Etiology of hospital mortality in children living in low- and middle-income countries: a systematic review and meta-analysis.

In 2019, 80% of the 7.4 million global child deaths occurred in low- and middle-income countries (LMICs). Global and regional estimates of cause of hospital death and admission in LMIC children are needed to guide global and local priority setting and resource allocation but are currently lacking. The study objective was to estimate global and regional prevalence for common causes of pediatric hospital mortality and admission in LMICs. We performed a systematic review and meta-analysis to identify LMIC observational studies published January 1, 2005-February 26, 2021. Eligible studies included: a general pediatric admission population, a cause of admission or death, and total admissions. We excluded studies with data before 2,000 or without a full text. Two authors independently screened and extracted data. We performed methodological assessment using domains adapted from the Quality in Prognosis Studies tool. Data were pooled using random-effects models where possible. We reported prevalence as a proportion of cause of death or admission per 1,000 admissions with 95% confidence intervals (95% CI). Our search identified 29,637 texts. After duplicate removal and screening, we analyzed 253 studies representing 21.8 million pediatric hospitalizations in 59 LMICs. All-cause pediatric hospital mortality was 4.1% [95% CI 3.4%-4.7%]. The most common causes of mortality (deaths/1,000 admissions) were infectious [12 (95% CI 9-14)]; respiratory [9 (95% CI 5-13)]; and gastrointestinal [9 (95% CI 6-11)]. Common causes of admission (cases/1,000 admissions) were respiratory [255 (95% CI 231-280)]; infectious [214 (95% CI 193-234)]; and gastrointestinal [166 (95% CI 143-190)]. We observed regional variation in estimates. Pediatric hospital mortality remains high in LMICs. Global child health efforts must include measures to reduce hospital mortality including basic emergency and critical care services tailored to the local disease burden. Resources are urgently needed to promote equity in child health research, support researchers, and collect high-quality data in LMICs to further guide priority setting and resource allocation.

Ascites is a poor prognostic factor in advanced pancreatic adenocarcinoma and may be undertreated: a prospective cohort study.

Pancreatic ductal adenocarcinoma (PDAC) is associated with significant morbidity and mortality as most patients present with advanced disease. The development of ascites has been associated with poor outcomes and further characterization and contemporary management strategies are needed. 437 patients enrolled in the Gastrointestinal Biobank at Cedars-Sinai Medical Center who had epithelial pancreatic malignancy were included in the prospective cohort group. 41.7% of patients included in the study developed ascites. The majority (>80%) of ascites patients had high serum-ascites albumin gradient (SAAG) ascites. In both univariate and multivariate analysis, history of >=1 form of chemotherapy was significantly associated with ascites. Estimated median OS in patients with ascites was significantly lower than in patients without ascites, 473 days vs. 573 days, and ascites had a HR of 1.37. Patients with ascites who received diuretics and indwelling peritoneal catheter had an estimated median survival of 133 days from diagnosis of ascites, and those that received only the indwelling peritoneal catheter without diuretics had an estimated median survival of only 54 days. The estimated median survival from the diagnosis of ascites was 92 days and median time to puncture was 7 days. Median time from first tap to death was 45 days. The use of diuretics is lower than would be expected for PDAC patients with elevated SAAG. Other therapies such as beta blockers should be investigated in this subset of patients. The etiology of ascites in these patients is poorly understood and further research is needed to establish treatment guidelines and improve outcomes.

Meningioma transcriptomic landscape demonstrates novel subtypes with regional associated biology and patient outcome.

Meningiomas, although mostly benign, can be recurrent and fatal. World Health Organization (WHO) grading of the tumor does not always identify high-risk meningioma, and better characterizations of their aggressive biology are needed. To approach this problem, we combined 13 bulk RNA sequencing (RNA-seq) datasets to create a dimension-reduced reference landscape of 1,298 meningiomas. The clinical and genomic metadata effectively correlated with landscape regions, which led to the identification of meningioma subtypes with specific biological signatures. The time to recurrence also correlated with the map location. Further, we developed an algorithm that maps new patients onto this landscape, where the nearest neighbors predict outcome. This study highlights the utility of combining bulk transcriptomic datasets to visualize the complexity of tumor populations. Further, we provide an interactive tool for understanding the disease and predicting patient outcomes. This resource is accessible via the online tool Oncoscape, where the scientific community can explore the meningioma landscape.

Meningioma: International Consortium on Meningiomas (ICOM) consensus review on scientific advances & treatment paradigms for clinicians, researchers, and patients.

Meningiomas are the most common primary intracranial tumors in adults and are increasing in incidence due to the aging population and the rising availability of neuroimaging. While most exhibit non-malignant behaviour, a subset of meningiomas are biologically aggressive and lead to significant neurological morbidity and mortality. In recent years, meaningful advances in our understanding of the biology of these tumors have led to the incorporation of molecular biomarkers into their grading and prognostication. However, unlike other central nervous system tumors, a unified molecular taxonomy for meningiomas has not yet been established and remains an overarching goal of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy-Not Official WHO (cIMPACT-NOW) working group. There also remains clinical equipoise on how specific meningioma cases and patient populations should be optimally managed. To address these existing gaps, members of the International Consortium on Meningiomas (ICOM) including field-leading experts, have prepared a comprehensive consensus narrative review directed towards clinicians, researchers, and patients. Included in this manuscript are detailed overviews of proposed molecular classifications, novel biomarkers, contemporary treatment strategies, trials on systemic therapies, health-related quality of life studies, and management strategies for unique meningioma patient populations. In each section we discuss the current state of knowledge as well as ongoing clinical and research challenges to road map future directions for further investigation.

Metabologenomic characterization uncovers a clinically aggressive IDH mutant glioma subtype.

Mutations in the pivotal metabolic isocitrate dehydrogenase (IDH) enzymes are recognized to drive the molecular footprint of diffuse gliomas, and patients with IDH mutant gliomas have overall favorable outcomes compared to patients with IDH wild-type tumors. However, survival still varies widely among patients with IDH mutated tumors. Here, we aimed to characterize molecular signatures that explain the range of IDH mutant gliomas. By integrating matched epigenome-wide methylome, transcriptome, and global metabolome data in 154 patients with gliomas, we identified a group of IDH mutant gliomas with globally altered metabolism that resembled IDH wild-type tumors. IDH-mutant gliomas with altered metabolism have significantly shorter overall survival from their IDH mutant counterparts that is not fully accounted for by recognized molecular prognostic markers of CDKN2A/B loss and glioma CpG Island Methylator Phenotype (GCIMP) status. IDH-mutant tumors with dysregulated metabolism harbored distinct epigenetic alterations that converged to drive proliferative and stem-like transcriptional profiles, providing a window to target novel dependencies in gliomas.

Management of Left Ventricular Intramural Hematoma- an Unusual Complication of Complete Atrioventricular Septal Defect Repair in a Child.

Postoperative survival for complete atrioventricular septal defect (cAVSD) is excellent. Common complications of surgery include valvular stenosis/regurgitation, left ventricular outflow tract obstruction, arrythmias, and residual defects. We report a challenging case of a 7-month old girl with Trisomy 21, preoperative obstructive sleep apnea with severe pulmonary hypertension, who underwent AVSD repair and required veno-arterial extracorporeal membrane oxygenation (V-A ECMO) while unable to come off cardiopulmonary bypass and developed left ventricular intramural hematoma during the course. This case highlights the challenges in management of an unusual complication.

Corrigendum: Grade 3 Meningioma Survival and Recurrence Outcomes in an International Multicenter Cohort.

[This corrects the article DOI: 10.1055/s-0044-1779888.].

Improving Nurse-Physician Bedside Communication Using a Patient Experience Quality Improvement Pilot Project at an Academic Medical Center.

Introduction  Patient experience is a crucial aspect of healthcare delivery, and it encompasses various elements that contribute to a patient's perception of the care they receive. Patient satisfaction and patient experience are related but distinct concepts. Patient experience focuses on whether specific aspects of care occurred, while patient satisfaction gauges whether patient expectations were met. It goes beyond mere satisfaction and delves into the broader aspects of how patients interact with the healthcare system and the quality of those interactions, with health plans, doctors, nurses, and staff in various healthcare facilities. Other aspects highly valued by patients include elements such as timely access to care and information, good communication with the healthcare team, and friendly staff. Patient experience can influence both the healthcare and financial outcomes of healthcare facilities. It is well understood that positive patient experiences may lead to better care adherence, improved clinical outcomes, enhanced patient safety, and better care coordination. Payers, both public and private, have recognized the importance of patient experience. Improving patient experience benefits healthcare facilities financially by strengthening customer loyalty, building a positive reputation, increasing referrals, and reducing medical malpractice risk and staff turnover.  Methodology A multidisciplinary retrospective quality improvement initiative was initiated to effectively improve nurse-physician communication and organizational outcomes in several hospital units. Results Using an innovative staff-developed and driven acronym, IMOMW (I'm on my way), the study demonstrated significant positive outcomes such as increased Epic documentation (Epic Systems Corporation, Verona, Wisconsin, United States) of physician and nursing rounding by 13%, a 10.5% rise in recommend facility net promoter score (NPS) patient experience survey scores, 13.4% increase in physician and nurse team communication, 5.4% increase in nursing communication, and a 5.3% increase in physician communication. Moreover, pilot units outperformed the control group consisting of medical-surgical units located in newer portions of the hospital. Conclusion This quality improvement study demonstrates improved interdisciplinary nurse-physician communication, Epic documentation, and patient experience scores. Further investigation is necessary to better understand the specific factors and/or processes that influence the sustainability of interventions that improve nurse-physician communication and patient experience.

Molecular prognostication in grade 3 meningiomas and p16/MTAP immunohistochemistry for predicting CDKN2A/B status.

Background: The World Health Organization 2021 classification introduces molecular grading criteria for anaplastic meningiomas, including TERT promoter (TERTp) mutations and CDKN2A/B homozygous deletion. Additional adverse prognostic factors include H3K27me3 and BAP1 loss. The aim of this study was to explore whether these molecular alterations stratified clinical outcomes in a single-center cohort of grade 3 meningiomas. Additionally, we examined whether p16 and MTAP immunohistochemistry can predict CDKN2A/B status. Methods: Clinical and histopathological information was obtained from the electronic medical records of grade 3 meningiomas resected at a tertiary center between 2007 and 2020. Molecular testing for TERTp mutations and CDKN2A/B copy-number status, methylation profiling, and immunohistochemistry for H3K27me3, BAP1, p16, and methylthioadenosine phosphorylase (MTAP) were performed. Predictors of survival were identified by Cox regression. Results: Eight of 15 cases demonstrated elevated mitotic index (≥20 mitoses per 10 consecutive high-power fields), 1 tumor exhibited BAP1 loss, 4 harbored TERTp mutations, and 3 demonstrated CDKN2A/B homozygous deletion. Meningiomas with TERTp mutations and/or CDKN2A/B homozygous deletion showed significantly reduced survival compared to anaplastic meningiomas with elevated mitotic index alone. Immunohistochemical loss of p16 and MTAP demonstrated high sensitivity (67% and 100%, respectively) and specificity (100% and 100%, respectively) for predicting CDKN2A/B status. Conclusions: Molecular alterations of grade 3 meningiomas stratify clinical outcomes more so than histologic features alone. Immunohistochemical loss of p16 and MTAP show promise in predicting CDKN2A/B status.

Single-Crystal Silicon Nanotubes, Hollow Nanocones, and Branched Nanotube Networks.

We report a general approach for the synthesis of single-crystal silicon nanotubes, involving epitaxial deposition of silicon shells on germanium nanowire templates followed by removal of the germanium template by selective wet etching. By exploiting advances in the synthesis of germanium nanowires, we were able to rationally tune the nanotube internal diameters (5-80 nm), wall thicknesses (3-12 nm), and taper angles (0-9°) and additionally demonstrated branched silicon nanotube networks. Field effect transistors fabricated from p-type nanotubes exhibited a strong gate effect, and fluid transport experiments demonstrated that small molecules could be electrophoretically driven through the nanotubes. These results demonstrate the suitability of silicon nanotubes for the design of nanoelectrofluidic devices.

Grade 3 meningioma survival and recurrence outcomes in an international multicenter cohort.

OBJECTIVE: Grade 3 meningioma represents a rare meningioma subtype, for which limited natural history data are available. The objective of this study was to identify demographics and pathologic characteristics, clinical and functional status outcomes, and prognostic factors in an international cohort of grade 3 meningioma patients. METHODS: Clinical and histopathological data were collected for patients treated at 7 sites across North America and Europe between 1991 and 2022. RESULTS: A total of 103 patients (54% female, median age 65 [IQR 52, 72] years) were included. Sixty-seven (65%) patients had de novo grade 3 lesions, whereas 29 (28%) had malignant transformations of lower-grade meningiomas. All patients underwent initial resection of their tumor. Patients were followed for a median of 46 (IQR 24, 108) months, during which time there were 65 (73%) recurrences and 50 (49%) deaths. The 5-year overall survival (OS) and progression-free survival (PFS) rates were 66% (95% CI 56%-77%) and 37% (95% CI 28%-48%), respectively. Age ≥ 65 years and male sex were independent predictors of worse OS and PFS in multivariate regression analysis, while postoperative radiotherapy was independently associated with improved OS. Karnofsky Performance Status (KPS) remained stable relative to baseline over 5 years postdiagnosis among participants who were alive at the end of the follow-up period. CONCLUSIONS: This large multicenter study provides insight into the longitudinal outcomes of grade 3 meningioma, with respect to recurrence, survival, and functional status. This study affirms the survival benefit conferred by radiotherapy in this population and suggests good functional status outcomes for patients surviving to 5 years postoperatively.

Impact of Δ9-Tetrahydrocannabinol and oxycodone co-administration on measures of antinociception, dependence, circadian activity, and reward in mice.

Oxycodone is commonly prescribed for moderate to severe pain disorders. While efficacious, long-term use can result in tolerance, physical dependence, and the development of opioid use disorder. Cannabis and its derivatives such as Δ9-Tetrahydrocannabinol (Δ9-THC) have been reported to enhance oxycodone analgesia in animal models and in humans. However, it remains unclear if Δ9-THC may facilitate unwanted aspects of oxycodone intake, such as tolerance, dependence, and reward at analgesic doses. This study sought to evaluate the impact of co-administration of Δ9-THC and oxycodone across behavioral measures related to antinociception, dependence, circadian activity, and reward in both male and female mice. Oxycodone and Δ9-THC produced dose-dependent antinociceptive effects in the hotplate assay that were similar between sexes. Repeated treatment (twice daily for 5 days) resulted in antinociceptive tolerance. Combination treatment of oxycodone and Δ9-THC produced a greater antinociceptive effect than either administered alone, and delayed the development of antinociceptive tolerance. Repeated treatment with oxycodone produced physical dependence and alterations in circadian activity, neither of which were exacerbated by co-treatment with Δ9-THC. Combination treatment of oxycodone and Δ9-THC produced CPP when co-administered at doses that did not produce preference when administered alone. These data indicate that Δ9-THC may facilitate oxycodone-induced antinociception without augmenting certain unwanted features of opioid intake (e.g. dependence, circadian rhythm alterations). However, our findings also indicate that Δ9-THC may facilitate rewarding properties of oxycodone at therapeutically relevant doses which warrant consideration when evaluating this combination for its potential therapeutic utility.

Seryl-tRNA synthetase promotes translational readthrough by mRNA binding and involvement of the selenocysteine incorporation machinery.

Translational readthrough of UGA stop codons by selenocysteine-specific tRNA (tRNASec) enables the synthesis of selenoproteins. Seryl-tRNA synthetase (SerRS) charges tRNASec with serine, which is modified into selenocysteine and delivered to the ribosome by a designated elongation factor (eEFSec in eukaryotes). Here we found that components of the human selenocysteine incorporation machinery (SerRS, tRNASec, and eEFSec) also increased translational readthrough of non-selenocysteine genes, including VEGFA, to create C-terminally extended isoforms. SerRS recognizes target mRNAs through a stem-loop structure that resembles the variable loop of its cognate tRNAs. This function of SerRS depends on both its enzymatic activity and a vertebrate-specific domain. Through eCLIP-seq, we identified additional SerRS-interacting mRNAs as potential readthrough genes. Moreover, SerRS overexpression was sufficient to reverse premature termination caused by a pathogenic nonsense mutation. Our findings expand the repertoire of selenoprotein biosynthesis machinery and suggest an avenue for therapeutic targeting of nonsense mutations using endogenous factors.

Fractionated radiotherapy for surgically resected intracranial meningiomas: A multicentre retrospective cohort study.

BACKGROUND: Aside from surgical resection, the only standard of care treatment modality for meningiomas is radiotherapy (RT). Despite this, few studies have focused on identifying clinical covariates associated with failure of fractionated RT following surgical resection (fRT), and the timing of fRT following surgery still remains controversial (adjuvant versus salvage fRT). We assessed the outcomes of the largest, multi-institutional cohort of surgically resected meningiomas treated with subsequent adjuvant and salvage fRT to identify factors associated with local freedom from recurrence (LFFR) over 3-10 years post-fRT and to determine the optimal timing of fRT. METHODS: Patients with intracranial meningiomas who underwent surgery and fRT between 1997 and 2018 were included. Primary endpoints were radiographic recurrence/progression and time to progression from the completion of fRT. RESULTS: 404 meningiomas were included for analysis. Of these, 167 (41.3%) recurred post-fRT. Clinical covariates independently associated with worse PFS post-fRT included receipt of previous RT to the meningioma, having a WHO grade 3 meningioma or recurrent meningioma, the meningioma having a higher MIB1-index or brain invasion on pathology, and older patient age at diagnosis. Subgroup analysis identified higher MIB1-index as a histological factor associated with poorer LFFR in WHO grade 2 meningiomas. 179 patients underwent adjuvant RT shortly after surgery whereas 225 patients had delayed, salvage fRT after recurrence/progression. Following propensity score matching, patients that underwent adjuvant fRT had improved LFFR post-fRT compared to those that received salvage fRT. CONCLUSION: There is a paucity of clinical factors that can predict a meningioma's response to fRT following surgery. Adjuvant fRT may be associated with improved PFS post-fRT compared to salvage fRT. Molecular biomarkers of RT-responsiveness are needed to better inform fRT treatment decisions.

Neuronal and Glial Metabolite Abnormalities in Participants With Persistent Neuropsychiatric Symptoms After COVID-19: A Brain Proton Magnetic Resonance Spectroscopy Study.

BACKGROUND: The aim of this study was to determine whether neurometabolite abnormalities indicating neuroinflammation and neuronal injury are detectable in individuals post-coronavirus disease 2019 (COVID-19) with persistent neuropsychiatric symptoms. METHODS: All participants were studied with proton magnetic resonance spectroscopy at 3 T to assess neurometabolite concentrations (point-resolved spectroscopy, relaxation time/echo time = 3000/30 ms) in frontal white matter (FWM) and anterior cingulate cortex-gray matter (ACC-GM). Participants also completed the National Institutes of Health Toolbox cognition and motor batteries and selected modules from the Patient-Reported Outcomes Measurement Information System. RESULTS: Fifty-four participants were evaluated: 29 post-COVID-19 (mean ± SD age, 42.4 ± 12.3 years; approximately 8 months from COVID-19 diagnosis; 19 women) and 25 controls (age, 44.1 ± 12.3 years; 14 women). When compared with controls, the post-COVID-19 group had lower total N-acetyl compounds (tNAA; ACC-GM: -5.0%, P = .015; FWM: -4.4%, P = .13), FWM glutamate + glutamine (-9.5%, P = .001), and ACC-GM myo-inositol (-6.2%, P = .024). Additionally, only hospitalized patients post-COVID-19 showed age-related increases in myo-inositol, choline compounds, and total creatine (interaction P = .029 to <.001). Across all participants, lower FWM tNAA and higher ACC-GM myo-inositol predicted poorer performance on several cognitive measures (P = .001-.009), while lower ACC-GM tNAA predicted lower endurance on the 2-minute walk (P = .005). CONCLUSIONS: In participants post-COVID-19 with persistent neuropsychiatric symptoms, the lower-than-normal tNAA and glutamate + glutamine indicate neuronal injury, while the lower-than-normal myo-inositol reflects glial dysfunction, possibly related to mitochondrial dysfunction and oxidative stress in Post-COVID participants with persistent neuropsychiatric symptoms.

ER chaperone GRP78/BiP translocates to the nucleus under stress and acts as a transcriptional regulator.

Cancer cells are commonly subjected to endoplasmic reticulum (ER) stress. To gain survival advantage, cancer cells exploit the adaptive aspects of the unfolded protein response such as upregulation of the ER luminal chaperone GRP78. The finding that when overexpressed, GRP78 can escape to other cellular compartments to gain new functions regulating homeostasis and tumorigenesis represents a paradigm shift. Here, toward deciphering the mechanisms whereby GRP78 knockdown suppresses EGFR transcription, we find that nuclear GRP78 is prominent in cancer and stressed cells and uncover a nuclear localization signal critical for its translocation and nuclear activity. Furthermore, nuclear GRP78 can regulate expression of genes and pathways, notably those important for cell migration and invasion, by interacting with and inhibiting the activity of the transcriptional repressor ID2. Our study reveals a mechanism for cancer cells to respond to ER stress via transcriptional regulation mediated by nuclear GRP78 to adopt an invasive phenotype.

Surgical Therapy of Non-Skull Base Meningiomas.

In a previous chapter, the surgical management of skull base meningiomas were discussed. However, the most common meningiomas that are diagnosed and operated on are non-skull base tumors located in the parasagittal/parafalcine region and convexity, and more rarely along the tentorium, and in an intraventricular location. These tumors present their own unique set of challenges given their unique anatomy and tend to be more biologically aggressive compared to skull base meningiomas, thereby reinforcing the importance of obtaining a gross total resection if possible, in order to delay recurrence. In this chapter we will cover the surgical management of non-skull base meningiomas with technical considerations for tumors located in each of the anatomical areas listed above.

Genomic Landscape of Meningiomas.

Despite being the most common primary brain tumor in adults, until recently, the genomics of meningiomas have remained quite understudied. In this chapter we will discuss the early cytogenetic and mutational changes uncovered in meningiomas, from the discovery of the loss of chromosome 22q and the neurofibromatosis-2 (NF2) gene to other non-NF2 driver mutations (KLF4, TRAF7, AKT1, SMO, etc.) discovered using next generation sequencing. We discuss each of these alterations in the context of their clinical significance and conclude the chapter by reviewing recent multiomic studies that have integrated our knowledge of these alterations together to develop novel molecular classifications for meningiomas.

Radiation-Induced Meningiomas.

While the majority of meningiomas encountered clinically are sporadic, there is a rare subset that arises due to early life or childhood irradiation. Sources of this radiation exposure may be due to treatment of other cancers such as acute childhood leukemia, other central nervous system tumors such as medulloblastoma, the treatment of tinea capitis (rarely and historically), or environmental exposures, as seen in some of the Hiroshima and Nagasaki atomic bomb survivors. Regardless of their etiology, however, radiation-induced meningiomas (RIMs) tend to be highly biologically aggressive irrespective of WHO grade and are usually refractory to the conventional treatment modalities of surgery and/or radiotherapy. In this chapter, we will discuss these RIMs in their historical context, their clinical presentation, their genomic features and ongoing efforts to better understand these tumors from a biological standpoint in order to develop better, more efficacious therapies for these patients.