Multiple microfermentor battery: a versatile tool for use with automated parallel cultures of microorganisms producing recombinant proteins and for optimization of cultivation protocols.
A multiple microfermentor battery was designed for high-throughput recombinant protein production in Escherichia coli. This novel system comprises eight aerated glass reactors with a working volume of 80 ml and a moving external optical sensor for measuring optical densities at 600 nm (OD600) ranging from 0.05 to 100 online. Each reactor can be fitted with miniature probes to monitor temperature, dissolved oxygen (DO), and pH. Independent temperature regulation for each vessel is obtained with heating/cooling Peltier devices. Data from pH, DO, and turbidity sensors are collected on a FieldPoint (National Instruments) I/O interface and are processed and recorded by a LabVIEW program on a personal computer, which enables feedback control of the culture parameters. A high-density medium formulation was designed, which enabled us to grow E. coli to OD600 up to 100 in batch cultures with oxygen-enriched aeration. Accordingly, the biomass and the amount of recombinant protein produced in a 70-ml culture were at least equivalent to the biomass and the amount of recombinant protein obtained in a Fernbach flask with 1 liter of conventional medium. Thus, the microfermentor battery appears to be well suited for automated parallel cultures and process optimization, such as that needed for structural genomics projects.


Total synthesis of (+/-)-mersicarpine.
The first total synthesis of the indole alkaloid mersicarpine is reported. Key steps include a beta-dicarbonyl radical cyclization, as well as an oxidation of the benzopyrrole moiety to establish the masked 1,2-dicarbonyl functionality. An X-ray crystal structure and discussion of the 1H NMR behavior of the natural product are also presented.


Double-stranded RNA and Toll-like receptor activation: a novel mechanism for blood pressure regulation.
Toll-like receptors (TLRs), such as TLR4 and 9, recognize pathogen-associated molecular pattern (PAMPs) and danger-associated molecular patterns (DAMPs) and are associated with increased blood pressure (BP). TLR3, residing in the endosomal compartment, is activated by viral double-stranded RNA (dsRNA) leading to activation of TIR receptor domain-containing adaptor inducing IFN-β (TRIF) dependent pathway. Besides foreign pathogens, the immune system responds to endogenous markers of cellular damage such as mitochondrial dsRNA (mtdsRNA). New evidence has shown a link between dsRNA and increased BP. Moreover, TLR3 activation during pregnancy was demonstrated to develop preeclampsia-like symptoms in both rats and mice. Hence, we hypothesize that the dsRNA derived from viral nucleic acids or cellular damage (mtdsRNA) will increase the inflammatory state through activation of TLR3, contributing to vascular dysfunction and increased BP. Therefore, inhibition of TLR3 could be a therapeutic target for the treatment of hypertension with potential improvement in vascular reactivity and consequently, a decrease in BP.


Trauma and dissociation in psychiatric outpatients.
We investigated the prevalence of exposure to traumatic events, the prevalence of post-traumatic suffering and dissociative symptoms, and the relationship between type of trauma and dissociation in a large sample of outpatient adults (ages 18-65) seeking treatment at an urban ambulatory mental health clinic in Jerusalem (N = 298). Study participants completed self-report measures regarding trauma history, post-traumatic symptoms of intrusion and avoidance phenomena, and both psychological and somatic dissociative phenomena. 98% of our sample reported experiencing at least one lifetime traumatic event, 83% of subjects who completed the Impact of Events Scale reported high levels of intrusion and avoidance symptoms, and 15% of the sample reported high levels of dissociative phenomena. Elevated dissociation was associated with physical and sexual abuse, particularly early childhood abuse, as well as increased prevalence of lifetime traumatic events. Diagnoses did not reflect the high levels of post-traumatic and dissociative symptoms. Our findings indicate the need for increased awareness and improved screening of traumatic exposure and its psychological impact upon psychiatric outpatients.


Healing potential of Anogeissus latifolia for dermal wounds in rats.
Wound healing potential of ethanolic extract of Anogeissus latifolia bark (ALE) for treatment of dermal wounds in rats was studied on excision and incision wound models. HPTLC of the total extract was recorded for the purpose of standardization. Various parameters of incision wound, viz. epithelization period, scar area, tensile strength and hydroxyproline measurements along with wound contraction, were used to evaluate the effect of A. latifolia on wound healing. The results obtained indicate that A. latifolia accelerates the wound healing process by decreasing the surface area of the wound and increasing the tensile strength. Nitrofurazone ointment was used as a positive control. Complete epithelization was observed within 15 days with ALE. Measurements of the healed area and the hydroxyproline level were in agreement. Antibacterial activity of ALE was studied against Gram-positive (Staphylococcus aureus) and Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae) compared to erythromycin and tetracycline. Moderate activity was observed against all organisms. The present study provides a scientific rationale for the traditional use of Anogeissus latifolia in the management of skin diseases such as sores, boils and itching.


Immunohistochemical detection of K-sam protein in stomach cancer.
The K-sam gene, originally isolated as an amplified gene from the stomach cancer cell line KATO-III, is characterized by its preferential amplification in the undifferentiated type (diffuse type) of stomach cancer and encodes one of the receptors for heparin-binding growth factors or fibroblast growth factors. The K-sam gene has been isolated by different methods and has been designated BEK, TK14, and Cek2. The receptor for keratinocyte growth factor was also found to be encoded by the same gene. To examine the expression of the K-sam protein in stomach cancer, polyclonal antibody pK1-2 was raised against the extracellular domain of the gene product. This antibody detected K-sam proteins by Western blot and flow cytometry analyses in stomach cancer cell lines KATO-III and HSC39, in which the K-sam gene is amplified and overexpressed. By immunohistochemical analysis, 20 of 38 cases of the undifferentiated type of advanced stomach cancer were K-sam positive, whereas none of 11 cases of the differentiated or intestinal type revealed K-sam staining. The K-sam product was observed predominantly in diffusely infiltrative lesions. In one autopsy case, the K-sam protein was detected only focally in the primary tumor, whereas markedly increased staining for the K-sam product was detected diffusely in the metastasized tumor in the lymph node and liver. These results suggest that K-sam overexpression is associated with the malignant phenotype of the undifferentiated type of stomach cancer, such as infiltrative growth and metastasis.


Valsartan in early-stage hypertrophic cardiomyopathy: a randomized phase 2 trial.
Hypertrophic cardiomyopathy (HCM) is often caused by pathogenic variants in sarcomeric genes and characterized by left ventricular (LV) hypertrophy, myocardial fibrosis and increased risk of heart failure and arrhythmias. There are no existing therapies to modify disease progression. In this study, we conducted a multi-center, double-blind, placebo-controlled phase 2 clinical trial to assess the safety and efficacy of the angiotensin II receptor blocker valsartan in attenuating disease evolution in early HCM. In total, 178 participants with early-stage sarcomeric HCM were randomized (1:1) to receive valsartan (320 mg daily in adults; 80-160 mg daily in children) or placebo for 2 years ( NCT01912534 ). Standardized changes from baseline to year 2 in LV wall thickness, mass and volumes; left atrial volume; tissue Doppler diastolic and systolic velocities; and serum levels of high-sensitivity troponin T and N-terminal pro-B-type natriuretic protein were integrated into a single composite z-score as the primary outcome. Valsartan (n = 88) improved cardiac structure and function compared to placebo (n = 90), as reflected by an increase in the composite z-score (between-group difference +0.231, 95% confidence interval (+0.098, +0.364); P = 0.001), which met the primary endpoint of the study. Treatment was well-tolerated. These results indicate a key opportunity to attenuate disease progression in early-stage sarcomeric HCM with an accessible and safe medication.


Translating research evidence into practice: a report from the 2nd International Conference on Maternal and Newborn Health from KLE University - Belagavi, India.
The Jawaharlal Nehru Medical College (JNMC) Women's and Children's Health Research Unit (WCHRU) of the Karnataka Lingayat Education (KLE) Academy of Higher Education and Research Deemed-to-be-University and its collaborators convened the '2nd International Conference on Maternal and Newborn Health -Translating Research Evidence to Practice' to address the common theme of improving maternal and newborn health in low- and middle- income countries (LMIC). This supplement, including 16 manuscripts, reflects much of the research presented at the conference, including analyses of the state of knowledge, as well as completed, ongoing and planned research in these areas conducted by the WCHRU in India together with many collaborators across high-income and LMIC. The first paper reviews maternal, fetal and neonatal mortality in low-income countries, considers their causes, as well as evidence for potential interventions to reduce mortality. A second paper addresses near miss maternal mortality. Several manuscripts address the research conducted by WCHRU and their colleagues in a multi-center research network. One study examines rates of miscarriage and medically terminated pregnancy in India and the risk factors for these occurrences. Another paper addresses stillbirth and its risk factors, both in India as well as in other LMIC. Haemorrhage and preeclampsia/eclampsia, important causes of maternal mortality, stillbirth and neonatal morbidity in LMIC, are addressed in a series of papers summarizing trials of interventions to reduce improve outcomes associated with these conditions. Poor maternal and infant nutritional status, which contribute to adverse outcomes, are addressed through papers which describe a number of important studies that the WCHRU and their colleagues have conducted to attempt to improve nutritional status. Another paper describes a study to investigate causes of stillbirth and deaths among preterm births, which will utilize new techniques to investigate the infectious causes of these deaths. Finally, the supplement addresses the process for dissemination of research results to inform public policy. Together these manuscripts represent a body of research to inform interventions to reduce maternal, fetal and newborn mortality and illustrates what a dedicated research group together with institutional support can accomplish.


Ba++ on the resting frog stomach: effects on electrical and secretory parameters.
Ba++ added to the nutrient solution bathing the resting frog stomach increased resistance, decreased the PD, and stimulated acid secretion. Under short-circuit conditions, the increase in H+-secretory rate was accompanied by a decrease in short-circuit current (I-sc). These changes were reversed by NaSCN (10 mM), suggesting that Ba++ had not impaired the current-generating mechanism per se. Histamine-induced acid secretion was associated with an increase in net Cl- flux, particularly in the N yields S flux (JNS). Ba++ increased acid secretion with no increase in JNS and a decrease in net Cl- flux. The effects of Ba++ were amplified by low-Cl- solutions. Histamine, in the presence of Ba++ and low-Cl- solutions, increased acid secretion and transmucosal resistance, suggesting the operation of a neutral pump in the secretion of HCl. It is concluded that Ba++ limits Cl- entry and also acts as a secretagogue.


Stereotactic radiosurgery of the brain: a review of common indications.
Over the past half-century since Lars Leksell first utilized radiation to address deep and difficult to treat lesions of the central nervous system (CNS), intracranial stereotactic radiosurgery (SRS) has become an increasingly valued tool in the hands of neurosurgeons and radiation oncologists. Following developments in medical imaging and radiation technology, radiosurgery has evolved from its first application in movement disorders to widespread use for a varied range of malignant and benign conditions. SRS remains a powerful, minimally invasive instrument that offers additional options for intervention to a diverse patient population. In this review, we will touch upon the common indications for SRS, including its use in brain metastases, malignant gliomas, meningiomas, arteriovenous malformations (AVMs), vestibular schwannomas, pituitary adenomas, and functional disorders, as well as consider the future possibilities of combining radiosurgery with immunotherapy.


Impact of treatment and socioeconomic status on racial disparities in survival among older women with breast cancer.
To examine racial/ethnic disparities in mortality and survival in a large nationwide and population-based cohort of women with breast cancer after simultaneously controlling for differences in comorbidity, treatment, and socioeconomic status. A cohort of 35,029 women with stage I-IIIA breast cancer at age > or = 65 from 1992 to 1999 was identified from the surveillance, epidemiology, and end results-medicare linked databases with up to 11 years of follow-up. Cox proportional hazard regression analysis was performed to determine the risk of all-cause and breast cancer-specific mortality. African-American women with breast cancer were more likely to live in the poorest quartiles of socioeconomic status at the census tract level than whites (73.7% versus 20.7%, P < 0.001). Those living in communities with the lowest socioeconomic status were 11% more likely to die than those in the highest (hazard ratio, 1.10; 95% confidence interval, 1.04-1.16). The risk of dying changed slightly after controlling for race/ethnicity (1.11; 1.05-1.18). Compared with white women with breast cancer, crude hazard ratios of all-cause and breast cancer-specific mortality were 1.35 (1.27-1.45) and 1.83 (1.56-2.16) for African-Americans. After adjusting for treatment and socioeconomic status, hazard ratio of all-cause mortality was no longer significant in African-Americans (1.02; 0.84-1.10), whereas the risk of breast cancer-specific mortality was marginally higher in African-Americans (1.21; 1.01-1.46). Racial disparities in overall survival between African-American and white women with breast cancer were not present after controlling for treatment and socioeconomic status. Efforts to eliminate these barriers have important public health implications for reducing disparities in health outcomes.


Increased susceptibility to measles in infants in the United States.
Women born in the United States after measles vaccine licensure in 1963 transfer less measles antibody to their infants than do older women. This may result in increased susceptibility to measles among infants. To determine the effect of maternal year of birth on the risk for measles in infants. We enrolled 128 unvaccinated infants </=15 months of age who had documented exposure to measles from 1990 through 1992 in a retrospective cohort study. We interviewed their mothers by telephone to obtain demographic data, medical and vaccination history, and details of measles exposure and outcome. We used logistic regression analysis to estimate the effect of maternal year of birth. Infants whose mothers were born after 1963 had a measles attack rate of 33%, compared with 12% for infants of older mothers. In logistic regression analysis, the adjusted odds ratio for maternal year of birth (born after 1963) was 7.5 (95% confidence interval 1.8, 30.6). Other significant risk factors were older infant age, mothers who developed measles after delivery, and exposure within 2 days of the rash onset of the exposing case. Infants whose mothers were born after 1963 are more susceptible to measles than are infants of older mothers. An increasing proportion of infants born in the United States may be susceptible to measles. Infants at high risk of exposure to measles should be vaccinated at 12 months of age. Vaccination programs that reduce transmission of the measles virus in the general population reduce the risk of infant exposure to measles.


Oseltamivir for influenza postexposure prophylaxis: economic evaluation for children aged 1-12 years in the U.S.
Postexposure prophylaxis (PEP) with oseltamivir (Tamiflu) has been shown to be effective and is approved in children exposed to a case of influenza in a household setting. Given limited healthcare budgets, it is important to understand the costs and cost effectiveness of PEP in children. This study aims to estimate the cost effectiveness of oseltamivir PEP for children aged 1-12 years in the U.S. A decision-tree model with a 1-year time horizon was used to assess the cost effectiveness of oseltamivir PEP for 10 days at approved doses compared with no prophylaxis for children aged 1-12 years who were exposed to a household index case of influenza from the U.S. societal and payer perspectives. Model inputs included U.S. influenza epidemiology data, efficacy data from oseltamivir PEP clinical trials, direct medical resource use and costs for PEP and influenza treatment derived from large U.S. databases, and indirect costs based on caregiver lost productivity. Base-case estimates were tested in extensive sensitivity analyses. For the societal perspective, the model estimated 12,184 fewer cases of influenza per 100,000 children exposed and an incremental cost-effectiveness ratio of $41,452 per quality-adjusted life-year (QALY) gained. Results were most sensitive to the influenza attack rate, PEP protective efficacy, and prescribing patterns for initiating PEP. Probabilistic sensitivity analyses showed that oseltamivir PEP was likely to be cost effective for all willingness-to-pay threshold values above $34,300 per QALY gained. Results were similar for the payer perspective. Although there is no official cost-effectiveness threshold in the U.S., results from the current study show that when compared with no prophylaxis, oseltamivir PEP for children has cost-effectiveness ratios similar to those of vaccines for preventing influenza.


Comparative study of four Mystus species (Bagridae, Siluriformes) from Thailand: insights into their karyotypic diversity.
Karyotypes of four catfishes of the genus Mystus Scopoli, 1777 (family Bagridae), M. atrifasciatus Fowler, 1937, M. mysticetus Roberts, 1992, M. singaringan (Bleeker, 1846) and M. wolffii (Bleeker, 1851), were analysed by conventional and Ag-NOR banding as well as fluorescence in situ hybridization (FISH) techniques. Microsatellite d(GC)15, d(CAA)10, d(CAT)10 and d(GAA)10 repeat probes were applied in FISH. The obtained data revealed that the four studied species have different chromosome complements. The diploid chromosome numbers (2n) and the fundamental numbers (NF) range between 52 and 102, 54 and 104, 56 and 98, or 58 and 108 in M. mysticetus, M. atrifasciatus, M. singaringan or M. wolffii, respectively. Karyotype formulae of M. mysticetus, M. atrifasciatus, M. singaringan and M. wolffii are 24m+26sm+4a, 26m+24sm+2a, 24m+18sm+14a and 30m+22sm+6a, respectively. A single pair of NORs was identified adjacent to the telomeres of the short arm of chromosome pairs 3 (metacentric) in M. atrifasciatus, 20 (submetacentric) in M. mysticetus, 15 (submetacentric) in M. singaringan, and 5 (metacentric) in M. wolffii. The d(GC)15, d(CAA)10, d(CAT)10 and d(GAA)10 repeats were abundantly distributed in species-specific patterns. Overall, we present a comparison of cytogenetic and molecular cytogenetic patterns of four species from genus Mystus providing insights into their karyotype diversity in the genus.


Association between intracytoplasmic sperm injection and neurodevelopmental outcomes among offspring.
To compare the risk of neurodevelopmental disorders in children conceived via intracytoplasmic sperm injection (ICSI) and those conceived naturally. A population-based cohort study using data retrieved from the Taipei Medical University Research Database (TMURD) from January, 2004 to August, 2016. The data included maternal pregnancy history, perinatal history and developmental follow up of their babies up to 5 years of age. The study included 23885 children, of whom 23148 were naturally conceived and 737 were conceived via ICSI. Neurodevelopmental disorders defined by 21 ICD-9-CM codes. Of the 23885 children enrolled for analysis, 2778 children were included for further subgrouping analysis after propensity matching to reduce bias from maternal factors. The single-birth group included 1752 naturally conceived (NC) children and 438 ICSI children. The multiple-birth group included 294 NC and 294 ICSI children. The risk of neurodevelopmental disorders was not increased for ICSI children in both groups (single birth: adjusted hazard ratio aHR = 0.70, 95% CI = 0.39-1.27, p = 0.243; multiple-birth group aHR = 0.77, 95% CI = 0.43-1.35, p = 0.853). In the single-birth group, multivariate analyses showed that male sex (aHR = 1.81, 95% CI = 1.29-2.54, p < 0.001), and intensive care unit (ICU) admission (aHR = 3.10, 95% CI = 1.64-5.86, p < 0.001) were risk factors for neurodevelopmental disorders. In the multiple-birth group, multivariate analyses demonstrated that ICU admission (aHR = 3.58, 95% CI = 1.82-7.04, p < 0.001), was risk factor for neurodevelopmental disorders. Our study indicated that the use of ICSI does not associated with higher risk of neurodevelopmental disorders in the offspring. But male sex, and ICU admission do have increased risk of neurodevelopmental disorders. However, long term follow up of this cohort on health outcomes in adolescence and adulthood will strengthen the conclusions that ICSI is safe regarding offspring long term outcome.


Cytomegalovirus PP65 antigenemia monitoring as a guide for preemptive therapy: a cost effective strategy for prevention of cytomegalovirus disease in adult liver transplant recipients.
The aim of the study was to assess the incidence of cytomegalovirus (CMV) infection and disease in adult liver transplant recipients, using routine preemptive therapy guided by the pp65 antigenemia test. Antigenemia was monitored weekly after liver transplantation (OLTX) for the first 3 months, and once a month for another 3 months. CMV seronegative recipients were treated preemptively for the first positive antigenemia. Seropositive recipients were treated only when their antigenemia count reached a threshold of > or =100 positive cells per 200,000 leukocytes. A total of 144 patients were included between June 1994 and April 1995, of which 137 (95%) were primary OLTX. The percentage of positive antigenemia and CMV disease was 55 and 8%, respectively. Seventy-eight (54%) patients were protocol-monitored for the entire follow-up (group 1) and received appropriate preemptive therapy, although 66 (46%) patients had protocol violation by having missed blood samples or blood drawn at unscheduled times (group 2). Using Cox's proportional hazards model, patients with a first antigenemia count of >11 leukocytes had a significantly higher rate of CMV disease compared to patients with an antigenemia count < or =11 leukocytes (RR = 7.3, 95% confidence interval = 2.2 to 24.5). In a multivariate Cox regression analysis, adjustments were made to control for: group 1 versus group 2, use of OKT3, and serology risk categories. This analysis showed that the relative rate of CMV disease was still significantly higher among patients with antigenemia count >11 leukocytes (adjusted RR = 4.9, 95% confidence interval = 1.3 to 18.1). The estimated cost of preemptive therapy was less than that of prophylaxis with i.v. (14-day course) or oral (90-day course) ganciclovir. Preemptive therapy guided by pp65 antigenemia is a useful and cost effective strategy for prevention of CMV disease.


Safer Housing for Homeless Women Veterans.
Homeless women veterans face unique vulnerability and significant mental health needs; it is important for their housing to include gender-specific safety measures. Providers of supportive housing for veterans can take important steps to accommodate the women they serve, including providing separate housing facilities or areas for women. More than half of all homeless women veterans were sexually assaulted during their military service, and many exhibit mental health disabilities as a result, which provides a strong legal basis for requiring gender-based accommodations. While significant progress has been made in addressing the needs of veterans who were sexually assaulted during their military service, the unique needs of homeless women veterans are still often overlooked. This oversight has consequences, particularly in the permanent supportive housing context, where male veterans significantly outnumber female veterans. Currently, there are no required minimum standards or safeguards for serving women veterans in these facilities, and most facilities provide no appropriate gender-specific accommodations. This failure persists despite the significant prior history of sexual assaults among this population and their extremely small number in veteran-only housing. Without basic gender-specific safeguards, permanent supportive housing facilities could worsen the mental health of homeless women veterans and expose them to further harm.


Effect of cerebroventricular anterior pituitary grafts on in situ expression of tyrosine hydroxylase in dopaminergic neurons of the aged animal.
The effect of cerebroventricular anterior pituitary (AP) grafts on brain tyrosine hydroxylase (TH) expression in the median eminence (ME), substantia nigra (SN), and corpus striatum (CS) has been investigated in young and aged female rats. TH expression was studied using the following indices: in situ TH activity, TH mass, and quantity of TH mRNA. The rate of synthesis of dihydroxyphenylalanine (DOPA) was evaluated by measuring its accumulation in the ME, SN, and CS. TH mRNA and TH mass were quantified by an S1 nuclease protection assay and an immunoblot assay, respectively. Viability of the grafts was demonstrated by histological examination and by their ability to secrete PRL into the cerebrospinal fluid (CSF). Liver grafts served as controls. In castrated young and castrated aged animals with AP grafts, the PRL concentrations in the CSF were 204 +/- 49 (mean +/- SE) and 345 +/- 83 ng/ml, respectively, compared to control values of 14 +/- 9 and 23 +/- 9. In intact aged animals, the concentration of PRL was 729 +/- 180 ng/ml in CSF of rats with AP grafts and 223 +/- 62 ng/ml in the controls. DOPA synthesis in the ME of castrated young rats and castrated aged rats with AP grafts was significantly (P less than 0.01) greater than that in controls with liver grafts. AP grafts did not stimulate DOPA synthesis in the ME of intact aged animals. The synthesis of DOPA in the SN and CS was not affected by AP grafts, regardless of the status of the animal. The amount of TH mRNA and the quantity of TH were not influenced by the AP grafts in any of the animal models. However, the in situ molar activity of TH in the ME was significantly greater in castrated young rats and castrated aged rats bearing AP grafts than in animals with liver grafts. The in situ molar activity of TH in the ME of castrated young rats was greater than that of castrated or intact aged animals. It is concluded that AP grafts secrete a substance that stimulates DOPA synthesis in the ME of young as well as aged castrated animals, but not in the nigrostriatal system. This stimulation is due to increased catalytic activity of a fixed number of TH molecules rather than an increase in the mass of TH.


Determining individual trajectories of joint space loss: improved statistical methods for monitoring knee osteoarthritis disease progression.
Knee osteoarthritis (KOA) progression is frequently monitored by calculating the change in knee joint space width (JSW) measurements. Such differences are small and sensitive to measurement error. We aimed to assess the utility of two alternative statistical modelling methods for monitoring KOA. We used JSW on radiographs from both the control arm of the Strontium Ranelate Efficacy in Knee Osteoarthritis trial (SEKOIA), a 3-year multicentre, double-blind, placebo-controlled phase three trial, and the Osteoarthritis Initiative (OAI), an open-access longitudinal dataset from the USA comprising participants followed over 8 years. Individual estimates of annualised change obtained from frequentist linear mixed effect (LME) and Bayesian hierarchical modelling, were compared with annualised crude change, and the association of these parameters with change in WOMAC pain was examined. Mean annualised JSW changes were comparable for all estimates, a reduction of around 0.14 mm/y in SEKOIA and 0.08 mm/y in OAI. The standard deviation (SD) of change estimates was lower with LME and Bayesian modelling than crude change (SEKOIA SD = 0.12, 0.12 and 0.21 respectively; OAI SD = 0.08, 0.08 and 0.11 respectively). Estimates from LME and Bayesian modelling were statistically significant predictors of change in pain in SEKOIA (LME P-value = 0.04, Bayes P-value = 0.04), while crude change did not predict change in pain (P-value = 0.10). Implementation of LME or Bayesian modelling in clinical trials and epidemiological studies, would reduce sample sizes by enabling all study participants to be included in analysis regardless of incomplete follow up, and precision of change estimates would improve. They provide increased power to detect associations with other measures.


Modular fixed-bearing total knee arthroplasty with retention of the posterior cruciate ligament. A study of patients followed for a minimum of fifteen years.
There have been a limited number of studies of total knee arthroplasties with durations of follow-up of fifteen years, but we are not aware of any involving modular fixed-bearing posterior cruciate-retaining prostheses. A consecutive series of 139 total knee arthroplasties in 109 patients (average age, sixty-seven years), performed by one surgeon using a nonconforming posterior cruciate-retaining prosthesis, was followed for fifteen years or longer. Forty-five patients (fifty-nine knees) were examined at a minimum of fifteen years postoperatively, fifty-seven patients (seventy knees) had died, five patients (eight knees) were too ill to return for assessment, and two patients (two knees) were considered lost to follow-up. The patients were assessed clinically with use of the Knee Society clinical rating system, and the knees were assessed radiographically. Survivorship analysis was performed with use of worst-case-scenario analysis and with failure defined as a reoperation for any reason. There were five reoperations, four of which were performed because of wear of the polyethylene insert. In addition, one loose cemented femoral component was revised at fifteen years. The survival rate without revision or a need for any reoperation was 92.6% at fifteen years. The mean Knee Society score and functional score at fifteen years were 96 and 78 points, respectively. The prevalence of radiolucent lines was 13%, with 2% around the femur, 11% around the tibia, and none around the patella. None of these lines were clinically relevant. There was no evidence of progressive radiolucent lines, and there was one case of asymptomatic femoral osteolysis. In this single-surgeon series, modular fixed-bearing posterior cruciate-retaining total knee arthroplasties had good clinical and radiographic results with excellent survivorship for up to fifteen years. These results are comparable with those in long-term studies of posterior stabilized implants and of prostheses with mobile-bearing and nonmodular tibial inserts.


Adults' knowledge and behaviors related to human papillomavirus infection.
Our objective was to assess adults' knowledge, risk behaviors, and preference for information about human papillomavirus (HPV). A cross-sectional study using a self-administered questionnaire given in 3 locations (a university health service and 2 community family practice offices); 289 people completed the questionnaire. The primary outcome measure was a knowledge score calculated from the responses on specific items in the questionnaire. This knowledge score was developed by other investigators and has acceptable psychometric properties. Knowledge about HPV was low, with an average knowledge score of 5.50 (possible scores ranged from 0 to 14) and a mode of 0. Knowledge scores were significantly higher in women (P =.001) and married adults (P =.001). Knowledge scores were inversely related to age (P =.004) and positively correlated with years of education (P =.001) and self-assessment of knowledge (P <.001). Knowledge scores were positively correlated with condom use (P =.05) but not significantly associated with other risk behaviors. The most frequently desired time to receive information about HPV was before becoming sexually active. Adults seen in a typical family physician's office have limited knowledge of HPV. One tool family physicians can use to identify those with the least amount of knowledge is to ask patients how informed they are about HPV. The preferred time to receive information about HPV was before a patient became sexually active. However, it remains unclear whether educational intervention or knowledge changes risky behaviors.


Modification of Caffeic Acid with Pyrrolidine Enhances Antioxidant Ability by Activating AKT/HO-1 Pathway in Heart.
Overproduction of free radicals during ischemia/reperfusion (I/R) injury leads to an interest in using antioxidant therapy. Activating an endogenous antioxidant signaling pathway is more important due to the fact that the free radical scavenging behavior in vitro does not always correlate with a cytoprotection effect in vivo. Caffeic acid (CA), an antioxidant, is a major phenolic constituent in nature. Pyrrolidinyl caffeamide (PLCA), a derivative of CA, was compared with CA for their antioxidant and cytoprotective effects. Our results indicate that CA and PLCA exert the same ability to scavenge DPPH in vitro. In response to myocardial I/R stress, PLCA was shown to attenuate lipid peroxydation and troponin release more than CA. These responses were accompanied with a prominent elevation in AKT and HO-1 expression and a preservation of mnSOD expression and catalase activity. PLCA also improved cell viability and alleviated the intracellular ROS level more than CA in cardiomyocytes exposed to H2O2. When inhibiting the AKT or HO-1 pathways, PLCA lost its ability to recover mnSOD expression and catalase activity to counteract with oxidative stress, suggesting AKT/HO-1 pathway activation by PLCA plays an important role. In addition, inhibition of AKT signaling further abolished HO-1 activity, while inhibition of HO-1 signaling attenuated AKT expression, indicating cross-talk between the AKT and HO-1 pathways. These protective effects may contribute to the cardiac function improvement by PLCA. These findings provide new insight into therapeutic approaches using a modified natural compound against oxidative stress from myocardial injuries.


COVID-19 and Care for the Elderly in Long-Term Care Facilities: The Role of Information Communication Technology.
To review the changes in communication in long-term care facilities (LTCF) during the COVID-19 pandemic. A systematic literature review was conducted through a keyword search of the PubMed and Ovid Embase databases. In accordance with the inclusion and exclusion criteria, 11 articles were selected and analysed qualitatively. The use of information communication technology was heterogeneous, and it was used to bring together several different groups of users: LCTF residents' families, hospitals, specialists, and general practitioners. The modes of communication and preferred ways to reduce the social isolation of LTCF residents from their family members were described. Various smartphone applications have been designed for both socializing and the use of telemedical solutions. Opportunities for peer-to-peer social interaction between the elderly through information communication technologies have been neglected. Video calls may bring greater satisfaction to residents and their families. Telemedicine and interdisciplinary cooperation between healthcare professionals have increased the quality of medical care in long-term care institutions during the COVID-19 pandemic.


Biomarkers of extracellular matrix turnover are associated with emphysema and eosinophilic-bronchitis in COPD.
Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction and loss of lung tissue mainly consisting of extracellular matrix (ECM). Three of the main ECM components are type I collagen, the main constituent in the interstitial matrix, type VI collagen, and elastin, the signature protein of the lungs. During pathological remodeling driven by inflammatory cells and proteases, fragments of these proteins are released into the bloodstream, where they may serve as biomarkers for disease phenotypes. The aim of this study was to investigate the lung ECM remodeling in healthy controls and COPD patients in the COPDGene study. The COPDGene study recruited 10,300 COPD patients in 21 centers. A subset of 89 patients from one site (National Jewish Health), including 52 COPD patients, 12 never-smoker controls and 25 smokers without COPD controls, were studied for serum ECM biomarkers reflecting inflammation-driven type I and VI collagen breakdown (C1M and C6M, respectively), type VI collagen formation (Pro-C6), as well as elastin breakdown mediated by neutrophil elastase (EL-NE). Correlation of biomarkers with lung function, the SF-36 quality of life questionnaire, and other clinical characteristics was also performed. The circulating concentrations of biomarkers C6M, Pro-C6, and EL-NE were significantly elevated in COPD patients compared to never-smoking control patients (all p < 0.05). EL-NE was significantly elevated in emphysema patients compared to smoking controls (p < 0.05) and never-smoking controls (p < 0.005), by more than 250%. C1M was inversely associated with forced expiratory volume in 1 s (FEV1) (r = -0.344, p = 0.001), as was EL-NE (r = -0.302, p = 0.004) and Pro-C6 (r = -0.259, p = 0.015). In the patients with COPD, Pro-C6 was correlated with percent predicted Forced Vital Capacity (FVC) (r = 0.281, p = 0.046) and quality of life using SF-36. C6M and Pro-C6, were positively correlated with blood eosinophil numbers in COPD patients (r = 0.382, p = 0.006 and r = 0.351, p = 0.012, respectively). These data suggest that type VI collagen turnover and elastin degradation by neutrophil elastase are associated with COPD-induced inflammation (eosinophil-bronchitis) and emphysema. Serological assessment of type VI collagen and elastin turnover may assist in identification of phenotypes likely to be associated with progression and amenable to precision medicine for clinical trials.


A role for SIRT2-dependent histone H3K18 deacetylation in bacterial infection.
Pathogens dramatically affect host cell transcription programs for their own profit during infection, but in most cases, the underlying mechanisms remain elusive. We found that during infection with the bacterium Listeria monocytogenes, the host deacetylase sirtuin 2 (SIRT2) translocates to the nucleus, in a manner dependent on the bacterial factor InlB. SIRT2 associates with the transcription start site of a subset of genes repressed during infection and deacetylates histone H3 on lysine 18 (H3K18). Infecting cells in which SIRT2 activity was blocked or using SIRT2(-/-) mice resulted in a significant impairment of bacterial infection. Thus, SIRT2-mediated H3K18 deacetylation plays a critical role during infection, which reveals an epigenetic mechanism imposed by a pathogenic bacterium to reprogram its host.


Transcriptional responses to estrogen and progesterone in mammary gland identify networks regulating p53 activity.
Estrogen and progestins are essential for mammary growth and differentiation but also enhance the activity of the p53 tumor suppressor protein in the mammary epithelium. However, the pathways by which these hormones regulate p53 activity are unknown. Microarrays were used to profile the transcriptional changes within the mammary gland after administration of either vehicle, 17beta-estradiol (E), or progesterone (P) individually and combined (EP). Treatment with EP yielded 1182 unique genes that were differentially expressed compared to the vehicle-treated group. Although 30% of genes were responsive to either E or P individually, combined treatment with both EP had a synergistic effect accounting for 60% of the differentially regulated genes. Analysis of protein-protein interactions identified p53, RelA, Snw1, and Igfals as common targets of genes regulated by EP. RelA and p53 form hubs within a network connected by genes that are regulated by EP and that may coordinate the competing functions of RelA and p53 in proliferation and survival of cells. Induction of early growth response 1 (Egr1) and Stratifin (Sfn) (also known as 14-3-3sigma) by EP was confirmed by reverse transcription-quantitative PCR and shown to be p53 independent. In luciferase reporter assays, Egr1 was shown to enhance transcriptional activation by p53 and inhibit nuclear factor kappaB activity. These results identify a gene expression network that provides redundant activation of RelA to support proliferation as well as sensitize p53 to ensure proper surveillance and integration of their competing functions through factors such as Egr1, which both enhance p53 and inhibit RelA.


Breaking Down the Bilingual Cost in Speech Production.
Bilinguals have been shown to perform worse than monolinguals in a variety of verbal tasks. This study investigated this bilingual verbal cost in a large-scale picture-naming study conducted in Spanish. We explored how individual characteristics of the participants and the linguistic properties of the words being spoken influence this performance cost. In particular, we focused on the contributions of lexical frequency and phonological similarity across translations. The naming performance of Spanish-Catalan bilinguals speaking in their dominant and non-dominant language was compared to that of Spanish monolinguals. Single trial naming latencies were analyzed by means of linear mixed models accounting for individual effects at the participant and item level. While decreasing lexical frequency was shown to increase naming latencies in all groups, this variable by itself did not account for the bilingual cost. In turn, our results showed that the bilingual cost disappeared when naming words with high phonological similarity across translations. In short, our results show that frequency of use can play a role in the emergence of the bilingual cost, but that phonological similarity across translations should be regarded as one of the most important variables that determine the bilingual cost in speech production. Low phonological similarity across translations yields worse performance in bilinguals and promotes the bilingual cost in naming performance. The implications of our results for the effect of phonological similarity across translations within the bilingual speech production system are discussed.


An Organometallic Strategy for Assembling Atomically Precise Hybrid Nanomaterials.
For decades, chemists have strived to mimic the intricate design and diverse functions of naturally occurring systems through the bioinspired synthesis of programmable inorganic nanomaterials. The development of thiol-capped gold nanoparticles (AuNPs) has driven advancement in this area; however, although versatile and readily accessible, hybrid AuNPs are rarely atomically precise, which limits control over their surface topology and therefore the study of complex structure-function relationships. Here, we present a bottom-up approach to the systematic assembly of atomically precise hybrid nanoclusters employing a strategy that mimics the synthetic ease with which thiol-capped AuNPs are normally constructed, while producing well-defined covalent nanoscale assemblies with diverse surface topologies. For the first time, using a structurally characterized cluster-based organometallic building block, we demonstrate the systematic synthesis of nanoclusters with multivalent binding capabilities to complex protein targets.


Bacopa monnieri alleviates aluminium chloride-induced anxiety by regulating plasma corticosterone level in Wistar rats.
Objectives Aluminium is present in food preparations, antacids and many medications. It causes neurodegeneration thereby resulting in a spectrum of neurological disorders such as dementia, Alzheimer's disease and anxiety. Bacopa monnieri (BM) is widely used in ayurvedic medicine to improve memory functions. Its anxiolytic property was investigated in this study by using elevated plus maze (EPM) and plasma corticosterone level. Methods Thirty rats were assigned into five groups. Control group received distilled water, and 0.5% tween 80, AlCl3 group received Aluminium Chloride (AlCl3), Protective groups (BM100 + AlCl3 group and BM200 + AlCl3 group) received AlCl3 and BM at two different doses, and the BM200 group received BM. The EPM experiment was performed at the end of the 4th week of oral administration of BM and AlCl3 followed by the measurement of plasma corticosterone. Results Oral administration of AlCl3 to rats increases the levels of anxiety as seen in a decrease in the percentage of entries into the open arms of EPM, an increase in grooming frequency and defecation index. However, the rats in the protective groups shown an increase in the percentage of open arm entries and rearing frequency, and decreased grooming frequency and defecation index. AlCl3 alone treated group showed a significant increase in the plasma corticosterone levels compared to the control group. Whereas the protective groups have shown a significant decrease in the plasma corticosterone levels than the AlCl3 alone treated group. Conclusions Hence the BM has potential role in reverting the anxiogenic effect of AlCl3 in the amygdala as it is evident from the plasma corticosterone levels and the EPM parameters of different groups under study.


Predicting drug metabolism: a site of metabolism prediction tool applied to the cytochrome P450 2C9.
The aim of the present study is to develop a method for predicting the site at which molecules will be metabolized by CYP 2C9 (cytochrome P450 2C9) using a previously reported protein homology model of the enzyme. Such a method would be of great help in designing new compounds with a better pharmacokinetic profile, or in designing prodrugs where the compound needs to be metabolized in order to become active. The methodology is based on a comparison between alignment-independent descriptors derived from GRID Molecular Interaction Fields for the CYP 2C9 active site, and a distance-based representation of the substrate. The predicted site of metabolism is reported as a ranking list of all the hydrogen atoms of each substrate molecule. Eighty-seven CYP 2C9-catalyzed oxidative reactions reported in the literature have been analyzed. In more than 90% of these cases, the hydrogen atom ranked at the first, second, or third position was the experimentally reported site of oxidation.


Multisensory Audiovisual Processing in Children With a Sensory Processing Disorder (II): Speech Integration Under Noisy Environmental Conditions.
Background: There exists a cohort of children and adults who exhibit an inordinately high degree of discomfort when experiencing what would be considered moderate and manageable levels of sensory input. That is, they show over-responsivity in the face of entirely typical sound, light, touch, taste, or smell inputs, and this occurs to such an extent that it interferes with their daily functioning and reaches clinical levels of dysfunction. What marks these individuals apart is that this sensory processing disorder (SPD) is observed in the absence of other symptom clusters that would result in a diagnosis of Autism, ADHD, or other neurodevelopmental disorders more typically associated with sensory processing difficulties. One major theory forwarded to account for these SPDs posits a deficit in multisensory integration, such that the various sensory inputs are not appropriately integrated into the central nervous system, leading to an overwhelming sensory-perceptual environment, and in turn to the sensory-defensive phenotype observed in these individuals. Methods: We tested whether children (6-16 years) with an over-responsive SPD phenotype (N = 12) integrated multisensory speech differently from age-matched typically-developing controls (TD: N = 12). Participants identified monosyllabic words while background noise level and sensory modality (auditory-alone, visual-alone, audiovisual) were varied in pseudorandom order. Improved word identification when speech was both seen and heard compared to when it was simply heard served to index multisensory speech integration. Results: School-aged children with an SPD show a deficit in the ability to benefit from the combination of both seen and heard speech inputs under noisy environmental conditions, suggesting that these children do not benefit from multisensory integrative processing to the same extent as their typically developing peers. In contrast, auditory-alone performance did not differ between the groups, signifying that this multisensory deficit is not simply due to impaired processing of auditory speech. Conclusions: Children with an over-responsive SPD show a substantial reduction in their ability to benefit from complementary audiovisual speech, to enhance speech perception in a noisy environment. This has clear implications for performance in the classroom and other learning environments. Impaired multisensory integration may contribute to sensory over-reactivity that is the definitional of SPD.


Acanthamoeba keratitis in a U.S. Army soldier after unauthorized use of contact lenses in the combat theater.
A 25-year-old active duty Army E-5 developed severe infectious keratitis in his left eye secondary to soft contact lens (CL) wear while deployed in Iraq, necessitating evacuation to Walter Reed Army Medical Center for further evaluation and treatment. Initial clinical examination at Walter Reed Army Medical Center was suggestive of Acanthamoeba keratitis, a serious corneal pathogen associated with CL wear. In vivo confocal microscopy demonstrated Acanthamoeba cysts in the epithelium and anterior stroma, and smears and cultures from an epithelial biopsy specimen confirmed the diagnosis of Acanthamoeba keratitis. To our knowledge this is the first reported case of Acanthamoeba keratitis in a soldier wearing CLs in the combat theater. Because of the inability to maintain proper lens hygiene in a combat or field environment, the risk of developing a potentially sight-threatening corneal infection is significant. This unfortunate case of a devastating eye infection serves as a reminder of the current Army policy, which prohibits the use of CLs during gas chamber exercises, field training, and combat.


Distortion-product otoacoustic emission reflection-component delays and cochlear tuning: estimates from across the human lifespan.
A consistent relationship between reflection-emission delay and cochlear tuning has been demonstrated in a variety of mammalian species, as predicted by filter theory and models of otoacoustic emission (OAE) generation. As a step toward the goal of studying cochlear tuning throughout the human lifespan, this paper exploits the relationship and explores two strategies for estimating delay trends-energy weighting and peak picking-both of which emphasize data at the peaks of the magnitude fine structure. Distortion product otoacoustic emissions (DPOAEs) at 2f1-f2 were recorded, and their reflection components were extracted in 184 subjects ranging in age from prematurely born neonates to elderly adults. DPOAEs were measured from 0.5-4 kHz in all age groups and extended to 8 kHz in young adults. Delay trends were effectively estimated using either energy weighting or peak picking, with the former method yielding slightly shorter delays and the latter somewhat smaller confidence intervals. Delay and tuning estimates from young adults roughly match those obtained from SFOAEs. Although the match is imperfect, reflection-component delays showed the expected bend (apical-basal transition) near 1 kHz, consistent with a break in cochlear scaling. Consistent with other measures of tuning, the term newborn group showed the longest delays and sharpest tuning over much of the frequency range.


Thalassemias in South Asia: clinical lessons learnt from Bangladesh.
Thalassemias are emerging as a global public health concern. Due to remarkable success in the reduction of childhood mortality by controlling infectious diseases in developing countries, thalassemias are likely to be a major public health concern in the coming decades in South Asia. Despite the fact that Bangladesh lies in the world's thalassemia belt, the information on different aspects (epidemiology, clinical course, mortality, complications and treatment outcomes) of thalassemias is lacking. In this comprehensive review, the aim is to to depict the epidemiological aspects of thalassemias, mutation profile and current treatment and management practices in the country by sharing the experience of dealing with 1178 cases over 2009-2014 time periods in a specialized thalassemia treatment centre. We have also discussed the preventative strategies of thalassemias from the context of Bangladesh which could be effective for other developing countries.


Prevalence of seroconversion symptoms and relationship to set-point viral load: findings from a subtype C epidemic, 1995-2009.
To describe symptoms, physical examination findings, and set-point viral load associated with acute HIV seroconversion in a heterosexual cohort of HIV-discordant couples in Zambia. We followed HIV serodiscordant couples in Lusaka, Zambia from 1995 to 2009 with HIV testing of negative partners and symptom inventories 3 monthly, and physical examinations annually. We compared prevalence of self-reported or treated symptoms (malaria syndrome, chronic diarrhea, asthenia, night sweats, and oral candidiasis) and annual physical examination findings (unilateral or bilateral neck, axillary, or inguinal adenopathy; and dermatosis) in seroconverting vs. HIV-negative or HIV-positive intervals, controlling for repeated observations, age, and sex. A composite score comprised of significant symptoms and physical examination findings predictive of seroconversion vs. HIV-negative intervals was constructed. We modeled the relationship between number of symptoms and physical examination findings at seroconversion and log set-point viral load using linear regression. Two thousand, three hundred and eighty-eight HIV-negative partners were followed for a median of 18 months; 429 seroconversions occurred. Neither symptoms nor physical examination findings were reported for most seroconverters. Seroconversion was significantly associated with malaria syndrome among nondiarrheic patients [adjusted odds ratio (aOR) = 4.0], night sweats (aOR = 1.4), and bilateral axillary (aOR = 1.6), inguinal (aOR = 2.2), and neck (aOR = 2.2) adenopathy relative to HIV-negative intervals. Median number of symptoms and findings was positively associated with set-point viral load (P < 0.001). Although most acute and early infections were asymptomatic, malaria syndrome was more common and more severe during seroconversion. When present, symptoms and physical examination findings were nonspecific and associated with higher set-point viremia.


Rates and predictors of mental stress in Rwanda: investigating the impact of gender, persecution, readiness to reconcile and religiosity via a structural equation model.
As a consequence of the 1994 Rwandan genocide, prevalences of mental disorders are elevated in Rwanda. More knowledge about determinants of mental stress can help to improve mental health services and treatment in the east-central African country. The present study aimed to investigate actual rates of mental stress (posttraumatic stress disorder, syndromal depression and syndromal anxiety) in Rwanda and to examine if gender, persecution during the genocide, readiness to reconcile as well as importance given to religiosity and quality of religiosity are predictors of mental stress. The study comprised a community sample of N = 200 Rwandans from Rwanda's capital Kigali, who experienced the Rwandan genocide. By conducting structured interviews, ten local Master level psychologists examined types of potentially lifetime traumatic events, symptoms of posttraumatic stress disorder (PTSD), depression and anxiety, readiness to reconcile and religiosity. Applying non-recursive structural equation modeling (SEM), the associations between gender, persecution, readiness to reconcile, religiosity and mental stress were investigated. Respondents had experienced an average number of 11.38 types of potentially lifetime traumatic events. Of the total sample, 11% met diagnostic criteria for PTSD, 19% presented with syndromal depression and 23% with syndromal anxiety. Female sex, persecution and readiness to reconcile were significant predictors of mental stress. Twofold association was found between centrality of religion (which captures the importance given to religiosity) and mental stress, showing, that higher mental stress provokes a higher centrality and that higher centrality reduces mental stress. The variables positive and negative religious functioning (which determine the quality of religiosity) respectively had an indirect negative and positive effect on mental stress. Study results provide evidence that rates of mental stress are still elevated in Rwanda and that female sex, persecution, readiness to reconcile, centrality and religious functioning are predictors of mental stress. Seventeen years after the genocide, there remains a large gap between the need for and provision of mental health services in Rwanda. Results underline the importance of improving the respective infrastructure, with a focus on the requirements of women and persons, who were persecuted during the genocide. They further highlight that the consideration of readiness to reconcile, centrality and religious functioning in therapeutic interventions can aid mental health in Rwanda.


Grouping Effects on Foveal Spatial Interactions in Children.
Grouping of flankers from the target can modulate crowding in adults. Visual acuity in children is measured clinically using charts with targets and different flankers to enhance spatial interactions. We investigated grouping effects on interactions using visual acuity letters, flanked by contours and letters, in children. Visual acuity for isolated and flanked letters was measured in 155 three- to 11-year old children and 32 adults. Flankers were one stroke width from the target and were a box or four bars and black or red letters. Magnitudes of interaction were flanked minus isolated logMAR acuities. Psychometric function slopes were also examined. Magnitudes of interaction by contours did not change significantly with age. They were 0.047 ± 0.014 logMAR more with bars than a box. Interaction from flanking letters reduced with age, adults being not different from 9- to 11-year-olds for black and red letter surrounds. It was weaker by 0.033 ± 0.013 logMAR when a black letter was surrounded by red rather than black letters. Psychometric function slopes for visual acuity were steepest for the youngest children (3-5 years). For contour and letter flankers, grouping effects on interaction magnitude are age independent. Grouping bars into a box forming a single object reduces magnitude of effect. Grouping letter flankers by color and ungrouping them from the target reduce interaction magnitude by ∼8%, suggesting that luminance-defined form dominates. Differently colored letter flankers of high-luminance contrast on acuity charts could draw attention to the target but retain significant interaction strength.


The reception by French physicians of Chagas' discovery of Trypanosoma cruzi and American trypanosomiasis (1909-1925).
As soon as they were published early in 1909, Chagas's articles on Trypanosoma cruzi and American trypanosomiasis became the topic of discussions in France. The description of T. cruzi and Chagas disease was added to parasitology textbooks as early as 1912, and elicited active research, particularly on the part of French parasitologist Emile Brumpt. He contributed towards eluciding the lifecycle of T. cruzi and the different ways it could infect humans. Laboratory research on T. cruzi was interrupted by First World War and was not resumed afterwards on the same scale, although interest in the epidemiology of Chagas disease continued.


Palliative pharmacological sedation for terminally ill adults.
Terminally ill people experience a variety of symptoms in the last hours and days of life, including delirium, agitation, anxiety, terminal restlessness, dyspnoea, pain, vomiting, and psychological and physical distress. In the terminal phase of life, these symptoms may become refractory, and unable to be controlled by supportive and palliative therapies specifically targeted to these symptoms. Palliative sedation therapy is one potential solution to providing relief from these refractory symptoms. Sedation in terminally ill people is intended to provide relief from refractory symptoms that are not controlled by other methods. Sedative drugs such as benzodiazepines are titrated to achieve the desired level of sedation; the level of sedation can be easily maintained and the effect is reversible. To assess the evidence for the benefit of palliative pharmacological sedation on quality of life, survival, and specific refractory symptoms in terminally ill adults during their last few days of life. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 11), MEDLINE (1946 to November 2014), and EMBASE (1974 to December 2014), using search terms representing the sedative drug names and classes, disease stage, and study designs. We included randomised controlled trials (RCTs), quasi-RCTs, non-RCTs, and observational studies (e.g. before-and-after, interrupted-time-series) with quantitative outcomes. We excluded studies with only qualitative outcomes or that had no comparison (i.e. no control group or no within-group comparison) (e.g. single arm case series). Two review authors independently screened titles and abstracts of citations, and full text of potentially eligible studies. Two review authors independently carried out data extraction using standard data extraction forms. A third review author acted as arbiter for both stages. We carried out no meta-analyses due to insufficient data for pooling on any outcome; therefore, we reported outcomes narratively. The searches resulted in 14 included studies, involving 4167 adults, of whom 1137 received palliative sedation. More than 95% of people had cancer. No studies were randomised or quasi-randomised. All were consecutive case series, with only three having prospective data collection. Risk of bias was high, due to lack of randomisation. No studies measured quality of life or participant well-being, which was the primary outcome of the review. Five studies measured symptom control, using four different methods, so pooling was not possible. The results demonstrated that despite sedation, delirium and dyspnoea were still troublesome symptoms in these people in the last few days of life. Control of other symptoms appeared to be similar in sedated and non-sedated people. Only one study measured unintended adverse effects of sedative drugs and found no major events; however, four of 70 participants appeared to have drug-induced delirium. The study noticed no respiratory suppression. Thirteen of the 14 studies measured survival time from admission or referral to death, and all demonstrated no statistically significant difference between sedated and non-sedated groups. There was insufficient evidence about the efficacy of palliative sedation in terms of a person's quality of life or symptom control. There was evidence that palliative sedation did not hasten death, which has been a concern of physicians and families in prescribing this treatment. However, this evidence comes from low quality studies, so should be interpreted with caution. Further studies that specifically measure the efficacy and quality of life in sedated people, compared with non-sedated people, and quantify adverse effects are required.


Paracoccus pantotrophus NapC can reductively activate cytochrome cd1 nitrite reductase.
The oxidized "as isolated" form of Paracoccus pantotrophus cytochrome cd1 nitrite reductase has a bis-histidinyl coordinated c heme and a histidine/tyrosine coordinated d1 heme. This form of the enzyme has previously been shown to be kinetically incompetent. Upon reduction, the coordination of both hemes changes and the enzyme is kinetically activated. Here, we show that P. pantotrophus NapC, a tetraheme c-type cytochrome belonging to a large family of such proteins, is capable of reducing, and hence activating, "as isolated" cytochrome cd1. NapC is the first protein from P. pantotrophus identified as being capable of this activation step and, given the periplasmic co-location and co-expression of the two proteins, is a strong candidate to be a physiological activation partner.


Is characterization of a single isolate sufficient for valid publication of a new genus or species? Proposal to modify recommendation 30b of the Bacteriological Code (1990 Revision).
From 1990 to 2000, the number of published named taxa based upon new isolates at species and genus levels in International Journal of Systematic and Evolutionary Microbiology, formerly International Journal of Systematic Bacteriology, have increased by approximately four- and sevenfold, respectively. New taxa based upon characterization of only a single isolate remained at around 40% for both categories. The Bacteriological Code (1990 Revision) has no recommendations on the number of strains required for definition of new taxa. For a few groups, a minimum number of 5-10 strains has been suggested in minimal standards. Since an exponential increase in new taxa can be expected in the future, the authors discuss problems related to naming new species and genera based upon descriptions of a single isolate and suggest that this practice is re-evaluated. It is proposed that the following should be added to Recommendation 30b of the Bacteriological Code: 'Descriptions should be based on as many strains as possible (minimum five), representing different sources with respect to geography and ecology in order to be well characterized both phenotypically and genotypically, to establish the centre (from which the type strain could be chosen) and the extent of the cluster to be named. In addition, comparative studies should be performed, including reference strains that represent neighbouring species and/or genera, in order to give descriptions that are sufficiently detailed to allow differentiation from these neighbours.'


A biodegradable polymeric system for peptide-protein delivery assembled with porous microspheres and nanoparticles, using an adsorption/infiltration process.
A biodegradable polymeric system is proposed for formulating peptides and proteins. The systems were assembled through the adsorption of biodegradable polymeric nanoparticles onto porous, biodegradable microspheres by an adsorption/infiltration process with the use of an immersion method. The peptide drug is not involved in the manufacturing of the nanoparticles or in obtaining the microspheres; thus, contact with the organic solvent, interfaces, and shear forces required for the process are prevented during drug loading. Leuprolide acetate was used as the model peptide, and poly(d,l-lactide-co-glycolide) (PLGA) was used as the biodegradable polymer. Leuprolide was adsorbed onto different amounts of PLGA nanoparticles (25 mg/mL, 50 mg/mL, 75 mg/mL, and 100 mg/mL) in a first stage; then, these were infiltrated into porous PLGA microspheres (100 mg) by dipping the structures into a microsphere suspension. In this way, the leuprolide was adsorbed onto both surfaces (ie, nanoparticles and microspheres). Scanning electron microscopy studies revealed the formation of a nanoparticle film on the porous microsphere surface that becomes more continuous as the amount of infiltrated nanoparticles increases. The adsorption efficiency and release rate are dependent on the amount of adsorbed nanoparticles. As expected, a greater adsorption efficiency (~95%) and a slower release rate were seen (~20% of released leuprolide in 12 hours) when a larger amount of nanoparticles was adsorbed (100 mg/mL of nanoparticles). Leuprolide acetate begins to be released immediately when there are no infiltrated nanoparticles, and 90% of the peptide is released in the first 12 hours. In contrast, the systems assembled in this study released less than 44% of the loaded drug during the same period of time. The observed release profiles denoted a Fickian diffusion that fit Higuchi's model (t(1/2)). The manufacturing process presented here may be useful as a potential alternative for formulating injectable depots for sensitive hydrophilic drugs such as peptides and proteins, among others.


Prevalence of sexual harassment of nurses and nursing students in China: a meta-analysis of observational studies.
Sexual harassment experienced by nurses and nursing students is common and significantly associated with negative consequences. This study is a meta-analysis of the pooled prevalence of sexual harassment of nurses and nursing students in China. Electronic databases (PubMed, EMBASE, PsycINFO, Web of Science and Ovid, China National Knowledge Internet, WanFang, SinoMed and Chinese VIP Information) were independently and systematically searched by two reviewers from their commencement date to 12 March 2018. Forty-one studies that reported the prevalence of sexual harassment were analyzed using the random-effects model. The pooled prevalence of sexual harassment was 7.5% (95% CI: 5.5%-10.1%), with 7.5% (5.5%-10.2%) in nurses and 7.2% (3.0%-16.2%) in nursing students. Subgroup analyses showed that the year of survey and sample size were significantly associated with the prevalence of sexual harassment, but not the seniority of nursing staff, department, hospital, economic region, timeframe, age, working experience or subtypes of harassment. In China, sexual harassment was found to be common in nurses and nursing students. Considering the significant negative impact of sexual harassment, effective preventive and workplace measures should be developed.


Wildflower Plantings Do Not Compete With Neighboring Almond Orchards for Pollinator Visits.
The engineering of flowering agricultural field borders has emerged as a research and policy priority to mitigate threats to pollinators. Studies have, however, rarely addressed the potential that flowering field borders might compete with neighboring crops for pollinator visits if they both are in bloom at the same time, despite this being a concern expressed by growers. We evaluated how wildflower plantings added to orchard borders in a large (512 ha) commercial almond orchard affected honey bee and wild bee visitation to orchard borders and the crop. The study was conducted over two consecutive seasons using three large (0.48 ha) wildflower plantings paired with control orchard borders in a highly simplified agricultural landscape in California. Honey bee (Apis mellifera L.) and wild bee visitation to wildflower plots were at least an order of magnitude higher than to control plots, but increased honey bee visitation to wildflower plots did not lead to any detectable shifts in honey bee visitation to almond flowers in the neighboring orchard. Wild bees were rarely observed visiting almond flowers irrespective of border treatment, indicating a limited short-term potential for augmenting crop pollination using wild bees in highly simplified agricultural landscapes. Although further studies are warranted on bee visitation and crop yield from spatially independent orchards, this study indicates that growers can support bees with alternative forage in almond orchards without risking competition between the wildflower plantings and the crop.


Globalization and Contemporary Fertility Convergence.
The rise of the global network of nation-states has precipitated social transformations throughout the world. This article examines the role of political and economic globalization in driving fertility convergence across countries between 1965 and 2009. While past research has typically conceptualized fertility change as a country-level process, this study instead employs a theoretical and methodological framework that examines differences in fertility between pairs of countries over time. Convergence in fertility between pairs of countries is hypothesized to result from increased cross-country connectedness and cross-national transmission of fertility-related schemas. I investigate the impact of various cross-country ties, including ties through bilateral trade, intergovernmental organizations, and regional trade blocs, on fertility convergence. I find that globalization acts as a form of social interaction to produce fertility convergence. There is significant heterogeneity in the effects of different cross-country ties. In particular, trade with rich model countries, joint participation in the UN and UNESCO, and joining a free trade agreement all contribute to fertility convergence between countries. Whereas the prevailing focus in fertility research has been on factors producing fertility declines, this analysis highlights specific mechanisms-trade and connectedness through organizations-leading to greater similarity in fertility across countries. Globalization is a process that propels the spread of culturally laden goods and schemas impinging on fertility, which in turn produces fertility convergence.


Patient activation and 30-day post-discharge hospital utilization.
Patient activation is linked to better health outcomes and lower rates of health service utilization. The role of patient activation in the rate of hospital readmission within 30 days of hospital discharge has not been examined. A secondary analysis using data from the Project RED-LIT randomized controlled trial conducted at an urban safety net hospital. Data from 695 English-speaking general medical inpatient subjects were analyzed. We used an adapted, eight-item version of the validated Patient Activation Measure (PAM). Total scores were categorized, according to standardized methods, as one of four PAM levels of activation: Level 1 (lowest activation) through Level 4 (highest activation). The primary outcome measure was total 30-day post-discharge hospital utilization, defined as total emergency department (ED) visits plus hospital readmissions including observation stays. Poisson regression was used to control for confounding. Of the 695 subjects, 67 (9.6 %) were PAM Level 1, 123 (17.7 %) were Level 2, 193 (27.8 %) were Level 3, and 312 (44.9 %) were Level 4. Compared with highly activated patients (PAM Level 4), a higher rate of 30-day post-discharge hospital utilization was observed for patients at lower levels of activation (PAM Level 1, incident rate ratio [IRR] 1.75, 95 % CI,1.18 to 2.60) and (PAM Level 2, IRR 1.50, 95 % CI 1.06 to 2.13). The rate of returning to the hospital among patients at PAM Level 3 was not statistically different than patients with PAM Level 4 (IRR 1.30, 95 % CI, 0.94 to 1.80). The rate ratio for PAM Level 1 was also higher compared with Level 4 for ED use alone (1.68(1.07 to 2.63)) and for hospital readmissions alone (1.93 [1.22 to 3.06]). Hospitalized adult medical patients in an urban academic safety net hospital with lower levels of Patient Activation had a higher rate of post-discharge 30-day hospital utilization.


Steroidal saponins from Asparagus officinalis and their cytotoxic activity.
Two oligofurostanosides were isolated from the seeds of Asparagus officinalis L and their structures characterized as 3-O-[alpha-L-rhamnopyranosyl-(1-->2)-(alpha-L-rhamnopyranosyl- (1-->4))-beta-D-glucopyranosyl]-26-O-[beta-D-glucopyranosyl]-(25R) -22 alpha-methoxyfurost-5-ene-3 beta,26-diol(methyl protodioscin) and its corresponding 22 alpha-hydroxy analogue (protodioscin). The structural identification was performed using detailed analysis of 1H- and 13C-NMR spectra including two-dimensional NMR spectroscopy (COSY, HMQC, NOESY and HMBC), and chemical conversions. These two compounds have been shown to inhibit the growth of human leukemia HL-60 cells in culture and macromolecular synthesis in a dose-dependent manner. The inhibitory effect on DNA synthesis was found to be irreversible.


SLC1A5 Prefers to Play as an Accomplice Rather Than an Opponent in Pancreatic Adenocarcinoma.
Background: SLC1A5, a ferroptosis regulator gene, plays a dual role in cancer regulation. However, the roles of SLC1A5 in pancreatic adenocarcinoma (PAAD) remain elusive. Methods: SLC1A5's expression and somatic mutation information were determined by TCGA, GEO, Oncomine, and cBioPortal databases. Its prognostic value was assessed in TCGA cohort and was validated in three independent cohorts. The effects of SLC1A5 on the tumor immune microenvironment were analyzed by the CIBERSORT algorithm, ssGSEA method, and TISIDB and TIMER databases. The "oncoPredict" R package, TIDE algorithm, ImmuCellAI online tool, and GSE35141 and GSE59357 datasets were used to ascertain its therapeutic correlations. GSEA and Western blot were applied to reveal the effects of SLC1A5 on the mTORC1 signaling pathway and ferroptosis process. The biofunctions of SLC1A5 were assessed by MTT, wound-healing, Transwell, and xenograft assays. Results: SLC1A5 was significantly upregulated in the PAAD samples but was not commonly accompanied with somatic mutation (2.3%). Overexpression of SLC1A5 led to a poor prognosis and was identified as an independent prognostic factor. Moreover, high SLC1A5 expression suppressed the antitumor immune process by changing the infiltrating levels of immune cells. As for therapeutic correlations, SLC1A5 was related to the efficacy of dasatinib, sunitinib, sorafenib, and imatinib but may not predict that of radiotherapy, chemotherapeutic drugs, and immune checkpoints inhibitors (ICIs). Notably, the overexpression of SLC1A5 could activate the mTORC1 signaling pathway and may increase the cellular sensitivity to ferroptosis. Finally, the overexpression of SLC1A5 markedly promoted proliferation, migration, and invasion of pancreatic cancer cells. At the in vivo level, SLC1A5 deletion inhibited tumor growth in a mice xenograft model. Conclusions: SLC1A5 prefers to play as an accomplice rather than an opponent in PAAD. Our findings provide novel insights into PAAD treatment.


Isolevuglandin-modified proteins, including elevated levels of inactive calpain-1, accumulate in glaucomatous trabecular meshwork.
We report that protein adducts of iso[4]levuglandin E2 (iso[4]LGE2), a highly reactive product of free radical-induced lipid oxidation, accumulate in human glaucomatous trabecular meshwork (TM) but not in controls. Reactive oxygen species play a pathogenic role in primary open angle glaucoma by fostering changes that reduce permeability of the TM tissue and consequently impede aqueous humor outflow resulting in elevated intraocular pressure. IsoLGs covalently modify proteins and are especially effective in causing protein-protein cross-linking. We found elevated levels of calpain-1 in glaucomatous TM. However, calpain activity in glaucomatous TM is only about 50% of that in controls. This paradox is explicable by the fact that modification by isoLGs renders calpain-1 inactive. Thus, treatment of calpain-1 with iso[4]LGE2 in vitro results in covalent modification, inactivation, the formation of high molecular weight aggregates (as determined by Western and dynamic light scattering analyses), and resistance to proteasomal digestion. Iso[4]LGE2-modified calpain-1 undergoes ubiquitination, and its loading impairs the cellular proteasome activity, consistent with competitive inhibition and formation of suicidal high molecular weight aggregates. These data suggest that interference with proteasomal activity, owing to protein modification by isoLGs, could contribute to glaucoma pathophysiology by decreasing the ability of the TM to modulate outflow resistance.


Effect of curing regime on the immobilization of municipal solid waste incineration fly ash in sustainable cement mortar.
Stabilizing/solidificating municipal solid waste incineration fly ash (MIFA) with cement is a common strategy, and it is critical to study the high-value utilization of MIFA in ordinary Portland cement (OPC) components. With this aim, binary-binding-system mortar was produced by partially replacing OPC (∼50%) with MIFA, and the effects of different curing regimes (steam curing and carbonation curing) on the properties of the cement mortar were studied. The results showed that the setting time of the cement paste was shorten with the increase of MIFA content, and steam curing accelerated the hardening of the mixture. Although the incorporation of MIFA reduced the strength of the mortar, compared to conventional curing method, steam curing and carbonation curing increased the 3-d strength of the mortar. For high-volume MIFA mortars, the CO2-cured samples had the highest long-term strength and lowest permeability. The incorporation of MIFA increased the initial porosity of the mortar, thereby significantly increasing the carbonation degree and crystallinity of the reaction product - CaCO3. Steam curing also further narrowed the difference in the hydration degree between MIFA-modified sample and plain paste, which may be due to the enhanced hydraulic reactivity of MIFA at high temperatures. Although the incorporation of MIFA increased the porosity of the mortar, this waste-derived SCM refined the bulk pore structure and decreased the interconnected porosity. Additionally, the heavy metal leaching contents of MIFA-modified mortars were all below 1%, which meet the requirements of Chinese standards. Compared with standard curing, steam curing and carbonation curing made the early-age and long-term performance of MIFA-modified mortar better, which can promote the efficient application of MIFA in OPC products.


3D-printed dimethyloxallyl glycine delivery scaffolds to improve angiogenesis and osteogenesis.
Angiogenesis-osteogenesis coupling processes are vital in bone tissue engineering. Normal biomaterials implanted in bone defects have issues in the sufficient formation of blood vessels, especially in the central part. Single delivery of vascular endothelial growth factors (VEGF) to foci in previous studies did not show satisfactory results due to low loading doses, a short protein half-life and low efficiency. Development of a hypoxia-mimicking microenvironment for cells by local prolyl-4-hydroxylase inhibitor release, which can stabilize hypoxia-inducible factor 1α (HIF-1α) expression, is an alternative method. The aim of this study was to design a dimethyloxallyl glycine (DMOG) delivering scaffold composed of mesoporous bioactive glasses and poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) polymers (MPHS scaffolds), so as to investigate whether the sustained release of DMOG promotes local angiogenesis and bone healing. The morphology and microstructure of composite scaffolds were characterized. The DMOG release patterns from scaffolds loaded with different DMOG dosages were evaluated, and the effects of DMOG delivery on human bone marrow stromal cell (hBMSC) adhesion, viability, proliferation, osteogenic differentiation and angiogenic-relative gene expressions with scaffolds were also investigated. In vivo studies were carried out to observe vascular formations and new bone ingrowth with DMOG-loaded scaffolds. The results showed that DMOG could be released in a sustained manner over 4 weeks from MPHS scaffolds and obviously enhance the angiogenesis and osteogenesis in the defects. Microfil perfusion showed a significantly increased formation of vessels in the defects with DMOG delivery. Furthermore, micro-CT imaging and fluorescence labeling indicated larger areas of bone formation for DMOG-loaded scaffolds. It is concluded that MPHS-DMOG scaffolds are promising for enhancing bone healing of osseous defects.


Association of Household Income With Life Expectancy and Cause-Specific Mortality in Norway, 2005-2015.
Examining causes of death and making comparisons across countries may increase understanding of the income-related differences in life expectancy. To describe income-related differences in life expectancy and causes of death in Norway and to compare those differences with US estimates. A registry-based study including all Norwegian residents aged at least 40 years from 2005 to 2015. Household income adjusted for household size. Life expectancy at 40 years of age and cause-specific mortality. In total, 3 041 828 persons contributed 25 805 277 person-years and 441 768 deaths during the study period (mean [SD] age, 59.3 years [13.6]; mean [SD] number of household members per person, 2.5 [1.3]). Life expectancy was highest for women with income in the top 1% (86.4 years [95% CI, 85.7-87.1]) which was 8.4 years (95% CI, 7.2-9.6) longer than women with income in the lowest 1%. Men with the lowest 1% income had the lowest life expectancy (70.6 years [95% CI, 69.6-71.6]), which was 13.8 years (95% CI, 12.3-15.2) less than men with the top 1% income. From 2005 to 2015, the differences in life expectancy by income increased, largely attributable to deaths from cardiovascular disease, cancers, chronic obstructive pulmonary disease, and dementia in older age groups and substance use deaths and suicides in younger age groups. Over the same period, life expectancy for women in the highest income quartile increased 3.2 years (95% CI, 2.7-3.7), while life expectancy for women in the lowest income quartile decreased 0.4 years (95% CI, -1.0 to 0.2). For men, life expectancy increased 3.1 years (95% CI, 2.5-3.7) in the highest income quartile and 0.9 years (95% CI, 0.2-1.6) in the lowest income quartile. Differences in life expectancy by income levels in Norway were similar to differences observed in the United States, except that life expectancy was higher in Norway in the lower to middle part of the income distribution in both men and women. In Norway, there were substantial and increasing gaps in life expectancy by income level from 2005 to 2015. The largest differences in life expectancy between Norway and United States were for individuals in the lower to middle part of the income distribution.


Prophylactic extended-field irradiation of para-aortic lymph nodes in stages IIB and bulky IB and IIA cervical carcinomas. Ten-year treatment results of RTOG 79-20.
To investigate whether irradiation to the standard pelvic field only improves the response rate and survival in comparison with pelvic plus para-aortic irradiation in patients with high-risk cervical carcinoma, and to investigate patterns of failure and treatment-related toxicity. Randomized controlled trial from November 1979 to October 1986, with stratification by histology, para-aortic nodal status, and International Federation of Gynecology and Obstetrics (FIGO) stage. Radiation Therapy Oncology Group (RTOG) multicenter clinical trial. A total of 367 patients with FIGO stage IB or IIA primary cervical cancers measuring 4 cm or greater in lateral diameter or with FIGO stage IIB cervical cancers were randomized to RTOG protocol 79-20 to receive either standard pelvic only irradiation or pelvic plus para-aortic irradiation. Pelvic only irradiation consisted of a midplane pelvic dose of 40 to 50 Gy in 4.5 to 6.5 weeks with daily fractions of 1.6 to 1.8 Gy for 5 d/wk. Pelvic plus para-aortic irradiation delivered 44 to 45 Gy in 4.5 to 6.5 weeks with daily fractions of 1.6 to 1.8 Gy for 5 d/wk. A total dose of 4000 to 5000 mg/h of radium equivalent or 30 to 40 Gy was provided by intracavitary brachytherapy to point A. Response rate, overall and disease-free survival, patterns of failure, and treatment-related toxicities. Ten-year overall survival was 44% for the pelvic only irradiation arm and 55% for the pelvic plus para-aortic irradiation am (P = .02). Cumulative incidence of death due to cervical cancer was estimated as significantly higher in the pelvic only arm at 10 years (P = .01). Disease-free survival was similar in both arms; 40% for the pelvic only arm and 42% for the pelvic plus para-aortic arm. Locoregional failures were similar at 10 years for both arms (pelvic only, 35%; pelvic plus para-aortic, 31%; P = .44). In complete responders, the patterns of locoregional failures were the same for both arms, but there was a lower cumulative incidence for first distant failure in the pelvic plus para-aortic irradiation arm (P = .053). Survival following first failure was significantly higher in the pelvic plus para-aortic arm (P = .007). A higher percentage of local failures were salvaged long-term on the pelvic plus para-aortic arm compared with the pelvic only arm (25% vs 8%). The cumulative incidence of grade 4 and 5 toxicities at 10 years in the pelvic plus para-aortic arm was 8%, compared with 4% in the pelvic only arm (P = .06). The death rate due to radiotherapy complications was higher in the pelvic plus para-aortic arm (four [2%] of 170) compared with the pelvic only arm (one [1%] of 167) (P = .38). The proportion of deaths due to radiotherapy complications in the pelvic plus para-aortic arm was higher than in the pelvic only arm (four [6%] of 67 vs one [1%] of 85; P = .24). If the patient had abdominal surgery prior to para-aortic irradiation, the estimated cumulative incidence of grade 4 and 5 complications was 11%, compared with 2% in the pelvic only arm. The statistically significant difference in overall survival at 10 years for the pelvic plus para-aortic irradiation arm, without a difference in disease-free survival, can be explained by the following two factors: (1) a lower incidence of distant failure in complete responders and (2) a better salvage in the complete responders who later failed locally.


Antibodies to a Plasmodium falciparum blood-stage antigen as a tool for predicting the protection levels of two malaria-exposed populations.
To evaluate the ability of antibodies to Plasmodium falciparum ring-infected erythrocyte surface antigen (Pf155/RESA) epitopes to discriminate between individuals well protected or poorly protected against malaria, a receiver operating characteristic analysis was performed in two populations living in Madagascar and Malawi. The definition of protection was based on longitudinal measurements of clinical malarial attacks during the season of high malaria transmission in the Madagascar study, and on a cross-sectional measurement of parasitemia in the Malawi study. Antibodies to peptides reproducing the 4-mer, 8-mer, and 11-mer of the Pf155/RESA were tested for their reactivities using the Falcon assay screening test-enzyme-linked immunosorbent assay. Maximal detection of poorly protected individuals (specificity = 100%) corresponded to high cutoff antibody titers (range = 1.65-3.0 optical density [OD] units in the Madagascar study and 0.67-1.42 OD units in the Malawi study) and a sensitivity less than 50%. For a given sensitivity of 50%, specificity ranged from 55% to 62% in the Madagascar study, and from 67% to 94% in the Malawi study. The antibody cutoff titers corresponding to minimal misclassification rates ranged from 0.24 to 1.73 OD units in the Madagascar study and from 0.15 to 0.55 OD units in the Malawi study. For each antibody, the highest detectability value as measured by the area under the curve was obtained for anti-R11 in the Malawi study (0.838). In demonstrating such qualities, antibodies to Pf155/RESA epitopes could be used for screening poorly protected populations in which malaria control programs have to be implemented.


Health-related quality of life assessment for patients with advanced or metastatic renal cell carcinoma treated with a tyrosine kinase inhibitor using electronic patient-reported outcomes in daily clinical practice (QUANARIE trial): study protocol.
Two main therapies, pazopanib and sunitinib, are used in the first-line setting for metastatic renal cell carcinoma (mRCC). These two tyrosine kinase inhibitors (TKI) are equally effective in terms of survival; however, they frequently induce adverse events. In this setting, Health-Related Quality of life (HRQoL) is a key element in the choice between these two treatments and the evaluation of treatment effectiveness. It could be of interest to evaluate HRQoL in daily clinical practice to aid adequate therapy choice and management. Currently, the development of information and communication technology may allow HRQoL monitoring in routine practice. The objective of the QUANARIE study is to evaluate the use of HRQoL assessment in daily clinical practice for patients with mRCC treated with TKI using electronic patient-reported outcomes (e-PRO). The present article describes the key elements of the study protocol. The QUANARIE study is an interventional, prospective, multicentre trial. Patients diagnosed with mRCC initiating sunitinib or pazopanib treatment will be invited to complete the EORTC QLQ-C30 questionnaire, nine additional questions from the EORTC items library, and the EuroQoL EQ-5D, prior to each visit with the physician. Questionnaires will be completed by patients using tablets and/or computer terminals via the e-PRO software. The physician will have real-time access to a visual summary of the HRQoL evaluation. The primary objective is to assess the proportion of patients having good compliance with Routine Electronic Monitoring of HRQoL (REMOQOL) during the first 12 months. Physicians' satisfaction with REMOQOL will be assessed as a secondary objective. We hypothesise that 80% of patients having good compliance with REMOQOL would be meaningful. A sample size of 56 patients would be needed. The results of this study will show whether REMOQOL is feasible on a large scale and whether patients are receptive to this new practice. This study will also determine how real-time multidimensional evaluation of patient perception can help physicians in their daily practice and how they used it in conjunction with other clinical information to manage patient care. ClinicalTrials.gov; Identifier: NCT03062410 ; First Posted: February 23, 2017; Last Update Posted: August 9, 2017.


Association between adiposity measures and COPD risk in Chinese adults.
Bodyweight and fat distribution may be related to COPD risk. Limited prospective evidence linked COPD to abdominal adiposity. We investigated the association of body mass index (BMI) and measures of abdominal adiposity with COPD risk in a prospective cohort study.The China Kadoorie Biobank recruited participants aged 30-79 years from 10 areas across China. Anthropometric indexes were objectively measured at the baseline survey during 2004-2008. After exclusion of participants with prevalent COPD and major chronic diseases, 452 259 participants were included and followed-up until the end of 2016. We used Cox models to estimate adjusted hazard ratios relating adiposity to risk of COPD hospitalisation or death.Over an average of 10.1 years of follow-up, 10 739 COPD hospitalisation events and deaths were reported. Compared with subjects with normal BMI (18.5-<24.0 kg·m-2), underweight (BMI <18.5 kg·m-2) individuals had increased risk of COPD, with adjusted hazard ratio 1.78 (95% CI 1.66-1.89). Overweight (BMI 24.0-<28.0 kg·m-2) and obesity (BMI ≥28.0 kg·m-2) were not associated with an increased risk after adjustment for waist circumference. A higher waist circumference (≥85 cm for males and ≥80 cm for females) was positively associated with COPD risk after adjustment for BMI. Additionally, waist-to-hip ratio and waist-to-height ratio were positively related to COPD risk.Abdominal adiposity and underweight were risk factors for COPD in Chinese adults. Both BMI and measures of abdominal adiposity should be considered in the prevention of COPD.


Structural and mechanistic diversity of multidrug transporters.
Covering: 2009 to mid 2016Multidrug transporters are common and prevalent in all orders of life, having diverse functions from the removal of toxins, resistance to cytotoxins, and the transport of specific eluents. In addition, multidrug transporters pose a significant threat to modern medicine. Able to transport structurally diverse small molecule drugs, these transporters are implicated in antibiotic resistant strains of bacteria, as well as chemotherapeutic-resistance cancer cells. Although important in such resistance, a relatively small number of multidrug transporters have been structurally characterized, primarily due to the difficulty in purifying and crystallizing active membrane proteins and protein complexes. This review will cover recent structural breakthroughs in the past six years that have led to increased knowledge of the mechanisms of multidrug transporter chemistry, and the role of these transporters in exporting secondary metabolites.