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.

An assessment of the impact of 1.5 versus 2 and 2.5°C global temperature increase on flooding in Jamaica: a case study from the Hope watershed.

Climate change models project that, within the Caribbean basin, rainfall intensity is likely to increase toward the end of this century, although the region is projected to be drier overall. This may affect the frequency and severity of floods in Jamaica and the Caribbean Small Island Developing States. We investigate how flood hazards may be affected by increases in global mean surface temperature of 1.5, 2.0 and 2.5°C above pre-industrial levels using a case study of a Jamaican watershed. Rainfall projections from the PRECIS regional climate model for the Caribbean are analysed. Six members from the Quantifying Uncertainty in Model Predictions (AENWH, AEXSA, AEXSC, AEXSK, AEXSL and AEXSM) were used to create 100-year flood inundation maps for the Hope river for different global warming levels using hydrological and hydraulic models. Model runs projected peak discharges at 2.0, 2.5 and 1.5°C warming that were higher than discharges in the historical record of events that damaged sections of the watershed. Projections from the hydraulic model show increased flow area, depth and extent for 1.5 followed by 2.0 and 2.5°C rises in temperature. These results imply continued flood risk for the vulnerable areas of the watershed. This article is part of the theme issue 'Developing resilient energy systems'.

The Neuropsychological Norms for the U.S.-Mexico Border Region in Spanish (NP-NUMBRS) Project: Overview and considerations for life span research and evidence-based practice.

OBJECTIVE: This paper summarizes the findings of the Neuropsychological Norms for the U.S.-Mexico Border Region in Spanish (NP-NUMBRS) Project and offers a roadmap for future research. METHODS: The NP-NUMBRS project represents the largest and most comprehensive co-normed neuropsychological battery to date for native Spanish-speaking healthy adults from the U.S. (California/Arizona)-Mexico borderland region (N = 254; ages 19-60 years). These norms provide demographic adjustments for tests across numerous domains (i.e., verbal fluency, processing speed, attention/working memory, executive function, episodic memory [learning and delayed recall], visuospatial, and fine motor skills). CONCLUSIONS: This project: 1) shows that the NP-NUMBRS norms consistently outperformed previously published norms for English-speaking non-Hispanic (White and African-American) adults in identifying impairment; 2) explores the role of Spanish-English bilingualism in test performance; and 3) provides support for the diagnostic validity of these norms in detecting HIV-associated neurocognitive impairment. Study limitations include the limited assessment of sociocultural variables and generalizability (e.g., other Latina/o populations, age limit [19 - 60 years]). Future research is needed to: 1) investigate these norms with U.S.-dwelling Spanish-speakers of non-Mexican heritage and other clinical subpopulations; 2) expand coverage of cognitive domains (e.g. language, visuospatial); 3) develop large normative datasets for children and older Latina/o populations; 4) examine how sociocultural factors impact performance (e.g., bilingualism, acculturation); 5) investigate these norms' diagnostic and ecological validity; and 6) develop norms for neurocognitive change across time. It is hoped that the NP-NUMBRS norms will aid researchers and clinicians working with U.S.-dwelling Spanish-speakers from the U.S.-Mexico borderland to conduct research and evidence-based neuropsychological evaluations in a more culturally responsive and ethical manner.

Demographically-adjusted norms for the processing speed subtests of the WAIS-III in a Spanish-speaking adult population: Results from the Neuropsychological Norms for the U.S.-Mexico Border Region in Spanish (NP-NUMBRS) project.

OBJECTIVE: The Wechsler Adult Intelligence Scale (WAIS) processing speed subtests are among the most ubiquitous indices of processing speed in the field. The aim of this study was to develop and examine demographically-adjusted normative data for Spanish language versions of the WAIS-III Digit Symbol Coding (DSC) and Symbol Search (SS) subtests for US-dwelling Spanish-speakers living in the US/Mexico border region. METHODS: The sample included 203 healthy participants who were part of the larger Neuropsychological Norms for the US-Mexico Border Region in Spanish (NP-NUMBRS) project (DSC: n = 201; SS: n = 200). RESULTS: Older age and higher education were both related to lower scores on the DSC and SS subtests (all ps < .0001). There were no significant effects for gender (all ps > .05). Raw-to-scaled score conversions were calculated for both subtests, and fractional polynomial equations were derived to compute demographically-adjusted T-scores accounting for age, education, and gender for each subtest and the Processing Speed Index. Published norms for English-speaking non-Hispanic white adults slightly overestimated impairment rates (T-scores <40) on both the DSC and SS subtests, while the norms for English-speaking non-Hispanic Black/African Americans and the new NP-NUMBRS norms Spanish-speakers both yielded impairment rates that fell within expected limits for healthy controls (i.e. 13%-14%). CONCLUSIONS: This study suggests that population-specific normative data can improve the diagnostic validity of these measures for U.S.-dwelling Spanish-speakers living in the US/Mexico border region. Future research is needed to investigate the utility of these norms for other U.S.-dwelling Spanish-speaking subpopulations (e.g. Caribbean, Central American, South American).

Demographically-adjusted norms for the WAIS-R Block Design and Arithmetic subtests: Results from the Neuropsychological Norms for the US-Mexico Border Region in Spanish (NP-NUMBRS) project.

OBJECTIVE: Wechsler Adult Intelligence Scale (WAIS) Block Design and Arithmetic subtests are frequently used as measures of visuospatial construction and verbal working memory, respectively. As part of a larger test adaptation and norming effort for this population, we generated and investigated demographically-adjusted interpretive norms for WAIS-R Block Design and Arithmetic in Spanish-speaking adults living in the US-Mexico border region. METHOD: Participants included 183 community-dwelling adults ages 20-55 (education range: 0-20 years; 58% women) from the NeuroPsychological-Norms for the US-Mexico Border Region in Spanish (NP-NUMBRS) Project. They completed the WAIS-R Block Design and Arithmetic subtests in Spanish. Demographically-adjusted T-scores were calculated for these subtests using fractional polynomial equations adjusting for linear and non-linear effects of age, education (continuous), and sex. We compared our rates of impairment (i.e. T < 40) against rates calculated using published English-speaking WAIS-R standardization sample norms adjusted for age, education, and sex. RESULTS: Education was positively associated with performance on Block Design and Arithmetic subtests, and men outperformed women on both subtests. The present Spanish-speaker norms for these subtests yielded expected rates of "impairment" (i.e. 15-16% impaired, a 1 SD cutoff), while existing norms for English-speakers underestimated impairment (i.e. 5-6% impaired) when applied to our Spanish-speaking sample. CONCLUSIONS: Regional normative data will improve interpretation of test performance on Block Design and Arithmetic subtests for Spanish-speakers living in the US-Mexico border region and may aid in bolstering the overall analysis of neuropsychological profile patterns in this population. Cross-validation with Spanish-speakers in other regions and/or with other national origins is needed.

Neurotrophin Signaling in Medulloblastoma.

Neurotrophins are a family of secreted proteins that act by binding to tropomyosin receptor kinase (Trk) or p75NTR receptors to regulate nervous system development and plasticity. Increasing evidence indicates that neurotrophins and their receptors in cancer cells play a role in tumor growth and resistance to treatment. In this review, we summarize evidence indicating that neurotrophin signaling influences medulloblastoma (MB), the most common type of malignant brain cancer afflicting children. We discuss the potential of neurotrophin receptors as new therapeutic targets for the treatment of MB. Overall, activation of TrkA and TrkC types of receptors seem to promote cell death, whereas TrkB might stimulate MB growth, and TrkB inhibition displays antitumor effects. Importantly, we show analyses of the gene expression profile of neurotrophins and their receptors in MB primary tumors, which indicate, among other findings, that higher levels of NTRK1 or NTRK2 are associated with reduced overall survival (OS) of patients with SHH MB tumors.

Expression of GNAS, TP53, and PTEN Improves the Patient Prognostication in Sonic Hedgehog (SHH) Medulloblastoma Subgroup.

Medulloblastoma (MB) is the most common malignant brain tumor in children. It is currently classified in four main molecular subgroups with different clinical outcomes: sonic hedgehog, wingless, group 3, and group 4 (MBSHH, MBWNT, MBGRP3, or MBGRP4). Presently, a 22-gene expression panel has been efficiently applied for molecular subgrouping using nCounter technology. In this study, formalin-fixed, paraffin-embedded samples from 164 Brazilian medulloblastomas were evaluated, applying the 22-gene panel, and subclassified into the low and high expression of nine key medulloblastoma-related genes. In addition, TP53 mutation status was assessed using TruSight Tumor 15 Panel, and its correlation with expression and prognostic impact was evaluated. Samples from 149 of 164 patients (90%) were classified into MBSHH (47.7%), MBWNT (16.1%), MBGRP3 (15.4%), and MBGRP4 (20.8%). GNAS presented the highest expression levels, with higher expression in MBSHH. TP53, MYCN, SOX2, and MET were also up-regulated in MBSHH, whereas PTEN was up-regulated in MBGRP4. GNAS, TP53, and PTEN low expression was associated with the unfavorable patient outcome only for MBSHH (P = 0.04, P = 0.01, and P = 0.02, respectively). TP53 mutations were detected in 28.57% of MBSHH cases and exhibited association with lower expression and worse clinical outcome, although not statistically significant. The 22-gene panel for molecular classification of medulloblastoma associated with the expression of GNAS, TP53, and PTEN improves the patient prognostication in MBSHH subgroup and can be easily incorporated in the 22-gene panel without any additional costs.

HDAC and MAPK/ERK Inhibitors Cooperate To Reduce Viability and Stemness in Medulloblastoma.

Medulloblastoma (MB), which originates from embryonic neural stem cells (NSCs) or neural precursors in the developing cerebellum, is the most common malignant brain tumor of childhood. Recurrent and metastatic disease is the principal cause of death and may be related to resistance within cancer stem cells (CSCs). Chromatin state is involved in maintaining signaling pathways related to stemness, and inhibition of histone deacetylase enzymes (HDAC) has emerged as an experimental therapeutic strategy to target this cell population. Here, we observed antitumor actions and changes in stemness induced by HDAC inhibition in MB. Analyses of tumor samples from patients with MB showed that the stemness markers BMI1 and CD133 are expressed in all molecular subgroups of MB. The HDAC inhibitor (HDACi) NaB reduced cell viability and expression of BMI1 and CD133 and increased acetylation in human MB cells. Enrichment analysis of genes associated with CD133 or BMI1 expression showed mitogen-activated protein kinase (MAPK)/ERK signaling as the most enriched processes in MB tumors. MAPK/ERK inhibition reduced expression of the stemness markers, hindered MB neurosphere formation, and its antiproliferative effect was enhanced by combination with NaB. These results suggest that combining HDAC and MAPK/ERK inhibitors may be a novel and more effective approach in reducing MB proliferation when compared to single-drug treatments, through modulation of the stemness phenotype of MB cells.

Antitumor Activities and Cellular Changes Induced by TrkB Inhibition in Medulloblastoma.

Neurotrophins are critically involved in regulating normal neural development and plasticity. Brain-derived neurotrophic factor (BDNF), a neurotrophin that acts by binding to the tropomyosin receptor kinase B (TrkB) receptor, has also been implicated in the progression of several types of cancer. However, its role in medulloblastoma (MB), the most common type of malignant brain tumor afflicting children, remains unclear. Here we show that selective TrkB inhibition with the small molecule compound ANA-12 impaired proliferation and viability of human UW228 and D283 MB cells, and slowed the growth of MB tumors xenografted into nude mice. These effects were accompanied by increased apoptosis, reduced extracellular-regulated kinase (ERK) activity, increased expression of signal transducer and activator of transcription 3 (STAT3), and differential modulation of p21 expression dependent on the cell line. In addition, MB cells treated with ANA-12 showed morphological alterations consistent with differentiation, increased levels of the neural differentiation marker ß-III Tubulin (TUBB3), and reduced expression of the stemness marker Nestin. These findings are consistent with the possibility that selective TrkB inhibition can display consistent anticancer effects in MB, possibly by modulating intracellular signaling and gene expression related to tumor progression, apoptosis, and differentiation.

Caribbean climate change vulnerability: Lessons from an aggregate index approach.

The study examines the potential influence of sub-regional variations in climate, and specifically heavy rain events, in determining relative vulnerabilities of locations in twelve Caribbean countries. An aggregate vulnerability index, referred to as the Caribbean Vulnerability Score (CVS), is created using historical demographic and socioeconomic data and climate data representing extreme rain events. Four scenarios are explored. Firstly, comparative vulnerabilities are determined when heavy rainfall is incorporated in CVS versus when it is excluded. The impact of climate change is also investigated using future climate data derived from statistical downscaling but holding demographic and socioeconomic sub-indices constant. The analysis is repeated with projections of future demographic structure from the Shared Socioeconomic Pathway data (SSP3), future climate projections and constant socioeconomic. Finally, the sensitivity of the results is examined with respect to applying different weights i.e. versus using equal weights for the climate and non-climatic components of CVS as is done for the first three scenarios. Results suggest that the inclusion of historical susceptibility to rainfall extremes influences relative vulnerabilities within the Caribbean when compared to the rankings of vulnerability derived using only socioeconomic and demographic inputs. In some cases significant increases in relative rankings are noted. Projected changes in the intensity of rain events across the Caribbean region in the 2030s and 2050s, do not significantly alter the top and lowest ranked vulnerable locations when demographic and socioeconomic indices are held constant. Changes may however occur in the order of the top ranked locations dependent on scenario and time slice. In general, future shifts in relative vulnerabilities were found to be dependent on (i) changes in both future climate and demographic scenarios, (ii) the time horizons being considered, and (iii) the weighting assigned to climate in the future.

Reproducibility of the NanoString 22-gene molecular subgroup assay for improved prognostic prediction of medulloblastoma.

Medulloblastoma is the most frequent malignant brain tumor in children. Four medulloblastoma molecular subgroups, MBSHH , MBWNT , MBGRP3 and MBGRP4 , have been identified by integrated high-throughput platforms. Recently, a 22-gene panel NanoString-based assay was developed for medulloblastoma molecular subgrouping, but the robustness of this assay has not been widely evaluated. Mutations in the gene for human telomerase reverse transcriptase (hTERT) have been found in medulloblastomas and are associated with distinct molecular subtypes. This study aimed to implement the 22-gene panel in a Brazilian context, and to associate the molecular profile with patients' clinical-pathological features. Formalin-fixed, paraffin-embedded (FFPE) medulloblastoma samples (n = 104) from three Brazilian centers were evaluated. Expression profiling of the 22-gene panel was performed by NanoString and a Canadian series (n = 240) was applied for training phase. hTERT mutations were analyzed by PCR followed by direct Sanger sequencing and the molecular profile was associated with patients' clinicopathological features. Overall, 65% of the patients were male, average age at diagnosis was 18 years and 7% of the patients presented metastasis at diagnosis. The molecular classification was attained in 100% of the cases, with the following frequencies: MBSHH (n = 51), MBWNT (n = 19), MBGRP4 (n = 19) and MBGRP3 (n = 15). The MBSHH and MBGRP3 subgroups were associated with older and younger patients, respectively. The MBGRP4 subgroup exhibited the lowest 5-year cancer-specific overall survival (OS), yet in the multivariate analysis, only metastasis at diagnosis and surgical resection were associated with OS. hTERT mutations were detected in 29% of the cases and were associated with older patients, increased hTERT expression and MBSHH subgroup. The 22-gene panel provides a reproducible assay for molecular subgrouping of medulloblastoma FFPE samples in a routine setting and is well-suited for future clinical trials.

"Contemplating the Next Maneuver": Functional Neuroimaging Reveals Intraoperative Decision-making Strategies.

OBJECTIVE: To investigate differences in the quality, confidence, and consistency of intraoperative surgical decision making (DM) and using functional neuroimaging expose decision systems that operators use. SUMMARY BACKGROUND DATA: Novices are hypothesized to use conscious analysis (effortful DM) leading to activation across the dorsolateral prefrontal cortex, whereas experts are expected to use unconscious automation (habitual DM) in which decisions are recognition-primed and prefrontal cortex independent. METHODS: A total of 22 subjects (10 medical student novices, 7 residents, and 5 attendings) reviewed simulated laparoscopic cholecystectomy videos, determined the next safest operative maneuver upon video termination (10 s), and reported decision confidence. Video paradigms either declared ("primed") or withheld ("unprimed") the next operative maneuver. Simultaneously, changes in cortical oxygenated hemoglobin and deoxygenated hemoglobin inferring prefrontal activation were recorded using Optical Topography. Decision confidence, consistency (primed vs unprimed), and quality (script concordance) were assessed. RESULTS: Attendings and residents were significantly more certain (P < 0.001), and decision quality was superior (script concordance: attendings = 90%, residents = 78.3%, and novices = 53.3%). Decision consistency was significantly superior in experts (P < 0.001) and residents (P < 0.05) than novices (P = 0.183). During unprimed DM, novices showed significant activation of the dorsolateral prefrontal cortex, whereas this activation pattern was not observed among residents and attendings. During primed DM, significant activation was not observed in any group. CONCLUSIONS: Expert DM is characterized by improved quality, consistency, and confidence. The findings imply attendings use a habitual decision system, whereas novices use an effortful approach under uncertainty. In the presence of operative cues (primes), novices disengage the prefrontal cortex and seem to accept the observed operative decision as correct.

Neogenin1 is a Sonic Hedgehog target in medulloblastoma and is necessary for cell cycle progression.

The canonical Sonic Hedgehog (Shh)/Gli pathway plays multiples roles during central nervous system (CNS) development. To elucidate the molecular repertoire of Shh mediators, we have recently described novel transcriptional targets in response to Shh pathway modulation. Among them, we were able to identify Neogenin1 (Neo1), a death dependence receptor, as a new direct Shh downstream regulator in neural precursor proliferation. As appropriate Shh signaling is required for cerebellar growth and alterations cause Shh-driven medulloblastoma (MB), here we have addressed the role of the Shh/Neogenin1 interaction in the context of cerebellar development and cancer. We demonstrate that the Shh pathway regulates Neogenin1 expression in mouse models that recapitulate the Shh MB subtype. We show that the canonical Shh pathway directly regulates the Neo1 gene acting through an upstream sequence in its promoter both in vitro and in vivo in granule neuron precursor cells. We also identified and characterized a functional Gli-binding site in the first intron of the human NEO1 gene. Gene expression profiling of more than 300 MB shows that NEO1 is indeed upregulated in SHH tumors compared to the other MB subgroups. Finally, we provide evidence that NEO1 is necessary for cell cycle progression in a human MB cell line, because a loss of function of NEO1 arrests cells in the G2/M phase. Taken together, these results highlight Neogenin1 as a novel downstream effector of the Shh pathway in MB and a possible therapeutic target.

Utility of routinely acquired primary care data for paediatric disease epidemiology and pharmacoepidemiology

BACKGROUND: The majority of medicines prescribed for children are prescribed in primary care for common acute and chronic conditions. This is in contrast to prescribing in secondary care where the population of children admitted is small but where a large number of different medicines are prescribed to treat more serious and less common conditions. METHODS: Data on prescribing was extracted from the General Practice Administration System for Scotland (GPASS) for the year November 1999 to October 2000 and prescribing patterns for children aged 0-16 years expressed as percentages. A comparison of age specific consultations for asthma, as an example of a common paediatric condition, was also made between two separate general practice data sets, the General Practice Research Database (GRPD) and the continuous morbidity recording (CMR) subset of GPASS. RESULTS: Of 214 medicines investigated for unlicensed and off-label prescribing no unlicensed prescribing was identified. Off-label prescribing due to age was most common among younger and older children. The most common reasons for off-label prescriptions were, in order of frequency, lower than recommended dose, higher than recommended dose, below the recommended age, and unlicensed formulation. Age and gender specific consultations for asthma were similar in the two representative databases, GPRD and CMR, both showing disappearance of the male predominance in the teenage years. CONCLUSIONS: Large primary care data sets available within a unified health care system such as the UK National Health Service (NHS) are likely to be broadly compatible and produce similar results. The prescribing of off-label medicines to children is common in primary care, most commonly due to prescribing out with the recommended dosage regimen.

Genetic evidence for local retention of pelagic larvae in a Caribbean reef fish.

The pelagic larvae of many marine organisms can potentially disperse across hundreds of kilometers, but whether oceanographic or behavioral mechanisms can constrain dispersal over periods sufficient for the evolution of genetic differentiation remains unclear. Here, we concurrently examine larval duration and genetic population differentiation in a cleaner goby, Elacatinus evelynae, a member of the most species-rich genus of Caribbean reef fishes. Despite evidence for extended pelagic duration (21 days), populations of E. evelynae show strong genetic differentiation: among color forms (1.36 to 3.04% divergent at mitochondrial cytochrome b) and among island populations within color forms (Phi(ST) up to 70%). These results suggest that marine populations can remain demographically closed for thousands of generations despite extended larval duration, and that recognition cues such as color may promote speciation when geographic barriers are transient or weak.