Peripheral artery disease (PAD) is the third most common form of atherosclerotic vascular disease and is characterized by significant functional disability and increased cardiovascular mortality. ...Recent genetic data support a role for a procoagulation protein variant, the factor V Leiden mutation, in PAD. The role of other hemostatic factors in PAD remains unknown. We evaluated the role of hemostatic factors in PAD using Mendelian randomization. Approach and Results: Two-sample Mendelian randomization to evaluate the roles of FVII (factor VII), FVIII (factor VIII), FXI (factor XI), VWF (von Willebrand factor), and fibrinogen in PAD was performed using summary statistics from GWAS for hemostatic factors performed within the Cohorts for Heart and Aging Research in the Genome Epidemiology Consortium and from GWAS performed for PAD within the Million Veteran Program. Genetically determined FVIII and VWF, but not FVII, FXI, or fibrinogen, were associated with PAD in Mendelian randomization experiments (FVIII: odds ratio, 1.41 95% CI, 1.23-1.62,
=6.0×10
, VWF: odds ratio, 1.28 95% CI, 1.07-1.52,
=0.0073). In single variant sensitivity analysis, the
locus was the strongest genetic instrument for both FVIII and VWF.
Our results suggest a role for hemostasis, and by extension, thrombosis in PAD. Further study is warranted to determine whether VWF and FVIII independently affect the biology of PAD.
Abstract Objective To evaluate the association of gastric acid suppression medications, including proton pump inhibitors and histamine type 2 blockers, with outcomes in patients with Clostridium ...difficile infection (CDI) in a population-based cohort. Patients and Methods To understand the association between acid suppression and outcomes in patients with CDI, we conducted a population-based study in Olmsted County, Minnesota, from January 1, 1991, through December 31, 2005. We compared demographic data and outcomes, including severe, severe-complicated, and recurrent CDI and treatment failure, in a cohort of patients with CDI who were treated with acid suppression medications with these outcomes in a cohort with CDI that was not exposed to acid-suppressing agents. Results Of 385 patients with CDI, 36.4% were undergoing acid suppression (23.4% with proton pump inhibitors, 13.5% with histamine type 2 blockers, and 0.5% with both). On univariate analysis, patients taking acid suppression medications were significantly older (69 vs 56 years; P <.001) and more likely to have severe (34.2% vs 23.6%; P =.03) or severe-complicated (4.4% vs 2.6% CDI; P =.006) infection than patients not undergoing acid suppression. On multivariable analyses, after adjustment for age and comorbid conditions, acid suppression medication use was not associated with severe or severe-complicated CDI. In addition, no association between acid suppression and treatment failure or CDI recurrence was found. Conclusion In this population-based study, after adjustment for age and comorbid conditions, patients with CDI who underwent acid suppression were not more likely to experience severe or severe-complicated CDI, treatment failure, or recurrent infection.
We report brigatinib long-term efficacy and safety from phase 1/2 and phase 2 (ALTA) trials in ALK–rearrangement positive (ALK+) NSCLC.
The phase 1/2 study evaluated brigatinib 30 to 300 mg/d in ...patients with advanced malignancies. ALTA randomized patients with crizotinib-refractory ALK+ NSCLC to brigatinib 90 mg once daily (arm A) or 180 mg once daily (7-d lead-in at 90 mg; arm B).
In the phase 1/2 study, 79 of 137 brigatinib-treated patients had ALK+ NSCLC; 71 were crizotinib pretreated. ALTA randomized 222 patients (n = 112 in arm A; n = 110 in arm B). Median follow-up at phase 1/2 study end (≈5.6 y after last patient enrolled) was 27.7 months; at ALTA study end (≈4.4 y after last patient enrolled), 19.6 months (A) and 28.3 months (B). Among patients with ALK+ NSCLC in the phase 1/2 study, median investigator-assessed progression-free survival (PFS) was 14.5 months (95% confidence interval CI: 10.8–21.2); median overall survival was 47.6 months (28.6–not reached). In ALTA, median investigator-assessed PFS was 9.2 months (7.4–11.1) in arm A and 15.6 months (11.1–18.5) in arm B; median independent review committee (IRC)-assessed PFS was 9.9 (7.4–12.8) and 16.7 (11.6–21.4) months, respectively; median overall survival was 25.9 (18.2–45.8) and 40.6 (32.5–not reached) months, respectively. Median intracranial PFS for patients with any brain metastases was 12.8 (9.2–18.4) months in arm A and 18.4 (12.6–23.9) months in arm B. No new safety signals were identified versus previous analyses.
Brigatinib exhibited sustained long-term activity and PFS with manageable safety in patients with crizotinib-refractory ALK+ NSCLC.
Study objective We determine the effect of crowding on emergency department (ED) waiting room, treatment, and boarding times across multiple sites and acuity groups. Methods This was a retrospective ...cohort study that included ED visit and inpatient medicine occupancy data for a 1-year period at 4 EDs. We measured crowding at 30-minute intervals throughout each patient's ED stay. We estimated the effect of crowding on waiting room time, treatment time, and boarding time separately, using discrete-time survival analysis with time-dependent crowding measures (ie, number waiting, number being treated, number boarding, and inpatient medicine occupancy rate), controlling for patient demographic and clinical characteristics. Results Crowding substantially delayed patients' waiting room and boarding times but not treatment time. During the day shift, when the number boarding increased from the 50th to the 90th percentile, the adjusted median waiting room time (range 26 to 70 minutes) increased by 6% to 78% (range 33 to 82 minutes), and the adjusted median boarding time (range 250 to 626 minutes) increased by 15% to 47% (range 288 to 921 minutes), depending on the site. Crowding delayed the care of high-acuity level 2 patients at all sites. During crowded periods (ie, 90%), the adjusted median waiting room times of high-acuity level 2 patients were 3% to 35% higher than during normal periods, depending on the site and crowding measure. Conclusion Using discrete-time survival analysis, we were able to dynamically measure crowding throughout each patient's ED visit and demonstrate its deleterious effect on the timeliness of emergency care, even for high-acuity patients.
H9N2 avian influenza viruses are continuously monitored by the World Health Organization because they are endemic; they continually reassort with H5N1, H7N9 and H10N8 viruses; and they periodically ...cause human infections. We characterized H9N2 influenza viruses carrying internal genes from highly pathogenic H7N3 viruses, which were isolated from chickens or quail from live-bird markets in Bangladesh between 2010 and 2013. All of the H9N2 viruses used in this study carried mammalian host-specific mutations. We studied their replication kinetics in normal human bronchoepithelial cells and swine tracheal and lung explants, which exhibit many features of the mammalian airway epithelium and serve as a mammalian host model. All H9N2 viruses replicated to moderate-to-high titers in the normal human bronchoepithelial cells and swine lung explants, but replication was limited in the swine tracheal explants. In Balb/c mice, the H9N2 viruses were nonlethal, replicated to moderately high titers and the infection was confined to the lungs. In the ferret model of human influenza infection and transmission, H9N2 viruses possessing the Q226L substitution in hemagglutinin replicated well without clinical signs and spread via direct contact but not by aerosol. None of the H9N2 viruses tested were resistant to the neuraminidase inhibitors. Our study shows that the Bangladeshi H9N2 viruses have the potential to infect humans and highlights the importance of monitoring and characterizing this influenza subtype to better understand the potential risk these viruses pose to humans.
Among the world’s most deadly toxins are a class of organophosphates that are used as chemical warfare agents (CWAs). It is imperative to continue to develop novel means for mitigation and protection ...against these chemical threats. Sensitizing the surface of metal oxide semiconductors with plasmonic nanoparticles for photocatalytic degradation of chemical threats has been a prominent area of research in recent years. Anisotropic silver nanoplateles were purposefully grown on the surface of TiO2 fibers, in order to determine the impact of silver nanoparticle shape on (1) the generation of hot electrons by the silver, (2) the subsequent transfer of those electrons from the silver into the TiO2, and (3) the photocatalytic behavior of the Ag–TiO2 composite. To elucidate the charge injection properties of the composites, transient absorption experiments (pump–probe experiments) were undertaken. These involved pumping the composite samples with a range of discrete visible wavelengths and probing the composite within the intraband transitions of the TiO2. As a complement to these experiments, the photocatalytic properties of the Ag–TiO2 composite fibers were studied via the photocatalytic hydrolysis of methyl paraoxon, a chemical warfare agent simulant. This involved exposure of the methyl paraoxon to either red, green, blue, or white LED illumination. For both the transient absorption and photocatalytic experiments, maximum efficiency was observed for those scenarios in which the resonance of the silver platelets most closely matched the wavelength of incident radiation. Furthermore, the composite with silver nanoplatelets clearly outperformed its counterpart with silver nanospheres, in terms of both charge injection and photocatalytic behavior. We believe these results shall serve as a basis for future catalytic research in which the resonance of anisotropic plasmonic nanoparticles (in a given composite) shall be designed to match the wavelength of incident radiation.
This paper presents the results of the irradiation, characterization and irradiation assisted stress corrosion cracking (IASCC) behavior of proton- and neutron-irradiated samples of 304SS and 316SS ...from the same heats. The objective of the study was to determine whether proton irradiation does indeed emulate the full range of effects of in-reactor neutron irradiation: radiation-induced segregation (RIS), irradiated microstructure, radiation hardening and IASCC susceptibility. The work focused on commercial heats of 304 stainless steel (heat B) and 316 stainless steel (heat P). Irradiation with protons was conducted at 360 °C to doses between 0.3 and 5.0 dpa to approximate those by neutron irradiation at 275 °C over the same dose range. Characterization consisted of grain boundary microchemistry, dislocation loop microstructure, hardness as well as stress corrosion cracking (SCC) susceptibility of both un-irradiated and irradiated samples in oxygenated and de-oxygenated water environments at 288 °C. Overall, microchemistry, microstructure, hardening and SCC behavior of proton- and neutron-irradiated samples were in excellent agreement. RIS analysis showed that in both heats and for both irradiating particles, the pre-existing grain boundary Cr enrichment transformed into a `W' shaped profile at 1.0 dpa and then into a `V' shaped profile between 3.0 and 5.0 dpa. Grain boundary segregation of Cr, Ni, Si, and Mo all followed the same trends and agreed well in magnitude. The microstructure of both proton- and neutron-irradiated samples was dominated by small, faulted dislocation loops. Loop size distributions were nearly identical in both heats over a range of doses. Saturated loop size following neutron irradiation was about 30% larger than that following proton irradiation. Loop density increased with dose through 5.0 dpa for both particle irradiations and was a factor of 3 greater in neutron-irradiated samples vs. proton-irradiated samples. Grain boundary denuded zones were only observed in neutron-irradiated samples. No cavities were observed for either irradiating particle. For both irradiating particles, hardening increased with dose for both heats, showing a more rapid increase and approach to saturation for heat B. In normal oxygenated water chemistry (NWC) at 288 °C, stress corrosion cracking in the 304 alloy was first observed at about 1.0 dpa and increased with dose. The 316 alloy was remarkably resistant to IASCC for both particle types. In hydrogen treated, de-oxygenated water (HWC), proton-irradiated samples of the 304 alloy exhibited IG cracking at 1.0 dpa compared to about 3.0 dpa for neutron-irradiated samples, although differences in specimen geometry, test condition and test duration can account for this difference. Cracking in heat P in HWC occurred at about 5.0 dpa for both irradiating particles. Thus, in all aspects of radiation effects, including grain boundary microchemistry, dislocation loop microstructure, radiation hardening and SCC behavior, proton-irradiation results were in good agreement with neutron-irradiation results, providing validation of the premise that the totality of neutron-irradiation effects can be emulated by proton irradiation of appropriate energy.
Background
In the esophagus, high‐resolution manometry (HRM) has become a standard diagnostic tool in the investigation of suspected motility disorders. However, at the opposite end of the digestive ...tract (i.e., the colon and anorectum), the use of HRM still remains in its infancy, with relatively few published studies in the scientific literature. Further, the clinical utility of those studies that have been performed is largely undetermined.
Purpose
This review assesses all of the HRM studies published to date from both the colon and anorectum, explores the catheter types used, and attempts to determine the worth of HRM over traditional ‘low‐resolution’ recordings from the same regions. Ultimately, this review addresses whether HRM currently provides information that will benefit patient diagnosis and treatment.
This review summarizes the findings from all high‐resolution manometry studies in the anorectum and colon, and indicates future directions for this field.
Summary
Background
Earlier studies have suggested that untreated coeliac disease may be associated with osteoporosis, but results are contradictory for the risk of long‐term fractures.
Aim
To study ...the association between coeliac disease and fractures.
Methods
We used Cox regresson to examine the future risk of hip fracture and fracture of any type in more than 13 000 individuals with coeliac disease and 65 000 age‐ and sex‐matched reference individuals in a general population‐based cohort.
Results
During follow‐up, 1365 first hip fractures and 4847 fractures of any type occurred. Coeliac disease was positively associated with subsequent hip fracture (hazard ratio = 2.1; 95% CI = 1.8–2.4) (in children: hazard ratio = 2.6; 95% CI = 1.1–6.2) and fractures of any type (hazard ratio = 1.4; 95% CI = 1.3–1.5) (in children: hazard ratio = 1.1; 95% CI = 1.0–1.2). The absolute excess risk of hip fractures in children with coeliac disease was 4/100 000 person‐years. Incidence ratios for hip fracture in individuals with CD were around two both prior to diagnosis of coeliac disease and afterwards; this risk increase remained 20 years after diagnosis of coeliac disease.
Conclusions
Individuals with coeliac disease, including children with coeliac disease, may be at increased risk of hip fracture and fracture of any type. Coeliac disease may be positively associated with long‐term hip fracture risk.
The axon initial segment is an excitable membrane highly enriched in voltage-gated sodium channels that integrates neuronal inputs and initiates action potentials. This study identifies Na v1.6 as ...the voltage-gated sodium channel isoform at mature Purkinje neuron initial segments and reports an essential role for ankyrin-G in coordinating the physiological assembly of Na v1.6, βIV spectrin, and the L1 cell adhesion molecules (L1 CAMs) neurofascin and NrCAM at initial segments of cerebellar Purkinje neurons. Ankyrin-G and βIV spectrin appear at axon initial segments by postnatal day 2, whereas L1 CAMs and Na v1.6 are not fully assembled at continuous high density along axon initial segments until postnatal day 9. L1 CAMs and Na v1.6 therefore do not initiate protein assembly at initial segments. βIV spectrin, Na v1.6, and L1 CAMs are not clustered in adult Purkinje neuron initial segments of mice lacking cerebellar ankyrin-G. These results support the conclusion that ankyrin-G coordinates the physiological assembly of a protein complex containing transmembrane adhesion molecules, voltage-gated sodium channels, and the spectrin membrane skeleton at axon initial segments.
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