Plasmodium falciparum genetic diversity typing and resistance monitoring and proposes how the different tools could be employed in resource-poor settings. Advanced approaches enabling targeted deep sequencing is valued as a sensitive method for assessing drug resistance and parasite diversity but remains out of the reach of most laboratories in sSA due to the high cost of development and maintenance. It is, however, feasible to equip a limited number of laboratories as Centres of Excellence in Africa (CEA), which will receive and process samples from a network of peripheral laboratories in the continent. Cheaper, sensitive and portable real-time PCR methods can be used in peripheral laboratories to pre-screen and select samples for targeted deep sequence or genome wide analyses at these CEAs.The intensification of malaria control interventions has resulted in its global decline, but it remains a significant public health burden especially in sub-Saharan Africa (sSA). Knowledge on the parasite diversity, its transmission dynamics, mechanisms of adaptation to environmental and interventional pressures could help refine or develop new control and elimination strategies. Critical to this is the accurate assessment of the parasite’s genetic diversity and monitoring of genetic markers of anti-malarial resistance across all susceptible populations. Such wide molecular surveillance will require selected tools and approaches from a variety of ever evolving advancements in technology and the changing epidemiology of malaria. The choice of an effective approach for specific endemic settings remains challenging, particularly for countries in sSA with limited access to advanced technologies. This article examines the current strategies and tools for  Malaria continues to cause significant morbidity and mortality across Africa, despite the intensification of control interventions . A worldPlasmodium falciparum as a parasite has been attributed partly to its enormous genetic diversity n, [T]n, and [TAA]n repeats [P. falciparum drug-resistance markers and flanking microsatellite loci can be employed to assess the genetic diversity and evolution of selective signatures around drug resistance genes [Microsatellites are tandem repeats of one to six base pairs (bp) that are highly polymorphic. They are abundant in the  repeats . Anderso repeats . These t repeats –79. Alsoce genes .msp/glurp typing, microsatellite typing depends on accurate DNA fragment amplification by PCR, which can result in artefacts. Accurate allele sizing requires expensive capillary electrophoresis equipment that are largely unavailable. Moreover, there are no methods for phase resolution of parasite haplotypes in mixed infections. However, thousands of P. falciparum genome sequences are now available for mining new microsatellite loci which can be developed into new assays for population diversity analyses. Low cost thermocyclers combined with HRM for determining sizes of DNA fragments can improve the availability of microsatellite typing to less specialized laboratories [Similar to ratories .P. falciparum isolates [I.A 96 genome-wide SNP panel used to assess the impact of decreased transmission on parasite diversity in Senegal and at the Thai-Burma border , 86. TheII.A 384-SNP custom GoldenGate Illumina Mass array that clearly resolved global patterns of genetic diversity and the structure of geographically distinct populations across global endemic populations .III.P. falciparum containing five mitochondrial and 18 SNPs of the apicoplast genomes thought to offer a higher resolution between isolates from different endemic blocs [P. falciparum isolates. This can identify imported cases of P. falciparum into elimination settings.23-SNP panel for ic blocs . The facIV.A recent malaria Taqman Array with 87 loci that enable both species classification and typing of markers across drug resistance and neutral loci . DeploymV.https://www.malariagen.net/projects/spotmalaria).The Spot malaria project currently provides a large panel of loci including targets for drug resistance and neutral sites for population diversity analysis. This has been constituted into a ‘Genetic Report Card’ (GenRE). This will become increasingly useful as the genotyping methods applied are sensitive enough to detect parasites genomes and alleles in very low-density infections  and the Human Hereditary and disease in Africa (H3Africa) Pan-African Genetic Epidemiology Network (PAMGEN). These programmes will expand access and application of WGS/GVA approaches to malaria elimination research in sSA. Effective deployment and translation could be further facilitated by sample pooling and employing cheaper but sensitive Real time PCR genotyping methods to pre-screen and select samples in peripheral laboratories prior to genome wide analyses at CEAs. Pre-screening could prioritize loci for diversity, drug or vaccine resistance most relevant to the local control and intervention strategies.Unlike the analysis of individual loci, which may be the target of strong natural selection, inferences from genome-wide diversity are less subject to target biases and, therefore, more accurately reflect overall patterns of Genetic epidemiology of malaria can improve understanding of parasite origins, flow rates between populations , drug resistance and potential susceptibility to candidate anti-malarial drugs and vaccines , 95, 96.Targeted deep and whole genome sequencing are sensitive and specific for detecting patterns of malaria parasite diversity and critical for ‘drug resistant intelligence’. Though they required significant investment in equipment and trained personnel, it is feasible to equip genomic Centres of Excellence in Africa, which will receive and process samples from a network of smaller laboratories with PCR capabilities. These centres will be hubs for developing field deployable genotyping assays for PCR and portable next-Generation sequencing technologies such as the Nanopore to boost genomic surveillance for malaria elimination in Africa. Centres of excellence and molecular surveillance nodes will need computational infrastructure to combine novel approaches for ancestry, relatedness, transmission models and machine learning to resolve spatial–temporal parasite flow, population structure and drug resistance , 99. Thu


With the rise in global older adult populations, university programs need to produce an effective, gerontology-trained workforce . Career decision-making involves interactive learning , as adults explore career options, engage in career learning, and understand curriculum integration within professional settings . Gerontology faculty can utilize career planning models that integrate intergenerational engagement within the curriculum to aid student career decisions . This paper provides an overview of a career planning model and highlights the ways intergenerational programs can be intentionally staged in research, service, and extracurricular domains to promote career planning and success in post-graduate employment. Data from our recent gerontology alumni survey including graduates since the program inception will be outlined to support the importance and success of developing strong applied intergenerational career programs in gerontology.


Two transport pathways  have long been proposed for entry of nanoparticles from the blood circulation into solid tumors. We examine and discuss available evidence supporting interendothelial and transendothelial transport processes and suggest new avenues for re-evaluating these pathways. Understanding of integrative mechanisms controlling nanoparticle extravasation into tumors is important for improving engineering and performance of anti-cancer nanopharmaceuticals. The enhanced permeability and retention effect (EPR) has become an equivocal concept in the targeting and development of anti-cancer nanomedicines. This concept has been recently scrutinized due to disappointing therapeutic efficacy and limited clinical success with anti-cancer nanomedicines compared with excellent results in small animal xenograft models  as well as many pathophysiological factors such as size heterogeneity seen in tumor vessel fenestrae (100–1200 nm), pore frequency/density, other architectural abnormalities, and stochastic intratumoral pressure  has contributed to ambiguity in transport pathways across tumor endothelium. Furthermore, the interaction between nanoparticles and vessel walls (and subsequent extravasation processes) might be controlled by the perfusing concentration of nanoparticles  as well as capillary architecture, and integrated mechanical and fluid dynamic factors that modulate local blood cell  stretching. Here, nanoparticle physicochemical properties such as size, shape, deformability, and surface characteristics all play important roles in establishing nanoparticle impaction with blood cells, contact with endothelium, and rolling on vessel walls. Recent developments in nanoparticle engineering include precision control of particle shape, mechanical stiffness, and surface properties (Moghimi et al.


Participation in risky health behaviors can increase the potential for cognitive decline. Smoking, alcohol consumption, and minimal physical activity are modifiable risk factors associated with worse performance on cognitive assessments; however, the relationship between subjective cognitive decline (SCD) and risky practices has not been assessed. As a potential early indicator of cognitive impairment, SCD may serve as a screening measure for dementia. The Behavioral Risk Factor Surveillance System is an annual, self-reported telephone survey of Americans that includes fifteen core and twenty-five optional sections. The present study included Behavioral Risk Factor Surveillance System participants age 45 or older who completed the core and cognitive decline modules in 2015 . Roughly 11% of participants endorsed worsening memory in the previous year. Logistic regression examined the impact of smoking, drinking, and inactivity on self-reported cognitive decline. Current or former smokers had greater odds of endorsing cognitive decline compared to those who never smoked . Individuals who consumed at least one alcoholic beverage in the previous month had lower SCD odds compared to non-drinkers . Respondents who engaged in little to no physical activity had greater odds of endorsing cognitive decline compared to active respondents . Individuals who endorsed cognitive decline engaged in unhealthy habits such as smoking or inactive lifestyles; however, low to moderate alcohol consumption may be beneficial for cognitive functioning.


Birds are a diverse and agile lineage of vertebrates that all use bipedal locomotion for at least part of their life. Thus birds provide a valuable opportunity to investigate how biomechanics and sensorimotor control are integrated for agile bipedal locomotion. This review summarizes recent work using terrain perturbations to reveal neuromechanical control strategies used by ground birds to achieve robust, stable, and agile running. Early experiments in running guinea fowl aimed to reveal the immediate intrinsic mechanical response to an unexpected drop (“pothole”) in terrain. When navigating the pothole, guinea fowl experience large changes in leg posture in the perturbed step, which correlates strongly with leg loading and perturbation recovery. Analysis of simple theoretical models of running has further confirmed the crucial role of swing-leg trajectory control for regulating foot contact timing and leg loading in uneven terrain. Coupling between body and leg dynamics results in an inherent trade-off in swing leg retraction rate for fall avoidance versus injury avoidance. Fast leg retraction minimizes injury risk, but slow leg retraction minimizes fall risk. Subsequent experiments have investigated how birds optimize their control strategies depending on the type of perturbation , visibility of terrain, and with ample practice negotiating terrain features. Birds use several control strategies consistently across terrain contexts: (1) independent control of leg angular cycling and leg length actuation, which facilitates dynamic stability through simple control mechanisms, (2) feedforward regulation of leg cycling rate, which tunes foot-contact timing to maintain consistent leg loading in uneven terrain , (3) load-dependent muscle actuation, which rapidly adjusts stance push-off and stabilizes body mechanical energy, and (4) multi-step recovery strategies that allow body dynamics to transiently vary while tightly regulating leg loading to minimize risks of fall and injury. In future work, it will be interesting to investigate the learning and adaptation processes that allow animals to adjust neuromechanical control mechanisms over short and long timescales. Birds are diverse and agile vertebrates capable of many combinations of aerial, terrestrial, and aquatic locomotion. Living birds vary in size from hummingbirds to ostriches, and exhibit diversity in the length and mass proportions of the wings and legs, reflecting adaptation for different locomotor ecologies . While wLegged locomotion is complex and dynamic, involving abrupt foot-contact transitions and uncertainty due to variable terrain and sensorimotor errors. Animals must precisely control limb dynamics to move effectively over varied and uncertain terrain while avoiding falls, collisions, and injury . It remaAvoiding slip, fall, and injury requires precise regulation of foot-contact timing and leg-substrate interaction forces . Yet, inOne inherent challenge of animal systems is sensorimotor delay that limits feedback response times ; 2013. SNerve transmission delays increase with the anatomical distances of neural pathways. This physical constraint creates a direct link between neuroanatomy and temporal scaling of control processes . ConsideThe phrase “passive-dynamics” has often been used to refer to the intrinsic mechanical response of the locomotor system. However, this phrase can be somewhat misleading, because the intrinsic mechanical response is actively tuned by the selection of a specific muscle activation pattern from the possible solutions that could meet the mechanical requirements of the task . Each muTerrain perturbations are ubiquitous in nature and disrupt the predictability and timing of foot–substrate interactions, requiring transient locomotor responses to recover from disturbances. Understanding transient locomotor dynamics is important for revealing natural locomotor behaviors, and for understanding the specific mechanical demands and constraints that have shaped animal locomotor control.in vivo muscle force–length dynamics, body dynamics, leg–substrate interaction forces, and joint mechanics during locomotion , and with ample practice negotiating visible terrain features. In comparing locomotor control strategies between hidden and visible potholes, guinea fowl slow down in anticipation of visible potholes when they encounter them for the first time, and actually stumble more when negotiating the visible drop . AlthougBlum and colleagues (2014) explored how animals manage the trade-off between terrain robustness and injury avoidance in leg angular control when given ample practice negotiating a visible drop in terrain. Under these conditions, guinea fowl converge upon a strategy similar to the hidden pothole strategy—they maintain high speeds and allow intrinsic leg mechanics to mediate the perturbation response . The autBlum et al. 2011In another series of experiments, Birn-Jeffery and colleagues investigated control strategies used by ground birds when negotiating visible obstacles, to investigate potential trade-offs in stance leg function . SimilarRegulation of leg cycling rate can be viewed as a combined feedforward plus ‘preflexive’ control strategy that minimizes the need for reactive adjustments by exploiting the intrinsic mechanical coupling between leg contact angle and leg loading. Experimental evidence from both humans and birds running over a range of terrain perturbations are consistent with leg angular trajectory as a key target of neural control . Humans Whereas leg angular trajectory appears insensitive to perturbations and adjusted over longer timescales, leg-length actuation shows high stride-to-stride variance, suggesting both predictive (feedforward) and reactive (feedback) adjustment in uneven terrain . Leg lenWhile modular control of leg angular trajectory and leg-length actuation have emerged as consistent control strategies for robustly stable running, it remains less clear whether, and under what circumstances, leg stiffness serves as a direct target of control. Research on humans running over soft and hard surfaces suggests that humans regulate leg stiffness to maintain steady body trajectory . HoweverDifferences between birds and humans in stiffness regulation could also relate to leg morphology. Birds have a more crouched leg posture with four segments, in contrast to the vertically oriented three-segment leg configuration of humans. The limb morphology of birds may allow more flexible adjustment of leg posture to accommodate terrain variation, minimizing the need for active regulation of leg stiffness. This idea is supported by evidence from a study that directly compared control strategies in humans and birds from a model-based perspective . Birds eIn vivo recordings of muscle force, length, and activation dynamics during perturbed locomotion can help reveal the relative contributions of intrinsic mechanical, feedback, and feedforward control mechanisms. These studies also help reveal how neuromechanics of locomotion are integrated across levels of organization, from individual muscle–tendon dynamics to joint, whole limb, and body dynamics. The relationship between muscle activation and mechanical output is known to be nonlinear and dynamically variable, depending on instantaneous fascicle length, velocity and recent strain history  during stance decreases by 81% during perturbed steps compared to steady strides, despite maintaining the same electromyography (EMG) activation levels  investigated context dependent shifts in sensorimotor control by comparing muscle activation patterns during obstacle negotiation at low and high speeds, and with low and high-contrast obstacles. In slower speed obstacle negotiation, anticipatory increases in muscle activity are apparent in the steps preceding obstacles. At higher running speeds, the neuromuscular response is largely reactive, occurring after foot contact with the obstacle . AnticipWhile neuromechanical control of locomotion involves a complex interplay of mechanical and sensorimotor mechanisms, studies of running birds have revealed several strategies for robust, stable, and agile bipedal locomotion that are consistent across terrain contexts: (1) independent control of leg angular cycling and leg length actuation, which facilitates dynamic stability through simple control mechanisms, (2) feedforward regulation of leg cycling rate to maintain consistent leg loading in uneven terrain, (3) load-dependent muscle actuation to stabilize body mechanical energy in response to disturbances, and (4) multi-step recovery strategies that allow body dynamics to transiently vary while tightly regulating leg loading to minimize risks of fall and injury. Muscle proprioceptive feedback arising from non-steady force–length dynamics likely plays important roles in effective tuning of perturbation responses over time, as well as maintaining accurate state estimates for internal models, path planning, and navigation in higher brain centers. However, it remains unclear how sensory feedback is integrated with spinal neural circuits and higher brain centers to adjust locomotor control over short and long time-scales. In future work, it will be interesting to investigate the learning and adaptation of neuromechanical control mechanisms through repeated exposure to perturbations in controlled conditions.


Most older adults prefer to “age in place” and maintain independent regarding activities of daily living (ADL). Dependency in ADL might be caused by frailty. This study explored the relationship between multidimensional frailty and ADL dependency, and if protective factors, derived from a systematic literature review, moderate this relationship. A longitudinal study with a 24-month follow-up was performed among 1,027 community-dwelling older adults. Multidimensional frailty was assessed with the Tilburg Frailty Indicator, and ADL dependency with the Groningen Activity Restriction Scale. Other measures included socio-demographic characteristics and seven protective factors against ADL dependency, such as physical activity and non-smoking. Logistic regression analyses showed that frail older people had a twofold risk of developing ADL dependency in comparison to non-frail older people after 24 months . Analyses with interaction terms indicated that the selected protective factors against ADL dependency did not signiﬁcantly moderate this relationship. Nonetheless, higher levels of physical activity and having suﬃcient ﬁnancial resources decreased the risk of becoming ADL dependent in the overall sample . In conclusion, multidimensional frail older people are at higher risk of developing ADL dependency and the studied factors against ADL dependency did not signiﬁcantly moderate this relationship. To develop prevention strategies for ADL dependency and facilitate aging in place, future studies might explore the relationship between each specific frailty domain and ADL dependency, and the role of (other) moderating factors.


O-glycans serve as attachment sites and metabolic substrates to the gut commensal bacteria, which have adapted to the mucosal environment. Technology progress has advanced our understanding of mucin biosynthesis, glycosylation and organization. However, the molecular mechanisms underpinning gut bacteria-mucin glycan interactions remain poorly defined. The mucus layer covering the gastrointestinal tract plays a critical role in maintaining a homeostatic relationship with our gut microbiota. The large intestine, which is home to most microbial species constituting the gut microbiota, is lined by a bi-layer of mucus. The outer layer provides a habitat for bacteria, whereas the inner layer maintains them at a safe distance from the epithelial surface. The terminal mucin Lactobacillus acidophilus [Helicobacter pylori [Akkermansia muciniphila, revealing its occurrence in other anatomical regions of the gastrointestinal tract although its optimal ecological niche remains the mucus layer in the colon [This issue gathers eight articles covering various mechanistic aspects of gut bacteria-mucus interactions and impact on health and disease. These include comprehensive overviews of the role of mucus in the interaction with the gut microbiota in humans  or in hodophilus  or pathor pylori  highlighr pylori . This adr pylori . Two artr pylori , food adr pylori  influenche colon . It is c


Post-surgical complications are most common in older adults. While a number of factors contribute, one key determinant is malnutrition. Malnutrition is seen in up to 86% of older adults at hospital admission. Malnutrition and post-surgical complications are linked through two critical observations: 1) malnutrition dramatically reduces the ability of older adults to overcome postsurgical health stressors, and 2) nutritional status is likely to deteriorate further during hospitalization and after discharge. Despite convincing evidence that perioperative nutrition intervention can improve surgical outcomes, nutrition screening and assessment in the preoperative period is not required or standardized. We will review issues surrounding screening and assessment of malnutrition in older adults preparing for elective surgery and present data on screening (NRS-2002) and assessment tools  used in this high-risk population. Finally, we will discuss best practices for identifying and intervening with malnourished older adults in the preoperative setting.


Lung cancer is among the most prevalent cancers and a leading cause of malignancy-related death . For a lThis morphological ITH goes along with multiple molecular alterations within primary and metastatic lesions of the same individual: Whole-exome sequencing of spatially separated tumor regions demonstrated extensive genetic and genomic ITH Figure  3]. App. App3]. EGFR and KRAS alterations with tumor cell content and the predominant morphological growth pattern, we recently analyzed central sections of 19 ADCs subdivided into 467 5×5 mm segments. We demonstrated that EGFR and KRAS driver mutations were present in all malignant segments, suggesting a clonal origin. Despite high levels of inter-and intratumor heterogeneity, we found a significant correlation between variant allele frequencies (VAFs) and morphological growth patterns, but not with tumor sizes [Despite this considerable ITH, only few studies performed an integrative analysis of molecular and morphological markers in NSCLC. To comprehensively compare the spatial distribution of In addition to genomic ITH we addressed somatic mutations of the mitochondrial genome (mtDNA), which were either ubiquitously distributed throughout a tumor section or restricted to specific regions . SpatialTo analyze tumor heterogeneity on the epigenomic level, we recently used a similar segmentation approach  and deteTo infer the phylogenetic relationships between the segments, we calculated distance matrices based on DNA methylation and CNVs. In line with a previous publication , methylaIncreasing evidence suggests a crucial role of ITH as a driver of tumor progression and therapy failure. Hence, ITH poses a major challenge for the treatment and prognosis of patients. However, only little is known about epigenomic ITH to date. Our results suggest that extensive inter-as well as intra-tumor variation shape the molecular and phenotypic heterogeneity of ADCs. The challenge of future research will be to understand the interplay between these multiple genomic and epigenomic layers Figure . While aTo overcome the limitations of single tissue biopsies and to avoid repeated multiregional tissue sampling, novel approaches are required. To this end, tumor DNA circulating in the blood might depict tumor heterogeneity and clonal evolution under therapy more comprehensively , 10. How


The gut microbiota is a central regulator of host metabolism. The composition and function of the gut microbiota is dynamic and affected by diet properties such as the amount and composition of lipids. Hence, dietary lipids may influence host physiology through interaction with the gut microbiota. Lipids affect the gut microbiota both as substrates for bacterial metabolic processes, and by inhibiting bacterial growth by toxic influence. The gut microbiota has been shown to affect lipid metabolism and lipid levels in blood and tissues, both in mice and humans. Furthermore, diseases linked to dyslipidemia, such as non-alcoholic liver disease and atherosclerosis, are associated with changes in gut microbiota profile. The influence of the gut microbiota on host lipid metabolism may be mediated through metabolites produced by the gut microbiota such as short-chain fatty acids, secondary bile acids and trimethylamine and by pro-inflammatory bacterially derived factors such as lipopolysaccharide. Here we will review the association between gut microbiota, dietary lipids and lipid metabolism The gut microbiota regulates many metabolic processes in the host including energy homeostasis, glucose metabolism and lipid metabolism . MicrobiLipid metabolism includes the biosynthesis and degradation of lipids such as fatty acids, triglycerides and cholesterol. Specialized lipoproteins facilitate the transport of lipids from the gut to the liver (the site of most lipid transformations) and between the liver and peripheral tissues. Obesity is linked to dysregulation of lipid metabolism, which may result in abnormal levels of blood lipids, ectopic lipid deposition and associated metabolic diseases such as non-alcoholic liver disease (NAFLD)  and atheThe gut microbiota has the capacity to perform many processes that cannot be carried out by the host. These processes can give rise to microbially produced or modulated metabolites that function as metabolic substrates and signaling molecules in the host, with major implications for host metabolism and health. Dietary composition is central to the metabolic output of the gut microbiota because: (1) the gut microbiota processes dietary nutrients into metabolites and (2) the diet affects the gut microbiota composition and thereby its metabolic potential and impact on the host. In particular, the importance of dietary fibers for gut microbiota composition and function has been extensively studied. In addition, several studies have reported an important role for dietary lipids.In this review, we will discuss interactions between lipids, the gut microbiota and the host. We will describe the current knowledge on how dietary lipids affect the gut microbiota, how interactions between dietary lipids and the gut microbiota influence host physiology and health, and how the gut microbiota affects host lipid metabolism.n-6 PUFA or n-3 PUFA) showed that diets with saturated fat or n-6 PUFA induced weight gain, but only saturated fat increased insulin resistance, colonic permeability, and mesenteric fat inflammation [n-3 PUFA diet differed from the other groups, whereas the gut microbiota of mice fed a saturated fat diet and a n-6 PUFA diet were similar. In another study where mice fed a high-fat diet containing lard, rich in saturated fat, were compared to mice fed a isocaloric high-fat diet containing fish oil, rich in n-3 PUFA, it was found that phylogenetic diversity and abundance of the beneficial bacteria Akkermansia muciniphila, Lactobacillus and Bifidobacterium were lower in mice on a lard diet [The gut microbiota has been shown to differ between mice fed diets that are high or low in fat and between diets that contain equal amounts of fat but from different sources –13  but not in GF mice when compared to palm oil [Not only fat sources with major differences in lipid composition, such as lard and fish oil, but also fat sources that are more similar, may give rise to different gut microbiota composition and function. Devkota et al showed that a diet with milk fat, but not diets with lard or safflower oil, increased expansion of  in mice . Milk fapalm oil . The larThe mechanisms by which dietary fatty acids affect gut microbiota are not well defined. Although most of the fatty acids consumed are absorbed in the small intestine, a minority will pass through the gastrointestinal tract and may therefore directly modulate colonic microbiota composition. Fatty acids have a broad spectrum of antibacterial activity including lysis and solubilization of bacterial cell membranes , 15 and Intestinal bacteria can also react with fatty acid double bonds to produce metabolites that cannot be synthesized by mammalian hosts. Bacterial processing of linoleic acid, for example, has been shown to produce metabolites that may influence host physiology and health. Conjugated linoleic acid (CLA) can be produced by several gut bacteria including Lactobacillus, Butyrivibrio, and Megasphaera , 20. DifBacterial production of CLAs is a multistep process involving several metabolic intermediates. These metabolites include several hydroxy fatty acids that affect processes related to host health. 10-hydroxy-cis-12-octadecenoic acid (HYA) enhances intestinal barrier function and suppresses the development of colitis in mice in a free fatty acids 1 (FFR1/GPR40)-dependent manner . AnotherStudies in gnotobiotic mice have shown that the gut microbiota affects host lipid metabolism. Importantly, GF mice are protected against diet-induced obesity through a combination of several mechanisms including increased fatty acid oxidation and decreased deposition of triglycerides in adipocytes compared to CONV-R mice . FurtherThe gut microbiota affects host lipid metabolism and lipid composition through interaction with the diet. In a recent study by Just et al, CONV-R and GF mice were fed palm oil or lard diet (both rich in saturated lipids) supplemented with bile acids . They foLactobacillus curvatus alone or together with Lactobacillus plantarum reduced cholesterol in plasma and liver and the two strains had a synergistic effect on hepatic triglycerides [Studies in mice treated with probiotics provide further evidence for a role of the gut microbiota in regulation of host lipid homeostasis. In mice fed a high-fat high-cholesterol diet, ycerides . Similarycerides .Overall, studies in mouse models show that the gut microbiota, in concert with the diet, regulates host lipid metabolism and lipid levels in serum and tissues.The fecal microbiota has also been linked to lipid metabolism in humans. Taxonomy and functional profiles of the bacteria differ between obese and lean subjects, but results from different studies are inconsistent, in part because of the complex nature of obesity but also because different methods have been used to analyze the microbiota . A numbeChanges in fecal microbiota composition are also present in individuals with pathophysiological conditions associated with dyslipidemia and ectopic fat deposition such as atherosclerosis and fatty liver. By analyzing the microbial composition of atherosclerotic plaques, fecal samples and the oral cavity in patients with symptomatic carotid artery stenosis , Koren eBacteroidetes in patients with fibrosis or NASH is the most consistent finding in these studies.Several studies have shown that the fecal microbiota composition in subjects with NAFLD differs from that of healthy controls and obese patients without fatty liver disease –45. HoylShort-chain fatty acids (SCFAs) such as acetate, propionate and butyrate are bacterial metabolites derived from fermentation of fibers in the colon Fig. . Both buGpr41 knockout mice are leaner and weigh less than their wild-type littermates, while these differences are not found in GF mice. Furthermore, the microbiota increases peptide YY (PYY) production through GPR41 [In addition to being metabolic substrates, SCFAs act as signaling molecules, notably through the G-protein coupled receptors GPR43/FFAR2 and GPR41/FFAR3. GPR43 protects against diet-induced-obesity in mice –55. Actigh GPR41 . Butyratgh GPR41 , and SCFgh GPR41 , reducedgh GPR41 .Overall, SCFAs have been shown to have a positive impact on metabolic health . Supplemde novo synthesis from cholesterol [Primary bile acids are synthesized from cholesterol and conjugated to taurine or glycine in the liver. The bile acids are stored in the gallbladder and excreted into the duodenum after food ingestion to aid emulsification of dietary lipids. Most of the bile acids are reabsorbed and recirculated to the liver, but bacterially mediated deconjugation of the glycine or taurine group reduces reabsorption. Deconjugated bile acids can be further metabolized to secondary bile acids through dehydrogenation, dehydroxylation and epimerization by colonic bacteria . Microbilesterol .In addition to their role in lipid digestion, bile acids can act as signaling molecules that regulate host metabolism by binding to the nuclear receptor farnesoid X receptor (FXR) and the Takeda G-protein coupled bile acid receptor TGR5. Microbial processing of bile acids increases the diversity of the bile acid pool and the different bile acids vary in their affinity to the receptors and can act as agonists or antagonists. Both of the primary bile acids cholic acid (CA) and chenodeoxycholic acid (CDCA) and the secondary bile acids lithocholic acid (LCA) and deoxycholic acid (DCA) are FXR agonists, but with different affinities . In humaFxr knockout mice with or without bacteria a high-fat diet, Parséus et al showed that microbiota-induced weight gain, steatosis and inflammation were dependent on FXR signaling [Fxr knockout donor mice, demonstrating that FXR may contribute to increased adiposity by altering the microbiota composition. Comparison of whole body and tissue-specific Fxr knockout mice have revealed that activation of the liver and intestinal FXR result in distinct metabolic outcomes in obesity models [FXR is involved in the regulation of lipid metabolism, especially triglyceride trafficking, synthesis and utilization . Microbiignaling . FXR alsy models –77. Sevey models , 77 but Bile acids have also been shown to influence host lipid metabolism through TGR5. TGR5 activation in skeletal muscle and brown adipose tissue promotes energy expenditure . In addiBile acids have been implicated in the pathogenesis of fatty liver disease. Patients with NASH have been shown to have altered fecal bile acid composition . In addiLipopolysaccharides (LPS), also known as endotoxins, are structural compounds in the outer membrane of Gram-negative bacteria. LPS induces inflammation through activation of TLR4, which is expressed on immune cells such as macrophages as well as on many other cell types including hepatocytes and adipocytes. The intestinal epithelium works as a barrier to prevent translocation of bacterially derived factors. However, weight gain, high-fat diet  and incrLPS interacts with blood lipids in various ways. First, it increases the concentration of blood triglycerides by multiple mechanisms. In rats, low-dose LPS increases hepatic synthesis of VLDL, whereas high-dose LPS decreases lipoprotein catabolism . Mice laLPS has been shown to promote atherosclerosis and cardiovascular disease. LPS-treated hypercholesterolemic rabbits have increased atherosclerosis compared with controls  and miceMouse studies have shown that hepatic steatosis is induced by a high-fat diet and associated with dysbiosis and increased intestinal permeability . MoreoveApoe knockout mice show that increased microbial capacity for TMA production increases aortic lesions[The gut microbiota metabolizes methylamine-containing nutrients such as choline, lecithin and L-carnitine to generate trimethylamine (TMA), which is further processed to trimethylamine N-oxide (TMAO) by flavin monooxygenases (FMO) in the liver. TMAO levels have been correlated with risk of cardiovascular events and prevc lesions.Fmo3 results in reduced atherosclerotic lesion areas, altered lipid and cholesterol metabolism, and decreased TMAO plasma levels [FMO3 is the primary enzyme converting TMA into TMAO. Knockdown of a levels , 120. FMa levels . Gut micThe mechanisms by which TMAO contributes to atherosclerosis appears to be complex and not fully understood. Antibiotic treatment reduces production of TMA and has been shown to suppress foam cell formation. TMAO can also contribute to atherosclerosis by inhibiting reverse cholesterol transport  and by iApoe knockout mice fed diets with or without choline supplementation found no effect of choline enrichment on aortic root atherosclerosis in mice[Although many studies have reported associations between plasma levels of choline, TMAO, and cardiovascular disease , 125 thes in mice. TMAO prs in mice. Similars in mice, 127.The gut microbiota has been targeted for treatment of diseases related to dyslipidemia. Strategies include supplementing the diet with fibers to enhance the growth or activity of beneficial bacteria (prebiotics), live bacteria (probiotics) or a combination of pre- and probiotics (symbiotics).A meta-analysis of 11 minor clinical trials using fermented milk and probiotics show beneficial effects on serum lipid profiles. AnotherStatins lower cholesterol levels by inhibiting HMG-CoA reductase, but may also exert a lipid-lowering effect through interaction with the gut microbiota. Liu et al demonstrated that the cholesterol-lowering effect of rosuvastatin was reflected in microbial alpha diversity measured after eight weeks of treatment . StudiesThe studies performed on microbiota-targeted therapy against dyslipidemia and NAFLD are heterogeneous, the cohorts small and the intervention periods short. Therefore, long-term benefits remain uncertain. Prevention of atherosclerosis by modulation of the gut microbiota has not been studied in humans and data in mice are conflicting–137.An intricate crosstalk links the gut microbiota, dietary lipids and host lipid metabolism. The microbiota processes lipids and other nutrient factors to produce metabolites with impacts on host lipid homeostasis and putative effects on pathophysiological processes. Studies in gnotobiotic and genetic mouse models have identified mechanisms behind these interactions, and studies in humans have found associations between microbial composition, lipid profiles and prevalence of metabolic diseases. However, although it is evident that fat from different sources has different effects on the gut microbiota, the role of specific fatty acids is not known. It also remains to be investigated how the combination of lipids with other nutrients - such as dietary fibers – affects the gut microbiota. Even though efforts have been made to understand how dietary pattern affect the gut microbiota, 139, th


Inflammaging is the chronic low-grade inflammation that occurs with age that contributes to the pathology of age-related diseases. Monocytes are innate immune cells that become dysregulated with age and which can contribute to inflammaging. Metabolism plays a key role in determining immune cell functions, with anti-inflammatory cells primarily relying on fatty acid oxidation and pro-inflammatory cells primarily relying on glycolysis. It was recently shown that lipopolysaccharide (LPS)-stimulated monocytes can compensate for a lack of glucose by utilizing fatty acid oxidation. Given that mitochondrial function decreases with age, we hypothesized that monocytes taken from aged individuals would have an impaired ability to upregulate oxidative metabolism and would have impaired effector functions. Aging did not impair LPS-induced oxygen consumption rate during glucose starvation as measured on a Seahorse XFp system. Additionally, aged monocytes maintained inflammatory gene expression responses and phagocytic capacity during LPS stimulation in the absence of glucose. In conclusion, aged monocytes maintain effector and metabolic functions during glucose starvation, at least in an ex vivo context.


Leaves are initiated as lateral outgrowths from shoot apical meristems throughout the vegetative life of the plant. To achieve proper developmental patterning, cell-type specification and growth must occur in an organized fashion along the proximodistal (base-to-tip), mediolateral , and adaxial–abaxial (top-bottom) axes of the developing leaf. Early studies of mutants with defects in patterning along multiple leaf axes suggested that patterning must be coordinated across developmental axes. Decades later, we now recognize that a highly complex and interconnected transcriptional network of patterning genes and hormones underlies leaf development. Here, we review the molecular genetic mechanisms by which leaf development is coordinated across leaf axes. Such coordination likely plays an important role in ensuring the reproducible phenotypic outcomes of leaf morphogenesis. Arabidopsis, the leaf is subdivided into the proximal petiole and distal lamina. Leaf development also involves specialization of the upper and lower leaf surfaces, defining an adaxial–abaxial (top-bottom) axis of asymmetry. At its inception, the leaf primordium possesses inherent asymmetry along this axis due to the proximity of the adaxial leaf surface to the SAM relative to the abaxial leaf surface ) and barley (NARROW LEAF DWARF1 [NLD1]), and yield comparable phenotypes when disrupted, although defects in margin patterning extend well into the leaf blade in these species ), petunia (MAEWEST [MAW]), and Medicago (STENEFOLIA [STF]) and have conserved roles in promoting the mediolateral outgrowth of the leaf blade . . miR319 YAB genes were linked to the control of abaxial cell identity in the leaf . . BOP gened light C 140]. . BOP genactivity ,142,143.KNOX genes by factors regulating development along all three axes. Clearly, KNOX repression is an essential and tightly regulated developmental program of the leaf. Additionally, coordinating factors frequently cross-regulate multiple patterning modules, as well as interact with a host of co-regulatory proteins to carry out their functions. Looking forward, advances in live imaging methods will allow for enhanced analysis of leaf development and its associated spatiotemporal gene expression patterns in real time. This, coupled with rapdily advancing genomics technologies, will provide a major boon to understanding the complex and interwoven leaf axial patterning pathways. Through such work, we will come closer to understanding the remarkable consistency of leaf patterning in three dimensions.Plants are capable of producing consistently patterned leaves throughout their lifespan, a feat that requires highly robust control of underlying genetic patterning factors. One way that such robustness may be achieved is through the close coordination of factors patterning the three growth axes of leaves, a prediction realized by the work of Waites and Hudson almost twenty five years ago. Here, we have described several genetic and hormonal factors that simultaneously regulate developmental patterning along multiple leaf axes simultaneously. Such control mechanisms likely ensure that growth along these axes proceeds in a synchronized and organized fashion. Perhaps most striking is the highly redundant repression of Class I


OBJECTIVES/SPECIFIC AIMS: Brown adipose tissue (BAT) increases energy expenditure by dissipating chemical energy as heat. The combustion of glucose and lipids produces beneficial metabolic effects and renders BAT an attractive target to battle obesity and associated diseases. The majority of adults do not display active BAT on positron emission tomography (PET) without prior cold exposure. Interestingly, a fraction of individuals with BAT positive PET scans exhibits excessive BAT (eBAT) activity, indicating a possible underlying genetic contributor. We aim to identify genetic determinants of BAT activity by studying individuals with eBAT activity using next-generation sequencing. A cellular model will be used to validate variants and perform in-depth pathway analysis. METHODS/STUDY POPULATION: We performed a retrospective review of PET scans over a period of 12 months in patients presenting with suspected or diagnosed cancer . The distribution of BAT positive individuals (n=1251) was used to implement a threshold to define eBAT activity. Samples from prospectively recruited individuals with BAT activity above the threshold will undergo whole exome sequencing. Variants associated with eBAT activity will be engineered into an immortalized BAT cell line using CRISPR to validate results and perform in-depth pathway analysis. RESULTS/ANTICIPATED RESULTS: We expect to identify genetic variants associated with eBAT. Studying the effects of these variants on thermogenesis followed by in-depth pathway analysis in genetically engineered cellular and mouse models may enable us to find new regulators of BAT activity. These findings may eventually contribute to the development of new drugs targeting obesity and its sequelae. DISCUSSION/SIGNIFICANCE OF IMPACT: The contribution of genetic factors to individual BAT activity is currently unknown. Identifying individuals with eBAT on PET scans and studying the underlying genetic determinants may provide the foundation for the discovery of new pathways for BAT activation.


Background: Both hearing loss and mobility decline are well-known risk factors of cognitive impairment among older adults. However, the effects of the accumulation of these functional impairments are still unclear. Thus, the present study examined whether the interactive effects of hearing loss and poor gait performance contribute to cognitive impairments. Methods: Hearing loss and gait performance were assessed in 716 community-dwelling older adults at baseline. Pure-tone audiometry was conducted to determine hearing loss at 1  and 4 kHz . Poor gait performance was defined as the lowest quartile (fourth quartile) of age- and sex-appropriate mean gait velocity. Participants were then classified into four groups according to the presence of hearing loss and poor gait performance. Cognitive function was assessed using MMSE and MoCA at baseline and four years later. Results: Older adults who had either hearing loss (low or high tone) or poor gait performance showed lower MMSE and MoCA scores at baseline. Multiple regression models showed that hearing loss and poor gait performance at baseline were significantly associated with decreased cognitive function at follow-up. Among older adults with low tone hearing loss, absence of slow gait was not associated with decreased cognitive function. Conclusions: Our results indicate the possibility that hearing loss and slow gait synergistically increase the risk of cognitive impairment. The results also suggest that the effect of slow gait on cognition exceeds the effects of hearing loss, indicating the importance of maintaining mobility in late life.


Vector-borne disease control relies on efficient vector surveillance, mostly carried out using traps whose number and locations are often determined by expert opinion rather than a rigorous quantitative sampling design. In this work we propose a framework for ecological sampling design which in its preliminary stages can take into account environmental conditions obtained from open data  not necessarily designed for ecological analysis. These environmental data are used to delimit the area into ecologically homogeneous strata. By employing Bayesian statistics within a model-based sampling design, the traps are deployed among the strata using a mixture of random and grid locations which allows balancing predictions and model-fitting accuracies. Sample sizes and the effect of ecological strata on sample sizes are estimated from previous mosquito sampling campaigns open data. Notably, we found that a configuration of 30 locations with four households each (120 samples) will have a similar accuracy in the predictions of mosquito abundance as 200 random samples. In addition, we show that random sampling independently from ecological strata, produces biased estimates of the mosquito abundance. Finally, we propose standardizing reporting of sampling designs to allow transparency and repetition/re-use in subsequent sampling campaigns. SamplinGenomic technologies are radically transforming our understanding of vector-borne disease transmission dynamics  due to tAnopheles, Culex and Aedes) a priori Finally, our framework can be applied to other ecological studies. For example, Wang and colleagues  includedIn conclusion, big and open data and research outputs could enhance the power of ecological and genomic studies , facilit


In most patients, epilepsy arises due to various initial precipitating injuries during the developmental stages. A major challenge in the neuroscience and neuroclinical fields is understanding how this precipitating injury produces a persistent reorganization of the brain's neural network, thereby transforming the normal brain into epileptogenesis. Identifying the pathological basis of epileptic seizure may lay the foundation for the development of new anti-epileptic drugs, benefiting 60 million people with epilepsy worldwide. This is why our editors chose the theme “The Developmental Seizure-Induced Hippocampal Mossy Fiber Sprouting: Target for Epilepsy Therapies?”Cavarsan et al.]. The development of mossy fiber sprouting may be associated with epilepsy comorbidities rather than with seizure incidence. For example, people with mesial temporal lobe epilepsy (mTLE) and depression show more sprouting than those with only mTLE . A 4-week zinc-deficient diet exacerbated MFS caused by developmental seizures, accompanied by cognitive deficits and reduced seizure thresholds. In contrast, zinc supplementation for 4 weeks significantly reduced MFS and improved the above-mentioned damage-related changes. Mitophagy-mediated zinc homeostasis via mitochondrial activation may be a potential mechanism [ and three reviews. With respect to the demographics of this Research Topic collection, the corresponding authors are from Japan, the United States, Canada, Brazil, South Korea, and China. We hope that the information gathered from this topic will help promote post-epilepsy MFS study and help promote clinical translational medical research to better prevent and treat these injuries in the near future.This Research Topic collects seven articles: four animal studies (including one HN wrote the draft. TK, BN, and CH reviewed the manuscript.BN was employed by the company Expesicor Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Heart failure (HF) with either reduced or preserved ejection fraction is an increasingly prevalent condition. Cardiac imaging plays a central role in trying to identify the underlying cause of the underlying systolic and diastolic dysfunction, as the imaging findings have implications for patient’s management and individualised treatment. The imaging modalities used more frequently in patients with heart failure in clinical routine are echocardiography and cardiac magnetic resonance. Both techniques keep some strengths and weakness due to their spatial and temporal resolution. Notably, several features in the diagnostic algorithm of heart failure with preserved systolic function (HFpEF) may be improved by an integrated approach. This review focuses on the role of each modality in characterising cardiac anatomy, systolic and diastolic function as well as myocardial tissue characterisation in the most common phenotypes of dilated and hypertrophied hearts. Cardiac imaging plays a central role in trying to phenotype the underlying cause of heart failure (HF) which has implications for patient’s management and individualised treatment. Heart failure has recently been classified as heart failure with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF) ; althougTwo-dimensional transthoracic echocardiography is the first line imaging tool providing information on function, cavity size, relative wall thickness (RWT) and myocardial mass which are used for classification of typical geometric phenotypes—concentric or eccentric hypertrophy and remodelling , 5. MoreCardiac magnetic resonance (CMR) is the gold standard for cardiac anatomical and functional quantification, with unique capabilities of non-invasive tissue characterisation –9, complNovel CMR tissue characterisation techniques are called CMR relaxometry (T1 and T2 mapping and extracellular volume fraction (ECV)) which allow a more detailed and quantitative approach to tissue characterisation and 4D-Flow which provides quantitative information on intracavitary flows. Current applications appear particularly useful for diastolic dysfunction detection although they deserve a specific comparison with traditional Doppler and Tissue Doppler analysis in order to confirm the applicability in clinical practice.The most common cardiomyopathic processes underpinning HFpEF (hypertrophied phenotypes) and HFrEF (dilated phenotypes) are discussed below.Left ventricular (LV) hypertrophy (LVH) is a consequence of an underlying genetic or acquired condition and it is accompanied by alterations in cardiac function and haemodynamics. The differential diagnosis between LVH due to physiological adaptation or underlying pathology can be challenging.Non-physiological left ventricular hypertrophy (LVH) regardless to the underlying cause leads to important cardiovascular complications such as atrial fibrillation, diastolic and systolic heart failure , and it Systemic blood pressure elevation is the most common cause of the increment in ventricular mass with a high RWT, which results in concentric or eccentric hypertrophy and concentric remodelling . These sGlobal longitudinal strain (GLS) is an emerging parameter currently available with both methods. GLS is typically reduced in advanced stages of HHD, and it is strongly associated with diastolic dysfunction, it is less dependent on afterload changes and degree of LVH compared with EF, and it has a role in differentiating HHD from other hypertrophic phenotypes , 22. CMRe′ velocity associated with increased E/e′ ratio. Myocardial deformation parameters or patterns of regional strain values such as relative apical sparing or septal apical-base longitudinal strain gradient may have a better differentiating capacity in detecting and differentiating cardiac amyloidosis from other hypertrophic substrates, including HCM, hypertrophy in aortic stenosis or metabolic cardiomyopathies [Infiltrative myocardial disease particularly cardiac amyloidosis can present with very heterogenous hypertrophic phenotypes with wide ranges of wall thicknesses including normal . Granulaopathies . Using dopathies . Howeveropathies . These nopathies .Dilated phenotypes are a heterogenous group characterised by large LV cavities with eccentric remodelling or hypertrophy and impaired contractility. Such phenotypes can be a response to abnormal loading conditions typically in valvular disease or hypertension, severe coronary or congenital disease  or predoReflecting perfusion contraction matching and mismatching, ischaemic heart failure (IHF) consists of a spectrum of pathophysiological states, from early remodelling characterised by wall thinning and dilatation to irreversible late remodelling resulting from myocardial fibrosis and scar . EchocarMutations in over 50 genes have been associated with dilated cardiomyopathy . MultiplThe longitudinal trajectories of LV ejection fraction vary between the two conditions in a very sensitive way. When adequate follow-up is available, repeat echocardiograms in HFpEF can detect a maximum of 2–5% fell in EF over 5 years, with a larger fall in the presence of coexisting coronary artery disease , 62. A sMore similarities, than discrepancies, instead, can be detected when looking at diastolic dysfunction in HFpEF vs. HFrEF patients. Diastolic dysfunction contributes to exercise intolerance, both in systolic and primary diastolic dysfunction. In both conditions, in fact, diastolic impairment limits exercise tolerance before resulting in symptoms at rest .E/e′ ratio have been debated. In theory, the occurrence of the above-mentioned picture is typical of a restrictive pattern and along with increased LA volume and increased pulmonary pressure, reflects high filling pressure in either HFrEF and HFpEF [E/e′ ratio in relation to wedge pressure, but a complete measurement of left chambers pressure is lacking [E/e′ ratio and LVEDP in a recent metanalysis appears modest and patients with atrial fibrillation (AF) were excluded [In the absence of mitral stenosis, the two major factors that determine the early diastolic mitral valve pressure gradient and the rate of LV filling are the rate of LV relaxation and the LA pressure at the time of mitral valve opening . With exnd HFpEF . However lacking , 72. Theexcluded . All theexcluded . We thinexcluded . Thus, fDiastolic dysfunction is a dominant feature in many HF patients. LV diastolic dysfunction causes LA dilatation, which can lead to AF . DespiteRecently, in characterising the governing role of the four-chamber (near) constant-volume pump physiology, wherein the atrial and ventricular volumes simultaneously reciprocate throughout the cardiac cycle, CMR has elucidated and characterised LA and LV phasic function, thereby quantifying the conduit contribution to ventricular filling as the integral of net, diastolic, instantaneous difference between synchronised atrial and ventricular volume curves . BecauseUsing single-beat simultaneous left atrial and ventricular full-volume 3D dataset, it was demonstrated that the atrial conduit contribution to ventricular filling has a direct relationship with the degree of underlying ventricular diastolic impairment in HF patients . More reIn addition to LA and LV volume curves, CMR can provide further information on myocardial tissue characteristics. Myocardial fibrosis have been implicated in the pathophysiology of HFpEF by promoting adverse ventricular remodelling, increasing myocardial stiffness, and in turn, causing diastolic dysfunction . DiffuseHeart failure is disease with large phenotypic variations in morphology, function and natural history. Such a heterogeneity in presentation is perhaps a reason why despite different clustering approaches, many interventions in clinical trials have not shown efficacy. Cardiac imaging provides diverse insights, but the ability to distinguish between overlapping phenotypes remains a challenging proposition. The evaluation of diastolic function by echocardiography and CMR with their traditional and novel techniques deserves specific analysis and a comparison with haemodynamic measurement before to be universally accepted. Diastolic function parameters derived by CMR may be applied in routine clinical care and matched with more feasible echo analysis in order to increase our awareness in the HFpEF mechanisms and reduces the current diagnostic gap. New parameters studying both radial and circumferential relaxation together with identification of extracellular collagen volume could facilitate the diagnosis and will play a central role in the identification of underlying pathophysiological mechanisms. Comparative imaging trials should be encouraged in order to discern which technique(s) alone, or in combination, could provide additional prognostic value.


Imaging plays a central role in evaluating responses to therapy in neuro-oncology patients. The advancing clinical use of immunotherapies has demonstrated that treatment-related inflammatory responses mimic tumor growth via conventional imaging, thus spurring the development of new imaging approaches to adequately distinguish between pseudoprogression and progressive disease. To this end, an increasing number of advanced imaging techniques are being evaluated in preclinical and clinical studies. These novel molecular imaging approaches will serve to complement conventional response assessments during immunotherapy. The goal of these techniques is to provide definitive metrics of tumor response at earlier time points to inform treatment decisions, which has the potential to improve patient outcomes. This review summarizes the available immunotherapy regimens, clinical response criteria, current state-of-the-art imaging approaches, and groundbreaking strategies for future implementation to evaluate the anti-tumor and immune responses to immunotherapy in neuro-oncology applications. Central nervous system (CNS) malignancies are associated with significant morbidity and mortality. In adults, the extremely aggressive glioblastoma (GBM) has the highest incidence of all gliomas and causes more deaths than all other primary CNS malignancies combined. GBM is associated with a median overall survival of less than two years despite surgery and chemo-radiotherapy Cancer immunotherapy strategies aim to stimulate innate or adaptive immune responses against malignant cells. During the last decade, immunotherapy regimens have made remarkable clinical progress in cancer patients, particularly those with recalcitrant solid tumors, by overcoming immune-suppressive signals present in the tumor microenvironment Non-invasive, longitudinal imaging is central to measuring the progression of disease and the efficacy of treatment in neuro-oncology. Historically, response criteria based on conventional imaging through computed tomography (CT) or magnetic resonance imaging (MRI) techniques were used to monitor changes in tumor morphology and responses to tumoricidal chemo-radiotherapy regimens, where shrinkage corresponded with malignant cell death and therapeutic response, while enlargement or appearance of new foci corresponded to therapeutic failure and progressive disease. Studies over the last two decades with emerging biologic or immunotherapy regimens, which are predominantly tumoristatic, have shown the failure of traditional morphologic response criteria and conventional imaging techniques to predict therapeutic outcomes. Inflammatory responses and related effects from immunotherapy are often indistinguishable from progressive disease during conventional imaging, particularly at early stages of treatment An expanding effort is being mounted to address these challenges through modified response criteria and advanced imaging techniques in research and clinical settings Non-invasive imaging in neuro-oncology aims to define widely applicable clinical response criteria for evaluating disease progression and comparing response outcomes across studies. However, distinguishing between tumor response, pseudoprogression, and progressive disease is a significant challenge in neuro-oncology patients treated with immunotherapy. Pseudoresponse is an alternative imaging pattern where the malignancy falsely appears to have responded to a particular therapy regimen The Macdonald criteria, proposed in 1990 The response assessment in neuro-oncology (RANO) criteria were introduced in 2010 There are currently hundreds of concurrent clinical trials investigating various immunotherapy strategies in neuro-oncology. These studies have shown ongoing challenges to monitor therapeutic efficacy due to variations in response patterns observed during immunotherapy as opposed to traditional chemo-radiotherapy. The immunotherapy RANO (iRANO) criteria were published in 2015 to guide response assessment specifically in neuro-oncology patients treated with immunotherapy The RANO and iRANO criteria were developed primarily for patients with GBM, with the understanding that separate criteria would be required to most effectively define responses to therapy in patients with low grade glioma or with metastases from non-CNS malignancies. RANO characterizes low grade glioma tumor burden by FLAIR signal area rather than by contrast enhancing area, but is otherwise homologous to high grade glioma criteria 18F]fluoro-D-glucose [FDG] or radiolabeled amino acids) in clinical care and in trials that monitor outcomes to therapy, with the expectation that PET parameters could be incorporated into future response criteria in neuro-oncology Non-invasive imaging techniques for neuro-oncology can be grouped into the following categories: 1) structural imaging through conventional CT or MRI, 2) physiological imaging through advanced MRI, positron emission tomography (PET), or single photon emission computed tomography (SPECT) and 3) molecular imaging through advanced MRI, PET, or SPECT  based on the expression of biomarkers that correspond to the therapeutic regimen. While biopsy or surgical tissue samples can provide information for tumor progression or biomarker expression, tissue sample analyses are subject to sampling error, may not be representative of spatial-temporal tumor heterogeneity, and are not always available from essential CNS regions or serial time points. Conversely, non-invasive advanced imaging strategies allow global, serial assessment to predict response to treatment or identify biomarker expression 1T MRI and/or extent of 2T hyperintense areas observed on FLAIR MRI sequences are currently standard parameters used to monitor tumor progression in neuro-oncology. However, enlargement of MRI contrast enhancing components and/or enlargement of FLAIR hyperintense areas can be seen both in tumor progression and in inflammatory responses associated with immunotherapy  metric is used in clinical practice and in clinical trials to evaluate response. This parameter is an indication of water diffusivity, which is inversely proportional to cellularity + cell densities at the interface between the brain and secondary brain metastases in a cohort of 26 patients, suggesting that DTI could be a surrogate marker for immune cell response + cells, suggesting that immune cell localization can be detected by low fractional anisotropy values in peritumoral regions. While the effects of immunotherapy were not investigated, these findings support future studies to determine if similar fractional anisotropy patterns occur during immunotherapy in patients with brain metastases or with GBM.i. Diffusion tensor imaging (DTI) MRI adds directionality to DWI and has been used as an anatomic tool to map white matter tracts . DTI is also useful in functional MRI assessment ii. Diffusion kurtosis imaging (DKI) MRI enables quantification of non-random diffusion of water due to structural features present in tissues. This metric is more sensitive to structural abnormalities in gray matter compared to DTI q-space imaging MRI uses Fourier transformation of water diffusivity at high b values to quantify non-Gaussian mean water displacement, thus providing structural information about tissues. Theoretical calculations indicate q-space imaging MRI can detect tissue-restricted water diffusion in white matter with high sensitivity, although the sequences require relatively long acquisition times compared to alternative DWI methods q-space imaging MRI in patients with low-grade glioma iii. iv. Neurite orientation dispersion and density index MRI differentiates water diffusion within linear cell structures (axons), free fluid , and constricted water flow in cells or extracellular spaces PWI MRI monitors time-intensity parameters of fluid flow through tissues of interest to assess vascularity in the tissues. Various PWI parameters have also been used to monitor response in several immunotherapy trials in neuro-oncology patients. Through these imaging techniques, progressive disease is identified by increased fluid flow due to neovascularization to support tumor growth. Early stages of immunotherapy may also show increased fluid movement due to inflammatory responses, subsequent stabilization of vascularity and permeability during continued response to therapy is anticipated to show lower perfusion values relative to progressive disease.i. Dynamic susceptibility-weighted contrast-enhanced (DSC) MRI is the most common PWI technique in clinical practice. DSC MRI monitors contrast agent dynamics during the first pass of the contrast material through the brain to determine relative cerebral blood volume as a surrogate for microvessel density, relative cerebral blood flow, mean transit time of the contrast agent, and time to peak for contrast agent accumulation at a location of interest, which are all useful parameters for tumor grading and assessing response to chemo-radiotherapy. Confounders include artifacts from disruption of the BBB (accumulation of contrast agent) or from signal susceptibility at bone interfaces 1T-weighted sequence acquired before, during, and after the injection of a Gd-based contrast agent and then fit to a two-compartment model to assess the rate of transfer from plasma to extravascular extracellular space (Ktrans), the extravascular extracellular volume (ev), the volume plasma (pv), and the “wash-out”, or the transfer from the extravascular extracellular space to the plasma (*epk) ii. Dynamic contrast-enhanced (DCE) MRI is a iii. Arterial spin label MRI utilizes endogenous signaling of water molecules within moving blood (compared to static parenchyma) before entering the brain to provide contrast for perfusion analyses. Compared to other techniques, arterial spin label MRI provides poor signal due to relaxation and to the low amount of “labeled” blood relative to “unlabeled” blood in the region of interest during the scan. This technique has not yet been widely explored in neuro-oncology patients treated with immunotherapy 18F]-fluoromisonidazole for imaging hypoxia, have favorable properties for imaging because they can access all CNS tissues and are selectively retained in hypoxic malignant regions Advanced imaging of hypoxic or acidic tumor microenvironments, which are commonly observed in GBM, is an alternative strategy for physiological imaging in neuro-oncology. BBB-permeable small compounds, such as the PET agent methionine -L-tyrosine ([18F]FET), and 3,4,-dihydroxy-6-[18F]fluoro-l-phenylalanine ([18F]FDOPA). System L amino acid transporters are overexpressed in malignant glioma and CNS metastases relative to normal cells Amino acid PET imaging is increasingly being recognized for its potential clinical utility in neuro-oncology Antibodies or antibody derivatives that bind to prognostic or therapeutically relevant proteins or receptors overexpressed on tumor cells  or immune cells  are gaining use in oncology applications. Attaching a PET radionuclide or MRI contrast agent to these macromolecules provides a diagnostic companion for “antibody-based” molecular imaging of the target cells or tissues 18F]fluorothymidine, [18F]FLT) have been used in clinical neuro-oncology studies. As normal astrocytes are not significantly proliferative, proliferation PET imaging has shown encouraging results in monitoring GBM progression in pilot human studies PET compounds that indirectly monitor cell proliferation  spectra are the most commonly used MRS parameters, although other nuclei, including 31P or metal ions, have also been measured by MRS and have demonstrated potential utility to monitor malignant growth during pilot studies in neuro-oncology patients 1H MRS, myoinositol, choline, creatine, amino acids, N-acetylaspartate, and lipid/lactate picks are captured. The choline peak is a marker of cell membrane turnover, the creatine peak indicates cellular energy reserves, and N-acetylaspartate is for normal neurons. High tissue concentration of lipid/ lactate or specific amino acids can be measured using MRS. Classically, gliomas show a reverse of the normal ratio of choline to N-acetylaspartate or creatine  by MRS analyses when compared to normal brain parenchyma  due to loss of normal neurons and high cell membrane turnover associated with tumor cell proliferation. The myoinositol peak is a marker of tissue inflammation N-acetylaspartate would remain high due to continued malignant cell proliferation.MRS techniques evaluate characteristic signals in the magnetic spectrum of a tissue to determine the relative amounts of specific molecules within the tissue. Similar to the boom in immunotherapy trials for non-CNS malignancies, a growing number of pilot studies and phase I, II, or III clinical trials have tested the efficacy of various types of immunotherapy to impact patient survival in neuro-oncology. The majority of these studies are beyond the scope of this review and will not be discussed. The following sections briefly discuss four main classes of immunotherapy regimens that are under investigation in neuro-oncology and how advanced physiological or molecular imaging techniques have contributed to assessing or predicting patient responses to these treatment regimens in human patients: 1) vaccine immunotherapy, 2) cell-based immunotherapy, 3) checkpoint inhibitor immunotherapy, and 4) virus immunotherapy  T-cells (and their variants), lymphokine-activated killer cells, T-cell receptor-transduced T-cells, and activated tumor infiltrating lymphocytes, among others In cell-based immunotherapy strategies Figure B, precurAdvanced imaging has also been used to monitor tumor responses during cell-based immunotherapy Checkpoint inhibitor immunotherapies Figure C were deA study of 10 patients with recurrent GBM treated with anti-PD-1 and/or anti-CTLA-4 checkpoint inhibitor immunotherapy used intermediate ADC DWI volume changes within FLAIR regions of relatively high cellularity to correlate imaging parameters with response to immunotherapy Figure  105. The18F]FET  at initial assessment. Only one of the five patients had both pre- and post-immunotherapy assessment by [18F]FLT, so no definitive conclusions could be made regarding changes in PET signal and therapeutic outcome. This patient was evaluated by PET with [18F]FLT upon entrance to the study and one month after treatment with nivolumab and ipilimumab. The second PET/MRI scan showed a mixed partial response in the five evaluable CNS lesions, where three lesions decreased in size and showed lower uptake of [18F]FLT relative to the baseline image. New, small lesions (less than 1 cm diameter) were also observed on the post-immunotherapy MRI scan, although these lesions did not show appreciable accumulation of [18F]FLT. The patient was switched to an alternative therapy and not further evaluated by PET in the reported study. The results from this study warrant future work to determine correlations between [18F]FLT signals in the tumor and outcomes to immunotherapy in neuro-oncology patients.A pilot study used fluoro-3-(hydroxymethyl)butyl]guanine. A recent publication demonstrated the results of this strategy in six additional patients with recurrent GBM butyl]guanine increased in all brain lesions after injection of the transformed CAR cells relative to the pre-treatment PET scan with the tracer. The pattern of the increase in the PET signal intensity and volume of distribution varied among patients, thus precluding the definitive assessment of CAR cell trafficking to the tumors in the small cohort of patients. These studies highlight the importance of distinguishing between non-specific pooling of PET imaging agents and specific immune cell trafficking within GBM tumors to assess immunotherapeutic efficacy through transgene PET imaging.b. Transgene/reporter gene studies with immune cells. Imaging of transgene expression through a PET reporter has been used in clinical research to monitor immune cell trafficking and response to therapy. An initial case report published in 2009 18F]fluoro-9-β-D-arabinofuranosyl-adenine and imaged by PET prior to and following treatment with a dendritic cell vaccine in combination with pembrolizumab or bevacizumab  correlate with clinical outcomes during therapy. Future trials incorporating larger cohorts of patients and their long-term outcomes to therapy will be needed to discern the most reliable metrics for monitoring responses to immunotherapy regimens.Besides the approaches discussed above, additional imaging agents and analytical techniques are being developed to define prognostic parameters for immunotherapy responses Expansions in advanced imaging have catalyzed the emergence of research and clinical strategies defining patterns of response to immunotherapy for neuro-oncology patients. However, significant obstacles must be overcome prior to routine clinical adoption of experimental imaging strategies. As the incidence of GBM is low and patients with secondary CNS metastases often have confounding clinical factors , a main hurdle has been implementing prospective clinical trials with sufficient numbers of neuro-oncology patients to demonstrate statistically reliable correlates between imaging parameters and therapeutic outcomes during immunotherapy. Most patients in these trials have received multiple, varying courses of therapy before enrollment in immunotherapy trials, further complicating the assignment of defined imaging response patterns to a specific therapeutic regimen. An additional challenge is in implementing standardized terminology and response criteria across neuro-oncology studies, as a recent report found that 63% of neuro-oncology publications after 2010 did not use the RANO criteria 18F]-FDG are available from the European Organization for Research and Treatment of Cancer (EORTC) for glioma and brain metastases, and from PET Response Criteria in Solid Tumors (PERCIST) guidelines for brain metastases. While recommended guidelines to compare multi-modality imaging parameters have not yet been established, integrating imaging parameters from various modalities has been shown in previous studies to increase diagnostic specificity and sensitivity relative to separate, single-modality imaging in neuro-oncology patients Most advanced imaging approaches to evaluate response to immunotherapy are still in initial, exploratory stages in neuro-oncology research. For the field to make rapid, meaningful advancement, it will be important to reach consensus across studies and institutions regarding acquisition parameters and reported findings for a particular imaging technique Imaging scientists should work closely with referring physicians, neuro-oncologists, and the clinical research team to best integrate advanced imaging into trial design and patient care. Considering the limited patient population and the poor prognosis associated with primary or metastatic CNS malignancies, simultaneously enrolling the same patients into both immunotherapy and imaging trials would enable streamlined evaluation of non-invasive imaging methods and responses to immunotherapy. Incorporating advanced imaging sessions into large cohorts of patients in phase II or III immunotherapy trials would aid accumulation of sufficient patient data to yield statistically meaningful results for both therapeutic outcome and matched imaging parameters.As addressed above, distinguishing tumor progression from inflammation and other treatment-related effects is a significant clinical challenge in neuro-oncology. Utilizing multi-modality imaging to differentiate between these separate biological processes is an attractive strategy to address this challenge. One way to potentially identify responses to immunotherapy regimens is to specifically monitor trafficking and activity of effector immune cells  across serial imaging time points, and to correlate these changes to a biological outcome  While much progress has been made in the fields of advanced molecular imaging and immunotherapy during the last decade, further developments are needed to determine how they can best be merged to improve the outcomes for neuro-oncology patients. No single agent or imaging technique has yet been clinically validated as a satisfactory prognostic indicator for response to immunotherapy regimens. The clinical and imaging communities eagerly await emerging results from ongoing neuro-oncology clinical trials that utilize investigational immunotherapy regimens, novel imaging strategies, and improved response criteria. As these forthcoming data become available, it is anticipated that prognostic patterns will be realized and incorporated into future practice to improve the outcomes of neuro-oncology patients.


Objective. To report a rare presentation of solitary retinal capillary hemangioma manifesting with combined retinal detachment as initial presentation and its successful management.Methods. A 35-year-old healthy Indian male presented with combined retinal detachment associated with solitary retinal capillary hemangioma as initial presentation; a clinical entity still not reported in literature. Patient was managed with pars plana vitrectomy combined with retinectomy, endolaser, & silicon oil tamponade with good visual & anatomical recovery.Results. Patient had good clinical outcome with final best-corrected visual acuity (BCVA) of 6/ 24 and well attached retina at last follow-up.Conclusion. Solitary retinal capillary hemangiomas can rarely present with advanced vitreo-retinal complications like combined retinal detachment as initial manifestation that can be effectively managed with skilled & appropriate surgical intervention.  Retinal hemangiomas are mainly asymptomatic but can present with vision loss that occurs due to exudation at the macular region or secondary tractional retinal detachment, which occurs due to development of gliotic tissue involving the macula [4]. Different treatment modalities undertaken for treatment of retinal hemangiomas include laser photocoagulation, cryotherapy, photodynamic therapy (PDT), anti-VEGF, and vitreo-retinal surgery depending on clinical presentation with variable outcome in these patients [5-9]. Retinal capillary hemangiomas are benign vascular tumors of the retina either occurring as isolated tumors or in association with tumors in other systems, especially central nervous system hemangioblastomas and renal cell carcinomas as part of von Hippel-Lindau (VHL) disease [We report a case of solitary retinal hemangioma that manifested with combined retinal detachment, a rare presenting feature of retinal hemangioma, and its successful management. To the best of our knowledge, this rare presentation has not been reported in published literature until now.Fig. 1) and examination of the left eye fundus was normal. We initially considered the differential diagnosis of retinal hemangioma and vasoproliferative tumors of the retina (VPRT). Fundus fluorescein angiography confirmed the diagnosis of retinal capillary hemangioma, showing typical feeder vessel with early hyperfluorescence of vascular mass and draining vein  in the right eye, with no evidence of hemangioma in the left eye.A 35-year-old, serving military soldier presented with diminution of vision in his right eye for the past 3 months, which has rapidly worsened over the last month. His systemic parameters were within normal limits. Ocular examination revealed a best-corrected visual acuity (BCVA) of hand movement close to face (HMCF) with accurate projection of rays in the right eye and 6/ 6 in the left eye. Examination of the anterior segment was normal in both eyes. Fundus examination in the right eye revealed total retinal detachment with about 6 Disc Diameter (DD) size reddish orange mass with two large stretch breaks stretching in the inferotemporal quadrant with surrounding fibrous tractions , thus showing a successful outcome in unusual presentation. Since the patient had already reached a stage in which the treatment modalities like laser photocoagulation, cryotherapy, photodynamic therapy (PDT), anti-VEGF, did not have any role due to total retinal detachment, he underwent combined surgery with sclera band buckle (240 size) with pars plana vitrectomy and endoresection of tumor with high viscosity silicon oil tamponade. There were no intra-operative complications with stable course post surgery and attached retina. Silicon oil was removed 5 months after the initial surgery, as soon as the emulsification was noted. At 9 months post surgery, BCVA in right eye had improved to 6/ 24 with attached retina, no evidence of remnant of tumor/ reproliferation and healthy well laser retinectomy site in temporal periphery  with pars plana vitrectomy, endoresection of tumor with high viscosity silicon oil tamponade. Patient had stable post-operative period with good visual recovery. He underwent silicon oil removal 5 months post initial surgery with good anatomical and visual outcome and no evidence of tumor proliferation/ redetachment at last follow-up, which was 9 months post vitrectomy.Thus, combined retinal detachment can be an unusual or atypical presentation of rare etiology like retinal capillary hemangiomas but appropriate and skilled vitreo-retinal surgical intervention can lead to successful visual and anatomical outcomes in these patients. Availability of Data & materialFreely available on request.Competing InterestNil.Conflict of InterestNo conflict of interest was declared by the authors.Financial DisclosureThe authors declared that this study received no financial support.AcknowledgementNil.


Upon sub-stratification, the prognostic value remained highly significant in the adenocarcinoma subtype (p = 0.002) but not in the squamous carcinoma subtype (p = 0.578). This finding highlights the importance of analysis of connexin expression at the protein level, particularly the subcellular localization. Elucidation of the underlying pathways regulating Cx43 localization may provide for novel therapeutic opportunities.Direct intercellular communication, mediated by gap junctions formed by the connexin transmembrane protein family, is frequently dysregulated in cancer. Connexins have been described as tumour suppressors, but emerging evidence suggests that they can also act as tumour promoters. This feature is connexin- and tissue-specific and may be mediated by complex signalling pathways through gap junctions or hemichannels or by completely junction-independent events. Lung cancer is the number one cancer in terms of mortality worldwide, and novel biomarkers and therapeutic targets are urgently needed. Our objective was to gain a better understanding of connexins in this setting. We used several in silico tools to analyse TCGA data in order to compare connexin mRNA expression between healthy lung tissue and lung tumours and correlated these results with gene methylation patterns. Using Kaplan-Meier plotter tools, we analysed a microarray dataset and an RNA-seq dataset of non-small cell lung tumours in order to correlate connexin expression with patient prognosis. We found that connexin mRNA expression is frequently either upregulated or downregulated in lung tumours. This correlated with both good and poor prognosis  in a clear connexin isoform-dependent manner. These associations were strongly influenced by the histological subtype (adenocarcinoma versus squamous cell carcinoma). We present an overview of all connexins but particularly focus on four isoforms implicated in lung cancer: Cx26, Cx30.3, Cx32 and Cx43. We further analysed the protein expression and localization of Cx43 in a series of 73 human lung tumours. We identified a subset of tumours that exhibited a unique strong nuclear Cx43 expression pattern that predicted worse overall survival ( The World Health Organization (WHO) currently estimates that 1.69 million deaths per year worldwide are due to lung cancer, far more than any other cancer type. Non-small cell lung cancer (NSCLC), which includes the two major subtypes of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), accounts for about 85% of lung cancers. In terms of the biology of lung cancer, significant advances have been made ) contains correlation analyses based on mRNA expression levels with respect to clinical outcome for 17 major cancer types and almost 8000 cancer patients [Kaplan-Meier survival curves (mRNA expression): Overall survival (OS) was derived both from TCGA array data of lung cancer and from pan-cancer RNA-seq data. All analyses were performed online  analysis tool [http://maplab.imppc.org/wanderer/) [Methylation analysis: We used an online (sis tool  to gain nderer/)  to analyIn conclusion we have found that major changes in some specific connexin mRNAs often occur in lung tumours but in general this do not correlate well in relation to changes in promoter methylation. Connexin mRNA expression can however correlate with both good and poor prognosis, which depends on the connexin isoform analysed and the histological subtype (LUAD versus LUSC). In addition to changes in mRNA expression, it is clear that protein location and functionality is critical. In this study, we identified a subset of tumours that exhibited a unique strong nuclear Cx43 expression pattern that predicted worse overall survival. The prognostic value was highly significant in LUAD, and larger cohorts will be needed to definitively assess the correlation in LUSC. This study highlights the importance of analysis of connexin expression at the protein level, particularly the subcellular localization. It also proposes that modulation of Cx43 trafficking may be a useful therapeutic strategy.


Epidemiology & Infection while also discussing advances in emerging infectious diseases.This invited editorial introduces a special issue of  World Health Organization (WHO) recently enumerated 10 threats to global health for 2019, notably emphasising Ebola and other high-threat emerging pathogens as growing priorities [annualised financial impact of a global pandemic has been estimated to be as high as US$80 billion, severely burdening already constrained national budgets and healthcare systems [The  systems . Outbrea systems . These fEpidemiology & Infection highlights new insights into many of the emerging infectious diseases mentioned in the WHO report, as well as re-emerging diseases that are gaining global prominence. They address a variety of diagnostic, therapeutic and epidemiological advances in outbreak preparedness. Several papers review data on priority pathogens with a focus on resource-limited settings. For example, Sikkema et al. present a systematic review on Middle East Respiratory Syndrome Coronavirus with the aim of characterising the distribution and spread of infection in dromedary camels [et al. review the recent Nipah virus outbreaks in Bangladesh and India, shedding light on transmission patterns of this emerging pathogen while also highlighting the importance of ongoing surveillance [et al. discusses genetic variations among avian influenza viruses circulating in Bangladesh and the impact of accumulating mutations noted in poultry. Lessons learned from the WHO response to the recent 2017 pneumonic plague outbreak in Madagascar are presented by Heitzinger et al., who highlight specifically the challenges of implementing rapid infection prevention and control measures in epidemic settings [This edition of y camels . Aditi eeillance . A reviesettings . These, Outbreaks of re-emerging infectious diseases in high-income countries are also discussed, often implicating products imported across borders as well as trans-national spread due to as yet unknown causes. Other papers discuss zoonotic and vector-borne disease epidemiology and present opportunities for predictive modelling. Several diagnostic advances are also mentioned, elucidating changing epidemiological trends in recently recognised re-emerging pathogens.Epidemiology & Infection represents a diverse overview of current concerns surrounding emerging infectious diseases globally. All highlight the importance of supporting ongoing surveillance efforts as the cornerstone of disease prevention. Early recognition of an outbreak allows control measures to be initiated in a timely way that can shift the epidemic curve, reducing its impact and possibly its geographic spread. Enhanced surveillance measures with an emphasis on innovation, transparency and incorporation of the One Health model are critical to epidemic preparedness measures in the future. It is also crucial to encourage research during outbreaks through rapid data sharing to facilitate rapid response efforts, as is promoted through organisations such as the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) [This issue of (ISARIC) . Vaccina(ISARIC) . These e(ISARIC) . Emergin


Writing and publication in an academic setting is vital for advancing careers and knowledge. Attempting to increase scholarly productivity, our division created a physician-writing group, led by a prolific humanities expert to hone our writing skills. An unexpected outcome was realized. Using a mix of reflective, intent-driven, impromptu writing exercises and group sharing we discovered new opportunities for personal and professional growth through empathy. During these 1-hour sessions, several organic themes emerged. These included gaining greater inner-personal insight and recognizing inter-personal similarities in career paths and provider benevolence as motivation to continue when experiencing emotional fatigue and burnout. Ultimately, while honing our professional writing skills we also stimulated compassion to ourselves and our colleagues, opening new sources of resilience. We plan to continue these sessions exploring the potential multifaceted impacts on professional/academic growth these sorts of writing groups can have for geriatric and palliative medicine professionals and other healthcare providers.


Mesothelioma is an incurable cancer caused by exposure to asbestos. Several countries have witnessed a growth in incidence of epidemic proportions over the last two decades, and approved treatment is limited to front-line chemotherapy . The recCOMMAND was negative, despite hopes of recapitulating preclinically observed synthetic lethality in the context of NF2 mutation , as wellSince the initiation of the COMMAND trial, comprehensive genomic studies have revealed extensive genetic disruption of hippo signaling in mesothelioma involving multiple components of this tumor suppressor pathway , 8. In tA phase II window of opportunity trial involving defactinib monotherapy in patients prior to surgical resection demonstrated a promising 80% disease control and 13% response rate . InteresAfter the initiation of the COMMAND trial, another important insight into FAK biology came to light. FAK plays a crucial role in regulating the tumour microenvironment via augmentation of Treg abundance . Inhibithippo defective biomarkers, or directly antagonizing YAP/TEAD transcription may provide next-generation approaches to phenocopying this important tumor suppressor pathway in mesothelioma.In summary, targeting the Hippo pathway remains a potentially promising strategy for controlling mesothelioma. Widening the net to capture more hippo deficient phenotypes through the use of comprehensive


We recently identified pathogenic soluble aggregated tau (tau oligomers) in the cerebral microvasculature of human patients with tauopathies, including Alzheimer’s disease (AD). The functional consequences of cerebrovascular tau accumulation are not yet understood. The aim of the present study was to determine whether pathogenic tau accumulation leads to cerebrovascular dysfunction. To this end, we measured neurovascular coupling (NVC), a highly regulated process that synchronizes cerebral blood flow to neuronal activation, using the PS19(P301S) mouse model of tauopathy. The change in cerebral blood flow evoked by whisker stimulation was measured using Laser Doppler flowmetry in PS19 and wildtype control mice and the functional contribution of neuronal and endothelial nitric oxide synthase  was calculated. Vascular reactivity was assessed using topical acetylcholine to evoke endothelium-dependent vasodilation. To assess the direct impact of pathogenic tau on cell-specific NOS function, we treated N2a neuroblastoma cells or mouse brain vascular endothelial cells with soluble tau aggregates and measured activity of nNOS and eNOS. Our data indicate isolated overexpression of mutant tau impairs NVC responses, and this deficit is mediated by a reduction in nNOS activity in vivo. Further, our studies suggest tauopathy also impairs endothelium-dependent vasoreactivity in the cortex. Additionally, soluble tau aggregates inhibit the phosphorylation of NOS in primary cultured cells. Therefore, inhibition of NOS phosphorylation by pathogenic soluble tau aggregates may underlie cerebrovascular dysfunction in tauopathies. Thus, therapeutic modulation of pathogenic tau may mitigate brain microvascular deficits, which occur prior to clinical onset in Alzheimer’s disease and potentially other tauopathies.