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Continuous flow left ventricular assist devices have improved outcomes in patients with end-stage heart failure that require mechanical circulatory support. Current devices have an adverse event profile that has hindered widespread application. The EVAHEART®2 left ventricular assist device (EVA2) has design features such as large blood gaps, lower pump speeds and an inflow cannula that does not protrude into the left ventricle that may mitigate the adverse events currently seen with other continuous flow devices.A prospective, multi-center randomized non-inferiority study, COMPETENCE Trial, is underway to assess non-inferiority of the EVA2 to the HeartMate 3 LVAS when used for the treatment of refractory advanced heart failure. The primary end-point is a composite of the individual primary outcomes: Survival to cardiac transplant or device explant for recovery; Free from disabling stroke; Free from severe Right Heart Failure after implantation of original device. Randomization is in a 2:1 (EVA2:HM3) ratio.The first patient was enrolled into the COMPETENCE Trial in December of 2020, and 25 subjects (16 EVA2 and 9 HM3) are currently enrolled. Enrollment of a safety cohort is projected to be completed by third quarter of 2022 at which time an interim analysis will be performed. Short-term cohort (92 EVA2 subjects) and long-term cohort is expected to be completed by the end of 2023 and 2024, respectively.The design features of the EVA2 such as a novel inflow cannula and large blood gaps may improve clinical outcomes but require further study. The ongoing COMPETENCE trial is designed to determine if the EVA2 is non-inferior to the HM3.

Triage is a key principle in the effective management of major incidents and is the process by which patients are prioritised on the basis of their clinical acuity. However, work published over the last decade has demonstrated that existing methods of triage perform poorly when trying to identify patients in need of life-saving interventions. As a result, a review of major incident triage was initiated by NHS England with the remit to determine the optimum way in which to triage patients of all ages in a major incident for the UK. This article describes the output from this review, the changes being undertaken to UK major incident triage and the introduction of the new NHS Major Incident Triage Tool from the Spring of 2023.

BackgroundThis study aimed to establish whether the modified 12-hour Scottish and Newcastle Antiemetic Protocol (SNAP) for paracetamol poisoning is associated with improvement in hospital length of stay (LoS), as well as to validate the performance of the protocol for the prevention of anaphylactoid reactions and total infusion duration.MethodsRetrospective chart review from 25 March 2019 to 25 September 2020. Patients aged 16 or older with a diagnosis of suspected or confirmed paracetamol overdose were included in the analysis if they received treatment for paracetamol poisoning, and the protocol used could be identified. Data were collected for LoS, number of extended treatment infusions used and evidence of anaphylactoid reaction.Results1167 records were assessed for eligibility, and 294 were included for analysis. Use of the SNAP was associated with a statistically significant reduction in LoS of −8.8 hours (95% CI −12.6 to −2.0), and a reduced risk of anaphylactoid reaction (Number Needed to Treat=10).ConclusionIn this retrospective study, use of the SNAP reduced the duration of inpatient admissions and rate of anaphylactoid reactions.

Background Motor vehicle collisions (MVCs), particularly those associated with entrapment, are a common cause of major trauma. Current extrication methods are focused on spinal movement minimisation and mitigation, but for many patients self-extrication may be an appropriate alternative. Older drivers and passengers are increasingly injured in MVCs and may be at an increased risk of entrapment and its deleterious effects. The aim of this study is to describe the injuries, trapped status, outcomes, and potential for self-extrication for patients following an MVC across a range of age groups. Methods This is a retrospective study using the Trauma Audit and Research Network (TARN) database. Patients were included if they were admitted to an English hospital following an MVC from 2012 to 2019. Patients were excluded when their outcomes were not known or if they were secondary transfers. Simple descriptive analysis was used across the age groups: 16–59, 60–69, 70–79 and 80+ years. Logistic regression was performed to develop a model with known confounders, considering the odds of death by age group, and examining any interaction between age and trapped status with mortality. Results 70,027 patients met the inclusion criteria. Older patients were more likely to be trapped and to die following an MVC (p p Conclusions Patients over the age of 80 are more likely to die when trapped following an MVC. Self-extrication should be considered the primary route of egress for patients of all ages unless it is clearly impracticable or unachievable. For those patients who cannot self-extricate, a minimally invasive extrication approach should be employed to minimise entrapment time.

UK National Guidelines stress the importance of reducing waiting times for mental health assessments and interventions for children. They stress the importance of early help, multidisciplinary working, and collaboration with families regarding treatment plans. We piloted a new assessment model (CARM) within a CAMHS service to: reduce non-attendance rates and subsequently waiting times; increase staff and patient satisfaction; and improve the quality of assessment. All waiting list patients and new referrals over a three-month period were contacted to self-book an hour session to meet two clinicians who utilised collaborative reflection and formulation to produce a care plan (CARM). Results revealed that non-attendance rates dropped from 33% over the month prior to CARM to 7% during CARM. Satisfaction levels were high. Qualitative feedback regarding satisfaction revealed the most common themes was feeling listened to and having the opportunity to listen to staff reflections. The themes of staff satisfaction included ‘feeling more supported’ and ‘feeling safer in their decision making’. All assessments were completed in the one appointment. A formulation-driven care plan was developed and discussed with the family. This approach has the potential to make services more effective, efficient and satisfying for both staff and families.

ObjectivesTo identify the differences between women and men in the probability of entrapment, frequency of injury and outcomes following a motor vehicle collision. Publishing sex-disaggregated data, understanding differential patterns and exploring the reasons for these will assist with ensuring equity of outcomes especially in respect to triage, rescue and treatment of all patients.DesignWe examined data from the Trauma Audit and Research Network (TARN) registry to explore sex differences in entrapment, injuries and outcomes. We explored the relationship between age, sex and trapped status using multivariate logistical regression.SettingTARN is a UK-based trauma registry covering England and Wales.ParticipantsWe examined data for 450 357 patients submitted to TARN during the study period (2012–2019), of which 70 027 met the inclusion criteria. There were 18 175 (26%) female and 51 852 (74%) male patients.Primary and secondary outcome measuresWe report difference in entrapment status, injury and outcome between female and male patients. For trapped patients, we examined the effect of sex and age on death from any cause.ResultsFemale patients were more frequently trapped than male patients (female patients (F) 15.8%, male patients (M) 9.4%; pConclusionsThere are significant differences between female and male patients in the frequency at which patients are trapped and the injuries these patients sustain. This sex-disaggregated data may help vehicle manufacturers, road safety organisations and emergency services to tailor responses with the aim of equitable outcomes by targeting equal performance of safety measures and reducing excessive risk to one sex or gender.

Mild, blast-induced traumatic brain injury (mbTBI) is a common combat brain injury characterized by typically normal neuroimaging findings, with unpredictable future cognitive recovery. Traditional methods of electroencephalography (EEG) analysis (e.g., spectral analysis) have not been successful in detecting the degree of cognitive and functional impairment in mbTBI. We therefore collected resting state EEG (5 minutes, 64 leads) from twelve patients with a history of mbTBI, along with repeat neuropsychological testing (D-KEFS Tower test) to compare two new methods for analyzing EEG (multifractal detrended fluctuation analysis (MF-DFA) and information transfer modeling (ITM)) with spectral analysis. For MF-DFA, we extracted relevant parameters from the resultant multifractal spectrum from all leads and compared with traditional power by frequency band for spectral analysis. For ITM, because the number of parameters from each lead far exceeded the number of subjects, we utilized a reduced set of 10 leads which were compared with spectral analysis. We utilized separate 30 second EEG segments for training and testing statistical models based upon regression tree analysis. ITM and MF-DFA models both generally had improved accuracy at correlating with relevant measures of cognitive performance as compared to spectral analytic models ITM and MF-DFA both merit additional research as analytic tools for EEG and cognition in TBI.

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.

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.

IntroductionA key principle in the effective management of major incidents is triage, the process of prioritising patients on the basis of their clinical acuity. In many countries including the UK, a two-stage approach to triage is practised, with primary triage at the scene followed by a more detailed assessment using a secondary triage process, the Triage Sort. To date, no studies have analysed the performance of the Triage Sort in the civilian setting. The primary aim of this study was to determine the performance of the Triage Sort at predicting the need for life-saving intervention (LSI).MethodsUsing the Trauma Audit Research Network (TARN) database for all adult patients (>18 years) between 2006 and 2014, we determined which patients received one or more LSIs using a previously defined list. The first recorded hospital physiology was used to categorise patient priority using the Triage Sort, National Ambulance Resilience Unit (NARU) Sieve and the Modified Physiological Triage Tool-24 (MPTT-24). Performance characteristics were evaluated using sensitivity and specificity with statistical analysis using a McNemar’s test.Results127 233patients (58.1%) had complete data and were included: 55.6% men, aged 61.4 (IQR 43.1–80.0 years), ISS 9 (IQR 9–16), with 24 791 (19.5%) receiving at least one LSI (priority 1). The Triage Sort demonstrated the lowest accuracy of all triage tools at identifying the need for LSI (sensitivity 15.7% (95% CI 15.2 to 16.2) correlating with the highest rate of under-triage (84.3% (95% CI 83.8 to 84.8), but it had the greatest specificity (98.7% (95% CI 98.6 to 98.8).ConclusionWithin a civilian trauma registry population, the Triage Sort demonstrated the poorest performance at identifying patients in need of LSI. Its use as a secondary triage tool should be reviewed, with an urgent need for further research to determine the optimum method of secondary triage.

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.

There are major gaps in our knowledge regarding the exact mechanisms and genetic basis of psoriasis. To investigate the pathogenesis of psoriasis, gene expression in 10 skin (5 lesional, 5 nonlesional) and 11 blood (6 psoriatic, 5 nonpsoriatic) samples were examined using Affymetrix HG-U95A microarrays. We detected 535 (425 upregulated, 110 downregulated) DEGs in lesional skin at 1% false discovery rate (FDR). Combining nine microarray studies comparing lesional and nonlesional psoriatic skin, 34.5% of dysregulated genes were overlapped in multiple studies. We further identified 20 skin and 2 blood associated transcriptional “hot spots” at specified genomic locations. At 5% FDR, 11.8% skin and 10.4% blood DEGs in our study mapped to one of the 12 PSORS loci. DEGs that overlap with PSORS loci may offer prioritized targets for downstream genetic fine mapping studies. Novel DEG “hot spots” may provide new targets for defining susceptibility loci in future studies.

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.

Central sleep apnea (CSA) may occasionally occur in patients with obstructive sleep apnea during titration with a continuous positive airway pressure (CPAP) device.To determine the prevalence and the natural history of CPAP-emergent CSA.This is a retrospective study of 1286 patients with a diagnosis of OSAwho underwent titration with a positive airway device during a 1-year period. Patients were seen in consultation and underwent full-night attended polysomnography followed by full-night attended CPAP titration. Four weeks after CPAP therapy, patients returned to the clinic for follow-up, and objective adherence to CPAP was recorded. In patients who had CSA on CPAP, a second full-night attended CPAP titration was recommended.Eighty-four of the 1286 patients developed a central apnea index (CAI) of 5 or greater per hour while on CPAP. The incidence of CSA varied from 3% to 10% monthly, with an overall incidence of 6.5%. Forty-two of the 84 patients returned for a second CPAP titration. In 33 patients, CSA was eliminated. In each of the remaining 9 patients, the CAI remained at 5 or greater per hour, with an average of 13 per hour. These patients characteristically had the most severe OSA, and 5 had a CAI of 5 or more per hour at baseline. Two of the 9 patients were on opioidsIn this large retrospective study of 1286 patients with a diagnosis of OSA, 6.5% had CPAP-emergent or persistent CSA. However, CPAP-emergent CSA was generally transitory and was eliminated within 8 weeks after CPAP therapy. The prevalence of CPAP-persistent CSA was about 1.5%. Severity of OSA, a CAI of 5 or greater per hour, and use of opioids were potential risk factors.

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.

Objective To examine emergency department (ED) staff's knowledge of traumatic stress in children, attitudes toward providing psychosocial care, and confidence in doing so, and also to examine differences in these outcomes according to demographic, professional, and organizational characteristics, and training preferences. Study design We conducted an online survey among staff in ED and equivalent hospital departments, based on the Psychological First Aid and Distress-Emotional Support-Family protocols. Main analyses involved descriptive statistics and multiple regressions. Respondents were 2648 ED staff from 87 countries (62.2% physicians and 37.8% nurses; mean years of experience in emergency care was 9.5 years with an SD of 7.5 years; 25.2% worked in a low- or middle-income country). Results Of the respondents, 1.2% correctly answered all 7 knowledge questions, with 24.7% providing at least 4 correct answers. Almost all respondents (90.1%) saw all 18 identified aspects of psychosocial care as part of their job. Knowledge and confidence scores were associated with respondent characteristics (eg, years of experience, low/middle vs high-income country), although these explained no more than 11%-18% of the variance. Almost all respondents (93.1%) wished to receive training, predominantly through an interactive website or one-off group training. A small minority (11.1%) had previously received training. Conclusions More education of ED staff regarding child traumatic stress and psychosocial care appears needed and would be welcomed. Universal education packages that are readily available can be modified for use in the ED.

Recent advances in neuroscience have raised the hypothesis that the underlying pattern of neuronal activation which results in electroencephalography (EEG) signals is via power-law distributed neuronal avalanches, while EEG signals are nonstationary. Therefore, spectral analysis of EEG may miss many properties inherent in such signals. A complete understanding of such dynamical systems requires knowledge of the underlying nonequilibrium thermodynamics. In recent work by Fielitz and Borchardt (2011, 2014), the concept of information equilibrium (IE) in information transfer processes has successfully characterized many different systems far from thermodynamic equilibrium. We utilized a publicly available database of polysomnogram EEG data from fourteen subjects with eight different one-minute tracings of sleep stage 2 and waking and an overlapping set of eleven subjects with eight different one-minute tracings of sleep stage 3. We applied principles of IE to model EEG as a system that transfers (equilibrates) information from the time domain to scalp-recorded voltages. We find that waking consciousness is readily distinguished from sleep stages 2 and 3 by several differences in mean information transfer constants. Principles of IE applied to EEG may therefore prove to be useful in the study of changes in brain function more generally.

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.)

We developed a strategy for use of microarray data to rapidly identify new downstream targets of transcription factors known to drive differentiation by following the time courses of gene expression as a relatively homogeneous population of stem/progenitor cells are differentiated to multiple phenotypes. Microarray assays were used to follow the differentiation of human marrow stromal cells (MSCs) into chondrocytes or adipocytes in three different experimental conditions. The steps of the analysis were the following: (a) hierarchical clustering was used to define groups of similarly behaving genes in each experiment, (b) candidates for new downstream targets of transcription factors that drive differentiation were then identified as genes that were consistently co-expressed with known downstream target genes of the transcription factors, and (c) the list of candidate new target genes was refined by identifying genes whose signal intensities showed a highly significant linear regression with the signal intensities of the known targets in all the data sets. Analysis of the data identified multiple new candidates for downstream targets for SOX9, SOX5, CCAAT/enhancer binding protein (C/EBP)-α, and peroxisome proliferator-activated receptor (PPAR)-γ. To validate the analysis, we demonstrated that PPAR-γ protein specifically bound to the promoters of four new targets identified in the analyses. The same multistep analysis can be used to identify new downstream targets of transcription factors in other systems. Also, the same analysis should make it possible to use MSCs from bone marrow to define new mutations that alter chondogenesis or adipogenesis in patients with a variety of syndromes.

Summary Objective To improve the measurement of core body temperature in the resuscitation room. Method This work was undertaken in the Emergency Department (ED) of a large District General Hospital. The clinical notes for all admissions to the resuscitation suite during a 2 month period were reviewed to establish the frequency of temperature measurement. Following a simple educational program, performance was re-audited using the same methodology. Results Of the first cohort 13.4% had had their temperature recorded. This improved to 71.6%. Conclusions The measurement of body temperature in the resuscitation room is important as hypothermia has profound effects on the cardiovascular, pulmonary, neurological and haemostatic systems. Clinical audit highlights poor current performance and enables improvement of practice through simple education.

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.

Adult stem cells from human bone marrow stroma, referred to as mesenchymal stem cells or marrow stromal cells (hMSCs), are attractive candidates for clinical use. The optimal conditions for hMSC expansion require medium supplemented with fetal calf serum (FCS). Some forms of cell therapy will involve multiple doses, raising a concern over immunological reactions caused by medium-derived FCS proteins. By a sensitive fluorescence-based assay we determined that 7 to 30 mg of FCS proteins are associated with a standard preparation of 100 million hMSCs, a dosage that probably will be needed for clinical therapies. Here we present ex vivo growth conditions for hMSCs that reduce the FCS proteins to less than 100 ng per 100 million hMSCs, approximately a 100,000-fold reduction. The cells maintain their proliferative capacity and sustain their ability for multilineage differentiation. Experiments in rats demonstrate that rat MSCs grown in 20% FCS induce a substantial humoral response after repeated administrations, whereas cells grown under the conditions described in this study reduce the immunogenicity in terms of IgG response over 1000-fold to barely detectable levels. Our results have the potential to dramatically improve cellular and genetic therapies using hMSCs and perhaps other cells.

Background: Individuals with Williams syndrome have good spontaneous language despite low levels of intelligence. This study explores the relationship between intelligence, word decoding and reading-related skills in 20 individuals with Williams syndrome. Methods: In addition to the KBIT, the participants were administered standardized measures of reading, vocabulary, rapid naming, phonological skills and an experimental measure of rhyme judgement. Results: There was wide variability in the reading achievement among the individuals with WS. While some participants were unable to recognize letters of the alphabet, others scored within the normal range of tests of single word reading and decoding. Reading scores were correlated with intelligence as measured on KBIT matrices but not with the vocabulary measures. Reading also correlated with phonological awareness tasks yet, surprisingly, not with rapid naming. Conclusion: It is suggested that in individuals with retardation, intelligence rather than language and language-related skills predict achievements in word reading.

To investigate stem cell differentiation in response to tissue injury, human mesenchymal stem cells (hMSCs) were cocultured with heat-shocked small airway epithelial cells. A subset of the hMSCs rapidly differentiated into epithelium-like cells, and they restored the epithelial monolayer. Immunocytochemistry and microarray analyses demonstrated that the cells expressed many genes characteristic of normal small airway epithelial cells. Some hMSCs differentiated directly after incorporation into the epithelial monolayer but other hMSCs fused with epithelial cells. Surprisingly, cell fusion was a frequent rather than rare event, in that up to 1% of the hMSCs added to the coculture system were recovered as binucleated cells expressing an epithelial surface epitope. Some of the fused cells also underwent nuclear fusion.

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.

There is considerable interest in the biology and therapeutic potential of adult stem cells from bone marrow stroma, variously referred to as mesenchymal stem cells or marrow stromal cells (MSCs). Human MSCs can expand rapidly in culture, but the rate of expansion and the yields of multipotential progenitors are inversely related to the plating density and incubation time of each passage. We have defined conditions for optimizing the yields of cultures enriched for early progenitors. Also, we developed a simple method for assessing the quality of the cultures by phase-contrast microscopy and image analysis or by forward light scatter in a flow cytometer. The cells expanded most rapidly on day 4 after plating, with a minimum average doubling time of about 10 hours for cells initially plated at 10 or 50 cells/cm(2). After plating the cells at 1 to 1000 cells/cm(2), the cultures underwent a time-dependent transition from early progenitors, defined as thin, spindle-shaped cells (RS-1A), to wider, spindle-shaped cells (RS-1B), and to still wider, spindle-shaped cells (RS-1C). Assays for adipogenesis demonstrated that the adipogenic potential of cultures was directly related to their ability to generate single-cell-derived colonies and their enrichment for RS-1A cells. In contrast, cultures enriched for RS-1B cells showed the greatest potential to differentiate into cartilage in a serum-free system. The results indicate that, when preparing cultures of human MSCs, it is necessary to compromise between conditions that provide the highest overall yields and those that provide the highest content of early progenitor cells.

Lupus erythematosus is a heterogeneous autoimmune condition affecting multiple organs including skin, which remains poorly understood. To investigate pathogenetic processes relevant to cutaneous lupus as compared to systemic disease, we generated genome-wide expression data from lesional and non-lesional skin of chronic cutaneous LE (CCLE) patients. We reveal LE skin-associated transcriptional profiles and identify prominent functional pathways. A subset of CCLE differentially expressed genes (DEGs) was found to overlap with systemic lupus, including those linked to interferon and apoptosis. We identified 13 skin associated transcriptional "hot spots" that represent activated chromosomal regions. Seventeen CCLE DEGs (eight within "hot spots") were found to overlap with previously reported SLE-associated susceptibility loci. Additionally, we identify chromosomal regions not previously associated with lupus, potentially harboring distinct susceptibility loci for CCLE. This study suggests that overlapping as well as distinct genetic factors underlie disease pathogenesis in systemic and cutaneous lupus.

Cellulitis is usually caused by organisms such as beta-hemolytic streptococci and Staphylococcus aureus. Citrobacter are gram-negative bacilli that can cause opportunistic infections in immunocompromised hosts. They are rarely implicated in skin or soft tissue infections. The genus Citrobacter has been respeciated according to genetic relatedness. Citrobacter braakii refers to the genomospecies 6 of the Citrobacter freundii complex. There are no detailed studies of infections caused by the newly formed specific genetic species. We report a case of C. braakii infection in a renal transplant patient receiving immunosuppressive therapy. The patient's lower extremity cellulitis did not respond to conventional antibiotic therapy. Blood cultures grew C. braakii. Sensitivity studies and treatment with appropriate antibiotics resulted in prompt recovery. Immunosuppressive therapy in renal transplant recipients predisposes to infection by unusual pathogens, and this should be suspected when lack of a clinical response to conventional antibiotics is observed. We believe this is the first reported case of C. braakii cellulitis and bacteremia in a renal transplant recipient.

We examine estimation of the parameters of Susceptible-Infective-Recovered (SIR) models in the context of least squares. We review the use of asymptotic statistical theory and sensitivity analysis to obtain measures of uncertainty for estimates of the model parameters and the basic reproductive number ($R_0$)---an epidemiologically significant parameter grouping. We find that estimates of different parameters, such as the transmission parameter and recovery rate, are correlated, with the magnitude and sign of this correlation depending on the value of $R_0$. Situations are highlighted in which this correlation allows $R_0$ to be estimated with greater ease than its constituent parameters. Implications of correlation for parameter identifiability are discussed. Uncertainty estimates and sensitivity analysis are used to investigate how the frequency at which data is sampled affects the estimation process and how the accuracy and uncertainty of estimates improves as data is collected over the course of an outbreak. We assess the informativeness of individual data points in a given time series to determine when more frequent sampling (if possible) would prove to be most beneficial to the estimation process. This technique can be used to design data sampling schemes in more general contexts.

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.

Although more than 2,400 genes have been shown to contain variants that cause Mendelian disease, there are still several thousand such diseases yet to be molecularly defined. The ability of new whole-genome sequencing technologies to rapidly indentify most of the genetic variants in any given genome opens an exciting opportunity to identify these disease genes. Here we sequenced the whole genome of a single patient with the dominant Mendelian disease, metachondromatosis (OMIM 156250), and used partial linkage data from her small family to focus our search for the responsible variant. In the proband, we identified an 11 bp deletion in exon four of PTPN11, which alters frame, results in premature translation termination, and co-segregates with the phenotype. In a second metachondromatosis family, we confirmed our result by identifying a nonsense mutation in exon 4 of PTPN11 that also co-segregates with the phenotype. Sequencing PTPN11 exon 4 in 469 controls showed no such protein truncating variants, supporting the pathogenicity of these two mutations. This combination of a new technology and a classical genetic approach provides a powerful strategy to discover the genes responsible for unexplained Mendelian disorders., Author Summary Metachondromatosis (MC) is an autosomal dominant condition characterized by exostoses (osteochondromas), commonly of the hands and feet, and enchondromas of long bone metaphyses and iliac crests. MC exostoses may regress or even resolve over time, and short stature is not characteristic of MC. Here, we sequenced the whole genome of a single patient with MC and used partial linkage data from her small family to focus our search for the responsible variant. In the proband, we identified an 11 bp deletion in exon four of PTPN11, which results in premature translation termination and co-segregates with the phenotype. In a second metachondromatosis family, we identified a nonsense mutation in exon 4 of PTPN11 that also co-segregates with the phenotype. Germline gain-of-function missense mutations in PTPN11 cause an overlapping but distinct group of dominant disorders with involvement of the face, heart, skeleton, skin, and brain, including Noonan syndrome (OMIM 163950), Noonan-like disorder with multiple giant cell lesion syndrome (OMIM 163955), and LEOPARD syndrome (OMIM 151100). Nonsense mutations in PTPN11 have not been described in humans and the loss-of-function PTPN11 mutations we report here are the first to be described in human disease.

Background There is considerable interest in the development of methods to efficiently identify all coding variants present in large sample sets of humans. There are three approaches possible: whole-genome sequencing, whole-exome sequencing using exon capture methods, and RNA-Seq. While whole-genome sequencing is the most complete, it remains sufficiently expensive that cost effective alternatives are important. Results Here we provide a systematic exploration of how well RNA-Seq can identify human coding variants by comparing variants identified through high coverage whole-genome sequencing to those identified by high coverage RNA-Seq in the same individual. This comparison allowed us to directly evaluate the sensitivity and specificity of RNA-Seq in identifying coding variants, and to evaluate how key parameters such as the degree of coverage and the expression levels of genes interact to influence performance. We find that although only 40% of exonic variants identified by whole genome sequencing were captured using RNA-Seq; this number rose to 81% when concentrating on genes known to be well-expressed in the source tissue. We also find that a high false positive rate can be problematic when working with RNA-Seq data, especially at higher levels of coverage. Conclusions We conclude that as long as a tissue relevant to the trait under study is available and suitable quality control screens are implemented, RNA-Seq is a fast and inexpensive alternative approach for finding coding variants in genes with sufficiently high expression levels.

Deletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.11 deletions, as well as other structural variation, in epilepsy disorders, we used genome-wide screens to identify copy number variation in 3812 patients with a diverse spectrum of epilepsy syndromes and in 1299 neurologically-normal controls. Large deletions (> 100 kb) at 16p13.11 were observed in 23 patients, whereas no control had a deletion greater than 16 kb. Patients, even those with identically sized 16p13.11 deletions, presented with highly variable epilepsy phenotypes. For a subset of patients with a 16p13.11 deletion, we show a consistent reduction of expression for included genes, suggesting that haploinsufficiency might contribute to pathogenicity. We also investigated another possible mechanism of pathogenicity by using hybridization-based capture and next-generation sequencing of the homologous chromosome for ten 16p13.11-deletion patients to look for unmasked recessive mutations. Follow-up genotyping of suggestive polymorphisms failed to identify any convincing recessive-acting mutations in the homologous interval corresponding to the deletion. The observation that two of the 16p13.11 deletions were larger than 2 Mb in size led us to screen for other large deletions. We found 12 additional genomic regions harboring deletions > 2 Mb in epilepsy patients, and none in controls. Additional evaluation is needed to characterize the role of these exceedingly large, non-locus-specific deletions in epilepsy. Collectively, these data implicate 16p13.11 and possibly other large deletions as risk factors for a wide range of epilepsy disorders, and they appear to point toward haploinsufficiency as a contributor to the pathogenicity of deletions., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

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.

Data is very limited on the demographics, epidemiology, grading, and management of truncal acne vulgaris. In this study completed in 5 cities across the US, 696 patients were assessed to evaluate the frequency and severity of truncal acne vulgaris. Approximately 50% of patients who presented with acne vulgaris demonstrated involvement on the chest and/or back, with more than 3% presenting with truncal acne lesions alone. Interestingly, approximately 1 out of 4 patients who presented with both facial and truncal acne involvement did not voluntarily mention the presence of truncal acne as part of their presenting complaint. In such cases, the presence of truncal acne lesions was detected by clinical examination. A grading system for truncal acne vulgaris is also presented. The majority of patients presenting with truncal acne vulgaris exhibited mild to moderate severity and more than 75% were interested in treatment for truncal acne lesions.

In this study, we used multipotential MSCs and microarray assays to follow the changing patterns of gene expression as MSCs were differentiated to osteoblasts. We analyzed co-expressed gene groups to identify new targets for known transcription factor VDR during differentiation. The roles of two genes (histamine receptor H1 and dermatopontin) as downstream targets for the VDR were confirmed by gel electromotility shift, siRNA inhibition, and chromatin immunoprecipitation assays. Introduction: Osteogenesis is stringently controlled by osteoblast-specific signaling proteins and transcription factors. Mesenchymal stem or multipotential stromal cells from bone marrow (MSCs) have been shown to differentiate into osteoblasts in the presence of vitamin D3. Materials and Methods: We used MSCs and microarray assays to follow the changing patterns of gene expression as MSCs were differentiated to osteoblasts. The data were analyzed with a previously developed strategy to identify new downstream targets of the vitamin D receptor (VDR), known osteogenesis transcription factor. Hierarchical clustering of the data identified 15 distinct patterns of gene expression. Three genes were selected that expressed in the same time-dependent pattern as osteocalcin, a known target for the VDR: histamine receptor H1 (HRH1), Spondin 2 (SPN), and dermatopontin (DPT). RT-PCR, electromotility shift, siRNA inhibition assays, and chromatin immunoprecipitation assays were used to analyze the role of VDR in activation of DPT and HRH1 during differentiation. Results and Conclusions: RT-PCR assays confirmed that the genes were expressed during differentiation of MSCs. The roles of two genes as downstream targets for the VDR were confirmed by gel electromotility shift and chromatin immunoprecipitation assays that showed the presence of VDR complex binding sequences. Overexpression of VDR in MG-63 osteosarcoma cells induced the expression of HRH1 and DPT. Inhibition studies with siRNA to DPT and HRH1 showed a decrease in MSC differentiation to osteogenic lineage. In addition, osteogenic differentiation of MSCs was inhibited by the HRH1 inhibitor mepyramine but not the HRH2 inhibitor ranitidine. In conclusion, we show that analysis of co-expressed gene groups is a good tool to identify new targets for known transcription factors.

Using the chick chorioallantoic membrane assay (CAM) and a novel histological technique, we investigated the ability of blood vessels to directly invade fibrin-based scaffolds. In our initial experiments utilizing vascular endothelial growth factor (VEGF165), we found no direct invasion. Instead, the fibrin was completely degraded and replaced with highly vascularized new tissue. Addition of fibroblast growth factor-2 (FGF-2), bone morphogenic protein-2 (BMP-2), or platelet-derived growth factor-BB (PDGF-BB) to the fibrin construct also did not result in construct vascularization. Because natural and regenerating tissues exhibit complex extracellular matrices (ECMs), we hypothesized that a more complex scaffold may improve blood vessel invasion. Addition of fibronectin, hyaluronic acid, and collagen type I within 20 mg/mL fibrin constructs resulted in no significant improvement. However, the same additive concentrations within 10 mg/mL fibrin constructs resulted in dramatic improvements, specifically with hyaluronic acid. Overall, we believe that these results indicate the importance of structural and functional cues of not only in the initial scaffold but also as the construct is degraded and remodeled. Furthermore, the CAM assay may represent a useful model for understanding ECM interactions as well as for screening and designing tissue-engineered scaffolds.

Understanding why some people establish and maintain effective control of HIV-1 and others do not is a priority in the effort to develop new treatments for HIV/AIDS. Using a whole-genome association strategy, we identified polymorphisms that explain nearly 15% of the variation among individuals in viral load during the asymptomatic set-point period of infection. One of these is found within an endogenous retroviral element and is associated with major histocompatibility allele human leukocyte antigen ( HLA )– B*5701 , whereas a second is located near the HLA-C gene. An additional analysis of the time to HIV disease progression implicated two genes, one of which encodes an RNA polymerase I subunit. These findings emphasize the importance of studying human genetic variation as a guide to combating infectious agents.

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.

Attempts have been made to develop cell and gene therapies using the adult stem cells from bone marrow referred to as mesenchymal stem cells or marrow stromal cells (MSCs). However, the results have been variable in part because there are no standardized protocols for preparing and characterizing MSCs. In the experiments presented here, we developed a standardized assay by light scattering to measure the content of rapidly self-renewing cells (RS cells) in preparations of MSCs. The assay quickly identifies preparations of MSCs that replicate rapidly in subsequent culture. In addition, the standardized assay enabled us to isolate RS cells that were up to 90% clonogenic and that generated single cell–derived colonies that differentiated into either mineralizing cells or adipocytes with appropriate additions to the medium.

Recently there has been interest in developing cell and gene therapies with adult stem cells from human bone marrow referred to as mesenchymal stem cells or marrow stromal cells (hMSCs). We incubated early-passage hMSCs in serum-free medium without cytokines or other supplements for 2 to 4 weeks. Surprisingly, a subpopulation of the cells survived serum deprivation and then began to proliferate in serum-containing medium. The cells selected by serum deprivation had longer telomeres than control cells. Also, the patterns of gene expression revealed by reverse transcriptase–polymerase chain reaction (RT-PCR) assays and microarray data indicated that the cells selected by serum deprivation were a subpopulation of very early progenitor cells with enhanced expression of octomer-binding transcription factor 4 (OCT-4) and several other genes characteristically expressed in embryonic cells.

• 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.