Childhood risk factors associated with adolescent gun carrying among Black and White males: An examination of self-protection, social influence, and antisocial propensity explanations.
Adolescent gun violence is a serious public health issue that disproportionately affects young Black males. Although it has been postulated that differential exposure to childhood risk factors might account for racial differences in adolescent gun carrying, no longitudinal studies have directly examined this issue. We examined whether childhood risk factors indexing neighborhood crime, peer delinquency, and conduct problems predicted the initiation of adolescent gun carrying among a community sample of Black and White boys. Analyses then examined whether racial differences in risk factors accounted for racial differences in gun carrying. Data came from a sample of 485 Black and White boys who were repeatedly assessed from 2nd grade until age 18. Multi-informant data collected across the first 3 years of the study were used to assess neighborhood crime, peer delinquency, and conduct problems. Illegal gun carrying was assessed annually from 5th grade through age 18. Growth curve analyses indicated that children with higher initial levels of conduct problems and delinquent peer involvement, as well as those who increased in conduct problems across childhood, were more likely to carry a gun prior to age 18. Black boys were also more likely to carry guns than Whites. Racial differences were greatly reduced, but not eliminated, after controlling for initial levels of conduct problems and delinquent peer involvement. Findings suggest that early prevention programs designed to reduce adolescent gun violence (including racial disparities in gun violence) should target boys with severe conduct problems and those who affiliate with delinquent peers during elementary school. (PsycINFO Database Record


PPAR Agonists and Cardiovascular Disease in Diabetes.
Peroxisome proliferators activated receptors (PPARs) are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostasis. To the extent that PPAR agonists improve diabetic dyslipidaemia and insulin resistance, these agents have been considered to reduce cardiovascular risk. However, data from murine models suggests that PPAR agonists also have independent anti-atherosclerotic actions, including the suppression of vascular inflammation, oxidative stress, and activation of the renin angiotensin system. Many of these potentially anti-atherosclerotic effects are thought to be mediated by transrepression of nuclear factor-kB, STAT, and activator protein-1 dependent pathways. In recent clinical trials, PPARalpha agonists have been shown to be effective in the primary prevention of cardiovascular events, while their cardiovascular benefit in patients with established cardiovascular disease remains equivocal. However, the use of PPARgamma agonists, and more recently dual PPARalpha/gamma coagonists, has been associated with an excess in cardiovascular events, possibly reflecting unrecognised fluid retention with potent agonists of the PPARgamma receptor. Newer pan agonists, which retain their anti-atherosclerotic activity without weight gain, may provide one solution to this problem. However, the complex biologic effects of the PPARs may mean that only vascular targeted agents or pure transrepressors will realise the goal of preventing atherosclerotic vascular disease.


Differential diagnosis, comorbidity, and treatment of attention-deficit/hyperactivity disorder in relation to bipolar disorder or borderline personality disorder in adults.
Attention-deficit/hyperactivity disorder (ADHD) in adults can resemble, and often co-occurs with, bipolar disorder (BD) and borderline personality disorder (BPD). This can lead to mistaken diagnoses and ineffective treatment, resulting in potentially serious adverse consequences. All three conditions can substantially impair well-being and functioning, while BD and BPD are associated with suicidality. To update clinicians on the overlap and differences in the symptomatology of ADHD versus BD and BPD in adults; differential diagnosis of ADHD from BD and BPD in adults; and diagnosis and treatment of adults with comorbid ADHD-BD or ADHD-BPD. We searched four databases, referred to the new Diagnostic and Statistical Manual of Mental Disorders, 5th edition, used other relevant literature, and referred to our own clinical experience. ADHD coexists in ∼20% of adults with BD or BPD. BD is episodic, with periods of normal mood although not necessarily function. In patients with comorbid ADHD-BD, ADHD symptoms are apparent between BD episodes. BPD and ADHD are associated with chronic trait-like symptoms and impairments. Overlapping symptoms of BPD and ADHD include impulsivity and emotional dysregulation. Symptoms of BPD but not ADHD include frantically avoiding real/imagined abandonment, suicidal behavior, self-harm, chronic feelings of emptiness, and stress-related paranoia/severe dissociation. Consensus expert opinion recommends that BD episodes should be treated first in patients with comorbid ADHD, and these patients may need treatment in stages (e.g. mood stabilizer[s], then a stimulant/atomoxetine). Data is scarce and mixed about whether stimulants or atomoxetine exacerbate mania in comorbid ADHD-BD. BPD is primarily treated with psychotherapy. Principles of dialectical behavioral treatment for BPD may successfully treat ADHD in adults, as an adjunct to medication. No fully evidence-based pharmacotherapy exists for core BPD symptoms, although some medications may be effective for individual symptom domains, e.g. impulsivity (shared by ADHD and BPD). In our experience, treatment of ADHD should be considered when treating comorbid personality disorders. It is important to accurately diagnose ADHD, BD, and BPD to ensure correct targeting of treatments and improvements in patient outcomes. However, there is a shortage of data about treatment of adults with ADHD and comorbid BD or BPD.


Effects of Cool-Water Immersion and High-Voltage Electric Stimulation for 3 Continuous Hours on Acute Edema in Rats.
OBJECTIVE: Cool-water immersion (CWI) at 12.8 degrees C (55 degrees F), cathodal high-voltage pulsed current (CHVPC) at 120 pulses per second and 90% of visible motor threshold, or the combination of CWI and CHVPC, applied 30 minutes on, 30 minutes off for 4 hours, are known to curb edema formation after blunt trauma to the hind limbs of rats. Our purpose was to examine the effects of extending treatment times to 3 continuous hours after blunt trauma to the hind limbs of rats. DESIGN AND SETTING: A randomized, parallel-groups design of 22 subjects was used. Volumes of traumatized limbs, randomly assigned to CWI (n = 7), CHVPC (n = 8), or CWI followed by CHVPC (n = 7) were compared with those of injured but untreated limbs with analysis of variance. SUBJECTS: Twenty-two anesthetized Zucker lean rats (mass = 293 +/- 27 g). MEASUREMENTS: We measured limb volumes immediately before and after trauma and every 30 minutes over the 4-hour experiment. RESULTS: Volumes of treated limbs of all 3 experimental groups were smaller than those of untreated limbs (P <.05). No treatment was more effective than another. CONCLUSIONS: Exposure to either 3 hours of CWI or CHVPC or to 1 hour of CWI followed by 2 hours of CHVPC effectively curbed edema after blunt injury. These results suggest that these common treatments are effective only during application and hint that application should be maintained throughout the period during which edema is forming.


Endosome pH measured in single cells by dual fluorescence flow cytometry: rapid acidification of insulin to pH 6.
The acidification of various ligands was measured on a cell by cell basis for cell suspensions by correlated dual fluorescence flow cytometry. Mouse 3T3 cells were incubated with a mixture of fluorescein- and rhodamine-conjugated ligands, and the ratio of fluorescein and rhodamine fluorescence was used as a measure of endosome pH. The calibration of this ratio by both fluorometry and flow cytometry is described. Dual parameter histograms of average endosome pH per cell versus amount of internalization were calculated from this data, for samples in the absence and presence of chloroquine added to neutralize acidic cellular vesicles. The kinetics of acidification of insulin were measured and compared with previous results obtained with the chloroquine ratio technique. Rapid acidification of internalized ligand was observed both for insulin, which was mostly internalized via nonspecific pathways, and for alpha 2-macroglobulin, which was mainly internalized by specific receptor-mediated endocytosis. The average pH observed for internalized insulin was less than pH 6 within 10 min after addition of insulin. At 30 min, the average pH began to decrease to approximately pH 5, presumably because of fusion of endosomes with lysosomes.


A gammaherpesvirus provides protection against allergic asthma by inducing the replacement of resident alveolar macrophages with regulatory monocytes.
The hygiene hypothesis postulates that the recent increase in allergic diseases such as asthma and hay fever observed in Western countries is linked to reduced exposure to childhood infections. Here we investigated how infection with a gammaherpesvirus affected the subsequent development of allergic asthma. We found that murid herpesvirus 4 (MuHV-4) inhibited the development of house dust mite (HDM)-induced experimental asthma by modulating lung innate immune cells. Specifically, infection with MuHV-4 caused the replacement of resident alveolar macrophages (AMs) by monocytes with regulatory functions. Monocyte-derived AMs blocked the ability of dendritic cells to trigger a HDM-specific response by the TH2 subset of helper T cells. Our results indicate that replacement of embryonic AMs by regulatory monocytes is a major mechanism underlying the long-term training of lung immunity after infection.


Implementation of Care Management: An Analysis of Recent AHRQ Research.
Care management (CM) is a promising team-based, patient-centered approach "designed to assist patients and their support systems in managing medical conditions more effectively." As little is known about its implementation, this article describes CM implementation and associated lessons from 12 Agency for Healthcare Research and Quality-sponsored projects. Two rounds of data collection resulted in project-specific narratives that were analyzed using an iterative approach analogous to framework analysis. Informants also participated as coauthors. Variation emerged across practices and over time regarding CM services provided, personnel delivering these services, target populations, and setting(s). Successful implementation was characterized by resource availability (both monetary and nonmonetary), identifying as well as training employees with the right technical expertise and interpersonal skills, and embedding CM within practices. Our findings facilitate future context-specific implementation of CM within medical homes. They also inform the development of medical home recognition programs that anticipate and allow for contextual variation.


AKAP150-mediated TRPV1 sensitization is disrupted by calcium/calmodulin.
The transient receptor potential vanilloid type1 (TRPV1) is expressed in nociceptive sensory neurons and is sensitive to phosphorylation. A-Kinase Anchoring Protein 79/150 (AKAP150) mediates phosphorylation of TRPV1 by Protein Kinases A and C, modulating channel activity. However, few studies have focused on the regulatory mechanisms that control AKAP150 association with TRPV1. In the present study, we identify a role for calcium/calmodulin in controlling AKAP150 association with, and sensitization of, TRPV1. In trigeminal neurons, intracellular accumulation of calcium reduced AKAP150 association with TRPV1 in a manner sensitive to calmodulin antagonism. This was also observed in transfected Chinese hamster ovary (CHO) cells, providing a model for conducting molecular analysis of the association. In CHO cells, the deletion of the C-terminal calmodulin-binding site of TRPV1 resulted in greater association with AKAP150, and increased channel activity. Furthermore, the co-expression of wild-type calmodulin in CHOs significantly reduced TRPV1 association with AKAP150, as evidenced by total internal reflective fluorescence-fluorescence resonance energy transfer (TIRF-FRET) analysis and electrophysiology. Finally, dominant-negative calmodulin co-expression increased TRPV1 association with AKAP150 and increased basal and PKA-sensitized channel activity. the results from these studies indicate that calcium/calmodulin interferes with the association of AKAP150 with TRPV1, potentially extending resensitization of the channel.


Expert consensus on dynamics of laboratory tests for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis.
To identify which laboratory tests that change over time are most valuable for the timely diagnosis of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA). A multistep process, based on a combination of expert consensus and analysis of real patient data, was conducted. A panel of experts was first asked to evaluate 115 profiles of patients with MAS, which included the values of laboratory tests at the pre-MAS visit and at MAS onset, and the change in values between the two time points. The experts were asked to choose the 5 laboratory tests in which change was most important for the diagnosis of MAS and to rank the 5 selected tests in order of importance. The relevance of change in laboratory parameters was further discussed and ranked by the same experts at a consensus conference. Platelet count was the most frequently selected test, followed by ferritin level, aspartate aminotransferase (AST), white cell count, neutrophil count, and fibrinogen and erythrocyte sedimentation rate. Ferritin was most frequently assigned the highest score. At the end of the process, platelet count, ferritin level and AST were the laboratory tests in which the experts found change over time to be most important. We identified the laboratory tests in which change over time is most valuable for the early diagnosis of MAS in sJIA. The dynamics of laboratory values during the course of MAS should be further scrutinised in a prospective study in order to establish the optimal cut-off values for their variation.


Identifying Existing Evidence to Potentially Develop a Machine Learning Diagnostic Algorithm for Cough in Primary Care Settings: Scoping Review.
Primary care is known to be one of the most complex health care settings because of the high number of theoretically possible diagnoses. Therefore, the process of clinical decision-making in primary care includes complex analytical and nonanalytical factors such as gut feelings and dealing with uncertainties. Artificial intelligence is also mandated to offer support in finding valid diagnoses. Nevertheless, to translate some aspects of what occurs during a consultation into a machine-based diagnostic algorithm, the probabilities for the underlying diagnoses (odds ratios) need to be determined. Cough is one of the most common reasons for a consultation in general practice, the core discipline in primary care. The aim of this scoping review was to identify the available data on cough as a predictor of various diagnoses encountered in general practice. In the context of an ongoing project, we reflect on this database as a possible basis for a machine-based diagnostic algorithm. Furthermore, we discuss the applicability of such an algorithm against the background of the specifics of general practice. The PubMed, Scopus, Web of Science, and Cochrane Library databases were searched with defined search terms, supplemented by the search for gray literature via the German Journal of Family Medicine until April 20, 2023. The inclusion criterion was the explicit analysis of cough as a predictor of any conceivable disease. Exclusion criteria were articles that did not provide original study results, articles in languages other than English or German, and articles that did not mention cough as a diagnostic predictor. In total, 1458 records were identified for screening, of which 35 articles met our inclusion criteria. Most of the results (11/35, 31%) were found for chronic obstructive pulmonary disease. The others were distributed among the diagnoses of asthma or unspecified obstructive airway disease, various infectious diseases, bronchogenic carcinoma, dyspepsia or gastroesophageal reflux disease, and adverse effects of angiotensin-converting enzyme inhibitors. Positive odds ratios were found for cough as a predictor of chronic obstructive pulmonary disease, influenza, COVID-19 infections, and bronchial carcinoma, whereas the results for cough as a predictor of asthma and other nonspecified obstructive airway diseases were inconsistent. Reliable data on cough as a predictor of various diagnoses encountered in general practice are scarce. The example of cough does not provide a sufficient database to contribute odds to a machine learning-based diagnostic algorithm in a meaningful way.


Surgically Induced Focal Retinal Detachment Does Not Cause Detectable SD-OCT Retinal Changes in Normal Human Retina.
Induction of focal retinal detachment (RD) for subretinal delivery of stem cells and gene therapy is increasingly common. In order to determine if this procedure has an adverse impact on the retina, we use spectral-domain optical coherence tomography (SD-OCT) to evaluate the pre- and postoperative retinal anatomy of the incidentally detached normal retina surrounding large submacular hemorrhages (SMH) during surgical displacement procedures. Retrospective, observational study of human subjects with monocular SMH evaluated before and after surgical displacement using clinical exam, fundus photography, and SD-OCT. Manual measurements of the inner retinal thickness (IRT), outer retinal thickness (ORT), and full retinal thickness (FRT) were made in regions involving the SMH and surrounding normal retina. Comparison of retinal thickness measurements was made using the Wilcoxon signed-rank test. Seven eyes were included in this study. All eyes successfully underwent surgical displacement of SMH. Visual acuity improved in 6/7 subjects and was unchanged in the remaining subject. Incidental RD of the normal retinal regions surrounding the SMH did not cause any significant change in IRT, ORT, or FRT that was detectable by SD-OCT. In contrast, mean FRT overlying regions with SMH was significantly greater before surgery compared to after displacement of SMH or normal adjacent retina. Surgically induced focal RD does not cause detectable retinal changes in the incidentally detached normal retina surrounding large SMH. Therefore, surgical induction of focal RD should not be considered to have the same adverse impact on the retina as pathologic RD.


Informed consent disclosure to vaccine trial subjects of risk of COVID-19 vaccines worsening clinical disease.
Patient comprehension is a critical part of meeting medical ethics standards of informed consent in study designs. The aim of the study was to determine if sufficient literature exists to require clinicians to disclose the specific risk that COVID-19 vaccines could worsen disease upon exposure to challenge or circulating virus. Published literature was reviewed to identify preclinical and clinical evidence that COVID-19 vaccines could worsen disease upon exposure to challenge or circulating virus. Clinical trial protocols for COVID-19 vaccines were reviewed to determine if risks were properly disclosed. COVID-19 vaccines designed to elicit neutralising antibodies may sensitise vaccine recipients to more severe disease than if they were not vaccinated. Vaccines for SARS, MERS and RSV have never been approved, and the data generated in the development and testing of these vaccines suggest a serious mechanistic concern: that vaccines designed empirically using the traditional approach (consisting of the unmodified or minimally modified coronavirus viral spike to elicit neutralising antibodies), be they composed of protein, viral vector, DNA or RNA and irrespective of delivery method, may worsen COVID-19 disease via antibody-dependent enhancement (ADE). This risk is sufficiently obscured in clinical trial protocols and consent forms for ongoing COVID-19 vaccine trials that adequate patient comprehension of this risk is unlikely to occur, obviating truly informed consent by subjects in these trials. The specific and significant COVID-19 risk of ADE should have been and should be prominently and independently disclosed to research subjects currently in vaccine trials, as well as those being recruited for the trials and future patients after vaccine approval, in order to meet the medical ethics standard of patient comprehension for informed consent.


The Sulfamate Small Molecule CAIX Inhibitor S4 Modulates Doxorubicin Efficacy.
Carbonic anhydrase IX (CAIX) is a tumor-specific protein that is upregulated during hypoxic conditions where it is involved in maintaining the pH balance. CAIX causes extracellular acidification, thereby limiting the uptake of weak basic chemotherapeutic agents, such as doxorubicin, and decreasing its efficacy. The aim of this study was to determine if doxorubicin efficacy can be increased when combined with the selective sulfamate CAIX inhibitor S4. The effect of S4 on doxorubicin efficacy was tested in vitro using cell viability assays with MDA-MB-231, FaDu, HT29 -CAIX high and HT29 -CAIX low cell lines. In addition, the efficacy of this combination therapy was investigated in tumor xenografts of the same cell lines. The addition of S4 in vitro increased the efficacy of doxorubicin in the MDA-MB-231 during hypoxic exposure (IC50 is 0.25 versus 0.14 µM, p = 0.0003). Similar results were observed for HT29-CAIX high with S4 during normoxia (IC50 is 0.20 versus 0.08 µM, p<0.0001) and in the HT29 -CAIX low cells (IC50 is 0.09 µM, p<0.0001). In vivo doxorubicin treatment was only effective in the MDA-MB-231 xenografts, but the efficacy of doxorubicin was decreased when combined with S4. In conclusion, the efficacy of doxorubicin treatment can be increased when combined with the selective sulfamate CAIX inhibitor S4 in vitro in certain cell lines. Nevertheless, in xenografts S4 did not enhance doxorubicin efficacy in the FaDu and HT29 tumor models and decreased doxorubicin efficacy in the MDA-MB-231 tumor model. These results stress the importance of better understanding the role of CAIX inhibitors in intratumoral pH regulation before combining them with standard treatment modalities, such as doxorubicin.


Use of an atrial lead with very short tip-to-ring spacing avoids oversensing of far-field R-wave.
The AVOID-FFS (Avoidance of Far-Field R-wave Sensing) study aimed to investigate whether an atrial lead with a very short tip-to-ring spacing without optimization of pacemaker settings shows equally low incidence of far-field R-wave sensing (FFS) when compared to a conventional atrial lead in combination with optimization of the programming. Patients receiving a dual chamber pacemaker were randomly assigned to receive an atrial lead with a tip-to-ring spacing of 1.1 mm or a lead with a conventional tip-to-ring spacing of 10 mm. Postventricular atrial blanking (PVAB) was programmed to the shortest possible value of 60 ms in the study group, and to an individually determined optimized value in the control group. Atrial sensing threshold was programmed to 0.3 mV in both groups. False positive mode switch caused by FFS was evaluated at one and three months post implantation. A total of 204 patients (121 male; age 73±10 years) were included in the study. False positive mode switch caused by FFS was detected in one (1%) patient of the study group and two (2%) patients of the control group (p = 0.62). The use of an atrial electrode with a very short tip-to-ring spacing avoids inappropriate mode switch caused by FFS without the need for individual PVAB optimization. ClinicalTrials.gov NCT00512915.


Light-Induced Polarization-Directed Growth of Optically Printed Gold Nanoparticles.
Optical printing has been proved a versatile and simple method to fabricate arbitrary arrays of colloidal nanoparticles (NPs) on substrates. Here, we show that is also a powerful tool for studying chemical reactions at the single NP level. We demonstrate that 60 nm gold NPs immobilized by optical printing can be used as seeds to obtain larger NPs by plasmon-assisted reduction of aqueous HAuCl4. The final size of each NP is simply controlled by the irradiation time. Moreover, we show conditions for which the growth occurs preferentially in the direction of light polarization, enabling the in situ anisotropic reshaping of the NPs in predetermined orientations.


Primary Anti-phospholipid Antibody Syndrome Presenting as Acute Nephritic Syndrome.
Primary anti-phospholipid antibody (APLA) syndrome in males most commonly presents with clinical manifestations of venous thrombosis, thrombocytopenia, and pulmonary embolism. Although most present with acute symptoms following arterial thrombosis, diagnosis following evaluation for elevated renal function tests and hypertension is less common. We report here a case of a 22-year-old man who presented with acute nephritic syndrome following an acute febrile illness. He was detected to have altered renal function tests with serum creatinine of 1.6 mg/dL (141.4 μmol/L), microscopic hematuria, and proteinuria along with hypertension. His 24-h urine protein was 1700 g/day. He was planned for a kidney biopsy. Subsequent evaluations revealed an isolated elevation of activated partial thromboplastin time. Further evaluation revealed positive APLA syndrome. He underwent kidney biopsy later which showed mesangial hypercellularity with no involvement of the renal parenchymal vasculature. The reported case is an unusual presentation of primary APLA syndrome with acute nephritic syndrome.


Steroid control and sexual differentiation of brain aromatase.
Brain aromatase (ARO) activity in the quail is markedly enhanced by testosterone (T). This effect only becomes detectable after several hours and reaches its maximum within a few days, which suggests enzymatic induction at the genomic level. This idea is reinforced by the fact that T also increases the ARO protein, as observed by immunocytochemistry (ICC) and the ARO mRNA, as measured by reverse transcriptase-polymerase chain reaction (RT-PCR). These changes can be mimicked by the administration of estrogens and therefore presumably require T aromatization. In our first test, injection of the non-steroidal ARO inhibitor, R76713 (racemic vorozole), unexpectedly revealed an increase in ARO immunoreactivity in the preoptic area (POA) of treated birds. This property of R76713 was shared by another non-steroidal inhibitor, fadrozole, but not by two steroidal inhibitors, androstatrienedione (ATD) and 4-hydroxy-androstenedione (OHA). These last two compounds markedly decreased the concentration of brain ARO as estimated by ICC. In parallel, ATD and OHA decreased ARO mRNA concentration measured by RT-PCR but vorozole and fadrozole had no effect on these concentrations in the POA, and only caused them to decrease slightly in the posterior hypothalamus. Together, these data indicate that the removal of estrogens caused by steroidal inhibitors decreases the synthesis of ARO, presumably at the transcriptional level. Additional regulatory mechanisms apparently take place after the injection of non-steroidal inhibitors and probably include increased half-life of the protein. The induction of ARO activity by steroids appears to be greater in males than in females, but this difference has been difficult to localize and confirm by assay methods. We therefore analysed by ICC the tridimensional distribution of ARO-ir neurons in the POA of males and females that were sexually mature or gonadectomized and treated with T-filled or control empty implants. Localized sex differences and effects of T were detected in this way. In particular, males had more ARO-ir cells than females in the lateral POA but a difference in the opposite direction was evident in the medial part of this area. These sex differences are largely activational (i.e. caused by the higher T levels in males) but they may also reflect organizational effects of neonatal steroids. Castration decreased ARO-ir cell numbers in the lateral POA, but increased it in the periventricular region. This anatomically specialized control by T may be mediated by three potential mechanisms that are discussed and comparatively evaluated: a migration of ARO neurons towards the ventricle after castration; a differential colocalization of ARO with estrogen receptors or a differential modulation of ARO neurons by catecholaminergic inputs.


Intramuscular Artesunate for Severe Malaria in African Children: A Multicenter Randomized Controlled Trial.
Current artesunate (ARS) regimens for severe malaria are complex. Once daily intramuscular (i.m.) injection for 3 d would be simpler and more appropriate for remote health facilities than the current WHO-recommended regimen of five intravenous (i.v.) or i.m. injections over 4 d. We compared both a three-dose i.m. and a three-dose i.v. parenteral ARS regimen with the standard five-dose regimen using a non-inferiority design (with non-inferiority margins of 10%). This randomized controlled trial included children (0.5-10 y) with severe malaria at seven sites in five African countries to assess whether the efficacy of simplified three-dose regimens is non-inferior to a five-dose regimen. We randomly allocated 1,047 children to receive a total dose of 12 mg/kg ARS as either a control regimen of five i.m. injections of 2.4 mg/kg (at 0, 12, 24, 48, and 72 h) (n = 348) or three injections of 4 mg/kg (at 0, 24, and 48 h) either i.m. (n = 348) or i.v. (n = 351), both of which were the intervention arms. The primary endpoint was the proportion of children with ≥ 99% reduction in parasitemia at 24 h from admission values, measured by microscopists who were blinded to the group allocations. Primary analysis was performed on the per-protocol population, which was 96% of the intention-to-treat population. Secondary analyses included an analysis of host and parasite genotypes as risks for prolongation of parasite clearance kinetics, measured every 6 h, and a Kaplan-Meier analysis to compare parasite clearance kinetics between treatment groups. A post hoc analysis was performed for delayed anemia, defined as hemoglobin ≤ 7 g/dl 7 d or more after admission. The per-protocol population was 1,002 children (five-dose i.m.: n = 331; three-dose i.m.: n = 338; three-dose i.v.: n = 333); 139 participants were lost to follow-up. In the three-dose i.m. arm, 265/338 (78%) children had a ≥ 99% reduction in parasitemia at 24 h compared to 263/331 (79%) receiving the five-dose i.m. regimen, showing non-inferiority of the simplified three-dose regimen to the conventional five-dose regimen (95% CI -7, 5; p = 0.02). In the three-dose i.v. arm, 246/333 (74%) children had ≥ 99% reduction in parasitemia at 24 h; hence, non-inferiority of this regimen to the five-dose control regimen was not shown (95% CI -12, 1; p = 0.24). Delayed parasite clearance was associated with the N86YPfmdr1 genotype. In a post hoc analysis, 192/885 (22%) children developed delayed anemia, an adverse event associated with increased leukocyte counts. There was no observed difference in delayed anemia between treatment arms. A potential limitation of the study is its open-label design, although the primary outcome measures were assessed in a blinded manner. A simplified three-dose i.m. regimen for severe malaria in African children is non-inferior to the more complex WHO-recommended regimen. Parenteral ARS is associated with a risk of delayed anemia in African children. Pan African Clinical Trials Registry PACTR201102000277177.


Antidepressant-like effects of young green barley leaf (Hordeum vulgare L.) in the mouse forced swimming test.
Young green barley leaf is one of the richest sources of antioxidants and has been widely consumed for health management in Japan. In this study, we examined whether oral administration of young green barley leaf has an antidepressant effect on the forced swimming test in mice. Mice were individually forced to swim in an open cylindrical container, one hour after oral administration of young green barley leaf (400 or 1000 mg / kg) or imipramine (100 mg / kg). Expression of mRNA for nerve growth factor (NGF), brain-derived neurotrophic factor, and glucocorticoid receptor in the brain was analyzed using real-time quantitative polymerase chain reaction (PCR). There was a significant antidepressant-like effect in the forced swimming test; both 400 and 1000 mg / kg young green barley leaves, as well as the positive control imipramine (100 mg / kg), reduced the immobility duration compared to the vehicle group. The expression of mRNA for NGF detected in the hippocampus immediately after the last swimming test was higher than that in the non-swimming group (Nil). Oral administration of imipramine suppressed this increase to the level of the Nil group. Young green barley leaf (400 and 1000 mg / kg) also showed a moderate decrease in the expression of mRNA for NGF, in a dose-dependent manner. Oral administration of young green barley leaf is able to produce an antidepressant-like effect in the forced swimming test. Consequently it is possible that the antidepressant-like effects of the young green barley leaf are, at least in part, mediated by an inhibition of the increase in the hippocampus levels of NGF.


Soliton rains in a normal dispersion fiber laser with dual-filter.
We demonstrate an experimental observation of soliton rains in an all normal dispersion Yb-fiber laser. The cavity consists of a narrow bandwidth filter and a birefringent plate (BP) filter. Soliton rain is obtained in the weak mode-locking regime, while multisolitons behaving as soliton bunches and harmonic mode-locking under strong mode-locking are also observed. Distinctive multisoliton interactions are observed via changing the pump power and adjustment of the waveplates as well as the BP. To the best of our knowledge, this is the first demonstration of soliton rains in normal dispersion fiber lasers.


Understanding How Consumers Categorise Health Related Claims on Foods: A Consumer-Derived Typology of Health-Related Claims.
The Nutrition and Health Claims Regulation (NHCR) EC No 1924/2006 aims to provide an appropriate level of consumer protection whilst supporting future innovation and fair competition within the EU food industry. However, consumers' interpretation of health claims is less well understood. There is a lack of evidence on the extent to which consumers are able to understand claims defined by this regulatory framework. Utilising the Multiple Sort Procedure (MSP), a study was performed (N = 100 participants across five countries: Germany, the Netherlands, Slovenia, Spain and the United Kingdom) to facilitate development of a framework of health-related claims encompassing dimensions derived from consumers. Our results provide useful insight into how consumers make sense of these claims and how claims may be optimised to enhance appropriate consumer understanding. They suggest consumers may not consciously differentiate between a nutrition claim and a health claim in the way that regulatory experts do and provide insight into where this might occur. A consumer-derived typology of health-related claims based on three key dimensions is proposed: (1) Familiarity with the nutrient, substance or food stated in the claim; (2) statement type in terms of simplicity/complexity; (3) relevance of the claim, either personally or for a stated population group.


Mechanisms for regulating expression of membrane isoforms of Fc gamma RIII (CD16).
Granulocyte and natural killer (NK) cell Fc receptors for immunoglobulin G (CD16) differ in only a few amino acids, yet have phosphatidylinositol glycan (PIG) or polypeptide membrane anchors, respectively. Mutagenesis shows that anchoring is regulated by a serine residue near the PIG anchor attachment site in the extracellular domain. The NK cell isoform was not expressed on the surface of COS cells unless cotransfected with a subunit that was expressed in NK cells and that was identical to the gamma subunit of the high affinity IgE Fc receptor (Fc epsilon RI). However, the CD16 sequence and not expression of the gamma subunit is dominant in regulating PIG reanchoring.


Time-course and treatment response with SNX-111, an N-type calcium channel blocker, in a rodent model of focal cerebral ischemia using diffusion-weighted MRI.
Diffusion-weighted magnetic resonance imaging (DWI) is capable of noninvasively imaging acute cerebral ischemia. We demonstrate the utility of this technique by evaluating SNX-111, a novel N-type calcium channel blocker with potential neuroprotective properties, in a rodent model of transient focal ischemia. Twenty-four Sprague-Dawley rats weighing between 310-350 g underwent occlusion of the middle cerebral artery (MCAO) for 105 min followed by 22.5 h of reperfusion. Thirty minutes following MCAO, animals were randomized to receive SNX-111 5 mg/kg intravenously over 1 h vs. placebo. DWI and T2-weighted MRIs (T2W) were performed at 0.5, 1.5 and 24 h after the onset of ischemia. Area fractions of increased signal intensity on the DWI and T2W images were measured. DWI area fractions at 1.5 and 24 h were also normalized to the initial, pre-treatment scans. Apparent diffusion coefficients (ADC) were calculated from fitted maps. Tri-phenyl tetrazolium chloride (TTC) staining was performed on brains at 24 h and infarct area fractions were measured. SNX-111 treated animals showed significantly improved 1.5-h DWI scan ratios compared to controls (ratios of 1.06 +/- 0.25 vs. 2.98 +/- 0.78 SNX vs. controls respectively, P < 0.05). A trend toward improved DWI ratios was seen by 24 h in the SNX-111 group (2.5 +/- 0.75 vs. 4.12 +/- 1.6, N.S.) DWI, T2W and TTC area fractions at 24 h also showed trends favoring a neuroprotective effect of SNX-111. Bright areas on DWI corresponded to ADC decreases of about 30% compared to the non-ischemic hemisphere. These decreases were the same in both treatment groups and at each time point. DWI, T2W and TTC area fractions at 24 h were strongly correlated (r = 0.98, DWI and TTC; r = 0.99, T2W and TTC; r = 0.97, T2W and DWI, P < 0.0001). We conclude that in this ischemic model, SNX-111 provides early neuroprotection and that serial DWI is a useful way of demonstrating this.


Numerical simulation of dip-coating in the evaporative regime.
A hydrodynamic model is used for numerical simulations of a polymer solution in a dip-coating-like experiment. We focus on the regime of small capillary numbers where the liquid flow is driven by evaporation, in contrast to the well-known Landau-Levich regime dominated by viscous forces. Lubrication approximation is used to describe the flow in the liquid phase. Evaporation in stagnant air is considered (diffusion-limited evaporation), which results in a coupling between liquid and gas phases. Self-patterning due to the solutal Marangoni effect is observed for some ranges of the control parameters. We first investigate the effect of evaporation rate on the deposit morphology. Then the role of the spatial variations in the evaporative flux on the wavelength and mean thickness of the dried deposit is ascertained, by comparing the 2D and 1D diffusion models for the gas phase. Finally, for the very low substrate velocities, we discuss the relative importance of diffusive and advective components of the polymer flux, and consequences on the choice of the boundary conditions.


Inhibition of PKCδ reduces cisplatin-induced nephrotoxicity without blocking chemotherapeutic efficacy in mouse models of cancer.
Cisplatin is a widely used cancer therapy drug that unfortunately has major side effects in normal tissues, notably nephrotoxicity in kidneys. Despite intensive research, the mechanism of cisplatin-induced nephrotoxicity remains unclear, and renoprotective approaches during cisplatin-based chemotherapy are lacking. Here we have identified PKCδ as a critical regulator of cisplatin nephrotoxicity, which can be effectively targeted for renoprotection during chemotherapy. We showed that early during cisplatin nephrotoxicity, Src interacted with, phosphorylated, and activated PKCδ in mouse kidney lysates. After activation, PKCδ regulated MAPKs, but not p53, to induce renal cell apoptosis. Thus, inhibition of PKCδ pharmacologically or genetically attenuated kidney cell apoptosis and tissue damage, preserving renal function during cisplatin treatment. Conversely, inhibition of PKCδ enhanced cisplatin-induced cell death in multiple cancer cell lines and, remarkably, enhanced the chemotherapeutic effects of cisplatin in several xenograft and syngeneic mouse tumor models while protecting kidneys from nephrotoxicity. Together these results demonstrate a role of PKCδ in cisplatin nephrotoxicity and support targeting PKCδ as an effective strategy for renoprotection during cisplatin-based cancer therapy.


Psychological treatment for insomnia in the management of long-term hypnotic drug use: a pragmatic randomised controlled trial.
To evaluate the clinical and cost impact of providing cognitive behaviour therapy (CBT) for insomnia (comprising sleep hygiene, stimulus control, relaxation and cognitive therapy components) to long-term hypnotic drug users in general practice. A pragmatic randomised controlled trial with two treatment arms (a CBT treated 'sleep clinic' group, and a 'no additional treatment' control group), with post-treatment assessments commencing at 3 and 6 months. Twenty-three general practices in Sheffield, UK. Two hundred and nine serially referred patients aged 31-92 years with chronic sleep problems who had been using hypnotic drugs for at least 1 month (mean duration = 13.4 years). At 3- and 6-month follow-ups patients treated with CBT reported significant reductions in sleep latency, significant improvements in sleep efficiency, and significant reductions in the frequency of hypnotic drug use (all P<0.01). Among CBT treated patients SF-36 scores showed significant improvements in vitality at 3 months (P<0.01). Older age presented no barrier to successful treatment outcomes. The total cost of service provision was 154.40 per patient, with a mean incremental cost per quality-adjusted life-year of 3416 (at 6 months). However, there was evidence of longer term cost offsets owing to reductions in sleeping tablet use and reduced utilisation of primary care services. In routine general practice settings, psychological treatments for insomnia can improve sleep quality and reduce hypnotic consumption at a favourable cost among long-term hypnotic users with chronic sleep difficulties.


The impact of nanosilver addition on element ions release form light-cured dental composite and compomer into 0.9% NaCl.
The aim of this paper was to identify and to assess in semi-quantified way the release of different ions from composite and compomer restorative materials subjected to 0.9% NaCl solution, which simulates the environment of the human body. In the present study, the number of ions (Al, Ag, Ba, Sr, Ti) released from dental fillings over time (one week, one month and 3 months), in different temperatures (23°C, 37°C) and depending on the materials applied (unmodified/modified with nanosilver) was investigated. The results suggest that nanosilver addition influences directly on the process of metal ion releasing into 0.9% NaCl solution. The increase in the number of counts of metal ions was observed in the solutions in which samples modified with nanosilver were kept. Higher amount of metal ion release was observed for composite samples rather than for compomer materials. The study revealed that in general the number of released metal ions increases with the time of storage (for metal ions: Ti, Ba, Sr) and at higher temperature (Ag, Ti, Ba). Reverse tendency observed for silver ion release versus incubation time may be caused by the process of silver adsorption, which takes place on the surface of analyzed material and test-tube walls, where samples were incubated.


Conversion of a helix-turn-helix motif sequence-specific DNA binding protein into a site-specific DNA cleavage agent.
Escherichia coli catabolite gene activator protein (CAP) is a helix-turn-helix motif sequence-specific DNA binding protein [de Crombrugghe, B., Busby, S. & Buc, H. (1984) Science 224, 831-838; and Pabo, C. & Sauer, R. (1984) Annu. Rev. Biochem. 53, 293-321]. In this work, CAP has been converted into a site-specific DNA cleavage agent by incorporation of the chelator 1,10-phenanthroline at amino acid 10 of the helix-turn-helix motif. [(N-Acetyl-5-amino-1,10-phenanthroline)-Cys178]CAP binds to a 22-base-pair DNA recognition site with Kobs = 1 x 10(8) M-1. In the presence of Cu(II) and reducing agent, [(N-acetyl-5-amino-1,10-phenanthroline)-Cys178]CAP cleaves DNA at four adjacent nucleotides on each DNA strand within the DNA recognition site. The DNA cleavage reaction has been demonstrated using 40-base-pair and 7164-base-pair DNA substrates. The DNA cleavage reaction is not inhibited by dam methylation of the DNA substrate. Such semisynthetic site-specific DNA cleavage agents have potential applications in chromosome mapping, cloning, and sequencing.


The Current State of Advanced Practice Provider Fellowships in Hospital Medicine: A Survey of Program Directors.
Postgraduate training for advanced practice providers (APPs) is a growing field in hospital medicine. As hospital programs continue to benefit from highly trained physician assistants (PAs) and nurse practitioners (NPs), fellowship programs have become more prevalent. However, little is known about the number of active programs or how they prepare trainees. To describe the existing APP fellowships in hospital medicine, with a focus on program characteristics, rationale, curricula, and learner assessment. An electronic survey was distributed by e-mail to hospital medicine program directors in May 2018. The survey consisted of 25 multiple choice and short answer questions. Descriptive statistics were calculated utilizing Stata 13 for data analysis. Of the 11 fellowships identified, 10 (91%) of directors responded to the survey. Eighty percent of programs accept both NPs and PAs and 80% are between 12 and 13 months long. All programs cite "training and retaining" as the main driver for their creation and 90% were founded in institutions with existing physician residencies. Ninety percent of program curricula are informed by Society of Hospital Medicine resources. Despite these similarities, there was wide variation in both curricular content and APP fellow assessment. APP fellowships in hospital medicine are quickly growing as a means to train and retain nonphysician hospitalists. While most programs accept similar types of applicants and share a common rationale for program development, there is little standardization in terms of curriculum or assessment. Further research may be valuable to characterize the best practices to guide the future of these fellowships.


Age-specific acceleration of cancer.
One of the great challenges of cancer research is to explain the epidemiological patterns of cancer incidence based on the molecular processes that lead to uncontrolled cellular proliferation. The epidemiological data demonstrate that the age-specific incidence of many cancers increases in an approximately linear way with age when plotted on a log-log scale, with different slopes for different cancers. However, those epidemiological data also show that cancers of various tissues depart from log-log linearity in particular ways. Here, I illustrate those departures from log-log linearity by introducing plots of the age-specific acceleration of cancer. I then develop a very general model of cancer progression, which I use to explain the observed differences between tissues in age-specific acceleration. In one application of the model, I show that the spectacular rise and fall in age-specific acceleration observed in prostate cancer may be explained by multiple rounds of clonal expansion. In a second application, I demonstrate that the steady decline in age-specific acceleration of breast cancer may occur because precancerous mutations accumulate in many cellular lineages.


Pathogen prevalence in ticks collected from the vegetation and livestock in Nigeria.
Ticks are important disease vectors that can cause considerable economic losses by affecting animal health and productivity, especially in tropical and subtropical regions. In this study, we investigated the prevalence and diversity of bacterial and protozoan tick-borne pathogens in ticks collected from the vegetation and cattle in Nigeria by PCR. The infection rates of questing ticks were 3.1% for Rickettsia species, 0.1% for Coxiella burnetii and 0.4% for Borrelia species. Other pathogens, such as Babesia, Theileria, Anaplasma, and Ehrlichia species, were not detected in ticks from the vegetation. Feeding ticks collected from cattle displayed infection rates of 12.5% for Rickettsia species, 14% for Coxiella burnetii, 5.9% for Anaplasma species, 5.1% for Ehrlichia species, and 2.9% for Theileria mutans. Babesia and Borrelia species were not detected in ticks collected from cattle. Mixed infections were found only in feeding ticks and mainly Rickettsia species and Coxiella burnetii were involved. The diversity of tick-borne pathogens in Nigeria was higher in feeding than in questing ticks, suggesting that cattle serve as reservoirs for at least some of the pathogens studied, in particular C. burnetii. The total estimated herd infection rates of 20.6% for a Rickettsia africae-like species, 27% for Coxiella burnetii, and 8.5% for Anaplasma marginale/centrale suggest that these pathogens may have considerable implications for human and animal health.


Full spatial characterization of a nanofocused x-ray free-electron laser beam by ptychographic imaging.
The emergence of hard X-ray free electron lasers (XFELs) enables new insights into many fields of science. These new sources provide short, highly intense, and coherent X-ray pulses. In a variety of scientific applications these pulses need to be strongly focused. In this article, we demonstrate focusing of hard X-ray FEL pulses to 125 nm using refractive x-ray optics. For a quantitative analysis of most experiments, the wave field or at least the intensity distribution illuminating the sample is needed. We report on the full characterization of a nanofocused XFEL beam by ptychographic imaging, giving access to the complex wave field in the nanofocus. From these data, we obtain the full caustic of the beam, identify the aberrations of the optic, and determine the wave field for individual pulses. This information is for example crucial for high-resolution imaging, creating matter in extreme conditions, and nonlinear x-ray optics.


Plasmonic meta-screen for alleviating the trade-offs in the near-field optics.
We propose a "meta-screen" design, consisting of a metallic sheet patterned with a dense array of nano-sized slot antennas, for inducing sub-wavelength optical spots in the near-field. Compared to other transmission screen topologies, our design overcomes the trade-off of low throughput versus resolution of a sub-wavelength aperture by inducing resonance in the slots. In addition, the antenna array serves to effectively narrow the spot size through the superposition of spatially shifted beams produced by each slot element. Such a design offers a practical approach for extending the near-field sensing/imaging distance at optical frequencies. The effectiveness of narrowing the spot size through the array topology is demonstrated by evaluating the full-width-half-maximum (FWHM) beamwidth at a distance of 0.1lambda(0) away from the screen. We show that an array with just three elements improves the beamwidth by more than 30% compared to a single resonant slot element. In this paper, important issues such as the operating principle and the design process of the meta-screen, the characteristics of plasmonic slot antenna, the impact of the number of array elements, and the effect of asymmetry due to the presence of a supporting substrate are discussed.


T helper cell subsets: diversification of the field.
Polarized T helper cell (Th cell) responses are important determinants of host protection. Th cell subsets tailor their functional repertoire of cytokines to their cognate antigens to efficiently contribute to their clearance. In contrast, in settings of immune abrogation, these polarized cytokine patterns of Th cells can mediate tissue damage and pathology resulting in allergy or autoimmunity. Recent technological developments in single-cell genomics and proteomics as well as advances in the high-dimensional bioinformatic analysis of complex datasets have challenged the prevailing Th cell subset classification into Th1, Th2, Th17, and other subsets. Additionally, systems immunology approaches have revealed that instructive input from the peripheral tissue microenvironment can have differential effects on the overall phenotype and molecular wiring of Th cells depending on their spatial distribution. Th cells from the blood or secondary lymphoid organs are therefore expected to follow distinct rules of regulation. In this review, the functional heterogeneity of Th cell subsets will be reviewed in the context of new technological developments and T-cell compartmentalization in tissue niches. This work will especially focus on challenges to the traditional boundaries of Th cell subsets and will discuss the underlying regulatory checkpoints, which could reveal new therapeutic strategies for various immune-mediated diseases.


Organometallic palladium reagents for cysteine bioconjugation.
Reactions based on transition metals have found wide use in organic synthesis, in particular for the functionalization of small molecules. However, there are very few reports of using transition-metal-based reactions to modify complex biomolecules, which is due to the need for stringent reaction conditions (for example, aqueous media, low temperature and mild pH) and the existence of multiple reactive functional groups found in biomolecules. Here we report that palladium(II) complexes can be used for efficient and highly selective cysteine conjugation (bioconjugation) reactions that are rapid and robust under a range of bio-compatible reaction conditions. The straightforward synthesis of the palladium reagents from diverse and easily accessible aryl halide and trifluoromethanesulfonate precursors makes the method highly practical, providing access to a large structural space for protein modification. The resulting aryl bioconjugates are stable towards acids, bases, oxidants and external thiol nucleophiles. The broad utility of the bioconjugation platform was further corroborated by the synthesis of new classes of stapled peptides and antibody-drug conjugates. These palladium complexes show potential as benchtop reagents for diverse bioconjugation applications.


The LRRK2 signalling system.
The LRRK2 gene is a major contributor to genetic risk for Parkinson's disease and understanding the biology of the leucine-rich repeat kinase 2 (LRRK2, the protein product of this gene) is an important goal in Parkinson's research. LRRK2 is a multi-domain, multi-activity enzyme and has been implicated in a wide range of signalling events within the cell. Because of the complexities of the signal transduction pathways in which LRRK2 is involved, it has been challenging to generate a clear idea as to how mutations and disease associated variants in this gene are altered in disease. Understanding the events in which LRRK2 is involved at a systems level is therefore critical to fully understand the biology and pathobiology of this protein and is the subject of this review.


Nanostructure-mediated drug delivery.
Nanotechnology is expected to have an impact on all industries including semiconductors, manufacturing, and biotechnology. Tools that provide the capability to characterize and manipulate materials at the nanoscale level further elucidate nanoscale phenomena and equip researchers and developers with the ability to fabricate novel materials and structures. One of the most promising societal impacts of nanotechnology is in the area of nanomedicine. Personalized health care, rational drug design, and targeted drug delivery are some of the benefits of a nanomedicine-based approach to therapy. This review will focus on the development of nanoscale drug delivery mechanisms. Nanostructured drug carriers allow for the delivery of not only small-molecule drugs but also the delivery of nucleic acids and proteins. Delivery of these molecules to specific areas within the body can be achieved, which will reduce systemic side effects and allow for more efficient use of the drug.


Higher hdl levels are a preventive factor for metabolic syndrome in obese Turkish children.
The definition of childhood metabolic syndrome has not been described clearly. Childhood obesity is increasing gradually, and the incidence of childhood metabolic syndrome is also rising. We aimed to show metabolic syndrome components and preventive factors for metabolic syndrome in obese children Methods: In the present study, 187 obese children and adolescents 5-18 years old were investigated retrospectively. Demographic data, anthropometric measurements, body mass index, blood pressure values, insulin levels, oral glucose tolerance test results, total cholesterol, high density lipoprotein, and triglyceride levels were obtained from hospital records. A body mass index > 95th percentile was considered obese. Insulin resistance was calculated according to the oral glucose tolerance test with 1.75 g/kg glucose maximum 75 g glucose. The insulin sensitivity index and homeostatic model assessment-insulin resistance (HOMA IR) were calculated and compared. Metabolic syndrome was diagnosed according to the modified WHO criteria adapted for metabolic syndrome in children. Abnormal glucose homeostasis was detected in 53% of subjects. Dyslipidaemia was present in 45.7% and hypertension in 16.6% of the patients. Metabolic syndrome was identified in 24.6% of obese children and adolescents. High HOMA-IR values and fasting glucose levels, elevated triglycerides and lower HDL levels were an indication of metabolic syndrome. Obesity and insulin resistance are significant factors for the development of metabolic syndrome in children and adolescents. In obese children higher HDL levels are preventive factor for metabolic syndrome. Preventing obesity and insulin resistance may decrease the prevalence of metabolic syndrome.


Molecular mechanisms of atrial fibrosis: implications for the clinic.
Recent research has unravelled an increasing list of cardiac conditions and risk factors that may be responsible for the abnormal underlying atrial substrate that predisposes to atrial fibrillation (AF). Atrial fibrosis has been demonstrated as the pivotal structural abnormality underpinning conduction disturbances that promote AF in different disease models. Despite the advancement in our discoveries of the molecular mechanisms involved in the profibrotic milieu, targeted therapeutics against atrial fibrosis remain lacking. Areas covered: This review is focused on detailing the key molecular signalling pathways that contribute to atrial fibrosis including: angiotensin II, transforming growth factor (TGF- ß1), connective tissue growth factor (CTGF) and endothelin-1. We also discussed the potential therapeutic options that may be useful in modulating the abnormal atrial substrate. In addition, we examined the new paradigm of AF care in lifestyle and risk factor management that has been shown to arrest and reverse the atrial remodelling process leading to improved AF outcomes. Expert commentary: The future of AF care is likely to require an integrated approach consisting of aggressive risk factor management in addition to the established paradigm of rate and rhythm management and anticoagulation. Translational studies on molecular therapeutics to combat atrial fibrosis is urgently needed.


Pharmacovigilance of artemether-lumefantrine in pregnant women followed until delivery in Rwanda.
The World Health Organization presently recommends Artemisinin-based combination therapy (ACT) as first-line therapy for uncomplicated P. falciparum malaria. Many malaria-endemic countries, including Rwanda, have adopted these treatment guidelines. The Artemisinin derivative Artemether, in combination with lumefantrine, is currently used in Rwanda for malaria during the second and third trimesters of pregnancy. Safety data on the use of ACT in pregnancy are still limited though and more data are needed. In this pharmacovigilance study, the exposed group (pregnant women with malaria given artemether-lumefantrine), and a matched non-exposed group (pregnant women without malaria and no exposure to artemether-lumefantrine) were followed until delivery. Data were collected at public health centres all over Rwanda during acute malaria, routine antenatal visits, after hospital delivery or within 48 hours after home delivery. Information gathered from patients included routine antenatal and peri-partum data, pregnancy outcomes (abortions, stillbirths, at term delivery), congenital malformations and other adverse events through history taking and physical examination of both mothers and newborns. The outcomes for the total sample of 2,050 women were for the treatment (n=1,072) and control groups (n=978) respectively: abortions: 1.3% and 0.4%; peri-natal mortality 3.7% and 2.8%; stillbirth 2.9% and 2.4%; neonatal death [less than or equal to]7 days after birth 0.5% and 0.4%; premature delivery 0.7% and 0.3%; congenital malformations 0.3% and 0.3%. A total of 129 obstetric adverse events in 127 subjects were reported (7.3% in the treatment group, 5.0% in the control group). In a multivariate regression model, obstetric complications were more frequent in the treatment group (OR (95% CI): 1.38 (0.95, 2.01)), and in primigravidae (OR (95% CI) 2.65 (1.71, 4.12) and at higher age (OR per year: 1.05 (1.01-1.09). There were no specific safety concerns related to artemether-lumefantrine treatment for uncomplicated falciparum malaria in pregnancy. However, more obstetric complications were observed in the treatment group. These increased occurrence of complications could, however, be caused by the malaria episode itself, but further assessment is required.


The perils of ignoring history: Big Tobacco played dirty and millions died. How similar is Big Food?
In 1954 the tobacco industry paid to publish the "Frank Statement to Cigarette Smokers" in hundreds of U.S. newspapers. It stated that the public's health was the industry's concern above all others and promised a variety of good-faith changes. What followed were decades of deceit and actions that cost millions of lives. In the hope that the food history will be written differently, this article both highlights important lessons that can be learned from the tobacco experience and recommends actions for the food industry. A review and analysis of empirical and historical evidence pertaining to tobacco and food industry practices, messages, and strategies to influence public opinion, legislation and regulation, litigation, and the conduct of science. The tobacco industry had a playbook, a script, that emphasized personal responsibility, paying scientists who delivered research that instilled doubt, criticizing the "junk" science that found harms associated with smoking, making self-regulatory pledges, lobbying with massive resources to stifle government action, introducing "safer" products, and simultaneously manipulating and denying both the addictive nature of their products and their marketing to children. The script of the food industry is both similar to and different from the tobacco industry script. Food is obviously different from tobacco, and the food industry differs from tobacco companies in important ways, but there also are significant similarities in the actions that these industries have taken in response to concern that their products cause harm. Because obesity is now a major global problem, the world cannot afford a repeat of the tobacco history, in which industry talks about the moral high ground but does not occupy it.


Shared traumatic stress and the long-term impact of 9/11 on Manhattan clinicians.
A sample of 481 social workers from Manhattan participated in a study of the impact of the September 11, 2001 (9/11) World Trade Center (WTC) attacks. A variety of risk factors associated with posttraumatic stress and secondary trauma were examined in relation to shared traumatic stress (STS), a supraordinate construct reflecting the dual nature of exposure to traumatic events. Risk factors included attachment style, exposure to potentially traumatic life events, and enduring distress attributed to the WTC attacks. It was expected that clinicians' resilience would mediate the relationship between these risk factors and STS. Using path analytic modeling, the findings support the study's hypotheses that insecure attachment, greater exposure to potentially traumatic life events in general, and the events of 9/11 in particular are predictive of higher levels of STS. Contrary to expectation, enduring distress attributed to 9/11 was not associated with resilience. Resilience, however, was found to be a mediator of the relationships between insecure attachment, exposure to potentially traumatic life events, and STS but did not mediate the relationship between enduring distress attributed to 9/11 and STS. Implications for theory, research, and practice are discussed.


Economic impact from unrestricted spread of potato cyst nematodes in australia.
ABSTRACT Potato cyst nematodes (PCN) (Globodera spp.) are quarantine pests with serious potential economic consequences. Recent new detections in Australia, Canada, and the United States have focussed attention on the consequences of spread and economic justifications for alternative responses. Here, a full assessment of the economic impact of PCN spread from a small initial incursion is presented. Models linking spread, population growth, and economic impact are combined to estimate costs of spread without restriction in Australia. Because the characteristics of the Australian PCN populations are currently unknown, the known ranges of parameters were used to obtain cost scenarios, an approach which makes the model predictions applicable generally. Our analysis indicates that mean annual costs associated with spread of PCN would increase rapidly initially, associated with increased testing. Costs would then increase more slowly to peak at over AUD$20 million per year approximately 10 years into the future. Afterward, this annual cost would decrease slightly due to discounting factors. Mean annual costs over 20 years were $18.7 million, with a 90% confidence interval between AUD$11.9 million and AUD$27.0 million. Thus, cumulative losses to Australian agriculture over 20 years may exceed $370 million without action to prevent spread of PCN and entry to new areas.


Emotionalism after stroke.
To estimate the prevalence of emotionalism after stroke, to assess its relation with other mood disorders, and to identify clinical variables with which it is associated. Descriptive study of a cohort of patients consecutively entered on a community stroke register. Community based research project. A total of 128 patients who had suffered first ever stroke. INTERVENTIONS AND END POINTS: Patients were interviewed by a psychiatrist at 1, 6, and 12 months after stroke. Mood state was assessed by standardised semistructured interview (present state examination) and self report (Beck depression inventory). Intellectual impairment was assessed by mini mental state examination and Frenchay aphasia screening test. In addition, stroke lesions were localised by computed tomography. Emotionalism was reported by 13 of 89 patients (15%) at one month, 25 of 119 (21%) at six months, and 12 of 112 (11%) at 12 months after stroke. Patients with emotionalism had higher scores on both measures of mood disorder (at 6 months: mean Beck score 10.5 v 6.4; present state examination score 7.2 v 5.1) and more diagnosable psychiatric disorder (at 6 months: 40% v 14%; odds ratio 4.2, 95% confidence interval 1.5 to 11.9). Almost all episodes were provoked by clearly identified and appropriate emotional experiences. Patients with emotionalism also had more intellectual impairment and larger lesions on computed tomography. Lesions in the left frontal and temporal regions were particularly associated with emotionalism: at 6 months 8 of 14 patients (57%) with such lesions had emotionalism compared with 10 of 52 (19%) of those with lesions elsewhere (odds ratio 5.6, 95% confidence interval 1.4 to 22). Emotionalism is common after stroke. It is neither emotionally meaningless and inappropriate, nor is it found mostly in patients with bilateral brain damage. Emotionalism is associated with symptoms of a more general mood disturbance and is found especially in patients with left frontal and temporal lesions.


The Place of Elastography in Evaluating the Efficacy of Radiofrequency Ablation of Thyroid Nodules.
The usage of radiofrequency ablation (RFA) therapy and elastography to treat thyroid nodules has been increasing recently. Elastography specifically measures the stiffness of tissue using ultrasonography (US). The aim of the present study was to evaluate the relationship between the elastography values of thyroid nodules and the efficacy of RFA therapy. Ultrasonography was performed on 49 patients who had a thyroid nodule with a diameter of 1 cm or greater before RFA therapy. The RFA was performed under local anesthesia, and elastography was used to measure the stiffness of the normal thyroid tissue, sternocleidomastoid muscle (SCM) and thyroid nodules three months after RFA. The nodule diameter significantly decreased three months after RFA (P < 0.05). According to a cross-evaluation of the mean elastography rates, the thyroid/SCM and nodule/thyroid elastography rates had an inverse relationship (P: 0.009). However, the thyroid/SCM elastography rates and nodule/SCM elastography rates (P: 0.022) and the thyroid/SCM elastography rates and the rates of reduction (%) of the nodule diameter before and three months after RFA (P: 0.016) had positive relationships. In conclusion, RFA therapy is more effective in patients with thyroid nodules if there are high thyroid tissue/SCM rates in elastography.


Robust modulation of arousal regulation, performance, and frontostriatal activity through central thalamic deep brain stimulation in healthy nonhuman primates.
The central thalamus (CT) is a key component of the brain-wide network underlying arousal regulation and sensory-motor integration during wakefulness in the mammalian brain. Dysfunction of the CT, typically a result of severe brain injury (SBI), leads to long-lasting impairments in arousal regulation and subsequent deficits in cognition. Central thalamic deep brain stimulation (CT-DBS) is proposed as a therapy to reestablish and maintain arousal regulation to improve cognition in select SBI patients. However, a mechanistic understanding of CT-DBS and an optimal method of implementing this promising therapy are unknown. Here we demonstrate in two healthy nonhuman primates (NHPs), Macaca mulatta, that location-specific CT-DBS improves performance in visuomotor tasks and is associated with physiological effects consistent with enhancement of endogenous arousal. Specifically, CT-DBS within the lateral wing of the central lateral nucleus and the surrounding medial dorsal thalamic tegmental tract (DTTm) produces a rapid and robust modulation of performance and arousal, as measured by neuronal activity in the frontal cortex and striatum. Notably, the most robust and reliable behavioral and physiological responses resulted when we implemented a novel method of CT-DBS that orients and shapes the electric field within the DTTm using spatially separated DBS leads. Collectively, our results demonstrate that selective activation within the DTTm of the CT robustly regulates endogenous arousal and enhances cognitive performance in the intact NHP; these findings provide insights into the mechanism of CT-DBS and further support the development of CT-DBS as a therapy for reestablishing arousal regulation to support cognition in SBI patients.


Acute onset lactic acidosis and pancreatitis in the third trimester of pregnancy in HIV-1 positive women taking antiretroviral medication.
We report the case histories of two HIV-1 positive women in the third trimester of pregnancy who presented with acute lactic acidosis and acute pancreatitis, respectively. One case was fatal for mother and baby. Both women had been stable on regimens containing stavudine and didanosine for at least 2 years before their acute presentations. We speculate on the differential diagnosis, discuss possible reasons for an increased risk of these presentations in pregnant women taking antiretrovirals, and advocate increased vigilance of these women, particularly in the last trimester.


Transfer of Kv3.1 voltage sensor features to the isolated Ci-VSP voltage-sensing domain.
Membrane proteins that respond to changes in transmembrane voltage are critical in regulating the function of living cells. The voltage-sensing domains (VSDs) of voltage-gated ion channels are extensively studied to elucidate voltage-sensing mechanisms, and yet many aspects of their structure-function relationship remain elusive. Here, we transplanted homologous amino acid motifs from the tetrameric voltage-activated potassium channel Kv3.1 to the monomeric VSD of Ciona intestinalis voltage-sensitive phosphatase (Ci-VSP) to explore which portions of Kv3.1 subunits depend on the tetrameric structure of Kv channels and which properties of Kv3.1 can be transferred to the monomeric Ci-VSP scaffold. By attaching fluorescent proteins to these chimeric VSDs, we obtained an optical readout to establish membrane trafficking and kinetics of voltage-dependent structural rearrangements. We found that motifs extending from 10 to roughly 100 amino acids can be readily transplanted from Kv3.1 into Ci-VSP to form engineered VSDs that efficiently incorporate into the plasma membrane and sense voltage. Some of the functional features of these engineered VSDs are reminiscent of Kv3.1 channels, indicating that these properties do not require interactions between Kv subunits or between the voltage sensing and the pore domains of Kv channels.


Residential Air Pollution and Associations with Wheeze and Shortness of Breath in Adults: A Combined Analysis of Cross-Sectional Data from Two Large European Cohorts.
Research examining associations between air pollution exposure and respiratory symptoms in adults has generally been inconclusive. This may be related in part to sample size issues, which also preclude analysis in potentially vulnerable subgroups. We estimated associations between air pollution exposures and the prevalence of wheeze and shortness of breath using harmonized baseline data from two very large European cohorts, Lifelines (2006-2013) and UK Biobank (2006-2010). Our aim was also to determine whether the relationship between air pollution and respiratory symptom prevalence differed between individuals with different characteristics. Cross-sectional analyses explored associations between prevalence of self-reported wheeze and shortness of breath and annual mean particulate matter with aerodynamic diameter <2.5μm, 2.5-10μm, and <10μm (PM2.5, PMcoarse, and PM10, respectively) and nitrogen dioxide (NO2) concentrations at place of residence using logistic regression. Subgroup analyses and tests for interaction were performed for age, sex, smoking status, household income, obesity status, and asthma status. All PM exposures were associated with respiratory symptoms based on single-pollutant models, with the largest associations seen for PM2.5 with prevalence of wheezing {odds ratio (OR)=1.16 per 5μg/m³ [95% confidence interval (CI): 1.11, 1.21]} and shortness of breath [OR=1.61 per 5μg/m³ (95% CI: 1.45, 1.78)]. The association between shortness of breath and a 5-μg/m³ increment in PM2.5 was significantly higher for individuals from lower-[OR=1.73 (95% CI: 1.52, 1.97)] versus higher-income households [OR=1.31 (95% CI: 1.11, 1.55); p-interaction=0.005), whereas the association between PM2.5 and wheeze was limited to lower-income participants [OR=1.30 (95% CI: 1.22, 1.38) vs. OR=1.02; (95% CI: 0.96, 1.08); p-interaction<0.001]. Exposure to NO2 also showed positive associations with wheeze and shortness of breath. Exposure to PM and NO2 air pollution was associated with the prevalence of wheeze and shortness of breath in this large study, with stronger associations between PM2.5 and both outcomes among lower- versus higher-income participants. https://doi.org/10.1289/EHP1353.


Implementation of the uterine fibroids Option Grid patient decision aids across five organizational settings: a randomized stepped-wedge study protocol.
Uterine fibroids are non-cancerous overgrowths of the smooth muscle in the uterus. As they grow, some cause problems such as heavy menstrual bleeding, pelvic pain, discomfort during sexual intercourse, and rarely pregnancy complications or difficulty becoming pregnant. Multiple treatment options are available. The lack of comparative evidence demonstrating superiority of any one treatment means that choosing the best option is sensitive to individual preferences. Women with fibroids wish to consider treatment trade-offs. Tools known as patient decision aids (PDAs) are effective in increasing patient engagement in the decision-making process. However, the implementation of PDAs in routine care remains challenging. Our aim is to use a multi-component implementation strategy to implement the uterine fibroids Option Grid™ PDAs at five organizational settings in the USA. We will conduct a randomized stepped-wedge implementation study where five sites will be randomized to implement the uterine fibroid Option Grid PDA in practice at different time points. Implementation will be guided by the Consolidated Framework for Implementation Research (CFIR) and Normalization Process Theory (NPT). There will be a 6-month pre-implementation phase, a 2-month initiation phase where participating clinicians will receive training and be introduced to the Option Grid PDAs (available in text, picture, or online formats), and a 6-month active implementation phase where clinicians will be expected to use the PDAs with patients who are assigned female sex at birth, are at least 18 years of age, speak fluent English or Spanish, and have new or recurrent symptoms of uterine fibroids. We will exclude postmenopausal patients. Our primary outcome measure is the number of eligible patients who receive the Option Grid PDAs. We will use logistic and linear regression analyses to compare binary and continuous quantitative outcome measures (including survey scores and Option Grid use) between the pre- and active implementation phases while adjusting for patient and clinician characteristics. This study may help identify the factors that impact the implementation and sustained use of a PDA in clinic workflow from various stakeholder perspectives while helping patients with uterine fibroids make treatment decisions that align with their preferences. Clinicaltrials.gov , NCT03985449. Registered 13 July 2019, https://clinicaltrials.gov/ct2/show/NCT03985449.


Functional interactions of a homolog of proliferating cell nuclear antigen with DNA polymerases in Archaea.
Proliferating cell nuclear antigen (PCNA) is an essential component of the DNA replication and repair machinery in the domain Eucarya. We cloned the gene encoding a PCNA homolog (PfuPCNA) from an euryarchaeote, Pyrococcus furiosus, expressed it in Escherichia coli, and characterized the biochemical properties of the gene product. The protein PfuPCNA stimulated the in vitro primer extension abilities of polymerase (Pol) I and Pol II, which are the two DNA polymerases identified in this organism to date. An immunological experiment showed that PfuPCNA interacts with both Pol I and Pol II. Pol I is a single polypeptide with a sequence similar to that of family B (alpha-like) DNA polymerases, while Pol II is a heterodimer. PfuPCNA interacted with DP2, the catalytic subunit of the heterodimeric complex. These results strongly support the idea that the PCNA homolog works as a sliding clamp of DNA polymerases in P. furiosus, and the basic mechanism for the processive DNA synthesis is conserved in the domains Bacteria, Eucarya, and Archaea. The stimulatory effect of PfuPCNA on the DNA synthesis was observed by using a circular DNA template without the clamp loader (replication factor C [RFC]) in both Pol I and Pol II reactions in contrast to the case of eukaryotic organisms, which are known to require the RFC to open the ring structure of PCNA prior to loading onto a circular DNA. Because RFC homologs have been found in the archaeal genomes, they may permit more efficient stimulation of DNA synthesis by archaeal DNA polymerases in the presence of PCNA. This is the first stage in elucidating the archaeal DNA replication mechanism.


Microbial tolerance in secondary peritonitis is dose dependent.
Local microbial tolerance was investigated in a murine model of peritonitis. Peritoneal bacterial burden and inflammatory cytokine concentrations were determined at different times, within 48h after infection. Peritoneal macrophages were harvested from naïve mice or from mice 48h after infection and underwent ex vivo stimulation with different concentrations of Klebsiella. Cytokine secretion was determined in the supernatants. Peritoneal bacteria concentrations, remained relatively steady between 24h (median: 5.04 log CFU) and 48h (median: 5.19 log CFU) after infection. Peritoneal cytokine concentrations peaked early but were already diminished at 48h after infection, despite persistent high bacteria levels. Macrophages, harvested from naïve mice responded vigorously to ex vivo stimulation with 10(5) CFU and 2 x 10(8) CFU Klebsiella. Cells harvested from animals 48h after infection, were unresponsive to an ex vivo stimulation with 10(5) CFU Klebsiella, but fully responded to 10(8) CFU. Persistent intraabdominal bacterial infection induced dose dependent microbial tolerance in peritoneal macrophages.


The proteolipid protein promoter drives expression outside of the oligodendrocyte lineage during embryonic and early postnatal development.
The proteolipid protein (Plp) gene promoter is responsible for driving expression of one of the major components of myelin--PLP and its splice variant DM-20. Both products are classically thought to express predominantly in oligodendrocytes. However, accumulating evidence suggests Plp expression is more widespread than previously thought. In an attempt to create a mouse model for inducing oligodendrocyte-specific gene deletions, we have generated transgenic mice expressing a Cre recombinase cDNA under control of the mouse Plp promoter. We demonstrate Plp promoter driven Cre expression is restricted predominantly to mature oligodendrocytes of the central nervous system (CNS) at postnatal day 28. However, crosses into the Rosa26(LacZ) and mT/mG reporter mouse lines reveal robust and widespread Cre activity in neuronal tissues at E15.5 and E10.5 that is not strictly oligodendrocyte lineage specific. By P28, all CNS tissues examined displayed high levels of reporter gene expression well outside of defined white matter zones. Importantly, our study reinforces the emerging idea that Plp promoter activity is not restricted to the myelinating cell lineage, but rather, has widespread activity both during embryonic and early postnatal development in the CNS. Specificity of the promoter to the oligodendrocyte cell lineage, as shown through the use of a tamoxifen inducible Plp-CreER(t) line, occurs only at later postnatal stages. Understanding the temporal shift in Plp driven expression is of consequence when designing experimental models to study oligodendrocyte biology.


Phased polyploid genomes provide deeper insight into the multiple origins of domesticated Saccharomyces cerevisiae beer yeasts.
Yeasts, and in particular Saccharomyces cerevisiae, have been used for brewing beer for thousands of years. Population genomic surveys highlighted that beer yeasts are polyphyletic, with the emergence of different domesticated subpopulations characterized by high genetic diversity and ploidy level. However, the different origins of these subpopulations are still unclear as reconstruction of polyploid genomes is required. To gain better insight into the differential evolutionary trajectories, we sequenced the genomes of 35 Saccharomyces cerevisiae isolates coming from different beer-brewing clades, using a long-read sequencing strategy. By phasing the genomes and using a windowed approach, we identified three main beer subpopulations based on allelic content (European dominant, Asian dominant, and African beer). They were derived from different admixtures between populations and are characterized by distinctive genomic patterns. By comparing the fully phased genes, the most diverse in our dataset are enriched for functions relevant to the brewing environment such as carbon metabolism, oxidoreduction, and cell wall organization activity. Finally, independent domestication, evolution, and adaptation events across subpopulations were also highlighted by investigating specific genes previously linked to the brewing process. Altogether, our analysis based on phased polyploid genomes has led to new insight into the contrasting evolutionary history of beer isolates.


Chromosome 5 suppresses tumorigenicity of PC3 prostate cancer cells: correlation with re-expression of alpha-catenin and restoration of E-cadherin function.
Considerable evidence now exists to support an important role for the E-cadherin-mediated cell-cell adhesion pathway as a suppressor of the invasive phenotype in adenocarcinoma cells. Previous studies have found that this pathway is frequently aberrant in prostate cancers, particularly those that are likely to metastasize. In this study, we report on the effects of re-establishment of this pathway in a prostate cancer cell line, PC-3, in which this adhesion system is dysfunctional by virtue of a deletion of the gene that codes for alpha-catenin, an E-cadherin-associated protein necessary for normal E-cadherin function. Re-expression of alpha-catenin was accomplished either by transfection of PC-3 cells with a copy of the alpha-catenin cDNA under the control of a heterologous promoter or by microcell-mediated transfer of chromosome 5, which contains the alpha-catenin gene and its normal regulatory elements. In both cases, re-expression of alpha-catenin is associated with a similar, dramatic alteration in cell morphology, whereby extensive cell-cell contact is observed. In the case of transfection of the cDNA, this expression is only transient, because the transfected cells either cease to proliferate or, more commonly, revert to the parental phenotype with concomitant cessation of alpha-catenin expression. In contrast, cells containing one or more copies of microcell-transferred chromosome 5 express alpha-catenin in a stable manner and continue to proliferate. Upon injection into nude mice, these latter cells are no longer tumorigenic, or form only slowly growing tumors with greatly extended doubling times when compared to the parental PC-3 cells. During passage in culture, clones that contain only one transferred copy of chromosome 5 reproducibly revert to the parental phenotype. This reversion is associated with loss of the chromosome 5 region containing the alpha-catenin gene and consequent loss of alpha-catenin expression, as well as re-emergence of tumorigenicity. Transfer of chromosome 5 into prostate cancer cells that are E-cadherin negative does not result in either morphological transformation or suppression of tumorigenicity, suggesting that these effects of alpha-catenin expression are dependent upon concomitant expression of E-cadherin. These data demonstrate the tumor suppressive ability of chromosome 5 in the PC-3 prostate cancer cells and suggest that re-expression of alpha-catenin with resultant restoration of E-cadherin function plays a critical role in this process.


Surgical pathology of skeletal coccidioidomycosis: a clinical and histopathologic analysis of 25 cases.
Skeletal coccidioidomycosis is a rare complication of pulmonary coccidioidomycosis that remains incompletely characterized, and its histopathologic features have not been systematically evaluated. All skeletal coccidioidal infections (2000 to 2012) were retrieved from the University of Arizona and Mayo Clinic in Arizona pathology archives. Clinical history and histologic features were reviewed. Among 25 patients (median age 40 y; 17 men), infections involved bones (2 cases), joints (6), or both (17), usually in the distal extremities (68%), especially the wrist (32%). History included previously documented coccidioidomycosis (13), autoimmune disease (8), diabetes (6), malignancy (4), and iatrogenic immunosuppression (10). Common symptoms (median 3 mo) included pain/arthralgia (21) and swelling (10). Cultures and serology were positive in 15 of 17 (88%) and 19 of 22 patients (86%), respectively. Treatment included surgical debridement(s) and chronic antifungal medication(s). Histologic review showed granulomas in all cases, ranging from poorly to well formed, with or without necrosis. Spherule density varied widely (mean 4.8/HPF; range <0.1 to 13.5/HPF). Composition of inflammatory infiltrates, degree of necrosis, and extent of fibrosis did not significantly differ between immunocompetent and immunocompromised patients. Eosinophils were only seen in one third of cases; when present, eosinophils were almost always rare. 10 patients experienced recurrent infection, 8 of whom were immunocompromised; the remaining patients recovered. In conclusion, distal extremities are the most common sites of skeletal coccidioidomycosis encountered by surgical pathologists. This condition is strongly associated with autoimmune disorders and immunosuppression. Spherules are sometimes rare, and multiple modalities including serology, culture, and histology may be required for diagnosis.


Impact of Electronic Versus Paper Vital Sign Observations on Length of Stay in Trauma Patients: Stepped-Wedge, Cluster Randomized Controlled Trial.
Electronic recording of vital sign observations (e-Obs) has become increasingly prevalent in hospital care. The evidence of clinical impact for these systems is mixed. The objective of our study was to assess the effect of e-Obs versus paper documentation (paper) on length of stay (time between trauma unit admission and "fit to discharge") for trauma patients. A single-center, randomized stepped-wedge study of e-Obs against paper was conducted in two 26-bed trauma wards at a medium-sized UK teaching hospital. Randomization of the phased intervention order to 12 study areas was computer generated. The primary outcome was length of stay. A total of 1232 patient episodes were randomized (paper: 628, e-Obs: 604). There were 37 deaths in hospital: 21 in the paper arm and 16 in the e-Obs arm. For discharged patients, the median length of stay was 5.4 (range: 0.2-79.0) days on the paper arm and 5.6 (range: 0.1-236.7) days on the e-Obs arm. Competing risks regression analysis for time to discharge showed no difference between the treatment arms (subhazard ratio: 1.05; 95% CI 0.82-1.35; P=.68). A greater proportion of patient episodes contained an Early Warning Score (EWS) ≥3 using the e-Obs system than using paper (subhazard ratio: 1.63; 95% CI 1.28-2.09; P<.001). However, there was no difference in the time to the subsequent observation, "escalation time" (hazard ratio 1.05; 95% CI 0.80-1.38; P=.70). The phased introduction of an e-Obs documentation system was not associated with a change in length of stay. A greater proportion of patient episodes contained an EWS≥3 using the e-Obs system, but this was not associated with a change in "escalation time." ISRCTN Registry ISRCTN91040762; http://www.isrctn.com/ISRCTN91040762 (Archived by WebCite at http://www.webcitation.org/72prakGTU).


Fast screening of ketamine in biological samples based on molecularly imprinted photonic hydrogels.
A novel label-free colorimetric chemosensor was developed for handy and fast screening of ketamine with high sensitivity and specificity based on molecularly imprinted photonic hydrogels (MIPHs) that combined the colloidal-crystal with molecular imprinting technique. The unique inverse opal arrays with a thin polymer wall in which the imprinted nanocavities of ketamine moleculars distributed allowed high sensitive, quick responsive, specific detection of the target analyte, and good regenerating ability in an aqueous environment. Due to the hierarchical inverse opal structural characteristics, the specific ketamine molecular recognition process can induce obvious swelling of the MIPHs to be directly transferred into visually perceptible optical signal (change in color) which can be detected by the naked eye through Bragg diffractive shifts of ordered macroporous arrays. In order to enhance the recognition ability in aqueous environments, the MIPHs were designed as water-compatible and synthesized in a water-methanol system. The molecular recognition mechanisms were investigated. The proposed MIPHs were successfully employed to screen trace level ketamine in human urine and saliva samples, exhibiting high sensitivity, rapid response, and specificity in the complex matrix. The smart chemosensor can provide an effective alternative for fast screening of ketamine on the spot for forensic investigations.


Virtual reality applications in improving postural control and minimizing falls.
Maintaining balance under all conditions is an absolute requirement for humans. Orientation in space and balance maintenance requires inputs from the vestibular, the visual, the proprioceptive and the somatosensory systems. All the cues coming from these systems are integrated by the central nervous system (CNS) to employ different strategies for orientation and balance. How the CNS integrates all the inputs and makes cognitive decisions about balance strategies has been an area of interest for biomedical engineers for a long time. More interesting is the fact that in the absence of one or more cues, or when the input from one of the sensors is skewed, the CNS "adapts" to the new environment and gives less weight to the conflicting inputs [1]. The focus of this paper is a review of different strategies and models put forward by researchers to explain the integration of these sensory cues. Also, the paper compares the different approaches used by young and old adults in maintaining balance. Since with age the musculoskeletal, visual and vestibular system deteriorates, the older subjects have to compensate for these impaired sensory cues for postural stability. The paper also discusses the applications of virtual reality in rehabilitation programs not only for balance in the elderly but also in occupational falls. Virtual reality has profound applications in the field of balance rehabilitation and training because of its relatively low cost. Studies will be conducted to evaluate the effectiveness of virtual reality training in modifying the head and eye movement strategies, and determine the role of these responses in the maintenance of balance.


Protective effects of L-arginine supplementation against exhaustive exercise-induced oxidative stress in young rat tissues.
Recently, we showed that L-arginine (L-Arg) supplementation could attenuate acute exercise-induced oxidative and inflammatory stress in aging rats. In this study, we investigate whether L-Arg supplementation protects cellular oxidative stress, inflammation, or the mitochondrial DNA 4834-bp large deletion (mtDNA4834 deletion) in 14-week-old young rats tissues during exhaustive exercise. Rats were randomly divided into four groups: sedentary control (SC); SC with L-Arg treatment (SC+Arg); exhaustive exercise (E); and exhaustive exercise with L-Arg treatment (E+Arg). Rats in the SC+Arg and E+Arg groups received supplemental 2% L-Arg diet. Rats in groups E and E+Arg performed an exhaustive running test on a treadmill. The results showed a significant increase in xanthine oxidase (XO) and myeloperoxidase (MPO) activities and lipid peroxide (malondialdehyde; MDA) levels of muscular, hepatic, and renal tissues in exercised rats as compared with sedentary rats. The increased XO, MPO, and MDA levels of these tissues significantly decreased in exercised rats supplemented with L-Arg. However, exhaustive exercise had no effect on mtDNA4834 deletions of muscular and hepatic tissues. The activities of creatine kinase (CK), aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), creatinine (CRE), lactate, uric acid, non-esterified fatty acid (NEFA), and D-3-hydroxybutyrate in the plasma significantly increased in the exercised rats compared with the sedentary rats, while the CK, lactate and uric acid levels in the plasma significantly decreased in L-Arg-supplemented exercised rats. These findings suggest that L-Arg supplementation reduces the oxidative damage to and inflammatory response in skeletal muscles, the liver, and kidneys caused by exhaustive exercise in young rats.


T-cell receptor cross-linking transiently stimulates adhesiveness through LFA-1.
Effective interaction between T cells and their targets requires that recognition of specific antigen be coordinated with increased cell-cell adhesion. We show that antigen-receptor cross-linking increases the strength of the adhesion mechanism between lymphocyte function-associated molecule-1 (LFA-1) and intercellular adhesion molecules (ICAMs), with intracellular signals transmitted from the T-cell antigen receptor to the LFA-1 adhesion molecule. The increase in avidity is rapid and transient, providing a dynamic mechanism for antigen-specific regulation of lymphocyte adhesion and de-adhesion.