Completion pancreatectomy or a pancreas-preserving procedure during relaparotomy for pancreatic fistula after pancreatoduodenectomy: a multicentre cohort study and meta-analysis.

BACKGROUND: Despite the fact that primary percutaneous catheter drainage has become standard practice, some patients with pancreatic fistula after pancreatoduodenectomy ultimately undergo a relaparotomy. The aim of this study was to compare completion pancreatectomy with a pancreas-preserving procedure in patients undergoing relaparotomy for pancreatic fistula after pancreatoduodenectomy. METHODS: This retrospective cohort study of nine institutions included patients who underwent relaparotomy for pancreatic fistula after pancreatoduodenectomy from 2005-2018. Furthermore, a systematic review and meta-analysis were performed according to the PRISMA guidelines. RESULTS: From 4877 patients undergoing pancreatoduodenectomy, 786 (16 per cent) developed a pancreatic fistula grade B/C and 162 (3 per cent) underwent a relaparotomy for pancreatic fistula. Of these patients, 36 (22 per cent) underwent a completion pancreatectomy and 126 (78 per cent) a pancreas-preserving procedure. Mortality was higher after completion pancreatectomy (20 (56 per cent) versus 40 patients (32 per cent); P = 0.009), which remained after adjusting for sex, age, BMI, ASA score, previous reintervention, and organ failure in the 24 h before relaparotomy (adjusted odds ratio 2.55, 95 per cent c.i. 1.07 to 6.08). The proportion of additional reinterventions was not different between groups (23 (64 per cent) versus 84 patients (67 per cent); P = 0.756). The meta-analysis including 33 studies evaluating 745 patients, confirmed the association between completion pancreatectomy and mortality (Mantel-Haenszel random-effects model: odds ratio 1.99, 95 per cent c.i. 1.03 to 3.84). CONCLUSION: Based on the current data, a pancreas-preserving procedure seems preferable to completion pancreatectomy in patients in whom a relaparotomy is deemed necessary for pancreatic fistula after pancreatoduodenectomy.

[Surgical treatment of nerve lesions]. / Operatieve behandeling van zenuwletsels.

A peripheral nerve lesion may result in loss of motor and sensory function and pain. Nerve surgery may lead to function recovery or contribute to pain reduction. Different surgical techniques are used depending on the specific type of lesion. Common techniques consist of coapting, grafting, moving or burying the nerve. The outcome depends on the interval between the time the lesion occurred and the time of repair as well as the patient's age. Here we present three case studies of patients with a different type of nerve lesion and its consequences. We describe the specific surgical intervention performed to treat the nerve lesion. Immediate repair of the nerve should be performed when the patient has an open wound. In closed lesions, the decision to repair a damaged nerve depends on the severity of the trauma, the nerve(s) involved, the location and the age of the patient. In general, repair should be performed as soon as possible.

Meta-analysis of epidural analgesia in patients undergoing pancreatoduodenectomy.

Background: The optimal analgesic technique after pancreatoduodenectomy remains under debate. This study aimed to see whether epidural analgesia (EA) has superior clinical outcomes compared with non-epidural alternatives (N-EA) in patients undergoing pancreatoduodenectomy. Methods: A systematic review with meta-analysis was performed according to PRISMA guidelines. On 28 August 2018, relevant literature databases were searched. Primary outcomes were pain scores. Secondary outcomes were treatment failure of initial analgesia, complications, duration of hospital stay and mortality. Results: Three RCTs and eight cohort studies (25 089 patients) were included. N-EA treatments studied were: intravenous morphine, continuous wound infiltration, bilateral paravertebral thoracic catheters and intrathecal morphine. Patients receiving EA had a marginally lower pain score on days 0-3 after surgery than those receiving intravenous morphine (mean difference (MD) -0·50, 95 per cent c.i. -0·80 to -0·21; P < 0·001) and similar pain scores to patients who had continuous wound infiltration. Treatment failure occurred in 28·5 per cent of patients receiving EA, mainly for haemodynamic instability or inadequate pain control. EA was associated with fewer complications (odds ratio (OR) 0·69, 95 per cent c.i. 0·06 to 0·79; P < 0·001), shorter duration of hospital stay (MD -2·69 (95 per cent c.i. -2·76 to -2·62) days; P < 0·001) and lower mortality (OR 0·69, 0·51 to 0 93; P = 0·02) compared with intravenous morphine. Conclusion: EA provides marginally lower pain scores in the first postoperative days than intravenous morphine, and appears to be associated with fewer complications, shorter duration of hospital stay and less mortality.

Antecedentes: La técnica analgésica óptima tras una duodenopancreatectomía permanece en debate. El objetivo de este estudio fue analizar si la analgesia epidural (epidural analgesia, EA) presenta resultados clínicos superiores en comparación con las alternativas no epidurales (non­epidural alternatives, N­EA) en pacientes que se someten a una duodenopancreatectomía. Métodos: Se realizó una revisión sistemática con metaanálisis de acuerdo con las recomendaciones PRISMA. El 28 de agosto de 2018, se realizó una búsqueda en las bases de datos relevantes de la literatura. El objetivo primario fueron las puntuaciones de dolor. Los objetivos secundarios fueron el fracaso del tratamiento de la analgesia inicial, las complicaciones, la duración de la estancia hospitalaria y la mortalidad. Resultados: Se incluyeron tres ensayos aleatorizados y controlados y ocho estudios de cohortes (25.089 pacientes). Las N­EA estudiadas fueron: morfina intravenosa (iv), infiltración continua de la herida, catéteres torácicos paravertebrales bilaterales y morfina intratecal. Los pacientes con EA tuvieron una puntuación de dolor marginalmente más baja en los días postoperatorios 0 a 3 en comparación con la morfina iv (diferencia de medias (MD) = ­ 0,50, i.c. del 95% ­0,80 a ­0,21; P < 0,001) y puntuaciones de dolor similares en comparación con la infiltración continua de la herida. El fallo del tratamiento ocurrió en el 28,5% de los pacientes con EA, principalmente por inestabilidad hemodinámica o control inadecuado del dolor. La EA se asoció con menos complicaciones (razón de oportunidades, odds ratio, OR = 0,69, i.c. del 95% 0,061 a 0,79; P < 0,001), menor duración de la estancia hospitalaria (MD = ­2,69 días, i.c. del 95% ­2,76 a ­2,62; P < 0,001) y menor mortalidad en comparación con la morfina iv (OR = 0,69, i.c. del 95% 0,51 a 0,93; P = 0,01). Conclusión: La EA proporciona puntuaciones de dolor ligeramente más bajas en los primeros días postoperatorios en comparación con la morfina iv y parece asociarse con menos complicaciones, menor duración de la estancia hospitalaria y menor mortalidad.

Impact of resection margin status on recurrence and survival in pancreatic cancer surgery.

BACKGROUND: The prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) is poor and selection of patients for surgery is challenging. This study examined the impact of a positive resection margin (R1) on locoregional recurrence (LRR) and overall survival (OS); and also aimed to identified tumour characteristics and/or technical factors associated with a positive resection margin in patients with PDAC. METHODS: Patients scheduled for pancreatic resection for PDAC between 2006 and 2016 were identified from an institutional database. The effect of resection margin status, patient characteristics and tumour characteristics on LRR, distant metastasis and OS was assessed. RESULTS: A total of 322 patients underwent pancreatectomy for PDAC. A positive resection (R1) margin was found in 129 patients (40·1 per cent); this was associated with decreased OS compared with that in patients with an R0 margin (median 15 (95 per cent c.i. 13 to 17) versus 22 months; P < 0·001). R1 status was associated with reduced time to LRR (median 16 versus 36 (not estimated, n.e.) months; P = 0·002). Disease recurrence patterns were similar in the R1 and R0 groups. Risk factors for early recurrence were tumour stage, positive lymph nodes (N1) and perineural invasion. Among 100 patients with N0 disease, R1 status was associated with shorter OS compared with R0 resection (median 17 (10 to 24) versus 45 (n.e.) months; P = 0·002), whereas R status was not related to OS in 222 patients with N1 disease (median 14 (12 to 16) versus 17 (15 to 19) months after R1 and R0 resection respectively; P = 0·068). CONCLUSION: Although pancreatic resection with a positive margin was associated with poor survival and early recurrence, particularly in patients with N1 disease, disease recurrence patterns were similar between R1 and R0 groups.

Outcomes following pancreatic surgery using three different thromboprophylaxis regimens.

BACKGROUND: Postpancreatectomy haemorrhage (PPH) and venous thromboembolism (VTE) are serious complications following pancreatic surgery. The aim was to assess the timing, occurrence and predictors of PPH and VTE. METHODS: Elective pancreatic resections undertaken in a single university hospital between November 2013 and September 2017 were assessed. Three intervals were reviewed, each with a different routine regimen of nadroparin: 2850 units once daily (single dose) administered in hospital only, or 5700 units once daily (double dose) or 2850 units twice daily (split dose) administered in hospital and continued for 6 weeks after surgery. Clinically relevant PPH (CR-PPH) was classified according to International Study Group of Pancreatic Surgery criteria. VTE was defined according to a number of key diagnostic criteria within 6 weeks of surgery. Cox regression analyses were performed to test the hypotheses that the double-dose group would experience more PPH than the other two groups, the single-dose group would experience more VTE than the other two groups, and the split-dose group would experience the fewest adverse events (PPH or VTE). RESULTS: In total, 240 patients were included, 80 per group. The double-dose group experienced significantly more CR-PPH (hazard ratio (HR) 2·14, 95 per cent c.i. 1·16 to 3·94; P = 0·015). More relaparotomies due to CR-PPH were performed in the double-dose group (16 versus 3·8 per cent; P = 0·002). The single-dose group did not experience more VTE (HR 1·41, 0·43 to 4·62; P = 0·570). The split dose was not associated with fewer adverse events (HR 0·77, 0·41 to 1·46; P = 0·422). Double-dose low molecular weight heparin (LMWH), high BMI and pancreatic fistula were independent predictors of CR-PPH. CONCLUSION: A double dose of LMWH prophylaxis continued for 6 weeks after pancreatic resection was associated with a twofold higher rate of CR-PPH, resulting in four times more relaparotomies. Patients receiving a single daily dose of LMWH in hospital only did not experience a higher rate of VTE.

Differences in Treatment and Outcome of Pancreatic Adenocarcinoma Stage I and II in the EURECCA Pancreas Consortium.

BACKGROUND: The EUropean REgistration of Cancer CAre (EURECCA) consortium aims to investigate differences in treatment and to improve cancer care through Europe. The purpose of this study was to compare neo- and adjuvant chemotherapy (ACT) and outcome after tumor resection for pancreatic adenocarcinoma stage I and II in the EURECCA Pancreas consortium. METHODS: The eight, collaborating national, regional, and single-center partners shared their anonymized dataset. Patients diagnosed in 2012-2013 who underwent tumor resection for pancreatic adenocarcinoma stage I and II were investigated with respect to treatment and survival and compared using uni- and multivariable logistic and Cox regression analyses. All comparisons were performed separately per registry type: national, regional, and single-center registries. RESULTS: In total, 2052 patients were included. Stage II was present in the majority of patients. The use of neo-ACT was limited in most registries (range 2.8-15.5%) and was only different between Belgium and The Netherlands after adjustment for potential confounders. The use of ACT was different between the registries (range 40.5-70.0%), even after adjustment for potential confounders. Ninety-day mortality was also different between the registries (range 0.9-13.6%). In multivariable analyses for overall survival, differences were observed between the national and regional registries. Furthermore, patients in ascending age groups and patients with stage II showed a significant worse overall survival. CONCLUSIONS: This study provides a clear insight in clinical practice in the EURECCA Pancreas consortium. The differences observed in (neo-)ACT and outcome give us the chance to further investigate the best practices and improve outcome of pancreatic adenocarcinoma.

Endoscopic resection of high-risk T1 colorectal carcinoma prior to surgical resection has no adverse effect on long-term outcomes.

OBJECTIVE: It is difficult to predict the presence of histological risk factors for lymph node metastasis (LNM) before endoscopic treatment of T1 colorectal cancer (CRC). Therefore, endoscopic therapy is propagated to obtain adequate histological staging. We examined whether secondary surgery following endoscopic resection of high-risk T1 CRC does not have a negative effect on patients' outcomes compared with primary surgery. DESIGN: Patients with T1 CRC with one or more histological risk factors for LNM (high risk) and treated with primary or secondary surgery between 2000 and 2014 in 13 hospitals were identified in the Netherlands Cancer Registry. Additional data were collected from hospital records, endoscopy, radiology and pathology reports. A propensity score analysis was performed using inverse probability weighting (IPW) to correct for confounding by indication. RESULTS: 602 patients were eligible for analysis (263 primary; 339 secondary surgery). Overall, 34 recurrences were observed (5.6%). After adjusting with IPW, no differences were observed between primary and secondary surgery for the presence of LNM (OR 0.97; 95% CI 0.49 to 1.93; p=0.940) and recurrence during follow-up (HR 0.97; 95% CI 0.41 to 2.34; p=0.954). Further adjusting for lymphovascular invasion, depth of invasion and number of retrieved lymph nodes did not alter this outcome. CONCLUSIONS: Our data do not support an increased risk of LNM or recurrence after secondary surgery compared with primary surgery. Therefore, an attempt for an en-bloc resection of a possible T1 CRC without evident signs of deep invasion seems justified in order to prevent surgery of low-risk T1 CRC in a significant proportion of patients.

Risk for Incomplete Resection after Macroscopic Radical Endoscopic Resection of T1 Colorectal Cancer: A Multicenter Cohort Study.

OBJECTIVES: The decision to perform secondary surgery after endoscopic resection of T1 colorectal cancer (CRC) depends on the risk of lymph node metastasis and the risk of incomplete resection. We aimed to examine the incidence and risk factors for incomplete endoscopic resection of T1 CRC after a macroscopic radical endoscopic resection. METHODS: Data from patients treated between 2000 and 2014 with macroscopic complete endoscopic resection of T1 CRC were collected from 13 hospitals. Incomplete resection was defined as local recurrence at the polypectomy site during follow-up or malignant tissue in the surgically resected specimen in case secondary surgery was performed. Multivariate regression analysis was performed to analyze factors associated with incomplete resection. RESULTS: In total, 877 patients with a median follow-up time of 36.5 months (interquartile range 16.0-68.3) were included, in whom secondary surgery was performed in 358 patients (40.8%). Incomplete resection was observed in 30 patients (3.4%; 95% confidence interval (CI) 2.3-4.6%). Incomplete resection rate was 0.7% (95% CI 0-2.1%) in low-risk T1 CRC vs. 4.4% (95% CI 2.7-6.5%) in high-risk T1 CRC (P=0.04). Overall adverse outcome rate (incomplete resection or metastasis) was 2.1% (95% CI 0-5.0%) in low-risk T1 CRC vs. 11.7% (95% CI 8.8-14.6%) in high-risk T1 CRC (P=0.001). Piecemeal resection (adjusted odds ratio 2.60; 95% CI 1.20-5.61, P=0.02) and non-pedunculated morphology (adjusted odds ratio 2.18; 95% CI 1.01-4.70, P=0.05) were independent risk factors for incomplete resection. Among patients in whom no additional surgery was performed, who developed recurrent cancer, 41.7% (95% CI 20.8-62.5%) died as a result of recurrent cancer. CONCLUSIONS: In the absence of histological high-risk factors, a 'wait-and-see' policy with limited follow-up is justified. Piecemeal resection and non-pedunculated morphology are independent risk factors for incomplete endoscopic resection of T1 CRC.

Endoscopic mucosal resection (EMR) versus endoscopic submucosal dissection (ESD) for resection of large distal non-pedunculated colorectal adenomas (MATILDA-trial): rationale and design of a multicenter randomized clinical trial.

BACKGROUND: Endoscopic mucosal resection (EMR) is currently the most used technique for resection of large distal colorectal polyps. However, in large lesions EMR can often only be performed in a piecemeal fashion resulting in relatively low radical (R0)-resection rates and high recurrence rates. Endoscopic submucosal dissection (ESD) is a newer procedure that is more difficult resulting in a longer procedural time, but is promising due to the high en-bloc resection rates and the very low recurrence rates. We aim to evaluate the (cost-)effectiveness of ESD against EMR on both short (i.e. 6 months) and long-term (i.e. 36 months). We hypothesize that in the short-run ESD is more time consuming resulting in higher healthcare costs, but is (cost-) effective on the long-term due to lower patients burden, a higher number of R0-resections and lower recurrence rates with less need for repeated procedures. METHODS: This is a multicenter randomized clinical trial in patients with a non-pedunculated polyp larger than 20 mm in the rectum, sigmoid, or descending colon suspected to be an adenoma by means of endoscopic assessment. Primary endpoint is recurrence rate at follow-up colonoscopy at 6 months. Secondary endpoints are R0-resection rate, perceived burden and quality of life, healthcare resources utilization and costs, surgical referral rate, complication rate and recurrence rate at 36 months. Quality-adjusted-life-year (QALY) will be estimated taking an area under the curve approach and using EQ-5D-indexes. Healthcare costs will be calculated by multiplying used healthcare services with unit prices. The cost-effectiveness of ESD against EMR will be expressed as incremental cost-effectiveness ratios (ICER) showing additional costs per recurrence free patient and as ICER showing additional costs per QALY. DISCUSSION: If this trial confirms ESD to be favorable on the long-term, the burden of extra colonoscopies and repeated procedures can be prevented for future patients. TRIAL REGISTRATION: NCT02657044 (Clinicaltrials.gov), registered January 8, 2016.

Autologous fat grafting in onco-plastic breast reconstruction: A systematic review on oncological and radiological safety, complications, volume retention and patient/surgeon satisfaction.

OBJECTIVE: This study presents an up-to-date overview of the literature on autologous fat grafting (AFG) in onco-plastic breast reconstruction, with respect to complications, oncological and radiological safety, volume retention and patient/surgeon satisfaction. BACKGROUND: Although AFG is increasingly being applied in onco-plastic breast reconstruction, a comprehensive overview of the available evidence for this procedure is still lacking. METHODS: A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement was conducted. Case series, cohort studies and randomized controlled trials (RCTs) reporting on relevant outcomes of breast reconstruction with supplemental AFG were included. RESULTS: In total, 43 studies were included reporting on 6260 patients with a follow-up period ranging from 12 to 136 months. The average locoregional and distant oncological recurrence rates after breast reconstruction with AFG were 2.5% (95% confidence interval (CI) 1.7-3.7) and 2.0% (95% CI 1.1-3.5), respectively. Fewer cysts and calcifications were seen on radiological images for this procedure than for other types of breast surgery. However, more biopsies were performed based on radiological findings (3.7% vs. 1.6%), and more cases of fat necrosis (9.0% vs 4.7%) were seen after treatment with AFG. The total complication rate of 8.4% (95% CI 7.6-9.1) is lower than those reported following other reconstructive breast procedures. The mean volume retention was 76.8% (range 44.7-82.6%) with a satisfaction rate of 93.4% for patients and 90.1% for surgeons. CONCLUSIONS: AFG in breast reconstruction is a promising technique. Safety is not compromised as cancer recurrence and complications are not observed. Whether AFG interferes with radiological follow-up remains to be elucidated. Randomized trials with sound methodology are needed to confirm these conclusions.

Calcium score of small coronary calcifications on multidetector computed tomography: results from a static phantom study.

INTRODUCTION: Multi detector computed tomography (MDCT) underestimates the coronary calcium score as compared to electron beam tomography (EBT). Therefore clinical risk stratification based on MDCT calcium scoring may be inaccurate. The aim of this study was to assess the feasibility of a new phantom which enables establishment of a calcium scoring protocol for MDCT that yields a calcium score comparable to the EBT values and to the physical mass. MATERIALS AND METHODS: A phantom containing 100 small calcifications ranging from 0.5 to 2.0mm was scanned on EBT using a standard coronary calcium protocol. In addition, the phantom was scanned on a 320-row MDCT scanner using different scanning, reconstruction and scoring parameters (tube voltage 80-135 kV, slice thickness 0.5-3.0mm, reconstruction kernel FC11-FC15 and threshold 110-150 HU). The Agatston and mass score of both modalities was compared and the influence of the parameters was assessed. RESULTS: On EBT the Agatston and mass scores were between 0 and 20, and 0 and 3mg, respectively. On MDCT the Agatston and mass scores were between 0 and 20, and 0 and 4 mg, respectively. All parameters showed an influence on the calcium score. The Agatston score on MDCT differed 52% between the 80 and 135kV, 65% between 0.5 and 3.0mm and 48% between FC11 and FC15. More calcifications were detected with a lower tube voltage, a smaller slice thickness, a sharper kernel and a lower threshold. Based on these observations an acquisition protocol with a tube voltage of 100 kV and two reconstructions protocols were defined with a FC12 reconstruction kernel; one with a slice thickness of 3.0mm and a one with a slice thickness of 0.5mm. This protocol yielded an Agatston score as close to the EBT as possible, but also a mass score as close to the physical phantom value as possible, respectively. CONCLUSION: With the new phantom one acquisition protocol and two reconstruction protocols can be defined which produces Agatston scores comparable to EBT values and to the physical mass.

Threshold adjusted calcium scoring using CT is less susceptible to cardiac motion and more accurate.

The purpose of this paper is to investigate calcium scoring on computed tomography (CT) using an adjusted threshold depending on the maximum Hounsfield value within the calcification (HU(peak)). The volume of 19 calcifications was retrospectively determined on 64-slice multidetector CT and dual source CT (DSCT) at different thresholds and the threshold associated with the physical volume was determined. In addition, approximately 10 000 computer simulations were done simulating the same process for calcifications with mixed density. Using these data a relation between the HU(peak) and the threshold could be established. Hereafter, this relation was assessed by scanning six calcifications in a phantom at 40-110 beats per minute using DSCT. The influence of motion was determined and the measured calcium scores were compared to the physical volumes and mass. A positive linear correlation was found between the scoring threshold and the HU(peak) of the calcifications both for the phantom measurements as for the computer simulations. Using this relation the individual threshold for each calcification could be calculated. Calcium scores of the moving calcifications determined with an adjusted threshold were approximately 30% less susceptible to cardiac motion compared to standard calcium scoring. Furthermore, these scores approximated the physical volume and mass at least 10% better than the standard calcium scores. The threshold in calcium scoring should be adjusted for each individual calcification based on the HU(peak) of the calcification. Calcium scoring using an adjusted threshold is less susceptible to cardiac motion and more accurate compared to the physical values.

64 slice MDCT generally underestimates coronary calcium scores as compared to EBT: a phantom study.

The objective of our study was the determination of the influence of the sequential and spiral acquisition modes on the concordance and deviation of the calcium score on 64-slice multi-detector computed tomography (MDCT) scanners in comparison to electron beam tomography (EBT) as the gold standard. Our methods and materials were an anthropomorphic cardio CT phantom with different calcium inserts scanned in sequential and spiral acquisition modes on three identical 64-slice MDCT scanners of manufacturer A and on three identical 64-slice MDCT scanners of manufacturer B and on an EBT system. Every scan was repeated 30 times with and 15 times without a small random variation in the phantom position for both sequential and spiral modes. Significant differences were observed between EBT and 64-slice MDCT data for all inserts, both acquisition modes, and both manufacturers of MDCT systems. High regression coefficients (0.90-0.98) were found between the EBT and 64-slice MDCT data for both scoring methods and both systems with high correlation coefficients (R2>0.94). System A showed more significant differences between spiral and sequential mode than system B. Almost no differences were observed in scanners of the same manufacturer for the Agatston score and no differences for the Volume score. The deviations of the Agatston and Volume scores showed regression dependencies approximately equal to the square root of the absolute score. The Agatston and Volume scores obtained with 64-slice MDCT imaging are highly correlated with EBT-obtained scores but are significantly underestimated (-10% to -2%) for both sequential and spiral acquisition modes. System B is more independent of acquisition mode to calcium score than system A. The Volume score shows no intramanufacturer dependency and its use is advocated versus the Agatston score. Using the same cut points for MDCT-based calcium scores as for EBT-based calcium scores can result in classifying individuals into a too low risk category. System information and scanprotocol is therefore needed for every calcium score procedure to ensure a correct clinical interpretation of the obtained calcium score results.

Epstein-Barr virus and disease activity in multiple sclerosis.

OBJECTIVES: To study in relapsing-remitting (RR) multiple sclerosis (MS) whether exacerbations and brain activity as measured by magnetic resonance imaging (MRI) are associated with plasma levels of anti-Epstein Barr (EBV) antibodies and EBV DNA. METHODS: This was a prospective study with 73 RR MS patients followed for an average of 1.7 years with frequent neurological examination and blood sampling. Antibodies to various EBV proteins were measured by ELISA and plasma EBV DNA was measured by PCR. RESULTS: All MS patients had IgG antibodies to EBV (viral capsid antigen (VCA) and/or EBV nuclear antigen (EBNA)), irrespective whether samples were taken at stable disease or exacerbation. A significantly elevated percentage of the patients (48%) had antibodies against EBV antigens (early antigen, EA) that indicate active viral replication, compared with the age matched healthy controls (25%). Antibodies against a control herpesvirus, cytomegalovirus, were similar between the two groups. The percentage of EA positive individuals and EA titres did not differ between stable disease or exacerbation. Anti-VCA IgM was positive in three cases, unrelated to disease activity. Using a highly sensitive PCR on 51 samples taken at exacerbation visits, only three patients were found to have one timepoint with viraemia, and this viraemia was unrelated to disease activity. Of special note was the fact that anti-EA seropositive patients remained seropositive during follow up, with stable titres over time. We hypothesised that these patients may constitute a subgroup with higher disease activity, due to the triggering effect of a chronic attempt of the virus to reactivate. The EA positive group did not differ from the EA negative with respect to clinical disease activity or other characteristics. However, in the EA positive group, analysis with gadolinium enhanced MRI indicated more MRI disease activity. CONCLUSIONS: There was no evidence for increased clinical disease activity in the subgroup of MS patients with serological signs of EBV reactivation. However, the observation that chronic EBV reactivation may be associated with increased inflammatory activity as assessed by gadolinium enhanced MRI lesions should be reproduced in a larger and independent dataset.

Evaluation of a multiplex reverse transcriptase PCR ELISA for the detection of nine respiratory tract pathogens.

BACKGROUND: A multiplex reverse transcription (RT) polymerase chain reaction combined with a microwell hybridization assay (m-RT-PCR-ELISA) was previously developed to detect nine different microorganisms: enterovirus (EV), influenza virus type A (IVA) and type B (IVB), respiratory syncytial virus (RSV), parainfluenzavirus type 1 (PIV1) and type 3 (PIV3), adenovirus (AV), Mycoplasma pneumoniae (Mpn), Chlamydia pneumoniae (Cpn) in a single test. These organisms do not usually colonize the respiratory tract of humans, but, if present, it may be assumed they are involved in respiratory disease. OBJECTIVES AND STUDY DESIGN: The m-RT-PCR-ELISA was tested on (i) culture supernatants of unknown contents, (ii) by determining the analytical sensitivity of 10-fold serial dilutions of culture supernatants and (iii) by determining clinical sensitivity in a retrospective study on 411 clinical specimens. The specimens were re-tested in parallel by m-RT-PCR-ELISA versus the gold standard culture and immunfluorescence, and versus individual RT-PCR. RESULTS: (i) The 9-valent m-RT-PCR-ELISA shows 83% to 100% concordant results on 103 culture supernatants containing different organisms. (ii) The analytical sensitivity was as follows: higher sensitivity of the 9-valent m-RT-PCR-ELISA in comparison to culture in the cases of PIV3, IVA and IVB (factor 10) and AV and EV (factor 100), and lower sensitivity in case of RSV and PIV1 (factor 10). (iii) The agreement with the gold standard in the kappa statistic was excellent for RSV (kappa = 0.937), IVA (kappa = 0.940), very good for PIV1 (kappa = 0.914), IVB (kappa = 0.907) and satisfactory for PIV3 (kappa = 0.410). For AV, EV and Mpn the m-RT-PCR-ELISA preliminary could be qualified as very good, based on the data derived on culture supernatants. Information about the validity for Cpn is limited. CONCLUSION: The m-RT-PCR-ELISA is a feasible, sensitive and specific method for detection of a broad spectrum of organisms. It is suitable for individual as well as epidemiological diagnosis.

New insights into onset mechanisms of atrial fibrillation and flutter after coronary artery bypass graft surgery.

OBJECTIVE: To determine by means of a monitoring study the onset mechanisms of atrial fibrillation (AF) after coronary artery bypass graft surgery (CABG). PATIENTS AND DESIGN: During elective CABG, 81 patients had one bipolar atrial and one ventricular epicardial electrode attached. These were connected to a Vitatron 900E external pacing device, which monitored the patients for four consecutive days. 12 lead ECGs were obtained if AF was clinically detected and Holter ECGs were obtained in 8 (33%) of these patients. RESULTS: 24 patients (30%) developed paroxysmal AF (50%), atrial flutter (17%), or both (33%). The number of AF episodes varied from 1-169 a day (median 5) and were usually of short duration (median 2.25 minutes). Pacemaker diagnostics showed much intrapatient and interpatient variability in onset mechanisms but the majority of AF onsets (71%) were preceded by either short runs of AF or multiple atrial extrasystoles. The final trigger was a conducted atrial extrasystole in 72% of cases. There were no bradycardic triggers. The Holter ECGs confirmed the device's data. CONCLUSIONS: The onset mechanisms of post-CABG AF are dominated by atrial extrasystoles with multiple atrial extrasystoles and short runs of AF preceding the main AF onset in the majority of cases. These results have major implications for the development of new preventive pacing algorithms.

Safety and immunogenicity of a novel recombinant subunit respiratory syncytial virus vaccine (BBG2Na) in healthy young adults.

A novel recombinant respiratory syncytial virus (RSV) subunit vaccine, designated BBG2Na, was administered to 108 healthy adults randomly assigned to receive 10, 100, or 300 microg of BBG2Na in aluminum phosphate or saline placebo. Each subject received 1, 2, or 3 intramuscular injections of the assigned dose at monthly intervals. Local and systemic reactions were mild, and no evidence of harmful properties of BBG2Na was reported. The highest ELISA and virus-neutralizing (VN) antibody responses were evident in the 100- and 300-microg groups; second or third injections provided no significant boosts against RSV-derived antigens. BBG2Na induced > or 2-fold and > or =4-fold increases in G2Na-specific ELISA units in up to 100% and 57% of subjects, respectively; corresponding RSV-A-specific responses were 89% and 67%. Furthermore, up to 71% of subjects had > or =2-fold VN titer increases. Antibody responses to 2 murine lung protective epitopes were also highly boosted after vaccination. Therefore, BBG2Na is safe, well tolerated, and highly immunogenic in RSV-seropositive adults.