Additional Adverse Events Research Articles

Management of walled-off necrosis with nasocystic irrigation with hydrogen peroxide versus biflanged metal stent: randomized controlled trial.

Background and study aims Walled-off necrosis (WON) is a known complication of acute necrotizing pancreatitis (ANP). There is no study comparing nasocystic irrigation with hydrogen peroxide (H 2 O 2 ) versus biflanged metal stent (BMS) in the management of WON. The aim of this study was to compare the clinical efficacy of both the treatment strategies. Patients and methods This study was conducted on patients with symptomatic WON who were randomized to nasocystic irrigation with H 2 O 2 (Group A) and BMS placement (Group B). Primary outcomes were clinical and technical success while secondary outcomes were procedure time, adverse events, need for additional procedures, duration of hospitalization, and mortality. Results Fifty patients were randomized into two groups. Group A (n = 25, age 37.8 ± 17.6 years, 16 men) and Group B (n = 25, age 41.8 ± 15.2 years, 17 men). There were no significant differences in baseline characteristics between the two groups. The most common etiology of pancreatitis was alcohol, observed in 27 (54 %) patients. Technical success (100 % vs 96 %, P = 0.98), clinical success (84 % vs 76 %, P = 0.76), requirement of additional procedures (16 % vs 24 %, P = 0.70) and adverse events (4 vs 7, P = 0.06) were comparable in both the groups. The duration to clinical success (34.4 ± 12 vs 14.8 ± 10.8 days, P = 0.001) and procedure time (36 ± 15 vs 18 ± 12 minutes, P = 0.01) were longer in Group A compared to Group B. Conclusions Nasocystic irrigation with H 2 O 2 and BMS are equally effective in the management of WON but time to clinical success and procedure time is longer with nasocystic irrigation.

Rosuvastatin and ezetimibe for the treatment of dyslipidemia and hypercholesterolemia

ABSTRACT Introduction: Statins are powerful lipid-lowering agents which reduce cardiovascular (CV)–related morbidity and mortality. However, a large proportion of patients cannot attain the target low-density lipoprotein cholesterol (LDL-C) levels, despite receiving maximally tolerated doses of high-intensity statins. Also, adherence to treatment may be reduced due to statin-induced myopathy or other side effects. For these reasons, guidelines recommend adding the cholesterol absorption inhibitor ezetimibe. Areas covered: Authors discuss the main pharmacological characteristics of rosuvastatin and ezetimibe, their lipid-lowering and pleiotropic effects, as well as the clinical effects of the fixed dose combination of these drugs when used to treat dyslipidemia. Expert opinion: The rosuvastatin/ezetimibe combination is safe and effective in patients with hypercholesterolemia or dyslipidemia with or without diabetes and with or without cardiovascular disease. This drug combination enabled higher proportions of patients to achieve recommended LDL-C goals than rosuvastatin monotherapy or the simvastatin/ezetimibe combination, without additional adverse events. Despite the lack of additional CV outcomes data and comparisons with atorvastatin/ezetimibe, rosuvastatin/ezetimibe appears as a potent and generally well-tolerated drug combination eligible for the management of hypercholesterolemia and dyslipidemia in adults. Recently, the 40 mg rosuvastatin/10 mg ezetimibe fixed combination was approved and is also evaluated.

Evidence of a gabapentinoid and diuretic prescribing cascade among older adults with lower back pain.

Gabapentinoids are commonly prescribed to relieve pain. The development of edema, an established adverse effect of gabapentinoids, may lead to a potentially harmful prescribing cascade whereby individuals are subsequently prescribed diuretics and exposed to diuretic-induced adverse events. The frequency of this prescribing cascade is unknown. Our objective was to measure the association between new dispensing of a gabapentinoid and the subsequent dispensing of a diuretic in older adults with new low back pain. Population-based cohort study. Ontario, Canada. A total of 260,344 community-dwelling adults aged 66 years or older, newly diagnosed with low back pain between April 1, 2011, and March 31, 2019. Exposure status was assigned using dispensed medications in the 1 week after low back pain diagnosis. Older adults newly dispensed a gabapentinoid (N=7867) were compared with older adults who were not newly dispensed a gabapentinoid (N=252,477). Hazard ratios (HRs) with 95% confidence intervals (CIs) for dispensing of a diuretic within 90 days of follow-up among older adults prescribed gabapentin relative to those who were not. Older adults newly dispensed a gabapentinoid had a higher risk of being subsequently dispensed a diuretic within 90 days compared with older adults who were not prescribed a gabapentinoid (2.0% vs. 1.3%). After covariate adjustment, new gabapentinoid users had a higher rate of being dispensed a diuretic compared with those not prescribed a gabapentinoid (HR: 1.44, 95% CI: 1.23, 1.70). The rate of diuretic prescription among new gabapentinoid users increased with increasing gabapentinoid dosages. We have demonstrated the presence of a potentially inappropriate and harmful prescribing cascade. Given the widespread use of gabapentinoids, the population-based scale of this problem may be substantial. Increased awareness of this prescribing cascade is required to reduce the unnecessary use of diuretics and the exposure of patients to additional adverse drug events.

The Long-Term Safety and Efficacy of Metreleptin in Various Forms of Partial Lipodystrophy

Abstract Metreleptin is an approved treatment for patients with generalized lipodystrophy but still under investigation for patients with partial forms of the disease in the US. This open-label single-arm study in partial lipodystrophy (PL) allowed continued treatment of patients who volunteered and completed treatment under our previous 1-year protocol and who derived significant clinical benefit. The primary outcome was percent change in fasting triglyceride levels and the secondary outcome was percent change in hemoglobin A1c levels (time frame: 5 years on metreleptin or last observation carried forward in both instances). The hypothesis was that these metabolic parameters would stay stable over the observation period. The study enrolled 11 participants (11 females; 3 ≤ 18 years; 8 between 18–65 years). Four patients had familial partial lipodystrophy type 2 (FPLD2) caused by LMNA pathogenic variants (R482Q in two subjects, R482W in one subject, and R349W in one subject), two patients had POLD1 associated PL (E1067K), four patients had FPLD1, and one patient had atypical PL. Variants of uncertain significance (VUS) in genes of interest were detected in two patients with FPLD1 and one patient with atypical PL. Four subjects completed 48 months (actual 60 months on metreleptin). Data from 3 subjects were excluded from final data analyses due to early loss to follow-up (n = 1), serious adverse event withdrawal (n = 1; development of persistent neutralizing antibody shortly after 18 months of drug exposure), and death (n = 1). The remaining 4 subjects withdrew from the study either through their own volition or due to the investigator decision (last observation carried forward in these 4 subjects). As expected, the median percent change from baseline triglyceride and hemoglobin A1c levels were not significant (55.76 percent (range: -66.79 to 203.80; p > 0.05), and 2.55 percent (range: -27.52 to 25.00; p > 0.05), respectively). Serious adverse events were reported in 8 of 11 patients and additional adverse events were observed in all patients. Apart from neutralizing antibody development in one subject causing substantial metabolic derangement, adverse events were considered not to be directly related to the study drug. Death was caused by a sudden cardiac event related to the specific molecular etiology (LMNA R349W) in one case. This interventional study provided valuable information on the efficacy and safety of long-term metreleptin in PL. Although nonsignificant fluctuations were observed in triglycerides, hemoglobin A1c levels were generally stable over time and the initial improvement seen in the first year were sustained. Adverse events were common but more likely due to the complex nature of the underlying disease. Although rare, neutralizing antibodies can develop in patients with PL treated with metreleptin.

Does the Intradiscal Injection of Platelet Rich Plasma Have Any Beneficial Role in the Management of Lumbar Disc Disease?

Study Design:Systematic review and meta-analysis.Objectives:We performed this meta-analysis to evaluate whether intradiscal Platelet Rich Plasma(PRP) injection has any beneficial role in the management of lumbar disc disease.Methods:We conducted independent and duplicate electronic database searches including PubMed, Embase, and Cochrane Library till September 2020 for studies investigating the role of intradiscal PRP in the management of lumbar disc disease. The analysis was performed in the R platform using OpenMeta[Analyst] software.Results:13 studies including 2 RCTs, 5 prospective, and 6 retrospective studies involving 319 patients were included in the meta-analysis. A single-arm meta-analysis of the included studies showed a beneficial effect of the intervention in terms of pain relief outcomes like VAS score (p < 0.001), pain component of SF-36 (p = 0.003) while such improvement was not seen in functional outcome measures like ODI score (p = 0.071), the physical component of SF-36 (p = 0.130) with significant heterogeneity noted among the included studies. No structural improvement in magnetic resonance imaging was observed (p = 0.106). No additional procedure-related adverse events were noted in the included studies (p = 0.662).Conclusion:There is a paucity of high-quality studies to give conclusive evidence on the benefits of intradiscal PRP for lumbar disc disease. Although intradiscal PRP injection has shown some beneficial effect in controlling pain for lumbar disc disease, we could not find structural or functional improvement from the included studies. Hence, we recommend large double-blind double-arm randomized controlled studies to analyze the benefits of the intervention being analyzed.

Endoscopic ultrasound-directed transgastric ERCP (EDGE): a systematic review describing the outcomes, adverse events, and knowledge gaps.

BACKGROUND : Endoscopic ultrasound-directed transgastric endoscopic retrograde cholangiopancreatography (EDGE) has emerged as a viable completely endoscopic method for performing pancreaticobiliary interventions in patients with Roux-en-Y gastric bypass anatomy. The aims of this systematic review were: (1) to describe the indications, outcomes, and complications of EDGE; and (2) to identify deficiencies in our knowledge of important technical approaches and clinical outcomes. METHODS : A systematic review was conducted via comprehensive searches of Medline, Scopus, CINAHL, and Cochrane to identify studies focusing on EDGE outcomes. Simple descriptive statistics were derived from case series only. Case reports were only included to qualitatively describe additional indications, techniques, and adverse events. RESULTS : The initial search identified 2143 abstracts. Nine case series and eight case reports were included. In the nine case series, 169 patients underwent EDGE. The technical success rate was 99 % (168 /169) for gastrogastrostomy/jejunogastrostomy creation and 98 % (166 /169) for subsequent ERCP. Minor adverse events specifically related to EDGE occurred in 18 % (31/169) and included intraprocedural stent migration/malposition (n = 27) and abdominal pain (n = 4). Moderate adverse events specific to EDGE occurred in 5 % (9/169): including bleeding (2 %), persistent fistula (1 %), and perforation (1 %). Severe adverse events occurred in one patient with a perforation requiring surgery. Deficiency in reporting on the clinical significance of adverse events was identified. CONCLUSION : Based on limited observational data, in expert hands, EDGE has a high rate of technical success and an acceptable rate of adverse events. As a novel procedure, many knowledge gaps need to be addressed to inform the design of meaningful comparative studies and guide informed consent.

The Burden of Radiation Exposure During Transcatheter Closure of Atrial Septal Defect

Radiation reduction in the pediatric cardiac catheterization laboratory is well-suited for targeted quality improvement (QI) interventions. Transcatheter atrial septal defect (ASD) closure was chosen for this QI project based on a homogenous procedural population and inter-operator variability in radiation usage, with the aim to reduce radiation exposure during ASD device closure by 50% over 1 year. The aim for this project was defined and a Key Driver Diagram (KDD) was created with three domains for change: modification of procedural practice, reporting and monitoring/feedback, and team engagement. All patients undergoing attempted transcatheter ASD closure were considered for inclusion. The primary outcome, % reduction in median radiation dose (DAP/Kg), was determined through comparison with a historical cohort. Additional radiation metrics, procedural characteristics, and adverse events (AE) were compared to the historical cohort. Radiation exposure (DAP/kg) was reduced by 55% with a median dose reduction from 26 (15, 61) in a historical cohort to 12 (6, 22) in the intervention population (p <0.001). Fluoroscopy time and cine acquisition utilization significantly decreased. Procedure time, procedural success (defined as successful delivery of the device) and AE did not increase in the QI cohort. Successful practice changes included standardized procedural strategies to limit fluoroscopy and cine acquisition, improved fluoroscopic practice, engagement of the multidisciplinary team, and feedback with data reporting by electronic and in-person reminders. In conclusion, application of QI methodologies such as KDD with engagement of a multidisciplinary team can effectively reduce radiation in the pediatric catheterization laboratory.

Intravenous immunoglobulin and intravenous methylprednisolone as optimal induction treatment in chronic inflammatory demyelinating polyradiculoneuropathy: protocol of an international, randomised, double-blind, placebo-controlled trial (OPTIC)

BackgroundInternational guidelines recommend either intravenous immunoglobulin (IVIg) or corticosteroids as first-line treatment for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). IVIg treatment usually leads to rapid improvement and is generally safe, but does not seem to lead to long-term remissions. Corticosteroids act more slowly and are associated with more side effects, but may induce long-term remissions. The hypothesis of this study is that combined IVIg and corticosteroid induction treatment will lead to more frequent long-term remissions than IVIg treatment alone.MethodsAn international, randomised, double-blind, placebo-controlled trial, in adults with ‘probable’ or ‘definite’ CIDP according to the EFNS/PNS 2010 criteria. Three groups of patients are included: (1) treatment naïve, (2) known CIDP patients with a relapse after > 1 year without treatment, and (3) patients with CIDP who improved within 3 months after a single course of IVIg, who subsequently deteriorate at any interval without having received additional treatment. Patients are randomised to receive 7 courses of IVIg and 1000 mg intravenous methylprednisolone (IVMP) (in sodium chloride 0.9%) or IVIg and placebo (sodium chloride 0.9%), every 3 weeks for 18 weeks. IVIg treatment consists of a loading dose of 2 g/kg (over 3–5 days) followed by 6 courses of IVIg 1/g/kg (over 1–2 days). The primary outcome is remission at 1 year, defined as improvement in disability from baseline, sustained between week 18 and week 52 without further treatment. Secondary outcomes include changes in disability, impairment, pain, fatigue, quality of life, care use and costs and (long-term) safety.DiscussionIn case of superiority of the combined treatment, patients will experience the advantages of two proven efficacious treatments, namely rapid improvement due to IVIg and long-term remission due to corticosteroids. Long-term remission would reduce the need for maintenance IVIg treatment and may decrease health care costs. Additionally, we expect that the combined treatment leads to a higher proportion of patients with improvement as some patients who do not respond to IVIg will respond to corticosteroids. Risks of short and long-term additional adverse events of the combined treatment need to be assessed.Trial registrationISRCTN registry ISRCTN15893334. Prospectively registered on 12 February 2018.

Abstract PS9-33: Cost-effectiveness of neratinib for the extended adjuvant treatment of adult patients with early-stage, HR+, HER2-overexpressed/amplified breast cancer who initiated neratinib within 1 year of completing trastuzumab in the US

Abstract Background: Neratinib, an oral, irreversible tyrosine kinase inhibitor of multiple human epidermal growth factor receptors (HERs), is indicated for the extended adjuvant treatment of adult patients with, HER2-positive early-stage breast cancer (eBC) to follow adjuvant trastuzumab-based therapy in the United States (US). However, greater efficacy has been seen in patients with hormone receptor-positive (HR+) breast cancer and who initiated neratinib within 1 year of completing trastuzumab. Objective: This study explores the cost-effectiveness of neratinib versus placebo from a US third-party payer perspective in adult patients with HR+ HER2-overexpressed/amplified eBC and who are less than 1 year from the completion of prior adjuvant trastuzumab-based therapy. Methods: A Markov model was constructed to model costs and health outcomes of neratinib and placebo over a lifetime horizon. The model consisted of five health states representing the primary stages of disease in eBC—disease-free, local recurrence, remission, distant recurrence, and dead—and corresponds to the primary and secondary endpoints in the neratinib ExteNET trial. Overall survival was modeled based on a combination of post-distant recurrence survival and general population mortality, assuming all cancer-related mortality would occur through the distant recurrence health state. Statistical extrapolation of invasive disease-free survival and post-distant recurrence survival were derived from the ExteNET clinical trial data as well as the proportion of local and distant recurrence and number of adverse events. Non-breast cancer-related mortality was derived from US life tables. Costs per treatment arm were calculated based on drug acquisition, administration, and monitoring costs as well as treatment costs for adverse events and health state-related medical resource use. Quality-adjusted life-years (QALYs) were estimated per health state, and disutilities were applied per adverse event independent of treatment. Utility values for the invasive disease-free survival health state and diarrhoea were estimated using the EQ-5D-3L data collected in ExteNET. Additional health state utilities and adverse events disutilities were identified from the literature. Costs were adjusted to 2020 US dollars. One-way (OWSA) and probabilistic sensitivity analyses (PSA) and scenario analyses were performed to investigate the robustness of the results. Further, analyses were performed to investigate the cost-effectiveness for the subgroup of patients who did not achieve a pathologic complete response (pCR) after neoadjuvant therapy. Results: The results of the base case analysis showed that, compared with placebo, neratinib treatment generated an additional 0.88 incremental QALYs, 0.99 incremental life-years, and a resulting cost per QALY gained of $56,367. The results were robust across multiple scenario analyses with incremental cost-effectiveness ratios (ICERs) below $70,000. OWSA showed that the parameters that most influenced the results were variations in treatment-related costs, efficacy, and health state utility values. The PSA indicated that the probability of neratinib being cost-effective at a $100,000 per QALY threshold was above 75%. The analysis for the subgroup of patients who did not achieve a pCR after neoadjuvant therapy resulted in an improved ICER. Conclusions: The current cost-effectiveness analysis shows that neratinib is a cost-effective therapy for treating adult patients with HR+ HER2-overexpressed/amplified eBC and who are less than 1 year from the completion of prior adjuvant trastuzumab-based therapy in the US and in patients who did not achieve a pCR after neoadjuvant treatment. Citation Format: Thor-Henrik Brodtkorb, Cheryl McDade, Deepa Lalla, Frankie Ann Holmes. Cost-effectiveness of neratinib for the extended adjuvant treatment of adult patients with early-stage, HR+, HER2-overexpressed/amplified breast cancer who initiated neratinib within 1 year of completing trastuzumab in the US [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-33.

Efficacy and Safety of Glucagon-Like Peptide1 Receptor Agonists for the Treatment of Type2 Diabetes Mellitus: A Network Meta-analysis.

IntroductionThe present study aimed to evaluate the effects of glucagon-like peptide 1 receptor agonists (GLP-1RAs) on clinical and safety outcomes including glycemic control and cardiometabolic indicators using network meta-analysis.MethodsMEDLINE, Embase, and Cochrane Library Central Register of Controlled Trials were searched from inception through June 30, 2019. Randomized clinical trials comparing one or more of six eligible GLP-1RAs with placebo or another eligible GLP-1RA were identified. We further screened studies that had 24–30 week follow-up periods and target endpoints. The primary outcome was change in hemoglobin A1c (HbA1c). Secondary outcomes included additional glycemic control indicators, cardiometabolic measures, and adverse events. Frequentist random-effect network meta-analyses were conducted for effect comparison.ResultsThe NMA synthesized evidence from 54 studies covering 23,209 patients and 18 GLP-1RA regimens. All included GLP-1RA regimens except liraglutide 0.3 mg once weekly (QW) significantly lowered HbA1c after 24–30 weeks compared with placebo. The pairwise comparison of HbA1c-lowering effect showed that dulaglutide 0.75 mg QW, dulaglutide 1.5 mg QW, exenatide 2 mg QW, liraglutide 0.9 mg QW, liraglutide 1.2 mg QW, liraglutide 1.8 mg QW, loxenatide 100 µg QW, and loxenatide 200 µg QW were not significantly outperformed by any of the other regimens. The effects on blood pressure, weight, and lipids were relatively mixed. The GLP-1RA regimens had comparable safety profiles with regard to hypoglycemia and adverse events.ConclusionRegimens of GLP-1RAs had differential glycemic control and cardiometabolic effectiveness. Policymaking and patient-centric clinical decisions should take into consideration the comparative effectiveness profiles.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01637-6.

The Effectiveness and Safety of Cinobufotalin Injection as an Adjunctive Treatment for Lung Cancer: A Meta-Analysis of Randomized Controlled Trials.

Cinobufotalin injection is a water-soluble preparation extracted from the skin secretion of Bufo bufo gargarizans Cantor or B. melanotictus Schneider, which has been widely used as an adjuvant treatment in lung cancer patients. This study aimed to evaluate the clinical efficacy and safety of cinobufotalin (PubChem CID: 259776) injection as an adjunctive treatment for lung cancer. We designed a meta-analysis that performed following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We aim to include randomized controlled trials by systematically searching the PubMed, EMBASE, CNKI, Wanfang database, VIP, CBM, the Cochrane Central Register of Controlled Trials, and Chinese Clinical Trial Registry from inception to Mar 1, 2020, comparing the difference between the use of cinobufotalin injection as an adjunctive treatment and a control group without cinobufotalin injection. The objective response rate (ORR) and quality of life (QOL) will be defined as the primary outcomes, and the disease control rate (DCR) and adverse events will be defined as the secondary outcomes. We included 21 articles with 1735 cases of lung cancer patients. Comparison results show that combining with cinobufotalin injection can improve ORR (OR = 1.77, 95% CI [1.43, 2.21], P < 0.001), with low heterogeneity (P = 0.94, I2 = 0%); DCR (OR = 2.20, 95% CI [1.70, 2.85], P < 0.001), with low heterogeneity (P = 0.60, I2 = 0%); KPS score (OR = 3.10, 95% CI [2.23, 4.32], P < 0.001), with low heterogeneity (P = 0.85, I2 = 0%); and the effect of pain relief (OR = 2.68, 95% CI [1.30, 5.55], P = 0.008), with low heterogeneity (P = 0.72, I2 = 0%). Low-to-moderate evidence shows that cinobufotalin injection combined with chemotherapy can significantly increase ORR, DCR, QOL, and the effect of pain relief. Meanwhile, cinobufotalin injection did not bring additional adverse events such as hematological toxicity, gastrointestinal toxicity, cardiotoxicity, hepatotoxicity, and nephrotoxicity; however, multicenter, large-sample, high-quality clinical research results are still needed to reveal the therapeutic effect of cinobufotalin injection in small-cell lung cancer (PROSPERO registration number: CRD42020170052).

Novel Pancreatic Cancer Therapy Targeting Cell Surface Glycans by Liposomes Modified with rBC2LCN Lectin

Introduction: Since the outermost layer of cancer cells is covered with various glycans, targeting these groups may serve as an effective strategy in cancer therapy. We previously reported that fucosylated glycans are specifically expressed on pancreatic cancer cells, and that a protein specifically binding to these glycans, namely rBC2LCN lectin, is a potential guiding drug carrier. In the present study, a novel type of glycan-targeting nanoparticle was developed by modifying the surface of doxorubicin-containing liposomes with rBC2LCN lectin. The efficiency and specificity of this formulation, termed Lec-Doxosome, were examined in vitro and in vivo in human pancreatic cancer models. Methods: Lec-Doxosome was prepared by a post-insertion method based on the insertion of rBC2LCN lectin into the liposomal surface via a lipid linker. The in vitro cellular binding, uptake, and cytotoxicity of Lec-Doxosome were compared with the corresponding parameters in the unmodified liposomes by applying to human pancreatic cancer cell line (Capan-1) with affinity for rBC2LCN lectin. For the in vivo assay, Lec-Doxosome was intravenously injected once per week for a total of 3 weeks into mice bearing subcutaneous tumors. Results: The in vitro application of Lec-Doxosome resulted in a 1.2- to 1.6-fold higher intracellular doxorubicin accumulation and a 1.5-fold stronger cytotoxicity compared with the respective rates of accumulation and cytotoxicity in the unmodified liposomes. In vivo, Lec-Doxosome reduced the mean tumor weight (368 mg) compared with that in mice treated with unmodified liposomes (456 mg), without causing any additional adverse events. Conclusion: It was demonstrated from the results obtained herein that rBC2LCN lectin is a potent modifier, as a means for boosting the efficiency of nanoparticles in the targeting of cancer cell surface glycans.

Supplementation of green coffee bean extract in healthy overweight subjects increases lean mass/fat mass ratio: A randomized, double-blind clinical study.

Objective:In this study, we have demonstrated that supplementation of a complex of chlorogenic acid isomers (CGA-7TM) could significantly mitigate the risk of obesity in healthy overweight subjects.Method:In a double-blind, placebo-controlled clinical study, healthy overweight (body mass index ⩾ 25 to <30 kg/m2) male and female subjects (N = 71) were randomly allocated to receive 500 mg CGA-7 or placebo daily for 12 weeks. Changes in body weight and body mass index were recorded alongside vital signs and anthropometric measurements at week 4, 8 and 12. Body composition was assessed at baseline and the end of treatment using dual-energy X-ray absorptiometry. Safety analysis included serum biochemical and haematological assessments and measurement of vital signs. In addition, any adverse or serious adverse events were recorded during the study.Results:Sixty subjects completed the study. Mean body weight and body mass index were significantly reduced in CGA-7 group as compared to placebo (p < 0.001). CGA-7 group showed significant changes in body fat (%), fat mass and lean mass in comparison with placebo group (1.38% ± 1.4% vs −0.22% ± 0.86%, 1.97 ± 1.44 kg vs −0.39 ± 1.31 kg; 0.81 ± 1.20 kg vs −0.13 ± 0.97 kg, p < 0.001). Consumption of CGA-7 significantly improved the serum lipid profile. Importantly, CGA-7 consumption in humans had no adverse effects and was well tolerated during the study. The blood biochemical and haematological parameters marginally varied in the treatment groups throughout the study.Conclusion:To conclude, this study provides scientific validation of the functionality of green coffee bean extract and recommends the safety of the supplementation in healthy individuals.

Caspofungin combined with TMP/SMZ as a first-line therapy for moderate-to-severe PCP in patients with human immunodeficiency virus infection.

ObjectivesThe effectiveness of trimethoprim/sulfamethoxazole (TMP/SMZ) for pneumocystis pneumonia (PCP) is limited with adverse events. Caspofungin, by inhibiting the cyst form of Pneumocystis jirovecii, may be an alternative therapy for PCP. However, the availability of clinical data about caspofungin combined with TMP/SMZ in the treatment of PCP in HIV‐infected patients is limited. Thus, we aimed to examine the clinical effectiveness and safety of caspofungin combined with TMP/SMZ as a first‐line therapy for moderate‐to‐severe PCP in HIV‐infected patients.MethodsFrom January 2017 to December 2019, data of HIV‐infected patients with moderate‐to‐severe PCP who received either TMP/SMZ alone or caspofungin combined with TMP/SMZ as first‐line therapy were retrospectively reviewed to assess the effectiveness and safety of each regimen. The Kaplan–Meier curve and log‐rank test were used for survival analysis.ResultsA total of 278 patients met the criteria. The overall positive response rate of PCP treatment was 48.92%, and the overall all‐cause in‐hospital mortality rate was 33.09%. Patients who received combination therapy consisting of caspofungin and TMP/SMZ had a better positive response rate (59.44% vs. 37.78%, P < 0.001) and lower all‐cause in‐hospital mortality rate (24.48% vs. 42.22%, P = 0.003). Also, patients who received combination therapy had higher survival rate during a hospital stay (75.52% vs. 57.78%, P = 0.004), and those who received longer combination therapy were more likely to have higher survival rate (P = 0.042). We found that age (P = 0.019), CD4 cell count (P = 0.001) and therapeutic regimen (P = 0.002) were significant risk factors for all‐cause in‐hospital mortality rate in univariate analysis. In multivariate analysis, only CD4 cell count and therapeutic regimen were statistically significant factors associated with all‐cause in‐hospital mortality rate. Patients with a CD4 count of > 30 cells/µL and patients who received combination therapy consisting of caspofungin and TMP/SMZ were more likely to survive from PCP (P = 0.011 and P = 0.002, respectively). There were no additional severe adverse events caused by adding caspofungin.ConclusionsFor HIV‐infected patients with moderate‐to‐severe PCP, combination therapy with caspofungin and TMP/SMZ is an effective and promising first‐line therapy with no greater number of adverse events compared with TMP/SMZ monotherapy. Patients who received caspofungin had better positive response rates and lower all‐cause in‐hospital mortality rates. Also, we recommend early initiation of caspofungin.

Entecavir combining Chinese herbal medicine for HBeAg-positive chronic hepatitis B patients: a randomized, controlled trial.

Traditional Chinese medicine (TCM) is widely accepted and prescribed in China alongside Nucleoside analogs (NAs). In this double-blind, placebo-controlled, randomized, multi-center trial, we evaluated whether entecavir (ETV) plus TCM formulas Tiao-Gan-Yi-Pi granule (TGYP) and Tiao-Gan-Jian-Pi-Jie-Du granule (TGJPJD) increase the rate of hepatitis B e antigen (HBeAg) loss in Chinese patients. 596 eligible participants were randomly assigned, in a 1:1 ratio, to two study groupsin this 108-week trial: The experiment group was assigned ETV plus the TCM formula. The control group was assigned ETV plus a TCM placebo. We compared the rate of HBeAg loss by the end of week 108 between the two arms as the primary outcome. Secondary outcomes included hepatitis B surface antigen (HBsAg) level, proportion of undetectable HBV-DNA, and liver enzymes (ALT, AST, GGT) at week 108. The combination therapy achieved superior HBeAg loss at 108weeks, without additional adverse events. The rate of HBeAg loss at week 108 was 37.54% (95% CI 31.9-43.2%) in the experiment group and 27.21% (95% CI 22.0-32.4%) in the control group. There was a statistically significant difference between the two arms of 10.33% (95% CI 8.4-12.3%, p = 0.008). The DNA loss rate, serum HBsAg level, and liver enzymes were similar between the groups by the end of 108th week. Combining the Chinese herbal formula with ETV therapy demonstrated superior HBeAg clearance compared with ETV monotherapy. This finding indicates that this combined therapy could produce an improved therapeutic effect and safety profile. ChiCTR-TRC-12002784 (Chinese Clinical Trial Registry).

Reduction of Blood Loss by Intra‐articular Injection of Tranexamic Acid Combined with Knee and Hip Flexion at 45° During Primary Total Knee Arthroplasty: A Randomized Controlled Trial

ObjectiveTo explore the hemostatic effect of intra‐articular administration of tranexamic acid (TXA) combined with knee flexion in total knee arthroplasty (TKA).MethodsThis randomized controlled trial was conducted at the Third Affiliated Hospital of Southern Medical University (Guangzhou, China) from January 2017 to February 2018. The patients were randomized 1:1 to the TXA group (TXA 500 mg into the joint after closure, knee, and hip flexed at 45° for 4 h) or the control group (physiological saline, with limb fully extended). The primary endpoint was postoperative hemoglobin reduction. The postoperative levels of hemoglobin were measured at four time points: 6 h after operation, and on the first, second, and third postoperative days. Calculated blood loss (CBL) at 3 days, transfusion rate, range of motion (ROM), VAS pain score, and knee circumference increment were the secondary endpoints. Ninety‐four (47/group) patients were analyzed.ResultsPostoperatively, there were statistically significant differences between the TXA and control groups in CBL (791 ± 212 mL vs 1175 ± 273 mL, P < 0.05). Hemoglobin reduction was significantly lower in the TXA group (2.0 ± 0.9 g/dL vs 4.5 ± 0.7 g/dL, P < 0.05). Based on the transfusion criteria, 3 out of 47 (6.4%) patients in the TXA group and 13 out of 47 (27.6%) patients in the control group received blood transfusions (P = 0.006). ROM (90.8° ± 6.2° vs 87.6° ± 6.4°, P = 0.004), VAS pain score (4.1 ± 1.1 vs 4.8 ± 1.3, P = 0.004), and KCI (2.4 ± 0.9 cm vs 3.2 ± 1.0 cm, P = 0.01) were better in the TXA group compared with thecontrols. There was no deep venous thrombosis (DVT), wound infection or other adverse events in either group. In the control group, 2 patients had a fever after blood transfusion.ConclusionIntra‐articular injection of TXA combined with knee and hip flexion at 45° can effectively attenuate CBL and hemoglobin reduction during primary TKA, without an additional adverse event.

Concomitant Administration of Direct Oral Anticoagulants in Chronic Phase Chronic Myeloid Leukemia Patients Treated with Tyrosine Kinase Inhibitors.

In the last decades, the chronic myeloid leukemia (CML) therapeutic landscape has changed dramatically with the introduction of tyrosine kinase inhibitors (TKIs), with 10-year survival rates improving to up to 80%. Long-lasting TKI treatment, in particular with second-generation TKIs, has enabled clinicians to manage the onset of several side effects and other co-morbidities, such as atrial fibrillation or venous thromboembolism (VTE). We retrospectively evaluated nine CML patients treated with TKIs between 2017 and 2020 who experienced atrial fibrillation or VTE and received concomitant administration of TKIs and direct oral anticoagulants (DOACs) outside clinical trials, to evaluate the efficacy and safety of this combination. Median age was 66 years at CML diagnosis (range 52-73 years) and 69 years at the time of starting DOACs. A female predominance was observed. The median follow-up of concomitant DOAC and TKI administration was 8.5 months; edoxaban was administered in six patients and apixaban in two patients, and one patient received rivaroxaban. Regarding CML treatment, four patients received imatinib, two patients bosutinib, and three nilotinib. In eight patients DOACs were started for atrial fibrillation and in one patient for VTE. In none of the patients treated with the combination were additional symptomatic thrombotic adverse events or major bleedings reported. In this small case series, the use of DOACs in CML patients seemed feasible. Additional data on long-term outcomes including a larger cohort of CML patients treated with DOACs are, however, needed.

Adverse events over the life course and later-life wellbeing and depressive symptoms in older people.

Exposures to adverse events are associated with impaired later-life psychological health. While these associations depend on the type of event, the manner in which associations for different event types depend on when they occur within the life course has received less attention. We investigated associations between counts of adverse events over the life course, and wellbeing and mental health outcomes in older people, according to their timing (age of occurrence), orientation (self or other) and, both their timing and orientation. Linear and logistic random-effects models for repeated observations. England, 2002-2015. A total of 4,208 respondents aged >50 years with 22,146 observations across Waves 1-7 of the English Longitudinal Study of Ageing. Cumulative adversity was measured by counts of 16 types of events occurring within four age ranges over the life course using retrospective life history data. These were categorized into other- (experienced through harms to others) and self-oriented events. Outcomes included CASP-12 (control, autonomy, self-realization, and pleasure), the eight-item Centre of Epidemiological Studies Depression Scale, and self-appraised subjective life satisfaction. Additional adverse events were associated with lower CASP-12 and life satisfaction scores, and higher odds of probable depressive caseness. In childhood, other-oriented events had a larger negative association with later-life wellbeing than self-oriented events; the converse was found for events occurring in adulthood. Events occurring at all life course stages were independently associated with both later-life wellbeing and depression in a cumulative fashion. Certain age ranges may represent sensitive periods for specific event types.

Prophylactic use of tranexamic acid for prevention of bleeding during transbronchial lung biopsies - A randomized, double-blind, placebo-controlled trial

BackgroundAlthough massive bleeding following transbronchial lung biopsies (TBLB) is rare, even minor hemorrhage may prolong the procedure and result in inadequate sampling. Tranexamic acid (TXA) is an antifibrinolytic agent, which reduces bleeding in numerous scenarios, however, its prophylactic use in mitigating post-TBLB bleeding has not been investigated. We conducted a prospective, randomized, double-blind, placebo-controlled trial to determine whether topical infusion of TXA prior to TBLB would reduce bleeding, shorten procedure duration and increase the number of biopsies obtained. MethodsWe blindly randomized patients undergoing TBLB to receive topical TXA or placebo in the lobar bronchus prior to biopsies. Vital signs, procedure length, fluid balance (as a measure of the amount of bleeding), operator's assessment of bleeding, and number of biopsies obtained were measured. Data was analyzed using the two-tailed Student's T-Test, Chi-square or Mann-Whitney tests as appropriate. ResultsFifty patients were randomized, 26 to the TXA arm. The bleeding in the TXA group was significantly lower (P = 0.0037), with more specimens being obtained (placebo 7 (6, 9) (median and interquartile range) vs. TXA 9 (8, 10), P = 0.023) and no difference in procedure length (placebo 30 min (29.3, 34.3) vs. TXA 30 (24.8, 36), P = 0.90). There were no clinically significant adverse events in any of the groups up to one month of follow up. ConclusionEndobronchial installation of TXA prior to obtaining TBLB results in less bleeding and allows more biopsies to be obtained with no additional adverse events. The prophylactic use of TXA during TBLB may be considered as standard.

Robotic Bronchoscopy for Peripheral Pulmonary Lesions: A Multicenter Pilot and Feasibility Study (BENEFIT)

BackgroundThe diagnosis of peripheral pulmonary lesions (PPL) continues to present clinical challenges. Despite extensive experience with guided bronchoscopy, the diagnostic yield has not improved significantly. Robotic-assisted bronchoscopic platforms have been developed potentially to improve the diagnostic yield for PPL. Presently, limited data exist that evaluate the performance of robotic systems in live human subjects.Research QuestionWhat is the safety and feasibility of robotic-assisted bronchoscopy in patients with PPLs?Study Design and MethodsThis was a prospective, multicenter pilot and feasibility study that used a robotic bronchoscopic system with a mother-daughter configuration in patients with PPL 1 to 5 cm in size. The primary end points were successful lesion localization with the use of radial probe endobronchial ultrasound (R-EBUS) imaging and incidence of procedure related adverse events. Robotic bronchoscopy was performed in patients with the use of direct visualization, electromagnetic navigation, and fluoroscopy. After the use of R-EBUS imaging, transbronchial needle aspiration was performed. Rapid on-site evaluation (ROSE) was used on all cases. Transbronchial needle aspiration alone was sufficient when ROSE was diagnostic; when ROSE was not diagnostic, transbronchial biopsy was performed with the use of the robotic platform, followed by conventional guided bronchoscopic approaches at the discretion of the investigator.ResultsFifty-five patients were enrolled at five centers. One patient withdrew consent, which left 54 patients for data analysis. Median lesion size was 23 mm (interquartile range, 15 to 29 mm). R-EBUS images were available in 53 of 54 cases. Lesion localization was successful in 51 of 53 patients (96.2%). Pneumothorax was reported in two of 54 of the cases (3.7%); tube thoracostomy was required in one of the cases (1.9 %). No additional adverse events occurred.InterpretationThis is the first, prospective, multicenter study of robotic bronchoscopy in patients with PPLs. Successful lesion localization was achieved in 96.2% of cases, with an adverse event rate comparable with conventional bronchoscopic procedures. Additional large prospective studies are warranted to evaluate procedure characteristics, such as diagnostic yield.Clinical Trial RegistrationClinicalTrials.gov; No.: NCT03727425; URL: www.clinicaltrials.gov.