hnRNPM protects against the dsRNA-mediated interferon response by repressing LINE-associated cryptic splicing.

RNA splicing is pivotal in post-transcriptional gene regulation, yet the exponential expansion of intron length in humans poses a challenge for accurate splicing. Here, we identify hnRNPM as an essential RNA-binding protein that suppresses cryptic splicing through binding to deep introns, maintaining human transcriptome integrity. Long interspersed nuclear elements (LINEs) in introns harbor numerous pseudo splice sites. hnRNPM preferentially binds at intronic LINEs to repress pseudo splice site usage for cryptic splicing. Remarkably, cryptic exons can generate long dsRNAs through base-pairing of inverted ALU transposable elements interspersed among LINEs and consequently trigger an interferon response, a well-known antiviral defense mechanism. Significantly, hnRNPM-deficient tumors show upregulated interferon-associated pathways and elevated immune cell infiltration. These findings unveil hnRNPM as a guardian of transcriptome integrity by repressing cryptic splicing and suggest that targeting hnRNPM in tumors may be used to trigger an inflammatory immune response, thereby boosting cancer surveillance.

Two C. elegans DM domain proteins, DMD-3 and MAB-3, function in late stages of male somatic gonad development.

To bring about sexual dimorphism in form, information from the sex determination pathway must trigger sex-specific modifications in developmental programs. DM-domain encoding genes have been found to be involved in sex determination in a multitude of animals, often at the level of male somatic gonad formation. Here we report our findings that the DM-domain transcription factors MAB-3 and DMD-3 function together in multiple steps during the late stages of C. elegans male somatic gonad development. Both mab-3 and dmd-3 are expressed in the linker cell and hindgut of L4 males and dmd-3 is also expressed in presumptive vas deferens cells. Furthermore, dmd-3, but not mab-3, expression in the linker cell is downstream of nhr-67, a nuclear hormone receptor that was previously shown to control late stages of linker cell migration. In mab-3; dmd-3 double mutant males, the last stage of linker cell migration is partially defective, resulting in aberrant linker cell shapes and often a failure of the linker cell to complete its migration to the hindgut. When mab-3; dmd-3 double mutant linker cells do complete their migration, they fail to be engulfed by the hindgut, indicating that dmd-3 and mab-3 activity are essential for this process. Furthermore, linker cell death and clearance are delayed in mab-3; dmd-3 double mutants, resulting in the linker cell persisting into adulthood. Finally, DMD-3 and MAB-3 function to activate expression of the bZIP transcription factor encoding gene zip-5 and downregulate the expression of the zinc metalloprotease ZMP-1 in the linker cell. Taken together, these results demonstrate a requirement for DM-domain transcription factors in controlling C. elegans male gonad formation, supporting the notion that the earliest DM-domain genes were involved in male somatic gonad development in the last common ancestor of the bilaterians.

Omega-3 Fatty Acids and Arrhythmias.

The pro- and antiarrhythmic effects of omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been extensively studied in preclinical and human trials. Despite early evidence of an antiarrhythmic role of n-3 PUFA in the prevention of sudden cardiac death and postoperative and persistent atrial fibrillation (AF), subsequent well-designed randomized trials have largely not shown an antiarrhythmic benefit. Two trials that tested moderate and high-dose n-3 PUFA demonstrated a reduction in sudden cardiac death, but these findings have not been widely replicated, and the potential of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to reduce arrhythmic death in combination, or as monotherapy, remains uncertain. The accumulated clinical evidence does not support supplementation of n-3 PUFA for postoperative AF or secondary prevention of AF. Several large, contemporary, randomized controlled trials of high-dose n-3 PUFA for primary or secondary cardiovascular prevention have demonstrated a small, significant, dose-dependent increased risk of incident AF compared with mineral oil or corn oil comparator. These findings were reproduced with both icosapent ethyl monotherapy and a mixed EPA+DHA formulation. The proarrhythmic mechanism of increased AF in contemporary cohorts exposed to high-dose n-3 PUFA is unknown. EPA and DHA and their metabolites have pleiotropic cardiometabolic and pro- and antiarrhythmic effects, including modification of the lipid raft microenvironment; alteration of cell membrane structure and fluidity; modulation of sodium, potassium, and calcium currents; and regulation of gene transcription, cell proliferation, and inflammation. Further characterization of the complex association between EPA, EPA+DHA, and DHA and AF is needed. Which formulations, dose ranges, and patient subgroups are at highest risk, remain unclear.

Comparative and integrative single cell analysis reveals new insights into the transcriptional immaturity of stem cell-derived ß cells.

Diabetes cell replacement therapy has the potential to be transformed by human pluripotent stem cell-derived ß cells (SC-ß cells). However, the precise identity of SC-ß cells in relationship to primary fetal and adult ß-cells remains unclear. Here, we used single-cell sequencing datasets to characterize the transcriptional identity of islets from in vitro differentiation, fetal islets, and adult islets. Our analysis revealed that SC-ß cells share a core ß-cell transcriptional identity with human adult and fetal ß-cells, however SC-ß cells possess a unique transcriptional profile characterized by the persistent expression and activation of progenitor and neural-biased gene networks. These networks are present in SC-ß cells, irrespective of the derivation protocol used. Notably, fetal ß-cells also exhibit this neural signature at the transcriptional level. Our findings offer insights into the transcriptional identity of SC-ß cells and underscore the need for further investigation of the role of neural transcriptional networks in their development.

Options for keeping the food system within environmental limits.

The food system is a major driver of climate change, changes in land use, depletion of freshwater resources, and pollution of aquatic and terrestrial ecosystems through excessive nitrogen and phosphorus inputs. Here we show that between 2010 and 2050, as a result of expected changes in population and income levels, the environmental effects of the food system could increase by 50-90% in the absence of technological changes and dedicated mitigation measures, reaching levels that are beyond the planetary boundaries that define a safe operating space for humanity. We analyse several options for reducing the environmental effects of the food system, including dietary changes towards healthier, more plant-based diets, improvements in technologies and management, and reductions in food loss and waste. We find that no single measure is enough to keep these effects within all planetary boundaries simultaneously, and that a synergistic combination of measures will be needed to sufficiently mitigate the projected increase in environmental pressures.

Bipolar radiofrequency ablation lesion areas and confluence: An ex vivo study and technical report.

INTRODUCTION: Radiofrequency ablation (RFA) has been used for nearly 100 years, treating an array of medical conditions including chronic pain. Radiofrequency (RF) energy depolarizes and repolarizes tissues adjacent to a probe producing heat and causing direct thermal injury. When positioned adjacent to neural structures, it leads to neural tissue injury and cell death interrupting pain signaling with the ultimate goal of providing lasting pain relief. Today, RFA is commonly used to treat cervical, thoracic, and lumbar zygapophyseal joints, sacroiliac joint, and more recently large peripheral joint-mediated pain. There are several applications of RFA systems, including bipolar, conventional thermal, cooled, protruding, and pulsed. As yet, no study has determined the best technical practice for bipolar RFA. OBJECTIVE: This ex vivo study examines RFA lesion midpoint (LMP) area and lesion confluence comparing three different commonly used gauge (g) probes (18-g, 20-g, and 22-g) with 10-mm active tips at various interprobe distances (IPD) to guide best technical practices for its clinical application. METHODS: Bipolar RFA lesions were generated in preservative-free chicken breast specimens using three different gauge probes (18-g, 20-g, and 22-g) with 10-mm active tips at various IPD (6, 8, 10, 12, 14, 16, and 18 mm). RF was applied for 105 s (15-s ramp time) at 80°C for each lesion at both room and human physiological temperature. The specimen tissues were dissected through the lesion to obtain a length, width, and depth, which were used to calculate the LMP area (mm2 ). The LMP areas of each thermal ablation were investigated using visualization and descriptive analysis. The Kruskal-Wallis test was performed to compare LMP areas between the two temperature groups and the three different gauge probe subgroups at the various IPDs. RESULTS: Of the 36 RF lesions (14: 18-g, 12: 20-g, and 10: 22-g) performed, 24 demonstrated lesion confluence. The average time to reach 80°C was 16-17 s; therefore, the average time of RF-energy delivery (at goal temperature) was 88-89 s despite varying needle size or IPD. Comparing the 25 and 37°C groups, 18-g probes produced mean LMP areas of 73.7 and 79.2 mm2 , respectively; 20-g probes produced mean LMP areas of 66 and 66.8 mm2 , respectively; 22-g probes produced mean LMP areas of 56.6 and 59.7 mm2 , respectively. There was no statistical evidence to state a difference regarding LMP area between temperature groups; however, the 18-g probes produced consistently larger LMP areas in the 37°C compared to 25°C specimen groups at each IPD. Lesion confluence was lost for 18-g, 20-g, and 22-g probes at IPD of 14, 12, and 10 mm, respectively, in both 25 and 37°C groups. LMP area was similar between 6 and 8 mm IPD in all of the three-gauge groups; however, there was a significant drop in LMP area from 8 mm IPD to 10 mm and greater. The 18-g, 20-g, and 22-g probes all demonstrated a sharp decline in LMP area when increasing the IPD from 8 to 10 mm. CONCLUSION: This ex vivo technical study evaluated bipolar RFA LMP areas and lesion confluence, and determined the recommended IPD of 18-g, 20-g, and 22-g probes to be less than 12, 10, and 8 mm, respectively, for best clinical practice. Placing bipolar probes at an IPD greater than 14, 12, and 10 mm, respectively, risks the loss of lesion confluence and failure to produce a clinically significant treatment response due to lack of nerve capture. In clinical practice, the use of injectate may produce larger lesions than demonstrated in this study. Additionally, in vivo factors may impact ablation zone size and ablation patterns. As there are a paucity of studies comparing various RFA applications and conventional RFA needles are least expensive, it is possible that bipolar conventional RFA is more cost-effective than other techniques.

Open and minimally invasive gastrectomy in Eastern and Western patient populations: A review of the literature and reasons for differences in outcomes.

Randomized trials in the East have established minimally invasive gastrectomy as possibly superior for short-term outcomes and noninferior for long-term survival. Smaller randomized studies from Western countries have supported these findings. However, there are marked disparities in morbidity, mortality, and overall survival noted between Eastern and Western studies. In this article, we review the literature comparing open and minimally invasive gastrectomy in the East and West, and describe the possible reasons for differences in outcomes.

Short and long-term outcomes of prophylactic total gastrectomy in 54 consecutive individuals with germline pathogenic mutations in the CDH1 gene.

BACKGROUND: Germline mutation of CDH1 is rare and leads to hereditary diffuse gastric cancer (DGC). METHODS: Patients (pts) with CDH1 mutation who underwent multidisciplinary counseling followed by open prophylactic total gastrectomy (PTG) by a single surgeon were reviewed. RESULTS: Fifty-four pts with a median age of 41 years (16-70 years) underwent PTG between 2006 and 2021. Median operative time was 161 min, and median hospital stay was 7 days (range 6-12). There were 5 complications (9.2%) within 30 days, and two complications (pulmonary embolism and pancreatitis) required readmission. There were no anastomotic leaks. The pathologic analysis of the first 10 pts included the entire gastric mucosa, revealing a median of 15 foci of DGC (range 5-136). The subsequent 44 pts with more limited analysis had a median of 2 foci (range 0-5), and two pts (3.7%) had no foci identified. Median maximum weight loss was 19%. In long-term follow-up (median 4.6 years) of 20 pts, median global QOL was 2.0 (very good), the majority had persistent difficulty with certain foods or liquids, and all stated they would again elect PTG over surveillance endoscopy. CONCLUSIONS: PTG can be performed safely at high-volume referral centers with very good QOL but nutritional sequelae persist.

Topological energy transfer in an optomechanical system with exceptional points.

Topological operations can achieve certain goals without requiring accurate control over local operational details; for example, they have been used to control geometric phases and have been proposed as a way of controlling the state of certain systems within their degenerate subspaces. More recently, it was predicted that topological operations can be used to transfer energy between normal modes, provided that the system possesses a specific type of degeneracy known as an exceptional point. Here we demonstrate the transfer of energy between two vibrational modes of a cryogenic optomechanical device using topological operations. We show that this transfer arises from the presence of an exceptional point in the spectrum of the device. We also show that this transfer is non-reciprocal. These results open up new directions in system control; they also open up the possibility of exploring other dynamical effects related to exceptional points, including the behaviour of thermal and quantum fluctuations in their vicinity.

Effects of diluted bitumen exposure on the survival, physiology, and behaviour of zebra finches (Taeniopygia guttata).

Diluted bitumen (dilbit) is an unconventional crude petroleum increasingly being extracted and transported to market by pipeline and tanker. Despite the transport of dilbit through terrestrial, aquatic, and coastal habitat important to diverse bird fauna, toxicity data are currently only available for fish and invertebrates. We used the zebra finch (Taeniopygia guttata) as a tractable, avian model system to investigate exposure effects of lightly weathered Cold Lake blend dilbit on survival, tissue residue, and a range of physiological and behavioural endpoints. Birds were exposed via oral gavage over 14-days with dosages of 0, 2, 4, 6, 8, 10, or 12 mL dilbit/kg bw/day. We identified an LD50 of 9.4 mL/kg/d dilbit, with complete mortality at 12 mL/kg/d. Mortality was associated with mass loss, external oiling, decreased pectoral and heart mass, and increased liver mass. Hepatic ethoxyresorufin-O-deethylase activity (EROD) was elevated in all dilbit-dosed birds compared with controls but there was limited evidence of sublethal effects of dilbit on physiological endpoints at doses < 10 mL/kg/d (hematocrit, hemoglobin, total antioxidants, and reactive oxygen metabolites). Dilbit exposure affected behavior, with more dilbit-treated birds foraging away from the feeder, more birds sleeping or idle at low dilbit doses, and fewer birds huddling together at high dilbit doses. Naphthalene, dibenzothiophene, and their alkylated congeners in particular (e.g. C2-napthalene and C2-dibenzothiophene) accumulated in the liver at greater concentrations in dilbit-treated birds compared to controls. Although directly comparable studies in the zebra finch are limited, our mortality data suggest that dilbit is more toxic than the well-studied MC252 conventional light crude oil with this exposure regime. A lack of overt sublethal effects at lower doses, but effects on body mass and composition, behaviour, high mortality, and elevated PAC residue at doses ≥ 10 mL/kg/d suggest a threshold effect.

Income, consumer preferences, and the future of livestock-derived food demand.

In recent decades there has been a sustained and substantial shift in human diets across the globe towards including more livestock-derived foods. Continuing debates scrutinize how these dietary shifts affect human health, the natural environment, and livelihoods. However, amidst these debates there remain unanswered questions about how demand for livestock-derived foods may evolve over the upcoming decades for a range of scenarios for key drivers of change including human population, income, and consumer preferences. Future trends in human population and income in our scenarios were sourced from three of the shared socioeconomic pathways. We used scenario-based modeling to show that average protein demand for red meat (beef, sheep, goats, and pork), poultry, dairy milk, and eggs across the globe would increase by 14% per person and 38% in total between the year 2020 and the year 2050 if trends in income and population continue along a mid-range trajectory. The fastest per person rates of increase were 49% in South Asia and 55% in sub-Saharan Africa. We show that per person demand for red meat in high-income countries would decline by 2.8% if income elasticities of demand (a partial proxy for consumer preferences, based on the responsiveness of demand to income changes) in high-income countries decline by 100% by 2050 under a mid-range trajectory for per person income growth, compared to their current trajectory. Prices are an important driver of demand, and our results demonstrate that the result of a decline in red meat demand in high-income countries is strongly related to rising red meat prices, as projected by our scenario-based modeling. If the decline in the income elasticity of demand occurred in all countries rather than only in high-income countries, then per person red meat demand in high-income countries would actually increase in 2050 by 8.9% because the income elasticity-driven decline in global demand reduces prices, and the effect of lower prices outweighs the effect of a decline in the income elasticity of demand. Our results demonstrate the importance of interactions between income, prices, and the income elasticity of demand in projecting future demand for livestock-derived foods. We complement the existing literature on food systems and global change by providing quantitative evidence about the possible space for the future demand of livestock-derived foods, which has important implications for human health and the natural environment.

Tuning π-Acceptor/σ-Donor Ratio of the 2-Isocyanoazulene Ligand: Non-Fluorinated Rival of Pentafluorophenyl Isocyanide and Trifluorovinyl Isocyanide Discovered.

Isocyanoazulenes (CNAz) constitute a relatively new class of isocyanoarenes that offers rich structural and electronic diversification of the organic isocyanide ligand platform. This article considers a series of 2-isocyano-1,3-X2-azulene ligands (X = H, Me, CO2Et, Br, and CN) and the corresponding zero-valent complexes thereof, [(OC)5Cr(2-isocyano-1,3-X2-azulene)]. Air- and thermally stable, X-ray structurally characterized 2-isocyano-1,3-dimethylazulene may be viewed as a non-benzenoid aromatic congener of 2,6-dimethyphenyl isocyanide (2,6-xylyl isocyanide), a longtime "workhorse" aryl isocyanide ligand in coordination chemistry. Single crystal X-ray crystallographic {Cr-CNAz bond distances}, cyclic voltametric {E1/2(Cr0/1+)}, 13C NMR {δ(13CN), δ(13CO)}, UV-vis {dπ(Cr) → pπ*(CNAz) Metal-to-Ligand Charge Transfer}, and FTIR {νN≡C, νC≡O, kC≡O} analyses of the [(OC)5Cr(2-isocyano-1,3-X2-azulene)] complexes provided a multifaceted, quantitative assessment of the π-acceptor/σ-donor characteristics of the above five 2-isocyanoazulenes. In particular, the following inverse linear relationships were documented: δ(13COtrans) vs. δ(13CN), δ(13COcis) vs. δ(13CN), and δ(13COtrans) vs. kC≡O,trans force constant. Remarkably, the net electron withdrawing capability of the 2-isocyano-1,3-dicyanoazulene ligand rivals those of perfluorinated isocyanides CNC6F5 and CNC2F3.

Towards prevention of post-traumatic osteoarthritis: report from an international expert working group on considerations for the design and conduct of interventional studies following acute knee injury.

OBJECTIVE: There are few guidelines for clinical trials of interventions for prevention of post-traumatic osteoarthritis (PTOA), reflecting challenges in this area. An international multi-disciplinary expert group including patients was convened to generate points to consider for the design and conduct of interventional studies following acute knee injury. DESIGN: An evidence review on acute knee injury interventional studies to prevent PTOA was presented to the group, alongside overviews of challenges in this area, including potential targets, biomarkers and imaging. Working groups considered pre-identified key areas: eligibility criteria and outcomes, biomarkers, injury definition and intervention timing including multi-modality interventions. Consensus agreement within the group on points to consider was generated and is reported here after iterative review by all contributors. RESULTS: The evidence review identified 37 studies. Study duration and outcomes varied widely and 70% examined surgical interventions. Considerations were grouped into three areas: justification of inclusion criteria including the classification of injury and participant age (as people over 35 may have pre-existing OA); careful consideration in the selection and timing of outcomes or biomarkers; definition of the intervention(s)/comparator(s) and the appropriate time-window for intervention (considerations may be particular to intervention type). Areas for further research included demonstrating the utility of patient-reported outcomes, biomarkers and imaging outcomes from ancillary/cohort studies in this area, and development of surrogate clinical trial endpoints that shorten the duration of clinical trials and are acceptable to regulatory agencies. CONCLUSIONS: These considerations represent the first international consensus on the conduct of interventional studies following acute knee joint trauma.

A comparison between point-of-care testing and venous glucose determination for the diagnosis of diabetes mellitus 6-12 weeks after gestational diabetes.

AIM: To evaluate point-of-care-testing (POCT) for the diagnosis of Type 2 diabetes mellitus 6-12 weeks post-partum in women with gestational diabetes (GDM). METHODS: Post-partum glucose assessment (75-mg oral glucose tolerance test, OGTT) was performed prospectively in 122 women with GDM (1 November 2015 to 1 November 2017) at Tygerberg Hospital, Cape Town, South Africa. Individuals with known pre-existing diabetes were excluded. The accuracy and clinical utility of POCT (capillary finger-prick) were compared with laboratory plasma glucose (hexokinase and glucokinase methods). The OGTT consisted of two time points (fasting and 2 h) during which concurrent glucose samples (POCT and laboratory) were obtained. Bland-Altman plots and paired analysis were used to assess the analytical accuracy of POCT, whereas its diagnostic performance was determined using positive and negative predictive values to calculate specificity and sensitivity. RESULTS: Spearman's ranked correlation analysis indicated a strong association between POCT and laboratory glucose values at both OGTT time points (fasting, r = 0.95, P < 0.0001; 2 h, r = 0.88, P < 0.0001). Thirty-six women were diagnosed with Type 2 diabetes based on gold standard laboratory glucose levels (fasting > 7 mmol/l; 2 h > 11.1 mmol/l). POCT correctly identified Type 2 diabetes in 78% of women (28 of 36) with a positive predictive value of 89.3% and a negative predictive value of 96.7% at the fasting time point. The sensitivity and specificity of POCT to diagnose Type 2 diabetes were 89% (fasting), 85.7% (2 h) and 96.7% (fasting), 98.5% (2 h) respectively. POCT proved less sensitive to diagnose pre-diabetes (69%) but displayed satisfactory specificity (92%) at both time points assessed. CONCLUSION: POCT accurately identifies women with Type 2 diabetes 6-12 weeks after GDM.

Positional Isomers of Isocyanoazulenes as Axial Ligands Coordinated to Ruthenium(II) Tetraphenylporphyrin: Fine-Tuning Redox and Optical Profiles.

Two isomeric ruthenium(II)/5,10,15,20-tetraphenylporphyrin complexes featuring axially coordinated redox-active, low-optical gap 2- or 6-isocyanoazulene ligands have been isolated and characterized by NMR, UV-vis, and magnetic circular dichroism (MCD) spectroscopic methods, high-resolution mass spectrometry, and single-crystal X-ray crystallography. The UV-vis and MCD spectra support the presence of the low-energy, azulene-centered transitions in the Q band region of the porphyrin chromophore. The first coordination sphere in new L2RuTPP complexes reflects compressed tetragonal geometry. The redox properties of the new compounds were assessed by electrochemical and spectroelectrochemical means and correlated with the electronic structures predicted by density functional theory and CASSCF calculations. Both experimental and theoretical data are consistent with the first two reduction processes involving the axial azulenic ligands, whereas the oxidation profile (in the direction of increasing potential) is exerted by the ruthenium ion, the porphyrin core, and the axial azulenic moieties.

Can sub-Saharan Africa feed itself?

Although global food demand is expected to increase 60% by 2050 compared with 2005/2007, the rise will be much greater in sub-Saharan Africa (SSA). Indeed, SSA is the region at greatest food security risk because by 2050 its population will increase 2.5-fold and demand for cereals approximately triple, whereas current levels of cereal consumption already depend on substantial imports. At issue is whether SSA can meet this vast increase in cereal demand without greater reliance on cereal imports or major expansion of agricultural area and associated biodiversity loss and greenhouse gas emissions. Recent studies indicate that the global increase in food demand by 2050 can be met through closing the gap between current farm yield and yield potential on existing cropland. Here, however, we estimate it will not be feasible to meet future SSA cereal demand on existing production area by yield gap closure alone. Our agronomically robust yield gap analysis for 10 countries in SSA using location-specific data and a spatial upscaling approach reveals that, in addition to yield gap closure, other more complex and uncertain components of intensification are also needed, i.e., increasing cropping intensity (the number of crops grown per 12 mo on the same field) and sustainable expansion of irrigated production area. If intensification is not successful and massive cropland land expansion is to be avoided, SSA will depend much more on imports of cereals than it does today.

The association between body mass index, primary healthcare use and morbidity in early childhood: findings from the Born In Bradford cohort study.

OBJECTIVES: The objective of the article was to examine the association between body mass index (BMI), health and general practice (GP) healthcare use in early childhood. STUDY DESIGN: This study is a prospective cohort study. METHODS: Multivariate Poisson and logistic regression models were used to explore the association between BMI and health outcomes using data from the Born In Bradford cohort study, linked to routine data capturing objective measures of BMI at age 5 years, alongside GP appointment rates, GP prescriptions and specific morbidities in the subsequent 3-year period. RESULTS: Compared with healthy weight, children who were obese at the age of 5 years had significantly higher rates of GP appointments (incident rate ratio 1.14, 95% confidence interval [CI]: 1.06-1.23), GP prescriptions (incident rate ratio 1.15, 95% CI: 1.04-1.27), asthma (odds ratio 1.46, 95% CI: 1.21-1.77), sleep apnoea (odds ratio 2.50, 95% CI: 1.36-4.58), infections (incident rate ratio 1.19, 95% CI: 1.08-1.30), antibiotic prescriptions (incident rate ratio 1.25, 95% CI: 1.10-1.42) and accidents (incident rate ratio 1.20, 95% CI: 1.01-1.42) in the subsequent 3 years. Underweight children were found to have higher rates of GP appointments (incident rate ratio 1.25, 95% CI: 1.04-1.52), but there were no differences between overweight and healthy weight children. CONCLUSIONS: Childhood obesity was found to be associated with increased primary healthcare use and a range of poorer health outcomes at the age of 8 years, underlining the importance of reducing childhood obesity in early childhood.

Agricultural investments and hunger in Africa modeling potential contributions to SDG2 - Zero Hunger.

We use IFPRI's IMPACT framework of linked biophysical and structural economic models to examine developments in global agricultural production systems, climate change, and food security. Building on related work on how increased investment in agricultural research, resource management, and infrastructure can address the challenges of meeting future food demand, we explore the costs and implications of these investments for reducing hunger in Africa by 2030. This analysis is coupled with a new investment estimation model, based on the perpetual inventory methodology (PIM), which allows for a better assessment of the costs of achieving projected agricultural improvements. We find that climate change will continue to slow projected reductions in hunger in the coming decades-increasing the number of people at risk of hunger in 2030 by 16 million in Africa compared to a scenario without climate change. Investments to increase agricultural productivity can offset the adverse impacts of climate change and help reduce the share of people at risk of hunger in 2030 to five percent or less in Northern, Western, and Southern Africa, but the share is projected to remain at ten percent or more in Eastern and Central Africa. Investments in Africa to achieve these results are estimated to cost about 15 billion USD per year between 2015 and 2030, as part of a larger package of investments costing around 52 billion USD in developing countries.

CCL5 derived from platelets increases megakaryocyte proplatelet formation.

In times of physiological stress, platelet count can transiently rise. What initiates this reactive thrombocytosis is poorly understood. Intriguingly, we found that treating megakaryocytes (MKs) with the releasate from activated platelets increased proplatelet production by 47%. Platelets store inflammatory cytokines, including the chemokine ligand 5 (CCL5, RANTES); after TRAP activation, platelets release over 25 ng/mL CCL5. We hypothesized that CCL5 could regulate platelet production by binding to its receptor, CCR5, on MKs. Maraviroc (CCR5 antagonist) or CCL5 immunodepletion diminished 95% and 70% of the effect of platelet releasate, respectively, suggesting CCL5 derived from platelets is sufficient to drive increased platelet production through MK CCR5. MKs cultured with recombinant CCL5 increased proplatelet production by 50% and had significantly higher ploidy. Pretreating the MK cultures with maraviroc prior to exposure to CCL5 reversed the augmented proplatelet formation and ploidy, suggesting that CCL5 increases MK ploidy and proplatelet formation in a CCR5-dependent manner. Interrogation of the Akt signaling pathway suggested that CCL5/CCR5 may influence proplatelet production by suppressing apoptosis. In an in vivo murine acute colitis model, platelet count significantly correlated with inflammation whereas maraviroc treatment abolished this correlation. We propose that CCL5 signaling through CCR5 may increase platelet counts during physiological stress.

Tamoxifen Directly Inhibits Platelet Angiogenic Potential and Platelet-Mediated Metastasis.

OBJECTIVE: Platelets, which are mainly known for their role in hemostasis, are now known to play a crucial role in metastasis. Tamoxifen is a selective estrogen receptor modulator that is widely used for the treatment of breast cancer. Tamoxifen and its metabolites have been shown to directly impact platelet function, suggesting that this drug has additional mechanisms of action. The purpose of this study was to determine whether tamoxifen exerts antitumor effects through direct platelet inhibition. APPROACH AND RESULTS: This study found that pretreatment with tamoxifen leads to a significant inhibition of platelet activation. Platelets exposed to tamoxifen released significantly lower amounts of proangiogenic regulator vascular endothelial growth factor. In vitro angiogenesis assays confirmed that tamoxifen pretreatment led to diminished capillary tube formation and decreased endothelial migration. Tamoxifen and its metabolite, 4-hydroxytamoxifen, also significantly inhibited the ability of platelets to promote metastasis in vitro. Using a membrane-based array, we identified several proteins associated with angiogenesis metastasis that were lower in activated releasate from tamoxifen-treated platelets, including angiogenin, chemokine (C-X-C motif) ligand 1, chemokine (C-C motif) ligand 5, epidermal growth factor, chemokine (C-X-C motif) ligand 5, platelet-derived growth factor dimeric isoform BB, whereas antiangiogenic angiopoietin-1 was elevated. Platelets isolated from patients on tamoxifen maintenance therapy were also found to have decreased activation responses, diminished vascular endothelial growth factor release, and lower angiogenic and metastatic potential. CONCLUSIONS: We demonstrate that tamoxifen and its metabolite 4-hydroxytamoxifen directly alter platelet function leading to decreased angiogenic and metastatic potential. Furthermore, this study supports the idea of utilizing targeted platelet therapies to inhibit the platelet's role in angiogenesis and malignancy.