This placebo-controlled study compared the effect of amiodarone and an implantable cardioverter–defibrillator (ICD) on mortality in patients with New York Heart Association class II or III congestive ...heart failure (CHF). Amiodarone had no benefit overall and slightly increased mortality among patients with class III CHF. ICD therapy reduced mortality overall, but the benefit appeared to be restricted to patients with class II CHF. These important results will broaden the use of ICD therapy.
This study compared the effect of amiodarone and an implantable cardioverter–defibrillator on mortality in patients with congestive heart failure.
Patients with congestive heart failure (CHF) can die suddenly and unpredictably from arrhythmia despite the use of proven medical therapies, such as beta-blockade. Two approaches have been developed specifically to prevent sudden death among patients with CHF: therapy with amiodarone and therapy with an implantable cardioverter–defibrillator (ICD). Despite findings in earlier clinical trials, the ability of amiodarone to reduce the risk of death among patients with CHF remains uncertain.
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The ability of an ICD to limit mortality in patients with CHF without prior cardiac arrest has been evaluated in small trials focused on patients with nonischemic cardiomyopathy
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and . . .
Inhibition of β-secretase BACE1 is considered one of the most promising approaches for treating Alzheimer's disease. Several structurally distinct BACE1 inhibitors have been withdrawn from ...development after inducing ocular toxicity in animal models, but the target mediating this toxicity has not been identified. Here we use a clickable photoaffinity probe to identify cathepsin D (CatD) as a principal off-target of BACE1 inhibitors in human cells. We find that several BACE1 inhibitors blocked CatD activity in cells with much greater potency than that displayed in cell-free assays with purified protein. Through a series of exploratory toxicology studies, we show that quantifying CatD target engagement in cells with the probe is predictive of ocular toxicity in vivo. Taken together, our findings designate off-target inhibition of CatD as a principal driver of ocular toxicity for BACE1 inhibitors and more generally underscore the power of chemical proteomics for discerning mechanisms of drug action.
Traumatic brain injury (TBI) is a risk factor for neurodegenerative disease, including chronic traumatic encephalopathy (CTE). Preliminary consensus criteria define the pathognomonic lesion of CTE as ...patchy tau pathology within neurons and astrocytes at the depths of cortical sulci. However, the specific tau isoform composition and post-translational modifications in CTE remain largely unexplored. Using immunohistochemistry, we performed tau phenotyping of CTE neuropathologies and compared this to a range of tau pathologies, including Alzheimer's disease, primary age-related tauopathy, ageing-related tau astrogliopathy and multiple subtypes of frontotemporal lobar degeneration with tau inclusions. Cases satisfying preliminary consensus diagnostic criteria for CTE neuropathological change (CTE-NC) were identified (athletes, n = 10; long-term survivors of moderate or severe TBI, n = 4) from the Glasgow TBI Archive and Penn Neurodegenerative Disease Brain Bank. In addition, material from a range of autopsy-proven ageing-associated and primary tauopathies in which there was no known history of exposure to TBI was selected as non-injured controls (n = 32). Each case was then stained with a panel of tau antibodies specific for phospho-epitopes (PHF1, CP13, AT100, pS262), microtubule-binding repeat domains (3R, 4R), truncation (Tau-C3) or conformation (GT-7, GT-38) and the extent and distribution of staining assessed. Cell types were confirmed with double immunofluorescent labelling. Results demonstrate that astroglial tau pathology in CTE is composed of 4R-immunoreactive thorn-shaped astrocytes, echoing the morphology and immunophenotype of astrocytes encountered in ageing-related tau astrogliopathy. In contrast, neurofibrillary tangles of CTE contain both 3R and 4R tau, with post-translational modifications and conformations consistent with Alzheimer's disease and primary age-related tauopathy. Our observations establish that the astroglial and neurofibrillary tau pathologies of CTE are phenotypically distinct from each other and recapitulate the tau immunophenotypes encountered in ageing and Alzheimer's disease. As such, the immunohistochemical distinction of CTE neuropathology from other mixed 3R/4R tauopathies of Alzheimer's disease and ageing may rest solely on the pattern and distribution of pathology.
Enzyme-treated cellulose nanofibrils (CNFs) were produced via a lab-scale mass colloider using bleached kraft pulp (BKP) to evaluate their processability and power requirements during refining and ...spray-drying operations. To evaluate the energy efficiency in the CNF refining process, the net energy consumption, degree of polymerization (DP), and viscosity were determined. Less energy was consumed to attain a given fines level by using the endoglucanase enzymes. The DP and viscosity were also decreased using the enzymes. The morphological properties of the enzyme-pretreated spray-dried CNF powders (SDCNFs) were measured. Subsequently, the enzyme-pretreated SDCNFs were added to a PP matrix with MAPP as a coupling agent. The mixture was then compounded through a co-rotating twin-screw extruder to determine whether the enzyme treatment of the CNFs affects the mechanical properties of the composites. Compared to earlier studies on enhancing PMCs with SDCNF powders, this research investigates the use of enzyme-pretreated SDCNF powders. It was confirmed that the strength properties of PP increased by adding SDCNFs, and the strength properties were maintained after adding enzyme-pretreated SDCNFs.
Immune checkpoint inhibitor-mediated colitis (IMC) is a common adverse event of treatment with immune checkpoint inhibitors (ICI). We hypothesize that genetic susceptibility to Crohn's disease (CD) ...and ulcerative colitis (UC) predisposes to IMC. In this study, we first develop a polygenic risk scores for CD (PRS
) and UC (PRS
) in cancer-free individuals and then test these PRSs on IMC in a cohort of 1316 patients with ICI-treated non-small cell lung cancer and perform a replication in 873 ICI-treated pan-cancer patients. In a meta-analysis, the PRS
predicts all-grade IMC (OR
=1.35 per standard deviation SD, 95% CI = 1.12-1.64, P = 2×10
) and severe IMC (OR
=1.49 per SD, 95% CI = 1.18-1.88, P = 9×10
). PRS
is not associated with IMC. Furthermore, PRS
predicts severe IMC among patients treated with combination ICIs (OR
=2.20 per SD, 95% CI = 1.07-4.53, P = 0.03). Overall, PRS
can identify patients receiving ICI at risk of developing IMC and may be useful to monitor patients and improve patient outcomes.
Mining operations in the Tri-State Mining District of Kansas, Missouri and Oklahoma (TSMD), once one of the major lead and zinc mining areas in the world, had completely ceased by 1970. As mining ...companies moved out, the land was left with underground tunnels and mine shafts and the surface with abandoned tailings piles, which progressively contaminated groundwater and soil. Despite remedial actions undertaken in the 1980's, areas within the TSMD still contain Cd, Pb, and Zn concentrations exceeding safe levels. Because of the large area and highly dispersed occurrence of wastes, environmental studies generally have been confined either to a stream basin or to a single state. Studies also have differed in their approach and analytical methodologies. An overview of the totality of the TSMD and its present state of contamination is presented here. Data show that metal content in sediments have the following common features: (1) a wide range of Pb and Zn concentrations, up to three orders of magnitude, (2) median values for Cd, Pb and Zn content in sediments and soils were similar among studies, (3) median values for most studies were at or above the guidelines recommended for aquatic habitats, and (4) highest content of Pb and Zn were closely associated with the geographical location of former mining and smelting centers. The above observations imply that mine wastes remain a problem and further remediation is needed. Cost-effective remedial alternatives for this area's geology, climate, and land use, are discussed.
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•Abandoned mining wastes continue to release metals to the environment.•Concentrations of Cd, Pb and Zn in sediments vary greatly and concentrate in sites of former mine operations.•Contaminated areas have been remediated differently in each of three Superfund sites in the area.•Remediation should be applied to highly contaminated sites, before contamination disperses further.
Nonendoscopic Barrett's esophagus (BE) screening may help improve esophageal adenocarcinoma outcomes. We previously demonstrated promising accuracy of methylated DNA markers (MDMs) for the ...nonendoscopic diagnosis of BE using samples obtained from a capsule sponge-on-string (SOS) device. We aimed to assess the accuracy of these MDMs in an independent cohort using a commercial grade assay.
BE cases had ≥ 1 cm of circumferential BE with intestinal metaplasia; controls had no endoscopic evidence of BE. The SOS device was withdrawn 8 minutes after swallowing, followed by endoscopy (the criterion standard). Highest performing MDMs from a previous study were blindly assessed on extracted bisulfite-converted DNA by target enrichment long-probe quantitative amplified signal (TELQAS) assays. Optimal MDM combinations were selected and analyzed using random forest modeling with in silico cross-validation.
Of 295 patients consented, 268 (91%) swallowed the SOS device; 112 cases and 89 controls met the pre-established inclusion criteria. The median BE length was 6 cm (interquartile range 4-9), and 50% had no dysplasia. The cross-validated sensitivity and specificity of a 5 MDM random forest model were 92% (95% confidence interval 85%-96%) and 94% (95% confidence interval 87%-98%), respectively. Model performance was not affected by age, gender, or smoking history but was influenced by the BE segment length. SOS administration was well tolerated (median interquartile range tolerability 2 0, 4 on 10 scale grading), and 95% preferred SOS over endoscopy.
Using a minimally invasive molecular approach, MDMs assayed from SOS samples show promise as a safe and accurate nonendoscopic test for BE prediction.
Immune checkpoint inhibitors have emerged as a revolutionary treatment option for patients with various types of malignancy. Although these agents afford a significant improvement in outcomes for ...melanoma and other previously untreatable malignancies, their novel mechanism of action may predispose patients to immune‐related adverse effects (irAEs). In the tumour neoantigen environment, these irAEs are due to the activation of the immune system by the blockade of suppressive checkpoints, leading to increases in T‐cell activation and proliferation. IrAEs have been reported in almost any organ and at any point in time, even months to years after discontinuation of therapy. Certain populations with distinct physiological changes, genetic risk factors, and specific antigen exposures may be more highly predisposed to develop irAEs. This review discusses the incidence and mechanisms of irAEs and the relationship between host factors and irAE occurrence.
To pool data across multiple institutions internationally and report on the cumulative experience of brainstem stereotactic radiosurgery (SRS).
Data on patients with brainstem metastases treated with ...SRS were collected through the International Gamma Knife Research Foundation. Clinical, radiographic, and dosimetric characteristics were compared for factors prognostic for local control (LC) and overall survival (OS) using univariate and multivariate analyses.
Of 547 patients with 596 brainstem metastases treated with SRS, treatment of 7.4% of tumors resulted in severe SRS-induced toxicity (grade ≥3, increased odds with increasing tumor volume, margin dose, and whole-brain irradiation). Local control at 12 months after SRS was 81.8% and was improved with increasing margin dose and maximum dose. Overall survival at 12 months after SRS was 32.7% and impacted by age, gender, number of metastases, tumor histology, and performance score.
Our study provides additional evidence that SRS has become an option for patients with brainstem metastases, with an excellent benefit-to-risk ratio in the hands of experienced clinicians. Prior whole-brain irradiation increases the risk of severe toxicity in brainstem metastasis patients undergoing SRS.
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