compare cost effectiveness for the treatment of atopic dermatitis. However, all NB-UVB studies depicted a reduced treatment cost per treatment period compared to studies assessing biologics, although this comparison does not account for efficacy. The results depict NB-UVB to be the most cost effective for the treatment of psoriasis and the least expensive per treatment period for the treatment of atopic dermatitis. However, certain factors need to be taken into account. Biologics may be more effective for more severe disease, do not require multiple weekly clinic visits, and the ease for patient compliance may lead some to favor biologic therapy. This study is necessary to allow physicians, patients, and health systems to make informed decisions regarding cost-efficacy for a variety of treatment options.

The Efficacy, Dose and Interval Of Sublingual Methylcobalamin Spray in Children: A Single-Center Experience

Introduction: Vitamin B12 deficiency is essential to treat because of hematologic and neurologic results. Sublingual methylcobalamin spray leads to easy, safe, and cost-effective treatment. However, studies reveal the different duration of treatment; age-specific dose is not precise. Here, we aimed to investigate the efficacy, dose adjustment, and durability of vitamin-B12 spray. Methods: This retrospective study includes seventeen children (3 months-17 years) diagnosed with nutritional Vitamin-B12 deficiency between January 2020- January 2021. The methylcobalamin doses were 500 mcg (&lt;1 year of age) and 1000 mcg (≥1 year of age) every day for the first week and every other day for seven weeks. In addition, serum Vitamin B12 and hemoglobin levels were studied at diagnosis and second, sixth, and twelfth months of treatment. Finally, we compared the beginning hemoglobin and Vitamin-B12 levels with the second month's values. Results: After two months of sublingual methylcobalamin treatment, the Vitamin B12 significantly increased (p=0.008) and kept normal ranges for twelve months. Hemoglobin levels tended to rise in two months, but the difference was not statistically significant (p=0.22). Conclusion: There is no consensus on the sublingual methylcobalamin dose and treatment schedule. However, we suggest that a 500 mcg dose of methylcobalamin for &lt;1 year of age and a 1000 mcg dose for ≥ 1 year with two months treatment period is appropriate and safe for nutritional Vitamin B12 deficiency.

Efficacy and safety of caspofungin for patients with hepatic insufficiency

BackgroundTo observe the changes of hepatic function and efficacy of conventional dosage of caspofungin in the treatment of patients with different Child–Pugh scores.MethodsIn total, 200 patients (Child–Pugh A group: 66 patients, Child–Pugh B group: 83 patients, Child–Pugh C group: 51 patients) treated with caspofungin from May 2018 to March 2021 in the Second Affiliated Hospital of Chongqing Medical University were enrolled. Main investigation items were as follows: sex, age, weight, duration of treatment, dosage, department, underlying diseases, risk factors for fungal infection, albumin, liver enzyme, total bilirubin, serum creatinine, estimated glomerular filtration rate. To investigate the changes of liver, kidney function tests and efficacy during the treatments of caspofungin. Patients were divided into three groups according to the duration of treatment of caspofungin:1-week group, 2-week group and 3-week group, respectively.ResultsIn the three groups, albumin, liver enzyme levels, total bilirubin and serum creatinine, estimated glomerular filtration rate had no significant difference (P > 0.05). The efficacy of different Child–Pugh scores and different duration of treatment was also significantly different (P > 0.05).ConclusionsCaspofungin is well tolerated and highly effective. And it will not exacerbate the hepatic and renal function when administered with the not-reducing dose, which indicate the clinical application value of caspofungin. Besides, extending the treatment duration has little effect on improving the efficacy of caspofungin. The drug should be withdrawn timely according to the patients’ clinical condition in order to reduce the adverse reactions and economic burden.

Corticosteroids for the treatment of Kawasaki disease in children.

Kawasaki disease (KD), or mucocutaneous syndrome, is the leading cause of childhood-acquired heart disease in high-income countries. There is much controversy on how best to treat children with KD and in particular who may benefit from additional treatment beyond the standard intravenous immunoglobulin (IVIG) and aspirin, such as the addition of corticosteroids. This is an update of the review first published in 2017. To assess the impact of corticosteroid use on the incidence of coronary artery abnormalities in KD as either first-line or second-line treatment. The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL and two trials registers to 8 February 2021. We searched the reference lists of relevant articles for additional studies. We selected randomised controlled trials involving children with all severities of KD who were treated with corticosteroids, including different types of corticosteroids, different durations of treatment, and where corticosteroids were used alone or in conjunction with other accepted KD treatments. We included trials using corticosteroids for both first- and second-line treatment. Two review authors independently selected studies, assessed study quality and extracted data using standard Cochrane methods. We performed fixed-effect model meta-analyses with odds ratios (ORs) or mean difference (MD) with 95% confidence intervals (CIs). We used a random-effects model when there was heterogeneity. We assessed the certainty of the evidence using GRADE. The outcomes of interest were incidence of coronary artery abnormalities, serious adverse events, mortality, duration of acute symptoms (such as fever), time for laboratory parameters to normalise, length of hospital stay and longer-term coronary morbidity. This update identified one new study, therefore the analysis included eight trials consisting of 1877 participants. Seven trials investigated the use of corticosteroids in first-line treatment and one investigated second-line treatment. The trials were all of good methodological quality. On pooled analysis, corticosteroid treatment reduced the subsequent occurrence of coronary artery abnormalities (OR 0.32, 95% CI 0.14 to 0.75; 8 studies, 986 participants; moderate-certainty evidence), without resultant serious adverse events (0 events; 6 studies, 737 participants; moderate-certainty) and mortality (0 events; 8 studies, 1075 participants; moderate-certainty evidence). In addition, corticosteroids reduced the duration of fever (MD -1.34 days, 95% CI -2.24 to -0.45; 3 studies, 290 participants; low-certainty evidence), time for laboratory parameters (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)) to normalise (MD -2.80 days, 95% CI -4.38 to -1.22; 1 study, 178 participants; moderate-certainty evidence), and length of hospital stay (MD -1.01 days, 95% CI -1.72 to -0.30; 2 studies, 119 participants; moderate-certainty evidence). None of the included studies reported long-term (greater than one year after disease onset) coronary morbidity. Moderate-certainty evidence shows that use of steroids in the acute phase of KD can be associated with reduced coronary artery abnormalities, reduced inflammatory markers and shorter duration of hospital stay when compared to no corticosteroids. There were no serious adverse events or deaths reported with or without corticosteroid use. Low-certainty evidence shows use of corticosteroids can reduce duration of clinical symptoms (fever and rash). None of the included studies reported on long-term (greater than one year after disease onset) coronary morbidity. Evidence presented in this systematic review agrees with current clinical guidelines on the use of corticosteroids in the first-line treatment in KD.

Evaluation of the efficacy of gold nanoparticles on Giardia lamblia infection in experimental animals

Giardia lamblia (G. lamblia) is an important cause of severe malabsorption, weight loss, physical and mental retardation especially in infants and children throughout the world. Metronidazole (MTZ) is the standard drug used for their treatment which possesses several drawbacks with low efficacy. Gold nanoparticles possess a broad-spectrum antimicrobial activity and could be considered as a future alternative to many microbial agents. This study aimed to evaluate the anti-Giardia effect of gold nanoparticles as an alternative to MTZ. This study was done on 70 experimentally albino rats that were divided into three main groups with seven subgroups (each of 10 rats). The effect of MTZ and gold nanoparticles as single or combined therapy were evaluated. The effect was assessed by counting Giardia fecal cysts in the stool and trophozoites in the intestinal wash, histopathological, transmission and scanning electron microscopic examinations of the small intestinal tissues. Toxic tests of biochemical parameters of liver and kidney function were also performed. A significant reduction of the parasite number in the stool and small intestinal sections was apparent in treated infected rats compared with the infected non-treated ones. Gold nanoparticles showed the best result and the highest effect in the eradication of the parasite from the stool and the intestine with marked improvement in the intestinal mucosal injury caused by G. lamblia trophozoites. Gold nanoparticles had a toxic effect on the liver, with no kidney toxicity. Nanogold can be considered as a potential therapeutic agent and as a promising alternative therapy for G. lamblia infection. Further studies using various dosages with different durations of treatment with gold nanoparticles can be tested on Giardia lamblia infection.

Comparison of Improvement in 2-Year Survival Rate of Patients with Stage II-III Non-Small Cell Lung Cancer Treated with Different Durations of Chinese Patent Medicine: A Retrospective Cohort Study.

Background: Chinese patent medicine is widely used among patients with malignant tumors, and current studies have shown that long-term treatment with Chinese patent medicine is related to improved outcomes of patients. Huisheng Oral Liquid is a kind of Chinese patent medicine with the effects of curing dispersion-thirst and dissipating blood stasis. However, little is known about how it affects the survival rate of patients. Thus, patients with stage II-III NSCLC (non-small-cell lung cancer) were chosen to participate in a retrospective cohort study, which was conducted to preliminarily investigate the effects of using Chinese patent medicine and Huisheng Oral Liquid for different treatment durations on patients’ 2-year survival rate and explore the prognostic factors affecting the 2-year survival rate of those patients.Purpose: This work compares the effect of different durations of treatment with Chinese patent medicine and Huisheng Oral Liquid on the 2-year survival rate of patients with stage II-III NSCLC and explores the prognostic factors of the patients' 2-year survival rate.Methods: This retrospective cohort study included patients with non-small cell lung cancer stage II-III according to the 2015 NCCN Guidelines: Non-Small Cell Lung Cancer. The Kaplan–Meier method was used to compare the 2-year survival rate of patients treated with different durations of Chinese medicine and Huisheng Oral Liquid. The relationship between different treatment durations and degree of improvement of 2-year survival rate was explored using the Cochran–Armitage trend test. The Cox proportional-hazards regression models were used to explore factors affecting the 2-year survival rate of patients.Results: A total of 614 patients with stage II-III NSCLC diagnosed from January 2015 to December 2018 were included in this study. Patients treated with Chinese patent medicine were divided into three groups by treatment durations: < 3 months, ≥ 3 months, and ≥6 months, and those treated with Huisheng Oral Liquid were divided into < 3 months and ≥3 and ≥6 months. The results showed that ① the 2-year survival rate of patients treated with Chinese patent medicine for ≥3 months and ≥6 months was higher than that of patients treated for <3 months and the difference was statistically significant (p < 0.05). Further analysis of Huisheng Oral Liquid treatment revealed that ② the 2-year survival rate of patients treated with Huisheng Oral Liquid for ≥3 months was higher than that of patients treated for <3 months (p < 0.05). Because the total number of patients treated with Huisheng Oral Liquid for ≥6 months and the number of patients with improved outcomes were too small, there was no statistically significant difference in the 2-year survival rate between the two groups (p > 0.05). The results of the Cochran–Armitage trend test showed that the 2-year survival rate tended to increase with the duration of Huisheng Oral Liquid treatment (p < 0.05). ③ The Cox proportional -hazards regression model revealed that among all 614 patients, surgery [HR = 0.48, 95% CI = (0.34, 0.68)], chemotherapy [HR = 0.46, 95% CI = (0.31,0.67)], and treatment with Huisheng Oral Liquid for ≥3 months were protective factors [HR = 0.48, 95%CI = (0.27,0.88)], whereas male gender [HR = 1.59, 95% CI = (1.01, 2.50)] and FIB ≥4 g/L [HR = 1.95, 95% CI = (1.37, 2.77)] were risk factors.Conclusion: Chinese patent medicine treatment for ≥3 months showed an improvement in the 2-year survival rate of patients with stage II-III NSCLC. Patients treated with Huisheng Oral liquid for ≥3 months also showed an improvement in the 2-year survival rate, and the 2-year survival rate tended to increase as the treatment duration increased. Finally, male and FIB ≥ 4 g/L were risk factors for prognosis.

Cytotoxic Evaluation of Mala aluation of Malaysian K ysian Kelulut Hone elulut Honey on Human y on Human Gingival Fibr al Fibroblast Cell Line using M oblast Cell Line using MTT Assay

Kelulut honey or stingless bee honey is a type of honey produced by stingless bees of the Trigona species where the nest is found in living trees. Objective: The aim of this study was to evaluate the cytotoxic potential of Malaysian Kelulut honey by employing MTT assay on a human gingival fibroblast cell line. Methods: Human gingival fibroblast cell line was cultured in minimal essential medium alpha (α-MEM) with 10% foetal bovine serum and 1% penicillin-streptomycin solution in a 5% CO2 incubator at 37°C in a humidified atmosphere. The cells were seeded at a cell density of 5x103 cells/well in a 96-well culture plate for 24 hours. The cells were treated with seven different concentrations (200, 100, 50, 25, 12.5, 6.25, and 3.125mg/ml) of Malaysian Kelulut honey and incubated in a CO2 incubator. The negative control comprised cells treated with growth media alone. The cell viability was assessed using MTT assay at 24, 48, and 72 hours. The test plate was shaken using a microplate shaker and the absorbance of the solution was measured at 570nm using an ELISA reader with the Magellan software. Statistical analysis of the data was carried out using Kruskal-Wallis test and SPSS 24.0.0 for Windows. A p value &lt;0.05 was considered as statistically significant. Results: There was no cytotoxic effect of Malaysian Kelulut honey on HGF-1 based on the MTT assay at different concentrations and at different time points tested as the cell viability was above 70%. The highest percentage of cell viability at all three different durations of treatment were observed at 3.125mg/ml, whereas the lowest cell viability was observed at 200mg/ml of Kelulut honey concentration. However, statistically significant differences were seen between some of the concentrations at various time points. Conclusion: Since the cell viability of HGF-1 treated with Malaysian Kelulut honey was more than 70% at all concentrations ranging from 3.125mg/ml to 200mg/ml at three different time points (24, 48 and 72 hours), Malaysian Kelulut honey can be considered as non-cytotoxic on human gingival fibroblasts based on MTT assay under the present test conditions

Influence of ball milling duration on the morphology, features of the structural-phase state and microhardness of 3Ni-Al powder mixture

The features of changes in the morphology, structural-phase state and microhardness of 3Ni-Al powder mixture after different duration of high-energy ball-milling have been studied. Three main stages of the evolution of the structural-phase state were revealed, which, corresponding to different duration of treatment, differ in the morphology of the powder mixture, distribution of components, phase compositions and the nature of changes in microhardness. It was found that under high-energy ball-milling conditions, the synthesis of intermetallic Ni3Al and NiAl phases begins at much lower temperatures compared to the phase diagram. It is shown that an increase in the duration of high-energy ball-milling is accompanied by a transformation of the phase composition, the features of which determine the level of strengthening of the powder mixture studied.

Rivaroxaban for the Treatment of Symptomatic Isolated Distal Deep Vein Thrombosis – RIDTS Study

Background: The optimal management of patients with isolated distal deep vein thrombosis (IDDVT) is uncertain. Observational studies report similar therapeutic strategies as for patients with proximal DVT or pulmonary embolism (PE), but shorter treatment duration. We compared two different durations of treatment with rivaroxaban in patients with symptomatic IDDVT. Methods: In a randomized, double-blind, placebo-controlled trial, patients with symptomatic IDDVT received 6 weeks of rivaroxaban at standard doses and were assigned to rivaroxaban 20 mg once daily or placebo for additional 6 weeks. Randomization was done using a computer-generated randomization list and was stratified by study center. Primary efficacy outcome was a composite of recurrent IDDVT, proximal DVT, symptomatic or fatal PE. Primary safety outcome was ISTH-defined major bleeding. We here report the results of the 6-month follow-up. Findings: Of the 402 randomized patients, 200 received rivaroxaban and 202 placebo. IDDVT was unprovoked in 41.0% and 42.6% of patients, respectively. The primary efficacy outcome occurred in 5 patients (2.5%) on rivaroxaban and 21 (10.4%) treated with placebo (p=0.001). Recurrent IDDVT occurred in 3 (1.5%) and 16 (7.9%)(p=0.002); proximal DVT or PE in 2 (1.0%) and 5 (2.5%) (p=0.45), respectively. There were 3 (0.7%) major bleeding events prior to randomization, none after randomization. Interpretation: Rivaroxaban administered for 3 months effectively and safely reduces recurrent venous thrombosis as compared to 6 weeks of treatment during a 6-month follow up. The incidence of proximal DVT and PE was low and similar between the two groups. Clinical Trial Registration Details: EudraCT Number: 2016-000958-36. Clinical Trial Gov identifier: NCT02722447. Funding Information: Unrestricted grant from Bayer Italy. Declaration of Interests: None to declare. Ethics Approval Statement: The study was approved by the local institutional review boards or ethics committees of all participating centers and was performed in accordance with the declaration of Helsinki (52nd WMA General Assembly, Edinburgh, Scotland, October 2000) as well as with the International Conference on Harmonisation (ICH) guidelines on Good Clinical Practise (GCP).

Treatment Outcomes of Clopidogrel in Patients With ACS and Diabetes Undergoing PCI-Analysis of Beijing Municipal Medical Insurance Database.

Background and AimsSeveral clinical trials have proved the efficacy of clopidogrel treatment for patients with percutaneous coronary intervention. There are few large-scale studies to identify the mortality associated with different durations of treatment of clopidogrel in patients with diabetes and ACS undergoing PCI in the Chinese population. The objective of this analysis was to determine the efficacy of long-term clopidogrel therapy (≥12 months) versus short-term use (<12 months) in Chinese patients with diabetes after PCI.Methods and ResultsWe used the Beijing Municipal Medical Insurance Database provided by the Beijing Municipal Medical Insurance Bureau. The Beijing Municipal Medical Insurance Database contained medical data of about 16 million people, including about 990,000 patients with diabetes and a history of taking antidiabetic medicines. Patients were divided into two groups, one group of 9,116 patients receiving consecutive clopidogrel for one year or more, and another group of 3290 patients receiving consecutive clopidogrel for less than one year. The primary outcomes of this analysis were the risk of all-cause death, myocardial infarction, and revascularization. In patients with diabetes after PCI, long-term clopidogrel treatment was associated with a reduced risk of all-cause death (HR, 0.57[95%CI, 0.49-0.67], P<0.0001), myocardial infarction (HR, 0.79[95%CI, 0.68-0.93], P=0.0035) and an increased risk of angina (HR, 1.18[95%CI, 1.10-1.27], P<0.0001]) and revascularization (HR, 1.07[95%CI, 1.01-1.13], P=0.02]). There was no significant difference in the prevalence of all-cause re-hospitalization, diabetes-related re-hospitalization, and cerebrovascular re-hospitalization.ConclusionThe present study concluded that long-term dual antiplatelet therapy including clopidogrel and aspirin could decrease the risks of all-cause death, myocardial infarction. But it could increase the risks of angina and revascularization. Further studies should interpret the cause of this question.

Hydroxychloroquine Does Not Increase the Risk of Cardiac Arrhythmia in Common Rheumatic Diseases: A Nationwide Population-Based Cohort Study.

ObjectivesHydroxychloroquine (HCQ) is widely used to treat rheumatic diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and Sjögren’s syndrome (SS). Cardiac arrhythmia has been concerned as important safety issue for HCQ. The aim of this study was to investigate whether hydroxychloroquine increases new-onset arrhythmia among patients with RA, SLE or SS.MethodsThis was a retrospective cohort study that conducted from the longitudinal health insurance database of Taiwan. Patients with newly diagnosed RA, SLE or SS with age ≥20 years old were selected from 2000 to 2012. Patients who received HCQ and without HCQ treatment groups were matched by propensity score to minimize the effect of selection bias and confounders. The Cox proportional hazard model was used to analyze the risk of arrhythmia between the two groups after controlling for related variables.ResultsA total of 15892 patients were selected to participate and finally 3575 patients were enrolled in each group after matching. There was no different risk of all arrhythmia in patients using HCQ than without HCQ (adjusted hazards ratio 0.81, 95% CI 0.61–1.07) and ventricular arrhythmia as well. The incidence of arrhythmia did not increase when HCQ co-administrated with macrolides. The arrhythmia risk was also not different regardless of daily HCQ dose <400mg or ≥400mg or follow-up duration of ≦4 months or >4 months.ConclusionThe administration of HCQ did not increase the risk of all cardiac arrhythmia and ventricular arrhythmia regardless of different duration of treatment (≦4 months or >4 months) or cumulative dose (<400mg or ≥400mg) in patients with common autoimmune diseases such as RA, SLE and SS.

Analysis of the Health and Budgetary Impact of Chondroitin Sulfate Prescription in the Treatment of Knee Osteoarthritis Compared to NSAIDs and COXIBs.

BackgroundChondroitin sulfate, alone or associated with glucosamine (CS), is an effective treatment of osteoarthritis, better tolerated than non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase 2 inhibitors (COXIBs) at gastrointestinal, cardiovascular and renal levels.ObjectiveTo estimate the health impact (toxicity by NSAIDs/COXIBs avoided with CS with or without glucosamine) and economic impact (savings due to avoided toxicities) of treatment of knee osteoarthritis with CS compared to NSAIDs/COXIBs, as a consequence of the avoidance of mild-moderate or severe gastrointestinal adverse effects (GIAE), ischaemic heart disease (IHD), acute kidney insufficiency (AKI) and chronic kidney failure (CKF).MethodsWe compared the current situation (available reimbursed prescription with CS) with a hypothetical situation without CS (treatment only with NSAIDs/COXIBs). The frequency of GIAE, IHD, AKI and CKF with CS and NSAIDs/COXIBs was obtained from published ad hoc studies. The cost of AE management and of the drugs (180 days of treatment) was obtained from Spanish sources. A probabilistic economic model was made for a 3-year period, both at national (NHS) and regional levels. Sensitivity analyses were performed for different durations of treatment (90 and 240 days).ResultsIn Spain, it is estimated that 519,130, 513,616 and 507,377 patients with knee osteoarthritis will be treated with NSAIDs/COXIBs and 112,775, 114,963 and 117,262 with CS in 2020, 2021 and 2022, respectively. Due to better CS tolerability, 55,098 mild-moderate GIAE, 3060 severe GIAE, 204 IHD, 1089 AKI and 733 CKF would be avoided in 3 years. Discounting the cost of the drugs, the three-year savings for the NHS would be 21.8 (12.7–29.5) million euros.ConclusionDue to its better tolerability profile, CS treatment is expected to prevent thousands of AEs over the next 3 years, some of which may be life-threatening for patients, while generating considerable savings for the NHS.

Uncaria tomentosa improves cognition, memory and learning in middle-aged rats.

Aging accelerates neurodegeneration, while natural and safe neuroprotective agents, such as Uncaria tomentosa, may help to overcome this problem. This study assessed the effects of U. tomentosa extract treatment on the aging process in the brain of Wistar rats. The spatial memory and learning, acetylcholinesterase (AChE) activity, and DNA damage were assessed. Animals of 14months were tested with different doses of U. tomentosa (5mg/kg, 15mg/kg, and 30mg/kg) and with different durations of treatment (one month and one year). In the Morris Water Maze (MWM), the escape latency was significantly (p<0.0001) shorter in rats that received 5mg/kg, 15mg/kg, and 30mg/kg of U. tomentosa for both one month and one year of treatment. There was a significant difference in time spent at the platform zone (p<0.05) of the middle-aged rats treated with U. tomentosa extract for one year when compared to the control rats. The cortex and hippocampus of rats treated with U. tomentosa for one year showed significant (p>0.05) reduction in AChE activity. DNA damage index on cortex was significantly lower (p<0.05) in animals treated with 30mg/kg of U. tomentosa for one month while all the tested doses demonstrated significant (p<0.001) reductions in DNA damage index in animals treated for one year. In conclusion, U. tomentosa may represent a source of phytochemicals that could enhance memory activity, repair DNA damage, and alter AChE activity, thereby providing neuroprotection during the aging process.

Cannabinoids in Chronic Non-Cancer Pain: A Systematic Review and Meta-Analysis

Background:For patients with chronic, non-cancer pain, traditional pain-relieving medications include opioids, which have shown benefits but are associated with increased risks of addiction and adverse effects. Medical cannabis has emerged as a treatment alternative for managing these patients and there has been a rise in the number of randomized clinical trials in recent years; therefore, a systematic review of the evidence was warranted.Objective:To analyze the evidence surrounding the benefits and harms of medical cannabinoids in the treatment of chronic, non-cancer-related pain.Design:Systematic review with meta-analysis.Data sources:Medline, Embase, CINAHL, SCOPUS, Google Scholar, and Cochrane Databases.Eligibility criteria:English language randomized clinical trials of cannabinoids for the treatment of chronic, non-cancer-related pain.Data extraction and synthesis:Study quality was assessed using the Cochrane risk of bias tool. All stages were conducted independently by a team of 6 reviewers. Data were pooled through meta-analysis with different durations of treatment (2 weeks, 2 months, 6 months) and stratified by route of administration (smoked, oromucosal, oral), conditions, and type of cannabinoids.Main outcomes and measures:Patient-reported pain and adverse events (AEs).Results:Thirty-six trials (4006 participants) were included, examining smoked cannabis (4 trials), oromucosal cannabis sprays (14 trials), and oral cannabinoids (18 trials). Compared with placebo, cannabinoids showed a significant reduction in pain which was greatest with treatment duration of 2 to 8 weeks (weighted mean difference on a 0-10 pain visual analogue scale −0.68, 95% confidence interval [CI], −0.96 to −0.40, I2 = 8%, P < .00001; n = 16 trials). When stratified by route of administration, pain condition, and type of cannabinoids, oral cannabinoids had a larger reduction in pain compared with placebo relative to oromucosal and smoked formulations but the difference was not significant (P[interaction] > .05 in all the 3 durations of treatment); cannabinoids had a smaller reduction in pain due to multiple sclerosis compared with placebo relative to other neuropathic pain (P[interaction] = .05) within 2 weeks and the difference was not significant relative to pain due to rheumatic arthritis; nabilone had a greater reduction in pain compared with placebo relative to other types of cannabinoids longer than 2 weeks of treatment but the difference was not significant (P[interaction] > .05). Serious AEs were rare, and similar across the cannabinoid (74 out of 2176, 3.4%) and placebo groups (53 out of 1640, 3.2%). There was an increased risk of non-serious AEs with cannabinoids compared with placebo.Conclusions:There was moderate evidence to support cannabinoids in treating chronic, non-cancer pain at 2 weeks. Similar results were observed at later time points, but the confidence in effect is low. There is little evidence that cannabinoids increase the risk of experiencing serious AEs, although non-serious AEs may be common in the short-term period following use.

Short-term benefits of balneotherapy for patients with chronic pelvic pain: a pilot study in Korea

The aim of this study was to evaluate whether balneotherapy might be effective in patients with chronic pelvic pain (CPP) in the short term. This was an open and prospective pilot study. The balneotherapy programme was performed in a spa resort located in Wando Island, Republic of Korea from August 26 2018 to September 1 2018. It consisted of 10 heated seawater baths (38 °C, 20 minutes) and 10 mud-pack applications (40 °C, 10 minutes) for five days. Sixteen patients were enrolled. Upon analysing responses from a patient questionnaire, we found improvement in parameters such as pain, bladder irrigation symptoms and quality of life after balneotherapy. Inflammatory marker IL-1 and TNF-α was significantly decreased after treatment compared to baseline. There were no adverse events during treatment. Our data suggest that five-day balneotherapy can be beneficial for patients with CPP in the short term.Impact statementWhat is already known on this subject? The majority of articles in the field of balneotherapy discuss the treatment of rheumatic or dermatological disease. However, data on the effectiveness of balneotherapy for chronic pelvic pain are very limited.What the results of this study add? Our study suggests that balneotherapy can be beneficial for patients with CPP in the short-term. The duration of balneotherapy was five days, which is shorter than that of the European studies. Intuitively, it may be doubtful whether short-term therapy has any practical effect. As most people living in Korea have a vacation period of about one week each in summer and winter, the choice of a five-day programme in our study reflects the reality of vacation schedules.What the implications are of these findings for clinical practice and/or further research? Further studies are necessary to demonstrate the persistence of these benefits on the long term, as well as their existence in appropriate control group and different duration of treatment.

"Insulin-like" effects of palmitate compromise insulin signalling in hypothalamic neurons.

Saturated fatty acids are implicated in the development of metabolic diseases, including obesity and type 2 diabetes. There is evidence, however, that polyunsaturated fatty acids can counteract the pathogenic effects of saturated fatty acids. To gain insight into the early molecular mechanisms by which fatty acids influence hypothalamic inflammation and insulin signalling, we performed time-course experiments in a hypothalamic cell line, using different durations of treatment with the saturated fatty acid palmitate, and the omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA). Western blot analysis revealed that palmitate elevated the protein levels of phospho(p)AKT in a time-dependent manner. This effect is involved in the pathogenicity of palmitate, as temporary inhibition of the PI3K/AKT pathway by selective PI3K inhibitors prevented the palmitate-induced attenuation of insulin signalling. Similar to palmitate, DHA also increased levels of pAKT, but to a weaker extent. Co-administration of DHA with palmitate decreased pAKT close to the basal level after 8h, and prevented the palmitate-induced reduction of insulin signalling after 12h. The monounsaturated fatty acid oleate had a similar effect on the palmitate-induced attenuation of insulin signalling, the polyunsaturated fatty acid linoleate had no effect. Measurement of the inflammatory markers pJNK and pNFκB-p65 revealed tonic elevation of both markers in the presence of palmitate alone. DHA alone transiently induced elevation of pJNK, returning to basal levels by 12h treatment. Co-administration of DHA with palmitate prevented palmitate-induced inflammation after 12h, but not at earlier timepoints.