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1.  Patient Perception of Natural Orifice Transluminal Endoscopic Surgery in an Endoscopy Screening Program in Korea 
Yonsei Medical Journal  2012;53(5):960-967.
Natural orifice transluminal endoscopic surgery (NOTES) is a new method of accessing intracavitary organs in order to minimize pain by avoiding incisions in the body wall. The aim of this study is to determine patients' acceptance of NOTES in Korea and to compare their views about laparoscopic surgery and NOTES for benign and malignant diseases.
Materials and Methods
The target number of total subjects was calculated to be 540. The subjects were classified into 18 sub-groups based on age groups, gender, and history of prior surgery. The questionnaire elicited information about demographic characteristics, medical check-ups, diseases, endoscopic and surgical histories, marital status and childbirth, the acceptance of NOTES, and the preferred routes for NOTES. In addition, the subjects chose laparoscopic surgery or NOTES for a hypothetical cholecystectomy and rectal cancer surgery, and responded to questions regarding the acceptable complication rate of NOTES, the appropriate cost of NOTES, and the reason(s) why they did not select NOTES.
486 of 540 patients (90.0%) who agreed to participate in this study completed the questionnaire. NOTES was preferred by the following patients: elderly; a history of treatment due to a disease; having regular check-ups; and a history of an endoscopic procedure (p<0.05). The most preferred route for NOTES was the stomach (67.1%). Eighty-four percent of the patients choosing NOTES responded that the complication rate of the new surgical method should be the same or lower than laparoscopic surgery. Vague anxiety over a new surgical method was the most common reason why NOTES was not selected in benign and malignant diseases (64% and 73%), respectively.
Patients appear to be interested in the potential benefits of NOTES and would embrace it if their concerns about safety are met. We believe that qualified surgical endoscopists can meet these safety concerns, and that NOTES development has the potential to flourish.
PMCID: PMC3423838  PMID: 22869479
NOTES; endoscopy; surgery; patient perception; survey
2.  Instrumentation for natural orifice translumenal endoscopic surgery and laparoendoscopic single-site surgery 
To describe the evolution of instrumentation and technology for natural orifice translumenal endoscopic surgery (NOTES) and laparoendoscopic single-site surgery (LESS) as applied to urologic procedures.
Materials and Methods:
We performed a search of published reports on PubMed and MEDLINE for the search terms NOTES, single-port, single-incision, single-site, natural orifice + surgery, SPA, LESS, incisionless, and scarless from 1990-2009. Studies relevant to this urologic symposium were chosen for detailed review.
Multiple case reports, case series, and review articles relevant to NOTES and LESS utilized for urologic surgery dating from 1991 to 2009 were identified. We were subsequently able to chronicle the technological advances in instrumentation utilized for NOTES, including transvaginal nephrectomy, transvesical NOTES, combination or hybrid NOTES, and robotic-assisted NOTES or R-NOTES. For LESS, we detailed the development of various access ports and operating platforms to facilitate performing urologic procedures through a single-port access site.
Significant progress has been made in developing new, multi-lumenal access ports and articulating or curved instruments to aid in triangulation necessary for certain urologic procedures. Magnetic anchoring guidance systems (MAGS) have further enhanced the approach to LESS, with the potential for future application to NOTES. NOTES and LESS have future implications for the armamentarium of urologic surgeons, although much more research is necessary to further improve instrumentation and overcome the learning curve necessary for new technology.
PMCID: PMC2978440  PMID: 21116360
Instruments; laparoendoscopic single-site surgery; natural orifice translumenal endoscopic surgery
3.  Effect of field notes on confidence and perceived competence 
Canadian Family Physician  2012;58(6):e352-e356.
To evaluate the effectiveness of field notes in assessing teachers’ confidence and perceived competence, and the effect of field notes on residents’ perceptions of their development of competence.
A faculty and resident survey completed 5 years after field notes were introduced into the program.
Five Dalhousie University family medicine sites—Fredericton, Moncton, and Saint John in New Brunswick, and Halifax and Sydney in Nova Scotia.
First- and second-year family medicine residents (as of May 2009) and core family medicine faculty.
Main outcome measures
Residents’ outcome measures included beliefs about the effects of field notes on performance, learning, reflection, clinical skills development, and feedback received. Faculty outcome measures included beliefs about the effect of field notes on guiding feedback, teaching, and reflection on clinical practice.
Forty of 88 residents (45.5%) participated. Fifteen of 50 faculty (30.0%) participated, which only permitted a discussion of trends for faculty. Residents believed field note–directed feedback reinforced their performance (81.1%), helped them learn (67.6%), helped them reflect on practice and learning (66.7%), and focused the feedback they received, making it more useful (62.2%) (P < .001 for all); 63.3% believed field note–directed feedback helped with clinical skills development (P < .01). Faculty believed field notes helped to provide more focused (86.7%) and effective feedback (78.6%), improved teaching (75.0%), and encouraged reflection on their own clinical practice (73.3%).
Most surveyed residents believed field note use improved the feedback they received and helped them to develop competence through improved performance, learning, reflection, and clinical skills development. The trends from faculty information suggested faculty believed field notes were an effective teaching, feedback, and reflection tool.
PMCID: PMC3374708  PMID: 22700743
4.  Quantifying clinical narrative redundancy in an electronic health record 
Although electronic notes have advantages compared to handwritten notes, they take longer to write and promote information redundancy in electronic health records (EHRs). We sought to quantify redundancy in clinical documentation by studying collections of physician notes in an EHR.
Design and methods
We implemented a retrospective design to gather all electronic admission, progress, resident signout and discharge summary notes written during 100 randomly selected patient admissions within a 6 month period. We modified and applied a Levenshtein edit-distance algorithm to align and compare the documents written for each of the 100 admissions. We then identified and measured the amount of text duplicated from previous notes. Finally, we manually reviewed the content that was conserved between note types in a subsample of notes.
We measured the amount of new information in a document, which was calculated as the number of words that did not match with previous documents divided by the length, in words, of the document. Results are reported as the percentage of information in a document that had been duplicated from previously written documents.
Signout and progress notes proved to be particularly redundant, with an average of 78% and 54% information duplicated from previous documents respectively. There was also significant information duplication between document types (eg, from an admission note to a progress note).
The study established the feasibility of exploring redundancy in the narrative record with a known sequence alignment algorithm used frequently in the field of bioinformatics. The findings provide a foundation for studying the usefulness and risks of redundancy in the EHR.
PMCID: PMC2995640  PMID: 20064801
5.  In vivo miniature robots for natural orifice surgery: State of the art and future perspectives 
Natural orifice translumenal endoscopic surgery (NOTES) is the integration of laparoscopic minimally invasive surgery techniques with endoscopic technology. Despite the advances in NOTES technology, the approach presents several unique instrumentation and technique-specific challenges. Current flexible endoscopy platforms for NOTES have several drawbacks including limited stability, triangulation and dexterity, and lack of adequate visualization, suggesting the need for new and improved instrumentation for this approach. Much of the current focus is on the development of flexible endoscopy platforms that incorporate robotic technology. An alternative approach to access the abdominal viscera for either a laparoscopic or NOTES procedure is the use of small robotic devices that can be implanted in an intracorporeal manner. Multiple, independent, miniature robots can be simultaneously inserted into the abdominal cavity to provide a robotic platform for NOTES surgery. The capabilities of the robots include imaging, retraction, tissue and organ manipulation, and precise maneuverability in the abdominal cavity. Such a platform affords several advantages including enhanced visualization, better surgical dexterity and improved triangulation for NOTES. This review discusses the current status and future perspectives of this novel miniature robotics platform for the NOTES approach. Although these technologies are still in pre-clinical development, a miniature robotics platform provides a unique method for addressing the limitations of minimally invasive surgery, and NOTES in particular.
PMCID: PMC2999241  PMID: 21160878
Robotic surgery; In vivo robots; Natural orifice surgery; Robotic surgical platforms
6.  The ANKLe Score: An Audit of Otolaryngology Emergency Clinic Record Keeping 
Accurate and legible medical records are essential to good quality patient care. Guidelines from The Royal College of Surgeons of England (RCSE) state the content required to form a complete medical record, but do not address legibility. An audit of otolaryngology emergency clinic record keeping was performed using a new scoring system.
The Adjusted Note Keeping and Legibility (ANKLe) score was developed as an objective and quantitative method to assess both the content and legibility of case notes, incorporating the RCSE guidelines. Twenty consecutive otolaryngology emergency clinic case notes from each of 7 senior house officers were audited against standards for legibility and content using the ANKLe score. A proforma was introduced to improve documentation and handwriting advice was given. A further set of 140 notes (20 notes for each of the 7 doctors) was audited in the same way to provide feedback.
The introduction of a proforma and advice on handwriting significantly increased the quality of case note entries in terms of content, legibility and overall ANKLe score.
Accurate note keeping can be improved by the use of a proforma. The legibility of handwriting can be improved using simple advice. The ANKLe score is an objective assessment tool of the overall quality of medical note documentation which can be adapted for use in other specialties.
PMCID: PMC2430432  PMID: 18430339
Medical audit; Medical records; Handwriting; Quality
7.  Natural orifice surgery applied for colorectal diseases 
Clinical natural orifice surgery has been applied to abdominal surgery in recent years, mostly using transvaginal and transgastric access. Rectal and transcolonic natural orifice transluminal endoscopic surgery (NOTES) were tested in animal and cadaver models by a few research groups. Despite the potential advantages of transcolonic NOTES for colorectal diseases, it has not yet been clinically applied. The first successful series of human applications of transcolonic NOTES in the literature from the NOTES Research Group in Brazil provide new possibilities in the field in new transrectal procedures for rectal cancer and benign disease. Successful first human reports on Transcolonic NOTES potentially brings new frontiers and applications for minimally invasive surgery. The treatment of colorectal diseases through flexible Perirectal NOTES Access is a promising new approach alongside existing laparoscopic and open surgery to improve patient care.
PMCID: PMC2999213  PMID: 21160847
Rectal cancer; Total mesorectal excision; Colorectal surgery; Natural orifice surgery; Natural orifice transluminal endoscopic surgery; Minimally invasive surgery.
8.  Natural orifice transluminal endoscopic surgery in urology: Review of the world literature 
Urology Annals  2012;4(1):1-5.
Natural orifice transluminal endoscopic surgery (NOTES) has gained momentum in the recent urologic literature as a new surgical approach for intra-abdominal organs with scarless and painless postoperative recoveries. We sought to review the published literature concerning the safety and reproducibility of NOTES in urology. PubMed literature review of articles published in the English language was performed over a 10-year period, i.e., between 2001 and 2011; all articles were critically reviewed and analyzed. Despite its novelty, pure or hybrid surgical approaches have been adapted in performing NOTES. NOTES essentially utilizes transluminal flexible endoscopic instruments along with laparoscopic instruments to gain access to abdominal, pelvic, and/or retroperitoneal cavities. The preliminary results of NOTES in surgery and to a limited extent in urology appear promising, yet further research in animal survival and human cadaveric models is requisite prior to human applications, especially for complex surgeries. Future innovative research, particularly biomedical engineering, should be directed to improving the technicality and mechanistic application of NOTES; hence, better safety and efficacy of NOTES.
PMCID: PMC3271442  PMID: 22346092
Natural orifice transluminal endoscopic surgery; urology; world literature
9.  Evaluating the impact of structured text and templates in ambulatory nursing. 
This evaluation looks at the use of templates for entering structured text nursing notes that generate both a legal text note that is the chart record and an underlying coded form of the note to support analysis and research. This study reflects the first phase of a prototype project of an integrated, computerized health record. Templates are notes that have been prewritten using a standard clinical vocabulary. Templates can be used as the basis of a new clinical note and can be either signed unchanged or modified to represent variations in clinical presentation. The prototype setting is a Primary Care clinic where both physicians and nurses are using the computer to enter clinical notes. In the prototype clinic team, nursing utilized the CPR for 100% of all documentation from day one. Use of templates was found to be the most frequent method of initiating a note.
PMCID: PMC2579186  PMID: 8563381
10.  Are Electronic Medical Records Trustworthy? Observations on Copying, Pasting and Duplication 
As routine use of on-line progress notes in US Department of Veterans Affairs facilities grew rapidly in the past decade, health information managers and clinicians began to notice that authors sometimes copied text from old notes into new notes. Other sources of duplication were document templates that inserted boilerplate text or patient data into notes. Word-processing and templates aided the transition to electronic notes, but enabled author copying and sometimes led to lengthy, hard-to-read records stuffed with data already available on-line. Investigators at a VA center recognized for pioneering a fully electronic record system analyzed author copying and template-generated duplication with adapted plagiarism-detection software. Nine percent of progress notes studied contained copied or duplicated text. Most copying and duplication was benign, but some introduced misleading errors into the record and some seemed possibly unethical or potentially unsafe. High-risk author copying occurred once for every 720 notes, but one in ten electronic charts contained an instance of high-risk copying. Careless copying threatens the integrity of on-line records. Clear policies, practitioner consciousness-raising and development of effective monitoring procedures are recommended to protect the value of electronic patient records.
PMCID: PMC1480345  PMID: 14728176
11.  Fit for purpose? Using the fit note with patients with chronic pain: a qualitative study 
The British Journal of General Practice  2011;61(593):e794-e800.
Staying in work may benefit patients with chronic pain, but can be difficult for GPs to negotiate with patients and their employers. The new fit note is designed to help this process, but little is known of how it is operating.
To explore GPs' views on the fit note, with particular reference to sickness certification for patients with chronic pain.
Design and setting
Qualitative study using semi-structured interviews in eight primary care trusts in south-west England.
In-depth interviews with 13 GPs.
GPs reported that the rationale behind the fit note is sound and that it may help patients with chronic pain to return to work earlier. However, GPs also reported barriers to successful fit note use, including the need to preserve doctor–patient relationships, inconsistent engagement from employers, GPs' lack of specialist occupational health knowledge, issues with fit note training, and whether a new form can achieve cultural shift.
While doctors agree that good work improves health outcomes, they do not think that fit notes will greatly alter sickness-certification rates without more concerted initiatives to manage the tripartite negotiation between doctor, patient, and employer.
PMCID: PMC3223777  PMID: 22137416
chronic disease; general practice; pain; sick leave
12.  Exploration of GPs' views and use of the fit note: a qualitative study in primary care 
The British Journal of General Practice  2012;62(598):e363-e370.
Sickness certification constitutes daily clinical practice for GPs. In April 2010, the UK sickness certification system changed to reflect the evidence that work is generally good for health and a new Statement of Fitness for Work — the ‘fit note’ — was introduced. Sickness certification is a contentious topic among GPs and the proposed fit note generated mixed reviews.
To explore GPs' views and use of the fit note during its first year of operation.
Design and setting
Qualitative interview study of GPs based in different geographical locations across the UK.
GPs (n = 15), who were recruited from a national sample, participated in semi-structured telephone interviews which were subject to constant comparative analysis.
Overall, the fit note was well received. GPs recognised that work is generally good for health and felt the fit note facilitated using an earlier return to work as a negotiation tool. GPs perceive employers as the major obstacle to early return to work. There were reports of scepticism towards the system that negatively impacted on some GPs' operation of sickness certification. Feedback over the fit note's impact on employer behaviour and the return of a mechanism that enables GPs to request early independent assessments would be welcomed.
A revised approach is needed to address the scepticism towards the sickness certification system that persists among some GPs. New strategies need to be designed to engage employers in facilitating an early return to work and to enable the objectives of the medical statement reforms to be achieved.
PMCID: PMC3338058  PMID: 22546596
general practice; health policy; qualitative research; sick leave; sickness certification
13.  Constrictive Pericarditis: A Diagnostic Perplexity 
Constrictive pericarditis is only diagnosed once in every 10,000 admissions. It is characterized by inflammation and fibrous scarring of the pericardium resulting in a thickened, rigid sac that impairs diastolic filling. Approximately 50% of cases are idiopathic, while post cardiac surgery and post radiation therapy account for 37% and 9% respectively. The scarcity of presenting symptoms and the rarity of diagnosis make it a challenge to recognize.
A 57 year-old man with no past medical history presented to the emergency room with progressing fatigue for two weeks and worsening lower extremity edema for one week, associated with dyspnea on exertion and decreased exercise tolerance. He was noted to be in atrial fibrillation with RVR upon admission to ER. Physical exam was significant for an 8 centimeter elevated JVP, and a Kussmaul's sign, which was noted sitting upright. Mild abdominal distention, hepatomegaly, and 3+ bilateral pitting edema to the upper thigh were also noted. Electrocardiogram showed non-specific low voltage QRS. A lateral chest x-ray showed significantly abundant calcifications along the anterior, inferior aspect of the cardiac silhouette. A subsequent tissue Doppler echocardiogram noted a septal bounce and an elevated early diastolic mitral annular velocity or E'. Cardiac catheterization showed an equalization of pressures, a dip and plateau sign, and ventricular interdependence. A phrenic-to-phrenic nerve pericardectomy was performed, removing a 5 millimeter thick, firm, calcified pericardium. A final diagnosis of idiopathic constrictive pericarditis was diagnosed as tissue pathology showed no abnormalities other than severe calcification. Five days post-operatively, significantly decreased leg edema, heart rate, dyspnea, abdominal distention, and JVP were noted. He was subsequently discharged two weeks post-operative with resolution of his symptoms.
This case illustrates the rarity of having multiple signs and symptoms associated with constrictive pericarditis as well as the new diagnostic capabilities of tissue Doppler. In constrictive pericarditis, elevated JVP is found in 86% of patients, dyspnea on exertion in 78%, edema in 54%, abdominal fullness in 68%, fatigue in 25%, a Kussmaul's sign in 21%, calcifications on chest x-ray in only 20%, and atrial fibrillation in only 10%. Newer data has also shown excellent specificity, 97%, for constrictive pericarditis when an elevated E' of greater than 12 cm/sec is noted. The presence of multiple rare signs and symptoms and the use of new diagnostic tissue Doppler signs make this case extremely unusual. Recognizing these signs and the proper use of cardiac catheterization and tissue Doppler is critical in differentiating constrictive pericarditis from restrictive cardiomyopathy and pericardial tamponade. It is also critical for the initiation of pericardectomy to prevent further deterioration or cardiac death.
PMCID: PMC3764578
14.  Spatial, temporal, molecular, and intraspecific differences of haemoparasite infection and relevant selected physiological parameters of wild birds in Georgia, USA☆ 
Graphical abstract
•Variable prevalences of different haemoparasite species noted among passerine hosts.•Different foraging guilds associated with different haemoparasite infections.•Prevalence of Haemoproteus, Plasmodium, and Trypanosoma higher in breeding season.•PCV differences noted between bird species but no effect of haemoparasites on PCV or polychromasia.•Novel haplotypes detected and new geographic and host associations noted for seven haplotypes.
The prevalence of five avian haemoparasite groups was examined for effects on health and associations with extrinsic factors. Overall, 786 samples were examined from six sites in two Georgia (USA) watersheds, during breeding and non-breeding periods in 2010 and 2011. Among the four most commonly infected species, Haemoproteus prevalence was significantly higher in Northern Cardinals (Cardinalis cardinalis) compared to Indigo Buntings (Passerina cyanea) and Tufted Titmice (Baeolophus bicolor) while prevalence in White-throated Sparrows (Zonotrichia albicollis) was significantly higher than in Indigo Buntings. Higher prevalence of Plasmodium was noted in Tufted Titmice and Northern Cardinals. While Leucocytozoon prevalence was highest in White-throated Sparrows, Trypanosoma prevalence was highest in Tufted Titmice. Interesting differences in infection probabilities were noted between foraging guilds with Haemoproteus associated with low-middle level strata and birds in the middle-upper strata were more likely to be infected with Plasmodium and Trypanosoma. In contrast, ground-foraging birds were more likely to be infected with Leucocytozoon. Breeding season was correlated with higher polychromasia counts and higher prevalence of Haemoproteus, Plasmodium and Trypanosoma. In addition, prevalence of infection with certain haemoparasite genera and packed cell volume (PCV) were different among host species. Body mass index was inversely correlated with prevalence of microfilaria infection but positively related to Haemoproteus infection. However, we found no relationship between PCV or polychromasia levels with haemoparasite infection. Molecular characterization of 61 samples revealed 19 unique Haemoproteus (n = 7) and Plasmodium (n = 12) haplotypes with numerous new host records. No differences were noted in haplotype diversity among birds with different migratory behaviors or foraging heights, thus additional studies are needed that incorporate molecular analysis, host biology, and vector biology into comprehensive models on parasite ecology. Detailed morphological examination of these parasites is also necessary to determine if closely related haplotypes represent single species or morphologically distinct, but closely related, haplotypes.
PMCID: PMC3862535  PMID: 24533333
Blood parasite; Body mass index; Breeding season; Haemoparasite; Hematology; Prevalence; Wild bird
15.  Needs Analysis for Developing a Virtual Reality NOTES Simulator 
Surgical endoscopy  2012;27(5):1607-1616.
Introduction and Study Aim
Natural orifice translumenal endoscopic surgery (NOTES) is an emerging surgical technique that requires a cautious adoption approach to ensure patient safety. High fidelity virtual reality-based simulators allow development of new surgical procedures and tools and train medical personnel without risk to human patients. As part of a project funded by the National Institutes of Health, we are developing a Virtual Transluminal Endoscopic Surgery Trainer (VTEST™) for this purpose. The objective of this study is to conduct a structured needs analysis to identify the design parameters for such a virtual reality-based simulator for NOTES.
A 30-point questionnaire was distributed at the 2011 NOSCAR meeting to get responses from the experts. Ordinal logistic regression and the Wilcoxon rank sum test were used for analysis.
A total of 22 NOTES experts participated in the study. Cholecystectomy (CE, 68%) followed by appendectomy (AE, 63%) (CE vs AE, p=0.0521) was selected as the first choice for simulation. Flexible (FL, 47%) and hybrid (HY, 47%) approaches were equally favorable compared to rigid (RI, 6%) with p<0.001 for both FL vs RI and HY vs RI. The transvaginal approach was preferred 3 to 1 to the transgastric. Most participants preferred two channel (2C) scopes (65%) compared to single (1C) or three (3C) or more channels with p<0.001 for both 2C vs 1C and 2C vs 3C. The importance of force feedback and the utility of a virtual NOTES simulator in training and testing new tools for NOTES were rated very high by the participants.
Our study reinforced the importance of developing a virtual NOTES simulator and clearly presented expert preferences. The results of this analysis will direct our initial development of the VTESTTM platform.
PMCID: PMC3618859  PMID: 23247736
NOTES; Natural orifice surgery; transgastric; transvaginal; virtual reality; simulator
16.  Natural orifice transluminal endoscopic surgery: New minimally invasive surgery come of age 
Although in the past two decades, laparoscopic surgery, considered as a great revolution in the minimally invasive surgery field, has undergone major development worldwide, another dramatic surgical revolution has quietly appeared in recent years. Ever since Kalloo’s first report on transgastric peritoneoscopy in a porcine model in 2004, interest in a new surgical procedure named natural orifice transluminal endoscopic surgery (NOTES) has blossomed worldwide. Considering that a NOTES procedure could theoretically avoid any abdominal incision, operation-related pain and scarring, many surgeons and endoscopists have been enthusiastic in their study of this new technique. In recent years, several NOTES studies have been carried out on porcine models and even on humans, including transvaginal cholecystectomy, transgastric appendectomy, transvaginal appendectomy, and transvesical peritoneoscopy. So what is the current situation of NOTES and how many challenges do we still face? This review discusses the current research progress in NOTES.
PMCID: PMC3218151  PMID: 22110263
Laparoscopic surgery; Natural orifice transluminal endoscopic surgery; Endoscopy
17.  Transvesical NOTES: Survival Study in Porcine Model 
Endoscopic cystotomy may allow safe and convenient abdominal access for NOTES procedures.
Background and Objectives:
The optimal access route and method for natural orifice transluminal endoscopic surgery (NOTES) has not been established. A transvesical approach, with its low rate of peritoneal contamination, is an effective clean portal of entry, but a safe urinary bladder closure has been a challenge. We developed a new technique for a safe, pure transvesical NOTES approach.
Four female piglets were used in the study. With the pigs under anesthesia, a flexible cystoscope (15Fr) was used to make an endoscopic cystotomy; diagnostic peritoneoscopy of the abdominal quadrants was done with biopsies and hemostasis. At the end, a Vicryl loop was pushed to close the bladder incision while the incision edges were pulled inwards. The pigs were euthanized after 2 wk, and necropsies were performed.
No bowel injury was noted in any of the 4 pigs. Satisfactory bladder closure was done in 2 pigs, while a partial closure was achieved in 1 case. In the postoperative period, the pigs showed no signs of pain or distress, voided normally, and had a good appetite. On necropsy, we noted healed cystotomy incisions, no intraabdominal adhesions, and no adhesions at the site.
Our new technique for endoscopic cystotomy overcomes previously reported risks for bowel injuries. Using this route gives good spatial orientation and access to all quadrants, including the pelvis. Biopsies with good hemostasis can be easily achieved. Lack of intraperitoneal changes postoperatively indicate that this procedure may be safe for humans.
PMCID: PMC3558900  PMID: 23484572
NOTES; Transvesical; Porcine model; Transvesical NOTES; Peritoneoscopy
18.  Trends in Compulsory Licensing of Pharmaceuticals Since the Doha Declaration: A Database Analysis 
PLoS Medicine  2012;9(1):e1001154.
Reed Beall and Randall Kuhn describe their findings from an analysis of use of compulsory licenses for pharmaceutical products by World Trade Organization members since 1995.
It is now a decade since the World Trade Organization (WTO) adopted the “Declaration on the TRIPS Agreement and Public Health” at its 4th Ministerial Conference in Doha. Many anticipated that these actions would lead nations to claim compulsory licenses (CLs) for pharmaceutical products with greater regularity. A CL is the use of a patented innovation that has been licensed by a state without the permission of the patent title holder. Skeptics doubted that many CLs would occur, given political pressure against CL activity and continued health system weakness in poor countries. The subsequent decade has seen little systematic assessment of the Doha Declaration's impact.
Methods and Findings
We assembled a database of all episodes in which a CL was publically entertained or announced by a WTO member state since 1995. Broad searches of CL activity were conducted using media, academic, and legal databases, yielding 34 potential CL episodes in 26 countries. Country- and product-specific searches were used to verify government participation, resulting in a final database of 24 verified CLs in 17 nations. We coded CL episodes in terms of outcome, national income, and disease group over three distinct periods of CL activity. Most CL episodes occurred between 2003 and 2005, involved drugs for HIV/AIDS, and occurred in upper-middle-income countries (UMICs). Aside from HIV/AIDS, few CL episodes involved communicable disease, and none occurred in least-developed or low-income countries.
Given skepticism about the Doha Declaration's likely impact, we note the relatively high occurrence of CLs, yet CL activity has diminished markedly since 2006. While UMICs have high CL activity and strong incentives to use CLs compared to other countries, we note considerable countervailing pressures against CL use even in UMICs. We conclude that there is a low probability of continued CL activity. We highlight the need for further systematic evaluation of global health governance actions.
Please see later in the article for the Editors' Summary
Editors' Summary
The development of a new drug is a time-consuming and expensive process. To stimulate investment in drug development, the creators of new drugs (including the pharmaceutical companies that undertake the development and testing that is needed before any drug can be used in patients) can apply for “intellectual property rights” (a patent). Intellectual property rights protect the investments made by companies during drug development by preventing other companies from making the new drug for a fixed period of time and by providing a means by which creators of new drugs can negotiate payment from other companies for the use of their creation. Until recently, the extent and enforcement of intellectual property rights varied widely around the world. Then, in 1995, the World Trade Organization (WTO) was established. By providing a set of ground rules for trade among nations, the WTO aims to ensure that trade flows as smoothly, predictably, and freely as possible around the world. One of the founding documents of the WTO is the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS Agreement), which attempts to bring the protection of intellectual property rights (including patents) under common international rules.
Why Was This Study Done?
Unfortunately, patent protection for drugs (pharmaceuticals) means that many medicines are too expensive for use in developing countries. While maintaining incentives for drug development, the TRIPS Agreement allows governments to license the use of patented inventions to someone else without the consent of the patent owner. Such “compulsory licensing” normally occurs only after negotiations for a voluntary license have failed, and the patent owner still receives an appropriate payment. It soon became clear that some governments were unsure of their right to use compulsory licensing and other flexibilities in the TRIPS Agreement, a situation likely to affect public health in poor countries by hindering universal access to medicines. Consequently, the WTO issued the “Declaration on the TRIPS Agreement and Public Health” at its 4th Ministerial Conference in Doha in November 2001. Reaction to the Doha Declaration, which reaffirms that the “TRIPS Agreement does not and should not prevent members from taking measures to protect public health,” has been mixed. Some experts predicted that it would increase compulsory licensing of pharmaceuticals, but others suggested that political pressure against compulsory licensing and health system weaknesses in poor countries would limit claims for compulsory licenses. In this database analysis, the researchers systematically assess the impact of the Doha Declaration on the compulsory licensing of pharmaceuticals.
What Did the Researchers Do and Find?
By systematically searching media archives for reports of WTO member states considering or announcing compulsory licensing of pharmaceuticals, the researchers identified 24 verified compulsory licensing episodes in 17 nations that occurred between January 1995 and June 2011. Half of these episodes ended with an announcement of a compulsory license, and the majority ended in a price reduction for a specific pharmaceutical product for the potential issuing nation through a compulsory license, a voluntary license, or a negotiated discount. Sixteen of the compulsory licensing episodes involved drugs for HIV/AIDS, four involved drugs for other communicable diseases, and four involved drugs for non-communicable diseases such as cancer. More than half the compulsory licensing episodes occurred in upper-middle-income countries (including Brazil and Thailand). Finally, most compulsory licensing episodes occurred between 2003 and 2005. There was a smaller peak of activity in the months leading up to the Doha conference, but after 2006 activity declined substantially.
What Do These Findings Mean?
Given these findings, the researchers suggest that the Doha Declaration is unlikely to have an important long-term impact on the use of compulsory licensing or on access to pharmaceuticals for communicable diseases other than HIV/AIDS in developing and low-income countries. Most notably, the researchers found no evidence of a spike in compulsory licensing episodes immediately after the Doha Declaration, and they note that the lagged spike that occurred between 2003 and 2005 could have resulted in large part from the global antiretroviral advocacy campaign. Moreover, compulsory licensing activity has diminished greatly since 2006. Thus, the researchers conclude, health advocates who pushed for the Doha Declaration reforms have had little success in engaging trade as a positive, proactive force for addressing health gaps.
Additional Information
Please access these websites via the online version of this summary at
The World Trade Organization provides information on intellectual property rights, on the TRIPS Agreement, on TRIPS and pharmaceutical patents, and on compulsory licensing of pharmaceuticals and TRIPS (in English, French, and Spanish); the Doha Declaration on the TRIPS Agreement and Public Health is also available
The World Health Organization provides information on the Doha Declaration on the TRIPS Agreement and Public Health and an analysis of the implications of the Doha Declaration
Wikipedia has pages on intellectual property rights, on the TRIPS Agreement, and on the Doha Declaration (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
PMCID: PMC3254665  PMID: 22253577
19.  472 Heterogeneity of the Ige Response to Allergenic Determinants of Cefotiam in Serum Samples From Patients with Cefotiam-induced Occupational Allergy 
Exposure to cefotiam could cause IgE-mediated occupational allergies in hospital personnel. However, the clinically available serologic test has not been widely accepted, and the antigenic determinant of this drug is unclear. We investigated patterns of the IgE response to cefotiam in patients with occupational allergies to cefotiam.
A total of 161 health care workers and 86 nonatopic healthy controls, never exposed to antibiotics, were recruited from a single tertiary hospital and the general population. A questionnaire regarding work-related symptoms associated with cefotiam was administered. Serum specific IgE antibodies to cefotiam-human serum albumin (HSA) conjugate was measured by enzyme-linked immunosorbent assay (ELISA). Patients with work-related symptoms to cefotiam and positive specific IgE antibody to cefotiam were selected and ELISA inhibition studies were performed using sera of these patients. The inhibitors included various concentrations of free and conjugated cefotiam, ceftriaxone, ceftizoxime, and HSA alone.
Four patients showed work-related upper respiratory symptoms and high levels of serum specific IgE to cefotiam-HSA conjugate compared to controls. Significant inhibition patterns to free cefotiam and cefotiam-HSA conjugate were noted in patient 1 on ELISA inhibition testing, while minimal inhibitions to the other cephalosporins, both free and conjugated, were noted. In the other 3 patients, significant dose-dependent inhibitions were noted with additions of cefotiam-HSA conjugate, while minimal inhibitions were noted with free cefotiam. Among the patients, patient 2 showed minimal inhibitions with the other cephalosporins, both free and conjugated, while patient 3 and 4 showed marked dose-dependent inhibition with ceftriaxone-HSA and ceftizoxime-HSA respectively.
The specific IgE response to cefotiam-HSA conjugate in patients with occupational allergies occurs against the hapten or new allergenic determinant in which heterogeneity of the antigenic determinant were noted depending on the individual.
PMCID: PMC3512713
20.  The acoustic and perceptual cues affecting melody segregation for listeners with a cochlear implant 
Our ability to listen selectively to single sound sources in complex auditory environments is termed “auditory stream segregation.”This ability is affected by peripheral disorders such as hearing loss, as well as plasticity in central processing such as occurs with musical training. Brain plasticity induced by musical training can enhance the ability to segregate sound, leading to improvements in a variety of auditory abilities. The melody segregation ability of 12 cochlear-implant recipients was tested using a new method to determine the perceptual distance needed to segregate a simple 4-note melody from a background of interleaved random-pitch distractor notes. In experiment 1, participants rated the difficulty of segregating the melody from distracter notes. Four physical properties of the distracter notes were changed. In experiment 2, listeners were asked to rate the dissimilarity between melody patterns whose notes differed on the four physical properties simultaneously. Multidimensional scaling analysis transformed the dissimilarity ratings into perceptual distances. Regression between physical and perceptual cues then derived the minimal perceptual distance needed to segregate the melody. The most efficient streaming cue for CI users was loudness. For the normal hearing listeners without musical backgrounds, a greater difference on the perceptual dimension correlated to the temporal envelope is needed for stream segregation in CI users. No differences in streaming efficiency were found between the perceptual dimensions linked to the F0 and the spectral envelope. Combined with our previous results in normally-hearing musicians and non-musicians, the results show that differences in training as well as differences in peripheral auditory processing (hearing impairment and the use of a hearing device) influences the way that listeners use different acoustic cues for segregating interleaved musical streams.
PMCID: PMC3818467  PMID: 24223563
auditory streaming; cochlear implant; music training; melody segregation; hearing impairment; pitch; loudness; timbre
21.  Toxoplasma antigens recognized by naturally occurring human antibodies. 
Journal of Clinical Microbiology  1986;24(6):1050-1054.
Sera of most adults have high agglutination test titers to Toxoplasma gondii whether or not the adults have other serological evidence of the infection. This finding has been attributed to the presence of naturally occurring antibodies to T. gondii. Consistent with this observation, we have recently noted that protein blots (PB) of sera of individuals not previously infected with T. gondii had immunoglobulin G (IgG) and IgM antibodies to antigens of the parasite. To further define the antigens recognized by these naturally occurring antibodies, we studied PB of sera of 44 adults and 9 children who had no serological evidence of the infection. Multiple antigens of T. gondii with molecular weights of 15,000 to greater than 205,000 were recognized by IgG and IgM natural antibodies of each of the sera. Although a relatively consistent pattern was noted on the IgM PB of the sera of the adults in the molecular weight range of 48,000 to 85,000, greater heterogeneity was noted on the IgG PB. The most common bands noted on the latter were of approximately 30,000 and 92,000 molecular weight. All of the PB obtained with the serial sera collected at yearly intervals from the children revealed bands; in some cases, new bands had appeared with time, and in others the pattern was constant. In children older than 8 years, the patterns of the PB were similar to those noted in PB of sera of the adults.
PMCID: PMC269097  PMID: 3536997
22.  Natural orifice transluminal endoscopic surgery: Where are we going? 
The foundation for natural orifice transluminal endoscopic surgery (NOTES) is to access the peritoneal and other body cavities through the wall of the alimentary tract via natural orifices, with the goal of performing procedures within the peritoneum and other cavities, without the need to make incisions in the abdominal wall. We have made great progress in the field of NOTES since the publication of the White Paper in 2006. There are still major fundamental goals as outlined by the Society of American Gastrointestinal and Endoscopic Surgeons/American Society for Gastrointestinal Endoscopy joint committee that need to be evaluated and answered before NOTES is ready for widespread clinical use. These include prevention of infection, instrument development, creation of a multitasking platform, and the ability to recognize and treat intraperitoneal complications such as hemorrhage and other physiological adverse events. In response to this need, recent abstracts and papers have focused on the management of intraoperative complications. The next phase is to focus on controlled prospective multicenter clinical trials that compare defined NOTES procedure to standard laparoscopy. The goal is to produce reliable and convincing data for the United States Food and Drug Administration, insurance companies, the physician community and the general public. At the present time, we still have many important milestones that still need to be met. Most investigators agree that a hybrid technique and not a pure NOTES practice should be advocated until devices can meet the current and new challenges in this field.
PMCID: PMC2941058  PMID: 20845502
Natural orifice transluminal endoscopic surgery; Endoscopic surgery; Gastrointestinal surgery; Laparoscopy
23.  Single-incision laparoscopic surgery - current status and controversies 
Scarless surgery is the Holy Grail of surgery and the very raison d’etre of Minimal Access Surgery was the reduction of scars and thereby pain and suffering of the patients. The work of Muhe and Mouret in the late 80s, paved the way for mainstream laparoscopic procedures and it rapidly became the method of choice for many intra-abdominal procedures. Single-incision laparoscopic surgery is a very exciting new modality in the field of minimal access surgery which works for further reducing the scars of standard laparoscopy and towards scarless surgery. Natural orifice translumenal endoscopic surgery (NOTES) was developed for scarless surgery, but did not gain popularity due to a variety of reasons. NOTES stands for natural orifice translumenal endoscopic surgery, a term coined by a consortium in 2005. NOTES remains a research technique with only a few clinical cases having been reported. The lack of success of NOTES seems to have spurred on the interest in single-incision laparoscopy as an eminently doable technique in the present with minimum visible scarring, rendering a ‘scarless’ effect. Laparo-endoscopic single-site surgery (LESS) is, a term coined by a multidisciplinary consortium in 2008 for single-incision laparoscopic surgery. These are complementary technologies with similar difficulties of access, lack of triangulation and inadequate instrumentation as of date. LESS seems to offer an advantage to surgeons with its familiar field of view and instruments similar to those used in conventional laparoscopy. LESS remains a evolving special technique used successfully in many a centre, but with a significant way to go before it becomes mainstream. It currently stands between standard laparoscopy and NOTES in the armamentarium of minimal access surgery. This article outlines the development of LESS giving an overview of all the techniques and devices available and likely to be available in the future.
PMCID: PMC3002008  PMID: 21197236
E-NOTES; LESS; single-incision laparoscopy; single-port access
24.  How Protein Stability and New Functions Trade Off 
PLoS Computational Biology  2008;4(2):e1000002.
Numerous studies have noted that the evolution of new enzymatic specificities is accompanied by loss of the protein's thermodynamic stability (ΔΔG), thus suggesting a tradeoff between the acquisition of new enzymatic functions and stability. However, since most mutations are destabilizing (ΔΔG>0), one should ask how destabilizing mutations that confer new or altered enzymatic functions relative to all other mutations are. We applied ΔΔG computations by FoldX to analyze the effects of 548 mutations that arose from the directed evolution of 22 different enzymes. The stability effects, location, and type of function-altering mutations were compared to ΔΔG changes arising from all possible point mutations in the same enzymes. We found that mutations that modulate enzymatic functions are mostly destabilizing (average ΔΔG = +0.9 kcal/mol), and are almost as destabilizing as the “average” mutation in these enzymes (+1.3 kcal/mol). Although their stability effects are not as dramatic as in key catalytic residues, mutations that modify the substrate binding pockets, and thus mediate new enzymatic specificities, place a larger stability burden than surface mutations that underline neutral, non-adaptive evolutionary changes. How are the destabilizing effects of functional mutations balanced to enable adaptation? Our analysis also indicated that many mutations that appear in directed evolution variants with no obvious role in the new function exert stabilizing effects that may compensate for the destabilizing effects of the crucial function-altering mutations. Thus, the evolution of new enzymatic activities, both in nature and in the laboratory, is dependent on the compensatory, stabilizing effect of apparently “silent” mutations in regions of the protein that are irrelevant to its function.
Author Summary
To perform its function, a protein must fold into a complex, three-dimensional structure that is maintained by a network of interactions between its amino acid residues. Evolution of a new protein function will be driven by mutation of amino acids in key positions (new-function mutations). Such mutation can also hamper interactions that ensure the stability of a protein's fold—sometimes to a degree that renders the protein non-functional. Indeed, previous studies have noted that the evolution of new enzymatic functions is accompanied by significant losses in protein stability, suggesting a “tradeoff” between acquisition of new enzymatic functions and stability. But since most mutations are destabilizing, we sought to compare new-function mutations with other types of mutations. We performed a comprehensive analysis of the type, location, and stability effects of mutations that have conferred new enzymatic functions in laboratory evolution experiments. We found that stability changes (ΔΔG) of new-function mutations are similar to those of all other mutations, but are weaker than those of mutations that characterize neutral evolutionary changes (mutations that accumulate with no change of structure and function). Our analysis also revealed the important role of neutral (i.e., “non-functional”) mutations in compensating for the destabilizing effects of the “new-function” mutations.
PMCID: PMC2265470  PMID: 18463696
25.  A new species of the Boophis rappiodes group (Anura, Mantellidae) from the Sahamalaza Peninsula, northwest Madagascar, with acoustic monitoring of its nocturnal calling activity 
ZooKeys  2014;111-132.
A new species of treefrog of the Boophis rappiodes group (Anura, Mantellidae) is described from the Sahamalaza – Iles Radama National Park in northwest Madagascar. This new species is green in colour with bright red speckling across its head and dorsum; similar in morphology to other species of this group including: B. bottae, B. rappiodes, B. erythrodactylus and B. tasymena. The new species can be distinguished by its advertisement call and by a genetic divergence of more than 4.9% in the analysed mitochondrial 16S rRNA gene fragment. Its call consists of two note types: a trill and a click; although similar sounding to B. bottae, the trill note of the new species has a faster pulse rate while the click note is predominantly two-pulsed rather than three. All individuals were detected from the banks of two streams in Ankarafa Forest. The new species represents the only member of the B. rappiodes group endemic to Madagascar’s western coast, with the majority of other members known from the eastern rainforest belt. Despite its conspicuous call, it has not been detected from other surveys of northwest Madagascar and it is likely to be a local endemic to the peninsula. The ranges of two other amphibian species also appear restricted to Sahamalaza, and so the area seems to support a high level of endemicity. Although occurring inside a National Park, this species is highly threatened by the continuing decline in the quality and extent of its habitat. Due to these threats it is proposed that this species should be classified as Critically Endangered according to the IUCN Red List criteria.
PMCID: PMC4141189  PMID: 25152689
Amphibia; Boophis ankarafensis sp. n.; Sahamalaza – Iles Radama National Park; advertisement call; conservation

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