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The 6-min walk test (6MWT) is a common means of functional assessment. Its relationship to disability-free survival (DFS) is uncertain.This sub-study of the Measurement of Exercise Tolerance for Surgery study had co-primary outcome measures: correlation of the preoperative 6MWT distance with 30 day quality of recovery (15-item quality of recovery) and 12 month WHO Disability Assessment Schedule scores. The prognostic utility of the 6MWT and other risk assessment tools for 12 month DFS was assessed with logistic regression and receiver-operating-characteristic-curve analysis.Of 574 patients recruited, 567 (99%) completed the 6MWT. Twelve months after surgery, 16 (2.9%) patients had died and 444 (77%) had DFS. The 6MWT correlated weakly with 30 day 15-item quality of recovery (ρ=0.14; P=0.001) and 12 month WHO Disability Assessment Schedule (ρ=-0.23; P0.0005) scores. When the cohort was split into 6MWT distance tertiles, the adjusted odds ratio of low vs high tertiles for DFS was 3.13 [95% confidence interval (CI): 1.54-6.35]. The only independent variable predictive of DFS was the Duke Activity Status Index (DASI) score (adjusted odds ratio: 1.06; P0.0005). The area under the receiver-operating-characteristic curve for DFS was 0.63 (95% CI: 0.57-0.70) for the 6MWT, 0.60 (95% CI: 0.53-0.67) for cardiopulmonary-exercise-testing-derived peak oxygen consumption, and 0.70 (95% CI: 0.64-0.76) for the DASI score.Of the risk assessment tools analysed, the DASI was the most predictive of DFS. The 6MWT was safe and comparable with cardiopulmonary exercise testing for all predictive assessments. Future research should aim to determine the optimal 6MWT distance thresholds for risk prediction.

Cutaneous wounds caused by an exposure to high doses of ionizing radiation remain a therapeutic challenge. While new experimental strategies for treatment are being developed, there are currently no off-the-shelf therapies for the treatment of cutaneous radiation injury that have been proven to promote repair of the damaged tissues. Plasma-based biomaterials are biologically active biomaterials made from platelet enriched plasma, which can be made into both solid and semi-solid forms, are inexpensive, and are available as off-the-shelf, nonrefrigerated products. In this study, the use of plasma-based biomaterials for the mitigation of acute and late toxicity for cutaneous radiation injury was investigated using a mouse model. A 2-cm diameter circle of the dorsal skin was irradiated with a single dose of 35 Gy followed by topical treatment with plasma-based biomaterial or vehicle once daily for 5 weeks postirradiation. Weekly imaging demonstrated more complete wound resolution in the plasma-based biomaterial vs. vehicle group which became statistically significant (p < 0.05) at weeks 12, 13, and 14 postmaximum wound area. Despite more complete wound healing, at 9 and 17 weeks postirradiation, there was no statistically significant difference in collagen deposition or skin thickness between the plasma-based biomaterial and vehicle groups based on Masson trichrome staining nor was there a statistically significant difference in inflammatory or fibrosis-related gene expression between the groups. Although significant improvement was not observed for late toxicity, plasma-based biomaterials were effective at promoting wound closure, thus helping to mitigate acute toxicity.

Background Accurate assessment of functional capacity, a predictor of postoperative morbidity and mortality, is essential to improving surgical planning and outcomes. We assessed if all 12 items of the Duke Activity Status Index (DASI) were equally important in reflecting exercise capacity. Methods In this secondary cross-sectional analysis of the international, multicentre Measurement of Exercise Tolerance before Surgery (METS) study, we assessed cardiopulmonary exercise testing and DASI data from 1455 participants. Multivariable regression analyses were used to revise the DASI model in predicting an anaerobic threshold (AT) >11 ml kg−1 min−1 and peak oxygen consumption (VO2 peak) >16 ml kg−1 min−1, cut-points that represent a reduced risk of postoperative complications. Results Five questions were identified to have dominance in predicting AT>11 ml kg−1 min−1 and VO2 peak>16 ml.kg−1min−1. These items were included in the M-DASI-5Q and retained utility in predicting AT>11 ml.kg−1.min−1 (area under the receiver-operating-characteristic [AUROC]-AT: M-DASI-5Q=0.67 vs original 12-question DASI=0.66) and VO2 peak (AUROC-VO2 peak: M-DASI-5Q 0.73 vs original 12-question DASI 0.71). Conversely, in a sensitivity analysis we removed one potentially sensitive question related to the ability to have sexual relations, and the ability of the remaining four questions (M-DASI-4Q) to predict an adequate functional threshold remained no worse than the original 12-question DASI model. Adding a dynamic component to the M-DASI-4Q by assessing the chronotropic response to exercise improved its ability to discriminate between those with VO2 peak>16 ml.kg−1.min−1 and VO2 peak Conclusions The M-DASI provides a simple screening tool for further preoperative evaluation, including with cardiopulmonary exercise testing, to guide perioperative management.

Lateral ankle instability that has failed conservative management can be physically debilitating. Good outcomes are obtained from Brostrom-Gould augmented repair techniques, however there are few studies evaluating the use of a gracilis autograft augmentation coupled with an accelerated rehabilitation program in high functional demand patients. We believe that the modified Brostrom-Gould technique utilizing a Gracilis autograft will provide significant improvements in stability while maintaining normal ankle biomechanics in young, high demand patients. The prospective cohort study involved 19 patients (20 ankles) who underwent surgery for chronic lateral ankle instability by a single surgeon, at a single institution between October 2014 and April 2016. Patients were followed for 33.8 ± 11.7 (range 12-48) months. Patients were assessed both pre- and postoperatively for talar tilt angle radiographically and with both American Orthopaedic Foot and Ankle Society Ankle and Hindfoot scores and Karlsson-Peterson scores. A Tegner activity score was taken at the last follow-up. The mean American Orthopaedic Foot and Ankle Society score increased from 68.85 ± 10.57 to 91.56 ± 5.31 points (p < .01) and mean Karlsson-Peterson score increased from 50.9 ± 15.53 to 88.11 ± 8.64 points (p value

Background The Duke Activity Status Index (DASI) questionnaire might help incorporate self-reported functional capacity into preoperative risk assessment. Nonetheless, prognostically important thresholds in DASI scores remain unclear. We conducted a nested cohort analysis of the Measurement of Exercise Tolerance before Surgery (METS) study to characterise the association of preoperative DASI scores with postoperative death or complications. Methods The analysis included 1546 participants (≥40 yr of age) at an elevated cardiac risk who had inpatient noncardiac surgery. The primary outcome was 30-day death or myocardial injury. The secondary outcomes were 30-day death or myocardial infarction, in-hospital moderate-to-severe complications, and 1 yr death or new disability. Multivariable logistic regression modelling was used to characterise the adjusted association of preoperative DASI scores with outcomes. Results The DASI score had non-linear associations with outcomes. Self-reported functional capacity better than a DASI score of 34 was associated with reduced odds of 30-day death or myocardial injury (odds ratio: 0.97 per 1 point increase above 34; 95% confidence interval [CI]: 0.96–0.99) and 1 yr death or new disability (odds ratio: 0.96 per 1 point increase above 34; 95% CI: 0.92–0.99). Self-reported functional capacity worse than a DASI score of 34 was associated with increased odds of 30-day death or myocardial infarction (odds ratio: 1.05 per 1 point decrease below 34; 95% CI: 1.00–1.09), and moderate-to-severe complications (odds ratio: 1.03 per 1 point decrease below 34; 95% CI: 1.01–1.05). Conclusions A DASI score of 34 represents a threshold for identifying patients at risk for myocardial injury, myocardial infarction, moderate-to-severe complications, and new disability.

BACKGROUND: Preoperative anaemia is associated with elevated risks of postoperative complications. This association may be explained by confounding related to poor cardiopulmonary fitness. We conducted a pre-specified substudy of the Measurement of Exercise Tolerance before Surgery (METS) study to examine the associations of preoperative haemoglobin concentration with preoperative cardiopulmonary exercise testing performance (peak oxygen consumption, anaerobic threshold) and postoperative complications. METHODS: The substudy included a nested cross-sectional analysis and nested cohort analysis. In the cross-sectional study (1279 participants), multivariate linear regression modelling was used to determine the adjusted association of haemoglobin concentration with peak oxygen consumption and anaerobic threshold. In the nested cohort study (1256 participants), multivariable logistic regression modelling was used to determine the adjusted association of haemoglobin concentration, peak oxygen consumption, and anaerobic threshold with the primary endpoint (composite outcome of death, cardiovascular complications, acute kidney injury, or surgical site infection) and secondary endpoint (moderate or severe complications). RESULTS: Haemoglobin concentration explained 3.8% of the variation in peak oxygen consumption and anaerobic threshold (P

Background An integrated clinical service for patients with end-stage heart failure (HF) was funded by Bromley Clinical Commissioning Group; Bromley has no community HF nurse specialists. Method Six GP practices participated and referral criteria were agreed. Patients were assessed and followed up by an Advanced Nurse Practitioner, with experience in HF and palliative care (PC), who worked closely with cardiology consultants and HF/PC hospital teams, the Community PC Team (St Christopher’s Hospice) and primary care colleagues. Following initial assessment, patients were discussed at joint MDMs to assess both cardiac and palliative needs. We report data from the service evaluation of this clinical pilot. Results 102 patients, mean age 84.2±10.2 years, were referred over 1 year. 89 were accepted. 55 (61.8%) had LVSD, 14 (15.7%) patients had HF with preserved ejection fraction, 13 (14.6%) had predominately valvular dysfunction, 5 (5.6%) had right sided HF. Patients had multiple co-morbidities, significant renal impairment and mental health diagnoses (depression and dementia). Two thirds required considerable assistance or were immobile >50% of the time, with 18% predominately bedbound. 29 (33%) lived alone, 49 (55%) with family, and 12% in care homes. The majority of carers were female (86%), 25% of carers frequently/nearly always ‘did not have time for themselves’ with 40% reporting a significant impact of caring on their own health. Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) scores were not accurate in predicting outcome. 44% of patients died during the pilot. Of these, 69% died at home/hospice (41%/28%) versus 31% in hospital. Further PROMs including integrated palliative care outcome scale (iPOS) will be presented. Conclusion This pilot was positive and demonstrates benefits and challenges of joint working between integrated teams. We will discuss how ongoing integrated practice can be developed locally with dissemination of good practice and joint working to other groups.

Introduction Cognitive behavioral therapy for insomnia (CBT-I) is recommended as first-line treatment for chronic insomnia disorder for all adults. Older adults are often prescribed sedative-hypnotics (e.g., benzodiazepine receptor agonists, BRAs) for insomnia, despite observational studies showing these medications increase risk of falls, fractures, and cognitive decline. In an ongoing randomized controlled trial, we are testing “Sleep EducatioN Information Sent Directly to Patients (SEND),” a novel program combining direct-to-patient mailing with information about access to an online CBT-I resource, compared to a similarly structured control condition. In the current study, we surveyed participants in both groups to examine their self-reported use of intervention or control materials. Methods In the larger trial, 1,672 Veteran participants (aged >=65 years, receiving care from a Colorado VA facility, and prescribed a BRA) were randomized to receive the SEND intervention brochure with information on how to access a free, anonymous online CBT-I resource (n=836) or control condition brochure with information about general sleep education (n=836). Six months after the initial brochure mailing, all participants were mailed a blinded survey querying participants’ recollection and use of the mailed materials. We used chi-squared tests to compare survey responses for SEND versus control groups. Results 354 surveys were returned by study participants (overall response rate: 21%; SEND: 172 [20%], control: 182 [22%]). Respondents were 94% male with mean age 71.7 years (no difference between groups). In the SEND group, 97 (56%) reported receiving the brochure, 18 (10%) visited the website, and 14 (8%) discussed the brochure with their provider. No significant differences between groups were observed in the number of participants who reported receiving the brochure (chi2=2.96, p=.085); visiting the website (chi2=0.0253, p=.874); or discussing the brochure with their provider (chi2=1.91, p=.167). Conclusion At 6-months follow-up, over half of participants recalled receiving a mailing about sedative-hypnotics. A modest number reported visiting the online CBT-I program and a similar number discussed the materials with their healthcare provider. Similar results between groups suggest successful blinding of the intervention and control participants. If successful, the SEND intervention may provide a low-touch, low-cost approach to address BRA over-use in some older adults. Support (if any)

Summary Background Functional capacity is an important component of risk assessment for major surgery. Doctors' clinical subjective assessment of patients' functional capacity has uncertain accuracy. We did a study to compare preoperative subjective assessment with alternative markers of fitness (cardiopulmonary exercise testing [CPET], scores on the Duke Activity Status Index [DASI] questionnaire, and serum N-terminal pro-B-type natriuretic peptide [NT pro-BNP] concentrations) for predicting death or complications after major elective non-cardiac surgery. Methods We did a multicentre, international, prospective cohort study at 25 hospitals: five in Canada, seven in the UK, ten in Australia, and three in New Zealand. We recruited adults aged at least 40 years who were scheduled for major non-cardiac surgery and deemed to have one or more risk factors for cardiac complications (eg, a history of heart failure, stroke, or diabetes) or coronary artery disease. Functional capacity was subjectively assessed in units of metabolic equivalents of tasks by the responsible anaesthesiologists in the preoperative assessment clinic, graded as poor ( 10). All participants also completed the DASI questionnaire, underwent CPET to measure peak oxygen consumption, and had blood tests for measurement of NT pro-BNP concentrations. After surgery, patients had daily electrocardiograms and blood tests to measure troponin and creatinine concentrations until the third postoperative day or hospital discharge. The primary outcome was death or myocardial infarction within 30 days after surgery, assessed in all participants who underwent both CPET and surgery. Prognostic accuracy was assessed using logistic regression, receiver-operating-characteristic curves, and net risk reclassification. Findings Between March 1, 2013, and March 25, 2016, we included 1401 patients in the study. 28 (2%) of 1401 patients died or had a myocardial infarction within 30 days of surgery. Subjective assessment had 19·2% sensitivity (95% CI 14·2–25) and 94·7% specificity (93·2–95·9) for identifying the inability to attain four metabolic equivalents during CPET. Only DASI scores were associated with predicting the primary outcome (adjusted odds ratio 0·96, 95% CI 0·83–0·99; p=0·03). Interpretation Subjectively assessed functional capacity should not be used for preoperative risk evaluation. Clinicians could instead consider a measure such as DASI for cardiac risk assessment. Funding Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research, Innovation and Science, UK National Institute of Academic Anaesthesia, UK Clinical Research Collaboration, Australian and New Zealand College of Anaesthetists, and Monash University.

Despite recent advances in treatment, hepatitis C remains a significant public health problem. The hepatitis C virus (HCV) is known to infiltrate the brain, yet findings from studies on associated neurocognitive and neuropathological changes are mixed. Furthermore, it remains unclear if HCV eradication improves HCV-associated neurological compromise. This study examined the longitudinal relationship between neurocognitive and neurophysiologic markers among healthy HCV- controls and HCV+ adults following successful HCV eradication. We hypothesized that neurocognitive outcomes following treatment would be related to both improved cognition and white matter integrity. Participants included 57 HCV+ participants who successfully cleared the virus at the end of treatment (sustained virologic responders [SVRs]) and 22 HCV- controls. Participants underwent neuropsychological testing and, for a nested subset of participants, neuroimaging (diffusion tensor imaging) at baseline and 12 weeks following completion of HCV therapy. Contrary to expectation, group-level longitudinal analyses did not reveal significant improvement in neurocognitive performance in the SVRs compared to the control group. However, a subgroup of SVRs demonstrated a significant improvement in cognition relative to controls, which was related to improved white matter integrity. Indeed, neuroimaging data revealed beneficial effects associated with clearing the virus, particularly in the posterior corona radiata and the superior longitudinal fasciculus. Findings suggest that a subgroup of HCV+ patients experienced improvements in cognitive functioning following eradication of HCV, which appears related to positive changes in white matter integrity. Future research should examine whether any additional improvements in neurocognition and white matter integrity among SVRs occur with longer follow-up periods.

The Emergency Department management of patients with ballistic trauma should include rapid assessment and life-saving intervention, followed by appropriate investigation and referral for definitive management depending on the haemodynamic status of the patient (Figs. 17.1–17.4).

Objective This study aimed to test the impact of a plasma-based, material (PBM) impregnated with amiodarone on atrial electrophysiology and atrial fibrillation susceptibility in a porcine post–cardiac surgery model. Methods Ten healthy pigs underwent implantation of transvenous pacing systems, after which sterile talc was infused into the pericardial sac via a pericardiotomy. In five animals, PBM was applied to the atrial epicardial surface just before talc infusion. Electrophysiologic evaluations were performed using the pacing system immediately after chest closure and 7 days later. Atrial histologic evaluations were performed. Results Immediately after chest closure, there were no significant differences in electrophysiologic parameters between talc-only and talc + PBM animals, and atrial fibrillation was largely noninducible. On postsurgical day 7, electrophysiologic evaluation revealed significantly shorter sinus cycle length and atrioventricular nodal refractoriness among talc-only animals relative to talc + PBM animals, possibly suggesting attenuated sympathetic nervous system activation in the latter. Atrial fibrillation inducibility and duration were significantly greater among talc-only animals. No significant differences in atrial refractoriness or conduction time between groups were apparent. Histologic evaluation revealed a relative reduction in epicardial inflammation and less myolysis among talc + PBM animals. Conclusions Epicardial application of a plasma-based, amiodarone-impregnated material was associated with a significant reduction in atrial inflammation and susceptibility to fibrillation.

The main histologic feature of celiac disease is increased intraepithelial lymphocytes (IELs) with or without villous atrophy of the duodenal mucosa. The aim of this study was to document a broad range of additional morphologic changes in intestinal mucosa biopsy specimens from patients with celiac disease. Our cohort comprised 150 patients with positive tissue transglutaminase serologic findings; 7 were at Corazza stage A1, 58 at stage B1, and 85 at stage B2. IEL counts per 100 epithelial cells ranged from 34 to 156 (mean, 88.6); a significant neutrophilic infiltrate was present in 85 cases (56.7%); eosinophil count ranged from 3 to 50 per high-power field (mean, 14.6). Additional findings included morphologic changes in enterocytes in 68.7%, subepithelial collagen thickening in 45.3%, and associated lymphocytic gastritis in 30.4% of patients. We demonstrated that these underrecognized features, which can be misleading, are not uncommon in celiac disease and were positively associated with more advanced stages of the disease (P < .0001).

Background The RATPAC trial showed that using a point-of-care panel of CK-MB(mass), myoglobin and troponin at baseline and 90 min increased the proportion of patients successfully discharged home, leading to reduced median length of initial hospital stay. However, it did not change mean hospital stay and may have increased mean costs per patient. The aim of this study was to explore variation in outcome and costs between participating hospitals. Methods RATPAC was a pragmatic multicentre randomised controlled trial (N¼2243) and economic analysis comparing diagnostic assessment using the panel to standard care for patients with acute chest pain due to suspected myocardial infarction at six hospitals. The difference in the proportion of patients successfully discharged (primary outcome) and mean costs per patient between the participating hospitals was compared. Results Point-of-care assessment led to a higher proportion of successful discharges in four hospitals, a lower proportion in one and was equivocal in another. The OR (95% CI) for the primary outcome varied from 0.12 (0.01 to 1.03) to 11.07 (6.23 to 19.66) with significant heterogeneity between the centres (p

The treatment of advanced hallux rigidus remains controversial, with many authors discussing arthrodesis versus arthroplasty. The purpose of this study is to report mid-term outcomes after implantation of a motion-preserving metatarsal head-resurfacing prosthetic and to present our technical considerations and modifications to the published technique to further enhance the clinical benefit of the procedure. Thirty-two implantations were performed in 30 patients. Twenty-three patients were women, 9 men. The average age was 62.8 years (range, 39-86 years). Patients were graded at baseline according to Hattrup and Johnson and completed the American Orthopaedic Foot & Ankle Surgery metatarsophalangeal clinical rating system preoperatively and postoperatively and a patient satisfaction question at final follow-up. Seventy-two percent of implantations were grade III hallux rigidus and 28% were grade II. The average follow-up was 27.3 months (range, 12-43 months). The mean change score for the overall American Orthopaedic Foot & Ankle Surgery scale was 236.8% (SD = 146.62, confidence interval [CI] = 186-287.6). A similar result was achieved between grade II (250.9%, SD = 240.3, CI = 93.9-407.9) and grade III (231.3%, SD = 95.83, CI = 195.14-270.46). No implants were revised or removed, and all patients stated that they were happy with their outcome and would repeat the procedure again if needed. In conclusion, metatarsal head resurfacing in combination with joint decompression, soft tissue mobilization, and debridement can achieve excellent results in grade II and III hallux rigidus. Salvage arthrodesis remains an option if future revisions are indicated.

Previous research concerning the relationship between conflict and public health finds that countries emerging from war face greater challenges in ensuring the well-being of their populations in comparison with states that have enjoyed political stability. This study seeks to extend this insight by considering how different civil war conflict strategies influence post-conflict public health. Drawing a distinction between deaths attributable to battle and those fatalities resulting from genocide/politicide, we find that the magnitude of genocide/politicide proves the more effective and consistent predictor of future rates of disability and death in the aftermath of civil war. The implications of this research are twofold. First, it lends support to an emerging literature suggesting that important distinctions exist between the forms of violence occurring during civil war. Second, of particular interest to policymakers, it identifies post-civil war states that have experienced the highest rates of genocide/politicide as the countries most in need of assistance in the aftermath of conflict.

Rationale: Opioids have become part of contemporary treatment in the management of chronic pain. However, chronic use of opioids has been associated with high prevalence of sleep apnea which could contribute to morbidity and mortality of such patients.

Background: Nonoperative management (NOM) of blunt splenic injuries (BSIs) has been used with increasing frequency in adult patients. There are currently no definitive guidelines established for how long BSI patients should be monitored for failure of NOM after injury. Methods: This study was performed to ascertain the length of inpatient observation needed to capture most failures, and to identify factors associated with failure of NOM. We utilized the National Trauma Data Bank to determine time to failure after BSI. Results: During the 5-year study period, 23,532 patients were identified with BSI, of which 2,366 (10% overall) were taken directly to surgery (within 2 hours of arrival). Of 21,166 patients initially managed nonoperatively, 18,506 were successful (79% of all-comers). Patients with isolated BSI are currently monitored ∼5 days as inpatients. Of patients failing NOM, 95% failed during the first 72 hours, and monitoring 2 additional days saw only 1.5% more failures. Factors influencing success of NOM included computed tomographic injury grade, severity of patient injury, and American College of Surgeons designation of trauma center. Importantly, patients who failed NOM did not seem to have detrimental outcomes when compared with patients with successful NOM. No statistically significant predictive variables could be identified that would help predict patients who would go on to fail NOM. Conclusions: We conclude that at least 80% of BSI can be managed successfully with NOM, and that patients should be monitored as inpatients for failure after BSI for 3 to 5 days.

Despite the increasing realization that health-related quality of life (HRQOL) is an important outcome in chronic HBV infection, there are no validated, disease-targeted instruments currently available. We sought to develop and validate the first disease-targeted HRQOL instrument in noncirrhotic HBV: the Hepatitis B Quality of Life instrument, version 1.0 (HBQOL v1.0). We established content validity for the HBQOL v1.0 by conducting a systematic literature review, an expert focus group, and cognitive interviews with HBV patients. We administered the resultant questionnaire to 138 HBV patients. We used factor analysis to test hypotheses regarding HRQOL domains and measured construct validity by comparing HBQOL v1.0 scores across several anchors, including viral response to treatment, SF-36 scores, and global health. Finally, we measured test–retest and internal consistency reliability. Content validation revealed that HBV affects multiple aspects of psychological, social, and physical health. The resultant questionnaire summarized this HRQOL impact with 31 items across six subscales: psychological well-being, anticipation anxiety, vitality, disease stigma, vulnerability, and transmissibility. Internal consistency and test–retest reliability were excellent. The HBQOL v1.0 discriminated between viral responders versus nonresponders and correlated highly with SF-36 scores and global health. Conclusion: Patients with chronic HBV infection attribute a wide range of negative psychological, social, and physical symptoms to their condition, even in the absence of cirrhosis or cancer. The HBQOL v1.0 is a valid and reliable measure that captures this HRQOL decrement. This instrument may be useful in everyday clinical practice and in future clinical trials. (HEPATOLOGY 2007;46:113–121.)

Pregnancy-associated plasma protein A (PAPP-A) is an IGF binding protein 4 protease that can function to increase local IGF-I bioavailability. Aside from its assumed role during pregnancy, in vitro and in vivo studies have indicated roles for PAPP-A in IGF-I-mediated wound healing, vascular repair, and bone formation. Because bone morphogenetic protein 2 (BMP-2) is known to up-regulate Igf-I gene expression, we hypothesized that PAPP-A may be involved in BMP-2 mechanisms in bone formation. To test this hypothesis, we quantified gene expression of Papp-A in response to BMP-2 treatment and runt-related transcription factor 2, Osterix, and Igf-I in response to PAPP-A protein treatment in human adult mesenchymal stem cells. Our results demonstrate that BMP-2 directly up-regulated Papp-A gene and protein expression. Purified PAPP-A protein directly up-regulated runt-related transcription factor 2 and Igf-I gene expression but not Osterix. When added in combination with recombinant human BMP-2, PAPP-A increased matrix mineralization in the absence of dexamethasone. PAPP-A further demonstrated an angiogenic effect in the chick chorioallontoic membrane, which implicates a critical developmental role and possible therapeutic potential. Our findings suggest that PAPP-A functions in the formation of mineralized tissues through direct up-regulation of key genes. Furthermore, PAPP-A is involved in the formation of new blood vessels, which is essential for proper bone regeneration.

The goal of the current study was to analyze the prospective clinical outcome of patients who failed closed or open treatment of a displaced intra-articular calcaneal fracture. This cohort of patients required a secondary subtalar fusion by distraction bone-block arthrodesis.Review of prospective, randomized trial database.Four level I trauma centers.Between April 1, 1991 and December 31, 1997, 424 patients with 471 displaced intra-articular calcaneal fractures were involved in a large, multicenter, randomized trial. Forty-four patients who required subtalar fusion following initial treatment of a displaced intra-articular calcaneal fracture were compared to the population of patients who did not require subtalar fusion. The variables compared between the two groups included Böhler angles, two computed tomography classification systems, and clinical scores including SF-36, visual analogue score, and oral analogue score.Subtalar distraction bone-block arthrodesis with tricortical bone graft was used in all 45 feet.The following were examined: x-ray fracture classification, specifically Böhler angles and Essex-Lopresti classification; computed tomography classification, specifically Sanders and Crosby; clinical scores, specifically validated visual analogue score, general health survey scores, oral analogue score, and other factors (i.e., patient demographics including age, sex, profession, smoking history, and Worker's Compensation Board involvement.Initial treatment of the 44 patients in our study was nonoperative in 37 (84%) patients and operative (open reduction and internal fixation) in 7 (16%) (1 patient had bilateral heel fractures). Patients requiring fusion differed demographically from those patients not requiring fusion. Mean age was 39 years in both the fusion and nonfusion group. The fusion group had 97% males, whereas the nonfusion group had 89% males. Sixty-four percent of the fusion patients were Worker's Compensation Board claims, whereas 35% of the nonfusion group were Worker's Compensation Board claims. Of those that required fusion, 77% were heavy laborers. On average, the fusion group had a Böhler angle 15 degrees less than the nonfusion group. Forty-six percent of the fusion patients were Sanders-type IV initial fractures. Logistic regression analysis revealed that the primary predictors of requiring fusion were Worker's Compensation Board status (odds ratio = 3.03, 95% confidence interval = 1.41-6.57), Sanders-type IV (odds ratio = 5.48, 95% confidence interval = 1.57-19.18), Böhler angle0 degrees (odds ratio = 10.64-95% confidence interval = 1.33-85.17), and nonoperative initial treatment (odds ratio = 5.86-95% confidence interval = 2.33-14.67).These data suggest that the amount of initial injury involved with the calcaneal fracture is the primary prognostic determinant of long-term patient outcome. Böhler angle on presentation of0 degrees was 10 times more likely to require a secondary subtalar fusion than a Böhler angle on presentation of15 degrees. Sanders-type IV calcaneal fractures were 5.5 times more likely to be fused than a simple Sanders type II fracture. Worker's Compensation Board patients were three times more likely to be fused than non-Worker's Compensation Board patients. Nonoperative care was six times more likely to lead to a late fusion as compared to open reduction and internal fixation treatment. Late fusion provided relief from pain and improved function as evidenced by an improvement in visual analogue score postsurgery. This study demonstrates that there is a distinct patient group with a displaced intra-articular calcaneal fracture who are at high risk of subtalar fusion. These include male Worker's Compensation Board patients who participate in heavy labor work with a fracture pattern with Böhler angle less than 0 degrees. If their initial treatment was nonoperative, the likelihood of requiring late subtalar fusion was significantly increased. Initial open reductional open reduction and internal fixation of patients with displaced intra-articular calcaneal fracture minimized the likelihood that subtalar fusion would be required.

Objective: This study examined neurologic abnormalities (as measured by proton magnetic resonance spectroscopy imaging and diffusion tensor imaging), neurocognitive performance, and fatigue among a sample of adults with hepatitis C virus (HCV). We hypothesized that HCV1 individuals would demonstrate structural brain abnormalities and neurocognitive compromise consistent with frontostriatal dysfunction as well as increased fatigue compared to controls. Method: Participants were 76 individuals diagnosed with HCV and 20 controls who underwent a comprehensive neurocognitive evaluation and clinical assessments. A subset of the HCV1 participants (n 5 29) and all controls underwent MRI. Results: Individuals diagnosed with chronic HCV infection demonstrated greater fractional anisotropy in the striatum as well as greater mean diffusivity in the fronto-occiptal fasciculus and external capsule compared to HCV2 controls. HCV1 participants also demonstrated lower levels of N-acetylaspartate in bilateral parietal white matter and elevations in myo-inosital (mI) in bilateral frontal white matter compared to HCV2 controls (all p values , 0.05). HCV1 participants also demonstrated significantly poorer neuropsychological performance, particularly in processing speed and verbal fluency. HCV1 patients reported higher levels of fatigue than controls, and fatigue was significantly correlated with diffusivity in the superior fronto-occipital fasciculus, elevations in mI in frontal white matter, and overall cognitive performance. Conclusions: Our results suggest that HCV-associated neurologic complications disrupt frontostriatal structures, which may result in increased fatigue and poorer cognitive performance, particularly in those cognitive domains regulated by frontostriatal regions. Neurol Neuroimmunol

Objective To assess the impact of triple marker testing on patient management and the diagnostic efficiencies of different biomarker strategies examined. Design A prospective randomised trial of triple marker testing by point-of-care testing (POCT); the Randomised Assessment of Panel Assay of Cardiac markers (RATPAC) study. Setting Six emergency departments. Patients Low-risk patients presenting with chest pain to diagnostic assessment with a cardiac panel measured by POCT or to diagnosis when biomarker measurement was based on central laboratory testing. Interventions 1125 patients were randomly assigned to POCT measurement of the triple marker panel of cardiac troponin I (cTnI), myoglobin and the MB isoenzyme of creatine kinase (CK-MB) on admission and 90 min from admission. Main Outcome Measures Myocardial infarction (MI) was defined by the universal definition of MI. The following diagnostic strategies were compared by receiver operator characteristic (ROC) curve analysis and comparison of area under the curve (AUC): individual marker values, change (Δ) in CK-MB and myoglobin and the combination of presentation or 90 min value plus Δ value. Results Admission sample measurement of cTnI was the most diagnostically efficient AUC 0.96 (0.93–0.98) with areas under the ROC curve statistically significantly greater than CK-MB 0.85 (0.80–0.90) and myoglobin 0.75 (0.68–0.81). At 90 min cTnI measurement had the highest AUC 0.95 (0.87–1.00) but was statistically significantly different only from Δmyoglobin and ΔCK-MB. Conclusion Measurement of cTnI alone is sufficient for diagnosis. Measurement of a marker panel does not facilitate diagnosis.

To extend the understanding of host genetic determinants of HIV-1 control, we performed a genome-wide association study in a cohort of 2,554 infected Caucasian subjects. The study was powered to detect common genetic variants explaining down to 1.3% of the variability in viral load at set point. We provide overwhelming confirmation of three associations previously reported in a genome-wide study and show further independent effects of both common and rare variants in the Major Histocompatibility Complex region (MHC). We also examined the polymorphisms reported in previous candidate gene studies and fail to support a role for any variant outside of the MHC or the chemokine receptor cluster on chromosome 3. In addition, we evaluated functional variants, copy-number polymorphisms, epistatic interactions, and biological pathways. This study thus represents a comprehensive assessment of common human genetic variation in HIV-1 control in Caucasians., Author Summary The ability to spontaneously control HIV-1 upon infection is highly variable between individuals. To evaluate the contribution of variation in human genes to differences in plasma viral load and in disease progression rates, we performed a genome-wide association study in >2,500 HIV–infected individuals. This study achieved two goals: it completed the analysis of common variation influencing viral control, and it re-assessed the majority of previously reported genetic associations. We show that genetic variants located near the HLA-B and HLA-C genes are the strongest determinants of viral control, and that other independent associations exist in the same region of chromosome 6, the Major Histocompatibility Complex, known to contain a large number of genes involved in immune defense. We could not replicate most of the previously published associations with HIV candidate genes in this large, well-characterized cohort. Overall, common human genetic variation, together with demographic variables, explains up to 22% of the variability in viral load in the Caucasian population.

A 49 year-old patient, with a history of rheumatoid arthritis, presents with suspected septic arthritis of the ankle and subtalar joints. The patient was found to have osteomyelitis of both the talus and calcaneus. The patient was treated by debridement, antibiotic impregnated PMMA beads, and ultimately, a subtalar joint fusion. This case illustrates the importance of the early recognition and diagnosis, the possible sequelae, and the need for aggressive treatment of a septic joint.

This cadaveric study sought to evaluate the feasibility of applying a locking proximal humerus plate with a novel minimally invasive technique. A unique pre-contoured locking plate was placed on cadaveric proximal humeri through a described minimally invasive approach. Proximity of the plate and screws to the axillary nerve and their respective surgical tracks were quantified. Safe screw hole placement with respect to the axillary nerve was determined. Risk of entrapment of the nerve beneath the plate was evaluated. Three of the holes near the middle of the locking plate consistently intersected the course of the axillary nerve and were unsafe for percutaneous placement of the screws. The axillary nerve could be palpated during the course of surgery and easily protected from injury. No entrapment of the axillary nerve occurred using this minimally invasive technique. The screw-in locking guide cannot be used with this technique as it caused tenting of the axillary nerve. Placement of a locking proximal humerus plate via a minimally invasive lateral trans-deltoid approach is safe if the locking screws are limited to superior and inferior holes. This can be done safely without entrapment of the axillary beneath the plate. Plate fixation of proximal humerus fractures may now be more desirable with the use of this approach.

The aim of this study was to define the chemosensitivity profile of a series of human ovarian cancer cell lines representing the human primary ovarian tumours under altered culture conditions and to compare the results with those from tumour-derived cells. In this study, we used a standardized ATP-based tumour chemosensitivity assay to measure the activity of cytotoxics in the seven ovarian carcinoma cell lines and ovarian tumour-derived cells. The use of adherence-free polypropylene plates and a serum-free medium slowed down cell proliferation in all cell lines tested, mimicking the slow growth rate of solid tumours in this type of plastic. The seeding density was optimized for each cell line and was in the range of 2000-4000 cells/well. Heterogenous sensitivity to different cytotoxics was observed in the seven ovarian cancer cell lines tested in the ATP-based tumour chemosensitivity assay. The human ovarian carcinoma cell line, OVCA433, was found to be the most resistant cell line and 75% of the drugs showed an Index SUM above 300. Our results suggest that the use of appropriate culture conditions i.e. a serum-free culture environment, adherence-free growth and optimum seeding density can induce cell lines to behave more like tumour-derived cells in response to cytotoxic agents. On the basis of the comparison of chemosensitivity profiles of tumour-derived cells and cell lines derived from the corresponding tumour, a panel of cell lines can be selected. Such a panel could be used to screen and develop anticancer drugs.

• OSTEOPOROSIS is a skeletal disorder that compromises bone strength, predisposing a person to an increased risk of fracture. An estimated 700,000 spinal fragility fractures, such as vertebral compression fractures, directly related to osteoporosis occur annually. • KYPHOPLASTY, a minimally invasive fracture reduction procedure, has become a treatment option for osteoporotic fractures. A balloon is used in place of the conventional bone tamp to reduce the fracture and create a void in cancellous spinal bone. Polymethylmethacrylate, a cement-like material, is injected into the void to stabilize the fracture. • EARLY DIAGNOSIS AND TREATMENT of vertebral compression fractures with kyphoplasty allows normal anatomy to be restored, ultimately decreasing the risk of patient morbidity. AORN J 78 (November 2003) 766–773.

OBJECTIVE: To provide a review of recent developments in the pharmacotherapy of epilepsy. DATA SOURCES: A MEDLINE search was performed to identify pertinent literature (1966–June 2001). Selected articles emphasized those published from 1997 to 2001. Bibliographies of identified articles were also evaluated. STUDY SELECTION AND DATA EXTRACTION: All identifiable sources written in English. DATA SYNTHESIS: Epilepsy is a common neurologic disorder, and antiepileptic drugs (AEDs) are the mainstays of therapy. The focus of this article is on the 3 latest AEDs — Levetiracetam, oxcarbazepine, and zonisamide. We discuss human data published as both original studies and reviews from the last 4 years, except where noted. We apply a general template for all 3 drugs and provide information on clinical trials, adverse effects, pharmacokinetics, drug interactions, and clinical use. CONCLUSIONS: Levetiracetam, oxcarbazepine, and zonisamide are reasonable options for many patients whose seizures are not yet controlled or who suffer from intolerable adverse effects. All 3 agents are approved for adjunctive use in patients with partial seizures. Oxcarbazepine also has approval for monotherapy in partial seizures. All 3 drugs are well tolerated by most patients and have characteristics that potentially make them easier to use with medications other than the older AEDs. Further clinical experience is needed before specific recommendations can be given for their place among older and newer AEDs.

Aim To discuss a little known anatomical structure, the glomus coccygeum, and its presence in an abdominoperineal resection (APR). Methods A 63-year-old male underwent APR for a low rectal carcinoma following neo-adjuvant chemo-radiation. No residual tumour was identified macroscopically or microscopically, however there was a 2.5 mm diameter well-circumscribed lesion at the posterior resection margin. Microscopy and immunohistochemis-try were utilised to diagnose the lesion. Results Microscopy revealed nests of cells with clear to eosino-philic cytoplasm and plump nuclei, in association with small vascular spaces and small nerves. Immunohistochemistry was performed to exclude residual rectal adenocarcinoma and other possible causes. The lesion was negative for Cam5.2, CK20, CEA, PSA, CD56, synaptophysin and chromogranin, and positive for vimentin and SMA. CD31 highlighted the vascular spaces. The lesion was diagnosed as a glomus coccygeum. Discussion The glomus coccygeum is a vestigial innervated arterio-venous anastomosis located adjacent to the coccyx. Although first described in 1859, glomus coccygeum is not well known, which may lead to diagnostic confusion. Previously they have been misdiagnosed as paragangliomas and glomus tumours. While glomus coccygeum has previously been found in coccy-geal resections and pilonidal sinus excisions, this is the first reported case of a glomus coccygeum in an abdominoperineal resection.

Aim To discuss a case of a solitary liver tumour occurring in an adult female with a past history of childhood Ewing sarcoma (treated with surgery and chemotherapy). Methods The clinical history and investigations were discussed. The macroscopic and microscopic findings were then presented, including results of special stains and immunohis-tochemistry. A literature review was also performed. Results While focal nodular hyperplasia was considered a likely diagnosis, and a recurrent malignant tumour needed to be excluded, the lesion was found to be a hepatocellular adenoma. Discussion Focal nodular hyperplasia (FNH) has been reported as a late complication in patients who received chemotherapy for malignancy. 1 One possible theory is that chemotherapy may injure the vascular endothelium and cause localised circulatory disturbances, with progression to FNH. Given the past history of chemotherapy and lack of exposure to the oral contraceptive pill, the final diagnosis of a hepatocellular adenoma (HCA) was unexpected. While 85% of patients with HCA are women who have taken the oral contraceptive pill for more than two years, in 15% of cases there is no history of taking the pill. 2 This case is therefore considered an unusual case of coincidental hepatocellular adenoma following chemotherapy for Ewing sarcoma.