Determining sea-level rise in the Caribbean: A shift from temperature to mass control.

Tropical Small Island Developing States (SIDS), such as those in the Caribbean, are among the most vulnerable to the impacts of climate change, most notably sea-level rise. The current sea-level rise in the Caribbean is 3.40 ± 0.3 mm/year (1993-2019), which is similar to the 3.25 ± 0.4 mm/year global mean sea-level (GMSL) rise (1993-2018). Throughout the year, Caribbean seasonal sea-level variability is found to respond to sea surface temperature variability. Over the past few decades, the trend in Caribbean Sea-level rise is also found to be variable. Satellite altimetry and steric sea-level records of the Caribbean region reveal a shift in the late 2003-early 2004, which separates two distinct periods of sea-level rise. Thermal expansion dominates the sea-level trend from 1993-2003. Following this period, there is an increased trend in sea-level rise, with a dominance of mass changes from 2004-2019, as confirmed by GRACE data. During this period, the sea-level trend is 6.15 ± 0.5 mm/year, which is 67% faster than the most recent estimates of global mean sea-level rise provided by the Intergovernmental Panel on Climate Change (3.69 ± 0.5 mm/year for the period 2006-2018). Despite its reduced importance, increasing temperatures contribute greatly to sea-level rise in the Caribbean region through thermal expansion of ocean water, hence there is a need to limit the current trend of global warming.

Protocol for preclinical evaluation of locoregionally delivered CAR T cells in patient-derived xenograft models of brain tumors.

Here, we present a protocol for preclinical evaluation of locoregionally delivered CAR T cells in patient-derived xenograft models of primary, metastatic, and recurrent brain tumors. We provide instructions for isolating peripheral blood mononuclear cells (PBMCs), producing CAR T cells in conjunction with locoregional delivery, and preclinical trial design and analysis involving CAR T cells. Additionally, we describe comprehensive preclinical readouts and guidelines for critical endpoint sample collections. In line with clinical trial procedures, our protocol broadens available treatment modalities for direct clinical translation. For complete details on the use and execution of this protocol, please refer to Donovan et al.1.

Operational relevance of the Sydney Declaration: The example of the Australian Federal Police (AFP) Forensics Command.

In 2022, a group of eminent forensic scientists published The Sydney Declaration - Revisiting the essence of forensic science through its fundamental principles in Forensic Science International. The Sydney Declaration was delivered to revisit "the essence of forensic science, its purpose, and fundamental principles". At its heart, revisiting these foundational principles is hoped to "benefit forensic science as a whole to be more relevant, effective and reliable". But can these principles be translated operationally by a forensic services provider to achieve the benefits prescribed? How do we make the leap from a theoretical concept and begin to put it into practice to bring about the real and meaningful change that the declaration hopes to achieve? In this paper we will attempt to discuss how the Australian Federal Police (AFP) Forensics Command has reflected on the Sydney Declaration by relating reforms developed and implemented to our operating model with some selected principles. We hope to show that while the Sydney Declaration could be perceived as academic and disconnected from operations, it has the potential to impact and positively influence reforms and changes for forensic science providers. The AFP Forensics Command experience shows the operational relevance of The Sydney Declaration.

IL-1ß disrupts the initiation of blood-brain barrier development by inhibiting endothelial Wnt/ß-catenin signaling.

During neuroinflammation, the proinflammatory cytokine interleukin-1ß (IL-1ß) impacts blood-brain barrier (BBB) function by disrupting brain endothelial tight junctions, promoting vascular permeability, and increasing transmigration of immune cells. Here, we examined the effects of Il-1ß on the in vivo initiation of BBB development. We generated doxycycline-inducible transgenic zebrafish to secrete Il-1ß in the CNS. To validate the utility of our model, we showed Il-1ß dose-dependent mortality, recruitment of neutrophils, and expansion of microglia. Using live imaging, we discovered that Il-1ß causes a significant reduction in CNS angiogenesis and barriergenesis. To demonstrate specificity, we rescued the Il-1ß induced phenotypes by targeting the zebrafish il1r1 gene using CRISPR-Cas9. Mechanistically, we determined that Il-1ß disrupts the initiation of BBB development by decreasing Wnt/ß-catenin transcriptional activation in brain endothelial cells. Given that several neurodevelopmental disorders are associated with inflammation, our findings support further investigation into the connections between proinflammatory cytokines, neuroinflammation, and neurovascular development.

The Virtual Child.

SUMMARY: We are building the world's first Virtual Child-a computer model of normal and cancerous human development at the level of each individual cell. The Virtual Child will "develop cancer" that we will subject to unlimited virtual clinical trials that pinpoint, predict, and prioritize potential new treatments, bringing forward the day when no child dies of cancer, giving each one the opportunity to lead a full and healthy life.

Metformin treatment results in distinctive skeletal muscle mitochondrial remodeling in rats with different intrinsic aerobic capacities.

The rationale for the use of metformin as a treatment to slow aging was largely based on data collected from metabolically unhealthy individuals. For healthspan extension metformin will also be used in periods of good health. To understand potential context specificity of metformin treatment on skeletal muscle, we used a rat model (HCR/LCR) with a divide in intrinsic aerobic capacity. Outcomes of metformin treatment differed based on baseline intrinsic mitochondrial function, oxidative capacity of the muscle (gastroc vs soleus), and the mitochondrial population (IMF vs SS). Metformin caused lower ADP-stimulated respiration in LCRs, with less of a change in HCRs. However, a washout of metformin resulted in an unexpected doubling of respiratory capacity in HCRs. These improvements in respiratory capacity were accompanied by mitochondrial remodeling that included increases in protein synthesis and changes in morphology. Our findings raise questions about whether the positive findings of metformin treatment are broadly applicable.

Childhood cancer mutagenesis caused by transposase-derived PGBD5.

Genomic rearrangements are a hallmark of most childhood tumors, including medulloblastoma, one of the most common brain tumors in children, but their causes remain largely unknown. Here, we show that PiggyBac transposable element derived 5 (Pgbd5) promotes tumor development in multiple developmentally accurate mouse models of Sonic Hedgehog (SHH) medulloblastoma. Most Pgbd5-deficient mice do not develop tumors, while maintaining normal cerebellar development. Ectopic activation of SHH signaling is sufficient to enforce cerebellar granule cell progenitor-like cell states, which exhibit Pgbd5-dependent expression of distinct DNA repair and neurodevelopmental factors. Mouse medulloblastomas expressing Pgbd5 have increased numbers of somatic structural DNA rearrangements, some of which carry PGBD5-specific sequences at their breakpoints. Similar sequence breakpoints recurrently affect somatic DNA rearrangements of known tumor suppressors and oncogenes in medulloblastomas in 329 children. This identifies PGBD5 as a medulloblastoma mutator and provides a genetic mechanism for the generation of oncogenic DNA rearrangements in childhood cancer.

Neuraxial clonidine is not associated with lower post-cesarean opioid consumption or pain scores in parturients on chronic buprenorphine therapy: a retrospective cohort study.

PURPOSE: Adequate post-cesarean delivery analgesia can be difficult to achieve for women diagnosed with opioid use disorder receiving buprenorphine. We sought to determine if neuraxial clonidine administration is associated with decreased opioid consumption and pain scores following cesarean delivery in women receiving chronic buprenorphine therapy. METHODS: This was a retrospective cohort study at a tertiary care teaching hospital of women undergoing cesarean delivery with or without neuraxial clonidine administration while receiving chronic buprenorphine. The primary outcome was opioid consumption (in morphine milligram equivalents) 0-6 h following cesarean delivery. Secondary outcomes included opioid consumption 0-24 h post-cesarean, median postoperative pain scores 0-24 h, and rates of intraoperative anesthetic supplementation. Multivariable analysis evaluating the adjusted effects of neuraxial clonidine on outcomes was conducted using linear regression, proportional odds model, and logistic regression separately. RESULTS: 196 women met inclusion criteria, of which 145 (74%) received neuraxial clonidine while 51 (26%) did not. In univariate analysis, there was no significant difference in opioid consumption 0-6 h post-cesarean delivery between the clonidine (8 [IQR 0, 15]) and control (1 [IQR 0, 8]) groups (P = 0.14). After adjusting for potential confounders, there remained no significant association with neuraxial clonidine administration 0-6 h (Difference in means 2.77, 95% CI [- 0.89 to 6.44], P = 0.14) or 0-24 h (Difference in means 8.56, 95% CI [- 16.99 to 34.11], P = 0.51). CONCLUSION: In parturients receiving chronic buprenorphine therapy at the time of cesarean delivery, neuraxial clonidine administration was not associated with decreased postoperative opioid consumption, median pain scores, or the need for intraoperative supplementation.

A therapeutically targetable positive feedback loop between lnc-HLX-2-7, HLX, and MYC that promotes group 3 medulloblastoma.

Recent studies suggest that long non-coding RNAs (lncRNAs) contribute to medulloblastoma (MB) formation and progression. We have identified an lncRNA, lnc-HLX-2-7, as a potential therapeutic target in group 3 (G3) MBs. lnc-HLX-2-7 RNA specifically accumulates in the promoter region of HLX, a sense-overlapping gene of lnc-HLX-2-7, which activates HLX expression by recruiting multiple factors, including enhancer elements. RNA sequencing and chromatin immunoprecipitation reveal that HLX binds to and activates the promoters of several oncogenes, including TBX2, LIN9, HOXM1, and MYC. Intravenous treatment with cerium-oxide-nanoparticle-coated antisense oligonucleotides targeting lnc-HLX-2-7 (CNP-lnc-HLX-2-7) inhibits tumor growth by 40%-50% in an intracranial MB xenograft mouse model. Combining CNP-lnc-HLX-2-7 with standard-of-care cisplatin further inhibits tumor growth and significantly prolongs mouse survival compared with CNP-lnc-HLX-2-7 monotherapy. Thus, the lnc-HLX-2-7-HLX-MYC axis is important for regulating G3 MB progression, providing a strong rationale for using lnc-HLX-2-7 as a therapeutic target for G3 MBs.

Measuring the impact of scientific publications and publication extenders: examples of novel approaches.

Different stakeholders, such as authors, research institutions, and healthcare professionals (HCPs) may determine the impact of peer-reviewed publications in different ways. Commonly-used measures of research impact, such as the Journal Impact Factor or the H-index, are not designed to evaluate the impact of individual articles. They are heavily dependent on citations, and therefore only measure impact of the overall journal or researcher respectively, taking months or years to accrue. The past decade has seen the development of article-level metrics (ALMs), that measure the online attention received by an individual publication in contexts including social media platforms, news media, citation activity, and policy and patent citations. These new tools can complement traditional bibliometric data and provide a more holistic evaluation of the impact of a publication. This commentary discusses the need for ALMs, and summarizes several examples - PlumX Metrics, Altmetric, the Better Article Metrics score, the EMPIRE Index, and scite. We also discuss how metrics may be used to evaluate the value of "publication extenders" - educational microcontent such as animations, videos and plain-language summaries that are often hosted on HCP education platforms. Publication extenders adapt a publication's key data to audience needs and thereby extend a publication's reach. These new approaches have the potential to address the limitations of traditional metrics, but the diversity of new metrics requires that users have a keen understanding of which forms of impact are relevant to a specific publication and select and monitor ALMs accordingly.

Different readers have different ways of deciding how important scientific articles are. The usual methods used to measure the impact of research, like the Journal Impact Factor or the H-index, are not meant to measure this for individual articles. These methods mainly look at how many times the articles are mentioned by others, and it can take a long time to see the impact.But in the past ten years, new tools called article-level metrics (ALMs) have been created. These tools measure how much attention an article gets online, like on social media, in the news, or when other researchers talk about it. ALMs are better at explaining how important a specific article is. They can work together with the usual methods to measure impact.This paper talks about why ALMs are important and gives examples of these tools, like PlumX Metrics, Altmetric, the Better Article Metrics score, the EMPIRE Index, and scite. It also explains how these tools can help us see the value of animations, videos, or summaries in simple language. These make it easier for more people to understand and learn from the articles.These new ways of measuring impact can help us see how important articles are in a more complete way. But because there are many different ways to measure this, it's important for users to understand which methods are relevant for a specific article and keep track of them.

Atomistic simulations for investigation of substrate and salt effects on lipid in-source fragmentation in secondary ion mass spectrometry: A follow-up study.

In-source fragmentation (ISF) poses a significant challenge in secondary ion mass spectrometry (SIMS). These fragment ions increase the spectral complexity and can lead to incorrect annotation of fragments as intact species. The presence of salt that is ubiquitous in biological samples can influence the fragmentation and ionization of analytes in a significant manner, but their influences on SIMS have not been well characterized. To elucidate the effect of substrates and salt on ISF in SIMS, we have employed experimental SIMS in combination with atomistic simulations of a sphingolipid on a gold surface with various NaCl concentrations as a model system. Our results revealed that a combination of bond dissociation energy and binding energy between N-palmitoyl-sphingomyelin and a gold surface is a good predictor of fragment ion intensities in the absence of salt. However, ion-fragment interactions play a significant role in determining fragment yields in the presence of salt. Additionally, the charge distribution on fragment species may be a major contributor to the varying effects of salt on fragmentation. This study demonstrates that atomistic modeling can help predict ionization potential when salts are present, providing insights for more accurate interpretations of complex biological spectra.

Prevalence of Low-Acuity Pediatric Emergency Medical Services Transports to a Pediatric Emergency Department in an Urban Area.

OBJECTIVES: Many patients transported by Emergency Medical Services (EMS) do not have emergent resource needs. Estimates for the proportion of pediatric EMS calls for low-acuity complaints, and thus potential candidates for alternative dispositions, vary widely and are often based on physician judgment. A more accurate reference standard should include patient assessments, interventions, and dispositions. The objective of this study was to describe the prevalence and characteristics of low-acuity pediatric EMS calls in an urban area. METHODS: This is a prospective observational study of children transported by EMS to a tertiary care pediatric emergency department. Patient acuity was defined using a novel composite measure that included physiologic assessments, resources used, and disposition. Bivariable and multivariable logistic regression were conducted to assess for factors associated with low-acuity status. RESULTS: A total of 996 patients were enrolled, of whom 32.9% (95% confidence interval, 30.0-36.0) were low acuity. Most of the sample was Black, non-Hispanic with a mean age of 7 years. When compared with adolescents, children younger than 1 year were more likely to be low acuity (adjusted odds ratio, 3.1 [1.9-5.1]). Patients in a motor vehicle crash were also more likely to be low acuity (adjusted odds ratio, 2.4 [1.2-4.6]). All other variables, including race, insurance status, chief complaint, and dispatch time, were not associated with low-acuity status. CONCLUSIONS: One third of pediatric patients transported to the pediatric emergency department by EMS in this urban area are for low-acuity complaints. Further research is needed to determine low-acuity rates in other jurisdictions and whether EMS providers can accurately identify low-acuity patients to develop alternative EMS disposition programs for children.

Gut microbiome of the sole surviving member of reptile order Rhynchocephalia reveals biogeographic variation, influence of host body condition and a substantial core microbiota in tuatara across New Zealand.

Tuatara are the sole extant species in the reptile order Rhynchocephalia. They are ecologically and evolutionarily unique, having been isolated geographically for ~84 million years and evolutionarily from their closest living relatives for ~250 million years. Here we report the tuatara gut bacterial community for the first time. We sampled the gut microbiota of translocated tuatara at five sanctuaries spanning a latitudinal range of ~1000 km within Aotearoa New Zealand, as well as individuals from the source population on Takapourewa (Stephens Island). This represents a first look at the bacterial community of the order Rhynchocephalia and provides the opportunity to address several key hypotheses, namely that the tuatara gut microbiota: (1) differs from those of other reptile orders; (2) varies among geographic locations but is more similar at sites with more similar temperatures and (3) is shaped by tuatara body condition, parasitism and ambient temperature. We found significant drivers of the microbiota in sampling site, tuatara body condition, parasitism and ambient temperature, suggesting the importance of these factors when considering tuatara conservation. We also derived a 'core' community of shared bacteria across tuatara at many sites, despite their geographic range and isolation. Remarkably, >70% of amplicon sequence variants could not be assigned to known genera, suggesting a largely undescribed gut bacterial community for this ancient host species.

Lymphatic endothelial-like cells promote glioblastoma stem cell growth through cytokine-driven cholesterol metabolism.

Glioblastoma is the most lethal primary brain tumor with glioblastoma stem cells (GSCs) atop a cellular hierarchy. GSCs often reside in a perivascular niche, where they receive maintenance cues from endothelial cells, but the role of heterogeneous endothelial cell populations remains unresolved. Here, we show that lymphatic endothelial-like cells (LECs), while previously unrecognized in brain parenchyma, are present in glioblastomas and promote growth of CCR7-positive GSCs through CCL21 secretion. Disruption of CCL21-CCR7 paracrine communication between LECs and GSCs inhibited GSC proliferation and growth. LEC-derived CCL21 induced KAT5-mediated acetylation of HMGCS1 on K273 in GSCs to enhance HMGCS1 protein stability. HMGCS1 promoted cholesterol synthesis in GSCs, favorable for tumor growth. Expression of the CCL21-CCR7 axis correlated with KAT5 expression and HMGCS1K273 acetylation in glioblastoma specimens, informing patient outcome. Collectively, glioblastomas contain previously unrecognized LECs that promote the molecular crosstalk between endothelial and tumor cells, offering potentially alternative therapeutic strategies.

Complications following resection of primary and recurrent pediatric posterior fossa ependymoma.

OBJECTIVE: Extent of resection (EOR) is the most important modifiable prognostic variable for pediatric patients with posterior fossa ependymoma. An understanding of primary and recurrent ependymoma complications is essential to inform clinical decision-making for providers, patients, and families. In this study, the authors characterize postsurgical complications following resection of primary and recurrent pediatric posterior fossa ependymoma in a molecularly defined cohort. METHODS: The authors conducted a 20-year retrospective single-center review of pediatric patients undergoing resection of posterior fossa ependymoma at the Hospital for Sick Children in Toronto, Canada. Complications were dichotomized into major and minor groups; EOR was compared across complication categories. The association between complication occurrence with length of stay (LOS) and mortality was also assessed using multivariable regressions. RESULTS: There were 60 patients with primary resection included, 41 (68%) of whom were alive at the time of data collection. Gross-total resection was achieved in 33 (58%) of 57 patients at primary resection. There were no 30-day mortality events following primary and recurrent ependymoma resection. Following primary resection, 6 patients (10%) had posterior fossa syndrome (PFS) and 36 (60%) developed cranial neuropathies, 56% of which recovered within 1 year. One patient (1.7%) required a tracheostomy and 9 patients (15%) required gastrostomy tubes. There were 14 ventriculoperitoneal shunts (23%) inserted for postoperative hydrocephalus. Among recurrent cases, there were 48 recurrent resections performed in 24 patients. Complications included new cranial neuropathy in 10 patients (21%), of which 5 neuropathies resolved within 1 year. There were no cases of PFS following resection of recurrent ependymoma. Gastrostomy tube insertion was required in 3 patients (6.3%), and 1 patient (2.0%) required a tracheostomy. Given the differences in the location of tumor recurrence, a direct comparison between primary and recurrent resection complications was not feasible. Following multivariate analysis adjusting for sex, age, molecular status, and EOR, occurrence of major complications was found to be associated with prolonged LOS but not mortality. CONCLUSIONS: These results detail the spectrum of postsurgical morbidity following primary and recurrent posterior fossa ependymoma resection. The crude complication rate following resection of infratentorial recurrent ependymoma was lower than that of primary ependymoma, although a statistical comparison revealed no significant differences between the groups. These results should serve to inform providers of the morbidity profile following surgical management of posterior fossa ependymoma and inform perioperative counseling of patients and their families.

Differences in Oligomerization of the SARS-CoV-2 Envelope Protein, Poliovirus VP4, and HIV Vpu.

Viroporins constitute a class of viral membrane proteins with diverse roles in the viral life cycle. They can self-assemble and form pores within the bilayer that transport substrates, such as ions and genetic material, that are critical to the viral infection cycle. However, there is little known about the oligomeric state of most viroporins. Here, we use native mass spectrometry in detergent micelles to uncover the patterns of oligomerization of the full-length SARS-CoV-2 envelope (E) protein, poliovirus VP4, and HIV Vpu. Our data suggest that the E protein is a specific dimer, VP4 is exclusively monomeric, and Vpu assembles into a polydisperse mixture of oligomers under these conditions. Overall, these results revealed the diversity in the oligomerization of viroporins, which has implications for the mechanisms of their biological functions as well as their potential as therapeutic targets.

Developmental basis of SHH medulloblastoma heterogeneity.

Many genes that drive normal cellular development also contribute to oncogenesis. Medulloblastoma (MB) tumors likely arise from neuronal progenitors in the cerebellum, and we hypothesized that the heterogeneity observed in MBs with sonic hedgehog (SHH) activation could be due to differences in developmental pathways. To investigate this question, here we perform single-nucleus RNA sequencing on highly differentiated SHH MBs with extensively nodular histology and observed malignant cells resembling each stage of canonical granule neuron development. Through innovative computational approaches, we connect these results to published datasets and find that some established molecular subtypes of SHH MB appear arrested at different developmental stages. Additionally, using multiplexed proteomic imaging and MALDI imaging mass spectrometry, we identify distinct histological and metabolic profiles for highly differentiated tumors. Our approaches are applicable to understanding the interplay between heterogeneity and differentiation in other cancers and can provide important insights for the design of targeted therapies.

DeepVelo: deep learning extends RNA velocity to multi-lineage systems with cell-specific kinetics.

Existing RNA velocity estimation methods strongly rely on predefined dynamics and cell-agnostic constant transcriptional kinetic rates, assumptions often violated in complex and heterogeneous single-cell RNA sequencing (scRNA-seq) data. Using a graph convolution network, DeepVelo overcomes these limitations by generalizing RNA velocity to cell populations containing time-dependent kinetics and multiple lineages. DeepVelo infers time-varying cellular rates of transcription, splicing, and degradation, recovers each cell's stage in the differentiation process, and detects functionally relevant driver genes regulating these processes. Application to various developmental and pathogenic processes demonstrates DeepVelo's capacity to study complex differentiation and lineage decision events in heterogeneous scRNA-seq data.

Ascorbic acid deficiency amongst spondylodiscitis patients.

BACKGROUND: Spondylodiscitis can be a disabling and life-threatening infection. Ascorbic Acid is crucial for neutrophil function and collagen formation. Its association and clinical relevance in spondylodiscitis has not been previously examined. AIMS: To determine the prevalence, characteristics, and clinical outcomes of spondylodiscitis patients with Ascorbic Acid deficiency. METHODS: Sixty-eight consecutive patients admitted with spondylodiscitis, between December 2021 and August 2023 were included. Clinical characteristics, Ascorbic Acid levels and clinical outcomes were evaluated. RESULTS: Thirty-seven patients had Ascorbic Acid levels taken during admission. The median initial Ascorbic Acid level was 15 µmol/L with an IQR 6.5-27 µmol/L. Depletion defined as <28 µmol/L was present in 78% of patients. Deficiency defined as ≤11 µmol/L was present in and 46% of patients. Patients with depletion were more likely to require Intensive Care Admission (absolute risk increase = 24.1%; 2.6%-45.7%). Fifteen patients had repeat serum levels taken during admission with median increase of 17 µmol/L and an IQR 0-26 µmol/L. Patients that received supplementation had a significantly greater increase in Ascorbic Acid levels compared with those that did not receive supplementation (P = 0.002). CONCLUSION: Ascorbic acid deficiency is highly prevalent amongst spondylodiscitis patients. Depletion was associated with worse outcomes. Replacement significantly increased serum levels in comparison to standard hospital diet. The clinical significance of replacement remains to be evaluated.