Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal ...antibodies against C. difficile toxins A and B, respectively.
We conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population.
In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% 67 of 386 vs. 28% 109 of 395; adjusted difference, -10.1 percentage points; 95% confidence interval CI, -15.9 to -4.3; P<0.001; MODIFY II: 16% 62 of 395 vs. 26% 97 of 378; adjusted difference, -9.9 percentage points; 95% CI, -15.5 to -4.3; P<0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% 61 of 383 vs. 28% 109 of 395; adjusted difference, -11.6 percentage points; 95% CI, -17.4 to -5.9; P<0.001; MODIFY II: 15% 58 of 390 vs. 26% 97 of 378; adjusted difference, -10.7 percentage points; 95% CI, -16.4 to -5.1; P<0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea.
Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. (Funded by Merck; MODIFY I and MODIFY II ClinicalTrials.gov numbers, NCT01241552 and NCT01513239 .).
Many neutron star properties, such as the proton fraction, reflect the symmetry energy contributions to the equation of state that dominate when neutron and proton densities differ strongly. To ...constrain these contributions at suprasaturation densities, we measure the spectra of charged pions produced by colliding rare isotope tin (Sn) beams with isotopically enriched Sn targets. Using ratios of the charged pion spectra measured at high transverse momenta, we deduce the slope of the symmetry energy to be 42<L<117 MeV. This value is slightly lower but consistent with the L values deduced from a recent measurement of the neutron skin thickness of ^{208}Pb.
The injection and mixing of contaminant mass into the fuel in inertial confinement fusion (ICF) implosions is a primary factor preventing ignition. ICF experiments have recently achieved an ...alpha-heating regime, in which fusion self-heating is the dominant source of yield, by reducing the susceptibility of implosions to instabilities that inject this mass. We report the results of unique separated reactants implosion experiments studying pre-mixed contaminant as well as detailed high-resolution three-dimensional simulations that are in good agreement with experiments. At conditions relevant to mixing regions in high-yield implosions, we observe persistent chunks of contaminant that do not achieve thermal equilibrium with the fuel throughout the burn phase. The assumption of thermal equilibrium is made in nearly all computational ICF modeling and methods used to infer levels of contaminant from experiments. We estimate that these methods may underestimate the amount of contaminant by a factor of two or more.
Objectives This study sought to determine if adenosine administration is required for the pressure-only assessment of coronary stenoses. Background The instantaneous wave-free ratio (iFR) is a ...vasodilator-free pressure-only measure of the hemodynamic severity of a coronary stenosis comparable to fractional flow reserve (FFR) in diagnostic categorization. In this study, we used hyperemic stenosis resistance (HSR), a combined pressure-and-flow index, as an arbiter to determine when iFR and FFR disagree which index is most representative of the hemodynamic significance of the stenosis. We then test whether administering adenosine significantly improves diagnostic performance of iFR. Methods In 51 vessels, intracoronary pressure and flow velocity was measured distal to the stenosis at rest and during adenosine-mediated hyperemia. The iFR (at rest and during adenosine administration iFRa), FFR, HSR, baseline, and hyperemic microvascular resistance were calculated using automated algorithms. Results When iFR and FFR disagreed (4 cases, or 7.7% of the study population), HSR agreed with iFR in 50% of cases and with FFR in 50% of cases. Differences in magnitude of microvascular resistance did not influence diagnostic categorization; iFR, iFRa, and FFR had equally good diagnostic agreement with HSR (receiver-operating characteristic area under the curve 0.93 iFR vs. 0.94 iFRa and 0.96 FFR, p = 0.48). Conclusions iFR and FFR had equivalent agreement with classification of coronary stenosis severity by HSR. Further reduction in resistance by the administration of adenosine did not improve diagnostic categorization, indicating that iFR can be used as an adenosine-free alternative to FFR. (Classification Accuracy of Pressure-Only Ratios Against Indices Using Flow Study CLARIFY; NCT01118481 )
COVID-19 is causing a major once-in-a-century global pandemic. The scientific and clinical community is in a race to define and develop effective preventions and treatments. The major features of ...disease are described but clinical trials have been hampered by competing interests, small scale, lack of defined patient cohorts and defined readouts. What is needed now is head-to-head comparison of existing drugs, testing of safety including in the background of predisposing chronic diseases, and the development of new and targeted preventions and treatments. This is most efficiently achieved using representative animal models of primary infection including in the background of chronic disease with validation of findings in primary human cells and tissues. We explore and discuss the diverse animal, cell and tissue models that are being used and developed and collectively recapitulate many critical aspects of disease manifestation in humans to develop and test new preventions and treatments.
Background
Acquired bilateral telangiectatic macules (ABTM) are a newly recognized disease entity, which manifest as multiple telangiectatic pigmented macules confined mostly to the upper arms.
...Objectives
To evaluate clinical and dermoscopic features in a group of 50 patients with ABTM and to determine the diagnostic usefulness of dermoscopy in ABTM.
Methods
Patients were selected from two tertiary teaching hospitals in Korea Pusan National University Hospitals (Busan and Yangsan). Fifty patients (41 males and 9 females; mean age 48.1 years; range 26–78 years) with ABTM were included in the study. The dermoscopic findings were graded using a 4‐point scale: none (0), mild (1), moderate (2) and severe (3). In addition, the results of 23 patients with and 27 patients without chronic liver disease (CLD) were compared to determine whether the presence of CLD affects dermoscopic findings.
Results
Three distinct dermoscopic patterns were observed; brown pigmentations, telangiectasia (linear‐irregular vessels) and an angioid streak pattern. Brown pigmentation in the group without CLD had higher severity score than those in CLD group (mean score: 2.00 vs. 1.48, P = 0.033). However, mean telangiectasia severity score was higher in the CLD group (2.14 vs. 1.39, P < 0.001). The angioid streak pattern was more severe and more common in patients with CLD than in those without 1.37 vs. 0.35 (P < 0.001) and 63.0% vs. 26.1%, respectively.
Conclusions
Detailed observations with dermoscopy can provide first clues of the presence of ABTM and underlying chronic liver disease.
Summary
Background Giant congenital melanocytic naevi (GCMN) are known risk factors for the development of melanoma. However, melanoma risk among Asians is rarely evaluated.
Objectives To evaluate ...the clinical characteristics and risk of melanoma development from GCMN in Koreans, we performed a nationwide retrospective cohort study in Korea. GCMN were defined as those comprising ≥ 5% body surface area in children or measuring ≥ 20 cm in adults.
Methods In total, 131 patients with GCMN were enrolled, with a mean age of 10·3 years (range: birth–70 years).
Results The posterior trunk was the most common site (67, 51·1%), followed by lateral trunk, anterior trunk, legs, both anterior and posterior trunk, buttocks, and arms. Satellite naevi were present in 69 cases (52·7%), and axial areas were more commonly involved in patients with satellite naevi than in those without satellite lesions. Atypical features such as rete ridge elongation and bridges were seen, and, among these, pagetoid spread and ballooning cell changes were more common in patients < 4 years old. Proliferative nodules were found in three cases. Melanomas had developed in three of 131 patients (2·3%; a 6‐year‐old girl, a 14‐year‐old girl and a 70‐year‐old man), and the incidence rate was 990 per 100 000 person‐years. Melanomas in these three patients consisted of two cutaneous melanomas and one extracutaneous meningeal melanoma.
Conclusions We should be aware of melanoma development from GCMN, and lifelong follow‐up is required due to the risk of melanoma arising in GCMN.
Large Area Light Detectors With MMC Readouts Kim, M. B.; Chung, J. S.; Jeon, J. A. ...
IEEE transactions on applied superconductivity,
08/2023, Volume:
33, Issue:
5
Journal Article
Peer reviewed
We present the development of the light detectors with magnetic microcalorimeter (MMC) readouts designed for the AMoRE neutrinoless double beta decay experiment. The detectors are composed of Ge or ...Si wafer as an absorber for scintillation light and an MMC detector to monitor the temperature of the wafer. Five measurements were carried out with one Ge wafer and four Si wafers prepared under various conditions. Different details of the light detector assembly have been tested to find the optimal configuration for the future AMoRE-II experiment. Direct comparisons in signal size were performed with the different wafers while considering favorable conditions for the future AMoRE setup. Moreover, a baseline resolution of 34.3 eV FWHM was obtained in a detector setup with a 2-inch Si wafer.
Polygenic inheritance plays a central role in Parkinson disease (PD). A priority in elucidating PD etiology lies in defining the biological basis of genetic risk. Unraveling how risk leads to ...disruption will yield disease-modifying therapeutic targets that may be effective. Here, we utilized a high-throughput and hypothesis-free approach to determine biological processes underlying PD using the largest currently available cohorts of genetic and gene expression data from International Parkinson’s Disease Genetics Consortium (IPDGC) and the Accelerating Medicines Partnership-Parkinson’s disease initiative (AMP-PD), among other sources. We applied large-scale gene-set specific polygenic risk score (PRS) analyses to assess the role of common variation on PD risk focusing on publicly annotated gene sets representative of curated pathways. We nominated specific molecular sub-processes underlying protein misfolding and aggregation, post-translational protein modification, immune response, membrane and intracellular trafficking, lipid and vitamin metabolism, synaptic transmission, endosomal–lysosomal dysfunction, chromatin remodeling and apoptosis mediated by caspases among the main contributors to PD etiology. We assessed the impact of rare variation on PD risk in an independent cohort of whole-genome sequencing data and found evidence for a burden of rare damaging alleles in a range of processes, including neuronal transmission-related pathways and immune response. We explored enrichment linked to expression cell specificity patterns using single-cell gene expression data and demonstrated a significant risk pattern for dopaminergic neurons, serotonergic neurons, hypothalamic GABAergic neurons, and neural progenitors. Subsequently, we created a novel way of building de novo pathways by constructing a network expression community map using transcriptomic data derived from the blood of PD patients, which revealed functional enrichment in inflammatory signaling pathways, cell death machinery related processes, and dysregulation of mitochondrial homeostasis. Our analyses highlight several specific promising pathways and genes for functional prioritization and provide a cellular context in which such work should be done.
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