East Asian summer monsoon delivers large abundances of very-short-lived organic chlorine substances to the lower stratosphere.

Deep convection in the Asian summer monsoon is a significant transport process for lifting pollutants from the planetary boundary layer to the tropopause level. This process enables efficient injection into the stratosphere of reactive species such as chlorinated very-short-lived substances (Cl-VSLSs) that deplete ozone. Past studies of convective transport associated with the Asian summer monsoon have focused mostly on the south Asian summer monsoon. Airborne observations reported in this work identify the East Asian summer monsoon convection as an effective transport pathway that carried record-breaking levels of ozone-depleting Cl-VSLSs (mean organic chlorine from these VSLSs ~500 ppt) to the base of the stratosphere. These unique observations show total organic chlorine from VSLSs in the lower stratosphere over the Asian monsoon tropopause to be more than twice that previously reported over the tropical tropopause. Considering the recently observed increase in Cl-VSLS emissions and the ongoing strengthening of the East Asian summer monsoon under global warming, our results highlight that a reevaluation of the contribution of Cl-VSLS injection via the Asian monsoon to the total stratospheric chlorine budget is warranted.

Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma.

BACKGROUND: Isocitrate dehydrogenase (IDH)-mutant grade 2 gliomas are malignant brain tumors that cause considerable disability and premature death. Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes, showed preliminary activity in IDH-mutant gliomas. METHODS: In a double-blind, phase 3 trial, we randomly assigned patients with residual or recurrent grade 2 IDH-mutant glioma who had undergone no previous treatment other than surgery to receive either oral vorasidenib (40 mg once daily) or matched placebo in 28-day cycles. The primary end point was imaging-based progression-free survival according to blinded assessment by an independent review committee. The key secondary end point was the time to the next anticancer intervention. Crossover to vorasidenib from placebo was permitted on confirmation of imaging-based disease progression. Safety was also assessed. RESULTS: A total of 331 patients were assigned to receive vorasidenib (168 patients) or placebo (163 patients). At a median follow-up of 14.2 months, 226 patients (68.3%) were continuing to receive vorasidenib or placebo. Progression-free survival was significantly improved in the vorasidenib group as compared with the placebo group (median progression-free survival, 27.7 months vs. 11.1 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.27 to 0.56; P<0.001). The time to the next intervention was significantly improved in the vorasidenib group as compared with the placebo group (hazard ratio, 0.26; 95% CI, 0.15 to 0.43; P<0.001). Adverse events of grade 3 or higher occurred in 22.8% of the patients who received vorasidenib and in 13.5% of those who received placebo. An increased alanine aminotransferase level of grade 3 or higher occurred in 9.6% of the patients who received vorasidenib and in no patients who received placebo. CONCLUSIONS: In patients with grade 2 IDH-mutant glioma, vorasidenib significantly improved progression-free survival and delayed the time to the next intervention. (Funded by Servier; INDIGO ClinicalTrials.gov number, NCT04164901.).

HAF prevents hepatocyte apoptosis and progression to MASH and HCC through transcriptional regulation of the NF-κB pathway.

BACKGROUND AND AIMS: HCC incidence is increasing worldwide due to the obesity epidemic, which drives metabolic dysfunction-associated steatohepatitis (MASH) that can lead to HCC. However, the molecular pathways driving MASH-HCC are poorly understood. We have previously reported that male mice with haploinsufficiency of hypoxia-associated factor (HAF) ( SART1+/ - ) spontaneously develop MASH-HCC. However, the cell type(s) responsible for HCC associated with HAF loss are unclear. APPROACH AND RESULTS: We generated SART1 -floxed mice, which were crossed with mice expressing Cre recombinase within hepatocytes (Alb-Cre; hepS -/- ) or myeloid cells (LysM-Cre, macS -/- ). HepS - / - mice (both male and female) developed HCC associated with profound inflammatory and lipid dysregulation, suggesting that HAF protects against HCC primarily within hepatocytes. HAF-deficient hepatocytes showed decreased P-p65 and P-p50 in many components of the NF-κB pathway, which was recapitulated using HAF small interfering RNA in vitro. HAF depletion also triggered apoptosis, suggesting that HAF protects against HCC by suppressing hepatocyte apoptosis. We show that HAF regulates NF-κB activity by regulating the transcription of TRADD and RIPK1 . Mice fed a high-fat diet showed marked suppression of HAF, P-p65, and TRADD within their livers after 26 weeks but showed profound upregulation of these proteins after 40 weeks, implicating deregulation of the HAF-NF-κB axis in the progression to MASH. In humans, HAF was significantly decreased in livers with simple steatosis but significantly increased in HCC compared with normal liver. CONCLUSIONS: HAF is a novel transcriptional regulator of the NF-κB pathway and is a key determinant of cell fate during progression to MASH and MASH-HCC.

Effects of a nuclear-disturbed environment on electromagnetic wave propagation through the atmosphere.

This paper investigates the effects of a nuclear-disturbed environment on the transmission of electromagnetic (EM) waves through the atmosphere. An atmospheric nuclear detonation can produce heightened free electron densities in the surrounding atmosphere that can disrupt EM waves that propagate through the disturbed region. Radiation transport models simulated the ionization and free electron densities created in the atmosphere from a 1 MT detonation at heights of burst of 5 km, 25 km, and 75 km. Recombination rates for the free electrons in the atmosphere were applied, from previous work in the literature, to determine the nuclear-induced electron densities as a function of time and space after the detonation. A ray-tracing algorithm was applied to determine the refraction and reflection of waves propagating in the different nuclear-disturbed environments. The simulation results show that the free electron plasma created from an atmospheric nuclear detonation depend on the height of burst of the weapon, the weapon yield, and the time after detonation. Detonations at higher altitudes produce higher free electron densities for greater durations and over larger ranges. The larger the free electron densities, the greater the impact on EM wavelengths in regards to refraction, reflection, and absorption in the atmosphere. An analysis of modern infrastructure and the effects of nuclear-disturbed atmospheres on different signal wavelengths and systems is discussed.

Behavioural responses of a large, heat-sensitive mammal to climatic variation at multiple spatial scales.

Climate warming creates energetic challenges for endothermic species by increasing metabolic and hydric costs of thermoregulation. Although endotherms can invoke an array of behavioural and physiological strategies for maintaining homeostasis, the relative effectiveness of those strategies in a climate that is becoming both warmer and drier is not well understood. In accordance with the heat dissipation limit theory which suggests that allocation of energy to growth and reproduction by endotherms is constrained by the ability to dissipate heat, we expected that patterns of habitat use by large, heat-sensitive mammals across multiple scales are critical for behavioural thermoregulation during periods of potential heat stress and that they must invest a large portion of time to maintain heat balance. To test our predictions, we evaluated mechanisms underpinning the effectiveness of bed sites for ameliorating daytime heat loads and potential heat stress across the landscape while accounting for other factors known to affect behaviour. We integrated detailed data on microclimate and animal attributes of moose Alces alces, into a biophysical model to quantify costs of thermoregulation at fine and coarse spatial scales. During summer, moose spent an average of 67.8% of daylight hours bedded, and selected bed sites and home ranges that reduced risk of experiencing heat stress. For most of the day, shade could effectively mitigate the risk of experiencing heat stress up to 10°C, but at warmer temperatures (up to 20°C) wet soil was necessary to maintain homeostasis via conductive heat loss. Consistent selection across spatial scales for locations that reduced heat load underscores the importance of the thermal environment as a driver of behaviour in this heat-sensitive mammal. Moose in North America have long been characterized as riparian-obligate species because of their dependence on woody plant species for food. Nevertheless, the importance of dissipating endogenous heat loads conductively through wet soil suggests riparian habitats also are critical thermal refuges for moose. Such refuges may be especially important in the face of a warming climate in which both high environmental temperatures and drier conditions will likely exacerbate limits to heat dissipation, especially for large, heat-sensitive animals.

Elevations in End-Tidal CO 2 With CO 2 Use During Pediatric Endoscopy With Airway Protection: Is This Physiologically Significant?

BACKGROUND: Inflation of the gastrointestinal lumen is vital for proper visualization during endoscopy. Air, insufflated via the endoscope, is gradually being replaced with carbon dioxide (CO 2 ) in many centers, with the intention of minimizing post-procedural discomfort due to retained gas. Recent studies suggest that the use of CO 2 during pediatric esophagogastroduodenoscopy (EGD) with an unprotected airway is associated with transient elevations in exhaled CO 2 (end-tidal CO 2 , EtCO 2 ), raising safety concerns. One possible explanation for these events is eructation of insufflation gas from the stomach. OBJECTIVES: To distinguish eructated versus absorbed CO 2 by sampling EtCO 2 from a protected airway with either laryngeal mask airway (LMA) or endotracheal tube (ETT), and to observe for changes in minute ventilation (MV) to exclude hypoventilation events. METHODS: Double-blinded, randomized clinical trial of CO 2 versus air insufflation for EGD with airway protection by either LMA or ETT. Tidal volume, respiratory rate, MV, and EtCO 2 were automatically recorded every minute. Cohort demographics were described with descriptive characteristics. Variables including the percent of children with peak, transient EtCO 2 ≥ 60 mmHg were compared between groups. RESULTS: One hundred ninety-five patients were enrolled for 200 procedures. Transient elevations in EtCO 2 of ≥60 mmHg were more common in the CO 2 group, compared to the air group (16% vs 5%, P = 0.02), but were mostly observed with LMA and less with ETT. Post-procedure pain was not different between groups, but flatulence was reported more with air insufflation ( P = 0.004). CONCLUSION: Transient elevations in EtCO 2 occur more often with CO 2 than with air insufflation during pediatric EGD despite protecting the airway with an LMA or, to a lesser degree, with ETT. These elevations were not associated with changes in MV. Although no adverse clinical effects from CO 2 absorption were observed, these findings suggest that caution should be exercised when considering the use of CO 2 insufflation, especially since the observed benefits of using this gas were minimal.

The Value of Etoposide for Recurrent Glioma.

BACKGROUND: For multiply recurrent glioma, options are few and choices are very limited. Etoposide in combination with carboplatin and/or bevacizumab has been evaluated in recurrent glioma with modest efficacy. This retrospective study describes the efficacy of etoposide monotherapy in adults with multiply recurrent diffuse glioma. METHODS: In this single center retrospective series, all adult patients with radiographically proven multiply recurrent diffuse glioma (WHO grade 2-4) treated with etoposide between 2016 and 2020 were evaluated. Progression-free survival (PFS) and overall survival (OS) after initiating etoposide were calculated for the total group and for different histologic tumor types. In addition, treatment-related toxicity was recorded. RESULTS: Totally, 48 patients with a median age 43 years-old (range 24-78) were included. Etoposide was given as 3rd line of treatment in 18 patients (37.5%) and as 4th or 5th line of treatment in 30 patients (62.5%). The majority were diagnosed with a glioblastoma, WHO grade 4 (27, 56.3%). The median PFS was 8.6 weeks (95% confidence interval [CI]: 8.3-8.9). The median OS of the total population was 4.0 months (95% CI: 2.4-5.6). Patients with an oligodendroglioma had the best OS (median 13 months), compared to astrocytoma and glioblastoma, but the difference was not statistically significant (p = 0.15). Etoposide was stopped due to progression in the majority of the patients (81.3%). Only 1 patient had a grade 3 toxicity. CONCLUSION: Etoposide is a well-tolerated chemotherapy in heavily pretreated patients with multiply recurrent glioma and could be considered when other options are not available. OS was 4 months after initiating etoposide.

Bevacizumab for Cerebral Radionecrosis: A Single-Center Experience.

BACKGROUND: Cerebral radionecrosis, a subacute or late effect of radiotherapy, can be debilitating and difficult to treat. Steroids can reduce symptoms, but have significant long-term side effects. Bevacizumab has been shown to reduce edema and other radiologic features associated with radionecrosis and improve patient symptoms. We report our experience using bevacizumab for cerebral radionecrosis. METHODS: We retrospectively reviewed the charts of all patients treated at our institution with bevacizumab for non-glioma-associated cerebral radionecrosis. We recorded change in symptoms, change in steroids, change in performance status, time to tumor progression, and time to death. We delineated the volume of necrosis pre- and post-bevacizumab on T1-post-gadolinium and fluid-attenuated inversion recovery (FLAIR) MRI scans. RESULTS: We identified 15 patients, 8 with brain metastases, 6 with meningioma, and 1 with nasopharyngeal carcinoma. Most received four doses of bevacizumab, 7.5 mg/kg q 3 weeks × 4 doses. Neuroimaging demonstrated a reduced T1 gadolinium-enhancing volume and edema in 14/15 patients (the average reduction in T1-post-gadolinium volume was 3.0 cm3, and average reduction in FLAIR volume was 27.9 cm3). There was no appreciable change in patient performance status. Steroid doses decreased in five of nine patients. There was a high rate (26%) of adverse events, including pulmonary embolism, stroke, and wound dehiscence. The median progression-free survival was 6.5 months. CONCLUSION: Although bevacizumab is commonly prescribed for cerebral radionecrosis, in our retrospective cohort, the clinical benefits were modest and there was significant toxicity.

Space-based quantum networking in the presence of a nuclear disturbed environment.

Space-based quantum networks provide a means for near-term long-distance transmission of quantum information. This article analyzed the performance of a downlink quantum network between a low-Earth-orbit satellite and an observatory operating in less-than-ideal atmospheric conditions. The effects from fog, haze, and a nuclear disturbed environment on the long-range distribution of quantum states were investigated. A density matrix that estimates the quantum state by capturing the effects from increased signal loss and elevated background noise to estimate the state fidelity of the transmitted quantum state was developed. It was found that the nuclear disturbed environment and other atmospheric effects have a degrading effect on the quantum state. These environments impede the ability to perform quantum communications for the duration of the effects. In the case of the nuclear disturbed environment, the nuclear effects subside quickly, and network performance should return to normal by the next satellite pass.

Incorporating species-specific morphology improves model predictions of thermal and hydric stress in the sand fiddler crab, Leptuca pugilator.

Understanding where and why organisms are experiencing thermal and hydric stress is critical for predicting species' responses to climate change. Biophysical models that explicitly link organismal functional traits like morphology, physiology, and behavior to environmental conditions can provide valuable insight into determinants of thermal and hydric stress. Here we use a combination of direct measurements, 3D modeling, and computational fluid dynamics to develop a detailed biophysical model of the sand fiddler crab, Leptuca pugilator. We compare the detailed model's performance to a model using a simpler ellipsoidal approximation of a crab. The detailed model predicted crab body temperatures within 1 °C of observed in both laboratory and field settings; the ellipsoidal approximation model predicted body temperatures within 2 °C of observed body temperatures. Model predictions are meaningfully improved through efforts to incorporate species-specific morphological properties rather than relying on simple geometric approximations. Experimental evaporative water loss (EWL) measurements indicate that L. pugilator can modify its permeability to EWL as a function of vapor density gradients, providing novel insight into physiological thermoregulation in the species. Body temperature and EWL predictions made over the course of a year at a single site demonstrate how such biophysical models can be used to explore mechanistic drivers and spatiotemporal patterns of thermal and hydric stress, providing insight into current and future distributions in the face of climate change.

Secreted Amyloid Precursor Protein Alpha (sAPPα) Regulates the Cellular Proteome and Secretome of Mouse Primary Astrocytes.

Secreted amyloid precursor protein alpha (sAPPα), processed from a parent mammalian brain protein, amyloid precursor protein, can modulate learning and memory. Recently it has been shown to modulate the transcriptome and proteome of human neurons, including proteins with neurological functions. Here, we analysed whether the acute administration of sAPPα facilitated changes in the proteome and secretome of mouse primary astrocytes in culture. Astrocytes contribute to the neuronal processes of neurogenesis, synaptogenesis and synaptic plasticity. Cortical mouse astrocytes in culture were exposed to 1 nM sAPPα, and changes in both the whole-cell proteome (2 h) and the secretome (6 h) were identified with Sequential Window Acquisition of All Theoretical Fragment Ion Spectra-Mass Spectrometry (SWATH-MS). Differentially regulated proteins were identified in both the cellular proteome and secretome that are involved with neurologically related functions of the normal physiology of the brain and central nervous system. Groups of proteins have a relationship to APP and have roles in the modulation of cell morphology, vesicle dynamics and the myelin sheath. Some are related to pathways containing proteins whose genes have been previously implicated in Alzheimer's disease (AD). The secretome is also enriched in proteins related to Insulin Growth Factor 2 (IGF2) signaling and the extracellular matrix (ECM). There is the promise that a more specific investigation of these proteins will help to understand the mechanisms of how sAPPα signaling affects memory formation.

Towards a Better Understanding of the Complexities of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition arising in susceptible people, predominantly following viral infection, but also other stressful events. The susceptibility factors discussed here are both genetic and environmental although not well understood. While the dysfunctional physiology in ME/CFS is becoming clearer, understanding has been hampered by different combinations of symptoms in each affected person. A common core set of mainly neurological symptoms forms the modern clinical case definition, in the absence of an accessible molecular diagnostic test. This landscape has prompted interest in whether ME/CFS patients can be classified into a particular phenotype/subtype that might assist better management of their illness and suggest preferred therapeutic options. Currently, the same promising drugs, nutraceuticals, or behavioral therapies available can be beneficial, have no effect, or be detrimental to each individual patient. We have shown that individuals with the same disease profile exhibit unique molecular changes and physiological responses to stress, exercise and even vaccination. Key features of ME/CFS discussed here are the possible mechanisms determining the shift of an immune/inflammatory response from transient to chronic in ME/CFS, and how the brain and CNS manifests the neurological symptoms, likely with activation of its specific immune system and resulting neuroinflammation. The many cases of the post viral ME/CFS-like condition, Long COVID, following SARS-CoV-2 infection, and the intense research interest and investment in understanding this condition, provide exciting opportunities for the development of new therapeutics that will benefit ME/CFS patients.

Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial.

BACKGROUND: Effective treatments are needed to improve outcomes for high-grade glioma and low-grade glioma. The activity and safety of dabrafenib plus trametinib were evaluated in adult patients with recurrent or progressive BRAFV600E mutation-positive high-grade glioma and low-grade glioma. METHODS: This study is part of an ongoing open-label, single-arm, phase 2 Rare Oncology Agnostic Research (ROAR) basket trial at 27 community and academic cancer centres in 13 countries (Austria, Belgium, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, South Korea, Spain, Sweden, and the USA). The study enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Patients with BRAFV600E mutation-positive high-grade glioma and low-grade glioma received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until unacceptable toxicity, disease progression, or death. In the high-grade glioma cohort, patients were required to have measurable disease at baseline using the Response Assessment in Neuro-Oncology high-grade glioma response criteria and have been treated previously with radiotherapy and first-line chemotherapy or concurrent chemoradiotherapy. Patients with low-grade glioma were required to have measurable non-enhancing disease (except pilocytic astrocytoma) at baseline using the Response Assessment in Neuro-Oncology low-grade glioma criteria. The primary endpoint, in the evaluable intention-to-treat population, was investigator-assessed objective response rate (complete response plus partial response for high-grade glioma and complete response plus partial response plus minor response for low-grade glioma). This trial is ongoing, but is closed for enrolment, NCT02034110. FINDINGS: Between April 17, 2014, and July 25, 2018, 45 patients (31 with glioblastoma) were enrolled into the high-grade glioma cohort and 13 patients were enrolled into the low-grade glioma cohort. The results presented here are based on interim analysis 16 (data cutoff Sept 14, 2020). In the high-grade glioma cohort, median follow-up was 12·7 months (IQR 5·4-32·3) and 15 (33%; 95% CI 20-49) of 45 patients had an objective response by investigator assessment, including three complete responses and 12 partial responses. In the low-grade glioma cohort, median follow-up was 32·2 months (IQR 25·1-47·8). Nine (69%; 95% CI 39-91) of 13 patients had an objective response by investigator assessment, including one complete response, six partial responses, and two minor responses. Grade 3 or worse adverse events were reported in 31 (53%) patients, the most common being fatigue (five [9%]), decreased neutrophil count (five [9%]), headache (three [5%]), and neutropenia (three [5%]). INTERPRETATION: Dabrafenib plus trametinib showed clinically meaningful activity in patients with BRAFV600E mutation-positive recurrent or refractory high-grade glioma and low-grade glioma, with a safety profile consistent with that in other indications. BRAFV600E testing could potentially be adopted in clinical practice for patients with glioma. FUNDING: Novartis.

Broadband polarization-entangled source for C+L-band flex-grid quantum networks.

The rising demand for transmission capacity in optical networks has motivated steady interest in expansion beyond the standard C-band (1530-1565 nm) into the adjacent L-band (1565-1625 nm) for an approximate doubling of capacity in a single stroke. However, in the context of quantum networking, the L-band has yet to be fully leveraged with the suite of advanced tools for characterization and management available from classical lightwave communications. In this work, we demonstrate an ultrabroadband two-photon source integrating both C- and L-band wavelength-selective switches for complete control of spectral routing and allocation across 7.5 THz in a single setup. Polarization state tomography of all 150 pairs of 25-GHz-wide channels reveals an average fidelity of 0.98 and total distillable entanglement greater than 181 kebits/s. This source is explicitly designed for flex-grid optical networks and can facilitate optimal utilization of entanglement resources across the full C+L-band.

Clinical features of glioma patients who develop pneumocystis pneumonia with temozolomide chemoradiotherapy.

INTRODUCTION: The treatment of glioma with temozolomide chemoradiotherapy predisposes patients to pneumocystis pneumonia (PCP). Because PCP is a rare outcome, very little is known about specific clinical risk factors for its development in patients with glioma. METHODS: We performed a population-based retrospective cohort study of glioma patients undergoing temozolomide chemoradiotherapy 2005 to 2019 in Ontario, Canada. We compared clinical features of patients who did not versus did develop PCP within one year of chemoradiotherapy. We examined the overall survival of patients by PCP status. RESULTS: There were 5130 patients with glioma treated with temozolomide chemoradiotherapy. Ultimately, 38 patients (0.74%) were diagnosed with PCP within 1 year of chemoradiotherapy. Most (71%) infections occurred between 0-90 days and 29% occurred between 91-365 days. Median survival was 12.3 months in patients who did not develop PCP and 8.6 months in those who did develop PCP (P < 0.001). Trough 90-day lymphocyte counts were lower in the PCP group. When the lymphocytes fell below 0.19 × 109/L (or 0.25 × 109/L among patients without PCP prophylaxis), the risk of PCP was > 3.5%. CONCLUSIONS: Pneumocystis pneumonia is rare in glioma patients who receive temozolomide chemoradiotherapy. Infection is associated with shorter survival and the development of lymphopenia. Reserving PCP prophylaxis for patients whose lymphocyte counts drop below 0.25 × 109/L may be a reasonable strategy.

Incidence, molecular characteristics, and imaging features of "clinically-defined pseudoprogression" in newly diagnosed glioblastoma treated with chemoradiation.

PURPOSE: Pseudoprogression (PsP) remains an elusive and clinically important, yet ill-defined, phenomena that, generally, involves a period of early radiographic progression (enhancement) followed by a period of radiographic stability or regression. In the current study, we utilized data from the control arm of a phase III clinical trial in newly-diagnosed glioblastoma to explore imaging characteristics of "clinically-defined PsP", or early radiographic progression (PFS < 6 months from chemoradiation) followed by a long post-progression residual overall survival (ROS > 12 months). METHODS: One hundred sixty-nine patients with newly-diagnosed GBM from the control arm of the AVAglio trial (NCT00943826) who presented with early radiographic progressive disease (PD) (< 6 months) were included. Clinical characteristics, topographical patterns, and radiomic features were compared between newly-diagnosed GBM exhibiting early PD and early death (< 12-month ROS, "true PD") with those exhibiting early PD and a long residual survival (> 12-month ROS, "clinically-defined PsP"). RESULTS: "Clinically-defined PsP" occurred to 38.5% of patients with early PD, and was more associated with MGMT methylation (P = 0.02), younger age (P = 0.003), better neurological performance (P = 0.01), and lower contrast-enhancing tumor volume (P = 0.002) at baseline. GBM showing "true PD" occurred more frequently in the right internal capsule, thalamus, lentiform nucleus, and temporal lobe than those with "clinical PsP". Radiomic analysis predicted "clinical PsP" with > 70% accuracy on the validation dataset. CONCLUSION: Patients with early PD that eventually exhibit "clinically-defined PsP" have distinct clinical, molecular, and MRI characteristics. This information may be useful for treating clinicians to better understand the potential risks and outcome in patients exhibiting early radiographic changes following chemoradiation.

Transient End-Tidal Carbon Dioxide Elevation During Pediatric Upper Endoscopy With Carbon Dioxide Insufflation: Is It True Hypercapnia?

BACKGROUND: Endoscopic insufflation, long performed using air, is being replaced by carbon dioxide (CO2) at many pediatric centers, despite limited published data on its use in children. We have previously demonstrated that CO2 use during esophagogastroduodenoscopy (EGD) in non-intubated children is associated with transient elevations of end-tidal CO2 (EtCO2). This observation raised concerns about possible CO2 inhalation and systemic absorption. Here, we investigate this concern by concurrently measuring both EtCO2 and transcutaneous CO2 (tCO2) during upper endoscopic procedures in children. AIM: To determine if elevations in EtCO2 levels seen in non-intubated children undergoing CO2 insufflation during EGD are associated with elevated systemic CO2 levels. METHODS: Double-blinded, prospective, randomized clinical trial. Children were randomized 1:1 to receive either CO2 or air for endoscopic insufflation. EtCO2 was sampled with a CO2-sampling nasal cannula and tCO2 was monitored using the Radiometer transcutaneous monitoring device. RESULTS: Fifty nine patients were enrolled; 30 patients in the CO2 insufflation group and 29 in the air group. All patients underwent a procedure involving an EGD. Transient elevations in EtCO2 (defined as >60 mmHg) were observed only in the CO2 insufflation group. This contrasted with the similar elevations of tCO2 between the CO2 and air insufflation groups. None of these events were of clinically significant magnitude or duration. CONCLUSION: This study demonstrates that the observed transient elevations in EtCO2 seen during EGD in non-intubated children receiving CO2 insufflation are most likely measurements of eructated CO2 without evidence of excessive systemic absorption of CO2.

Dynamic Epigenetic Changes during a Relapse and Recovery Cycle in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease with variable severity. Patients experience frequent relapses where symptoms increase in severity, leaving them with a marked reduction in quality of life. Previous work has investigated molecular differences between ME/CFS patients and healthy controls, but not the dynamic changes specific to each individual patient. We applied precision medicine here to map genomic changes in two selected ME/CFS patients through a period that contained a relapse recovery cycle. DNA was isolated from two patients and a healthy age/gender matched control at regular intervals and captured the patient relapse in each case. Reduced representation DNA methylation sequencing profiles were obtained spanning the relapse recovery cycle. Both patients showed a significantly larger methylome variability (10-20-fold) through the period of sampling compared with the control. During the relapse, changes in the methylome profiles of the two patients were detected in regulatory-active regions of the genome that were associated, respectively, with 157 and 127 downstream genes, indicating disturbed metabolic, immune and inflammatory functions. Severe health relapses in the ME/CFS patients resulted in functionally important changes in their DNA methylomes that, while differing between the two patients, led to very similar compromised physiology. DNA methylation as a signature of disease variability in ongoing ME/CFS may have practical applications for strategies to decrease relapse frequency.

Beta-Amyloid (Aß1-42) Increases the Expression of NKCC1 in the Mouse Hippocampus.

Alzheimer's disease (AD) is a neurodegenerative disorder with an increasing need for developing disease-modifying treatments as current therapies only provide marginal symptomatic relief. Recent evidence suggests the γ-aminobutyric acid (GABA) neurotransmitter system undergoes remodeling in AD, disrupting the excitatory/inhibitory (E/I) balance in the brain. Altered expression levels of K-Cl-2 (KCC2) and N-K-Cl-1 (NKCC1), which are cation-chloride cotransporters (CCCs), have been implicated in disrupting GABAergic activity by regulating GABAA receptor signaling polarity in several neurological disorders, but these have not yet been explored in AD. NKCC1 and KCC2 regulate intracellular chloride [Cl-]i by accumulating and extruding Cl-, respectively. Increased NKCC1 expression in mature neurons has been reported in these disease conditions, and bumetanide, an NKCC1 inhibitor, is suggested to show potential therapeutic benefits. This study used primary mouse hippocampal neurons to explore if KCC2 and NKCC1 expression levels are altered following beta-amyloid (Aß1-42) treatment and the potential neuroprotective effects of bumetanide. KCC2 and NKCC1 expression levels were also examined in 18-months-old male C57BL/6 mice following bilateral hippocampal Aß1-42 stereotaxic injection. No change in KCC2 and NKCC1 expression levels were observed in mouse hippocampal neurons treated with 1 nM Aß1-42, but NKCC1 expression increased 30-days post-Aß1-42-injection in the CA1 region of the mouse hippocampus. Primary mouse hippocampal cultures were treated with 1 nM Aß1-42 alone or with various concentrations of bumetanide (1 µM, 10 µM, 100 µM, 1 mM) to investigate the effect of the drug on cell viability. Aß1-42 produced 53.1 ± 1.4% cell death after 5 days, and the addition of bumetanide did not reduce this. However, the drug at all concentrations significantly reduced cell viability, suggesting bumetanide is highly neurotoxic. In summary, these results suggest that chronic exposure to Aß1-42 alters the balance of KCC2 and NKCC1 expression in a region-and layer-specific manner in mouse hippocampal tissue; therefore, this process most likely contributes to altered hippocampal E/I balance in this model. Furthermore, bumetanide induces hippocampal neurotoxicity, thus questioning its suitability for AD therapy. Further investigations are required to examine the effects of Aß1-42 on KCC2 and NKCC1 expression and whether targeting CCCs might offer a therapeutic approach for AD.

Adjuvant and concurrent temozolomide for 1p/19q non-co-deleted anaplastic glioma (CATNON; EORTC study 26053-22054): second interim analysis of a randomised, open-label, phase 3 study.

BACKGROUND: The CATNON trial investigated the addition of concurrent, adjuvant, and both current and adjuvant temozolomide to radiotherapy in adults with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas. The benefit of concurrent temozolomide chemotherapy and relevance of mutations in the IDH1 and IDH2 genes remain unclear. METHODS: This randomised, open-label, phase 3 study done in 137 institutions across Australia, Europe, and North America included patients aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0-2. Patients were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59·4 Gy in 33 fractions; three-dimensional conformal radiotherapy or intensity-modulated radiotherapy), radiotherapy with concurrent oral temozolomide (75 mg/m2 per day), radiotherapy with adjuvant oral temozolomide (12 4-week cycles of 150-200 mg/m2 temozolomide given on days 1-5), or radiotherapy with both concurrent and adjuvant temozolomide. Patients were stratified by institution, WHO performance status score, age, 1p loss of heterozygosity, the presence of oligodendroglial elements on microscopy, and MGMT promoter methylation status. The primary endpoint was overall survival adjusted by stratification factors at randomisation in the intention-to-treat population. A second interim analysis requested by the independent data monitoring committee was planned when two-thirds of total required events were observed to test superiority or futility of concurrent temozolomide. This study is registered with ClinicalTrials.gov, NCT00626990. FINDINGS: Between Dec 4, 2007, and Sept 11, 2015, 751 patients were randomly assigned (189 to radiotherapy alone, 188 to radiotherapy with concurrent temozolomide, 186 to radiotherapy and adjuvant temozolomide, and 188 to radiotherapy with concurrent and adjuvant temozolomide). Median follow-up was 55·7 months (IQR 41·0-77·3). The second interim analysis declared futility of concurrent temozolomide (median overall survival was 66·9 months [95% CI 45·7-82·3] with concurrent temozolomide vs 60·4 months [45·7-71·5] without concurrent temozolomide; hazard ratio [HR] 0·97 [99·1% CI 0·73-1·28], p=0·76). By contrast, adjuvant temozolomide improved overall survival compared with no adjuvant temozolomide (median overall survival 82·3 months [95% CI 67·2-116·6] vs 46·9 months [37·9-56·9]; HR 0·64 [95% CI 0·52-0·79], p<0·0001). The most frequent grade 3 and 4 toxicities were haematological, occurring in no patients in the radiotherapy only group, 16 (9%) of 185 patients in the concurrent temozolomide group, and 55 (15%) of 368 patients in both groups with adjuvant temozolomide. No treatment-related deaths were reported. INTERPRETATION: Adjuvant temozolomide chemotherapy, but not concurrent temozolomide chemotherapy, was associated with a survival benefit in patients with 1p/19q non-co-deleted anaplastic glioma. Clinical benefit was dependent on IDH1 and IDH2 mutational status. FUNDING: Merck Sharpe & Dohme.