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1.  Sleep Physiology, Abnormal States, and Therapeutic Interventions 
The Ochsner Journal  2012;12(2):122-134.
Sleep is essential. Unfortunately, a significant portion of the population experiences altered sleep states that often result in a multitude of health-related issues. The regulation of sleep and sleep-wake cycles is an area of intense research, and many options for treatment are available. The following review summarizes the current understanding of normal and abnormal sleep-related conditions and the available treatment options. All clinicians managing patients must recommend appropriate therapeutic interventions for abnormal sleep states. Clinicians' solid understanding of sleep physiology, abnormal sleep states, and treatments will greatly benefit patients regardless of their disease process.
PMCID: PMC3387837  PMID: 22778676
Abnormal sleep; apnea; dyssomnia; parasomnia; sleep physiology
2.  Informed consent and medical devices: the case of the contact lens 
doi:10.1136/bjo.2004.062315
PMCID: PMC1772680  PMID: 15923528
contact lens; informed consent
3.  A Changing Healthcare System Model: The Effectiveness of Knowledge, Attitude, and Skill of Nursing Assistants Who Attend Senile Dementia Patients in Nursing Homes in Xi'an, China - A Questionnaire Survey 
The Ochsner Journal  2014;14(3):328-334.
Background
In 2010, China had an elderly population of 1.78 billion people. As in other societies around the world, China is facing a growing challenge in providing care for its elderly citizens. Ensuring the highest quality of care for elderly patients, many of whom have senile dementia, is directly related to the performance of nursing assistants.
Methods
With the goal of investigating the knowledge, attitudes, and skills of nursing assistants who care for senile dementia patients in nursing homes in Xi'an, China, we distributed a survey and analyzed the responses.
Results
Nursing assistants showed dedication and sincerity in their care for senile dementia patients. However, their performances in the categories of life nursing and mental nursing reveal room for improvement. Further, the nursing assistants did not display adequate knowledge about senile dementia. Based on survey results, the knowledge of the nursing assistants concerning nursing safety was comparatively adequate.
Conclusion
Nursing assistants who care for senile dementia patients in nursing homes in Xi'an, China, require further training that expands their knowledge and increases their capabilities. We recommend that nursing homes in Xi'an offer a standardized professional nurse/nurse assistant training course that focuses on care for elderly patients with senile dementia.
PMCID: PMC4171789  PMID: 25249797
Dementia; health knowledge–attitudes–practice; nursing; nursing home
4.  Practical Guide to the Management of Acute and Chronic Pain in the Presence of Drug Tolerance for the Healthcare Practitioner 
The Ochsner Journal  2014;14(3):426-433.
Background
Drug tolerance has been on the rise in recent years worldwide, and consequently, pain management in our population has become challenging.
Methods
Discussed in this review are commonly abused drugs and considerations for treating acute and chronic pain states in patients with substance disorders.
Results
After marijuana, alcohol, and tobacco, the most widely abused substances are oxycodone (Oxycontin), diazepam (Valium), and methylphenidate (Ritalin). Urine testing can detect metabolites of drugs used by patients and is useful for assessing drug abuse, medication diversion, and drug interactions. The comprehensive treatment of pain in a patient with addictive disorder or tolerance must address 3 issues: the patient's addiction, any associated psychiatric conditions, and the patient's pain. Eliciting a detailed history of drug abuse—illicit drugs as well as prescription drugs—and ascertaining if the patient is currently enrolled in a methadone maintenance program for the treatment of drug addiction is vital.
Conclusion
Medical observation, supportive care, multidisciplinary pain management, and timely interventions as necessary are the keys to safe outcomes in these patients.
PMCID: PMC4171802  PMID: 25249810
Drug tolerance; pain management; substance-related disorders
5.  Basic Concepts in Opioid Prescribing and Current Concepts of Opioid-Mediated Effects on Driving 
The Ochsner Journal  2013;13(4):525-532.
Background
Many patients with chronic pain receive substandard analgesic therapy. Incomplete or inadequate care often stems from physician fears of patient addiction and/or drug toxicity. As a result, many chronic pain patients are undertreated and have unrelieved pain that tempts them to overuse or to abuse prescribed pharmacologic treatments. In the last few years, educational efforts have targeted physicians who treat chronic, nonmalignant pain with information to improve prescribing strategies and to appreciate side effects. Additionally, opioid prescribing guidelines and educational programs, including World Health Organization-published guidelines for the management of cancer pain in 1986 and the American Pain Society's promotion of pain as the 5th vital sign, have increased the propensity of pharmacists, physicians, and pain specialists to dispense pain treatments.
Methods
Controversial and evolving consequences from this explosion of prescription opioid use have emerged and are discussed in this review, including prescribing principles, opioid analgesic side effects, and driving concerns.
Conclusion
With additional appreciation for the untoward effects of chronic analgesia and a better understanding of opioid pharmacology, physicians can utilize pain management treatments in a safer and more effective manner.
PMCID: PMC3865831  PMID: 24358001
Analgesics—opioid; chronic pain; medication therapy management; opioid-related disorders
6.  Serotonin Syndrome 
The Ochsner Journal  2013;13(4):533-540.
Background
Serotonin syndrome is a potentially life-threatening syndrome that is precipitated by the use of serotonergic drugs and overactivation of both the peripheral and central postsynaptic 5HT-1A and, most notably, 5HT-2A receptors. This syndrome consists of a combination of mental status changes, neuromuscular hyperactivity, and autonomic hyperactivity. Serotonin syndrome can occur via the therapeutic use of serotonergic drugs alone, an intentional overdose of serotonergic drugs, or classically, as a result of a complex drug interaction between two serotonergic drugs that work by different mechanisms. A multitude of drug combinations can result in serotonin syndrome.
Methods
This review describes the presentation and management of serotonin syndrome and discusses the drugs and interactions that can precipitate this syndrome with the goal of making physicians more alert and aware of this potentially fatal yet preventable syndrome.
Conclusion
Many commonly used medications have proven to be the culprits of serotonin syndrome. Proper education and awareness about serotonin syndrome will improve the accuracy of diagnosis and promote the institution of the appropriate treatment that may prevent significant morbidity and mortality.
PMCID: PMC3865832  PMID: 24358002
Drug toxicity; serotonin syndrome
7.  Persistence of HIV-1 Transmitted Drug Resistance Mutations 
The Journal of Infectious Diseases  2013;208(9):1459-1463.
There are few data on the persistence of individual human immunodeficiency virus type 1 (HIV-1) transmitted drug resistance (TDR) mutations in the absence of selective drug pressure. We studied 313 patients in whom TDR mutations were detected at their first resistance test and who had a subsequent test performed while ART-naive. The rate at which mutations became undetectable was estimated using exponential regression accounting for interval censoring. Most thymidine analogue mutations (TAMs) and T215 revertants (but not T215F/Y) were found to be highly stable, with NNRTI and PI mutations being relatively less persistent. Our estimates are important for informing HIV transmission models.
doi:10.1093/infdis/jit345
PMCID: PMC3789571  PMID: 23904291
persistence; transmitted; HIV-1; resistance; mutations
8.  Benzodiazepine Pharmacology and Central Nervous System–Mediated Effects 
The Ochsner Journal  2013;13(2):214-223.
Background
Owing to the low therapeutic index of barbiturates, benzodiazepines (BZDs) became popular in this country and worldwide many decades ago for a wide range of conditions. Because of an increased understanding of pharmacology and physiology, the mechanisms of action of many BZDs are now largely understood, and BZDs of varying potency and duration of action have been developed and marketed. Although BZDs have many therapeutic roles and BZD-mediated effects are typically well tolerated in the general population, side effects and toxicity can result in morbidity and mortality for some patients. The elderly; certain subpopulations of patients with lung, liver, or kidney dysfunction; and patients on other classes of medication are especially prone to toxicity.
Methods
This review details the present knowledge about BZD mechanisms of action, drug profiles, clinical actions, and potential side effects. In addition, this review describes numerous types of BZD-mediated central nervous system effects.
Conclusion
For any patient taking a BZD, the prescribing physician must carefully evaluate the risks and benefits, and higher-risk patients require careful considerations. Clinically appropriate use of BZDs requires prudence and the understanding of pharmacology.
PMCID: PMC3684331  PMID: 23789008
Adverse effects; benzodiazepines; central nervous system
9.  Perioperative Management of Neurofibromatosis Type 1 
The Ochsner Journal  2012;12(2):111-121.
Neurofibromatosis type 1 (neurofibromatosis-1), a relatively common single-gene disorder, is caused by a mutation of the NF1 gene that results in a loss of activity or in a nonfunctional neurofibromin protein. Clinical anesthesiologists may find patients with neurofibromatosis-1 challenging because this condition may affect most organ systems and result in a wide variety of presentations and clinical implications. Current neurofibromatosis-1 research studies include genotype-phenotype correlations, investigation of the pathoetiology behind the different clinical manifestations of neurofibromatosis-1, and the search for treatment options for the different features of the disorder. Neurofibromatosis-1–associated complications of the central nervous, respiratory, cardiovascular, musculoskeletal, and gastrointestinal and genitourinary systems all present various degrees of considerations for anesthesiologists. Additionally, neurofibromatosis-1 has dramatic implications for pregnant women.
PMCID: PMC3387836  PMID: 22778675
Anesthesia; café-au-lait macules; NF1 gene; neurofibromatosis type 1
10.  Smoking Cessation in Pain Patients 
The Ochsner Journal  2012;12(1):17-20.
Background
Chronic pain patients often have comorbidities, including social habits such as tobacco abuse, they use to cope with pain states. This study tested the hypothesis that physician activism, communication, and interest in smoking cessation can reduce or eliminate tobacco use.
Methods
We developed a survey to evaluate patients' smoking habits and to determine if active physician participation changed these habits.
Results
We surveyed a total of 112 patients. Of the 56 smokers, 59% reported they had previously tried to stop. Smokers initially reported smoking 25.5 cigarettes per day for an average of 18.4 years. After receiving monthly physician messages regarding smoking, 51 of the smokers (91%) reported a reduction. These patients reported an average of 7.2 cigarettes smoked per day. Of the smoking patients, 79% indicated that they were influenced to reduce or stop smoking at the clinic, and 86% recalled that they heard specific statements from their doctor in the clinic. After reducing the number of cigarettes smoked, patients reported breathing better (68%), feeling better (66%), and experiencing less pain (34%).
Conclusion
Physician influence correlated with smoking reduction in this study.
PMCID: PMC3307498  PMID: 22438776
Nicotine; pain management; smoking; tobacco abuse
11.  Intraoperative Pulseless Electrical Activity and Acute Cardiogenic Shock After Administration of Phenylephrine, Epinephrine, and Ketamine 
The Ochsner Journal  2010;10(3):205-209.
The use of phenylephrine has been well described as a potential cause of morbidity and mortality. A thorough literature review of phenylephrine use is presented in this article. The use of ketamine and epinephrine with phenylephrine can precipitate an even more potentially lethal and catastrophic syndrome. We present the case of a 21-year-old man with Hodgkin's lymphoma and lupus who experienced an abrupt hypertensive crisis followed by pulseless electrical activity and cardiogenic shock after application of 2.5% phenylephrine-soaked nasal pledgets prior to excision of a large nasopharyngeal tumor. This case report adds to the current literature on the potential dangers of phenylephrine in clinical practice and describes a case of reversible severe left ventricular dysfunction in the setting of excessive pharmacologically induced sympathetic stimulation.
PMCID: PMC3096216  PMID: 21603379
Cardiogenic shock; Hodgkin's lymphoma; lupus; phenylephrine
12.  Disruption of Myc-Tubulin Interaction by Hyperphosphorylation of c-Myc during Mitosis or by Constitutive Hyperphosphorylation of Mutant c-Myc in Burkitt's Lymphoma 
Molecular and Cellular Biology  2000;20(14):5276-5284.
Somatic mutations at Thr-58 of c-Myc have been detected in Burkitt's lymphoma (BL) tumors and have been shown to affect the transforming potential of the Myc oncoprotein. In addition, the N-terminal domain of c-Myc has been shown to interact with microtubules in vivo, and the binding of c-Myc to α-tubulin was localized to amino acids 48 to 135 within the c-Myc protein. We demonstrate that c-Myc proteins harboring a naturally occurring mutation at Thr-58 from BL cell lines have increased stability and are constitutively hyperphosphorylated, which disrupts the in vivo interaction of c-Myc with α-tubulin. In addition, we show that wild-type c-Myc–α-tubulin interactions are also disrupted during a transient mitosis-specific hyperphosphorylation of c-Myc, which resembles the constitutive hyperphosphorylation pattern of Thr-58 in BL cells.
PMCID: PMC85977  PMID: 10866684
13.  The N-terminal domain of c-Myc associates with alpha-tubulin and microtubules in vivo and in vitro. 
Molecular and Cellular Biology  1995;15(9):5188-5195.
The polymerization of alpha- and beta-tubulin into microtubules results in a complex network of microfibrils that have important structural and functional roles in all eukaryotic cells. In addition, microtubules can interact with a diverse family of polypeptides which are believed to directly promote the assembly of microtubules and to modulate their functional activity. We have demonstrated that the c-Myc oncoprotein interacts in vivo and in vitro with alpha-tubulin and with polymerized microtubules and have defined the binding site to the N-terminal region within the transactivation domain of c-Myc. In addition, we have shown that c-Myc colocalizes with microtubules and remains tightly bound to the microtubule network after detergent extraction of intact cells. These findings suggest a potential role for Myc-tubulin interaction in vivo.
PMCID: PMC230766  PMID: 7651436
14.  Susceptibilities of anaerobic bacteria to cefoperazone and other antibiotics. 
Two hundred fifty clinical isolates of anaerobic bacteria were tested for suceptibility to cefoperazone, cefamandole, cefoxitin, carbenicillin, clindamycin, and chloramphenicol. Anaerobic gram-positive cocci were susceptible to all of the antibiotics tested. Clindamycin was the most active agent against Bacteroides species, followed by chloramphenicol and then cefoxitin. Cefoperazone was less active than cefoxitin and equal in activity to carbenicillin. Cefamandole was the least active antibiotic against Bacteroides. B. distasonis, B. vulgatus, B. thetaiotaomicron, and B. ovatus were more resistant to the antibiotics than B. melaninogenicus, B. oralis, or B. bivius. Clindamycin was the most active agent against Clostridium species, followed by chloramphenicol; the three cephalosporins and carbenicillin were about equal in activity. Clindamycin was the most active antibiotic against Fusobacterium species, followed by chloramphenicol, carbenicillin, and cefoperazone (which were about equally active) and then cefamandole.
PMCID: PMC283910  PMID: 6447475
15.  THE FINE STRUCTURE AND CHEMICAL COMPOSITION OF NUCLEI DURING SPERMIOGENESIS IN THE HOUSE CRICKET  
The Journal of Cell Biology  1966;31(1):159-179.
The early stages of nuclear differentiation in spermatids of the house cricket are described with regard to the fine structural elements and chemical components which occur. Particular attention is given to the loss of nonhistone protein from the nucleus and its relation to chromatin structure. Granular elements about 25 to 80 mµ in diameter, and fibers about 8 mµ in diameter occur in the earliest spermatid nucleus. The fibers are found in diffuse and condensed chromatin while granules are found only in diffuse material. DNA and histone parallel the chromatin fibers in distribution, while nonhistone protein and RNA parallel the granules in distribution. The granules and most of the nonhistone protein are lost, simultaneously, after the early spermatid stage. The protein loss occurs without detectable change in the structure of chromatin fibers. Chromatin fibers first show a structural change in mid spermiogenesis, when they become thicker and very contorted. Unusually thin fibers (about 5 mµ) also appear in mid spermatid nuclei; they are apparently composed of nonhistone protein and free of DNA and histone.
PMCID: PMC2107043  PMID: 5971969
17.  Growth Patterns in the First Year of Life Differ in Infants Born to Perinatally vs. Non-Perinatally HIV-infected Women 
AIDS (London, England)  2015;29(1):111-116.
Objective
To compare growth patterns in the first year of life between children born to perinatally HIV-infected (PHIV) vs. non-perinatally HIV-infected (NPHIV) women in the U.S.
Design
Retrospective cohort study of HIV-infected pregnant women who received care and delivered a liveborn at two urban tertiary centers from January 2004 - March 2012.
Methods
We collected data via chart review on demographics, behavioral risk factors, HIV clinical markers, combination antiretroviral therapy (cART), mode of HIV acquisition, pregnancy outcomes, and infant anthropometrics on study subjects. Mixed effects models were used to assess the association between maternal mode of HIV acquisition and weight-for-age (WAZ), length-for-age (LAZ), and weight-for-length (WLZ) z-scores.
Results
Of 152 pregnancies evaluated, 32 and 120 infants were born to 25 PHIV and 99 NPHIV women respectively. Infants of PHIV women exhibited lower mean WAZ and LAZ throughout the first year of life in unadjusted analyses. After adjusting for potential confounders, the relationship between PHIV & LAZ persisted (β=−0.54, p=0.026). Small for gestational age for each birth anthropometric parameter [birth length, birth weight, and both birth length and weight] was associated with decreased LAZ (β=−0.48, p=0.007), WAZ (β=−0.99, p<0.001) and WLZ (β=−0.36, p=0.027) respectively. A delivery HIV RNA level <400 copies/mL was associated with increased WAZ & WLZ (β=0.43, p=0.015; β=0.38, p=0.021).
Conclusions
Infants of PHIV women may remain at persistently decreased lengths throughout the first year of life. Further studies aimed at understanding intrauterine and environmental factors in PHIV women are warranted.
doi:10.1097/QAD.0000000000000501
PMCID: PMC4326225  PMID: 25562495
18.  Health Department Accreditation as a Catalyst to Foster the Development of a Future Public Health Workforce 
doi:10.3389/fpubh.2015.00020
PMCID: PMC4313594
public health accreditation; workforce; undergraduate education; health department; training support
19.  Dynamic consent: a patient interface for twenty-first century research networks 
Biomedical research is being transformed through the application of information technologies that allow ever greater amounts of data to be shared on an unprecedented scale. However, the methods for involving participants have not kept pace with changes in research capability. In an era when information is shared digitally at the global level, mechanisms of informed consent remain static, paper-based and organised around national boundaries and legal frameworks. Dynamic consent (DC) is both a specific project and a wider concept that offers a new approach to consent; one designed to meet the needs of the twenty-first century research landscape. At the heart of DC is a personalised, digital communication interface that connects researchers and participants, placing participants at the heart of decision making. The interface facilitates two-way communication to stimulate a more engaged, informed and scientifically literate participant population where individuals can tailor and manage their own consent preferences. The technical architecture of DC includes components that can securely encrypt sensitive data and allow participant consent preferences to travel with their data and samples when they are shared with third parties. In addition to improving transparency and public trust, this system benefits researchers by streamlining recruitment and enabling more efficient participant recontact. DC has mainly been developed in biobanking contexts, but it also has potential application in other domains for a variety of purposes.
doi:10.1038/ejhg.2014.71
PMCID: PMC4130658  PMID: 24801761
20.  Risk Factors and Outcomes for Patients with Bloodstream Infection Due to Acinetobacter baumannii-calcoaceticus Complex 
Identifying patients at risk for bloodstream infection (BSI) due to Acinetobacter baumannii-Acinetobacter calcoaceticus complex (ABC) and providing early appropriate therapy are critical for improving patient outcomes. A retrospective matched case-control study was conducted to investigate the risk factors for BSI due to ABC in patients admitted to the Detroit Medical Center (DMC) between January 2006 and April 2009. The cases were patients with BSI due to ABC; the controls were patients not infected with ABC. Potential risk factors were collected 30 days prior to the ABC-positive culture date for the cases and 30 days prior to admission for the controls. A total of 245 case patients were matched with 245 control patients. Independent risk factors associated with BSI due to ABC included a Charlson's comorbidity score of ≥3 (odds ratio [OR], 2.34; P = 0.001), a direct admission from another health care facility (OR, 4.63; P < 0.0001), a prior hospitalization (OR, 3.11; P < 0.0001), the presence of an indwelling central venous line (OR, 2.75; P = 0.011), the receipt of total parenteral nutrition (OR, 21.2; P < 0.0001), the prior receipt of β-lactams (OR, 3.58; P < 0.0001), the prior receipt of carbapenems (OR, 3.18; P = 0.006), and the prior receipt of chemotherapy (OR, 15.42; P < 0.0001). The median time from the ABC-positive culture date to the initiation of the appropriate antimicrobial therapy was 2 days (interquartile range [IQR], 1 to 3 days). The in-hospital mortality rate was significantly higher among case patients than among control patients (OR, 3.40; P < 0.0001). BSIs due to ABC are more common among critically ill and debilitated institutionalized patients, who are heavily exposed to health care settings and invasive devices.
doi:10.1128/AAC.02441-14
PMCID: PMC4135982  PMID: 24890594
21.  Population Structure of KPC-Producing Klebsiella pneumoniae Isolates from Midwestern U.S. Hospitals 
Genome sequencing of carbapenem-resistant Klebsiella pneumoniae isolates from regional U.S. hospitals was used to characterize strain diversity and the blaKPC genetic context. A phylogeny based on core single-nucleotide variants (SNVs) supports a division of sequence type 258 (ST258) into two distinct groups. The primary differences between the groups are in the capsular polysaccharide locus (cps) and their plasmid contents. A strict association between clade and KPC variant was found. The blaKPC gene was found on variants of two plasmid backbones. This study indicates that highly similar K. pneumoniae subpopulations coexist within the same hospitals over time.
doi:10.1128/AAC.00125-14
PMCID: PMC4136011  PMID: 24913165
22.  TOX3 is expressed in mammary ER+ epithelial cells and regulates ER target genes in luminal breast cancer 
BMC Cancer  2015;15:22.
Background
A breast cancer susceptibility locus has been mapped to the gene encoding TOX3. Little is known regarding the expression pattern or biological role of TOX3 in breast cancer or in the mammary gland. Here we analyzed TOX3 expression in murine and human mammary glands and in molecular subtypes of breast cancer, and assessed its ability to alter the biology of breast cancer cells.
Methods
We used a cell sorting strategy, followed by quantitative real-time PCR, to study TOX3 gene expression in the mouse mammary gland. To study the expression of this nuclear protein in human mammary glands and breast tumors, we generated a rabbit monoclonal antibody specific for human TOX3. In vitro studies were performed on MCF7, BT474 and MDA-MB-231 cell lines to study the effects of TOX3 modulation on gene expression in the context of breast cancer cells.
Results
We found TOX3 expression in estrogen receptor-positive mammary epithelial cells, including progenitor cells. A subset of breast tumors also highly expresses TOX3, with poor outcome associated with high expression of TOX3 in luminal B breast cancers. We also demonstrate the ability of TOX3 to alter gene expression in MCF7 luminal breast cancer cells, including cancer relevant genes TFF1 and CXCR4. Knockdown of TOX3 in a luminal B breast cancer cell line that highly expresses TOX3 is associated with slower growth. Surprisingly, TOX3 is also shown to regulate TFF1 in an estrogen-independent and tamoxifen-insensitive manner.
Conclusions
These results demonstrate that high expression of this protein likely plays a crucial role in breast cancer progression. This is in sharp contrast to previous studies that indicated breast cancer susceptibility is associated with lower expression of TOX3. Together, these results suggest two different roles for TOX3, one in the initiation of breast cancer, potentially related to expression of TOX3 in mammary epithelial cell progenitors, and another role for this nuclear protein in the progression of cancer. In addition, these results can begin to shed light on the reported association of TOX3 expression and breast cancer metastasis to the bone, and point to TOX3 as a novel regulator of estrogen receptor-mediated gene expression.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1018-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-015-1018-2
PMCID: PMC4324787  PMID: 25632947
TOX3; Luminal B breast cancer; TFF1; HMG-box factor; ER target gene activation; Mammary epithelial progenitor
23.  Data sharing policy design for consortia: challenges for sustainability 
Genome Medicine  2014;6(1):4.
The field of human genomics has led advances in the sharing of data with a view to facilitating translation of research into innovations for human health. This change in scientific practice has been implemented through new policy developed by many principal investigators, project managers and funders, which has ultimately led to new forms of practice and innovative governance models for data sharing. Here, we examine the development of the governance of data sharing in genomics, and explore some of the key challenges associated with the design and implementation of these policies. We examine how the incremental nature of policy design, the perennial problem of consent, the gridlock caused by multiple and overlapping access systems, the administrative burden and the problems with incentives and acknowledgment all have an impact on the potential for data sharing to be maximized. We conclude by proposing ways in which the scientific community can address these problems, to improve the sustainability of data sharing into the future.
doi:10.1186/gm523
PMCID: PMC3978924  PMID: 24475754
24.  Evaluation of a Minimally Invasive Cell Sampling Device Coupled with Assessment of Trefoil Factor 3 Expression for Diagnosing Barrett's Esophagus: A Multi-Center Case–Control Study 
PLoS Medicine  2015;12(1):e1001780.
Background
Barrett's esophagus (BE) is a commonly undiagnosed condition that predisposes to esophageal adenocarcinoma. Routine endoscopic screening for BE is not recommended because of the burden this would impose on the health care system. The objective of this study was to determine whether a novel approach using a minimally invasive cell sampling device, the Cytosponge, coupled with immunohistochemical staining for the biomarker Trefoil Factor 3 (TFF3), could be used to identify patients who warrant endoscopy to diagnose BE.
Methods and Findings
A case–control study was performed across 11 UK hospitals between July 2011 and December 2013. In total, 1,110 individuals comprising 463 controls with dyspepsia and reflux symptoms and 647 BE cases swallowed a Cytosponge prior to endoscopy. The primary outcome measures were to evaluate the safety, acceptability, and accuracy of the Cytosponge-TFF3 test compared with endoscopy and biopsy.
In all, 1,042 (93.9%) patients successfully swallowed the Cytosponge, and no serious adverse events were attributed to the device. The Cytosponge was rated favorably, using a visual analogue scale, compared with endoscopy (p < 0.001), and patients who were not sedated for endoscopy were more likely to rate the Cytosponge higher than endoscopy (Mann-Whitney test, p < 0.001). The overall sensitivity of the test was 79.9% (95% CI 76.4%–83.0%), increasing to 87.2% (95% CI 83.0%–90.6%) for patients with ≥3 cm of circumferential BE, known to confer a higher cancer risk. The sensitivity increased to 89.7% (95% CI 82.3%–94.8%) in 107 patients who swallowed the device twice during the study course. There was no loss of sensitivity in patients with dysplasia. The specificity for diagnosing BE was 92.4% (95% CI 89.5%–94.7%). The case–control design of the study means that the results are not generalizable to a primary care population. Another limitation is that the acceptability data were limited to a single measure.
Conclusions
The Cytosponge-TFF3 test is safe and acceptable, and has accuracy comparable to other screening tests. This test may be a simple and inexpensive approach to identify patients with reflux symptoms who warrant endoscopy to diagnose BE.
Editors' Summary
Background
Barrett's esophagus is a condition in which the cells lining the esophagus (the tube that transports food from the mouth to the stomach) change and begin to resemble the cells lining the intestines. Although some people with Barrett's esophagus complain of burning indigestion or acid reflux from the stomach into the esophagus, many people have no symptoms or do not seek medical advice, so the condition often remains undiagnosed. Long-term acid reflux (gastroesophageal reflux disease), obesity, and being male are all risk factors for Barrett's esophagus, but the condition's exact cause is unclear. Importantly, people with Barrett's esophagus are more likely to develop esophageal cancer than people with a normal esophagus, especially if a long length (segment) of the esophagus is affected or if the esophagus contains abnormally growing “dysplastic” cells. Although esophageal cancer is rare in the general population, 1%–5% of people with Barrett's esophagus develop this type of cancer; about half of people diagnosed with esophageal cancer die within a year of diagnosis.
Why Was This Study Done?
Early detection and treatment of esophageal cancer increases an affected individual's chances of survival. Thus, experts recommend that people with multiple risk factors for Barrett's esophagus undergo endoscopic screening—a procedure that uses a small camera attached to a long flexible tube to look for esophageal abnormalities. Once diagnosed, patients with Barrett's esophagus generally enter an endoscopic surveillance program so that dysplastic cells can be identified as soon as they appear and removed using endoscopic surgery or “radiofrequency ablation” to prevent cancer development. However, although endoscopic screening of everyone with reflux symptoms for Barrett's esophagus could potentially reduce deaths from esophageal cancer, such screening is not affordable for most health care systems. In this case–control study, the researchers investigate whether a cell sampling device called the Cytosponge coupled with immunohistochemical staining for Trefoil Factor 3 (TFF3, a biomarker of Barrett's esophagus) can be used to identify individuals who warrant endoscopic investigation. A case–control study compares the characteristics of patients with and without a specific disease. The Cytosponge is a small capsule-encased sponge that is attached to a string. The capsule rapidly dissolves in the stomach after being swallowed, and the sponge collects esophageal cells for TFF3 staining when it is retrieved by pulling on the string.
What Did the Researchers Do and Find?
The researchers enrolled 463 individuals attending 11 UK hospitals for investigational endoscopy for dyspepsia and reflux symptoms as controls, and 647 patients with Barrett's esophagus who were attending hospital for monitoring endoscopy. Before undergoing endoscopy, the study participants swallowed a Cytosponge so that the researchers could evaluate the safety, acceptability, and accuracy of the Cytosponge-TFF3 test for the diagnosis of Barrett's esophagus compared with endoscopy. Nearly 94% of the participants swallowed the Cytosponge successfully, there were no adverse effects attributed to the device, and those participants that swallowed the device generally rated the experience as acceptable. The overall sensitivity of the Cytosponge-TFF3 test (its ability to detect true positives) was 79.9%. That is, 79.9% of the individuals with endoscopically diagnosed Barrett's esophagus were identified as having the condition using the new test. The sensitivity of the test was greater among patients who had a longer length of affected esophagus and importantly was not reduced in patients with dysplasia. Compared to endoscopy, the specificity of the Cytosponge-TFF3 test (its ability to detect true negatives) was 92.4%. That is, 92.4% of people unaffected by Barrett's esophagus were correctly identified as being unaffected.
What Do These Findings Mean?
The case–control design of this study means that its results are not generalizable to a primary care population. Also, the study used only a single measure of the acceptability of the Cytosponge-TFF3 test, Nevertheless, these findings indicate that this minimally invasive test for Barrett's esophagus is safe and acceptable, and that its accuracy is similar to that of colorectal cancer and cervical cancer screening tests. The Cytosponge-TFF3 test might, therefore, provide a simple, inexpensive way to identify those patients with reflux symptoms who warrant endoscopy to diagnose Barrett's esophagus, although randomized controlled trials of the test are needed before its routine clinical implementation. Moreover, because most people with Barrett's esophagus never develop esophageal cancer, additional biomarkers ideally need to be added to the test before its routine implementation to identify those individuals who have the greatest risk of esophageal cancer, and thereby avoid overtreatment of Barrett's esophagus.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001780.
The US National Institute of Diabetes and Digestive and Kidney Diseases provides detailed information about Barrett's esophagus and gastroesophageal reflux disease
The US National Cancer Institute provides information for patients and health professionals about esophageal cancer (in English and Spanish)
Cancer Research UK (a non-profit organization) provides detailed information about Barrett's esophagus (including a video about having the Cytosponge test and further information about this study, the BEST2 Study) and about esophageal cancer
The UK National Health Service Choices website has pages on the complications of gastroesophageal reflux and on esophageal cancer (including a real story)
Heartburn Cancer Awareness Support is a non-profit organization that aims to improve public awareness and provides support for people affected by Barrett's esophagus; the organization's website explains the range of initiatives to promote education and awareness as well as highlighting personal stories of those affected by Barrett's esophagus and esophageal cancer
The British Society of Gastroenterology has published guidelines on the diagnosis and management of Barrett's esophagus
The UK National Institute for Health and Care Excellence has published guidelines for gastroesophageal reflux
The Barrett's Esophagus Campaign is a UK-based non-profit organization that supports research into the condition and provides support for people affected by Barrett's esophagus; its website includes personal stories about the condition
In a multi-center case-control study, Rebecca Fitzgerald and colleagues examine whether a minimally invasive cell sampling device could be used to identify patients who warrant endoscopy to diagnose Barrett's esophagus.
doi:10.1371/journal.pmed.1001780
PMCID: PMC4310596  PMID: 25634542
25.  Characteristics of hepatocellular carcinoma in cirrhotic and non-cirrhotic non-alcoholic fatty liver disease 
AIM: To determine characteristics and prognostic predictors of patients with hepatocellular carcinoma (HCC) in association with non-alcoholic fatty liver disease (NAFLD).
METHODS: We reviewed the records of all patients with NAFLD associated HCC between 2000 and 2012. Data collected included demographics; histology; presence or absence of cirrhosis, size and number of HCC, alpha-fetoprotein, body mass index (BMI), and the presence of diabetes, hypertension, or dyslipidaemia.
RESULTS: Fifty-four patients with NAFLD associated HCC were identified. Mean age was 64 years with 87% male. Fifteen percent (8/54) were not cirrhotic. 11%, 24% and 50% had a BMI of < 25 kg/m2, 25-29 kg/m2 and ≥ 30 kg/m2 respectively. Fifty-nine percent were diabetic, 44% hypertensive and 26% hyperlipidaemic. Thirty-four percent of the patients had ≤ 1 of these risk factors. Non-cirrhotics had a significantly larger mean tumour diameter at diagnosis than cirrhotics (P = 0.041). Multivariate analysis did not identify any other patient characteristics that predicted the size or number of HCC.
CONCLUSION: HCC can develop in NAFLD without cirrhosis. At diagnosis such tumours are larger than those in cirrhotics, conferring a poorer prognosis.
doi:10.3748/wjg.v21.i4.1189
PMCID: PMC4306163  PMID: 25632192
Hepatocellular carcinoma; Non-alcoholic fatty liver disease; Cryptogenic cirrhosis; Metabolic syndrome; Screening

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