Use of different postmenopausal hormone therapies and risk of histology- and hormone receptor-defined invasive breast cancer.
We previously found that the risk of invasive breast cancer varied according to the progestagen component of combined postmenopausal hormone therapy (CHT): progesterone, dydrogesterone, or other progestagens. We conducted the present study to assess how these CHTs were associated with histology- and hormone receptor-defined breast cancer. We used data from the French E3N cohort study, with 80,391 postmenopausal women followed for a mean duration of 8.1 years; 2,265 histologically confirmed invasive breast cancers were identified through biennial self-administered questionnaires completed from 1990 to 2002. The relative risks (RRs) were estimated using Cox proportional hazards models. Compared with postmenopausal hormone therapy (HT) never-use, ever-use of estrogen+progesterone was not significantly associated with the risk of any breast cancer subtype, but increasing duration of estrogen+progesterone was associated with increasing risks of lobular (P = .06) and estrogen receptor-positive/progesterone receptor-negative (ER+/PR-; P = .02). Estrogen+dydrogesterone was associated with a significant increase in risk of lobular carcinoma (RR, 1.7; 95% CI, 1.1 to 2.6). Estrogen+other progestagens was associated with significant increases in risk of ductal and lobular carcinomas (RR, 1.6; 95% CI, 1.3 to 1.8; and 2.0; 95% CI, 1.5 to 2.7, respectively), of ER+/PR+ and ER+/PR- carcinomas (RR, 1.8; 95% CI, 1.5 to 2.1; and 2.6; 95% CI, 1.9 to 3.5, respectively), but not of ER-/PR+ or ER-/PR- carcinomas (RR, 1.0; 95% CI, 0.5 to 2.1; and 1.4; 95% CI, 0.9 to 2.0, respectively). The increase in risk of breast cancer observed with the use of CHTs other than estrogen+progesterone and estrogen+dydrogesterone seems to apply preferentially to ER+ carcinomas, especially those ER+/PR-, and to affect both ductal and lobular carcinomas.


Hybrid-image visualization for large viewing environments.
We present a first investigation into hybrid-image visualization for data analysis in large-scale viewing environments. Hybrid-image visualizations blend two different visual representations into a single static view, such that each representation can be perceived at a different viewing distance. Our work is motivated by data analysis scenarios that incorporate one or more displays with sufficiently large size and resolution to be comfortably viewed by different people from various distances. Hybrid-image visualizations can be used, in particular, to enhance overview tasks from a distance and detail-in-context tasks when standing close to the display. By using a perception-based blending approach, hybrid-image visualizations make two full-screen visualizations accessible without tracking viewers in front of a display. We contribute a design space, discuss the perceptual rationale for our work, provide examples, and introduce a set of techniques and tools to aid the design of hybrid-image visualizations.


In Vivo Gene Essentiality and Metabolism in Bordetella pertussis.
Bordetella pertussis is the causative agent of whooping cough, a serious respiratory illness affecting children and adults, associated with prolonged cough and potential mortality. Whooping cough has reemerged in recent years, emphasizing a need for increased knowledge of basic mechanisms of B. pertussis growth and pathogenicity. While previous studies have provided insight into in vitro gene essentiality of this organism, very little is known about in vivo gene essentiality, a critical gap in knowledge, since B. pertussis has no previously identified environmental reservoir and is isolated from human respiratory tract samples. We hypothesize that the metabolic capabilities of B. pertussis are especially tailored to the respiratory tract and that many of the genes involved in B. pertussis metabolism would be required to establish infection in vivo In this study, we generated a diverse library of transposon mutants and then used it to probe gene essentiality in vivo in a murine model of infection. Using the CON-ARTIST pipeline, 117 genes were identified as conditionally essential at 1 day postinfection, and 169 genes were identified as conditionally essential at 3 days postinfection. Most of the identified genes were associated with metabolism, and we utilized two existing genome-scale metabolic network reconstructions to probe the effects of individual essential genes on biomass synthesis. This analysis suggested a critical role for glucose metabolism and lipooligosaccharide biosynthesis in vivo This is the first genome-wide evaluation of in vivo gene essentiality in B. pertussis and provides tools for future exploration.IMPORTANCE Our study describes the first in vivo transposon sequencing (Tn-seq) analysis of B. pertussis and identifies genes predicted to be essential for in vivo growth in a murine model of intranasal infection, generating key resources for future investigations into B. pertussis pathogenesis and vaccine design.


Benchmark structures and binding energies of small water clusters with anharmonicity corrections.
For (H(2)O)(n) where n = 1-10, we used a scheme combining molecular dynamics sampling with high level ab initio calculations to locate the global and many low lying local minima for each cluster. For each isomer, we extrapolated the RI-MP2 energies to their complete basis set limit, included a CCSD(T) correction using a smaller basis set and added finite temperature corrections within the rigid-rotor-harmonic-oscillator (RRHO) model using scaled and unscaled harmonic vibrational frequencies. The vibrational scaling factors were determined specifically for water clusters by comparing harmonic frequencies with VPT2 fundamental frequencies. We find the CCSD(T) correction to the RI-MP2 binding energy to be small (<1%) but still important in determining accurate conformational energies. Anharmonic corrections are found to be non-negligble; they do not alter the energetic ordering of isomers, but they do lower the free energies of formation of the water clusters by as much as 4 kcal/mol at 298.15 K.


Therapeutic effects of saffron (Crocus sativus L.) in digestive disorders: a review.
Saffron, the dried red-orange stigmas of Crocus sativus L, has been known as a flavoring agent, food coloring and traditional herbal medicine. Pharmacological effects of saffron are mainly attributed to crocin, crocetin, picrocrocin and safranal. These components especially crocin, have significant effects including antidepressant and anticonvulsant, analgesic, anti-cancer and other therapeutic effects on different parts of our body namely cardiovascular, immune, respiratory, genital-urinary and central nervous system. According to the reports and findings, saffron plays a key role to cure different digestive system disorders via chemopreventive, inhibition of cell proliferation, induction of apoptosis, antioxidant effects and radical scavenging, genoprotective property, prevention of lipid peroxidation and anti-inflammatory processes. The outcome of the above mentioned mechanisms shows potential therapeutic properties of saffron against liver cancer, hepatotoxicity, fatty liver, hyperlipidemia, stomach cancer, peptic ulcer, colon cancer, ulcerative colitis, diabetes and pancreas cancer and ileum contractions. According to global statistics, the susceptibility to intestinal diseases is considered as a significant matter and can be important in health planning in any community. Several strategies for treatment and prevention of the digestive system diseases have provided that the use of herbal remedies seems effective and useful. Considering the available findings, the present study aims to introduce saffron as a prophylactic and therapeutic agent against gastrointestinal tract disorders. However, further clinical studies seem necessary in various aspects of saffron effects in different parts of body to verify these findings.


Cancer incidence of workers in the Swedish petroleum industry.
To estimate the risk of cancer due to occupational exposure to petroleum products in the Swedish transport and refinery industries. In a retrospective cohort study the cancer incidence in 4128 men and 191 women, who had worked for at least one year in the petroleum industry, was compared with the incidence in the general population. The job titles and employment times for each person were found in personal files in the industries. The men had on average worked in jobs exposed to petroleum for 11.6 years at the end of the observation period. The cases of cancer were identified by record linkage with the Swedish cancer register. In total there were 146 cases of cancer v 157.6 expected (standardised mortality ratio (SMR) 0.93 90% confidence interval (90% CI) 0.80 to 1.1). Operators at refineries had an increased risk of leukaemia (6 cases v 1.7 expected, 90% CI of relative risk (RR) 1.5 to 7.0). Five of the six cases had started to work at the refineries in the 1950s or later. No other significantly increased risk of cancer was found. Distribution workers had a decreased incidence of lung cancer (no cases, 90% CI of RR 0 to 0.4). Operators at Swedish refineries had an increased risk of leukaemia. A possible cause is exposure to benzene. There was no increased risk of leukaemia in distribution workers. Distribution workers had a decreased risk of lung cancer.


Ursolic Acid Improves Intestinal Damage and Bacterial Dysbiosis in Liver Fibrosis Mice.
Liver fibrosis is a reversible process of extracellular matrix deposition or scar formation after liver injury. Intestinal damage and bacterial dysbiosis are important concomitant intestinal changes in liver fibrosis and may in turn accelerate the progression of liver fibrosis through the gut-liver axis. RhoA, an important factor in the regulation of the cytoskeleton, plays an important role in intestinal damage. We investigated the effects of ursolic acid (UA), a traditional Chinese medicine with anti-fibrotic effects, on intestinal damage and bacterial disorder through the RhoA pathway. UA treatment reduced intestinal damage by inhibiting the inflammatory factor TNF-α and increasing the expression of tight junction proteins and antibacterial peptides to protect the intestinal barrier. Moreover, the corrective effect of UA on bacterial dysbiosis was also confirmed by sequencing of the 16S rRNA gene. Potential beneficial bacteria, such as the phylum Firmicutes and the genera Lactobacillus and Bifidobacterium, were increased in the UA group compared to the CCl4 group. In liver fibrosis mice with RhoA inhibition via injection of adeno-associated virus, the liver fibrosis, intestinal damage, and flora disturbances were improved. Moreover, UA inhibited the expression of RhoA pathway components. In conclusion, UA improves intestinal damage and bacterial dysbiosis partly via the RhoA pathway. This may be a potential mechanism by which UA exerts its anti-fibrotic effects and provides effective theoretical support for the future use of UA in clinical practice.


No evidence for transhemispheric diaschisis after human cerebral infarction.
Forty-four studies of regional cerebral blood flow (rCBF), fractional oxygen extraction (rOER) and oxygen consumption (rCMRO2) were made on twenty-five patients with recent internal carotid artery territory infarcts. The purpose was to study flow-metabolism relationships in the contralateral hemispheres, and to investigate whether contralateral rCMRO2 was depressed as a result of the recent infarcts. Two groups of controls were included for comparison--seventeen normal volunteers, and ten patients with proven extracranial cerebrovascular disease but without evidence of cerebral infarction. The results demonstrated that: contralateral hemispheric rCMRO2 was less variable than regional oxygen availability (the product of rCBF and arterial oxygen content). This was due, in part, to the effect of individual variations in PaCO2 on rCBF, but other uncontrolled factors, such as intracranial pressure, may have had influences. As a result, rCMRO2 did not correlate with rCBF; mean rCMRO2 in the contralateral hemispheres was 12% lower than normal (a significant difference), but was not different from the value found in patients with extracranial vascular disease in whom there was no evidence of infarction or ischemia; contralateral rCMRO2 did not correlate with the size of the infarct in the opposite hemisphere. It is concluded that rCMRO2 cannot be inferred from rCBF measurements in uncontrolled human studies (as frequently done in the past), and that depression of contralateral rCMRO2 may have preceded infarction in the opposite hemisphere, a consequence of the previous influences of diseases that predispose to stroke.


Mapping of an autosomal dominant gene for Dupuytren's contracture to chromosome 16q in a Swedish family.
Mapping of an autosomal dominant gene for Dupuytren's contracture to chromosome 16q in a Swedish family.Dupuytren's contracture (DC) (OMIM 126900) is the most common connective tissue disease of mankind and has both heritable and sporadic forms. The inherited form is most frequently observed among the xanthochroi peoples of Northern Europe where its most common manifestations are thickening of the palmar fascia and contracture of the fingers. We ascertained a five-generation Swedish family in which DC is inherited in an autosomal dominant manner with high, but incomplete, penetrance by the end of the fifth decade. Blood was collected from all affected and informative unaffected family members for the performance of a genome-wide scan at a resolution of approximately 8 cM for all autosomes. Linkage was established to a single 6 cM region between markers D16S419 and D16S3032 on chromosome 16. A maximal two-point logarithm of odds (LOD) score of 3.18 was achieved at microsatellite marker D16S415 with four other markers in the region producing LODs of >1.5.


A randomised controlled trial and cost analysis of problem-solving treatment for emotional disorders given by community nurses in primary care.
We set out to investigate whether community nurses could be trained in problem-solving therapy and, once trained, how effective they would be in treating emotional disorders in primary care. Seventy patients with an emotional disorder in primary care were randomly allocated to receive either problem-solving therapy from a trained community nurse or treatment as usual from their general practitioner. Interview and self-rated assessments of clinical and economic outcome were made pretreatment, at eight weeks and at 26 weeks after treatment. There was no difference in clinical outcome between patients who received problem-solving treatment and patients who received the general practitioner's usual treatment. However, patients who received problem-solving treatment had fewer disability days and fewer days off work. The health care cost of problem-solving was greater than that of the general practitioner's usual treatment but this was more than offset by savings in the cost of days off work. Problem-solving treatment can be given by trained community nurses. The clinical effectiveness and cost-benefit of the treatment will depend on the selection of appropriate patients.


Determining the Effects of Geraniol on Liver Regeneration Via the Nuclear Factor kB Pathway After Partial Hepatectomy.
Context • Nuclear factor kB (NF-κB) is a dimeric transcription factor that is involved in the regulation of regenerative and apoptosic genes and plays a key role in liver regeneration after a partial hepatectomy (PH). Complementary medicine is used to treat various diseases and can be obtained from a large number of plants that are found in nature. One such plant is geraniol, and no studies have yet occurred assessing its in vivo effects on liver regeneration. Objective • The current study intended to assess the effects of geraniol on liver regeneration after a 70% PH in rats. Design • The research team studied geraniol in a rat model in vivo. Setting • The study took place in the medical and surgical experimental research center at Eskisehir Osmangazi University (Eskisehir, Turkey). Animals • The animals were Wistar albino male rats. Intervention • The rats were divided into 8 groups with 6 rats in each group. Two groups were the sham control groups. The other 6 groups received an injection of a single dose of saline, the negative control; silymarin, the negative control; or geraniol, the intervention. The injections were given intraperitoneally immediately after PH. A laparotomy was performed on the rats all of those groups at either 24 h or 48 h after the PH. Outcome Measures • Using the reverse transcription (RT)- polymerase chain reaction (PCR) method (RT-PCR) and Western blot analysis, the NF-κB, tumor necrosis factor α, and interleukin 6 gene expression and protein levels were measured. Moreover, the levels of the heat shock proteins (HSPs) HSP27 and HSP60 were examined by Western blot. Results • The data showed that geraniol had a significant role (P < .05) in increasing the process of liver regeneration when given intraperitoneally, and it protected the liver as assessed by histology and the HSP levels. In rats receiving 100 mg/kg geraniol intraperitoneally, the agent induced hepatic regeneration 24 h and 48 h after PH (70%).


Dietary components in the development of leptin resistance.
Classically, leptin resistance has been associated with increased body fat and circulating leptin levels, and the condition is believed to contribute to the onset and/or maintenance of obesity. Although a great deal is known about the central nervous system mechanisms mediating leptin resistance, considerably less is known about the role of diet in establishing and maintaining this altered hormonal state. An exciting new finding has recently been published demonstrating the existence of leptin resistance in normal-weight rats with lean leptin levels by feeding them a high-concentration-fructose diet. This finding has opened the possibility that specific macronutrients may be capable of inducing leptin resistance, independently of the amount of body fat or circulating leptin present in the treated animals. This review describes several lines of research that have recently emerged indicating that specific types of dietary sugars and fats are capable of inducing leptin resistance in experimental rodent models. The results further show that diet-induced leptin resistance is capable of increasing energy intake and elevating body weight gain under appropriate dietary challenges. It appears that biological mechanisms on multiple levels may underlie the dietary induction of leptin resistance, including alterations in the leptin blood-to-brain transport system, in peripheral glucose metabolism, and in central leptin receptor signaling pathways. What is clear from the findings reviewed here is that diet-induced leptin resistance can occur in the absence of elevated circulating leptin levels and body weight, rendering it a potential cause and/or predisposing factor to excess body weight gain and obesity.


Sacrificial bonds and hidden length in biomaterials: a kinetic constitutive description of strength and toughness in bone.
Sacrificial bonds and hidden length in structural molecules account for the greatly increased fracture toughness of biological materials compared to synthetic materials without such structural features by providing a molecular-scale mechanism for energy dissipation. One example is in the polymeric glue connection between collagen fibrils in animal bone. In this paper we propose a simple kinetic model that describes the breakage of sacrificial bonds and the release of hidden length, based on Bell's theory. We postulate a master equation governing the rates of bond breakage and formation. This enables us to predict the mechanical behavior of a quasi-one-dimensional ensemble of polymers at different stretching rates. We find that both the rupture peak heights and maximum stretching distance increase with the stretching rate. In addition, our theory naturally permits the possibility of self-healing in such biological structures.


Designs of colonoscopic adenoma detection trials: more positive results with tandem than with parallel studies - an analysis of studies on imaging techniques and mechanical devices.
Adenoma detection rate (ADR) has been shown to correlate with interval cancers after screening colonoscopy and is commonly used as surrogate parameter for its outcome quality. ADR improvements by various techniques have been studied in randomised trials using either parallel or tandem methodololgy. A systematic literature search was done on randomised trials (full papers, English language) on tandem or parallel studies using either adenoma miss rates (AMR) or ADR as main outcome to test different novel technologies on imaging (new endoscope generation, narrow band imaging, iScan, Fujinon intelligent chromoendoscopy/blue laser imaging and wide angle scopes) and mechanical devices (transparent caps, endocuff, endorings and balloons). Available meta analyses were also screened for randomised studies. Overall, 24 randomised tandem trials with AMR (variable definitions and methodology) and 42 parallel studies using ADR (homogeneous methodology) as primary outcome were included. Significant differences in favour of the new method were found in 66.7% of tandem studies (8222 patients) but in only 23.8% of parallel studies (28 059 patients), with higher rates of positive studies for mechanical devices than for imaging methods. In a random-effects model, small absolute risk differences were found, but these were double in magnitude for tandem as compared with parallel studies (imaging: tandem 0.04 (0.01, 0.07), parallel 0.02 (0.00, 0.04); mechanical devices: tandem 0.08 (0.00, 0.15), parallel 0.04 (0.01, 0.07)). Nevertheless, 94.2% of missed adenomas in the tandem studies were small (<1 cm) and/or non-advanced. A tandem study is more likely to yield positive results than a simple parallel trial; this may be due to the use of different parameters, variable definitions and methodology, and perhaps also a higher likelihood of bias. Therefore, we suggest to accept positive results of tandem studies only if accompanied by positive results from parallel trials.


Calcium, cancer and killing: the role of calcium in killing cancer cells by cytotoxic T lymphocytes and natural killer cells.
Killing cancer cells by cytotoxic T lymphocytes (CTL) and by natural killer (NK) cells is of vital importance. Cancer cell proliferation and apoptosis depend on the intracellular Ca(2+) concentration, and the expression of numerous ion channels with the ability to control intracellular Ca(2+) concentrations has been correlated with cancer. A rise of intracellular Ca(2+) concentrations is also required for efficient CTL and NK cell function and thus for killing their targets, in this case cancer cells. Here, we review the data on Ca(2+)-dependent killing of cancer cells by CTL and NK cells. In addition, we discuss emerging ideas and present a model how Ca(2+) may be used by CTL and NK cells to optimize their cancer cell killing efficiency. This article is part of a Special Issue entitled: 12th European Symposium on Calcium.


Immunotherapy for metastatic renal cell carcinoma.
Since the mid-2000s, the field of metastatic renal cell carcinoma (mRCC) has experienced a paradigm shift from non-specific therapy with broad-acting cytokines to specific regimens, which directly target the cancer, the tumour microenvironment, or both.Current guidelines recommend targeted therapies with agents such as sunitinib, pazopanib or temsirolimus (for people with poor prognosis) as the standard of care for first-line treatment of people with mRCC and mention non-specific cytokines as an alternative option for selected patients.In November 2015, nivolumab, a checkpoint inhibitor directed against programmed death-1 (PD-1), was approved as the first specific immunotherapeutic agent as second-line therapy in previously treated mRCC patients. To assess the effects of immunotherapies either alone or in combination with standard targeted therapies for the treatment of metastatic renal cell carcinoma and their efficacy to maximize patient benefit. We searched the Cochrane Library, MEDLINE (Ovid), Embase (Ovid), ISI Web of Science and registers of ongoing clinical trials in November 2016 without language restrictions. We scanned reference lists and contacted experts in the field to obtain further information. We included randomized controlled trials (RCTs) and quasi-RCTs with or without blinding involving people with mRCC. We collected and analyzed studies according to the published protocol. Summary statistics for the primary endpoints were risk ratios (RRs) and mean differences (MD) with their 95% confidence intervals (CIs). We rated the quality of evidence using GRADE methodology and summarized the quality and magnitude of relative and absolute effects for each primary outcome in our 'Summary of findings' tables. We identified eight studies with 4732 eligible participants and an additional 13 ongoing studies. We categorized studies into comparisons, all against standard therapy accordingly as first-line (five comparisons) or second-line therapy (one comparison) for mRCC.Interferon (IFN)-α monotherapy probably increases one-year overall mortality compared to standard targeted therapies with temsirolimus or sunitinib (RR 1.30, 95% CI 1.13 to 1.51; 2 studies; 1166 participants; moderate-quality evidence), may lead to similar quality of life (QoL) (e.g. MD -5.58 points, 95% CI -7.25 to -3.91 for Functional Assessment of Cancer - General (FACT-G); 1 study; 730 participants; low-quality evidence) and may slightly increase the incidence of adverse events (AEs) grade 3 or greater (RR 1.17, 95% CI 1.03 to 1.32; 1 study; 408 participants; low-quality evidence).There is probably no difference between IFN-α plus temsirolimus and temsirolimus alone for one-year overall mortality (RR 1.13, 95% CI 0.95 to 1.34; 1 study; 419 participants; moderate-quality evidence), but the incidence of AEs of 3 or greater may be increased (RR 1.30, 95% CI 1.17 to 1.45; 1 study; 416 participants; low-quality evidence). There was no information on QoL.IFN-α alone may slightly increase one-year overall mortality compared to IFN-α plus bevacizumab (RR 1.17, 95% CI 1.00 to 1.36; 2 studies; 1381 participants; low-quality evidence). This effect is probably accompanied by a lower incidence of AEs of grade 3 or greater (RR 0.77, 95% CI 0.71 to 0.84; 2 studies; 1350 participants; moderate-quality evidence). QoL could not be evaluated due to insufficient data.Treatment with IFN-α plus bevacizumab or standard targeted therapy (sunitinib) may lead to similar one-year overall mortality (RR 0.37, 95% CI 0.13 to 1.08; 1 study; 83 participants; low-quality evidence) and AEs of grade 3 or greater (RR 1.18, 95% CI 0.85 to 1.62; 1 study; 82 participants; low-quality evidence). QoL could not be evaluated due to insufficient data.Treatment with vaccines (e.g. MVA-5T4 or IMA901) or standard therapy may lead to similar one-year overall mortality (RR 1.10, 95% CI 0.91 to 1.32; low-quality evidence) and AEs of grade 3 or greater (RR 1.16, 95% CI 0.97 to 1.39; 2 studies; 1065 participants; low-quality evidence). QoL could not be evaluated due to insufficient data.In previously treated patients, targeted immunotherapy (nivolumab) probably reduces one-year overall mortality compared to standard targeted therapy with everolimus (RR 0.70, 95% CI 0.56 to 0.87; 1 study; 821 participants; moderate-quality evidence), probably improves QoL (e.g. RR 1.51, 95% CI 1.28 to 1.78 for clinically relevant improvement of the FACT-Kidney Symptom Index Disease Related Symptoms (FKSI-DRS); 1 study, 704 participants; moderate-quality evidence) and probably reduces the incidence of AEs grade 3 or greater (RR 0.51, 95% CI 0.40 to 0.65; 1 study; 803 participants; moderate-quality evidence). Evidence of moderate quality demonstrates that IFN-α monotherapy increases mortality compared to standard targeted therapies alone, whereas there is no difference if IFN is combined with standard targeted therapies. Evidence of low quality demonstrates that QoL is worse with IFN alone and that severe AEs are increased with IFN alone or in combination. There is low-quality evidence that IFN-α alone increases mortality but moderate-quality evidence on decreased AEs compared to IFN-α plus bevacizumab. Low-quality evidence shows no difference for IFN-α plus bevacizumab compared to sunitinib with respect to mortality and severe AEs. Low-quality evidence demonstrates no difference of vaccine treatment compared to standard targeted therapies in mortality and AEs, whereas there is moderate-quality evidence that targeted immunotherapies reduce mortality and AEs and improve QoL.


The current status and environmental impacts of glyphosate-resistant crops: a review.
Glyphosate [N-(phosphonomethyl) glycine]-resistant crops (GRCs), canola (Brassica napus L.), cotton (Gossypium hirsutum L.), maize (Zea mays L.), and soybean [Glycine max (L.) Merr.] have been commercialized and grown extensively in the Western Hemisphere and, to a lesser extent, elsewhere. Glyphosate-resistant cotton and soybean have become dominant in those countries where their planting is permitted. Effects of glyphosate on contamination of soil, water, and air are minimal, compared to some of the herbicides that they replace. No risks have been found with food or feed safety or nutritional value in products from currently available GRCs. Glyphosate-resistant crops have promoted the adoption of reduced- or no-tillage agriculture in the USA and Argentina, providing a substantial environmental benefit. Weed species in GRC fields have shifted to those that can more successfully withstand glyphosate and to those that avoid the time of its application. Three weed species have evolved resistance to glyphosate in GRCs. Glyphosate-resistant crops have greater potential to become problems as volunteer crops than do conventional crops. Glyphosate resistance transgenes have been found in fields of canola that are supposed to be non-transgenic. Under some circumstances, the largest risk of GRCs may be transgene flow (introgression) from GRCs to related species that might become problems in natural ecosystems. Glyphosate resistance transgenes themselves are highly unlikely to be a risk in wild plant populations, but when linked to transgenes that may impart fitness benefits outside of agriculture (e.g., insect resistance), natural ecosystems could be affected. The development and use of failsafe introgression barriers in crops with such linked genes is needed.


Fiber-optic temperature sensor based on internally generated thermal radiation.
This paper presents a theoretical and experimental study of a method of sensing temperature with optical fibers with the radiation thermally generated within the fiber. Using quartz fibers it is possible to read temperatures in the range from room temperature to over 1000 degrees C. We have demonstrated operation as low as 135 degrees C using nonoptimum fibers and detectors. The method also allows the determination of the location and length of a hot spot along the fiber. The purpose of this type of sensor is to monitor the development of hot spots in electrical machinery, such as generators and transformers, where conventional measurement techniques cannot be effectively applied. If such optical fibers can be incorporated in the manufacturing process of electrical equipment, these temperature monitors may contribute in avoiding catastrophic breakdown.


Lifestyle risk factors for lower limb venous reflux in the general population: Edinburgh Vein Study.
Varicose veins occur commonly in the general population but the aetiology is not well established. Varicosities are associated frequently with reflux of blood in the leg veins due to valvular incompetence. Our aim was to determine in the general population which lifestyle factors were related to reflux and thus implicated in the aetiology of varicose veins. In the Edinburgh Vein Study, 1566 men and women aged 18-64 years were sampled randomly from the general population in the city of Edinburgh, Scotland, and had duplex scans to measure reflux in eight venous segments in each leg. A self-administered questionnaire enquired about occupation, mobility at work, smoking, obstetric history, dietary fibre intake and bowel habit. A bowel record form was completed subsequently. In women, venous reflux was associated with decreased sitting at work (odds ratio [OR] = 0.76, 95% CI : 0.61-0.94), previous pregnancy (OR = 1.20, 95% CI : 0.93-1.54), and a lower prior use of oral contraceptives (OR = 0.84, 95% CI : 0.66-1.06). Mean body mass index was greater in women with superficial reflux compared to those with no reflux: 26.2 kg/m(2) (95% CI : 25.5-27.0) versus 25.2 kg/m(2) (95% CI : 24.8-25.6). On age adjustment, sitting at work remained related to reflux (OR = 0.78, 95% CI : 0.63-0.98) and prior use of oral contraceptives to superficial reflux (OR = 0.71, 95% CI : 0.50-1.01). In age-adjusted analyses in men, height was related to reflux, (OR = 1.13, 95% CI : 1.02-1.26) and straining at stool was related to superficial reflux (OR = 1.94, 95% CI : 1.12-3.35). No associations were found in either sex between reflux and social class, lifetime cigarette consumption, dietary fibre intake and intestinal transit time. This population study did not identify strong and consistent lifestyle risk factors for venous reflux although previous pregnancy, lower use of oral contraceptives, obesity and mobility at work in women and height and straining at stool in men may be implicated.


Development and validation of prediction scores for nosocomial infections, reoperations, and adverse events in the daily clinical setting of neurosurgical patients with cerebral and spinal tumors.
Various quality indicators are currently under investigation, aiming at measuring the quality of care in neurosurgery; however, the discipline currently lacks practical scoring systems for accurately assessing risk. The aim of this study was to develop three accurate, easy-to-use risk scoring systems for nosocomial infections, reoperations, and adverse events for patients with cerebral and spinal tumors. The authors developed a semiautomatic registry with administrative and clinical data and included all patients with spinal or cerebral tumors treated between September 2017 and May 2019. Patients were further divided into development and validation cohorts. Multivariable logistic regression models were used to develop risk scores by assigning points based on β coefficients, and internal validation of the scores was performed. In total, 1000 patients were included. An unplanned 30-day reoperation was observed in 6.8% of patients. Nosocomial infections were documented in 7.4% of cases and any adverse event in 14.5%. The risk scores comprise variables such as emergency admission, nursing care level, ECOG performance status, and inflammatory markers on admission. Three scoring systems, NoInfECT for predicting the incidence of nosocomial infections (low risk, 1.8%; intermediate risk, 8.1%; and high risk, 26.0% [p < 0.001]), LEUCut for 30-day unplanned reoperations (low risk, 2.2%; intermediate risk, 6.8%; and high risk, 13.5% [p < 0.001]), and LINC for any adverse events (low risk, 7.6%; intermediate risk, 15.7%; and high risk, 49.5% [p < 0.001]), showed satisfactory discrimination between the different outcome groups in receiver operating characteristic curve analysis (AUC ≥ 0.7). The proposed risk scores allow efficient prediction of the likelihood of adverse events, to compare quality of care between different providers, and further provide guidance to surgeons on how to allocate preoperative care.


Survivability of a probiotic Lactobacillus casei in the gastrointestinal tract of healthy human volunteers and its impact on the faecal microflora.
The aim of this study was to measure the gastrointestinal survival of Lactobacillus casei and its impact on the gut microflora in healthy human volunteers. Twenty healthy volunteers took part in a double-blind placebo-controlled probiotic feeding study (10 fed probiotic, 10 fed placebo). The probiotic was delivered in two 65 ml aliquots of fermented milk drink (FMD) daily for 21 days at a dose of 8.6 +/- 0.1 Log(10)Lact. casei CFU ml(-1) FMD. Faecal samples were collected before, during and after FMD or placebo consumption, and important groups of faecal bacteria enumerated by fluorescent in situ hybridization (FISH) using oligonucleotide probes targeting the 16S rRNA. The fed Lact. casei was enumerated using selective nutrient agar and colony identity confirmed by pulsed field gel electrophoresis. Seven days after ingestion of FMD, the Lact. casei was recovered from faecal samples taken from the active treatment group at 7.1 +/- 0.4 Log(10) CFU g(-1) faeces (mean +/- SD, n = 9) and numbers were maintained at this level until day 21. Lact. casei persisted in six volunteers until day 28 at 5.0 +/- 0.9 Log(10) CFU g(-1) faeces (mean +/- SD, n = 6). Numbers of faecal lactobacilli increased significantly upon FMD ingestion. In addition, the numbers of bifidobacteria were higher on days 7 and 21 than on days 0 and 28 in both FMD fed and placebo fed groups. Consumption of Lact. casei had little discernible effect on other bacterial groups enumerated. Daily consumption of FMD enabled a probiotic Lact. casei strain to be maintained in the gastrointestinal tract of volunteers at a stable relatively high population level during the probiotic feeding period. The study has confirmed that this probiotic version of Lact. casei survives well within the human gastrointestinal tract.


Dissection of H-2Db-restricted cytotoxic T-lymphocyte epitopes on simian virus 40 T antigen by the use of synthetic peptides and H-2Dbm mutants.
Five distinct cytotoxic T-lymphocyte (CTL) recognition sites were identified in the simian virus 40 (SV40) T antigen by using H-2b cells that express the truncated T antigen or antigens carrying internal deletions of various sizes. Four of the CTL recognition determinants, designated sites I, II, III, and V, are H-2Db restricted, while site IV is H-2Kb restricted. The boundaries of CTL recognition sites I, II, and III, clustered in the amino-terminal half of the T antigen, were further defined by use of overlapping synthetic peptides containing amino acid sequences previously determined to be required for recognition by T-antigen site-specific CTL clones by using SV40 deletion mutants. CTL clone Y-1, which recognizes epitope I and whose reactivity is affected by deletion of residues 193 to 211 of the T antigen, responded positively to B6/PY cells preincubated with a synthetic peptide corresponding to T-antigen amino acids 205 to 219. CTL clones Y-2 and Y-3 lysed B6/PY cells preincubated with large-T peptide LT220-233. To distinguish further between epitopes II and III, Y-2 and Y-3 CTL clones were reacted with SV40-transformed cells bearing mutations in the major histocompatibility complex class I antigen. Y-2 CTL clones lysed SV40-transformed H-2Dbm13 cells (bm13SV) which carry several amino acid substitutions in the putative antigen-binding site in the alpha 2 domain of the H-2Db antigen but not bm14SV cells, which contain a single amino acid substitution in the alpha 1 domain. Y-3 CTL clones lysed both mutant transformants. Y-1 and Y-5 CTL clones failed to lyse bm13SV and bm14SV cells; however, these cells could present synthetic peptide LT205-219 to CTL clone Y-1 and peptide SV26(489-503) to CTL clone Y-5, suggesting that the endogenously processed T antigen yields fragments of sizes or sequences different from those of synthetic peptides LT205-219 and SV26(489-503).


Structure-based discovery of selective serotonin 5-HT(1B) receptor ligands.
The development of safe and effective drugs relies on the discovery of selective ligands. Serotonin (5-hydroxytryptamine [5-HT]) G protein-coupled receptors are therapeutic targets for CNS disorders but are also associated with adverse drug effects. The determination of crystal structures for the 5-HT1B and 5-HT2B receptors provided an opportunity to identify subtype selective ligands using structure-based methods. From docking screens of 1.3 million compounds, 22 molecules were predicted to be selective for the 5-HT1B receptor over the 5-HT2B subtype, a requirement for safe serotonergic drugs. Nine compounds were experimentally verified as 5-HT1B-selective ligands, with up to 300-fold higher affinities for this subtype. Three of the ligands were agonists of the G protein pathway. Analysis of state-of-the-art homology models of the two 5-HT receptors revealed that the crystal structures were critical for predicting selective ligands. Our results demonstrate that structure-based screening can guide the discovery of ligands with specific selectivity profiles.


Canadian physicians: the struggle with health reform.
The Canadian health system is now in an era of significant change. Decentralization, the changing role of government consumer movement and new views on health greatly affect physicians' relationships with patients, consumers and other health professionals, and will determine the governance and mandate of medical associations. While the Canada Health Act requires coverage of all medically necessary health services provided by hospitals and medical practiitioners, the understanding of the term medically necessary appears to be changing to include issues related to financial sustainability and scientific appropriateness. As goverments become interventionist in the health care system as a reaction to fiscal imperatives, their traditional role as funder and planner is changing as they begin in a more explicit manner, to manage the health care system and to engage in directly influencing patient management decision-making. These new directions will have a major influence on the practice of medicine in the 21st century.


Interactions of nucleotide cofactors with the Escherichia coli replication factor DnaC protein.
Quantitative analyses of the interactions of nucleotide cofactors with the Escherichia coli replicative factor DnaC protein have been performed using thermodynamically rigorous fluorescence titration techniques. This approach allowed us to obtain stoichiometries of the formed complexes and interaction parameters, without any assumptions about the relationship between the observed signal and the degree of binding. The stoichiometry of the DnaC-nucleotide complex has been determined in direct binding experiments with fluorescent nucleotide analogues, MANT-ATP and MANT-ADP. The stoichiometry of the DnaC complexes with unmodified ATP and ADP has been determined using the macromolecular competition titration method (MCT). The obtained results established that at saturation the DnaC protein binds a single nucleotide molecule per protein monomer. Analyses of the binding of fluorescent analogues and unmodified nucleotides to the DnaC protein show that ATP and ADP have the same affinities for the nucleotide-binding site, albeit the corresponding complexes have different structures, specifically affected by the presence of magnesium cations in solution. Although the presence of the gamma-phosphate does not affect the affinity, the structure of the triphosphate group is critical. While the affinity of ATP-gamma-S is the same as the affinity of ATP, the affinities of AMP-PNP and AMP-PCP are approximately 2 and approximately 4 orders lower than that of ATP, respectively. Moreover, the ribose plays a significant role in forming a stable complex. The binding constants of dATP and dADP are approximately 2 orders of magnitude lower than those for ribose nucleotides. The nucleotide-binding site of the DnaC protein is highly base specific. The intrinsic affinity of adenosine triphosphates and diphosphates is at least 3-4 orders of magnitude higher than for any of the other examined nucleotides. The obtained data indicate that the recognition mechanism of the nucleotide by the structural elements of the binding site is complex with the base providing the specificity and the ribose, as well as the second phosphate group contributing to the affinity. The significance of the results for the functioning of the DnaC protein is discussed.


The lid domain of the MCP hydrolase DxnB2 contributes to the reactivity toward recalcitrant PCB metabolites.
DxnB2 and BphD are meta-cleavage product (MCP) hydrolases that catalyze C-C bond hydrolysis of the biphenyl metabolite 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoic acid (HOPDA). BphD is a bottleneck in the bacterial degradation of polychlorinated biphenyls (PCBs) by the Bph catabolic pathway due in part to inhibition by 3-Cl HOPDAs. By contrast, DxnB2 from Sphingomonas wittichii RW1 catalyzes the hydrolysis of 3-Cl HOPDAs more efficiently. X-ray crystallographic studies of the catalytically inactive S105A variant of DxnB2 complexed with 3-Cl HOPDA revealed a binding mode in which C1 through C6 of the dienoate are coplanar. The chlorine substituent is accommodated by a hydrophobic pocket that is larger than the homologous site in BphDLB400 from Burkholderia xenovorans LB400. The planar binding mode observed in the crystalline complex was consistent with the hyper- and hypsochromically shifted absorption spectra of 3-Cl and 3,9,11-triCl HOPDA, respectively, bound to S105A in solution. Moreover, ES(red), an intermediate possessing a bathochromically shifted spectrum observed in the turnover of HOPDA, was not detected, suggesting that substrate destabilization was rate-limiting in the turnover of these PCB metabolites. Interestingly, electron density for the first α-helix of the lid domain was poorly defined in the dimeric DxnB2 structures, unlike in the tetrameric BphDLB400. Structural comparison of MCP hydrolases identified the NC-loop, connecting the lid to the α/β-hydrolase core domain, as a determinant in the oligomeric state and suggests its involvement in catalysis. Finally, an increased mobility of the DxnB2 lid may contribute to the enzyme's ability to hydrolyze PCB metabolites, highlighting how lid architecture contributes to substrate specificity in α/β-hydrolases.


Development and learning of saccadic eye movements in 7- to 42-month-old children.
From birth, infants move their eyes to explore their environment, interact with it, and progressively develop a multitude of motor and cognitive abilities. The characteristics and development of oculomotor control in early childhood remain poorly understood today. Here, we examined reaction time and amplitude of saccadic eye movements in 93 7- to 42-month-old children while they oriented toward visual animated cartoon characters appearing at unpredictable locations on a computer screen over 140 trials. Results revealed that saccade performance is immature in children compared to a group of adults: Saccade reaction times were longer, and saccade amplitude relative to target location (10° eccentricity) was shorter. Results also indicated that performance is flexible in children. Although saccade reaction time decreased as age increased, suggesting developmental improvements in saccade control, saccade amplitude gradually improved over trials. Moreover, similar to adults, children were able to modify saccade amplitude based on the visual error made in the previous trial. This second set of results suggests that short visual experience and/or rapid sensorimotor learning are functional in children and can also affect saccade performance.


Influence of intensive pine management on Dipteran community structure in coastal North Carolina.
Intensive pine (Pinus spp.) management is a primary land use in the southeastern United States. In eastern North Carolina, intensively managed pine stands often occur on land previously ditched and drained. Because modification of natural vegetation and water sources are known to affect dipteran community structure, we studied effects of intensive pine management on abundance and diversity of dipteran families in the northern coastal plain of North Carolina during 2006 and 2007. We used malaise traps and emergence traps to sample different types of forest stands (n = 143 sample nights) and water sources (n = 147 sample nights) in a managed pine forest and a natural forested wetland. Cecidomyiids were more abundant in stands with canopy cover, chironomids were more abundant at edges between forested stands and open canopy stands, and chloropids were more abundant in open canopy stands. Families Ceratopogonidae, Dolichopodidae, Ephydridae, Muscidae, Psychodidae, and Tipulidae were more abundant in the natural forested wetland than in all types of modified water sources. Dipteran diversity and evenness were highest in stands with open canopy and at forest edges, and highest in the natural forested wetland. Unmanaged, natural stands on the intensively managed landscape did not support a higher abundance or diversity of dipteran families than intensively managed stands. Restoration of natural wetlands may increase dipteran diversity in unmanaged stands. Heliponds, a modified water source, supported a comparable dipteran abundance to that of the natural forested wetland. Increased numbers of heliponds may facilitate higher dipteran abundance in managed pine landscapes.


Putting the "M" back in maternal-fetal medicine.
Although maternal death remains rare in the United States, the rate has not decreased for 3 decades. The rate of severe maternal morbidity, a more prevalent problem, is also rising. Rise in maternal age, in rates of obesity, and in cesarean deliveries as well as more pregnant women with chronic medical conditions all contribute to maternal mortality and morbidity in the United States. We believe it is the responsibility of maternal-fetal medicine (MFM) subspecialists to lead a national effort to decrease maternal mortality and morbidity. In doing so, we hope to reestablish the vital role of MFM subspecialists to take the lead in the performance and coordination of care in complicated obstetrical cases. This article will summarize our initial recommendations to enhance MFM education and training, to establish national standards to improve maternal care and management, and to address critical research gaps in maternal medicine.


Dendritic cell derived cytokines in human natural killer cell differentiation and activation.
Dendritic cells (DCs) and natural killer (NK) cells shape each other's functions early during immune responses. DCs activate NK cells and NK cells can mature or kill DCs. In this review we will discuss which DC and NK cell subsets are mainly affected by this interaction, where these encounters might take place and which signals are exchanged. Finally, we will point out what the clinical benefit of understanding this interaction might be and how it changed our view on NK cells as innate lymphocytes.


A role for cell-cycle-regulated histone H3 lysine 56 acetylation in the DNA damage response.
DNA breaks are extremely harmful lesions that need to be repaired efficiently throughout the genome. However, the packaging of DNA into nucleosomes is a significant barrier to DNA repair, and the mechanisms of repair in the context of chromatin are poorly understood. Here we show that lysine 56 (K56) acetylation is an abundant modification of newly synthesized histone H3 molecules that are incorporated into chromosomes during S phase. Defects in the acetylation of K56 in histone H3 result in sensitivity to genotoxic agents that cause DNA strand breaks during replication. In the absence of DNA damage, the acetylation of histone H3 K56 largely disappears in G2. In contrast, cells with DNA breaks maintain high levels of acetylation, and the persistence of the modification is dependent on DNA damage checkpoint proteins. We suggest that the acetylation of histone H3 K56 creates a favourable chromatin environment for DNA repair and that a key component of the DNA damage response is to preserve this acetylation.


Promoting reflection in mental health nursing practice: a case illustration using problem-based learning.
Reflective practice in nursing has been shown to improve both client care and nurses role satisfaction. Students require regular and guided opportunities to learn the necessary reflective skills that underpin best practice. Problem-based learning (PBL) processes based on comprehensive learning packages developed from actual clinical cases provide a contextualized and realistic means for students to develop and hone their reflective skills for use as mental health practitioners. This paper uses a case illustration to demonstrate the usefulness of PBL as a mechanism for developing reflective practice in the mental health context. Students analysed five cases drawn from actual documented clinical materials that included nursing, medical and allied health professionals' assessments, treatment regimes, and progress notes. One student's written analysis of the five cases and an interview with the student is presented as a case illustration. The case illustrates the student's reflections on the theme of 'hope' for the clients and identified three obstacles. These were: (i) a lack of acknowledgement by health professionals of traumatic life events; (ii) overlooking less tangible losses; and (iii) a central focus on drug treatment. Reflective learning strategies can be incorporated in on- and off-campus learning environments and used to assist the learner to practise critical reflective skills in a controlled and safe manner. Reflective processes are more meaningful if the PBL package that students encounter represents real clinical scenarios with comprehensive resource materials.


Seasonal community succession of the phyllosphere microbiome.
The leaf microbiome is influenced by both biotic and abiotic factors. Currently, we know little about the relative importance of these factors in determining microbiota composition and dynamics. To explore this issue, we collected weekly leaf samples over a 98-day growing season from multiple cultivars of common bean, soybean, and canola planted at three locations in Ontario, Canada, and performed Illumina-based microbiome analysis. We find that the leaf microbiota at the beginning of the season is very strongly influenced by the soil microbiota but, as the season progresses, it differentiates, becomes significantly less diverse, and transitions to having a greater proportion of leaf-specific taxa that are shared among all samples. A phylogenetic investigation of communities by reconstruction of unobserved states imputation of microbiome function inferred from the taxonomic data found significant differences between the soil and leaf microbiome, with a significant enrichment of motility gene categories in the former and metabolic gene categories in the latter. A network co-occurrence analysis identified two highly connected clusters as well as subclusters of putative pathogens and growth-promoting bacteria. These data reveal some of the complex ecological dynamics that occur in microbial communities over the course of a growing season and highlight the importance of community succession.


What Drives the Development of Social Inequality Over the Life Course? The German TwinLife Study.
The German twin family study 'TwinLife' was designed to enhance our understanding of the development of social inequalities over the life course. The interdisciplinary project investigates mechanisms of social inequalities across the lifespan by taking into account psychological as well as social mechanisms, and their genetic origin as well as the interaction and covariation between these factors. Main characteristics of the study are: (1) a multidimensional perspective on social inequalities, (2) the assessment of developmental trajectories in childhood, adolescence, and young adulthood in a longitudinal design by using (3) a combination of a multi-cohort cross-sequential and an extended twin family design, while (4) capturing a large variation of behavioral and environmental factors in a representative sample of about 4,000 German twin families. In the present article, we first introduce the theoretical and empirical background of the TwinLife study, and second, describe the design, content, and implementation of TwinLife. Since the data will be made available as scientific use file, we also illustrate research possibilities provided by this project to the scientific community.


Acetylshikonin, a Novel AChE Inhibitor, Inhibits Apoptosis via Upregulation of Heme Oxygenase-1 Expression in SH-SY5Y Cells.
Acetylcholinesterase inhibitors are prominent alternative in current clinical treatment for AD patients. Therefore, there is a continued need to search for novel AChEIs with good clinical efficacy and less side effects. By using our in-house natural product database and AutoDock Vina as a tool in docking study, we have identified twelve phytochemicals (emodin, aloe-emodin, chrysophanol, and rhein in Rhei Radix Et Rhizoma; xanthotoxin, phellopterin, alloisoimperatorin, and imperatorin in Angelicae dahuricae Radix; shikonin, acetylshikonin, isovalerylshikonin, and β,β-dimethylacrylshikonin in Arnebiae Radix) as candidates of AChEIs that were not previously reported in the literature. In addition to AChEI activity, a series of cell-based experiments were conducted for the investigation of their neuroprotective activities. We found that acetylshikonin and its derivatives prevented apoptotic cell death induced by hydrogen peroxide in human and rat neuronal SH-SY5Y and PC12 cells at 10 μM. We showed that acetylshikonin exhibited the most potent antiapoptosis activity through the inhibition of the generation of reactive oxygen species as well as protection of the loss of mitochondria membrane potential. Furthermore, we identified for the first time that the upregulation of heme oxygenase 1 by acetylshikonin is a key step mediating its antiapoptotic activity from oxidative stress in SH-SY5Y cells.


A pilot study of application of the Stroke Riskometer mobile app for assessment of the course and clinical outcomes of COVID-19 among hospitalised patients.
Early determination of COVID-19 severity and health outcomes could facilitate better treatment of patients. Different methods and tools have been developed for predicting outcomes of COVID-19, but they are difficult to use in routine clinical practice. We conducted a prospective cohort study of inpatients aged 20-92 years, diagnosed with COVID-19 to determine whether their individual 5-year absolute risk of stroke at the time of hospital admission predicts the course of COVID-19 severity and mortality. The risk of stroke was determined by the Stroke Riskometer mobile application. We examined 385 patients hospitalised with COVID-19 (median age 61 years). The participants were categorised based on COVID-19 severity: 271 (70.4%) to the "Not severe" and 114 (29.6%) to the "Severe" groups. The median risk of stroke the next day after hospitalisation was significantly higher among patients in the Severe group (2.83 [95% CI 2.35-4.68]) vs the Not severe group (1.11 [95% CI 1.00-1.29]). The median risk of stroke and median systolic blood pressure (SBP) were significantly higher among non-survivors (12.04 [95% CI 2.73-21.19]) and (150 [95% CI 140-170]) vs survivors (1.31 [95% CI 1.14-1.52]), 134 [95% CI 130-135]), respectively. Those who spent more than 2.5 hours a week on physical activity were 3.1 times more likely to survive from COVID-19. Those who consumed more than one standard alcohol drink a day, or suffered with atrial fibrillation, or had poor memory were 2.5, 2.3, and 2.6 times more likely not to survive from COVID-19, respectively. High risk of stroke, physical inactivity, alcohol intake, high SBP, and atrial fibrillation are associated with severity and mortality of COVID-19. Our findings suggest that the Stroke Riskometer app could be used as a simple predictive tool of COVID-19 severity and mortality.


Cardenolide, Potassium, and Pyrethroid Insecticide Combinations Reduce Growth and Survival of Monarch Butterfly Caterpillars (Lepidoptera: Nymphalidae).
The monarch butterfly, Danaus plexippus L., has evolved to be insensitive to milkweed cardenolides via genetic modifications of Na+/K+-ATPase. There is concern for insecticide exposures near agriculture, with little information on monarch caterpillar toxicology. It is unclear how cardenolide insensitivity may affect the sensitivity of monarch caterpillars to pyrethroid insecticides. Additionally, potassium fertilizers may affect monarch caterpillar physiology and cardenolide sequestration. Here, we investigated the growth, survival, and development of caterpillars exposed to the cardenolide ouabain, bifenthrin, and potassium chloride (KCl) alone and in combination. Caterpillars were either exposed to 1) ouabain from third- to fifth-instar stage, 2) KCl at fifth-instar stage, 3) KCl and bifenthrin at fifth-instar stage, or 4) combinations of ouabain at third-instar stage + KCl + bifenthrin at fifth-instar stage. Caterpillar weight, diet consumption, frass, and survival were recorded for the duration of the experiments. It was observed that 1-3 mg ouabain/g diet increased body weight and diet consumption, whereas 50 mg KCl/g diet decreased body weight and diet consumption. Caterpillars feeding on KCl and treated with 0.2 µg/µl bifenthrin consumed significantly less diet compared to individuals provided untreated diet. However, there was no effect on survival or body weight. Combinations of KCl + ouabain did not significantly affect caterpillar survival or body weight following treatment with 0.1 µg/µl bifenthrin. At the concentrations tested, there were no effects observed for bifenthrin sensitivity with increasing cardenolide or KCl concentrations. Further studies are warranted to understand how milkweed-specific cardenolides, at increasing concentrations, and agrochemical inputs can affect monarch caterpillar physiology near agricultural landscapes.


Association of a Negative Wealth Shock With All-Cause Mortality in Middle-aged and Older Adults in the United States.
A sudden loss of wealth-a negative wealth shock-may lead to a significant mental health toll and also leave fewer monetary resources for health-related expenses. With limited years remaining to regain lost wealth in older age, the health consequences of these negative wealth shocks may be long-lasting. To determine whether a negative wealth shock was associated with all-cause mortality during 20 years of follow-up. The Health and Retirement Study, a nationally representative prospective cohort study of US adults aged 51 through 61 years at study entry. The study population included 8714 adults, first assessed for a negative wealth shock in 1994 and followed biennially through 2014 (the most recent year of available data). Experiencing a negative wealth shock, defined as a loss of 75% or more of total net worth over a 2-year period, or asset poverty, defined as 0 or negative total net worth at study entry. Mortality data were collected from the National Death Index and postmortem interviews with family members. Marginal structural survival methods were used to account for the potential bias due to changes in health status that may both trigger negative wealth shocks and act as the mechanism through which negative wealth shocks lead to increased mortality. There were 8714 participants in the study sample (mean [SD] age at study entry, 55 [3.2] years; 53% women), 2430 experienced a negative wealth shock during follow-up, 749 had asset poverty at baseline, and 5535 had continuously positive wealth without shock. A total of 2823 deaths occurred during 80 683 person-years of follow-up. There were 30.6 vs 64.9 deaths per 1000 person-years for those with continuously positive wealth vs negative wealth shock (adjusted hazard ratio [HR], 1.50; 95% CI, 1.36-1.67). There were 73.4 deaths per 1000 person-years for those with asset poverty at baseline (adjusted HR, 1.67; 95% CI, 1.44-1.94; compared with continuously positive wealth). Among US adults aged 51 years and older, loss of wealth over 2 years was associated with an increased risk of all-cause mortality. Further research is needed to better understand the possible mechanisms for this association and determine whether there is potential value for targeted interventions.


Clinical features in a series of fast channel congenital myasthenia syndrome.
Fast channel congenital myasthenic syndromes are rare, but frequently result in severe weakness. We report a case of 12 fast channel patients to highlight clinical features and management difficulties. Patients were diagnosed through genetic screening and identification of mutations shown to cause fast channel syndrome. Data was obtained from clinical notes, history, examination and follow up. Patterns of muscle weakness involved limb, trunk, bulbar, respiratory, facial and extraocular muscles. Patients responded to treatment with anticholinesterase medication and 3,4-diaminopyridine. Fast channel syndrome contrasted with AChR deficiency in the occurrence of severe respiratory crises in infancy and childhood. The death of two children even when on treatment and the family histories of sibling deaths re-inforces the need for accurate genetic diagnosis, optimised pharmacological treatment and additional supportive measures to manage acute respiratory crises. Referral to a specialist paediatric respiratory centre and regular resuscitation training for parents are recommended.


Special issue commentary: the changing face of inflammation in the brain.
The study of inflammation in the brain has been extended to include a wide range of conditions, but there remains plenty of argument over semantics and the precise definition of what constitutes inflammation in these pathologies. In this special issue, we sought to highlight the diversity of what is considered to be inflammation in the brain, and we have accepted that the presence of microglia cells with altered morphology remains a useful starting point. However, it is clear that whatever is the molecular expression profile that accompanies an activated microglial cell, it is not static and it is influenced by factors both intrinsic and extrinsic to the brain. This article is part of a Special Issue entitled 'Neuroinflammation in neurodegeneration and neurodysfunction'.


Hand-Exoskeleton Assisted Progressive Neurorehabilitation using Impedance Adaptation based Challenge Level Adjustment Method.
This paper presents an underactuated design of a robotic hand exoskeleton and a challenge based neurorehabilitation strategy. The exoskeleton is designed to reproduce natural human fingertip paths during extension and grasping, keeping minimal kinematic complexity. It facilitates an impedance adaptation based trigged assistance control strategy by a switching between active non-assist and passive assistance modes. In active non-assist mode, the exoskeleton motion follows the applied fingertip forces based on an impedance model. If the applied fingertip forces are inadequate, the passive assistance mode is triggered. The impedance parameters are updated at regular intervals based on the user performance, to implement a challenge based rehabilitation strategy. A six-week long hand therapy, conducted on four chronic stroke patients results in significant (p-value<0.05) increase in force generation capacity and decrease (p-value<0.05) in the required assistance. Also, there was a significant (p-value<0.05) increase in the system impedance parameters which adequately challenged the patients. The change in the Action-Research-Arm-Test (ARAT) scores from baseline are also found to be significant (p-value<0.05) and beyond the minimal clinically important difference (MCID) limit. Thus the results prove that the proposed control strategy with has the potential to be a clinically effective solution for personalized rehabilitation of poststroke hand functionality.


Short, medium, and long deferral of umbilical cord clamping compared with umbilical cord milking and immediate clamping at preterm birth: a systematic review and network meta-analysis with individual participant data.
Deferred (also known as delayed) cord clamping can improve survival of infants born preterm (before 37 weeks of gestation), but the optimal duration of deferral remains unclear. We conducted a systematic review and individual participant data network meta-analysis with the aim of comparing the effectiveness of umbilical cord clamping strategies with different timings of clamping or with cord milking for preterm infants. We searched medical databases and trial registries from inception until Feb 24, 2022 (updated June 6, 2023) for randomised controlled trials comparing cord clamping strategies for preterm infants. Individual participant data were harmonised and assessed for risk of bias and quality. Interventions were grouped into immediate clamping, short deferral (≥15 s to <45 s), medium deferral (≥45 s to <120 s), long deferral (≥120 s), and intact cord milking. The primary outcome was death before hospital discharge. We calculated one-stage, intention-to-treat Bayesian random-effects individual participant data network meta-analysis. This study was registered with PROSPERO, CRD42019136640. We included individual participant data from 47 trials with 6094 participants. Of all interventions, long deferral reduced death before discharge the most (compared with immediate clamping; odds ratio 0·31 [95% credibility interval] 0·11-0·80; moderate certainty). The risk of bias was low for 10 (33%) of 30 trials, 14 (47%) had some concerns, and 6 (20%) were rated as having a high risk of bias. Heterogeneity was low, with no indication of inconsistency. This study found that long deferral of clamping leads to reduced odds of death before discharge in preterm infants. In infants assessed as requiring immediate resuscitation, this finding might only be generalisable if there are provisions for such care with the cord intact. These results are based on thoroughly cleaned and checked individual participant data and can inform future guidelines and practice. Australian National Health and Medical Research Council.


Luminescent alkynyl-gold(I) coumarin derivatives and their biological activity.
The synthesis and characterization of three propynyloxycoumarins are reported in this work together with the formation of three different series of gold(i) organometallic complexes. Neutral complexes are constituted by water soluble phosphines (PTA and DAPTA) which confer water solubility to them. The X-ray crystal structure of 7-(prop-2-in-1-yloxy)-1-benzopyran-2-one and its corresponding dialkynyl complex is also shown and the formation of rectangular dimers for the gold derivative in the solid state can be observed. A detailed analysis of the absorption and emission spectra of both ligands and complexes allows us to attribute the luminescent behaviour to the coumarin organic ligand. Moreover, the presence of the gold(i) metal atom seems to be responsible for an increase of coumarin phosphorescence emission. The biological activity of the complexes showed that the anionic complexes triggered strong cytotoxic effects in two different cell lines whereas the neutral gold alkynyl complexes led to lower effects against tumor cell growth. Thioredoxin reductase (TrxR) inhibition was very strong in the case of the neutral complexes (IC50 values below 0.1 μM) but moderate for the anionic complexes (IC50 values above 0.8 μM).


Dynamically Driven Allostery in MHC Proteins: Peptide-Dependent Tuning of Class I MHC Global Flexibility.
T cell receptor (TCR) recognition of antigenic peptides bound and presented by class I major histocompatibility complex (MHC) proteins underlies the cytotoxic immune response to diseased cells. Crystallographic structures of TCR-peptide/MHC complexes have demonstrated how TCRs simultaneously interact with both the peptide and the MHC protein. However, it is increasingly recognized that, beyond serving as a static platform for peptide presentation, the physical properties of class I MHC proteins are tuned by different peptides in ways that are not always structurally visible. These include MHC protein motions, or dynamics, which are believed to influence interactions with a variety of MHC-binding proteins, including not only TCRs, but other activating and inhibitory receptors as well as components of the peptide loading machinery. Here, we investigated the mechanisms by which peptides tune the dynamics of the common class I MHC protein HLA-A2. By examining more than 50 lengthy molecular dynamics simulations of HLA-A2 presenting different peptides, we identified regions susceptible to dynamic tuning, including regions in the peptide binding domain as well as the distal α3 domain. Further analyses of the simulations illuminated mechanisms by which the influences of different peptides are communicated throughout the protein, and involve regions of the peptide binding groove, the β2-microglobulin subunit, and the α3 domain. Overall, our results demonstrate that the class I MHC protein is a highly tunable peptide sensor whose physical properties vary considerably with bound peptide. Our data provides insight into the underlying principles and suggest a role for dynamically driven allostery in the immunological function of MHC proteins.


High-efficiency third harmonic generation at 355nm based on La2CaB10O19.
La2CaB10O19 (LCB) crystals with size up to 55 × 35 × 25 mm3 have been grown by the top-seeded solution growth (TSSG) method. The refractive indices were accurately measured over the full transmission range, and the second-order nonlinear optical coefficients were determined by the Maker fringe technique. The phase-matching(PM) conditions were calculated for third-harmonic generation (THG) at different wavelengths. The THG experiments for type I and type II LCB crystals were performed. For type I LCB, a 355 nm UV light output of 5.0 mW corresponding to the conversion efficiency of 28.3% was generated under a picosecond Nd:YAG laser, and 16 W with the efficiency of 17.5% was generated under a nanosecond 1064 nm pumping source. For type II LCB, 3.5mW THG output with conversion efficiency of 21.1% was obtained under a picosecond Nd:YAG laser, and 7.6 W with the efficiency of 7.9% was generated under a nanosecond 1064 nm pumping source. The results indicated that the LCB crystal is a promising UV nonlinear optical material because of its good THG performance and nonhygroscopicity.


Hierarchical benchmark graphs for testing community detection algorithms.
Hierarchical organization is an important, prevalent characteristic of complex systems; to understand their organization, the study of the underlying (generally complex) networks that describe the interactions between their constituents plays a central role. Numerous previous works have shown that many real-world networks in social, biologic, and technical systems present hierarchical organization, often in the form of a hierarchy of community structures. Many artificial benchmark graphs have been proposed to test different community detection methods, but no benchmark has been developed to thoroughly test the detection of hierarchical community structures. In this study, we fill this vacancy by extending the Lancichinetti-Fortunato-Radicchi (LFR) ensemble of benchmark graphs, adopting the rule of constructing hierarchical networks proposed by Ravasz and Barabási. We employ this benchmark to test three of the most popular community detection algorithms and quantify their accuracy using the traditional mutual information and the recently introduced hierarchical mutual information. The results indicate that the Ravasz-Barabási-Lancichinetti-Fortunato-Radicchi (RB-LFR) benchmark generates a complex hierarchical structure constituting a challenging benchmark for the considered community detection methods.


Anti-Helicobacter pylori therapy in primary MALT lymphoma of rectum.
Primary rectal MALT lymphoma is a very rare entity among extranodal MALT lymphomas and its therapeutic management has not been standardized. Different approaches including surgery, chemotherapy and radiotherapy have been proposed in the last decades. There have been reports on complete responses after anti-Helicobacter pylori therapy, also in patients without serological or histological evidence of Helicobacter pylori infection. In our patient we obtained a complete response with anti-Helicobacter pylori therapy and a disease-free survival of 34 months. Endoscopic ultrasound was useful for diagnosis and follow-up. Although the mechanisms that determined this response remain a matter of debate, anti-Helicobacter pylori therapy can be considered as first-line therapy in stage IE, nonbulky primary rectal MALT lymphoma. Endoscopic ultrasound could play a relevant role in the management of this rare condition.


Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders.
Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. We show that KMTs and KDMs that are associated with, or are candidates for, dominant developmental disorders tend to have a higher level of transcription, longer canonical transcripts, more interactors, and a higher number and more types of post-translational modifications than other KMT and KDMs. We provide evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders. Whereas KMT2C or ASH1L haploinsufficiency results in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations cause an overgrowth syndrome with intellectual disability. We further expand the phenotypic spectrum of KMT2B-related disorders and show that some individuals can have severe developmental delay without dystonia at least until mid-childhood. Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly. Collectively, these results emphasize the significance of histone lysine methylation in normal human development and the importance of this process in human developmental disorders. Our results demonstrate that systematic clinically oriented pathway-based analysis of genomic data can accelerate the discovery of rare genetic disorders.


Neuroinvasive arboviral disease in the United States: 2003 to 2012.
To describe the epidemiologic and clinical syndromes associated with pediatric neuroinvasive arboviral infections among children in the United States from 2003 through 2012. We reviewed data reported by state health departments to ArboNET, the national arboviral surveillance system, for 2003 through 2012. Children (<18 years) with neuroinvasive arboviral infections (eg, meningitis, encephalitis, or acute flaccid paralysis) were included. Demographic, clinical syndrome, outcome, geographic, and temporal data were analyzed for all cases. During the study period, 1217 cases and 22 deaths due to pediatric neuroinvasive arboviral infection were reported from the 48 contiguous states. La Crosse virus (665 cases; 55%) and West Nile virus (505 cases; 41%) were the most common etiologies identified. Although less common, Eastern equine encephalitis virus (30 cases; 2%) resulted in 10 pediatric deaths. La Crosse virus primarily affected younger children, whereas West Nile virus was more common in older children and adolescents. West Nile virus disease cases occurred throughout the country, whereas La Crosse and the other arboviruses were more focally distributed. Neuroinvasive arboviral infections were an important cause of pediatric disease from 2003 through 2012. Differences in the epidemiology and clinical disease result from complex interactions among virus, vector, host, and the environment. Decreasing the morbidity and mortality from these agents depends on vector control, personal protection to reduce mosquito and tick bites, and blood donor screening. Effective surveillance is critical to inform clinicians and public health officials about the epidemiologic features of these diseases and to direct prevention efforts.


Chemical composition and anti-inflammatory activities of essential oil from Trachydium roylei.
Chemical composition, anti-inflammatory activity, and cytotoxicity of essential oils obtained from the aerial parts of Trachydium roylei were investigated in this study. The chemical composition of T. roylei essential oil was analyzed using gas chromatography mass spectrometry. Fifty-nine components, representing 98.87% of the oils, were characterized. The oils were predominated by aromatic compounds and monoterpene hydrocarbons, and the main components were myristicin (25.35%), β-phellandrene (22.95%), elemicine (7.69%), isoelemicin (5.48%), and cedrol (5.26%). The anti-inflammatory activity of the oil in lipopolysaccharide-stimulated murine RAW 264.7 cells was evaluated. The oils downregulated the production of proinflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, and significantly increased the anti-inflammatory cytokine IL-10 levels. Results indicated that the oils effectively inhibited the secretion of nitric oxide and prostaglandin E2 in lipopolysaccharide-stimulated macrophages. Western blot analyses were performed to determine whether the inhibitory effects of the oils on proinflammatory mediators (nitric oxide and prostaglandin E2) were related to the modulation of inducible nitric oxide synthase and cyclooxygenase-2 expression. These findings suggest that T. roylei essential oils exert an anti-inflammatory effect by regulating the expression of inflammatory cytokines.


Negative Consequences of Family Caregiving for Veterans With PTSD and Dementia.
Recent research shows veterans with posttraumatic stress disorder (PTSD) are twice as likely as other veterans to develop dementia. However, no studies to date have examined the impact of co-existing PTSD and dementia on family caregivers, who provide the majority of care to these veterans. Using the Stress Process Model, the current investigation explored the similarities and differences in psychosocial, health, and service use outcomes among caregivers assisting veterans with PTSD and dementia compared with caregivers assisting veterans with dementia only. Caregivers of veterans with PTSD and dementia indicated that their relative exhibited more difficult behavior symptoms and used more community services. These caregivers also reported more difficulties understanding veterans' memory problems and more physical strain. Together, results suggested caregivers of veterans with both PTSD and dementia were at greater risk of negative caregiving consequences. Implications and suggestions for future research are discussed.


Developing seasonal ammonia emission estimates with an inverse modeling technique.
Significant uncertainty exists in magnitude and variability of ammonia (NH3) emissions, which are needed for air quality modeling of aerosols and deposition of nitrogen compounds. Approximately 85% of NH3 emissions are estimated to come from agricultural nonpoint sources. We suspect a strong seasonal pattern in NH 3 emissions; however, current NH3 emission inventories lack intra-annual variability. Annually averaged NH 3 emissions could significantly affect model-predicted concentrations and wet and dry deposition of nitrogen-containing compounds. We apply a Kalman filter inverse modeling technique to deduce monthly NH3 emissions for the eastern U.S. Final products of this research will include monthly emissions estimates from each season. Results for January and June 1990 are currently available and are presented here. The U.S. Environmental Protection Agency (USEPA) Community Multiscale Air Quality (CMAQ) model and ammonium (NH4+) wet concentration data from the National Atmospheric Deposition Program (NADP) network are used. The inverse modeling technique estimates the emission adjustments that provide optimal modeled results with respect to wet NH4+ concentrations, observational data error, and emission uncertainty. Our results suggest that annual average NH 3 emissions estimates should be decreased by 64% for January 1990 and increased by 25% for June 1990. These results illustrate the strong differences that are anticipated for NH3 emissions.


Precompetitive achievement goals, stress appraisals, emotions, and coping among athletes.
Grounded in Lazarus's (1991, 1999, 2000) cognitive-motivational-relational theory of emotions, we tested a model of achievement goals, stress appraisals, emotions, and coping. We predicted that precompetitive achievement goals would be associated with appraisals, appraisals with emotions, and emotions with coping in our model. The mediating effects of emotions among the overall sample of 827 athletes and two stratified random subsamples were also explored. The results of this study support our proposed model in the overall sample and the stratified subsamples. Further, emotion mediated the relationship between appraisal and coping. Mediation analyses revealed that there were indirect effects of pleasant and unpleasant emotions, which indicates the importance of examining multiple emotions to reveal a more accurate representation of the overall stress process. Our findings indicate that both appraisals and emotions are just as important in shaping coping.


Analysis of thyme essential oils using gas-phase broadband rotational spectroscopy.
A semi-quantitative analysis of the components of two natural essential oils has been carried out using broadband rotational spectroscopy, which is inherently molecule specific. The samples under study were two thyme essential oils from Spain with different compositions: (a) with thymol as the most abundant species (thyme I) and (b) with linalool and 4-carvomenthenol being the most abundant ones (thyme II). Relative intensity measurements of selected rotational transitions were carried out to estimate the abundances of the different species present in these complex mixtures, taking into account the square of the respective dipole moment components. One strength of rotational spectroscopy is its structure sensitivity. Here, we also re-investigated the microwave spectrum of linalool and determined the accurate experimental gas-phase structures of thymol and linalool through the assignment of all 13C isotopologues of their lowest energy conformers. A characteristic splitting pattern of the rotational transitions due to internal rotation of two non-equivalent methyl groups of linalool was observed in the thyme II spectrum. Their internal rotation barriers were experimentally determined to 4.7703(96) kJ mol-1 and 9.2581(74) kJ mol-1, respectively.


Impact of PEG additives and pore rim functionalization on water transport through sub-1 nm carbon nanotube porins.
Carbon nanotubes represent one of the most interesting examples of a nanofluidic channel that combines extremely small diameters with atomically smooth walls and well-defined chemical functionalities at the pore entrance. In the past, sub-1 nm diameter carbon nanotube porins (CNTPs) embedded in a lipid membrane matrix demonstrated extremely high water permeabilities and strong ion selectivities. In this work, we explore additional factors that can influence transport in these channels. Specifically, we use stopped-flow transport measurements to focus on the effect of chemical modifications of the CNT rims and chaotropic polyethyleneglycol (PEG) additives on CNTP water permeability and Arrhenius activation energy barriers for water transport. We show that PEG, especially in its more chaotropic coiled configuration, enhances the water transport and reduces the associated activation energy. Removal of the static charges on the CNTP rim by converting -COOH groups to neutral methylamide groups also reduces the activation energy barriers and enhances water transport rates.


Abh and AbrB control of Bacillus subtilis antimicrobial gene expression.
The Bacillus subtilis abh gene encodes a protein whose N-terminal domain has 74% identity to the DNA-binding domain of the global regulatory protein AbrB. Strains with a mutation in abh showed alterations in the production of antimicrobial compounds directed against some other Bacillus species and gram-positive microbes. Relative to its wild-type parental strain, the abh mutant was found deficient, enhanced, or unaffected for the production of antimicrobial activity. Using lacZ fusions, we examined the effects of abh upon the expression of 10 promoters known to be regulated by AbrB, including five that transcribe well-characterized antimicrobial functions (SdpC, SkfA, TasA, sublancin, and subtilosin). For an otherwise wild-type background, the results show that Abh plays a negative regulatory role in the expression of four of the promoters, a positive role for the expression of three, and no apparent regulatory role in the expression of the other three promoters. Binding of AbrB and Abh to the promoter regions was examined using DNase I footprinting, and the results revealed significant differences. The transcription of abh is not autoregulated, but it is subject to a degree of AbrB-afforded negative regulation. The results indicate that Abh is part of the complex interconnected regulatory system that controls gene expression during the transition from active growth to stationary phase.


Pembrolizumab in Relapsed or Refractory Primary Mediastinal Large B-Cell Lymphoma.
Patients with relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL) have a poor prognosis, and their treatment represents an urgent and unmet need. Because PMBCL is associated with genetic aberrations at 9p24 and overexpression of programmed cell death-1 (PD-1) ligands (PD-L1), it is hypothesized to be susceptible to PD-1 blockade. In the phase IB KEYNOTE-013 (ClinicalTrials.gov identifier: NCT01953692) and phase II KEYNOTE-170 (ClinicalTrials.gov identifier: NCT02576990) studies, adults with rrPMBCL received pembrolizumab for up to 2 years or until disease progression or unacceptable toxicity. The primary end points were safety and objective response rate in KEYNOTE-013 and objective response rate in KEYNOTE-170. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Exploratory end points included association between biomarkers and pembrolizumab activity. The objective response rate was 48% (7 complete responses; 33%) among 21 patients in KEYNOTE-013 and 45% (7 complete responses; 13%) among 53 patients in KEYNOTE-170. After a median follow-up time of 29.1 months in KEYNOTE-013 and 12.5 months in KEYNOTE-170, the median duration of response was not reached in either study. No patient with complete response experienced progression, including 2 patients with complete response for at least 1 year off therapy. Treatment-related adverse events occurred in 24% of patients in KEYNOTE-013 and 23% of patients in KEYNOTE-170. There were no treatment-related deaths. Among 42 evaluable patients, the magnitude of the 9p24 gene abnormality was associated with PD-L1 expression, which was itself significantly associated with progression-free survival. Pembrolizumab is associated with high response rate, durable activity, and a manageable safety profile in patients with rrPMBCL.


Reversible Inhibitors Arrest ClpP in a Defined Conformational State that Can Be Revoked by ClpX Association.
Caseinolytic protease P (ClpP) is an important regulator of Staphylococcus aureus pathogenesis. A high-throughput screening for inhibitors of ClpP peptidase activity led to the identification of the first non-covalent binder for this enzyme class. Co-crystallization of the small molecule with S. aureus ClpP revealed a novel binding mode: Because of the rotation of the conserved residue proline 125, ClpP is locked in a defined conformational state, which results in distortion of the catalytic triad and inhibition of the peptidase activity. Based on these structural insights, the molecule was optimized by rational design and virtual screening, resulting in derivatives exceeding the potency of previous ClpP inhibitors. Strikingly, the conformational lock is overturned by binding of ClpX, an associated chaperone that enables proteolysis by substrate unfolding in the ClpXP complex. Thus, regulation of inhibitor binding by associated chaperones is an unexpected mechanism important for ClpP drug development.


Is childhood stress associated with shorter telomeres?
It has been shown that severe stress in childhood is harmful to later health. New research aims to ascertain whether – and if so, how – the telomeres, the protective caps at the end of our chromosomes, may be one of the links between this type of experience and later morbidity. Here we present an overview of studies which have examined the association between stress in childhood and length of telomeres. The review encompasses 26 original studies found through a literature search in PubMed. We included studies of the relationship between length of telomeres and various stress-inducing factors from conception throughout childhood and adolescence. The studies were grouped into four topics. The empirical research base for mother's stress in pregnancy and parents' ability to care for their children is too small to draw any conclusions. Psychosocial stress in childhood was associated with shorter telomere length in 12 of 14 studies. Socioeconomic status in childhood was not unequivocally associated with telomere length. Shorter telomeres are possibly associated with psychosocial stress in childhood. This field of research is still new, and more longitudinal studies are needed with an emphasis on childhood experiences and coordination of measurement variables and results measurement in order to confirm this association.


Diversity and genetic structure of the native Brazil nut tree (Bertholletia excelsa Bonpl.) population.
The present study was carried out in a native Brazil nut tree population (Bertholletia excelsa Bonpl., Lecythidaceae) to assess its genetic diversity and structure. Ten microsatellite markers were used to genotype 198 adult trees (B. excelsa). The population presented high genetic diversity and inbreeding absence rates. The empirical Bayesian method showed three distinct groups in the structure of this population. Molecular analysis of variance showed 98% variability within groups, and 2% between groups. The genetic divergence (FST) indicated little difference between groups; thus, suggesting efficient gene flow between the analyzed B. excelsa adult trees.


Lifetime prevalence, associated factors, and circumstances of non-volitional sex in women and men in Britain: findings from the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3).
Sexual violence is increasingly recognised as a public health issue. Information about prevalence, associated factors, and consequences for health in the population of Britain (England, Scotland, and Wales) is scarce. The third National Survey of Sexual Health Attitudes and Lifestyles (Natsal-3) is the first of the Natsal surveys to include questions about sexual violence and the first population-based survey in Britain to explore the issue outside the context of crime. Between Sept 6, 2010, and Aug 31, 2012, we did a probability sample survey of women and men aged 16-74 years living in Britain. We asked participants about their experience of sex against their will since age 13 years and the circumstances surrounding the most recent occurrence. We explored associations between ever experiencing non-volitional sex and a range of sociodemographic, health, and behavioural factors. We used logistic regression to estimate age-adjusted odds ratios to analyse factors associated with the occurrence of completed non-volitional sex in women and men. We interviewed 15,162 people. Completed non-volitional sex was reported by 9·8% (95% CI 9·0-10·5) of women and 1·4% (1·1-1·7) of men. Median age (interdecile range) at most recent occurrence was 18 years (14-32) for women and 16 years (13-30) for men. Completed non-volitional sex varied by family structure and, in women, by age, education, and area-level deprivation. It was associated with poor health, longstanding illness or disability, and treatment for mental health conditions, smoking, and use of non-prescription drugs in the past year in both sexes, and with binge drinking in women. Completed non-volitional sex was also associated with reporting of first heterosexual intercourse before 16 years of age, same-sex experience, more lifetime sexual partners, ever being diagnosed with a sexually transmitted infection, and low sexual function in both sexes, and, in women, with abortion and pregnancy outcome before 18 years of age. In most cases, the person responsible was known to the individual, although the nature of the relationship differed by age at most recent occurrence. Participants who were younger at interview were more likely to have told someone about the event and to have reported it to the police than were older participants. These data provide the first population prevalence estimates of non-volitional sex in Britain. We showed it to be mainly an experience of young age and strongly associated with a range of adverse health outcomes in both women and men. Grants from the UK Medical Research Council and the Wellcome Trust, with support from the Economic and Social Research Council and the Department of Health.


Class action litigation in correctional psychiatry.
Class action litigation has been instrumental in jail and prison reform during the past two decades. Correctional mental health systems have significantly benefited from such litigation. Forensic psychiatrists have been crucial in the litigation process and the subsequent evolution of correctional mental health care systems. This article summarizes information concerning basic demographics of correctional populations and costs of correctional health care and provides a brief history of such litigation. The role of psychiatric experts, with particular reference to standards of care, is described. Specifically discussed are issues relevant to suicide prevention, the prevalence of mentally ill inmates in supermax prisons, and discharge planning.