Primary Ciliary Dyskinesia Knowles, Michael R; Zariwala, Maimoona; Leigh, Margaret
Clinics in chest medicine,
09/2016, Letnik:
37, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Primary ciliary dyskinesia (PCD) is a recessive genetically heterogeneous disorder of motile cilia with chronic otosinopulmonary disease and organ laterality defects in ∼50% of cases. The prevalence ...of PCD is difficult to determine. Recent diagnostic advances through measurement of nasal nitric oxide and genetic testing has allowed rigorous diagnoses and determination of a robust clinical phenotype, which includes neonatal respiratory distress, daily nasal congestion, and wet cough starting early in life, along with organ laterality defects. There is early onset of lung disease in PCD with abnormal airflow mechanics and radiographic abnormalities detected in infancy and early childhood.
Background Familial hypercholesterolemia (FH) is a hereditary condition caused by various genetic mutations that lead to significantly elevated low-density lipoprotein cholesterol levels and ...resulting in a 20-fold increased lifetime risk for premature cardiovascular disease. Although its prevalence in the United States is 1 in 300 to 500 individuals, <10% of FH patients are formally diagnosed, and many are not appropriately treated. Contemporary data are needed to more fully characterize FH disease prevalence, treatment strategies, and patient experiences in the United States. Design The Familial Hypercholesterolemia Foundation (a patient-led nonprofit organization) has established the CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia (CASCADE FH) Registry as a national, multicenter initiative to identify US FH patients, track their treatment, and clinical and patient-reported outcomes over time. The CASCADE FH will use multiple enrollment strategies to maximize identification of FH patients. Electronic health record screening of health care systems will provide an efficient mechanism to identify undiagnosed patients. A group of specialized lipid clinics will enter baseline and annual follow-up data on demographics, laboratory values, treatment, and clinical events. Patients meeting prespecified low-density lipoprotein or total cholesterol criteria suspicious for FH will have the opportunity to self-enroll in an online patient portal with information collected directly from patients semiannually. Registry patients will be provided information on cascade screening and will complete an online pedigree to assist with notification of family members. Summary The Familial Hypercholesterolemia Foundation CASCADE FH Registry represents a novel research paradigm to address gaps in knowledge and barriers to comprehensive FH screening, identification, and treatment.
We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed ...with prior results from the Psychiatric Genomics Consortium Bipolar Disorder Working Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; P=3.28 × 10
) that includes the brain-enriched cytoskeleton protein adducin 3 (ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P (XPNPEP1). Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I SNP-h
=0.35; BD II SNP-h
=0.25; P=0.02). The genetic correlation between BD I and BD II was 0.78, whereas the genetic correlation was 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for schizophrenia and BD in patients with BD I compared with patients with BD II, and a greater load of schizophrenia risk alleles in patients with the bipolar type of schizoaffective disorder compared with patients with either BD I or BD II. These results point to a partial difference in the genetic architecture of BD subtypes as currently defined.
Summary Antibiotics have saved countless lives and enabled the development of modern medicine over the past 70 years. However, it is clear that the success of antibiotics might only have been ...temporary and we now expect a long-term and perhaps never-ending challenge to find new therapies to combat antibiotic-resistant bacteria. A broader approach to address bacterial infection is needed. In this Review, we discuss alternatives to antibiotics, which we defined as non-compound approaches (products other than classic antibacterial agents) that target bacteria or any approaches that target the host. The most advanced approaches are antibodies, probiotics, and vaccines in phase 2 and phase 3 trials. This first wave of alternatives to antibiotics will probably best serve as adjunctive or preventive therapies, which suggests that conventional antibiotics are still needed. Funding of more than £1·5 billion is needed over 10 years to test and develop these alternatives to antibiotics. Investment needs to be partnered with translational expertise and targeted to support the validation of these approaches in phase 2 trials, which would be a catalyst for active engagement and investment by the pharmaceutical and biotechnology industry. Only a sustained, concerted, and coordinated international effort will provide the solutions needed for the future.
Background In the US familial hypercholesterolemia (FH), patients are underidentified, despite an estimated prevalence of 1:200 to 1:500. Criteria to identify FH patients include Simon Broome, Dutch ...Lipid Clinic Network (DLCN), or Make Early Diagnosis to Prevent Early Deaths (MEDPED). The use of these criteria in US clinical practices remains unclear. Objective To characterize the FH diagnostic criteria applied by US lipid specialists participating in the FH Foundation's CASCADE FH (CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia) patient registry. Methods We performed an observational, cross-sectional analysis of diagnostic criteria chosen for each adult patient, both overall and by baseline patient characteristics, at 15 clinical sites that had contributed data to the registry as of September 8, 2015. A sample of 1867 FH adults was analyzed. The median age at FH diagnosis was 50 years, and the median pretreatment low-density lipoprotein cholesterol (LDL-C) value was 238 mg/dL. The main outcome was the diagnostic criteria chosen. Diagnostic criteria were divided into five nonexclusive categories: “clinical diagnosis,” MEDPED, Simon Broome, DLCN, and other. Results Most adults enrolled in CASCADE FH (55.0%) received a “clinical diagnosis.” The most commonly used formal criteria was Simon–Broome only (21%), followed by multiple diagnostic criteria (16%), MEDPED only (7%), DLCN only (1%), and other (0.5%), P < .0001. Of the patients with only a “clinical diagnosis,” 93% would have met criteria for Simon Broome, DLCN, or MEDPED based on the data available in the registry. Conclusions Our findings demonstrate heterogeneity in the application of FH diagnostic criteria in the United States. A nationwide consensus definition may lead to better identification, earlier treatment, and ultimately CHD prevention.
Background The November 2013 ACC/AHA cholesterol guidelines recommend the use of high-intensity statins for patients with atherosclerotic cardiovascular disease (ASCVD). We sought to determine how ...these guidelines are being adopted at the Veterans Affairs (VA) Health System and identify treatment gaps. Methods We examined administrative data from the VA 12 months prior to the index dates of 4/1/2013 and after 4/1/2014 to identify patients ≤75 years of age with ≥2 codes for ASCVD. We identified those on high-intensity statin therapy (atorvastatin 40 mg or 80 mg, rosuvastatin 20 mg or 40 mg, and simvastatin 80 mg) during the six months after the index date. Results The study sample included 331,927 and 326,759 eligible adults with ASCVD, before and after the release of the new guidelines, respectively. Overall, high-intensity statin use increased from 28% to 35% after guideline release. High-intensity statin use was lowest in Hispanics and Native Americans, though all groups showed an increase over time. Among those on low- or moderate-intensity statin therapy, 15.6% were intensified to a high-intensity statin after guideline release. Groups less likely to undergo statin intensification were older adults OR = 0.78 for each 10 year increase; 95% CI (0.76, 0.81), women OR = 0.86; 95% CI (0.75, 0.99) and certain minority groups. Academic teaching hospitals and hospitals on the west coast were more likely to intensify statins after release of the new guidelines. Conclusion High-intensity statin use increased in the VA following release of the ACC/AHA cholesterol treatment guidelines, though disparities persist for certain patient groups including older adults, women, and certain minority groups.
Although it is known that OCT4-NANOG are required for maintenance of pluripotent cells in vitro, the upstream signals that regulate this circuit during early development in vivo have not been ...identified. Here we demonstrate, for the first time, signal transducers and activators of transcription 3 (STAT3)-dependent regulation of the OCT4-NANOG circuitry necessary to maintain the pluripotent inner cell mass (ICM), the source of in vitro-derived embryonic stem cells (ESCs). We show that STAT3 is highly expressed in mouse oocytes and becomes phosphorylated and translocates to the nucleus in the four-cell and later stage embryos. Using leukemia inhibitory factor (Lif)-null embryos, we found that STAT3 phosphorylation is dependent on LIF in four-cell stage embryos. In blastocysts, interleukin 6 (IL-6) acts in an autocrine fashion to ensure STAT3 phosphorylation, mediated by janus kinase 1 (JAK1), a LIF- and IL-6-dependent kinase. Using genetically engineered mouse strains to eliminate Stat3 in oocytes and embryos, we firmly establish that STAT3 is essential for maintenance of ICM lineages but not for ICM and trophectoderm formation. Indeed, STAT3 directly binds to the Oct4 and Nanog distal enhancers, modulating their expression to maintain pluripotency of mouse embryonic and induced pluripotent stem cells. These results provide a novel genetic model of cell fate determination operating through STAT3 in the preimplantation embryo and pluripotent stem cells in vivo.
Since it was first proposed in the early eighties, the local approach to cleavage fracture, or Beremin model, has been applied to a wide range of engineering problems. However, several results have ...cast doubts on both the predictive capabilities and fundamental assumptions of the Beremin model. This three-part paper shows that most problems encountered with the original Beremin model result from an unnecessarily oversimplified description of the local cleavage event. A new statistical local criterion for cleavage is proposed, which expresses the necessity of maintaining a critical dynamic connectivity between microcrack nucleation and unstable propagation in order for cleavage fracture to occur.
Determining tensile properties from small punch test is being pursued actively in the nuclear industry due to the limited volume of material such tests use compared with standard tests which can be ...critical when considering active or development samples. One of the crucial challenges in harnessing the full potential of this technique is formulating methodologies which correlate the small punch specimen’s deflection to equivalent uniaxial tensile properties. Existing approaches for correlation rely on deflection obtained from a single point on the small punch test specimen, used with empirical equations to make the correlation. However, the deflection and strain accumulation in a small punch specimen is highly heterogeneous and data from a single point does not represent the gross deformation evolving in the specimen. This data when used in conjunction with the empirical formulations for deriving equivalent uniaxial tensile properties, would not result in accurate identification of material properties. In this work we offer an alternative approach which uses the full field deflection of the specimen mapped through in-situ digital image correlation. The use of digital image correlation combined with inverse finite element analysis augments the existing method of material properties identification from single point deflection data thereby significantly improving the reliability of the measurements.
•Full field deflection of small punch test specimen was mapped using in-situ DIC.•Deflections were used in inverse FEM for estimating mechanical properties.•Better estimate of properties was achieved using deflections from multiple points.
Familial hypercholesterolemia (FH) is a genetic disease characterized by substantial elevations of low-density lipoprotein cholesterol, unrelated to diet or lifestyle. Untreated FH patients have 20 ...times the risk of developing coronary artery disease, compared with the general population. Estimates indicate that as many as 1 in 500 people of all ethnicities and 1 in 250 people of Northern European descent may have FH; nevertheless, the condition remains largely undiagnosed. In the United States alone, perhaps as little as 1% of FH patients have been diagnosed. Consequently, there are potentially millions of children and adults worldwide who are unaware that they have a life-threatening condition. In countries like the Netherlands, the United Kingdom, and Spain, cascade screening programs have led to dramatic improvements in FH case identification. Given that there are currently no systematic approaches in the United States to identify FH patients or affected relatives, the patient-centric nonprofit FH Foundation convened a national FH Summit in 2013, where participants issued a “call to action” to health care providers, professional organizations, public health programs, patient advocacy groups, and FH experts, in order to bring greater attention to this potentially deadly, but (with proper diagnosis) eminently treatable, condition.
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