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Background There is a medical need for new drugs in patients with BRAF wild-type metastatic melanoma. Pazopanib is a multitarget tyrosine kinase inhibitor with antitumour and antiangiogenic activity. Objectives The primary aim was to investigate the metabolic response to pazopanib monotherapy and pazopanib plus paclitaxel in patients with BRAF wild-type melanoma. Secondary end points were the early cytokine and chemokine profiles and histological findings. Methods Pazopanib (400 mg twice daily) was administered orally from days 1 to 10 and from days 14 to 70. An intravenous infusion with paclitaxel (150 mg m−2 body surface) was administered on days 14, 35 and 56. Metabolic response evaluation was performed before treatment, after treatment with pazopanib (day 10) and after treatment with pazopanib and paclitaxel (day 70). Skin biopsy of metastatic tissue for chemokine and cytokine expression analysis and histology and immunohistochemistry ( CD68, CD163) evaluation, and blood samples were taken at the same time points. Results Two patients failed screening and 17 were dosed. Of 67 adverse events, nine (13%) were grade 3 or 4. Five of 14 evaluable patients had a partial metabolic response at day 10 under pazopanib monotherapy. The response rate at day 70 under combined pazopanib-paclitaxel treatment was 0%. Immunohistochemistry revealed an increase of M2-like macrophages in nonresponders compared with responders. We observed a significant upregulation of five cytokines ( CXCL1, CXCL2, CXCL13, CCL22 and SPP1) in responding vs. nonresponding lesions. Overall, the median progression-free survival was 70 days (range 5-331), which did not differ significantly between responders (148 days) and nonresponders (70 days, P = 0·17). Conclusions In this patient population pazopanib efficacy was limited. Response is associated with low M2-like macrophage density and increased expression of several chemokines. [ABSTRACT FROM AUTHOR]

Phan-Hug F, Thurneysen E, Theintz G, Ruffieux C, Grouzmann E. Impact of videogame playing on glucose metabolism in children with type 1 diabetes. Time spent playing videogames (VG) occupies a continually increasing part of children's leisure time. They can generate an important state of excitation, representing a form of mental and physical stress. This pilot study aimed to assess whether VG influences glycemic balance in children with type 1 diabetes. Twelve children with type 1 diabetes were subjected to two distinct tests at a few weeks interval: (i) a 60-min VG session followed by a 60-min rest period and (ii) a 60-min reading session followed by a 60-min rest period. Heart rate, blood pressure, glycemia, epinephrine (E), norepinephrine (NE), cortisol (F), and growth hormone (GH) were measured at 30 min intervals from −60 to +120 min. Non-parametric Wilcoxon tests for paired data were performed on Δ-values computed from baseline (0 min). Rise in heart rate (p = 0.05) and NE increase (p = 0.03) were shown to be significantly higher during the VG session when compared to the reading session and a significant difference of Δ-glycemic values was measured between the respective rest periods. This pilot study suggests that VG playing could induce a state of excitation sufficient to activate the sympathetic system and alter the course of glycemia. Dietary and insulin dose recommendations may be needed to better control glycemic excursion in children playing VG. [ABSTRACT FROM AUTHOR]

Abstract: The tumor suppressor merlin is encoded by the neurofibromatosis type 2 gene (NF2) which is located on chromosome 22q12 and mutations in this gene have been found in 40% of mesothelioma. Mutations including deletions and insertions lead to truncated and inactivated merlin. Experimental animal models indicate that disruption of the NF2 signalling pathway, together with a deficiency in ink4a, is essential for mesothelioma development. Our hypothesis was that in human mesothelioma without detectable NF2 mutations, regulators of NF2/merlin activity such as CPI-17 would be altered. CPI-17 is an oncogene inhibiting the NF2/merlin phosphatase which is necessary to maintain NF2/merlin activity. Samples obtained from 44 mesothelioma, 3 asbestosis patients and 6 normal pleura from non-asbestos related disease patients were analyzed. Truncated NF2 transcripts or presence of isoform II only were observed in 11 mesothelioma samples. In all other mesothelioma samples only NF2 isoform I or isoforms I and II were detected. 18 mesothelioma and 1 normal pleura samples also expressed splicing variant delE2/3. Unexpected variants in addition to wild-type were identified in 24 mesothelioma samples. NF2 protein was either truncated or phosphorylated on Ser 518 in primary cultures derived from 25 tumors. CPI-17 expression was significantly increased in tumor samples without deleted NF2 compared to normal pleura and tumor expressing truncated NF2. Our results support the hypothesis that the disruption of NF2 signalling is essential for the development of human mesothelioma. In tumors where no NF2 truncation can be detected, NF2 is rendered inactive by phosphorylation of Ser 518 and this can be explained at least in part by an increased expression of CPI-17. [Copyright &y& Elsevier]

Na+/Ca2+ exchange activity is known to be expressed throughout the brain in both glial and neuronal tissue. mRNA of all three major subtypes of the mammalian Na+/Ca2+ exchanger protein (NCX1, NCX2, NCX3) has been detected in most brain areas, albeit at varying densities. [The term ‘subtype’ is used for exchangers that are products of different genes (NCX1, NCX2, NCX3); ‘isoform’ is used for splice variants of a single gene product]. However, for lack of subtype specific labels, the cellular expression pattern of this transport protein has remained largely unknown. We have now used three subtype-specific antibodies, two monoclonal and one polyclonal, to identify the cellular distribution of the exchanger subtypes in rat hippocampus cell cultures. Surprisingly, we found little overlap for the expression of this membrane protein in different cell types. NCX1 labeled mainly the membranes of neuronal cells and their associated dendritic network. It was found in nearly all neuronal cells of the population growing in culture. In cultures maintained for more than 3 weeks, NCX1 was increasingly detected in the membrane of glia cells. NCX2 immunoreactivity was predominantly localized in various types of glia cells. It was also detected in the membranes of a few neuronal cell bodies but never in the dendritic network. In addition to labeling membranes, the NCX2 antibody strongly cross-reacted with an unidentified glial fibrillar protein. NCX3 expression appeared very low in hippocampus cultures and was restricted to a small subpopulation of neuronal cells. It was never detected in glia cells. Our results provide novel information on the cell-specific expression of the three Na+/Ca2+ exchanger subtypes (NCX1, NCX2 and NCX3) in mammalian brain. These data may reflect functional differences among the subtypes that are not obvious from studies in recombinant cell lines and hence, may help to understand the functional role of specific glia- or neuron-associated Ca2+ transport systems. [Copyright &y& Elsevier]

A letter to the editor is presented in response to the article "Homeopathy for Attention Deficit/Hyperactivity Disorder: A Pilot Randomized-Controlled Trial," by Jennifer Jacobs and colleagues.

• Swiss healthcare professionals are generally opposed to vaccine mandates. • Swiss federal health authorities have clearly stated that vaccination is voluntary. • Swiss healthcare professionals expressed concerns about COVID-19 vaccine mandates. • Consequences of vaccine mandates for HCPs are currently unclear in Switzerland. • Vaccination policy in Switzerland should be clarified for healthcare professionals. There currently are no mandatory vaccines in Switzerland. However, Swiss federal legislation allows for vaccination mandates in settings where the risk of transmission to vulnerable groups is high, such as healthcare professionals (HCPs) working with vulnerable patients. Since HCPs are trusted information sources, a priority population for COVID-19 vaccination, and potentially subjected to mandates, we investigated HCP perspectives on mandates. A national online survey was administered to HCPs (October 2020-March 2021), including vaccine mandates questions concerning patients (measles) and HCPs (influenza). We qualitatively investigated HCP mandate perspectives through: (1) 34 interviews with HCPs, HCP professional society representatives, and health authorities; (2) a focus group discussion (FGD) with complementary medicine (CM) and biomedical physicians, and Swiss Federal Vaccination Commission members. 1933 participants (496 physicians, 226 pharmacists, 607 nurses, 604 midwives) responded to the survey. Quantitative results show all professional groups preferred shared parent-HCP measles vaccine decisions (65%, 54%, 50%, 48%, respectively; p for trend < 0.001). Midwives (87%) and nurses (70%) preferred individual influenza vaccination decisions for HCPs, while physicians (49%) and pharmacists (44%) preferred shared employee-employer decisions (p for trend < 0.001). Physicians (p <.001) and pharmacists (p <.01) with CM training favored individual influenza vaccination decisions. Qualitative results show general HCP opposition to vaccine mandates, mainly because participants argued how other approaches, such as HCP training and better information, could encourage uptake. Arguments against COVID-19 mandates included insufficiently documented long-term safety/efficacy data. From participants' perspectives, mandated vaccination should be used as a last resort. Some participants expressed fear that with mandates, notably for influenza and COVID-19, some HCPs might leave their jobs. HCPs were unsure what vaccine mandates would concretely look like in practice, particularly regarding sanctions for non-compliance and enforcement. In Switzerland, HCPs generally were opposed to vaccination mandates. Clarity and guidance are needed from health authorities to better inform discussions around vaccine mandates. [ABSTRACT FROM AUTHOR]

Unlabelled: An increasing number of parents turn to homeopathy for treatment of their hyperactive child. Two publications, a randomised, partially blinded trial and a clinical observation study, conclude that homeopathy has positive effects in patients with attention deficit hyperactivity disorder (ADHD). The aim of this study was to obtain scientific evidence of the effectiveness of homeopathy in ADHD. A total of 83 children aged 6-16 years, with ADHD diagnosed using the Diagnostic and Statistical Manual of Mental Disorders-IV criteria, were recruited. Prior to the randomised, double blind, placebo controlled crossover study, they were treated with individually prescribed homeopathic medications. 62 patients, who achieved an improvement of 50% in the Conners' Global Index (CGI), participated in the trial. Thirteen patients did not fulfill this eligibility criterion (CGI). The responders were split into two groups and received either verum for 6 weeks followed by placebo for 6 weeks (arm A), or vice-versa (arm B). At the beginning of the trial and after each crossover period, parents reported the CGI and patients underwent neuropsychological testing. The CGI rating was evaluated again at the end of each crossover period and twice in long-term follow-up. At entry to the crossover trial, cognitive performance such as visual global perception, impulsivity and divided attention, had improved significantly under open label treatment (P<0.0001). During the crossover trial, CGI parent-ratings were significantly lower under verum (average 1.67 points) than under placebo (P =0.0479). Long-term CGI improvement reached 12 points (63%, P <0.0001).Conclusion: The trial suggests scientific evidence of the effectiveness of homeopathy in the treatment of attention deficit hyperactivity disorder, particularly in the areas of behavioural and cognitive functions. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide Open in new tab Download slide OBJECTIVES: Our goal was to determine the optimal timing and choice of surgical antimicrobial prophylaxis (SAP) in patients having cardiac surgery. METHODS: The setting was the Swiss surgical site infection (SSI) national surveillance system with a follow-up rate of >94%. Participants were patients from 14 hospitals who had cardiac surgery from 2009 to 2017 with clean wounds, SAP with cefuroxime, cefazolin or a vancomycin/cefuroxime combination and timing of SAP within 120 min before the incision. Exposures were SAP timing and agents; the main outcome was the incidence of SSI. We fitted generalized additive and mixed-effects generalized linear models to describe effects predicting SSIs. RESULTS: A total of 21 007 patients were enrolled with an SSI incidence of 5.5%. Administration of SAP within 30 min before the incision was significantly associated with decreased deep/organ space SSI [adjusted odds ratio (OR) 0.73, 95% confidence interval (CI) 0.54–0.98; P  = 0.035] compared to administration of SAP 60–120 min before the incision. Cefazolin (adjusted OR 0.64, 95% CI 0.49–0.84; P  = 0.001) but not vancomycin/cefuroxime combination (adjusted OR 1.05, 95% CI 0.82–1.34; P  = 0.689) was significantly associated with a lower risk of overall SSI compared to cefuroxime alone. Nevertheless, there were no statistically significant differences between the SAP agents and the risk of deep/organ space SSI. CONCLUSIONS: The results from this large prospective study provide substantial arguments that administration of SAP close to the time of the incision is more effective than earlier administration before cardiac surgery, making compliance with SAP administration easier. The choice of SAP appears to play a significant role in the prevention of all SSIs, even after adjusting for confounding variables. [ABSTRACT FROM AUTHOR]

Homeopathic preparations are used in homeopathy and anthroposophic medicine. Although there is evidence of effectiveness in several clinical studies, including double-blinded randomized controlled trials, their nature and mode of action could not be explained with current scientific approaches yet. Several physical methods have already been applied to investigate homeopathic preparations but it is yet unclear which methods are best suited to identify characteristic physicochemical properties of homeopathic preparations. The aim of this study was to investigate homeopathic preparations with UV-spectroscopy. In a blinded, randomized, controlled experiment homeopathic preparations of copper sulfate (CuSO4; 11c–30c), quartz (SiO2; 10c– 30c, i.e., centesimal dilution steps) and sulfur (S; 11×–30×, i.e., decimal dilution steps) and controls (one-time succussed diluent) were investigated using UV-spectroscopy and tested for contamination by inductively coupled plasma mass spectrometry (ICPMS). The UV transmission for homeopathic preparations of CuSO4 preparations was significantly lower than in controls. The transmission seemed to be also lower for both SiO2 and S, but not significant. The mean effect size (95% confidence interval) was similar for the homeopathic preparations: CuSO4 (pooled data) 0.0544% (0.0260–0.0827%), SiO2 0.0323% (–0.0064% to 0.0710%) and S 0.0281% (–0.0520% to 0.1082%). UV transmission values of homeopathic preparations had a significantly higher variability compared to controls. In none of the samples the concentration of any element analyzed by ICP-MS exceeded 100 ppb. Lower transmission of UV light may indicate that homeopathic preparations are less structured or more dynamic than their succussed pure solvent. [ABSTRACT FROM AUTHOR]

Objective: To evaluate clinical and cost-effectiveness of individualised homeopathic treatment of children diagnosed with attention deficit hyperactivity disorder (ADHD) between age 6 and 16 during 10 years. Methods: Public lectures made families with inattentive or hyperactive children children getting interested in a randomized, double blind, placebo controlled trial (RCT), embedded in a prospective observational study. After diagnostic screening and a primary run-in phase of homeopathic treatment, crossover RCT was followed by open-label long-term follow-up and cost-effectiveness evaluation. At diagnosis, beginning of, and after each crossover period, and at yearly intervals during long-term follow-up, parents reported Conners' Global Index (CGI, 10 items, rated 0-3 points each; primary variable) by questionnaire or telephone interview. Results: A total of 140 children was recruited, 43 were excluded by a screening questionnaire, another 14 did not meet strict diagnostic criteria (according to DSM-IV), resulting in 83 children treated with individually prescribed homeopathic remedies. As 13 patients did not improve at least 50% in CGI values (RCT inclusion criterion), the remaining 62 children (84%) participated in, and 58 finished the double-blind cross-over RCT phase. After ten years of open-label therapy, 56/62 children were eligible for follow-up (90%). According to ITT-analysis, 38/62 (62%) children were without any homeopathic (HOM) or medical treatment. In the remaining children, successful results were achieved in 6 with HOM, 9 with methylphenidate (MPH) and 3 with both, HOM and MPH. During cross-over RCT, CGI values detected clinically and statistically significant differences in verum and placebo phase, respectively. Cost-effectiveness evaluation demonstrated non-inferiority of homeopathic treatment compared to stimulant treatment, even in the first year including case-taking and repertory analysis. Discussion: The innovative design of this study enabled both, to show clinical and cost-effectiveness of integrated homeopathic treatment in children dignosed with ADHD, and to detect a specific effect of the individual homeopathic remedy. The clinical result is comparable to conventional stimulant treatment. This again raises the question about the mode of action of homeopathically potentized substances. Conclusion: In children with ADHD, individualized homeopathic therapy and conventional stimulant treatment have comparable both, clinically significant, and specific effects persistent over ten years. [ABSTRACT FROM AUTHOR]