Comparison of haemodynamic- and electroencephalographic-monitored effects evoked by four combinations of effect-site concentrations of propofol and remifentanil, yielding a predicted tolerance to laryngoscopy of 90.

This prospective study evaluates haemodynamic and electroencephalographic effects observed when administering four combinations of effect-site concentrations of propofol (CePROP) and remifentanil (CeREMI), all yielding a single predicted probability of tolerance of laryngoscopy of 90% (PTOL = 90%) according to the Bouillon interaction model. We aimed to identify combinations of CePROP and CeREMI along a single isobole of PTOL that result in favourable hypnotic and haemodynamic conditions. This knowledge could be of advantage in the development of drug advisory monitoring technology. 80 patients (18-90 years of age, ASA I-III) were randomized into four groups and titrated towards CePROP (Schnider model, ug⋅ml-1) and CeREMI (Minto model, ng⋅ml-1) of respectively 8.6 and 1, 5.9 and 2, 3.6 and 4 and 2.0 and 8. After eleven minutes of equilibration, baseline measurements of haemodynamic endpoints and bispectral index were compared with three minutes of responsiveness measurements after laryngoscopy. Before laryngoscopy, bispectral index differed significantly (p < 0.0001) between groups in concordance with CePROP. Heart rate decreased with increasing CeREMI (p = 0.001). The haemodynamic and arousal responses evoked by laryngoscopy were not significantly different between groups, but CePROP = 3.6 µg⋅ml-1 and CeREMI = 4 ng⋅ml-1 evoked the lowest median value for ∆HR and ∆SAP after laryngoscopy. This study provides clinical insight on the haemodynamic and hypnotic consequences, when a model based predicted PTOL is used as a target for combined effect-site controlled target- controlled infusion of propofol and remifentanil. Heart rate and bispectral index were significantly different between groups despite a theoretical equipotency for PTOL, suggesting that each component of the anaesthetic state (immobility, analgesia, and hypnotic drug effect) should be considered as independent neurophysiological and pharmacological phenomena. However, claims of (in)accuracy of the predicted PTOL must be considered preliminary because larger numbers of observations are required for that goal.

Patient and physician satisfaction in an observational study with methyl aminolevulinate daylight photodynamic therapy in the treatment of multiple actinic keratoses of the face and scalp in six European countries.

BACKGROUND: Guidelines recommend treating actinic keratoses (AKs) as they are recognized as precursors of invasive squamous cell carcinoma. OBJECTIVE: The objective of this study was to collect real-world clinical data on the use of methyl aminolevulinate daylight photodynamic therapy (MAL DL-PDT) for the treatment of face and scalp AK in Europe. METHODS: A prospective, multicenter, non-interventional study was conducted in six European countries in patients receiving a single treatment of MAL DL-PDT for face and/or scalp AK. Patient-reported outcomes were assessed by patient questionnaires at baseline and at 3 months after treatment, efficacy was assessed at 3 months using a 6-point global improvement scale, and adverse events (AE) were recorded at each visit. RESULTS: Overall, 325 patients were enrolled from 52 investigational centres, 314 of whom attended the 3-month visit. Most patients had multiple lesions (58.4% had >10 lesions) with lesions mainly located on the scalp (60.0%) and/or forehead (54.2%). AKs were predominantly grade I (39.4%) or grade II (33.2%), and 10.5% of patients had grade III lesions. The proportions of patients and physicians that were overall satisfied to very satisfied with the MAL DL-PDT treatment were 80.4% and 90.3%, respectively. The vast majority of patients (90.0%) would consider using MAL DL-PDT again if needed. Physician-assessed efficacy at 3 months was at least much improved in 83.5% of patients, with 45.9% of patients requiring no retreatment. Related AEs were reported in 15% of patients. CONCLUSION: Use of MAL DL-PDT for multiple face and/or scalp AKs resulted in high levels of patient and physician satisfaction in clinical practice in Europe, reflecting the good efficacy and high tolerability of this convenient procedure.

Daylight photodynamic therapy with methyl aminolevulinate cream is effective and nearly painless in treating actinic keratoses: a randomised, investigator-blinded, controlled, phase III study throughout Europe.

BACKGROUND: Unmet needs exist in actinic keratosis (AK) treatment. Daylight photodynamic therapy (DL-PDT) has shown good efficacy and safety results compared to conventional PDT (c-PDT) in a recent Phase III multi-centre randomised controlled trial in Australia among 100 subjects with AKs. OBJECTIVES: Demonstrate non-inferior efficacy and superior safety of DL-PDT compared to c-PDT in treating multiple mild and/or moderate facial/scalp AKs. METHODS: Phase III, 12 week, multi-centre, randomised, investigator-blinded, controlled, intra-individual study conducted at different latitudes in Europe. AKs of adult subjects were treated once with methyl aminolevulinate (MAL) DL-PDT on one side of the face and MAL c-PDT contralaterally. Endpoints for DL-PDT concerned efficacy (non-inferiority regarding complete lesion response at week 12) and safety (superiority regarding subject's assessment of pain after treatment, on an 11-point numeric rating scale). Safety evaluation also included incidence of adverse events. Subject satisfaction was described using a questionnaire at baseline and last visit. RESULTS: At week 12, the total lesion complete response rate with DL-PDT was similar (non-inferior) to c-PDT (70% vs. 74%, respectively; 95% CI [-9.5; 2.4] in PP analysis, confirmed in ITT analysis). In addition, efficacy of DL-PDT was demonstrated regardless of weather conditions (sunny or cloudy). DL-PDT was nearly painless compared to c-PDT (0.7 vs. 4.4, respectively; P < 0.001), better tolerated and resulted in higher subject satisfaction. CONCLUSION: DL-PDT in comparison with c-PDT was as effective, better tolerated and nearly painless with high patient satisfaction, and may be considered a treatment of choice to meet needs of patients with mild or moderate facial/scalp AKs.

Effectiveness and safety of fumaric acid esters in children with psoriasis: a retrospective analysis of 14 patients from The Netherlands.

BACKGROUND: Fumaric acid esters (FAE) are used as an effective and safe oral treatment for plaque psoriasis in adult patients, but little is known about their efficacy and safety in children with psoriasis. OBJECTIVES: To assess the effectiveness and safety of FAE in the treatment of paediatric psoriasis. METHODS: This is a retrospective analysis of 14 paediatric patients with psoriasis (age <18 years) treated with FAE between 2004 and 2012 at several Dutch university and regional clinics. Patients were identified through databases or registries. RESULTS: The median age at the start of FAE treatment was 15 years (range 8-17 years). The median duration of FAE treatment was 10 months (range 1-80 months), and the median maintenance dosage per day was 360 mg dimethylfumarate (range 240-600 mg). Five patients (36%) achieved a complete clearance of their psoriasis, one patient (7%) had a good improvement, three patients (21%) had a partial response and five patients (36%) were nonresponders. FAE treatment was well tolerated, but two patients (14%) discontinued FAE, one with severe diarrhoea and one with flushes. Five patients (36%) had transient, slightly abnormal laboratory values of liver-function tests or leucocytes that did not necessitate FAE dosage reduction or treatment discontinuation. No serious adverse events occurred. CONCLUSIONS: In this retrospective case series FAE seemed to be an effective and safe treatment for children with psoriasis. FAE may be an attractive therapeutic alternative to the currently used systemic immunosuppressive agents for paediatric patients with psoriasis. Further studies are needed to evaluate the suitability of FAE in paediatric psoriasis.

Impact of the definition of renal dysfunction on EuroSCORE performance.

AIM: Renal dysfunction is an important variable in the EuroSCORE (European System for Cardiac Operative Risk Evaluation) model and is currently defined as creatinine >200 mmol/L. The aim of this study was to examine whether using other definitions of renal dysfunction could improve the predictive ability of the EuroSCORE. METHODS: Between January 2004 and January 2006, 1 205 patients underwent cardiac surgery. Their preoperative glomerular filtration rate and EuroSCORE were calculated. Four recalibrated EuroSCORE models were constructed using 1) creatinine as a binary variable; 2) creatinine as a continuous variable; 3) glomerular filtration rate as a categorical variable; or 4) glomerular filtration rate as a continuous variable. The predictive ability of these models was assessed using receiver operating characteristic curve analysis. RESULTS: Hospital mortality was 4% (N.=47). Receiver operating characteristic curve values were: 0.78 for the original EuroSCORE, 0.80 for the recalibrated binary creatinine model, 0.83 for the continuous creatinine model, 0.83 for the categorical glomerular filtration rate model, and 0.82 for the continuous glomerular filtration rate model. CONCLUSIONS: The use of creatinine as a continuous variable or glomerular filtration rate as a categorical or continuous variable improves the predictive accuracy of the EuroSCORE model for hospital mortality. Given the increasing incidence of preoperative renal dysfunction and its impact on hospital mortality, future risk stratification models should include continuous creatinine or glomerular filtration rate rather than creatinine as a binary variable.

Fluctuating reproductive rates in Hawaii's humpback whales, Megaptera novaeangliae, reflect recent climate anomalies in the North Pacific.

Alongside changing ocean temperatures and ocean chemistry, anthropogenic climate change is now impacting the fundamental processes that support marine systems. However, where natural climate aberrations mask or amplify the impacts of anthropogenic climate change, identifying key detrimental changes is challenging. In these situations, long-term, systematic field studies allow the consequences of anthropogenically driven climate change to be distinguished from the expected fluctuations in natural resources. In this study, we describe fluctuations in encounter rates for humpback whales, Megaptera novaeangliae, between 2008 and 2018. Encounter rates were assessed during transect surveys of the Au'Au Channel, Maui, Hawaii. Initially, rates increased, tracking projected growth rates for this population segment. Rates reached a peak in 2013, then declined through 2018. Specifically, between 2013 and 2018, mother-calf encounter rates dropped by 76.5%, suggesting a rapid reduction in the reproductive rate of the newly designated Hawaii Distinct Population Segment of humpback whales during this time. As this decline coincided with changes in the Pacific decadal oscillation, the development of the NE Pacific marine heat wave and the evolution of the 2016 El Niño, this may be another example of the impact of this potent trifecta of climatic events within the North Pacific.

Genome-wide methylation profiling of Beckwith-Wiedemann syndrome patients without molecular confirmation after routine diagnostics.

Beckwith-Wiedemann syndrome (BWS) is caused due to the disturbance of imprinted genes at chromosome 11p15. The molecular confirmation of this syndrome is possible in approximately 85% of the cases, whereas in the remaining 15% of the cases, the underlying defect remains unclear. The goal of our research was to identify new epigenetic loci related to BWS. We studied a group of 25 patients clinically diagnosed with BWS but without molecular conformation after DNA diagnostics and performed a whole genome methylation analysis using the HumanMethylation450 Array (Illumina).We found hypermethylation throughout the methylome in two BWS patients. The hypermethylated sites in these patients overlapped and included both non-imprinted and imprinted regions. This finding was not previously described in any BWS-diagnosed patient.Furthermore, one BWS patient exhibited aberrant methylation in four maternally methylated regions-IGF1R, NHP2L1, L3MBTL, and ZDBF2-that overlapped with the differentially methylated regions found in BWS patients with multi-locus imprinting disturbance (MLID). This finding suggests that the BWS phenotype can result from MLID without detectable methylation defects in the primarily disease-associated loci (11p15). Another patient manifested small but significant aberrant methylation in disease-associated loci at 11p near H19, possibly confirming the diagnosis in this patient.

A genome-wide DNA methylation signature for SETD1B-related syndrome.

SETD1B is a component of a histone methyltransferase complex that specifically methylates Lys-4 of histone H3 (H3K4) and is responsible for the epigenetic control of chromatin structure and gene expression. De novo microdeletions encompassing this gene as well as de novo missense mutations were previously linked to syndromic intellectual disability (ID). Here, we identify a specific hypermethylation signature associated with loss of function mutations in the SETD1B gene which may be used as an epigenetic marker supporting the diagnosis of syndromic SETD1B-related diseases. We demonstrate the clinical utility of this unique epi-signature by reclassifying previously identified SETD1B VUS (variant of uncertain significance) in two patients.

[Meningoradiculitis caused by herpes simplex virus type 2]. / Meningoradiculitis door herpes-simplexvirus type 2.

A 24-year-old immune-competent woman was admitted to hospital with a three-day history of fever and headache. On examination bilateral facial nerve palsy, lumbosacral radicular pain, reduced sacral sensibility and urinary retention were found. Open perianal lesions were suspect for genital herpes. The symptoms were compatible with a meningoradiculitis including a sacral polyradiculitis. On testing, cerebrospinal fluid was found to be abnormal with a lymphocytic cell reaction. Polymerase chain reaction (PCR) of cerebrospinal fluid and of the perianal lesions was positive for herpes simplex virus type 2 (HSV-2). An MRI scan showed colouration of part of the cauda equina. The patient was treated by intravenous injections of acyclovir 10 mg/kg t.i.d. for 21 days, after which she completely recovered. HSV-2 infection of the nervous system can cause lymphocytic, and sometimes recurrent meningitis as well as sacral polyradiculitis. It may also occur without any symptomatic genital herpes infection. A positive result from a PCR test of the cerebrospinal fluid confirms this diagnosis. Treatment with acyclovir should be started as soon as possible.

A young man with nonhealing venous ulcers.

A 35-year-old man presented with nonhealing ulcers at an atypical location on his left foot, caused by a combination of venous insufficiency (after deep venous thrombosis) and arterial insufficiency. The underlying cause was Buerger's disease.

Short-term and 5-year outcome after primary isolated coronary artery bypass graft surgery: results of risk stratification in a bilocation center.

OBJECTIVE: We retrospectively investigated the short and mid-term outcome of non-emergent primary isolated coronary artery bypass graft (CABG) surgery in relation to risk stratification in the fully equipped university location (FE) and the low volume, limited facility location (LVLF) of our department. METHODS: Between September 1995 and December 1996, 832 patients were referred to our department to undergo a primary isolated CABG operation. The surgical team selected 482 patients (58%) as being at low-risk. These were treated in the LVLF hospital. The other 350 patients with mixed-risk were treated in the FE hospital. The selection consisted primarily of exclusion of patients with moderate or poor left ventricular function, severe COPD or renal impairment, from surgery in the LVLF location. Finally, the prognostic value of the EuroSCORE and the Parsonnet score was tested on our patient population. RESULTS: Overall in-hospital mortality was 1.6% (13 patients). One patient died in the LVLF group (0.2%) and 12 patients (3.4%) in the FE group. LVLF patients experienced less complications during the hospital period compared to the FE patients (5 versus 21%; P=0.0001). The Parsonnet risk model and the EuroSCORE risk model showed both a good relation with in-hospital mortality. After discharge, an increased risk of late mortality was observed up to 1 year postoperative in the FE group compared to the LVLF group (2.7 versus 0.5%; P=0.01). Risk factors for 5-year mortality were pre-operative renal impairment (blood creatinine >150 micromol/l) (hazard ratio (HR): 2.8; 95% confidence interval (CI): 1.4-5.5), diabetes (HR: 2.1; 95% CI: 1.3-3.5), impaired LVEF (HR: 1.9; 95% CI: 1.2-3.0), COPD (HR: 1.9; 95% CI: 1.1-3.5) and older age (HR: 1.07 per year; 95% CI: 1.01-1.10). Lipid-lowering therapy was a predictor of lower mortality at 5-years (HR: 0.5; 95% CI: 0.4-0.9). CONCLUSION: By careful decision making, selection of low-risk patients for a low volume and limited facility location resulted in excellent in-hospital survival with very low complication rates.

Sub- and supercritical fluid chromatography on packed columns: a versatile tool for the enantioselective separation of basic and acidic drugs.

Various chiral stationary phases were investigated in sub- and supercritical fluid chromatography for the separation, without derivatization, of basic (beta-blockers, benzodiazepines) and acidic (nonsteroidal anti-inflammatory drugs, beta-agonists) pharmaca. For all racemates, baseline separation was achieved within short analysis times. For several solutes, the high resolution obtained allowed injection of milligram amounts and semipreparative collection of the enantiomers. The parameters affecting enantioselectivity (column efficiency, influence of modifiers and basic or acidic additives, and temperature) have been studied. Enantiomerization of 3-OH-benzodiazepines could be suppressed by working at low temperatures or by using acetonitrile as a comodifier. Serial coupling of different chiral stationary phase columns resulted in a column triplet (Chiralpak AD, an amylose derivative; Chiralcel OD, a cellulose derivative; and Chirex 3022, a Brush-type with pi-donor characteristics) on which all solutes investigated could be baseline separated.

Congenital naevi treated with erbium:YAG laser (Derma K) resurfacing in neonates: clinical results and review of the literature.

BACKGROUND: Giant congenital melanocytic naevi (CMN) are often disfiguring, potentially malignant pigmented lesions present at birth. Their management is based on two main considerations: attempt to minimize the risk of malignancy and to obtain an acceptable cosmetic result. In the past various approaches have been used to treat these naevi. OBJECTIVES: To describe clinical and histopathological results after treatment of CMN in neonates with erbium:YAG (Er:YAG) laser resurfacing. METHODS: Ten children with CMN were treated with Er:YAG laser resurfacing in the first weeks of life. RESULTS: Laser ablation was well tolerated by all children and immediate results were good. At a total follow-up ranging from 3 to 36 months we saw good results, with no or minimal repigmentation, in eight of 10 patients. Patients experienced minimal side-effects such as postoperative pain, bleeding and scar formation. Postoperative histopathology showed disappearance of heavily pigmented cells in the upper part of the dermis. CONCLUSIONS: Er:YAG laser resurfacing is an effective method of ablating CMN, with minimal scarring and postoperative complications.