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Hyperthermia induced by phenethylamines, such as 3,4–methylenedioxymethamphetamine (MDMA), can lead to life-threatening complications and death. Activation of the sympathetic nervous system and subsequent release of norepinephrine and activation of uncoupling proteins have been demonstrated to be the key mediators of phenethylamine-induced hyperthermia (PIH). Recently, the gut microbiome was shown to also play a contributing role in PIH. Here, the hypothesis that bile acids (BAs) produced by the gut microbiome are essential to PIH was tested. Changes in the serum concentrations of unconjugated primary BAs cholic acid (CA) and chenodeoxycholic acid (CDCA) and secondary BA deoxycholic acid (DCA) were measured following MDMA (20 mg/kg, sc) treatment in antibiotic treated and control rats. MDMA-induced a significant hyperthermic response and reduced the serum concentrations of three BAs 60 min post-treatment. Pretreatment with antibiotics (vancomycin, bacitracin and neomycin) in the drinking water for five days resulted in the depletion of BAs and a hypothermic response to MDMA. Gut bacterial communities in the antibiotic-treated group were distinct from the MDMA or saline treatment groups, with decreased microbiome diversity and alteration in taxa. Metagenomic functions inferred using the bioinformatic tool PICRUSt2 on 16S rRNA gene sequences indicated that bacterial genes associated to BA metabolism are less abundant in the antibiotic-MDMA treated group. Overall, these findings suggest that gut bacterial produced BAs might play an important role in MDMA-induced hyperthermia. [ABSTRACT FROM AUTHOR]

The main contribution of this paper is the development and demonstration of a novel methodology that can be followed to develop a simulation twin of a railway track switch system to test the functionality in a digital environment. This is important because, globally, railway track switches are used to allow trains to change routes; they are a key part of all railway networks. However, because track switches are single points of failure and safety-critical, their inability to operate correctly can cause significant delays and concomitant costs. In order to better understand the dynamic behaviour of switches during operation, this paper has developed a full simulation twin of a complete track switch system. The approach fuses finite element for the rail bending and motion, with physics-based models of the electromechanical actuator system and the control system. Hence, it provides researchers and engineers the opportunity to explore and understand the design space around the dynamic operation of new switches and switch machines before they are built. This is useful for looking at the modification or monitoring of existing switches, and it becomes even more important when new switch concepts are being considered and evaluated. The simulation is capable of running in real time or faster meaning designs can be iterated and checked interactively. The paper describes the modelling approach, demonstrates the methodology by developing the system model for a novel "REPOINT" switch system, and evaluates the system level performance against the dynamic performance requirements for the switch. In the context of that case study, it is found that the proposed new actuation system as designed can meet (and exceed) the system performance requirements, and that the fault tolerance built into the actuation ensures continued operation after a single actuator failure. [ABSTRACT FROM AUTHOR]

B cells play a central role in humoral immunity but also have antibody-independent functions. Studies to date have focused on B cells in blood and secondary lymphoid organs but whether B cells reside in non-lymphoid organs (NLO) in homeostasis is unknown. Here we identify, using intravenous labeling and parabiosis, a bona-fide tissue-resident B cell population in lung, liver, kidney and urinary bladder, a substantial proportion of which are B-1a cells. Tissue-resident B cells are present in neonatal tissues and also in germ-free mice NLOs, albeit in lower numbers than in specific pathogen-free mice and following co-housing with 'pet-store' mice. They spatially co-localise with macrophages and regulate their polarization and function, promoting an anti-inflammatory phenotype, in-part via interleukin-10 production, with effects on bacterial clearance during urinary tract infection. Thus, our data reveal a critical role for tissue-resident B cells in determining the homeostatic 'inflammatory set-point' of myeloid cells, with important consequences for tissue immunity. The function of B cells in peripheral blood and secondary lymphoid organs has long been appreciated but whether and how they contribute to tissue immune homeostasis is lesser known. Non-lymphoid organs harbour tissue-resident B cells that include a substantial population of B-1 cells and promote homeostatic anti-inflammatory macrophage polarization via IL-10, with profound effects on bacterial clearance during local infection. [ABSTRACT FROM AUTHOR]

Here we show that striated muscle preferentially expressed protein kinase α (Spegα) maintains cardiac function in hearts with Spegβ deficiency. Speg is required for stability of excitation-contraction coupling (ECC) complexes and interacts with esterase D (Esd), Cardiomyopathy-Associated Protein 5 (Cmya5), and Fibronectin Type III and SPRY Domain Containing 2 (Fsd2) in cardiac and skeletal muscle. Mice with a sequence encoding a V5/HA tag inserted into the first exon of the Speg gene (HA-Speg mice) display a >90% decrease in Spegβ but Spegα is expressed at ~50% of normal levels. Mice deficient in both Spegα and Speg β (Speg KO mice) develop a severe dilated cardiomyopathy and muscle weakness and atrophy, but HA-Speg mice display mild muscle weakness with no cardiac involvement. Spegα in HA-Speg mice suppresses Ca2+ leak, proteolytic cleavage of Jph2, and disruption of transverse tubules. Despite it's low levels, HA-Spegβ immunoprecipitation identified Esd, Cmya5 and Fsd2 as Spegβ binding partners that localize to triads and dyads to stabilize ECC complexes. This study suggests that Spegα and Spegβ display functional redundancy, identifies Esd, Cmya5 and Fsd2 as components of both cardiac dyads and skeletal muscle triads and lays the groundwork for the identification of new therapeutic targets for centronuclear myopathy. A new mouse model of Spegβ deficiency shows that Spegα prevents the development of dilated cardiomyopathy and decreases atrophy and loss force generation in skeletal muscle. Speg-β interacts with Esd, Fsd2, and Cmya5 and stabilizes interactions among excitation-contraction coupling proteins in triads and dyads. [ABSTRACT FROM AUTHOR]

The high antibiotic resistance of Pseudomonas aeruginosa (PA) makes it critical to develop alternative antimicrobial agents that are effective and affordable. One of the many applications of silver nanoparticles (Ag NPs) is their use as an antimicrobial agent against bacteria resistant to common antibiotics. The key purpose of this research was to assess the antibacterial and antibiofilm effectiveness of biosynthesized Ag NPs against six biofilm-forming clinically isolated strains of PA and one reference strain (ATCC 27853). Ag NPs were biosynthesized using a seed extract of Peganum harmala as a reducing agent. Ag NPs were characterized by Ultraviolet–visible (UV–Vis) spectroscopy and scanning transmission electron microscopy (STEM). The effect of Ag NPs on biofilm formation and eradication was examined through micro-titer plate assays, and the minimal inhibitory (MIC) and minimum bactericidal (MBC) concentrations determined. In addition, real-time polymerase chain reactions (RT-PCR) were performed to examine the effects of Ag NPs on the expression of seven PA biofilm-encoding genes (LasR, LasI, LssB, rhIR, rhII, pqsA and pqsR). The biosynthesized Ag NPs were spherically-shaped with a mean diameter of 11 nm. The MIC for each PA strain was 15.6 µg/ml, while the MBC was 31.25 µg/ml. All PA strains exposed to Ag NPs at sub-inhibitory concentrations (0.22–7.5 µg/ml) showed significant inhibitory effects on growth and biofilm formation. Biomass and biofilm metabolism were reduced dependent on Ag NP concentration. The expression of the quorum-sensing genes of all strains were significantly reduced at an Ag NP concentration of 7.5 µg/ml. The results demonstrate the extensive in-vitro antibacterial and antibiofilm performance of Ag NPs and their potential in the treatment of PA infection. It is recommended that future studies examine the possible synergy between Ag NPs and antibiotics. [ABSTRACT FROM AUTHOR]

There is a limitation in the range of effectual antibiotics due to the Pseudomonas aeruginosa (PA) infection due to its innate antimicrobial resistance. Researchers have therefore been concentrating their efforts to discover advanced and cost effective antibacterial agents among the ever-increasing PA bacterial resistance strains. It has been discovered that various nanoparticles can be employed as antimicrobial agents. Here, we evaluated the antibacterial properties of the Zinc Oxide nanoparticles (ZnO NPs), which was biosynthesized, being examined on six hospital strains of PA alongside a reference strain (ATCC 27853). A chemical approach was applied to biosynthesize the ZnO NPs from Olea europaea was performed, and confirmed by using X-ray diffraction and Scanning Electron Microscopes. The nanoparticles then applied their antibacterial properties to examine them against six clinically isolated PA strains alongside the reference strain. This process tested for the results of the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC). The Growth, biofilm formation and eradication were analyzed. The influence of the differentiating degrees ZnO NPs in regard to Quorom sensing gene expression were further examined. The ZnO NPs exhibited a crystalline size and diameter (Dc) of 40–60 nm and both the MIC and MBC tests revealed positive outcomes of concentrations of 3 and 6 mg/ml for each PA strain, respectively. At sub inhibitory concentration, The ZnO NPs were found to significantly inhibit the growth and biofilm formation of all PA strains and decreases in the biomass and metabolic behavior of PA established biofilms; these decreases varied depending on the dosage. At ZnO NPs concentrations of 900 µg/ml, the expression of majority of quorum sensing genes of all strains were significantly reduced, at ZnO NPs concentrations of 300 µg/ml, few genes were significantly impacted. In conclusion, the treatment of PA and could be other antibiotic resistant bacteria can therefore be approached by using ZnO NPs as it has been uncovered that they withhold advanced antibacterial properties. [ABSTRACT FROM AUTHOR]

Studies of microbiota reveal inter-relationships between the microbiomes of the gut and lungs. This relationship may influence the progression of lung disease, particularly in patients with cystic fibrosis (CF), who often experience extraoesophageal reflux (EOR). Despite identifying this relationship, it is not well characterised. Our hypothesis is that the gastric and lung microbiomes in CF are related, with the potential for aerodigestive pathophysiology. We evaluated gastric and sputum bacterial communities by culture and 16S rRNA gene sequencing in 13 CF patients. Impacts of varying levels of bile acids, pepsin and pH on patient isolates of Pseudomonas aeruginosa (Pa) were evaluated. Clonally related strains of Pa and NTM were identified in gastric and sputum samples from patients with symptoms of EOR. Bacterial diversity was more pronounced in sputa compared to gastric juice. Gastric and lung bile and pepsin levels were associated with Pa biofilm formation. Analysis of the aerodigestive microbiomes of CF patients with negative sputa indicates that the gut can be a reservoir of Pa and NTM. This combined with the CF patient's symptoms of reflux and potential aspiration, highlights the possibility of communication between microorganisms of the gut and the lungs. This phenomenon merits further research. [ABSTRACT FROM AUTHOR]

Skeletal muscle can repair and regenerate due to resident stem cells known as satellite cells. The muscular dystrophies are progressive muscle wasting diseases underscored by chronic muscle damage that is continually repaired by satellite cell-driven regeneration. Here we generate a genetic strategy to mediate satellite cell ablation in dystrophic mouse models to investigate how satellite cells impact disease trajectory. Unexpectedly, we observe that depletion of satellite cells reduces dystrophic disease features, with improved histopathology, enhanced sarcolemmal stability and augmented muscle performance. Mechanistically, we demonstrate that satellite cells initiate expression of the myogenic transcription factor MyoD, which then induces re-expression of fetal genes in the myofibers that destabilize the sarcolemma. Indeed, MyoD re-expression in wildtype adult skeletal muscle reduces membrane stability and promotes histopathology, while MyoD inhibition in a mouse model of muscular dystrophy improved membrane stability. Taken together these observations suggest that satellite cell activation and the fetal gene program is maladaptive in chronic dystrophic skeletal muscle. Boyer et al. created genetic mouse models of muscular dystrophy in which satellite cells were selectively depleted. The depletion of satellite cells at select times was protective. Myofibers no longer had plasma membrane instability leading to tissue wasting in the muscular dystrophies. [ABSTRACT FROM AUTHOR]

Background: Allogenic blood and marrow transplant (allo-BMT) is an arduous treatment used increasingly for many life-threatening conditions. Recognition of the profound impacts of the long term and late effects is ever-growing, as is the healthcare workload (treatment burden) of survivorship. Purpose: To quantify the treatment burden of long-term survival following allo-BMT, regarding the range of health services, therapies and investigations accessed by survivors. Methods: A large, multi-centre cross-sectional survey of adult allo-BMT survivors transplanted between 2000 and 2012 in Sydney, Australia. Participants completed six validated instruments and one purposed designed for the study, the Sydney Post BMT Study (SPBS), answering questions relating to medication use, medical treatments, referrals, assessments and frequency of hospital/clinic attendance. Results: Of the 441 allo-BMT survivors, over a quarter who were more than 2 years post BMT attended the hospital clinic at least monthly, and 26.7% required a number of regular medical procedures (e.g. venesection, extracorpororeal photopheresis). Specialist medical and allied health referral was very common, and compliance with internationally recommended long-term follow-up (LTFU) care was suboptimal and decreased as time from BMT increased. Conclusion: Respondents reported a large medication (conventional and complementary), screening, assessment and health care burden. Implications for Cancer Survivors: Treatment burden contributes significantly to the 'workload' of survivorship and can have a severe and negative impact on BMT survivors, carers and the healthcare system—making it difficult to comply with optimal care. Clinicians must be primed with skills to identify survivors who are overburdened by the health care required for survival and develop strategies to help ease the burden. [ABSTRACT FROM AUTHOR]

Background: There are few data describing practice patterns related to the use of sedation/anesthesia for diagnostic imaging in pediatric radiology departments. Objective: To understand current practice patterns related to imaging with sedation/anesthesia in pediatric radiology departments based on a survey of the Society of Chiefs of Radiology at Children's Hospitals (SCORCH) in conjunction with the American College of Radiology's Pediatric Imaging Sedation and Anesthesia Committee. Materials and methods: A multi-question survey related to imaging with sedation/anesthesia in pediatric radiology departments was distributed to SCORCH member institutions in January 2019. A single reminder email was sent. Descriptive statistical analyses were performed. Results: Of the 84 pediatric radiology departments, 23 (27%) completed the survey. Fifty-seven percent of the respondents self-identified as academic/university-affiliated and 13% as a division/section in an adult radiology department. Imaging sedation (excluding general anesthesia) is commonly performed by pediatric anesthesiologists (76%) and intensive care unit physicians (intensivists, 48%); only 14% of departments expect their pediatric radiologists to supervise imaging sedation. Ninety-six percent of departments use child life specialists for patient preparation. Seventy percent of departments have preparatory resources available on a website, including simulation videos (26%) and audio clips (17%). Nearly half (48%) of the departments have a mock scanner to aid in patient preparation. Imaging sedation/anesthesia is most often scheduled at the request of ordering clinicians (65%), while 57% of departments allow schedulers to place patients into imaging sedation/anesthesia slots based on specified criteria. Conclusion: Imaging sedation/anesthesia practice patterns vary among pediatric radiology departments, and understanding current approaches can help with standardization and practice improvement. [ABSTRACT FROM AUTHOR]

One must process others' facial affect proficiently to facilitate social functioning, and both social functioning and processing of facial affect can be impaired in sleep-deficient states. Based on mood-salience, decreased positive affect and increased negative affect experienced from sleep deficits or from depression might differentially modulate attentional responses to others' positive and negative facial expressions. The present study examined this possibility by assessing college students' subjective sleep–wake experience and their P3 event-related potentials responses, which indicate attention allocation. Fifty-five participants completed the Pittsburgh Sleep Quality Index (PSQI), assessments of current and past depressive symptoms, and a modified oddball task including affective facial expression stimuli. Factor analysis was conducted on PSQI data, and structural equation models were estimated to examine associations between PSQI latent factors and oddball P3 amplitude, controlling for current and past depressive symptomatology. Results indicated that one of the two identified PSQI factors (dysfunctional sleep insufficiency) was negatively associated with P3 amplitude in response to happy facial stimuli, while PSQI factor associations with sad and neutral stimuli were non-significant. Findings suggest that particular self-reported sleep–wake problems (dynamic interplay of sleep duration, sleep quality, and psychosocial functioning) can be related to decreased elaborated attention towards others' positive facial expressions, potentially a marker of decreased inclination towards social rewards. This pattern may be particularly relevant in college, a context that can present important social opportunities and reinforce problematic sleep habits. Future longitudinal research that includes assessments of social functioning and diverse samples would be beneficial. [ABSTRACT FROM AUTHOR]

Irradiated Queensland fruit flies (Bactrocera tryoni) used in Sterile Insect Technique (SIT) programmes are marked with fluorescent dyes to distinguish them from wild flies when recaptured in monitoring traps. However, coating sterile pupae with powdered dyes can reduce emergence rates and fly quality and can sometimes produce insufficiently certain discrimination through inadequate coating or because the dye is transferred to wild flies through contact. Here we created a phenotypically distinct B. tryoni strain that lacks typical melanisation patterns through CRISPR/Cas9-mediated mutagenesis of tandemly duplicated yellow-y genes and then assessed effects of this visible trait on fly performance. Recessive mutations are only required in one of these copies to restrict melanisation and generate a phenotype clearly distinguished from wild type. The yellow strain showed significant declines in eclosion rates and in the percentage of fliers directly after emergence. Locomotor activity was greater in the yellow strain, and these mutations did not generally affect mating probability, copula latency, or copula duration. The longevity of yellow flies was approximately 10 days shorter than wild-type flies in both sexes. Overall, replacing dyes with yellow body marker for SIT can simplify production, eliminate a step that is known to reduce fly quality, remove potentially hazardous dyes from production, enable accurate discrimination from wild flies, and improve cost-effectiveness; however, direct comparisons of the decrements in performance associated with dyes on mass-reared wild-type flies and disruption of yellow-y genes are now required to determine the relative suitability of these marking methods for B. tryoni SIT. [ABSTRACT FROM AUTHOR]

Mass releases of sterilized male insects, in the frame of sterile insect technique programs, have helped suppress insect pest populations since the 1950s. In the major horticultural pests Bactrocera dorsalis, Ceratitis capitata, and Zeugodacus cucurbitae, a key phenotype white pupae (wp) has been used for decades to selectively remove females before releases, yet the gene responsible remained unknown. Here, we use classical and modern genetic approaches to identify and functionally characterize causal wp− mutations in these distantly related fruit fly species. We find that the wp phenotype is produced by parallel mutations in a single, conserved gene. CRISPR/Cas9-mediated knockout of the wp gene leads to the rapid generation of white pupae strains in C. capitata and B. tryoni. The conserved phenotype and independent nature of wp− mutations suggest this technique can provide a generic approach to produce sexing strains in other major medical and agricultural insect pests. The white pupae (wp) phenotype has been used for decades to selectively remove females of tephritid species in genetic sexing, but the determining gene is unknown. Here, the authors show that wp phenotype is produced by parallel mutations in a Major Facilitator Superfamily domain containing gene across multiple species. [ABSTRACT FROM AUTHOR]

Background: Despite their important role in railway operations, switches and crossings (S&C) have changed little since their conception over a century ago. It stands now that the existing designs for S&C are reaching their maximum point of incremental performance improvement, and only a radical redesign can overcome the constraints that current designs are imposing on railway network capacity. This paper describes the process of producing novel designs for next generation switches and crossings, as part of the S-CODE project. Methods: Given the many aspects that govern a successful S&C design, it is critical to adopt multi criteria decision making (MCDM) processes to identify a specific solution for the next generation of switches and crossings. However, a common shortcoming of these methods is that their results can be heavily influenced by external factors, such as uncertainty in criterium weighting or bias of the evaluators, for example. This paper therefore proposes a process based on the Pugh Matrix method to reduce such biases by using sensitivity analysis to investigate them and improve the reliability of decision making. Results: In this paper, we analysed the influences of three different external factors, measuring the sensitivity of ranking due to (a) weightings, (b) organisational and (c) discipline bias. The order of preference of the results was disturbed only to a minimum while small influences of bias were detected. Conclusions: Through this case study, we believe that the paper demonstrates an effective case study for a quantitative process that can improve the reliability of decision making. [ABSTRACT FROM AUTHOR]

The diamondback moth, Plutella xylostella is a cosmopolitan pest that has evolved resistance to all classes of insecticide, and costs the world economy an estimated US $4-5 billion annually. We analyse patterns of variation among 532 P. xylostella genomes, representing a worldwide sample of 114 populations. We find evidence that suggests South America is the geographical area of origin of this species, challenging earlier hypotheses of an Old-World origin. Our analysis indicates that Plutella xylostella has experienced three major expansions across the world, mainly facilitated by European colonization and global trade. We identify genomic signatures of selection in genes related to metabolic and signaling pathways that could be evidence of environmental adaptation. This evolutionary history of P. xylostella provides insights into transoceanic movements that have enabled it to become a worldwide pest. The diamondback moth, Plutella xylostella is a cosmopolitan agricultural pest. By analyzing 532 genomes from 114 populations around the world, the authors find evidence supporting a South American origin of this moth, and look for signatures of positive selection. [ABSTRACT FROM AUTHOR]

Introduction: Training surgeons in minimally invasive surgery (MIS) requires surgical residents to operate under the direction of a consultant. The inability of the instructing surgeon to point at the laparoscopic monitor without releasing the instruments remains a barrier to effective instruction. The wireless hands-free surgical pointer (WHaSP) has been developed to aid instruction during MIS.Methods: The objective of this study was to evaluate the effectiveness and likeability of the WHaSP as an instructional tool compared with the conventional methods. Data were successfully collected during 103 laparoscopic cholecystectomy procedures, which had been randomized to use or not use the WHaSP as a teaching tool. Audio and video from the surgeries were recorded and analyzed. Instructing surgeons, operating surgeons, and camera assistants provided feedback through a post-operative questionnaire that used a five-level Likert scale. The questionnaire results were analyzed using a Mann-Whitney U test.Results: There were no negative effects on surgery completion time or instruction practice due to the use of the WHaSP. The number of times an instructor surgeon pointed to the laparoscopic screen with their hand was significantly reduced when the WHaSP was utilized (p < 0.001). The questionnaires showed that WHaSP users found it to be comfortable, easy to use, and easy to control. Compared to when the WHaSP was not used, users found that communication was more effective (p = 0.002), locations were easier to communicate (p < 0.001), and instructions were easier to follow (p = 0.005).Conclusions: The WHaSP system was successfully used in surgery. It integrated seamlessly into existing equipment within the operating room and did not affect flow. The positive outcomes of utilizing the WHaSP were improved communication in the OR, improved efficiency and safety of the surgery, easy to use, and comfortable to wear. The surgeons showed a preference for utilizing the WHaSP if given a choice. [ABSTRACT FROM AUTHOR]

Background: The evidence on coagulation changes with frailty is not consistent and clinical studies suggest that frail older people may be at an increased risk of bleeding complications with anticoagulant therapy. Aims: This study aims to assess the impact of frailty on coagulation function and on response to warfarin. Methods: Inpatients aged over 65 years with atrial fibrillation (AF) were recruited. Frailty was determined using the Reported Edmonton Frail Scale. The Overall Haemostatic Potential (OHP) and Calibrated Automated Thrombogram (CAT) were used to globally assess coagulation function. Results: Data of 95 participants were analysed, mean age 85.5 ± 6.2, 40% female, and 50.5% frail. Among participants not on anticoagulants ( N = 36), there was an increased fibrin generation and decreased thrombin generation compared to the local established normal ranges in young healthy volunteers; the frail had significantly reduced fibrin generation compared to the non-frail. In the warfarin-treated group ( N = 59), there was no difference on coagulation profiles between the frail and the non-frail from any of the coagulation tests. Conclusion: In this cohort of acute hospitalised patients with AF, the observed decreased fibrin generation in the frail may reflect decreased acute phase response as suggested with the lower plasma fibrinogen in that group. There was no difference in coagulation profiles between the frail and the non-frail amongst those taking warfarin. Compared to young healthy volunteers, older inpatients had increased fibrin generation and decreased thrombin generation. The findings reflect the complex interaction between age, frailty, acute illness, and coagulation. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this qualitative study was to gain a rich understanding of the impact that haematopoietic stem cell transplantation (HSCT) has on long-term survivor's quality of life (QoL).Method: Participants included 441 survivors who had undergone HSCT for a malignant or non-malignant disease. Data were obtained by a questionnaire positing a single open-ended question asking respondents to list the three issues of greatest importance to their QoL in survivorship. Responses were analysed and organised into QoL themes and subthemes.Results: Major themes identified included the following: the failing body and diminished physical effectiveness, the changed mind, the loss of social connectedness, the loss of the functional self and the patient for life. Each of these themes manifests different ways in which HSCT survivor's world and opportunities had diminished compared to the unhindered and expansive life that they enjoyed prior to the onset of disease and subsequent HSCT.Conclusions: HSCT has a profound and pervasive impact on the life of survivors-reducing their horizons and shrinking various parts of their worlds. While HSCT survivors can describe the ways in which their life has changed, many of their fears, anxieties, regrets and concerns are existential in nature and are ill-defined-making it exceeding unlikely that they would be adequately captured by standard psychometric measures of QoL post HSCT. [ABSTRACT FROM AUTHOR]

Purpose: The aims of this study were to describe the long-term nutrition, body weight and body image issues facing survivors of Allogeneic Blood and Marrow Transplant (BMT) and their impact on quality of life. It also describes survivors' perception of enteral feeding during BMT.Methods: Four hundred and forty-one survivors who had undergone a BMT in NSW, Australia between 2000 and 2012 (n = 441/583) completed the Sydney Post BMT Study Survey (SPBS).Results: Forty-five percent of survivors less than 2-year post-transplant reported a dry mouth, 36 % reported mouth ulcers and 19 % had diarrhoea. This was consistent across all survivor groups, regardless of time since transplant. Patients with one or more gastrointestinal (GI) symptoms had significantly lower quality of life scores. There was a significant difference in quality of life scores when comparing those with no GI symptoms to those with one or more symptoms (P = <0.0001). Quality of life was significantly higher in those who once again enjoyed mealtimes (P < 0.0001). Males were more likely to be satisfied with their body weight compared to females (P = 0.009). The median body mass index (BMI) for all patients reporting body weight satisfaction was significantly lower (BMI 23.5) than those reporting dissatisfaction (BMI 27.5) (P = <0.0001). Survivors who had a normal BMI had significantly higher rates of body weight satisfaction compared to underweight, overweight and obese survivors (P = <0.0001). Those survivors who were overweight or obese were significantly more likely to be diabetic (P = 0.008).Conclusion: This study revealed an important relationship between gastrointestinal symptoms, body weight and body image and survivor's quality of life. It provides further support for the importance of nutrition therapy post-BMT. [ABSTRACT FROM AUTHOR]

There is a healthcare crisis in developing and resource-constrained countries that is attributable to the burden of communicable diseases and the rapid rise of non-communicable diseases. The first line of treatment for both communicable and non-communicable diseases is the use of pharmaceuticals. Almost all drugs deemed to be 'essential medicines' by the World Health Organization are off-patent and available as generics and nearly all of the patented, brand-name essential medicines are deeply discounted in developing countries, often matching generic prices. However, despite this, one-third of the world's population does not have access to essential medicines. There is no scientific evidence that patents or price are major barriers to market access, or causatively associated with worse health outcomes, in developing and resource-constrained markets. The pharmaceutical industry, like almost all industries, uses differential pricing worldwide wherein prices are inverted to the elasticity of demand. The real barriers to access in these countries are money, power, politics, and ideologies, which manifest themselves in market failure, corruption, and the lack of political will to create stable, ethical, and law-abiding government administrations that will ensure products arrive where they are destined without delay, diversion, theft, or unnecessary tariffs. There is a need for infrastructure, roads, communications, health human resources, provider compliance, patient adherence, political stability, and professional regulatory structures and protections. Enhanced state capacity to serve indigenous populations and the rule of law-including harmonized intellectual property protection-are integral to promoting global health and healthcare, in which pharmaceuticals play a vital role. There are no quick-fix solutions. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented from doctors discussing mutation in GPIbΒ gene concomitant with severely reduced surface levels of CD9 protein.

Numerous preclinical and clinical studies investigating the neurodevelopmental and neurocognitive effects of exposure to anesthesia and the combination of anesthesia and surgery have demonstrated histopathological and both temporary and long-term cognitive and behavioral effects at the extremes of the human age spectrum. Increasing coverage in the lay press for both our youngest and oldest patient populations has led to heightened concerns regarding the potential harmful side effects of almost all commonly used anesthetic drug regimens. Although the majority of information regarding anesthetic risks in the developing brain derives from preclinical work in rodents, research involving the aged brain has identified a well-defined postoperative cognitive phenotype in humans. While preclinical and clinical data appear to support some association between anesthesia and surgery and the development of detrimental cognitive changes in both the developing and the aged brain, correlation between anesthesia and surgery and poor neurological outcomes does not imply causation. Given this information, no single anesthetic or group of anesthetics can be recommended over any other in terms of causing or preventing negative neurocognitive outcomes in either population. This review summarizes the growing body of preclinical and clinical literature dedicated to the detrimental effects of anesthesia on both the developing and the aging brain. [ABSTRACT FROM AUTHOR]

Introduction: Frailty is associated with changes in inflammation, coagulation, and possibly platelet function. Aspirin is still prescribed for stroke prevention in older patients with atrial fibrillation, although not recommended by current guidelines. In frail older people, it is unclear whether platelet aggregability and response to aspirin are altered. This study aims to investigate the effects of frailty and chronological age on platelet aggregability and on responses to aspirin in older patients with atrial fibrillation. Methods: Inpatients with atrial fibrillation aged ≥65 years were recruited from a tertiary referral hospital in Sydney, Australia. Frailty was determined using the Reported Edmonton Frail Scale. Platelet aggregation studies were performed using whole blood impedance aggregometry. Results: Data from 115 participants were analyzed (mean age 85 ± 6 years, 41% female, 52% frail). Spearman correlation coefficients found no significant associations of platelet aggregation with chronological age or with frailty score. Comparison between frail and non-frail groups showed that there was no impact of frailty status on aggregation assays amongst participants who were not taking any antiplatelet drugs. Amongst participants taking aspirin, the frail had higher adjusted arachidonic acid agonist (ASPI) test measures (AU per platelet) than the non-frail (0.11 ± 0.11 vs. 0.05 ± 0.04; p = 0.04), suggesting that in frail participants, platelet aggregation is less responsive to aspirin than in non-frail. Conclusions: We found no effect of chronological age or frailty status on platelet aggregation amongst older patients with atrial fibrillation in this pilot study. However, frailty could be associated with reduced aspirin responsiveness among older patients with atrial fibrillation. [ABSTRACT FROM AUTHOR]

Dysfunction of many ciliary proteins has been linked to a list of diseases, from cystic kidney to obesity and from hypertension to mental retardation. We previously proposed that primary cilia are unique communication organelles that function as microsensory compartments that house mechanosensory molecules. Here we report that primary cilia exhibit membrane swellings or ciliary bulbs, which based on their unique ultrastructure and motility, could be mechanically regulated by fluid-shear stress. Together with the ultrastructure analysis of the swelling, which contains monosialodihexosylganglioside (GM3), our results show that ciliary bulb has a distinctive set of functional proteins, including GM3 synthase (GM3S), bicaudal-c1 (Bicc1), and polycystin-2 (PC2). In fact, results from our cilia isolation demonstrated for the first time that GM3S and Bicc1 are members of the primary cilia proteins. Although these proteins are not required for ciliary membrane swelling formation under static condition, fluid-shear stress induced swelling formation is partially modulated by GM3S. We therefore propose that the ciliary bulb exhibits a sensory function within the mechano-ciliary structure. Overall, our studies provided an important step towards understanding the ciliary bulb function and structure. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disease in which weakness, increased susceptibility to muscle injury, and inadequate repair underlie the pathology. While most attention has focused within the muscle fiber, we recently demonstrated significant alterations in the neuromuscular junction (NMJ) morphology and resulting neuromuscular transmission failure (NTF) 24 h after injury in mdx mice (murine model for DMD). Here we determine the contribution of NMJ morphology and NTF to the recovery of muscle contractile function post-injury. NMJ morphology and NTF rates were assessed day 0 (immediately after injury) and days 1, 7, 14 and 21 after quadriceps injury. Eccentric injury of the quadriceps resulted in a significant loss of maximal torque in both WT (39 ± 6 %) and mdx (76 ± 8 %) with a full recovery in WT by day 7 and in mdx by day 21. Post-injury alterations in NMJ morphology and NTF were found only in mdx, were limited to days 0 and 1, and were independent of changes in MuSK or AChR expression. Such early changes at the NMJ after injury are consistent with mechanical disruption rather than newly forming NMJs. Furthermore, we show that the dense microtubule network that underlies the NMJ is significantly reduced and disorganized in mdx compared to WT. These structural changes at the NMJ may play a role in the increased NMJ disruption and the exaggerated loss of nerve-evoked muscle force seen after injury to dystrophic muscles. [ABSTRACT FROM AUTHOR]

Engraftment outcomes following autologous transplantation correlate poorly to infused stem cell number. We evaluated 446 consecutive patients who underwent autologous transplantation at our centre between 2001 and 2012. The impact of pre-transplant and collection factors together with CD34 dosing ranges on engraftment, hospital length of stay (LOS) and survival endpoints were assessed in order to identify factors which might be optimized to improve outcomes for patients undergoing autologous transplantation using haemopoietic progenitor cells-apheresis (HPC-A). Infused CD34 cell dose correlated to platelet but not neutrophil recovery. Time to platelet engraftment was significantly delayed in those receiving low versus medium or high CD34 doses. Non-remission status was associated with slower neutrophil and platelet recovery. Increasing neutrophil contamination of HPC-A was strongly associated with slower neutrophil recovery with infused neutrophil dose/kg recipient body weight ≥3 × 10/kg having a significant impact on time to neutrophil engraftment ( p = 0.001). Higher neutrophil doses/kg in HPC-A were associated with days of granulocyte colony stimulation factor (G-CSF) use, HPC-A volumes >500 ml and higher NCC in HPC-A. High infused neutrophil dose/kg and age >65 years were associated with longer hospital LOS ( p = 0.002 and 0.011 respectively). Only age, disease and disease status predicted disease-free survival (DFS) and overall survival (OS) in our cohort ( p < 0.005). Non-relapse mortality was not affected by low dose of CD34 (<2 × 10/kg). In conclusion, our study shows that CD34 remains a useful and convenient marker for assessing haemotopoietic stem cell content and overall engraftment capacity post-transplant. Neutrophil contamination of HPC-A appears to be a key factor delaying neutrophil recovery. Steps to minimize the degree of neutrophil contamination in HPC-A product may be associated with more rapid neutrophil engraftment and reduced hospital LOS. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via the original article. [ABSTRACT FROM AUTHOR]

Obscurin comprises a family of giant modular proteins that play key structural and regulatory roles in striated muscles. Immunoglobulin domains 58/59 (Ig58/59) of obscurin mediate binding to essential modulators of muscle structure and function, including canonical titin, a smaller splice variant of titin, termed novex-3, and phospholamban (PLN). Importantly, missense mutations localized within the obscurin-Ig58/59 region that affect binding to titins and/or PLN have been linked to the development of myopathy in humans. To elucidate the pathophysiological role of this region, we generated a constitutive deletion mouse model, Obscn-ΔIg58/59, that expresses obscurin lacking Ig58/59, and determined the consequences of this manipulation on cardiac morphology and function under conditions of acute stress and through the physiological process of aging. Our studies show that young Obscn-ΔIg58/59 mice are susceptible to acute β-adrenergic stress. Moreover, sedentary Obscn-ΔIg58/59 mice develop left ventricular hypertrophy that progresses to dilation, contractile impairment, atrial enlargement, and arrhythmia as a function of aging with males being more affected than females. Experiments in ventricular cardiomyocytes revealed altered Ca2+ cycling associated with changes in the expression and/or phosphorylation levels of major Ca2+ cycling proteins, including PLN, SERCA2, and RyR2. Taken together, our work demonstrates that obscurin-Ig58/59 is an essential regulatory module in the heart and its deletion leads to age- and sex-dependent cardiac remodeling, ventricular dilation, and arrhythmia due to deregulated Ca2+ cycling. [ABSTRACT FROM AUTHOR]

This corrects the article DOI: 10.1038/srep12637 [ABSTRACT FROM AUTHOR]

We have previously shown that E-cadherin regulates the naive pluripotent state of mouse embryonic stem cells (mESCs) by enabling LIF-dependent STAT3 phosphorylation, with E-cadherin null mESCs exhibiting over 3000 gene transcript alterations and a switch to Activin/Nodal-dependent pluripotency. However, elucidation of the exact mechanisms associated with E-cadherin function in mESCs is compounded by the difficulty in delineating the structural and signalling functions of this protein. Here we show that mESCs treated with the E-cadherin neutralising antibody DECMA-1 or the E-cadherin binding peptide H-SWELYYPLRANL-NH2 (Epep) exhibit discrete profiles for pluripotent transcripts and NANOG protein expression, demonstrating that the type of E-cadherin inhibitor employed dictates the cellular phenotype of mESCs. Alanine scanning mutation of Epep revealed residues critical for Tbx3, Klf4 and Esrrb transcript repression, cell-cell contact abrogation, cell survival in suspension, STAT3 phosphorylation and water solubility. STAT3 phosphorylation was found to be independent of loss of cell-cell contact and Activin/Nodal-dependent pluripotency and a peptide is described that enhances STAT3 phosphorylation and Nanog transcript and protein expression in mESCs. These peptides represent a useful resource for deciphering the structural and signalling functions of E-cadherin and demonstrate that complete absence of E-cadherin protein is likely required for hierarchical signalling pathway alterations in mESCs. [ABSTRACT FROM AUTHOR]

The cystic fibrosis (CF) airway surface liquid (ASL) provides a nutrient rich environment for bacterial growth including elevated glucose, which together with defective bacterial killing due to aberrant HCO3− transport and acidic ASL, make the CF airways susceptible to colonisation by respiratory pathogens such as Pseudomonas aeruginosa. Approximately half of adults with CF have CF related diabetes (CFRD) and this is associated with increased respiratory decline. CF ASL contains elevated lactate concentrations and hyperglycaemia can also increase ASL lactate. We show that primary human bronchial epithelial (HBE) cells secrete lactate into ASL, which is elevated in hyperglycaemia. This leads to ASL acidification in CFHBE, which could only be mimicked in non-CF HBE following HCO3− removal. Hyperglycaemia-induced changes in ASL lactate and pH were exacerbated by the presence of P. aeruginosa and were attenuated by inhibition of monocarboxylate lactate-H+ co-transporters (MCTs) with AR-C155858. We conclude that hyperglycaemia and P. aeruginosa induce a metabolic shift which increases lactate generation and efflux into ASL via epithelial MCT2 transporters. Normal airways compensate for MCT-driven H+ secretion by secreting HCO3−, a process which is dysfunctional in CF airway epithelium leading to ASL acidification and that these processes may contribute to worsening respiratory disease in CFRD. [ABSTRACT FROM AUTHOR]

Myosin Binding Protein-C slow (sMyBP-C), encoded by MYBPC1, comprises a family of regulatory proteins of skeletal muscles that are phosphorylated by PKA and PKC. MYBPC1 missense mutations are linked to the development of Distal Arthrogryposis-1 (DA-1). Although structure-function details for this myopathy are evolving, function is undoubtedly driven by sequence variations and post-translational modifications in sMyBP-C. Herein, we examined the phosphorylation profile of sMyBP-C in mouse and human fast-twitch skeletal muscles. We used Flexor Digitorum Brevis (FDB) isolated from young (~2-months old) and old (~14-months old) wild type and mdx mice, and human Abductor Hallucis (AH) and gastrocnemious muscles carrying the DA-1 mutations. Our results indicate both constitutive and differential phosphorylation of sMyBP-C in aged and diseased muscles. We report a 7-35% reduction in the phosphorylation levels of select sites in old wild type and young or old mdx FDB mouse muscles, compared to young wild type tissue. Similarly, we observe a 30-70% decrease in the phosphorylation levels of all PKA and PKC phospho-sites in the DA-1 AH, but not gastrocnemius, muscle. Overall, our studies show that the phosphorylation pattern of sMyBP-C is differentially regulated in response to age and disease, suggesting that phosphorylation plays important roles in these processes. [ABSTRACT FROM AUTHOR]