National burden of influenza-associated hospitalizations in Cambodia, 2015 and 2016

The burden of influenza in Cambodia is not well known, but it would be useful for understanding the impact of seasonal epidemics and pandemics and to design appropriate policies for influenza prevention and control. The severe acute respiratory infection (SARI) surveillance system in Cambodia was used to estimate the national burden of SARI hospitalizations in Cambodia.This work was financially supported by the World Health Organization Pandemic and Epidemic Diseases grant for Burden of Disease studies HQPED1611421. The Melbourne WHO Collaborating Centre for Reference and Research on Influenza is supported by the Australian Government Department of Health. The corresponding author was supported by an Australian Government Research Training Program Scholarship

A Century of Drought in Hawaiʻi: Geospatial Analysis and Synthesis across Hydrological, Ecological, and Socioeconomic Scales

Drought is a prominent feature of Hawaiʻi’s climate. However, it has been over 30 years since the last comprehensive meteorological drought analysis, and recent drying trends have emphasized the need to better understand drought dynamics and multi-sector effects in Hawaiʻi. Here, we provide a comprehensive synthesis of past drought effects in Hawaiʻi that we integrate with geospatial analysis of drought characteristics using a newly developed 100-year (1920–2019) gridded Standardized Precipitation Index (SPI) dataset. The synthesis examines past droughts classified into five categories: Meteorological, agricultural, hydrological, ecological, and socioeconomic drought. Results show that drought duration and magnitude have increased significantly, consistent with trends found in other Pacific Islands. We found that most droughts were associated with El Niño events, and the two worst droughts of the past century were multi-year events occurring in 1998–2002 and 2007–2014. The former event was most severe on the islands of O’ahu and Kaua’i while the latter event was most severe on Hawaiʻi Island. Within islands, we found different spatial patterns depending on leeward versus windward contrasts. Droughts have resulted in over $80 million in agricultural relief since 1996 and have increased wildfire risk, especially during El Niño years. In addition to providing the historical context needed to better understand future drought projections and to develop effective policies and management strategies to protect natural, cultural, hydrological, and agricultural resources, this work provides a framework for conducting drought analyses in other tropical island systems, especially those with a complex topography and strong climatic gradients

LKB1 as the ghostwriter of crypt history

Familial cancer syndromes present rare insights into malignant tumor development. The molecular background of polyp formation and the cancer prone state in Peutz-Jeghers syndrome remain enigmatic to this day. Previously, we proposed that Peutz-Jeghers polyps are not pre-malignant lesions, but an epiphenomenon to the malignant condition. However, Peutz-Jeghers polyp formation and the cancer-prone state must both be accounted for by the same molecular mechanism. Our contribution focuses on the histopathology of the characteristic Peutz-Jeghers polyp and recent research on stem cell dynamics and how these concepts relate to Peutz-Jeghers polyposis. We discuss a protracted clonal evolution scenario in Peutz-Jeghers syndrome due to a germline LKB1 mutation. Peutz-Jeghers polyp formation and malignant transformation are separately mediated through the same molecular mechanism played out on different timescales. Thus, a single mechanism accounts for the development of benign Peutz-Jeghers polyps and for malignant transformation in Peutz-Jeghers syndrome

Multicenter Comparison of Molecular Tumor Boards in The Netherlands:Definition, Composition, Methods, and Targeted Therapy Recommendations

Background Molecular tumor boards (MTBs) provide rational, genomics-driven, patient-tailored treatment recommendations. Worldwide, MTBs differ in terms of scope, composition, methods, and recommendations. This study aimed to assess differences in methods and agreement in treatment recommendations among MTBs from tertiary cancer referral centers in The Netherlands. Materials and Methods MTBs from all tertiary cancer referral centers in The Netherlands were invited to participate. A survey assessing scope, value, logistics, composition, decision-making method, reporting, and registration of the MTBs was completed through on-site interviews with members from each MTB. Targeted therapy recommendations were compared using 10 anonymized cases. Participating MTBs were asked to provide a treatment recommendation in accordance with their own methods. Agreement was based on which molecular alteration(s) was considered actionable with the next line of targeted therapy. Results Interviews with 24 members of eight MTBs revealed that all participating MTBs focused on rare or complex mutational cancer profiles, operated independently of cancer type-specific multidisciplinary teams, and consisted of at least (thoracic and/or medical) oncologists, pathologists, and clinical scientists in molecular pathology. Differences were the types of cancer discussed and the methods used to achieve a recommendation. Nevertheless, agreement among MTB recommendations, based on identified actionable molecular alteration(s), was high for the 10 evaluated cases (86%). Conclusion MTBs associated with tertiary cancer referral centers in The Netherlands are similar in setup and reach a high agreement in recommendations for rare or complex mutational cancer profiles. We propose a "Dutch MTB model" for an optimal, collaborative, and nationally aligned MTB workflow. Implications for Practice Interpretation of genomic analyses for optimal choice of target therapy for patients with cancer is becoming increasingly complex. A molecular tumor board (MTB) supports oncologists in rationalizing therapy options. However, there is no consensus on the most optimal setup for an MTB, which can affect the quality of recommendations. This study reveals that the eight MTBs associated with tertiary cancer referral centers in The Netherlands are similar in setup and reach a high agreement in recommendations for rare or complex mutational profiles. The Dutch MTB model is based on a collaborative and nationally aligned workflow with interinstitutional collaboration and data sharing

Climatic control on palaeohydrology and cyclical sediment distribution in the Plio-Quaternary deposits of the Guadix Basin (Betic Cordillera, Spain)

A cyclical pattern can be observed in the central sector of the Guadix Basin (southern Spain) in the Late Pliocene-Quaternary alluvial fan deposits prograding into its axial valley. A climatic significance has been attributed to this cyclicity on the basis of sedimentological and preliminary isotopic studies. The progradation phases of the alluvial fans are here attributed to more arid time intervals in which the vegetation cover would be less developed, erosion and sediment supply would be higher, and base level would be lower. In contrast, the time intervals during which the fluvial system sediments dominated the area are inferred to be wetter and base level higher, with vegetation cover retaining the soils and preventing erosion. Permanent water supply to the river would therefore facilitate the aggradation of the floodplain and prevent progradation of the fans. Starting from a litho-, bio- and magnetostratigraphical frame provided for the area, an age is assigned to the alternation of the reddish sediments of the transverse alluvial fans and the greyish to white fluvio-lacustrine sediments of the axial drainage system. A cyclicity of ca. 100 ky has been identified in most of the alluvial fan progradation phases, falling within Milankovitch high-frequency eccentricity periodicities. Correlation of the phases with insolation curves is accordingly discussed as a possible origin for the cyclicity. Finally, the results offer new insights into early hominin occupation patterns in the region, through the identification of predictable resources of permanent fresh water that would have remained available throughout the recorded time span (that includes the Early–Middle Pleistocene transition) even during times of aridification.The study was supported by the Project CGL2009-07830/BTE and the Working Group RNM-369JA

TGF-β in tolerance, development and regulation of immunity

AbstractThe TGF-β superfamily is an ancient metazoan protein class which cuts across cell and tissue differentiation, developmental biology and immunology. Its many members are regulated at multiple levels from intricate control of gene transcription, post-translational processing and activation, and signaling through overlapping receptor structures and downstream intracellular messengers. We have been interested in TGF-β homologues firstly as key players in the induction of immunological tolerance, the topic so closely associated with Ray Owen. Secondly, our interests in how parasites may manipulate the immune system of their host has also brought us to study the TGF-β pathway in infections with longlived, essentially tolerogenic, helminth parasites. Finally, within the spectrum of mammalian TGF-β proteins is an exquisitely tightly-regulated gene, anti-Müllerian hormone (AMH), whose role in sex determination underpins the phenotype of freemartin calves that formed the focus of Ray’s seminal work on immunological tolerance

Sensing of Dietary Lipids by Enterocytes: A New Role for SR-BI/CLA-1

BACKGROUND: The intestine is responsible for absorbing dietary lipids and delivering them to the organism as triglyceride-rich lipoproteins (TRL). It is important to determine how this process is regulated in enterocytes, the absorptive cells of the intestine, as prolonged postprandial hypertriglyceridemia is a known risk factor for atherosclerosis. During the postprandial period, dietary lipids, mostly triglycerides (TG) hydrolyzed by pancreatic enzymes, are combined with bile products and reach the apical membrane of enterocytes as postprandial micelles (PPM). Our aim was to determine whether these micelles induce, in enterocytes, specific early cell signaling events that could control the processes leading to TRL secretion. METHODOLOGY/PRINCIPAL FINDINGS: The effects of supplying PPM to the apex of Caco-2/TC7 enterocytes were analyzed. Micelles devoid of TG hydrolysis products, like those present in the intestinal lumen in the interprandial period, were used as controls. The apical delivery of PPM specifically induced a number of cellular events that are not induced by interprandial micelles. These early events included the trafficking of apolipoprotein B, a structural component of TRL, from apical towards secretory domains, and the rapid, dose-dependent activation of ERK and p38MAPK. PPM supply induced the scavenger receptor SR-BI/CLA-1 to cluster at the apical brush border membrane and to move from non-raft to raft domains. Competition, inhibition or knockdown of SR-BI/CLA-1 impaired the PPM-dependent apoB trafficking and ERK activation. CONCLUSIONS/SIGNIFICANCE: These results are the first evidence that enterocytes specifically sense postprandial dietary lipid-containing micelles. SR-BI/CLA-1 is involved in this process and could be a target for further study with a view to modifying intestinal TRL secretion early in the control pathway

Recommendations for the clinical interpretation and reporting of copy number gains using gene panel NGS analysis in routine diagnostics

Next-generation sequencing (NGS) panel analysis on DNA from formalin-fixed paraffin-embedded (FFPE) tissue is increasingly used to also identify actionable copy number gains (gene amplifications) in addition to sequence variants. While guidelines for the reporting of sequence variants are available, guidance with respect to reporting copy number gains from gene-panel NGS data is limited. Here, we report on Dutch consensus recommendations obtained in the context of the national Predictive Analysis for THerapy (PATH) project, which aims to optimize and harmonize routine diagnostics in molecular pathology. We briefly d

Multicenter Comparison of Molecular Tumor Boards in The Netherlands: Definition, Composition, Methods, and Targeted Therapy Recommendations

Background: Molecular tumor boards (MTBs) provide rational, genomics-driven, patient-tailored treatment recommendations. Worldwide, MTBs differ in terms of scope, composition, methods, and recommendations. This study aimed to assess differences in methods and agreement in treatment recommendations among MTBs from tertiary cancer referral centers in The Netherlands. Materials and Methods: MTBs from all tertiary cancer referral centers in The Netherlands were invited to participate. A survey assessing scope, value, logistics, composition, decision-making method, reporting, and registration of the MTBs was completed through on-site interviews with members from each MTB. Targeted therapy recommendations were compared using 10 anonymized cases. Participating MTBs were asked to provide a treatment recommendation in accordance with their own methods. Agreement was based on which molecular alteration(s) was considered actionable with the next line of targeted therapy. Results: Interviews with 24 members of eight MTBs revealed that all participating MTBs focused on rare or complex mutational cancer profiles, operated independently of cancer type–specific multidisciplinary teams, and consisted of at least (thoracic and/or medical) oncologists, pathologists, and clinical scientists in molecular pathology. Differences were the types of cancer discussed and the methods used to achieve a recommendation. Nevertheless, agreement among MTB recommendations, based on identified actionable molecular alteration(s), was high for the 10 evaluated cases (86%). Conclusion: MTBs associated with tertiary cancer referral centers in The Netherlands are similar in setup and reach a high agreement in recommendations for rare or complex mutational cancer profiles. We propose a “Dutch MTB model” for an optimal, collaborative, and nationally aligned MTB workflow. Implications for Practice: Interpretation of genomic analyses for optimal choice of target therapy for patients with cancer is becoming increasingly complex. A molecular tumor board (MTB) supports oncologists in rationalizing therapy options. However, there is no consensus on the most optimal setup for an MTB, which can affect the quality of recommendations. This study reveals that the eight MTBs associated with tertiary cancer referral centers in The Netherlands are similar in setup and reach a high agreement in recommendations for rare or complex mutational profiles. The Dutch MTB model is based on a collaborative and nationally aligned workflow with interinstitutional collaboration and data sharing