Cholesterol and lipid microdomains stabilize the postsynapse at the neuromuscular junction.
Stabilization and maturation of synapses are important for development and function of the nervous system. Previous studies have implicated cholesterol-rich lipid microdomains in synapse stabilization, but the underlying mechanisms remain unclear. We found that cholesterol stabilizes clusters of synaptic acetylcholine receptors (AChRs) in denervated muscle in vivo and in nerve-muscle explants. In paralyzed muscles, cholesterol triggered maturation of nerve sprout-induced AChR clusters into pretzel shape. Cholesterol treatment also rescued a specific defect in AChR cluster stability in cultured src(-/-);fyn(-/-) myotubes. Postsynaptic proteins including AChRs, rapsyn, MuSK and Src-family kinases were strongly enriched in lipid microdomains prepared from wild-type myotubes. Microdomain disruption by cholesterol-sequestering methyl-beta-cyclodextrin disassembled AChR clusters and decreased AChR-rapsyn interaction and AChR phosphorylation. Amounts of microdomains and enrichment of postsynaptic proteins into microdomains were decreased in src(-/-);fyn(-/-) myotubes but rescued by cholesterol treatment. These data provide evidence that cholesterol-rich lipid microdomains and SFKs act in a dual mechanism in stabilizing the postsynapse: SFKs enhance microdomain-association of postsynaptic components, whereas microdomains provide the environment for SFKs to maintain interactions and phosphorylation of these components.


Annual Research Review: Adolescent mental health in the digital age: facts, fears, and future directions.
Adolescents are spending an increasing amount of their time online and connected to each other via digital technologies. Mobile device ownership and social media usage have reached unprecedented levels, and concerns have been raised that this constant connectivity is harming adolescents' mental health. This review synthesized data from three sources: (a) narrative reviews and meta-analyses conducted between 2014 and 2019, (b) large-scale preregistered cohort studies and (c) intensive longitudinal and ecological momentary assessment studies, to summarize what is known about linkages between digital technology usage and adolescent mental health, with a specific focus on depression and anxiety. The review highlights that most research to date has been correlational, focused on adults versus adolescents, and has generated a mix of often conflicting small positive, negative and null associations. The most recent and rigorous large-scale preregistered studies report small associations between the amount of daily digital technology usage and adolescents' well-being that do not offer a way of distinguishing cause from effect and, as estimated, are unlikely to be of clinical or practical significance. Implications for improving future research and for supporting adolescents' mental health in the digital age are discussed.


Neutropenia and Neutropenic Complications in ABVD Chemotherapy for Hodgkin Lymphoma.
A combination of Adriamycin (a.k.a. Doxorubicin), Bleomycin, Vinblastine, and Dacarbazine (ABVD) is the most commonly used chemotherapy regime for Hodgkin lymphoma. This highly effective treatment is associated with a significant risk of neutropenia. Various strategies are adopted to counter this commonly encountered problem, including dose modification, use of colony stimulating factors, and prophylactic or therapeutic use of antibiotics. Data to support these approaches is somewhat controversial, and in keeping with the paucity of definitive evidence, there is a wide disparity in the management of neutropenia in patients receiving ABVD chemotherapy. This paper summarizes the evidence for managing ABVD-related neutropenia during the treatment of Hodgkin lymphoma.


10th Anniversary of ALPPS-Lessons Learned and quo Vadis.
Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) has been tested in various indications and clinical scenarios, leading to steady improvements in safety. This report presents the current status of ALPPS. ALPPS offers improved resectability, but drawbacks are regularly pointed out regarding safety and oncologic benefits. During the 12th biennial congress of the European African-Hepato-Pancreato-Biliary Association (Mainz, Germany, May 23-26, 2017) an expert meeting "10th anniversary of ALPP" was held to discuss indications, management, mechanisms of regeneration, as well as pitfalls of this novel technique. The aim of the meeting was to make an inventory of what has been achieved and what remains unclear in ALPPS. Precise knowledge of liver anatomy and its variations is paramount for success in ALPPS. Technical modifications, mainly less invasive approaches like partial, mini- or laparoscopic ALPPS, mostly aiming at minimizing the extensiveness of the first-stage procedure, are associated with improved safety. In fibrotic/cirrhotic livers the degree of future liver remnant hypertrophy after ALPPS appears some less than that in noncirrhotic. Recent data from the only prospective randomized controlled trial confirmed significant higher resection rates in ALPPS with similar peri-operative morbidity and mortality rates compared with conventional 2-stage hepatectomy including portal vein embolization. ALPPS is effective reliably even after failure of portal vein embolization. Although ALPPS is now an established 2-stage hepatectomy additional data are warranted to further refine indication and technical aspects. Long-term oncological outcome results are needed to establish the place of ALPPS in patients with initially nonresectable liver tumors.


Predictors of HIV transmission risk behavior and seroconversion among Latino men who have sex with men in Project EXPLORE.
In the US, Latino MSM are disproportionately affected by HIV, yet there is a paucity of data for this risk group. To this end, we examined data on Latino and non-Latino white MSM who participated across six cities in a 2-year randomized behavioral intervention study-Project EXPLORE. At baseline, Latinos reported significantly more serodiscordant unprotected anal intercourse (SDUA) than non-Latinos. Longitudinal predictors of SDUA included marijuana, poppers, amphetamines and heavy drinking, as well as lower self-efficacy, poorer communication skills, weaker safe-sex norms and more enjoyment of risky sex. For HIV infection, Latinos had significantly higher seroconversion rate over follow-up than non-Latinos. Longitudinal predictors of seroconversion among Latinos included poppers and SDUA. Intervention effects did not significantly differ between Latino and non-Latinos. Findings support HIV intervention work with Latino MSM that includes skills training/counseling to address attitudes about safe sex and impact of substance use on HIV-risk behavior and acquisition.


Sharks need the lateral line to locate odor sources: rheotaxis and eddy chemotaxis.
Odor plumes are complex, dynamic, three-dimensional structures used by many animals to locate food, mates, home sites, etc. Yet odor itself has no directional properties. Animals use a variety of different senses to obtain directional information. Since most odor plumes are composed of dispersing odor patches and dissipating vorticity eddies, aquatic animals may localize odor sources by simultaneous analysis of chemical and hydrodynamic dispersal fields, a process referred to as eddy chemotaxis. This study examines the contributions of olfaction, mechanoreception and vision to odor source localization in a shark, the smooth dogfish Mustelus canis. Two parallel, turbulent plumes were created in an 8 m flume: squid rinse odor and seawater control. Minimally turbulent ;oozing' sources of odor and seawater control were physically separated from sources of major turbulence by placing a brick downstream from each oozing source, creating two turbulent wakes, one or the other flavored with food odor. This created four separate targets for the sharks to locate. Animals were tested under two light conditions (fluorescent and infrared) and in two sensory conditions (lateral line intact and lateral line lesioned by streptomycin). Intact animals demonstrated a preference for the odor plume over the seawater plume and for the source of odor/turbulence (the brick on the odor side) over the source of the odor alone (the odor-oozing nozzle). Plume and target preference and search time were not significantly affected by light condition. In the light, lesioning the lateral line increased search time but did not affect success rate or plume preference. However, lesioned animals no longer discriminated between sources of turbulent and oozing odor. In the dark, search time of lesioned animals further increased, and the few animals that located any of the targets did not discriminate between odor and seawater plumes, let alone targets. These results demonstrate for the first time that sharks require both olfactory and lateral line input for efficient and precise tracking of odor-flavored wakes and that visual input can improve food-finding performance when lateral line information is not available. We distinguish between rheotaxis: orientation to the large-scale flow field (olfaction, vision and superficial lateral line), eddy chemotaxis: tracking the trail of small-scale, odor-flavored turbulence (olfaction and lateral line canals), and pinpointing the source of the plume (lateral line canals and olfaction).


Characteristics of people with self-reported stress-precipitated seizures.
Stress is the most common patient-reported seizure precipitant. We aimed to determine mood and epilepsy characteristics of people who report stress-precipitated seizures. Sequential patients at a tertiary epilepsy center were surveyed about stress as a seizure precipitant. We asked whether acute (lasting minutes-hours) or chronic (lasting days-months) stress was a seizure precipitant, whether stress reduction had been tried, and what effect stress reduction had on seizure frequency. We collected information on antiepileptic drugs, history of depression and anxiety disorder, prior or current treatment for depression or anxiety, and scores on the Neurological Disorders Depression Inventory (NDDI-E) and Generalized Anxiety Disorders-7 (GAD-7) instruments, which are administered at every visit in our Epilepsy Center. We also asked whether respondents thought that they could predict their seizures to determine if stress as a seizure precipitant was correlated with seizure self-prediction. Two hundred sixty-six subjects were included: 219 endorsed stress as a seizure precipitant [STRESS (+)] and 47 did not [STRESS (-)]. Among STRESS (+) subjects, 85% endorsed chronic stress as a seizure precipitant, and 68% endorsed acute stress as a seizure precipitant. In STRESS (+) subjects, 57% had used some type of relaxation or stress reduction method (most commonly yoga, exercise and meditation), and, of those who tried, 88% thought that these methods improved seizures. Among STRESS (-) subjects, 25% had tried relaxation or stress reduction, and 71% thought that seizures improved. Although univariate analysis showed multiple associations with stress as a seizure precipitant, in the multivariable logistic regression, only the GAD-7 score was associated with STRESS (+) (OR = 1.18 [1.03-1.35], p = 0.017). Subjects who reported stress as a seizure precipitant were more likely to report an ability to self-predict seizures (p < 0.001). Stress-precipitated seizures are commonly reported by patients, may be associated with either acute stress or chronic stress, and are associated with higher scores on anxiety tests. Patients frequently use stress reduction methods to self-treat and report high success rates. A prospective, randomized trial of stress reduction for seizures is indicated.


Trapping Methylglyoxal by Genistein and Its Metabolites in Mice.
Increasing evidence supports dicarbonyl stress such as methylglyoxal (MGO) as one of the major pathogenic links between hyperglycemia and diabetic complications. In vitro studies have shown that dietary flavonoids can inhibit the formation of advanced glycation end products (AGEs) by trapping MGO. However, whether flavonoids can trap MGO in vivo and whether biotransformation limits the trapping capacity of flavonoids remain virtually unknown. In this study, we investigated whether genistein (GEN), the major soy isoflavone, could trap MGO in mice by promoting the formation of MGO adducts of GEN and its metabolites. Two different mouse studies were conducted. In the acute study, a single dose of MGO and GEN were administered to mice via oral gavage. In the chronic study, MGO was given to mice in drinking water for 1 month and then GEN was given to mice for 4 consecutive days via oral gavage. Two mono-MGO adducts of GEN and six mono-MGO adducts of GEN phase I and microbial metabolites were identified in mouse urine samples from these studies using liquid chromatography/electrospray ionization tandem mass spectrometry. The structures of these MGO adducts were confirmed by analyzing their MS(n) (n = 1-4) spectra as well as by comparing them with the tandem mass spectra of authentic standards. All of the MGO adducts presented in their phase II conjugated forms in mouse urine samples in the acute and chronic studies. To our knowledge, this is the first in vivo evidence to demonstrate the trapping efficacy of GEN in mice and to show that the metabolites of GEN remain bioactive.


The firing of hippocampal place cells in the dark depends on the rat's recent experience.
Hippocampal "place cells" fire when a freely moving rat is in a given location. The firing of these cells is controlled by visual and nonvisual environmental cues. The effects of darkness on the firing of place cells was studied using the task of Muller et al. (1987), in which rats were trained to chase randomly scattered food pellets in a cylindrical drum with a white cue-card attached to the wall. The position of the rats was tracked via an infrared LED on the headstage with a video system linked to computer. Two experimental protocols were used: in the first, lights were turned off after the rat had already been placed in the chamber; in the second, the rat was placed in the darkened chamber. The dark segments produced by these 2 methods were identical with respect to light and other cues but differed with respect to the rat's experience. The firing patterns of 24 of 28 cells were unaffected by darkness when it was preceded by a light period. In contrast, the firing patterns of 14 of 22 cells changed dramatically when the rats were put into the darkened chamber. Furthermore, the majority of cells that changed their firing pattern in initial darkness maintained that change when the lights were turned on. These results show that place cells can fire differently in identical cue situations and that the best predictor of firing pattern is a combination of current cues and the rat's recent experience. The results are discussed in terms of mnemonic properties of hippocampal cells and "remapping" of place cell representations.


Inhibition of Chikungunya virus infection in cultured human muscle cells by furin inhibitors: impairment of the maturation of the E2 surface glycoprotein.
Chikungunya virus (CHIKV) is a mosquito-transmitted Alphavirus that causes in humans an acute infection characterized by polyarthralgia, fever, myalgia, and headache. Since 2005 this virus has been responsible for an epidemic outbreak of unprecedented magnitude. By analogy with other alphaviruses, it is thought that cellular proteases are able to process the viral precursor protein E3E2 to produce the receptor-binding E2 protein that associates as a heterodimer with E1. Destabilization of the heterodimer by exposure to low pH allows viral fusion and infection. We show that among a large panel of proprotein convertases, membranous furin but also PC5B can process E3E2 from African CHIKV strains at the HRQRR(64) / ST site, whereas a CHIKV strain of Asian origin is cleaved at RRQRR(64) / SI by membranous and soluble furin, PC5A, PC5B, and PACE4 but not by PC7 or SKI-1. Using fluorogenic model peptides and recombinant convertases, we observed that the Asian strain E3E2 model peptide is cleaved most efficiently by furin and PC5A. This cleavage was also observed in CHIKV-infected cells and could be blocked by furin inhibitor decanoyl-RVKR-chloromethyl ketone. This inhibitor was compared with chloroquine for its ability to inhibit CHIKV spreading in myoblast cell cultures, a cell-type previously described as a natural target of this virus. Our results demonstrate the role of furin-like proteases in the processing of CHIKV particles and point out new approaches to inhibit this infection.


PhoB regulates the survival of Bacteroides fragilis in peritoneal abscesses.
In response to phosphate limitation, bacteria employ the Pho regulon, a specific regulatory network for phosphate acquisition. The two-component signal transduction system of PhoRB plays a crucial role in the induction of Pho regulon genes, leading to the adaptation to phosphate starvation. Herein, we identified the PhoRB system in Bacteroides fragilis, a commensal gut bacterium, and evaluated its role in gut colonization and survival in peritoneal abscesses. BF1575 and BF1576 encoded PhoR (sensor histidine kinase) and PhoB (response regulator) in the sequenced B. fragilis strain YCH46, respectively. Transcriptome analysis revealed that deletion of phoB affected the expression of 585 genes (more than 4-fold change) in B. fragilis, which included genes for stress response (chaperons and heat shock proteins), virulence (capsular polysaccharide biosynthesis) and phosphate metabolism. Deletion of phoB reduced the ability of the bacterium to persist in peritoneal abscesses induced by an intra-abdominal challenge of B. fragilis. Furthermore, PhoB was necessary for survival of this anaerobe in peritoneal abscesses but not for in vitro growth in rich media or in intestinal colonization. These results indicate that PhoB plays an important role in the survival of B. fragilis under stressful extraintestinal conditions.


Impact of sustained virological response on the extrahepatic manifestations of chronic hepatitis C: a meta-analysis.
Extrahepatic manifestations of HCV are responsible for morbidity and mortality in many chronically infected patients. New, interferon-free antiviral treatment regimens, which present the opportunity to treat all HCV-infected patients, call for a better understanding of the benefits of treating non-cirrhotic chronically infected individuals. A systematic review was conducted. Identified studies from targeted database searches on Embase and Medline were screened. The methodological quality of the included publications was evaluated. Random-effect model meta-analyses were performed. Strength of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation system. Data were extracted from a total of 48 identified studies. Achieving sustained virological response (SVR) was associated with reduced extrahepatic mortality (vs no SVR, OR 0.44 (95% CI 0.28 to 0.67)). SVR was associated with higher complete remissions in patients with cryoglobulinemia vasculitis (OR 20.76 (6.73 to 64.05)) and a higher objective response in those with malignant B-cell lymphoproliferative diseases (OR 6.49 (2.02 to 20.85)). Achieving SVR was also associated with reduced insulin resistance at follow-up (OR 0.42 (0.33 to 0.53)) and a significant protective effect on the incidence of diabetes (OR 0.34 (0.21 to 0.56)). Lack of randomised data comparing SVR versus non-SVR patients for the relevant extrahepatic indications attenuated these analyses. Antiviral therapy can reduce extrahepatic manifestations related to HCV when SVR is achieved. Higher quality data, and reporting over longer follow-up periods, will be required to thoroughly explore comprehensive HCV treatment strategies.


Regulation of the Intestinal Extra-Adrenal Steroidogenic Pathway Component LRH-1 by Glucocorticoids in Ulcerative Colitis.
Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) and can be treated with glucocorticoids (GC), although some patients are unresponsive to this therapy. The transcription factor LRH-1/NR5A2 is critical to intestinal cortisol production (intestinal steroidogenesis), being reduced in UC patients. However, the relationship between LRH-1 expression and distribution with altered corticosteroid responses is unknown. To address this, we categorized UC patients by their steroid response. Here, we found that steroid-dependent and refractory patients presented reduced glucocorticoid receptor (GR)-mediated intestinal steroidogenesis compared to healthy individuals and responder patients, possibly related to increased colonic mucosa GR isoform beta (GRβ) content and cytoplasmic LRH-1 levels in epithelial and lamina propria cells. Interestingly, an intestinal epithelium-specific GR-induced knockout (GRiKO) dextran sodium sulfate (DSS)-colitis mice model presented decreased epithelial LRH-1 expression, whilst it increased in the lamina propria compared to DSS-treated control mice. Mechanistically, GR directly induced NR5A2 gene expression in CCD841CoN cells and human colonic organoids. Furthermore, GR bound to two glucocorticoid-response elements within the NR5A2 promoter in dexamethasone-stimulated CCD841CoN cells. We conclude that GR contributes to intestinal steroidogenesis by inducing LRH-1 in epithelial cells, suggesting LRH-1 as a potential marker for glucocorticoid-impaired response in UC. However, further studies with a larger patient cohort will be necessary to confirm role of LRH-1 as a therapeutic biomarker.


The genetics of benign neutropenia.
In Israel, Yemenite Jews and other populations including Ethiopian Jews and Bedouins have a low neutrophil count. This phenomenon has been called "benign neutropenia" since it has not been associated with any increased risk of infection and has also been described in other populations around the world including Africans, African Americans and Afro-Carribeans. Here we describe the recent success in mapping the gene that underlies benign neutropenia in African American populations. We discuss the known function of the gene and consider potential mechanisms for the effect on neutropenia. We also consider the possibility that this gene underlies the same effect observed in Yemenite Jews, Ethiopian Jews and Bedouins in Israel.


Helicobacter pylori outer membrane vesicle proteins induce human eosinophil degranulation via a β2 Integrin CD11/CD18- and ICAM-1-dependent mechanism.
Eosinophil cationic protein (ECP), a cytotoxic protein contained in eosinophils granules, can contribute to various inflammatory responses. Although Helicobacter pylori infection increases infiltration of eosinophils, the mechanisms of eosinophil degranulation by H. pylori infection are largely unknown. The goal of this study was to investigate the role of H. pylori outer membrane vesicles (OMVs) in modulating eosinophil degranulation. We found that eosinophils treated with H. pylori OMVs released significantly more ECP compared with untreated controls. In addition, eosinophils cocultured with OMV-preexposed primary gastric epithelial cells exhibited significantly increased ECP release. Similarly, eosinophils cocultured with culture supernatant (CM) from primary gastric epithelial cells exposed to OMVs (OMV-CM) released significantly higher amounts of ECP compared with eosinophils cocultured with CM from unexposed control cells. Furthermore, OMVs and OMV-CM both induced the upregulation of ICAM-1 on gastric epithelial cells and β2 integrin CD11b on eosinophils. In addition, both transduction of ICAM-1 shRNA into gastric epithelial cells and treatment with neutralizing mAbs to CD18 significantly decreased OMV-mediated or OMV-CM-mediated release of ECP. These results suggest that the eosinophil degranulation response to H. pylori OMVs occurs via a mechanism that is dependent on both β2 integrin CD11/CD18 and ICAM-1.


[Effect of cardiovascular risk factors on individual and population medical expenditures: a 10-year cohort study of 4,535 National Health Insurance beneficiaries in Shiga].
A 10-year follow-up cohort study of 4,535 National Health Insurance beneficiaries aged 40 to 69 years in Shiga was performed as part of a research project conducted by the Health Promotion Research Committee of the Shiga National Health Insurance Organizations in 2002. The relationship between cardiovascular risk factors and medical expenditures during the 10-year study period has been examined in this cohort. For example, there was a positively graded correlation between blood pressure and individual total medical expenditures per month. The odds ratio for cumulative hospitalization and hazard ratio for all-cause mortality in severe hypertensives were also higher than those in normotensives. However, from the viewpoint of the entire population, the excess medical expenditures attributable to hypertension within the total medical expenditures were higher for mild-to-moderate hypertensives than for severe hypertensives. On the other hand, although individual medical expenditures per month were 1.7-fold higher for participants with 2 or 3 risk factors and obesity, which was broadly equivalent to metabolic syndrome, than for those without these factors, the excess medical expenditures determined by risk clustering within the total medical expenditures were higher in normal-weight people than in obese people because of the higher prevalence of normal weight. These findings suggest that high-risk individuals are a good target of a high-risk approach, such as intensive health guidance, from the viewpoint of medical expenditures. However, another approach for the majority with a low-to-moderate cardiovascular risk should be considered, because they account for a greater proportion of the excess medical expenditures. Another way to solve this problem may be a population approach with an effective method of providing information to citizens.


Effects of hypolipidemic drugs on the expression of genes involved in high density lipoprotein metabolism in the rat.
Since plasma high density lipoprotein (HDL) concentrations are inversely related to the development of atherosclerosis, induction of HDL after pharmacological treatment is considered of benefit. To study whether currently used hypolipidemic drugs affect HDL metabolism by modulating the expression of genes involved in HDL metabolism, liver and intestinal apolipoprotein (apo) AI, apo-AII and apo-AIV gene expression was evaluated in rats treated with different classes of hypolipidemic drugs, and correlated to the changes in plasma lipid and apolipoprotein concentrations. In rats, the most pronounced hypolipidemic effects were observed after treatment with the fibrates clofibrate and fenofibrate, which lowered plasma lipid, apo-AI and apo-AIV concentrations. This decrease was accompanied by lowered liver apo-AI, apo-AII and apo-AIV mRNA levels. None of the other compounds tested affected plasma cholesterol, whereas probucol and simvastatin decreased plasma triglyceride concentrations. Apo-AI and apo-AII mRNA remained constant after nicotinic acid and probucol, whereas liver apo-AIV mRNA levels decreased. Cholestyramine increased hepatic apo-AI and apo-AII, but not apo-AIV mRNA levels. Simvastatin treatment increased apo-AI mRNA nearly threefold, whereas apo-AII and apo-AIV decreased by more than 50%. Similarly as after cholestyramine, the alteration in hepatic apo-AI mRNA levels did not result in changed plasma apo-AI concentrations. Remarkably, none of the drugs tested significantly affected intestinal apolipoprotein mRNA levels. These results indicate that hypolipidemic drugs may act on plasma lipoprotein metabolism by regulating apolipoprotein gene expression. Further studies in humans and primates are therefore warranted.


Misclassification of Plasmodium infections by conventional microscopy and the impact of remedial training on the proficiency of laboratory technicians in species identification.
Malaria diagnosis is largely dependent on the demonstration of parasites in stained blood films by conventional microscopy. Accurate identification of the infecting Plasmodium species relies on detailed examination of parasite morphological characteristics, such as size, shape, pigment granules, besides the size and shape of the parasitized red blood cells and presence of cell inclusions. This work explores misclassifications of four Plasmodium species by conventional microscopy relative to the proficiency of microscopists and morphological characteristics of the parasites on Giemsa-stained blood films. Ten-day malaria microscopy remedial courses on parasite detection, species identification and parasite counting were conducted for public health and research laboratory personnel. Proficiency in species identification was assessed at the start (pre) and the end (post) of each course using known blood films of Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale and Plasmodium vivax infections with densities ranging from 1,000 to 30,000 parasites/μL. Outcomes were categorized as false negative, positive without speciation, P. falciparum, P. malariae, P. ovale, P. vivax and mixed infections. Reported findings are based on 1,878 P. falciparum, 483 P. malariae, 581 P. ovale and 438 P. vivax cumulative results collated from 2008 to 2010 remedial courses. Pre-training false negative and positive misclassifications without speciation were significantly lower on P. falciparum infections compared to non-falciparum infections (p < 0.0001). Post-training misclassifications decreased significantly compared to pre- training misclassifications which in turn led to significant improvements in the identification of the four species. However, P. falciparum infections were highly misclassified as mixed infections, P. ovale misclassified as P. vivax and P. vivax similarly misclassified as P. ovale (p < 0.05). These findings suggest that the misclassification of malaria species could be a common occurrence especially where non-falciparum infections are involved due to lack of requisite skills in microscopic diagnosis and variations in morphological characteristics within and between Plasmodium species. Remedial training might improve reliability of conventional light microscopy with respect to differentiation of Plasmodium infections.


Spinal cord grey matter abnormalities are associated with secondary progression and physical disability in multiple sclerosis.
In multiple sclerosis (MS), pathological studies have identified substantial demyelination and neuronal loss in the spinal cord grey matter (GM). However, there has been limited in vivo investigation of cord GM abnormalities and their possible functional effects using MRI combined with clinical evaluation. We recruited healthy controls (HC) and people with a clinically isolated syndrome (CIS), relapsing remitting (RR) and secondary progressive (SP) MS. All subjects had 3 T spinal cord MRI with measurement of cord cross-sectional area and diffusion tensor imaging metrics in the GM and posterior and lateral column white matter tracts using region of interest analysis. Physical disability was assessed using the expanded disability status scale (EDSS) and motor components of the MS functional composite scale. We calculated differences between MS and HC using a ANOVA and associations with disability using linear regression. 113 people were included in this study: 30 controls, 21 CIS, 33 RR and 29 SPMS. Spinal cord radial diffusivity (RD), fractional anisotropy and mean diffusivity in the GM and posterior columns were significantly more abnormal in SPMS than in RRMS. Spinal cord GM RD (β=0.33, p<0.01) and cord area (β=-0.45, p<0.01) were independently associated with EDSS (R(2)=0.77); spinal cord GM RD was also independently associated with a 9-hole peg test (β=-0.33, p<0.01) and timed walk (β=-0.20, p=0.04). The study findings suggest that pathological involvement of the spinal cord GM contributes significantly to physical disability in relapse-onset MS and SPMS in particular.


Is perchlorate metabolized or re-translocated within lettuce leaves? A stable-isotope approach.
Perchlorate is an environmental contaminant that is found in drinking water and a variety of foodstuffs, but many questions regarding its uptake, transport, and persistence in higher plants remain unanswered. In a series of hydroponic experiments, a stable-isotope tracer of perchlorate (95% 37ClO4(-)) was utilized to determine the extent of in vivo metabolism and of phloem re-translocation of perchlorate at low (i.e., nmol/kg of fresh weight (FW)) concentrations in lettuce. Chlorate and chlorite metabolites were not detected in lettuce leaves at detection limits of 13.1 and 291 nmol/kg FW, respectively, and chloride isotopic signatures were not substantially different from natural chloride. Perchlorate exhibited no significant movement from older leaves into new leaves, nor to roots. Stable isotopes proved useful in assessing perchlorate metabolism and re-translocation within lettuce at nmol/kg levels. The absence of any metabolism or re-translocation indicates that perchlorate is relatively persistent within leafy produce, and that the primary mode of transport of perchlorate is through the xylem of higher plants.


Attentional Bias for Reward and Punishment in Overweight and Obesity: The TRAILS Study.
More than 80% of obese adolescents will become obese adults, and it is therefore important to enhance insight into characteristics that underlie the development and maintenance of overweight and obesity at a young age. The current study is the first to focus on attentional biases towards rewarding and punishing cues as potentially important factors. Participants were young adolescents (N = 607) who were followed from the age of 13 until the age of 19, and completed a motivational game indexing the attentional bias to general cues of reward and punishment. Additionally, self-reported reward and punishment sensitivity was measured. This study showed that attentional biases to cues that signal reward or punishment and self-reported reward and punishment sensitivity were not related to body mass index or the change in body mass index over six years in adolescents. Thus, attentional bias to cues of reward and cues of punishment, and self-reported reward and punishment sensitivity, do not seem to be crucial factors in the development and maintenance of overweight and obesity in adolescents. Exploratory analyses of the current study suggest that the amount of effort to gain reward and to avoid punishment may play a role in the development and maintenance of overweight and obesity. However, since the effort measure was a construct based on face validity and has not been properly validated, more studies are necessary before firm conclusions can be drawn.


A study of behavioural responses of non-human primates to air transport and re-housing.
More long-tailed macaques (Macaca fascicularis) than any other primate are imported into the UK for research, and journey times may be of up to 58 h. Whilst a number of studies have examined the stress associated with transport, these have typically involved laboratory rodents and livestock, and little is known of its effect on non-human primates. This paper reports the results of a study of behavioural changes in a group of long-tailed macaques transported by air from standard breeding conditions and then re-housed in standard laboratory primate conditions. The animals were studied prior to their departure, immediately after their arrival, and 3 weeks after that. Data were collected on individual time budgets using focal animal sampling and on hierarchy using a feeding trial. The data were analysed for changes in behavioural repertoires and for social perturbation that would be reflected in hierarchical changes. Changes in behaviour occurred which reflected heightened levels of stress in the study group. It was also clear that although there was some adjustment of behaviour, after an initial change on arrival at the new establishment, there was no return to levels observed at the breeding facility within the first month. This study demonstrates that, as a whole, the process of international air transport and re-housing in laboratory conditions may result in the compromising of the welfare of the study animals.


Modeling the complex dynamics of enzyme-pathway coevolution.
Metabolic pathways must have coevolved with the corresponding enzyme gene sequences. However, the evolutionary dynamics ensuing from the interplay between metabolic networks and genomes is still poorly understood. Here, we present a computational model that generates putative evolutionary walks on the metabolic network using a parallel evolution of metabolic reactions and their catalyzing enzymes. Starting from an initial set of compounds and enzymes, we expand the metabolic network iteratively by adding new enzymes with a probability that depends on their sequence-based similarity to already present enzymes. Thus, we obtain simulated time courses of chemical evolution in which we can monitor the appearance of new metabolites, enzyme sequences, or even entire organisms. We observe that new enzymes do not appear gradually but rather in clusters which correspond to enzyme classes. A comparison with Brownian motion dynamics indicates that our system displays biased random walks similar to diffusion on the metabolic network with long-range correlations. This suggests that a quantitative molecular principle may underlie the appearance of punctuated equilibrium dynamics, whereby enzymes occur in bursts rather than by phyletic gradualism. Moreover, the simulated time courses lead to a putative time-order of enzyme and organism appearance. Among the patterns we detect in these evolutionary trends is a significant correlation between the time of appearance and their enzyme repertoire size. Hence, our approach to metabolic evolution may help understand the rise in complexity at the biochemical and genomic levels.


Nightmares and the Cannabinoids.
The cannabinoids, Δ9 tetrahydrocannabinol and its analogue, nabilone, have been found to reliably attenuate the intensity and frequency of post-traumatic nightmares. This essay examines how a traumatic event is captured in the mind, after just a single exposure, and repeatedly replicated during the nights that follow. The adaptive neurophysiological, endocrine and inflammatory changes that are triggered by the trauma and that alter personality and behavior are surveyed. These adaptive changes, once established, can be difficult to reverse. But cannabinoids, uniquely, have been shown to interfere with all of these post-traumatic somatic adaptations. While cannabinoids can suppress nightmares and other symptoms of post-traumatic stress disorder, they are not a cure. There may be no cure. The cannabinoids may best be employed, alone, but more likely in conjunction with other agents, in the immediate aftermath of a trauma to mitigate or even abort the metabolic changes which are set in motion by the trauma and which may permanently alter the reactivity of the nervous system. Steps in this direction have already been taken.


Benefits and challenges of collaborative research: lessons from supportive and palliative care.
To describe the processes of establishing and running the Cancer Experiences Collaborative (CECo), and reflect upon the benefits and challenges of undertaking collaborative research in supportive and palliative care. A descriptive analysis of a 5-year research collaborative initiated in 2006. Research groups at the Universities of Lancaster, Liverpool, Manchester, Nottingham and Southampton, England. 26 UK organisations including the four largest hospices in England, hospital cancer centres, Help the Hospices (a national charity supporting independent hospices) and user representatives. The aim of CECo was to enhance the value, quality and productivity of scientific research in supportive and palliative care, and to increase research capacity and improve the coordination of collaborative research. Three programmatic themes of research were established: (i) innovative approaches to complex symptoms, (ii) planning for the care of older adults towards the end of life and (iii) research methodology including narrative approaches. Four benefits and challenges are highlighted: strategic leadership and management structures for cross-institutional work, working in multidisciplinary groups and linking research with practice settings, capacity building, and user involvement. The activities of CECo have resulted in significant benefits with an increase in good quality research studies that have led to the production of a significant number of peer-reviewed papers, and learning between academics, clinicians and users, which has contributed to raising the standards of supportive and palliative care research. However, the future of such research initiatives is fragile, with concerns about the sustainability of collaboration in the face of diminishing resources.


Liver failure caused by prolonged state of malnutrition following bariatric surgery.
Bariatric surgery is an effective tool in the treatment of patients with morbid obesity. In these case reports we describe 2 patients who developed liver failure after currently-practiced types of bariatric surgery, caused by a prolonged state of malnutrition provoked by psychiatric problems. Despite intensive guidance of a psychologist and dieticians after surgery, our patients deteriorated psychologically, resulting in a prolonged state of severe malnutrition and anorexia. Finally, a state of starvation was reached, passing a critical level of the liver capacity. Patients who present with signs of severe protein malnutrition after bariatric surgery should be closely monitored and checked for nutritional status. Specific attention should be given to patients who develop psychiatric problems post-bariatric surgery. If refeeding does not result in clinical improvement, reversal surgery should be considered in a timely manner.


Active compensation for changes in TDH3 expression mediated by direct regulators of TDH3 in Saccharomyces cerevisiae.
Genetic networks are surprisingly robust to perturbations caused by new mutations. This robustness is conferred in part by compensation for loss of a gene's activity by genes with overlapping functions, such as paralogs. Compensation occurs passively when the normal activity of one paralog can compensate for the loss of the other, or actively when a change in one paralog's expression, localization, or activity is required to compensate for loss of the other. The mechanisms of active compensation remain poorly understood in most cases. Here we investigate active compensation for the loss or reduction in expression of the Saccharomyces cerevisiae gene TDH3 by its paralogs TDH1 and TDH2. TDH1 and TDH2 are upregulated in a dose-dependent manner in response to reductions in TDH3 by a mechanism requiring the shared transcriptional regulators Gcr1p and Rap1p. Other glycolytic genes regulated by Rap1p and Gcr1p show changes in expression similar to TDH2, suggesting that the active compensation by TDH3 paralogs is part of a broader homeostatic response mediated by shared transcriptional regulators.


Crystallographic studies on the reaction of isopenicillin N synthase with an unsaturated substrate analogue.
Isopenicillin N synthase (IPNS) catalyses conversion of the linear tripeptide delta-(L-alpha-aminoadipoyl)-L-cysteinyl-D-valine (ACV) to isopenicillin N (IPN), the central step in biosynthesis of the beta-lactam antibiotics. The unsaturated substrate analogue delta-(L-alpha-aminoadipoyl)-L-cysteinyl-D-vinylglycine (ACvG) has previously been incubated with IPNS and single product was isolated, a 2-alpha-hydroxymethyl isopenicillin N (HMPen), formed via a monooxygenase mode of reactivity. ACvG has now been crystallised with IPNS and the structure of the anaerobic IPNS:Fe(II):ACvG complex determined to 1.15 A resolution. Furthermore, by exposing the anaerobically grown crystals to high-pressure oxygen gas, a structure corresponding to the bicyclic product HMPen has been obtained at 1.60 A resolution. In light of these and other IPNS structures, and recent developments with related dioxygenases, the [2 + 2] cycloaddition mechanism for HMPen formation from ACvG has been revised, and a stepwise radical mechanism is proposed. This revised mechanism remains consistent with the observed stereospecificity of the transformation, but fits better with apparent constraints on the coordination geometry around the active site iron atom.


Childhood risk factors for high adult blood pressure: the Muscatine Study.
In adult populations, elevated blood pressure is related to the development of occlusive atherosclerosis, stroke, and renal disease. The significance of blood pressure levels in childhood, unless extremely elevated, has not been related to disease outcomes. In this study, the risk of high blood pressure in young adult life is evaluated based on the observations of blood pressure and other factors made during the school-aged years. Subjects, 2445 in number, were first observed at ages 7 through 18 years and again between 20 and 30 years. During childhood, measurements of blood pressure, height, and weight were made in alternate years. At adult ages, the same measurements were again made and a health questionnaire was administered. According to the data, adult blood pressure is correlated with childhood blood pressure, body size, and change in ponderosity from childhood to adult life. Adult ponderosity is related to childhood ponderosity, and those who are most obese as adults show the greatest increase in weight for height from their childhood years. These observations suggest that strategies to prevent the acquisition of excess ponderosity during adolescence may be useful in preventing adult hypertension.


Vitamin B6-responsive ornithine aminotransferase deficiency with a novel mutation G237D.
Ornithine aminotransferase (OAT) deficiency (MIM: 258870) is a rare congenital metabolic disorder characterized by gyrate atrophy of the choroid and retina. Here, we report a 37-year-old male with gyrate atrophy of the choroid and retina who has been treated for 18 years. At the age of 7 years, the patient consulted an ophthalmologist due to progressive loss of vision. A large atrophied area was observed in his retina, and OAT deficiency was suspected. At the age of 19 years, amino acid analysis revealed high serum ornithine levels (1,140 nmol/ml), with the normal range being 40-100 nmol/ml. He was treated with vitamin B(6) 300 mg/day for 6 months, which successfully reduced his serum ornithine levels by 20-30%. For 18 years since, his serum ornithine levels have been maintained with vitamin B(6) medication. There was no further impairment of vision or increase in the atrophied area, as judged by ophthalmoscopic examination. OAT activity was undetected in white blood cells of the patient and was 105% and 45% of normal values in his wife and son, respectively. OAT gene analysis revealed a novel mutation of Gly237Asp in exon 7 (710G > A) in both alleles of the patient, while his son was a heterozygote for the mutation. Notably, this novel mutation is associated with a vitamin B6-responsive phenotype. Therefore, early diagnosis and treatment with vitamin B(6) may prevent loss of vision in some patients with OAT deficiency.


Lamina-specific connectivity in the brain: regulation by N-cadherin, neurotrophins, and glycoconjugates.
In the vertebrate brain, neurons grouped in parallel laminae receive distinct sets of synaptic inputs. In the avian optic tectum, arbors and synapses of most retinal axons are confined to 3 of 15 laminae. The adhesion molecule N-cadherin and cell surface glycoconjugates recognized by a plant lectin are selectively associated with these "retinorecipient" laminae. The lectin and a monoclonal antibody to N-cadherin perturbed laminar selectivity in distinct fashions. In contrast, neurotrophins increased the complexity of retinal arbors without affecting their laminar distribution. Thus, cell surface molecules and soluble trophic factors may collaborate to shape lamina-specific arbors in the brain, with the former predominantly affecting their position and the latter their size.


Positive biodiversity-productivity relationship predominant in global forests.
The biodiversity-productivity relationship (BPR) is foundational to our understanding of the global extinction crisis and its impacts on ecosystem functioning. Understanding BPR is critical for the accurate valuation and effective conservation of biodiversity. Using ground-sourced data from 777,126 permanent plots, spanning 44 countries and most terrestrial biomes, we reveal a globally consistent positive concave-down BPR, showing that continued biodiversity loss would result in an accelerating decline in forest productivity worldwide. The value of biodiversity in maintaining commercial forest productivity alone-US$166 billion to 490 billion per year according to our estimation-is more than twice what it would cost to implement effective global conservation. This highlights the need for a worldwide reassessment of biodiversity values, forest management strategies, and conservation priorities.


Osteoporosis associated vertebral fractures-Health economic implications.
Osteoporosis-associated vertebral fractures represent an increasing clinical and public health problem, one with important socioeconomic effects within western countries. The purpose of this study was to analyse demographic, medical, gender and socioeconomic aspects of osteoporotic vertebral fractures of the thoracic or lumbar spine over a period of at least 10-years. Included for analysis were 694 patients who had suffered a vertebral fracture due to primary or secondary osteoporosis, and who were treated at our Level-I trauma center between 2000 and 2013. Collected data included demographic, medical and socioeconomic aspects. Clinical results revealed that 669 patients (96%) were treated conservatively. The remaining 25 patients (4%) underwent surgical therapy: 4 were treated with vertebroplasty, 15 with kyphoplasty and 6 patients with posterior stabilization. The mean age was 75.6 years (range: 50-98), with the vast majority of patients being female (n = 515). A statistically significant demographic difference (i.e., increase) in fractures was observed between the age groups 60-69 and 70-79 (p = 0.041). Concerning socioeconomic aspects, statistical analysis showed that the number of sick leaves and the need for professional domestic help was higher in female patients. Concerning treatment costs, statistical analysis did not reveal any significant differences between female and male patients. Significant gender differences-to the detriment of the female population-could be demonstrated within this study. A regrettably low rate of adequate treatment after diagnosis of osteoporosis and its associated fractures-specifically relating to primary and secondary prevention-could also be identified. To prospectively avoid complications and consequential cost increases, more awareness of the necessity for prevention, early diagnosis and adequate treatment of osteoporosis and its related fractures should be considered.


Neural crest specification by noncanonical Wnt signaling and PAR-1.
Neural crest (NC) cells are multipotent progenitors that form at the neural plate border, undergo epithelial-mesenchymal transition and migrate to diverse locations in vertebrate embryos to give rise to many cell types. Multiple signaling factors, including Wnt proteins, operate during early embryonic development to induce the NC cell fate. Whereas the requirement for the Wnt/β-catenin pathway in NC specification has been well established, a similar role for Wnt proteins that do not stabilize β-catenin has remained unclear. Our gain- and loss-of-function experiments implicate Wnt11-like proteins in NC specification in Xenopus embryos. In support of this conclusion, modulation of β-catenin-independent signaling through Dishevelled and Ror2 causes predictable changes in premigratory NC. Morpholino-mediated depletion experiments suggest that Wnt11R, a Wnt protein that is expressed in neuroectoderm adjacent to the NC territory, is required for NC formation. Wnt11-like signals might specify NC by altering the localization and activity of the serine/threonine polarity kinase PAR-1 (also known as microtubule-associated regulatory kinase or MARK), which itself plays an essential role in NC formation. Consistent with this model, PAR-1 RNA rescues NC markers in embryos in which noncanonical Wnt signaling has been blocked. These experiments identify novel roles for Wnt11R and PAR-1 in NC specification and reveal an unexpected connection between morphogenesis and cell fate.


A double-blind study comparing the effect of glycerin and urea on dry, eczematous skin in atopic patients.
Moisturizing creams have beneficial effects in the treatment of dry, scaly skin, but they may induce adverse skin reactions. In a randomized double-blind study, 197 patients with atopic dermatitis were treated with one of the following: a new moisturizing cream with 20% glycerin, its cream base without glycerin as placebo, or a cream with 4% urea and 4% sodium chloride. The patients were asked to apply the cream at least once daily for 30 days. Adverse skin reactions and changes in skin dryness were assessed by the patient and a dermatologist. Adverse skin reactions such as smarting (a sharp local superficial sensation) were felt significantly less among patients using the 20% glycerin cream compared with the urea-saline cream, because 10% of the patients judged the smarting as severe or moderate when using glycerin cream, whereas 24% did so using urea-saline cream (p < 0.0006). No differences were found regarding skin reactions such as stinging, itching and dryness/irritation. The study showed equal effects on skin dryness as judged by the patients and the dermatologist. In conclusion, a glycerin containing cream appears to be a suitable alternative to urea/sodium chloride in the treatment of atopic dry skin.


Long-Term Survival of Transplanted Autologous Canine Liver Organoids in a COMMD1-Deficient Dog Model of Metabolic Liver Disease.
The shortage of liver organ donors is increasing and the need for viable alternatives is urgent. Liver cell (hepatocyte) transplantation may be a less invasive treatment compared with liver transplantation. Unfortunately, hepatocytes cannot be expanded in vitro, and allogenic cell transplantation requires long-term immunosuppression. Organoid-derived adult liver stem cells can be cultured indefinitely to create sufficient cell numbers for transplantation, and they are amenable to gene correction. This study provides preclinical proof of concept of the potential of cell transplantation in a large animal model of inherited copper toxicosis, such as Wilson's disease, a Mendelian disorder that causes toxic copper accumulation in the liver. Hepatic progenitors from five COMMD1-deficient dogs were isolated and cultured using the 3D organoid culture system. After genetic restoration of COMMD1 expression, the organoid-derived hepatocyte-like cells were safely delivered as repeated autologous transplantations via the portal vein. Although engraftment and repopulation percentages were low, the cells survived in the liver for up to two years post-transplantation. The low engraftment was in line with a lack of functional recovery regarding copper excretion. This preclinical study confirms the survival of genetically corrected autologous organoid-derived hepatocyte-like cells in vivo and warrants further optimization of organoid engraftment and functional recovery in a large animal model of human liver disease.


Thirty-Year Trends in Mortality from Cerebrovascular Diseases in Korea.
Cerebrovascular disease is a leading cause of mortality and morbidity in Korea. Understanding of cerebrovascular disease mortality trends is important to reduce the health burden from cerebrovascular diseases. We examined the changing pattern of mortality related to cerebrovascular disease in Korea over 30 years from 1983 to 2012. Numbers of deaths from cerebrovascular disease, hemorrhagic stroke, and cerebral infarction were obtained from the national Cause of Death Statistics. Crude and age-adjusted mortality rates were calculated for men and women for each year. Penalized B-spline methods, which reduce bias and variability in curve fitting, were used to identify the trends of 30-year mortality and identify the year of highest mortality. During the 30 years, cerebrovascular disease mortality has markedly declined. The age-adjusted cerebrovascular disease mortality rate has decreased by 78% in men and by 68% in women. In the case of hemorrhagic stroke, crude mortality peaked in 2001 but age-adjusted mortality peaked in 1994. Between 1994 and 2012, age-adjusted mortality from hemorrhagic stroke has decreased by 68% in men and 59% in women. In the case of cerebral infarction, crude and age-adjusted mortality rates steeply increased until 2004 and 2003, respectively, and both rates decreased rapidly thereafter. Cerebrovascular disease mortality rate has significantly decreased over the last 30 years in Korea, but remains a health burden. The prevalence of major cardiovascular risk factors are still highly prevalent in Korea.


Glucocorticoid treatment inhibits annexin-1 expression in rheumatoid arthritis CD4+ T cells.
Annexin-1 (Anx-A1) has been recently shown to play a key role in T-cell activation and to be highly expressed in T cells from RA patients. Here, we investigated the effects of glucocorticoids (GCs) on Anx-A1 expression in T cells in vitro and in vivo. To evaluate the effects of dexamethasone (Dex) on Anx-A1 expression, human peripheral blood T cells were incubated with Dex and then analysed by real-time PCR and western blotting. Similar experiments were carried out in vivo by measuring Anx-A1 levels in T cells from patients with RA before and after administration of steroids. Incubation of T cells with Dex decreased Anx-A1 levels in a time-dependent fashion and almost abolished its expression after 12 h. Stimulation of T cells pre-incubated with Dex for 12 h with anti-CD3/CD28 led to significant reduction of IL-2 production. Addition of human recombinant Anx-A1 to Dex-treated cells reversed the inhibitory effects of the steroids on anti-CD3/CD28-induced IL-2 production. Treatment of RA patients with steroid decreased Anx-A1 expression in T cells. GCs suppress Anx-A1 expression in T cells in vitro and in vivo. These results provide evidence for a novel pathway by which steroids regulate the adaptive immune response and suggest that Anx-A1 may represent a target for the treatment of autoimmune diseases.


MtDNA of Fulani nomads and their genetic relationships to neighboring sedentary populations.
Despite the large size of the contemporary nomadic Fulani population (roughly 13 million people), the genetic diversity and degree of differentiation of Fulanis compared to other sub-Saharan populations remain unknown. We sampled four Fulani nomad populations (n = 186) in three countries of sub-Saharan Africa (Chad, Cameroon, and Burkina Faso) and analyzed sequences of the first hypervariable segment of the mitochondrial DNA. Most of the haplotypes belong to haplogroups of West African origin, such as L1b, L3b, L3d, L2b, L2c, and L2d (79.6% in total), which are all well represented in each of the four geographically separated samples. The haplogroups of Western Eurasian origin, such as J1b, U5, H, and V, were also detected but in rather low frequencies (8.1% in total). As in African hunter-gatherers (Pygmies and Khoisan) and some populations from central Tunisia (Kesra and Zriba), three of the Fulani nomad samples do not reveal significant negative values of Fu's selective neutrality test. The multidimensional scaling of FST genetic distances of related sub-Saharan populations and the analysis of molecular variance (AMOVA) show clear and close relationships between all pairs of the four Fulani nomad samples, irrespective of their geographic origin. The only group of nomadic Fulani that manifests some similarities with geographically related agricultural populations (from Guinea-Bissau and Nigeria) comes from Tcheboua in northern Cameroon.


PPAR-alpha activation required for decreased glucose uptake and increased susceptibility to injury during ischemia.
The transcription of key metabolic regulatory enzymes in the heart is altered in the diabetic state, yet little is known of the underlying mechanisms. The aim of this study was to investigate the role of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) in modulating cardiac insulin-sensitive glucose transporter (GLUT-4) protein levels in altered metabolic states and to determine the functional consequences by assessing cardiac ischemic tolerance. Wild-type and PPAR-alpha-null mouse hearts were isolated and perfused 6 wk after streptozotocin administration or after 14 mo on a high-fat diet or after a 24-h fast. Myocardial d-[2-(3)H]glucose uptake was measured during low-flow ischemia, and differences in GLUT-4 protein levels were quantified using Western blotting. In wild-type mice in all three metabolic states, elevated plasma free fatty acids were associated with lower total cardiac GLUT-4 protein levels and decreased glucose uptake during ischemia, resulting in poor postischemic functional recovery. Although PPAR-alpha-null mice also had elevated plasma free fatty acids, they had neither decreased cardiac GLUT-4 levels nor decreased glucose uptake during ischemia and, consequently, did not have poor recovery during reperfusion. We conclude that elevated plasma free fatty acids are associated with increased injury during ischemia due to decreased cardiac glucose uptake resulting from lower cardiac GLUT-4 protein levels, the levels of GLUT-4 being regulated, probably indirectly, through PPAR-alpha activation.


In vivo depth-resolved oxygen saturation by Dual-Wavelength Photothermal (DWP) OCT.
Microvasculature hemoglobin oxygen saturation (SaO2) is important in the progression of various pathologies. Non-invasive depth-resolved measurement of SaO2 levels in tissue microvasculature has the potential to provide early biomarkers and a better understanding of the pathophysiological processes allowing improved diagnostics and prediction of disease progression. We report proof-of-concept in vivo depth-resolved measurement of SaO(2) levels in selected 30 µm diameter arterioles in the murine brain using Dual-Wavelength Photothermal (DWP) Optical Coherence Tomography (OCT) with 800 nm and 770 nm photothermal excitation wavelengths. Depth location of back-reflected light from a target arteriole was confirmed using Doppler and speckle contrast OCT images. SaO(2) measured in a murine arteriole with DWP-OCT is linearly correlated (R(2)=0.98) with systemic SaO(2) values recorded by a pulse-oximeter. DWP-OCT are steadily lower (10.1%) than systemic SaO(2) values except during pure oxygen breathing. DWP-OCT is insensitive to OCT intensity variations and is a candidate approach for in vivo depth-resolved quantitative imaging of microvascular SaO(2) levels.


Exposure to mitochondrial genotoxins and dopaminergic neurodegeneration in Caenorhabditis elegans.
Neurodegeneration has been correlated with mitochondrial DNA (mtDNA) damage and exposure to environmental toxins, but causation is unclear. We investigated the ability of several known environmental genotoxins and neurotoxins to cause mtDNA damage, mtDNA depletion, and neurodegeneration in Caenorhabditis elegans. We found that paraquat, cadmium chloride and aflatoxin B1 caused more mitochondrial than nuclear DNA damage, and paraquat and aflatoxin B1 also caused dopaminergic neurodegeneration. 6-hydroxydopamine (6-OHDA) caused similar levels of mitochondrial and nuclear DNA damage. To further test whether the neurodegeneration could be attributed to the observed mtDNA damage, C. elegans were exposed to repeated low-dose ultraviolet C radiation (UVC) that resulted in persistent mtDNA damage; this exposure also resulted in dopaminergic neurodegeneration. Damage to GABAergic neurons and pharyngeal muscle cells was not detected. We also found that fasting at the first larval stage was protective in dopaminergic neurons against 6-OHDA-induced neurodegeneration. Finally, we found that dopaminergic neurons in C. elegans are capable of regeneration after laser surgery. Our findings are consistent with a causal role for mitochondrial DNA damage in neurodegeneration, but also support non mtDNA-mediated mechanisms.


Paraneoplastic porphyria cutanea tarda associated with cholangiocarcinoma: case report.
The porphyrias are a group of disorders of the heme biosynthesis pathway that present with acute neurovisceral symptoms, skin lesions or both. Porphyria cutanea tarda, presenting as a non-acute form, is the most common type of porphyria that encompasses a group of related disorders, all of which arise from deficient activity of the heme synthetic enzyme, uroporphyrinogen decarboxylase, in the liver. In the literature, concomitant presentation of porphyria with hepatocellular carcinoma is common; however, no case of porphyria cutanea tarda associated with cholangiocarcinoma has been seen. Here, we present a case of porphyria cutanea tarda seen in the course of cholangiocarcinoma, which can be attributed to a paraneoplastic syndrome. Our case is of interest because of its rarity. We also give a brief review of the literature regarding porphyria and cholangiocarcinoma.


Nanostructural Diversity of Synapses in the Mammalian Spinal Cord.
Functionally distinct synapses exhibit diverse and complex organisation at molecular and nanoscale levels. Synaptic diversity may be dependent on developmental stage, anatomical locus and the neural circuit within which synapses reside. Furthermore, astrocytes, which align with pre and post-synaptic structures to form 'tripartite synapses', can modulate neural circuits and impact on synaptic organisation. In this study, we aimed to determine which factors impact the diversity of excitatory synapses throughout the lumbar spinal cord. We used PSD95-eGFP mice, to visualise excitatory postsynaptic densities (PSDs) using high-resolution and super-resolution microscopy. We reveal a detailed and quantitative map of the features of excitatory synapses in the lumbar spinal cord, detailing synaptic diversity that is dependent on developmental stage, anatomical region and whether associated with VGLUT1 or VGLUT2 terminals. We report that PSDs are nanostructurally distinct between spinal laminae and across age groups. PSDs receiving VGLUT1 inputs also show enhanced nanostructural complexity compared with those receiving VGLUT2 inputs, suggesting pathway-specific diversity. Finally, we show that PSDs exhibit greater nanostructural complexity when part of tripartite synapses, and we provide evidence that astrocytic activation enhances PSD95 expression. Taken together, these results provide novel insights into the regulation and diversification of synapses across functionally distinct spinal regions and advance our general understanding of the 'rules' governing synaptic nanostructural organisation.


Genomic, prognostic, and cell-signaling advances in uveal melanoma.
Uveal melanoma (UM) is the second-most common form of melanoma and the most common primary intraocular malignancy. Up to one-half of patients are at risk for fatal metastatic disease. The metastatic potential of an individual tumor can be accurately determined by analysis of a fine-needle aspirate with gene expression profiling assay that is available for routine clinical use through a commercial Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. The test renders one of two results-class 1 (low metastatic risk) or class 2 (high metastatic risk)-and has been extensively validated in multiple centers. Until recently, the genetic mutations and signaling aberrations in UM were largely unknown. With the advent of new genomic sequencing technologies, however, the molecular landscape of UM is rapidly emerging. Mutations in the Gq alpha subunits GNAQ and GNA11 are mutually exclusive and represent early or initiating events that constitutively activate the MAPK pathway. Mutations in BRCA1-associated protein-1 (BAP1) and splicing factor 3B subunit 1 (SF3B1) also appear to be largely mutually exclusive, and they occur later in tumor progression. BAP1 mutations are strongly associated with metastasis, whereas SF3B1 mutations are associated with a more favorable outcome. BAP1 mutations can arise in the germ line, leading to a newly described BAP1 familial cancer syndrome. These discoveries have led to new clinical trials to assess several classes of compounds, including MEK, protein kinase C, and histone deacetylase inhibitors, in the adjuvant setting for high-risk patients identified as class 2, as well as in the setting of advanced disseminated disease.


(Poly)phenol-digested metabolites modulate alpha-synuclein toxicity by regulating proteostasis.
Parkinson's disease (PD) is an age-related neurodegenerative disease associated with the misfolding and aggregation of alpha-synuclein (aSyn). The molecular underpinnings of PD are still obscure, but nutrition may play an important role in the prevention, onset, and disease progression. Dietary (poly)phenols revert and prevent age-related cognitive decline and neurodegeneration in model systems. However, only limited attempts were made to evaluate the impact of digestion on the bioactivities of (poly)phenols and determine their mechanisms of action. This constitutes a challenge for the development of (poly)phenol-based nutritional therapies. Here, we subjected (poly)phenols from Arbutus unedo to in vitro digestion and tested the products in cell models of PD based on the cytotoxicity of aSyn. The (poly)phenol-digested metabolites from A. unedo leaves (LPDMs) effectively counteracted aSyn and H2O2 toxicity in yeast and human cells, improving viability by reducing aSyn aggregation and inducing its clearance. In addition, LPDMs modulated pathways associated with aSyn toxicity, such as oxidative stress, endoplasmic reticulum (ER) stress, mitochondrial impairment, and SIR2 expression. Overall, LPDMs reduced aSyn toxicity, enhanced the efficiency of ER-associated protein degradation by the proteasome and autophagy, and reduced oxidative stress. In total, our study opens novel avenues for the exploitation of (poly)phenols in nutrition and health.


Lived experience of Indonesian nurses in Japan: A phenomenological study.
The movement of Indonesian nurses via a bilateral agreement with Japan has led to a substantial number of migrants to work as nurses in that nation's healthcare system. The purpose of this research was to develop a deeper understanding of the meaningful experiences of Indonesian nurses while working in Japanese hospitals. In this phenomenological study, sampling was purposive and was based on information shared by five Indonesian nurses. The data were collected in interviews; the analysis was thematic. Six key themes were identified: (i) seeking better than before; (ii) communication challenges; (iii) the nursing examination as a culmination; (iv) differences in nursing practice; (v) cultural differences; and (vi) the benefits of living in developed country. Among these challenges, communication as the basis of shared meaning and understanding was viewed as a complex issue, by both patients and coworkers. The results of this study call for further intervention in supporting Indonesian nurses living in Japan in their struggle with the issue of communication. The emphasis on language acquisition for personal and professional objectives, and the bridging of cultural differences as well, should be considered in an international context.


Computerized clinical pathways (care plans): piloting a strategy to enhance quality patient care.
Having paper and electronic documentation can interfere with staff communication and workflow. In this 950-bed multicampus acute healthcare network in the southeastern United States, paper pathways did not clearly demonstrate multidisciplinary documentation and involvement in the plan of care. The majority of documentation was computerized, but clinical pathways remained in the paper chart. Limited literature findings, incomplete pathway documentation, and nurse dissatisfaction with cumbersome documentation processes created the impetus for this practice change. To provide a sound basis for transitioning the pathways into the electronic medical record, a pilot was conducted on 1 medical-surgical department using 1 computerized pathway. Outcomes were measured utilizing pathway documentation audits and staff perception surveys. PROJECT OUTCOMES: Pilot results revealed improvements in pathway documentation and staff satisfaction with use of the computerized pathway. There was a 69% increase in the documentation of barriers to patient progression/utilization of the problem list, 10% increase in documentation of patient medication teaching, and 31% increase in documentation by ancillary staff using the computerized pathway. According to the survey results, staff perceived that the computerized pathway was a more useful tool in (1) prompting them to educate the patient (36% increase compared with paper); (2) communicating pertinent patient information during shift report (34% increase compared with paper); and (3) documenting barriers to patient progression (30% increase in comparison to paper). Based on these results, approval was obtained from health network administrators to move forward with system-wide implementation. In order for clinical pathways to be effective, patient-centered communication tools, they must be easily accessible, be utilized by all health team members, and complement day-to-day workflow. Piloting innovative practice changes helps to garnish buy-in and support from all levels of the healthcare team. Automation provides a first step to easier accessibility and linkage of pathways to other pertinent information and multidisciplinary patient care processes. Computerized pathways may be an impetus for healthcare providers to view automation as a key step to improving multidisciplinary care delivery and patient care quality.


Muscle blood flow and muscle metabolism during exercise and heat stress.
The effect of heat stress on blood flow and metabolism in an exercising leg was studied in seven subjects walking uphill (12-17%) at 5 km/h on a treadmill for 90 min or until exhaustion. The first 30 min of exercise were performed in a cool environment (18-21 degrees C); then subjects moved to an adjacent room at 40 degrees C and continued to exercise at the same speed and inclination for a further 60 min or to exhaustion, whichever occurred first. The rate of O2 consumption, 2.6 l/min (1.8-3.3) (average from cool and hot conditions), corresponded to 55-77% of their individual maximums. In the cool environment a steady state was reached at 30 min. When the subjects were shifted to the hot room, the core temperature and heart rate started to rise and reached values greater than 39 degrees C and near-maximal values, respectively, at the termination of the exercise. The leg blood flow (thermodilution method), femoral arteriovenous O2 difference, and consequently leg O2 consumption were unchanged in the hot compared with the cool condition. There was no increase in release of lactate and no reduction in glucose and free net fatty acid uptake in the exercising leg in the heat. Furthermore, the rate of glycogen utilization in the gastrocnemius muscle was not elevated in the hot environment. There was a tendency for cardiac output to increase in the heat (mean 15.2 to 18.4 l/min), which may have contributed to the increase in skin circulation, together with a possible further reduction in flow to other vascular beds, because muscle blood flow was not reduced.(ABSTRACT TRUNCATED AT 250 WORDS)


Multiple Nonsense-Mediated mRNA Processes Require Smg5 in Drosophila.
The nonsense-mediated messenger RNA (mRNA) decay (NMD) pathway is a cellular quality control and post-transcriptional gene regulatory mechanism and is essential for viability in most multicellular organisms . A complex of proteins has been identified to be required for NMD function to occur; however, there is an incomplete understanding of the individual contributions of each of these factors to the NMD process. Central to the NMD process are three proteins, Upf1 (SMG-2), Upf2 (SMG-3), and Upf3 (SMG-4), which are found in all eukaryotes, with Upf1 and Upf2 being absolutely required for NMD in all organisms in which their functions have been examined. The other known NMD factors, Smg1, Smg5, Smg6, and Smg7, are more variable in their presence in different orders of organisms and are thought to have a more regulatory role. Here we present the first genetic analysis of the NMD factor Smg5 in Drosophila Surprisingly, we find that unlike the other analyzed Smg genes in this organism, Smg5 is essential for NMD activity. We found this is due in part to a requirement for Smg5 in both the activity of Smg6-dependent endonucleolytic cleavage, as well as an additional Smg6-independent mechanism. Redundancy between these degradation pathways explains why some Drosophila NMD genes are not required for all NMD-pathway activity. We also found that while the NMD component Smg1 has only a minimal role in Drosophila NMD during normal conditions, it becomes essential when NMD activity is compromised by partial loss of Smg5 function. Our findings suggest that not all NMD complex components are required for NMD function at all times, but instead are utilized in a context-dependent manner in vivo.


Surgical management of ruptured middle cerebral artery aneurysms with large intraparenchymal or sylvian fissure hematomas.
Craniotomy for hematoma evacuation and aneurysm clipping is the treatment modality of choice for ruptured middle cerebral artery (MCA) aneurysms with intracranial hematomas. Recent literature suggests that endovascular coil embolization followed by hematoma evacuation can be an acceptable alternative. To determine neurological outcomes in patients with ruptured MCA aneurysms and intraparenchymal or sylvian fissure hematomas. The records of 49 patients with ruptured MCA aneurysms with large intracranial hematomas treated with hematoma evacuation and aneurysm clipping between January 2000 and December 2013 were retrospectively reviewed. Within this cohort, 35 patients (71.4%) were Hunt and Hess grade IV or V on presentation. The mean hematoma volume was 100.4 ± 77.2 mL. Craniectomy was performed in 40 patients (81.6%). Angiographic vasospasm developed in 15 patients (30.6%). The in-hospital mortality rate was 28.6% (14 patients). At a mean of 25.3 ± 34.0 months follow-up, a good outcome (modified Rankin Scale [mRS] score 0-3) was observed in 18 patients (36.7%). Significant factors associated with poor outcome or death (mRS scores of 4-6) included increasing age (P < .01), increasing Hunt and Hess grade (P = .03), increasing modified Fisher grade (P = .01), presence of intraventricular hemorrhage (P < .01), decreasing percentage of hematoma evacuation (P < .05), need for craniectomy (P <. 01), need for external ventricular drainage (P = .04), and angiographic vasospasm (P = .02). MCA aneurysm rupture with concomitant large intraparenchymal or sylvian fissure hematoma formation carries a grave prognosis. Simultaneous hematoma evacuation and aneurysm clipping with or without craniectomy can be an effective treatment modality.


Non-gastric Gastrointestinal Xanthomas: Case Series and Literature Review.
Gastrointestinal xanthomas are infrequent non-neoplastic lesions characterized by the accumulation of foam cells in the lamina propria. They are commonly seen in association with dyslipidemia, chemotherapy or radiotherapy, and infections in immunosuppressed patients. However, no clear connection to hyperlipidemia has been found. They occur more frequently in the stomach, and are very rare in the small bowel and esophagus. We identified all cases of non-gastric xanthoma or xanthomatosis reported in the English literature by searching the PubMed database and retrospectively reviewed the clinical, endoscopic, and histopathologic features of the 11 cases of non-gastric gastrointestinal xanthomas diagnosed in our hospital. Nine lesions were located in the large bowel, one in the duodenum and one in the esophagus. All xanthomas were small (<5 mm) sessile polyps except the esophageal xanthoma, which measured 13 mm. Two cases in the large bowel and the case in the small bowel were multiple. Most patients with large bowel xanthomas had hypercholesterolemia, unlike esophageal and small bowel cases. The esophageal lesion occurred in a patient with a history of partial fundoplication due to gastroesophageal reflux disease and the small bowel case was associated to chronic atrophic gastritis with intense activity. In our search of the English literature, we found 19 cases of xanthoma or xanthomatosis in the esophagus, 13 cases in the small bowel and 61 cases in the large bowel. In conclusion, gastrointestinal xanthomas, other than the gastric ones, are rare, and are usually incidental findings.


Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor.
A series of dipyridodiazepinones have been shown to be potent inhibitors of human immunodeficiency virus-1 (HIV-1) reverse transcriptase (RT). One compound, BI-RG-587, had a Ki of 200 nanomolar for inhibition of HIV-1 RT that was noncompetitive with respect to deoxyguanosine triphosphate. BI-RG-587 was specific for HIV-1 RT, having no effect on feline and simian RT or any mammalian DNA polymerases. BI-RG-587 inhibited HIV-1 replication in vitro as demonstrated by in situ hybridization, inhibition of protein p24 production, and the lack of syncytia formation in cultured human T cell lines and freshly isolated human peripheral blood lymphocytes. Cytotoxicity studies of BI-RG-587 on human cells showed a high therapeutic index (greater than 8000) in culture.


A review of cost-effectiveness, cost-containment and economics curricula in graduate medical education.
Numerous studies performed over the last 30 years suggest that doctors have poor knowledge of the costs of medical care. In most graduate medical education programmes, trainees do not receive formal training in cost-effective medical practice. Comprehensive literature search of electronic bibliographic databases for articles that describe health economics, cost-containment and cost-effectiveness curricula in graduate medical education. Critical appraisal of the literature and qualitative description is presented. Heterogeneity of curricula precluded quantitative summary of data. We identified 40 articles that met the inclusion criteria for this review. Internal medicine residents were the targeted learners in 27 studies (68%); Family Medicine and Surgery residents were each targeted in five studies (13%); Rehabilitation, Paediatrics and Emergency Medicine residents were each targeted in one study. In general, the methodological quality of the included studies was poor to moderate and mostly targeted knowledge of health economics or cost-containment as opposed to targeting cost-effectiveness. In terms of describing the standard curricular components, studies sufficiently described the different educational strategies (e.g. didactics, interactive, experiential, self-directed) and the component of learner assessment, but lacked the description of other elements such as needs assessment and curriculum evaluation. Cost-effectiveness curricula in graduate medical education are lacking and clearly needed.


The inaugural Qatar Critical Care Conference with its Qatar Medical Journal Special Issue - An important milestone.
Dr. Ibrahim Fawzy Hassan Local Host and QCCC 2019 Conference Chair Dear Friends and Colleagues, It is an honour to welcome everyone to the first Qatar Critical Care Conference (QCCC). It has been a long journey to make it happen, but this event has been much awaited by the local critical care community. Over the last few years, we have hosted a number of related events of various scales, ranging from Critical Care Grand Rounds targeting Hamad Medical Corporation (HMC) critical care clinicians, ran specialised courses, through to organising an international medical conference on extracorporeal life support in 2017.1 This inaugural QCCC event is the fruit of much planning and collaboration. The programme spans from 28th to 31st October 2019 and consists of two days of pre-conference workshops and two days for the main conference. The vast majority of the pre-conference workshops will be held in the state-of-the-art ITQAN Clinical Simulation and Innovation Centre located within Hamad bin Khalifa Medical City. Although the facility is yet to be offically inaugurated and opened, we have the privilege to have been granted access to it as a way of showcasing our forthcoming continuing professional development capability. "Itqan" in Arabic means quality and striving for perfection, which is very much in line with the mission of our established Critical Care Network (CCNW).2 Simulation-based education is an area in which we have started to be very active through various immersive courses as well as innovative technological developments to train our extracorporeal membrane oxygenation (ECMO) specialists.3,4 The scientific part of the conference will be hosted in the iconic Sheraton Grand Doha Resort & Convention Hotel in the West Bay area. It includes a varied selection of topics presented by many renowned experts in their respective domain. This comprehensive programme with a line-up of lectures and workshops addressing e-CPR, ECMO simulation, ECMO cannulation, hemodynamics and so much more will facilitate the exchange of knowledge and experiences to improve patient care in Qatar and beyond. We anticipate that the programme will appeal to a broad audience and hence will bring together clinicians from all professions involved with caring for acutely ill patients. It is QCCC's aim to connect and explore new insights and expertise at a national and international level through networking with other professionals in a multidisciplinary setting. We hope that during this event many fruitful discussions will take place and that it will enhance opportunities for collaboration to develop everyone's practice in critical care. The HMC Critical Care family has a capacity of 163 and 109 intensive care unit (UCI) beds, respectively for adult and paediatric patients, across 7 hospitals spread throughout Qatar. These numbers are complemented by another 52 adult and paediatric beds from non-HMC hospitals. This gives us a national ICU bed capacity of 11.8 per 100,000 inhabitants considering a current population of nearly 2,750,000 inhabitants.5 Although this number remains below the international benchmark which can be considered to be around 15/100,000 population,6 this quota in Qatar has more than quadrupled over the last ten years, which represents a very significant improvement in the care that can be provided to acutely ill patients. Within HMC only, it is supported by a workforce of 159 intensive care physicians, 1122 intensive care nurses, and many other clinical staff, all of whom undergo a well regulated programme of continuing professional development and are licensed to practise by the Qatar Council for Healthcare Practitioners (QCHP).7 The work they do across the various sites is coordinated and monitored by the CCNW2 who ensures the best level of care, up-to-date technology, and evidence-based practices are consistently adopted for the wellbeing of our patients. Once again, on behalf of the Scientific and Organizing Committees, it is my pleasure to welcome you all to Doha and we hope that you enjoy and gain meaningful insights during the conference regarding our local critical care setting and practices, but also learn from the experiences and best practices shared by our international guest speakers. Prof. Guillaume Alinier Guest Managing Editor, Qatar Medical Journal QCCC Special Issue and Abstracts Chair of the QCCC Scientific Committee. Dear Contributors and Conferences Delegates, Welcome to this special issue of the Qatar Medical Journal (QMJ) which has been dedicated to the inaugural conference of the Hamad Medical Corporation (HMC) Qatar Critical Care Network (QCCN) which celebrates its fifth anniversary in 2019. I would like to start by thanking everyone who has supported this arduous publication endeavour through their extended abstract submission(s) and the reviewers for the valuable feedback they have provided to the authors to ensure this publication is a representative legacy of the calibre of this conference which includes many local and international experts in their respective field of practice or interest. All the accepted abstracts are being published Open Access thanks to the support of the conference sponsors and this contributes greatly to the sharing of experiences and best practices worldwide, but also showcases the good work that is being done in Qatar in the domain of critical care thanks to the work of dedicated clinicians and the leadership of the CCNW.2 Being the Guest Managing Editor of the special issue of a journal is an honour but also an arduous task, especially when a large number of submissions from international authors needs to be handled. It is the second time that I have accepted to take on that role for Qatar Medical Journal as the previous time was in 2017 on the occasion of hosting the South West Asia and African Chapter (SWAAC) of the Extracorporeal Life Support Organisation (ELSO) in Doha.1 This was only a couple of years after HMC had established its Extracorporeal Membrane Oxygenation (ECMO) programme, and it was a very successful event with many of its associated open access publications having been downloaded hundreds of times from the QScience.com publishing platform. Working on this new Special Issue really made me reflect on how the domain of critical care is vast and encompasses so many aspects of patient care and so many professions and specialties. The topics of the abstracts published in this special issue of QMJ cover dietetics,8 sepsis,9 delirium,10,11 physical therapy,12 end of life care and organ donation,13,14 dealing with families,15 as well as education and training of clinicians,16,17 to only highlight a few. Critical care is fast moving as new clinical practices and technological innovations are adopted and contribute to continuously improving patient care. This is especially true in Qatar where significant investments are constantly made to develop and support healthcare in a strategic way.18 At HMC, the critical care phase that some patients have to go through so their medical needs can be met is well integrated across all stakeholder departments that can possibly be involved.2 The patient's journey through the healthcare system can be seen as a continuum of care facilitated by the fact that all parties involved belong to the same overarching organisation, HMC, which is the government funded main provider of secondary and tertiary healthcare in Qatar. This means that from initial contact with the Ambulance Service bringing a patient to the Emergency Department for example, right through to rehabilitation and even possible access upon discharge to a mobile healthcare service supported by family physicians, nurses, and paramedics, patients can expect the same high standards of care.19 Critical care provision relies on multidisciplinary communication during transition of care as well as during any acute episode. This needs to be underpinned by medical knowledge and understanding of the potential contributions of other professions as nothing can be left to chance when a patient's life is hanging by a thread. The present collection of editorials and abstracts brings different perspectives on a broad range of topics which should be highly relevant to all clinicians involved with critical care and contribute to improving patient outcome and satisfaction, and hence that of the multidisciplinary team members also involved in caring for them. We hope that the Qatar Medical Journal Special Issue publications on critical care meets your needs and expectations. The complete record of QCCC publications including additional open access abstracts and editorials relating to this conference will be made available in Qatar Medical Journal at the following link: https://www.qscience.com/content/journals/qmj. Thanks again to everyone for your contributions, and beyond our email communications, I now hope to meet you in person during the conference!


And the winner is . . . ? Forecasting the outcome of others' competitive efforts.
People frequently forecast the outcomes of competitive events. Some forecasts are about oneself (e.g., forecasting how one will perform in an athletic competition, school or job application, or professional contest), while many other forecasts are about others (e.g., predicting the outcome of another individual's athletic competition, school or job application, or professional contest). In this research, we examine people's forecasts about others' competitive outcomes, illuminate a systematic bias in these forecasts, and document the source of this bias as well as its downstream consequences. Eight experiments with a total of 3,219 participants in a variety of competitive contexts demonstrate that when observers forecast the outcome that another individual will experience, observers systematically overestimate the probability that this individual will win. This misprediction stems from a previously undocumented lay belief-the belief that other people generally achieve their intentions-that skews observers' hypothesis testing. We find that this lay belief biases observers' forecasts even in contexts in which the other person's intent is unlikely to generate the person's intended outcome, and even when observers are directly incentivized to formulate an accurate forecast. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Uterine amulets and Greek uterine medicine.
This article publishes for the first time a hematite uterine amulet in the author's possession. After a brief look at this amulet I offer a summary of previous scholarship on uterine amulets, and then focus on three specific aspects -the amulets' relation to Greek medical texts on gynecological topics; evidence for the use of perishable and non-perishable amulets by Greek women prior to the proliferation of the hematite examples in the Roman period (ca. II CE). I conclude with a discussion of the derivation and meaning of ororiouth, based on my correspondence with Dr. Roy Kotansky.


Spatially Resolving the Enhancement Effect in Surface-Enhanced Coherent Anti-Stokes Raman Scattering by Plasmonic Doppler Gratings.
Well-designed plasmonic nanostructures can mediate far and near optical fields and thereby enhance light-matter interactions. To obtain the best overall enhancement, structural parameters need to be carefully tuned to obtain the largest enhancement at the input and output frequencies. This is, however, challenging for nonlinear light-matter interactions involving multiple frequencies because obtaining the full picture of structure-dependent enhancement at individual frequencies is not easy. In this work, we introduce the platform of plasmonic Doppler grating (PDG) to experimentally investigate the enhancement effect of plasmonic gratings in the input and output beams of nonlinear surface-enhanced coherent anti-Stokes Raman scattering (SECARS). PDGs are designable azimuthally chirped gratings that provide broadband and spatially dispersed plasmonic enhancement. Therefore, they offer the opportunity to observe and compare the overall enhancement from different combinations of enhancement in individual input and output beams. We first confirm PDG's capability of spatially separating the input and output enhancement in linear surface-enhanced fluorescence and Raman scattering. We then investigate spatially resolved enhancement in nonlinear SECARS, where coherent interaction of the pump, Stokes, and anti-Stokes beams is enhanced by the plasmonic gratings. By mapping the SECARS signal and analyzing the azimuthal angle-dependent intensity, we characterize the enhancement at individual frequencies. Together with theoretical analysis, we show that while simultaneous enhancement in the input and output beams is important for SECARS, the enhancement in the pump and anti-Stokes beams plays a more critical role in the overall enhancement than that in the Stokes beam. This work provides an insight into the enhancement mechanism of plasmon-enhanced spectroscopy, which is important for the design and optimization of plasmonic gratings. The PDG platform may also be applied to study enhancement mechanisms in other nonlinear light-matter interactions or the impact of plasmonic gratings on the fluorescence lifetime.


The pattern of secondary cancers in patients with Kaposi sarcoma in the United States.
In the U.S., Kaposi sarcoma (KS) occurs mostly in HIV-infected patients, who are also at increased risk of developing secondary cancers. The trends in secondary cancer risk are unclear in the HAART era. We extracted data from the SEER database on patients diagnosed with KS between 1981 and 2013, stratified into the pre-HAART (1981-1995) and HAART (1996-2013) eras. We compared the risk of secondary cancer in KS patients and the general population, and estimated the absolute risk. We followed 13,535 KS patients for 49,813 person-years, during which 1,041 secondary cancers were diagnosed: 774 in the pre-HAART and 267 in the HAART era. In the pre-HAART era, non-Hodgkin's lymphoma (NHL) and anal carcinomas were the most common secondary cancers. The standard incidence ratio of secondary cancers decreased from 3.44 (pre-HAART era) to 1.94 (HAART era) in patients aged <70 years. The absolute excess risk decreased from 178 to 68 cases per 10,000 person-years. The risk of NHL decreased, while the risk of anal carcinoma did not change significantly. The risk of lung cancer was lower in KS patients than in the general population. The absolute risk of non-AIDS-defining cancers increased fourfold in the HAART era. The absolute risk of non-AIDS-defining secondary cancers has increased in KS patients in the HAART era. However, the overall relative risk of secondary cancers has decreased, mainly due to a significant decrease in the risk of NHL.