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Intensive Care Medicine Jan 2024We assessed long-term outcomes in acutely admitted adult patients with delirium treated in intensive care unit (ICU) with haloperidol versus placebo. (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
We assessed long-term outcomes in acutely admitted adult patients with delirium treated in intensive care unit (ICU) with haloperidol versus placebo.
METHODS
We conducted pre-planned analyses of 1-year outcomes in the Agents Intervening against Delirium in the ICU (AID-ICU) trial, including mortality and health-related quality of life (HRQoL) assessed by Euroqol (EQ) 5-dimension 5-level questionnaire (EQ-5D-5L) index values and EQ visual analogue scale (EQ VAS) (deceased patients were assigned the numeric value zero). Outcomes were analysed using logistic and linear regressions with bootstrapping and G-computation, all with adjustment for the stratification variables (site and delirium motor subtype) and multiple imputations for missing HRQoL values.
RESULTS
At 1-year follow-up, we obtained vital status for 96.2% and HRQoL data for 83.3% of the 1000 randomised patients. One-year mortality was 224/501 (44.7%) in the haloperidol group versus 251/486 (51.6%) in the placebo group, with an adjusted absolute risk difference of - 6.4%-points (95% confidence interval [CI] - 12.8%-points to - 0.2%-points; P = 0.045). These results were largely consistent across the secondary analyses. For HRQoL, the adjusted mean differences were 0.04 (95% CI - 0.03 to 0.11; P = 0.091) for EQ-5D-5L-5L index values, and 3.3 (95% CI - 9.3 to 17.5; P = 0.142) for EQ VAS.
CONCLUSIONS
In acutely admitted adult ICU patients with delirium, haloperidol treatment reduced mortality at 1-year follow-up, but did not statistically significantly improve HRQoL.
Topics: Adult; Humans; Delirium; Haloperidol; Hospitalization; Intensive Care Units; Quality of Life
PubMed: 38170227
DOI: 10.1007/s00134-023-07282-7 -
Therapeutic Advances in Cardiovascular... Jun 2016Following extensive clinical research, drugs affecting the renin-angiotensin system have been used for the treatment of patients with congestive heart failure,... (Review)
Review
Following extensive clinical research, drugs affecting the renin-angiotensin system have been used for the treatment of patients with congestive heart failure, myocardial infarction, hypertension, diabetic nephropathy, chronic renal failure and for reducing the risk of developing major cardiovascular (CV) events. This review examines all mega trials (those involving >1000 patients) and smaller pivotal trials involving angiotensin-converting enzyme inhibitors (ACE-Is; 25 mega trials) and angiotensin receptor blockers (ARBs; 27 mega trials) to provide perspective on the huge database of evidence that has accumulated on the use of these drugs. Our review demonstrates that ACE-Is and ARBs are generally as effective as conventional therapies in the treatment of hypertension, but offer additional cardioprotective benefits in patients with heart failure, and in those who have experienced myocardial infarction. Also, both ACE-Is and ARBs are capable of renal protection in addition to their blood-pressure-lowering effects. Although ACE-Is and ARBs provide major benefits to CV patients, doubts remain over the concept of blood-pressure-independent CV protection offered by both classes of drugs. ACE-Is and ARBs appear to be equally effective with respect to morbidity and mortality endpoints, but ARBs are better tolerated. Considering the available evidence, the combined use of an ACE-I and ARB should be avoided and full doses of either ACE-I or ARB should be aimed for as evidence suggests they provide a greater prognostic benefit.
Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Heart Failure; Humans; Hypertension; Stroke
PubMed: 27271312
DOI: 10.1177/1753944716644131 -
BioRxiv : the Preprint Server For... May 2023Evidence supports significant interactions among microbes, immune cells, and tumor cells in at least 10-20% of human cancers, emphasizing the importance of further...
Evidence supports significant interactions among microbes, immune cells, and tumor cells in at least 10-20% of human cancers, emphasizing the importance of further investigating these complex relationships. However, the implications and significance of tumor-related microbes remain largely unknown. Studies have demonstrated the critical roles of host microbes in cancer prevention and treatment responses. Understanding interactions between host microbes and cancer can drive cancer diagnosis and microbial therapeutics (bugs as drugs). Computational identification of cancer-specific microbes and their associations is still challenging due to the high dimensionality and high sparsity of intratumoral microbiome data, which requires large datasets containing sufficient event observations to identify relationships, and the interactions within microbial communities, the heterogeneity in microbial composition, and other confounding effects that can lead to spurious associations. To solve these issues, we present a bioinformatics tool, MEGA, to identify the microbes most strongly associated with 12 cancer types. We demonstrate its utility on a dataset from a consortium of 9 cancer centers in the Oncology Research Information Exchange Network (ORIEN). This package has 3 unique features: species-sample relations are represented in a heterogeneous graph and learned by a graph attention network; it incorporates metabolic and phylogenetic information to reflect intricate relationships within microbial communities; and it provides multiple functionalities for association interpretations and visualizations. We analyzed 2704 tumor RNA-seq samples and MEGA interpreted the tissue-resident microbial signatures of each of 12 cancer types. MEGA can effectively identify cancer-associated microbial signatures and refine their interactions with tumors.
PubMed: 37292990
DOI: 10.1101/2023.05.24.541982 -
Indian Journal of Orthopaedics Apr 2020Mega-prostheses required for reconstructing large gaps in bone after limb-saving surgeries for osteo-sarcoma patients have a long development cycle. This includes design...
AIM
Mega-prostheses required for reconstructing large gaps in bone after limb-saving surgeries for osteo-sarcoma patients have a long development cycle. This includes design of prosthesis components and surgical armamentarium, followed by pilot batch production, lab testing, human clinical trials and regulatory approvals. Most manufacturers stay away due to small market size coupled with the difficulties and high costs involved. Prostheses developed in the West are often unsuitable and unaffordable for the majority of Indian patients. There is a need for high-quality yet low-cost prostheses that are compatible with the anatomy and functionality of local population.
METHOD
An inter-disciplinary group comprising orthopedic oncologists, mechanical engineers and materials scientists from three different organizations in India took up the above challenge. They developed a novel modular tumour knee prosthesis with rotating hinge, as well as surgical armamentarium with femoral and tibial cutting jigs and other instruments. Knee simulator and testing machines were developed to test the prosthesis. A dedicated pilot production facility along with inspection and quality management system was set up.
RESULT
The new prosthesis provides flexion-extension up to 120 degrees and axial rotation of ±5 degrees. It successfully completed ten million cycles of fatigue and wear testing. The regulatory body of the government and institutional ethical committees of hospitals approved the human clinical trials, which are currently in progress.
CONCLUSION
The design, manufacturing and testing of the prosthesis components and armamentarium took more than a decade and presented many challenges. These were overcome by several technological innovations by the engineering team and continuous feedback from the surgeons. The experience is expected to be useful to all others interested in this field.
PubMed: 32257029
DOI: 10.1007/s43465-019-00033-1 -
The New England Journal of Medicine Sep 2017Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL)... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes.
METHODS
We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization.
RESULTS
During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events.
CONCLUSIONS
Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .).
Topics: Aged; Anticholesteremic Agents; Atherosclerosis; Cholesterol; Cholesterol Ester Transfer Proteins; Coronary Disease; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Incidence; Kaplan-Meier Estimate; Male; Medication Adherence; Middle Aged; Oxazolidinones
PubMed: 28847206
DOI: 10.1056/NEJMoa1706444 -
European Journal of Heart Failure Sep 2020Over the last 30 years, many medicine development programmes in acute and chronic heart failure (HF) with preserved ejection fraction (HFpEF) have failed, in contrast... (Meta-Analysis)
Meta-Analysis
AIMS
Over the last 30 years, many medicine development programmes in acute and chronic heart failure (HF) with preserved ejection fraction (HFpEF) have failed, in contrast to those in HF with reduced ejection fraction (HFrEF). We explore how the neutral results in larger HF trials may be attributable to chance and/or the dilution of statistical power.
METHODS AND RESULTS
Using simulations, we examined the probability that a positive finding in a Phase 2 trial would result in the study of a truly effective medicine in a Phase 3 trial. We assessed the similarity of clinical trial and registry patient populations. We conducted a meta-analysis of paired Phase 2 and 3 trials in HFrEF and acute HF examining the associations of trial phase and size with placebo event rates and treatment effects for HF events and death. We estimated loss in trial power attributable to dilution with increasing trial size. Appropriately powered Phase 3 trials should have yielded ∼35% positive results. Patient populations in Phase 3 trials are similar to those in Phase 2 trials but both differ substantially from the populations of 'real-life' registries. We observed decreasing placebo event rates and smaller treatment effects with increasing trial size, especially for HF events (and less so for mortality). This was more pronounced in trials in acute HF patients.
CONCLUSIONS
The selection of more positive Phase 2 trials for further development does not explain the failure of HFpEF and acute HF medicine development. Increasing sample size may lead to reduced event rates and smaller treatment effects, resulting in a high rate of neutral Phase 3 trials.
Topics: Chronic Disease; Heart Failure; Humans; Prognosis; Registries; Stroke Volume; Ventricular Dysfunction, Left
PubMed: 32227620
DOI: 10.1002/ejhf.1780 -
Acute Medicine & Surgery 2023Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by widespread intravascular activation of coagulation, which can be caused by... (Review)
Review
Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by widespread intravascular activation of coagulation, which can be caused by infectious and noninfectious insults, such as trauma, postcardiac arrest syndrome, and malignant diseases. At present, diagnosis and treatment of DIC clearly differ between Japan and Western countries; in Japan, DIC has long been considered a therapeutic target, and much evidence on DIC has been published. However, there has recently been no international consensus on whether DIC should be a therapeutic target with anticoagulant therapy. This review describes the coagulofibrinolytic system abnormalities associated with sepsis and discusses related management strategies. It also explores the reasons why DIC is perceived differently in different regions. There is a major discrepancy between diagnostic and treatment options in Japan, which are based on holistic assessments of trials, as well as the results of post hoc subgroup analyses and observational studies, and those in Western countries, which are based mainly on the results of sepsis mega trials, especially randomized controlled trials. The differences might also be due to various patient factors in each region, especially racial characteristics in thrombolytic mechanisms, and differences in interpretation of evidence for candidate drugs. Hence, Japanese researchers need to distribute their high-quality clinical research data not only to Japan but also to the rest of the world.
PubMed: 37153869
DOI: 10.1002/ams2.843 -
Journal of the Royal College of... 1995
Topics: Clinical Protocols; Controlled Clinical Trials as Topic; Randomized Controlled Trials as Topic
PubMed: 7473339
DOI: No ID Found -
Cancers Jul 2022Surgery and radiofrequency ablation remain the gold standard to achieve cure in patients with hepatocellular carcinoma (HCC). After a decade in which only sorafenib was... (Review)
Review
Surgery and radiofrequency ablation remain the gold standard to achieve cure in patients with hepatocellular carcinoma (HCC). After a decade in which only sorafenib was available for advanced and metastatic HCC, the emergence of other molecularly targeted drugs and immune checkpoint inhibitors (ICIs) has significantly improved the patients` prognosis. In particular, the use of ICIs has shown promising results and has revolutionized the treatment algorithm in HCC patients. Indeed, preclinical and clinical data have documented a high density of immunosuppressive cells and an increased expression of the programmed death-1 (PD-1) receptor and cytotoxic T-cell associated protein-4 (CTLA-4) in HCC. However, despite these observations, no validated biomarker is available and the molecular groundwork responsible for response to ICIs remains elusive. The anti-CTLA4 monoclonal antibody tremelimumab and the anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab were the first ICIs to be tested in HCC. Recently, the combination of the anti-programmed death-ligand 1 (PD-L1) inhibitor atezolizumab and the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab demonstrated an improvement in patient outcome compared to sorafenib, becoming the standard of care in the frontline setting of advanced disease. Other immunotherapeutic agents such as pembrolizumab or the combination nivolumab-ipilimumab have shown promising results that have to be confirmed in phase III studies. Currently, the combination of different ICIs (i.e., ipilimumab, durvalumab) and anti-angiogenic agents (i.e., regorafenib, lenvatinib) is currently being tested in several trials and will hopefully revolutionize the treatment of HCC. To date, numerous studies are underway evaluating ICIs in adjuvant and neoadjuvant settings to improve survival in early and intermediate stages. Thus, this review focuses on the rationale for ICIs and their potential use for early or intermediate HCC stages.
PubMed: 35884392
DOI: 10.3390/cancers14143332 -
Frontiers in Immunology 2022Activation of the cGAS-STING pathway by cytoplasmic DNA induces the production of Type-1 interferons. Recent advances in research suggest that the cGAS-STING pathway is... (Review)
Review
Activation of the cGAS-STING pathway by cytoplasmic DNA induces the production of Type-1 interferons. Recent advances in research suggest that the cGAS-STING pathway is involved in different parts of the cancer-immunity cycle (CIC) to promote or suppress antitumor immune responses. Combination therapy of STING agonists has made certain progress in preclinical as well as clinical trials, but the selection of combination therapy regimens remains a challenge. In this review, we summarize the role of the cGAS-STING in all aspects of CIC, and focus on the combination immunotherapy strategies of STING agonists and current unsolved challenges.
Topics: Humans; DNA; Immunotherapy; Membrane Proteins; Neoplasms; Nucleotidyltransferases
PubMed: 36353640
DOI: 10.3389/fimmu.2022.996663