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1.  Disclosure of Incidental Findings From Next-Generation Sequencing in Pediatric Genomic Research 
Pediatrics  2013;131(3):564-571.
Next-generation sequencing technologies will likely be used with increasing frequency in pediatric research. One consequence will be the increased identification of individual genomic research findings that are incidental to the aims of the research. Although researchers and ethicists have raised theoretical concerns about incidental findings in the context of genetic research, next-generation sequencing will make this once largely hypothetical concern an increasing reality. Most commentators have begun to accept the notion that there is some duty to disclose individual genetic research results to research subjects; however, the scope of that duty remains unclear. These issues are especially complicated in the pediatric setting, where subjects cannot currently but typically will eventually be able to make their own medical decisions at the age of adulthood. This article discusses the management of incidental findings in the context of pediatric genomic research. We provide an overview of the current literature and propose a framework to manage incidental findings in this unique context, based on what we believe is a limited responsibility to disclose. We hope this will be a useful source of guidance for investigators, institutional review boards, and bioethicists that anticipates the complicated ethical issues raised by advances in genomic technology.
doi:10.1542/peds.2012-0084
PMCID: PMC3581837  PMID: 23400601
pediatrics; ethics; incidental findings; whole genome sequencing; whole exome sequencing; return of results
2.  Legal obligation of physicians to disclose information to patients. 
Obtaining a patient's consent is a routine daily process for physicians, although many are unaware of the scope of this legal obligation. In 1980 the Supreme Court of Canada changed the law relating to informed consent; promotion of patient autonomy shifted the focus from a standard of professional disclosure to one of a "reasonable patient." Physicians have a legal obligation to disclose to patients specific information, the scope of which is determined by a court on the basis of a reasonable patient's expectation and the circumstances of the case. This gives rise to many controversies in the practice of clinical medicine. It is difficult for physicians to know which treatment risks require disclosure, since this is decided by a court in a retrospective analysis of the evidence. Will the court recognize exceptions to the duty of disclosing information? If several health care professionals are involved in a patient's care who has the duty to disclose information? Can this duty be delegated? This paper provides physicians with guidelines that are consistent with the promotion of patient autonomy and comply with the doctrine of informed consent. In addition, it suggests ways of improving awareness of the doctrine and procedures to ease its application.
PMCID: PMC1453086  PMID: 1998927
3.  Informed Consent and Genomic Incidental Findings: IRB Chair Perspectives 
It is unclear how genomic incidental finding (GIF) prospects should be addressed in informed consent processes. An exploratory study on this topic was conducted with 34 purposively sampled Chairs of institutional review boards (IRBs) at centers conducting genome-wide association studies. Most Chairs (96%) reported no knowledge of local IRB requirements regarding GIFs and informed consent. Chairs suggested consent processes should address the prospect of, and study disclosure policy on, GIFs; GIF management and follow-up; potential clinical significance of GIFs; potential risks of GIF disclosure; an opportunity for participants to opt out of GIF disclosure; and duration of the researcher's duty to disclose GIFs. Chairs were concerned about participant disclosure preferences changing over time; inherent limitations in determining the scope and accuracy of claims about GIFs; and making consent processes longer and more complex. IRB Chair and other stakeholder perspectives can help advance informed consent efforts to accommodate GIF prospects.
doi:10.1525/jer.2011.6.4.53
PMCID: PMC3616513  PMID: 22228060
informed consent; genomic incidental findings; institutional review board
4.  Researcher Perspectives on Disclosure of Incidental Findings in Genetic Research 
Genetic research can produce information that is beyond the aims of the research study yet may be of clinical or personal interest to study participants. We conducted semi-structured interviews with 44 researchers who were asked to describe how they would respond to a hypothetical vignette regarding the disclosure of findings with unanticipated clinical significance to research study participants. Interviews were transcribed and analyzed using content and thematic analyses. Researchers’ decision-making processes about whether to disclose incidental findings were governed by potentially conflicting duties in three primary domains: information quality, adherence to rules, and participant welfare. There are several actions researchers can take to prepare for incidental findings, including: adding specific language in informed consent documents to state clearly how investigators will handle disclosure; exploring how prepared participants might be during the consent process to make decisions about how they would like to be approached in the event of incidental findings; developing procedures for appropriately communicating individual results and providing follow-up support based on participant preferences; and, in genetic research, having an awareness of the range of traits expressed by the genes under study.
doi:10.1525/jer.2010.5.3.31
PMCID: PMC3413406  PMID: 20831419
incidental findings; genetic studies; decision-making processes; communication of results; disclosure; qualitative research; vignette study
5.  Bioethics for clinicians: 8. Confidentiality 
Physicians are obliged to keep information about their patients secret. The understanding that the physician will not disclose private information about the patient provides a foundation for trust in the therapeutic relationship. Respect for confidentiality is firmly established in codes of ethics and in law. It is sometimes necessary, however, for physicians to breach confidentiality. Physicians should familiarize themselves with legislation in their own province governing the disclosure of certain kinds of information without the patient's authorization. Even when no specific legislation applies, the duty to warn sometimes overrides the duty to respect confidentiality. The physician should disclose only that information necessary to prevent harm, and should reveal this information only to those who need to know it in order to avert harm. Whenever possible any breach of confidentiality should be discussed with the patient beforehand.
PMCID: PMC1232782  PMID: 9054822
6.  Legal and ethical issues in genetic testing and counseling for susceptibility to breast, ovarian and colon cancer. 
The prediction of susceptibility to heritable breast, ovarian and colon cancer raises important legal and ethical concerns. Health care professionals have a duty to disclose sufficient information to enable patients to make informed decisions. They must also safeguard the confidentiality of patient data. These duties may come into conflict if a positive finding in one patient implies that family members are also at risk. A legal distinction is made between a breach of confidentiality and the legitimate sharing of information in a patient's interest or to prevent harm to a third party. Physicians also have a fiduciary duty to warn. Other issues concern the legal liability assumed by genetic counsellors, whose disclosures may influence decisions about childbearing, for example, and the risk of socioeconomic discrimination faced by people with a known genetic susceptibility. Traditional ethical orientations and principals may be applied to these and other questions, but feminist ethics will likely have particular importance in the development of an ethical stance toward testing and counseling for heritable breast and ovarian cancer.
PMCID: PMC1487772  PMID: 8634959
7.  Re-examining ethical obligations in the intensive care unit: HIV disclosure to surrogates 
Critical Care  2007;11(2):125.
Physicians treating newly incapacitated patients often must help navigate surrogate decision-makers through a difficult course of treatment decisions, while safeguarding the patient's autonomy. We offer guidance for intensive care physicians who must frequently address the difficult questions concerning disclosure of confidential information to surrogates. Three clinical vignettes will highlight the ethical challenges to physician disclosure of a critically ill patient's HIV status. Two key distinctions are offered that influence the propriety of disclosure: first, whether HIV infection represents a 'primary cause' for the patient's critical illness; and second, whether the surrogate may be harmed by failure to disclose HIV status. This balanced consideration of the direct duties of physicians to patients, and their indirect duties to surrogates and third-party contacts, may be used as a framework for considering other ethical obligations in the intensive care unit. We also provide a tabulation of individual US state laws relevant to disclosure of HIV status.
doi:10.1186/cc5720
PMCID: PMC2206453  PMID: 17466079
8.  Confidentiality and the duties of care 
Journal of Medical Ethics  2003;29(1):36-40.
Doctors have an ethical and legal duty to respect patient confidentiality. We consider the basis for this duty, looking particularly at the meaning and value of autonomy in health care. Enabling patients to decide how information about them is disclosed is an important element in autonomy and helps patients engage as active partners in their care.
Good quality data is, however, essential for research, education, public health monitoring, and for many other activities essential to provision of health care. We discuss whether it is necessary to choose between individual rights and the wider public interest and conclude that this should only rarely be necessary. The paper makes some recommendations on practical steps which could help ensure that good quality information is available for work which benefits society and the public health, while still enabling patients' autonomy to be respected.
doi:10.1136/jme.29.1.36
PMCID: PMC1733678  PMID: 12569194
9.  High Resolution 12-lead Electrocardiograms of On-Duty Professional Firefighters: A Pilot Feasibility Study 
Background
Cardiovascular deaths among on-duty firefighters are high; double that of police officers and quadruple that of first responders. The aim of this pilot study was to establish the feasibility of obtaining high resolutions ECGs of on-duty firefighters useful for detecting ECG predictors for cardiac events.
Methods
Twenty-eight professional firefighters (age, 46 ± 6 years) wore a 12-lead ECG Holter for 24 hours (16 hours while on-duty and 8 hours post-duty). All activities including fire and medical calls were monitored.
Results
On average the recordings were 92% analyzable. All were in sinus with a heart rate of 80 ±11bpm (35–188 range). The average rr50 over the 24-hour Holter study was 6.2 ±6% (range: 1–23%) and rms-SD was 81 ± 55 (range: 24–209). Using the QRS/Tsimple formula, the average spatial QRS-T angle was 104 ±17 degrees (range 78–132 degrees). Nonsustained ventricular tachycardia occurred irrespectively of activity or time of day in three (11%) firefighters, which was significantly higher than in comparable normal populations (p<0.05).
Conclusions
This preliminary work demonstrates that it is feasible to obtain high resolution ECGs during firefighting activities and further points to the high prevalence of arrhythmias among firefighters. The strategy of continuous field monitoring of firefighters could provide new insight into the association between their specific professional lifestyle and high cardiac risks.
doi:10.1097/JCN.0b013e3181a4b250
PMCID: PMC3057646  PMID: 21206348
12-lead ECG; firefighter; (sudden) cardiac death; Holter; nonsustained ventricular tachycardia
10.  Why Residents Consider Working Beyond the Duty Hour Limits: Implications of the ACGME 2011 Duty Hour Standards 
Background
The Accreditation Council for Graduate Medical Education 2011 duty hour standards became effective on 7 1, 2011. One of the new standards allows residents to exceed the limit on continuous duty hours in unusual circumstances relating to patient or family need or rare educational opportunities. There are no data about how often or in what circumstances residents would consider exceeding their duty hour limits using this new provision in the standards. We surveyed internal medicine residents to explore these questions.
Methods
We conducted an anonymous cross-sectional survey of internal medicine residents at a midwestern tertiary-care hospital to determine how often they had considered exceeding duty hour limits in the preceding 2 weeks. We analyzed responses using descriptive statistics and χ2 tests for comparisons.
Results
We obtained responses from 51 of 86 residents (59%). Of those residents, 69% (35/51) indicated that they had wanted to exceed duty hour limits at least once in the prior 2 weeks. The most common reason cited was to provide continuity of care for a patient. The 24 + 6–hour rule was the standard most likely to be broken (cited by 66%; 23/35).
Conclusions
Program leadership should anticipate that residents will commonly identify situations in which they will consider exceeding duty hour limits. It will be important to provide guidance to residents early in the year about the situations that would be appropriate for the application of this new standard.
doi:10.4300/JGME-D-11-00069.1
PMCID: PMC3244329  PMID: 23205212
11.  Genetics specialists’ perspectives on disclosure of genomic incidental findings in the clinical setting 
Patient education and counseling  2012;90(1):133-138.
Objective
Evidence documenting management of incidental findings (IFs) from clinical genomic testing is limited. The aim of this study was to examine genetics specialists’ perspectives regarding current and preferred disclosure of clinical genomic IFs.
Methods
50 genetics specialists, including medical geneticists, laboratory professionals, genetic counselors, and nurses participated in structured telephone interviews. Data were analyzed using qualitative content analysis and descriptive statistics.
Results
Most specialists had encountered IFs, but definitions of IFs varied. They discussed challenges with informing patients about the prospect of IFs and disclosing IFs to patients. Causing psychological harm to patients was a concern. Participants were divided on whether IFs needed to be clinically significant and/or actionable in order to be disclosed to patients. Creating formal disclosure guidelines was considered useful, but only if they were flexible. Additional counseling, more interdisciplinary communication, maintaining contact with patients, and a centralized database to interpret IFs were also proposed.
Conclusion
Genetics specialists offer insights into the challenges of defining IFs, knowing when and how to disclose them, and the potential need for flexible disclosure guidelines.
Practice Implications
Further discussion between practicing genetics specialists is needed to develop consensus on the development of best-practice guidelines for IF management.
doi:10.1016/j.pec.2012.09.010
PMCID: PMC3522795  PMID: 23068909
Genomics; incidental findings; clinical genetics; disclosure
12.  Factors Associated with Disclosure of Intimate Partner Violence among Women in Lagos, Nigeria 
Abstract:
Background:
Though the prevalence of Intimate Partner Violence (IPV) remains high in less developed countries, data suggest that these figures may represent an underestimation considering that many women are unwilling to disclose abuse. This paper aims to determine women's willingness to report abuse, factors determining willingness to disclose IPV, and to whom such disclosure is made.
Methods:
A total of 911 women visiting reproductive health facility responded to the questionnaire, and the collected data was analyzed using multivariate analysis.
Results:
About 54% (n=443) of the participating women reported that would not disclose IPV. Among those willing to disclose abuse, 68% (n=221) would opt to disclose to close relatives in contrast to 32% (n=103) who would disclose to some form of institutions (i.e. religious leaders, law enforcement officers). Ethnicity, woman's own use of alcohol and autonomy in decision making such as having a say on household purchases, money use and visitation, independently predicted willingness to disclose IPV.
conclusions:
The role of family is still important in the Nigeria context and the implications for research and intervention are discussed.
doi:10.5249/jivr.v1i1.15
PMCID: PMC3134900  PMID: 21483190
13.  Can "presumed consent" justify the duty to treat infectious diseases? An analysis 
Background
AIDS, SARS, and the recent epidemics of the avian-flu have all served to remind us the debate over the limits of the moral duty to care. It is important to first consider the question of whether or not the "duty to treat" might be subject to contextual constraints. The purpose of this study was to investigate the opinions and beliefs held by both physicians and dentists regarding the occupational risks of infectious diseases, and to analyze the argument that the notion of "presumed consent" on the part of professionals may be grounds for supporting the duty to treat.
Methods
For this cross-sectional survey, the study population was selected from among physicians and dentists in Ankara. All of the 373 participants were given a self-administered questionnaire.
Results
In total, 79.6% of the participants said that they either had some degree of knowledge about the risks when they chose their profession or that they learned of the risks later during their education and training. Of the participants, 5.2% said that they would not have chosen this profession if they had been informed of the risks. It was found that 57% of the participants believed that there is a standard level of risk, and 52% of the participants stated that certain diseases would exceed the level of acceptable risk unless specific protective measures were implemented.
Conclusion
If we use the presumed consent argument to establish the duty of the HCW to provide care, we are confronted with problems ranging over the difficulty of choosing a profession autonomously, the constant level of uncertainty present in the medical profession, the near-impossibility of being able to evaluate retrospectively whether every individual was informed, and the seemingly inescapable problem that this practice would legitimize, and perhaps even foster, discrimination against patients with certain diseases. Our findings suggest that another problem can be added to the list: one-fifth of the participants in this study either lacked adequate knowledge of the occupational risks when they chose the medical profession or were not sufficiently informed of these risks during their faculty education and training. Furthermore, in terms of the moral duty to provide care, it seems that most HCWs are more concerned about the availability of protective measures than about whether they had been informed of a particular risk beforehand. For all these reasons, the presumed consent argument is not persuasive enough, and cannot be used to justify the duty to provide care. It is therefore more useful to emphasize justifications other than presumed consent when defining the duty of HCWs to provide care, such as the social contract between society and the medical profession and the fact that HCWs have a greater ability to provide medical aid.
doi:10.1186/1471-2334-8-29
PMCID: PMC2311313  PMID: 18325112
14.  Impact of Timing of Birth and Resident Duty-Hour Restrictions on Outcome of Small Preterm Infants 
Pediatrics  2010;126(2):222-231.
OBJECTIVE
To examine the impact of birth at night, on the weekend, and during July or August – the first months of the academic year – and the impact of resident duty-hour restrictions on mortality and morbidity of VLBW infants.
METHODS
Outcomes were analyzed for 11,137 infants with birth weight 501–1250 grams enrolled in the NICHD Neonatal Research Network registry 2001–2005. Approximately half were born before the introduction of resident duty-hour restrictions in 2003. Follow-up assessment at 18–22 months was completed for 4,508 infants. Mortality (7-day and 28-day), short-term morbidities, and neurodevelopmental outcome were examined with respect to the timing of birth: night vs day, weekend vs weekday, and July or August vs other months, and after vs before implementation of resident duty-hour restrictions.
RESULTS
There was no effect of hour, day, or month of birth on mortality and no impact on the risks of short-term morbidities except the risk of ROP requiring operative treatment was lower for infants born during the late night hours than during the day. There was no impact of timing of birth on neurodevelopmental outcome except the risk of hearing impairment or death was slightly lower among infants born in July or August compared with other months. The introduction of resident and fellow duty-hour restrictions had no impact on mortality or neurodevelopmental outcome. The only change in short-term morbidity after duty-hour restrictions were introduced was an increase in the risk of ROP (stage 2 or higher).
CONCLUSION
In this network of academic centers, the timing of birth and the introduction of duty-hour restrictions had little effect on the risks of mortality and morbidity of VLBW infants, suggesting that staffing patterns were adequate to provide consistent care.
doi:10.1542/peds.2010-0456
PMCID: PMC2924191  PMID: 20643715
Neonatal; preterm infants; morbidity/mortality; resident education/training; workforce
15.  Availability and End-to-end Reliability in Low Duty Cycle Multihop Wireless Sensor Networks 
Sensors (Basel, Switzerland)  2009;9(3):2088-2116.
A wireless sensor network (WSN) is an ad-hoc technology that may even consist of thousands of nodes, which necessitates autonomic, self-organizing and multihop operations. A typical WSN node is battery powered, which makes the network lifetime the primary concern. The highest energy efficiency is achieved with low duty cycle operation, however, this alone is not enough. WSNs are deployed for different uses, each requiring acceptable Quality of Service (QoS). Due to the unique characteristics of WSNs, such as dynamic wireless multihop routing and resource constraints, the legacy QoS metrics are not feasible as such. We give a new definition to measure and implement QoS in low duty cycle WSNs, namely availability and reliability. Then, we analyze the effect of duty cycling for reaching the availability and reliability. The results are obtained by simulations with ZigBee and proprietary TUTWSN protocols. Based on the results, we also propose a data forwarding algorithm suitable for resource constrained WSNs that guarantees end-to-end reliability while adding a small overhead that is relative to the packet error rate (PER). The forwarding algorithm guarantees reliability up to 30% PER.
doi:10.3390/s90302088
PMCID: PMC3345823  PMID: 22574002
Wireless sensor networks; reliability; availability; QoS
16.  Laparoscopic Appendectomy in Patients With a Body Mass Index of 25 or Greater: Results of a Double Blind, Prospective, Randomized Trial 
Background:
The reported advantages of the laparoscopic approach to appendectomy are shortened hospital stay, less postoperative pain, and earlier return to usual activities (work). However, a prospective, randomized, double-blind trial comparing laparoscopic appendectomy with open appendectomy in active-duty males failed to disclose a benefit of laparoscopic appendectomy with regards to postoperative pain and return to work. The aim of our study was to compare open and laparoscopic appendectomy in overweight patients.
Methods:
We conducted a prospective, randomized, double-blind study to determine whether laparoscopic appendectomy or the open procedure in overweight patients offers a significant reduction in lost workdays, postoperative pain, or operative time from. Open appendectomy in overweight patients (those with a body mass index ≥25) may be more difficult due to excessive sub-cutaneous adipose tissue. The open incision may be of considerable size, which may result in increased postoperative pain and a prolonged convalescence.
Results:
There was a statistically significant increase in operative time for laparoscopic appendectomy of 11 minutes. As expected, the aggregate incision length for open appendectomy was twice that of the laparoscopic appendectomy.
Conclusion:
The data from this prospective, randomized, double-blind study failed to demonstrate any significant reduction in lost workdays, postoperative pain, or operative time with laparoscopic appendectomy.
PMCID: PMC3015793  PMID: 17663093
Appendectomy; Body Mass Index
17.  Changing perspectives in biobank research: from individual rights to concerns about public health regarding the return of results 
European Journal of Human Genetics  2009;17(12):1544-1549.
During the past decade, various guidelines that imply a duty for researchers to disclose information obtained through research to participants have emerged. The character and extent of this obligation have been debated extensively, with much attention devoted to the decisiveness of the validity and utility of the results in question. The aim of this paper is to argue that individual results from research on materials stored in large-scale biobanks, consisting of samples taken within the healthcare system or of altruistically donated materials, should not be returned. We will defend the thesis that medical research on these biobanks should be viewed as a collective project to improve public health, and that available resources should be utilized to pursue this goal. We argue that there is a need for a change of perspectives. Medical research should not primarily be viewed as a danger that individuals must be protected from, but rather be recognized as constituting a necessary defense against current and future diseases. Research that bears the prospect of advancing medicine and that can be carried out at no risk to individuals should be endorsed and facilitated. This calls for a shift of focus from autonomy and individual rights toward collective responsibility and solidarity.
doi:10.1038/ejhg.2009.87
PMCID: PMC2987027  PMID: 19471310
biobanks; returning results; solidarity; public health; altruism
18.  Ethical issues in genetic counselling with special reference to haemoglobinopathies 
Genetic counselling is provided in places where genetic tests are carried out. The process involves pre-test counselling as well as post-test counselling to enable the individuals to face the situation and take appropriate decisions with the right frame of mind. Major ethical principles which govern the attitudes and actions of counsellors include: respect for patient autonomy, non-maleficence, beneficence, or taking action to help benefit others and prevent harm, both physical and mental, and justice, which requires that services be distributed fairly to those in need. Other moral issues include veracity, the duty to disclose information or to be truthful, and respect for patient confidentiality. Nondirective counselling, a hallmark of this profession, is in accordance with the principle of individual autonomy. High prevalence of haemoglobinopathies with availability of good and sensitive carrier detection tests and prenatal diagnostic techniques makes these good candidates for population screening of carriers along with genetic counselling for primary prevention of the disease. Screening of the extended family members of the affected child, high risk communities and general population screening including antenatal women are the main target groups for planning a Haemoglobinopathy control programme. A critical mass of trained genetic counsellors who have understanding of the ethical issues and its appropriate handling with the required sensitivity is needed in India.
PMCID: PMC3237255  PMID: 22089619
Carrier detection; ethical issues; genetic counselling; genetic counsellor; genetic disorders; haemoglobinopathies; prenatal diagnosis
19.  Exploring resources for intrafamilial communication of cancer genetic risk: we still need to talk 
While the importance of intrafamilial communication of hereditary cancer risk has been acknowledged, the factors that promote and act as barriers to patients disclosing their information to their families are complex and emerging. This raises the question: How are patients guided in practice to contemplate intrafamilial communication? Focusing on breast cancer, we conducted an exploratory study examining current resources supporting patients and health-care professionals, and isolated the messages surrounding intrafamilial communication of cancer risk. We find the duty for health-care professionals to counsel patients regarding intrafamilial communication is acknowledged to varying degrees by multiple actors in the cancer care delivery landscape, including health-care professional associations, health service organizations, and patient groups. A range of medical, psychosocial, and other factors underlying intrafamilial communication are acknowledged in messages to patients. Patients, however, are often referred to a single group of health-care professionals to discuss their diverse and complex needs. At the same time, messages aimed at patients appear to place the emphasis on barriers that could exist for patients contemplating intrafamilial communication, while highlighting the benefits families derive from such communication. Taken together, this points to a lack of coherence within materials directed to patients and suggests the need to do coordinated research among stakeholders to address two related issues: (1) determining who are the actors best positioned to send messages surrounding intrafamilial communication to patients and (2) addressing the content of messages conveyed in patient materials.
doi:10.1038/ejhg.2012.286
PMCID: PMC3746262  PMID: 23340514
intrafamilial communication; hereditary cancer risk; patient materials
20.  The legal risks of returning results of genomics research 
Published guidelines suggest that research results and incidental findings should be offered to study participants under some circumstances. Although some have argued against the return of results in research, many cite an emerging consensus that there is an ethical obligation to return at least some results; the debate quickly turns to issues of mechanics (e.g., which results? who discloses? for how long does the obligation exist?). Although commentators are careful to distinguish this as an ethical rather than legal obligation, we worry that return of results may unjustifiably become standard of care based on this growing “consensus,” which could quickly lead to a legal (negligence-based) duty to offer and return individualized genetic research results. We caution against this and argue in this essay that the debate to date has failed to give adequate weight to a number of fundamental ethical and policy issues that should undergird policy on return of research results in the first instance, many of which go to the fundamental differences between research and clinical care. We confine our comments to research using data from large biobanks, the topic of the guidelines proposed in this symposium issue.
doi:10.1038/gim.2012.10
PMCID: PMC3779603  PMID: 22323070
biobanking; ethics; genetics; law; policy; return of results
21.  Differentially regulated splice variants and systems biology analysis of Kaposi's sarcoma-associated herpesvirus-infected lymphatic endothelial cells 
Nucleic Acids Research  2011;39(16):6970-6985.
Alternative RNA splicing greatly increases proteome diversity, and the possibility of studying genome-wide alternative splicing (AS) events becomes available with the advent of high-throughput genomics tools devoted to this issue. Kaposi's sarcoma associated herpesvirus (KSHV) is the etiological agent of KS, a tumor of lymphatic endothelial cell (LEC) lineage, but little is known about the AS variations induced by KSHV. We analyzed KSHV-controlled AS using high-density microarrays capable of detecting all exons in the human genome. Splicing variants and altered exon–intron usage in infected LEC were found, and these correlated with protein domain modification. The different 3′-UTR used in new transcripts also help isoforms to escape microRNA-mediated surveillance. Exome-level analysis further revealed information that cannot be disclosed using classical gene-level profiling: a significant exon usage difference existed between LEC and CD34+ precursor cells, and KSHV infection resulted in LEC-to-precursor, dedifferentiation-like exon level reprogramming. Our results demonstrate the application of exon arrays in systems biology research, and suggest the regulatory effects of AS in endothelial cells are far more complex than previously observed. This extra layer of molecular diversity helps to account for various aspects of endothelial biology, KSHV life cycle and disease pathogenesis that until now have been unexplored.
doi:10.1093/nar/gkr405
PMCID: PMC3167639  PMID: 21646333
22.  Comparative genomics study of polyhydroxyalkanoates (PHA) and ectoine relevant genes from Halomonas sp. TD01 revealed extensive horizontal gene transfer events and co-evolutionary relationships 
Background
Halophilic bacteria have shown their significance in industrial production of polyhydroxyalkanoates (PHA) and are gaining more attention for genetic engineering modification. Yet, little information on the genomics and PHA related genes from halophilic bacteria have been disclosed so far.
Results
The draft genome of moderately halophilic bacterium, Halomonas sp. TD01, a strain of great potential for industrial production of short-chain-length polyhydroxyalkanoates (PHA), was analyzed through computational methods to reveal the osmoregulation mechanism and the evolutionary relationship of the enzymes relevant to PHA and ectoine syntheses. Genes involved in the metabolism of PHA and osmolytes were annotated and studied in silico. Although PHA synthase, depolymerase, regulator/repressor and phasin were all involved in PHA metabolic pathways, they demonstrated different horizontal gene transfer (HGT) events between the genomes of different strains. In contrast, co-occurrence of ectoine genes in the same genome was more frequently observed, and ectoine genes were more likely under coincidental horizontal gene transfer than PHA related genes. In addition, the adjacent organization of the homologues of PHA synthase phaC1 and PHA granule binding protein phaP was conserved in the strain TD01, which was also observed in some halophiles and non-halophiles exclusively from γ-proteobacteria. In contrast to haloarchaea, the proteome of Halomonas sp. TD01 did not show obvious inclination towards acidity relative to non-halophilic Escherichia coli MG1655, which signified that Halomonas sp. TD01 preferred the accumulation of organic osmolytes to ions in order to balance the intracellular osmotic pressure with the environment.
Conclusions
The accessibility of genome information would facilitate research on the genetic engineering of halophilic bacteria including Halomonas sp. TD01.
doi:10.1186/1475-2859-10-88
PMCID: PMC3227634  PMID: 22040376
Halomonas spp.; PHB; polyhydroxyalkanoates; osmolytes; genome; PhaC
23.  Reconstruction of an Integrated Genome-Scale Co-Expression Network Reveals Key Modules Involved in Lung Adenocarcinoma 
PLoS ONE  2013;8(7):e67552.
Our goal of this study was to reconstruct a “genome-scale co-expression network” and find important modules in lung adenocarcinoma so that we could identify the genes involved in lung adenocarcinoma. We integrated gene mutation, GWAS, CGH, array-CGH and SNP array data in order to identify important genes and loci in genome-scale. Afterwards, on the basis of the identified genes a co-expression network was reconstructed from the co-expression data. The reconstructed network was named “genome-scale co-expression network”. As the next step, 23 key modules were disclosed through clustering. In this study a number of genes have been identified for the first time to be implicated in lung adenocarcinoma by analyzing the modules. The genes EGFR, PIK3CA, TAF15, XIAP, VAPB, Appl1, Rab5a, ARF4, CLPTM1L, SP4, ZNF124, LPP, FOXP1, SOX18, MSX2, NFE2L2, SMARCC1, TRA2B, CBX3, PRPF6, ATP6V1C1, MYBBP1A, MACF1, GRM2, TBXA2R, PRKAR2A, PTK2, PGF and MYO10 are among the genes that belong to modules 1 and 22. All these genes, being implicated in at least one of the phenomena, namely cell survival, proliferation and metastasis, have an over-expression pattern similar to that of EGFR. In few modules, the genes such as CCNA2 (Cyclin A2), CCNB2 (Cyclin B2), CDK1, CDK5, CDC27, CDCA5, CDCA8, ASPM, BUB1, KIF15, KIF2C, NEK2, NUSAP1, PRC1, SMC4, SYCE2, TFDP1, CDC42 and ARHGEF9 are present that play a crucial role in cell cycle progression. In addition to the mentioned genes, there are some other genes (i.e. DLGAP5, BIRC5, PSMD2, Src, TTK, SENP2, PSMD2, DOK2, FUS and etc.) in the modules.
doi:10.1371/journal.pone.0067552
PMCID: PMC3708931  PMID: 23874428
24.  Genome macrorestriction analysis of diversity and variability of Pseudomonas aeruginosa strains infecting cystic fibrosis patients. 
Journal of Clinical Microbiology  1993;31(9):2320-2326.
Genome macrorestriction fingerprinting with XbaI and DraI was used to analyze the relatedness of 166 Pseudomonas aeruginosa isolates collected from 31 cystic fibrosis patients over a 1- to 20-month period and to correlate their genotype with patterns of resistance to 14 antimicrobial agents. Quantitative comparison of intra- and interpatient similarities of P. aeruginosa macrorestriction patterns disclosed two discrete ranges that clearly discriminated subclonal variation (> 80% relatedness) and clonal diversity (10 to 70% relatedness). Cloning-derived mutants exhibited up to 20% divergence of genomic macrorestriction patterns during the course of chronic colonization of individual patients. Change of susceptibility to multiple antimicrobial agents developed in 50% of sequential pairs of isolates from individual patients. Only 19% of these susceptibility changes were attributable to strain substitution, while the majority (56%) of resistance changes were associated with minor genomic variations of a persistent strain. Sixty-six percent of patients harbored one strain, and 33% carried two strains. Three common strains colonized 5 (28%) of 18 patients attending a cystic fibrosis clinic, and another two strains colonized two patient pairs (31%) of 13 patients staying at a rehabilitation center, suggesting potential cross-infection in these settings. By indexing regional polymorphisms throughout the chromosome structure, macrorestriction analysis can monitor subclonal evolution of P. aeruginosa and identify isogenic resistance mutants. Quantitative macrorestriction fingerprinting enables discrimination between clonal variants and clones of distinct origins and should therefore provide a reliable tool for investigating the mode of acquisition of P. aeruginosa in cystic fibrosis patients.
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PMCID: PMC265754  PMID: 8408549
25.  Genomic Diversity of Clinical and Environmental Vibrio cholerae Strains Isolated in Brazil between 1991 and 2001 as Revealed by Fluorescent Amplified Fragment Length Polymorphism Analysis 
Journal of Clinical Microbiology  2003;41(5):1946-1950.
Vibrio cholerae is a ubiquitous and abundant organism in aquatic environments, particularly in coastal areas, estuaries, and rivers. This organism was the cause of a considerable number of deaths in Brazil during the last decade. In this study we applied the genomic fingerprinting technique fluorescent amplified fragment length polymorphism (FAFLP) to analyze 106 V. cholerae O1 and non-O1 and non-O139 strains isolated from clinical specimens and the environment between 1991 and 2001. Numerical analysis of the FAFLP patterns disclosed seven main groups of genomes, all of them originated from a variety of different places in different years, suggesting that V. cholerae is a very diverse species. O1 and non-O1 and non-O139 strains were distinguishable by FAFLP, although clinical and environmental strains clustered together in a few cases. The persistence of some strains of highly related genomes during several years and in completely different geographical regions suggests that these strains are highly successful in adapting to changing environmental conditions.
doi:10.1128/JCM.41.5.1946-1950.2003
PMCID: PMC154745  PMID: 12734232

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