Epigenomic alterations define lethal CIMP-positive ependymomas of infancy.

Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.

What information can the lay public find about osteoporosis treatment? A descriptive study coding the content and quality of bisphosphonate information on the internet.

Despite its effectiveness, bisphosphonate use for osteoporosis is low. We assessed bisphosphonate information on the internet and found the most commonly listed benefits/risks were bone density loss, gastrointestinal issues, and jaw necrosis, that risk quantification was rare, and information quality varied. Findings underscore the importance of clinical communication about bisphosphonates. INTRODUCTION: The US Preventative Services Task Force recommends osteoporosis screening and treatment with bisphosphonates in high-risk populations. However, bisphosphonate use among individuals with osteoporosis remains low. The content and quality of information from outside sources may influence individuals' bisphosphonate decisions. Therefore, we sought to assess the content and quality of osteoporosis treatment information available to the public by conducting an internet search and coding available bisphosphonate information. METHODS: Eleven search terms about osteoporosis and bisphosphonates were entered into four search engines. Two raters assessed websites for information about bisphosphonates, whether and how benefits and side effects were described and quantified, contraindications, and dosing instructions. Coders also assessed website interface and slant/balance of information. RESULTS: One thousand four hundred seventy-three websites were identified. Two hundred twenty-seven websites met inclusion criteria and were coded. The most common bisphosphonate benefit described was prevention of bone density loss (77.1% of websites). The most common side effects described were gastrointestinal problems (66.1%) and jaw osteonecrosis (58.6%). Most websites did not quantify bisphosphonate benefits (78.0%) or side effects (82.4%). Complementary/integrative health websites (p < .001) and pharmaceutical litigation websites (p < .001) were more often slanted against taking bisphosphonates, compared to all websites coded. General medical knowledge websites were more balanced than other websites (p = .023). CONCLUSIONS: The quality of bisphosphonate information on the internet varies substantially. Providers counseling patients about osteoporosis treatment should inquire about patients' baseline bisphosphonate knowledge. Providers can complement accurate information and address potential bisphosphonate misconceptions.

Review of perioperative falls.

Falls are a known public health problem, and there is increasing recognition of the importance of perioperative falls for risk prediction and quality assessment. Our objective was to review existing literature regarding the occurrence, injuries, and risk factors of preoperative and postoperative falls. A systematized search of PubMed entries between 1947 and November 2015 produced 24 articles that met inclusion criteria. Most studied orthopaedic surgery patients older than 65 yr. Four were rated 'good' quality. Interrater reliability for the quality assessment was moderate (κ = 0.77). In the 3-12 months before surgery, the proportion of preoperative patients who fell ranged from 24 to 48%. Injuries were common (70%). The rate of postoperative falls ranged from 0.8 to 16.3 per 1000 person-days, with a gradual decline in the months after surgery. Injuries from postoperative falls occurred in 10-70% of fallers, and 5-20% experienced a severe injury. Risk factors were not well studied. Prospective studies reported a higher percentage of falls and fall-related injuries than retrospective studies, suggesting that there may be underdetection of falls and injuries with retrospective studies. Perioperative falls were more common than falls reported in the general community, even up to 12 months after surgery. Surgery-related falls may therefore occur beyond the hospitalization period. Future studies should use a prospective design, validated definitions, and broader populations to study perioperative falls. In particular, investigations of risk factors and follow-up after hospitalization are needed. REGISTRY NUMBER: PROSPERO registration number CRD42015029971.

Fiber chirped pulse amplifier at 2.08 µm emitting 383-fs pulses at 10 nJ and 7 MHz.

An all-polarization maintaining (PM) fiber chirped pulse amplifier system at 2.08 µm based on thulium:holmium codoped gain fibers is reported. An inhouse built oscillator emits pulses at a repetition rate of 7 MHz with a spectral full width at half-maximum (FWHM) bandwidth of 23.5 nm at 2.8 mW average output power. The pulses are temporally stretched and subsequently amplified in a double-stage amplifier setup. The stretched pulses are compressed to 383 fs by use of a Martinez-style setup at an output pulse energy of 10.2 nJ. By neglecting temporal stretching, high peak powers in a single amplifier stage led to Raman soliton formation at 2.3 µm.

Which types of bony changes in the maxillary sinus indicate chronic sinusitis?

OBJECTIVES: To determine which types of bone lesion (spicules, lobules, porous bone) in the maxillary sinus indicate sinusitis METHODS: Subadjacent dental disease is a cause of maxillary sinusitis; if a lesion type indicates sinusitis it should be more common above diseased posterior maxillary teeth than a lesion type that is not indicative of sinusitis. The study sample is a British Mediaeval human skeletal collection. RESULTS: Porous bone lesions (chiefly new bone deposits) in maxillary sinuses are associated with subadjacent dental disease; spicules/lobules of bone in the sinus are not. CONCLUSIONS: The results support the idea that porous lesions indicate sinusitis but the spicules/lobules may not. Spicules, lobules and porous lesions within the maxillary sinus should be analysed separately in biocultural studies; it would be prudent to regard only the porous lesions as indicative of sinusitis. SIGNIFICANCE: Maxillary sinusitis is commonly used as a health indicator in palaeopathology, and spicular deposits are generally the most common type of alterations. By assuming that they are indicative of sinusitis we may have been greatly overestimating the prevalence of bony sinusitis in the past. LIMITATIONS: These conclusions are provisional. Further work on larger, more diverse samples, together with more detailed anatomical studies on lesion location and structure is ongoing.

Nonlinear amplification of side-modes in frequency combs.

We investigate how suppressed modes in frequency combs are modified upon frequency doubling and self-phase modulation. We find, both experimentally and by using a simplified model, that these side-modes are amplified relative to the principal comb modes. Whereas frequency doubling increases their relative strength by 6 dB, the growth due to self-phase modulation can be much stronger and generally increases with nonlinear propagation length. Upper limits for this effect are derived in this work. This behavior has implications for high-precision calibration of spectrographs with frequency combs used for example in astronomy. For this application, Fabry-Pérot filter cavities are used to increase the mode spacing to exceed the resolution of the spectrograph. Frequency conversion and/or spectral broadening after non-perfect filtering reamplify the suppressed modes, which can lead to calibration errors.

Discretely calibrated regulatory loops controlled by ppGpp partition gene induction across the 'feast to famine' gradient in Escherichia coli.

Bacteria comprehensively reorganize their global gene expression when faced with starvation. The alarmone ppGpp facilitates this massive response by co-ordinating the downregulation of genes of the translation apparatus, and the induction of biosynthetic genes and the general stress response. Such a large reorientation requires the activities of multiple regulators, yet the regulatory network downstream of ppGpp remains poorly defined. Transcription profiling during isoleucine depletion, which leads to gradual starvation (over > 100 min), allowed us to identify genes that required ppGpp, Lrp and RpoS for their induction and to deduce the regulon response times. Although the Lrp and RpoS regulons required ppGpp for their activation, they were not induced simultaneously. The data suggest that metabolic genes, i.e. those of the Lrp regulon, require only a low level of ppGpp for their induction. In contrast, the RpoS regulon was induced only when high levels of ppGpp accumulated. We tested several predictions of a model that explains how bacteria allocate transcriptional resources between metabolism and stress response by discretely tuning two regulatory circuits to different levels of ppGpp. The emergent regulatory structure insures that stress survival circuits are only triggered if homeostatic metabolic networks fail to compensate for environmental deficiencies.

Extreme supercontinuum generation to the deep UV.

We report the formation of an ultrabroad supercontinuum down to 280 nm in the deep UV by pumping sharply tapered (5-30 mm taper lengths) solid-core photonic crystal fibers with 130 fs, 2 nJ pulses at 800 nm. The taper moves the point of soliton fission to a position where the core is narrower, a process that requires normal dispersion at the input face of the fiber. We find that the generation of deep-UV radiation is limited by strong two-photon absorption in the silica.

Supercontinuum generation in chalcogenide-silica step-index fibers.

We explore the use of a highly nonlinear chalcogenide-silica waveguide for supercontinuum generation in the near infrared. The structure was fabricated by a pressure-assisted melt-filling of a silica capillary fiber (1.6 µm bore diameter) with Ga4Ge21Sb10S65 glass. It was designed to have zero group velocity dispersion (for HE11 core mode) at 1550 nm. Pumping a 1 cm length with 60 fs pulses from an erbium-doped fiber laser results in the generation of octave-spanning supercontinuum light for pulse energies of only 60 pJ. Good agreement is obtained between the experimental results and theoretical predictions based on numerical solutions of the generalized nonlinear Schrödinger equation. The pressure-assisted melt-filling approach makes it possible to realize highly nonlinear devices with unusual combinations of materials. For example, we show numerically that a 1 cm long As2S3:silica step-index fiber with a core diameter of 1 µm, pumped by 60 fs pulses at 1550 nm, would generate a broadband supercontinuum out to 4 µm.

14 GHz visible supercontinuum generation: calibration sources for astronomical spectrographs.

We report the use of a specially designed tapered photonic crystal fiber to produce a broadband optical spectrum covering the visible spectral range. The pump source is a frequency doubled Yb fiber laser operating at a repetition rate of 14 GHz and emitting sub-5 pJ pulses. We experimentally determine the optimum core diameter and achieve a 235 nm broad spectrum. Numerical simulations are used to identify the underlying mechanisms and explain spectral features. The high repetition rate makes this system a promising candidate for precision calibration of astronomical spectrographs.

Soliton blueshift in tapered photonic crystal fibers.

We show that solitons undergo a strong blueshift in fibers with a dispersion landscape that varies along the direction of propagation. The experiments are based on a small-core photonic crystal fiber, tapered to have a core diameter that varies continuously along its length, resulting in a zero-dispersion wavelength that moves from 731 nm to 640 nm over the transition. The central wavelength of a soliton translates over 400 nm towards a shorter wavelength. This is accompanied by strong emission of radiation into the UV and IR spectral regions. The experimental results are confirmed by numerical simulation.

Antibodies that are specific for a single amino acid interchange in a protein epitope use structurally distinct variable regions.

We have analyzed how the immune system generates antibodies that are specific for analogues of an epitope on the influenza virus hemagglutinin (HA) that differ solely by the presence of Asp or Gly at amino acid 225. Most antibodies induced in response to HA(Asp225) use one of a few closely related variable (V) region structures that are encoded by characteristic VH/Vk gene segment combinations. Remarkably, none of these VH/Vk combinations was induced in response to HA(Gly225). Instead of modifying the HA(Asp225)-specific V regions by junctional variation or somatic mutation to recognize the altered epitope, new VH/Vk combinations were used. The expression of unique VH/Vk combinations appears to confer exquisite specificity to the selection of HA-specific B cells from the pre-immune repertoire.

Activation and negative selection of functionally distinct subsets of antibody-secreting cells by influenza hemagglutinin as a viral and a neo-self antigen.

We have compared transgenic mice that express the influenza virus PR8 hemagglutinin (PR8 HA) as a membrane-bound neo-self antigen (HA104 mice) with nontransgenic (non-Tg) mice for their ability to generate HA-specific B cell responses after primary immunization with PR8 virus. HA-specific, IgM-secreting B cells were induced with similar frequencies in HA104 and non-Tg mice. In addition, a B cell clonotype (C4) that is characteristic of anti-HA immune responses of BALB/c mice was identified among HA-specific IgM hybridomas from HA104 mice. A subset of HA-specific, IgG-secreting B cells that arises rapidly after primary virus immunization in non-Tg mice, however, was substantially reduced in HA104 mice. Likewise, a B cell clonotype (C12) that dominates HA-specific IgG hybridomas generated after primary immunization of non-Tg mice was present at greatly reduced frequencies among hybridomas from HA104 mice. Because HA-specific, IgG-secreting B cells were generated by HA104 mice in response to a mutant HA containing an amino acid interchange in a B cell antigenic site, we conclude that these PR8 HA-specific, IgG-secreting B cells are negatively selected in HA104 mice as a result of their specificity for the neo-self PR8 HA. The findings demonstrate that HA-specific B cells that display distinct phenotypic potentials in non-Tg mice also differ in their susceptibility to negative selection from the primary B cell repertoire of HA104 mice: a subset of B cells that undergo rapid differentiation to become HA-specific IgG antibody-secreting cells (ASC) after activation in non-Tg mice is negatively selected in HA104 mice. By contrast, a subset that gives rise to HA-specific, IgM-secreting ASC persists in the primary repertoire of HA104 mice and can be activated by virus immunization.

Efficacy and safety of two different antifungal pastes in infants with diaper dermatitis: a randomized, controlled study.

BACKGROUND: Diaper dermatitis (DD) is the most common type of irritative dermatitis in infancy. It is frequently complicated by Candida superinfection. OBJECTIVE: Comparison of efficacy and safety of two antifungal pastes (Imazol = 1% clotrimazole; Multilind = 100,000 IU nystatin/g + 20% zinc oxide) in infants with DD. METHODS: A total of 96 infants were included in this multi-centre, controlled, randomized, evaluator-blinded phase IV trial and treated with pastes containing either clotrimazole (n = 45) or nystatin (n = 46) twice daily for 14 days. In all, 91 children (age 12.1 +/- 5.3 months; 48 females) with DD were evaluable. Total symptom score after 7 days (TSS7) was assessed as primary parameter. Secondary efficacy parameters were TSS at 14 days (TSS14), clinical and microbiological cure rates and global assessment (GA) of clinical response. RESULTS: TSS improved markedly with both pastes. Decreases in symptom score were 4.5 +/- 2.1 (day 7) and 6.1 +/- 1.9 (day 14) with clotrimazole compared with 4.2 +/- 2.3 and 5.4 +/- 2.4 with nystatin (P < 0.0001). With respect to TSS14, clotrimazole was superior to nystatin (P = 0.0434). Clinical cure rate was higher with clotrimazole [36.2% (day 7) and 68.1% (day 14)] compared with 28.6% and 46.9% (nystatin). GA was very good in 26 (55.3%) clotrimazole-treated children (nystatin: 16 [32.7%], P = 0.0257). Frequency of adverse events was comparable in both treatment groups. CONCLUSION: Clotrimazole was superior to nystatin with respect to reduction in symptom score and GA. Microbiological cure rate was 100% for both agents. Both treatments were safe and well-tolerated.

[Complementary system of health care in cooperation with migrant communities--requirements for successful integration in health care]. / Gesundheitshilfen für und mit Migranten--Voraussetzungen für erfolgreiche Integration im Gesundheitswesen.

National and ethnic diversities among and within groups of migrants present great challenges to health care, not only in Germany. Access to regular health care, in particular for relatively small migrant groups and new immigrants is sometimes difficult. In addition, specific cultural aspects and legal implications--such as the residence status--must be taken into account when setting up a complementary system of health care. Methods and arrangements should make use of already existing resources of the health care system as well as proceed to direct cooperation with migrant communities. The public health service with its wide range of technical and organisational efficiency can play a key role here, especially in the municipal sector, both for an effective medical care for those who have difficulties in gaining access to the system, as well as for developing municipal networks, cooperating with a maximum number of medical service providers, organisations, and regarding specific migrant lifestyles. Social and ethic aspects of medical care for people living in precarious conditions ought to be supplemented by practice models which render a flexible and economic organisation of a complementary system of health care, the only way to a sustainable medical care for small migrant groups or not optimally integrated immigrant populations.

Comparisons of self-reported and register data on sickness absence among public employees in Sweden.

AIM: Self-reported assessments of sickness absence are often performed in epidemiological studies. The objective of this study was to compare the number of sick-leave days according to self-reported data over 12 months with data from the employer's register for the same period. An additional aim was to ascertain whether the self-reported information and the recorded data would show equivalent associations with self-reported general health. METHODS: The study was based on a cohort of 4869 municipal employees in Sweden, about 80% women, who answered a questionnaire in 2001-2. The responses provided by the employees included information on number of sick-leave days and self-rated health. Data on sick-leave days, occupation and age were derived from the employers' computerised registers. The questionnaire information on sick-leave days was compared with the corresponding information retrieved from the employer register by means of calculating sensitivity and specificity, using the employers' data as the "gold standard". RESULTS: The annual number of sick-leave days was lower according to the self-reported information than to the register data. For women the agreement between the two sickness absence measures for no sick-leave days, 1-7 days and >/=28 days were 74%, 72% and 67%, respectively. The sensitivity of questionnaire versus register information regarding any self-reported sick-leave day was 91% and the specificity was 74%. Sensitivity and specificity for sickness absence >/=28 days were 67% and 98%, respectively. The results for men were similar to those for women. Self-reported and recorded sickness absence were both associated with self-rated health. The odds ratios were 7.27 and 8.25, for subjects with >/=28 recorded and self-reported number of sick-leave days respectively, compared to subjects with no sickness absence. CONCLUSIONS: Good agreement was found between self-reported and register information on sickness absence. Self-reported data on sickness absence may be useful in common epidemiological applications.

Carbonate chemistry of an in-situ free-ocean CO2 enrichment experiment (antFOCE) in comparison to short term variation in Antarctic coastal waters.

Free-ocean CO2 enrichment (FOCE) experiments have been deployed in marine ecosystems to manipulate carbonate system conditions to those predicted in future oceans. We investigated whether the pH/carbonate chemistry of extremely cold polar waters can be manipulated in an ecologically relevant way, to represent conditions under future atmospheric CO2 levels, in an in-situ FOCE experiment in Antarctica. We examined spatial and temporal variation in local ambient carbonate chemistry at hourly intervals at two sites between December and February and compared these with experimental conditions. We successfully maintained a mean pH offset in acidified benthic chambers of -0.38 (±0.07) from ambient for approximately 8 weeks. Local diel and seasonal fluctuations in ambient pH were duplicated in the FOCE system. Large temporal variability in acidified chambers resulted from system stoppages. The mean pH, Ωarag and fCO2 values in the acidified chambers were 7.688 ± 0.079, 0.62 ± 0.13 and 912 ± 150 µatm, respectively. Variation in ambient pH appeared to be mainly driven by salinity and biological production and ranged from 8.019 to 8.192 with significant spatio-temporal variation. This experiment demonstrates the utility of FOCE systems to create conditions expected in future oceans that represent ecologically relevant variation, even under polar conditions.

[Travel medicine and vaccination as a task of infection prevention--data of the special consultation hours of the public health department Frankfurt on the Main, Germany, 2002-2004]. / Reisemedizinische Beratungen und Impfungen als infektionspräventive Aufgabe--Daten der Sprechstunde des Stadtgesundheitsamtes Frankfurt am Main 2002-2004.

UNLABELLED: Infection prevention is one of the main tasks of the Public Health authorities. Because of hundreds of travel associated infections imported by travellers every year and considering increasing travel activities to tropical countries, travel medicine and consultation on the correct prevention measures including vaccination is becoming more and more important. Hence the data of the special consultation hours of the public health department of Frankfurt am Main are reported and discussed with regard to possible improvements. MATERIAL AND METHODS: The public health department of Frankfurt am Main has been offering special consultation hours for travel medicine for many years. Here, data derived from the anamneses of the clients from 2002 - 2004 are reported: personal data such as age, sex, travel destination as well as medical data such as vaccination and malaria prevention. RESULTS: 2002 - 2004, more than 14,000 persons were seen in the consultation hours, more than 66% of them asked for travel health advice, about 25% of them asked for standard vaccination (such as influenza), some others asked for attestation or certification. More than 20,000 doses of vaccines were given, the most important vaccination against hepatitis A (n = 5791), hepatitis B (n = 4064), typhoid fever (n = 2718) and yellow fever (n = 2473). 2814 were informed with regard to malaria prevention, including recipes. 7814 persons with complete data on their reason for travel were subjected to more detailed analysis: 75% of them were holiday tourists, 18% travelled as "hikers", 7% were business travellers and less than 1% of them planned a round-the-world tour. The most frequent travel destinations were: Asian or African countries about 33% each, 25% Middle or South America. Thailand, South Africa with Namibia, Brazil and India were the most important countries. The time from health consultation to the beginning of the journey was too short for full vaccine protection against typhoid fever and meningococcal disease in 10% and against rabies in 44% of the consultants. There were no significant differences between holiday tourists, business and "hikers" travellers. CONCLUSION: According to many studies, only one-third of the travellers going abroad, especially to developing countries, obtain travel health information. Hence, the clients of our consultation hours are a positive selection. Nevertheless, great need for improvement could be seen as well. In many of the clients the time from getting health information and vaccination was too short for obtaining complete vaccination protection. People travelling to countries where most hepatitis A infections are obtained and re-imported home, such as Turkey and Tunisia and other Mediterranean countries almost never came for health advice and vaccination. Therefore, public health authorities should improve and increase their publicity campaigns for travel health and vaccination in order to prevent travel-associated infections and re-importation of such diseases.

Protocol for the Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) study: a pragmatic, randomised clinical trial.

INTRODUCTION: Postoperative delirium, arbitrarily defined as occurring within 5 days of surgery, affects up to 50% of patients older than 60 after a major operation. This geriatric syndrome is associated with longer intensive care unit and hospital stay, readmission, persistent cognitive deterioration and mortality. No effective preventive methods have been identified, but preliminary evidence suggests that EEG monitoring during general anaesthesia, by facilitating reduced anaesthetic exposure and EEG suppression, might decrease incident postoperative delirium. This study hypothesises that EEG-guidance of anaesthetic administration prevents postoperative delirium and downstream sequelae, including falls and decreased quality of life. METHODS AND ANALYSIS: This is a 1232 patient, block-randomised, double-blinded, comparative effectiveness trial. Patients older than 60, undergoing volatile agent-based general anaesthesia for major surgery, are eligible. Patients are randomised to 1 of 2 anaesthetic approaches. One group receives general anaesthesia with clinicians blinded to EEG monitoring. The other group receives EEG-guidance of anaesthetic agent administration. The outcomes of postoperative delirium (≤5 days), falls at 1 and 12 months and health-related quality of life at 1 and 12 months will be compared between groups. Postoperative delirium is assessed with the confusion assessment method, falls with ProFaNE consensus questions and quality of life with the Veteran's RAND 12-item Health Survey. The intention-to-treat principle will be followed for all analyses. Differences between groups will be presented with 95% CIs and will be considered statistically significant at a two-sided p<0.05. ETHICS AND DISSEMINATION: Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) is approved by the ethics board at Washington University. Recruitment began in January 2015. Dissemination plans include presentations at scientific conferences, scientific publications, internet-based educational materials and mass media. TRIAL REGISTRATION NUMBER: NCT02241655; Pre-results.

Mechanism of alternating bundle branch aberrancy with atrial bigeminy: electrocardiographic-electrophysiologic correlates.

The mechanism of alternating bundle branch aberrancy in response to atrial bigeminy with fixed coupling intervals lacks adequate explanation. In this report, electrophysiologic studies on five patients with fixed coupled atrial bigeminy, identical impulse intervals arriving at the His bundle and alternating bundle branch aberrancy are presented. The mechanism of alternating bundle branch aberrancy in these patients appears to be alternating changes in the refractory periods of the bundle branches resulting from differences in the activation sequence of the distal bundle branches. These findings provide further insight into the mechanism of aberrant conduction.