Screening with the double surprise question to predict deterioration and death: an explorative study.

BACKGROUND: Early identification of palliative patients is challenging. The Surprise Question (SQ1; Would I be surprised if this patient were to die within 12 months?) is widely used to identify palliative patients. However, its predictive value is low. Therefore, we added a second question (SQ2) to SQ1: 'Would I be surprised if this patient is still alive after 12 months?' We studied the accuracy of this double surprise question (DSQ) in a general practice. METHODS: We performed a prospective cohort study with retrospective medical record review in a general practice in the eastern part of the Netherlands. Two general practitioners (GPs) answered both questions for all 292 patients aged ≥75 years (mean age 84 years). Primary outcome was 1-year death, secondary outcomes were aspects of palliative care. RESULTS: SQ1 was answered with 'no' for 161/292 patients. Of these, SQ2 was answered with 'yes' in 22 patients. Within 12 months 26 patients died, of whom 24 had been identified with SQ1 (sensitivity: 92%, specificity: 49%). Ten of them were also identified with SQ2 (sensitivity: 42%, specificity: 91%). The latter group had more contacts with their GP and more palliative care aspects were discussed. CONCLUSIONS: The DSQ appears a feasible and easy applicable screening tool in general practice. It is highly effective in predicting patients in high need for palliative care and using it helps to discriminate between patients with different life expectancies and palliative care needs. Further research is necessary to confirm the findings of this study.

Waning and boosting: on the dynamics of immune status.

The aim is to describe the distribution of immune status (as captured by antibody level) on the basis of a within-host submodel for continuous waning and occasional boosting. Inspired by Feller's fundamental work and the more recent delay equation formulation of models for the dynamics of physiologically structured populations, we derive, for given force of infection, a linear renewal equation. The solution is obtained by generation expansion, with the generation number corresponding to the number of times the individual became infected. Our main result provides a precise characterization of the stable distribution of immune status.

Immunoglobulin M, C-reactive protein and complement activation in rat hepatic ischemia-reperfusion injury.

BACKGROUND: Ischemia-reperfusion (I/R) models have shown that C-reactive protein (CRP) and immunoglobulin M (IgM) are involved in complement activation. Binding of CRP and IgM to damaged cell membranes initiates complement activation and aggravates I/R injury in various organs. However, the time course of CRP- and IgM-mediated complement activation and the relation to hepatocellular injury and inflammation in liver I/R are unknown. AIM: To evaluate the time course of IgM- and CRP-related complement activation and the relation to hepatocellular injury and inflammation in a hepatic I/R rat model. METHODS: Male Wistar rats were allocated to (1) five groups of animals exposed to 60 min of partial ischemia (70%) induced via clamping of the left segmental portal triad, followed by 0, 3, 6, 12 or 24 h of reperfusion (n = 6 in each group); (2) five groups of sham-operated animals with corresponding reperfusion times (n = 5), and (3) a control group sacrificed before ischemia (n = 5). Hepatocellular injury, inflammatory response, rat plasma CRP and IgM levels and immunohistochemical depositions of CRP, IgM and C3 were assessed for each group. RESULTS: Histopathological injury scores of hematoxylin and eosin sections of ischemic liver lobes demonstrated increasing values throughout the reperfusion time with a peak at 12 h. Plasma aminotransferases (alanine aminotransferase and aspartate aminotransferase) significantly increased after 3 h of reperfusion, peaking at 6 h (3,100 ± 800 U/l; p < 0.05). Hepatic neutrophil influx significantly increased from 3 to 6 h of reperfusion (p < 0.05) and demonstrated the highest value at 12 h (1.1 ± 0.2 U/mg of protein). Plasma IL-6 levels in the ischemia groups showed peak values after 6 h of reperfusion, decreasing significantly thereafter (p < 0.05). Plasma CRP values reached highest levels after 3 h of reperfusion (mean 91 ± 5% of control pool), decreasing significantly thereafter. Rat IgM concentrations in plasma did not significantly change throughout the reperfusion time. Immunohistochemical depositions of IgM, CRP and C3 in ischemic lobes demonstrated a similar pattern in time, reaching maximum values at 12 h of reperfusion. The percentages of depositions of CRP and IgM were significantly correlated [r(S) = 0.569; p < 0.001; Spearman test]. The time course of C3 and CRP depositions throughout reperfusion and C3 and IgM staining were significantly similar [r(S) = 0.797 and r(S) = 0.656, respectively; p < 0.0001; ANOVA]. CONCLUSIONS: CRP and IgM depositions demonstrate a parallel time course throughout the reperfusion to hepatocellular damage, inflammatory response and activated complement deposition in this rat hepatic I/R model. Furthermore, the time course of CRP and IgM depositions was significantly similar to that of activated complement depositions.

Hepatic regeneration and functional recovery following partial liver resection in an experimental model of hepatic steatosis treated with omega-3 fatty acids.

BACKGROUND: Omega-3 fatty acids (FAs) have been shown to reduce experimental hepatic steatosis and protect the liver from ischaemia-reperfusion injury. The aim of this study was to examine the effects of omega-3 FAs on regeneration of steatotic liver. METHODS: Steatosis was induced in rats by a 3-week methionine/choline-deficient diet, which was continued for an additional 2 weeks in conjunction with oral administration of omega-3 FAs or saline solution. Steatosis was graded histologically and quantified by proton magnetic resonance spectroscopy ((1) H-MRS) before and after the diet/treatment. Liver function was determined by (99m) Tc-labelled mebrofenin hepatobiliary scintigraphy (HBS). In separate experiments, the hepatic regenerative capacity and functional recovery of omega-3 FA-treated, saline-treated or non-steatotic (control) rats were investigated 1, 2, 3 and 5 days after partial (70 per cent) liver resection by measurement of liver weight change and hepatocyte proliferation (Ki-67) and HBS. RESULTS: Severe steatosis (over 66 per cent) in the saline group was reduced by omega-3 FAs to mild steatosis (less than 33 per cent), and hepatic fat content as assessed by (1) H-MRS decreased 2·2-fold. (99m) Tc-mebrofenin uptake in the saline group was more than 50 per cent lower than in the control group, confirming the functional effects of steatosis. (99m) Tc-mebrofenin uptake and regenerated liver mass were significantly greater in the omega-3 group compared with the saline group on days 1 and 3. The posthepatectomy proliferation peak response was delayed until day 2 in saline-treated rats, compared with day 1 in the omega-3 and control groups. CONCLUSION: Omega-3 FAs effectively reduced severe hepatic steatosis, which was associated with improved liver regeneration and functional recovery following partial hepatectomy.

A Multiclass Classification Model for Tooth Removal Procedures.

Surprisingly little is known about tooth removal procedures. This might be due to the difficulty of gaining reliable data on these procedures. To improve our understanding of these procedures, machine learning techniques were used to design a multiclass classification model of tooth removal based on force, torque, and movement data recorded during tooth removal. A measurement setup consisting of, among others, robot technology was used to gather high-quality data on forces, torques, and movement in clinically relevant dimensions. Fresh-frozen cadavers were used to match the clinical situation as closely as possible. Clinically interpretable variables or "features" were engineered and feature selection took place to process the data. A Gaussian naive Bayes model was trained to classify tooth removal procedures. Data of 110 successful tooth removal experiments were available to train the model. Out of 75 clinically designed features, 33 were selected for the classification model. The overall accuracy of the classification model in 4 random subsamples of data was 86% in the training set and 54% in the test set. In 95% and 88%, respectively, the model correctly classified the (upper or lower) jaw and either the right class or a class of neighboring teeth. This article discusses the design and performance of a multiclass classification model for tooth removal. Despite the relatively small data set, the quality of the data was sufficient to develop a first model with reasonable performance. The results of the feature engineering, selection process, and the classification model itself can be considered a strong first step toward a better understanding of these complex procedures. It has the potential to aid in the development of evidence-based educational material and clinical guidelines in the near future.

Muscle Fibre Typology as a Novel Risk Factor for Hamstring Strain Injuries in Professional Football (Soccer): A Prospective Cohort Study.

BACKGROUND: Hamstring strain injuries (HSI) are prevalent in team sports and occur frequently in the later phase of matches. In the search for interindividual factors that determine muscle fatigue and possibly injury risk, muscle fibre typology is a likely candidate. OBJECTIVE: The aim of the study was to determine whether muscle fibre typology is a risk factor for HSI. METHODS: A prospective cohort study was conducted over three seasons in professional football players competing in the Belgian Jupiler Pro League (n = 118) and in the English Premier League (n = 47). A total of 27 HSI were sustained during this period. Muscle fibre typology was non-invasively estimated using proton magnetic resonance spectroscopy and was characterized as a fast, slow, or intermediate typology based on the carnosine concentration in the soleus. A multivariate Cox model was used to identify risk factors for HSI. RESULTS: Football players exhibited a wide variety of muscle typologies (slow 44.9%, intermediate 39.8%, fast 15.3%). In the combined cohort, players with a fast typology displayed a 5.3-fold (95% confidence interval [CI] 1.92-14.8; P = 0.001) higher risk of sustaining an index HSI than slow typology players. This was also independently observed in both leagues separately as, respectively, a 6.7-fold (95% CI 1.3-34.1; P = 0.023) and a 5.1-fold (95% CI 1.2-20.4; P = 0.023) higher chance was found in fast typology players than in slow typology players of the Jupiler Pro League and the Premier League cohort. CONCLUSION: We identified muscle fibre typology as a novel and potent risk factor for HSI in team sports.

Increase in future remnant liver function after preoperative portal vein embolization.

BACKGROUND: Preoperative portal vein embolization (PVE) is performed in patients with insufficient future remnant liver (FRL) to allow safe resection. Although many studies have demonstrated an increase in FRL volume after PVE, little is known about the increase in FRL function. This study evaluated the increase in FRL function after PVE using (99m) Tc-labelled mebrofenin hepatobiliary scintigraphy (HBS) with single photon emission computed tomography (SPECT) and compared this with the increase in FRL volume. METHODS: In 24 patients, computed tomography volumetry and (99m) Tc-labelled mebrofenin HBS with SPECT were performed before and 3-4 weeks after PVE to measure FRL volume, standardized FRL and FRL function. A hypothetical model was used to assess safe resectability after PVE. The limit for safe resection for FRL function was set at an uptake of 2·69 per cent per min per m². For FRL volume and standardized FRL, 25 or 40 per cent of total liver volume was used, depending on the presence of underlying liver disease. RESULTS: After PVE, FRL function increased significantly more than FRL volume. The correlation between the increase in FRL volume and FRL function was poor. Using the hypothetical model, seven patients did not achieve a sufficient increase in FRL function to allow safe resection 3-4 weeks after PVE, compared with 12 and nine patients based on FRL volume and standardized FRL respectively. CONCLUSION: The increase in FRL function after PVE is more pronounced than the increase in FRL volume, suggesting that the necessary waiting time until resection may be shorter than indicated by volumetric parameters.

Predicted coverage by 4CMenB vaccine against invasive meningococcal disease cases in the Netherlands.

Neisseria meningitidis serogroup B is a major cause of invasive meningococcal disease in Europe. In the absence of a conjugate serogroup B vaccine, a subcapsular 4CMenB vaccine was developed. Data on 4CMenB vaccine efficacy is still limited. Recently, genomic MATS (Meningococcal Antigen Typing System) was developed as a tool to predict strain coverage, using vaccine antigens sequence data. We characterized all invasive meningococcal isolates received by the Netherlands Reference Laboratory for Bacterial Meningitis (NRLBM) in two epidemiological years 2017-2019 using whole-genome sequencing and determined serogroup, clonal complex (cc) and estimated 4CMenB vaccine coverage by gMATS. Of 396 cases of invasive meningococcal disease, corresponding to an incidence of 1.22 cases/105 inhabitants, 180 (45%) were serogroup W, 155 (39%) serogroup B, 46 (12%) serogroup Y, 10 (3%) serogroup C, 2 non-groupable (0.5%) and 3 (0.7%) unknown. The incidence was the highest among 0-4 years olds (4 cases/105 inhabitants), and 57/72 (79%) of these cases were serogroup B. Serogroup W predominated among persons 45 years of age or older with 110/187 (59%) cases. Serogroup B isolates comprised 11 different clonal complexes, with 103/122 (84%) isolates belonging to 4 clonal complexes: cc32, cc41/44, cc269 and cc213. In contrast, serogroup W isolates were genetically similar with 95% belonging to cc11. Of 122 serogroup B isolates, 89 (73%; 95% CI: 64-80%) were estimated to be covered by 4CMenB and the degree of coverage varied largely by clonal complex and age. Among the 0-4 year olds, 25 of 43 (58%; 95% CI: 43-72%) MenB isolates were estimated to be covered. Since the coverage of the 4CMenB vaccine is dependent on circulating clonal complexes, our findings emphasize the need for surveillance of circulating meningococcal strains. In addition, estimation of age specific coverage is relevant to determine the right target age group for vaccination.

Deletion of FMR1 in Purkinje cells enhances parallel fiber LTD, enlarges spines, and attenuates cerebellar eyelid conditioning in Fragile X syndrome.

Absence of functional FMRP causes Fragile X syndrome. Abnormalities in synaptic processes in the cerebral cortex and hippocampus contribute to cognitive deficits in Fragile X patients. So far, the potential roles of cerebellar deficits have not been investigated. Here, we demonstrate that both global and Purkinje cell-specific knockouts of Fmr1 show deficits in classical delay eye-blink conditioning in that the percentage of conditioned responses as well as their peak amplitude and peak velocity are reduced. Purkinje cells of these mice show elongated spines and enhanced LTD induction at the parallel fiber synapses that innervate these spines. Moreover, Fragile X patients display the same cerebellar deficits in eye-blink conditioning as the mutant mice. These data indicate that a lack of FMRP leads to cerebellar deficits at both the cellular and behavioral levels and raise the possibility that cerebellar dysfunctions can contribute to motor learning deficits in Fragile X patients.

Adhesive strength of fibrinogen-coated collagen patch or liquid fibrin sealant in an experimental liver resection model in pigs.

AIM: The aim of this study was to assess the efficacy of sealing bile ducts by determining the adhesive strength of 2 different sealing agents, i.e. a fibrinogen-coated collagen patch (TachoSil) and a liquid fibrin sealant (Tissucol), in an experimental partial liver resection model in pigs. METHODS: Pigs underwent laparotomy and partial resection of the left medial liver lobe. A 16-Ch silicon catheter was introduced into the common bile duct. Pigs were randomly assigned to 2 groups (n = 4 each). In group 1, TachoSil was applied on the resection surface, and in group 2 Tissucol was applied. After 2 h, pressure in the intrabiliary system was gradually increased. RESULTS: No significant differences in the hemostasis times between TachoSil and Tissucol were observed (210.0 +/- 12.9 vs. 208.8 +/- 14.2 s; p = 0.9506). The pressure that could be resisted with Tissucol was significantly lower compared to TachoSil (77.0 +/- 8.6 vs. 131.8 +/- 16.3 mm Hg; p = 0.0405). CONCLUSIONS: The application of TachoSil on the resection surface is equally effective in obtaining hemostasis and in sealing of biliary ducts as Tissucol. The adhesive strength of TachoSil on the resection surface, however, is superior to Tissucol.

Machine perfusion preservation of the pig liver using a new preservation solution, polysol.

INTRODUCTION: The current gold standard for donor liver preservation is cold storage in a preservation solution (4 degrees C), such as Celsior or the University of Wisconsin solution (UW). Recent studies have suggested the benefits of machine perfusion (MP) over cold storage. To improve the results of MP, an enriched preservation solution (named Polysol) was developed, which in a rat liver preservation model proved to be superior to the UW-gluconate solution. The aim of this study was to assess Polysol in a pig liver preservation model. MATERIALS AND METHODS: Female pigs (35 to 40 kg) were used as liver donors. After heparinization, the liver was washed out using Ringer's lactate, followed by the preservation solution (4 degrees C). The liver was preserved for 24 hours by either cold storage using Celsior (n=5) or MP using Polysol (n=5). For analysis of liver damage and function, livers were reperfused for 60 minutes using oxygenated Krebs-Henseleit buffer. RESULTS: CS-Celsior caused significantly more damage compared with MP-Polysol (t=60, AST: 622+/-215 versus 222+/-55; ALT: 17+/-6 versus 5+/-1). Intravascular resistance during reperfusion was significantly higher after CS-Celsior compared with MP-Polysol (t=0, 0.20+/-0.01 and 0.11+/-0.02 mm Hg/mL/min, respectively). No differences were seen regarding ammonia clearance and urea production. In both groups, no bile was produced during reperfusion. CONCLUSIONS: In an ex vivo pig liver preservation model significantly less damage was observed after machine perfusion preservation using Polysol, in comparison to cold storage using Celsior.

Linking the seroresponse to infection to within-host heterogeneity in antibody production.

A recently published model for the serum antibody response to infection appeared well suited for use in statistical analyses of longitudinal serological data. The published model assumed exponential decay with fixed rates for pathogen and serum antibody kinetics, ignoring any within-host heterogeneity in the seroresponse. A bi-exponential model shows that there is rapid initial decay followed by a prolonged period of persistent low serum antibody concentrations. We propose a small modification of the decay model that greatly increases its flexibility by allowing for non-exponential antibody decay. The modified model produces power functions that may be interpreted as a mixture of exponential decay curves, with a mixing distribution representing the relative contribution of many centres of antibody production to the serum antibody concentration. Fitting the power function decay model to observed longitudinal data for pertussis shows improved goodness of fit compared to the exponential decay model, with estimates for the shape parameter (r=2.2; 95% CI (1.7-2.8)) that differ from exponential shape (r=1). The power function decay model predicts more persistent antibody concentrations in the long term (symptomatic threshold reached >30 years after infection) which, when used in biomarker studies, will lead to lower estimates of seroconversion rates compared to exponential antibody decay.

High dietary fat intake and cigarette smoking as risk factors for ischaemic heart disease in Bangladeshi male immigrants in East London.

A study was made of smoking and dietary habits in middle aged Bangladeshi men living in East London to investigate possible causes of the previously described high ischaemic heart disease risk in this group. The results showed that these individuals were 50% more likely to smoke than Caucasians living in the same area, after adjusting for age and social class. More striking, however, was the very high fat intake of over 200 g/day, which is twice the national average and accounted for nearly 60% of total energy intake. Interestingly, much of the dietary fat was from vegetable oil, and the ratio of polyunsaturated to saturated fatty acids exceeded the accepted recommended minimum.

Embryonic loss from 30 to 60 days post breeding and the effect of palpation per rectum on pregnancy.

This study was conducted over a 12-mo period to determine the rate of bovine embryo death between 30 and 60 d of gestation. In addition, palpation per rectum as a means of pregnancy detection was evaluated as a possible cause of embryo death. Estrus was synchronized in Holstein heifers (n = 1358), weighing > or = 385 kg, with a single intramuscular injection of 25 mg prostaglandin F(2alpha). Estrus was primarily detected by the absence of paint marks on the tailhead. The heifers were artificially inseminated with semen from 5 Holstein sires. Blood was collected between 30 and 45 d after breeding, and sera were evaluated for the presence of bovine pregnancy-specific protein B (bPSPB) by RIA to determine pregnancy. Palpation for fetal membrane slip was conducted by an experienced technician in approximately one-half of the inseminated heifers. To determine embryonic survival, a second blood sample was collected at approximately 60 d from 862 heifers that were determined to be pregnant at the first blood sampling. Embryonic loss averaged 5.3% during the interval between the initial detection of pregnancy at 30 to 45 d and the subsequent detection of pregnancy at 60 d of gestation. Embryo loss in heifers that were palpated was 6.5% compared with that of 4.3% in the control heifers (X(2): P = 0.145). These findings establish that there was substantial loss of embryos between 30 and 60 d post breeding but that embryo loss was not affected by palpation per rectum.

A two-phase within-host model for immune response and its application to serological profiles of pertussis.

We present a simple phenomenological within-host model describing both the interaction between a pathogen and the immune system and the waning of immunity after clearing of the pathogen. We implement the model into a Bayesian hierarchical framework to estimate its parameters for pertussis using Markov chain Monte Carlo methods. We show that the model captures some essential features of the kinetics of titers of IgG against pertussis toxin. We identify a threshold antibody level that separates a large increase in antibody level upon infection from a small increase and accordingly might be interpreted as a threshold separating clinical from subclinical infections. We contrast predictions of the model with observations reported in the literature and based on independent data and find a remarkable correspondence.

Portal vein embolization before liver resection: a systematic review.

PURPOSE: This is a review of literature on the indications, technique, and outcome of portal vein embolization (PVE). METHODS: A systematic literature search on outcome of PVE from 1990 to 2011 was performed in Medline, Cochrane, and Embase databases. RESULTS: Forty-four articles were selected, including 1,791 patients with a mean age of 61 ± 4.1 years. Overall technical success rate was 99.3 %. The mean hypertrophy rate of the FRL after PVE was 37.9 ± 0.1 %. In 70 patients (3.9 %), surgery was not performed because of failure of PVE (clinical success rate 96.1 %). In 51 patients (2.8 %), the hypertrophy response was insufficient to perform liver resection. In the other 17 cases, 12 did not technically succeed (0.7 %) and 7 caused a complication leading to unresectability (0.4 %). In 6.1 %, resection was cancelled because of local tumor progression after PVE. Major complications were seen in 2.5 %, and the mortality rate was 0.1 %. A head-to-head comparison shows a negative effect of liver cirrhosis on hypertrophy response. The use of n-butyl cyanoacrylate seems to have a greater effect on hypertrophy, but the difference with other embolization materials did not reach statistical significance. No difference in regeneration is seen in patients with cholestasis or chemotherapy. CONCLUSIONS: Preoperative PVE has a high technical and clinical success rate. Liver cirrhosis has a negative effect on regeneration, but cholestasis and chemotherapy do not seem to have an influence on the hypertrophy response. The use of n-butyl cyanoacrylate may result in a greater hypertrophy response compared with other embolization materials used.

Multicontrast MR imaging at 7T in multiple sclerosis: highest lesion detection in cortical gray matter with 3D-FLAIR.

BACKGROUND AND PURPOSE: 7T MR imaging has led to improved detection and classification of cortical MS lesions, mainly based on T2*-weighted gradient-echo sequences. Depiction of cortical GM by using the recommended MS imaging protocol has not yet been investigated at 7T. We aimed to investigate prospectively which recommended sequence for clinical use has the highest value at 7T, in terms of GM and WM lesion detection. MATERIALS AND METHODS: Thirty-seven patients with MS (mean age, 43.8 years; 25 women) and 7 healthy controls (mean age, 40.4 years; 5 women) underwent multicontrast 7T MR imaging including the recommended clinical 2D-T2WI, 3D-T1WI, 3D-FLAIR, and GM-specific 3D-DIR. Lesions were scored and categorized anatomically by 3 raters, in consensus. The value of sequences was evaluated lesion-wise and patient-wise (Wilcoxon signed-rank test). RESULTS: At 7T, 3D-FLAIR detected the highest number of total cortical GM lesions (217), 89% more than 3D-DIR and 87% and 224% more than 2D-T2WI and 3D-T1WI. Patient-wise analysis showed that this difference between 3D-FLAIR and 3D-DIR was statistically significant (P<.04), and most pronounced for the number of mixed lesions (P<.03). 3D-FLAIR also detected the highest number of total WM lesions (2605), but the difference with 3D-DIR and 3D-T1WI was not significant. CONCLUSIONS: When using recommended clinical sequences at 7T, the best way to detect cortical GM lesions is with 3D-FLAIR and not by GM-specific 3D-DIR or by conventional 2D-T2WI and 3D-T1WI sequences.

On the formulation of epidemic models (an appraisal of Kermack and McKendrick).

The aim of this paper is to show that a large class of epidemic models, with both demography and non-permanent immunity incorporated in a rather general manner, can be mathematically formulated as a scalar renewal equation for the force of infection.