VO2max--new concepts on an old theme.

This symposium "VO2max--new concepts on an old theme" is dedicated to the memory of Hermann Rahn, whose inspiration has led many young investigators to explore new horizons. In the debate on factors limiting VO2max at altitude Hermann Rahn stimulated further discussion between those camps supporting the central circulation as limiting VO2max and those proposing a peripheral diffusion limitation.     

Abnormal esophageal transit in patients with typical reflux symptoms but normal endoscopic and pH profiles

There is a small, well-known cohort of patients who, despite classic reflux symptoms, have a normal esophageal pH profile and endoscopic picture. The treatment of these patients has proved problematic. In an attempt at determining the pathophysiology of this subgroup, we investigated the esophageal transit, using the radiolabeled solid bolus esophageal egg transit technique, in 58 such patients: 25 males, 33 females, mean age 39.5 years (range: 13 to 65 years). The egg transit was normal in 31 (53.4%) patients. In the remaining 27 (46.6%) patients, the condensed image analysis showed the following specific abnormal transit patterns: "step" delay pattern, demonstrating segmental hold-up in mid- or distal esophagus in 16 (59.3%); nonspecific delay in 6 (22.2%); oscillatory pattern in 3 (11.1%); and total nonclearance during the study period (4 minutes) in 2 (7.4%) patients. The patients with abnormal transit patterns had demographic parameters and symptom scores similar to those found in patients with normal transit. This study shows that almost 50% of patients with reflux symptoms and negative pH and endoscopy have abnormal esophageal transit, and almost two thirds of these patients display segmental transit delay in the lower half of the esophagus. The effect on symptomatology by prokinetic agents in the patient subgroup needs evaluation.     

The evolution of a vascular surgeon at a district general hospital: is sub-specialisation inevitable?

We report a 15-year retrospective audit to evaluate the change in arterial surgical commitment on general surgical case mix of a single surgeon with a vascular interest at a district general hospital. There was a 409% increase in the number of arterial procedures performed combined with a fall of 52% in the total number of operations over the study period. We conclude that, with such a rapidly growing arterial caseload, sub-specialisation to vascular surgery is inevitable.     

Liver allotransplantation after extracorporeal hepatic support with transgenic (hCD55/hCD59) porcine livers: clinical results and lack of pig-to-human transmission of the porcine endogenous retrovirus

BACKGROUND: Whole organ extracorporeal perfusion of a genetically modified humanized (transgenic) pig liver has been proposed as a technology that may sustain patients with severe liver failure while awaiting human liver transplantation. METHODS: We report on two cases of successful extracorporeal perfusion of a transgenic pig liver in patients awaiting transplantation for fulminant hepatic failure. The pig livers used were transgenic for human CD55 (decay-accelerating factor) and human CD59. These transgenic modifications are designed to reduce or eliminate the hyperacute rejection inherent in pig-to-primate xenotransplants. We also report on the results of serial surveillance testing for presence of the porcine endogenous retrovirus (PoERV) in these two patients. RESULTS: Extracorporeal perfusion in two patients was performed for 6.5 and 10 hr, respectively, followed by the successful transplantation of a human liver and resultant healthy patients (18 and 5 months later as of this writing). The porcine livers showed evidence of synthetic and secretory function (decreasing protime and bilirubin, bile production). Serial polymerase chain reaction analysis of these patients' peripheral blood mononuclear cells has failed to show presence of PoERV DNA sequences. CONCLUSIONS: The CD55/CD59 transgenic porcine liver appears capable of safely "bridging" a patient to liver transplantation. Human PoERV infection from these livers has yet to be demonstrated.     

Assessing the need to update prevention guidelines: a comparison of two methods.

BACKGROUND: An important concern for developers of clinical practice guidelines is how best to determine when guidelines require updating to ensure they remain current and evidence based. Because of the high costs associated with updating guidelines, recent attention has focused on approaches that can reliably assess the extent of updating required. Recently, Shekelle and colleagues proposed a model of limited literature searches with modest expert involvement as a way to reduce the cost and time requirements for assessing whether a guideline needs updating. METHODS: The main objective of this study was to compare the Shekelle et al. assessment model (review approach) and a conventional process using typical systematic review methods (traditional approach) in terms of comprehensiveness and effort. We modeled the review approach on that by Shekelle and colleagues but refined it iteratively over three phases to achieve greater efficiency. Using both methods independently, we assessed the need to update six topics from the 1996 Guide to Clinical Preventive Services from the US Preventive Services Task Force. Main outcomes included completeness of study identification, importance of missed studies and the effort involved. RESULTS: Although the review approach identified fewer eligible studies than the traditional approach, none of the studies missed was rated as important by task force members acting as liaisons to the project with respect to whether the topic required an update. On average, the review approach produced substantially fewer citations to review than the traditional approach. The effort involved and potential time saving depended largely on the scope of the topic. CONCLUSIONS: The revised review approach provides an efficient and acceptable method for judging whether a guideline requires updating.     

Experience of combined endoscopic percutaneous stenting with ultrasound guidance for drainage of pancreatic pseudocycts

The therapeutic options for treatment of pancreatic pseudocysts are numerous. We report our experience of combined endoscopic and ultrasound guided percutaneous stenting for pancreatic pseudocysts. Data were prospectively collected for 20 consecutive patients. All patients had undergone a standard technique of combined endoscopic and ultrasound guided percutaneous placement of double J stents, between a pancreatic pseudocyst and the stomach. Patients age ranged between 25 and 84 years. Thirteen of the pseudocysts were due to acute pancreatitis and 7 were due to chronic pancreatitis. The duration of the combined procedure was mean 50 min (range 30-95 min). The length of hospital stay was mean 5 days (range 2-77 days. Only two patients suffered postoperative complications; one was re-admitted 2 weeks following stenting with acute cholecystitis, the other suffering a perforated duodenal ulcer 3 weeks after stenting. There were two failures early in the series, both due to stent migration, these stents were of a small size, (4.7 French). Following this the stent size was increased to at least 7 French, no further failures occurred. There was no operative mortality for the series. Follow-up ranged between 6 months and 5 years. We conclude that a combined percutaneous and endoscopic cyst-gastrostomy stent is a safe and effective treatment for patients with suitably placed pseudocysts.     

An automated process for building reliable and optimal in vitro/in vivo correlation models based on Monte Carlo simulations

Many mathematical models have been proposed for establishing an in vitro/in vivo correlation (IVIVC). The traditional IVIVC model building process consists of 5 steps: deconvolution, model fitting, convolution, prediction error evaluation, and cross-validation. This is a time-consuming process and typically a few models at most are tested for any given data set. The objectives of this work were to (1) propose a statistical tool to screen models for further development of an IVIVC, (2) evaluate the performance of each model under different circumstances, and (3) investigate the effectiveness of common statistical model selection criteria for choosing IVIVC models. A computer program was developed to explore which model(s) would be most likely to work well with a random variation from the original formulation. The process used Monte Carlo simulation techniques to build IVIVC models. Data-based model selection criteria (Akaike Information Criteria [AIC], R2) and the probability of passing the Food and Drug Administration "prediction error" requirement was calculated. To illustrate this approach, several real data sets representing a broad range of release profiles are used to illustrate the process and to demonstrate the advantages of this automated process over the traditional approach. The Hixson-Crowell and Weibull models were often preferred over the linear. When evaluating whether a Level A IVIVC model was possible, the model selection criteria AIC generally selected the best model. We believe that the approach we proposed may be a rapid tool to determine which IVIVC model (if any) is the most applicable.     

Epidemiological analysis of the first 1000 cases of SARS‐CoV‐2 lineage BA.1 (B.1.1.529, Omicron) compared with co‐circulating Delta in Wales,UK

BackgroundThe Omicron (lineage B.1.1.529) variant of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) was first reported in Wales, UK, on 3 December 2021. The aim of the study was to describe the first 1000 cases of the Omicron variant by demographic, vaccination status, travel and severe outcome status and compare this to contemporaneous cases of the Delta variant.MethodsTesting, typing and contact tracing data were collected by Public Health Wales and analysis undertaken by the Communicable Disease Surveillance Centre (CDSC). Risk ratios for demographic factors and symptoms were calculated comparing Omicron cases to Delta cases identified over the same time period.ResultsBy 14 December 2021, 1000 cases of the Omicron variant had been identified in Wales. Of the first 1000, just 3% of cases had a prior history of travel revealing rapid community transmission. A higher proportion of Omicron cases were identified in individuals aged 20–39, and most cases were double vaccinated (65.9%) or boosted (15.7%). Age‐adjusted analysis also revealed that Omicron cases were less likely to be hospitalised (0.4%) or report symptoms (60.8%). Specifically a significant reduction was observed in the proportion of Omicron cases reporting anosmia (8.9%).ConclusionKey findings include a lower risk of anosmia and a reduced risk of hospitalisation in the first 1000 Omicron cases compared with co‐circulating Delta cases. We also identify that existing measures for travel restrictions to control importations of new variants identified outside the United Kingdom did not prevent the rapid ingress of Omicron within Wales.