Aetiology of cerebrospinal fluid rhinorrhoea in a Dutch retrospective cohort from two tertiary referral centres.

BACKGROUND: Cerebrospinal fluid (CSF) rhinorrhoea has different aetiologies, with spontaneous leaks related to female gender and obesity. Limited data is available on patient characteristics and surgical outcomes across different aetiologies of CSF leaks in relatively non-obese populations. METHODS: Retrospective cohort study from two tertiary referral centres including adult patients that underwent surgical closure of a CSF leak, divided into four aetiologies: traumatic, iatrogenic, secondary to structural intracranial pathology (SIP), and spontaneous. Data included patient characteristics, presenting symptoms, preoperative radiologic findings, intracranial pressure (ICP) and surgical outcomes. RESULTS: 72 patients were included: 9 traumatic, 15 iatrogenic, 4 SIP and 44 spontaneous leaks. Primary surgical success was 79%, rising to 93% with reinterventions. Spontaneous leak cases displayed highest female proportion and BMI. A meningo(-encephalo)cele was present in 33 patients and was associated with surgical failure and previous meningitis. No significant differences were observed between different aetiologies regarding patient characteristics, presenting symptoms, or surgical success rates. CONCLUSIONS: Even in a relatively non-obese population, the majority of CSF leaks is spontaneous and associated with female gender and obesity. Otherwise, no differences exist across aetiologies regarding patient characteristics, presenting symptoms or surgical success.

Low-noise φ-OTDR employing nonlinear optical preamplification for distributed acoustic sensing.

A phase sensitive optical time domain reflectometry sensing scheme employing a two-stage nonlinear optical preamplification system is proposed to reduce the blind spot effect in Rayleigh scattering by improving the optical power distribution and to enhance the resolution at locations of low-backscatter intensity measurements, providing a higher signal-to-noise ratio for distributed acoustic measurements; the developed system has been tested in-laboratory and on in-field monitoring of a survey well in Cottessen, The Netherlands. The characterization shows strain noise levels below 1 nɛ for a 10 kHz sampling rate.

NWChem: Past, present, and future.

Specialized computational chemistry packages have permanently reshaped the landscape of chemical and materials science by providing tools to support and guide experimental efforts and for the prediction of atomistic and electronic properties. In this regard, electronic structure packages have played a special role by using first-principle-driven methodologies to model complex chemical and materials processes. Over the past few decades, the rapid development of computing technologies and the tremendous increase in computational power have offered a unique chance to study complex transformations using sophisticated and predictive many-body techniques that describe correlated behavior of electrons in molecular and condensed phase systems at different levels of theory. In enabling these simulations, novel parallel algorithms have been able to take advantage of computational resources to address the polynomial scaling of electronic structure methods. In this paper, we briefly review the NWChem computational chemistry suite, including its history, design principles, parallel tools, current capabilities, outreach, and outlook.

Association of vitamin B12, methylmalonic acid, and functional parameters.

INTRODUCTION: Diagnosis of vitamin B12 deficiency is difficult, as there is no conclusive single test for this disorder. We evaluated the association of serum B12 and methylmalonic acid (MMA) with haematologic parameters and physical and cognitive functioning in an effort to use such clinical parameters to improve the interpretation of serum values. METHODS: We used data of participants > 19 years of age from NHANES 2011-2012 and 2013-2014, a cross-sectional survey in the United States. Functional status was assessed with questionnaires on current health condition, disability, hospital utilisation, cognitive functioning, mental health and depression, and physical functioning. Muscle strength assessed with a handgrip dynamometer was used as a performance parameter. Results were evaluated both for the entire population and participants of Western European descent. Because renal function influences MMA concentrations and is a proxy for both frailty and comorbidity, all results were additionally stratified for individuals with normal vs impaired renal function (eGFR < 60 ml/min). RESULTS: In total, data of 9645 participants (mean age 49 (SD 17) years, 49.3% males) were included. Out of all participants with serum B12 < 140, 140-300, and 301-1000 pmol/l, 56.2%, 13.5%, and 4.1%, respectively had elevated MMA. MMA concentrations were more strongly associated with poor functional status and physical performance than serum B12. We identified a significant and independent association of MMA concentrations, as well as haemoglobin and co-morbidity with muscle strength. CONCLUSIONS/INTERPRETATIONS: A large proportion of individuals with a decreased serum B12 concentration still has normal MMA concentrations. Elevated MMA concentrations were more strongly associated with poor functional performance than serum B12.

Guidelines on the benefit-risk assessment of the presence of phthalates in certain medical devices covering phthalates which are carcinogenic, mutagenic, toxic to reproduction (CMR) or have endocrine-disrupting (ED) properties.

By the new Medical Device Regulation (MDR, EU 2017/745) the use of certain phthalates which are carcinogenic, mutagenic, toxic to reproduction (CMR) or have endocrine-disrupting (ED) properties, above 0.1% by weight (w/w) is only allowed after a proper justification. The SCHEER provide Guidelines on the benefit-risk assessment (BRA) of the presence of such phthalates in certain medical devices. The Guidelines describe the methodology on how to perform a BRA for the justification of the presence of CMR/ED phthalates in medical devices and/or or parts or materials used therein at percentages above 0.1% w/w. They also describe the evaluation of possible alternatives for these phthalates used in medical devices, including alternative materials, designs or medical treatments. Relevant stakeholders e.g. manufacturers, notified bodies and regulatory bodies, can use the guidelines. The approach of these guidelines may also be used for a BRA of other CMR/ED substances present in medical devices. SCHEER noticed that a number of BRA methodologies are theoretically available. However, there is a considerable lack of data needed for the BRA for potential relevant alternatives to be used in medical devices. Therefore, SCHEER encourages manufacturers to generate data of high quality on such alternatives for CMR/ED phthalates in medical devices.

Exceptional response of brain metastases to short course nivolumab while on high-dose steroids.

In this manuscript, we describe a patient with an exceptional response of brain metastases from lung cancer to short course nivolumab while on high-dose steroids. This case shows that immunotherapy can cause delayed and enduring responses even in patients with poor predictive parameters for treatment success, such as low programmed death ligand-1 (PDL1) expression and long-term treatment with high-dose corticosteroids. Secondly, it underscores the importance of follow up after the administration of immunotherapy, even in cases with a deemed poor prognosis and few received cycles of immunotherapy.

Dutch healthcare professionals' opinion on vaccination and education to prevent infections in immunocompromised patients: A mixed-method study with recommendations for daily practice.

BACKGROUND: The fast-growing population of immunocompromised patients (ICP) is more vulnerable to infectious diseases, demanding strategies to protect them. These strategies seem inconsistent in available guidelines and in practices. We aim to evaluate healthcare professionals' (HCP) opinions on vaccination to reduce the number and severity of infections in ICP. METHODS: A mixed-method study, with an exploratory sequential design, was performed. Medical specialists from various departments in a tertiary care center in the Netherlands were invited for semi-structured interviews to explore their perspective on preventive care of ICP. Topics that play a substantial role in daily practice for ICP were translated into a survey to gain insight into what extent opinions were generalizable to Erasmus Medical Center. RESULTS: Surveys were completed by 689 HCP (43% of the invitees), 269 of them treated at least two ICP weekly on average and were considered eligible for further analysis. Quantitative data showed that according to 80 percent of HCP, preventive care for ICP can be improved. Education was chosen by 40 percent as the most important intervention to reduce the number and severity of infections. Vaccinations were valued as important by seventeen percent of HCP. Except for influenza, vaccinations were not regularly discussed during routine consultations. Difficulties to administer vaccinations were experienced by 75 percent of HCP. CONCLUSION: According to our respondents, education is the most promising intervention to reduce the number and severity of infections in ICP. To reach a higher vaccine uptake, we recommend HCP to address vaccinations more frequently during consultations and to search for solutions to alleviate barriers to vaccinate.

Intradiscal delivery of celecoxib-loaded microspheres restores intervertebral disc integrity in a preclinical canine model.

Low back pain, related to degeneration of the intervertebral disc (IVD), affects millions of people worldwide. Clinical studies using oral cyclooxygenase-2 (COX-2) inhibitors have shown beneficial effects, although side-effects were reported. Therefore, intradiscal delivery of nonsteroidal anti-inflammatory drugs can be an alternative treatment strategy to halt degeneration and address IVD-related pain. In the present study, the controlled release and biologic potency of celecoxib, a selective COX-2 inhibitor, from polyesteramide microspheres was investigated in vitro. In addition, safety and efficacy of injection of celecoxib-loaded microspheres were evaluated in vivo in a canine IVD degeneration model. In vitro, a sustained release of celecoxib was noted for over 28 days resulting in sustained inhibition of inflammation, as indicated by decreased prostaglandin E2 (PGE2) production, and anti-catabolic effects in nucleus pulposus (NP) cells from degenerated IVDs on qPCR. In vivo, there was no evidence of adverse effects on computed tomography and magnetic resonance imaging or macroscopic evaluation of IVDs. Local and sustained delivery of celecoxib prevented progression of IVD degeneration corroborated by MRI, histology, and measurement of NP proteoglycan content. Furthermore, it seemed to harness inflammation as indicated by decreased PGE2 tissue levels and decreased neuronal growth factor immunopositivity, providing indirect evidence that local delivery of a COX-2 inhibitor could also address pain related to IVD degeneration. In conclusion, intradiscal controlled release of celecoxib from polyesteramide microspheres prevented progression of IVD degeneration both in vitro and in vivo. Follow-up studies are warranted to determine the clinical efficacy of celecoxib-loaded PEAMs in chronic back pain.

Polypharmacology Within the Full Kinome: a Machine Learning Approach.

Protein kinases generate nearly a thousand different protein products and regulate the majority of cellular pathways and signal transduction. It is therefore not surprising that the deregulation of kinases has been implicated in many disease states. In fact, kinase inhibitors are the largest class of new cancer therapies. Understanding polypharmacology within the full kinome, how drugs interact with many different kinases, would allow for the development of safer and more efficacious cancer therapies. A full understanding of these interactions is not experimentally feasible making highly accurate computational predictions extremely useful and important. This work aims at making a machine learning model useful for investigating the full kinome. We evaluate many feature sets for our model and get better performance over molecular docking with all of them. We demonstrate that you can achieve a nearly 60% increase in success rate at identifying binding compounds using our model over molecular docking scores.

Out-of-hospital cardiac arrest: the prospect of E-CPR in the Maastricht region.

AIM: The current outcome of out-of-hospital cardiac arrest (OHCA) patients in the Maastricht region was analysed with the prospect of implementing extracorporeal cardiopulmonary resuscitation (E-CPR). METHODS: A retrospective analysis of adult patients who were resuscitated for OHCA during a 24-month period was performed. RESULTS: 195 patients (age 66 [57-75] years, 82 % male) were resuscitated for OHCA by the emergency medical services and survived to admission at the emergency department. Survival to hospital discharge was 46.2 %. Notable differences between non-survivors and survivors were observed and included: age (70 [58-79] years) vs. (63 [55-72] years, p = 0.01), chronic heart failure (18 vs. 7 %, p = 0.02), shockable rhythm (67 vs. 99 %, p < 0.01), and return of spontaneous circulation (ROSC) at departure from the site of the arrest (46 vs. 99 %, p < 0.01) and on arrival to the emergency department (43 vs. 98 %, p < 0.01), respectively. Acute coronary syndrome was diagnosed in 32 % of non-survivors vs. 59 % among survivors, p < 0.01. Therapeutic hypothermia was provided in non-survivors (20 %) vs. survivors (43 %), p < 0.01. Percutaneous coronary intervention (PCI) was performed in 14 % of non-survivors while 52 % of survivors received PCI (p < 0.01). No statistical significance was observed in terms of gender, witnessed arrest, bystander CPR, or automated external defibrillator deployed among the cohort. At hospital discharge, moderately severe neurological disability was present in six survivors. CONCLUSION: These observations are compatible with the notion that a shockable rhythm, ROSC, and post-arrest care improve survival outcome. Potentially, initiating E-CPR in the resuscitation phase in patients with a shockable rhythm and no ROSC might serve as a bridge to definite treatment and improve survival outcome.

The effect of acute alcohol intoxication on gut wall integrity in healthy male volunteers; a randomized controlled trial.

The aim of the study is to determine the effect of acute alcohol consumption on enterocytes. Chronic alcohol consumption has been known to induce a decrease in gut wall integrity in actively drinking alcoholics and patients with alcohol-induced liver disease. Data on the extent of the damage induced by acute alcohol consumption in healthy human beings is scarce. Studies show that heavy incidental alcohol consumption is a growing problem in modern society. Data on this matter may provide insights into the consequences of this behavior for healthy individuals. In a randomized clinical trial in crossover design, 15 healthy volunteers consumed water one day and alcohol the other. One blood sample was collected pre-consumption, five every hour post-consumption, and one after 24 h. Intestinal fatty acid binding protein (I-FABP) was used as a marker for enterocyte damage. Liver fatty acid binding protein (L-FABP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT) were used as markers for hepatocyte damage. Lipopolysaccharide binding protein (LBP) and soluble CD14 (sCD14) were used as a measure of translocation. Interleukin-6 (IL-6) was used to assess the acute inflammatory response to endotoxemia. Alcohol consumption caused a significant increase in serum I- and L-FABP levels, compared to water consumption. Levels increased directly post-consumption and decreased to normal levels within 4 h. LBP, sCD14, and IL-6 levels were not significantly higher in the alcohol group. Moderate acute alcohol consumption immediately damages the enterocyte but does not seem to cause endotoxemia.

Ion chromatography for the precise analysis of chloride and sodium in sweat for the diagnosis of cystic fibrosis.

BACKGROUND: Measurement of chloride in sweat is an essential part of the diagnostic algorithm for cystic fibrosis. The lack in sensitivity and reproducibility of current methods led us to develop an ion chromatography/high-performance liquid chromatography (IC/HPLC) method, suitable for the analysis of both chloride and sodium in small volumes of sweat. METHODS: Precision, linearity and limit of detection of an in-house developed IC/HPLC method were established. Method comparison between the newly developed IC/HPLC method and the traditional Chlorocounter was performed, and trueness was determined using Passing Bablok method comparison with external quality assurance material (Royal College of Pathologists of Australasia). RESULTS: Precision and linearity fulfill criteria as established by UK guidelines are comparable with inductively coupled plasma-mass spectrometry methods. Passing Bablok analysis demonstrated excellent correlation between IC/HPLC measurements and external quality assessment target values, for both chloride and sodium. With a limit of quantitation of 0.95 mmol/L, our method is suitable for the analysis of small amounts of sweat and can thus be used in combination with the Macroduct collection system. CONCLUSIONS: Although a chromatographic application results in a somewhat more expensive test compared to a Chlorocounter test, more accurate measurements are achieved. In addition, simultaneous measurements of sodium concentrations will result in better detection of false positives, less test repeating and thus faster and more accurate and effective diagnosis. The described IC/HPLC method, therefore, provides a precise, relatively cheap and easy-to-handle application for the analysis of both chloride and sodium in sweat.

Plasma levels of free metanephrines and 3-methoxytyramine indicate a higher number of biochemically active HNPGL than 24-h urinary excretion rates of catecholamines and metabolites.

CONTEXT: A substantial number of patients with head and neck paragangliomas (HNPGLs) have biochemically active tumors, evidenced by increased urinary excretion of catecholamines and metabolites, including 3-methoxytyramine (3MT). It is unclear whether plasma levels of these parameters are more sensitive to detect biochemical activity in HNPGL patients than urinary excretion rates. OBJECTIVE: To compare plasma free levels vs urinary excretion rates of deconjugated 3MT and combined metanephrines (MNs) in patients with HNPGL. PATIENTS AND METHODS: We included 124 consecutive patients with HNPGL for screening of catecholamine excess by measurement of 24-h urinary excretion rates of deconjugated (nor)metanephrine, (nor)epinephrine, dopamine, vanillylmandelic acid, 3MT, and plasma free levels of (nor)metanephrine and 3MT. RESULTS: Plasma free 3MT levels were increased in 35 of the 124 patients (28%), whereas 24-h urinary excretion of deconjugated 3MT was increased in 30 patients (24%) (P=0.13). Plasma free MN levels were increased in seven patients (6%) and urinary deconjugated MN levels in six patients (5%) (P=1.00). Plasma free normetanephrine (NMN) levels were increased in seven patients (6%), and five patients had increased urinary excretion of deconjugated NMN (4%) (P=0.69). Plasma free combined MN levels (NMN, MN, and 3MT) were increased in 41 patients (33%), whereas 24-h urinary excretion rates of deconjugated combined MNs were increased in 33 patients (27%, P<0.05). CONCLUSIONS: The combined levels of free MNs and free 3MT in plasma indicate a higher number of biochemically active HNPGLs than the 24-h urinary excretion rates of these markers.

Furfural degradation in a dilute acidic and saline solution in the presence of glucose.

A kinetic study has been performed on the degradation of furfural in a dilute acidic and saline solution with and without the presence of glucose. Experiments have been performed in a stirred batch reactor. The degradation of furfural alone was accurately predicted both using a first- and a second-order kinetic model. It was shown that furfural is degrading significantly faster when glucose is present in the reaction mixture. In the series with glucose present distinct second-order reaction kinetics were observed. From experiments with varying concentrations of glucose it turned out that an additional (second-order) reaction had to be added to the reaction mechanism in order to satisfactorily predict the experimental data. This additional reaction incorporated the initial glucose concentration as a constant in the Arrhenius expression for the reaction rate constant. Furthermore, it has been argued that this second-order reaction could well be a Diels-Alder reaction.

Variation of the mineral density in cortical bone may serve to keep strain amplitudes within a physiological range.

Within-bone variation in mineral density could be functional. A heterogeneous mineral-density distribution might serve to maintain habitual amplitudes of bone strain within a non-harmful, i.e., physiological range. Regions of a bone that would be strained the most on the basis of architecture alone might have a higher mineral density to make them more stiff and resistant to strain. We hypothesised that the cortical bone of the rabbit mandible contains such a functional distribution of mineral density. We thereby expected similar mineral-density patterns in the mandibles of different individuals due to the shared masticatory function. Secondly, we hypothesised that the highest mineral densities occur in mandibular regions predicted to be exposed to the largest amplitudes of strain-when taking into account bone architecture only. Mineral-density maps of the cortical bone of rabbit mandibles were obtained using micro-computed tomography (µCT). The µCT scans of two rabbits were converted into finite-element models (FEMs). To predict mandibular deformation during biting, these models were loaded by muscle forces and reaction forces. The forces acted on the condyles and on either the incisal or molar bite point. The FEMs were assigned a homogeneous material stiffness to calculate the strain amplitudes that would occur when only the architecture of the mandibular bone would be of influence. We found the cortical bone-mineral density patterns to be similar in all six mandibles. The mineral density of the corpus was higher than that of the ramus. A second consistent feature of the mandibular mineral-density distribution was that the medial ridge of the temporal-muscle insertion groove contained more mineral than its surrounding regions. The strain amplitudes calculated with the FEMs were variable and did not feature clear corpo-ramal differences. However, specific mandibular bone sites calculated to be exposed to the largest amplitudes of strain, including the medial ridge of the temporal-muscle insertion groove, did correspond with high-mineral-density regions. We conclude that, in the rabbit mandible, the heterogeneous mineral-density distribution might serve to suppress bone-strain amplitudes in regions architecturally susceptible to the largest deformations during loading.

Furfural formation from d-xylose: the use of different halides in dilute aqueous acidic solutions allows for exceptionally high yields.

Starting from the results achieved in a previous work on the effects of Cl(-) ions on furfural formation in aqueous acid solution [Marcotullio, G. et al., Green Chem.2010, 12, 1739], the general effect of different halides is addressed. Experimental results show the halides to influence at least two distinct steps in the reaction leading from d-xylose to furfural under acidic conditions, via different mechanisms. The nucleophilicity of the halides appears to be critical for the dehydration, but not for the initial enolization reaction. By combining different halides synergic effects become evident resulting in very high selectivities and furfural yields.

The role of masticatory muscles in the continuous loading of the mandible.

Muscles are considered to play an important role in the ongoing daily loading of bone, especially in the masticatory apparatus. Currently, there are no measurements describing this role over longer periods of time. We made simultaneous and wireless in vivo recordings of habitual strains of the rabbit mandible and masseter muscle and digastric muscle activity up to ∼25 h. The extent to which habitually occurring bone strains were related to muscle-activity bursts in time and in amplitude is described. The data reveal the masseter muscle to load the mandible almost continuously throughout the day, either within cyclic activity bouts or with thousands of isolated muscle bursts. Mandibular strain events rarely took place without simultaneous masseter activity, whereas the digastric muscle only played a small role in loading the mandible. The average intensity of masseter-muscle activity bouts was strongly linked to the average amplitude of the concomitant bone-strain events. However, individual pairs of muscle bursts and strain events showed no relation in amplitude within cyclic loading bouts. Larger bone-strain events, presumably related to larger muscle-activity levels, had more constant principal-strain directions. Finally, muscle-to-bone force transmissions were detected to take place at frequencies up to 15 Hz. We conclude that in the ongoing habitual loading of the rabbit mandible, the masseter muscle plays an almost non-stop role. In addition, our results support the possibility that muscle activity is a source of low-amplitude, high-frequency bone loading.

Blunt splenic trauma in children: are we too careful?

INTRODUCTION: There has been a shift from operative treatment (OT) to non-operative treatment (NOT) of splenic injury. We evaluated the outcomes of treatment of pediatric patients with blunt splenic trauma in our hospital, with special focus on the outcomes after NOT. PATIENTS AND METHODS: The data of all patients <18 years with radiologically proven blunt splenic injury admitted between 1988 and 2007 were retrospectively analyzed. Mechanism of injury, type of treatment, ICU stay, total hospital stay, morbidity and mortality were assessed. Patients suffering isolated splenic injuries were assessed separately from patients with multiple injuries. Patients were subsequently divided into those admitted before and after 2000. RESULTS: There were 64 patients: 49 males and 15 females with a mean age of 13 years (range 0-18). 3 patients died shortly after admission due to severe neurological injury and were excluded. In the remaining 61 patients concomitant injuries, present in 62%, included long bone fractures (36%), chest injuries (16%), abdominal injuries (33%) and head injuries (30%). Mechanisms of injury were: car accidents (26%), motorcycle (20%), bicycle (19%), fall from height (17%) and pedestrians struck by a moving vehicle (8%). A change in treatment strategy was evident for the pre- and post-2000 periods. Significantly more patients had NOT after 2000 in both the isolated splenic injury group and the multi-trauma group [4/11 (36%) before vs. 10/11 (91%) after (p=0.009); 15/19 (79%) before vs. 8/20 (40%) after 2000 (p=0.03)]. There was also a significant shift to spleen-preserving operations. All life-threatening complications occurred within <24 h after injury. Mortality for the entire cohort was 7%; all of these patients were treated operatively. When comparing the median ICU and hospital stay before and after 2000 it was found to be significantly higher in the isolated injury group and remained statistically the same in the multi-trauma group. CONCLUSION: Splenic injury in children is associated with substantial mortality. This is due to concomitant injuries and not to the splenic injury. Non-operative treatment is increasingly preferred to operative procedures when treating splenic injuries in hemodynamically, stable children. ICU and hospital stay have, despite the change from OT to NOT, remained the same. Complications after NOT are rare. We are still observing children in hospital for a longer period than is necessary.

Selective production of hemicellulose-derived carbohydrates from wheat straw using dilute HCl or FeCl3 solutions under mild conditions. X-ray and thermo-gravimetric analysis of the solid residues.

The present work explores the combined production of hemicellulose-derived carbohydrates and an upgraded solid residue from wheat straw using a dilute-acid pretreatment at mild temperature. Dilute aqueous HCl solutions were studied at temperatures of 100 and 120°C, and they were compared to dilute FeCl(3) under the same conditions. Comparable yields of soluble sugars and acetic acid were obtained, affording an almost complete removal of pentoses when using 200 mM aqueous solutions at 120°C. The solid residues of pretreatment were characterized showing a preserved crystallinity of the cellulose, and a almost complete removal of ash forming matter other than Si. Results showed upgraded characteristic of the residues for thermal conversion applications compared to the untreated wheat straw.