Temporal and spatial variability of prehistoric aquatic resource procurement: a case study from Mesolithic Northern Iberia

Prehistoric shell middens hold valuable evidence of past human–environment interactions. In this study, we used carbon (δ13C) and oxygen (δ18O) stable isotopes of Mytilus galloprovincialis shells excavated from El Perro, La Fragua and La Chora, three Mesolithic middens in Cantabria, Northern Spain, to examine hunter-gatherer subsistence strategies in terms of seasonality and collection areas. Furthermore, we used shell δ18O to reconstruct water temperature during the early Holocene. Stable isotopes reveal a shellfish harvesting diversification trend represented by the gradual establishment of the upper estuaries as new procurement areas and an increase of harvesting mobility in both coastal and in-land sites. These innovations in subsistence strategies during the Mesolithic coincided with major changes in the surrounding environment as attested by the water temperature reconstructions based on δ18O and backed by several global and regional records. Overall, our results show that shell δ13C and δ18O stable isotopes have an underexplored potential as provenance proxies which stimulates their application to the archaeological record to further understand prehistoric human resource procurement and diet.This research was performed as part of the projects HAR2016-75605-R and HAR2017-86262-P, funded by the Spanish Ministry of Economy and Competitiveness, MINECO

Current evidence of antifungal prophylaxis and therapy in pediatric patients

Invasive fungal infections (IFI) are an important complication in pediatric haematological and oncological patients who undergo intensive chemotherapy for leukemia, solid tumour at advanced stage or relapsed, and hematopoietic stem cell transplantation. The incidence of IFI is lower than bacterial infection but mortality rate remains high. This review is designed to help paediatric oncologists in choosing the appropriate anti-fungal strategy and agents for prophylaxis, empirical, pre-emptive and specific therapy on the basis of published evidence

The effects of environment on Arctica islandica shell formation and architecture

Mollusks record valuable information in their hard parts that reflect ambient environmental conditions. For this reason, shells can serve as excellent archives to reconstruct past climate and environmental variability. However, animal physiology and biomineralization, which are often poorly understood, can make the decoding of environmental signals a challenging task. Many of the routinely used shell-based proxies are sensitive to multiple different environmental and physiological variables. Therefore, the identification and interpretation of individual environmental signals (e.g., water temperature) often is particularly difficult. Additional proxies not influenced by multiple environmental variables or animal physiology would be a great asset in the field of paleoclimatology. The aim of this study is to investigate the potential use of structural properties of Arctica islandica shells as an environmental proxy. A total of 11 specimens were analyzed to study if changes of the microstructural organization of this marine bivalve are related to environmental conditions. In order to limit the interference of multiple parameters, the samples were cultured under controlled conditions. Three specimens presented here were grown at two different water temperatures (10 and 15 °C) for multiple weeks and exposed only to ambient food conditions. An additional eight specimens were reared under three different dietary regimes. Shell material was analyzed with two techniques; (1) confocal Raman microscopy (CRM) was used to quantify changes of the orientation of microstructural units and pigment distribution, and (2) scanning electron microscopy (SEM) was used to detect changes in microstructural organization. Our results indicate that A. islandica microstructure is not sensitive to changes in the food source and, likely, shell pigment are not altered by diet. However, seawater temperature had a statistically significant effect on the orientation of the biomineral. Although additional work is required, the results presented here suggest that the crystallographic orientation of biomineral units of A. islandica may serve as an alternative and independent proxy for seawater temperature

ALDH1A3 Is the Key Isoform That Contributes to Aldehyde Dehydrogenase Activity and Affects <i>in Vitro</i> Proliferation in Cardiac Atrial Appendage Progenitor Cells.

High aldehyde dehydrogenase (ALDH &lt;sup&gt;hi&lt;/sup&gt; ) activity has been reported in normal and cancer stem cells. We and others have shown previously that human ALDH &lt;sup&gt;hi&lt;/sup&gt; cardiac atrial appendage cells are enriched with stem/progenitor cells. The role of ALDH in these cells is poorly understood but it may come down to the specific ALDH isoform(s) expressed. This study aimed to compare ALDH &lt;sup&gt;hi&lt;/sup&gt; and ALDH &lt;sup&gt;lo&lt;/sup&gt; atrial cells and to identify the isoform(s) that contribute to ALDH activity, and their functional role. &lt;b&gt;Methods and Results:&lt;/b&gt; Cells were isolated from atrial appendage specimens from patients with ischemic and/or valvular heart disease undergoing heart surgery. ALDH &lt;sup&gt;hi&lt;/sup&gt; activity assessed with the Aldefluor reagent coincided with primitive surface marker expression (CD34 &lt;sup&gt;+&lt;/sup&gt; ). Depending on their ALDH activity, RT-PCR analysis of ALDH &lt;sup&gt;hi&lt;/sup&gt; and ALDH &lt;sup&gt;lo&lt;/sup&gt; cells demonstrated a differential pattern of pluripotency genes (Oct 4, Nanog) and genes for more established cardiac lineages (Nkx2.5, Tbx5, Mef2c, GATA4). ALDH &lt;sup&gt;hi&lt;/sup&gt; cells, but not ALDH &lt;sup&gt;lo&lt;/sup&gt; cells, formed clones and were culture-expanded. When cultured under cardiac differentiation conditions, ALDH &lt;sup&gt;hi&lt;/sup&gt; cells gave rise to a higher number of cardiomyocytes compared with ALDH &lt;sup&gt;lo&lt;/sup&gt; cells. Among 19 ALDH isoforms known in human, ALDH1A3 was most highly expressed in ALDH &lt;sup&gt;hi&lt;/sup&gt; atrial cells. Knocking down ALDH1A3, but not ALDH1A1, ALDH1A2, ALDH2, ALDH4A1, or ALDH8A1 using siRNA decreased ALDH activity and cell proliferation in ALDH &lt;sup&gt;hi&lt;/sup&gt; cells. Conversely, overexpressing ALDH1A3 with a retroviral vector increased proliferation in ALDH &lt;sup&gt;lo&lt;/sup&gt; cells. &lt;b&gt;Conclusions:&lt;/b&gt; ALDH1A3 is the key isoform responsible for ALDH activity in ALDH &lt;sup&gt;hi&lt;/sup&gt; atrial appendage cells, which have a propensity to differentiate into cardiomyocytes. ALDH1A3 affects &lt;i&gt;in vitro&lt;/i&gt; proliferation of these cells

Validation of the ONKOTEV Risk Prediction Model for Venous Thromboembolism in Outpatients With Cancer

Importance: The assessment of the risk of venous thromboembolism (VTE) among outpatients with cancer represents an unsolved topic. Current international guidelines recommend primary prophylaxis for patients at intermediate to high risk of VTE, indicated by a Khorana score of 2 or more. A previous prospective study developed the ONKOTEV score, a 4-variable risk assessment model (RAM) consisting of a Khorana score of more than 2, metastatic disease, vascular or lymphatic compression, and previous VTE event. Objective: To validate the ONKOTEV score as a novel RAM to assess the risk of VTE among outpatients with cancer. Design, setting, and participants: ONKOTEV-2 is a noninterventional prognostic study conducted in 3 European centers located in Italy, Germany, and the United Kingdom among a prospective cohort of 425 ambulatory patients with a histologically confirmed diagnosis of a solid tumor who were receiving active treatments. The total study duration was 52 months, with an accrual period of 28 months (from May 1, 2015, to September 30, 2017) and an overall follow up-period of 24 months (data were censored September 30, 2019). Statistical analysis was performed in October 2019. Exposures: The ONKOTEV score was calculated for each patient at baseline by collecting clinical, laboratory, and imaging data from tests performed for routine practice. Each patient was then observed to detect any thromboembolic event throughout the study period. Main outcomes and measures: The primary outcome of the study was the incidence of VTE, including deep vein thrombosis and pulmonary embolism. Results: A total of 425 patients (242 women [56.9%]; median age, 61 years [range, 20-92 years]) were included in the validation cohort of the study. The cumulative incidences for the risk of developing VTE at 6 months were 2.6% (95% CI, 0.7%-6.9%), 9.1% (95% CI, 5.8%-13.2%), 32.3% (95% CI, 21.0%-44.1%), and 19.3% (95% CI, 2.5%-48.0%), respectively, among 425 patients with an ONKOTEV score of 0, 1, 2, and greater than 2 (P < .001). The time-dependent area under the curve at 3, 6, and 12 months was 70.1% (95% CI, 62.1%-78.7%), 72.9% (95% CI, 65.6%-79.1%), and 72.2% (95% CI, 65.2%-77.3%), respectively. Conclusions and relevance: This study suggests that, because the ONKOTEV score has been validated in this independent study population as a novel predictive RAM for cancer-associated thrombosis, it can be adopted into practice and into clinical interventional trials as a decision-making tool for primary prophylaxis

MET inhibition sensitizes rhabdomyosarcoma cells to NOTCH signaling suppression

Rhabdomyosarcoma (RMS) is a pediatric myogenic soft tissue sarcoma. The Fusion-Positive (FP) subtype expresses the chimeric protein PAX3-FOXO1 (P3F) while the Fusion-Negative (FN) is devoid of any gene translocation. FP-RMS and metastatic FN-RMS are often unresponsive to conventional therapy. Therefore, novel therapeutic approaches are needed to halt tumor progression. NOTCH signaling has oncogenic functions in RMS and its pharmacologic inhibition through gamma-secretase inhibitors blocks tumor growth in vitro and in vivo. Here, we show that NOTCH signaling blockade resulted in the up-regulation and phosphorylation of the MET oncogene in both RH30 (FP-RMS) and RD (FN-RMS) cell lines. Pharmacologic inhibition of either NOTCH or MET signaling slowed proliferation and restrained cell survival compared to control cells partly by increasing Annexin V and CASP3/7 activation. Co-treatment with NOTCH and MET inhibitors significantly amplified these effects and enhanced PARP1 cleavage in both cell lines. Moreover, it severely hampered cell migration, colony formation, and anchorage-independent growth compared to single-agent treatments in both cell lines and significantly prevented the growth of FN-RMS cells grown as spheroids. Collectively, our results unveil the overexpression of the MET oncogene by NOTCH signaling targeting in RMS cells and show that MET pathway blockade sensitizes them to NOTCH inhibition

The Role of Attitudes Toward Medication and Treatment Adherence in the Clinical Response to LAIs: Findings From the STAR Network Depot Study

Background: Long-acting injectable (LAI) antipsychotics are efficacious in managing psychotic symptoms in people affected by severe mental disorders, such as schizophrenia and bipolar disorder. The present study aimed to investigate whether attitude toward treatment and treatment adherence represent predictors of symptoms changes over time. Methods: The STAR Network \u201cDepot Study\u201d was a naturalistic, multicenter, observational, prospective study that enrolled people initiating a LAI without restrictions on diagnosis, clinical severity or setting. Participants from 32 Italian centers were assessed at three time points: baseline, 6-month, and 12-month follow-up. Psychopathological symptoms, attitude toward medication and treatment adherence were measured using the Brief Psychiatric Rating Scale (BPRS), the Drug Attitude Inventory (DAI-10) and the Kemp's 7-point scale, respectively. Linear mixed-effects models were used to evaluate whether attitude toward medication and treatment adherence independently predicted symptoms changes over time. Analyses were conducted on the overall sample and then stratified according to the baseline severity (BPRS &lt; 41 or BPRS 65 41). Results: We included 461 participants of which 276 were males. The majority of participants had received a primary diagnosis of a schizophrenia spectrum disorder (71.80%) and initiated a treatment with a second-generation LAI (69.63%). BPRS, DAI-10, and Kemp's scale scores improved over time. Six linear regressions\u2014conducted considering the outcome and predictors at baseline, 6-month, and 12-month follow-up independently\u2014showed that both DAI-10 and Kemp's scale negatively associated with BPRS scores at the three considered time points. Linear mixed-effects models conducted on the overall sample did not show any significant association between attitude toward medication or treatment adherence and changes in psychiatric symptoms over time. However, after stratification according to baseline severity, we found that both DAI-10 and Kemp's scale negatively predicted changes in BPRS scores at 12-month follow-up regardless of baseline severity. The association at 6-month follow-up was confirmed only in the group with moderate or severe symptoms at baseline. Conclusion: Our findings corroborate the importance of improving the quality of relationship between clinicians and patients. Shared decision making and thorough discussions about benefits and side effects may improve the outcome in patients with severe mental disorders

Off-label long acting injectable antipsychotics in real-world clinical practice: a cross-sectional analysis of prescriptive patterns from the STAR Network DEPOT study

Introduction Information on the off-label use of Long-Acting Injectable (LAI) antipsychotics in the real world is lacking. In this study, we aimed to identify the sociodemographic and clinical features of patients treated with on- vs off-label LAIs and predictors of off-label First- or Second-Generation Antipsychotic (FGA vs. SGA) LAI choice in everyday clinical practice. Method In a naturalistic national cohort of 449 patients who initiated LAI treatment in the STAR Network Depot Study, two groups were identified based on off- or on-label prescriptions. A multivariate logistic regression analysis was used to test several clinically relevant variables and identify those associated with the choice of FGA vs SGA prescription in the off-label group. Results SGA LAIs were more commonly prescribed in everyday practice, without significant differences in their on- and off-label use. Approximately 1 in 4 patients received an off-label prescription. In the off-label group, the most frequent diagnoses were bipolar disorder (67.5%) or any personality disorder (23.7%). FGA vs SGA LAI choice was significantly associated with BPRS thought disorder (OR = 1.22, CI95% 1.04 to 1.43, p = 0.015) and hostility/suspiciousness (OR = 0.83, CI95% 0.71 to 0.97, p = 0.017) dimensions. The likelihood of receiving an SGA LAI grew steadily with the increase of the BPRS thought disturbance score. Conversely, a preference towards prescribing an FGA was observed with higher scores at the BPRS hostility/suspiciousness subscale. Conclusion Our study is the first to identify predictors of FGA vs SGA choice in patients treated with off-label LAI antipsychotics. Demographic characteristics, i.e. age, sex, and substance/alcohol use co-morbidities did not appear to influence the choice towards FGAs or SGAs. Despite a lack of evidence, clinicians tend to favour FGA over SGA LAIs in bipolar or personality disorder patients with relevant hostility. Further research is needed to evaluate treatment adherence and clinical effectiveness of these prescriptive patterns