Rhythm as a coordinating device: entrainment with disordered speech.
The rhythmic entrainment (coordination) of behavior during human interaction is a powerful phenomenon, considered essential for successful communication, supporting social and emotional connection, and facilitating sense-making and information exchange. Disruption in entrainment likely occurs in conversations involving those with speech and language impairment, but its contribution to communication disorders has not been defined. As a first step to exploring this phenomenon in clinical populations, the present investigation examined the influence of disordered speech on the speech production properties of healthy interactants. Twenty-nine neurologically healthy interactants participated in a quasi-conversational paradigm, in which they read sentences (response) in response to hearing prerecorded sentences (exposure) from speakers with dysarthria (n = 4) and healthy controls (n = 4). Recordings of read sentences prior to the task were also collected (habitual). Findings revealed that interactants modified their speaking rate and pitch variation to align more closely with the disordered speech. Production shifts in these rhythmic properties, however, remained significantly different from corresponding properties in dysarthric speech. Entrainment offers a new avenue for exploring speech and language impairment, addressing a communication process not currently explained by existing frameworks. This article offers direction for advancing this line of inquiry.


Polysaccharide nano-vesicular multidrug carriers for synergistic killing of cancer cells.
Multi-drug delivery based on polymer nano-scaffolds is an essential protocol to be developed for better administration of anticancer drugs to enhance their therapeutic efficacies against cancer cells. Here, we report dual delivery polysaccharide nano-vesicles that are capable of loading and delivering both water soluble and water insoluble drugs together in a single polymer scaffold. The selective rupture of the nano-vesicular assembly under intracellular enzyme conditions allowed the simultaneous delivery of a hydrophobic drug camptothecin (CPT) and hydrophilic drug doxorubicin (DOX) supporting their synergistic killing of breast and colon cancer cells. The polysaccharide nano-vesicles have allowed us to address a few important questions regarding the need for multiple drug administration in cancer cells including (a) the role of simultaneous drug release, (b) antagonistic versus synergistic effects of drug combinations and (c) how these are affected by the ratio of drugs. Further, evaluation of the role of caveolae in endocytosis of these polymer scaffolds was also made. The vesicular scaffolds were found to preserve and deliver DOX resulting in 50-60% better killing of cancer cells than the free drug. Additionally, dual loaded nano-vesicles when compared to drug cocktails with individual drugs in separate nano-vesicles (at comparable molar ratios) suggest the relative drug concentration following release and mode of delivery to be both important in cancer cell killing. Results from these experiments have revealed newly developed polysaccharide nano-vesicles loaded with DOX and CPT drugs as potential candidates for improved breast cancer cell killing. Thus, these custom-designed polysaccharide nano-vesicles provide a new perspective on multi-anticancer drug delivery systems and their efficacy.


Predicting seizure freedom with AED treatment in newly diagnosed patients with MRI-negative epilepsy: A large cohort and multicenter study.
We developed and validated a prediction score for predicting the probability of 6-month and 12-month seizure freedom of antiepileptic drug (AED) treatment in newly diagnosed patients with magnetic resonance imaging (MRI)-negative epilepsy. The development cohort included 543 consecutive patients from the Epilepsy Center of Henan Provincial People's Hospital, while the validation cohorts included 493 consecutive patients in two independent cohorts. Univariate analysis and a forward and backward elimination of multivariate Cox regression analysis were used to select predictive factors. The performance of the score was evaluated with C-index, calibration plots, and decision curve analysis. The risk stratification was also performed. The score included five routinely available predictors including Circadian rhythms, Electroencephalography before AED treatment, Neuropsychiatric disorders, Perinatal brain injury, and History of central nervous system infection (CENPH score). When applied to the external validation cohort, the score showed good discrimination with C-index (development group: 0.83; validation group: 0.78), and calibration plots indicated well calibration, as well as the decision curve analysis showed good predictive accuracy and clinical values in four cohorts. The points of the score were categorized to the following three probability levels for predicting seizure freedom: high probability (0-83.11 points), medium probability (83.11-122.71 points), and low probability (>122.71 points). And online calculator was established to make this score easily applicable in clinical practice. We established a simple, practical, and evidence-based prediction score for predicting seizure freedom with AEDs to aid in the clinical consultation and treatment decision for the newly diagnosed patients with MRI-negative epilepsy.


What matters to women in the postnatal period: A meta-synthesis of qualitative studies.
The postnatal period is an underserved aspect of maternity care. Guidelines for postnatal care are not usually informed by what matters to the women who use it. This qualitative systematic review was undertaken to identify what matters to women in the postnatal period, to inform the scope of a new World Health Organization (WHO) postnatal guideline. We searched MEDLINE, CINAHL, PsycINFO, POPLINE, Global Index Medicus, EMBASE, LILACS, AJOL, and reference lists of eligible studies published January 2000-July 2019, reporting qualitative data on women's beliefs, expectations, and values relating to the postnatal period. Author findings were extracted, coded and synthesised using techniques derived from thematic synthesis. Confidence in the quality, coherence, relevance and adequacy of data underpinning the resulting findings was assessed using GRADE-CERQual. We included 36 studies from 15 countries, representing the views of more than 800 women. Confidence in most results was moderate to high. What mattered to women was a positive postnatal experience where they were able to adapt to their new self-identity and develop a sense of confidence and competence as a mother; adjust to changes in their intimate and family relationships, including their relationship to their baby; navigate ordinary physical and emotional challenges; and experience the dynamic achievement of personal growth as they adjust to the 'new normal' of motherhood and parenting in their own cultural context. This review provides evidence that what matters to women in the postnatal period is achieving positive motherhood (including maternal self-esteem, competence, and autonomy), as well as fulfilling adaptation to changed intimate and family relationships, and (re)gaining health and wellbeing for both their baby, and themselves. Where this process is optimal, it also results in joy, self-confidence, and an enhanced capacity to thrive in the new integrated identity of 'woman and mother'.


Rhodococcus equi venous catheter infection: a case report and review of the literature.
Rhodococcus equi is an animal pathogen that was initially isolated from horses and is being increasingly reported as a cause of infection in humans with impaired cellular immunity. However, this pathogen is underestimated as a challenging antagonist and is frequently considered to be a mere contaminant despite the potential for life-threatening infections. Most case reports have occurred in immunocompromised patients who have received organ transplants (for example kidney, heart, bone marrow) or those with human immunodeficiency virus infection. Infections often manifest as pulmonary involvement or soft tissue abscesses. Bacteremia related to R. equi infections of tunneled central venous catheters has rarely been described. We report the case of a 63-year-old non-transplant recipient, non-HIV infected Caucasian woman with endometrial carcinoma who developed recurrent bloodstream infections and septic shock due to R. equi and ultimately required the removal of her port catheter, a subcutaneous implantable central venous catheter. We also review the medical literature related to human infections with R. equi. R. equi should be considered a serious pathogen, not a contaminant, particularly in an immunocompromised patient who presents with a central venous catheter-related bloodstream infection. Counseling patients with central venous catheters who participate in activities involving exposure to domesticated animals is recommended.


The new world atlas of artificial night sky brightness.
Artificial lights raise night sky luminance, creating the most visible effect of light pollution-artificial skyglow. Despite the increasing interest among scientists in fields such as ecology, astronomy, health care, and land-use planning, light pollution lacks a current quantification of its magnitude on a global scale. To overcome this, we present the world atlas of artificial sky luminance, computed with our light pollution propagation software using new high-resolution satellite data and new precision sky brightness measurements. This atlas shows that more than 80% of the world and more than 99% of the U.S. and European populations live under light-polluted skies. The Milky Way is hidden from more than one-third of humanity, including 60% of Europeans and nearly 80% of North Americans. Moreover, 23% of the world's land surfaces between 75°N and 60°S, 88% of Europe, and almost half of the United States experience light-polluted nights.


Chlamydia pneumoniae: modern insights into an ancient pathogen.
Chlamydia pneumoniae is an enigmatic human and animal pathogen. Originally discovered in association with acute human respiratory disease, it is now associated with a remarkably wide range of chronic diseases as well as having a cosmopolitan distribution within the animal kingdom. Molecular typing studies suggest that animal strains are ancestral to human strains and that C. pneumoniae crossed from animals to humans as the result of at least one relatively recent zoonotic event. Whole genome analyses appear to support this concept - the human strains are highly conserved whereas the single animal strain that has been fully sequenced has a larger genome with several notable differences. When compared to the other, better known chlamydial species that is implicated in human infection, Chlamydia trachomatis, C. pneumoniae demonstrates pertinent differences in its cell biology, development, and genome structure. Here, we examine the characteristic facets of C. pneumoniae biology, offering insights into the diversity and evolution of this silent and ancient pathogen.


Possible contribution of 2-aminoethoxydiphenyl-borate-sensitive Ca2+ mobilization to adrenocorticotropin-induced glucocorticoid synthesis in rat adrenocortical cells.
Cytoplasmic calcium ([Ca(2+)](i)) provided through voltage-dependent Ca(2+) channels (VDCC) plays an important role in adrenocorticotropin (ACTH)-induced steroidogenesis in adrenocortical cells. To identify alternative mechanisms for [Ca(2+)](i) supply, we investigated the 2-aminoethoxydiphenyl borate (2APB)-sensitive pathway as one of the possible signaling pathways involved in [Ca(2+)](i) supply for ACTH-induced steroidogenesis. In monolayers of cultured rat adrenal fasciculate and reticularis cells, ACTH at 10(-11) M stimulated corticosterone synthesis without increasing intracellular cAMP, and corticosterone synthesis was decreased by 10 microM 2APB by 51.8% (6.71 +/- 0.97 vs. 3.23 +/- 0.05 ng/mL/4 hours; p<0.05). Furthermore, 2APB significantly decreased the 10(-11) M ACTH-stimulated [Ca(2+)](i). ACTH increased the intracellular inositol-1,4,5-trisphosphate (IP3) content with a peak at 10(-13) M ACTH, which illustrates the possibility that ACTH activates IP3/diacylglycerol- dependent protein kinase C signal transduction. However, the difference in ACTH concentrations between that responsible for the IP3 increase and steroidogenesis without elevated cAMP, suggest a hypothesis that IP3 is not required for steroidogenesis, but does involve an unknown messenger, which stimulates the release of Ca(2+) from the ER or the subsequent store-operated Ca(2+) entry (SOCE). The pregnenolone concentration in the culture medium was increased by ACTH, which was significantly suppressed by 2APB, showing that the 2APB-sensitive Ca(2+) supply affects cholesterol transport into the mitochondrial membrane via steroidogenic acute regulatory protein. Therefore, the SOCE may contribute to ACTH-induced steroidogenesis in the mitochondrial region. In conclusion, the [Ca(2+)](i) used for steroidogenesis may be derived from a 2APB-sensitive pathway and via VDCCs, particularly at physiological concentrations of ACTH. We suggest that ACTH receptors activate steroidogenesis via inositol triphosphate, or an unknown downstream messenger, which could be inhibited by 2APB.


Terrestrial support of lake food webs: Synthesis reveals controls over cross-ecosystem resource use.
Widespread evidence that organic matter exported from terrestrial into aquatic ecosystems supports recipient food webs remains controversial. A pressing question is not only whether high terrestrial support is possible but also what the general conditions are under which it arises. We assemble the largest data set, to date, of the isotopic composition (δ2H, δ13C, and δ15N) of lake zooplankton and the resources at the base of their associated food webs. In total, our data set spans 559 observations across 147 lakes from the boreal to subtropics. By predicting terrestrial resource support from within-lake and catchment-level characteristics, we found that half of all consumer observations that is, the median were composed of at least 42% terrestrially derived material. In general, terrestrial support of zooplankton was greatest in lakes with large physical and hydrological connections to catchments that were rich in aboveground and belowground organic matter. However, some consumers responded less strongly to terrestrial resources where within-lake production was elevated. Our study shows that multiple mechanisms drive widespread cross-ecosystem support of aquatic consumers across Northern Hemisphere lakes and suggests that changes in terrestrial landscapes will influence ecosystem processes well beyond their boundaries.


Sept5 deficiency exerts pleiotropic influence on affective behaviors and cognitive functions in mice.
Deletion or duplication of the human chromosome 22q11.2 is associated with many behavioral traits and neuropsychiatric disorders, including autism spectrum disorders and schizophrenia. However, why phenotypes vary widely among individuals with identical deletions or duplications of 22q11.2 and which specific 22q11.2 genes contribute to these phenotypes are still poorly understood. Previous studies have identified a approximately 200 kb 22q11.2 region that contributes to behavioral phenotypes in mice. We tested the role of Septin 5 (Sept5), a gene encoded in the approximately 200 kb region, in affective behaviors, cognitive capacities and motor activity. To evaluate the impact of genetic backgrounds on behavioral phenotypes of Sept5 deficiency, we used mice on two genetic backgrounds. Our data show that Sept5 deficiency decreased affiliative active social interaction, but this phenotypic expression was influenced by genetic backgrounds. In contrast, Sept5 deficiency decreased anxiety-related behavior, increased prepulse inhibition and delayed acquisition of rewarded goal approach, independent of genetic background. These data suggest that Sept5 deficiency exerts pleiotropic effects on a select set of affective behaviors and cognitive processes and that genetic backgrounds could provide an epistatic influence on phenotypic expression.


Extensive basal ganglia edema caused by a traumatic carotid-cavernous fistula: a rare presentation related to a basal vein of Rosenthal anatomical variation.
The authors report a very rare presentation of traumatic carotid-cavernous fistula (CCF) with extensive edema of the basal ganglia and brainstem because of an anatomical variation of the basal vein of Rosenthal (BVR). A 45-year-old woman was admitted to the authors' institution for left hemiparesis, dysarthria, and a comatose state caused by right orbital trauma from a thin metal rod. Brain MRI showed a right CCF and vasogenic edema of the right side of the brainstem, right temporal lobe, and basal ganglia. Digital subtraction angiography confirmed a high-flow direct CCF and revealed a hypoplastic second segment of the BVR responsible for the hypertension in inferior striate veins and venous congestion. Endovascular treatment was performed on an emergency basis. One month after treatment, the patient's symptoms and MRI signal abnormalities almost totally disappeared. Basal ganglia and brainstem venous congestion may occur in traumatic CCF in cases of a hypoplastic or agenetic second segment of the BVR and may provoke emergency treatment.


Red blood cell acetylcholinesterase and plasma butyrylcholinesterase status: important indicators for the treatment of patients poisoned by organophosphorus compounds.
Inhibition of acetylcholinesterase (AChE) is regarded as the primary toxic mechanism of organophosphorus compounds (OP). Therapeutic strategies are directed to antagonise overstimulation of muscarinic receptors with atropine and to reactivate inhibited AChE with oximes. Reactivation is crucial within the neuromuscular synapse, where atropine is ineffective, since peripheral neuromuscular block eventually leads to respiratory failure. Patients with OP intoxication have to be identified as early as possible. During an international NBC-defence exercise anesthetised pigs were poisoned with sarin, followed by treatment with atropine and oxime. Blood samples were drawn and red blood cell (RBC)-AChE activity determined with a fielded test system on-site. Within a few minutes the poisoning was verified. After administration of HI-6, RBC-AChE activity increased rapidly. Blood samples were reanalysed in our laboratory in Munich. Almost identical course of the AChE activities was recorded by both systems.The more comprehensive cholinesterase status was determined in Munich. Oxime administration can be stopped when AChE is aged completely, but has to be continued as long as poison is present in the body and reactivation is possible. To aid the on-site physician in optimising diagnosis and treatment, a fielded test system should be available to allow rapid determination of the complete cholinesterase status.


Development of a behaviour-based measurement tool with defined intervention level for assessing acute pain in cats.
To develop a composite measure pain scale tool to assess acute pain in cats and derive an intervention score. To develop the prototype composite measure pain scale-feline, words describing painful cats were collected, grouped into behavioural categories and ranked. To assess prototype validity two observers independently assigned composite measure pain scale-feline and numerical rating scale scores to 25 hospitalised cats before and after analgesic treatment. Following interim analysis the prototype was revised (revised composite measure pain scale-feline). To determine intervention score, two observers independently assigned revised composite measure pain scale-feline and numerical rating scale scores to 116 cats. A further observer, a veterinarian, stated whether analgesia was necessary. Mean ± sd decrease in revised composite measure pain scale-feline and numerical rating scale scores following analgesia were 2 · 4 ± 2 · 87 and 1 · 9 ± 2 · 34, respectively (95% confidence interval for mean change in revised composite measure pain scale-feline between 1 · 21 and 3 · 6). Changes in revised composite measure pain scale-feline and numerical rating scale were significantly correlated (r = 0 · 8) (P < 0001). Intervention level score of ≥4/16 was derived for revised composite measure pain scale-feline (26 · 7% misclassification) and ≥3/10 for numerical rating scale (14 · 5% misclassification). A valid instrument with a recommended analgesic intervention level has been developed to assess acute clinical pain in cats that should be readily applicable in practice.


Identifying Systemically Important Companies by Using the Credit Network of an Entire Nation.
The notions of systemic importance and systemic risk of financial institutions are closely related to the topology of financial liability networks. In this work, we reconstruct and analyze the financial liability network of an entire economy using data of 50,159 firms and banks. Our analysis contains 80.2% of the total liabilities of firms towards banks and all interbank liabilities in the Austrian banking system. The combination of firm-bank networks and interbank networks allows us to extend the concept of systemic risk to the real economy. In particular, the systemic importance of individual companies can be assessed, and for the first time, the financial ties between the financial and the real economy become explicitly visible. We find that firms contribute to systemic risk in similar ways as banks do. We identify a set of mid-sized companies that carry substantial systemic risk. Their default would affect up to 40% of the Austrian financial market. We find that all firms together create more systemic risk than the entire financial sector. In 2008, the total systemic risk of the Austrian interbank network amounted to only 29% of the total systemic risk of the entire financial network consisting of firms and banks. The work demonstrates that the notions of systemically important financial institutions (SIFIs) can be directly extended to firms.


Posterior suture annuloplasty for functional tricuspid regurgitation.
Functional tricuspid regurgitation (TR) is primarily caused by enlargement of the tricuspid annulus due to right ventricular dilation, frequently secondary to left sided valvular disease. Early techniques for the treatment of functional TR were introduced by Jerome Kay in 1965 and Norberto DeVega in 1972. Modified suture annuloplasty is a modification of DeVega's semicircular purse string technique, however, it is based on Kay's principle of obliteration of the posterior segment of the annulus only. While ring annuloplasty is the procedure of choice for severe functional TR, posterior suture annuloplasty is a technically simpler option for patients with moderate functional TR.


Contribution of alpha6 integrins to hematopoietic stem and progenitor cell homing to bone marrow and collaboration with alpha4 integrins.
The laminin receptor integrin alpha6 chain is ubiquitously expressed in human and mouse hematopoietic stem and progenitor cells. We have studied its role for homing of stem and progenitor cells to mouse hematopoietic tissues in vivo. A function-blocking anti-integrin alpha6 antibody significantly reduced progenitor cell homing to bone marrow (BM) of lethally irradiated mice, with a corresponding retention of progenitors in blood. Remarkably, the anti-integrin alpha6 antibody profoundly inhibited BM homing of long-term multilineage engrafting stem cells, studied by competitive repopulation assay and analysis of donor-derived lymphocytes and myeloid cells in blood 16 weeks after transplantation. A similar profound inhibition of long-term stem cell homing was obtained by using a function-blocking antibody against alpha4 integrin, studied in parallel. Furthermore, the anti-integrin alpha6 and alpha4 antibodies synergistically inhibited homing of short-term repopulating stem cells. Intravenous injection of anti-integrin alpha6 antibodies, in contrast to antibodies against alpha4 integrin, did not mobilize progenitors or enhance cytokine-induced mobilization by G-CSF. Our results provide the first evidence for a distinct functional role of integrin alpha6 receptor during hematopoietic stem and progenitor cell homing and collaboration of alpha6 integrin with alpha4 integrin receptors during homing of short-term stem cells.


Cognitive-behavioral therapy for generalized anxiety disorder with integrations from interpersonal and experiential therapies.
After providing background information on the definition and nature of generalized anxiety disorder, this article describes cognitive-behavioral therapy (CBT) methods that have been empirically supported in the treatment of this disorder. Subsequent to this description, relevant outcome literature is briefly reviewed, along with evidence that the addition of other techniques beyond traditional CBT methods may be necessary to maximize clinical outcome. A description is then provided of an integrated interpersonal/emotional processing therapy that the authors have recently added to their CBT protocol. CBT with and without this integrated treatment is currently being evaluated in an experimental trial.


Comparative IgE responses to extracts of five species of house dust mite, using western blotting.
IgE responses towards extracts of Dermatophagoides pteronyssinus, D. farinae, D. microceras, Euroglyphus maynei and Gymnoglyphus longior have been evaluated with sera from a mite sensitive population and the international reference pool of sera, NIBSC 82/528, using Western blotting. Using mite body and faecal extracts 21 of 29 mite protein bands responded to by sera were common to all five species of mite. All sera were unique with respect to proteins bound and species recognized. Mite proteins bound by more than 40% of sera included the Group II and III main allergens and protein bands 14 (MW 40.4 kD) and 21 (MW 27.8 kD), all of which were found in every mite species studied. The Group I allergen, found in all species, was bound by 29.4% of sera. Similar response profiles between mite species suggest that human specific IgE may bind predominantly to crossreactive determinants on mite allergens.


Activation by zinc of the human gastrin gene promoter in colon cancer cells in vitro and in vivo.
Over-expression of growth factors can contribute to the development and progression of cancer, and gastrins in particular have been implicated in accelerating the development of gastrointestinal cancers. Previously our group showed that hypoxia, cobalt chloride (a hypoxia mimetic) and zinc chloride could activate the expression of the gastrin gene in vitro. To characterise activation of the gastrin promoter by zinc ions further in vivo, TALEN technology was used to engineer a luciferase reporter construct into the endogenous human gastrin gene promoter in SW480 colon cancer cells. Gastrin promoter activity in the resultant Gast(luc) SW480 colon cancer cells was then measured by bioluminescence in cell culture and in tumour xenografts in SCID mice. Activation of intracellular signalling pathways was assessed by Western blotting. Activation of the gastrin promoter by zinc ions was concentration dependent in vitro and in vivo. Zinc ions significantly stimulated phosphorylation of ERK1/2 (MAPK pathway) but not of Akt (PI3K pathway). We conclude that the endogenous gastrin promoter is responsive to zinc ions, likely via activation of the MAPK pathway.


Impulsivity in Multiplayer Online Battle Arena Gamers: Preliminary Results on Experimental and Self-Report Measures.
Background and aims Multiplayer Online Battle Arena (MOBA) games have become the most popular type of video games played worldwide, superseding the playing of Massively Multiplayer Online Role-Playing Games and First-Person Shooter games. However, empirical studies focusing on the use and abuse of MOBA games are still very limited, particularly regarding impulsivity, which is an indicator of addictive states but has not yet been explored in MOBA games. In this context, the objective of the present study is to explore the associations between impulsivity and symptoms of addictive use of MOBA games in a sample of highly involved League of Legends (LoL, currently the most popular MOBA game) gamers. Methods Thirty-six LoL gamers were recruited and completed both experimental (Single Key Impulsivity Paradigm) and self-reported impulsivity assessments (s-UPPS-P Impulsive Behavior Scale, Barratt Impulsiveness Scale), in addition to an assessment of problematic video game use (Problematic Online Gaming Questionnaire). Results Results showed links between impulsivity-related constructs and signs of excessive MOBA game involvement. Findings indicated that impaired ability to postpone rewards in an experimental laboratory task was strongly related to problematic patterns of MOBA game involvement. Although less consistent, several associations were also found between self-reported impulsivity traits and signs of excessive MOBA game involvement. Conclusions Despite these results are preliminary and based upon a small (self-selected) sample, the present study highlights potential psychological factors related to the addictive use of MOBA games.


Safety of the BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting.
Preapproval trials showed that messenger RNA (mRNA)-based vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had a good safety profile, yet these trials were subject to size and patient-mix limitations. An evaluation of the safety of the BNT162b2 mRNA vaccine with respect to a broad range of potential adverse events is needed. We used data from the largest health care organization in Israel to evaluate the safety of the BNT162b2 mRNA vaccine. For each potential adverse event, in a population of persons with no previous diagnosis of that event, we individually matched vaccinated persons to unvaccinated persons according to sociodemographic and clinical variables. Risk ratios and risk differences at 42 days after vaccination were derived with the use of the Kaplan-Meier estimator. To place these results in context, we performed a similar analysis involving SARS-CoV-2-infected persons matched to uninfected persons. The same adverse events were studied in the vaccination and SARS-CoV-2 infection analyses. In the vaccination analysis, the vaccinated and control groups each included a mean of 884,828 persons. Vaccination was most strongly associated with an elevated risk of myocarditis (risk ratio, 3.24; 95% confidence interval [CI], 1.55 to 12.44; risk difference, 2.7 events per 100,000 persons; 95% CI, 1.0 to 4.6), lymphadenopathy (risk ratio, 2.43; 95% CI, 2.05 to 2.78; risk difference, 78.4 events per 100,000 persons; 95% CI, 64.1 to 89.3), appendicitis (risk ratio, 1.40; 95% CI, 1.02 to 2.01; risk difference, 5.0 events per 100,000 persons; 95% CI, 0.3 to 9.9), and herpes zoster infection (risk ratio, 1.43; 95% CI, 1.20 to 1.73; risk difference, 15.8 events per 100,000 persons; 95% CI, 8.2 to 24.2). SARS-CoV-2 infection was associated with a substantially increased risk of myocarditis (risk ratio, 18.28; 95% CI, 3.95 to 25.12; risk difference, 11.0 events per 100,000 persons; 95% CI, 5.6 to 15.8) and of additional serious adverse events, including pericarditis, arrhythmia, deep-vein thrombosis, pulmonary embolism, myocardial infarction, intracranial hemorrhage, and thrombocytopenia. In this study in a nationwide mass vaccination setting, the BNT162b2 vaccine was not associated with an elevated risk of most of the adverse events examined. The vaccine was associated with an excess risk of myocarditis (1 to 5 events per 100,000 persons). The risk of this potentially serious adverse event and of many other serious adverse events was substantially increased after SARS-CoV-2 infection. (Funded by the Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute.).


Neural mechanisms of perceptual decision-making and their link to neuropsychiatric symptoms in multiple sclerosis.
Decision-making (DM) capabilities are impaired in multiple sclerosis (MS). A variety of researchers hypothesized that this impairment is associated with reduced quality of life (QoL) and neuropsychiatric symptoms. Studies explicitly testing this hypothesis, however, are rare, provided inconclusive results, or evaluated only a limited selection of DM domains. Consequently, we conducted the first MS study on perceptual DM (e.g. deciding whether a car will fit into a parking lot based on a visual percept) to test this assumption. Specifically, we used an fMRI task that measured brain activity in 30 MS patients and 19 healthy controls (HCs) while the participants repeatedly decided whether objects referenced indirectly via their written object names would fit into a shoebox to investigate neural mechanisms of perceptual DM. The objects varied in size and thus decision difficulty. From these data, we determined voxel-wise brain activity parameters reflecting (i) decision difficulty and (ii) decision speed and related them to behavioral DM performance, QoL, mild to moderate depressive symptoms, and fatigue. Patients showed reduced DM performance. Activity reflecting decision difficulty in the middle temporal gyrus was negatively related to DM performance across MS patients and HCs; activity reflecting decision speed in MS patients was associated with depressive symptoms and fatigue in areas of the dorsal visual stream. The study shows that the perceptual DM capacity is reduced in MS. Moreover, the link between neural mechanisms of perceptual DM and neuropsychiatric symptoms suggests that an impairment in this domain is clinically relevant.


The complete DNA sequence of myxoma virus.
Myxomatosis in European rabbits is a severely debilitating disease characterized by profound systemic cellular immunosuppression and a high rate of mortality. The causative agent, myxoma virus, is a member of the poxvirus family and prototype of the Leporipoxvirus genus. As a major step toward defining the genetic strategies by which the virus circumvents host antiviral responses, the genomic DNA sequence of myxoma virus, strain Lausanne, was determined. A total of 171 open reading frames were assigned to cover the 161.8-kb genome, including two copies each of the 12 genes that map within the 11.5-kb terminal inverted repeats. Database searches revealed a central core of approximately 120 kb that encodes more than 100 genes that exhibit close relationships to the conserved genes of members of other poxvirus genera. Open reading frames with predicted signal sequences, localization motifs, or homology to known proteins with immunomodulatory or host-range functions were examined more extensively for predicted features such as hydrophobic regions, nucleic acid binding domains, ankyrin repeats, serpin signatures, lectin domains. and structural cysteine spacings. As a result, several novel, potentially immunomodulatory proteins have been identified, including a family with multiple ankyrin-repeat domains, an OX-2 like member of the neural cell adhesion molecule family, a third myxoma serpin, a putative chemokine receptor fragment, two natural killer receptor-like species, and a variety of species with domains closely related to diverse host immune regulatory proteins. Coupled with the genomic sequencing of the related leporipoxvirus Shope fibroma virus, this work affirms the existence of a conserved complement of poxvirus-specific core genes and expands the growing repertoire of virus genes that confer the unique capacity of each poxvirus family member to counter the immune responses of the infected host.


Selection of sustainable sanitation technologies for urban slums--a case of Bwaise III in Kampala, Uganda.
Provision of sanitation solutions in the world's urban slums is extremely challenging due to lack of money, space, access and sense of ownership. This paper presents a technology selection method that was used for the selection of appropriate sanitation solutions for urban slums. The method used in this paper takes into account sustainability criteria, including social acceptance, technological and physical applicability, economical and institutional aspects, and the need to protect and promote human health and the environment. The study was carried out in Bwaise III; a slum area in Kampala (Uganda). This was through administering of questionnaires and focus group discussions to obtain baseline data, developing a database to compare different sanitation options using technology selection criteria and then performing a multi-criteria analysis of the technology options. It was found that 15% of the population uses a public pit latrine; 75% uses a shared toilet; and 10% has private, non-shared sanitation facilities. Using the selection method, technologies such as Urine Diversion Dry Toilet (UDDT) and biogas latrines were identified to be potentially feasible sanitation solutions for Bwaise III. Sanitation challenges for further research are also presented.


Isotopic diversity as an unexplored mind-matter dimension.
The existence of several stable isotopes for most chemical elements is a well known and widely used fact of chemistry. Nevertheless, despite all the attention given to the stable and radioactive isotopes of individual elements, there have been very few, if any, attempts to look at isotopicity as a single phenomenon in its own right. Some possible links between isotopicity and various structural and functional levels of organization of the material and informational realm are put forward in this article, which presents isotopicity as an independent and informationally active level of spontaneous pattern formation and self-organization, giving a flexible link between morphogenetic potentialia and the microscopic operational level of physico-chemical processing. A dynamical parallel is drawn between Anderson localization induced by an isotopic disorder and holographic mental processing interpretable as self-focusing of mental patterns and spontaneous creativity.


Vitamin B12 Deficiency as a Cause of Neurotrophic Keratopathy.
Neurotrophic keratitis is a rare degenerative corneal disease caused by an impairment of trigeminal corneal innervation, leading to a decrease or absence of corneal sensation. Here, we present a case of neurotrophic keratopathy caused by B12 deficiency in a 34 years old man who had a progressive decrease in visual acuity and corneal involvement since 3 months before being referred to our ophthalmology clinic. Based on our clinical findings and with the diagnosis of B12 deficiency we started B12 treatment for the patient. After 3 weeks the patient showed a dramatic response with corneal sensation reversal, an increase of visual acuity, improved neurotrophic keratopathy and significantly improved neurological findings. To the best of our knowledge, there is no report regarding vitamin B12 deficiency induced keratopathy and this is the first report that describes this aspect of vitamin B12 deficiency.


Segmentation of gated Tl-SPECT images and computation of ejection fraction: a different approach.
We describe a set of image processing algorithms and mathematical models that can be advantageously used in schemes for the segmentation of thallium-201-single photon emission computed tomography (SPECT) images and for computation of left ventricular ejection fraction (EF). The system consists of two independent blocs for image segmentation and computation of function. The former is based on a multiresolution elliptical coordinate transformation and dynamic contour tracking. Computation of EF is formulated on the basis of both the endocardial and epicardial contours, and we compare this formulation with that using only the endocardial border for images with low signal-to-noise ratios. The accuracy of border detection was validated against manual border tracing on FDG-PET images, simulated Tl-201-SPECT images where the true underlying borders were known, and actual Tl-201-SPECT images. Finally, we compared EFs computed for FDG-PET, technetium-99m-SPECT and Tl-201-SPECT with those obtained from planar gated blood pool imaging. The automatically obtained results always were within the manual uncertainty range. Agreement between myocardial volumes from positron emission tomography and automatically obtained values from the simulated Tl-201-SPECT images was excellent (r = 0.95, n = 32). Agreement between EFs from planar gated blood pool imaging and the other image modalities was good (FDG-PET: y = 5.89 + 1.21x, r = 0.92, see = 6.24, n = 19, Tc-99m-SPECT: y = -3.86 + 1.06x, r = 0.88, see = 7.78, n = 9, Tl-201-SPECT: y = 17.8 + 0.81x, r = 0.77, see = 7.44, n = 26). For noisy input data the combined use of information from epicardial and endocardial contours gives more accurate EF values than the traditional formula on the basis of the endocardial contour only. Alternate approaches for segmentation and computation of function have been presented and validated. They might also be advantageously incorporated into other existing techniques.


Bayesian estimation of diagnostic accuracy of fecal culture and PCR-based tests for the detection of Salmonella enterica in California cull dairy cattle.
Epidemiological studies of low prevalence disease problems are often hindered by the high cost of diagnostic testing. The objective of this study was to evaluate PCR screening of both individual and pooled fecal samples from culled dairy cows for the invA gene of Salmonella followed by culture to determine if the sensitivity and specificity were comparable to the results from traditional culture methods applied to individual samples. Cows from six different dairies were sampled in all four seasons. A total of 240 individual cow fecal samples, 24 fecal pools and 24 pools of 24-hour tetrathionate enrichment broth were tested. Diagnostic sensitivity of PCR screening followed by culture of PCR positive or indeterminate samples (i.e PCR-CUL method) was lower than that of culture (CUL) when applied to individual fecal samples (94.8%, 99.5%), however the specificity was comparable (99.6% and 97.7% respectively). For pools of five fecal samples and pools of five, 24 h tetrathionate broth samples, the specificity of both tests were comparable (∼98%); however, their sensitivity was only comparable in pooled fecal samples (∼93%) but greater for culture compared to PCR-CUL in pooled broth samples (∼99% versus ∼93%). Compared to culture results from testing of individual fecal samples, testing pooled fecal samples by culture had a relative sensitivity of 74% and relative specificity of 96%, testing pooled fecal samples by PCR-CUL resulted in relative sensitivity of 90% and relative specificity of 96%. Testing of pooled 24-hour enrichment broth by PCR-CUL increased the relative sensitivity and specificity to 100%. PCR testing followed by culture of positive or indeterminate samples is a time saving alternative to traditional methods. In addition, pooling of samples may be a useful method for decreasing cost if study aims can accommodate a moderate loss of relative sensitivity.


The characterization of the exposure to immune mediated apoptosis and the regulation of immune cytotoxic activity in the environment of a neoplasm and in decidua.
Acquiring the immune-mediated apoptosis and the ability to regulate the cytotoxic immune response are the main phenomena playing fundamental roles in such situations as neoplasm survival and creation of immune tolerance during pregnancy. The aim of this study was to investigate these phenomena through the evaluation of metallothionein and RCAS1 proteins in neoplasm and its healthy environment (clear surgical margin), physiological conditions in placenta and its environment (decidua) and the comparison to non-neoplasmatic lesions originating from the environment (nasal polyps, endometriosis). We have shown that the growth of RCAS1 expression was simultaneous to the infiltration of activated immunological cells of tumor environment as well as decidua. The activity of immunological cells was in our study selectively suppressed. Metallothionein expression growth was also observed in healthy tumors stroma and in decidua probably in response to the growing cytotoxic activity and tumor spread. Alterations in RCAS1 and Metallothionein expression seem to be associated with local immune dysfunction in nasal polyps and endometriosis. In conclusion, the ability to compensate the growing cytotoxic immune response is physiologically observed in decidua, the lost of this ability in tumor environment might participate in the development of tumor spread.


Plasma noradrenaline concentration in hypertensive and normotensive 40-year-old individuals: relationship to plasma renin concentration.
1. Forty-year-old individuals with mild essential hypertension, identified during a survey of a population born in 1936, were investigated. Forty-year-old normotensive subjects, drawn from the same population, served as a control group. 2. Plasma noradrenaline concentration and plasma renin concentration at rest supine and after acute stimulation, as induced by frusemide intravenously and ambulation, did not differ from reference values in the 40-year-old normotensive controls. In the hypertensive group a close correlation (r = 0.77, P less than 0.001) was found between plasma noradrenaline and plasma renin concentration after acute stimulation. 3. Sympathetic nerve activity, as defined by measurements of plasma noradrenaline, is normal in mild essential hypertension. Discrepancies described in the literature are probably related to a lack of comparability between hypertensive and normotensive study populations.


The calcar screw in angular stable plate fixation of proximal humeral fractures--a case study.
With new minimally-invasive approaches for angular stable plate fixation of proximal humeral fractures, the need for the placement of oblique inferomedial screws ('calcar screw') has increasingly been discussed. The purpose of this study was to investigate the influence of calcar screws on secondary loss of reduction and on the occurrence of complications. Patients with a proximal humeral fracture who underwent angular stable plate fixation between 01/2007 and 07/2009 were included. On AP views of the shoulder, the difference in height between humeral head and the proximal end of the plate were determined postoperatively and at follow-up. Additionally, the occurrence of complications was documented. Patients with calcar screws were assigned to group C+, patients without to group C-. Follow-up was possible in 60 patients (C+ 6.7 ± 5.6 M/C- 5.0 ± 2.8 M). Humeral head necrosis occurred in 6 (C+, 15.4%) and 3 (C-, 14.3%) cases. Cut-out of the proximal screws was observed in 3 (C+, 7.7%) and 1 (C-, 4.8%) cases. In each group, 1 patient showed delayed union. Implant failure or lesions of the axillary nerve were not observed. In 44 patients, true AP and Neer views were available to measure the head-plate distance. There was a significant loss of reduction in group C- (2.56 ± 2.65 mm) compared to C+ (0.77 ± 1.44 mm; p = 0.01). The placement of calcar screws in the angular stable plate fixation of proximal humeral fractures is associated with less secondary loss of reduction by providing inferomedial support. An increased risk for complications could not be shown.


Overexpression of IgG2 in patients resembling IgG4-related disease with normal IgG4.
IgG4-Related Disease (IgG4-RD) results from tissue infiltration by IgG4-expressing plasma cells and lymphocytes, leading to fibrosis and organomegaly. Clinical presentation is remarkably variable according to organ involvement, and high IgG4 serum concentration, initially considered a diagnostic hallmark of IgG4-RD, tends to be forgone as an indispensable criterion for its diagnosis; it can indeed be absent in some patients, highlighting the diversity of presentation of this dysimmune condition. Nevertheless, elevation of IgG4 serum concentration in suggestive settings remains an argument in favour of IgG4-RD, and while other IgG subclasses can be elevated, this biological feature lacks any diagnostic value. We retrospectively studied 9 patients (5 females, 4 males, 31-81 years old) for whom a diagnosis of IgG4-RD had been considered, based on clinical, imaging or histological criteria, but appeared to display abnormally high serum IgG2 while IgG4 levels were normal. Increased serum IgG1 in one case and increased IgG3 in another one were also noticed. Immunohistochemical analyses of intracellular immunoglobulins could be performed on tissue lymph node biopsies from 2 patients, which demonstrated strong infiltration with IgG2-expressing plasma cells. Thus, overexpression of IgG2 subclass may highlight cases of dysimmune disorders resembling IgG4-RD, although the disease trigger might be different, notably infectious. We suggest measuring all serum IgG subclass levels in patients with features consistent with IgG4-RD.


Drinking Patterns Among Older Couples: Longitudinal Associations With Negative Marital Quality.
Research with younger couples indicates that alcohol use has powerful effects on marital quality, but less work has examined the effects of drinking among older couples. This study examined whether dyadic patterns of drinking status among older couples are associated with negative marital quality over time. Married participants (N = 4864) from the Health and Retirement Study reported on alcohol consumption (whether they drink alcohol and average amount consumed per week) and negative marital quality (e.g., criticism and demands) across two waves (Wave 1 2006/2008 and Wave 2 2010/2012). Concordant drinking couples reported decreased negative marital quality over time, and these links were significantly greater among wives. Wives who reported drinking alcohol reported decreased negative marital quality over time when husbands also reported drinking and increased negative marital quality over time when husbands reported not drinking. The present findings stress the importance of considering the drinking status rather than the amount of alcohol consumed of both members of the couple when attempting to understand drinking and marital quality among older couples. These findings are particularly salient given the increased drinking among baby boomers and the importance of marital quality for health among older couples.


Cost and occurrence of thrombocytopenia in patients receiving venous thromboembolism prophylaxis following major orthopaedic surgeries.
Many factors impact the choice of anticoagulant used for venous thromboembolism prophylaxis following orthopaedic surgery. Thrombocytopenia (TCP) is an important factor from both clinical and economic perspectives, warranting assessment between the available agents. Thus, a retrospective cohort analysis was conducted to: (1) report the occurrence of TCP in a treatment and no treatment group, (2) evaluate the impact of anticoagulant choice on TCP within the treatment group, and (3) assess the clinical and economic implications of TCP in the treatment group. Administrative claims from a hospital database were used to identify patients with hip replacement, knee replacement, or hip fracture surgery. The treatment group (n = 144,806) included patients receiving one of the following injectable anticoagulants post-operatively: dalteparin (n = 16,109); enoxaparin (n = 97,827); fondaparinux (n = 12,532); or unfractionated heparin (UFH) (n = 18,338). The no treatment group consisted of patients who did not receive one of the four injectable anticoagulants (n = 112,574) post-operatively. Outcomes were assessed for the hospitalization period plus 2 months post-discharge while controlling for relevant demographic and clinical characteristics. The occurrence of TCP was 1.0% in the no treatment group and 1.7% in the treatment group. Within the treatment group, patients who received dalteparin, enoxaparin, and UFH were significantly more likely to experience coded thrombocytopenia than those in the no treatment group. The risk of TCP among patients who received fondaparinux was not significantly different from the no treatment cohort (odds ratio [OR] = 1.15, 95% CI: 0.96-1.37, P = 0.13). Patients in the treatment group with coded TCP had 22% higher adjusted mean total healthcare costs (relative cost difference) compared to those without ($19,134 vs. $15,400, respectively, P < 0.0001), greater mean length of stay (LOS) (8.4 vs. 5.7, respectively), and a greater likelihood of experiencing a venous thromboembolic (VTE) event (6.1% vs. 2.4%, respectively). Patients treated with fondaparinux did not have a significant increase in the risk of TCP compared to patients not on prophylaxis. In contrast, the risk was increased in those treated with enoxaparin, dalteparin, and UFH compared to the patients not on prophylaxis. Patients in the treatment group with coded TCP experienced more thrombotic events, incurred greater per patient healthcare costs, and experienced longer LOS than patients without coded TCP. Therefore, the risk of TCP should be considered when evaluating the profile of injectable anticoagulants since TCP may have important clinical and economic implications.


A comprehensive model for the humoral coagulation network in humans.
Coagulation is an important process in hemostasis and comprises a complicated interaction of multiple enzymes and proteins. We have developed a mechanistic quantitative model of the coagulation network. The model accurately describes the time courses of coagulation factors following in vivo activation as well as in vitro blood coagulation tests of prothrombin time (PT, often reported as international normalized ratio (INR)) and activated partial thromboplastin time (aPTT). The model predicts the concentration-time and time-effect profiles of warfarin, heparins, and vitamin K in humans. The model can be applied to predict the time courses of coagulation kinetics in clinical situations (e.g., hemophilia) and for biomarker identification during drug development. The model developed in this study is the first quantitative description of the comprehensive coagulation network.


High altitude hypoxia and blood pressure dysregulation in adult chickens.
Although it is accepted that impaired placental perfusion in complicated pregnancy can slow fetal growth and programme an increased risk of cardiovascular dysfunction at adulthood, the relative contribution of reductions in fetal nutrition and in fetal oxygenation as the triggering stimulus remains unclear. By combining high altitude (HA) with the chick embryo model, we have previously isolated the direct effects of HA hypoxia on embryonic growth and cardiovascular development before hatching. This study isolated the effects of developmental hypoxia on cardiovascular function measured in vivo in conscious adult male and female chickens. Chick embryos were incubated, hatched and raised at sea level (SL, nine males and nine females) or incubated, hatched and raised at HA (seven males and seven females). At 6 months of age, vascular catheters were inserted under general anaesthesia. Five days later, basal blood gas status, basal cardiovascular function and cardiac baroreflex responses were investigated. HA chickens had significantly lower basal arterial PO2 and haemoglobin saturation, and significantly higher haematocrit than SL chickens, independent of the sex of the animal. HA chickens had significantly lower arterial blood pressure than SL chickens, independent of the sex of the animal. Although the gain of the arterial baroreflex was decreased in HA relative to SL male chickens, it was increased in HA relative to SL female chickens. We show that development at HA lowers basal arterial blood pressure and alters baroreflex sensitivity in a sex-dependent manner at adulthood.


Changes in RANKL and osteoprotegerin expression after chronic exposure to indoor air pollution as a result of cooking with biomass fuel.
The impact of indoor air pollution as a result of cooking with unprocessed biomass on membrane-bound and serum receptor activator of nuclear factor-kappa ligand 1 (RANKL), its soluble decoy receptor osteoprotegerin (OPG) and osteoclast precursor CD14(+) CD16(+) monocytes was investigated. Seventy-four pre-menopausal women from eastern India using biomass and 65 control women who cooked with cleaner liquefied petroleum gas were enrolled. PM10 and PM2.5 levels in their indoor air were measured with real-time aerosol monitors. The levels of membrane-bound RANKL on leukocytes and percentage CD14(+) CD16(+) monocytes in the subjects' blood were assayed by flow cytometry. Soluble RANKL and OPG in serum were measured by ELISA. The results showed that PM10 and PM2.5 levels were significantly higher in the indoor air of biomass-using households. Compared with the control women, the levels of CD4(+) and CD19(+) lymphocytes and circulating granulocytes with elevated levels of membrane-bound RANKL were higher in biomass users. The serum levels of RANKL were increased by 41% whereas serum OPG was reduced by 22% among biomass users. The absolute number of CD14(+) CD16(+) monocytes was significantly increased in biomass users than the control women. After controlling for potential confounders, PM10 and PM2.5 levels were found to be positively associated with leukocyte and serum RANKL and CD14(+) CD16(+) monocyte levels, but negatively with serum OPG. From these results, we can conclude that chronic exposure to biomass smoke increased membrane-bound and soluble RANKL and circulating osteoclast precursors but decreased OPG, suggesting an increased risk of bone resorption and consequent osteoporosis in biomass-exposed women of a child-bearing age. Copyright © 2015 John Wiley & Sons, Ltd.


Critical review of health effects of soyabean phyto-oestrogens in post-menopausal women.
A consensus view of soyabean phyto-oestrogens in clinical interventions in post-menopausal women is presented that is based on data from the EU-funded project Phytohealth. The phyto-oestrogens, primarily genistein and daidzein, were given as soyabean-protein isolates, whole-soyabean foods or extracts, supplements or pure compounds. A comprehensive literature search was conducted with well-defined inclusion or exclusion criteria. For areas for which substantial research exists only placebo-controlled double-blind randomised controlled trials (RCT) conducted on healthy post-menopausal women were included. For emerging areas all available human studies in post-menopausal women were reviewed. In order to make cross comparisons between studies the doses of isoflavones were calculated as aglycone equivalents. There is a suggestion, but no conclusive evidence, that isoflavones from the sources studied so far have a beneficial effect on bone health. The consumption of whole-soyabean foods and soyabean-protein isolates has some beneficial effects on lipid markers of cardiovascular risk. The consumption of isolated isoflavones does not affect blood lipid levels or blood pressure, although it may improve endothelial function. For menopausal symptoms there is currently limited evidence that soyabean-protein isolates, soyabean foods or red-clover (Trifolium pratense L.) extract are effective but soyabean isoflavone extracts may be effective in reducing hot flushes. There are too few RCT studies to reach conclusions on the effects of isoflavones on breast cancer, colon cancer, diabetes or cognitive function. The health benefits of soyabean phyto-oestrogens in healthy post-menopausal women are subtle and even some well-designed studies do not show protective effects. Future studies should focus on high-risk post-menopausal women, especially in the areas of diabetes, CVD, breast cancer and bone health.


Cell-Based Systems Biology Analysis of Human AS03-Adjuvanted H5N1 Avian Influenza Vaccine Responses: A Phase I Randomized Controlled Trial.
Vaccine development for influenza A/H5N1 is an important public health priority, but H5N1 vaccines are less immunogenic than seasonal influenza vaccines. Adjuvant System 03 (AS03) markedly enhances immune responses to H5N1 vaccine antigens, but the underlying molecular mechanisms are incompletely understood. We compared the safety (primary endpoint), immunogenicity (secondary), gene expression (tertiary) and cytokine responses (exploratory) between AS03-adjuvanted and unadjuvanted inactivated split-virus H5N1 influenza vaccines. In a double-blinded clinical trial, we randomized twenty adults aged 18-49 to receive two doses of either AS03-adjuvanted (n = 10) or unadjuvanted (n = 10) H5N1 vaccine 28 days apart. We used a systems biology approach to characterize and correlate changes in serum cytokines, antibody titers, and gene expression levels in six immune cell types at 1, 3, 7, and 28 days after the first vaccination. Both vaccines were well-tolerated. Nine of 10 subjects in the adjuvanted group and 0/10 in the unadjuvanted group exhibited seroprotection (hemagglutination inhibition antibody titer > 1:40) at day 56. Within 24 hours of AS03-adjuvanted vaccination, increased serum levels of IL-6 and IP-10 were noted. Interferon signaling and antigen processing and presentation-related gene responses were induced in dendritic cells, monocytes, and neutrophils. Upregulation of MHC class II antigen presentation-related genes was seen in neutrophils. Three days after AS03-adjuvanted vaccine, upregulation of genes involved in cell cycle and division was detected in NK cells and correlated with serum levels of IP-10. Early upregulation of interferon signaling-related genes was also found to predict seroprotection 56 days after first vaccination. Using this cell-based systems approach, novel mechanisms of action for AS03-adjuvanted pandemic influenza vaccination were observed. ClinicalTrials.gov NCT01573312.


Mobile phone affects cerebral blood flow in humans.
Mobile phones create a radio-frequency electromagnetic field (EMF) around them when in use, the effects of which on brain physiology in humans are not well known. We studied the effects of a commercial mobile phone on regional cerebral blood flow (rCBF) in healthy humans using positron emission tomography (PET) imaging. Positron emission tomography data was acquired using a double-blind, counterbalanced study design with 12 male subjects performing a computer-controlled verbal working memory task (letter 1-back). Explorative and objective voxel-based statistical analysis revealed that a mobile phone in operation induces a local decrease in rCBF beneath the antenna in the inferior temporal cortex and an increase more distantly in the prefrontal cortex. Our results provide the first evidence, suggesting that the EMF emitted by a commercial mobile phone affects rCBF in humans. These results are consistent with the postulation that EMF induces changes in neuronal activity.


Assessing reproductive isolation in highly diverse communities of the lichen-forming fungal genus peltigera.
The lichen-forming fungal genus Peltigera includes a number of species that are extremely widespread, both geographically and ecologically. However, morphological variability has lead to doubts about the distinctness of some species, and it has been suggested that hybridization is common in nature. We examined species boundaries by looking for evidence of hybridization and gene flow among seven described species collected at five sites in British Columbia, Canada. We found no evidence of gene flow or hybridization between described species, with fixed differences between species for two or more of the three loci examined. Reproductive isolation did not reflect a solely clonal mode of reproduction as there was evidence of ongoing gene flow within species. In addition, we found five undescribed species that were reproductively isolated, although there was evidence of ongoing or historical gene flow between two of the new species. These results indicate that the genus Peltigera is more diverse in western North America than originally perceived, and that morphological variability is due largely to the presence of undescribed species rather than hybridization or intraspecific variation.


Clinical outcomes with canagliflozin according to baseline body mass index: results from post hoc analyses of the CANVAS Program.
Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce several cardiovascular risk factors, including plasma glucose, blood pressure, albuminuria and body weight. Long-term treatment lowers risks of cardiovascular and renal events. The objective of this post hoc analysis was to determine the effects of canagliflozin treatment versus placebo on clinical outcomes in relation to body mass index (BMI). The CANVAS Program randomized 10 142 participants with type 2 diabetes to canagliflozin or placebo. These analyses tested the consistency of canagliflozin treatment effects across BMI levels for cardiovascular, renal, safety and body weight outcomes in three groups defined by baseline BMI: <25, 25-<30 and ≥30 kg/m2 . In total, 10 128 participants with baseline BMI measurements were included. There were 966 participants with BMI <25 kg/m2 , 3153 with BMI 25-<30 kg/m2 and 6009 with BMI ≥30 kg/m2 . Mean percent body weight reduction with canagliflozin compared with placebo was greater at 12 months [-2.77% (95% confidence interval (CI): -2.95, -2.59)] than at 3 months [-1.72% (95% CI: -1.83, -1.62)]. The hazard ratios (HRs) for canagliflozin compared with placebo control for the composite outcome of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke were 1.03 (95% CI: 0.66, 1.59) in participants with BMI <25 kg/m2 , 0.97 (0.76, 1.23) with BMI 25-<30 kg/m2 and 0.79 (0.67, 0.93) with BMI ≥30 kg/m2 (P for heterogeneity = 0.55). The effects of canagliflozin on each component of the composite were also similar across BMI subgroups, as were effects on heart failure and renal outcomes (P for heterogeneity ≥0.19). The effects on safety outcomes were also broadly similar. Canagliflozin improved cardiovascular and renal outcomes consistently across patients with a broad range of BMI levels.


Expression and functional phenotype of mouse ERG K+ channels in the inner ear: potential role in K+ regulation in the inner ear.
An outcome of the intricate K+ regulation in the cochlear duct is the endocochlear potential (EP), approximately 80 mV, the "battery" that runs hair-cell transduction; however, the detailed molecular mechanisms for the generation of the EP remain unclear. We provide strong evidence indicating that the intermediate cells (ICs) of the stria vascularis (StV) express outward K+ current that rectifies inwardly at positive potentials. The channel belongs to the ether-a-go-go-related gene (erg) family of K+ channels. We cloned an ERG1a channel in the mouse inner ear (MERG1a). The cellular distribution of MERG1a in the cochlea displayed the highest levels of immunoreactivity in the ICs and modest reactivity in the marginal cells as well as in several extrastrial cells (e.g., hair cells). Functional expression of the StV-specific MERG1a channel reveals a current that activates at relatively negative potentials (approximately-50 mV) and shows rapid inactivation reflected as inward rectification at depolarized potentials. The current was sensitive to the methanesulfonanilide drug E-4031 (IC50, approximately 165 nM) and the recombinant peptide rBeKm-1 (IC50, approximately 16 nM), and the single-channel conductance in symmetrical K+ was approximately 14 pS. The site of expression of MERG1a and its functional phenotype (e.g., modulation of the current by external K+ make it one of the most likely candidates for establishing the high throughput of K+ ions across ICs to generate EP. In addition, the property of the channel that produces marked K+ extrusion in increased external K+ may be important in shaping the dynamics of K+ cycling in the inner ear.


Molecular functions of the histone acetyltransferase chaperone complex Rtt109-Vps75.
Histone acetylation and nucleosome remodeling regulate DNA damage repair, replication and transcription. Rtt109, a recently discovered histone acetyltransferase (HAT) from Saccharomyces cerevisiae, functions with the histone chaperone Asf1 to acetylate lysine K56 on histone H3 (H3K56), a modification associated with newly synthesized histones. In vitro analysis of Rtt109 revealed that Vps75, a Nap1 family histone chaperone, could also stimulate Rtt109-dependent acetylation of H3K56. However, the molecular function of the Rtt109-Vps75 complex remains elusive. Here we have probed the molecular functions of Vps75 and the Rtt109-Vps75 complex through biochemical, structural and genetic means. We find that Vps75 stimulates the kcat of histone acetylation by approximately 100-fold relative to Rtt109 alone and enhances acetylation of K9 in the H3 histone tail. Consistent with the in vitro evidence, cells lacking Vps75 showed a substantial reduction (60%) in H3K9 acetylation during S phase. X-ray structural, biochemical and genetic analyses of Vps75 indicate a unique, structurally dynamic Nap1-like fold that suggests a potential mechanism of Vps75-dependent activation of Rttl09. Together, these data provide evidence for a multifunctional HAT-chaperone complex that acetylates histone H3 and deposits H3-H4 onto DNA, linking histone modification and nucleosome assembly.


Spider's super-glue: thread anchors are composite adhesives with synergistic hierarchical organization.
Silk is a key innovation in spiders, fascinating both biologists and material scientists. However, to fulfil their biological function silken threads must be strongly fastened to substrates or other threads. The majority of modern spiders produce a unique and rather unexplored bio-adhesive: the two-compound pyriform secretion, which is spun into elaborate patterns (so called attachment discs) and used to anchor silken threads to substrates. Strong adhesion is achieved on a high variety of surfaces with a minimum of material consumption. Pyriform threads polymerize under ambient conditions, become functional within less than a second and can remain stable for years. They are biodegradable, biocompatible and highly versatile - the adhesion and the overall toughness of the attachment disc can be controlled by spinneret movements on a macroscopic level (ref. 1: V. Sahni et al., Nat. Commun., 2012, 3, 1106, DOI: 10.1038/ncomms2099). We found that the pyriform thread is a silk fibre that is coated with glue-like cement consisting of aligned nanofibrils, lipid enclosures and a dense, isotropic boundary layer. The threads are spun in a meshwork pattern that promotes stress distribution and crack arresting. Our results demonstrate, that hierarchical organization and fibre embedding may explain the high adhesive strength and flaw tolerance of a structure made by the same, rather simple type of silk glands.


Individual differences in the forced swimming test and the effect of environmental enrichment: searching for an interaction.
Animals with low and high immobility in the forced swimming test (FST) differ in a number of neurobehavioral factors. A growing body of evidence suggests that the exposure to enriched environments mediates a number of changes in the brain. Therefore, we studied if animals' individuality can somehow modulate the response to environmental stimuli. Male rats were classified according to their immobility time scores in the FST test session as animals with low, medium or high immobility. Then, rats from groups with low and high immobility were randomly distributed in two groups to be reared in different housing conditions (i.e., enriched and standard conditions) during 8weeks. Animals were subjected to the open field test (OFT) before and 6weeks after the start of housing protocol. Rats with high immobility in the FST also showed high ambulation and high rearing time in the first OFT. Such findings were not observed in the second OFT. Conversely, an effect of environmental enrichment was found in the second OFT where enriched animals showed lower ambulation and higher grooming time than the standard control group. Rats were sacrificed after the housing protocol and neurochemical content and/or gene expression were studied in three different brain regions: the prefrontal cortex, the hippocampus and the nucleus accumbens. Rats with low immobility showed significantly higher accumbal 5-HT levels than animals with high immobility, whereas no neurochemical differences were observed between enriched and standard animals. Regarding expression data, however, an effect of enrichment on accumbal corticotropin-releasing factor (CRF) and its receptor 1 (CRFR1) levels was observed, and such effect depended on immobility levels. Thus, our results not only allowed us to identify a number of differences between animals with low and high immobility or animals housed in standard and enriched conditions, but also suggested that animals' individuality modulated in some way the response to environmental stimuli.


Novel neutrophil-derived proteins in bronchoalveolar lavage fluid indicate an exaggerated inflammatory response in pediatric cystic fibrosis patients.
Airway inflammation in cystic fibrosis (CF) is exaggerated and characterized by neutrophil-mediated tissue destruction, but its genesis and mechanisms remain poorly understood. To further define the pulmonary inflammatory response, we conducted a proteome-based screen of bronchoalveolar lavage fluid (BALF) collected from young children with and without CF experiencing endobronchial infection. We collected BALF samples from 45 children younger than 5 years and grouped them according to the presence of respiratory pathogens: > or = 1 x 10(5) colony-forming units (CFU)/mL BALF (18 and 12 samples with and without CF, respectively) and <1 x 10(5) CFU/mL (23 and 15 samples). BALF proteins were analyzed with SELDI-TOF mass spectrometry (MS) and H4 ProteinChips. Proteins were identified and characterized using trypsin digestion, tandem MS, Fourier transform ion cyclotron resonance MS, immunoblotting, and ELISA. The SELDI-TOF MS BALF profiles contained 53 unique, reliably detected proteins. Peak intensities of 24 proteins differed significantly between the CF and non-CF samples. They included the neutrophil proteins, alpha-defensin 1 and 2, S100A8, S100A9, and S100A12, as well as novel forms of S100A8 and S100A12 with equivalent C-terminal deletions. Peak intensities of these neutrophil proteins and immunoreactive concentrations of selected examples were significantly higher in CF than non-CF samples. Small neutrophil-derived BALF proteins, including novel C-terminal truncated forms of S100A proteins, are easily detected with SELDI-TOF MS. Concentrations of these molecules are abnormally high in early CF lung disease. The data provide new insights into CF lung disease and identify novel proteins strongly associated with CF airway inflammation.


Identifying Stable Reference Genes for qRT-PCR Normalisation in Gene Expression Studies of Narrow-Leafed Lupin (Lupinus angustifolius L.).
Quantitative Reverse Transcription PCR (qRT-PCR) is currently one of the most popular, high-throughput and sensitive technologies available for quantifying gene expression. Its accurate application depends heavily upon normalisation of gene-of-interest data with reference genes that are uniformly expressed under experimental conditions. The aim of this study was to provide the first validation of reference genes for Lupinus angustifolius (narrow-leafed lupin, a significant grain legume crop) using a selection of seven genes previously trialed as reference genes for the model legume, Medicago truncatula. In a preliminary evaluation, the seven candidate reference genes were assessed on the basis of primer specificity for their respective targeted region, PCR amplification efficiency, and ability to discriminate between cDNA and gDNA. Following this assessment, expression of the three most promising candidates [Ubiquitin C (UBC), Helicase (HEL), and Polypyrimidine tract-binding protein (PTB)] was evaluated using the NormFinder and RefFinder statistical algorithms in two narrow-leafed lupin lines, both with and without vernalisation treatment, and across seven organ types (cotyledons, stem, leaves, shoot apical meristem, flowers, pods and roots) encompassing three developmental stages. UBC was consistently identified as the most stable candidate and has sufficiently uniform expression that it may be used as a sole reference gene under the experimental conditions tested here. However, as organ type and developmental stage were associated with greater variability in relative expression, it is recommended using UBC and HEL as a pair to achieve optimal normalisation. These results highlight the importance of rigorously assessing candidate reference genes for each species across a diverse range of organs and developmental stages. With emerging technologies, such as RNAseq, and the completion of valuable transcriptome data sets, it is possible that other potentially more suitable reference genes will be identified for this species in future.


The N-terminal domain of an archaeal multidrug and toxin extrusion (MATE) transporter mediates proton coupling required for prokaryotic drug resistance.
As a contributor to multidrug resistance, the family of multidrug and toxin extrusion (MATE) transporters couples the efflux of chemically dissimilar compounds to electrochemical ion gradients. Although divergent transport mechanisms have been proposed for these transporters, previous structural and functional analyses of members of the MATE subfamily DinF suggest that the N-terminal domain (NTD) supports substrate and ion binding. In this report, we investigated the relationship of ligand binding within the NTD to the drug resistance mechanism of the H+-dependent MATE from the hyperthermophilic archaeon Pyrococcus furiosus (PfMATE). To facilitate this study, we developed a cell growth assay in Escherichia coli to characterize the resistance conferred by PfMATE to toxic concentrations of the antimicrobial compound rhodamine 6G. Expression of WT PfMATE promoted cell growth in the presence of drug, but amino acid substitutions of conserved NTD residues compromised drug resistance. Steady-state binding analysis with purified PfMATE indicated that substrate affinity was unperturbed in these NTD variants. However, exploiting Trp fluorescence as an intrinsic reporter of conformational changes, we found that these variants impaired formation of a unique H+-stabilized structural intermediate. These results imply that disruption of H+ coupling is the origin of compromised toxin resistance in PfMATE variants. These findings support a model mechanism wherein the NTD mediates allosteric coupling to ion gradients through conformational changes to drive substrate transport in PfMATE. Furthermore, the results provide evidence for diverging transport mechanisms within a prokaryotic MATE subfamily.


Frontolimbic activity in a frustrating task: covariation between patterns of coping and individual differences in externalizing and internalizing symptoms.
Many problem behaviors in youth have been attributed to maladaptive self-regulation in response to frustration. Frontolimbic networks that promote flexible as well as over- and undercontrolled regulation could provide evidence linking cortical mechanisms of self-regulation to the development of internalizing or externalizing symptomology. Specifically, ineffective dorsally mediated inhibitory control may be associated with rule-breaking and substance use behaviors, whereas overengagement of ventral limbic systems responsible for self-monitoring of errors may increase risk of developing anxious and depressed symptomology. In this study, a sample of 9- to 13-year-old children were presented with an emotional go/no-go task. Event-related potentials were used to identify differences in cortical mechanisms related to inhibitory control (indexed with the stimulus-locked medial frontal negativity) and self-monitoring (indexed with the error-related negativity). These measurements were then related to externalizing and internalizing behaviors. As predicted, externalizing problems were associated with smaller medial frontal negativity amplitudes, which indicate undercontrolled self-regulation and poor dorsal mediation of actions. Internalizing symptoms were related to larger error-related negativity amplitudes, demonstrating overregulation and overengagement of ventral limbic systems. These findings suggest that the use of event-related potential methodology with paradigms that elicit cognition-emotion can provide insight into the neural mechanisms of regulatory deficits that result in problem behaviors in youth.


Sorting pain out of salience: assessment of pain facial expressions in the human fetus.
The question of whether the human fetus experiences pain has received substantial attention in recent times. With the advent of high-definition 4-dimensional ultrasound (4D-US), it is possible to record fetal body and facial expressions. To determine whether human fetuses demonstrate discriminative acute behavioral responses to nociceptive input. This cross-sectional study included 5 fetuses with diaphragmatic hernia with indication of intrauterine surgery (fetoscopic endoluminal tracheal occlusion) and 8 healthy fetuses, who were scanned with 4D-US in 1 of 3 conditions: (1) acute pain group: Fetuses undergoing intrauterine surgery were assessed in the preoperative period during the anesthetic injection into the thigh; (2) control group at rest: Facial expressions at rest were recorded during scheduled ultrasound examinations; and (3) control group acoustic startle: Fetal facial expressions were recorded during acoustic stimulus (500-4000 Hz; 60-115 dB). Raters blinded to the fetuses' groups scored 65 pictures of fetal facial expressions based on the presence of 12 items (facial movements). Analyses of redundancy and usefulness excluded 5 items for being of low discrimination capacity (P>0.2). The final version of the pain assessment tool consisted of a total of 7 items: brow lowering/eyes squeezed shut/deepening of the nasolabial furrow/open lips/horizontal mouth stretch/vertical mouth stretch/neck deflection. Odd ratios for a facial expression to be detected in acute pain compared with control conditions ranged from 11 (neck deflection) to 1,400 (horizontal mouth stretch). Using the seven-item final tool, we showed that 5 is the cutoff value discriminating pain from nonpainful startle and rest. This study inaugurates the possibility to study pain responses during the intrauterine life, which may have implications for the postoperative management of pain after intrauterine surgical interventions.


Good cop, bad cop: federal prosecution of state-legalized medical marijuana use after United States v. Lopez.
The Supreme Court's recent decisions in United States v. Lopez and United States v. Morrison articulate a vision of federalism under which Congress's regulatory authority under the Commerce Clause is severely limited in favor of returning traditional areas of state concern, particularly criminal law enforcement, to local or state control. The Court's decisions in these cases coincide with ballot initiatives legalizing the medical use of marijuana garnering a majority of the vote in California, Arizona, Alaska, Colorado, Nevada, Oregon, Washington, Maine, and Washington D.C. Those who use marijuana for medical purposes under sanction of state law, however, still face the threat of federal prosecution under the Controlled Substances Act. Medical marijuana proponents have traditionally, and unsuccessfully, contested federal prosecution using individual rights arguments under theories of equal protection or substantive due process. This Comment argues that after Lopez and Morrison, the federal government's authority to regulate intrastate use of marijuana for medicinal purposes is not the foregone conclusion it once was. The author suggests that proponents of medical marijuana use should invoke the federalism arguments of Lopez and Morrison and argue for state legislative independence from the federal government on this issue.


Effect of frequent hemodialysis on residual kidney function.
Frequent hemodialysis can alter volume status, blood pressure, and the concentration of osmotically active solutes, each of which might affect residual kidney function (RKF). In the Frequent Hemodialysis Network Daily and Nocturnal Trials, we examined the effects of assignment to six compared with three-times-per-week hemodialysis on follow-up RKF. In both trials, baseline RKF was inversely correlated with number of years since onset of ESRD. In the Nocturnal Trial, 63 participants had non-zero RKF at baseline (mean urine volume 0.76 liter/day, urea clearance 2.3 ml/min, and creatinine clearance 4.7 ml/min). In those assigned to frequent nocturnal dialysis, these indices were all significantly lower at month 4 and were mostly so at month 12 compared with controls. In the frequent dialysis group, urine volume had declined to zero in 52% and 67% of patients at months 4 and 12, respectively, compared with 18% and 36% in controls. In the Daily Trial, 83 patients had non-zero RKF at baseline (mean urine volume 0.43 liter/day, urea clearance 1.2 ml/min, and creatinine clearance 2.7 ml/min). Here, treatment assignment did not significantly influence follow-up levels of the measured indices, although the range in baseline RKF was narrower, potentially limiting power to detect differences. Thus, frequent nocturnal hemodialysis appears to promote a more rapid loss of RKF, the mechanism of which remains to be determined. Whether RKF also declines with frequent daily treatment could not be determined.


Scene-based nonuniformity correction and enhancement: pixel statistics and subpixel motion.
We propose a framework for scene-based nonuniformity correction (NUC) and nonuniformity correction and enhancement (NUCE) that is required for focal-plane array-like sensors to obtain clean and enhanced-quality images. The core of the proposed framework is a novel registration-based nonuniformity correction super-resolution (NUCSR) method that is bootstrapped by statistical scene-based NUC methods. Based on a comprehensive imaging model and an accurate parametric motion estimation, we are able to remove severe/structured nonuniformity and in the presence of subpixel motion to simultaneously improve image resolution. One important feature of our NUCSR method is the adoption of a parametric motion model that allows us to (1) handle many practical scenarios where parametric motions are present and (2) carry out perfect super-resolution in principle by exploring available subpixel motions. Experiments with real data demonstrate the efficiency of the proposed NUCE framework and the effectiveness of the NUCSR method.


Comparison of cytotoxicity and genotoxicity of 4-hydroxytamoxifen in combination with Tualang honey in MCF-7 and MCF-10A cells.
The Malaysian Tualang honey (TH) is not only cytotoxic to human breast cancer cell lines but it has recently been reported to promote the anticancer activity induced by tamoxifen in MCF-7 and MDA-MB-231 cells suggesting its potential as an adjuvant for the chemotherapeutic agent. However, tamoxifen produces adverse effects that could be due to its ability to induce cellular DNA damage. Therefore, the study is undertaken to determine the possible modulation of the activity of 4-hydroxytamoxifen (OHT), an active metabolite of tamoxifen, by TH in non-cancerous epithelial cell line, MCF-10A, in comparison with MCF-7 cells. MCF-7 and MCF-10A cells were treated with TH, OHT or the combination of both and cytotoxicity and antiproliferative activity were determined using LDH and MTT assays, respectively. The effect on cellular DNA integrity was analysed by comet assay and the expression of DNA repair enzymes was determined by Western blotting. OHT exposure was cytotoxic to both cell lines whereas TH was cytotoxic to MCF-7 cells only. TH also significantly decreased the cytotoxic effect of OHT in MCF-10A but not in MCF-7 cells. TH induced proliferation of MCF10A cells but OHT caused growth inhibition that was abrogated by the concomitant treatment with TH. While TH enhanced the OHT-induced DNA damage in the cancer cells, it dampened the genotoxic effect of OHT in the non-cancerous cells. This was supported by the increased expression of DNA repair proteins, Ku70 and Ku80, in MCF-10A cells by TH. The findings indicate that TH could afford protection of non-cancerous cells from the toxic effects of tamoxifen by increasing the efficiency of DNA repair mechanism in these cells.


Oxidised metabolites of the omega-6 fatty acid linoleic acid activate dFOXO.
Obesity-induced inflammation, or meta-inflammation, plays key roles in metabolic syndrome and is a significant risk factor in diabetes and cardiovascular disease. To investigate causal links between obesity, meta-inflammation, and insulin signaling we established a Drosophila model to determine how elevated dietary fat and changes in the levels and balance of saturated fatty acids (SFAs) and polyunsaturated fatty acids (PUFAs) influence inflammation. We observe negligible effect of saturated fatty acid on inflammation but marked enhancement or suppression by omega-6 and omega-3 PUFAs, respectively. Using combined lipidomic and genetic analysis, we show omega-6 PUFA enhances meta-inflammation by producing linoleic acid-derived lipid mediator 9-hydroxy-octadecadienoic acid (9-HODE). Transcriptome analysis reveals 9-HODE functions by regulating FOXO family transcription factors. We show 9-HODE activates JNK, triggering FOXO nuclear localisation and chromatin binding. FOXO TFs are important transducers of the insulin signaling pathway that are normally down-regulated by insulin. By activating FOXO, 9-HODE could antagonise insulin signaling providing a molecular conduit linking changes in dietary fatty acid balance, meta-inflammation, and insulin resistance.


Machine Learning for the Discovery, Design, and Engineering of Materials.
Machine learning (ML) has become a part of the fabric of high-throughput screening and computational discovery of materials. Despite its increasingly central role, challenges remain in fully realizing the promise of ML. This is especially true for the practical acceleration of the engineering of robust materials and the development of design strategies that surpass trial and error or high-throughput screening alone. Depending on the quantity being predicted and the experimental data available, ML can either outperform physics-based models, be used to accelerate such models, or be integrated with them to improve their performance. We cover recent advances in algorithms and in their application that are starting to make inroads toward (a) the discovery of new materials through large-scale enumerative screening, (b) the design of materials through identification of rules and principles that govern materials properties, and (c) the engineering of practical materials by satisfying multiple objectives. We conclude with opportunities for further advancement to realize ML as a widespread tool for practical computational materials design.


Evaluation of Availability of Survey Data About Cannabis Use.
In response to increasing public support for cannabis legalization, understanding associations of state and federal policy changes related to cannabis legalization with patterns of cannabis use is important. A challenge for public health monitoring and research is significant variation in data availability related to cannabis use behaviors and perceptions across and within states and over time, including the availability of prelegalization vs postlegalization data. To review data available on cannabis use and related behaviors over time in Massachusetts and the US. This case series examined state and national surveys on public health and related behaviors and outcomes to review availability of cannabis-related data for Massachusetts for 8 key indicators over time. Additionally, the Behavioral Risk Factor Surveillance System (BRFSS) and Youth Risk Behavior Surveillance System for all states were reviewed. The analysis was conducted between February 1, 2019, and March 18, 2020. Surveys that enable state-level estimation of cannabis use and related behaviors. Eight key indicators related to cannabis use behaviors and perceptions: lifetime cannabis use, age of initiation, frequency of use, location of use, method of use, source of cannabis, perceptions of cannabis, and reason for use (ie, medical vs nonmedical). There were 7 surveys that monitored cannabis use and related behaviors in Massachusetts for adolescents and adults. No surveys monitored all 8 indicators of interest, and availability over time was limited. In the most recent BRFSS, 24 states asked cannabis-related questions, meaning BRFSS data on cannabis use was lacking for more than half of the US adult population. In the Youth Risk Behavior Surveillance System, 36 states asked standard cannabis questions; most other states had at least 1 question related to cannabis use and frequency. These findings of limitations of existing surveys, and particularly the lack of national questions in the BRFSS and Youth Risk Behavior Surveillance System, suggest that available data have substantial limitations for monitoring cannabis use. As cannabis policy changes continue, there is a need to remain focused on the availability of high-quality data sources that allow for critical public health research.


Id4 promotes the elimination of the pro-activation factor Ascl1 to maintain quiescence of adult hippocampal stem cells.
Quiescence is essential for the long-term maintenance of adult stem cells but how stem cells maintain quiescence is poorly understood. Here, we show that neural stem cells (NSCs) in the adult mouse hippocampus actively transcribe the pro-activation factor Ascl1 regardless of their activated or quiescent states. We found that the inhibitor of DNA binding protein Id4 is enriched in quiescent NSCs and that elimination of Id4 results in abnormal accumulation of Ascl1 protein and premature stem cell activation. Accordingly, Id4 and other Id proteins promote elimination of Ascl1 protein in NSC cultures. Id4 sequesters Ascl1 heterodimerization partner E47, promoting Ascl1 protein degradation and stem cell quiescence. Our results highlight the importance of non-transcriptional mechanisms for the maintenance of NSC quiescence and reveal a role for Id4 as a quiescence-inducing factor, in contrast with its role of promoting the proliferation of embryonic neural progenitors.


Necrotizing fasciitis from invasive Phycomycetes.
Invasive phycomycotic fungal infections are life-threatening complications in patients with impaired immune response. A successful outcome usually depends on early aggressive treatment. Hyperbaric oxygen (HBO) therapy has been suggested as adjuvant therapy based on theoretical considerations and in vitro evidence of fungal growth retardation. A standard gas gangrene HBO protocol was used to treat a progressive necrotizing polymicrobial soft-tissue infection of the lower extremity in a patient with normal host defenses. Progression of the fungal infection was stopped only after radical surgical debridement. This Phycomycetes (Apophycomyces elegans) has not been previously reported as a pathogen in man.


Association Between Menopausal Hormone Therapy and Risk for Parkinson's Disease.
The relationship between menopausal hormone therapy (MHT) and risk of Parkinson's disease (PD) remains controversial. This nationwide population-based cohort study investigated the association between MHT and PD development. Data from the National Health Insurance System of South Korea from 2007 to 2020 were used. The MHT group included women who underwent MHT for the first time between 2011-2014, while the non-MHT group included women who visited a healthcare provider for menopause during the same period but never received hormonal therapy. We used propensity score matching (1 : 1) to adjust for potential confounders, and Cox regression models to assess the association between MHT and PD. We selected 303,260 female participants (n = 151,630 per MHT and non-MHT groups). The median age of the participants was 50 (48-54) years, and the follow-up period lasted 7.9 (6.9-8.9) years. Cox regression analysis revealed an increased risk of PD with MHT (hazard ratio [HR] 1.377, 95% confidence interval [CI] 1.184-1.602), particularly with tibolone (HR 1.554, 95% CI 1.297-1.861) and estrogen alone (HR 1.465, 95% CI 1.054-2.036). Tibolone and estrogen alone were linked to PD within three years; however, no association was observed after three years. In contrast, the use of combined estrogen-progesterone was linked to a higher risk of PD, which increased with the duration of MHT (HR 1.885, 95% CI 1.218-2.918 for over five years). This study demonstrated that the MHT is closely associated with the risk of PD in a regimen- and duration-specific manner.


Autopsy Histopathologic Cardiac Findings in 2 Adolescents Following the Second COVID-19 Vaccine Dose.
Myocarditis in adolescents has been diagnosed clinically following the administration of the second dose of an mRNA vaccine for coronavirus disease 2019 (COVID-19). To examine the autopsy microscopic cardiac findings in adolescent deaths that occurred shortly following administration of the second Pfizer-BioNTech COVID-19 dose to determine if the myocarditis described in these instances has the typical histopathology of myocarditis. Clinical and autopsy investigation of 2 teenage boys who died shortly following administration of the second Pfizer-BioNTech COVID-19 dose. The microscopic examination revealed features resembling a catecholamine-induced injury, not typical myocarditis pathology. The myocardial injury seen in these postvaccine hearts is different from typical myocarditis and has an appearance most closely resembling a catecholamine-mediated stress (toxic) cardiomyopathy. Understanding that these instances are different from typical myocarditis and that cytokine storm has a known feedback loop with catecholamines may help guide screening and therapy.