Abstract Background Many genes have been implicated in the development of congenital heart disease (CHD). Next-generation sequencing offers opportunities for genetic testing but is often complicated ...by logistic and interpretative hurdles. Objectives This study sought to apply next-generation sequencing technology to CHD families with multiple affected members using a purpose-designed gene panel to assess diagnostic potential for future clinical applications. Methods We designed a targeted next-generation sequencing gene panel for 57 genes previously implicated in CHD. Probands were screened in 16 families with strong CHD histories and in 15 control subjects. Variants affecting protein-coding regions were classified in silico using prediction programs and filtered according to predicted mode of inheritance, minor allele frequencies, and presence in databases such as dbSNP (Single Nucleotide Polymorphism Database) and ESP (Exome Sequencing Project). Disease segregation studies were conducted in variants identified in CHD cases predicted to be deleterious and with minor allele frequencies <0.1%. Results Thirteen potential disease-causing variants were identified in 9 families. Of these, 5 variants segregated with disease phenotype, revealing a likely molecular diagnosis in 31% of this cohort. Significant increases in the number of “indels, nonsense, and splice” variants, as well as variants classified as “probably damaging” were identified in CHD cases but not in control subjects. Also, there was a significant increase in the total number of “rare” and “low” frequency variants (minor allele frequencies <0.05) in the CHD cases. Conclusions When multiple relatives are affected by CHD, a gene panel–based approach may identify its cause in up to 31% of families. Identifying causal variants has implications for clinical care and future family planning.
Illness management is a broad set of strategies designed to help individuals with serious mental illness collaborate with professionals, reduce their susceptibility to the illness, and cope ...effectively with their symptoms. Recovery occurs when people with mental illness discover, or rediscover, their strengths and abilities for pursuing personal goals and develop a sense of identity that allows them to grow beyond their mental illness. The authors discuss the concept of recovery from psychiatric disorders and then review research on professional-based programs for helping people manage their mental illness. Research on illness management for persons with severe mental illness, including 40 randomized controlled studies, indicates that psychoeducation improves people's knowledge of mental illness; that behavioral tailoring helps people take medication as prescribed; that relapse prevention programs reduce symptom relapses and rehospitalizations; and that coping skills training using cognitive-behavioral techniques reduces the severity and distress of persistent symptoms. The authors discuss the implementation and dissemination of illness management programs from the perspectives of mental health administrators, program directors, people with a psychiatric illness, and family members.
Sleep disruption is an emergent military health issue, but remarkably little is known of its prevalence or comorbidities in the combat zone. This study was designed to quantify the prevalence and ...mental health correlates of sleep disruption among military personnel serving within a ground combat zone during Operation Enduring Freedom. This was a large, cross-sectional survey of active duty and reserve U.S. Navy personnel (N = 3,175). Self-reported sleep measures included total hours of sleep per day, total hours of sleep required to feel well-rested, difficulty falling asleep, and difficulty staying asleep. The survey also measured mental health symptoms, including post-traumatic stress symptoms, anxiety, and depression. Participants reported an average of 5.9 hours of sleep per day despite requiring on average 6.8 hours to feel well rested. More than half (56%) were classified as sleep deficient, and 67% reported 6 or fewer hours of sleep per day. Adjusted for covariates, individuals endorsing sleep disruption were at substantially elevated risk of meeting criteria for post-traumatic stress disorder, generalized anxiety disorder, and major depressive disorder. This study documents the prevalence of sleep disruption in a very large and difficult-to-access sample of military members serving in a combat zone, and details robust associations with mental health.
As hospitals and physician organizations increasingly vertically integrate, there is an important opportunity to use health systems to improve performance. Prior research has largely relied on ...secondary data sources, but little is known about how health systems are organized "on the ground" and what mechanisms are available to influence physician practice at the front line of care.
We collected in-depth information on eight health systems through key informant interviews, descriptive surveys, and document review. Qualitative data were systematically coded. We conducted analyses to identify organizational structures and mechanisms through which health systems influence practice.
As expected, we found that health systems vary on multiple dimensions related to organizational structure (e.g., size, complexity) which reflects history, market and mission. With regard to levers of influence, we observed within-system variation both in mechanisms (e.g., employment of physicians, system-wide EHR, standardization of service lines) and level of influence. Concepts such as "core" versus "peripheral" were more salient than "ownership" versus "contract."
Data from secondary sources can help identify and map health systems, but they do not adequately describe them or the variation that exists within and across systems. To examine the degree to which health systems can influence performance, more detailed and nuanced information on health system characteristics is necessary.
The mixed-methods data accrual approach used in this study provides granular qualitative data that enables researchers to describe multi-layered health systems, grasp the context in which they operate, and identify the key drivers of performance.
Recognizing both the medical and operational costs of tobacco use, the Department of Defense has made tobacco cessation a top health promotion priority. Military tobacco rates remain high, however, ...especially among younger personnel and, particularly, in the Marine Corps. Tobacco is prohibited during basic training, but relapse is common following boot camp graduation. The objective of this study was to determine patterns and prevalence of tobacco use among Marine Corps recruits before entering basic training. Over a period of 14 months, 15,689 graduating male recruits completed a survey of their preservice tobacco use. Approximately 81% reported having tried tobacco at least once and 57% were classified as at-risk users. Compared to their civilian peers, more recruits were daily users and many more used smokeless tobacco. Approximately 67% of users evidenced at least one indicator of dependence. There is a clear need for additional tobacco cessation efforts to target this high-risk population.
In 1999, the Department of the Navy (DoN) began a suicide surveillance program using the DoN Suicide Incident Report (DONSIR) to collect data on completed suicides in the Navy and Marine Corps. The ...DONSIR significantly advances the capability of DoN to track and analyze data on completed suicides over time. The long-term goal of this program is to improve suicide prevention by identifying and modifying military-specific risk factors. A DONSIR has been completed on 98% of the 200 DoN suicides that occurred from 1999 to 2001. Most DoN suicides occurred outside the military work environment and involved the use of a firearm. Most decedents were men, had experienced a recent relationship problem, and did not use any military support services in the 30 days before suicide. Results suggest that the promotion of support services may improve the effectiveness of DoN suicide prevention.
Modern radiologic imaging is an aid to treatment planning for localized renal cancer, enabling characterization of mass lesions. For patients who present with advanced renal cancer, new imaging ...techniques enable a functional assessment of treatment response not possible using anatomic measurements alone. Multidetector CT urography permits simultaneous assessment of the kidneys and urinary tract for patients with unexplained hematuria. Both CT and MRI play a significant role in staging and follow up of patients treated for urothelial cancer. Newer imaging methods such as diffusion-weighted MRI have shown promising results for improving accuracy of staging and follow up of urothelial cancer.
NMR (1H and 31P) and HPLC techniques were used to study the partitioning of phosphoramide mustard (PM) and its aziridinium ions among alkylation and P-N bond hydrolysis reactions as a function of the ...concentration and strength of added nucleophiles at 37 degrees C and pH 7.4. With water as the nucleophile, bisalkylation accounted for only 10-13% of the product distribution given by PM. The remainder of the products resulted from P-N bond hydrolysis reactions. With 50 mM thiosulfate or 55-110 mM glutathione (GSH), bisalkylation by a strong nucleophile increased to 55-76%. The rest of the PM was lost to either HOH alkylation or P-N bond hydrolysis reactions. Strong experimental and theoretical evidence was obtained to support the hypothesis that the P-N bond scission observed at neutral pH does not occur in the parent PM to produce nornitrogen mustard; rather it is an aziridinium ion derived from PM which undergoes P-N bond hydrolysis to give chloroethylaziridine. In every buffer studied (bis-Tris, lutidine, triethanolamine, and Tris), the decomposition of PM (with and without GSH) gave rise to 31P NMR signals which could not be attributed to products of HOH or GSH alkylation or P-N bond hydrolysis. The intensities of these unidentified signals were dependent on the concentration of buffer.
Cytosolic aldehyde dehydrogenase (ALDH), an enzyme responsible for oxidizing intracellular aldehydes, has an important role in ethanol, vitamin A, and cyclophosphamide metabolism. High expression of ...this enzyme in primitive stem cells from multiple tissues, including bone marrow and intestine, appears to be an important mechanism by which these cells are resistant to cyclophosphamide. However, although hematopoietic stem cells (HSC) express high levels of cytosolic ALDH, isolating viable HSC by their ALDH expression has not been possible because ALDH is an intracellular protein. We found that a fluorescent aldehyde, dansyl aminoacetaldehyde (DAAA), could be used in flow cytometry experiments to isolate viable mouse and human cells based on their ALDH content. The level of dansyl fluores-cence exhibited by cells after incubation with DAAA paralleled cytosolic ALDH levels determined by Western blotting and the sensitivity of the cells to cyclophosphamide. Moreover, DAAA appeared to be a more sensitive means of assessing cytosolic ALDH levels than Western blotting. Bone marrow progenitors treated with DAAA proliferated normally. Furthermore, marrow cells expressing high levels of dansyl fluorescence after incubation with DAAA were enriched for hematopoietic progenitors. The ability to isolate viable cells that express high levels of cytosolic ALDH could be an important component of methodology for identifying and purifying HSC and for studying cyclophosphamide-resis-tant tumor cell populations.
Cognitive measures of Vietnam-era prisoners of war Williams, Diane; Hilton, Susan M; Moore, Jeffrey
JAMA : the journal of the American Medical Association,
2002-Aug-07, Letnik:
288, Številka:
5
Journal Article
PDF
