Prolonged enoxaparin therapy compared with standard-of-care antithrombotic therapy in opiate-treated patients undergoing primary percutaneous coronary intervention.

A novel enoxaparin regimen consisting of intra-arterial bolus (0.75 mg/kg) followed by intravenous infusion (0.75 mg/kg/6 hours) has been developed as a possible solution to the delayed absorption of oral P2Y12 inhibitors in opiate-treated ST-elevation myocardial infarction (STEMI) patients undergoing primary angioplasty. We aimed to study the feasibility of this regimen as an alternative to standard-of-care treatment (SOC) with unfractionated heparin ± glycoprotein IIb/IIIa antagonist (GPI). One hundred opiate-treated patients presenting with STEMI and accepted for primary angioplasty were randomized (1:1) to either enoxaparin or SOC. Fifty patients were allocated enoxaparin (median age 61, 40% females) and 49 allocated SOC (median age 62, 22% females). One developed stroke before angiography and was withdrawn. One SOC patient had a gastrointestinal bleed resulting in 1 g drop in hemoglobin and early cessation of GPI infusion. Two enoxaparin patients had transient minor bleeding: one transient gingival bleed and one episode of coffee ground vomit with no hemoglobin drop or hemodynamic instability. Two SOC and no enoxaparin group patients had acute stent thrombosis. These preliminary data support further study of this novel 6-hour enoxaparin regimen in opiate-treated PPCI patients.

Study of Two Dose Regimens of Ticagrelor Compared With Clopidogrel in Patients Undergoing Percutaneous Coronary Intervention for Stable Coronary Artery Disease.

BACKGROUND: Ticagrelor has superior efficacy to clopidogrel in the management of acute coronary syndromes but has not been assessed in patients undergoing percutaneous coronary intervention for stable coronary artery disease. We compared the pharmacodynamic effects of ticagrelor and clopidogrel in this stable population. METHODS: One hundred eighty aspirin-treated stable coronary artery disease patients, who were planned to undergo elective percutaneous coronary intervention in a single center, were randomized 1:1:1 to either a standard clopidogrel regimen or 1 of 2 regimens of ticagrelor, either 90 mg (T90) or 60 mg twice daily (T60), both with a 180 mg loading dose. Cellular adenosine uptake was assessed, at the time of the procedure and pre- and postdose at 1 month, by adding adenosine 1 µmol/L to aliquots of anticoagulated whole blood and mixing with a stop solution at 0, 15, 30, and 60 seconds, then measuring residual plasma adenosine concentration by high-performance liquid chromatography. Systemic plasma adenosine concentration and platelet reactivity were assessed at the same timepoints. High-sensitivity troponin T was measured pre- and 18 to 24 hours postpercutaneous coronary intervention. RESULTS: One hundred seventy-four patients underwent an invasive procedure, of whom 162 received percutaneous coronary intervention (mean age 65 years, 18% female, 21% with diabetes mellitus). No effect on in vitro adenosine uptake was seen postdose at 1 month for either ticagrelor dose compared with clopidogrel (residual adenosine at 15 seconds, mean±SD: clopidogrel 0.274±0.101 µmol/L; T90 0.278±0.134 µmol/L; T60 0.288±0.149 µmol/L; P=0.37). Similarly, no effect of ticagrelor on in vitro adenosine uptake was seen at other timepoints, nor was plasma adenosine concentration affected (all P>0.1). Both maintenance doses of ticagrelor achieved more potent and consistent platelet inhibition than clopidogrel (VerifyNow P2Y12 reaction units, 1 month, mean±SD: predose, T60: 62±47, T90: 40±38, clopidogrel 181±44; postdose, T60: 34±30, T90: 24±21, clopidogrel 159±57; all P<0.0001 for ticagrelor versus clopidogrel). High platelet reactivity was markedly less with both T60 and T90 compared with clopidogrel (VerifyNow P2Y12 reaction units>208, 1 month postdose: 0%, 0%, and 21%, respectively). Median (interquartile range) high-sensitivity troponin T increased 16.9 (6.5-46.9) ng/L for clopidogrel, 22.4 (5.5-53.8) ng/L for T60, and 17.7 (8.1-43.5) ng/L for T90 (P=0.95). There was a trend toward less dyspnea with T60 versus T90 (7.1% versus 19.0%; P=0.09). CONCLUSIONS: Maintenance therapy with T60 or T90 had no detectable effect on cellular adenosine uptake at 1 month, nor was there any effect on systemic plasma adenosine levels. Both regimens of ticagrelor achieved greater and more consistent platelet inhibition than clopidogrel but did not appear to affect troponin release after percutaneous coronary intervention. CLINICAL TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov. Unique identifier: NCT02327624.

Rare Presentation of a Marjolin's Ulcer Secondary to a Post-Traumatic Injury.

Marjolin's ulcer is a rare and aggressive cutaneous malignancy arising from previously traumatized skin, most commonly at the site of previous burns. We present a unique case of Marjolin's ulceration secondary to an orthopedic injury and a nonburn history of trauma. The patient had been involved in a motorcycle accident >20 years earlier. For 17 months, the patient had refused to acknowledge the severity of his disease state. He had refused the standard of care and opted for local wound care only until a minor fall caused a pathologic fracture, leading to an above the knee amputation. Road traffic incidents remain an uncommon cause of subsequent Marjolin's transformation in developed countries. As such, we present the case of a patient with a unique combination of a continued lack of compliance after diagnosis and the unusual cause of his initial trauma.

Transformation-optics-inspired anti-reflective coating design for gradient index lenses.

Recent developments in transformation optics have led to burgeoning research on gradient index lenses for novel optical systems. Such lenses hold great potential for the advancement of complex optics for a wide range of applications. Despite the plethora of literature on gradient index lenses, previous works have not yet considered the application of anti-reflective coatings to these systems. Reducing system reflections is crucial to the development of this technology for highly sensitive optical applications. Here, we present effective anti-reflective-coating designs for gradient index lens systems. Conventional anti-reflective-design methodologies are leveraged in conjunction with transformation optics to develop coatings that significantly reduce reflections of a flat gradient index lens. Finally, the resulting gradient-index anti-reflective coatings are compared and contrasted with conventional homogeneous anti-reflective coatings.

Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type.

Methylmalonic aciduria and homocystinuria, cblC type (OMIM 277400), is the most common inborn error of vitamin B(12) (cobalamin) metabolism, with about 250 known cases. Affected individuals have developmental, hematological, neurological, metabolic, ophthalmologic and dermatologic clinical findings. Although considered a disease of infancy or childhood, some individuals develop symptoms in adulthood. The cblC locus was mapped to chromosome region 1p by linkage analysis. We refined the chromosomal interval using homozygosity mapping and haplotype analyses and identified the MMACHC gene. In 204 individuals, 42 different mutations were identified, many consistent with a loss of function of the protein product. One mutation, 271dupA, accounted for 40% of all disease alleles. Transduction of wild-type MMACHC into immortalized cblC fibroblast cell lines corrected the cellular phenotype. Molecular modeling predicts that the C-terminal region of the gene product folds similarly to TonB, a bacterial protein involved in energy transduction for cobalamin uptake.

Epistasis between mouse Klra and major histocompatibility complex class I loci is associated with a new mechanism of natural killer cell-mediated innate resistance to cytomegalovirus infection.

Experimental infection with mouse cytomegalovirus (MCMV) has been used to elucidate the intricate host-pathogen mechanisms that determine innate resistance to infection. Linkage analyses in F(2) progeny from MCMV-resistant MA/My (H2 (k)) and MCMV-susceptible BALB/c (H2 (d)) and BALB.K (H2 (k)) mouse strains indicated that only the combination of alleles encoded by a gene in the Klra (also called Ly49) cluster on chromosome 6, and one in the major histocompatibility complex (H2) on chromosome 17, is associated with virus resistance. We found that natural killer cell-activating receptor Ly49P specifically recognized MCMV-infected cells, dependent on the presence of the H2 (k) haplotype. This binding was blocked using antibodies to H-2D(k) but not antibodies to H-2K(k). These results are suggestive of a new natural killer cell mechanism implicated in MCMV resistance, which depends on the functional interaction of the Ly49P receptor and the major histocompatibility complex class I molecule H-2D(k) on MCMV-infected cells.

Duration of triple antithrombotic therapy and clinical outcomes after percutaneous coronary intervention in atrial fibrillation.

BACKGROUND: Triple antithrombotic therapy (TAT) with aspirin, a P2Y12 inhibitor, and oral anticoagulation in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) raises concerns about increased bleeding. Regimens incorporating more potent P2Y12 inhibitors over clopidogrel have not been investigated adequately. RESEARCH DESIGN AND METHODS: A retrospective observational study was performed on 387 patients with AF receiving TAT for 1 month (n = 236) or ≤1 week (n = 151) after PCI. Major and clinically relevant non-major bleeding and major adverse cardiac and cerebrovascular events (MACCE) were assessed up to 30 days post-procedure. RESULTS: Bleeding was less frequent with ≤1 week versus 1 month of TAT (3.3 vs 9.3%; p = 0.025) while MACCE were similar (4.6 vs 4.7%; p = 0.998). No differences in bleeding or MACCE were observed between ticagrelor/prasugrel and clopidogrel regimens. For patients receiving ≤1 week of TAT, no excess of MACCE was seen in the subgroup given no further aspirin post-PCI compared with those given aspirin for up to 1 week (3.6 vs 5.2%). CONCLUSIONS: TAT post-PCI for ≤1 week was associated with less bleeding despite greater use of ticagrelor/prasugrel but similar MACCE versus 1-month TAT. These findings support further studies on safety and efficacy of dual therapy with ticagrelor/prasugrel immediately after PCI.

Modelled impact of virtual fractional flow reserve in patients undergoing coronary angiography (VIRTU-4).

BACKGROUND: The practical application of 'virtual' (computed) fractional flow reserve (vFFR) based on invasive coronary angiogram (ICA) images is unknown. The objective of this cohort study was to investigate the potential of vFFR to guide the management of unselected patients undergoing ICA. The hypothesis was that it changes management in >10% of cases. METHODS: vFFR was computed using the Sheffield VIRTUheart system, at five hospitals in the North of England, on 'all-comers' undergoing ICA for non-ST-elevation myocardial infarction acute coronary syndrome (ACS) and chronic coronary syndrome (CCS). The cardiologists' management plan (optimal medical therapy, percutaneous coronary intervention (PCI), coronary artery bypass surgery or 'more information required') and confidence level were recorded after ICA, and again after vFFR disclosure. RESULTS: 517 patients were screened; 320 were recruited: 208 with ACS and 112 with CCS. The median vFFR was 0.82 (0.70-0.91). vFFR disclosure did not change the mean number of significantly stenosed vessels per patient (1.16 (±0.96) visually and 1.18 (±0.92) with vFFR (p=0.79)). A change in intended management following vFFR disclosure occurred in 22% of all patients; in the ACS cohort, there was a 62% increase in the number planned for medical management, and in the CCS cohort, there was a 31% increase in the number planned for PCI. In all patients, vFFR disclosure increased physician confidence from 8 of 10 (7.33-9) to 9 of 10 (8-10) (p<0.001). CONCLUSION: The addition of vFFR to ICA changed intended management strategy in 22% of patients, provided a detailed and specific 'all-in-one' anatomical and physiological assessment of coronary artery disease, and was accompanied by augmentation of the operator's confidence in the treatment strategy.

Treatment of Nonhealing Diabetic Foot Wounds with Vaporous Hyperoxia Therapy in Conjunction with Standard Wound Care.

BACKGROUND: Vaporous hyperoxia therapy (VHT), a patented US Food and Drug Administration 510 (k)-cleared technology, is an adjunct therapy used in conjunction with standard wound care (SWC). Vaporous hyperoxia therapy is said to improve the health of wounded tissue by administering a low-frequency, noncontact, nonthermal, ionic, antimicrobial hydrating mist alternating with concentrated topical oxygen therapy. METHODS: Vaporous hyperoxia therapy was used to treat 36 subjects with chronic diabetic foot ulcers (DFUs) that were previously treated unsuccessfully with SWC. The average age of DFUs in the study was 11 months and the average size was over 3 cm2. Wounds were Wagner grade 2 or 3 and most commonly on the plantar surface around the midfoot. Treatment consisted of twice-weekly applications of VHT and wound debridement. Subjects were followed to wound closure, 20 weeks, or 40 treatments, whichever came first. RESULTS: The combination of SWC and VHT in the group that met and maintained compliance throughout the study period achieved an 83% DFU closure rate within a 20-week period. The average time for DFU closure in this study was 9.4 weeks. CONCLUSIONS: Historical analysis of SWC shows a 30.9% healing rate of all wounds, not differentiating chronic wounds. Accordingly, SWC/VHT increases chronic diabetic foot ulcer healing rates by 2.85 times compared with SWC alone. The purpose of this study was two-fold: first, to observe the effect of VHT on healing rates and time to healing in previously nonhealing DFUs; and second, to compare VHT with SWC, topical oxygen therapy, hyperbaric oxygen therapy, and ultrasound therapy.

Cerebral Protection Device Deployment Via Left Radial Artery During TAVI in Presence of Truncus Bicaroticus.

Patients with anomalous aortic arch undergoing transcatheter aortic valve implantation may require modifications to the deployment protocols of cerebral protection device systems. We share the first reported case, to our knowledge, of a cerebral protection device via the left radial artery and using a distal basket alone in a patient with truncus bicaroticus and arteria lusoria. (Level of Difficulty: Intermediate.).

Susceptibility to progressive Cryptococcus neoformans pulmonary infection is regulated by loci on mouse chromosomes 1 and 9.

Genetic factors that regulate the pathogenesis of pneumonia caused by the fungus Cryptococcus neoformans are poorly understood. Through a phenotypic strain survey we observed that inbred C3H/HeN mice develop a significantly greater lung fungal burden than mice of the resistant CBA/J strain 4 weeks following intratracheal infection with C. neoformans ATCC 24067. The aim of the present study was to characterize the inflammatory response of C3H/HeN mice following C. neoformans pulmonary infection and to identify genetic loci that regulate host defense. Following cryptococcal infection, C3H/HeN mice demonstrated a Th2 immune response with heightened airway and tissue eosinophilia, goblet cell metaplasia, and significantly higher lung interleukin-5 (IL-5) and IL-13 protein expression relative to CBA/J mice. Conversely, CBA/J mice exhibited greater airway and tissue neutrophilia that was associated with significantly higher pulmonary expression of gamma interferon, CXCL10, and IL-17 proteins than C3H/HeN mice. Using the fungal burden at 4 weeks postinfection as a phenotype, genome-wide quantitative trait locus (QTL) analysis among 435 segregating (C3H/HeN × CBA/J)F2 (C3HCBAF2) hybrids identified two significant QTLs on chromosomes 1 (Cnes4) and 9 (Cnes5) that control susceptibility to cryptococcal pneumonia in an additive manner. Susceptible C3H/HeN mice carry a resistance allele at Cnes4 and a susceptibility allele at Cnes5. These studies reveal additional genetic complexity of the host response to C. neoformans that is associated with divergent patterns of pulmonary inflammation.

Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy.

BACKGROUND: IgE-mediated peanut allergy is a complex trait with strong heritability, but its genetic basis is currently unknown. Loss-of-function mutations within the filaggrin gene are associated with atopic dermatitis and other atopic diseases; therefore, filaggrin is a candidate gene in the etiology of peanut allergy. OBJECTIVE: To investigate the association between filaggrin loss-of-function mutations and peanut allergy. METHODS: Case-control study of 71 English, Dutch, and Irish oral food challenge-positive patients with peanut allergy and 1000 non peanut-sensitized English population controls. Replication was tested in 390 white Canadian patients with peanut allergy (defined by food challenge, or clinical history and skin prick test wheal to peanut ≥ 8 mm and/or peanut-specific IgE ≥ 15 kUL(-1)) and 891 white Canadian population controls. The most prevalent filaggrin loss-of-function mutations were assayed in each population: R501X and 2282del4 in the Europeans, and R501X, 2282del4, R2447X, and S3247X in the Canadians. The Fisher exact test and logistic regression were used to test for association; covariate analysis controlled for coexistent atopic dermatitis. RESULTS: Filaggrin loss-of-function mutations showed a strong and significant association with peanut allergy in the food challenge-positive patients (P = 3.0 × 10(-6); odds ratio, 5.3; 95% CI, 2.8-10.2), and this association was replicated in the Canadian study (P = 5.4 × 10(-5); odds ratio, 1.9; 95% CI, 1.4-2.6). The association of filaggrin mutations with peanut allergy remains significant (P = .0008) after controlling for coexistent atopic dermatitis. CONCLUSION: Filaggrin mutations represent a significant risk factor for IgE-mediated peanut allergy, indicating a role for epithelial barrier dysfunction in the pathogenesis of this disease.

Coronary sinus thrombosis as a complication of myocardial infarction-associated ventricular wall rupture: an unusual cause of collapse.

Coronary sinus thrombosis is a rare phenomenon, most commonly occurring following invasive cardiac procedures. Spontaneous thrombosis is extremely rare and little is known about the natural history or optimal management. We present a case of coronary sinus thrombosis occurring in the context of myocardial infarction with concealed ventricular wall rupture.

The use of ticagrelor in a patient at increased risk of stent thrombosis resistant to multiple thienopyridines.

Ticagrelor has been shown to be superior to clopidogrel in patients presenting with acute myocardial infarction who undergo early invasive treatment. We discuss a hitherto unreported use of ticagrelor in the management of a patient resistant to multiple thienopyridines at high risk of stent thrombosis.

The Impact of Virtual Fractional Flow Reserve and Virtual Coronary Intervention on Treatment Decisions in the Cardiac Catheter Laboratory.

BACKGROUND: Using fractional flow reserve (FFR) to guide percutaneous coronary intervention for patients with coronary artery disease (CAD) improves clinical decision making but remains underused. Virtual FFR (vFFR), computed from angiographic images, permits physiologic assessment without a pressure wire and can be extended to virtual coronary intervention (VCI) to facilitate treatment planning. This study investigated the effect of adding vFFR and VCI to angiography in patient assessment and management. METHODS: Two cardiologists independently reviewed clinical data and angiograms of 50 patients undergoing invasive management of coronary syndromes, and their management plans were recorded. The vFFRs were computed and disclosed, and the cardiologists submitted revised plans. Then, using VCI, the physiologic results of various interventional strategies were shown and further revision was invited. RESULTS: Disclosure of vFFR led to a change in strategy in 27%. VCI led to a change in stent size in 48%. Disclosure of vFFR and VCI resulted in an increase in operator confidence in their decision. Twelve cases were reviewed by 6 additional cardiologists. There was limited agreement in the management plans between cardiologists based on either angiography (kappa = 0.31) or vFFR (kappa = 0.39). CONCLUSIONS: vFFR has the potential to alter decision making, and VCI can guide stent sizing. However, variability in management strategy remains considerable between operators, even when presented with the same anatomic and physiologic data.

The C3H/HeJ inbred mouse is a model of vesico-ureteric reflux with a susceptibility locus on chromosome 12.

Vesico-ureteric reflux is the most common congenital anomaly of the urinary tract, characterized by a defective uretero-vesical junction with retrograde urine flow from the bladder toward the kidneys. Because there is strong evidence for a genetic basis for some cases of vesico-ureteric reflux, we screened 11 inbred mouse strains for reflux and kidney size and identified one strain, C3H/HeJ, that has a 100 percent incidence of vesico-ureteric reflux with otherwise normal kidneys at birth. These mice are predisposed to reflux as a result of a defective uretero-vesical junction characterized by a short intravesical ureter. This defect results from a delay in urinary tract development initially manifested by a ureteric bud arising from a more caudal location along the mesonephric duct. In contrast, C57BL/6J mice (resistant to reflux at birth) have long intravesical ureters, normally positioned ureteric buds, and no delay in urinary tract development. Genome-wide and additional fine mapping of backcross mice, derived from C3H/HeJ and C57BL/6J crosses, identified a significant reflux susceptibility locus, Vurm1, on chromosome 12 (peak logarithm of the odds=7.39). The C3H/HeJ mouse is a model of vesico-ureteric reflux without renal malformation, and further characterization of this model will allow for the identification of a pathway important for urinary tract development, a finding that will serve as a model for the human disorder.

Association between genome-wide association studies reported SNPs and pediatric-onset Crohn's disease in Canadian children.

A recent pediatric-focused genome-wide association study has implicated three novel susceptibility loci for Crohn' disease (CD).We aimed to investigate whether the three recently reported and other previously reported genes/loci were also associated with CD in Canadian children. A case-control design was implemented at three pediatric gastroenterology clinics in Canada. Children <19 years of age with a confirmed diagnosis of CD were recruited along with controls. Single nucleotide polymorphisms (SNPs) in 19 reported genes/loci were genotyped. Associations between individual SNPs and CD were examined. A total of 563 cases and 553 controls were studied. The mean (+/-SD) age of the cases was 12.3 (+/-3.2) years. Most cases were male (56.0%), had ileo-colonic disease (L3 +/- L4, 48.8%) and inflammatory behavior (B1 +/- p, 87.9%) at diagnosis. Allelic association analysis (two-tailed) showed that 8 of the 19 targeted SNPs were significantly associated with overall susceptibility for CD. Associations with one additional SNP was borderline non-significant. Significantly associated SNPs included SNPs rs1250550 (p = 0.026) and rs8049439 (p = 0.04), recently reported to be specifically associated with pediatric-onset CD.Based on the results, we confirmed associations between two of the three novel pediatric-CD loci and other regions reported for associations with either pediatric and/or adult-onset CD.

Disseminated intravascular coagulation, meningococcal infection, and ischemic changes affecting the lower extremities: a case study.

A middle-aged woman presented from an outside hospital with a diagnosis of Neisseria meningitidis and meningococcemia. A nonpalpable purpuric skin rash evolved into multiple wounds, with gradual necrosis of bilateral lower and upper extremities. Throughout the course of hospitalization, the patient developed ventricular tachycardia, normocytic anemia, thrombocytosis, Clostridium difficile infection, depression, and transient right eye blindness. The finding of decreased CH50 in the complement cascade was considered as the potential cause of the meningococcemia. The subsequent ischemia and necrosis of extremities were attributed to the systemic effect and trauma ensuing from N. meningitidis.

Investigation of reported associations between the 20q13 and 21q22 loci and pediatric-onset Crohn's disease in Canadian children.

OBJECTIVES: A recent pediatric-focused genome-wide association study has reported novel associations of the 20q13 and 21q22 loci with inflammatory bowel disease (IBD). We aimed to investigate these associations with Crohn's disease (CD) in Canadian children. METHODS: A combined case-control and case-parent design was implemented at three pediatric gastroenterology clinics in Canada. Children less than 20 years of age with a confirmed diagnosis of CD were recruited along with controls. For a subset of the patients, biological parents were also recruited. Three single-nucleotide polymorphisms (SNPs) at the 20q13 locus and 1 SNP at the 21q22 locus were genotyped. Associations between individual SNPs and haplotypes were examined. RESULTS: A total of 410 cases, 415 controls, and 302 parents were studied. The mean (+/-s.d.) age for the cases was 12.3 (+/-3.2) years. Most cases were men (56.1%) who had ileocolonic disease (L3+/-L4, 52.2%) and inflammatory behavior (B1+/-B4, 87.0%) at diagnosis. Single SNP analysis showed that all 3 SNPs at the 20q13 locus were significantly associated with CD (rs2297441, P=2.24x10(-4); rs2315008, P=4.77x10(-4); rs4809330, P=6.08x10(-3)). Haplotype analysis suggested that the association signal at 20q13 resided on a common haplotype comprising the minor allele of rs2297441 (P=2.8x10(-5)). SNP rs2836878 at the 21q22 locus showed a trend for association with CD that was statistically not significant (P=0.06). CONCLUSIONS: Our results support an association between the 20q13 locus and CD in Canadian children. Positional cloning studies are required to further dissect the potential causative genes in the region.