Fibromyxoid nephrogenic adenoma: a newly recognized variant mimicking mucinous adenocarcinoma.
Nephrogenic adenomas demonstrate a variety of morphologic patterns that may occasionally be confused with malignant processes, including urothelial and prostatic carcinoma. In this series, we describe 8 cases of nephrogenic adenoma that contain an admixture of the classic tubular form of nephrogenic adenoma and an unusual spindled and fibromyxoid form of nephrogenic adenoma that closely mimics infiltrating carcinoma. In all cases, the classic tubular form of nephrogenic adenoma composed only a small proportion of the lesion, whereas the remainder consisted of compressed spindled cells within a fibromyxoid background, with only rare tubular and cordlike structures. On close examination, minimal nuclear atypia was identified in 2 cases, which included small, pinpoint nucleoli, and nuclear pseudoinclusions. All 8 patients were elderly men who had a prior or concurrent history of acinar prostate cancer (n=4), combined acinar prostate and urothelial carcinoma (n=1), urothelial-type adenocarcinoma of the prostate (n=1), bladder urothelial carcinoma (n=1), or no prior reported prostatic or urothelial abnormalities (n=1). Five patients received prior treatment with radiotherapy, 1 patient received intravesical mitomycin-C, and 1 also received bacillus Calmette-Guerin. The epithelial component of the lesions was positive in all cases for pancytokeratin (AE1/3) and racemase and demonstrated a variable cuff of type IV collagen surrounding the tubules. PAX-2 was positive with variable extent of labeling. Immunostains for prostate-specific antigen were negative. Histochemical stains identified some of the background matrix as mucin, with intense staining for periodic acid-Schiff and focal staining for mucicarmine. Stains for reticulin and amyloid (Congo red stain) and immunohistochemistry for Tamm-Horsfall protein were negative. This case series is the first report of a fibromyxoid subtype of nephrogenic adenoma. Awareness of this entity and the use of ancillary techniques can aid in the diagnosis of this unusual form of nephrogenic adenoma.


Muscular mitochondrial function in amyotrophic lateral sclerosis is progressively altered as the disease develops: a temporal study in man.
We performed repeated analysis of mitochondrial respiratory function in skeletal muscle (SM) of patients with early-stage sporadic amyotrophic lateral sclerosis (SALS) to determine whether mitochondrial function was altered as the disease advanced. SM biopsies were obtained from 7 patients with newly diagnosed SALS, the same 7 patients 3 months later, and 7 sedentary controls. Muscle fibers were permeabilized with saponin, then skinned and placed in an oxygraphic chamber to measure basal and maximal adenosine diphosphate (ADP)-stimulated respiration rates and to assess mitochondrial regulation by ADP. We found that the maximal oxidative phosphorylation capacity of muscular mitochondria significantly increased, and muscular mitochondrial respiratory complex IV activity significantly decreased as the disease advanced. This temporal study demonstrates for the first time that mitochondrial function in SM in human SALS is progressively altered as the disease develops.


Vaccine delivery: a matter of size, geometry, kinetics and molecular patterns.
Researchers working on the development of vaccines face an inherent dilemma: to maximize immunogenicity without compromising safety and tolerability. Early vaccines often induced long-lived protective immune responses, but tolerability was a major problem. Newer vaccines have very few side effects but can be of limited immunogenicity. One way to tackle this problem is to design vaccines that have all the properties of pathogens with the exception of causing disease. Key features of pathogens that can be mimicked by vaccine delivery systems are their size, shape and surface molecule organization. In addition, pathogen-associated molecular patterns can be used to induce innate immune responses that promote adaptive immunity. In this Review, we discuss the approaches currently being used to optimize the delivery of antigens and enhance vaccine efficacy.


Effect of pedometer-based walking on depression, anxiety and insomnia among postmenopausal women.
Insomnia, anxiety, and depression are some psychological symptoms associated with menopause. The aim of this study was to evaluate the effect of pedometer-based walking on anxiety, insomnia, and depression among postmenopausal women. In this randomized, controlled trial, 106 postmenopausal women were randomly assigned to two groups (n = 53 in each group). Their anxiety, insomnia, and depression levels were assessed using the GHQ-28 and Beck questionnaires in the 4th, 8th, and 12th weeks of intervention. The depression level was assessed in the beginning, and in the 12th week of the trial. The members of the intervention group each received a pedometer and were asked to increase their steps by 500 per week. Data were analyzed using the independent t-test, χ(2) and repeated-measures tests. The levels of anxiety and insomnia decreased in the 8th (4.2 ± 2.1 vs. 5.4 ± 2.3, p = 0.007) and 12th week (4.3 ± 2.8 vs. 7.2 ± 2.6, p < 0.001) in the intervention group, compared with the control group. The depression intensity decreased in the intervention group, compared with the control group, after 12 weeks (13.7 ± 5 vs. 19.6 ± 4.79, p < 0.001). The intervention group increased their step count from 76,377 steps per month in the first month, to 106 398 in the 3rd month (p < 0.001). This study showed that pedometer-based walking had a positive effect on depression, insomnia and anxiety among postmenopausal women. A walking training program can be considered for postmenopausal women in Iran.


Indicatrices of the earth's surface reflection from Landsat MSS data.
A method of obtaining an indicatrix or a scattering diagram of the earth's surface is developed. When we regard the earth's surface as a kind of irregular surface, the indicatrix of scattered radiation is a way of effective representation of its surface roughness. The indicatrices of radiation over the sands of a seashore, a downtown area of Tokyo, and some of its suburban areas are obtained from Landsat MSS data. The radiant intensity decreases within the range of 32 degrees to 65 degrees of scattering angles in accordance with the degree of urbanization. Experimental results obtained by a remote sensing simulator are compared with those of Landsat MSS data analysis.


Hyperglycemia and adverse pregnancy outcomes.
It is controversial whether maternal hyperglycemia less severe than that in diabetes mellitus is associated with increased risks of adverse pregnancy outcomes. A total of 25,505 pregnant women at 15 centers in nine countries underwent 75-g oral glucose-tolerance testing at 24 to 32 weeks of gestation. Data remained blinded if the fasting plasma glucose level was 105 mg per deciliter (5.8 mmol per liter) or less and the 2-hour plasma glucose level was 200 mg per deciliter (11.1 mmol per liter) or less. Primary outcomes were birth weight above the 90th percentile for gestational age, primary cesarean delivery, clinically diagnosed neonatal hypoglycemia, and cord-blood serum C-peptide level above the 90th percentile. Secondary outcomes were delivery before 37 weeks of gestation, shoulder dystocia or birth injury, need for intensive neonatal care, hyperbilirubinemia, and preeclampsia. For the 23,316 participants with blinded data, we calculated adjusted odds ratios for adverse pregnancy outcomes associated with an increase in the fasting plasma glucose level of 1 SD (6.9 mg per deciliter [0.4 mmol per liter]), an increase in the 1-hour plasma glucose level of 1 SD (30.9 mg per deciliter [1.7 mmol per liter]), and an increase in the 2-hour plasma glucose level of 1 SD (23.5 mg per deciliter [1.3 mmol per liter]). For birth weight above the 90th percentile, the odds ratios were 1.38 (95% confidence interval [CI], 1.32 to 1.44), 1.46 (1.39 to 1.53), and 1.38 (1.32 to 1.44), respectively; for cord-blood serum C-peptide level above the 90th percentile, 1.55 (95% CI, 1.47 to 1.64), 1.46 (1.38 to 1.54), and 1.37 (1.30 to 1.44); for primary cesarean delivery, 1.11 (95% CI, 1.06 to 1.15), 1.10 (1.06 to 1.15), and 1.08 (1.03 to 1.12); and for neonatal hypoglycemia, 1.08 (95% CI, 0.98 to 1.19), 1.13 (1.03 to 1.26), and 1.10 (1.00 to 1.12). There were no obvious thresholds at which risks increased. Significant associations were also observed for secondary outcomes, although these tended to be weaker. Our results indicate strong, continuous associations of maternal glucose levels below those diagnostic of diabetes with increased birth weight and increased cord-blood serum C-peptide levels.


Intra-breath changes in respiratory mechanics assessed from multi-frequency oscillometry measurements.
Objective. Recent studies in respiratory system impedance (Zrs) with single-frequency oscillometry have demonstrated the utility of novel intra-breath measures of Zrs in the detection of pathological alterations in respiratory mechanics. In the present work, we addressed the feasibility of extracting intra-breath information from Zrs data sets obtained with conventional oscillometry.Approach. Multi-frequency recordings obtained in a pulmonology practice were re-analysed to track the 11 Hz component of Zrs during normal breathing and compare the intra-breath measures to that obtained with a single 10 Hz signal in the same subjects. A nonlinear model was employed to simulate changes in Zrs in the breathing cycle. The values of resistance (R) and reactance (X) at end expiration and end inspiration and their corresponding differences (ΔRand ΔX) were compared.Main results. All intra-breath measures exhibited similar mean values at 10 and 11 Hz in each subject; however, the variabilities were higher at 11 Hz, especially for ΔRand ΔX. The poorer quality of the 11 Hz data was primarily caused by the overlapping of modulation side lobes of adjacent oscillation frequencies. This cross-talk was enhanced by double breathing frequency components due to flow nonlinearities.Significance. Retrospective intra-breath assessment of large or special data bases of conventional oscillometry can be performed to better characterise respiratory mechanics in different populations and disease groups. The results also have implications in the optimum design of multiple-frequency oscillometry (avoidance of densely spaced frequencies) and the use of filtering procedures that preserve the intra-breath modulation information.


Vitamin A for treating measles in children.
Measles is a leading cause of childhood morbidity and mortality. Vitamin A deficiency is a recognised risk factor for severe measles. The World Health Organization (WHO) recommends administration of an oral dose of 200,000 IU (or 100,000 IU in infants) of vitamin A per day for two days to children with measles in areas where vitamin A deficiency may be present. The purpose of this review is to determine whether vitamin A when commenced after measles has been diagnosed, is beneficial in preventing mortality, pneumonia and other complications in children. MEDLINE and the Cochrane Library, Issue 4, 1999 were searched. Only randomized controlled trials in which children with measles were given vitamin A or placebo along with standard treatment were considered. Studies were assessed independently by two reviewers. The analysis of dichotomous outcomes was done using the StatExact software package. Sub-group analyses were done for dose, formulation, age, hospitalisation and pneumonia specific mortality. Weighted mean difference with 95% CI were calculated for continuous outcomes. The relative risks (RR) and 95% Confidence Intervals (CI) are based on the estimates from the StatExact software package. There was no significant reduction in mortality in the vitamin A group when all the studies were pooled together (RR 0.60; 95% CI 0.32 to 1.12)(Statexact estimate). There was a 64% reduction in the risk of mortality in children who were given two doses of 200,000 IU of vitamin A (RR=0.36; 95% CI 0.14 to 0.82) as compared to placebo. Two doses of water based vitamin A were associated with a 81% reduction in risk of mortality (RR=0.19; 95% CI 0.02 to 0.85) as compared to 48% seen in two doses of oil based preparation (RR=0.52; 95% CI 0.16 to 1.40). Two doses of oil and water based vitamin A were associated with a 82% reduction in the risk of mortality in children under the age of 2 years (RR=0.18; 95% CI 0.03 to 0.61) and a 67% reduction in the risk of pneumonia specific mortality (RR=0.33; 95% CI 0.08 to 0.92). There was no evidence that vitamin A in a single dose of 200,000 IU was associated with a reduced risk of mortality among children with measles (RR=0.77; 95% CI 0.34 to 1.78). Sub-groups like age, dose, formulation, hospitalisation and case fatality in the study area were highly correlated and there were not enough studies to separate out the individual effects of these factors. There was a 47% reduction in the incidence of croup (RR=0.53; 95% CI 0.29 to 0.89), while there was no significant reduction in the incidence of pneumonia (RR=0.92; 95% CI 0.69 to 1.22) or of diarrhoea (RR=0.80; 95% CI 0.27 to 2.34). Duration of diarrhoea was measured in days and there was a reduction in its duration of almost two days WMD -1.92, 95% CI -3.40 to -0.44. Only one study evaluated otitis media and found a 74% reduction in its incidence (RR=0.26, 95% CI, 0.05 to 0.92). We did not find evidence that a single dose of 200,000 IU of vitamin A per day, given in oil-based formulation in areas with low case fatality, was associated with reduced mortality among children with measles. However, there was evidence that the same dose given for two days was associated with a reduced risk of overall mortality and pneumonia specific mortality. Although we did not find evidence that a single dose of 200,000 IU of vitamin A per day was associated with reduced mortality among children with measles, there was evidence that the same dose given for two days was associated with a reduced risk of overall mortality and pneumonia specific mortality. The effect was greater in children under the age of two years. There were no trials that compared a single dose with two doses, although the precision of the estimates of trials that used a single dose were similar to the trials that used two doses.


Cardiovascular adaptation to hypoxia and the role of peripheral resistance.
Systemic vascular pressure in vertebrates is regulated by a range of factors: one key element of control is peripheral resistance in tissue capillary beds. Many aspects of the relationship between central control of vascular flow and peripheral resistance are unclear. An important example of this is the relationship between hypoxic response in individual tissues, and the effect that response has on systemic cardiovascular adaptation to oxygen deprivation. We show here how hypoxic response via the HIF transcription factors in one large vascular bed, that underlying the skin, influences cardiovascular response to hypoxia in mice. We show that the response of the skin to hypoxia feeds back on a wide range of cardiovascular parameters, including heart rate, arterial pressures, and body temperature. These data represent the first demonstration of a dynamic role for oxygen sensing in a peripheral tissue directly modifying cardiovascular response to the challenge of hypoxia.


[Marked improvement of anemia during treatment with deferasirox in patients with primary myelofibrosis and acute myeloid leukemia with myelodysplasia-related changes].
We report two patients who achieved a marked improvement of hematopoiesis with the use of deferasirox (DSX) for transfusional iron overload. Case 1 is an 81-year-old male who was diagnosed with primary myelofibrosis in July, 2007. He required regular red blood cell (RBC) transfusion of 4 units/month when he was started on DSX treatment in June, 2009. Four months after the treatment, he became transfusion independent, and has maintained hemoglobin levels of around 13 g/dl until today. Case 2 is a 70-year-old female with acute myeloid leukemia with myelodysplasia-related changes. She had been on RBC transfusion of 4 units/month when she was started on DSX treatment in January, 2010. Two months after the treatment, she became transfusion-independent, and 5 months after treatment, blast cells completely disappeared in the peripheral blood, together with normalization of white blood cell and neutrophil counts. Achieving durable transfusion-independency and normalization of white blood cell count and differential with a single use of DSX is a very rare event. Prospective accumulation of more patients and research to understand the mechanism underlying these effects are clearly warranted.


Aldose reductase inhibition prevents metaplasia of airway epithelial cells.
Goblet cell metaplasia that causes mucus hypersecretion and obstruction in the airway lumen could be life threatening in asthma and chronic obstructive pulmonary disease patients. Inflammatory cytokines such as IL-13 mediate the transformation of airway ciliary epithelial cells to mucin-secreting goblet cells in acute as well as chronic airway inflammatory diseases. However, no effective and specific pharmacologic treatment is currently available. Here, we investigated the mechanisms by which aldose reductase (AR) regulates the mucus cell metaplasia in vitro and in vivo. Metaplasia in primary human small airway epithelial cells (SAEC) was induced by a Th2 cytokine, IL-13, without or with AR inhibitor, fidarestat. After 48 h of incubation with IL-13 a large number of SAEC were transformed into goblet cells as determined by periodic acid-schiff (PAS)-staining and immunohistochemistry using antibodies against Mucin5AC. Further, IL-13 significantly increased the expression of Mucin5AC at mRNA and protein levels. These changes were significantly prevented by treatment of the SAEC with AR inhibitor. AR inhibition also decreased IL-13-induced expression of Muc5AC, Muc5B, and SPDEF, and phosphorylation of JAK-1, ERK1/2 and STAT-6. In a mouse model of ragweed pollen extract (RWE)-induced allergic asthma treatment with fidarestat prevented the expression of IL-13, phosphorylation of STAT-6 and transformation of epithelial cells to goblet cells in the lung. Additionally, while the AR-null mice were resistant, wild-type mice showed goblet cell metaplasia after challenge with RWE. The results show that exposure of SAEC to IL-13 caused goblet cell metaplasia, which was significantly prevented by AR inhibition. Administration of fidarestat to mice prevented RWE-induced goblet cell metaplasia and AR null mice were largely resistant to allergen induced changes in the lung. Thus our results indicate that AR inhibitors such as fidarestat could be developed as therapeutic agents to prevent goblet cell metaplasia in asthma and related pathologies.


Changes in neural and lens competence in Xenopus ectoderm: evidence for an autonomous developmental timer.
The ability of a tissue to respond to induction, termed its competence, is often critical in determining both the timing of inductive interactions and the extent of induced tissue. We have examined the lens-forming competence of Xenopus embryonic ectoderm by transplanting it into the presumptive lens region of open neural plate stage embryos. We find that early gastrula ectoderm has little lens-forming competence, but instead forms neural tissue, despite its location outside the neural plate; we believe that the transplants are being neuralized by a signal originating in the host neural plate. This neural competence is not localized to a particular region within the ectoderm since both dorsal and ventral portions of early gastrula ectoderm show the same response. As ectoderm is taken from gastrulae of increasing age, its neural competence is gradually lost, while lens competence appears and then rapidly disappears during later gastrula stages. To determine whether these developmental changes in competence result from tissue interactions during gastrulation, or are due to autonomous changes within the ectoderm itself, ectoderm was removed from early gastrulae and cultured for various periods of time before transplantation. The loss of neural competence, and the gain and loss of lens competence, all occur in ectoderm cultured in vitro with approximately the same time course as seen in ectoderm in vitro. Thus, at least from the beginning of gastrulation onwards, changes in competence occur autonomously within ectoderm. We propose that there is a developmental timing mechanism in embryonic ectoderm that specifies a sequence of competences solely on the basis of the age of the ectoderm.


Morphological aspects of tympanic bulla after lateral osteotomy in cats.
To evaluate tympanic bulla healing after experimental lateral osteotomy in cats. Twenty adult cats were submitted to unilateral lateral bulla osteotomy and divided into two groups: cats of B1 group (n=10) were euthanized at 8 weeks and cats of B2 group (n=10), at 16 weeks postoperative. Oblique lateral radiographs taken immediately postoperative showed interruption in the contour of the external acoustic meatus of the operated bullae in all cats of both groups (McNemar test: p=0.0010*). This feature was still observed in the radiographs taken after 8 and 16 weeks postoperative (McNemar test: B1 p=0.0020*; B2 p=0.0312*). Macroscopic examination showed that the operated bullae were similar to the normal ones, with preservation of the tympanic cavity. Connective tissue at the osteotomy site was significantly found in the operated bullae in both groups (McNemar test: B1 p=0.0020*; B2 p=0.0010*). The length of connective tissue at the osteotomy site was measured by histomorphometry. There was no statistically significant difference between the values of B1 group and B2 group (Mann-Whitney test: p=0.0524). Experimental lateral osteotomy did not alter significantly the tympanic bulla conformation and complete regeneration of the tympanic bulla frequently did not occur before 16 weeks of postoperative period.


Discovery of genetic variants of the kinases that activate tenofovir among individuals in the United States, Thailand, and South Africa: HPTN067.
Tenofovir (TFV), a nucleotide reverse transcriptase inhibitor, requires two phosphorylation steps to form a competitive inhibitor of HIV reverse transcriptase. Adenylate kinase 2 (AK2) has been previously demonstrated to phosphorylate tenofovir to tenofovir-monophosphate, while creatine kinase, muscle (CKM), pyruvate kinase, muscle (PKM) and pyruvate kinase, liver and red blood cell (PKLR) each have been found to phosphorylate tenofovir-monophosphate to the pharmacologically active tenofovir-diphosphate. In the present study, genomic DNA isolated from dried blood spots collected from 505 participants from Bangkok, Thailand; Cape Town, South Africa; and New York City, USA were examined for variants in AK2, CKM, PKM, and PKLR using next-generation sequencing. The bioinformatics tools SIFT and PolyPhen predicted that 19 of the 505 individuals (3.7% frequency) carried variants in at least one kinase that would result in a decrease or loss of enzymatic activity. To functionally test these predictions, AK2 and AK2 variants were expressed in and purified from E. coli, followed by investigation of their activities towards tenofovir. Interestingly, we found that purified AK2 had the ability to phosphorylate tenofovir-monophosphate to tenofovir-diphosphate in addition to phosphorylating tenofovir to tenofovir-monophosphate. Further, four of the six AK2 variants predicted to result in a loss or decrease of enzyme function exhibited a ≥30% decrease in activity towards tenofovir in our in vitro assays. Of note, an AK2 K28R variant resulted in a 72% and 81% decrease in the formation of tenofovir-monophosphate and tenofovir-diphosphate, respectively. These data suggest that there are naturally occurring genetic variants that could potentially impact TFV activation.


Respiratory syncytial virus co-opts host mitochondrial function to favour infectious virus production.
Although respiratory syncytial virus (RSV) is responsible for more human deaths each year than influenza, its pathogenic mechanisms are poorly understood. Here high-resolution quantitative imaging, bioenergetics measurements and mitochondrial membrane potential- and redox-sensitive dyes are used to define RSV's impact on host mitochondria for the first time, delineating RSV-induced microtubule/dynein-dependent mitochondrial perinuclear clustering, and translocation towards the microtubule-organizing centre. These changes are concomitant with impaired mitochondrial respiration, loss of mitochondrial membrane potential and increased production of mitochondrial reactive oxygen species (ROS). Strikingly, agents that target microtubule integrity the dynein motor protein, or inhibit mitochondrial ROS production strongly suppresses RSV virus production, including in a mouse model with concomitantly reduced virus-induced lung inflammation. The results establish RSV's unique ability to co-opt host cell mitochondria to facilitate viral infection, revealing the RSV-mitochondrial interface for the first time as a viable target for therapeutic intervention.


Heat stress in chemical protective clothing: porosity and vapour resistance.
Heat strain in chemical protective clothing is an important factor in industrial and military practice. Various improvements to the clothing to alleviate strain while maintaining protection have been attempted. More recently, selectively permeable membranes have been introduced to improve protection, but questions are raised regarding their effect on heat strain. In this paper the use of selectively permeable membranes with low vapour resistance was compared to textile-based outer layers with similar ensemble vapour resistance. For textile-based outer layers, the effect of increasing air permeability was investigated. When comparing ensembles with a textile vs. a membrane outer layer that have similar heat and vapour resistances measured for the sum of fabric samples, a higher heat strain is observed in the membrane ensemble, as in actual wear, and the air permeability of the textile version improves ventilation and allows better cooling by sweat evaporation. For garments with identical thickness and static dry heat resistance, but differing levels of air permeability, a strong correlation of microclimate ventilation due to wind and movement with air permeability was observed. This was reflected in lower values of core and skin temperatures and heart rate for garments with higher air permeability. For heart rate and core temperature the two lowest and the two highest air permeabilities formed two distinct groups, but they did not differ within these groups. Based on protection requirements, it is concluded that air permeability increases can reduce heat strain levels allowing optimisation of chemical protective clothing. STATEMENT OF RELEVANCE: In this study on chemical, biological, radiological and nuclear (CBRN) protective clothing, heat strain is shown to be significantly higher with selectively permeable membranes compared to air permeable ensembles. Optimisation of CBRN personal protective equipment needs to balance sufficient protection with reduced heat strain. Using selectively permeable membranes may optimise protection but requires thorough consideration of the wearer's heat strain.


One-sided anterior urethroplasty: a new dorsal onlay graft technique.
To investigate the feasibility, tolerability, safety and efficacy of using a new surgical technique for the repair of anterior urethral strictures to preserve vascular supply to the urethra and its entire muscular and neurogenic support. In all, 24 patients (mean age 46 years) underwent a new one-sided anterior dorsal oral mucosal graft urethroplasty while preserving the lateral vascular supply to the urethra, the central tendon of the perineum, the bulbospongiosum muscle and its perineal innervation. The cause of stricture was instrumentation in three cases (12%), unknown in five (21%), infection in four (17%), and lichen sclerosus in 12 (50%). The stricture site was bulbar in 12 cases (50%) and panurethral in 12 (50%). The mean stricture length was 4.2 cm in patients with bulbar strictures and 10 cm in patients with panurethral strictures. Of 24 patients, 20 patients (83%) had received previous treatments. Clinical outcome was considered a failure when any postoperative instrumentation was needed, including dilatation. The overall mean (range) follow-up was 22 (12-55) months. Of the 24 patients, 22 (92%) had a successful outcome and two (8%) were failures. One failure was treated using definitive perineal urethrostomy and another failure underwent successful internal urethrotomy. The preservation of the one-sided vascular supply to the urethra and its entire muscular and neurogenic support should represent a slight but significant step toward perfecting the surgical technique of urethral reconstruction using a minimally invasive approach.


Protocol for the CHORD project (community health outreach to reduce diabetes): a cluster-randomized community health worker trial to prevent diabetes.
Type 2 diabetes mellitus (DM) affects 9.4% of US adults and children, while another 33.9% of Americans are at risk of DM. Health care institutions face many barriers to systematically delivering the preventive care needed to decrease DM incidence. Community health workers (CHWs) may, as frontline public health workers bridging clinic and community, help overcome these challenges. This paper presents the protocol for a pragmatic, cluster-randomized trial integrating CHWs into two primary care clinics to support DM prevention for at-risk patients. The trial will randomize 15 care teams, stratified by practice site (Bellevue Hospital and Manhattan VA), totaling 56 primary care physicians. The study cohort will consist of ~ 2000 patients who are 18-75 years of age, actively enrolled in a primary care team, able to speak English or Spanish, and have at least one glycosylated hemoglobin (HbA1c) result in the prediabetic range (5.7-6.4%) since 2012. Those with a current DM diagnosis or DM medication prescription (other than metformin) are ineligible. The intervention consists of four core activities - setting health goals, health education, activation for doctor's appointments, and referrals to DM prevention programs - adjustable according to the patient's needs and readiness. The primary outcome is DM incidence. Secondary outcomes include weight loss, HbA1C, and self-reported health behaviors. Clinical variables and health behaviors will be obtained through electronic medical records and surveys, respectively. Implementation outcomes, namely implementation fidelity and physicians' perspectives about CHW integration into the clinic, will be assessed using interviews and CHW activity logs and analyzed for the influence of moderating organizational factors. This is the first rigorous, pragmatic trial to test the effectiveness of integrating CHWs into primary care for DM prevention reaching a population-based sample. Our study's limitations include language-based eligibility and the use of HbA1c as a measure of DM risk. It will measure both clinical and implementation outcomes and potentially broaden the evidence base for CHWs and patient-centered medical home implementation. Further, the intervention's unique features, notably patient-level personalization and referral to existing programs, may offer a scalable model to benefit patients at-risk of DM. Clinicaltrials.gov NCT03006666 (Received 12/27/2016).


Mutant Trp repressors with new DNA-binding specificities.
Oligonucleotide-directed mutagenesis of the codons for glutamine-68 (Gln68), lysine-72 (Lys72), isoleucine-79 (Ile79), alanine-80 (Ala80), and threonine-81 (Thr81) of the Escherichia coli trpR (tryptophan aporepressor) gene was used to make mutant repressors with each of 36 different amino acid changes. Mutant repressors were tested for binding to each member of a set of 28 different operators closely related to the consensus trp operator. Of the 36 mutant repressors, 11 bind a subset of the 28 operators; 5 of these have new binding specificities. These new specificities indicate that the hydroxyl group of Thr81 makes a specific contact with one of the four critical base pairs in a trp operator half-site, and the methyl group of Thr81 determines specificity at a second, critical base pair. The Trp repressor does not use the first two amino acids of its "recognition alpha-helix," Ile79 and Ala80, to make sequence-specific DNA contacts, and interacts with its operator in vivo in a way fundamentally different from the way that phage lambda repressor, lambda Cro protein, and coliphage 434 repressor contact their respective binding sites.


Rural emergency medical volunteers and their communities: a demographic comparison.
This research compares the personal, household, and professional characteristics volunteer emergency medical service (EMS) providers in Ulster County, NY with those of the general population of this rural upstate county, using a survey instrument implemented by the author in conjunction with the 1990 U.S. Census data. A principal objective of this research was to identify the characteristics of these volunteers in order to support the recruitment and retention efforts of volunteer EMS organizations. Statistically significant deviations between these two sample populations include age distribution, maximum educational attainment, size of household, years in residence, type of employer, employing industry, occupation, household income, and commuting distance from work. Population differences for race, sex, marital status, household site, home ownership, housing costs, and in-county employment were not statistically significant. Additional data reported for the EMS volunteers include total emergency responses, active squad membership, length of service, level of medical qualifications, and intensity and nature of individual participation, age of recruitment, family involvement, tenure in the community, rates of household work participation, other volunteer activity, motivation, and receptivity to alternative incentive programs. The relevance of these data is interpreted with respect to the prospects for effective recruitment of volunteers, the level of commitment and retention of the volunteers, the degree of support which volunteers can expect from their communities, and the extent of cohesiveness and integration which volunteer EMS squads provide to their communities.


Bismuth-rhodamine: a new red light-excitable photosensitizer.
Bismuth-rhodamine (BiR) was developed as a new photosensitizer scaffold, and its photophysical properties were evaluated. BiR showed significant red-shifted absorption and emission compared with other xanthene-based photosensitizers, together with an efficient quantum yield for the generation of 1O2. BiR showed efficient cell-permeability as well as photo-triggered generation of 1O2 in cells.


Reirradiation combined with hyperthermia in breast cancer recurrences: overview of experience in Erasmus MC.
For superficial hyperthermia a custom-built multi-applicator multi-amplifier superficial hyperthermia system operating at 433 MHz is utilised. Up to 6 Lucite Cone applicators can be used simultaneously to treat an area of 600 cm2. Temperatures are measured continuously with fibre optic multi-sensor probes. For patients with non-standard clinical problems, hyperthermia treatment planning is used to support decision making with regard to treatment strategy. In 74% of our patients with recurrent breast cancer treated with a reirradiation scheme of 8 fractions of 4 Gy in 4 weeks, combined with 4 or 8 hyperthermia treatments, a complete response is achieved, approximately twice as high as the CR rate following the same reirradation alone. The CR rate in tumours smaller than 30 mm is 80-90%, for larger tumours it is 65%. Hyperthermia appears beneficial for patients with microscopic residual tumour as well. To achieve high CR rates it is important to heat the whole radiotherapy field, and to use an adequate heating technique.


Heat stabilities of acid phosphatases from pinto bean leaves.
Two acid phosphatases were demonstrable by polyacrylamide gel electrophoresis. They had different mobilities and different heat stabilities in 1.0M acetate buffer, pH 5.2. Both phosphatases had the same electro-phoretic mobility in tris buffer at pH 7.5, gave one boundary in the analytical ultracentrifuge in tris or acetate buffer, and had the same sedimentation coefficient. The difference in these properties suggests an alteration in conformation of the proteins by the buffer systems.


The unappreciated challenges of between-unit handoffs: negotiating and coordinating across boundaries.
Although interest in studying and improving handoffs has grown considerably in recent years, a general tendency to treat handoff as a single type of activity has resulted in overlooking important variation and in understudying one consequential type: between-unit handoffs. Using the admission handoff between emergency departments and inpatient services as an example, this conceptual article identifies 2 distinguishing structural features of between-unit transitions and demonstrate how these features create negotiation and coordination challenges that are further complicated by several contextual factors. Between-unit handoffs are distinguished from within-unit handoffs because the former are triggered by patient conditions as opposed to shift schedules and entail working across organizational boundaries rather than within them. Consequently, between-unit handoffs are challenged by several contextual factors, including interprofessional differences, unequal distributions of power among units, frequent lack of established relationships among the involved parties, infrequent face-to-face communication, a lack of awareness of the other unit's state, and the fact that responsibility and control of patients are transferred separately. Implications for improvement are discussed.


Olanzapine-Induced Activation of Hypothalamic Astrocytes and Toll-Like Receptor-4 Signaling via Endoplasmic Reticulum Stress Were Related to Olanzapine-Induced Weight Gain.
The antipsychotic drug olanzapine is associated with serious obesity side effects. Hypothalamic astrocytes and associated toll-like receptor-4 (TLR4) signaling play an essential role in obesity pathogenesis. This study investigated the effect of olanzapine on astrocytes and TLR4 signaling both in vitro and in the rat hypothalamus and their potential role in olanzapine-induced weight gain. We found that olanzapine treatment for 24 h dose-dependently increased cell viability, increased the protein expression of astrocyte markers including glial fibrillary acidic protein (GFAP) and S100 calcium binding protein B (S100B), and activated TLR4 signaling in vitro. In rats, 8- and 36-day olanzapine treatment caused weight gain accompanied by increased GFAP and S100B protein expression and activated TLR4 signaling in the hypothalamus. These effects still existed in pair-fed rats, suggesting that these effects were not secondary effects of olanzapine-induced hyperphagia. Moreover, treatment with an endoplasmic reticulum (ER) stress inhibitor, 4-phenylbutyrate, inhibited olanzapine-induced weight gain and ameliorated olanzapine-induced changes in hypothalamic GFAP, S100B, and TLR4 signaling. The expression of GFAP, S100B, and TLR4 correlated with food intake and weight gain. These findings suggested that olanzapine-induced increase in hypothalamic astrocytes and activation of TLR4 signaling were related to ER stress, and these effects may be related to olanzapine-induced obesity.


Effect of PUVA, narrow-band UVB and cyclosporin on inflammatory cells of the psoriatic plaque.
Because antigen presenting is necessary for T-cell activation, antigen-presenting cells should be involved in the pathogenesis of psoriasis. In this study, our purpose was to evaluate and compare effects of PUVA, cyclosporine A and narrow-band UVB on dendritic cells and activated lymphocytes in the psoriatic lesions. Forty-five volunteered patients (15 patients in each treatment group as PUVA, cyclosporin A and narrow-band UVB) were enrolled in this study. Lesional skin biopsies were taken from each patient before and after treatments. Fresh frozen biopsies were studied for the expressions of CD1a, CD68, CD86, CD4, CD8 and HLA-DR proteins by immunohistochemistry. There was no correlation between severity of the lesions and expressions of the antigens. Only PUVA significantly decreased CD1a+ epidermal Langerhans cells' (LCs) counts. Treatment modalities decreased expression of costimulator CD86, and most of them decrease antigen-presenting capacity of skin by decreasing HLA class-II expression. All treatment modalities equally reduce lymphocytes, macrophages and dendritic cells. PUVA is the only treatment that decreases epidermal LCs. All treatments effectively diminish expression of CD86 and inhibit this step of inflammation.


Improvement of photorefractive properties and holographic applications of lithium niobate crystal.
Based on analyzing and synthesizing the effects of In doping, Fe doping and oxidation state, we propose an efficient way to improve photorefractive properties of LiNbO3 crystal. According to the proposed way, a sample of In:Fe:LiNbO3 crystal is grown and achieves larger dynamic range, higher sensitivity and better signal-to-noise ratio thanFe:LiNbO3 crystal (Fe:0.03wt.%) that is generally considered as a preferable storage medium for high-density holographic data storage. In a coherent volume 0.074cm3 of this crystal, 2030 holograms have been successfully multiplexed and exactly identified in a compact volume holographic data storage and correlation recognition system.


Alkaline Phosphatase-To-Albumin Ratio as a Prognostic Indicator in Pancreatic Ductal Adenocarcinoma after Curative Resection.
Background: The prognosis of pancreatic ductal adenocarcinoma (PDAC) remains poor and the models for survival prediction in PDAC patients after curative resection are still limited. Preoperative alkaline phosphatase-to-albumin ratio (APAR), an original inflammation-based score, has been established to analyze the prognostic significance in PDAC. Therefore, in this study, we aim to formulate a valuable prognostic nomogram for PDAC following curative resection. Methods: A total of 354 patients with PDAC undergoing curative resection were retrospectively enrolled in this study. The prognostic value of APAR was analyzed in primary cohort containing 220 randomly selected PDAC patients with curative resection and prognostic nomogram incorporating APAR into the American Joint Commission on Cancer (AJCC) 8th edition was established to obtain superior discriminatory abilities. The predictive performance of APAR was further validated in another independent cohort of 134 PDAC patients. Results: Patients with higher serum APAR level were probable to sustain poorer overall survival (OS). Significant positive correlations were found between APAR and tumor site, and several serum biochemical indexes, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), etc. The results of multivariate analysis showed, APAR was also identified as an independent prognostic indicator for OS in both primary and validation cohorts (P=0.004, P=0.038, respectively). Compared with the AJCC 8th edition, the nomogram consisting of APAR, pathological differentiation and the TNM staging system of AJCC 8th edition showed superior predictive accuracy for OS. All these results were further verified in the validation cohort. Conclusions: APAR can be considered as a novel independent prognostic biomarker for PDAC following curative resection. One more accurate and advanced predictive model will be achieved via the incorporation of APAR into nomogram.


How Does a Sport Psychological Intervention Help Professional Cyclists to Cope With Their Mental Health During the COVID-19 Lockdown?
All around the world in March, due to COVID-19, competitive sport calendars were suddenly canceled, jeopardizing the training programs of athletes. Moreover, in Italy, the government banned all non-essential travel across the entire country from the beginning of March. Consequently, Italian cyclists were banned from leaving their homes and therefore unable to perform their ordinary training activities. The Italian Association of Professional Cyclists (ACCPI) early on during that period noticed that several cyclists were experiencing a worrying decrease in their mental well-being and asked the authors to set up an online Sport Psychology Intervention (SPI) during lockdown to enhance the athletes' mental health. Through a number of unprecedented events and considerations, the aim of the current investigation was to assess the Italian cyclists' mental health during the lockdown and its changes after the SPI. We validated the Italian version of the Sport Mental Health Continuum Short Form (Sport MHC-SF)-presented in Study 1-and then applied it to a sample of Italian professional cyclists-presented in Study 2-prior to and after the SPI. To achieve these objectives, the reliability and construct validity of the Italian version of the Sport MHC-SF were tested in Study 1. RM-MANOVA tests were run to evaluate the effect of SPI on cyclists in Study 2. A total of 185 Italian athletes were involved in the validation of the MHC in Study 1 and 38 professional cyclists in Study 2. Results from Study 1 suggested a three-factor higher order model of Sport MHC-SF [Model fit: χ2(df) = 471.252 (252), p < 0.000; CFI = 0.951; RMSEA = 0.049; RMR= 0.048]. MCFA showed that the default model kept invariance among groups of athletes (i.e., female, male, individual, and team sports). Results from Study 2 highlighted that professional cyclists who followed the SPI were able to cope better with psychological stressors, showing improved well-being compared to the athletes that did not. No significant differences were found for emotional and social well-being. The present multi-study paper contributes to the theoretical field with a validated measure of Sport MHC-SF translated in the Italian language and culture. It also provides practical implications related to cases of reduced mental health due to injury, illness, or similar situations of home confinement in the future.


All-optical binary counter.
We experimentally demonstrate an all-optical binary counter composed of four semiconductor optical amplifier based all-optical switching gates. The time-of-flight optical circuit operates with bit-differential delays between the exclusive-OR gate used for modulo-2 binary addition and the AND gate used for binary carry detection. A movie of the counter operating in real time is presented.


Opportunities, Challenges and Pitfalls of Using Cannabidiol as an Adjuvant Drug in COVID-19.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may lead to coronavirus disease 2019 (COVID-19) which, in turn, may be associated with multiple organ dysfunction. In this review, we present advantages and disadvantages of cannabidiol (CBD), a non-intoxicating phytocannabinoid from the cannabis plant, as a potential agent for the treatment of COVID-19. CBD has been shown to downregulate proteins responsible for viral entry and to inhibit SARS-CoV-2 replication. Preclinical studies have demonstrated its effectiveness against diseases of the respiratory system as well as its cardioprotective, nephroprotective, hepatoprotective, neuroprotective and anti-convulsant properties, that is, effects that may be beneficial for COVID-19. Only the latter two properties have been demonstrated in clinical studies, which also revealed anxiolytic and antinociceptive effects of CBD (given alone or together with Δ9-tetrahydrocannabinol), which may be important for an adjuvant treatment to improve the quality of life in patients with COVID-19 and to limit post-traumatic stress symptoms. However, one should be aware of side effects of CBD (which are rarely serious), drug interactions (also extending to drugs acting against COVID-19) and the proper route of its administration (vaping may be dangerous). Clearly, further clinical studies are necessary to prove the suitability of CBD for the treatment of COVID-19.


Regulation and Function of Lentiviral Vector-Mediated TCIRG1 Expression in Osteoclasts from Patients with Infantile Malignant Osteopetrosis: Implications for Gene Therapy.
Infantile malignant osteopetrosis (IMO) is a rare, recessive disorder characterized by increased bone mass caused by dysfunctional osteoclasts. The disease is most often caused by mutations in the TCIRG1 gene encoding a subunit of the V-ATPase involved in the osteoclasts capacity to resorb bone. We previously showed that osteoclast function can be restored by lentiviral vector-mediated expression of TCIRG1, but the exact threshold for restoration of resorption as well as the cellular response to vector-mediated TCIRG1 expression is unknown. Here we show that expression of TCIRG1 protein from a bicistronic TCIRG1/GFP lentiviral vector was only observed in mature osteoclasts, and not in their precursors or macrophages, in contrast to GFP expression, which was observed under all conditions. Thus, vector-mediated TCIRG1 expression appears to be post-transcriptionally regulated, preventing overexpression and/or ectopic expression and ensuring protein expression similar to that of wild-type osteoclasts. Codon optimization of TCIRG1 led to increased expression of mRNA but lower levels of protein and functional rescue. When assessing the functional rescue threshold in vitro, addition of 30 % CB CD34+ cells to IMO CD34+ patient cells was sufficient to completely normalize resorptive function after osteoclast differentiation. From both an efficacy and a safety perspective, these findings will clearly be of benefit during further development of gene therapy for osteopetrosis.


Activation of the mitogen-activated protein kinase pathways by heat shock.
In addition to inducing new transcriptional activities that lead within a few hours to the accumulation of heat shock proteins (Hsps), heat shock activates within minutes the major signaling transduction pathways involving mitogen-activated protein kinases, extracellular signal-regulated kinase, stress-activated protein kinase 1 (SAPK1)-c-Jun N-terminal kinase, and SAPK2-p38. These kinases are involved in both survival and death pathways in response to other stresses and may, therefore, contribute significantly to the heat shock response. In the case of p38, the activation leads to the phosphorylation and activation of one of the Hsps, Hsp27. Phosphorylation occurs very early during stress, is tightly regulated, and results from the triggering of a highly specific heat shock-sensing pathway.


Response compatibility and the relationship between event-related potentials and the timing of a motor response.
1. Earlier studies have shown that changes in the difficulty of sensory discrimination in a choice reaction time task result in a prolongation of the peak latency for several components of the long-latency event-related potential (ERP). With the use of the technique of response-locked averaging, we have previously shown that manipulation of the difficulty of sensory discrimination also affects response execution as assessed by the interval between the ERP and onset of the response. In the present paper we examine the hypothesis that changing the compatibility of the responses may also affect the difficulty of the discrimination, as well as the execution of the response, as assessed by the interval between stimulus onset and the ERP. Such an effect of response compatibility would provide further evidence for the close integration of motor and sensory processes in the performance of choice reaction time tasks. 2. We continuously recorded the electroencephalogram (EEG) from the scalp and the electromyogram (EMG) from the responding muscles in both compatible and noncompatible visual choice reaction time tasks. In the compatible task subjects responded to a lateralized visual stimulus with the hand ipsilateral to the stimulus, whereas in the noncompatible task they responded with the contralateral hand. EEG and EMG responses were analyzed and averaged off-line, aligning the waveforms by either stimulus onset (stimulus-synchronized averages) or response onset (response-synchronized averages), and averaged separately for both correct and incorrect response outcomes. 3. Response times were significantly faster for frequent stimuli than rare stimuli and were significantly faster to rare stimuli in the compatible than the noncompatible condition. In responses to the frequent stimuli (where both hands were required to respond), the right hand was slightly but consistently faster than the left hand. The right hand also accounted for 83% of the errors made. 4. Stimulus-synchronized and response-synchronized ERPs to either frequent or rare stimuli had a similar appearance for correct responses in both the compatible and noncompatible conditions. The coupling of the response to the ERP for the rare stimuli, however, was different for the two conditions: the response occurred later relative to the ERP components in the response-synchronized average in the noncompatible condition compared with the compatible condition. By contrast, the coupling of the ERPs to the onset of the stimulus was the same in the two conditions. 5. Stimulus-synchronized averages for error responses in which the rare tone was mistaken for a frequent tone showed early sensory processing (as judged by the ERPs) that was similar to that of correct responses to the rare stimuli. After the apparent positive (P2) component of the cerebral response, however, the processing differed, with a superimposed broad negativity possibly reflecting awareness by the subject that a mistake had been made. By contrast, the response-synchronized averages for these error trials appeared like those to frequent stimuli, with the response being coupled to the P2 component of the cerebral response. 6. These results suggest that response compatibility affects response selection processes but does not alter sensory discrimination. However, despite the similarly tight coupling of the response to the ERP in both the compatible and noncompatible conditions, the response occurred later relative to the ERPs in the noncompatible condition. This suggests that different components of the ERP are responsible for triggering the response in different circumstances. Our observations on the error trials suggests that the decision to respond (on these trials) is based on the occurrence of cerebral events that are evoked by either rare or frequent stimuli, whereas this decision (on correct response trials) is based on cerebral events elicited only by the rare stimuli.


Early lesions in experimental bladder cancer: experimental design and light microscopic findings.
N-[4-(5-Nitro-2-furyl)-2-thiazolyl]formamide (FANFT) fed to male and female Fischer rats at a dose of 0.2% of the diet induces lesions of the urinary bladder which progress from mild hyperplasia at 2 to 4 weeks, to moderate hyperplasia at 6 to 8 weeks, severe nodular and papillary hyperplasia at 10 to 14 weeks, and microinvasive carcinomas by 25 weeks as observed by light microscopy. Male Fischer rats fed FANFT for 2 to 4 weeks and then maintained on control diet show regression of the bladder lesions within 2 weeks to normal-appearing mucosa which persists through 50 weeks. Rats fed FANFT for 6 weeks show regression of the moderately hyperplastic epithelium to normal within 4 weeks after being placed on control diet which persists through 50 weeks. Rats fed FANFT for 8 to 10 weeks show regression of the hyperplastic bladder epithelium within 2 weeks of receiving control diet, but focal areas of mild hyperplasia are detectable through the 20th week of the experiment. By the 50th week the rats fed FANFT for 8 weeks all had moderate to marked hyperplasia, but the rats fed FANFT for 10 weeks had transitional cell tumors, one of which was invasive through the entire thickness of the bladder wall. The lesions present in rats fed FANFT for 12, 14, or 20 weeks continued to progress to invasive tumors (microinvasive or invasion of muscle) after the rats had been maintained on control diet through 50 weeks. Thus, the hyperplastic lesions developing through 6 weeks of FANFT administration appear to be reversible if FANFT is discontinued, but later lesions appear to be irreversible.


Yeast KRE2 defines a new gene family encoding probable secretory proteins, and is required for the correct N-glycosylation of proteins.
We have cloned, sequenced and disrupted the KRE2 gene of Saccharomyces cerevisiae, identified by killer-resistant mutants with a defective cell wall receptor for the toxin. The KRE2 gene is close to PHO8 on chromosome 4, and encodes a predicted 49-kD protein, Kre2p, that probably enters the secretory pathway. Haploid cells carrying a disruption of the KRE2 locus grow more slowly than wild-type cells at 30 degrees, and fail to grow at 37 degrees. At 30 degrees, kre2 mutants showed altered N-linked glycosylation of proteins, as the average size of N-linked outer chains was reduced. We identified two other genes, YUR1 on chromosome 10, and KTR1 on chromosome 15, whose predicted products share 36% identity with Kre2p over more than 300 amino acid residues. Yur1p has an N-terminal signal sequence like Kre2p, while Ktr1p has a predicted topology consistent with a type 2 membrane protein. In all cases the conserved regions of these proteins appear to be on the lumenal side of secretory compartments, suggesting related function. KRE2, KTR1 and YUR1 define a new yeast gene family.


Short-term clinical outcomes of Kyocera Modular Limb Salvage System designed cementless stems for the endoprosthetic reconstruction of lower extremities: a Japanese Musculoskeletal Oncology Group multi-institutional study.
The high rate of aseptic loosening of cemented stems has led to their frequent use in endoprosthetic reconstruction. However, problems, such as stem breakage and stress shielding at the insertion site, remain. The Japanese Musculoskeletal Oncology Group (JMOG) has developed Kyocera Modular Limb Salvage System (KMLS) cementless stems with a unique tapered press-fit and short fixation design. This study aimed to clarify the short-term postoperative outcomes of this prosthesis and validate the stem design. One hundred cases of KMLS cementless stems (51 male patients; median age, 49 years; mean follow-up period, 35 months), with a minimum follow-up of 2 years, for the proximal femur (PF), distal femur (DF), and proximal tibia were prospectively registered for use. Prosthesis survival, complication rates, postoperative functional, and radiographical evaluation were analyzed. Complications or failures after insertion of the KMLS endoprostheses were classified into five types and functional results were analyzed according to the MSTS scoring system at postoperative 1 year. The diaphyseal interface and anchorage were graded by the ISOLS system at postoperative 2 years. The overall prosthesis survival rates at 2 and 4 years were 88.2 and 79.6%, respectively. The prosthesis-specific survival rate excluding infection and tumor recurrence was 90.2 and 87.9%, respectively. Younger age (p = 0.045) and primary tumor (p = 0.057) were associated with poor prognosis of prosthesis-specific survival excluding infection and tumor recurrence. Complications were observed in 31 patients, 13 patients underwent revision surgery. The mean MSTS functional score at 1 year postoperatively was 68%. Early implant loosening was significantly more common in the DF (p = 0.006) and PF/DF straight stem (p = 0.038). The ISOLS radiographic evaluation at 2 years after surgery revealed good bone remodeling and anchorage in most cases (bone remodeling: 90% / excellent and good, anchorage: 97% / excellent and good). Tumor endoprosthesis long-term fixation to the diaphysis of the lower extremity remains challenging. The KMLS cementless stem with a unique tapered press fit design showed good short-term results in maintaining bone stock. To prevent early loosening, a curved stem should be used in PF and DF, but long-term follow-up is necessary.


Climate and stomatal traits drive covariation in nighttime stomatal conductance and daytime gas exchange rates in a widespread C4 grass.
Nighttime stomatal conductance (gsn ) varies among plant functional types and species, but factors shaping the evolution of gsn remain unclear. Examinations of intraspecific variation in gsn as a function of climate and co-varying leaf traits may provide new insight into the evolution of gsn and its adaptive significance. We grew 11 genotypes of Panicum virgatum (switchgrass) representing differing home-climates in a common garden experiment and measured nighttime and daytime leaf gas exchange, as well as stomatal density (SD) and size during early-, mid-, and late-summer. We used piecewise structural equation modelling to determine direct and indirect relationships between home-climate, gas exchange, and stomatal traits. We found no direct relationship between home-climate and gsn . However, genotypes from hotter climates possessed higher SD, which resulted in higher gsn . Across genotypes, higher gsn was associated with higher daytime stomatal conductance and net photosynthesis. Our results indicate that higher gsn may arise in genotypes from hotter climates via increased SD. High SD may provide benefits to genotypes from hotter climates through enhanced daytime transpirational cooling or by permitting maximal gas exchange when conditions are suitable. These results highlight the role of climate and trait coordination in shaping genetic differentiation in gsn .


N6-adenine DNA methylation is associated with the linker DNA of H2A.Z-containing well-positioned nucleosomes in Pol II-transcribed genes in Tetrahymena.
DNA N6-methyladenine (6mA) is newly rediscovered as a potential epigenetic mark across a more diverse range of eukaryotes than previously realized. As a unicellular model organism, Tetrahymena thermophila is among the first eukaryotes reported to contain 6mA modification. However, lack of comprehensive information about 6mA distribution hinders further investigations into its function and regulatory mechanism. In this study, we provide the first genome-wide, base pair-resolution map of 6mA in Tetrahymena by applying single-molecule real-time (SMRT) sequencing. We provide evidence that 6mA occurs mostly in the AT motif of the linker DNA regions. More strikingly, these linker DNA regions with 6mA are usually flanked by well-positioned nucleosomes and/or H2A.Z-containing nucleosomes. We also find that 6mA is exclusively associated with RNA polymerase II (Pol II)-transcribed genes, but is not an unambiguous mark for active transcription. These results support that 6mA is an integral part of the chromatin landscape shaped by adenosine triphosphate (ATP)-dependent chromatin remodeling and transcription.


Susceptibility of Anopheles gambiae to insecticides used for malaria vector control in Rwanda.
The widespread emergence of resistance to pyrethroids is a major threat to the gains made in malaria control. To monitor the presence and possible emergence of resistance against a variety of insecticides used for malaria control in Rwanda, nationwide insecticide resistance surveys were conducted in 2011 and 2013. Larvae of Anopheles gambiae sensu lato mosquitoes were collected in 12 sentinel sites throughout Rwanda. These were reared to adults and analysed for knock-down and mortality using WHO insecticide test papers with standard diagnostic doses of the recommended insecticides. A sub-sample of tested specimens was analysed for the presence of knockdown resistance (kdr) mutations. A total of 14,311 mosquitoes were tested and from a sample of 1406 specimens, 1165 (82.9%) were identified as Anopheles arabiensis and 241 (17.1%) as Anopheles gambiae sensu stricto. Mortality results indicated a significant increase in resistance to lambda-cyhalothrin from 2011 to 2013 in 83% of the sites, permethrin in 25% of the sites, deltamethrin in 25% of the sites and DDT in 50% of the sites. Mosquitoes from 83% of the sites showed full susceptibility to bendiocarb and 17% of sites were suspected to harbour resistance that requires further confirmation. No resistance was observed to fenitrothion in all study sites during the entire survey. The kdr genotype results in An. gambiae s.s. showed that 67 (50%) possessed susceptibility (SS) alleles, while 35 (26.1%) and 32 (23.9%) mosquitoes had heterozygous (RS) and homozygous (RR) alleles, respectively. Of the 591 An. arabiensis genotyped, 425 (71.9%) possessed homozygous (SS) alleles while 158 (26.7%) and 8 (1.4%) had heterozygous (RS) and homozygous (RR) alleles, respectively. Metabolic resistance involving oxidase enzymes was also detected using the synergist PBO. This is the first nationwide study of insecticide resistance in malaria vectors in Rwanda. It shows the gradual increase of insecticide resistance to pyrethroids (lambda-cyhalothrin, deltamethrin, permethrin) and organochlorines (DDT) and the large presence of target site insensitivity. The results demonstrate the need for Rwanda to expand monitoring for insecticide resistance including further metabolic resistance testing and implement an insecticide resistance management strategy to sustain the gains made in malaria control.


IMJENSE: Scan-specific Implicit Representation for Joint Coil Sensitivity and Image Estimation in Parallel MRI.
Parallel imaging is a commonly used technique to accelerate magnetic resonance imaging (MRI) data acquisition. Mathematically, parallel MRI reconstruction can be formulated as an inverse problem relating the sparsely sampled k-space measurements to the desired MRI image. Despite the success of many existing reconstruction algorithms, it remains a challenge to reliably reconstruct a high-quality image from highly reduced k-space measurements. Recently, implicit neural representation has emerged as a powerful paradigm to exploit the internal information and the physics of partially acquired data to generate the desired object. In this study, we introduced IMJENSE, a scan-specific implicit neural representation-based method for improving parallel MRI reconstruction. Specifically, the underlying MRI image and coil sensitivities were modeled as continuous functions of spatial coordinates, parameterized by neural networks and polynomials, respectively. The weights in the networks and coefficients in the polynomials were simultaneously learned directly from sparsely acquired k-space measurements, without fully sampled ground truth data for training. Benefiting from the powerful continuous representation and joint estimation of the MRI image and coil sensitivities, IMJENSE outperforms conventional image or k-space domain reconstruction algorithms. With extremely limited calibration data, IMJENSE is more stable than supervised calibrationless and calibration-based deep-learning methods. Results show that IMJENSE robustly reconstructs the images acquired at 5× and 6× accelerations with only 4 or 8 calibration lines in 2D Cartesian acquisitions, corresponding to 22.0% and 19.5% undersampling rates. The high-quality results and scanning specificity make the proposed method hold the potential for further accelerating the data acquisition of parallel MRI.


Self-validation theory: An integrative framework for understanding when thoughts become consequential.
Self-validation theory (SVT) is introduced and presented as a series of six postulates. The core notion of SVT is that thoughts become more consequential for judgment and action as the perceived validity of the thoughts is increased. Instead of focusing on the objective accuracy of thoughts, self-validation research focuses on a subjective sense that one's thoughts are valid or appropriate to use. People come to rely on any thought more when they perceive that thought is likely to be true (cognitive validation) or because they feel good about the thought (affective validation). Perceptions of thought validity are influenced by thought-relevant as well as incidental factors (e.g., one's moods, sense of ease), and the impact of these factors can vary with their meaning. Individual and situational factors moderate when people rely on their assessments of validity and what thoughts are salient to validate. In short, SVT is a comprehensive and integrative framework from which to examine the use of thoughts across many seemingly diverse variables, outcomes, and domains in psychology. The theory is also relevant to understanding judgments in numerous applied contexts. By identifying moderators and mediators of thought validation processes and outcomes, SVT is capable of specifying when and why many different variables have an impact on judgments and actions. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Rates of asthma exacerbations and mortality and associated factors in Uganda: a 2-year prospective cohort study.
Data on asthma treatment outcomes in Africa are limited. 449 patients with asthma (age 5-93 years) in Uganda were followed up for 2 years to determine rates of exacerbations and mortality and associated factors. During follow-up the median number of exacerbations per patient was 1 (IQR 0-5) and 17 patients died (3.7%, 27.3 deaths per 1000 person years). Considering only the first year of follow-up, 59.6% of the patients experienced at least one exacerbation, 32.4% experienced three or more exacerbations. A multivariable model showed that the likelihood of experiencing at least one exacerbation in the first year of follow-up was lower with better baseline asthma control (higher asthma control test (ACT) score), with OR 0.87 (95% CI: 0.82 to 0.93, P=0.000), and was higher with more exacerbations in the year prior to enrolment (OR for log number of exacerbations 1.28, 95% CI: 1.04 to 1.57, P=0.018). Better asthma control (OR 0.93, 95% CI: 0.88 to 0.99, P=0.021) and number of baseline exacerbations (OR 1.35,95% CI: 1.11 to 1.66, P=0.005) were also the only factors that were independently associated with experiencing three or more exacerbations during the first year of follow-up. The only factor found to be associated with all-cause mortality was FEV1, with higher recent FEV1 associated with lower all-cause mortality (OR 0.30, 95% CI: 0.14 to 0.65; P=0.002). Rates of asthma exacerbations and mortality are high in Uganda and are associated with poor asthma control. Health systems should be strengthened to care for asthma patients.


Intraoral widening and lengthening of the mandible in baboons by distraction osteogenesis.
The purpose of this study was to analyze the skeletal and dental positional changes and histomorphology of the distraction regenerates and mucogingival periosteal tissues that occurred after simultaneous widening and bilateral lengthening of the mandible in baboons by a miniaturized intraoral bone-borne distraction appliance. Distraction appliances were activated 5 days after vertical ramus and symphyseal osteotomies at a rate of 0.9 mm/d for 10 days. The appliances were then stabilized for 8 weeks, after which the animals were killed. The distraction gaps and gingival tissues were analyzed clinically, histologically, and by standardized radiographic studies. Positional changes of the canines and incisor apices were proportional to the skeletal movements. Tipping of both incisors toward the center of the distraction gap was observed. Proportionate movement of the superior and inferior portion of the distracted segments was noted. Newly formed longitudinal trabecular columns parallel to the vector of distraction originated from the intact margins of alveolar bone contiguous with the adjacent teeth. Active histogenesis occurred in the stretched mucogingival periosteal tissues located in the distraction gaps. The results of this investigation support the clinical use of the miniaturized intraoral bone-borne distraction appliance to selectively widen and lengthen the mandible. The orientation of the mandibular distractors must be parallel to the common vector of distraction, which should be parallel to the maxillary occlusal plane. The formation of a bone regenerate in the alveolar region depends on the presence of an adequate bone interface on either side of the distraction gap.


Timing of initial well-child visit and readmissions of newborns.
Recommendations for the timing of the first well-child visit (WCV) after discharge from a well-baby nursery (WBN) suggest that the visit occur within 48 hours of discharge for those with a WBN length of stay of ≤48 hours and within 3 to 5 days for those with a WBN length of stay of >48 hours. The purpose of these early visits is to detect conditions that may cause readmission in the first weeks after birth, but the effectiveness of early visits to accomplish this has not been shown. The objectives of this study were to determine (1) the frequency of early visits and (2) to compare readmission rates for those who had an early visit compared with those who did not. Using data from a large health care system in Utah, we determined the readmission rates newborns with an estimated gestational age ≥34 weeks and compared the rates for those who had an early WCV with those who did not. Of 79 720 newborns, 50 606 (63%) were discharged within 48 hours of birth. Of these, 7638 (15%) had a visit within 72 hours of discharge. The readmission rate for newborns who had a visit within the recommended time frame was 15.7 per 1000 compared with 18.4 for those with a later visit (odds ratio 0.85; 95% confidence interval 0.73-0.99) CONCLUSIONS: The frequency of first WCVs that occurred within the recommended time frames was low. Early visits were associated with a 15% reduction in the rate of readmissions.


Neural responses to facial and vocal expressions of fear and disgust.
Neuropsychological studies report more impaired responses to facial expressions of fear than disgust in people with amygdala lesions, and vice versa in people with Huntington's disease. Experiments using functional magnetic resonance imaging (fMRI) have confirmed the role of the amygdala in the response to fearful faces and have implicated the anterior insula in the response to facial expressions of disgust. We used fMRI to extend these studies to the perception of fear and disgust from both facial and vocal expressions. Consistent with neuropsychological findings, both types of fearful stimuli activated the amygdala. Facial expressions of disgust activated the anterior insula and the caudate-putamen; vocal expressions of disgust did not significantly activate either of these regions. All four types of stimuli activated the superior temporal gyrus. Our findings therefore (i) support the differential localization of the neural substrates of fear and disgust; (ii) confirm the involvement of the amygdala in the emotion of fear, whether evoked by facial or vocal expressions; (iii) confirm the involvement of the anterior insula and the striatum in reactions to facial expressions of disgust; and (iv) suggest a possible general role for the perception of emotional expressions for the superior temporal gyrus.


Combinatorial small-molecule therapy prevents uropathogenic Escherichia coli catheter-associated urinary tract infections in mice.
Catheter-associated urinary tract infections (CAUTIs) constitute the majority of nosocomial urinary tract infections (UTIs) and pose significant clinical challenges. These infections are polymicrobial in nature and are often associated with multidrug-resistant pathogens, including uropathogenic Escherichia coli (UPEC). Urinary catheterization elicits major histological and immunological alterations in the bladder that can favor microbial colonization and dissemination in the urinary tract. We report that these biological perturbations impact UPEC pathogenesis and that bacterial reservoirs established during a previous UPEC infection, in which bacteriuria had resolved, can serve as a nidus for subsequent urinary catheter colonization. Mannosides, small molecule inhibitors of the type 1 pilus adhesin, FimH, provided significant protection against UPEC CAUTI by preventing bacterial invasion and shifting the UPEC niche primarily to the extracellular milieu and on the foreign body. By doing so, mannosides potentiated the action of trimethoprim-sulfamethoxazole in the prevention and treatment of CAUTI. In this study, we provide novel insights into UPEC pathogenesis in the context of urinary catheterization, and demonstrate the efficacy of novel therapies that target critical mechanisms for this infection. Thus, we establish a proof-of-principle for the development of mannosides to prevent and eventually treat these infections in the face of rising antibiotic-resistant uropathogens.


Neurodevelopmental evaluation of children with cyanotic congenital heart disease.
The aim of the study was to perform a neurodevelopmental evaluation of the children with cyanotic congenital heart disease and to determine the factors that affect the neurodevelopmental status. The study was performed in the Pediatric Cardiology Department of Behcet Uz Children's Hospital between February and August 2013. Children between the age of six to forty-two months were included in the study and were evaluated in three groups (two patient groups and the control group). In group A, patients with isolated cyanotic congenital heart disease were enrolled. Group B consisted of the patients with cyanotic congenital heart disease with other concomitant diseases. Group C included the healthy control group. For the neurodevelopmental evaluation Bayley Scale of Infant Development- II (BSID-II) was used. Mental Developmental Index (MDI) and Psychmotor Developmental Index (PDI) scores were calculated. Factors possibly effective on neurodevelopment were evaluated. Thirty eight patients (32 in group A and 6 in group B) and 33 healthy subjects in group C were included in the study. Mean age of the patient group was 22.5±11.2 months. In group A mean MDI Score (82.5±14.7) was significantly lower than group C (92.3±6.9) (P=0.001). Similarly mean PDI Score in group A (82.0±18.2) was found significantly lower than group C (92.5±7.4) (P=0.003). When group A and B were compared, mean MDI and PDI scores were lower in group B, but the difference was not statistically significant. For group A, according to the psychomotor development index, 41.6% of the patients were found to be mildly to severely retarded. In terms of the mental development index, 34.4% of the patients had moderate or mild retardation. The sex, socioeconomic status, gestational age, birth weight, comorbidities, history of surgery and reoperation, length of stay in intensive care unit were not found influential on the MDI and PDI scores of the patients. Mental-motor retardation is frequently encountered in children with cyanotic congenital heart disease. These patients may benefit from motor, language, speech, developmental and educational therapies. For this reason, these children have to be under regular follow up for neurodevelopmental status.


Imaging cell morphology and physiology using X-rays.
Morphometric measurements, such as quantifying cell shape, characterizing sub-cellular organization, and probing cell-cell interactions, are fundamental in cell biology and clinical medicine. Until quite recently, the main source of morphometric data on cells has been light- and electron-based microscope images. However, many technological advances have propelled X-ray microscopy into becoming another source of high-quality morphometric information. Here, we review the status of X-ray microscopy as a quantitative biological imaging modality. We also describe the combination of X-ray microscopy data with information from other modalities to generate polychromatic views of biological systems. For example, the amalgamation of molecular localization data, from fluorescence microscopy or spectromicroscopy, with structural information from X-ray tomography. This combination of data from the same specimen generates a more complete picture of the system than that can be obtained by a single microscopy method. Such multimodal combinations greatly enhance our understanding of biology by combining physiological and morphological data to create models that more accurately reflect the complexities of life.


Black tea prevents cigarette smoke-induced apoptosis and lung damage.
Cigarette smoking is a major cause of lung damage. One prominent deleterious effect of cigarette smoke is oxidative stress. Oxidative stress may lead to apoptosis and lung injury. Since black tea has antioxidant property, we examined the preventive effect of black tea on cigarette smoke-induced oxidative damage, apoptosis and lung injury in a guinea pig model. Guinea pigs were subjected to cigarette smoke exposure from five cigarettes (two puffs/cigarette) per guinea pig/day for seven days and given water or black tea to drink. Sham control guinea pigs were exposed to air instead of cigarette smoke. Lung damage, as evidenced by inflammation and increased air space, was assessed by histology and morphometric analysis. Protein oxidation was measured through oxyblot analysis of dinitrophenylhydrazone derivatives of the protein carbonyls of the oxidized proteins. Apoptosis was evidenced by the fragmentation of DNA using TUNEL assay, activation of caspase 3, phosphorylation of p53 as well as over-expression of Bax by immunoblot analyses. Cigarette smoke exposure to a guinea pig model caused lung damage. It appeared that oxidative stress was the initial event, which was followed by inflammation, apoptosis and lung injury. All these pathophysiological events were prevented when the cigarette smoke-exposed guinea pigs were given black tea infusion as the drink instead of water. Cigarette smoke exposure to a guinea pig model causes oxidative damage, inflammation, apoptosis and lung injury that are prevented by supplementation of black tea.


Role of plasma exchange in stiff person syndrome.
Stiff person syndrome (SPS) is commonly associated with antibodies directed against 65-kDa glutamic acid decarboxylase (GAD65). Therapeutic Plasma Exchange (TPE) has been used as an adjunct therapy in patients who do not respond well to conventional treatment, which includes immunosuppression therapies, anti-anxiety medications, muscle relaxants, anticonvulsants, and pain relievers. We retrospectively analyzed the clinical data and outcomes of ten patients with the clinical diagnosis of anti-GAD65 positive SPS in which TPE was employed to improve symptoms refractory to conventional treatment during an eight-year period. TPE was initiated as complementary therapy in patients with worsening of symptoms characteristic of SPS. Six patients underwent chronic treatment with TPE following an initial course, of which the frequency of TPE was guided by the clinical response. Two patients only had transient improvements with further disease progression. Four patients developed a relapse of symptoms when the interval between procedures was increased. One of the four patients dependent on TPE had worsening of symptoms following complete cessation of TPE due to lack of insurance coverage. Four patients underwent only an acute hospitalized course of treatment with TPE; one demonstrated complete resolution of symptoms; one had a partial response; and two experienced no improvement. Our study supports previous reports that TPE may be beneficial for the management of patients with anti-GAD65 positive SPS, both for acute exacerbations and long-term maintenance, either as an adjunct therapy, or in lieu of treatment with disease modifying agents.


How an outbreak became a pandemic: a chronological analysis of crucial junctures and international obligations in the early months of the COVID-19 pandemic.
Understanding the spread of SARS-CoV-2, how and when evidence emerged, and the timing of local, national, regional, and global responses is essential to establish how an outbreak became a pandemic and to prepare for future health threats. With that aim, the Independent Panel for Pandemic Preparedness and Response has developed a chronology of events, actions, and recommendations, from December, 2019, when the first cases of COVID-19 were identified in China, to the end of March, 2020, by which time the outbreak had spread extensively worldwide and had been characterised as a pandemic. Datapoints are based on two literature reviews, WHO documents and correspondence, submissions to the Panel, and an expert verification process. The retrospective analysis of the chronology shows a dedicated initial response by WHO and some national governments, but also aspects of the response that could have been quicker, including outbreak notifications under the International Health Regulations (IHR), presumption and confirmation of human-to-human transmission of SARS-CoV-2, declaration of a Public Health Emergency of International Concern, and, most importantly, the public health response of many national governments. The chronology also shows that some countries, largely those with previous experience with similar outbreaks, reacted quickly, even ahead of WHO alerts, and were more successful in initially containing the virus. Mapping actions against IHR obligations, the chronology shows where efficiency and accountability could be improved at local, national, and international levels to more quickly alert and contain health threats in the future. In particular, these improvements include necessary reforms to international law and governance for pandemic preparedness and response, including the IHR and a potential framework convention on pandemic preparedness and response.


Nontraumatic Testicular Pain due to Sacroiliac-Joint Dysfunction: A Case Report.
To discuss the case of a 49-year-old man who presented to the sports medicine staff with pelvic pain of 10 years' duration consistent with pudendal neuralgia. Testicular pain in men is often provoked by direct trauma or may indicate an oncologic process. Epididymitis, athletic pubalgia, testicular tumor, sacroiliac joint dysfunction, lumbar radiculopathy. The patient responded positively to treatment and rehabilitation to restore normal mechanics to the lumbo-pelvic-hip complex. Several flare-ups since the initial treatment have been of short duration (<2 days) and less intense. Pudendal neuralgia tends to affect females more than males due to changes in the alignment and stability of the pelvis from a combination of a shorter, wider pelvis and muscle imbalances associated with childbirth. Typically, males with testicular pain suffer from epididymitis or some type of testicular torsion, which was not the situation in this case. Compression is also a common cause of pudendal neuralgia, although it was not responsible for this patient's pain, making diagnosis and treatment complex. Many pain syndromes can be treated with removal of the original stimulus. However, recognizing the factors contributing to pelvic pain and dysfunction in males can be a challenge for the sports medicine professional. A vigilant and unassuming approach to male pelvic pain is warranted, particularly by health care providers in diverse practice settings.


In situ studies of protein adsorptions on poly(pyrrole-co-pyrrole propylic acid) film by electrochemical surface plasmon resonance.
Poly(pyrrole-co-pyrrole propylic acid) (PPy/PPa) composite films were prepared for the first time by electrochemical copolymerization in mixed pyrrole propylic acid (Pa) and pyrrole solutions. The electrochemical growth process was investigated by in situ electrochemical surface plasmon resonance (ESPR). Atomic force microscopy and Fourier transform infrared spectroscopy were applied to characterize the prepared films. Using bovine serum albumin as a model protein, the adsorption kinetics of the protein on PPy/PPa films were studied in situ by SPR. The composition of Pa, the isoelectric point of proteins, the pH of buffers, and surfactant treatment showed dramatic effects on the protein adsorption on the PPy/PPa film. Experimental results indicated that the electrostatic interaction between the PPy/PPa film and proteins plays a critical role in protein adsorption and provided a novel strategy to efficiently immobilize proteins and to reduce nonspecific bindings of proteins in an immunobiosensor.


The irbesartan in heart failure with preserved systolic function (I-PRESERVE) trial: rationale and design.
Although 40% to 50% of patients with chronic heart failure (HF) have relatively preserved systolic function (PSF), few trials have been conducted in this population and treatment guidelines do not include evidence-based recommendations. The Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE) is enrolling 4100 subjects with HF-PSF to evaluate whether 300 mg irbesartan is superior to placebo in reducing mortality and prespecified categories of cardiovascular hospitalizations. The principal inclusion criteria are age > or =60 years, heart failure symptoms, an ejection fraction > or =45%, and either hospitalization for heart failure within 6 months or corroborative evidence of heart failure or the substrate for diastolic heart failure. Additional secondary end points include cardiovascular mortality, cause-specific mortality and morbidity, change in New York Heart Association functional class, quality of life, and N-terminal pro-BNP measurements. Follow-up will continue until 1440 patients experience a primary end point. Substudies will evaluate changes in echocardiographic measurements and serum collagen markers. I-PRESERVE is the largest trial in this understudied area and will provide crucial information on the characteristics and course of the syndrome, as well as the efficacy of the angiotensin receptor blocker irbesartan.


Phase stability and electronic structure of iridium metal at the megabar range.
The 5d transition metals have attracted specific interest for high-pressure studies due to their extraordinary stability and intriguing electronic properties. In particular, iridium metal has been proposed to exhibit a recently discovered pressure-induced electronic transition, the so-called core-level crossing transition at the lowest pressure among all the 5d transition metals. Here, we report an experimental structural characterization of iridium by x-ray probes sensitive to both long- and short-range order in matter. Synchrotron-based powder x-ray diffraction results highlight a large stability range (up to 1.4 Mbar) of the low-pressure phase. The compressibility behaviour was characterized by an accurate determination of the pressure-volume equation of state, with a bulk modulus of 339(3) GPa and its derivative of 5.3(1). X-ray absorption spectroscopy, which probes the local structure and the empty density of electronic states above the Fermi level, was also utilized. The remarkable agreement observed between experimental and calculated spectra validates the reliability of theoretical predictions of the pressure dependence of the electronic structure of iridium in the studied interval of compressions.


Alpha-interferon in superficial bladder cancer: a Northern California Oncology Group Study.
Thirty-five patients with superficial transitional carcinoma of the bladder were treated intravesically with escalating doses of recombinant alpha-2-interferon administered weekly for 8 weeks. Of the 19 patients with high-grade intraepithelial neoplasia (17 carcinoma in situ [CIS], two severe dysplasia, all cytology positive), six (32%) had complete resolution of all histologic and cytologic evidence of disease (complete response). An additional three patients (16%) had complete resolution of CIS, but the interval appearance of a low-grade transitional cell neoplasm. Five (26%) had a partial response (complete resolution of all evidence of CIS on multiple bladder biopsies but persistently positive cytologic preparations). Sixteen patients with recurrent papillary tumors and extensive prior therapy were also treated. Four (25%) had a complete response. Twenty-three of the 35 patients had prior intravesical therapy. Seven of the 23 (30%) patients with prior intravesical chemotherapy or immunotherapy had a complete or partial response to interferon, while eight of the 12 patients (67%) without prior intravesical treatment responded. These responses were achieved with minimal local and systemic toxicity. Of the ten complete responders, five remain in continuous unmaintained remission for 18+ to 37+ months. Intracavitary alpha-2-interferon is an effective new treatment for some patients with bladder cancer.


Pain, Side Effects, and Abortion Experience Among People Seeking Abortion Care in the Second Trimester.
There is limited documentation about pain and side effects associated with dilation and evacuation (D&E) abortion, yet, pain and side effects are important factors that can affect a client's abortion experience. In 2016, Hope Clinic for Women, an independent abortion clinic in Illinois, altered its cervical preparation protocols before D&E to reduce the total time of the abortion process and improve the client experience. This analysis addresses the gap in data on client experience of abortion in the later second trimester by evaluating pain, side effects, and acceptability by gestational age. Abortion clients obtaining services at the clinic between March 2017 and June 2018 were eligible to participate if they had viable singleton pregnancies of 16-23.6 weeks' gestation, spoke English, and were at least 18 years old. Eligible participants completed a two-part survey about their abortion experience. We found that respondents seeking abortion care at later gestations in the second trimester were more likely to report pain during their abortions. We did not find any association between side effects and gestational age. Although most respondents were prepared for the pain they experienced, some reported experiencing more pain than they expected, and more effective pain relief was commonly reported as a way to improve the service. More research on patient experiences of later abortion is needed, particularly on experiences of pain and options for pain management.


MRI Evaluation of Rectal Cancer: Staging and Restaging.
Magnetic resonance imaging (MRI) plays an important role in the staging and restaging of rectal cancer. Multiplanar high-resolution (≤3-mm section thickness) T2-weighted images are the primary sequences used for rectal cancer staging. No preprocedural bowel cleansing regimen, intravenous contrast material, nor endorectal coil is necessary. MRI is highly accurate for differentiating T1-T2 disease from T3 and T4 disease, an important distinction as patients with T3 and T4 tumors typically undergo preoperative neoadjuvant chemoradiation before resection. At MRI, the muscularis propria appears as a thin black line encircling the outer wall of the rectum, and tumor extension through this line indicates T3 disease. Further tumor extension into adjacent organs indicates T4 disease. Endorectal ultrasound is generally preferred to differentiate T1 (submucosal involvement) from T2 (extension into but no disruption of muscularis propria) disease. MRI is also accurate in the assessment of tumor involvement of the mesorectal fascia. Tumor involvement of the mesorectal fascia increases the likelihood of recurrence following resection. MRI is less accurate for determination of lymph node status, though heterogeneous signal intensity and irregular margins are suggestive of node positive disease. Approximately 10%-30% of patients who undergo preoperative chemoradiation experience a complete pathologic response that is defined as no residual tumor found at histopathologic analysis of the resected specimen. The addition of diffusion-weighted images to T2-weighted images improves the accuracy of restaging examinations for determination of complete pathologic responders.


Idraparinux versus standard therapy for venous thromboembolic disease.
Venous thromboembolism is treated with unfractionated heparin or low-molecular-weight heparin, followed by a vitamin K antagonist. We investigated the potential use of idraparinux, a long-acting inhibitor of activated factor X, as a substitute for standard therapy. We conducted two randomized, open-label noninferiority trials involving 2904 patients with deep-vein thrombosis and 2215 patients with pulmonary embolism to compare the efficacy and safety of idraparinux versus standard therapy. Patients received either subcutaneous idraparinux (2.5 mg once weekly) or a heparin followed by an adjusted-dose vitamin K antagonist for either 3 or 6 months. The primary efficacy outcome was the 3-month incidence of symptomatic recurrent venous thromboembolism (nonfatal or fatal). In the study of patients with deep venous thrombosis, the incidence of recurrence at day 92 was 2.9% in the idraparinux group as compared with 3.0% in the standard-therapy group (odds ratio, 0.98; 95% confidence interval [CI], 0.63 to 1.50), a result that satisfied the prespecified noninferiority requirement. At 6 months, the hazard ratio for idraparinux was 1.01. The rates of clinically relevant bleeding at day 92 were 4.5% in the idraparinux group and 7.0% in the standard-therapy group (P=0.004). At 6 months, bleeding rates were similar. In the study of patients with pulmonary embolism, the incidence of recurrence at day 92 was 3.4% in the idraparinux group and 1.6% in the standard-therapy group (odds ratio, 2.14; 95% CI, 1.21 to 3.78), a finding that did not meet the noninferiority requirement. In patients with deep venous thrombosis, once-weekly subcutaneous idraparinux for 3 or 6 months had an efficacy similar to that of heparin plus a vitamin K antagonist. However, in patients with pulmonary embolism, idraparinux was less efficacious than standard therapy. (ClinicalTrials.gov numbers, NCT00067093 [ClinicalTrials.gov] and NCT00062803 [ClinicalTrials.gov].).