What Are the Complications, Survival, and Outcomes After Revision to Reverse Shoulder Arthroplasty in Patients Older Than 80 Years?
By the time patients with a failed shoulder arthroplasty require revision surgery, a substantial number are older than 80 years. The risk of complications of revision arthroplasty in this elderly population is largely unknown and needs to be considered when contemplating whether these patients are too frail for revision surgery. (1) What are the 90-day medical and surgical complications after revision to reverse shoulder arthroplasty (RSA) in patients older than 80 years? (2) What are the 2- and 5-year survival rates after revision? (3) Was there an improvement in pain at rest or with activity, range of motion (ROM), and strength after revision surgery? Between 2004 and 2013, 38 patients who were older than 80 years (84 ± 3 years) underwent revision surgery to a RSA. Of those, five were lost to followup before 2 years, and two had died within 2 years of revision surgery, leaving 31 for analysis of our survivorship, pain, ROM, and strength endpoints at a minimum of 2 years or until revision surgery had occurred (mean, 28 months; range, 1-77 months); all 38 patients were included for purposes of evaluating medical and surgical complications at 90 days. During the period in question, our general indication for using RSA included failure of previous shoulder arthroplasty because of instability, glenoid loosening with bone loss, or rotator cuff insufficiency. The indication for revision to RSA did not change during the study period. The index procedure (revision to RSA at the age of 80 years or older) was the first revision arthroplasty in 33 (87%) patients and the second in five (13%) patients. We tallied 90-day medical and surgical complications by performing a retrospective chart and institutional joint registry review. The cumulative incidence of implant loosening (implant migration or tilting, or complete radiolucent lines present) and revision surgery was calculated at 2 and 5 years using competing risk of death method. Pain levels at rest or with activity (rated in a 1 to 5 Likert-type scale) were collected through a retrospective chart review and values before and after surgery were compared. Medical complications occurred in three of 38 (8%) patients and surgical complications occurred in five of 38 (13%) patients. The 90-day mortality was 3% (one of 38 patients), and the total mortality was 26% (10 of 38 patients). The cumulative incidence of revision was 11% (95% CI, 0%-20%) at 2 years and 16% (95% CI, 1%-30%) at 5 years; the cumulative incidence of loosening was 8% (95% CI, 0%-20%) at 2 years and 16% (95% CI, 1%-30%) at 5 years. Pain at rest or with activity improved from pre- to postoperation (preoperative: median, 4 [range, 2-5]; postoperative: median, 1 [range, 1-4]; median difference: -2, 95% CI -3 to 0; p < 0.000). The active ROM improved during the preoperative compared with postoperative periods: mean ± SD forward flexion of 52° ± 40° to 109° ± 44°, respectively (mean difference: 56; 95% CI, 40-72; p < 0.000), and mean ± SD external rotation of 15° ± 22° to 31° ± 21°, respectively (mean difference: 16; 95% CI, 8-25; p < 0.000). Age should not be used as a reason to not consider revision surgery to RSA in patients older than 80 years. Further studies with a prospective design, larger sample size, investigating risk factors for complications or poor outcome, and incorporation of functional scores are required. Level IV, therapeutic study.


Synchrotron based phase contrast X-ray imaging combined with FTIR spectroscopy reveals structural and biomolecular differences in spikelets play a significant role in resistance to Fusarium in wheat.
Fusarium head blight (FHB), a scab principally caused by Fusarium graminearum Schw., is a serious disease of wheat. The purpose of this study is to evaluate the potential of combining synchrotron based phase contrast X-ray imaging (PCI) with Fourier Transform mid infrared (FTIR) spectroscopy to understand the mechanisms of resistance to FHB by resistant wheat cultivars. Our hypothesis is that structural and biochemical differences between resistant and susceptible cultivars play a significant role in developing resistance to FHB. Synchrotron based PCI images and FTIR absorption spectra (4000-800 cm(-1)) of the floret and rachis from Fusarium-damaged and undamaged spikes of the resistant cultivar 'Sumai3', tolerant cultivar 'FL62R1', and susceptible cultivar 'Muchmore' were collected and analyzed. The PCI images show significant differences between infected and non-infected florets and rachises of different wheat cultivars. However, no pronounced difference between non-inoculated resistant and susceptible cultivar in terms of floret structures could be determined due to the complexity of the internal structures. The FTIR spectra showed significant variability between infected and non-infected floret and rachis of the wheat cultivars. The changes in absorption wavenumbers following pathogenic infection were mostly in the spectral range from 1800-800 cm(-1). The Principal Component Analysis (PCA) was also used to determine the significant chemical changes inside floret and rachis when exposed to the FHB disease stress to understand the plant response mechanism. In the floret and rachis samples, PCA of FTIR spectra revealed differences in cell wall related polysaccharides. In the florets, absorption peaks for Amide I, cellulose, hemicellulose and pectin were affected by the pathogenic fungus. In the rachis of the wheat cultivars, PCA underlines significant changes in pectin, cellulose, and hemicellulose characteristic absorption spectra. Amide II and lignin absorption peaks, persistent in the rachis of Sumai3, together with increased peak shift at 1245 cm(-1) after infection with FHB may be a marker for stress response in which the cell wall compounds related to pathways for lignification are increased. Synchrotron based PCI combined with FTIR spectroscopy show promising results related to FHB in wheat. The combined technique is a powerful new tool for internal visualisation and biomolecular monitoring before and during plant-microbe interactions to understand both the differences between cultivars and their different responses to disease stress.


Substance P activation of enteric neurons in response to intraluminal Clostridium difficile toxin A in the rat ileum.
Nerves have been suggested to mediate the effects of bacterial toxins in intestinal diseases. However, the mechanisms involved are unknown. This study examined endogenous substance P (SP) activation of the substance P receptor (SPR) on enteric neurons in the rat ileum after exposure to intraluminal Clostridium difficile toxin A. After intraluminal injection of toxin A in ileal loops, tissue was examined for pathological changes by histology and for SPR activation by immunocytochemical analysis of SP-induced SPR endocytosis. After toxin A administration, > 70% of enteric neurons showed SPR endocytosis and became swollen with thickened dendrites. In contrast, SPRs in control rats were largely confined to the plasma membrane. Rats denervated of primary afferent fibers with neonatal capsaicin injection and animals pretreated with a nonpeptide SPR antagonist showed few endosomal SPRs, and the pathological inflammatory effects of toxin A were ablated. Intraluminal toxin A causes the release of SP from primary afferent neurons: this endogenous SP then acts on enteric neurons in the submucosal and myenteric plexuses. SP is the primary mediator of an axon reflex mediating neurogenic inflammation in the intestine. SPR blockade may prove to be a novel therapy used to prevent intestinal inflammation.


Outcomes of ankle fractures in patients with uncomplicated versus complicated diabetes.
Patients with diabetes who sustain an ankle fracture are at increased risk for complications including higher rates of in hospital mortality, in-hospital postoperative complications, length of stay and non-routine discharges. The purpose of this study was to retrospectively compare the complications associated with operatively treated ankle fractures in a group of patients with uncomplicated diabetes versus a group of patients with complicated diabetes. Complicated diabetes was defined as diabetes associated with end organ damage such as peripheral neuropathy, nephropathy and/or PAD. Uncomplicated diabetes was defined as diabetes without any of these associated conditions. Our hypothesis was that patients with uncomplicated diabetes would experience fewer complications than those patients with complicated diabetes. We compared the complication rates of ankle fracture repair in 46 patients with complicated diabetes and 59 patients with uncomplicated diabetes and calculated odds ratios (OR) for significant findings. At a mean followup of 21.4 months we found that patients with complicated diabetes had 3.8 times increased risk of overall complications 3.4 times increased risk of a non-infectious complication (malunion, nonunion or Charcot arthropathy) and 5 times higher likelihood of needing revision surgery/arthrodesis when compared to patients with uncomplicated diabetes. Open ankle fractures in this diabetic population were associated with a three times higher rate of complications and 3.7 times higher rate of infection. Patients with complicated diabetes have an increased risk of complications after ankle fracture surgery compared to patients with uncomplicated diabetes. Careful preoperative evaluation of the neurovascular status is mandatory, since many patients with diabetes do not recognize that they have neuropathy and/or peripheral artery disease.


IκB kinase ε-dependent phosphorylation and degradation of X-linked inhibitor of apoptosis sensitizes cells to virus-induced apoptosis.
X-linked inhibitor of apoptosis (XIAP) is a potent antagonist of caspase 3-, 7-, and 9-dependent apoptotic activities that functions as an E3 ubiquitin ligase, and it targets caspases for degradation. In this study, we demonstrate that Sendai virus (SeV) infection results in the IKKε- or TBK1-mediated phosphorylation of XIAP in vivo at Ser430, resulting in Lys(48)-linked autoubiquitination at Lys322/328 residues, followed by the subsequent proteasomal degradation of XIAP. Interestingly, IKKε expression and XIAP turnover increases SeV-triggered mitochondrion-dependent apoptosis via the release of caspase 3, whereas TBK1 expression does not increase apoptosis. Interestingly, phosphorylation also regulates XIAP interaction with the transcription factor IRF3, suggesting a role in IRF3-Bax-mediated apoptosis. Our findings reveal a novel function of IKKε as a regulator of the virus-induced triggering of apoptosis via the phosphorylation-dependent turnover of XIAP.


Comparison of ATD to PMHS Response in the Under-Body Blast Environment.
A blast buck (Accelerative Loading Fixture, or ALF) was developed for studying underbody blast events in a laboratory-like setting. It was designed to provide a high-magnitude, high-rate, vertical loading environment for cadaver and dummy testing. It consists of a platform with a reinforcing cage that supports adjustable-height rigid seats for two crew positions. The platform has a heavy frame with a deformable floor insert. Fourteen tests were conducted using fourteen PMHS (post mortem human surrogates) and the Hybrid III ATD (Anthropomorphic Test Device). Tests were conducted at two charge levels: enhanced and mild. The surrogates were tested with and without PPE (Personal Protective Equipment), and in two different postures: nominal (knee angle of 90°) and obtuse (knee angle of 120°). The ALF reproduces damage in the PMHS commensurate with injuries experienced in theater, with the most common damage being to the pelvis and ankle. Load is transmitted through the surrogates in a caudal-to-cranial sequential fashion. Damage to the PMHS lower extremities begins within 2 ms after the initiation of foot/floor motion. The Hybrid III cannot assume the posture of the PMHS in rigid seats and exhibits a stiffer overall response compared to the PMHS. The ATD does not mimic the kinematic response of the PMHS lower extremities. Further, the Hybrid III does not have the capability to predict the potential for injury in the high-rate, vertical loading environment. A new ATD dedicated to under-body blast is needed to assist in the effort to mitigate injuries sustained by the mounted soldier.


Cost-effectiveness of internet-based cognitive behavior therapy for irritable bowel syndrome: results from a randomized controlled trial.
Irritable Bowel Syndrome (IBS) is highly prevalent and is associated with a substantial economic burden. Cognitive behavior therapy (CBT) has been shown to be effective in treating IBS. The aim of this study was to evaluate the cost-effectiveness of a new treatment alternative, internet-delivered CBT based on exposure and mindfulness exercises. Participants (N = 85) with IBS were recruited through self-referral and were assessed via a telephone interview and self-report measures on the internet. Participants were randomized to internet-delivered CBT or to a discussion forum. Economic data was assessed at pre-, post- and at 3-month and 1 year follow-up. Significant cost reductions were found for the treatment group at $16,806 per successfully treated case. The cost reductions were mainly driven by reduced work loss in the treatment group. Results were sustained at 3-month and 1 year follow-up. Internet-delivered CBT appears to generate health gains in IBS treatment and is associated with cost-savings from a societal perspective.


The role of the intestinal microbiome in ocular inflammatory disease.
The intestinal commensal microbiota are important in shaping immune cell repertoire and are influenced by host genetics. Because of this intricate interaction, an intestinal dysbiosis has been associated with multiple immune-mediated polygenic diseases. This review summarizes the literature on how alterations in the intestinal microbiota contribute to immune-mediated ocular disease, and how to potentially target the gut microbiome for therapeutic benefit. Several groups have demonstrated the importance of the intestinal microbiome in uveitis pathogenesis. Two groups showed that altering the microbiota with oral antibiotics results in reduced uveitis severity, and another group demonstrated that a commensal bacterial antigen activates retina-specific autoreactive T cells, potentially indicating a commensal trigger for uveitis. We have found that commensal bacterial metabolites, short chain fatty acids, can suppress autoimmune uveitis. Age-related macular degeneration is associated with an intestinal dysbiosis, which can be influenced by genetic risk alleles and age-related eye disease study (AREDS) supplementation. Strategies that might be effective for targeting the intestinal microbiota might involve several approaches, including the use of antibiotics, drugs that supplement beneficial bacterial components or target inflammatory bacterial strains, dietary strategies or microbial transplantation. The intestinal microbiota are potentially crucial in propagating inflammatory diseases of the eye, and can be targeted for therapeutic benefit.


Are accessory hearing structures linked to inner ear morphology? Insights from 3D orientation patterns of ciliary bundles in three cichlid species.
Cichlid fishes show considerable diversity in swim bladder morphology. In members of the subfamily Etroplinae, the connection between anterior swim bladder extensions and the inner ears enhances sound transmission and translates into an improved hearing ability. We tested the hypothesis that those swim bladder modifications coincide with differences in inner ear morphology and thus compared Steatocranus tinanti (vestigial swim bladder), Hemichromis guttatus (large swim bladder without extensions), and Etroplus maculatus (intimate connection between swim bladder and inner ears). We applied immunostaining together with confocal imaging and scanning electron microscopy for the investigation of sensory epithelia, and high-resolution, contrast-enhanced microCT imaging for characterizing inner ears in 3D, and evaluated otolith dimensions. Compared to S. tinanti and H. guttatus, inner ears of E. maculatus showed an enlargement of all three maculae, and a particularly large lacinia of the macula utriculi. While our analysis of orientation patterns of ciliary bundles on the three macula types using artificially flattened maculae uncovered rather similar orientation patterns of ciliary bundles, interspecific differences became apparent when illustrating the orientation patterns on the 3D models of the maculae: differences in the shape and curvature of the lacinia of the macula utriculi, and the anterior arm of the macula lagenae resulted in an altered arrangement of ciliary bundles. Our results imply that improved audition in E. maculatus is associated not only with swim bladder modifications but also with altered inner ear morphology. However, not all modifications in E. maculatus could be connected to enhanced auditory abilities, and so a potential improvement of the vestibular sense, among others, also needs to be considered. Our study highlights the value of analyzing orientation patterns of ciliary bundles in their intact 3D context in studies of inner ear morphology and physiology.


Ten-year study of pediatric drownings and near-drownings in King County, Washington: lessons in injury prevention.
The factors associated with submersion events among less than 20-year-old persons that occurred in King County from 1974 to 1983 were studied to focus prevention efforts. Near-drowning (n = 103) and drowning (n = 96) victims were identified from medical examiners' reports, paramedics' reports, and hospital discharge registers. Annual incidence was 5.5; the mortality rate was 2.6 per 100,000 children. Although preschool-aged children had the largest incidence (12.8), followed by older adolescents (4.9), adolescents had the largest case fatality rate, 77%. Lake and river victims had the largest incidence, mortality, and case fatality rate; swimming pools, the smallest case fatality rate (25%). A total of 89% of all victims had absent or no supervision; victims supervised by lifeguards had a 42% case fatality rate. Prior seizures were part of the history of 7.5% of all victims; 25% of fatal submersions by adolescents were associated with alcohol. Bathtub submersions were associated with child abuse in three of 16 preschool-aged children and epilepsy in four of five older children. Certain age groups and sites combined had the greatest incidence: preschool-aged children in swimming pools, infants in bathtubs, teenagers in lakes and rivers. Incidence decreased in public and semipublic pools coincident with fencing regulations. These findings suggest prevention strategies: extending fencing requirements to private pools, discouraging alcohol consumption during water sports, changing bathing practices of epileptics, and improving lifeguard efficacy.


Conversion disorder: current problems and potential solutions for DSM-5.
Conversion disorder in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) describes neurological symptoms, including weakness, numbness and events resembling epilepsy or syncope, which can be positively identified as not being due to recognised neurological disease. This review combines perspectives from psychiatry, psychology and neurology to identify and discuss key problems with the current diagnostic DSM-IV criteria for conversion disorder and to make the following proposals for DSM-5: (a) abandoning the label "conversion disorder" and replacing it with an alternative term that is both theoretically neutral and potentially more acceptable to patients and practitioners; (b) relegating the requirements for "association of psychological factors" and the "exclusion of feigning" to the accompanying text; (c) adding a criterion requiring clinical findings of internal inconsistency or incongruity with recognised neurological or medical disease and altering the current 'disease exclusion' criteria to one in which the symptom must not be 'better explained' by a disease if present, (d) adding a 'cognitive symptoms' subtype. We also discuss whether conversion symptoms are better classified with other somatic symptom disorders or with dissociative disorders and how we might address the potential heterogeneity of conversion symptoms in classification.


Which cheek to turn? The effect of gender and emotional expressivity on posing behavior.
Nicholls et al. (1999, Proc. Royal Soc. B, 266, 1517-1522) demonstrated that models turn their left or right cheeks when expressing or concealing emotion, respectively. This study examined whether emotionally expressive individuals are more likely to turn their left cheek when posing for a photograph than less emotionally expressive individuals. One hundred twenty-four normal participants completed an Emotional Expressivity Scale (EES) and posed for a photograph. Females had a higher EES than males and there was a trend for left cheek posers to have a higher EES than right cheek posers. Females were more likely to turn their left cheek than were males. Results support our argument that emotionally expressive individuals turn their left cheek when posing. The higher incidence of leftward poses in females than males may reflect the higher EES for females. These results support the proposition that the leftward bias in painted portraits is related to a desire to capture the emotive qualities of the left side of the face.


Disruption of saccadic adaptation with repetitive transcranial magnetic stimulation of the posterior cerebellum in humans.
Saccadic eye movements are driven by motor commands that are continuously modified so that errors created by eye muscle fatigue, injury, or-in humans-wearing spectacles can be corrected. It is possible to rapidly adapt saccades in the laboratory by introducing a discrepancy between the intended and actual saccadic target. Neurophysiological and lesion studies in the non-human primate as well as neuroimaging and patient studies in humans have demonstrated that the oculomotor vermis (lobules VI and VII of the posterior cerebellum) is critical for saccadic adaptation. We studied the effect of transiently disrupting the function of posterior cerebellum with repetitive transcranial magnetic stimulation (rTMS) on the ability of healthy human subjects to adapt saccadic eye movements. rTMS significantly impaired the adaptation of the amplitude of saccades, without modulating saccadic amplitude or variability in baseline conditions. Moreover, increasing the intensity of rTMS produced a larger impairment in the ability to adapt saccadic size. These results provide direct evidence for the role of the posterior cerebellum in man and further evidence that TMS can modulate cerebellar function.


The association of penicillin-binding proteins with cell elongation and septum formation in Bacillus megaterium.
Analysis of the penicillin-binding proteins in the membranes from germinated spores of Bacillus megaterium and a filamentous mutant indicated that (a) no specific synthesis of any penicillin-binding protein occurred before or during two relatively synchronous cell divisions, (b) penicillin-binding proteins 1, 3a and 3b may be involved in cell elongation and (c) filamentation of the mutant may be due to a decrease in the concentration of penicillin-binding protein 1.


Transfer of learning and patient outcome in simulated crisis resource management: a systematic review.
Simulation-based learning is increasingly used by healthcare professionals as a safe method to learn and practice non-technical skills, such as communication and leadership, required for effective crisis resource management (CRM). This systematic review was conducted to gain a better understanding of the impact of simulation-based CRM teaching on transfer of learning to the workplace and subsequent changes in patient outcomes. Studies on CRM, crisis management, crew resource management, teamwork, and simulation published up to September 2012 were searched in MEDLINE(®), EMBASE™, CINAHL, Cochrane Central Register of Controlled Trials, and ERIC. All studies that used simulation-based CRM teaching with outcomes measured at Kirkpatrick Level 3 (transfer of learning to the workplace) or 4 (patient outcome) were included. Studies measuring only learners' reactions or simple learning (Kirkpatrick Level 1 or 2, respectively) were excluded. Two authors independently reviewed all identified titles and abstracts for eligibility. Nine articles were identified as meeting the inclusion criteria. Four studies measured transfer of simulation-based CRM learning into the clinical setting (Kirkpatrick Level 3). In three of these studies, simulation-enhanced CRM training was found significantly more effective than no intervention or didactic teaching. Five studies measured patient outcomes (Kirkpatrick Level 4). Only one of these studies found that simulation-based CRM training made a clearly significant impact on patient mortality. Based on a small number of studies, this systematic review found that CRM skills learned at the simulation centre are transferred to clinical settings, and the acquired CRM skills may translate to improved patient outcomes, including a decrease in mortality.


Bound soliton pairs in photonic crystal fiber.
We demonstrate experimentally the formation and stable propagation of bound soliton pairs in a highly nonlinear photonic crystal fiber. The bound pairs occur at a particular power as the consequence of high-order soliton fission. They propagate over long distances with constant inter-soliton frequency and time separation. During propagation, the soliton self-frequency shift causes the central frequency of the pairs to move towards longer wavelength. The formation and characteristics of the bound soliton pairs are confirmed numerically. We believe this to be the first experimental observation of such bound soliton pairs.


Remodeling of substrate consumption in the murine sTAC model of heart failure.
Energy metabolism and substrate selection are key aspects of correct myocardial mechanical function. Myocardial preference for oxidizable substrates changes in both hypertrophy and in overt failure. Previous work has shown that glucose oxidation is upregulated in overpressure hypertrophy, but its fate in overt failure is less clear. Anaplerotic flux of pyruvate into the tricarboxylic acid cycle (TCA) has been posited as a secondary fate of glycolysis, aside from pyruvate oxidation or lactate production. A model of heart failure that emulates both valvular and hypertensive heart disease, the severe transaortic constriction (sTAC) mouse, was assayed for changes in substrate preference using metabolomic and carbon-13 flux measurements. Quantitative measures of O2 consumption in the Langendorff perfused mouse heart were paired with 13C isotopomer analysis to assess TCA cycle turnover. Since the heart accommodates oxidation of all physiological energy sources, the utilization of carbohydrates, fatty acids, and ketones were measured simultaneously using a triple-tracer NMR method. The fractional contribution of glucose to acetyl-CoA production was upregulated in heart failure, while other sources were not significantly different. A model that includes both pyruvate carboxylation and anaplerosis through succinyl-CoA produced superior fits to the data compared to a model using only pyruvate carboxylation. In the sTAC heart, anaplerosis through succinyl-CoA is elevated, while pyruvate carboxylation was not. Metabolomic data showed depleted TCA cycle intermediate pool sizes versus the control, in agreement with previous results. In the sTAC heart failure model, the glucose contribution to acetyl-CoA production was significantly higher, with compensatory changes in fatty acid and ketone oxidation not reaching a significant level. Anaplerosis through succinyl-CoA is also upregulated, and is likely used to preserve TCA cycle intermediate pool sizes. The triple tracer method used here is new, and can be used to assess sources of acetyl-CoA production in any oxidative tissue.


Reduction of C-reactive protein is not associated with reduced cardiovascular risk and mortality in patients treated with statins. A meta-analysis of 22 randomized trials.
The association between C-reactive protein (CRP) levels and risk of cardiovascular (CV) events has been reported in several studies. However, it is unclear whether a reduction in CRP is associated with a reduction in risk of clinical events. Therefore we sought to investigate, in a meta-regression analysis of randomized studies enrolling patients treated by statins, whether changes in CRP are associated with changes in risk of CV events or overall survival. Randomized trials enrolling patients treated by statins, reporting CRP at baseline and at end of follow-up, CV events [myocardial infarction (MI) and stroke], CV and all-cause mortality were selected. Twenty-two trials enrolling 54,213 participants were included in the analysis. Meta-analysis showed that active treatment significantly reduced risk of all-cause death by 8%, myocardial infarction by 11%, stroke by 10.3% and the composite outcome (including CV death, MI and stroke) by 8%, whereas risks of CV mortality was not significantly reduced. Meta-regression analysis revealed that reduction in CRP levels was significantly associated only with the reduction of MI, whereas no relationship was identified between changes in CRP and risk of stroke, CV and all-cause mortality, and the composite outcome. These findings demonstrate that statin-induced changes in CRP do not correlate with major CV events apart from the risk of MI nor with overall survival in high-risk patients. These data suggest that although CRP may be a surrogate marker for coronary risk, it should not be used for predicting the effectiveness of statin therapy.


Cardio-Oncology: How New Targeted Cancer Therapies and Precision Medicine Can Inform Cardiovascular Discovery.
Cardio-oncology (the cardiovascular care of cancer patients) has developed as a new translational and clinical field based on the expanding repertoire of mechanism-based cancer therapies. Although these therapies have changed the natural course of many cancers, several may also lead to cardiovascular complications. Many new anticancer drugs approved over the past decade are "targeted" kinase inhibitors that interfere with intracellular signaling contributing to tumor progression. Unexpected cardiovascular and cardiometabolic effects of patient treatment with these inhibitors have provided unique insights into the role of kinases in human cardiovascular biology. Today, an ever-expanding number of cancer therapies targeting novel kinases and other specific cellular and metabolic pathways are being developed and tested in oncology clinical trials. Some of these drugs may affect the cardiovascular system in detrimental ways and others perhaps in beneficial ways. We propose that the numerous ongoing oncology clinical trials are an opportunity for closer collaboration between cardiologists and oncologists to study the cardiovascular and cardiometabolic changes caused by the modulation of these pathways in patients. In this regard, cardio-oncology represents an opportunity and a novel platform for basic and translational investigation and can serve as a potential avenue for optimization of anticancer therapies and for cardiovascular research and drug discovery.


Mental Imagery and Post-Traumatic Stress Disorder: A Neuroimaging and Experimental Psychopathology Approach to Intrusive Memories of Trauma.
This hypothesis and theory paper presents a pragmatic framework to help bridge the clinical presentation and neuroscience of intrusive memories following psychological trauma. Intrusive memories are a hallmark symptom of post-traumatic stress disorder (PTSD). However, key questions, including those involving etiology, remain. In particular, we know little about the brain mechanisms involved in why only some moments of the trauma return as intrusive memories while others do not. We first present an overview of the patient experience of intrusive memories and the neuroimaging studies that have investigated intrusive memories in PTSD patients. Next, one mechanism of how to model intrusive memories in the laboratory, the trauma film paradigm, is examined. In particular, we focus on studies combining the trauma film paradigm with neuroimaging. Stemming from the clinical presentation and our current understanding of the processes involved in intrusive memories, we propose a framework in which an intrusive memory comprises five component parts; autobiographical (trauma) memory, involuntary recall, negative emotions, attention hijacking, and mental imagery. Each component part is considered in turn, both behaviorally and from a brain imaging perspective. A mapping of these five components onto our understanding of the brain is described. Unanswered questions that exist in our understanding of intrusive memories are considered using the proposed framework. Overall, we suggest that mental imagery is key to bridging the experience, memory, and intrusive recollection of the traumatic event. Further, we suggest that by considering the brain mechanisms involved in the component parts of an intrusive memory, in particular mental imagery, we may be able to aid the development of a firmer bridge between patients' experiences of intrusive memories and the clinical neuroscience behind them.


miR-107 activates ATR/Chk1 pathway and suppress cervical cancer invasion by targeting MCL1.
MicroRNAs (miRNAs) are a class of single-stranded, non-coding RNAs of about 22 nucleotides in length. Increasing evidence implicates miRNAs may function as oncogenes or tumor suppressors. Here we showed that miR-107 directly targeted MCL1 and activated ATR/Chk1 pathway to inhibit proliferation, migration and invasiveness of cervical cancer cells. Moreover, we found that MCL1 was frequently up-regulated in cervical cancer, and knockdown of MCL1 markedly inhibited cancer cell proliferation, migration and invasion, whereas ectopic expression of MCL1 significantly enhances these properties. The restoration of MCL1 expression can counteract the effect of miR-107 on the cancer cells. Together, miR-107 is a new regulator of MCL1, and both miR-107 and MCL1 play important roles in the pathogenesis of cervical cancer. We have therefore identified a mechanism for ATR/Chk1 pathway which involves an increase in miR-107 leading to a decrease in MCL1. Correspondingly, our results revealed that miR-107 affected ATR/Chk1 signalling and gene expression, and implicated miR-107 as a therapeutic target in human cervical cancer. We also demonstrated that taxol attenuated migration and invasion in cervical cancer cells by activating the miR-107, in which miR-107 play an important role in regulating the expression of MCL1. Elucidation of this discovered MCL1 was directly regulated by miR-107 will greatly enhance our understanding of the mechanisms responsible for cervical cancer and will provide an additional arm for the development of anticancer therapies.


Automatic Bayesian classification of healthy controls, bipolar disorder, and schizophrenia using intrinsic connectivity maps from FMRI data.
We present a method for supervised, automatic, and reliable classification of healthy controls, patients with bipolar disorder, and patients with schizophrenia using brain imaging data. The method uses four supervised classification learning machines trained with a stochastic gradient learning rule based on the minimization of Kullback-Leibler divergence and an optimal model complexity search through posterior probability estimation. Prior to classification, given the high dimensionality of functional MRI (fMRI) data, a dimension reduction stage comprising two steps is performed: first, a one-sample univariate t-test mean-difference T(score) approach is used to reduce the number of significant discriminative functional activated voxels, and then singular value decomposition is performed to further reduce the dimension of the input patterns to a number comparable to the limited number of subjects available for each of the three classes. Experimental results using functional brain imaging (fMRI) data include receiver operation characteristic curves for the three-way classifier with area under curve values around 0.82, 0.89, and 0.90 for healthy control versus nonhealthy, bipolar disorder versus nonbipolar, and schizophrenia patients versus nonschizophrenia binary problems, respectively. The average three-way correct classification rate (CCR) is in the range of 70%-72%, for the test set, remaining close to the estimated Bayesian optimal CCR theoretical upper bound of about 80% , estimated from the one nearest-neighbor classifier over the same data.


M2b macrophage elimination and improved resistance of mice with chronic alcohol consumption to opportunistic infections.
Alcohol abuse was found to predispose persons to opportunistic infections. In this study, we tried to improve the host antibacterial resistance of chronic alcohol-consuming (CAC) mice to opportunistic infections. Bactericidal macrophages with functions to produce IL-12 and to express mRNAs for CXCL9 and inducible nitric oxide synthase (M1 macrophages) were characterized as the main effector cells in host antibacterial innate immunities against infections with opportunistic pathogens. However, CAC mice were found to be carriers of M2b macrophages [macrophages with functions to produce IL-10 and to express mRNAs for CD163, chemokine ligand (CCL)1, and LIGHT (homologous to lymphotoxin, exhibits inducible expression, competes with herpes simplex virus glycoprotein D for high-voltage electron microscopy on T cells)], which were inhibitory on macrophage conversion from resident macrophages to M1 macrophages. Under treatment with CCL1 antisense oligodeoxynucleotides, a specific inhibitor of M2b macrophages, CAC mouse macrophages reverted to resident macrophages, and M1 macrophages were induced by a bacterial antigen from macrophages of CAC mice that were previously treated with the oligodeoxynucleotides. Opportunistic infections (enterococcal translocation and Klebsiella pneumonia) in CAC mice were completely controlled by CCL1 antisense oligodeoxynucleotides. These results indicate that certain opportunistic infections in alcoholics are controllable through the modulation of M2b macrophages.


Directly observed therapy and tuberculosis: how can a systematic review of qualitative research contribute to improving services? A qualitative meta-synthesis.
This paper reports the findings from a qualitative meta-synthesis concerning people with, or at risk of, tuberculosis, service providers and policymakers and their experiences and perceptions of tuberculosis and treatment. Directly observed therapy is part of a package of interventions to improve tuberculosis treatment and adherence. A Cochrane systematic review of trials showed an absence of evidence for or against directly observed therapy compared with people treating themselves. Qualitative systematic review methods were used to search, screen, appraise and extract data thematic analysis was used to synthesize data from 1990 to 2002, and an update of literature to December 2005. Two questions were addressed: 'What does qualitative research tell us about the facilitators and barriers to accessing and complying with tuberculosis treatment?' and 'What does qualitative research tell us about the diverse results and effect sizes of the randomized controlled trials included in the Cochrane review?' Findings help explain the diverse trial results in a Cochrane systematic review of directly observed therapy and tuberculosis and consider implications for research, policy and practice. Five themes emerged from the 1990 to 2002 synthesis: socio-economic circumstances, material resources and individual agency; explanatory models and knowledge systems in relation to tuberculosis and its treatment; the experience of stigma and public discourses around tuberculosis; sanctions, incentives and support, and the social organization and social relationships of care. Two additional themes emerged from the 2005 update. The qualitative meta-synthesis improved the relevance and scope of the Cochrane review of trials. The findings make a major contribution to the development of theory concerning global WHO-branded disease control and the practicality of local delivery to people.


Smoking cessation advice: Swiss physicians lack training.
To assess the use and appropriateness of medical advice for smoking cessation provided by registrars in a General Medicine Outpatient Department to an unselected patient population in Switzerland. A prospective observational study in which 314 consecutive outpatients were contacted by phone within 24h after their consultation. Questions and information concerning smoking asked and/or provided by the registrar to patients were collected. Eleven registrars (mean age 34 years (range 29-40), 54% females, mean of 5 years (range 3.5-6 years) postgraduate medical training) worked in the Basel University Hospital Medical Outpatient Department during the study period from 01.01.2006 to 31.03.2006. In total 314 participants (mean 48 years, age range 16-71 years, 50% females) completed the study. Registrars queried 81% of the patients about smoking, but inquired about smoking duration only in 44% of the patients. Twenty-eight percent of the patients received information about the risks related to smoking, whereas cessation was discussed only with 10% and offered to 9% of the patients. Though most junior physicians in the survey asked about smoking, they failed to appropriately address tobacco-related health issues and offer cessation advice in the majority of cases. Extended regular training for physicians on smoking-related issues will be necessary in order to improve counselling of smokers and meet the global tobacco challenge.


The economic burden of cancer in Korea in 2009.
Cancer imposes a significant economic burden on individuals, families and society. The purpose of this study was to estimate the economic burden of cancer using the healthcare claims and cancer registry data in Korea in 2009. The economic burden of cancer was estimated using the prevalence data where patients were identified in the Korean Central Cancer Registry. We estimated the medical, non-medical, morbidity and mortality cost due to lost productivity. Medical costs were calculated using the healthcare claims data obtained from the Korean National Health Insurance (KNHI) Corporation. Non-medical costs included the cost of transportation to visit health providers, costs associated with caregiving for cancer patients, and costs for complementary and alternative medicine (CAM). Data acquired from the Korean National Statistics Office and Ministry of Labor were used to calculate the life expectancy at the time of death, age- and gender-specific wages on average, adjusted for unemployment and labor force participation rate. Sensitivity analysis was performed to derive the current value of foregone future earnings due to premature death, discounted at 3% and 5%. In 2009, estimated total economic cost of cancer amounted to $17.3 billion at a 3% discount rate. Medical care accounted for 28.3% of total costs, followed by non-medical (17.2%), morbidity (24.2%) and mortality (30.3%) costs. Given that the direct medical cost sharply increased over the last decade, we must strive to construct a sustainable health care system that provides better care while lowering the cost. In addition, a comprehensive cancer survivorship policy aimed at lower caregiving cost and higher rate of return to work has become more important than previously considered.


Functional Biology and Molecular Mechanisms of Host-Pathogen Interactions for Aflatoxin Contamination in Groundnut (Arachis hypogaea L.) and Maize (Zea mays L.).
Aflatoxins are secondary metabolites produced by soilborne saprophytic fungus Aspergillus flavus and closely related species that infect several agricultural commodities including groundnut and maize. The consumption of contaminated commodities adversely affects the health of humans and livestock. Aflatoxin contamination also causes significant economic and financial losses to producers. Research efforts and significant progress have been made in the past three decades to understand the genetic behavior, molecular mechanisms, as well as the detailed biology of host-pathogen interactions. A range of omics approaches have facilitated better understanding of the resistance mechanisms and identified pathways involved during host-pathogen interactions. Most of such studies were however undertaken in groundnut and maize. Current efforts are geared toward harnessing knowledge on host-pathogen interactions and crop resistant factors that control aflatoxin contamination. This study provides a summary of the recent progress made in enhancing the understanding of the functional biology and molecular mechanisms associated with host-pathogen interactions during aflatoxin contamination in groundnut and maize.


How do patients and the public understand overtesting and overdiagnosis? A protocol for a thematic meta-synthesis of qualitative research.
Examining patient and public understanding of overtesting and overdiagnosis (OverTD) is vital for reducing the burden of OverTD. Studies from disparate contexts, disciplines and focusing on disparate healthcare issues have examined patient and public understanding of OverTD. A synthesis is needed to bring this literature together, examine common themes, strengthen conclusions and identify gaps. This will help steer further research, policy and practice to improve patient and public understanding of OverTD. The objective of this study is to synthesise qualitative research data about patient and public understanding of OverTD. A thematic meta-synthesis will be used to synthesise primary qualitative research and qualitative components of primary mixed-methods research about patient and public understanding of OverTD. Studies published in English will be included. These will be identified using systematic searches from inception to March 2020 in the Scopus, CINAHL, PsycINFO and MEDLINE databases. Studies that satisfy eligibility criteria will be assessed for methodological quality using the Critical Appraisal Skills Programme (CASP) checklist. Thematic meta-synthesis will comprise three stages: (1) line-by-line coding; (2) generation of descriptive themes and (3) generation of analytic themes. Confidence in the synthesis findings will be assessed using the Grading of Recommendations Assessment, Development and Evaluation Confidence in Evidence (GRADE CERQual) approach. A summary of GRADE CERQual results will be presented alongside the key themes. Study eligibility screening, data extraction, analysis and the CASP and GRADE CERQual assessments will be undertaken independently by two review authors. Ethics approval is not required for this secondary analysis of published data. The results will be disseminated in peer-reviewed journals and may be presented in conference papers and elsewhere. CRD42020156838.


Experiences of lower limb prosthesis users in Kenya: a qualitative study to understand motivation to use and satisfaction with prosthetic outcomes.
To explore the personal and system factors that motivate and enhance outcomes for patients accessing a prosthetic service and using a lower-limb prosthesis within a low resource setting. This study employed a qualitative approach to explore the motivations and satisfaction of individuals with lower limb loss engaging with a prosthetic service in Mombasa, Kenya. In-depth interviews were conducted over Microsoft Teams with 10 lower limb prosthesis users and thematic analysis was applied. Five key themes emerged: acceptance, self-determination, hope, clinician relationship and perception. These findings demonstrate the importance of hopeful thinking and a supportive community in overcoming physical and stigmatising challenges. The findings further highlight the value of the service provider relationship beyond just prescribing an assistive device. These results have relevance in developing patient-centred services, assistive devices and personnel training that are responsive, motivating, and cognisant of the service user. This is of particular interest as assistive technology services are newly developed in low resource settings.IMPLICATIONS FOR REHABILITATIONThis research provides an understanding of lower-limb prosthesis users' satisfaction of a device and motivation for engaging with a prosthetic service within a low resource setting.The relationship the rehabilitation professional has with the service user plays a significant role in facilitating motivation during rehabilitation.Rehabilitation professionals should consider how they can foster a network of support amongst service users when planning services in remote, rural locations.Rehabilitation professionals should be aware of how hopeful thinking can be facilitated during rehabilitation to support motivation.When reviewing the success of services, or designing new service models, the service users should be consulted on what they would deem as a successful outcome.


Identification of positive allosteric modulators VU0155094 (ML397) and VU0422288 (ML396) reveals new insights into the biology of metabotropic glutamate receptor 7.
Metabotropic glutamate receptor 7 (mGlu7) is a member of the group III mGlu receptors (mGlus), encompassed by mGlu4, mGlu6, mGlu7, and mGlu8. mGlu7 is highly expressed in the presynaptic active zones of both excitatory and inhibitory synapses, and activation of the receptor regulates the release of both glutamate and GABA. mGlu7 is thought to be a relevant therapeutic target for a number of neurological and psychiatric disorders, and polymorphisms in the GRM7 gene have been linked to autism, depression, ADHD, and schizophrenia. Here we report two new pan-group III mGlu positive allosteric modulators, VU0155094 and VU0422288, which show differential activity at the various group III mGlus. Additionally, both compounds show probe dependence when assessed in the presence of distinct orthosteric agonists. By pairing studies of these nonselective compounds with a synapse in the hippocampus that expresses only mGlu7, we have validated activity of these compounds in a native tissue setting. These studies provide proof-of-concept evidence that mGlu7 activity can be modulated by positive allosteric modulation, paving the way for future therapeutics development.


Stressful and traumatic life events are associated with burnout-a cross-sectional twin study.
Most burnout studies focus on symptoms of burnout in relation to work-related stress. However, recent studies have found that familial factors and stress in the personal life may also be of importance. Stressful and traumatic life events influence how individuals cope with stress over the life course and may therefore be associated with burnout symptoms. This study aims to assess the associations between stressful and traumatic life events and burnout symptoms in a population-based sample of twins, adjusting for familial confounding. In this cross-sectional questionnaire-based study of 25,378 Swedish twins, odds ratios (OR) with 95% confidence intervals (CI) were calculated using logistic regression analysis. First, the whole sample was analysed. Secondly, a matched co-twin analysis was conducted of the same-sex twin pairs discordant on burnout, in order to adjust for familial factors. A history of traumatic life events was independently associated with burnout symptoms, with a cumulative effect with increasing number of events. ORs adjusted for familial confounding: 1-3 events OR 1.58 (CI = 1.21-2.07) 4 or more events OR 2.00 (CI = 1.45-2.75). Independent associations between the stressful life events: serious family problems OR 1.71 (CI = 1.36-2.15), physical illness OR 1.44 (CI = 1.17-1.77), divorce or separation OR 1.40 (CI = 1.15-1.70), and burnout symptoms were also found. The results indicate that stressful and traumatic life events are of importance in the burnout process. This finding may have implications in efforts to prevent burnout.


Sex differences in empathy and its relation to juvenile offending.
Implicit in most theoretical accounts of sex differences in offending is the assumption that females are less likely than males to engage in crime--especially serious, violent crime--in part because of their comparatively higher levels of concern for others and stronger affiliative ties. Much research suggests that significant sex differences in both empathy and serious offending emerge in adolescence, with females displaying notably higher levels of empathy and males engaging in notably higher levels of serious offending. However, there has been little empirical work assessing the degree to which sex differences in empathy among adolescents can account for sex differences in offending. This research uses data from a sample of adolescents attending public high schools in Philadelphia (n = 425) and a sample of adolescents incarcerated in the California Youth Authority (CYA) (n = 232) to examine the relation between empathy and serious offending. Results suggest that empathy acts as a protective factor for both males and females but that there are subtle differences among males and females in the relation between empathy and offending.


Novel non-linear curve fitting to resolve protein unfolding transitions in intrinsic fluorescence differential scanning fluorimetry.
In biotherapeutic protein research, an estimation of the studied protein's thermal stability is one of the important steps that determine developability as a function of solvent conditions. Differential Scanning Fluorimetry (DSF) can be applied to measure thermal stability. Label-free DSF measures amino acid fluorescence as a function of temperature, where conformational changes induce observable peak deformation, yielding apparent melting temperatures. The estimation of the stability parameters can be hindered in the case of multidomain, multimeric or aggregating proteins when multiple transitions partially coincide. These overlapping protein unfolding transitions are hard to evaluate by the conventional methodology, as peak maxima are shifted by convolution. We show how non-linear curve fitting of intrinsic fluorescence DSF can deconvolute highly overlapping transitions in formulation screening in a semi-automated process. The proposed methodology relies on synchronous, constrained fits of the fluorescence intensity, ratio and their derivatives, by combining linear baselines with generalized logistic transition functions. The proposed algorithm is applied to data from three proteins; a single transition, a double separated transition and a double overlapping transition. Extracted thermal stability parameters; apparent melting temperatures Tm,1, Tm,2 and melting onset temperature Tonset are obtained and compared with reference software analysis. The fits show R2 = 0.94 for single and R2 = 0.88 for separated transitions. Obtaining values and trends for Tonset in a well-described and automated way, will aid protein scientist to better evaluate the thermal stability of proteins.


Survey-based analysis of risk factors for injury among dogs participating in agility training and competition events.
To identify potential risk factors for agility-related injuries among dogs. Internet-based, retrospective, cross-sectional survey. 3,801 privately owned dogs participating in agility training or trials. A retrospective electronic survey was used to investigate potential risk factors for injury among dogs participating in agility-related activities. Respondents were handlers recruited through member lists of large canine agility associations in Canada and the United Kingdom and through promotion on an agility blog site. Variables evaluated included demographic information for handlers and dogs, exposure variables (eg, frequency of agility practice and competition in the past year), and use of preventive measures intended to keep dogs fit for agility (warmup, cooldown, or conditioning exercises; alternative therapeutic treatments [eg, acupuncture, massage, or chiropractic care]; or dietary supplement products). Data were collected from 1,669 handlers of 3,801 agility dogs internationally; 1,209 (32%) dogs incurred ≥ 1 injury. Previous injury (OR, 100.5), ≤ 4 years of agility experience for dogs (OR, 1.5), use of alternative therapeutic treatments (OR, 1.5), and Border Collie breed (OR, 1.7) were associated with increased odds of injury. Handlers having 5 to 10 or > 10 years of experience (OR, 0.8 and 0.6, respectively) and dogs having > 4 years of experience in the sport (OR, 0.6) were associated with decreased odds of injury. Specific factors were associated with agility-related injuries in dogs. Educational prevention strategies should target at-risk populations in an effort to reduce potential injuries. Future research should focus on the biomechanical factors associated with agility-related injuries.


Therapeutic vaccination expands and improves the function of the HIV-specific memory T-cell repertoire.
The licensing of herpes zoster vaccine has demonstrated that therapeutic vaccination can help control chronic viral infection. Unfortunately, human trials of immunodeficiency virus (HIV) vaccine have shown only marginal efficacy. In this double-blind study, 17 HIV-infected individuals with viral loads of <50 copies/mL and CD4(+) T-cell counts of >350 cells/µL were randomly assigned to the vaccine or placebo arm. Vaccine recipients received 3 intramuscular injections of HIV DNA (4 mg) coding for clade B Gag, Pol, and Nef and clade A, B, and C Env, followed by a replication-deficient adenovirus type 5 boost (10(10) particle units) encoding all DNA vaccine antigens except Nef. Humoral, total T-cell, and CD8(+) cytotoxic T-lymphocyte (CTL) responses were studied before and after vaccination. Single-copy viral loads and frequencies of latently infected CD4(+) T cells were determined. Vaccination was safe and well tolerated. Significantly stronger HIV-specific T-cell responses against Gag, Pol, and Env, with increased polyfunctionality and a broadened epitope-specific CTL repertoire, were observed after vaccination. No changes in single-copy viral load or the frequency of latent infection were observed. Vaccination of individuals with existing HIV-specific immunity improved the magnitude, breadth, and polyfunctionality of HIV-specific memory T-cell responses but did not impact markers of viral control. NCT00270465.


Transformation of chicken embryo fibroblasts by v-src uncouples beta1 integrin-mediated outside-in but not inside-out signaling.
Adhesion of cells to extracellular matrix is mediated by integrin family receptors. The process of receptor-ligand binding is dependent on metabolic energy and is regulated by intracellular signals, termed inside-out signals. The strength of the initial alpha5beta1-mediated adhesion of v-src-transformed chicken embryo fibroblasts (v-srcCEF) was similar to that of normal CEF. A chemically cross-linked fibronectin substrate was able to restore cell spreading and the ability of v-srcCEF to assemble a fibronectin matrix. Over time, v-srcCEF showed decreased adhesion due to the reduction of alpha5beta1-fibronectin bonds consequent on the reduction of substrate-bound fibronectin due to the secretion of proteases by v-srcCEF. Excess synthesis of hyaluronic acid by v-srcCEF also reduced the alpha5beta1-fibronectin bonds and contributed to cell detachment at later times in culture. Thus, the adhesion defects were not due to a failure of alpha5beta1 function and adhesion of the v-srcCEF was alpha5beta1 dependent. Integrin-mediated adhesion also produces signals that affect cell proliferation and cell differentiation. An early consequence of these "outside-in" signals was the phosphorylation of FAK Y397 in direct proportion to the number of alpha5beta1-fibronectin bonds formed. In contrast, v-srcCEF had an increased level of phosphorylation on five different tyrosines in FAK, and none of these phosphorylation levels were sensitive to the number of alpha5beta1-fibronectin bonds. In the absence of serum, CEF proliferation was sensitive to changes in alpha5beta1-mediated adhesion levels. Transformation by v-src increased the serum-free proliferation rate and made it insensitive to alpha5beta1-mediated adhesion. Thus, the v-srcCEF were insensitive to the normal outside-in signals from alpha5beta1 integrin.


Tuberculosis screening at the Sainte-Anne Hospital in Paris - results of first and second IGRA.
Healthcare workers (HCWs) are exposed to Mycobacterium tuberculosis (MTB) and therefore are screened for tuberculosis (TB). Results of TB screenings with the Interferon-γ Release Assay (IGRA) in a French psychiatric hospital without a TB ward are described. At the Sainte-Anne Hospital, a referral centre for psychiatric patients throughout the municipal region of Paris, IGRA screening is performed during pre-employment and general health examination or after potential contact to MTB. The QuantiFERON Gold in tube (QFT) is used and data on TB history are assessed in a standardized manner. Between August 2008 und August 2013 in total 1.192 HCWs were tested and the QFT was positive in 265 (22.2%). Probability of a positive QFT increased with age. A second QFT was performed in 144 HCWs with a positive QFT and 53 (36.8%) HCWs had a reversion. With a positive QFT close to the cut-off (e.g. 0.35-0.7 IU/ml) the odds ratio for a reversion was 4.6 compared to an INF-γ concentration of ≥3.0 IU/ml. Probability of reversion was not influenced by preventive chemotherapy, which was completed by 28 (19.4%) HCWs with a positive QFT. No active TB was detected. Prevalence of positive IGRA is high in French HCWs as is the number of reversions in IGRA. Reversion rate is particularly high around the cut-off of the IGRA. A borderline zone will therefore reduce the influence of test variability.


Conditional mutations in the yeast DNA primase genes affect different aspects of DNA metabolism and interactions in the DNA polymerase alpha-primase complex.
Different pri1 and pri2 conditional mutants of Saccharomyces cerevisiae altered, respectively, in the small (p48) and large (p58) subunits of DNA primase, show an enhanced rate of both mitotic intrachromosomal recombination and spontaneous mutation, to an extent which is correlated with the severity of their defects in cell growth and DNA synthesis. These effects might be attributable to the formation of nicked and gapped DNA molecules that are substrates for recombination and error-prone repair, due to defective DNA replication in the primase mutants. Furthermore, pri1 and pri2 mutations inhibit sporulation and affect spore viability, with the unsporulated mutant cells arresting with a single nucleus, suggesting that DNA primase plays a critical role during meiosis. The observation that all possible pairwise combinations of two pri1 and two pri2 alleles are lethal provides further evidence for direct interaction of the primase subunits in vivo. Immunopurification and immunoprecipitation studies on wild-type and mutant strains suggest that the small subunit has a major role in determining primase activity, whereas the large subunit directly interacts with DNA polymerase alpha, and either mediates or stabilizes association of the p48 polypeptide in the DNA polymerase alpha-primase complex.


Visually guided adjustments of body posture in the roll plane.
Body position relative to gravity is continuously updated to prevent falls. Therefore, the brain integrates input from the otoliths, truncal graviceptors, proprioception and vision. Without visual cues estimated direction of gravity mainly depends on otolith input and becomes more variable with increasing roll-tilt. Contrary, the discrimination threshold for object orientation shows little modulation with varying roll orientation of the visual stimulus. Providing earth-stationary visual cues, this retinal input may be sufficient to perform self-adjustment tasks successfully, with resulting variability being independent of whole-body roll orientation. We compared conditions with informative (earth-fixed) and non-informative (body-fixed) visual cues. If the brain uses exclusively retinal input (if earth-stationary) to solve the task, trial-to-trial variability will be independent from the subject's roll orientation. Alternatively, central integration of both retinal (earth-fixed) and extra-retinal inputs will lead to increasing variability when roll-tilted. Subjects, seated on a motorized chair, were instructed to (1) align themselves parallel to an earth-fixed line oriented earth-vertical or roll-tilted 75° clockwise; (2) move a body-fixed line (aligned with the body-longitudinal axis or roll-tilted 75° counter-clockwise to it) by adjusting their body position until the line was perceived earth-vertical. At 75° right-ear-down position, variability increased significantly (p < 0.05) compared to upright in both paradigms, suggesting that, despite the earth-stationary retinal cues, extra-retinal input is integrated. Self-adjustments in the roll-tilted position were significantly (p < 0.01) more precise for earth-fixed cues than for body-fixed cues, underlining the importance of earth-stable visual cues when estimates of gravity become more variable with increasing whole-body roll.


Quantifying pathogen risks associated with potable reuse: A risk assessment case study for Cryptosporidium.
This study evaluated the reliability and equivalency of three different potable reuse paradigms: (1) surface water augmentation via de facto reuse with conventional wastewater treatment; (2) surface water augmentation via planned indirect potable reuse (IPR) with ultrafiltration, pre-ozone, biological activated carbon (BAC), and post-ozone; and (3) direct potable reuse (DPR) with ultrafiltration, ozone, BAC, and UV disinfection. A quantitative microbial risk assessment (QMRA) was performed to (1) quantify the risk of infection from Cryptosporidium oocysts; (2) compare the risks associated with different potable reuse systems under optimal and sub-optimal conditions; and (3) identify critical model/operational parameters based on sensitivity analyses. The annual risks of infection associated with the de facto and planned IPR systems were generally consistent with those of conventional drinking water systems [mean of (9.4 ± 0.3) × 10-5 to (4.5 ± 0.1) × 10-4], while DPR was clearly superior [mean of (6.1 ± 67) × 10-9 during sub-optimal operation]. Because the advanced treatment train in the planned IPR system was highly effective in reducing Cryptosporidium concentrations, the associated risks were generally dominated by the pathogen loading already present in the surface water. As a result, risks generally decreased with higher recycled water contributions (RWCs). Advanced treatment failures were generally inconsequential either due to the robustness of the advanced treatment train (i.e., DPR) or resiliency provided by the environmental buffer (i.e., planned IPR). Storage time in the environmental buffer was important for the de facto reuse system, and the model indicated a critical storage time of approximately 105 days. Storage times shorter than the critical value resulted in significant increases in risk. The conclusions from this study can be used to inform regulatory decision making and aid in the development of design or operational criteria for IPR and DPR systems.


Quantifying the contribution of riparian soils to the provision of ecosystem services.
Riparian areas, the interface between land and freshwater ecosystems, are considered to play a pivotal role in the supply of regulating, provisioning, cultural and supporting services. Most previous studies, however, have tended to focus on intensive agricultural systems and only on a single ecosystem function. Here, we present the first study which attempts to assess a wide range of ecological processes involved in the provision of the ecosystem service of water quality regulation across a diverse range of riparian typologies. Specifically, we focus on 1) evaluating the spatial variation in riparian soils properties with respect to distance with the river and soil depth in contrasting habitat types; 2) gaining further insights into the underlying mechanisms of pollutant removal (i.e. pesticide sorption/degradation, denitrification, etc.) by riparian soils; and 3) quantify and evaluate how riparian vegetation across different habitat types contribute to the provision of watercourse shading. All the habitats were present within a single large catchment and included: (i) improved grassland, (ii) unimproved (semi-natural) grassland, (iii) broadleaf woodland, (iv) coniferous woodland, and (iv) mountain, heath and bog. Taking all the data together, the riparian soils could be statistically separated by habitat type, providing evidence that they deliver ecosystem services to differing extents. Overall, however, our findings seem to contradict the general assumption that soils in riparian area are different from neighbouring (non-riparian) areas and that they possess extra functionality in terms of ecosystem service provision. Watercourse shading was highly habitat specific and was maximal in forests (ca. 52% shade cover) in comparison to the other habitat types (7-17%). Our data suggest that the functioning of riparian areas in less intensive agricultural areas, such as those studied here, may be broadly predicted from the surrounding land use, however, further research is required to critically test this across a wider range of ecosystems.


Selection of alternative 5' splice sites: role of U1 snRNP and models for the antagonistic effects of SF2/ASF and hnRNP A1.
The first component known to recognize and discriminate among potential 5' splice sites (5'SSs) in pre-mRNA is the U1 snRNP. However, the relative levels of U1 snRNP binding to alternative 5'SSs do not necessarily determine the splicing outcome. Strikingly, SF2/ASF, one of the essential SR protein-splicing factors, causes a dose-dependent shift in splicing to a downstream (intron-proximal) site, and yet it increases U1 snRNP binding at upstream and downstream sites simultaneously. We show here that hnRNP A1, which shifts splicing towards an upstream 5'SS, causes reduced U1 snRNP binding at both sites. Nonetheless, the importance of U1 snRNP binding is shown by proportionality between the level of U1 snRNP binding to the downstream site and its use in splicing. With purified components, hnRNP A1 reduces U1 snRNP binding to 5'SSs by binding cooperatively and indiscriminately to the pre-mRNA. Mutations in hnRNP A1 and SF2/ASF show that the opposite effects of the proteins on 5'SS choice are correlated with their effects on U1 snRNP binding. Cross-linking experiments show that SF2/ASF and hnRNP A1 compete to bind pre-mRNA, and we conclude that this competition is the basis of their functional antagonism; SF2/ASF enhances U1 snRNP binding at all 5'SSs, the rise in simultaneous occupancy causing a shift in splicing towards the downstream site, whereas hnRNP A1 interferes with U1 snRNP binding such that 5'SS occupancy is lower and the affinities of U1 snRNP for the individual sites determine the site of splicing.


Does Publication Bias Inflate the Apparent Efficacy of Psychological Treatment for Major Depressive Disorder? A Systematic Review and Meta-Analysis of US National Institutes of Health-Funded Trials.
The efficacy of antidepressant medication has been shown empirically to be overestimated due to publication bias, but this has only been inferred statistically with regard to psychological treatment for depression. We assessed directly the extent of study publication bias in trials examining the efficacy of psychological treatment for depression. We identified US National Institutes of Health grants awarded to fund randomized clinical trials comparing psychological treatment to control conditions or other treatments in patients diagnosed with major depressive disorder for the period 1972-2008, and we determined whether those grants led to publications. For studies that were not published, data were requested from investigators and included in the meta-analyses. Thirteen (23.6%) of the 55 funded grants that began trials did not result in publications, and two others never started. Among comparisons to control conditions, adding unpublished studies (Hedges' g = 0.20; CI95% -0.11~0.51; k = 6) to published studies (g = 0.52; 0.37~0.68; k = 20) reduced the psychotherapy effect size point estimate (g = 0.39; 0.08~0.70) by 25%. Moreover, these findings may overestimate the "true" effect of psychological treatment for depression as outcome reporting bias could not be examined quantitatively. The efficacy of psychological interventions for depression has been overestimated in the published literature, just as it has been for pharmacotherapy. Both are efficacious but not to the extent that the published literature would suggest. Funding agencies and journals should archive both original protocols and raw data from treatment trials to allow the detection and correction of outcome reporting bias. Clinicians, guidelines developers, and decision makers should be aware that the published literature overestimates the effects of the predominant treatments for depression.


Mechanism of glycoside hydrolysis: A comparative QM/MM molecular dynamics analysis for wild type and Y69F mutant retaining xylanases.
Computational simulations have been performed using hybrid quantum-mechanical/molecular-mechanical potentials to investigate the catalytic mechanism of the retaining endo-beta-1, 4-xylanase (BCX) from B. circulans. Two-dimensional potential-of-mean-force calculations based upon molecular dynamics with the AM1/OPLS method for wild-type BCX with a p-nitrophenyl xylobioside substrate in water clearly indicates a stepwise mechanism for glycosylation: the rate-determining step is nucleophilic substitution by Glu78 to form the covalently bonded enzyme-substrate intermediate without protonation of the leaving group by Glu172. The geometrical configuration of the transition state for the enzymic reaction is essentially the same as found for a gas-phase model involving only the substrate and a propionate/propionic acid pair to represent the catalytic glutamate/glutamic acid groups. In addition to stabilizing the (2,5)B boat conformation of the proximal xylose in the non-covalent reactant complex of the substrate with BCX, Tyr69 lowers the free-energy barrier for glycosylation by 42 kJ mol(-1) relative to that calculated for the Y69F mutant, which lacks the oxygen atom O(Y). B3LYP/6-31+G* energy corrections reduce the absolute height of the barrier to reaction. In the oxacarbenium ion-like transition state O(Y) approaches closer to the endocyclic oxygen O(ring) of the sugar ring but donates its hydrogen bond not to O(ring) but rather to the nucleophilic oxygen of Glu78. Comparison of the average atomic charge distributions for the wild-type and mutant indicates that charge separation along the bond between the anomeric carbon and O(ring) is matched in the former by a complementary separation of charge along the O(Y)-H(Y) bond, corresponding to a pair of roughly antiparallel bond dipoles, which is not present in the latter.


An ultrastructural analysis of the effects of ethanol self-administration on the hypothalamic paraventricular nucleus in rhesus macaques.
A bidirectional relationship between stress and ethanol exists whereby stressful events are comorbid with problematic ethanol use and prolonged ethanol exposure results in adaptations of the physiological stress response. Endocrine response to stress is initiated in the hypothalamic paraventricular nucleus (PVN) with the synthesis and release of corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP). Alterations in CRH and AVP following long-term ethanol exposure in rodents is well demonstrated, however little is known about the response to ethanol in primates or the mechanisms of adaptation. We hypothesized that long-term ethanol self-administration in nonhuman primates would lead to ultrastructural changes in the PVN underlying adaptation to chronic ethanol. Double-label immunogold electron microscopy (EM) was used to measure presynaptic gamma-aminobutyric acid (GABA) and glutamate density within synaptic terminals contacting CRH- and AVP-immunoreactive dendrites. Additionally, pituitary-adrenal hormones (ACTH, cortisol, DHEA-s and aldosterone) under two conditions (low and mild stress) were compared before and after self-administration. All hormones were elevated in response to the mild stressor independent of ethanol consumption. The presynaptic glutamate density in recurrent (i.e., intra-hypothalamic) CRH terminals was highly related to ethanol intake, and may be a permissive factor in increased drinking due to stress. Conversely, glutamate density within recurrent AVP terminals showed a trend-level increase following ethanol, but was not related to average daily consumption. Glutamate density in non-recurrent AVP terminals was related to aldosterone under the low stress condition while GABAergic density in this terminal population was related to water consumption. The results reveal distinct populations of presynaptic terminals whose glutamatergic or GABAergic density were uniquely related to water and ethanol consumption and circulating hormones.


Estimating the health care costs of non-melanoma skin cancer in Saskatchewan using physician billing data.
Given the high occurrence and morbidity of non-melanoma skin cancer (nmsc), its economic burden on the Canadian health care system is a cause for concern. Despite that relevance, few studies have used patient-level data to calculate the cost of nmsc. The objective of the present study was to use physician billing data to describe the health care costs and service utilization associated with nmsc in Saskatchewan. The Saskatchewan Cancer Agency's cancer registry was used to identify patients diagnosed with nmsc between 2004 and 2008. Treatment services and costs were based on physician billing claims, which detail physician services performed in an outpatient setting. Total and annual outpatient costs for nmsc and mean outpatient cost per person were calculated by skin cell type, lesion site, and geographic location. Service utilization and costs by physician specialty were also explored. Total outpatient costs grew 12.08% annually, to $845,954.98 in 2008 from $527,458.76 in 2004. The mean outpatient cost per person was estimated at $397.86. Differences in the cost-per-person estimates were observed when results were stratified by skin cell type ($403.41 for basal cell carcinoma vs. $377.85 for squamous cell carcinoma), lesion site ($425.27 for the face vs. $317.80 for an upper limb), and geographic location ($415.07 urban vs. $363.48 rural). Investigation of service utilization found that 92.14% of treatment was delivered by general practice and plastic surgery/otolaryngology physicians; dermatology delivered only 6.33% of services. Our results underestimate the direct costs of nmsc because inpatient services and non-physician costs were not included in the calculations. The present research represents a first step in understanding the cost burden of nmsc in Saskatchewan.


Living with early-stage dementia: a review of qualitative studies.
This paper presents a literature review whose aim was to provide better understanding of living with early-stage dementia. Even in the early stages, dementia may challenge quality of life. Research on early-stage dementia is mainly in the domain of biomedical aetiology and pathology, providing little understanding of what it means to live with dementia. Knowledge of the lived experience of having dementia is important in order to focus pro-active care towards enhancing quality of life. Qualitative research is fundamentally well suited to obtaining an insider's view of living with early-stage dementia. We performed a meta-synthesis of qualitative research findings. We searched MEDLINE, CINAHL, and PsycINFO and reviewed the papers cited in the references of pertinent articles, the references cited in a recently published book on the subjective experience of dementia, one thesis, and the journal Dementia. Thirty-three pertinent articles were identified, representing 28 separate studies and 21 different research samples. Findings were coded, grouped, compared and integrated. Living with dementia is described from the stage a person discovers the memory impairment, through the stage of being diagnosed with dementia, to that of the person's attempts to integrate the impairment into everyday life. Memory loss often threatens perceptions of security, autonomy and being a meaningful member of society. At early stages of memory loss, individuals use self-protecting and self-adjusting strategies to deal with perceived changes and threats. However, the memory impairment itself may make it difficult for an individual to deal with these changes, thereby causing frustration, uncertainty and fear. Our analysis supports the integration of proactive care into the diagnostic process, because even early-stage dementia may challenge quality of life. Moreover, this care should actively involve both the individual with dementia and their family so that both parties can adjust positively to living with dementia.


Optical wave equation for light scattering in micro- and nanostructured media and its application.
An optical wave equation for scattered light in materials with macroscopic spatial inhomogeneities is presented and analyzed. The equation is applicable to a variety of linear and nonlinear optical interactions in media with intrinsic, induced, or engineered inhomegeneities. While it is valid regardless of the spatial scale of these inhomogeneities, the strongest effect is expected from inhomogeneities of a subwavelength scale size typical for nanostructured optical media.


p24 as a predictor of mortality in a cohort of HIV-1-infected adults in rural Africa.
Implementation of antiretroviral treatment in sub-Saharan Africa requires efficient tools to monitor HIV patients. p24 measurements have been proposed as an alternative to HIV-RNA because of the low cost of reagents and equipment needed. Here, we evaluate p24 as a prognostic marker in a cohort of HIV-1-infected individuals in Zimbabwe. Treatment-naive HIV-1-infected individuals (n=198) from the Mupfure Schistosomiasis and HIV Cohort were followed until death or censoring (3-4.3 years). At baseline, p24, HIV-RNA, CD4 cell counts, and clinical staging (Centers for Disease Control and Prevention classification) were assessed. p24 correlated with HIV-RNA (P<0.0001, R: 0.44). Ten percent of p24 but only 1% of HIV-RNA measurements was undetectable. p24 predicted Centers for Disease Control and Prevention category (P<0.001) stronger than CD4 count (P=0.34) in multivariate logistic regression. p24 predicted mortality in univariate Cox analysis (P<0.0001) and in multivariate analysis, but it was inferior to HIV-RNA and CD4 count. This is the first study to evaluate the prognostic strength of p24 in an area with a predominance of HIV subtype C infections. p24 correlated with HIV-RNA and predicted clinical stage better than CD4 count. It predicted mortality in both univariate and multivariate analysis, but in multivariate analysis, it was inferior to HIV-RNA and CD4 count.


[Research and development of the free radical scavenger edaravone as a neuroprotectant].
Increasing data suggest that oxygen free radical species play detrimental roles in ischemic diseases. A free radical scavenger capable of inhibiting oxidative injury is expected to become a new drug for the treatment of ischemic diseases such as cerebral ischemia. Edaravon (3-methyl-1-phenyl-2-pyrazolin-5-one), which has been developed as an neuroprotective agent for more than 15 years since its discovery, is approved for the treatment of acute cerebral infarction. In this paper, the pharmacologic characteristics and clinical effects of edaravone are reviewed. In early stage of investigation, edaravone was found to have promising activities as an antioxidative radical scavenger, quenching hydroxyl radical (.OH) and inhibiting both .OH-dependent and .OH-independent lipid peroxidation. Edaravone showed inhibitory effects on both water-soluble and lipid-soluble peroxyl radical-induced peroxidation systems, which are different from the inhibitory effects of vitamins C and E in each system, respectively. Oxidative injury to cultured endothelial cells caused by arachidonate (AA) peroxides is prevented in the existence of edaravone. To clarify the characteristics of this free radical scavenger, further investigation was carried out. Edaravone ameliorated exacerbation of cortical edema induced by a focal ischemia-reperfusion model in rats, suggesting inhibitory effects on oxidative injury to the blood-brain barrier (BBB). Additionally, edaravone also prevented rat cortical edema caused by intracortical AA infusion in which free radical production and subsequent oxidative injury to the BBB are involved. With advances in in vivo measurement technology of oxygen radicals, edaravone was shown to inhibit postischemic increases in .OH production and tissue injury in the penumbral or recirculated area in rat cerebral ischemia models. In clinical studies, edaravone improved the core neurologic deficits, activities of daily living, and functional outcome of stroke patients. Furthermore, a study using proton magnetic resonance spectroscopic techniques showed that edaravone preserved N-acetyl-aspartate in stroke patients, a promising neuronal marker in the brain. Further investigation is essential for a better understanding of free radical-mediated cerebral injury during ischemia followed by recirculation. We hope that edaravone represents a promising neuroprotectant for drug therapy in acute cerebral ischemia.


shinyheatmap: Ultra fast low memory heatmap web interface for big data genomics.
Transcriptomics, metabolomics, metagenomics, and other various next-generation sequencing (-omics) fields are known for their production of large datasets, especially across single-cell sequencing studies. Visualizing such big data has posed technical challenges in biology, both in terms of available computational resources as well as programming acumen. Since heatmaps are used to depict high-dimensional numerical data as a colored grid of cells, efficiency and speed have often proven to be critical considerations in the process of successfully converting data into graphics. For example, rendering interactive heatmaps from large input datasets (e.g., 100k+ rows) has been computationally infeasible on both desktop computers and web browsers. In addition to memory requirements, programming skills and knowledge have frequently been barriers-to-entry for creating highly customizable heatmaps. We propose shinyheatmap: an advanced user-friendly heatmap software suite capable of efficiently creating highly customizable static and interactive biological heatmaps in a web browser. shinyheatmap is a low memory footprint program, making it particularly well-suited for the interactive visualization of extremely large datasets that cannot typically be computed in-memory due to size restrictions. Also, shinyheatmap features a built-in high performance web plug-in, fastheatmap, for rapidly plotting interactive heatmaps of datasets as large as 105-107 rows within seconds, effectively shattering previous performance benchmarks of heatmap rendering speed. shinyheatmap is hosted online as a freely available web server with an intuitive graphical user interface: http://shinyheatmap.com. The methods are implemented in R, and are available as part of the shinyheatmap project at: https://github.com/Bohdan-Khomtchouk/shinyheatmap. Users can access fastheatmap directly from within the shinyheatmap web interface, and all source code has been made publicly available on Github: https://github.com/Bohdan-Khomtchouk/fastheatmap.


Permeability evaluation through chitosan membranes using taguchi design.
In the present study, chitosan membranes capable of imitating permeation characteristics of diclofenac diethylamine across animal skin were prepared using cast drying method. The effect of concentration of chitosan, concentration of cross-linking agent (NaTPP), crosslinking time was studied using Taguchi design. Taguchi design ranked concentration of chitosan as the most important factor influencing the permeation parameters of diclofenac diethylamine. The flux of the diclofenac diethylamine solution through optimized chitosan membrane (T9) was found to be comparable to that obtained across rat skin. The mathematical model developed using multilinear regression analysis can be used to formulate chitosan membranes that can mimic the desired permeation characteristics. The developed chitosan membranes can be utilized as a substitute to animal skin for in vitro permeation studies.


Low-power communication with a photonic heat pump.
An optical communication channel is constructed using a heated thermo-electrically pumped, high efficiency infrared light-emitting diode (LED). In these devices, electro-luminescent cooling is observed, resulting in greater than unity (> 100%) efficiency in converting electrical power to optical power. The average amount of electrical energy required to generate a photon (4.3 meV) is much less than the optical energy in that photon (520 meV). Such a light source can serve as a test-bed for fundamental studies of energy-efficient bosonic communication channels. In this low energy consumption mode, we demonstrate data transmission at 3 kilobits per second (kbps) with only 120 picowatts of input electric power. Although the channel employs a mid-infrared source with limited quantum efficiency, a binary digit can be communicated using 40 femtojoules with a bit error rate of 3 x 10-3.


Occurrence and antibiotic resistance of mesophilic Aeromonas in three riverine freshwaters of Marrakech, Morocco.
In order to evaluate the impact of pollution and sewage on the occurrence and antibiotic resistance of mesophilic aeromonads in riverine freshwaters of Marrakech, samples were collected from three rivers (Oukaimeden, Ourika, and Tensift) upstream and downstream from the principal bordering villages. During a 2-year study, indicators of pollution increased dramatically in the downstream waters. Bacterial indicators (faecal coliforms and faecal streptococci) correlated with mesophilic aeromonads only in heavily polluted waters. In low and moderately polluted sources, densities of mesophilic aeromonads were independent of water quality indicators and did not correlate statistically with faecal indicators. Average counts of Aeromonas in low and heavily polluted waters were 2.5 x 10(3) and 2.1 x 10(6) colony forming units per 100 ml, respectively. The biochemical identification of 841 isolates indicated a predominance of A. caviae in heavily and moderately polluted water and sediment. A. hydrophila was dominant only in low polluted waters and when the temperature was below 12 degrees C. High densities of A. sobria were found in low, moderately polluted, or cleaned waters and when the water temperature was above 18 degrees C. All selected isolates (total = 841) were tested for antibiotic susceptibility against 21 antibiotics. Antibiotic resistance frequencies recorded were: ampicillin and amoxicillin, 100%; novobiocin, 96%; cefalotin, 81%; colistin, 72%; sulfamethoxazole, 40%; cefamandole, 37%; polymyxin B, 23%; trimethoprim, 17%; erythromycin, 15%; streptomycin, 8%; amoxicillin-clavulanate, 5%. Resistance to cefotaxime, kanamycin, gentamycin, chloramphenicol, tetracycline, oxytetracycline, nalidixic acid, rifampicin, or trimethoprim-sulfameth-oxazole was found to be <5%. Antibiotic resistance rates did vary according to the source of a strain"s isolation, and high numbers of antibiotic resistant strains were recorded in polluted samples. Since no correlation between mesophilic aeromonads and conventional faecal pollution indicators was observed in low or moderately polluted waters, and since these freshwaters are used for domestic supply, we propose the use of mesophilic aeromonads as complementary water pollution indicators to ensure the safety of water.


Four-port fiber frequency shifter with a null taper coupler.
A prototype of a new design of fiber frequency shifter, based on a special four-port fused taper coupler with a null maximum coupling ratio, is reported. In this coupler the constituent fibers are so dissimilar that the maximum coupling is (ideally) zero. In the presence of a flexural acoustic wave, light is coupled between the fibers, acquiring a frequency shift in the process. Near 100% conversion with 30-dB sideband and carrier suppression is achieved, in an unoptimized device, for just 1 mW of electrical drive power.


Polymorphism in α-sexithiophene crystals: relative stability and transition path.
We present a joint theoretical and experimental study to investigate polymorphism in α-sexithiophene (6T) crystals. By means of density-functional theory calculations, we clarify that the low-temperature phase is favorable over the high-temperature one, with higher relative stability up to 50 meV per molecule. This result is in agreement with our thermal desorption measurements. We also propose a transition path between the high- and low-temperature 6T polymorphs, estimating an upper bound for the energy barrier of about 1 eV per molecule. The analysis of the electronic properties of the investigated 6T crystal structures complements our study.


Evaluation of Hearing Aids in Everyday Life Using Ecological Momentary Assessment: What Situations Are We Missing?
Background Ecological momentary assessment (EMA) is a method to evaluate hearing aids in everyday life that uses repeated smartphone-based questionnaires to assess a situation as it happens. Although being ecologically valid and avoiding memory bias, this method may be prone to selection biases due to questionnaires being skipped or the phone not being carried along in certain situations. Purpose This investigation analyzed which situations are underrepresented in questionnaire responses and physically measured objective EMA data (e.g., sound level), and how such underrepresentation may depend on different triggers. Method In an EMA study, 20 subjects with hearing impairment provided daily information on reasons for missed data, that is, skipped questionnaires or missing connections between their phone and hearing aids. Results Participants often deliberately did not bring the study phone to social situations or skipped questionnaires because they considered it inappropriate, for example, during church service or when engaging in conversation. They answered fewer questions in conversations with multiple partners and were more likely to postpone questionnaires when not in quiet environments. Conclusion Data for social situations will likely be underrepresented in EMA. However, these situations are particularly important for the evaluation of hearing aids, as individuals with hearing impairment often have difficulties communicating in noisy situations. Thus, it is vital to optimize the design of the study to find a balance between avoiding memory bias and enabling subjects to report retrospectively on situations where phone usage may be difficult. The implications for several applications of EMA are discussed. Supplemental Material https://doi.org/10.23641/asha.12746849.


Microbe-driven chemical ecology: past, present and future.
In recent years, research in the field of Microbial Ecology has revealed the tremendous diversity and complexity of microbial communities across different ecosystems. Microbes play a major role in ecosystem functioning and contribute to the health and fitness of higher organisms. Scientists are now facing many technological and methodological challenges in analyzing these complex natural microbial communities. The advances in analytical and omics techniques have shown that microbial communities are largely shaped by chemical interaction networks mediated by specialized (water-soluble and volatile) metabolites. However, studies concerning microbial chemical interactions need to consider biotic and abiotic factors on multidimensional levels, which require the development of new tools and approaches mimicking natural microbial habitats. In this review, we describe environmental factors affecting the production and transport of specialized metabolites. We evaluate their ecological functions and discuss approaches to address future challenges in microbial chemical ecology (MCE). We aim to emphasize that future developments in the field of MCE will need to include holistic studies involving organisms at all levels and to consider mechanisms underlying the interactions between viruses, micro-, and macro-organisms in their natural environments.