Tumour characteristics provide evidence for germline mismatch repair missense variant pathogenicity.

BACKGROUND: Pathogenic variants in mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2) increase risk for Lynch syndrome and related cancers. We quantified tumour characteristics to assess variant pathogenicity for germline MMR genes. METHODS: Among 4740 patients with cancer with microsatellite instability (MSI) and immunohistochemical (IHC) results, we tested MMR pathogenic variant association with MSI/IHC status, and estimated likelihood ratios which we used to compute a tumour characteristic likelihood ratio (TCLR) for each variant. Predictive performance of TCLR in combination with in silico predictors, and a multifactorial variant prediction (MVP) model that included allele frequency, co-occurrence, co-segregation, and clinical and family history information was assessed. RESULTS: Compared with non-carriers, carriers of germline pathogenic/likely pathogenic (P/LP) variants were more likely to have abnormal MSI/IHC status (p<0.0001). Among 150 classified missense variants, 73.3% were accurately predicted with TCLR alone. Models leveraging in silico scores as prior probabilities accurately classified >76.7% variants. Adding TCLR as quantitative evidence in an MVP model (MVP +TCLR Pred) increased the proportion of accurately classified variants from 88.0% (MVP alone) to 98.0% and generated optimal performance statistics among all models tested. Importantly, MVP +TCLR Pred resulted in the high yield of predicted classifications for missense variants of unknown significance (VUS); among 193 VUS, 62.7% were predicted as P/PL or benign/likely benign (B/LB) when assessed according to American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines. CONCLUSION: Our study demonstrates that when used separately or in conjunction with other evidence, tumour characteristics provide evidence for germline MMR missense variant assessment, which may have important implications for genetic testing and clinical management.

Clinical value of 2D speckle tracking imaging in evaluating the effect of percutaneous intramyocardial septal radiofrequency ablation in patients with hypertrophic obstructive cardiomyopathy.

PURPOSE: To explore the short-term changes after percutaneous intramyocardial septal radiofrequency ablation (PIMSRA) in patients with hypertrophic obstructive cardiomyopathy (HOCM), using quantitative analysis of two-dimensional speckle tracking imaging (2D-STI). METHODS: This prospective self-controlled study included 30 HOCM patients treated with PIMSRA. The study for each patient spanned over at least 1 year. Interventricular septal thickness and the left ventricular outflow tract peak pressure gradient (LVOT-PG) were measured through echocardiography, and 2D-STI was used to evaluate the left ventricular (LV) systolic function and synchrony. Cardiac function was assessed using the New York Heart Association's (NYHA) functional classification for cardiac disease, and through the serum levels of cardiac troponin I (cTnI) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Biomarkers procollagen type I carboxy-terminal propeptide (PICP) and matrix metalloproteinases-2 (MMP-2) were detected for noninvasive assessment of myocardial fibrosis. RESULTS: The patients' interventricular septal thickness, LVOT-PG, NYHA class, and plasma PICP and MMP-2 levels at the first month postoperatively were significantly lower than before operation (all P < .05). The 2D-STI quantitative variables of LV systolic function and synchrony improved significantly (all P < .05). They improved further 1 year postoperatively (P < .01 or P < .001). Serum cTnI and NT-proBNP levels increased 1 month postoperatively, but significantly decreased 1 year postoperatively (both P < .05). Pearson or Spearman correlation analysis showed that the improvement of interventricular septal thickness, LVOT-PG, NYHA class, and the levels of cTnI, NT-proBNP, PICP and MMP-2, were in positive correlation with the restoration of LV systolic function and synchrony (P < .01 or P < .001). CONCLUSION: The changes in 2D-STI quantitative variables related to LV systolic function and synchrony are closely correlated with the improvement of cardiac function in HOCM patients after PIMSRA. These 2D-STI variables can serve for objective, accurate, and noninvasive evaluation of the HOCM treatment.

Therapeutic effects of percutaneous coronary intervention on acute myocardial infarction complicated with multiple organ dysfunction syndrome.

OBJECTIVE: To evaluate the clinical efficacy of percutaneous coronary intervention (PCI) on patients with acute myocardial infarction (AMI) complicated with multiple organ dysfunction syndrome (MODS). METHODS: A total of 216 patients with AMI complicated with MODS enrolled from January 2016 to March 2018 were divided into a PCI group (n=98) and a drug treatment group (n=118). The baseline clinical data, the incidence of each dysfunction organ, the number of dysfunctional organs and the mortality were compared between the two groups. RESULTS: The number of patients with ST-segment elevation AMI in the PCI group was higher than in the drug treatment group, and the rate of patients with non-ST-segment elevation AMI was lower than in the drug treatment group (P<0.05). The use of temporary pacemakers and IABP was similar between the two groups (P>0.05). The recanalization rate in PCI group was much higher than that in the drug treatment group (P<0.05). The two groups had similar incidence of organ dysfunction in the heart, lungs, kidneys, stomach and intestine, etc. and the PCI group had lower organ dysfunction incidence in the liver, brain and hematological system than the drug treatment group (P<0.05). The dysfunction incidence rate of two organs was higher in PCI group than in drug treatment group (P<0.05), the dysfunction incidence rate of 3 organs was similar between the two groups, and the dysfunction incidence rate of three organs or more was significantly lower in PCI group than in drug treatment group (P<0.05). CONCLUSION: Despite the high risk and high mortality of patients with AMI plus MODS, clinical improvement can still be achieved when effective PCI is performed.

Clinical efficacy and ultrasound inspection of the treatment of hypertensive heart patients with Valsartan combined with hydrochlorothiazide.

To observe and analyze the clinical efficacy and ultrasound detection results of treatment of hypertensive patients with heart disease with valsartan combined with hydrochlorothiazide. The 160 hypertensive patients with heart disease who were treated in our hospital were selected as study subjects and randomly divided into study group and reference group, each with 80 patients. Where, the reference group was solely treated with valsartan, while the study group received hydrochlorothiazide treatment on this basis. The therapeutic effects of the two groups were observed and analyzed. Comparison of the overall treatment efficacy and incidence of adverse reactions between the two groups showed that the study group had more significant advantages than the reference group, P<0.05; in comparison of systolic blood pressure and diastolic blood pressure after treatment between the two groups, the study group had higher improvement degree than the reference group, P<0.05; ultrasonic ECG inspection showed that the study group was superior to the reference group with better recovery in indexes including left ventricular mass index, left ventricular posterior wall thickness, left ventricular ejection fraction, P<0.05. The combination of Valsartan and hydrochlorothiazide for hypertensive patients with heart disease can significantly improve the treatment effect and significantly reduce the incidence of adverse reactions. Therefore, it is worthy of popularization and application.

Changes in left ventricular synchrony and systolic function in dilated cardiomyopathy patients with fragmented QRS complexes.

AIMS: Fragmented QRS (f-QRS) complexes are associated with adverse cardiovascular events in patients with coronary heart disease; however, the effects on patients with dilated cardiomyopathy (DCM) remain elusive. This study is to investigate the changes of left ventricular (LV) synchrony and systolic function in DCM patients with f-QRS complexes. METHODS AND RESULTS: Twenty DCM patients with f-QRS complexes and 29 DCM patients without f-QRS (n-QRS) complexes were enrolled. The LV segmental longitudinal, radial and circumferential time to peak strain and general longitudinal systolic strain, radial strain, circumferential strain were measured, respectively, by speckle tracking imaging. The LV segmental standard deviations and maximal differences were also calculated. The LV dyssynchrony was defined as the time in peak anteroseptal wall to posterior wall strain >130 ms or longitudinal strain delay index >25%. The mean QRS durations in f-QRS and n-QRS groups were not different (P = ns). The incidence of LV dyssynchrony was 15/20 (75%) vs. 5/29 (17%) in two groups (P < 0.01). Two patients died of sudden death in f-QRS group during 2 years follow-up; however, no death in n-QRS group (P < 0.05). Patients in f-QRS group showed worsening LV dyssynchrony in f-QRS group after 2 years follow-up (P < 0.05). Overall, LV function was comparable at baseline (P = ns), but had significantly worsened only in the f-QRS group (P < 0.05). CONCLUSION: The f-QRS complex is significantly associated with LV dyssynchrony in DCM patients and can be used as a reliable index to evaluate ventricular synchrony and predict the prognosis in DCM patients with narrow QRS complexes.

A multicenter study to standardize reporting and analyses of fluorescence-activated cell-sorted murine intestinal epithelial cells.

Fluorescence-activated cell sorting (FACS) is an essential tool for studies requiring isolation of distinct intestinal epithelial cell populations. Inconsistent or lack of reporting of the critical parameters associated with FACS methodologies has complicated interpretation, comparison, and reproduction of important findings. To address this problem a comprehensive multicenter study was designed to develop guidelines that limit experimental and data reporting variability and provide a foundation for accurate comparison of data between studies. Common methodologies and data reporting protocols for tissue dissociation, cell yield, cell viability, FACS, and postsort purity were established. Seven centers tested the standardized methods by FACS-isolating a specific crypt-based epithelial population (EpCAM+/CD44+) from murine small intestine. Genetic biomarkers for stem/progenitor (Lgr5 and Atoh 1) and differentiated cell lineages (lysozyme, mucin2, chromogranin A, and sucrase isomaltase) were interrogated in target and control populations to assess intra- and intercenter variability. Wilcoxon's rank sum test on gene expression levels showed limited intracenter variability between biological replicates. Principal component analysis demonstrated significant intercenter reproducibility among four centers. Analysis of data collected by standardized cell isolation methods and data reporting requirements readily identified methodological problems, indicating that standard reporting parameters facilitate post hoc error identification. These results indicate that the complexity of FACS isolation of target intestinal epithelial populations can be highly reproducible between biological replicates and different institutions by adherence to common cell isolation methods and FACS gating strategies. This study can be considered a foundation for continued method development and a starting point for investigators that are developing cell isolation expertise to study physiology and pathophysiology of the intestinal epithelium.

Phase 1/2 trial of total marrow and lymph node irradiation to augment reduced-intensity transplantation for advanced hematologic malignancies.

This phase 1/2 study assessed the augmentation of reduced-intensity conditioning (RIC) with total marrow and lymph node irradiation (TMLI), for peripheral blood stem cell transplantation, in patients with advanced hematologic disease. The regimen consisted of fludarabine 25 mg/m(2) per day for 5 days, melphalan 140 mg/m(2) for one day, and TMLI radiation at 150 cGy/fraction in 8 fractions over 4 days. Eligible patients were over 50 years old and/or had compromised organ function. Median age of the 33 evaluable patients was 55.2 years. Eighteen events of nonhematologic grade III or higher toxicities occurred in 9 patients. Day 30 and day 100 mortalities were 3% and 15%, respectively. Patients achieved myeloid and platelet engraftment at a median of 14 days after transplantation. Long-term toxicities occurred in 2 patients: hypokalemia and tremor, both grade III, on days 370 and 361 after transplantation. Fourteen patients died, 7 of relapse-related causes and 7 of non-relapse-related causes. With a median follow-up for living patients of 14.7 months, 1-year overall survival, event-free survival, and non-relapse-related mortality were 75%, 65%, and 19%, respectively. Addition of TMLI to RIC is feasible and safe and could be offered to patients with advanced hematologic malignancies who might not otherwise be candidates for RIC.

The association of hospital volume with rectal cancer surgery outcomes.

PURPOSE: An association between hospital volume and postoperative mortality has been identified for several oncologic surgical procedures. Our objective was to analyze differences in surgical outcomes for patients with rectal cancer according to hospital volume in the state of California. METHODS: A cross-sectional study from 2000 to 2005 was performed using the state of California Office of Statewide Health Planning and Development database. Hospitals were categorized into low (≤30)-, medium (31-60)-, and high (>60)-volume groups based on the total number of rectal cancer operations performed during the study period. RESULTS: Overall, 7,187 rectal cancer operations were performed. Of the 321 hospitals in the study cohort, 72 % (n = 232), 20 % (n = 65), and 8 % (n = 24) were low-, medium-, and high-volume hospitals, respectively. Postoperative mortality was significantly lower- in high-volume hospitals (0.9 %) when compared to medium- (1.1 %) and low-volume hospitals (2.1 %; p < 0.001). High-volume hospitals also performed more sphincter-preserving procedures (64 %) when compared to medium- (55 %) and low-volume hospitals (51 %; p < 0.001). CONCLUSIONS: These data indicate that hospital volume correlates with improved outcomes in rectal cancer surgery. Rectal cancer patients may benefit from lower mortality and increased sphincter preservation in higher-volume centers.

[The impact of cardiac resynchronization therapy on left ventricular diastolic function evaluated by speckle tracking imaging in patients with dilated cardiomyopathy].

OBJECTIVE: To investigate the effects of cardiac resynchronization therapy (CRT) on left ventricular (LV) diastolic function measured by speckle tracking imaging (STI) in patients with dilated cardiomyopathy (DCM). METHODS: CRT was performed in 21 DCM patients [15 male, mean age: 61.2 ± 11.2 (49-82) years].LV synchronization, LV systolic function and LV diastolic function were evaluated with conventional echocardiography, tissue Doppler imaging and STI before and 6 months after CRT.NYHA heart function was also assessed. Clinic Response to CRT was defined as improvement of more than 1 NYHA class.Response to CRT in echocardiography was defined as ≥ 15% reduction in LV end systolic volume at 6 months post CRT. RESULTS: There were 16 responders and 5 non-responders at 6 months post CRT.In terms of diastolic function, conventional echocardiography derived deceleration time was both prolonged in non-responders and responders. At 6 months post CRT, STI derived LV isovolumetric diastolic strain rate [(0.19 ± 0.11) /s vs.(0.14 ± 0.09)/s, P < 0.001] was significantly increased while early diastolic mitral valve blood flow velocity/left ventricular isovolumetric diastolic strain rate (680 ± 600 vs.787 ± 690, P < 0.04) was significantly reduced in responder group while remained unchanged in non-responder group.Furthermore, left ventricular isovolumetric diastolic strain rate negatively correlated with plasma brain natriuretic peptide level (r = -0.68, P < 0.05). CONCLUSION: In CRT responders of DCM patients, LV diastolic function is significantly improved and this change could be detected more effectively by STI derived LV diastolic function parameters.

[Evaluation of left ventricular function and twist in patients with diabetic cardiovascular autonomic neuropathy by speckle tracking imaging].

OBJECTIVE: To evaluate left ventricular (LV) function and twist in patients with diabetic cardiovascular autonomic neuropathy (CAN) by two-dimensional speckle tracking imaging (STI). METHODS: STI was performed in 56 subjects with type 2 diabetes mellitus (DM) (35 with DM only: group A, 21 with CAN: group B) and 34 normal subjects (Control) from LV short-axis view. LV peak systolic, peak early (E') and peak late (A') diastolic circumferential strain in 18 myocardial segments were measured at the levels of mitral annulus, papillary muscle and apex and the rotation at mitral annulus and apex levels were also measured. LV peak systolic and the ratio of E' and A' of global and three levels, twist, untwisting rate and untwisting half-time were calculated. RESULTS: In group A, compared with control group, LV peak systolic radial circumferential strain has no significant difference (P > 0.05), E'/A' was reduced (P < 0.05), twist at aortic valve closure and twist at mitral valve opening were significantly increased (P < 0.05), untwisting rate reduced, and untwisting half time delayed. In group B, compared with control group and group A, circumferential strain parameters [(-12.64 ± 6.49)% vs. (-19.11 ± 9.98)% and (-21.14 ± 10.13)%, P < 0.05] and E'/A' [(0.90 ± 0.35) vs. (1.24 ± 0.47) and (1.98 ± 0.63), P < 0.05] were significantly decreased, twist at aortic valve closure [(19.08 ± 5.62)° vs. (16.57 ± 2.84)° and (14.36 ± 4.06)°, P < 0.05] and twist at mitral valve opening [(13.99 ± 2.31)° vs. (11.36 ± 2.63)° and (9.04 ± 5.63)°, P < 0.05] were significantly increased, untwisting rate [(0.40 ± 0.28)%/ms vs. (0.46 ± 0.14)%/ms and (0.53 ± 0.21)%/ms, P < 0.05] reduced, and untwisting half time [(489.61 ± 97.14) ms vs. (445.21 ± 54.53) ms and (410.60 ± 50.23) ms, P < 0.05] delayed. CONCLUSION: Speckle tracking imaging could be used to evaluate early changes on LV twist deformation and LV systolic function in patients with type 2 diabetes mellitus.

Serial changes in liquid biopsy-derived variant allele frequency predict immune checkpoint inhibitor responsiveness in the pan-cancer setting.

Major immunotherapy challenges include a limited number of predictive biomarkers and the unusual imaging features post-therapy, such as pseudo-progression, which denote immune infiltrate-mediated tumor enlargement. Such phenomena confound clinical decision-making, since the cancer may eventually regress, and the patient should stay on treatment. We prospectively evaluated serial, blood-derived cell-free DNA (cfDNA) (baseline and 2-3 weeks post-immune checkpoint inhibitors [ICIs]) for variant allele frequency (VAF) and blood tumor mutation burden (bTMB) changes (next-generation sequencing) (N = 84 evaluable patients, diverse cancers). Low vs. high cfDNA-derived average adjusted ΔVAF (calculated by a machine-learning model) was an independent predictor of higher clinical benefit rate (stable disease ≥6 months/complete/partial response) (69.2% vs. 22.5%), and longer median progression-free (10.1 vs. 2.25 months) and overall survival (not reached vs. 6.1 months) (all P < .001, multivariate). bTMB changes did not correlate with outcomes. Therefore, early dynamic changes in cfDNA-derived VAF were a powerful predictor of pan-cancer immunotherapy outcomes.

Mutational and splicing landscape in a cohort of 43,000 patients tested for hereditary cancer.

DNA germline genetic testing can identify individuals with cancer susceptibility. However, DNA sequencing alone is limited in its detection and classification of mRNA splicing variants, particularly those located far from coding sequences. Here we address the limitations of splicing variant identification and interpretation by pairing DNA and RNA sequencing and describe the mutational and splicing landscape in a clinical cohort of 43,524 individuals undergoing genetic testing for hereditary cancer predisposition.

Relationship between Quantitative Parameters of Echocardiography and Vascular Endothelial Function in Patients with Chronic Heart Failure and Its Predictive Value for Short-Term MACE Risk.

Objective: To investigate the relationship between quantitative parameters of echocardiography and vascular endothelial function in patients with chronic heart failure (CHF) and the predictive value of short-term major adverse cardiovascular events (MACE). Methods: From February 2018 to February 2020, 86 CHF patients in our hospital were selected as the observation group, and 46 healthy subjects were selected as the control group during the same period. Quantitative parameters of echocardiography (left ventricular ejection fraction (LVEF), left ventricular short-axis shortening rate (FS), and ratio of peak flow velocity between early and late mitral valve diastole (E/A)) and endothelial function indexes (endothelin-1 (ET-1)/nitric oxide (NO)) were compared between the two groups. The correlation between quantitative parameters of echocardiography and vascular endothelial function in patients with CHF was analyzed. A logistic regression equation was used to analyze the risk factors of MACE in patients with CHF. The receiver operating characteristic curve (ROC) was used to analyze the predictive value of quantitative parameters of echocardiography and NO/ET-1 for the risk of MACE in patients with CHF. Result: LVEF, FS, and NO/ET-1 in the observation group were lower than those in the control group, while E/A was higher than that in the control group (P < 0.05). In CHF patients, LVEF and FS were positively correlated with NO/ET-1, while E/A was negatively correlated with NO/ET-1 (P < 0.05). Logistic regression analysis showed that the decrease of LVEF, FS, NO/ET-1, and E/A were risk factors for MACE (P < 0.05) after adjusting for age, body mass index, and cardiac function grading. The AUC value of short-term MACE predicted by quantitative parameters of echocardiography and NO/ET-1 combined was 0.883, with a corresponding sensitivity of 86.21% and specificity of 73.13%. Conclusion: Quantitative parameters of echocardiography in CHF patients are related to vascular endothelial function, and their combination can effectively predict the risk of MACE in the near future, providing reference for clinical treatment.

[Evaluation on left ventricular systolic synchronicity and cardiac function in patients with permanent cardiac pacing by real-time three-dimensional echocardiography].

OBJECTIVE: To determine the feasibility on the left ventricular systolic synchronism and cardiac function evaluation in patients with permanent cardiac pacing by real-time three-dimensional echocardiography. METHODS: Fifteen patients with sick sinus syndrome post dual-chamber pacemaker implantation were enrolled in this study. Pacemakers were programmed to AAI, DDD, and VVI respectively. After pacing for 5 minutes in each mode, participants were examined with real-time three-dimensional echocardiography. Images in different pacing modes were obtained and analyzed by the off-line Qlab 4.2 software. Parameters including global and 17-segmental volume-time curves (VTCs), dispersion of time to minimal regional volume for 16, 12, and 6 left ventricular segments (Tmsv16-s, Tmsv12-s, Tmsv6-s), and maximal difference of time to minimal regional volume for l6, 12 and 6 left ventricular segments (Tmsv16-dif, Tmsv12-dif, Tmsv6-dif), end diastolic volume (EDV), end systolic volume (ESV), left ventricular ejection fraction (LVEF) were measured respectively. Parameters of peak filling rate (PFR), regional end diastolic volume (rEDV), regional end systolic volume (rESV), and regional ejection fraction (rEF) were also calculated. RESULTS: Left ventricular systolic synchronism as reflected by VTCs, Tmsv16-s, Tmsv12-s, Tmsv6-s, Tmsv16-dif, Tmsv12-dif and Tmsv6-dif as well as parameters reflecting ventricular function, i.e., LVEF, PFR were significantly better in AAI mode than in DDD and VVI models (all P < 0.05). All above indexes were similar between DDD and VVI models (all P > 0.05). rEFs of left inferior wall in base, septum in base and apex were significantly lower in DDD and VVI models compared that in AAI mode (P < 0.05). CONCLUSION: Real-time three-dimensional echocardiography can objectively and accurately evaluate left ventricular systolic synchronism and cardiac function in patients with permanent cardiac pacing and AAI mode is superior to DDD and VVI models.

Monoallelic MUTYH carrier status is not associated with increased breast cancer risk in a multigene panel cohort.

Whether monoallelic MUTYH mutations increase female breast cancer risk remains controversial. This study aimed to determine if monoallelic MUTYH mutations are associated with increased breast cancer risk in women undergoing multigene panel testing (MGPT). The prevalence of monoallelic MUTYH mutations was compared between Non-Hispanic white female breast cancer cases (n = 30,456) and cancer-free controls (n = 12,289), all of whom underwent MGPT that included MUTYH. We tested breast cancer associations with MUTYH alleles using Fisher's exact test, followed by multivariate logistic regression adjusted for age at testing and MGPT type ordered. Frequencies of the two most common MUTYH founder mutations, p.G396D and p.Y179C, were compared independently between the breast cancer cases and MGPT controls, as well as the healthy UK10K control population (n = 2640). Comparing cases to MGPT controls, no association was observed between female breast cancer and any monoallelic MUTYH carrier status (OR 0.86-1.36, p = 0.21-0.96). Similarly, comparisons to UK10K controls revealed no significant increase in breast cancer risk associated with p.G396D (OR 1.20, p = 0.44) or p.Y179C (OR 1.71, p = 0.24). This study did not find a significant increase in breast cancer risk associated with monoallelic MUTYH mutations.

REVEL and BayesDel outperform other in silico meta-predictors for clinical variant classification.

Many in silico predictors of genetic variant pathogenicity have been previously developed, but there is currently no standard application of these algorithms for variant assessment. Using 4,094 ClinVar-curated missense variants in clinically actionable genes, we evaluated the accuracy and yield of benign and deleterious evidence in 5 in silico meta-predictors, as well as agreement of SIFT and PolyPhen2, and report the derived thresholds for the best performing predictor(s). REVEL and BayesDel outperformed all other meta-predictors (CADD, MetaSVM, Eigen), with higher positive predictive value, comparable negative predictive value, higher yield, and greater overall prediction performance. Agreement of SIFT and PolyPhen2 resulted in slightly higher yield but lower overall prediction performance than REVEL or BayesDel. Our results support the use of gene-level rather than generalized thresholds, when gene-level thresholds can be estimated. Our results also support the use of 2-sided thresholds, which allow for uncertainty, rather than a single, binary cut-point for assigning benign and deleterious evidence. The gene-level 2-sided thresholds we derived for REVEL or BayesDel can be used to assess in silico evidence for missense variants in accordance with current classification guidelines.

Skin-sparing mastectomy: a survey based approach to defining standard of care.

Skin-sparing mastectomy (SSM) followed by immediate reconstruction has been advocated as an effective treatment option for patients with early-stage breast carcinoma. It markedly improves the quality of breast reconstruction through preservation of the natural skin envelope and a smaller incision. The purpose of this study was to investigate general surgeons' attitudes towards SSM. A postal questionnaire survey of California general surgeons was conducted regarding SSM. Of 370 respondents who stated they performed breast cancer surgery, 331 perform mastectomy for cancer with planned immediate reconstruction. Ninety per cent of respondents did not feel that SSM resulted in higher rates of local recurrence. In addition, 70 per cent felt that the cosmetic results of immediate breast reconstruction after SSM were better than those after a standard mastectomy. Despite this, only 61 per cent perform SSM in most cases when immediate breast reconstruction is planned. The majority of general surgeons perform SSM and therefore it should be considered standard of care. Despite a growing body of literature demonstrating high rates of patient satisfaction and long-term oncologic safety with SSM, there remains significant variation in practice patterns among general surgeons. Additional effort in general surgery education regarding the feasibility and safety of SSM is needed.

[The value of diagnosis of the harmonic imaging ultrasonic integrated backscatter on the very early stage of acute myocardial infarction].

OBJECTIVE: To study change and the value of diagnosis of harmonic imaging ultrasonic integrated backscatter (IBS) on the very early diagnosis of acute myocardial infarction (AMI). METHOD: 72 patients were divided 2 groups, A group 30 cases with AMI at the very early stage of acute myocardial infarction (in 2 hours), B group 42 cases with typical acute myocardial infarction (in 2 - 12 hours) were examined by IBS and the cyclic variation of integrated backscatter (CVIB) with HP-5500 ultrasonic system in the segment of myocardial infarction and no myocardial infarction. RESULTS: In A group the IBS of the segment of AMI are very higher than that of the segment of no AMI [(18.8 +/- 3.4) dB vs (8.3 +/- 1.2) dB, P < 0.01], the CVIB are lower [(6.3 +/- 0.7) dB vs (7.6 +/- 1.1) dB, P < 0.01]. But in the meanwhile there are no obvious changes in ECG. In B group the IBS of the segment of AMI is obvious higher than the normal person and no infarction segment in the same heart [(22.2 +/- 4.1) dB vs (8.3 +/- 1.2) dB, (21.1 +/- 3.2) dB vs (8.7 +/- 0.9) dB, P < 0.05], but CVIB is obvious lower than the normal person and no infarction segment in the same heart [(5.6 +/- 0.8) dB vs (7.6 +/- 1.1) dB, P < 0.05; (5.8 +/- 0.7) dB vs (9.3 +/- 0.9) dB, P < 0.01], the changes of the ultrasonic is coincidence with ECG. The change of IBS are very obvious just as in ECG. CONCLUSION: The result demonstrate that ultrasonic tissue characterization with harmonic imaging integrated backscatter can be used for diagnosis the very early stage of AMI, and can judge the segment range of AMI and function of the whole heart.

A Bayesian framework for efficient and accurate variant prediction.

There is a growing need to develop variant prediction tools capable of assessing a wide spectrum of evidence. We present a Bayesian framework that involves aggregating pathogenicity data across multiple in silico scores on a gene-by-gene basis and multiple evidence statistics in both quantitative and qualitative forms, and performs 5-tiered variant classification based on the resulting probability credible interval. When evaluated in 1,161 missense variants, our gene-specific in silico model-based meta-predictor yielded an area under the curve (AUC) of 96.0% and outperformed all other in silico predictors. Multifactorial model analysis incorporating all available evidence yielded 99.7% AUC, with 22.8% predicted as variants of uncertain significance (VUS). Use of only 3 auto-computed evidence statistics yielded 98.6% AUC with 56.0% predicted as VUS, which represented sufficient accuracy to rapidly assign a significant portion of VUS to clinically meaningful classifications. Collectively, our findings support the use of this framework to conduct large-scale variant prioritization using in silico predictors followed by variant prediction and classification with a high degree of predictive accuracy.

Single nucleotide polymorphisms of tumor necrosis factor-alpha and the susceptibility to bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease of infancy. A "New" BPD has been characterized in preterm infants that may begin in utero, and then progress post-natally, resulting in arrested lung development and alveolar hypoplasia. Foundations for this "New" BPD may be derived from pro-inflammatory genes including tumor necrosis factor-alpha (TNFalpha). The hypothesis of the current study is that single nucleotide polymorphisms (SNPs) of the pro-inflammatory TNFalpha gene place preterm infants at increased risk for BPD. Preterm infants (105 in number) with birthweights