DNA methylation meta-analysis confirms the division of the genome into two functional groups

Based on a meta-analysis of human genome methylation data, we tested a theoretical model in which aging is explained by the redistribution of limited resources in cells between two main tasks of the organism: its selfsustenance based on the function of the Housekeeping Gene Group (HG) and functional differentiation, provided by the (IntG) integrative gene group. A meta-analysis of methylation of 100 genes, 50 in the HG group and 50 in IntG, showed significant differences (p<0.0001) between our groups in the level of absolute methylation values of genes bodies and its promoters. We showed a reliable decrease of absolute methylation values in IntG with rising age in contrast to HG, where this level remained constant. The one-sided decrease in methylation in the IntG group is indirectly confirmed by the dispersion data analysis, which also decreased in the genes of this group. The imbalance between HG and IntG in methylation levels suggests that this IntG-shift is a side effect of the ontogenesis grownup program and the main cause of aging. The theoretical model of functional genome division also suggests the leading role of slow dividing and post mitotic cells in triggering and implementing the aging process.Published versio

A bi-directional adversarial explainability for decision support

In this paper we present an approach to creating Bi-directional Decision Support System (DSS) as an intermediary between an expert (U) and a machine learning (ML) system for choosing an optimal solution. As a first step, such DSS analyzes the stability of expert decision and looks for critical values in data that support such a decision. If the expert’s decision and that of a machine learning system continue to be different, the DSS makes an attempt to explain such a discrepancy. We discuss a detailed description of this approach with examples. Three studies are included to illustrate some features of our approach.Accepted manuscrip

Performance of Primary Care Physicians and Other Providers on Key Process Measures in the Treatment of Diabetes

OBJECTIVE Studies have shown that patients without a consistent primary care provider have inferior outcomes. However, little is known about the mechanisms for these effects. This study aims to determine whether primary care physicians (PCPs) provide more frequent medication intensification, lifestyle counseling, and patient encounters than other providers in the primary care setting. RESEARCH DESIGN AND METHODS This retrospective cohort study included 584,587 encounters for 27,225 patients with diabetes and elevated A1C, blood pressure, and/or LDL cholesterol monitored for at least 2 years. Encounters occurred at primary care practices affiliated with two teaching hospitals in eastern Massachusetts. RESULTS Of the encounters documented, 83% were with PCPs, 13% were with covering physicians, and 5% were with midlevel providers. In multivariable analysis, the odds of medication intensification were 49% (P < 0.0001) and 26% (P < 0.0001) higher for PCPs than for covering physicians and midlevel providers, respectively, whereas the odds of lifestyle counseling were 91% (P < 0.0001) and 21% (P = 0.0015) higher. During visits with acute complaints, covering physicians were even less likely, by a further 52% (P < 0.0001), to intensify medications, and midlevel providers were even less likely, by a further 41% (P < 0.0001), to provide lifestyle counseling. Compared with PCPs, the hazard ratios for time to the next encounter after a visit without acute complaints were 1.11 for covering physicians and 1.19 for midlevel providers (P < 0.0001 for both). CONCLUSIONS PCPs provide better care through higher rates of medication intensification and lifestyle counseling. Covering physicians and midlevel providers may enable more frequent encounters when PCP resources are constrained

Methylation Level Differences between the Housekeeping and the Specialized Genes Identified during Ontogenesis

The genome methylation is one of the leading areas in the study of aging. The theoretical model we proposed earlier explains aging by redistribution of limited resources between two main tasks of the organism: its self-sustenance based on the function of the housekeeping gene group (HG) and functional differentiation provided by the IntG integrative gene group. To test our model, we used methylation level data of 100 genes, (gene body and its promoter) of 50 in the HG group and 50 in IntG. We found reliable differences ( p<0.0001) between our groups in the level of absolute methylation values, more pronounced in the promoters of the studied genes. We showed their significant decrease in IntG with age in contrast to HG, where this level remained relatively constant. The decrease in methylation in the IntG group is indirectly confirmed by the analysis of data variance, which also decreased in the genes of this group. The increasing imbalance between HG and IntG by methylation levels suggests that this IntG-shift reflects a side effect of the ontogenesis program and its connection to the main cause of aging.Othe

Clinical Outcome of Breast Cancer Occurring after Treatment for Hodgkin's Lymphoma: Case-Control Analysis

Background: To evaluate diagnosis, management and outcome of breast cancer (BC) occurring after irradiation for Hodgkin's lymphoma (HL). Methods: 39 cases of BC in 28 HL survivors were retrospectively reviewed. 21 patients were included in a case-control analysis. Results: The median age at diagnosis of HL and BC was 25.3 and 45.3 years, respectively. The median interval to develop BC was 16.1 years. Eleven women (39.2%) had bilateral disease. Mode of detection of the index breast cancers was by mammographic screening in 17 patients (60.7%), palpable lump in 8 patients (28.6%), clinical examination in two patients (7.1%), and unknown in one patient (3.6%). Case-control analysis showed that histological features and prognosis of BC after HL were similar to those of primary BC, however, for BC after HL, mastectomy was the predominant surgery (P = .001) and adjuvant radiotherapy and anthracycline-based chemotherapy were less frequently used as compared to primary BC (P < .001 and .003, respectively). Conclusion: The previous history of HL does not appear to be a poor prognostic factor for BC occurring thereafter

Clinical outcome of breast cancer occurring after treatment for Hodgkin's lymphoma: case-control analysis

<p>Abstract</p> <p>Background</p> <p>To evaluate diagnosis, management and outcome of breast cancer (BC) occurring after irradiation for Hodgkin's lymphoma (HL).</p> <p>Methods</p> <p>39 cases of BC in 28 HL survivors were retrospectively reviewed. 21 patients were included in a case-control analysis.</p> <p>Results</p> <p>The median age at diagnosis of HL and BC was 25.3 and 45.3 years, respectively. The median interval to develop BC was 16.1 years. Eleven women (39.2%) had bilateral disease. Mode of detection of the index breast cancers was by mammographic screening in 17 patients (60.7%), palpable lump in 8 patients (28.6%), clinical examination in two patients (7.1%), and unknown in one patient (3.6%). Case-control analysis showed that histological features and prognosis of BC after HL were similar to those of primary BC, however, for BC after HL, mastectomy was the predominant surgery (<it>P </it>= .001) and adjuvant radiotherapy and anthracycline-based chemotherapy were less frequently used as compared to primary BC (<it>P </it>< .001 and .003, respectively).</p> <p>Conclusion</p> <p>The previous history of HL does not appear to be a poor prognostic factor for BC occurring thereafter.</p

"Summary Page": a novel tool that reduces omitted data in research databases

<p>Abstract</p> <p>Background</p> <p>Data entry errors are common in clinical research databases. Omitted data are of particular concern because they are more common than erroneously inserted data and therefore could potentially affect research findings. However, few affordable strategies for their prevention are available.</p> <p>Methods</p> <p>We have conducted a prospective observational study of the effect of a novel tool called "<it>Summary Page</it>" on the frequency of correction of omitted data errors in a radiation oncology research database between July 2008 and March 2009. "<it>Summary Page</it>" was implemented as an optionally accessed screen in the database that visually integrates key fields in the record. We assessed the frequency of omitted data on the example of the <it>Date of Relapse </it>field. We considered the data in this field to be omitted for all records that had empty <it>Date of Relapse </it>field and evidence of relapse elsewhere in the record.</p> <p>Results</p> <p>A total of 1,156 records were updated and 200 new records were entered in the database over the study period. "<it>Summary Page</it>" was accessed for 44% of all updated records and for 69% of newly entered records. Frequency of correction of the omitted date of cancer relapse was six-fold higher in records for which "<it>Summary Page</it>" was accessed (p = 0.0003).</p> <p>Conclusions</p> <p>"<it>Summary Page</it>" was strongly associated with an increased frequency of correction of omitted data errors. Further, controlled, studies are needed to confirm this finding and elucidate its mechanism of action.</p

The Use of Radiation Therapy in the Management of Selected Patients with Atypical Lipomas

Background and Objectives. Atypical lipomas are uncommon, slow-growing benign tumors. While surgery has been the primary treatment modality, we have managed some patients with radiation (RT) as a component of the treatment and have reported their outcomes in this study. Methods. A retrospective review of all cases of extremity and trunk atypical lipomas in The Sarcoma Database at the study institution was conducted. Results. Thirteen patients were identified. All patients underwent surgical resection at initial presentation and received pre- or postoperative radiation for subtotal resection (n = 2), local recurrence (n = 8), or progressive disease (n = 3). The median total radiation dose was 50 Gy. Median followup was 65.1 months. All patients treated with RT remained free of disease at the last followup. No grade 3 or higher late toxicity from radiation was observed. No cases of tumor dedifferentiation occurred. Conclusion. For recurrent or residual atypical lipomas, a combination of reexcision and RT can provide long-term local control with acceptable morbidity. For recurrent tumors, pre-op RT of 50 Gy appears to be an effective and well-tolerated management approach

Light scattering spectroscopy identifies the malignant potential of pancreatic cysts during endoscopy

Pancreatic cancers are usually detected at an advanced stage and have poor prognosis. About one fifth of these arise from pancreatic cystic lesions. Yet not all lesions are precancerous, and imaging tools lack adequate accuracy for distinguishing precancerous from benign cysts. Therefore, decisions on surgical resection usually rely on endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). Unfortunately, cyst fluid often contains few cells, and fluid chemical analysis lacks accuracy, resulting in dire consequences, including unnecessary pancreatic surgery for benign cysts and the development of cancer. Here, we report an optical spectroscopic technique, based on a spatial gating fibre-optic probe, that predicts the malignant potential of pancreatic cystic lesions during routine diagnostic EUS-FNA procedures. In a double-blind prospective study in 25 patients, with 14 cysts measured in vivo and 13 postoperatively, the technique achieved an overall accuracy of 95%, with a 95%confidence interval of 78–99%, in cysts with definitive diagnosis