Transforming Medical Education is the Key to Meeting North Carolina's Physician Workforce Needs.

To meet the needs of the population of North Carolina, an epic transformation is under way in health care. This transformation requires that we find new ways to educate and train physicians and other health care professionals. In this commentary, we propose that the success of the Brody School of Medicine in preparing a primary care physician workforce can serve as a model for meeting the state's future physician workforce needs. Other considerations include increasing graduate medical education positions through state funding and providing incentives for medical students who stay in North Carolina.

5th National Audit Project (NAP5) on accidental awareness during general anaesthesia: protocol, methods, and analysis of data.

BACKGROUND: Accidental awareness during general anaesthesia (AAGA) with recall is a potentially distressing complication of general anaesthesia that can lead to psychological harm. The 5th National Audit Project (NAP5) was designed to investigate the reported incidence, predisposing factors, causality, and impact of accidental awareness. METHODS: A nationwide network of local co-ordinators across all the UK and Irish public hospitals reported all new patient reports of accidental awareness to a central database, using a system of monthly anonymized reporting over a calendar year. The database collected the details of the reported event, anaesthetic and surgical technique, and any sequelae. These reports were categorized into main types by a multidisciplinary panel, using a formalized process of analysis. RESULTS: The main categories of accidental awareness were: certain or probable; possible; during sedation; on or from the intensive care unit; could not be determined; unlikely; drug errors; and statement only. The degree of evidence to support the categorization was also defined for each report. Patient experience and sequelae were categorized using current tools or modifications of such. CONCLUSIONS: The NAP5 methodology may be used to assess new reports of AAGA in a standardized manner, especially for the development of an ongoing database of case reporting. This paper is a shortened version describing the protocols, methods, and data analysis from NAP5--the full report can be found at http://www.nationalauditprojects.org.uk/NAP5_home.

5th National Audit Project (NAP5) on accidental awareness during general anaesthesia: patient experiences, human factors, sedation, consent, and medicolegal issues.

The 5th National Audit Project (NAP5) of the Royal College of Anaesthetists and the Association of Anaesthetists of Great Britain and Ireland into accidental awareness during general anaesthesia (AAGA) yielded data related to psychological aspects from the patient, and the anaesthetist, perspectives; patients' experiences ranged from isolated auditory or tactile sensations to complete awareness. A striking finding was that 75% of experiences were for <5 min, yet 51% of patients [95% confidence interval (CI) 43-60%] experienced distress and 41% (95% CI 33-50%) suffered longer term adverse effect. Distress and longer term harm occurred across the full range of experiences but were particularly likely when the patient experienced paralysis (with or without pain). The patient's interpretation of what is happening at the time of the awareness seemed central to later impact; explanation and reassurance during suspected AAGA or at the time of report seemed beneficial. Quality of care before the event was judged good in 26%, poor in 39%, and mixed in 31%. Three-quarters of cases of AAGA (75%) were judged preventable. In 12%, AAGA care was judged good and the episode not preventable. The contributory and human factors in the genesis of the majority of cases of AAGA included medication, patient, and education/training. The findings have implications for national guidance, institutional organization, and individual practice. The incidence of 'accidental awareness' during sedation (~1:15,000) was similar to that during general anaesthesia (~1:19,000). The project raises significant issues about information giving and consent for both sedation and anaesthesia. We propose a novel approach to describing sedation from the patient's perspective which could be used in communication and consent. Eight (6%) of the patients had resorted to legal action (12, 11%, to formal complaint) at the time of reporting. NAP5 methodology provides a standardized template that might usefully inform the investigation of claims or serious incidents related to AAGA.

5th National Audit Project (NAP5) on accidental awareness during general anaesthesia: summary of main findings and risk factors.

We present the main findings of the 5th National Audit Project (NAP5) on accidental awareness during general anaesthesia (AAGA). Incidences were estimated using reports of accidental awareness as the numerator, and a parallel national anaesthetic activity survey to provide denominator data. The incidence of certain/probable and possible accidental awareness cases was ~1:19,600 anaesthetics (95% confidence interval 1:16,700-23,450). However, there was considerable variation across subtypes of techniques or subspecialities. The incidence with neuromuscular block (NMB) was ~1:8200 (1:7030-9700), and without, it was ~1:135,900 (1:78,600-299,000). The cases of AAGA reported to NAP5 were overwhelmingly cases of unintended awareness during NMB. The incidence of accidental awareness during Caesarean section was ~1:670 (1:380-1300). Two-thirds (82, 66%) of cases of accidental awareness experiences arose in the dynamic phases of anaesthesia, namely induction of and emergence from anaesthesia. During induction of anaesthesia, contributory factors included: use of thiopental, rapid sequence induction, obesity, difficult airway management, NMB, and interruptions of anaesthetic delivery during movement from anaesthetic room to theatre. During emergence from anaesthesia, residual paralysis was perceived by patients as accidental awareness, and commonly related to a failure to ensure full return of motor capacity. One-third (43, 33%) of accidental awareness events arose during the maintenance phase of anaesthesia, mostly due to problems at induction or towards the end of anaesthesia. Factors increasing the risk of accidental awareness included: female sex, age (younger adults, but not children), obesity, anaesthetist seniority (junior trainees), previous awareness, out-of-hours operating, emergencies, type of surgery (obstetric, cardiac, thoracic), and use of NMB. The following factors were not risk factors for accidental awareness: ASA physical status, race, and use or omission of nitrous oxide. We recommend that an anaesthetic checklist, to be an integral part of the World Health Organization Safer Surgery checklist, is introduced as an aid to preventing accidental awareness. This paper is a shortened version describing the main findings from NAP5--the full report can be found at http://www.nationalauditprojects.org.uk/NAP5_home.

The 5th National Audit Project (NAP5) on accidental awareness during general anaesthesia: protocol, methods and analysis of data.

Accidental awareness during general anaesthesia with recall is a potentially distressing complication of general anaesthesia that can lead to psychological harm. The 5th National Audit Project was designed to investigate the reported incidence, predisposing factors, causality and impact of accidental awareness. A nationwide network of local co-ordinators across all UK and Irish public hospitals reported all new patient reports of accidental awareness to a central database, using a system of monthly anonymised reporting over a calendar year. The database collected the details of the reported event, anaesthetic and surgical technique, and any sequelae. These reports were categorised into main types by a multidisciplinary panel, using a formalised process of analysis. The main categories of accidental awareness were: certain or probable; possible; during sedation; on or from the intensive care unit; could not be determined; unlikely; drug errors; and statement only. The degree of evidence to support the categorisation was also defined for each report. Patient experience and sequelae were categorised using current tools or modifications of such. The 5th National Audit Project methodology may be used to assess new reports of accidental awareness during general anaesthesia in a standardised manner, especially for the development of an ongoing database of case reporting. This paper is a shortened version describing the protocols, methods and data analysis from 5th National Audit Project - the full report can be found at http://www.nationalauditprojects.org.uk/NAP5_home#pt.

The 5th National Audit Project (NAP5) on accidental awareness during general anaesthesia: summary of main findings and risk factors.

We present the main findings of the 5th National Audit Project on accidental awareness during general anaesthesia. Incidences were estimated using reports of accidental awareness as the numerator, and a parallel national anaesthetic activity survey to provide denominator data. The incidence of certain/probable and possible accidental awareness cases was ~1:19 600 anaesthetics (95% CI 1:16 700-23 450). However, there was considerable variation across subtypes of techniques or subspecialties. The incidence with neuromuscular blockade was ~1:8200 (1:7030-9700), and without it was ~1:135 900 (1:78 600-299 000). The cases of accidental awareness during general anaesthesia reported to 5th National Audit Project were overwhelmingly cases of unintended awareness during neuromuscular blockade. The incidence of accidental awareness during caesarean section was ~1:670 (1:380-1300). Two thirds (82, 66%) of cases of accidental awareness experiences arose in the dynamic phases of anaesthesia, namely induction of and emergence from anaesthesia. During induction of anaesthesia, contributory factors included: use of thiopental; rapid sequence induction; obesity; difficult airway management; neuromuscular blockade; and interruptions of anaesthetic delivery during movement from anaesthetic room to theatre. During emergence from anaesthesia, residual paralysis was perceived by patients as accidental awareness, and commonly related to a failure to ensure full return of motor capacity. One third (43, 33%) of accidental awareness events arose during the maintenance phase of anaesthesia, most due to problems at induction or towards the end of anaesthesia. Factors increasing the risk of accidental awareness included: female sex; age (younger adults, but not children); obesity; anaesthetist seniority (junior trainees); previous awareness; out-of-hours operating; emergencies; type of surgery (obstetric, cardiac, thoracic); and use of neuromuscular blockade. The following factors were not risk factors for accidental awareness: ASA physical status; race; and use or omission of nitrous oxide. We recommend that an anaesthetic checklist, to be an integral part of the World Health Organization Safer Surgery checklist, is introduced as an aid to preventing accidental awareness. This paper is a shortened version describing the main findings from 5th National Audit Project - the full report can be found at http://www.nationalauditprojects.org.uk/NAP5_home#pt.

The 5th National Audit Project (NAP5) on accidental awareness during general anaesthesia: patient experiences, human factors, sedation, consent and medicolegal issues.

The 5th National Audit Project of the Royal College of Anaesthetists and the Association of Anaesthetists of Great Britain and Ireland into accidental awareness during general anaesthesia yielded data related to psychological aspects from the patient, and the anaesthetist, perspectives; patients' experiences ranged from isolated auditory or tactile sensations to complete awareness. A striking finding was that 75% of experiences were for < 5 min, yet 51% of patients (95% CI 43-60%) experienced distress and 41% (95% CI 33-50%) suffered longer-term adverse effect. Distress and longer-term harm occurred across the full range of experiences but were particularly likely when the patient experienced paralysis (with or without pain). The patient's interpretation of what is happening at the time of the awareness seemed central to later impact; explanation and reassurance during suspected accidental awareness during general anaesthesia or at the time of report seemed beneficial. Quality of care before the event was judged good in 26%, poor in 39% and mixed in 31%. Three quarters of cases of accidental awareness during general anaesthesia (75%) were judged preventable. In 12% of cases of accidental awareness during general anaesthesia, care was judged good and the episode not preventable. The contributory and human factors in the genesis of the majority of cases of accidental awareness during general anaesthesia included medication, patient and education/training. The findings have implications for national guidance, institutional organisation and individual practice. The incidence of 'accidental awareness' during sedation (~1:15 000) was similar to that during general anaesthesia (~1:19 000). The project raises significant issues about information giving and consent for both sedation and anaesthesia. We propose a novel approach to describing sedation from the patient's perspective which could be used in communication and consent. Eight (6%) of the patients had resorted to legal action (12, 11%, to formal complaint) at the time of reporting. The 5th National Audit Project methodology provides a standardised template that might usefully inform the investigation of claims or serious incidents related to accidental awareness during general anaesthesia.

The effect of the European Working Time Directive on anaesthetic working patterns and training.

There is concern that the European Working Time Directive 2009 has led to reduced time available for training, and this study examined if this has been the case. For two identical six-month periods in 1999 (pre-Directive) and 2009 (post-Directive), weekly data were collected on the total number of sessions attended by trainees, the number of supervised sessions and the leave days taken. A total of 5925 theatre sessions were analysed (2353 in 1999 and 3572 in 2009). For ST1-2 trainees, there was a 37% increase in theatre sessions attended (p=0.02), with a 77% increase in the number of these sessions supervised by a consultant (p=0.02). For ST3-7 trainees, there was a reduction in the number of theatre sessions attended of 27% (p=0.03), but this was not accompanied by a significant increase in the number of consultant-supervised sessions (11% increase; p=0.18). The aggregate median increase in weekly consultant-supervised theatre sessions per trainee increased for ST1-2 trainees (70% increase; p=0.0016) but not for ST3-7 trainees (11% increase; p=0.31). For neither trainee group did training time decline. Our data contradict the hypothesis that the European Working Time Directive has reduced access to training, or suggest that if it has, other factors (such as improved trainee rostering) have overridden its effect.

Transverse sinus thrombosis after internal jugular vein ligation.

BACKGROUND: Cerebral vein and dural sinus thrombosis is a rare condition with a wide range of causes and a highly variable presentation. It can lead to significant morbidity, but scant literature is available describing diagnosis and treatment when this occurs after ligation of the internal jugular vein. OBJECTIVES: To discuss potential risk factors for cerebral vein and dural sinus thrombosis after ligation of the internal jugular vein, and present current options for diagnosis and treatment. CASE REPORT: A 23-year-old male construction worker was brought to the Emergency Department by Emergency Medical Services after sustaining a severe neck laceration from a hand-held grinder. He was treated with ligation of the left internal jugular vein, but subsequently developed severe headaches and symptoms of increased intracranial pressure. A magnetic resonance venogram of the head revealed a left transverse sinus thrombosis requiring treatment with anticoagulation. The placement of a lumboperitoneal shunt was ultimately needed for relief of his symptoms. CONCLUSIONS: Early diagnosis and aggressive therapeutic interventions are critical to prevent further morbidity in patients who develop cerebral vein and dural sinus thrombosis after ligation of the internal jugular vein.

Glycation of collagen: the basis of its central role in the late complications of ageing and diabetes.

The most serious late complication of ageing and diabetes mellitus follow similar patterns in the dysfunction of retinal capillaries, renal tissue, and the cardiovascular system. The changes are accelerated in diabetic patients owing to hyerglycaemia and are the major cause of premature morbidity and mortality. These tissues and their optimal functioning are dependent on the integrity of their supporting framework of collagen. It is the modification of the properties by glycation that results in many of the damaging late complications. Initially glycation affects the interactions of collagen with cells and other matrix components, but the most damaging effects are caused by the formation of glucose-mediated intermolecular cross-links. These cross-links decrease the critical flexibility and permeability of the tissues and reduce turnover. In contrast to the renal and retinal tissue, the cardiovascular system also contains a significant proportion of other fibrous connective tissue protein elastin, and its properties are similarly modified by glycation. The nature of these glycation cross-links is now being unravelled and this knowledge is crucial in any attempt to inhibit these deleterious glycation reactions.

The effect of advanced glycation end-product formation upon cell-matrix interactions.

The formation of advanced glycation end-products plays a central role in the progressive deterioration of tissues with age, a process that is accelerated in diabetes. Collagen in addition to providing structure and tensile strength to tissues also provides a dynamic matrix for cells to interact with, and due to its long-lived nature is particularly susceptible to modification with age and disease. We have recently identified methylglyoxal as a key intermediate in this process, reacting predominantly with arginine residues to form imidazolone compounds. We therefore postulated that modification of RGD sequences in collagen with methylglyoxal would interfere with crucial cell-matrix interactions. To investigate this concept we studied the interaction of two cell lines, MG63 and HT1080, with collagen modified to varying degrees with respect to arginine. Adhesion and subsequent spreading of both cell lines was significantly decreased by minimal methylglyoxal modification leading to the conclusion that such modification of collagen severely inhibits cell matrix interactions, most likely via the loss of specific arginine residues involved in integrin mediated cell attachment. This is the first demonstration that methylglyoxal modification of collagen can affect cell-matrix interactions and introduces a possible mechanism by which some of the deleterious changes in tissues with age and disease are occurring.

Biomechanical and biochemical study of a standardized wound healing model.

Standardized protocols were developed for use in a detailed investigation into the biomechanical and biochemical properties of a dermal wound healing model in the rat. The use of a rapid freezing method at -80 degrees C minimized the detrimental effects of freezing on the biomechanical properties of the tissue and also allowed for convenient inter-laboratory collaboration to be performed. The methodology described allowed for the simultaneous and reproducible measurement of tensile strength, collagen cross-linking and proteolytic enzyme activity. Increases in the tensile properties of the tissue with time were consistent with an active process of remodelling process as indicated by changes in the cross-link and enzyme profiles. Initially the granulation tissue was comparatively rich in the keto-imine cross-link hydroxylysino-keto-norleucine, which was later replaced by the aldimine cross-link dehydro-hydroxy-lysinonorleucine. The mature cross-link histidino-hydroxy-lysinonorleucine was not observed within the granulation tissue at any stage and was also absent in aged control skin. A peak of matrix metalloproteinase-9 activity was observed at early timepoints (48 hr) and then decreased rapidly to normal levels and is consistent with an acute inflammatory response. In contrast matrix metalloproteinase-2 activity peaked later (3 days) and then decreased gradually, consistent with its role as one of the predominant enzymes involved in the remodelling process. The results described validate the animal model used and emphasize its potential for use in combined biomechanical and biochemical studies of acute wound healing.

Mechanisms of maturation and ageing of collagen.

The deleterious age-related changes in collagen that manifest in the stiffening of the joints, the vascular system and the renal and retinal capillaries are primarily due to the intermolecular cross-linking of the collagen molecules within the tissues. The formation of cross-links was elegantly demonstrated by Verzar over 40 years ago but the nature and mechanisms are only now being unravelled. Cross-linking involves two different mechanisms, one a precise enzymically controlled cross-linking during development and maturation and the other an adventitious non-enzymic mechanism following maturation of the tissue. It is this additional non-enzymic cross-linking, known as glycation, involving reaction with glucose and subsequent oxidation products of the complex, that is the major cause of dysfunction of collagenous tissues in old age. The process is accelerated in diabetic subjects due to the higher levels of glucose. The effect of glycation on cell-matrix interactions is now being studied and may be shown to be an equally important aspect of ageing of collagen. An understanding of these mechanisms is now leading to the development of inhibitors of glycation and compounds capable of cleaving the cross-links, thus alleviating the devastating effects of ageing.

Reversible parkinsonism and cognitive impairment with chronic valproate use.

Following our initial report of the insidious development of reversible, valproate-induced hearing, motor, and cognitive dysfunction in two patients, we evaluated 36 patients in an epilepsy clinic who had been taking therapeutic levels of valproate for at least 12 months; 29 of these patients were examined according to a prospective protocol. We observed varying degrees of parkinsonism and cognitive impairment, from none to severe. Discontinuation of valproate in 32 affected patients led to subjective and objective improvement on follow-up testing at least 3 months later. Improvement was greatest in patients who were affected most. We conclude that a syndrome of reversible parkinsonism and cognitive impairment may develop insidiously in patients who have been treated with valproate for more than 12 months. The association with valproate may be overlooked due to the insidious onset.

A surgical rat model of human Roux-en-Y gastric bypass.

Obesity affects 30% of the United States population and its detrimental effects are obesity-related metabolic diseases. For patients refractory to conventional weight loss therapy, gastric bypass surgery is one of the proven methods for inducing a sustained weight loss and reversing the metabolic sequelae of obesity. To understand the mechanisms of weight loss and the amelioration of related metabolic comorbid conditions, a reproducible animal model is needed. We report our developmental experience with rat models of sequential Roux-en-Y gastric bypass after reproducing the diet-induced obesity that characterizes the hallmarks of human obesity. Four experiments were performed to induce weight reduction through successive modifications: In Experiment 1 a 20% stapled gastric pouch with a 16 cm biliary-pancreatic limb and a 10 cm alimentary limb accomplished sufficient weight loss within 10 days to ameliorate metabolic changes associated with obesity, but the occurrence of gastrogastric fistulas prevented sustained weight loss; in Experiment 2 the model was improved by dividing the stomach to avoid gastrogastric fistula, but again sustained weight loss was not achieved; in Experiment 3 the biliary-pancreatic limb was lengthened from 16 to 30 cm, reducing the common channel to approximately 18 cm. Sustained weight loss was achieved for 28 days. In Experiment 4 the model in Experiment 3 was modified by dividing the stomach between two rows of staples. Sustained weight loss was observed for 67 days. We developed a reproducible rat model of Roux-en-Y gastric bypass. The existence of this model opens a new field of research in which to study the metabolic sequelae of obesity and the mechanisms of weight loss.

Extruded collagen fibres for tissue-engineering applications: influence of collagen concentration and NaCl amount.

Extruded collagen fibres have been shown to be a competitive biomaterial for tissue-engineering applications. Since different tissues are coming in different textures, as far as it is concerned their fibre diameter and consequently their mechanical properties, herein we aim to investigate the influence of the collagen concentration and the amount of NaCl on the properties of these fibres. Scanning electron microscopy study revealed that the substructure of the collagen fibres was the same, regardless of the treatment. The thermal properties were found to be independent of the collagen concentration or the amount of NaCl utilized (P > 0.05). An inversely proportional relationship between dry fibre diameter and stress at break was observed. Increasing the collagen concentration yielded fibres with significant higher diameter (P < 0.002), strain (P < 0.009) and force (P < 0.001) values, whilst the stress (P < 0.008) and modulus (P < 0.009) values were decreased. For the fabrication of fibres with reproducible properties, 20% NaCl was found to be the optimum. Overall, reconstituted collagen fibres were produced with properties similar to native or synthetic fibres to suit a wide range of tissue-engineering applications.

Post-self-assembly experimentation on extruded collagen fibres for tissue engineering applications.

Extruded collagen fibres have been shown to constitute a biomimetic three-dimensional scaffold with numerous tissue engineering applications. The multi-step fabrication process of this material provides opportunities for further advancements to improve the properties of the final product. Herein we investigated the influence of the post-self-assembly washing baths on the structural, mechanical and thermal properties of these fibres. The surface morphology and the inter-fibre packing were similar for every treatment. The overnight incubation in isopropanol yielded fibres with the highest temperature and energy of denaturation (p<0.013). Typical s- and j-shape stress-strain curves were obtained for all treatments in the dry and wet state respectively. Rehydration of the fibres resulted in increased fibre diameter (p<0.006) and reduced stress (p<0.001), force (p<0.001) and modulus (p<0.002) values for every treatment. In the dry state, the alcohol-treated fibres were characterized by the highest stress (p<0.002) values; whilst in the wet state the Tris-HCl-treated fibres were the weakest (p<0.006). For every treatment, in both dry and wet state, a strong and inverse relationship between the fibre diameter and the stress at break was observed. Overall, the fibres produced were characterized by properties similar to those of native tissues.

Factors influencing the properties of reconstituted collagen fibers prior to self-assembly: animal species and collagen extraction method.

This research work allows a direct comparison between collagen solutions of equal concentration derived from the two widely used collagen sources: bovine Achilles tendon (BAT) and rat tail tendon (RTT), and extraction methods: acid (AS) and pepsin (PS) solubilization on the properties of extruded collagen fibers. Scanning electron microscopy revealed that the substructure of the collagen fibers was the same independent of the treatment. Transmission electron microscopy revealed that the AS collagen-derived fibers were comprised of thick quarter-staggered fibrils, while the coexistence of thin nonbanded and thick banded fibrils was apparent for the PS collagen-derived fibers. The BAT-derived fibers demonstrated higher denaturation temperature than the RTT-derived ones (p < 0.05). The extraction method had no influence on the thermal characteristics of the fibers produced (p > 0.05). ASBAT collagen was of higher viscosity than both ASRTT and PSBAT (p < 0.002), and therefore larger diameter fibers were obtained (p < 0.001). An inversely proportional relationship between dry-fiber diameter and stress at break was observed within the treatments. The PS yielded 10 times more soluble collagen from BAT and the derived fibers were of similar tensile strength, stiffness, and elongation (p > 0.05) as those derived from the AS collagen. No significant difference was observed for the stress at break for the ASBAT and the ASRTT, while significant difference was observed for the elongation and modulus values (p < 0.005). Overall, reconstituted collagen fibers were produced with properties similar to native or synthetic fibers to suit a wide range of tissue engineering applications.