Melanism evolution in the cat family is influenced by intraspecific communication under low visibility.
Melanism in the cat family has been associated with functions including camouflage, thermoregulation and parasite resistance. Here we investigate a new hypothesis proposing that the evolution of melanism in cats has additionally been influenced by communication functions of body markings. To evaluate this hypothesis, we assembled a species-level data set of morphological (body marks: white marks on the backs of ears) and ecological (circadian activity: arrhythmic/nocturnal, and environmental preference: open/closed) characteristics that could be associated with communication via body markings, and combined these data with a dated molecular phylogeny. Next, we tested the association between melanism and communication, first by relating species' body marks with their ecological conditions, using a Bayesian implementation of the threshold model. Second, to explore the evolution of characteristics potentially influencing melanism in cat species, we modeled their evolution relative to melanism using models of coordinated vs. independent character changes. Our results suggest that white marks are associated with intraspecific communication between individuals that have non-melanistic phenotypes, as well as towards melanistic individuals (without white marks). The absence of white marks in a melanistic individual tends to be a limiting condition for intraspecific visual communication at night, resulting in an evolutionary dilemma for these species, i.e. to be almost invisible at night, but not to communicate visually. The comparative analysis of several evolutionary models indicated more support for the evolution of melanism being coordinated with the evolution of arrhythmic activity and white marks on the backs of ears.


An epidemiological study of myopathies in Warmblood horses.
There are few detailed reports describing muscular disorders in Warmblood horses. To determine the types of muscular disorders that occur in Warmblood horses, along with presenting clinical signs, associated risk factors and response to diet and exercise recommendations, and to compare these characteristics between horses diagnosed with polysaccharide storage myopathy (PSSM), those diagnosed with a neuromuscular disorder other than PSSM (non-PSSM) and control horses. Subject details, muscle biopsy diagnosis and clinical history were compiled for Warmblood horses identified from records of biopsy submissions to the University of Minnesota Neuromuscular Diagnostic Laboratory. A standardised questionnaire was answered by owners at least 6 months after receiving the muscle biopsy report for an affected and a control horse. Polysaccharide storage myopathy (72/132 horses) was the most common myopathy identified followed by recurrent exertional rhabdomyolysis (RER) (7/132), neurogenic or myogenic atrophy (7/132), and nonspecific myopathic changes (14/132). Thirty-two biopsies were normal. Gait abnormality, 'tying-up', Shivers, muscle fasciculations and atrophy were common presenting clinical signs. Forty-five owners completed questionnaires. There were no differences in sex, age, breed, history or management between control, PSSM and non-PSSM horses. Owners that provided the recommended low starch fat supplemented diet and regular daily exercise reported improvement in clinical signs in 68% (19/28) of horses with a biopsy submission and 71% of horses diagnosed with PSSM (15/21). Muscle biopsy evaluation was a valuable tool to identify a variety of myopathies in Warmblood breeds including PSSM and RER. These myopathies often presented as gait abnormalities or overt exertional rhabdomyolysis and both a low starch fat supplemented diet and regular exercise appeared to be important in their successful management. Warmbloods are affected by a variety of muscle disorders, which, following muscle biopsy diagnosis can be improved through changes in diet and exercise regimes.


Dentin permeability: sealing the dentin in crown preparations.
Provisional restorations of full crown preparations may permit more microleakage of bacteria and their products than the final castings do. However, most investigations of the sealing qualities of cemented castings have reported that they too permit dye leakage. One approach to the problem is to seal the dentin with dentin bonding agents at the completion of the crown preparation. This study evaluated the ability of six different dentin bonding agents to seal the dentin of crown preparations of human teeth in vitro using two independent techniques. The first technique quantitated fluid filtration across dentin before and after treatment with dentin bonding agents at one hour, one day, one week, and one month and after thermocycling. The second method measured silver nitrate penetration of the thin veneers of dentin bonding agents into the dentin. Both methods correlated well with each other. The best seals were obtained with Prisma Universal Bond 2 or Superbond powder plus liquid. The worst seals were found using Gluma and Superbond liquid only. Clearfil PhotoBond, Amalgambond, and Scotchbond 2 gave intermediate results. Although the dentin bonding agents tend to accumulate on chamfers, thereby increasing their thickness to 200-300 microns, the method looks promising as a simple way to protect the pulp from the consequences of microleakage.


Restricted outbreak of American tegumentary leishmaniasis with high microfocal transmission.
Cutaneous leishmaniasis is endemic in Salta, the northwestern province of Argentina. We describe an outbreak involving five recreational hunters whose exposure was limited to several hours in a residual patch of primary forest. All patients presented with typical cutaneous lesions after a mean incubation period of 59 days (range 15-78), and one developed simultaneous mucosal involvement. Polymerase chain reaction analysis of lesions confirmed Leishmania (V.) braziliensis as the etiologic agent in three cases. All patients were cured with anti-Leishmania treatment. Entomologic surveys in the transmission area revealed a predominance of Lutzomyia neivai. This outbreak report confirms a microfocal transmission pattern of tegumentary leishmaniasis in the Americas and based on a well-determined exposure, allows the determination of incubation times for leishmaniasis caused by Leishmania braziliensis.


Association Between Self-Reported and Objective Activity Levels by Demographic Factors: Ecological Momentary Assessment Study in Children.
To address the limitations of the retrospective self-reports of activity, such as its susceptibility to recall bias, researchers have shifted toward collecting real-time activity data on mobile devices via ecological momentary assessment (EMA). Although EMA is becoming increasingly common, it is not known how EMA self-reports of physical activity and sedentary behaviors relate to the objective measures of activity or whether there are factors that may influence the strength of association between these two measures. Understanding the relationship between EMA and accelerometry can optimize future instrument selection in studies assessing activity and health outcomes. The aim of this study was to examine the associations between EMA-reported sports or exercise using the accelerometer-measured moderate-to-vigorous physical activity (MVPA) and EMA-reported TV, videos, or video games with the accelerometer-measured sedentary time (ST) in children during matched 2-h windows and test potential moderators. Children (N=192; mean age 9.6 years; 94/192, 49.0% male; 104/192, 54.2% Hispanic; and 73/192, 38.0% overweight or obese) wore an accelerometer and completed up to 7 EMA prompts per day for 8 days during nonschool time, reporting on past 2-h sports or exercise and TV, videos, or video games. Multilevel models were used to assess the relationship between the accelerometer-measured ST and EMA-reported TV, videos, or video games. Given the zero-inflated distribution of MVPA, 2-part models were used assess the relationship between the accelerometer-measured MVPA and EMA-reported sports or exercise. EMA-reported TV, videos, or video games were associated with a greater accelerometer-measured ST (beta=7.3, 95% CI 5.5 to 9.0, P<.001). This relationship was stronger in boys (beta=9.9, 95% CI 7.2 to 12.6, P<.001) than that in girls (beta=4.9, 95% CI 2.6 to 7.2, P≤.001). EMA-reported sports or exercise was associated with a greater accelerometer-measured MVPA (zero portion P<.001; positive portion P<.001). This relationship was stronger on weekends, in older children, and in non-Hispanic children (zero portion all P values<.001; positive portion all P values<.001). EMA reports highly relate to accelerometer measures. However, the differences in the strength of association depending on various demographic characteristics suggest that future research should use both EMA and accelerometers to measure activity to collect complementary activity data.


Three-layered silver nanoparticles to trace dissolution and association to a green alga.
Core-shell silver nanoparticles (NPs) consisting of an inner Ag core and successive layers of Au and Ag (Ag@Au@Ag) were used to measure the simultaneous association of Ag NPs and ionic Ag by the green alga Chlamydomonas (C.) reinhardtii. Dissolution of the inner Ag core was prevented by a gold (Au) layer, while the outer Ag layer was free to dissolve. In short-term experiments, we exposed C. reinhardtii to a range of environmentally realistic Ag concentrations added as AgNO3 or as NPs. Results provide three lines of evidence for the greater cell-association of NPs compared to dissolved Ag over the concentration range tested, assuming that cell-association comprises both uptake and adsorption. First, the cell-association rate constants (kuw) for total Ag (AgNP+D), NPs (AgNP) and AuNP were similar and 2.2-fold higher than the one from AgD exposure, suggesting predominant association of the particles over the dissolved form. Second, model calculations based on Ag fluxes suggested that only 6-33% of algal burden was from AgD. Third, the significantly lower AgNP/Au ratio measured with the algae after exposure (2.1 ± 0.1) compared to the AgNP/Au ratio of the NPs in the media (2.47 ± 0.05) suggests cell-association of NPs depleted in Ag. Core-shell NPs provide an innovative tool to understand NP behavior and to directly delineate Ag accumulation from ion and NPs in aquatic systems.


A thermal transition of passive calcium efflux in fragmented sarcoplasmic reticulum.
The temperature dependence of passive Ca2+ efflux from skeletal muscle fragmented sarcoplasmic reticulum (FSR) was studied by dilution of a suspension of the vesicles into which 1 mM (CaCl2 + 45Ca) had been passively incorporated by overnight incubation at 3 degrees. It was found that in the presence of 5 mM Mg2+, Ca2+ efflux could be resolved into two simultaneous first-order processes between 5 degrees and 35 degrees, but only a single first-order process appeared between 37 degrees and 55 degrees. Two independent functional transitions were found at 30 degrees, indicating an abrupt membrane molecular reorganization at that temperature: (1) The two components of Ca2+ efflux at 5 degrees--35 degrees contributed equally to the total observed initial efflux at temperatures up to 30 degrees. Between 30 degrees and 35 degrees, the relative contribution of the fast component progressively diminished until, by 37 degrees, only the slow component remained. (2) The slow component, which persisted throughout the entire temperature range 5 degrees--55 degrees, exhibited a break in its Arrhenius plot at 30 degrees--32 degrees. Elevation of internal Ca2+ concentration to 10 mM failed either to produce saturation kinetics of efflux or appreciably change its first-order rate constant. Omitting Mg2+ in the low temperature range accelerated Ca2+ efflux about 20-fold and eliminated the fast component, whereas including Ca2+ in the external medium in the high temperature range retarded Ca2+ efflux by about the same factor and generated a fast component. Omitting Mg2+ in the high-temperature range, however, had little effect on Ca2+ efflux. The failure of external divalent cation to stimulate Ca2+ efflux thus precludes an obligatory carrier-mediated exchange mechanism. Furthermore, participation of the catalytic turnover function of the Ca2+-ATPase molecule in Ca2+ efflux was unlikely because (1) the 30 degrees transition temperature for efflux did not coincide with those previously determined for active Ca2+ uptake, ATPase activity, and reversal of the Ca2+ pump, and (2) above the transition temperature, the activation enthalpy and activation entropy increased for efflux but decreased for both active Ca2+ uptake and ATPase activity. Ca2+ efflux therefore probably involved simple diffusion through a membrane pore (Ca2+ "leak"). By comparison to the results of others using artificial and biological membranes, the effect of external divalent cation to produce a fast component of Ca2+ efflux from FSR is tentatively attributed to the formation of aggregates of SR vesicles.


Impairment of T cell activation in burn patients: a possible mechanism of thermal injury-induced immunosuppression.
In the burn patient, the mechanisms leading to impaired T lymphocyte activity are unclear. The capacity for T cell proliferation and the expression of Tac antigen (IL-2 receptor) was assessed during the post-burn period in patients with injuries ranging from 5-68% total body surface area. T cell-dependent (polyclonal) immunoglobulin synthesis, mixed lymphocyte reaction and Interleukin-2 production were also determined in these patients and correlated with survival. Surviving patients demonstrated a transient reduction while terminal patients exhibited a permanent reduction in the number of Tac (+) lymphocytes, unrelated to the absolute number of T cells, during the post-burn period. The reduced percentage of IL-2 receptor-expressing T cells coincided with the suppressed antibody response and reduced alloreactivity. Although the concentration of IL-2 was decreased in all patients throughout the hospitalization period, surviving patients showed a gradual increase in its production while terminal patients gradually decreased to undetectable levels. Exogenous recombinant IL-2 induced a significant enhancement of in-vitro polyclonal immunoglobulin production and blastogenesis in the mixed lymphocyte reaction in immunosuppressed patients who demonstrated up to 50% reduction in the percentage of IL-2 receptor positive cells. Thus, the reduced capacity for production of and response to IL-2 after thermal injury may lead to the immunosuppression due to a lack of T lymphocyte clonal expansion. The permanent nature of this defect in patients who died from fatal sepsis may suggest a causative relationship.


Electron-scale measurements of magnetic reconnection in space.
Magnetic reconnection is a fundamental physical process in plasmas whereby stored magnetic energy is converted into heat and kinetic energy of charged particles. Reconnection occurs in many astrophysical plasma environments and in laboratory plasmas. Using measurements with very high time resolution, NASA's Magnetospheric Multiscale (MMS) mission has found direct evidence for electron demagnetization and acceleration at sites along the sunward boundary of Earth's magnetosphere where the interplanetary magnetic field reconnects with the terrestrial magnetic field. We have (i) observed the conversion of magnetic energy to particle energy; (ii) measured the electric field and current, which together cause the dissipation of magnetic energy; and (iii) identified the electron population that carries the current as a result of demagnetization and acceleration within the reconnection diffusion/dissipation region.


No Acute Effects of Exogenous Glucose-Dependent Insulinotropic Polypeptide on Energy Intake, Appetite, or Energy Expenditure When Added to Treatment With a Long-Acting Glucagon-Like Peptide 1 Receptor Agonist in Men With Type 2 Diabetes.
Dual incretin receptor agonists in clinical development have shown reductions in body weight and hemoglobin A1c (HbA1c) in patients with type 2 diabetes, but the impact of glucose-dependent insulinotropic polypeptide (GIP) receptor activation remains unclear. Here, we evaluated the effects of high-dose exogenous GIP on energy intake, energy expenditure, plasma glucose, and glucose-regulating hormones in patients with type 2 diabetes treated with a long-acting glucagon-like peptide 1 receptor (GLP-1R) agonist. In a randomized, double-blind design, men with type 2 diabetes (n = 22, mean ± SEM HbA1c 6.8 ± 0.1% [51 ± 1.5 mmol/mol]) treated with metformin and long-acting GLP-1R agonists were subjected to two 5-h continuous infusions (separated by a washout period of ≥3 days): one with GIP (6 pmol/kg/min) and another with saline (placebo). After 60 min of infusion, a liquid mixed-meal test was performed, and after 270 min of infusion, an ad libitum meal was served for evaluation of energy intake (primary end point). Energy intake was similar during GIP and placebo infusion (648 ± 74 kcal vs. 594 ± 55 kcal, respectively; P = 0.480), as were appetite measures and energy expenditure. Plasma glucagon and glucose were higher during GIP infusion compared with placebo infusion (P = 0.026 and P = 0.017) as assessed by area under the curve. In patients with type 2 diabetes, GIP infusion on top of treatment with metformin and a long-acting GLP-1R agonist did not affect energy intake, appetite, or energy expenditure but increased plasma glucose compared with placebo. These results indicate no acute beneficial effects of combining GIP and GLP-1.


Energy efficiency of optical interconnections using photorefractive holograms.
We propose and demonstrate the use of a Fourier transform to achieve maximum energy efficiency in a photorefractive optical interconnection. The results of experimental investigations on reconfigurable optical interconnections using photorefractive holograms in a barium titanate crystal are presented and discussed. High energy efficiency is achieved by matched amplification at the Fourier plane.


Phasic activation and state-dependent inhibition: an explicit solution for a three-state ion channel system.
Ion channels can exist in three broad classes of states: closed (C), open (O), and desensitized or inactivated (I). Many ion channel modulators interact preferentially with one of these states giving rise to use or state dependent effects and often complex interactions with phasic stimulation. Although mathematical descriptions of three-state systems at steady-state or following a single perturbation are well known, a solution to the boundary problem of how such a system interacts with regular phasic perturbations or stimuli has not previously been reported. In physiological systems, ion channels typically experience phasic stimulation and an explicit mathematical description of the interaction between phasic activation and use-dependent modulation within the framework of a three-state system should be useful. Here we present derivations of generalized, recurrent and explicit formulae describing this interaction that allow prediction of the degree of use dependent modulation at any point during a train of repeated stimuli. Each state is defined by two functions of time (y or z) that define the fraction of channels in that state during the alternating stimulation and resting phases, respectively. For a train of repeated stimuli we defined vector Z2n that has coordinates Z2nO and Z(2n)I representing the values for O and I states at the end of the n-th resting phase. We then defined a recurrent relationship, [symbol: see formula]. Therefore, for the steady state: [symbol: see formula], where [symbol: see formula] E is the identity matrix. Matrix and vector elements, Cif, are defined in terms of duration of the repeated stimulation and resting phases and the two sets of six rate constants that describe the three-state model during those two phases. Several conclusions can be deduced from the formulation: (I) in order to determine an occupancy of any state under the cyclic stimulus-rest protocol it is necessary to know at least two occupancy levels-either of the same state but related to different phases of the stimulus protocol or of different states at the same point in the stimulus protocol, for instance: [symbol: see text] (2) the solution Z2n can be approximated by a matrix-exponential function, with the precision of the approximation depending on the interval between stimuli; (3) for all steady-state solutions, the matrix F is such that [symbol: see text] is a zero-matrix. Application of this approach is illustrated using experimentally derived parameters describing desensitization of GABA, receptors and modulation of that process by the anesthetic propofol.


Gastrin: a distinct fate of neurogenin3 positive progenitor cells in the embryonic pancreas.
Neurogenin3(+) (Ngn3(+)) progenitor cells in the developing pancreas give rise to five endocrine cell types secreting insulin, glucagon, somatostatin, pancreatic polypeptide and ghrelin. Gastrin is a hormone produced primarily by G-cells in the stomach, where it functions to stimulate acid secretion by gastric parietal cells. Gastrin is expressed in the embryonic pancreas and is common in islet cell tumors, but the lineage and regulators of pancreatic gastrin(+) cells are not known. We report that gastrin is abundantly expressed in the embryonic pancreas and disappears soon after birth. Some gastrin(+) cells in the developing pancreas co-express glucagon, ghrelin or pancreatic polypeptide, but many gastrin(+) cells do not express any other islet hormone. Pancreatic gastrin(+) cells express the transcription factors Nkx6.1, Nkx2.2 and low levels of Pdx1, and derive from Ngn3(+) endocrine progenitor cells as shown by genetic lineage tracing. Using mice deficient for key transcription factors we show that gastrin expression depends on Ngn3, Nkx2.2, NeuroD1 and Arx, but not Pax4 or Pax6. Finally, gastrin expression is induced upon differentiation of human embryonic stem cells to pancreatic endocrine cells expressing insulin. Thus, gastrin(+) cells are a distinct endocrine cell type in the pancreas and an alternative fate of Ngn3+ cells.


Cardiogenic shock complicating acute myocardial infarction: predictors of death. GUSTO Investigators. Global Utilization of Streptokinase and Tissue-Plasminogen Activator for Occluded Coronary Arteries.
Current knowledge of predictors of death among patients with cardiogenic shock complicating myocardial infarction is limited. We aimed to develop a risk assessment prognostic algorithm of 30-day mortality, including clinical and hemodynamic data prospectively collected among patients with cardiogenic shock in the 41,021-patient Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) trial. We used logistic regression modeling techniques to evaluate the relations between demographic, clinical, and hemodynamic characteristics and 30-day mortality rate for the entire shock population (n = 2968) and for patients who underwent right-heart catheterization (n = 995). The odds (95% confidence interval) of dying were 1.49 times higher (1.27-1.74) for patients 10 years older and 1.70 times higher (1.19-2.44) for patients with prior infarction. Findings derived from physical examination, such as altered sensorium and cold, clammy skin, were important independent predictors of prognosis (odds of dying 1.68 times higher for each [1.19-2.39 and 1.15-2.46]). The odds of dying were also 2.25 times higher (1.61-3.15) in patients with oliguria. Mortality rate was lowest for cardiac output and pulmonary capillary wedge measurements of 5.1 L/min and 20 mm Hg, respectively, and increased with either higher or lower values. Patients with shock had better outcomes than patients in whom shock developed later, although for the latter subgroup, prognosis was worse in patients who had heart failure (Killip class II to III). We devised a prognostic algorithm for patients with cardiogenic shock complicating acute myocardial infarction. In addition to demographic and easily derived physical examination features, data derived from right-heart catheterization added valuable information that increased the ability to predict outcome in this high-risk population.


Individual-based and continuum models of growing cell populations: a comparison.
In this paper we compare two alternative theoretical approaches for simulating the growth of cell aggregates in vitro: individual cell (agent)-based models and continuum models. We show by a quantitative analysis of both a biophysical agent-based and a continuum mechanical model that for densely packed aggregates the expansion of the cell population is dominated by cell proliferation controlled by mechanical stress. The biophysical agent-based model introduced earlier (Drasdo and Hoehme in Phys Biol 2:133-147, 2005) approximates each cell as an isotropic, homogeneous, elastic, spherical object parameterised by measurable biophysical and cell-biological quantities and has been shown by comparison to experimental findings to explain the growth patterns of dense monolayers and multicellular spheroids. Both models exhibit the same growth kinetics, with initial exponential growth of the population size and aggregate diameter followed by linear growth of the diameter and power-law growth of the cell population size. Very sparse monolayers can be explained by a very small or absent cell-cell adhesion and large random cell migration. In this case the expansion speed is not controlled by mechanical stress but by random cell migration and can be modelled by the Fisher-Kolmogorov-Petrovskii-Piskounov (FKPP) reaction-diffusion equation. The growth kinetics differs from that of densely packed aggregates in that the initial spread, as quantified by the radius of gyration, is diffusive. Since simulations of the lattice-free agent-based model in the case of very large random migration are too long to be practical, lattice-based cellular automaton (CA) models have to be used for a quantitative analysis of sparse monolayers. Analysis of these dense monolayers leads to the identification of a critical parameter of the CA model so that eventually a hierarchy of three model types (a detailed biophysical lattice-free model, a rule-based cellular automaton and a continuum approach) emerge which yield the same growth pattern for dense and sparse cell aggregates.


COMSEP: an overview of its history, mission, and relationship to pediatrics.
The reader may wonder, "What is COMSEP, and how does an article from COMSEP affect me?" COMSEP, the Council on Medical Student Education in Pediatrics, is a community of pediatric clerkship directors and other educators whose mission is to improve the health of children and their families by advancing the art and science of medical student education in pediatrics.(1) This is the first in what is envisioned to be a quarterly report from the COMSEP to the readership of Pediatrics. In writing these articles, we hope to accomplish 3 key objectives. First, we want to keep the readership updated on trends that could affect both practice and pediatric education, whether they involve the rise of the pediatric hospitalist service or use of electronic medical records. Second, we hope to share educational techniques or strategies that allow for efficient and effective teaching, particularly in community practice settings. Third, we wish to be a voice for the huge number of pediatric practitioners who are critical not only as role models but also as mentors for the next generation of pediatric care providers. To better understand who and what COMSEP is, this first article is dedicated to the history, structure, and fundamental principles of the organization.


Thyroid-stimulating hormone pituitary adenomas.
Thyroid-stimulating hormone (TSH)-secreting pituitary adenomas are rare, representing < 2% of all pituitary adenomas. The authors conducted a retrospective analysis of patients with TSH-secreting or clinically silent TSH-immunostaining pituitary tumors among all pituitary adenomas followed at their institution between 1987 and 2003. Patient records, including clinical, imaging, and pathological and surgical characteristics were reviewed. Twenty-one patients (6 women and 15 men; mean age 46 years, range 26-73 years) were identified. Of these, 10 patients had a history of clinical hyperthyroidism, of whom 7 had undergone ablative thyroid procedures (thyroid surgery/(131)I ablation) prior to the diagnosis of pituitary adenoma. Ten patients had elevated TSH preoperatively. Seven patients presented with headache, and 8 presented with visual field defects. All patients underwent imaging, of which 19 were available for imaging review. Sixteen patients had macroadenomas. Of the 21 patients, 18 underwent transsphenoidal surgery at the authors' institution, 2 patients underwent transsphenoidal surgery at another facility, and 1 was treated medically. Patients with TSH-secreting tumors were defined as in remission after surgery if they had no residual adenoma on imaging and had biochemical evidence of hypo-or euthyroidism. Patients with TSH-immunostaining tumors were considered in remission if they had no residual tumor. Of these 18 patients, 9 (50%) were in remission following surgery. Seven patients had residual tumor; 2 of these patients underwent further transsphenoidal resection, 1 underwent a craniotomy, and 4 underwent postoperative radiation therapy (2 conventional radiation therapy, 1 Gamma Knife surgery, and 1 had both types of radiation treatment). Two patients had persistently elevated TSH levels despite the lack of evidence of residual tumor. On pathological analysis and immunostaining of the surgical specimen, 17 patients had samples that stained positively for TSH, 8 for alpha-subunit, 10 for growth hormone, 7 for prolactin, 2 for adrenocorticotrophic hormone, and 1 for follicle-stimulating hormone/luteinizing hormone. Eleven patients (61%) ultimately required thyroid hormone replacement therapy, and 5 (24%) required additional pituitary hormone replacement. Of these, 2 patients required treatment for new anterior pituitary dysfunction as a complication of surgery, and 2 patients with preoperative partial anterior pituitary dysfunction developed complete panhypopituitarism. One patient had transient diabetes insipidus. The remainder had no change in pituitary function from their preoperative state. Thyroid-stimulating hormone-secreting pituitary lesions are often delayed in diagnosis, are frequently macroadenomas and plurihormonal in terms of their pathological characteristics, have a heterogeneous clinical picture, and are difficult to treat. An experienced team approach will optimize results in the management of these uncommon lesions.


Tissue quality assessment using a novel direct elasticity assessment device (the E-finger): a cadaveric study of prostatectomy dissection.
Minimally invasive radical prostatectomy (RP) (robotic and laparoscopic), have brought improvements in the outcomes of RP due to improved views and increased degrees of freedom of surgical devices. Robotic and laparoscopic surgeries do not incorporate haptic feedback, which may result in complications secondary to inadequate tissue dissection (causing positive surgical margins, rhabdosphincter damage, etc). We developed a micro-engineered device (6 mm2 sized) [E-finger]) capable of quantitative elasticity assessment, with amplitude ratio, mean ratio and phase lag representing this. The aim was to assess the utility of the device in differentiating peri-prostatic tissue types in order to guide prostate dissection. Two embalmed and 2 fresh frozen cadavers were used in the study. Baseline elasticity values were assessed in bladder, prostate and rhabdosphincter of pre-dissected embalmed cadavers using the micro-engineered device. A measurement grid was created to span from the bladder, across the prostate and onto the rhabdosphincter of fresh frozen cadavers to enable a systematic quantitative elasticity assessment of the entire area by 2 independent assessors. Tissue was sectioned along each row of elasticity measurement points, and stained with haematoxylin and eosin (H&E). Image analysis was performed with Image Pro Premier to determine the histology at each measurement point. Statistically significant differences in elasticity were identified between bladder, prostate and sphincter in both embalmed and fresh frozen cadavers (p = < 0.001). Intra-class correlation (ICC) reliability tests showed good reliability (average ICC = 0.851). Sensitivity and specificity for tissue identification was 77% and 70% respectively to a resolution of 6 mm2. This cadaveric study has evaluated the ability of our elasticity assessment device to differentiate bladder, prostate and rhabdosphincter to a resolution of 6 mm2. The results provide useful data for which to continue to examine the use of elasticity assessment devices for tissue quality assessment with the aim of giving haptic feedback to surgeons performing complex surgery.


Differences in magnetic resonance findings between symptomatic and asymptomatic pre-collapse osteonecrosis of the femoral head.
The purpose of this study was to assess the differences in magnetic resonance (MR) findings between the symptomatic and asymptomatic pre-collapse stage of osteonecrosis of the femoral head (ONFH). This study reviewed 123 consecutive hips in 91 patients in the pre-collapse stage of ONFH based on plain radiographic findings. These 123 hips were divided into symptomatic and asymptomatic groups according to the pain domain score in the Harris hip score system. Bone marrow edema (BME), synovial fluid effusion, and subchondral fracture were evaluated using MR imaging. Odds ratios (ORs) were calculated between these three parameters and symptoms. The subsequent clinical course after MR examination was also assessed for each hip that could be followed more than 1 year. Forty-six hips (37.4%) were categorized as symptomatic and 77 hips (62.6%) as asymptomatic. The prevalence of BME, synovial fluid effusion, and subchondral fracture were 87.0% (40/46), 80.4% (37/46), and 34.8% (16/46), respectively, in the symptomatic group, and 0%, 28.6% (22/77), and 0%, respectively, in the asymptomatic group, indicating significant differences between the two groups (p < 0.0001). Among these parameters, BME showed the highest OR with regard to the presence or absence of symptoms (BME, 965.8; joint effusion, 10.3; subchondral fracture, 83.9). Due to persistent pain and subsequent collapse, 30 of 35 (85.7%) symptomatic hips with BME subsequently underwent surgical treatment at a mean interval of 3.47 months after MR examination, while 25 of 66 (37.9%) asymptomatic hips without BME underwent surgical treatment at a mean interval of 20.7 months after MR examination. This study demonstrated that symptomatic pre-collapse ONFH diagnosed based on plain radiographic findings could be distinguished from asymptomatic pre-collapse ONFH by the presence of BME on MR imaging, and thus BME may be a sign of occult fracture.


Severity of current depression and remission status are associated with structural connectome alterations in major depressive disorder.
Major depressive disorder (MDD) is associated to affected brain wiring. Little is known whether these changes are stable over time and hence might represent a biological predisposition, or whether these are state markers of current disease severity and recovery after a depressive episode. Human white matter network ("connectome") analysis via network science is a suitable tool to investigate the association between affected brain connectivity and MDD. This study examines structural connectome topology in 464 MDD patients (mean age: 36.6 years) and 432 healthy controls (35.6 years). MDD patients were stratified categorially by current disease status (acute vs. partial remission vs. full remission) based on DSM-IV criteria. Current symptom severity was assessed continuously via the Hamilton Depression Rating Scale (HAMD). Connectome matrices were created via a combination of T1-weighted magnetic resonance imaging (MRI) and tractography methods based on diffusion-weighted imaging. Global tract-based metrics were not found to show significant differences between disease status groups, suggesting conserved global brain connectivity in MDD. In contrast, reduced global fractional anisotropy (FA) was observed specifically in acute depressed patients compared to fully remitted patients and healthy controls. Within the MDD patients, FA in a subnetwork including frontal, temporal, insular, and parietal nodes was negatively associated with HAMD, an effect remaining when correcting for lifetime disease severity. Therefore, our findings provide new evidence of MDD to be associated with structural, yet dynamic, state-dependent connectome alterations, which covary with current disease severity and remission status after a depressive episode.


Identification of one of the apurinic/apyrimidinic lyase active sites of topoisomerase V by structural and functional studies.
Topoisomerase V (Topo-V) is the only member of a novel topoisomerase subtype. Topo-V is unique because it is a bifunctional enzyme carrying both topoisomerase and DNA repair lyase activities within the same protein. Previous studies had shown that the topoisomerase domain spans the N-terminus of the protein and is followed by 12 tandem helix-hairpin-helix [(HhH)(2)] domains. There are at least two DNA repair lyase active sites for apurinic/apyrimidinic (AP) site processing, one within the N-terminal region and the second within the C-terminal domain of Topo-V, but their exact locations and characteristics are unknown. In the present study, the N-terminal 78-kDa fragment of Topo-V (Topo-78), containing the topoisomerase domain and one of the lyase DNA repair domains, was characterized by structural and biochemical studies. The results show that an N-terminal 69-kDa fragment is the minimal fragment with both topoisomerase and AP lyase activities. The lyase active site of Topo-78 is at the junction of the fifth and sixth (HhH)(2) domains. From the biochemical and structural data, it appears that Lys571 is the most probable nucleophile responsible for the lyase activity. Our experiments also suggest that Topo-V most likely acts as a Class I AP endonuclease in vivo.


Spatial correlations of entangled polymer dynamics.
The spatial correlations of entangled polymer dynamics are examined by molecular dynamics simulations and neutron spin-echo spectroscopy. Due to the soft nature of topological constraints, the initial spatial decays of intermediate scattering functions of entangled chains are, to the first approximation, surprisingly similar to those of an unentangled system in the functional forms. However, entanglements reveal themselves as a long tail in the reciprocal-space correlations, implying a weak but persistent dynamic localization in real space. Comparison with a number of existing theoretical models of entangled polymers suggests that they cannot fully describe the spatial correlations revealed by simulations and experiments. In particular, the strict one-dimensional diffusion idea of the original tube model is shown to be flawed. The dynamic spatial correlation analysis demonstrated in this work provides a useful tool for interrogating the dynamics of entangled polymers. Lastly, the failure of the investigated models to even qualitatively predict the spatial correlations of collective single-chain density fluctuations points to a possible critical role of incompressibility in polymer melt dynamics.


Interaction with the SH3 domain protein Bem1 regulates signaling by the Saccharomyces cerevisiae p21-activated kinase Ste20.
The Saccharomyces cerevisiae PAK (p21-activated kinase) family kinase Ste20 functions in several signal transduction pathways, including pheromone response, filamentous growth, and hyperosmotic resistance. The GTPase Cdc42 localizes and activates Ste20 by binding to an autoinhibitory motif within Ste20 called the CRIB domain. Another factor that functions with Ste20 and Cdc42 is the protein Bem1. Bem1 has two SH3 domains, but target ligands for these domains have not been described. Here we identify an evolutionarily conserved binding site for Bem1 between the CRIB and kinase domains of Ste20. Mutation of tandem proline-rich (PxxP) motifs in this region disrupts Bem1 binding, suggesting that it serves as a ligand for a Bem1 SH3 domain. These PxxP motif mutations affect signaling additively with CRIB domain mutations, indicating that Bem1 and Cdc42 make separable contributions to Ste20 function, which cooperate to promote optimal signaling. This PxxP region also binds another SH3 domain protein, Nbp2, but analysis of bem1Delta versus nbp2Delta strains shows that the signaling defects of PxxP mutants result from impaired binding to Bem1 rather than from impaired binding to Nbp2. Finally, the PxxP mutations also reduce signaling by constitutively active Ste20, suggesting that postactivation functions of PAKs can be promoted by SH3 domain proteins, possibly by colocalizing PAKs with their substrates. The overall results also illustrate how the final signaling function of a protein can be governed by combinatorial addition of multiple, independent protein-protein interaction modules.


Using a fluorescent cytosine analogue tC(o) to probe the effect of the Y567 to Ala substitution on the preinsertion steps of dNMP incorporation by RB69 DNA polymerase.
Residues in the nascent base pair binding pocket (NBP) of bacteriophage RB69 DNA polymerase (RB69pol) are responsible for base discrimination. Replacing Tyr567 with Ala leads to greater flexibility in the NBP, increasing the probability of misincorporation. We used the fluorescent cytosine analogue, 1,3-diaza-2-oxophenoxazine (tC(o)), to identify preinsertion step(s) altered by NBP flexibility. When tC(o) is the templating base in a wild-type (wt) RB69pol ternary complex, its fluorescence is quenched only in the presence of dGTP. However, with the RB69pol Y567A mutant, the fluorescence of tC(o) is also quenched in the presence of dATP. We determined the crystal structure of the dATP/tC(o)-containing ternary complex of the RB69pol Y567A mutant at 1.9 Å resolution and found that the incoming dATP formed two hydrogen bonds with an imino-tautomerized form of tC(o). Stabilization of the dATP/tC(o) base pair involved movement of the tC(o) backbone sugar into the DNA minor groove and required tilting of the tC(o) tricyclic ring to prevent a steric clash with L561. This structure, together with the pre-steady-state kinetic parameters and dNTP binding affinity, estimated from equilibrium fluorescence titrations, suggested that the flexibility of the NBP, provided by the Y567 to Ala substitution, led to a more favorable forward isomerization step resulting in an increase in dNTP binding affinity.


Criminal thinking patterns, aggression styles, and the psychopathic traits of late high school bullies and bully-victims.
This study explored the current psychological characteristics and criminal behavior history of individuals who retrospectively reported being bullies, bully-victims, victims, or controls (i.e. neither victims nor bullies) during their last 2 years of high school. College students (n = 960) completed measures of criminal thinking, aggression, psychopathy, and criminal behavior online. We predicted bullies and bully-victims would demonstrate the highest scores for criminal thinking, proactive aggression, psychopathy, and have the most criminal infractions. Bullies and bully-victims had significantly higher scores on criminal thinking, aggression, psychopathy, and criminal behaviors than victims or controls. Additionally, men were significantly higher in criminal thinking, aggression, psychopathy, and had more criminal acts than women. There were no gender by bully group interactions. Logistic regression analyses differentiated bully-victims from bullies. Bully-victims tended to be male, higher in criminal thinking, and higher in reactive aggression. In addition, bully-victims were distinct from victims, showing higher criminal thinking and higher proactive aggression.


Causation and evidence-based practice: an ontological review.
This paper explores the nature of causation within the framework of evidence-based practice (EBP) for health care. The aims of the paper were first to define and evaluate how causation is presently accounted for in EBP; second, to present an alternative causal account by which health care can develop in both its clinical application and its scientific research activity. The paper was premised on the idea that causation underlies medical and health care practices and impacts on the way we understand health science research and daily clinical practice. The question of what causation is should therefore be of utmost relevance for all concerned with the science, philosophy and progress of EBP. We propose that the way causation is thought of in contemporaneous health care is exposed by evidential frameworks, which categorize research methods on their epistemological strengths. It is then suggested that the current account of causation is limited in respect of both the functionality of EBP, and its inherent scientific processes. An alternative ontology of causation is provided, which has its roots in dispositionalism. Here, causes are not seen as regular events necessitating an effect, but rather phenomena that are highly complex, context-sensitive and that tend towards an effect. We see this as a better account of causation for evidence-based health care.


Sudden onset dyspnea caused by Bochdalek diaphragmatic hernia in an adult: a case report.
Bochdalek diaphragmatic hernia is a developmental defect of the posterolateral portion of the diaphragm. This defect may allow abdominal contents to abnormally occupy the thoracic cavity, resulting in most cases in the compression of the developing lungs. Signs are typically shown during early childhood since the defect is usually present during development. In exceptional cases, however, Bochdalek diaphragmatic hernia can be observed in asymptomatic adult patients, or in those whose initial diagnosis may include common respiratory pathologies such as asthma. Here we describe the case of a 31-year-old Mestizo female patient admitted to the emergency room owing to sudden onset of pain in the left hypochondrium and in epigastrium, as well as signs of respiratory distress. Soon after admission, the patient entered cardiorespiratory arrest, and advanced cardiac life support was provided for 45 minutes without success. The patient was declared dead 1 hour 40 minutes after admission. Clinical autopsy concluded that cause of death was respiratory failure as a complication of a previously undiagnosed Bochdalek diaphragmatic hernia. We report an exceptional case of Bochdalek diaphragmatic hernia as the cause of rapid-onset respiratory failure and death in an adult. Unfortunately, due to its unusual presentation, Bochdalek diaphragmatic hernia is rarely considered among the list of differential diagnoses when admitting an adult patient with respiratory symptoms. By reporting this case, we encourage the medical community and trainees to consider diaphragmatic defects when approaching a patient with sudden onset of abdominal pain with concomitant respiratory symptoms.


Normalized grip strength is a sensitive outcome measure through all stages of Duchenne muscular dystrophy.
The main aim was to explore the changes in hand-grip strength in patients with Duchenne muscular dystrophy (DMD) aged 5-29 years. Secondary aims were to test the effect of mutation, ambulatory status and glucocorticoid use on grip strength and its changes over time and to compute the number of subjects needed for a clinical trial to stabilize grip strength. The analysis was performed on data collected during five international natural history studies on a cohort of DMD patients. Two hundred and two patients with genetically proven DMD were pooled from five different natural history studies. Excepting 13 patients with only one visit, the mean duration of follow-up was 2.2 ± 1.6 years. A total of 977 measurement points were collected. Grip strength was measured on the dominant side with a high precision dynamometer. The analysis was performed using absolute values and normalized values expressed in percentage of predicted values for age. For absolute values, grip strength typically increased in ambulatory boys and decreased in non-ambulatory patients. However, when normalized, grip strength was already reduced at age 5 years and thereafter continued to fall away from normal values. The weaker the patients, the less strength they are prone to lose over again. Grip strength constitutes a sensitive and continuous outcome measure that can be used across all stages of DMD. Its measurement is easy to standardized, can be used in ambulatory and non-ambulatory patients and does not present any floor or ceiling effect. It is thus attractive as an outcome measure in therapeutic trials.


Coherent Control of a Single Trapped Rydberg Ion.
Trapped Rydberg ions are a promising novel approach to quantum computing and simulations. They are envisaged to combine the exquisite control of trapped ion qubits with the fast two-qubit Rydberg gates already demonstrated in neutral atom experiments. Coherent Rydberg excitation is a key requirement for these gates. Here, we carry out the first coherent Rydberg excitation of an ion and perform a single-qubit Rydberg gate, thus demonstrating basic elements of a trapped Rydberg ion quantum computer.


Dexmedetomidine versus fentanyl added to bupivacaine for epidural analgesia in combination with general anesthesia for elective lumbar disc operations: A prospective, randomized double-blinded study.
The literature on drugs used for combined general anesthesia and epidural analgesia (CGE) in lumbar operations is scarce. The purpose of the study was to compare the addition of either dexmedetomidine or fentanyl to bupivacaine for epidural analgesia in combination with general anesthesia with regard to efficacy and adverse events in such operations. This prospective, randomized, double-blinded study was conducted on 80 patients who were scheduled for an elective lumbar disc operation, age 20-65 years, of either sex and American Society of Anesthesiologists physical status I or II. They were randomly allocated into one of the two groups - group bupivacaine-dexmedetomidine (BD) (n = 40): patients who received CGE with 15 mL of bupivacaine 0.20% plus 50 μg of dexmedetomidine and group bupivacaine-fentanyl (BF) (n = 40): patients who received CGE with 15 mL of bupivacaine 0.20% plus 50 μg fentanyl. The primary outcome was time to first analgesic requirement, whereas the secondary outcomes were the total opioid consumption and pain scores during the first 24 h. The incidence of adverse postoperative (PO) effects related to the study drugs, such as sedation, nausea and vomiting, pruritus, shivering, and respiratory depression, was also documented. Patients in the BD group experienced a significantly prolonged pain-free period, lower total opioid consumption, and lower pain scores than patients in the BF group (P < 0.001). Patients in the BD group showed a significantly lower intraoperative heart rate and mean blood pressure (P < 0.001). Regarding adverse events, there were greater PO sedation scores (P < 0.001) and less frequent episodes of PO nausea and vomiting in the BD group. In addition, patients in the BD group showed less pruritis and shivering. There were no reported cases of respiratory depression in either group. CGE with bupivacaine plus dexmedetomidine provided better PO pain control than bupivacaine plus fentanyl, with fewer adverse events overall.


Early Detection of Septic Shock Onset Using Interpretable Machine Learners.
Developing a decision support system based on advances in machine learning is one area for strategic innovation in healthcare. Predicting a patient's progression to septic shock is an active field of translational research. The goal of this study was to develop a working model of a clinical decision support system for predicting septic shock in an acute care setting for up to 6 h from the time of admission in an integrated healthcare setting. Clinical data from Electronic Health Record (EHR), at encounter level, were used to build a predictive model for progression from sepsis to septic shock up to 6 h from the time of admission; that is, T = 1, 3, and 6 h from admission. Eight different machine learning algorithms (Random Forest, XGBoost, C5.0, Decision Trees, Boosted Logistic Regression, Support Vector Machine, Logistic Regression, Regularized Logistic, and Bayes Generalized Linear Model) were used for model development. Two adaptive sampling strategies were used to address the class imbalance. Data from two sources (clinical and billing codes) were used to define the case definition (septic shock) using the Centers for Medicare & Medicaid Services (CMS) Sepsis criteria. The model assessment was performed using Area under Receiving Operator Characteristics (AUROC), sensitivity, and specificity. Model predictions for each feature window (1, 3 and 6 h from admission) were consolidated. Retrospective data from April 2005 to September 2018 were extracted from the EHR, Insurance Claims, Billing, and Laboratory Systems to create a dataset for septic shock detection. The clinical criteria and billing information were used to label patients into two classes-septic shock patients and sepsis patients at three different time points from admission, creating two different case-control cohorts. Data from 45,425 unique in-patient visits were used to build 96 prediction models comparing clinical-based definition versus billing-based information as the gold standard. Of the 24 consolidated models (based on eight machine learning algorithms and three feature windows), four models reached an AUROC greater than 0.9. Overall, all the consolidated models reached an AUROC of at least 0.8820 or higher. Based on the AUROC of 0.9483, the best model was based on Random Forest, with a sensitivity of 83.9% and specificity of 88.1%. The sepsis detection window at 6 h outperformed the 1 and 3-h windows. The sepsis definition based on clinical variables had improved performance when compared to the sepsis definition based on only billing information. This study corroborated that machine learning models can be developed to predict septic shock using clinical and administrative data. However, the use of clinical information to define septic shock outperformed models developed based on only administrative data. Intelligent decision support tools can be developed and integrated into the EHR and improve clinical outcomes and facilitate the optimization of resources in real-time.


Etiology of childhood bacteremia and timely antibiotics administration in the emergency department.
Bacteremia is now an uncommon presentation to the children's emergency department (ED) but is associated with significant morbidity and mortality. Its evolving etiology may affect the ability of clinicians to initiate timely, appropriate antimicrobial therapy. A retrospective time series analysis of bacteremia was conducted in the Alder Hey Children's Hospital ED between 2001 and 2011. Data on significant comorbidities, time to empirical therapy, and antibiotic susceptibility were recorded. A total of 575 clinical episodes were identified, and Streptococcus pneumoniae (n = 109), Neisseria meningitidis (n = 96), and Staphylococcus aureus (n = 89) were commonly isolated. The rate of bacteremia was 1.42 per 1000 ED attendances (95% confidence interval: 1.31-1.53). There was an annual reduction of 10.6% (6.6%-14.5%) in vaccine-preventable infections, and an annual increase of 6.7% (1.2%-12.5%) in Gram-negative infections. The pneumococcal conjugate vaccine was associated with a 49% (32%-74%) reduction in pneumococcal bacteremia. The rate of health care-associated bacteremia increased from 0.17 to 0.43 per 1000 ED attendances (P = .002). Susceptibility to empirical antibiotics was reduced (96.3%-82.6%; P < .001). Health care-associated bacteremia was associated with an increased length of stay of 3.9 days (95% confidence interval: 2.3-5.8). Median time to antibiotics was 184 minutes (interquartile range: 63-331) and 57 (interquartile range: 27-97) minutes longer in Gram-negative bacteremia than in vaccine-preventable bacteremia. Changes in the etiology of pediatric bacteremia have implications for prompt, appropriate empirical treatment. Increasingly, pediatric bacteremia in the ED is health care associated, which increases length of inpatient stay. Prompt, effective antimicrobial administration requires new tools to improve recognition, in addition to continued etiological surveillance.


Psychological factors related to the experience of and reaction to electroconvulsive therapy.
Aside from the focus on satisfaction levels, psychological aspects of the experience of electroconvulsive therapy (ECT) have not traditionally been the focus of significant research. Given that clinical psychologists work closely with professionals involved in administering ECT, and have increasing involvement with decisions about ECT, there is a potential role for clinical psychologists in this area. To review the diverse sources of literature regarding how patients psychologically experience, and react to, ECT. A literature search identified relevant published papers related to the patient experience of ECT. Reviewed articles included clinician and service user led research, comprising qualitative and quantitative research approaches and policy documents. Patients have multiple and diverse reactions to ECT. These can be considered under the themes of consent, fear, powerlessness, memory and identity. The experience of ECT can significantly impact on patients and this can have a negative long-term influence. Clinical psychologists need to be actively involved in consent procedures, use clinical formulation to understand the perspective of patients, and empower patients to share their views of ECT with mental health professionals and service developers. Further research into how patients experience ECT, particularly using qualitative methods, is recommended.


Controllable self-assembled plasmonic vesicle-based three-dimensional SERS platform for picomolar detection of hydrophobic contaminants.
Hydrophobic contaminants in food and the environment seriously threaten human health. The ultrasensitive detection of these pollutants can minimize their damage. However, current ultrasensitive sensing strategies are limited to solid substrate-based surface-enhanced Raman spectroscopy (SERS) detection. Herein, we report a controllable and reproducible solution-based SERS detection platform for the direct and ultrasensitive detection of hydrophobic contaminants by using self-assembled three-dimensional plasmonic vesicles. To this end, amphiphilic gold nanoparticles (AuNPs) tethered with linear block copolymer (BCP) of polystyrene-b-poly (ethylene oxide) (PS-b-PEO) were designed, which display dual functions for improving detection sensitivity, including serving as building blocks for the construction of plasmonic vesicles to yield large numbers of hot-spots for SERS enhancement, and providing hydrophobic PS layers to enrich and concentrate target hydrophobic molecules for direct SERS detection with hydrophobic interaction. By modulating the AuNP size and the length of BCP chains, the ultrahigh detection sensitivity, down to the picomolar level, was obtained via using 80 nm AuNPs tethered with BCP of PEO45-b-PS900-SH. In addition, the proposed method exhibits excellent reproducibility, universality, practicability, as well as multiplexing detection capacity in actual contaminant-spiked soil samples. Briefly, the designed self-assembled plasmonic vesicle-based SERS platform provides an ideal generic methodology for the ultrasensitive detection of hydrophobic contaminants that can greatly accelerate on-site testing in food and environmental monitoring.


Clinicopathologic predictors of survival in patients with desmoplastic melanoma.
Desmoplastic melanoma is a unique subtype of melanoma which typically affects older patients who often have comorbidities that can adversely affect survival. We sought to identify melanoma-specific factors influencing survival in patients with desmoplastic melanoma. Retrospective review from 1993 to 2011 identified 316 patients with primary desmoplastic melanoma. Clinicopathologic characteristics were correlated with nodal status and outcome. Fifty-five patients (17.4%) had nodal disease: 33 had a positive sentinel lymph node biopsy and 22 developed nodal recurrences (no sentinel lymph node biopsy or false-negative sentinel lymph node biopsy). Nodal disease occurred more often in younger patients and in cases with mixed compared with pure histology (26.7% vs. 14.6%); both of these variables significantly predicted nodal status on multivariable analysis (p<0.05). After a median follow-up of 5.3 years, recurrence developed in 87 patients (27.5%), and 111 deaths occurred. The cause of death was known in 79 cases, with 47 deaths (59.5%) being melanoma-related. On multivariable analysis, Breslow thickness, mitotic rate ≥ 1/mm(2) and nodal status significantly predicted melanoma-specific survival (p<0.05). Nodal status predicts melanoma-specific survival in patients with desmoplastic melanoma. However, since patients with desmoplastic melanoma represent an older population, and a considerable proportion of deaths are not melanoma-related (40.5%), comorbidities should be carefully considered in making staging and treatment decisions in this population.


Faecal incontinence in adults.
Faecal incontinence can affect individuals of all ages and in many cases greatly impairs quality of life, but incontinent patients should not accept their debility as either inevitable or untreatable. Education of the general public and of health-care providers alike is important, because most cases are readily treatable. Many cases of mild incontinence respond to simple medical therapy, whereas patients with more advanced incontinence are best cared for after complete physiological assessment. Recent advances in therapy have led to promising results, even for patients with refractory incontinence. Health-care providers must make every effort to communicate fully with incontinent patients and to help restore their self-esteem, eliminate their self-imposed isolation, and allow them to resume an active and productive lifestyle.


Nanometric resolution in the hydrodynamic size analysis of ligand-stabilized gold nanorods.
The stability and hydrodynamic size of ligand-coated gold nanorods (GNRs; aspect ratio 3.6) have been characterized by nanoparticle tracking analysis (NTA)-a single-particle counting method that can measure size distributions with low nanometer resolution. Stable aqueous suspensions of citrate-stabilized GNRs (cit-GNRs) are amenable to surface functionalization without loss of dispersion control. Cit-GNRs can be treated with chemisorptive ligands (thiols and dithiocarbamates), nonionic surfactants (Tween 20), and proteins (human serum albumin), all of which produce stable suspensions at low surfactant concentrations. The precision of NTA (relative standard deviation 10-12%, standard error <2%) is sufficient to allow differences in the hydrodynamic size of coated GNRs to be interpreted in terms of surfactant structure and conformation.


Pleiotropic Clostridioides difficile Cyclophilin PpiB Controls Cysteine-Tolerance, Toxin Production, the Central Metabolism and Multiple Stress Responses.
The Gram-positive pathogen Clostridioides difficile is the main bacterial agent of nosocomial antibiotic associated diarrhea. Bacterial peptidyl-prolyl-cis/trans-isomerases (PPIases) are well established modulators of virulence that influence the outcome of human pathologies during infections. Here, we present the first interactomic network of the sole cyclophilin-type PPIase of C. difficile (CdPpiB) and show that it has diverse interaction partners including major enzymes of the amino acid-dependent energy (LdhA, EtfAB, Had, Acd) and the glucose-derived (Fba, GapA, Pfo, Pyk, Pyc) central metabolism. Proteins of the general (UspA), oxidative (Rbr1,2,3, Dsr), alkaline (YloU, YphY) and cold shock (CspB) response were found bound to CdPpiB. The transcriptional (Lrp), translational (InfC, RFF) and folding (GroS, DnaK) control proteins were also found attached. For a crucial enzyme of cysteine metabolism, O-acetylserine sulfhydrylase (CysK), the global transcription regulator Lrp and the flagellar subunit FliC, these interactions were independently confirmed using a bacterial two hybrid system. The active site residues F50, F109, and F110 of CdPpiB were shown to be important for the interaction with the residue P87 of Lrp. CysK activity after heat denaturation was restored by interaction with CdPpiB. In accordance, tolerance toward cell wall stress caused by the exposure to amoxicillin was reduced. In the absence of CdPpiB, C. difficile was more susceptible toward L-cysteine. At the same time, the cysteine-mediated suppression of toxin production ceased resulting in higher cytotoxicity. In summary, the cyclophilin-type PPIase of C. difficile (CdPpiB) coordinates major cellular processes via its interaction with major regulators of transcription, translation, protein folding, stress response and the central metabolism.


Identification and genetics of 6-thioguanine secreted by Erwinia species and its interference with the growth of other bacteria.
We identified a compound in culture supernatants of Erwinia species, such as Erwinia amylovora, E. pyrifoliae, E. billingiae, E. tasmaniensis, E. persicina and E. rhapontici absorbing at 340 nm, which was associated before with the yellow pigment produced by E. amylovora on media containing copper ions. The compound was purified from E. tasmaniensis strain Et1/99 supernatants by chromatography on Dowex-1 and Dowex-50 columns and identified by HPLC/MS and NMR analysis as 6-thioguanine (6TG). Its signal at 167 Da matched with the expected molecular mass. By random mutagenesis with miniTn5, we obtained mutants defective in the genes for pyrimidine and purine metabolism. A specific gene cluster with ycf genes described by us before, absent in the corresponding region of Escherichia coli, was identified in the genome sequence of three Erwinia species and named tgs region for thioguanine synthesis. Clones of the tgs gene cluster promoted 6TG synthesis and secretion in E. coli, when the bacteria were grown in minimal medium supplemented with amino acids. 6TG was bacteriostatic for E. coli and Salmonella typhimurium strains, with cell growth resumed after prolonged incubation. Similar results were obtained with P. agglomerans strains. Bacteria from the genus Pectobacterium were barely and Rahnella or Gibbsiella species were not inhibited by 6TG. Adenine and guanine relieved the toxic effect of 6TG on E. coli. Non-producing strains were fully virulent on host plants. 6TG synthesis may help erwinias to interfere with growth of some microorganisms in the environment.


DJ-1 positively regulates the androgen receptor by impairing the binding of PIASx alpha to the receptor.
DJ-1 was first identified as a novel candidate of the oncogene product that transformed mouse NIH3T3 cells in cooperation with an activated ras. Later DJ-1 was also found to be an infertility-related protein that was reduced in rat sperm treated with sperm toxicants that cause infertility in rats. To determine the functions of DJ-1, cDNAs encoding DJ-1-binding proteins were screened by the yeast two-hybrid method. Of several proteins identified, PIASx alpha/ARIP3, a modulator of androgen receptor (AR), was first characterized as the DJ-1-binding protein in this study. DJ-1 directly bound to the AR-binding region of PIASx alpha by an in vitro coimmunoprecipitation assay and also bound to PIASx alpha in human 293T cells. Both proteins were co-localized in the nuclei. PIASx alpha inhibited the AR transcription activity in a dose-dependent manner in cotransfected monkey CV1 cells with an androgen responsive element-luciferase reporter. Introduction of DJ-1 into CV1 cells in a state of inhibition of AR activity by PIASx alpha restored AR transcription activity by absorbing PIASx alpha from the AR-PIASx alpha complex, while a DJ-1 mutant harboring an amino acid substitution at number 130 from lysine to arginine did not restore it. These results indicate that DJ-1 is a positive regulator of the androgen receptor.


Nutritional aspects of body water dislocations in postoperative and depleted patients.
Measurements of plasma volume with 125I human serum albumin, extracellular water (ECW) with 82Br-minus, and total body water (TBW) with 3-H2O were made on 16 postoperative patients, 15 depleted patients, and three control subjects. Intracellular water (ICW) was calculated as the difference between TBW and ECW. The observed findings for the series as a whole showed no change in blood volume, an increase of 3.7 I in ECW, and a decrease of 1.5 I in ICW as compared to predicted values based on current weight. Compared to predicted values based on normal (pre-illness) weight, the observed body weight decreased 16% and ICW decreased 22%; this suggests that body weight consistently under-estimates the extent of nutritional depletion. Severe depletion seen in postoperative patients indicates that frequently earlier use of total parenteral nutrition would be beneficial. ICW was found to be the most reliable single index of moderate or severe nutritional depletion; errors in estimating normal values interfere with its use in mild depletion. The ratio of ECW:TBW best reflects distortion of body water composition; it is largely independent of weight, and is a more sensitive index than absolute values of ICW. Repeat measurements of body composition were made on 9 patients given total parenteral nutrition for an average period of 18 days. On the average, there was an ECW decrease of 1.8 I, a body weight increase of 2 kg, and an ICW increase of 3.2 I after parenteral nutrition. The increased ICW represents the repletion of half of the average initial deficit of 6.1 The initial ratio of ECW:TBW of 0.58 was reduced to 0.50, returning it about three-quarters of the way to the expected normal value of 0.48. Intravenous administration of 5% glucose as sole source of calories may be a factor in distortion of body water compartments.


Gaze stabilization by efference copy signaling without sensory feedback during vertebrate locomotion.
Self-generated body movements require compensatory eye and head adjustments in order to avoid perturbation of visual information processing. Retinal image stabilization is traditionally ascribed to the transformation of visuovestibular signals into appropriate extraocular motor commands for compensatory ocular movements. During locomotion, however, intrinsic "efference copies" of the motor commands deriving from spinal central pattern generator (CPG) activity potentially offer a reliable and rapid mechanism for image stabilization, in addition to the slower contribution of movement-encoding sensory inputs. Using a variety of in vitro and in vivo preparations of Xenopus tadpoles, we demonstrate that spinal locomotor CPG-derived efference copies do indeed produce effective conjugate eye movements that counteract oppositely directed horizontal head displacements during undulatory tail-based locomotion. The efference copy transmission, by which the extraocular motor system becomes functionally appropriated to the spinal cord, is mediated by direct ascending pathways. Although the impact of the CPG feedforward commands matches the spatiotemporal specificity of classical vestibulo-ocular responses, the two fundamentally different signals do not contribute collectively to image stabilization during swimming. Instead, when the CPG is active, horizontal vestibulo-ocular reflexes resulting from head movements are selectively suppressed. These results therefore challenge our traditional understanding of how animals offset the disruptive effects of propulsive body movements on visual processing. Specifically, our finding that predictive efference copies of intrinsic, rhythmic neural signals produced by the locomotory CPG supersede, rather than supplement, reactive vestibulo-ocular reflexes in order to drive image-stabilizing eye adjustments during larval frog swimming, represents a hitherto unreported mechanism for vertebrate ocular motor control.


Variation in Barrett's esophageal wall thickness: is it associated with histology or segment length?
To measure esophageal wall thickness (EWT) with endoscopic ultrasound (EUS) in patients with and without Barrett's esophagus (BE). Segment length and histology are used to evaluate BE. The development of varying depths of ablation therapy has renewed interest in using EUS for BE. In this prospective study, EWT measurements were taken from the balloon-mucosal interface to the outer most hyper-echoic line. These measurements were correlated with the highest grade of BE dysplasia and segment length, and then compared with the measurements from control group. Between 2004 to 2007, 76 BE patients (69 men, mean age 68 y, 4 ND, 14 low-grade dysplasia, 52 high-grade dysplasia, 6 carcinoma in situ) and 53 normal controls (18 men, mean age 60 y) underwent EUS. The mean EWT was 2.4 mm for controls, 3.1 mm for nondysplastic BE, 3.2 mm for low-grade dysplasia, 3.4 mm for high-grade dysplasia, and 3.9 mm for carcinoma in situ. In the control group of 53 patients, the mean EWT was 2.4 mm. Compared with normal controls, the mean EWT was significantly greater in all histologic subgroups of BE patients (P<0.001). No statistically significant correlation was seen between EWT and BE histology grade. There were no correlations between age, gender, or BE segment length and EWT (P=0.55). EWT is greater among patients with BE compared with control patients; however, there were no systematic differences in EWT were found among BE patients, based on histology and segment length.


Deconstructing the principles of ductal network formation in the pancreas.
The mammalian pancreas is a branched organ that does not exhibit stereotypic branching patterns, similarly to most other glands. Inside branches, it contains a network of ducts that undergo a transition from unconnected microlumen to a mesh of interconnected ducts and finally to a treelike structure. This ductal remodeling is poorly understood, both on a microscopic and macroscopic level. In this article, we quantify the network properties at different developmental stages. We find that the pancreatic network exhibits stereotypic traits at each stage and that the network properties change with time toward the most economical and optimized delivery of exocrine products into the duodenum. Using in silico modeling, we show how steps of pancreatic network development can be deconstructed into two simple rules likely to be conserved for many other glands. The early stage of the network is explained by noisy, redundant duct connection as new microlumens form. The later transition is attributed to pruning of the network based on the flux of fluid running through the pancreatic network into the duodenum.


ERG oncoprotein inhibits ANXA2 expression and function in prostate cancer.
Overexpression of ERG in the prostate epithelium, due to chromosomal translocations, contributes to prostate tumorigenesis. Here, genomic analysis of ERG siRNA-treated prostate cells harboring the endogenous TMPRSS2-ERG fusion revealed an inverse relationship between ERG and Annexin A2 (ANXA2) expression at both the RNA and protein level. ANXA2, a Ca(2+)-dependent and phospholipid-binding protein, is involved in various cellular functions, including maintenance of epithelial cell polarity. Mechanistic studies defined the prostate-specific transcription start site of ANXA2 and showed that the recruitment of ERG to the ANXA2 promoter is required for transcriptional repression by ERG. Knockdown of ERG enhanced the apical localization of ANXA2, the bundling of actin filaments at cell-cell junctions and formation of a polarized epithelial phenotype. ERG overexpression disrupted ANXA2-mediated cell polarity and promoted epithelial-mesenchymal transition (EMT) by inhibiting CDC42 and RHOA, and by activating cofilin. Immunohistochemistry demonstrated a reciprocal relationship of ANXA2 and ERG expression in a large fraction of primary prostate cancer clinical specimens. ANXA2 was absent or markedly reduced in ERG(+) tumors, which were mostly well differentiated. ERG(-) tumors, meanwhile, expressed moderate to high levels of ANXA2, and were either poorly differentiated or displayed subsets of poorly differentiated cells. Taken together, the transcriptional repression of ANXA2 by ERG in prostate epithelial cells plays a critical role in abrogating differentiation, promoting EMT, and in the reciprocal correlation of ERG and ANXA2 expression observed in human prostate cancer. ANXA2 is a new component of the ERG network with potential to enhance biologic stratification and therapeutic targeting of ERG-stratified prostate cancers.


Does meditation enhance cognition and brain plasticity?
Meditation practices have various health benefits including the possibility of preserving cognition and preventing dementia. While the mechanisms remain investigational, studies show that meditation may affect multiple pathways that could play a role in brain aging and mental fitness. For example, meditation may reduce stress-induced cortisol secretion and this could have neuroprotective effects potentially via elevating levels of brain derived neurotrophic factor (BDNF). Meditation may also potentially have beneficial effects on lipid profiles and lower oxidative stress, both of which could in turn reduce the risk for cerebrovascular disease and age-related neurodegeneration. Further, meditation may potentially strengthen neuronal circuits and enhance cognitive reserve capacity. These are the theoretical bases for how meditation might enhance longevity and optimal health. Evidence to support a neuroprotective effect comes from cognitive, electroencephalogram (EEG), and structural neuroimaging studies. In one cross-sectional study, meditation practitioners were found to have a lower age-related decline in thickness of specific cortical regions. However, the enthusiasm must be balanced by the inconsistency and preliminary nature of existing studies as well as the fact that meditation comprises a heterogeneous group of practices. Key future challenges include the isolation of a potential common element in the different meditation modalities, replication of existing findings in larger randomized trials, determining the correct "dose," studying whether findings from expert practitioners are generalizable to a wider population, and better control of the confounding genetic, dietary and lifestyle influences.


Iontophoretic delivery of nitric oxide donor improves local skin flap viability.
The dimensions of local flaps are often limited by the vascular supply to the distal aspect of the flap. Distal flap necrosis occurs if the vascular supply is inadequate. The purpose of this study was to investigate the use of iontophoretic delivery of nitric oxide (NO) donors to a local skin flap model to improve the survival area of the flap. Thirty-two male Sprague-Dawley rats (300 g) were divided into seven experimental groups to determine the effect of iontophoretic delivery of NO on surface perfusion and flap survival area. A caudally based 3 x 11 cm dorsal skin flap was used to measure the effect of iontophoretic delivery of NO donors to a local skin flap to improve survival area of the flap. Iontophoretic delivery of the NO donors sodium nitroprusside (SNP) and diethylenetriamine NONOate (DETA-NO) resulted in a significant increase in survival area and surface perfusion when compared with sham controls. Iontophoretic delivery of saline was associated with a 13% improvement in flap survival when compared with nontreated controls. Iontophoretic delivery and subcutaneous injection of NO donors (SNP and DETA-NO) increased skin flap viability by demonstrating improved flap survival areas. The results of this study suggest that NO may serve as a postoperative treatment of skin flaps to encourage skin flap survival and prevent distal necrosis.


Same day discharge following multivessel off-pump coronary artery bypass via sternotomy.
In 1993 coronary artery bypass surgery resulted in a mean postoperative length of stay of about 8.5 days. With changing reimbursements and fast tract protocols this was decreased to about 7.0 days by 2002. However, with the use of new techniques it is possible to perform reliable and reproducible coronary artery bypass without the use of cardiopulmonary bypass. This has resulted in the ability to further decrease postoperative lengths of stay. Presented here is a case report regarding how an aggressive perioperative regimen can result in same day discharge following multivessel off-pump coronary artery bypass.


Exploiting the explosion of information associated with whole genome sequencing to tackle Shiga toxin-producing Escherichia coli (STEC) in global food production systems.
The rates of foodborne disease caused by gastrointestinal pathogens continue to be a concern in both the developed and developing worlds. The growing world population, the increasing complexity of agri-food networks and the wide range of foods now associated with STEC are potential drivers for increased risk of human disease. It is vital that new developments in technology, such as whole genome sequencing (WGS), are effectively utilized to help address the issues associated with these pathogenic microorganisms. This position paper, arising from an OECD funded workshop, provides a brief overview of next generation sequencing technologies and software. It then uses the agent-host-environment paradigm as a basis to investigate the potential benefits and pitfalls of WGS in the examination of (1) the evolution and virulence of STEC, (2) epidemiology from bedside diagnostics to investigations of outbreaks and sporadic cases and (3) food protection from routine analysis of foodstuffs to global food networks. A number of key recommendations are made that include: validation and standardization of acquisition, processing and storage of sequence data including the development of an open access "WGSNET"; building up of sequence databases from both prospective and retrospective isolates; development of a suite of open-access software specific for STEC accessible to non-bioinformaticians that promotes understanding of both the computational and biological aspects of the problems at hand; prioritization of research funding to both produce and integrate genotypic and phenotypic information suitable for risk assessment; training to develop a supply of individuals working in bioinformatics/software development; training for clinicians, epidemiologists, the food industry and other stakeholders to ensure uptake of the technology and finally review of progress of implementation of WGS. Currently the benefits of WGS are being slowly teased out by academic, government, and industry or private sector researchers around the world. The next phase will require a coordinated international approach to ensure that it's potential to contribute to the challenge of STEC disease can be realized in a cost effective and timely manner.


Country-specific estimates of unintended pregnancy and abortion incidence: a global comparative analysis of levels in 2015-2019.
Internationally comparable estimates of unintended pregnancy and abortion incidence can illuminate disparities in sexual and reproductive health and autonomy. Country-specific estimates are essential to enable international comparison, and to inform country-level policy and programming. We developed a Bayesian model which jointly estimated unintended pregnancy and abortion rates using information on contraceptive needs and use, contraceptive method mix, birth rates, the proportions of births from unintended pregnancies and abortion incidence data. Main outcomes were the estimated rates of unintended pregnancy and abortion for 150 countries and territories, reported for the 5-year period 2015-2019, as annual averages per 1000 women aged 15-49 years. Estimated unintended pregnancy rates ranged from 11 (80% uncertainty interval: 9 to 13) in Montenegro to 145 (131 to 159) in Uganda per 1000 women aged 15-49 years. Between-country heterogeneity was substantial in all Sustainable Development Goal (SDG) regions, but was greatest in sub-Saharan Africa. Estimated abortion rates ranged from 5 (5 to 6) in Singapore to 80 (55 to 113) in Georgia. Variation between country estimates was similar in all SDG regions except for Europe and Northern America, where estimated abortion rates were generally lower. The estimates reflect variation in the degree to unintended pregnancy and abortion that are experienced in countries throughout the world. This evidence highlights the importance of investing in access to contraception and comprehensive abortion care, including in regions which may have lower rates of unintended pregnancy or abortion, respectively, as countries may differ substantially from regional averages.


Lower limb reaction time discriminates between multiple and single fallers.
Despite research supporting its validity in predicting falls, simple reaction time (SRT) is not typically included in a clinical falls assessment battery because there is no standardised, clinically feasible testing protocol with published cutoff scores. This study aimed to determine whether SRT scores obtained using a clinically viable protocol could discriminate between multiple and single fallers. SRT scores were obtained from 147 participants (88 women and 59 men) over the age of 65 years (mean 80.1 years; SD 8.4 years) who had reported one or more falls in the previous 12 months. Forty-eight single and 99 multiple fallers were recruited from the subacute public hospital sector. SRT scores significantly discriminated between faller groups (Wilk's λ = 0.89, p = 0.05), with SRT score being the dominating predictor between groups. A receiver operating characteristic (ROC) curve showed good diagnostic accuracy with the area under curve = 0.78. A cutoff score of 394.5 ms provided the best balance between sensitivity and specificity. Once data were dichotomized as being above or below this cutoff value, a binary regression analysis revealed an odds ratio of 7.18 (95% CI 3.3-15.6), with a positive predictive value of 84.5%. The clinically feasible lower limb SRT testing protocol described provided good discrimination between single and multiple fallers. This test may be useful in clinical practice to help identify older people at greater risk of future falls.


Very high incidence of syphilis in HIV-infected men who have sex with men in Buenos Aires city: a retrospective cohort study.
The incidence of sexually transmitted infections (STIs), particularly syphilis, is high and continues to rise among some populations, especially among men who have sex with men (MSM). Furthermore, a higher incidence of STIs has been reported in HIV-positive than in HIV-negative MSM. To determine the incidence of syphilis in a cohort of men with HIV in Buenos Aires city. Retrospective cohort study. We examined the records and visits made by men with HIV aged >18 years in our institution during a 1-year period. Venereal Disease Reference Laboratory (VDRL) results for all the men in our cohort during the study period were analysed. We considered a case of syphilis as incident if a person had a VDRL result of ≥16 DILS, provided that this was increased at least fourfold compared with a previous determination. All VDRL results ≤8 were investigated, and analysed together with the medical records, to determine if they were new cases. We analysed the VDRL results and the clinical records of 1150 men followed up in our centre during the study period. Mean age was 40.9 years. According to the definition used, we registered 171 new cases of syphilis-that is, an incidence of 14.9/100 patients/year (95% CI 12.9 to 17.0). No significant differences in incidence according to age group were found, but there was a trend towards a lower incidence in older men. Ten men had two new episodes during the study. The incidence of syphilis in this cohort of men with HIV (predominantly MSM) was very high. In addition to maintaining high surveillance for early diagnosis and treatment, it is necessary to implement newer and more effective measures to prevent syphilis and other STIs in this population.


Distinct patterns of comorbidity prior to diagnosis of incident systemic lupus erythematosus in the Danish population.
The objective of this study was to assess the cumulative prevalence of pre-existing comorbidities among patients diagnosed with systemic lupus erythematosus (SLE) in Denmark. The study included patients aged ≥18 years at the index date set to the date of first registration of SLE in the Danish National Patient Registry (DNPR) between 1996 and 2018. Up to 19 age- and sex-matched general population comparators per case were selected. Comorbidity diagnoses were retrieved from the DNPR based on International Classification of Diseases codes. We estimated cumulative prevalence of various comorbidities among cases and comparators, prevalence differences (PDs), and prevalence ratios (PRs), with PDs and PRs adjusted for age and sex, at the index date and 1, 2, 5, and 10 years before the index date. We identified 3,010 SLE cases and 57,046 comparators (mean age at index date: 47.3 years). Most comorbidities occurred more often in SLE patients versus comparators at the index date and up to 10 years before. Overrepresented comorbidities in SLE patients 10 years before SLE diagnosis included neuropsychiatric, cardiovascular, and venous thromboembolic diseases; PDs (95% CI) were 2.3% (1.4-3.3%), 1.3% (0.6-1.9%), and 1.1% (0.6-1.5%), respectively; corresponding PRs (95% CI) were 1.5 (1.3-1.8), 1.7 (1.4-2.1), and 4.3 (3.1-6.1). We found a higher prevalence of multiple comorbidities-not only at the time of SLE diagnosis but likewise during the 10-year pre-diagnosis period-among individuals with SLE. These findings underscore the importance of early clinical vigilance toward comorbidities starting in the diagnostic phase of SLE.


Physiological profiles and sport specific fitness of Asian elite squash players.
There is a scarcity of descriptive data on the physiological characteristics of elite Asian squash players. The purpose of this study was to evaluate the physiological profile and sports specific fitness of Hong Kong elite squash players. It was conducted before the selection of the Hong Kong national squash team for the 1992 Asian Squash Championship. Ten elite squash players were selected as subjects for the study. Maximum oxygen uptake was measured using a continuous treadmill running test. A sports specific field test was performed in a squash court. The following means (s.d.) were observed: height 172.6(4.3) cm; weight 67.7(6.9) kg; body fat 7.4(3.4)%; forced vital capacity (FVC) 5.13(0.26) litres; maximum oxygen uptake (VO2max) 61.7(3.4) ml.kg-1.min-1; anaerobic threshold (AT) 80.2(3.3)% of VO2max; alactic power index 15.5(1.8) W.kg-1; lactic work index 323.5(29.4) J.kg-1, peak isokinetic dominant knee extensor and flexor strengths 3.11(0.29) Nm.kg-1 and 1.87(0.18) Nm.kg-1. The results show that the Hong Kong squash players have relatively high cardiorespiratory sports specific fitness and muscle strength which may be one of the key factors that contributed to the success of the Hong Kong team in the Asian Championship.


Curcumin attenuates lupus nephritis upon interaction with regulatory T cells in New Zealand Black/White mice.
Curcumin has been used in Asian traditional medicine for its medicinal properties. Recent studies have demonstrated that curcumin has antioxidant, anti-tumour and anti-inflammatory activities. The aim of the present study is to investigate the effects of curcumin on established lupus nephritis (LN) in New Zealand Black/White (NZB/W) F1 female mice, in particular, its interaction with regulatory T (Treg) cells. Starting at 18 weeks of age, mice were fed a standard diet or a diet containing 1 % curcumin until the end of the study. The proteinuria level and the serum levels of IgG1, IgG2a and anti-double-stranded DNA (dsDNA) IgG antibodies were measured. Additionally, IgG immune complex deposition in the glomeruli and renal inflammation were compared between curcumin-treated mice and control mice. Curcumin decreased the proteinuria level and serum levels of IgG1, IgG2a and anti-dsDNA IgG antibodies in NZB/W F1 female mice. IgG immune complex deposition in the glomeruli was reduced in curcumin-treated mice. Furthermore, renal inflammation was also decreased after curcumin treatment. Interestingly, these therapeutic effects of curcumin disappeared after Treg depletion by anti-CD25 antibody injection. Curcumin exerted a protective effect against LN in NZB/W F1 mice. We speculate that the protective effects of curcumin in LN may involve, at least in part, its interaction with Treg cells.


The Effects of Racism in Medical Education on Students' Decisions to Practice in Underserved or Minority Communities.
The purpose of this study was to examine the relationship between manifestations of racism in medical school and subsequent changes in graduating medical students' intentions to practice in underserved or minority communities, compared with their attitudes and intentions at matriculation. The authors used repeated-measures data from a longitudinal study of 3,756 students at 49 U.S. medical schools that were collected from 2010 to 2014. They conducted generalized linear mixed models to estimate whether manifestations of racism in school curricula/policies, school culture/climate, or student attitudes/behaviors predicted first- to fourth-year changes in students' intentions to practice in underserved communities or primarily with minority populations. Analyses were stratified by students' practice intentions (no/undecided/yes) at matriculation. Students' more negative explicit racial attitudes were associated with decreased intention to practice with underserved or minority populations at graduation. Service learning experiences and a curriculum focused on improving minority health were associated with increased intention to practice in underserved communities. A curriculum focused on minority health/disparities, students' perceived skill at developing relationships with minority patients, the proportion of minority students at the school, and the perception of a tense interracial environment were all associated with increased intention to care for minority patients. This study provides evidence that racism manifested at multiple levels in medical schools was associated with graduating students' decisions to provide care in high-need communities. Strategies to identify and eliminate structural racism and its manifestations in medical school are needed.


Reduced respiratory capacity in muscle mitochondria of obese subjects.
The extent of weight gain varies among individuals despite equal calorie overconsumption. Furthermore, weight gain is often less than expected from energy excess. This suggests differences in metabolic efficiency and basal metabolism. Since mitochondrial uncoupling accounts for a substantial portion of the basal metabolic rate, we compared skeletal muscle mitochondrial respiration in obese subjects to normal-weight reference groups with various degrees of physical activity. Muscle biopsies were taken from the vastus lateralis muscle of 9 healthy obese subjects (BMI 40 ± 3). Mitochondria were isolated and analyzed for coupled (state 3) and uncoupled (state 4) respirations as well as mitochondrial efficiency (P/O ratio) using pyruvate as a substrate. Respiratory data were compared to reference groups A, normal-weight untrained (BMI 24 ± 0.7), and B, normal-weight trained (BMI 24 ± 0.6). Obese subjects had a decreased respiratory capacity per mitochondrial volume compared to the reference groups: this was evident in state 4 (65% and 35% of reference group A and B, respectively) and state 3 (53% and 29% of A and B, respectively) (p < 0.05). Obese subjects had a low capacity for fuel oxidation, which may play a role in the predisposition of obesity. However, whether lower mitochondrial capacity is a cause or a consequence of obesity requires further research.


Millimeter-wave arbitrary waveform generation with a direct space-to-time pulse shaper.
By using tailored pulse sequences from a novel, 1.5-microm direct space-to-time pulse shaper driving a high-speed photodetector, we have achieved, for the first time to our knowledge, millimeter-wave arbitrary waveform generation at center frequencies approaching 50 GHz. By appropriately designing the driving optical pulse sequences, we demonstrate the ability to synthesize strongly phase- and frequency-modulated millimeter-wave electrical signals on a cycle-by-cycle basis.


Learning from Binary Multiway Data: Probabilistic Tensor Decomposition and its Statistical Optimality.
We consider the problem of decomposing a higher-order tensor with binary entries. Such data problems arise frequently in applications such as neuroimaging, recommendation system, topic modeling, and sensor network localization. We propose a multilinear Bernoulli model, develop a rank-constrained likelihood-based estimation method, and obtain the theoretical accuracy guarantees. In contrast to continuous-valued problems, the binary tensor problem exhibits an interesting phase transition phenomenon according to the signal-to-noise ratio. The error bound for the parameter tensor estimation is established, and we show that the obtained rate is minimax optimal under the considered model. Furthermore, we develop an alternating optimization algorithm with convergence guarantees. The efficacy of our approach is demonstrated through both simulations and analyses of multiple data sets on the tasks of tensor completion and clustering.