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.

COVID-19 Impact on Family Medicine Residents Exam Performance.

BACKGROUND AND OBJECTIVES: The COVID-19 pandemic began interrupting family medicine residency training in spring 2020. While a decline in scores on the American Board of Family Medicine In-Training Examination (ITE) has been observed, whether this decline has translated into the high-stakes Family Medicine Certification Examination (FMCE) is unclear. The goal of this study was to systematically assess the magnitude of COVID-19 impact on medical knowledge acquisition during residency, as measured by the ITE and FMCE. METHODS: A total of 19,101 initial certification candidates from 2017 to 2022 were included in this study. Annual ITE scores and FMCE scores were reported on the same scale (200-800) and served as the outcome measure. We conducted multilevel regression analysis to determine ITE score growth and FMCE scores compared to cohorts prior to COVID-19. RESULTS: During COVID-19, the increase in ITE scores from postgraduate year 2 (PGY-2) to PGY-3 was 25.5 points less, representing a 57.6% relative decrease; and from PGY-3 ITE to FMCE, it was 8.6 points less, a 12.7% relative decrease, compared with cohorts prior to COVID-19. FMCE scores were 6.6 points less during COVID-19, representing a 1.2% relative decline from the average FMCE score prior to COVID-19. CONCLUSIONS: This study found nonsubstantive COVID-19 impact on FMCE scores, but a considerable knowledge acquisition decline during residency, especially during the PGY-2 to PGY-3 period. While COVID-19 impacted learning, our findings indicated that residencies were largely able to remediate knowledge deficits before residents took the FMCE.

Differences in methylation profiles between long-term survivors and short-term survivors of IDH-wild-type glioblastoma.

Background: Patients with glioblastoma (GBM) have a median overall survival (OS) of approximately 16 months. However, approximately 5% of patients survive >5 years. This study examines the differences in methylation profiles between long-term survivors (>5 years, LTS) and short-term survivors (<1 year, STS) with isocitrate dehydrogenase (IDH)-wild-type GBMs. Methods: In a multicenter retrospective analysis, we identified 25 LTS with a histologically confirmed GBM. They were age- and sex-matched to an STS. The methylation profiles of all 50 samples were analyzed with EPIC 850k, classified according to the DKFZ methylation classifier, and the methylation profiles of LTS versus STS were compared. Results: After methylation profiling, 16/25 LTS and 23/25 STS were confirmed to be IDH-wild-type GBMs, all with +7/-10 signature. LTS had significantly increased O6-methylguanine methyltransferase (MGMT) promoter methylation and higher prevalence of FGFR3-TACC3 fusion (P = .03). STS were more likely to exhibit CDKN2A/B loss (P = .01) and higher frequency of NF1 (P = .02) mutation. There were no significant CpGs identified between LTS versus STS at an adjusted P-value of .05. Unadjusted analyses identified key pathways involved in both LTS and STS. The most common pathways were the Hippo signaling pathway and the Wnt pathway in LTS, and GPCR ligand binding and cell-cell signaling in STS. Conclusions: A small group of patients with IDH-wild-type GBM survive more than 5 years. While there are few differences in the global methylation profiles of LTS compared to STS, our study highlights potential pathways involved in GBMs with a good or poor prognosis.

Differences in Physician Performance and Self-rated Confidence on High- and Low-Stakes Knowledge Assessments in Board Certification.

INTRODUCTION: Evidence links assessment to optimal learning, affirming that physicians are more likely to study, learn, and practice skills when some form of consequence ("stakes") may result from an assessment. We lack evidence, however, on how physicians' confidence in their knowledge relates to performance on assessments, and whether this varies based on the stakes of the assessment. METHODS: Our retrospective repeated-measures design compared differences in patterns of physician answer accuracy and answer confidence among physicians participating in both a high-stakes and a low-stakes longitudinal assessment of the American Board of Family Medicine. RESULTS: After 1 and 2 years, participants were more often correct but less confident in their accuracy on a higher-stakes longitudinal knowledge assessment compared with a lower-stakes assessment. There were no differences in question difficulty between the two platforms. Variation existed between platforms in time spent answering questions, use of resources to answer questions, and perceived question relevance to practice. DISCUSSION: This novel study of physician certification suggests that the accuracy of physician performance increases with higher stakes, even as self-reported confidence in their knowledge declines. It suggests that physicians may be more engaged in higher-stakes compared with lower-stakes assessments. With medical knowledge growing exponentially, these analyses provide an example of the complementary roles of higher- and lower-stakes knowledge assessment in supporting physician learning during continuing specialty board certification.

Circulating Oncometabolite 2-hydroxyglutarate as a Potential Biomarker for Isocitrate Dehydrogenase (IDH1/2) Mutant Cholangiocarcinoma.

Isocitrate dehydrogenase (IDH) enzymes catalyze the decarboxylation of isocitrate to alpha-ketoglutarate (αKG). IDH1/2 mutations preferentially convert αKG to R-2-hydroxyglutarate (R2HG), resulting in R2HG accumulation in tumor tissues. We investigated circulating 2-hydroxyglutate (2HG) as potential biomarkers for patients with IDH-mutant (IDHmt) cholangiocarcinoma (CCA). R2HG and S-2-hydroxyglutarate (S2HG) levels in blood and tumor tissues were analyzed in a discovery cohort of patients with IDHmt glioma and CCA. Results were validated in cohorts of patients with CCA and clear-cell renal cell carcinoma. The R2HG/S2HG ratio (rRS) was significantly elevated in tumor tissues, but not in blood for patients with IDHmt glioma, while circulating rRS was elevated in patients with IDHmt CCA. There were overlap distributions of circulating R2HG and total 2HG in patients with both IDHmt and wild-type (IDHwt) CCA, while there was minimal overlap in rRS values between patients with IDHmt and IDHwt CCA. Using the rRS cut-off value of 1.5, the sensitivity of rRS was 90% and specificity was 96.8%. Circulating rRS is significantly increased in patients with IDHmt CCA compare with patients with IDHwt CCA. Circulating rRS is a sensitive and specific surrogate biomarker for IDH1/2 mutations in CCA. It can potentially be used as a tool for monitoring IDH-targeted therapy.

Barriers to the employability of people with disabilities in the South African public service.

Background: South African public sector efforts to employ people with disabilities (PWDs) in the post-apartheid have been less successful, resulting in a poor transformation record during the past 27 years (1994-2021) due to the failure to integrate PWDs into mainstream employment in government departments. Objective: The objective of this article is to identify and highlight some of the barriers to the employability of PWDs in the South African public service. Method: The research was framed as a case study within the transformative research paradigm. A typical department in the Western Cape provincial government was selected for the study. In-depth interviews were conducted with selected top managers within the Western Cape provincial government. Convenience sampling technique of the purposive sampling method was adopted to select targeted respondents (n = 10). Thematic analysis was employed to condense the data collected into a small number of significant themes. Atlas.ti version 7 was also used to enhance the analysis. Results: The study found, among others, that there are conceptual, infrastructural, managerial and organisational factors affecting the employability of PWDs in mainstream public service. Conclusion: The study concludes that barriers to the socio-economic progression of PWDs, including infrastructural and psychosocial factors, continue to prevail and cause the socio-economic marginalisation of PWDs. Contribution: The study contributes towards efforts aimed at the inclusion of PWDs in the workplace by offering both internal and society-wide actions. Internally, successful inclusion of PWDs involves eliminating barriers, removing bureaucracy, initiating management development for disability matters, introducing appropriate talent development measures, and implementing collaborative management of PWDs. External or society-wide measures include campaigns to demystify disability and change attitudes, engage society structures, and improve societal knowledge of disability.

A pilot study on the immune cell proteome of long COVID patients shows changes to physiological pathways similar to those in myalgic encephalomyelitis/chronic fatigue syndrome.

Of those infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ~ 10% develop the chronic post-viral debilitating condition, long COVID (LC). Although LC is a heterogeneous condition, about half of cases have typical post-viral fatigue with onset and symptoms that are very similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). A key question is whether these conditions are closely related. ME/CFS is a post-stressor fatigue condition that arises from multiple triggers. To investigate the pathophysiology of LC, a pilot study of patients (n = 6) and healthy controls (n = 5) has used quantitative proteomics to discover changes in peripheral blood mononuclear cell (PBMC) proteins. A principal component analysis separated all long COVID patients from healthy controls. Analysis of 3131 proteins identified 162 proteins differentially regulated, of which 37 were related to immune functions, and 21 to mitochondrial functions. Markov cluster analysis identified clusters involved in immune system processes, and two aspects of gene expression-spliceosome and transcription. These results were compared with an earlier dataset of 346 differentially regulated proteins in PBMC's from ME/CFS patients (n = 9) analysed by the same methodology. There were overlapping protein clusters and enriched molecular pathways particularly in immune functions, suggesting the two conditions have similar immune pathophysiology as a prominent feature, and mitochondrial functions involved in energy production were affected in both conditions.

Climate Spaces and Cliffs: A Novel Bovine Thermodynamic and Mass Balances Model.

The effects of climate change on animals are typically viewed in terms of survivability and wellbeing. In this study, we broaden that purview to include climate impacts on reproductive capability. There are not only climate spaces for daily function, but climate cliffs that represent reproductive failures in the face of climate warming. This alternative focus suggests that climate warming challenges may be more immediate and profound than initially imagined. This research describes a state-of-the-art mechanistic model, Dairy Niche Mapper (DNM), and independent validation tests. Where test data are absent, the calculated results are consistent with expected responses. Simulations of metabolic chamber conditions reveal the local steady-state impacts of climate and animal variables on milk production capacity, metabolic rate, food consumption and water needs. Simulations of a temperature humidity index (THI) show strengths and limitations of that approach. Broader time- and spatial-scale calculations applied in the western and eastern halves of the northern hemisphere identify current and future monthly latitudinal climate change impacts on milk production potential, feed and water needs in dairy cows of different sizes. Dairy Niche Mapper (DNM) was developed from a broadly tested mechanistic microclimate-animal model, Niche Mapper (NM). DNM provides an improved quantitative understanding of the complex nonlinear interactions of climate variation and dairy bovine properties' effects on current and future milk production, feed and water needs for grazing and confinement dairy operations. DNM outputs include feasible activity times, milk production and water and feed needs of different-sized Holstein cows on high-grain (confinement feeding) versus high-forage (grazing feeding) diets at three arbitrary north latitudes, 12°, 30° and 60°, for North and Central America and for Asia. These three latitudes encompass current northern hemisphere bovine production environments and possible future production locations. The greatest impacts of climate change will be in the low elevations in tropical and subtropical regions. Global regions above 30° and below 60° latitude with reliable rainfall will be least affected by current projected levels of climate change. This work provides the basis for computational animal design for guiding agricultural development via breeding programs, genetic engineering, management options including siting or the manipulation of other relevant environmental and animal variables.

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.

Bispecific T-Cell Engagers and Chimeric Antigen Receptor T-Cell Therapies in Glioblastoma: An Update.

Glioblastoma is the most common malignant primary brain tumor in adults. The prognosis is extremely poor even with standard treatment of maximal safe resection, radiotherapy, and chemotherapy. Recurrence is inevitable within months, and treatment options are very limited. Chimeric antigen receptor T-cell therapy (CART) and bispecific T-cell engagers (TCEs) are two emerging immunotherapies that can redirect T-cells for tumor-specific killing and have shown remarkable success in hematological malignancies and been under extensive study for application in glioblastoma. While there have been multiple clinical trials showing preliminary evidence of safety and efficacy for CART, bispecific TCEs are still in the early stages of clinical testing, with preclinical studies showing very promising results. However, there are multiple shared challenges that need to be addressed in the future, including the route of delivery, antigen escape, the immunosuppressive tumor microenvironment, and toxicity resulting from the limited choice of tumor-specific antigens. Efforts are underway to optimize the design of both these treatments and find the ideal combination therapy to overcome these challenges. In this review, we describe the work that has been performed as well as novel approaches in glioblastoma and in other solid tumors that may be applicable in the future.

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.

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.

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.).

BRAF Mutations in CNS Tumors-Prognostic Markers and Therapeutic Targets.

Gliomas are a heterogeneous group of brain tumors with limited therapeutic options. However, identification of BRAF V600E mutations in a subset of gliomas has provided a genomic-targeted approach for management of these diseases. In this review, we aimed to review the role of BRAF V600E in gliomagenesis, to characterize concurrent genomic alterations and their potential prognostic implications, and to review comprehensively the efficacy data of BRAF inhibitors (combined or not with MEK inhibitors) for the treatment of low- and high-grade gliomas. We also provide a summary of the toxicity of these agents and describe resistance mechanisms that may be circumvented by alternative genomic approaches. Although the efficacy of targeted therapy for management of BRAF V600E-mutant gliomas has mostly been assessed in small retrospective and phase 2 studies with heterogeneous populations, the data generated so far are a proof of concept that genomic-directed therapies improve outcomes of patients with refractory/relapsed glioma and underpin the need of comprehensive genomic assessments for these difficult-to-treat diseases. In the future, the role of targeted therapy in the first-line setting and of genomic-directed therapies to overcome resistance mechanisms should be assessed in well-designed clinical trials.

miRNA-1 promotes acute myeloid leukemia cell pathogenesis through metabolic regulation.

Acute myeloid leukemia (AML) is a heterogeneous and deadly disease characterized by uncontrolled expansion of malignant blasts. Altered metabolism and dysregulated microRNA (miRNA) expression profiles are both characteristic of AML. However, there is a paucity of studies exploring how changes in the metabolic state of the leukemic cells regulate miRNA expression leading to altered cellular behavior. Here, we blocked pyruvate entry into mitochondria by deleting the Mitochondria Pyruvate Carrier (MPC1) gene in human AML cell lines, which decreased Oxidative Phosphorylation (OXPHOS). This metabolic shift also led to increased expression of miR-1 in the human AML cell lines tested. AML patient sample datasets showed that higher miR-1 expression correlates with reduced survival. Transcriptional and metabolic profiling of miR-1 overexpressing AML cells revealed that miR-1 increased OXPHOS, along with key metabolites that fuel the TCA cycle such as glutamine and fumaric acid. Inhibition of glutaminolysis decreased OXPHOS in miR-1 overexpressing MV4-11 cells, highlighting that miR-1 promotes OXPHOS through glutaminolysis. Finally, overexpression of miR-1 in AML cells exacerbated disease in a mouse xenograft model. Together, our work expands current knowledge within the field by uncovering novel connections between AML cell metabolism and miRNA expression that facilitates disease progression. Further, our work points to miR-1 as a potential new therapeutic target that may be used to disrupt AML cell metabolism and thus pathogenesis in the clinic.

Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial.

Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2-20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1-69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7-13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05-0.87). A total of 56.2% (95% CI 41.1-70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406).

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.

Review of 20 years of adult medulloblastoma treatment: Chemotherapy prescription trends and survival.

Background: The historic standard of care for adult medulloblastoma has been considered surgery and radiation, while chemotherapy is increasingly being prescribed. This study reviewed 20-year chemotherapy trends at a high-volume center, as well as overall and progression free-survival. Methods: Adults with medulloblastoma treated at an academic center from January 1, 1999 to -December 31, 2020 were reviewed. Patient baseline data were summarized and Kaplan-Meier estimators were used for survival. Results: Forty-nine patients were included; median age was 30 years and male: female ratio was 2:1. Desmoplastic and classical histologies were most common. Of all patients, 23 (47%) were high risk and 7 (14%) metastatic at diagnosis. Only 10 (20%) received initial chemotherapy, of which 70% were high risk and 30% metastatic, with most treated from 2010 to 2020. Forty percent of initial chemotherapy patients received salvage chemotherapy for recurrence or metastases (of all patients, 49% required salvage). Initial chemotherapy regimens were mainly cisplatin/lomustine/vincristine, and at recurrence cisplatin/etoposide. Median overall survival was 8.6 years (95% CI 7.5-∞), with 1-, 5-, and 10-year survival at 95.8%, 72%, and 46.7%. Median overall survival for those who did not receive initial chemotherapy was 12.4 years and 7.4 years for those who did (P-value .2). Conclusions: Twenty years of adult medulloblastoma treatment was reviewed. Initial chemotherapy patients, most of whom were high risk, trended towards worse survival, but this was nonsignificant. The ideal timing and choice of chemotherapy for adult medulloblastoma is unknown-challenges of administering chemotherapy following photon craniospinal irradiation may have prevented it from becoming routine.

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.