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The use of exome and genome sequencing has increased rapidly nowadays. After primary analysis, further analysis can be performed to identify secondary findings that offer medical benefit for patient care. Multiple studies have been performed to evaluate secondary findings in different ethnicities. However, relevant data are limited in Chinese. Here, with the use of a cohort consisted of 1116 Hong Kong Chinese exome sequencing data, we evaluated the secondary findings in the 59 genes recommended by the American College of Medical Genetics and Genomics. Fifteen unique pathogenic or likely pathogenic variants in 17 individuals were identified, representing a frequency of 1.52% in our cohort. Although 20 individuals harboured pathogenic or likely pathogenic variants in recessive conditions, none carried bi-allelic mutations in the same gene. Our finding was in accordance with the estimation from the American College of Medical Genetics and Genomics that about 1% individuals harbour secondary findings.

International audience; We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.

Background Pharmacogenetics is the study of variability in drug response caused by genetic variations. It is estimated that over two million hospitalized patients develop severe adverse drug reactions in the United States annually, incurring a direct medical cost of 200 billion US dollars (USD). This indicates a huge potential in reducing healthcare costs even if only a small proportion of adverse drug reactions are preventable by genotype-guided prescription. The current clinical applications of pharmacogenetics are mostly limited to reactive pharmacogenetic testing, in which investigations are ordered only when certain high-risk medications are prescribed, or after an adverse drug reaction has occurred. In contrast, preemptive pharmacogenetic testing allows the optimization of dosing based on genotype information at the time of prescription, minimizing the risk of undesired outcomes. Objectives Pharmacogenetics (PGx) encompasses the potential to improve therapeutic response and reduce adverse drug reaction in the era of precision medicine. However, Chinese PGx data is limited. To address this issue, we examined the spectrum of 133 actionable pharmacogenetic variants and rare deleterious variants in 108 pharmacogenes and estimated the proportion of dispensed drugs that may potentially benefit from genotype-guided prescriptionusing an exome sequencing (ES) cohort. Methods Secondary analysis of ES data was conducted to study pharmacogenetics in 1116 HK Chinese, which included 622 males and 494 females. The projected preemptive pharmacogenetic testing prescription impact was evaluated based on the patient prescription data between January 1, 2019 and December 31, 2019 in the HK public healthcare system, serving 7.5 million people and accounting for approximately 90% of all secondary and tertiary healthcare services provided. Results Twenty-nine actionable pharmacogenetic variants/alleles were identified in our cohort. Nearly all (99.6%) subjects carried at least one actionable pharmacogenetic variant, with a median of four variants, whereas 93.5% of subjects harbored at least one rare deleterious pharmacogenetic variant, with a median of two variants. The frequency of actionable genotypes was the highest in recipients of clopidogrel (57.21%), tacrolimus (43.38%), and warfarin (43.13%). Based on the prescription data of the public healthcare system in 2019, 13.4% of the HK population was prescribed with drugs with implicated actionable pharmacogenotypes in the HK population. The total expenditure on actionable drugs was 33,520,000 USD, and it was estimated that 8,219,000 USD (24.5%) worth of drugs were prescribed to patients with an implicated actionable genotype. Conclusions In conclusion, nearly all individuals carried at least one actionable pharmacogenetic variant and one rare, deleterious pharmacogenetic variant in our cohort. It was estimated that oneseventh of the HK population received at least one of the 36 drugs with CPIC guideline recommendations, and 8,219,000 USD worth of drugs were prescribed to patients with an implicated actionable genotype. The results showed that secondary use of ES data is feasible for pharmacogenetic analysis, and preemptive pharmacogenetic testing has the potential to support prescription decisions in inpatient and specialist outpatient settings in the HK Chinese population.

Balanced chromosomal abnormalities (BCAs) are changes in the localization or orientation of a chromosomal segment without visible gain or loss of genetic material. BCAs occur at a frequency of 1 in 500 newborns and are associated with an increased risk of multiple congenital anomalies and/or neurodevelopmental disorders, especially if it is a de novo mutation. In this pilot project, we used short read genome sequencing (GS) to retrospectively re-sequence ten prenatal subjects with de novo BCAs and compared the performance of GS with the original karyotyping. GS characterized all BCAs found by conventional karyotyping with the added benefit of precise sub-band delineation. By identifying BCA breakpoints at the nucleotide level using GS, we found disruption of OMIM genes in three cases and identified cryptic gain/loss at the breakpoints in two cases. Of these five cases, four cases reached a definitive genetic diagnosis while the other one case had a BCA interpreted as unknown clinical significance. The additional information gained from GS can change the interpretation of the BCAs and has the potential to improve the genetic counseling and perinatal management by providing a more specific genetic diagnosis. This demonstrates the added clinical utility of using GS for the diagnosis of BCAs.

Background Mitochondrial diseases (MDs) are a group of clinically and genetically heterogeneous disorders characterized by defects in oxidative phosphorylation. Since clinical phenotypes of MDs may be non-specific, genetic diagnosis is crucial for guiding disease management. In the current study, whole-exome sequencing (WES) was performed for our paediatric-onset MD cohort of a Southern Chinese origin, with the aim of identifying key disease-causing variants in the Chinese patients with MDs. Methods We recruited Chinese patients who had paediatric-onset MDs and a minimum mitochondrial disease criteria (MDC) score of 3. Patients with positive target gene or mitochondrial DNA sequencing results were excluded. WES was performed, variants with population frequency ≤ 1% were analysed for pathogenicity on the basis of the American College of Medical Genetics and Genomics guidelines. Results Sixty-six patients with pre-biopsy MDC scores of 3–8 were recruited. The overall diagnostic yield was 35% (23/66). Eleven patients (17%) were found to have mutations in MD-related genes, with COQ4 having the highest mutation rate owing to the Chinese-specific founder mutation (4/66, 6%). Twelve patients (12/66, 18%) had mutations in non-MD-related genes: ATP1A3 (n = 3, two were siblings), ALDH5A1, ARX, FA2H, KCNT1, LDHD, NEFL, NKX2-2, TBCK, and WAC. Conclusions We confirmed that the COQ4:c.370G>A, p.(Gly124Ser) variant, was a founder mutation among the Southern Chinese population. Screening for this mutation should therefore be considered while diagnosing Chinese patients suspected to have MDs. Furthermore, WES has proven to be useful in detecting variants in patients suspected to have MDs because it helps to obtain an unbiased and precise genetic diagnosis for these diseases, which are genetically heterogeneous.

Preemptive pharmacogenetic testing has the potential to improve drug dosing by providing point-of-care patient genotype information. Nonetheless, its implementation in the Chinese population is limited by the lack of population-wide data. In this study, secondary analysis of exome sequencing data was conducted to study pharmacogenomics in 1116 Hong Kong Chinese. We aimed to identify the spectrum of actionable pharmacogenetic variants and rare, predicted deleterious variants that are potentially actionable in Hong Kong Chinese, and to estimate the proportion of dispensed drugs that may potentially benefit from genotype-guided prescription. The projected preemptive pharmacogenetic testing prescription impact was evaluated based on the patient prescription data of the public healthcare system in 2019, serving 7.5 million people. Twenty-nine actionable pharmacogenetic variants/ alleles were identified in our cohort. Nearly all (99.6%) subjects carried at least one actionable pharmacogenetic variant, whereas 93.5% of subjects harbored at least one rare deleterious pharmacogenetic variant. Based on the prescription data in 2019, 13.4% of the Hong Kong population was prescribed with drugs with pharmacogenetic clinical practice guideline recommendations. The total expenditure on actionable drugs was 33,520,000 USD, and it was estimated that 8,219,000 USD (24.5%) worth of drugs were prescribed to patients with an implicated actionable phenotype. Secondary use of exome sequencing data for pharmacogenetic analysis is feasible, and preemptive pharmacogenetic testing has the potential to support prescription decisions in the Hong Kong Chinese population., Author summary Pharmacogenetic testing provides relevant drug phenotype information to guide personalized drug prescription, which potentially improves drug efficacy and prevent adverse drug reactions. However, its implementation in the Chinese population is limited by the lack of Chinese-specific pharmacogenetics data. In this study, we studied the spectrum of 133 actionable pharmacogenetic variants and rare deleterious variants in 108 pharmacogenes using an exome sequencing consisting of 1116 Hong Kong Chinese subjects. It was found that nearly all individuals carried at least one actionable pharmacogenetic variant and one rare, predicted deleterious pharmacogenetic variant. In addition, we projected the potential prescription impact of actionable pharmacogenetic variants using prescription data of the Hong Kong's public healthcare system. We estimated that one-seventh of the Hong Kong population received at least one of the 36 drugs with clinical pharmacogenetics guideline recommendations. The findings demonstrated the potential of pharmacogenetic testing in improving patient care and resource allocation in Chinese. The cohort dataset also supports clinical implementation of pharmacogenetics in the Chinese population.

Background Rapid whole-exome sequencing (rWES) offers the potential for early diagnosis-predicated precision medicine. Previous evidence focused predominantly on infants from the intensive care unit (ICU). This study sought to examine the diagnostic and clinical utility, and the economic impact on clinical management of rWES in patients beyond infancy and ICU setting. Methods rWES was performed on a prospective cohort of patients with suspected monogenic disorder referred from territory-wide paediatric ICUs and non-ICUs in Hong Kong urging for rapid genetic diagnosis. All eligible families were invited. We aimed to achieve a rapid turnaround time (TAT) of 14 days. Clinical utility and costs associated with clinical management were assessed in diagnosed cases. Actual quantitative changes in healthcare utilisation were compared with a counterfactual diagnostic trajectory and/or with matched historical control whenever possible. Findings rWES were offered to 102 families and 32/102 (31%) patients received a molecular diagnosis, with a median TAT of 11 days. Clinical management changed in 28 of 32 diagnosed patients (88%), including but not limited to modifications in treatment, avoidance of surgeries, and informing decisions on redirection of care. Cost analysis was performed in eight patients. rWES was estimated to reduce hospital length of stay by 566 days and decrease healthcare costs by HKD$8,044,250 (GBP£796,460) for these eight patients. The net cost-savings after inclusion of rWES costs were estimated to be HKD$5,325,187 (GBP£527,246). Interpretation This study replicates the diagnostic capacity and rapid TAT of rWES in predominantly Chinese patients, and demonstrates diagnosis-predicated precision medicine and net healthcare savings. Findings were corroborated by evidence from multinational cohorts, combined as part of a meta-analysis. rWES merits consideration as a first-tier diagnostic tool for patients with urgent needs in the clinical setting. Funding Health and Medical Research Fund, HKU Seed Fund for Basic Research, The Society for the Relief of Disabled Children, and Edward and Yolanda Wong Fund.

Background Autosomal recessive or compound heterozygous mutations in KLHL40 cause nemaline myopathy 8, which is one of the most severe forms of nemaline myopathy. The KLHL40 c.1516A>C variant has recently been reported as a founder mutation in southern Chinese. Methods We report six cases of nemaline myopathy 8 which involves the c.1516A>C variant, from five unrelated families of non‐consanguineous southern Chinese. The pre‐ and postnatal phenotypes of these cases were reviewed with emphasis on prenatal clinical features. Genetic testing for the founder mutation was performed on three patients with homozygous mutations. Results Common prenatal features included reduced fetal movement, polyhydramnios, breech presentation, and clubfeet. Two pregnancies were terminated. Four live‐born patients had postnatal features typical of nemaline myopathy 8. The length of survival ranged from 49 days to 17 months, with respiratory failure and infections being the principal causes of death. Haplotype analysis in three patients with homozygous mutation showed a shared haplotype block of 1.1727 cM spanning over the c.1516A>C variant, suggesting it is a southern Chinese‐specific founder mutation. Conclusion Analysis of the KLHL40 c.1516A>C variant should be considered in prenatal diagnosis of Chinese pregnant patients with suspected congenital neuromuscular disorders or with significant family history of congenital myopathies., We reported six cases from five unrelated families of non‐consanguineous southern Chinese affected by nemaline myopathy 8, with either homozygous variants or compound heterozygous variants involving c.1516A>C in KLHL40. Pre‐ and postnatal phenotypes of the cases were reviewed, with emphasis on the prenatal clinical features.

Exome sequencing (ES) has become one of the important diagnostic tools in clinical genetics with a reported diagnostic rate of 25–58%. Many studies have illustrated the diagnostic and immediate clinical impact of ES. However, up to 75% of individuals remain undiagnosed and there is scarce evidence supporting clinical utility beyond a follow-up period of >1 year. This is a 3-year follow-up analysis to our previous publication by Mak et al. (NPJ Genom. Med. 3:19, 2018), to evaluate the long-term clinical utility of ES and the diagnostic potential of exome reanalysis. The diagnostic yield of the initial study was 41% (43/104). Exome reanalysis in 46 undiagnosed individuals has achieved 12 new diagnoses. The additional yield compared with the initial analysis was at least 12% (increased from 41% to at least 53%). After a median follow-up period of 3.4 years, change in clinical management was observed in 72.2% of the individuals (26/36), leading to positive change in clinical outcome in four individuals (11%). There was a minimum healthcare cost saving of HKD$152,078 (USD$19,497; €17,282) annually for these four individuals. There were a total of six pregnancies from five families within the period. Prenatal diagnosis was performed in four pregnancies; one fetus was affected and resulted in termination. None of the parents underwent preimplantation genetic diagnosis. This 3-year follow-up study demonstrated the long-term clinical utility of ES at individual, familial and health system level, and the promising diagnostic potential of subsequent reanalysis. This highlights the benefits of implementing ES and regular reanalysis in the clinical setting.

Contains fulltext : 218289.pdf (Publisher’s version ) (Closed access) MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/10 individuals. Rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery. MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3' region of exon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. We propose that the condition described here, MN1 C-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis.

Summary Objective Early onset drug‐resistant epilepsy is a neurologic disorder in which 2 antiepileptic drugs fail to maintain the seizure‐free status of the patient. Heterogeneous clinical presentations make the diagnosis challenging. We aim to identify the underlying genetic causes of a pediatric cohort with drug‐resistant epilepsy and evaluate whether the findings can provide information on patient management. Methods We include patients with drug‐resistant epilepsy onset before 18 years of age. Singleton clinical chromosomal microarray (CMA) followed by whole exome sequencing (WES) was performed using genomic DNA. In the first‐tier analysis of the exome data, we aimed to identify disease‐causing mutations in 546 genes known to cause, or to be associated with, epilepsy. For negative cases, we proceeded to exome‐wide analysis. Rare coding variants were interrogated for pathogenicity based on the American College of Medical Genetics and Genomics (ACMG) guidelines. Results We recruited 50 patients. We identified 6 pathogenic or likely pathogenic mutations, giving a diagnostic yield of 12%. Mutations were found in 6 different genes: SCN8A, SCN1A, MECP2, CDKL5, DEPDC5, and CHD2. The CDKL5 variant was found to be mosaic. One variant of unknown significance (VUS) in KCNT1 was found in a patient with compatible clinical features. Of note, a reported pathogenic SCN5A mutation known to contribute to Brugada syndrome, was also found in the patient with an SCN1A mutation. Significance Our study suggests that singleton WES is an effective diagnostic tool for drug‐resistant epilepsy. Genetic diagnosis can help to consolidate the clinical diagnosis, to facilitate phenotypic expansion, and to influence treatment and management options for seizure control in our patients. In our study, a significant portion of the genetic findings are known to be associated with an increased risk of sudden unexpected death in epilepsy (SUDEP). These findings could assist with more appropriate management in patients with epilepsy.

Background Whole-exome sequencing (WES) has become an invaluable tool for genetic diagnosis in paediatrics. However, it has not been widely adopted in the prenatal setting. This study evaluated the use of WES in prenatal genetic diagnosis in fetuses with structural congenital anomalies (SCAs) detected on prenatal ultrasound. Method Thirty-three families with fetal SCAs on prenatal ultrasonography and normal chromosomal microarray results were recruited. Genomic DNA was extracted from various fetal samples including amniotic fluid, chorionic villi, and placental tissue. Parental DNA was extracted from peripheral blood when available. We used WES to sequence the coding regions of parental-fetal trios and to identify the causal variants based on the ultrasonographic features of the fetus. Results Pathogenic mutations were identified in three families (n = 3/33, 9.1%), including mutations in DNAH11, RAF1 and CHD7, which were associated with primary ciliary dyskinesia, Noonan syndrome, and CHARGE syndrome, respectively. In addition, variants of unknown significance (VUSs) were detected in six families (18.2%), in which genetic changes only partly explained prenatal features. Conclusion WES identified pathogenic mutations in 9.1% of fetuses with SCAs and normal chromosomal microarray results. Databases for fetal genotype-phenotype correlations and standardized guidelines for variant interpretation in prenatal diagnosis need to be established to facilitate the use of WES for routine testing in prenatal diagnosis. Electronic supplementary material The online version of this article (10.1186/s12920-018-0409-z) contains supplementary material, which is available to authorized users.

Introduction: Loncastuximab tesirine (loncastuximab tesirine-lpyl; Lonca) is an FDA-approved CD19-directed antibody-drug conjugate (ADC) indicated for the treatment of adult patients with relapsed or refractory (R/R) large B-cell lymphoma after ≥2 lines of systemic therapy, including patients with high-grade B-cell lymphoma. In the Phase 2 LOTIS-2 trial (NCT03589469), Lonca was evaluated as a single agent in patients with R/R diffuse large B-cell lymphoma (DLBCL) and the overall response rate (ORR) was 48.3% (Caimi PF, et al. Lancet Oncol. 2021; 22:790-800). In an analysis of the 11 patients from the LOTIS-2 clinical trial with high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBCL; data cutoff: April 6, 2020), 45.5% (n=5) achieved an overall response. In this patient subgroup, the median duration of response was 13.37 months, and the median progression-free survival was 9.13 months. The aim of this analysis (data cut off: March 1, 2021) was to further characterize the clinical characteristics and efficacy of Lonca in patients with HGBCL enrolled in the LOTIS-2 clinical trial. Methods: The methodology for the LOTIS-2 trial has been published. Briefly, Lonca (0.15 mg/kg for the first 2 cycles followed by 0.075 mg/kg for subsequent cycles) was administered as a single 30-minute infusion, once every 3 weeks for up to 1 year, until progressive disease or unacceptable toxicity. The primary outcome was ORR defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR), assessed by independent review. Investigator assessment of histopathology according to the 2016 WHO classification was used to define HGBCL. Results: The demographics and disease characteristics of the 11 patients with HGBCL are shown in Table 1. The median age was 74 years; 5 patients (45.5%) were age ≥75 years. The majority of patients received ≥3 prior lines of therapy (n = 8; 72.7%). One patient had a prior stem cell transplant (autologous; 9.1%). Of the 11 patients with HGBCL, the overall response rate was 45.5%, with all 5 patients achieving CR. The median (min, max) time to first CR or PR response was 43.0 (38, 148) days and the median time to first CR response was 79.0 (38, 148) days. All five responding patients (45.5%) had a duration of response ≥1 year; median duration of response has not been reached at the time of data cutoff. Conclusions: Efficacy data from this small subgroup of patients with HGBCL enrolled in the LOTIS-2 clinical trial are consistent with the overall trial population. These results suggest that Lonca is active in the treatment of this high-risk lymphoma subgroup, achieving comparable response rates with other risk groups and with long-term disease control in responding patients. Funding: This study was funded by ADC Therapeutics; medical writing support was provided by CiTRUS Health Group. Figure 1 Figure 1. Disclosures Alderuccio: Inovio Pharmaceuticals: Other: Family member; Agios Pharmaceuticals: Other: Family member; Puma Biotechnology: Other: Family member; ADC Therapeutics: Consultancy, Research Funding; Oncinfo / OncLive: Honoraria; Forma Therapeutics: Other: Family member. Ai: Kymria, Kite, ADC Therapeutics, BeiGene: Consultancy. Radford: ADC Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria, Speakers Bureau; BMS: Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Current holder of individual stocks in a privately-held company. Solh: Jazz Pharmaceuticals: Consultancy; BMS: Consultancy; Partner Therapeutics: Research Funding; ADCT Therapeutics: Consultancy, Research Funding. Ardeshna: Gilead, Beigene, Celegene, Novartis and Roche: Honoraria; Norvartis, BMS, Autolus, ADCT, Pharmocyclics and Jansen: Research Funding; Gilead, Beigene, Celegene, Novartis and Roche: Membership on an entity's Board of Directors or advisory committees. Lunning: AbbVie: Consultancy; Novartis: Consultancy; Beigene: Consultancy; ADC Therapeutics: Consultancy; Daiichi-Sankyo: Consultancy; Spectrum: Consultancy; Acrotech: Consultancy; AstraZeneca: Consultancy; Myeloid Therapeutics: Consultancy; Janssen: Consultancy; Verastem: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; Kite, a Gilead Company: Consultancy; Kyowa Kirin: Consultancy; Karyopharm: Consultancy; TG Therapeutics: Consultancy; Morphosys: Consultancy; Legend: Consultancy. Hess: BMS: Speakers Bureau; ADC Therapeutics: Consultancy. Zinzani: EUSAPHARMA: Consultancy, Other, Speakers Bureau; SANDOZ: Other: Advisory board; ROCHE: Other, Speakers Bureau; MSD: Consultancy, Other: Advisory board, Speakers Bureau; NOVARTIS: Consultancy, Other, Speakers Bureau; TG Therapeutics: Other: Advisory board, Speakers Bureau; KYOWA KIRIN: Other, Speakers Bureau; TAKEDA: Other: Advisory board, Speakers Bureau; Beigene: Other, Speakers Bureau; Incyte: Other, Speakers Bureau; ADC Therap.: Other; SERVIER: Other: Advisory board, Speakers Bureau; BMS: Other: Advisory board, Speakers Bureau; JANSSEN-CILAG: Other: Advisory board, Speakers Bureau; GILEAD: Other: Advisory board, Speakers Bureau; CELLTRION: Other: Advisory board, Speakers Bureau; VERASTEM: Consultancy, Other: Advisory board, Speakers Bureau. Stathis: Abbvie and PharmaMar: Other: travel grant; Pfizer, ADC Therapeutics, Bayer, Roche, Merck, Novartis, MEI Therapeutics and Abbvie: Research Funding; Bayer / Eli Lilly: Consultancy. Carlo-Stella: Sanofi: Consultancy, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Janssen Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees. Hamadani: Sanofi, Genzyme, AstraZeneca, BeiGene: Speakers Bureau; Janssen, Incyte, ADC Therapeutics, Omeros, Morphosys, Kite: Consultancy; Takeda, Spectrum Pharmaceuticals and Astellas Pharma: Research Funding. Kahl: AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding; AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy. Ungar: ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Kilavuz: ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Yu: ADC Therapeutics: Current Employment. Qin: ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Caimi: TG Therapeutics: Honoraria; Amgen Therapeutics.: Consultancy; XaTek: Patents & Royalties: Royalties from patents (wife); ADC Theraputics: Consultancy, Research Funding; Seattle Genetics: Consultancy; Verastem: Consultancy; Genentech: Research Funding; Kite Pharmaceuticals: Consultancy.

Additive-manufacturing techniques show more and more utilization potentialities in today’s aviation industry. In order to ensure safe operation of additive-manufactured parts, it is important to have their mechanical properties well-characterized and assessed. In this study, elevated temperature fatigue behaviours and tensile properties of a selective laser melting (SLM) fabricated K536 alloy are investigated for horizontal and vertical building orientation, respectively. A series of tensile tests at 20 oC ~700 oC temperature range and stress-controlled fatigue tests at 400oC and 600oC are conducted. Effects of building orientation and temperature on tensile and fatigue behaviours are analysed. Scanning Electron Microscopy (SEM) is used to examine the fracture surfaces of fatigue specimens to qualify the failure mechanism and crack initiation sites. K536 parts manufactured via SLM are shown to exhibit anisotropic tensile properties at different testing temperatures. Anisotropy of fatigue properties is not obvious at 400oC and 600oC. Cracks are likely to initiate at the surface sliding or subsurface crystallographic plane of fatigue specimens in middle life regime and at subsurface or central zone crystallographic plane in longer life regime. In shorter life regime, cracks are easy to initiate at un-melted zones of fatigue specimens.

Additive manufacturing (AM) technologies are increasing in importance for aerospace application, where the demand for a fundamental understanding and predictability of static and dynamic material properties are high. As the most widely used and studied alloy for this technology, Selective laser melting (SLM) produced Ti6Al4V alloy is evaluated on tensile and fatigue crack growth (FCG) performances at RT and 400℃. Conventionally manufactured Ti6Al4V alloys are concerned for comparison. Different orientations are considered to investigate the anisotropy of tensile and FCG behavior. The results show that, the tensile properties at RT and 400℃ are highly dependent on the specimen orientation relative to build direction. The FCG resistance is related to specimen orientation in the near threshold region but no relationship with specimen orientation in the steady growth stage at RT. The FCG resistance is much less influenced by specimen orientation at 400℃. The tensile strength at RT and 400℃ of SLM alloy reaches even exceeds the strength level of conventionally manufactured alloys such as forging, bar and casting. The steady stage FCG resistance under stress ratio of 0.1 of SLM alloy is also comparable to conventionally manufactured alloys. The SLM alloy shows higher FCG resistance under stress ratio of 0.1 than 0.5, but the da/dN-△K curves of the two stress ratios are very close to each other. The steady stage FCG rate at RT is slower than 400℃ in the lower △K region and faster in the higher △K region.

Background Neuromuscular disorders (NMDs) comprise a group of heterogeneous genetic diseases with a broad spectrum of overlapping the clinical presentations that makes diagnosis challenging. Notably, the recent introduction of whole‐exome sequencing (WES) is introducing rapid changes on the genetic diagnosis of NMDs. We aimed to investigate the diagnostic value of WES for pediatric‐onset NMDs. Methods We applied integrated diagnostic approach and performed WES in 50 Chinese subjects (30 males, 20 females) with undiagnosed pediatric‐onset NMDs despite previous specific tests. The patients were categorized in four subgroups according to phenotyping and investigation findings. Variants on NMDs gene list and open exome analysis for those with initial negative findings were identified. Results WES identified causative variants in ACTA1 (n = 2), POMT1, COL6A1 (n = 2), MTMR2, LMNA, SELENON, DNM2, TGFB1, MPZ, IGHMBP2, and LAMA2 in 13 patients. Two subjects have variants of uncertain significance (VUSs) in TTN and SCN11A, unlikely to be pathogenic due to incompatible phenotypes. The mean interval time from symptom onset to genetic diagnosis was 10.4 years (range from 1 month to 33 years). The overall diagnostic yield of WES in our cohort was 26%. Open exome analysis was necessary to identify the pathogenic variant in TGFB1 that caused skeletal dysplasia with neuromuscular presentation. Conclusion Our study shows a clear role of WES in the pathway of integrated diagnostic approach to shorten the diagnostic odyssey in patients with rare NMDs., Our study achieved a diagnostic yield from WES of 26% (13/50). These cases were diagnostically challenging as prior investigations failed to give clues on specific genetic diagnosis. Our findings are compatible to previous studies observing the diagnostic yield tends to be lower in cohorts that have already undergone prior extensive evaluations.

Primary coenzyme Q10 deficiency-7 (COQ10D7) is a rare mitochondrial disease caused by biallelic mutations in COQ4. Here we report the largest cohort of COQ10D7 to date, with 11 southern Chinese patients confirmed with biallelic COQ4 mutations. Five of them have the classical neonatal-onset encephalo-cardiomyopathy, while the others have infantile onset with more heterogeneous clinical presentations. We also identify a founder mutation COQ4 (NM_016035.5): c.370G>A, p.(Gly124Ser) for COQ10D7, suggesting a higher chance of occurrence in the southern Chinese. This study helps improve understanding of the clinical spectrum of this disorder.

Huge variations exist in cardiology training programs across the world. In developing (middle-income) countries, such as Brazil, to find the right balance between training improvements and social and economic conditions of the country may be a difficult task. Adding more training years or different mandatory rotations, for instance, may be costly and not have an immediate direct impact on enhancing patient care or public health. In this text, we compare the Brazilian cardiology training system with other proposals implemented in developed countries from North America and Europe, aiming to point out issues worth of future discussion. Factors such as training rotations and competencies, and program duration and distribution across the countries are presented. The number of first year cardiology trainees per inhabitants is similar between Brazil and the United States (0.24 medical residents/100,000 inhabitants in Brazil and 0.26 medical residents/100,000 inhabitants in the USA). These numbers should be analyzed considering the inequality in training program distribution across Brazil, since most centers are located in the Southeast and South regions. Having more residency programs in distant areas could improve cardiovascular care in these areas. Duration of cardiology Residency Training is shorter in Brazil (two years) in comparison with developed countries (> 3 years). Brazilian residency programs give less emphasis to scientific research and diagnostic methods. Unifying minimum training requirements across the globe would facilitate the development of international learning opportunities and even professional exchange around the world.

We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n=35,584 total samples, 11,986 with ASD). Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 53 show higher frequencies in individuals ascertained for ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most of the risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In human cortex single-cell gene expression data, expression of risk genes is enriched in both excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.

Supplemental Digital Content is available in the text., Background: Human heterotaxy is a group of congenital disorders characterized by misplacement of one or more organs according to the left-right axis. The genetic causes of human heterotaxy are highly heterogeneous. Methods: We performed exome sequencing in a cohort of 26 probands with heterotaxy followed by gene burden analysis for the enrichment of novel rare damaging mutations. Transcription activator-like effector nuclease was used to generate somatic loss-of-function mutants in a zebrafish model. Ciliary defects were examined by whole-mount immunostaining of acetylated α-tubulin. Results: We identified a significant enrichment of novel rare damaging mutations in the CC2D1A gene. Seven occurrences of CC2D1A mutations were found to affect 4 highly conserved amino acid residues of the protein. Functional analyses in the transcription activator-like effector nuclease–mediated zebrafish knockout models were performed, and heterotaxy phenotypes of the cardiovascular and gastrointestinal systems in both somatic and germline mutants were observed. Defective cilia were demonstrated by whole-mount immunostaining of acetylated α-tubulin. These abnormalities were rescued by wild-type cc2d1a mRNA but not cc2d1a mutant mRNA, strongly suggesting a loss-of-function mechanism. On the other hand, overexpression of cc2d1a orthologous mutations cc2d1a P559L and cc2d1a G808V (orthologous to human CC2D1A P532L and CC2D1A G781V) did not affect embryonic development. Conclusions: Using a zebrafish model, we were able to establish a novel association of CC2D1A with heterotaxy and ciliary dysfunction in the F2 generation via a loss-of-function mechanism. Future mechanistic studies are needed for a better understanding of the role of CC2D1A in left-right patterning and ciliary dysfunction.

Spinocerebellar ataxia 35 (SCA35) has been associated with pathogenic mutations in the gene TGM6. In a Chinese exome sequencing cohort, we identified 8 families with reported TGM6 variants sharing no features of SCA35. Considering this finding, we reviewed the public database gnomAD and found these variants to be significantly more common in the East Asians than in other ethnic groups (P 0.0001). Gene constraint metrics showed that both missense and loss-of-function variants in TGM6 are likely to be tolerated and there is no regional constraint. By performing inflation analysis, it demonstrated that the cumulative frequency of TGM6 reported pathogenic variants is at least 111-fold inflated over disease prevalence of all autosomal dominant SCAs, indicating a high chance of misdiagnosis or low penetrance. Misclassification of benign or low penetrant variants as pathogenic is a significant problem that often results in genetic misdiagnosis. This highlights the necessity of evaluating variant pathogenicity with sequencing of genomes from diverse populations, both from asymptomatic controls and phenotypically different patients, in order to ensure accurate classification of variants.

Background Childhood cancer survivors treated with anthracycline chemotherapy are at an increased risk of long-term cardiac toxicity, and guidelines recommend that exposed survivors undergo echocardiography every 1–5 years. However, it is unclear whether survivors should undergo echocardiographic screening indefinitely, or if a period of echocardiographic stability indicates that screening is no longer necessary. The objective of this study was to evaluate the outcomes of echocardiographic screening to aid in the refinement of existing guidelines. Methods We retrospectively analyzed the results of echocardiographic screening in a cohort of adult survivors of childhood cancer treated with anthracyclines and/or cardiac radiation therapy. Interval regression analysis was performed to identify predictors of single-episode or sustained abnormal echocardiograms. Results The cohort constituted 333 survivors, with median follow-up time of 15.8 years post-treatment (range: 5.0–47.9), and median age at treatment of 8 years (range: 1.5–18). Forty-nine survivors had an abnormal echocardiogram (14.7%), and 29 (8.7%) had reproducible abnormal findings. An ongoing continual increase in the incidence of sustained echocardiographic abnormality was seen among patients treated with >250 mg/m2 doxorubicin at age

Cognitive and procedural skills required of cardiologists have increased in the past 10 years. What is unknown is whether residents consistently meet recommended volumes during training and what their own subjective assessments of their competency are after training. The purpose of this study was to (1) determine whether current training provides residents with opportunities to develop skills to function independently and (2) identify whether residents perceive gaps in their skills. We surveyed current and recent graduates of adult cardiology programs in Canada. One hundred ten responses from 425 surveys were received. Procedural and diagnostic test interpretation volumes were recorded, as were the optimum number the respondents believed were important to complete to function independently. These volumes were compared with the 2008 American College of Cardiology Core Cardiology Training Symposium (COCATS 3) and the Canadian Cardiovascular Society (CCS) recommendations for training. The proportion of residents meeting recommended volumes for diagnostic test interpretation ranged from 7% (Holter monitors) to 91% (echocardiograms). For procedures, the range was from 71% (echocardiography) to 100% (cardioversion). The ratio of residents' perceived minimum numbers believed to be required for proficiency for diagnostic test interpretation to those recommended ranged from 14% (electrocardiograms) to 116% (echocardiograms), and for procedures, the ratio was 66% (temporary pacemaker placement) to 116% (echocardiography). Recent graduates' perception of minimum required numbers to achieve competency is underestimated compared with COCATS 3 and CCS recommendations. Few graduates achieved the recommended volume targets suggested for diagnostic test interpretation.

By means of the stress–strain finite element method (FEM) in elastic–plastic regime, the influences of the applied stress on the distribution of von Mises stress and evolution of shape regularity of γ′ phase in a [0 1 1] oriented single crystal nickel-based superalloy are investigated. Results show that, after full heat treatment, the microstructure of [0 1 1] oriented single crystal superalloy consists of the cuboidal γ′ phase embedded coherently in the γ matrix phase, and on (1 0 0) plane aligned regularly at angle of 45° relative to the [0 1 1] orientation. During compressive creep, the cuboidal γ′ phase is transformed into the mesh-like lamellar rafted structure on (1 0 0) plane. Therefore, the changes of the lattice strain, the strain energy density and interfacial energy are thought to be the driving forces of the element diffusion and γ′ phase directional growth. During compressive creep, the lattice contraction occurs on (1 0 0) plane of the cuboidal γ′ phase along [0 0 1] and [0 1 0] directions, whose extruding effect may repel Al, Ti atoms with bigger radius. Therefore, the expanding strain of lattices along [1 0 0] direction on (0 1 0) and (0 0 1) planes of the cuboidal γ′ phase may trap Al, Ti atoms to promote the directional growth of γ′ phase on (1 0 0) plane along [0 0 1] and [0 1 0] directions, which is thought to be the main reason for the γ′ phase growing directionally into the mesh-like lamellar structure.

A chemical shock tube driven by a detonation driver is described in the present paper. This shock tube can produce a single controlled high-temperature pulse for studies of gas-phase reaction kinetics, but the difficulty associated with the timing for the rupture of diaphragms in the conventional chemical shock tube is overcome, because the detonation wave in the driver section can be predicted correctly and shows a good repeatability. In addition, this shock tube is capable of providing higher temperature conditions for the test gas than the conventional high-pressure shock tube, owing to the inherently high-driving capability of the detonation driver. The feasibility of this shock tube is examined by numerical simulations and preliminary experiments.

In this study, we present morphology control investigations on zinc oxide (ZnO) nanorods synthesized by microwave heating of a mixture of zinc nitrate hexahydrate and hexamethylenetetramine (HMTA) precursors in deionized water (DI water). To study the morphology and structural variations of the obtained ZnO nanorods in different molar ratio of zinc nitrate hexahydrate to HMTA, X-ray diffraction (XRD), scanning electron microscopy (SEM) images, Raman scattering, and photoluminescence (PL) spectroscopy were measured. XRD and SEM images are utilized to examine the crystalline quality as well as the morphological properties of the ZnO nanorods. It is found that morphology control can be achieved by simply adjusting the reactant concentrations and the molar ratio of zinc nitrate hexahydrate to HMTA. Raman scattering and PL spectroscopy measurements were demonstrated to study the size- and shape-dependent optical response of the ZnO nanorods. The Raman scattering result shows that the intensity of LO mode at around 576 cm−1 decreases with the increase in the molar ratio of zinc nitrate hexahydrate to HMTA, indicating the reduction of defect concentrations in the synthesized ZnO nanorods. Room temperature PL spectrum of the synthesized ZnO nanorods reveals an ultraviolet (UV) emission peak and a broad visible emission. An enhancement of UV emission appears in the PL spectra as the molar ratio of zinc nitrate hexahydrate to HMTA increases, indicating that the defect concentration of the synthesized ZnO nanorods can be reduced by increasing the molar ratio.

In this study, a series of nanocomposite polymer electrolytes (CPEs), PAN/LiClO4/SAP, with high conductivity are prepared based on polyacrylonitrile (PAN), LiClO4 and low content of the silica aerogel powder (SAP) prepared by the sol–gel method with ionic liquid (IL) as the template. The effect of addition of SAP on the properties of the CPEs is investigated by FTIR, AC impedance, linear sweep voltagrams and cyclic voltammetry measurements as well as the charge–discharge performance. It is found that the ionic conductivity of the CPE is significantly improved by addition of SAP. The maximum ambient ionic conductivity of CPEs is about 12.5 times higher than that without addition of SAP. The results of the voltammetry measurements of CPE-3, which contained 3 wt% of SAP, show that the anodic and cathodic peaks are well maintained after 100 cycles, showing excellent electrochemical stability and cyclability over the potential range between 0 V and 4 V vs. Li/Li+. Besides, the room temperature discharge capacity measured at 0.5C for the coin cell based on CPE-3 is 120 mAh g−1 and the capacity is retained after 20 cycles discharge, indicating the potential for practical use. This is perhaps the first report of the room temperature charge–discharge performance on the solid composite polymer electrolyte to the best of our knowledge.

Low-voltage thin-film transistors (TFTs) with ZnO nanocrystal channel layers and mesoporous SiO 2 gate dielectric are fabricated on glass substrates at room-temperature. The resulting n-type TFTs operate at a low voltage of 2.0 V. The equivalent field-effect electron mobility, current on/off ratio and subthreshold voltage swing is estimated to be 28.8 cm 2 V −1 s −1 , 3×10 6 and 84 mV/decade, respectively. The possible mechanism for low-voltage operation is discussed based on the electric double layer effect. Such room-temperature-processed low-voltage TFTs are very promising for low-power macroelectronics on temperature-sensitive substrates.

One of the disadvantages of ionic liquids-saturated ionomeric polymer transducers has been known to be their slower speeds of actuation. In this study, a novel membrane structure of nanofibrous mats-based on a copolymer of polytetrafluoroethylene and fluorinated vinyl ether sulfonate (Nafion™) was proposed. The Nafion™ nanofibrous mats were prepared using the electro-spinning process, and their morphology, ionic conductivity and actuating behavior were compared with the conventional film type of Nafion™ membranes. Although the fibers mats did not show any advantages in terms of ionic conductivity for water-hydrated condition, for the ionic liquids-saturated condition they showed about three folds improvements in ionic conductivity compared with that of conventional film type of membranes having a similar thickness dimension. Also the fabricated fibers mats-based transducers showed higher strain speed of 1.34%/s, which is 52% faster than the films-based actuators.

Continuing Medical Education Course for "American Society of Echocardiography Consensus Statement on the Clinical Applications of Ultrasonic Contrast Agents in Echocardiography" Accreditation Statement The American Society of Echocardiography (ASE) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ASE designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit .™ Physicians should only claim credit commensurate with the extent of their participation in the activity. The American Registry of Diagnostic Medical Sonographers and Cardiovascular Credentialing International recognize the ASE's certificates and have agreed to honor the credit hours toward their registry requirements for sonographers. The ASE is committed to resolving all conflict-of-interest issues, and its mandate is to retain only those speakers with financial interests that can be reconciled with the goals and educational integrity of the educational program. Disclosure of faculty and commercial support sponsor relationships, if any, have been indicated. Target Audience This activity is designed for all cardiovascular physicians, cardiac sonographers, and nurses with a primary interest and knowledge base in the field of echocardiography; in addition, residents, researchers, clinicians, sonographers, and other medical professionals having a specific interest in contrast echocardiography may be included. Objectives Upon completing this activity, participants will be able to: 1. Demonstrate an increased knowledge of the applications for contrast echocardiography and their impact on cardiac diagnosis. 2. Differentiate the available ultrasound contrast agents and ultrasound equipment imaging features to optimize their use. 3. Recognize the indications, benefits, and safety of ultrasound contrast agents, acknowledging the recent labeling changes by the US Food and Drug Administration (FDA) regarding contrast agent use and safety information. 4. Identify specific patient populations that represent potential candidates for the use of contrast agents, to enable cost-effective clinical diagnosis. 5. Incorporate effective teamwork strategies for the implementation of contrast agents in the echocardiography laboratory and establish guidelines for contrast use. 6. Use contrast enhancement for endocardial border delineation and left ventricular opacification in rest and stress echocardiography and unique patient care environments in which echocardiographic image acquisition is frequently challenging, including intensive care units (ICUs) and emergency departments. 7. Effectively use contrast echocardiography for the diagnosis of intracardiac and extracardiac abnormalities, including the identification of complications of acute myocardial infarction. 8. Assess the common pitfalls in contrast imaging and use stepwise, guideline-based contrast equipment setup and contrast agent administration techniques to optimize image acquisition. Author Disclosures Sharon L. Mulvagh: research grant, Lantheus Medical Imaging, GE Healthcare, and Astellas Pharma; consultant/advisory, Acusphere, Point Biomedical. Mani A. Vannan: research grant, other research support, speaker bureau/honoraria, and consultant/advisory board, Lantheus Medical Imaging. Harald Becher: research grant, Philips, Sonosite, and Toshiba; speaker bureau/honoraria, Lantheus Medical Imaging; consultant/advisory board, Point Biomedical, Bracco, Acusphere, ICON, Lantheus Medical Imaging. S. Michelle Bierig: research grant, Lantheus Medical Imaging, Amersham. Peter N. Burns: consultant/advisory board, Philips Ultrasound, Lantheus Medical Imaging. Dalane W. Kitzman: research grant, Lantheus Medical Imaging, IMCOR, Sonus; speakers bureau, Lantheus Medical Imaging; consultant/advisory board, Lantheus Medical Imaging, Acusphere. Itzhak Kronzon: research grant, GE Healthcare. Arthur J. Labovitz: consultant/advisory board, ICON Medical. Roberto M. Lang: research grant, Acusphere, Point Biomedical; speaker bureau, Lantheus Medical Imaging; consultant/advisory board, Lantheus Medical Imaging. Julio E. Perez: consultant/advisory board, Biomedical Systems. Thomas R. Porter: research grant, Lantheus Medical Imaging; consultant/advisory board, Acusphere, ImaRx. Judy Rosenbloom: paid consultant with ultrasound equipment manufacturers. Kevin Wei: research grant, Lantheus Medical Imaging, Philips Ultrasound; consultant/advisory board, Acusphere. The following stated no disclosures: Harry Rakowski, Sahar S. Abdelmoneim, Ramon Castello, Patrick D. Coon, Mary E. Hagen, James G. Jollis, Thomas R. Kimball, Joseph Mathew, Stuart Moir, Sherif F. Nagueh, Alan S. Pearlman, G. Monet Strachan, Srihari Thanigaraj, Anna Woo, Eric H. C. Yu, and William A. Zoghbi. Conflicts of Interest: The authors have no conflicts of interest to disclose except as noted above. Estimated Time to Complete This Activity: 1 hour

We sought to determine the prognostic value of myocardial contrast echocardiography (MCE) in patients with known or suggested coronary artery disease compared with technetium-99m sestamibi single photon emission computed tomography (SPECT)-myocardial perfusion imaging (MPI).The prognostic value of SPECT-MPI is well established for patients with coronary artery disease. It is less well defined by MCE.In all, 51 consecutive patients with suggested coronary artery disease prospectively underwent MCE and SPECT-MPI at baseline and after dipyridamole infusion. MCE and SPECT-MPI were independently analyzed for myocardial perfusion. Cardiac events during the follow-up period were determined, and event-free survival was calculated for MCE and SPECT-MPI techniques separately.MCE (log rank P.005) and SPECT-MPI (log rank P.05) demonstrated equivalent event-free survival. The negative predictive value for events for both MCE and SPECT-MPI was 100%.MCE accurately classifies patients at risk for cardiac events and provides prognostic information comparable with validated SPECT-MPI techniques.

Objectives We sought to assess the relationship between traditional measures of proficiency in echocardiography and an objective assessment of technical and interpretative skills. Background Determination of competency in echocardiography is currently based on the number of months of training, echocardiograms scanned, and echocardiograms interpreted. It has not been established whether completion of these requirements is a surrogate for competency. Methods In all, 22 cardiology fellows underwent an echocardiography objective structured clinical examination (OSCE). Results There was a correlation between the number of echocardiograms scanned and the interpretation ( r = 0.45, P = .038) and scanning ( r = 0.42, P = .048) scores. There was a weak correlation between the number of echocardiograms interpreted and interpretation scores ( r = 0.33); and number of months of training and the scanning ( r = 0.39) and interpretation ( r = 0.42) scores. Conclusions Technical and interpretative proficiency in echocardiography is not related to traditional measures. An objective assessment of acquisition and interpretation of echocardiographic data should beincorporated into the assessment of proficiency in echocardiography.

In this paper, hollow and porous Cu2O nanoparticles were prepared by adjusting the cationic surfactant cetyltrimethylammonium (CTAB) concentration in the solution-phase reaction. Structural investigations reveal that Cu2O nanoparticles can be either well-defined hollow nanoboxes or porous nanocubes depending on the synthesis conditions. The transmission electron microscopy (TEM) observations demonstrated that the nanoparticles in general are composed of small grains coherently growing along certain preferred orientations.

Sympathetic activation and sleep apnea are present in most patients with symptomatic systolic heart failure (HF). Acutely, obstructive and central apneas increase muscle sympathetic activity (MSNA) during sleep by eliciting recurrent hypoxia, hypercapnia, and arousal. In obstructive sleep apnea patients with normal systolic function, this increase persists after waking. Whether coexisting sleep apnea augments daytime MSNA in HF is unknown. We tested the hypothesis that its presence exerts additive effects on MSNA during wakefulness. Overnight sleep studies and morning MSNA recordings were performed on 60 subjects with ejection fraction P =0.005; 58±2 versus 50±3 bursts/min, P =0.037), irrespective of its etiology (the mean difference for central sleep apnea was 17 bursts per 100 heartbeats; n=14; P =0.006; and for obstructive sleep apnea, 11 bursts per 100 heartbeats; n=29; P =0.032). In a subgroup (n=8), treatment of obstructive sleep apnea lowered MSNA by 12 bursts per 100 heartbeats ( P =0.003). Convergence of independent excitatory influences of HF and sleep apnea on central sympathetic neurons results in higher MSNA during wakefulness in HF patients with coexisting sleep apnea. This additional stimulus to central sympathetic outflow may accelerate the progression of HF; its attenuation by treatment of sleep apnea represents a novel nonpharmacological opportunity.

Transmission electron microscopy (TEM) observations reveal the presence of complex superstructures and remarkable phase separation in association with Na-ordering phenomenon in gamma-Na0.5CoO2. Resistivity and magnetization measurements indicate that three phase transitions at the temperatures of 25, 53 and 90 K, respectively, appear commonly in gamma-Na0.5CoO2 samples. Under a high pressure up to 10 kbar, the low-temperature transport properties show certain changes below the charge order transition; under an applied magnetic field of 7 T, phase transitions at around 25 and 53 K, proposed fundamentally in connection with alternations of magnetic structure and charge ordering maintain almost unchanged. (c) 2005 Elsevier B.V. All rights reserved.

The ternary oxide functional nanomaterial Zn2SnO4 has been synthesized by the thermal evaporation method. The products in general contain numerous kinds of nanowires. In the present work, a remarkable type of Zn2SnO4 nanowires with a pseudoperiodical twinning structure has been investigated by transmission electron microscopy (TEM). These nanowires with a diameter of about 100 nm grow along the 〈111〉 direction. High-resolution TEM examinations suggest that a large fraction of the (111) twin boundaries are extended to a thickness of a few nanometers. The twining plane for the perfect case is localized on the Zn atom layer.

We have prepared two sets of YBaSrCu3-xFexOy (0 less than or equal to x less than or equal to 1.0) samples under a high pressure of 6 GPa and the ambient condition, respectively. All materials synthesized under the high pressure are superconductors, in contrast, materials prepared under the ambient condition show superconducting transitions merely in the range of 0 less than or equal to x < 0.3. Electron-energy-loss spectroscopy analyses indicate that the density of the charge carriers (holes) in the high-pressure samples is much higher than that in the samples prepared under the ambient condition. Some microstructure features and lattice defects in the high-pressure samples have been investigated by high-resolution electron microscopy and selected-area electron diffraction. (C) 2004 Elsevier B.V. All rights reserved.

The microstructural features of silver nanorods with the average length of 50 μm and diameters of around 100 nm have been investigated by means of SEM, X-ray diffraction, and transmission-electron microscopy (TEM). Silver nanorods in general have a pentagonal shape with a remarkable fivefold symmetry as revealed in cross-section observations. The fivefold axis, i.e. the growth direction, normally goes along the [110]-zone axis direction of the basic fcc Ag-structure. The twinning relationships and relevant twin boundaries among the five subunits in the pentagonal nanorod have been examined by high-resolution TEM and selected-area electron diffraction. Defects and stacking faults in this kind of nanorods have been briefly analyzed.

Structural distortions arising from the condensations of two essential kinds of phonon modes: the triply degenerate rotational modes (phi(x), phi(y), phi(z)) of MnO6 and the doubly degenerate Jahn-Teller active modes (Q(1), Q(2)) have been systematically investigated in the perovskite manganites. Microstructural features associated with certain types of distortions have been observed by transmission electron microscopy (TEM). In RMnO3 and La(Sr)(2)NiO4, we characterize the local structure, charge ordered states and orbital ordering by means of low-temperature TEM. We present direct evidence that the stripe modulation in La(Sr)(2)NiO4 is indeed one-dimensional within each NiO2 plane. Several typical kinds of defect structures, including antiphase boundaries and the 90degrees-twin domains, appear commonly in the charge-ordered states. (C) 2004 Elsevier Ltd. All rights reserved.

Structural features of pentagonal Ag nanorods have been investigated by means of transmission electron microscopy (TEM). Cross-section observations directly reveal the remarkable fivefold twinning structure and related defects in this kind of nanomaterial. High-resolution TEM observations in combination with fast-Fourier processing indicate that the well-defined twinning relationship appears on at least two of the five twinning boundaries. Electron-energy-loss spectroscopy analysis on the center regions of the nanorods demonstrates that the Ag-M-4,M-5 peaks shift to lower energy in comparison with results from the Ag crystal.

Objectives The purpose of this study was to compare the assessment of myocardial perfusion by myocardial parametric quantification (MPQ) with technetium-99m sestamibi single-photon emission computed tomographic (SPECT) imaging in humans. Background Accurate visual interpretation of myocardial contrast echocardiographic (MCE) images is qualitative and requires considerable experience. Current computer-assisted quantitative perfusion protocols are tedious and lack spatial resolution. Myocardial parametric quantification is a novel method that quantifies, color encodes, and displays perfusion data as a set of myocardial parametric images according to the relative degree of perfusion. Methods Forty-six consecutive patients underwent prospective stress/rest technetium-99m sestamibi gated-SPECT imaging and MCE using intravenous Optison or Definity. Apical two- and four-chamber cine loops at rest and after dipyridamole (0.56 mg/kg) stress were acquired. For each patient, the following assessments of myocardial perfusion were performed: 1) visual cine-loop assessment (VIS); 2) MPQ assessment; and 3) combined VIS + MPQ assessment. Results The segmental rates of agreement for myocardial perfusion with SPECT were 83%, 89%, and 92% (kappa = 0.46, 0.58, and 0.68) for VIS, MPQ, and VIS + MPQ, respectively. Similar trends were seen for the classification of the presence or absence of a moderate to severe perfusion defect, with the agreement for VIS, MPQ, and VIS + MPQ being 92%, 97%, and 97%, respectively. Conclusions Myocardial parametric quantification demonstrates good agreement with SPECT and incremental agreement with VIS. Analysis strategies that incorporate MPQ demonstrate better agreement with SPECT than visual analysis alone.

Otoacoustic emissions (OAEs) have been widely used as an objective and noninvasive method of assessing outer hair cell function of the cochlea for infants. This paper is aimed at investigating the infant hearing screening service in Hong Kong using distraction test and distortion product otoacoustic emissions (DPOAEs). In Study 1, the DPOAE results were obtained using two criteria: Criterion I was (DP response - noise floor) > 2 standard deviations above noise floor; and Criterion II was (DP response - noise floor) > 6 dB. The results were compared with pure tone audiograms for 43 young children who were able to give reliable responses in play audiometry. Criterion I was found to be superior to Criterion II in view of its higher specificity (86.5%). Hence Criterion I was used in a subsequent study, Study 2. In that second study, 144 (73%) out of 196 infants who failed the distraction test passed the DPOAE hearing screening. Most infants who failed the distraction test were under 6 months old (122...

Manual endocardial tracing using Simpson's method (MANUAL SIMP) provides an accurate assessment of left-ventricular ejection fraction (LVEF). We have previously demonstrated in patients who are difficult to image: (1) the incremental accuracy of contrast-enhanced power harmonic imaging and MANUAL SIMP in the calculation of LVEF; and (2) the use of intravenous contrast-combined MANUAL SIMP was the most accurate method of LVEF determination. However, MANUAL SIMP is time-consuming, requires accurate planimetry of the endocardial borders, and is difficult to apply routinely in the clinical situation. The current study prospectively studied the accuracy of intravenous contrast and a semiautomated endocardial border detection algorithm in the determination of LVEF in 51 patients with suboptimal images. LVEF was also calculated using contrast-enhanced power harmonic imaging and MANUAL SIMP. We demonstrated that there was good agreement between LVEF determined using both MANUAL SIMP and semiautomated endocardial border detection, and radionuclide angiography (standard of comparison).

Guidelines for the provision of echocardiography in Canada were jointly developed and published by the Canadian Cardiovascular Society and the Canadian Society of Echocardiography in 2005. Since their publication, recognition of the importance of echocardiography to patient care has increased, along with the use of focused, point-of-care echocardiography by physicians of diverse clinical backgrounds and variable training. New guidelines for physician training and maintenance of competence in adult echocardiography were required to ensure that physicians providing either focused, point-of-care echocardiography or comprehensive echocardiography are appropriately trained and proficient in their use of echocardiography. In addition, revision of the guidelines was required to address technological advances and the desire to standardize echocardiography training across the country to facilitate the national recognition of a physician's expertise in echocardiography. This paper summarizes the new Guidelines for Physician Training and Maintenance of Competency in Adult Echocardiography, which are considerably more comprehensive than earlier guidelines and address many important issues not previously covered. These guidelines provide a blueprint for physician training despite different clinical backgrounds and help standardize physician training and training programs across the country. Adherence to the guidelines will ensure that physicians providing echocardiography have acquired sufficient expertise required for their specific practice. The document will also provide a framework for other national societies to standardize their training programs in echocardiography and will provide a benchmark by which competency in adult echocardiography may be measured.

In this study, a UV-filter encapsulated in a mesoporous silica, MCX-MS, was prepared by the in-situ sol–gel polymerization of tetraethyl orthosilicate (TEOS) with an ionic liquid (IL) as solvent and pore-forming agent and octal methoxycinnamate (MCX) as an additive. MCX-MS was characterized by Fourier transformation infrared (FT-IR) spectroscopy and transmission electron microscopy (TEM). The result of the thermogravimetric analysis (TGA) showed that the amount of MCX encapsulated in MS was about 65 wt.% of MCX-MS. Comparing with that of the free MCX, the SPF value of the MCX-MS-containing sunscreen cream increased by about 57%, indicating significant enhancement of the UV protection ability of MCX by encapsulation in the mesoporous silica matrix. Furthermore, because the average particle size of MCX-MS emulsion droplets was big enough, damage by penetration through the skin is expected to be prevented.

Achieving competency at electrocardiogram (ECG) interpretation among cardiology subspecialty residents has traditionally focused on interpreting a target number of ECGs during training. However, there is little evidence to support this approach. Further, there are no data documenting the competency of ECG interpretation skills among cardiology residents, who become de facto the gold standard in their practice communities. We tested 29 Cardiology residents from all 3 years in a large training program using a set of 20 ECGs collected from a community cardiology practice over a 1-month period. Residents interpreted half of the ECGs using a standard analytic framework, and half using their own approach. Residents were scored on the number of correct and incorrect diagnoses listed. Overall diagnostic accuracy was 58%. Of 6 potentially life-threatening diagnoses, residents missed 36% (123 of 348) including hyperkalemia (81%), long QT (52%), complete heart block (35%), and ventricular tachycardia (19%). Residents provided additional inappropriate diagnoses on 238 ECGs (41%). Diagnostic accuracy was similar between ECGs interpreted using an analytic framework vs ECGs interpreted without an analytic framework (59% vs 58%; F 1,1333 = 0.26; P = 0.61). Cardiology resident proficiency at ECG interpretation is suboptimal. Despite the use of an analytic framework, there remain significant deficiencies in ECG interpretation among Cardiology residents. A more systematic method of addressing these important learning gaps is urgently needed.