Otorhinolaryngological Toxicities of New Drugs in Oncology.
Many new or relatively new cancer drugs-personalized anticancer agents-have been approved for use in various clinical settings in oncology or are still under evaluation in clinical trials. Targeted therapies as well as new immune checkpoint blockers have toxicity profiles that differ from conventional cytotoxic chemotherapy, and many can cause adverse effects that affect the mouth and pharynx, the nasal cavities, and the larynx. This review aims to provide an overview of current knowledge concerning these side effects and contemporary management. Adverse effects of the mouth/pharynx, nasal cavities, larynx, and cochlear-vestibular system are generally low grade (according to the Common Terminology Criteria for Adverse Events) and generally present non-life-threatening symptoms. However, the impact on patients' quality of life could be important. The incidence and severity vary according to the drug, its target(s), and dose, but there are currently no known predictive factors, and each patient has an individual toxicity profile. Management guidelines are based on expert opinion. These ear, nose, and throat adverse effects are not frequently mentioned in the literature because of the often non-specific nature of the symptoms and their mildness, but also the absence of specific treatment. These symptoms can contribute to decreased quality of life and lead to drug compliance issues if not diagnosed and managed appropriately.


Inconsistent Patient Responses May Limit the Value of Using Multiple Total Knee Arthroplasty Assessment Tools to Define Implant Performance.
Prior studies have suggested that using single validated instruments may not adequately characterize total knee arthroplasty (TKA) performance. However, the consistency of patient responses when answering multiple inventories has not been defined. We retrospectively evaluated 269 patient responses to four postoperative TKA inventories, including 24 parallel questions related to 6 low demand activities. The influence of patient age, sex, and race on response consistency was assessed. Thirty percent of patients gave discordant responses for at least 2 of 11 question categories, unaffected by chronological or categorical age. Discordant answers were more commonly obtained from minority and female patients (P<0.01). Combining multiple instruments to assess TKA outcomes may introduce confounding effects that limit their benefit.


A facile and versatile approach for controlling electroosmotic flow in capillary electrophoresis via mussel inspired polydopamine/polyethyleneimine co-deposition.
Electroosmotic flow (EOF), which reveals the charge property of capillary inner surface, has an important impact on the separation performance and reproducibility of capillary electrophoresis (CE). In this study, a novel, facile and versatile method to achieve diverse and controllable EOF in CE was reported based on the co-deposition of mussel-inspired polydopamine (PDA) and branched polyethyleneimine (PEI) on the capillary inner surface as the hybrid functional coating. After these PDA/PEI co-deposited columns were reinforced by the post-incubation of FeCl3, various magnitude and direction of EOF in CE could be easily achieved by varying a number of preparation parameters, including the mass ratio of DA/PEI and the molecular weight of PEI (including PEI-600, PEI-1800, PEI-10000 and PEI-70000). The separation effectiveness and stability of the hybrid coated columns were verified by the analysis of aromatic acids and aniline derivatives. The results showed that the controllable and diverse EOF was important in enhancing the separation performance of the analytes. The baseline separation of all the five aromatic acids can be achieved in 7 min with high separation efficiency by using the PDA/PEI-600 co-deposited column with the mass ratio of 6:1. On the other hand, with the PDA/PEI-70000 co-deposited column with the mass ratio of 6:1, the aniline compounds were easily baseline separated within 10 min. By contrast, using the bare and PDA coated columns, the migration of the aromatic acids was very slow and the baseline separation of the aniline compounds cannot be obtained. Moreover, the co-deposited columns showed long lifetime and good stability. The relative standard deviations for intra-day, inter-day and capillary-to-capillary repeatability of the PDA/PEI-600 co-deposited column with the mass ratio of 6:1, which was reinforced by the post-incubation of FeCl3, were all lower than 5%.


Early benefits of empagliflozin in patients with or without heart failure: findings from EMPA-REG OUTCOME.
The EMPA-REG OUTCOME trial demonstrated reductions in cardiovascular (CV) death and heart failure (HF) outcomes with empagliflozin, a sodium-glucose co-transporter 2 inhibitor, in patients with type 2 diabetes and established CV disease over a study period of 3 years. We aimed to investigate the early benefit-risk profile of empagliflozin in patients enrolled in the EMPA-REG OUTCOME trial according to HF status at baseline. The effects of treatments on glycated haemoglobin, systolic blood pressure and body weight, and on the HF endpoints of hospitalization for HF (HHF), HHF or CV death, and HHF or all-cause mortality were evaluated at 12 weeks, 6 months, and 1 year after randomization. Occurrence of adverse events (AEs) during these time points was also evaluated. Compared with placebo, empagliflozin lowered glycated haemoglobin, systolic blood pressure, and body weight and rates of all the HF endpoints, as early as at 12 weeks, regardless of HF status at baseline. Favourable clinical and metabolic effects were maintained over time. AEs were generally higher in those with HF than without HF; however, compared with placebo, empagliflozin did not increase risk of developing AEs over the first year of treatment. In the EMPA-REG OUTCOME trial, the use of empagliflozin led to early and beneficial effects on clinical, metabolic, and HF outcomes in patients with type 2 diabetes with or without HF at baseline, which were already apparent within 12 weeks from initiation of treatment. Over the first year of treatment, no safety concern was detected with the use of empagliflozin.


Challenging presentation of primary vasculitis of the central nervous system.
To show a patient with a diagnosis of primary vasculitis of the nervous system and review this entity's literature. Male 32 years, with two events; first, with a transient monoparesis of the right upper extremity, improve with steroids in days. Now, with a motor Jacksonian progression from the upper to the lower right extremities and generalized seizures. After; aphasia, right hemiparesis, and delirium. In the antiresonance, the finding of multiple arterial cerebral "beading." With an in-depth study, the diagnosis of primary cerebral vasculitis was made. The management with levetiracetam, steroids, and Azathioprine offers a satisfactory evolution. The primary CNS vasculitis is an exclusion diagnosis, with angio-MRI is possible to suspect it, but it is always obligate to discard a secondary etiology by infection, systemic diseases, neoplasia, and drugs. Although this problem is infrequent, we must consider this possibility. Opportune treatment can restore the quality of life.


Package inserts for antihypertensive drugs: use by the patients and impact on adverse drug reactions.
In Belgium, all dispensed drugs are provided with package inserts. Traditional physician-orientated inserts are gradually being replaced by patient package inserts (PPIs). The present survey is focused on the use of inserts for antihypertensive drugs and their impact on the reported occurrence and attribution of adverse drug reactions (ADRs). A group of 28 general practitioners (GPs) from the Flemish part of Belgium collected data from 702 hypertensive patients. Each participating GP submitted a consecutive sample of his patients to an interview in the Spring 1989, when 25% of the antihypertensive specialties carried a PPI-version. 1049 prescriptions for antihypertensive drugs had been dispensed. Two thirds of the patients, mostly those with a higher educational level, had read the package inserts. PPIs accounted for 16% of the inserts, and they had not been read significantly more than the traditional inserts. Reporting by the patients of possible drug-related health problems (spontaneously + after having heard the items on a check-list) was not affected by reading the insert or by the type of insert. However, the PPI did bring about spontaneous reporting, especially by patients with a low educational level. Attribution of at least one health problem to the medication was not affected by reading in itself but by the type of insert. Attribution was higher when the patient had received a PPI, except in the case of highly educated patients. Spontaneous reporting and attribution of health problems to the medications prescribed was found more frequently among patients with higher education, who did not seem to need a PPI to recognize problems as being drug-related.


Use of the estimated intraclass correlation for correcting differences in effect size by level.
In a meta-analysis of intervention or group comparison studies, researchers often encounter the circumstance in which the standardized mean differences (d-effect sizes) are computed at multiple levels (e.g., individual vs. cluster). Cluster-level d-effect sizes may be inflated and, thus, may need to be corrected using the intraclass correlation (ICC) before being combined with individual-level d-effect sizes. The ICC value, however, is seldom reported in primary studies and, thus, may need to be computed from other sources. This article proposes a method for estimating the ICC value from the reported standard deviations within a particular meta-analysis (i.e., estimated ICC) when an appropriate default ICC value (Hedges, 2009b) is unavailable. A series of simulations provided evidence that the proposed method yields an accurate and precise estimated ICC value, which can then be used for correct estimation of a d-effect size. The effects of other pertinent factors (e.g., number of studies) were also examined, followed by discussion of related limitations and future research in this area.


Clinical pharmacokinetics of midazolam in intensive care patients, a wide interpatient variability?
The pharmacokinetics of midazolam and its metabolites were studied in 17 patients on mechanical ventilation in a general intensive care unit who were receiving a continuous intravenous infusion of midazolam, adjusted according to the level of induced sedation. Three patients were studied twice. Serum midazolam and alpha-hydroxymidazolamglucuronide levels were determined during and after infusion. The sedation level was scored on a four-point scale. Half of the observed patients were still drowsy or asleep 10 hours after termination of midazolam infusion. In only one patient was midazolam serum elimination half-life less than 2 hours and in six patients the half-life was greater than 10 hours. A wide range of midazolam serum levels was associated with adequate sedation, and similarly the midazolam levels at the moment of awakening were highly variable. The serum concentration ratio of midazolam/alpha-hydroxymidazolamglucuronide at the end of the infusion varied from 0.03 to 15.6. Renal function could account for only a part of this variation.


Redox regulation of Fcgamma receptor-mediated phagocytosis: implications for host defense and tissue injury.
Recent advances in our understanding of the mechanisms that regulate acute and chronic inflammatory responses have revealed a key role for reactive oxygen intermediates in modulating the activation of neutrophils. Opsonized microbes and immune complexes initiate the oxidative burst by the engagement of receptors for immunoglobulin G, termed Fcgamma receptors. The regulation of phagocytic cell function by oxidant-sensitive signaling pathways optimizes host defense capabilities, but it also amplifies tissue damage. This review will focus on the cross-talk between Fcgamma receptors and reactive oxygen intermediates at sites of inflammation and its role in microbial immunity.


Software-based correction of single compartment series resistance errors.
Resistance across a patch pipette following seal formation and attainment of the whole cell recording configuration can introduce considerable and sometimes non-intuitive errors into voltage clamp recordings. These errors can be corrected actively on most commercially available amplifiers, although decisions during the experiment often must be made concerning the degree of correction to be employed, and the decision is essentially irreversible once the data is recorded. Amplifier-based corrections assume a single compartment, and thus any degree of compensation could be applied after data collection with a delay of only a single digitization interval. This report describes computer algorithms that correct capacitative filtering that results from pipette series resistance as well as the voltage error for current responses with either linear or non linear current voltage curves. The algorithms are designed to operate on data that are recorded at a single holding potential rather than in response to voltage steps. The simplest algorithm for correction of responses with linear IV consists of about a dozen lines of C code and can easily be incorporated into data analysis programs, spreadsheets, and mathematical analysis packages. Code, sample programs, and spreadsheets that implement these algorithms are available from ftp.pharm.emory.edu.


Compensatory Structural and Functional Adaptation after Radical Nephrectomy for Renal Cell Carcinoma According to Preoperative Stage of Chronic Kidney Disease.
We investigated structural hypertrophy and functional hyperfiltration as compensatory adaptations after radical nephrectomy in patients with renal cell carcinoma according to the preoperative chronic kidney disease stage. We retrospectively identified 543 patients who underwent radical nephrectomy for renal cell carcinoma between 1997 and 2012. Patients were classified according to preoperative glomerular filtration rate as no chronic kidney disease--glomerular filtration rate 90 ml/minute/1.73 m(2) or greater (230, 42.4%), chronic kidney disease stage II--glomerular filtration rate 60 to less than 90 ml/minute/1.73 m(2) (227, 41.8%) and chronic kidney disease stage III--glomerular filtration rate 30 to less than 60 ml/minute/1.73 m(2) (86, 15.8%). Computerized tomography performed within 2 months before surgery and 1 year after surgery was used to assess functional renal volume for measuring the degree of hypertrophy of the remnant kidney, and the preoperative and postoperative glomerular filtration rate per unit volume of functional renal volume was used to calculate the degree of hyperfiltration. Among all patients (mean age 56.0 years) mean preoperative glomerular filtration rate, functional renal volume and glomerular filtration rate/functional renal volume were 83.2 ml/minute/1.73 m(2), 340.6 cm(3) and 0.25 ml/minute/1.73 m(2)/cm(3), respectively. The percent reduction in glomerular filtration rate was statistically significant according to chronic kidney disease stage (no chronic kidney disease 31.2% vs stage II 26.5% vs stage III 12.8%, p <0.001). However, the degree of hypertrophic functional renal volume in the remnant kidney was not statistically significant (no chronic kidney disease 18.5% vs stage II 17.3% vs stage III 16.5%, p=0.250). The change in glomerular filtration rate/functional renal volume was statistically significant (no chronic kidney disease 18.5% vs stage II 20.1% vs stage III 45.9%, p <0.001). Factors that increased glomerular filtration rate/functional renal volume above the mean value were body mass index (p=0.012), diabetes mellitus (p=0.023), hypertension (p=0.015) and chronic kidney disease stage (p <0.001). Patients with a lower preoperative glomerular filtration rate had a smaller reduction in postoperative renal function than those with a higher preoperative glomerular filtration rate due to greater degrees of functional hyperfiltration.


The cloned dopa decarboxylase gene is developmentally regulated when reintegrated into the Drosophila genome.
The Drosophila dopa decarboxylase gene, Ddc, functions normally when reintroduced into flies. DNA containing a cloned Ddc gene inserted into a P element transposon was injected into early embryos. Transformants were identified by suppression of the cuticular phenotype of a Ddc mutant allele. The reintegrated genes are expressed in the proper tissue and at the proper stages during development even though their positions within the genome are different from that of the wild-type Ddc gene. Absolute levels of DDC enzyme activity are within 35% of that found in wild-type Canton S flies, the source of the transforming DNA. The transformants' Ddc RNA is indistinguishable from that of wild type. One reintegrated Ddc gene, inserted on the X chromosome, is affected by the dosage compensation mechanism that leads to sex-specific differences in the expression of many X-chromosome genes.


Extracorporeal shockwave lithotripsy versus ureteroscopy: a comparison of intraoperative radiation exposure during the management of nephrolithiasis.
Both shockwave lithotripsy (SWL) and ureteroscopy (URS) may be used in the treatment of similar stones and both need fluoroscopic imaging to achieve this. Fluoroscopy, however, is a source of ionizing radiation. The purpose of this study is to compare the effective radiation dose (ERD) between patients undergoing SWL vs URS. The ERD was measured among consecutive patients who were undergoing either SWL or URS between January 2010 and February 2011. For SWL, ERD was calculated using fluoroscopic exposure time, current, voltage, skin-to-source distance, and field size. For URS, it was calculated from the measured dose-area product. We measured several patient and stone factors. Univariate and multivariate analyses were performed. A total of 190 patients were included (87 SWL and 103 URS). In the univariate analyses, no differences were found in ERD (7.32 vs 6.00 mSv, P=0.262 and 7.23 vs 6.07 mSv, P=0.198, for renal and ureteral stones, respectively). In the multivariate analyses, among renal stones, SWL was associated with a higher ERD than URS (β=2.06, P=0.026), and body mass index and stone size were also significant predictors (β=0.212, P=0.045 and β=0.452, P=0.004, respectively). Among ureteral stones, no differences were found (β=0.425, P=0.674), and only the presence of a stent was related to ERD (β=2.53, P=0.013). Among patients with renal stones, SWL was associated with a modest increase in ERD compared with URS, but for ureteral stones, both modalities were associated with similar levels of radiation. This information may be relevant for frequent stone formers needing treatments for which cumulative exposures may become significant.


Naloxone decreases the duration of primary apnea with neonatal asphyxia.
Naloxone, a specific opiate antagonist with no agonist properties, in doses of 0.4 and 4.0 mg/kg was found to markedly reduce the duration of primary apnea in asphyxiated newborn rabbits. There was no effect on the duration of the hyperpneic phase (time to primary apnea) or on survival time (time to last gasp). It is suggested that endogenous opiate-like peptides are released during asphyxia and are the major factor in the suppression of medullary inspiratory neuronal discharge during primary apnea.


Renal cell carcinoma with concomitant solid pseudopapillary tumor of the pancreas: A case report.
Solid pseudopapillary tumor (SPT) of pancreas is an unusual low-grade malignant epithelial tumor that usually occurs in young women and can be treated with surgical resection. Renal cell carcinoma (RCC) is the most common solid lesion of the kidney and primarily a disease of the elderly patient. In this article we present a case of RCC with concomitant SPT of the pancreas who was treated successfully with a radical nephrectomy and distal pancreatectomy. RCC with concomitant SPT may associated in β-catenin gene mutation. But no prior reports have described RCC with concomitant SPT of the pancreas in the same patient. To the best of our knowledge, this is the first report of RCC with concomitant SPT of the pancreas in the same patient.


Early microbiota, antibiotics and health.
The colonization of the neonatal digestive tract provides a microbial stimulus required for an adequate maturation towards the physiological homeostasis of the host. This colonization, which is affected by several factors, begins with facultative anaerobes and continues with anaerobic genera. Accumulating evidence underlines the key role of the early neonatal period for this microbiota-induced maturation, being a key determinant factor for later health. Therefore, understanding the factors that determine the establishment of the microbiota in the infant is of critical importance. Exposure to antibiotics, either prenatally or postnatally, is common in early life mainly due to the use of intrapartum prophylaxis or to the administration of antibiotics in C-section deliveries. However, we are still far from understanding the impact of early antibiotics and their long-term effects. Increased risk of non-communicable diseases, such as allergies or obesity, has been observed in individuals exposed to antibiotics during early infancy. Moreover, the impact of antibiotics on the establishment of the infant gut resistome, and on the role of the microbiota as a reservoir of resistance genes, should be evaluated in the context of the problems associated with the increasing number of antibiotic resistant pathogenic strains. In this article, we review and discuss the above-mentioned issues with the aim of encouraging debate on the actions needed for understanding the impact of early life antibiotics upon human microbiota and health and for developing strategies aimed at minimizing this impact.


A pecan-enriched diet reduced postprandial appetite intensity and enhanced peptide YY secretion: A randomized control trial.
Tree nuts have been shown to have satiating qualities; however, little is known concerning the effect of pecans on measures of appetite. The purpose of this study was to examine the impact of a pecan-enriched diet on subjective, physiological, and direct measures of appetite in older adults. This was a randomized, controlled trial in which healthy older adults (50-75 y) were randomized to either consume 68 g of pecans/day (pecan; n = 21) or avoid all nuts (control; n = 23) for 4 weeks. At pre- (V1) and post-diet (V2) visits body weight (BW) and body fat percentage (BF) were assessed and actual change in these outcomes for pecan were compared to theoretical changes if pecans were consumed without compensation. Subjective appetite was measured using visual analog scale (VAS), and blood was collected to assess changes in physiological appetite before and every 30 min for 4 h following a high-fat meal. Energy intake (EI) at a buffet meal was then assessed in the laboratory ("in-lab"). VAS assessments continued hourly for the next 7 h and EI ("at-home") was self-reported. BW and BF did not change for pecan or control across the intervention and theoretical change in BW (theoretical: 2.2 ± 0.1 vs. actual: 0.4 ± 0.2 kg; p < 0.0001) and BF (theoretical: 0.4 ± 0.04 vs. actual: 0.2 ± 0.2%; p < 0.0001) was significantly greater than actual change for pecan. From V1 to V2, there was an increase in fasting (pecan: 77.0 ± 4.6 to 93.5 ± 6.1 vs control: 76.0 ± 5.0 to 72.5 ± 5.0 pg/mL; p = 0.01) and postprandial peptide YY for pecan vs. control (p = 0.04); however, fasting and postprandial cholecystokinin and ghrelin did not differ (p > 0.05). There were no differences in the change in subjective appetite ratings at fasting, following the high-fat meal (in-lab), at-home, or across the full day between groups (p > 0.05 for all). However, there was a significant suppression of peak desire to eat ratings for pecan vs. control (pecan: 67.9 ± 4.6 to 57.1 ± 5.2 vs. control: 61.9 ± 4.2 to 60.6 ± 4.3 mm; p = 0.04). Combined, buffet meal, and at-home EI did not differ significantly within pecan and control; however, there was a trend (p = 0.11) for a between group difference in buffet meal EI driven by increased EI for control (+137 ± 86 kcal) vs. decreased EI for pecan (-45 ± 77 kcal). A 4-week pecan-enriched diet led to enhanced satietogenic metrics compared to a diet void of all nuts. As weight remained stable during the intervention, adding pecans to the daily diet may be beneficial to appetite control and weight maintenance in a healthy older population. ClinicalTrials.gov: NCT04385537.


Postnatal management of prenatally diagnosed abdominal masses and anomalies.
Rapid advancement in fetal diagnostic imaging has increased our ability to diagnose a multitude of anomalies in the prenatal period. The purpose of this chapter is to review our current understanding of prenatally diagnosed intra-abdominal lesions, and describe the current guidelines for the postnatal management and subsequent outcome for these lesions.


Scavenger receptor for hemoglobin in preterm prelabor rupture of membranes pregnancies complicated by histological chorioamnionitis.
We sought to evaluate the distribution of scavenger receptor for hemoglobin positive (CD163(+)) cells in the placenta and fetal membranes from pregnancies complicated by preterm prelabor rupture of membranes with respect to the presence and absence of histological chorioamnionitis. Sixty-two women with singleton pregnancies with a gestational age between 24+0 and 36+6 weeks were included in a prospective cohort study. CD163 was evaluated by immunohistochemistry in the placenta and fetal membranes. The number of CD163(+) cells and neutrophils was counted in the following locations: fetal membranes' amnion, chorion, and decidua, as well as the placenta's amnion, chorionic plate, subchorionic fibrin, stem villi, terminal villi, and decidua. CD163(+) cells were found in all compartments of the placenta and the fetal membranes regardless of the inflammatory status. A positive correlation between the number of CD163(+) cells and neutrophils in the subchorionic fibrin and the chorionic plate was found. The number of CD163(+) cells was higher in the placental subchorionic fibrin and chorionic plate when histological chorioamnionitis was present. The presence of histological chorioamnionitis affected the number of CD163(+) cells in the placental chorionic plate and in the subchorionic fibrin but not in the fetal membranes.


Establishing targets for hypertension control in patients with comorbidities.
Most current guidelines recommend tighter blood pressure (BP) control in hypertensive patients with comorbidities. These recommendations are based on epidemiologic data indicating that cardiovascular risk increases at lower BP levels in hypertensive patients with comorbidities than in those without comorbidities. Hypertension guidelines usually reflect outcomes from previous studies, but current recommendations for patients with comorbidities have preceded the evidence. We review recent studies investigating whether these new targets can be achieved, whether they are well tolerated, and whether they positively affect the outcomes. The results of the few current studies about outcomes in lower BP target groups are either negative or somewhat--but not decidedly--positive. There is a need for new trials designed to evaluate the validity of current recommendations for tighter BP control in hypertensive patients with comorbidities. Additionally, existing data from published trials could be reanalyzed to provide further clarification.


A compartmentalized chamber for studying dopamine neurons in an hypothalamo-pituitary explant.
An in vitro technique was developed which could be used to study whole neurons of the tuberohypophyseal dopaminergic (THDA) tract. Explants containing the medial basal hypothalamus (MBH; THDA cell bodies), pituitary stalk (THDA axons) and posterior pituitary (PP; THDA nerve terminals) were carefully dissected and placed in specially designed chambers. The chambers consist of separate compartments for the incubation of the MBH and PP while maintaining an intact pituitary stalk which traverses through a notched barrier. Dopamine (DA) synthesis in the explants was constant for 3 h and was significantly elevated by electrical stimulation. Electrical stimulation of both the PP and MBH increased endogenous DA release from the PP. DA release in response to potassium depolarization and dopaminergic drugs was significantly lower in explants than in the isolated PP even though spontaneous release was similar. (1) this method is suitable for studying intact THDA neurons in vitro, and (2) intact THDA neurons respond differently to various stimuli than their excised terminals.


Indicators for tracking programmes to strengthen health research capacity in lower- and middle-income countries: a qualitative synthesis.
The monitoring and evaluation of health research capacity strengthening (health RCS) commonly involves documenting activities and outputs using indicators or metrics. We sought to catalogue the types of indicators being used to evaluate health RCS and to assess potential gaps in quality and coverage. We purposively selected twelve evaluations to maximize diversity in health RCS, funders, countries, and approaches to evaluation. We explored the quality of the indicators and extracted them into a matrix across individual, institutional, and national/regional/network levels, based on a matrix in the ESSENCE Planning, Monitoring and Evaluation framework. We synthesized across potential impact pathways (activities to outputs to outcomes) and iteratively checked our findings with key health RCS evaluation stakeholders. Evaluations varied remarkably in the strengths of their evaluation designs. The validity of indicators and potential biases were documented in a minority of reports. Indicators were primarily of activities, outputs, or outcomes, with little on their inter-relationships. Individual level indicators tended to be more quantitative, comparable, and attentive to equity considerations. Institutional and national-international level indicators were extremely diverse. Although linkage of activities through outputs to outcomes within evaluations was limited, across the evaluations we were able to construct potential pathways of change and assemble corresponding indicators. Opportunities for improving health RCS evaluations include work on indicator measurement properties and development of indicators which better encompass relationships with knowledge users. Greater attention to evaluation design, prospective indicator measurement, and systematic linkage of indicators in keeping with theories of change could provide more robust evidence on outcomes of health RCS.


Monoclonal antibody analysis of serotype-restricted and unrestricted bluetongue viral antigenic determinants.
Twenty-one monoclonal antibodies that react with bluetongue virus (BTV) and have restricted or unrestricted serotype specificities were identified in culture supernatants of hybridomas derived from lymphocytes of mice immunized with BTV serotype 17. Hybridomas were screened and antibody specificities characterized in a solid-phase radioimmunoassay and by immunoprecipitation with radiolabeled, BTV 17-infected cell lysates. Three general serotype specificities were demonstrated by 13 antibodies that precipitated structural viral protein 9 (VP 9). One antibody precipitated VP 7, a 48,000 dalton nonstructural protein, and reacted in radioimmunoassay with 20 BTV serotypes and Epizootic Hemorrhagic Disease of Deer Virus serotype 1 (EHDV 1), EHDV 2, and Ibaraki virus, but not with uninfected cells. One serotype-specific antibody neutralized infectivity, inhibited hemagglutination by BTV 17, and precipitated VP 2 and VP 3. A second antibody, with restricted serotype specificity, precipitated VP 2 and VP 8. These results confirm those of others (Huismans and Erasmus, Onderstepoort J. Vet. Res. 48, 51-58, 1981) that BTV serotype-specific and neutralizing epitopes are associated with VP 2.


Comparative antigenic structure of carbonic anhydrases CA I and CA II from human and mammalian origin.
1. Isolated carbonic anhydrases CA I and CA II from different species (man, ox, sheep, pig, dog and rat) have been analyzed by immunodiffusion techniques using rabbit specific CA I or CA II antisera. 2. Immunodiffusion shows the absence of cross-reactivity between CA I and CA II isoenzymes. 3. Common antigenic determinants (cross-reactivities) were evidenced between the CA I of the different species under study. 4. To the contrary, cross-reactivity between CA II of the species mentioned above, can clearly be demonstrated only between bovine and sheep CA II.


Locating the global governance of HIV and AIDS: exploring the geographies of transnational advocacy networks.
Over the last two decades, HIV and AIDS have been framed as a "global problem". In the process, transnational advocacy networks have emerged as important actors, and particular places are recognised as key nodes in global HIV and AIDS governance. Using the example of London, UK, this paper examines how these networks are involved in local articulations of global governance and reveals that 'global' processes are inflected by the locations through which networks are routed. The example suggests the need for further analysis of the geographies through which HIV and AIDS is reconfiguring power relations at a variety of spatial scales.


Modeling and hexahedral meshing of cerebral arterial networks from centerlines.
Computational fluid dynamics (CFD) simulation provides valuable information on blood flow from the vascular geometry. However, it requires extracting precise models of arteries from low-resolution medical images, which remains challenging. Centerline-based representation is widely used to model large vascular networks with small vessels, as it encodes both the geometric and topological information and facilitates manual editing. In this work, we propose an automatic method to generate a structured hexahedral mesh suitable for CFD directly from centerlines. We addressed both the modeling and meshing tasks. We proposed a vessel model based on penalized splines to overcome the limitations inherent to the centerline representation, such as noise and sparsity. The bifurcations are reconstructed using a parametric model based on the anatomy that we extended to planar n-furcations. Finally, we developed a method to produce a volume mesh with structured, hexahedral, and flow-oriented cells from the proposed vascular network model. The proposed method offers better robustness to the common defects of centerlines and increases the mesh quality compared to state-of-the-art methods. As it relies on centerlines alone, it can be applied to edit the vascular model effortlessly to study the impact of vascular geometry and topology on hemodynamics. We demonstrate the efficiency of our method by entirely meshing a dataset of 60 cerebral vascular networks. 92% of the vessels and 83% of the bifurcations were meshed without defects needing manual intervention, despite the challenging aspect of the input data. The source code is released publicly.


On the design principles of metabolic flux sensing.
Metabolism is precisely coordinated, with the goal of balancing fluxes to maintain robust growth. However, coordinating fluxes requires information about rates, which can only be inferred through concentrations. While flux-sensitive metabolites have been reported, the design principles underlying such sensing have not been clearly elucidated. Here we use kinetic modeling to show that substrate concentrations of thermodynamically constrained reactions reflect upstream flux and therefore carry information about rates. Then we use untargeted multi-omic data from Escherichia coli and Saccharomyces cerevisiae to show that the concentrations of some metabolites in central carbon metabolism reflect fluxes as a result of thermodynamic constraints. We then establish, using 37 real concentration-flux relationships across both organisms, that in vivo ΔG∘≥-4 kJ/mol is the threshold above which substrates are likely to be sensitive to upstream flux(es).


Expression of luteinizing hormone and follicle-stimulating hormone receptor in the dog prostate.
A possible role for gonadotrophins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the prostate physiology has been suggested in humans and rats. This study aimed at investigating the presence of receptors for LH and FSH (LHR and FSHR) in the canine prostate. Prostates were collected at post mortem from 6 clinically healthy, sexually intact beagles free from any prostatic disorder. Tissue was sampled from dorsal, middle and ventral regions of each prostate. Immunohistochemical localization was performed on wax-embedded sections using polyclonal antibodies for LHR or FSHR. The pattern and intensity of staining in the parenchyma (glandular epithelium) and stroma were determined using a semiquantitative histologic assessment. Receptors for LH and FSH were consistently present in both the glandular epithelium and the stroma in all tissue samples examined. Expression for both receptors was higher in the glandular epithelium than the stroma of all prostatic regions (P < 0.001). In the glandular epithelium, LHR (P < 0.01) and FSHR (P < 0.05) expression was lower in the lateral than the other regions, and there was no difference between dorsal and ventral regions. However, variations in the expression for LHR and FSHR among prostatic regions were not found in the stroma. These findings have demonstrated that LHR and FSHR are expressed in the dog prostate, and the variation observed in their levels of expression among its regions and tissue layers suggests a potential role of gonadotrophins LH and FSH in the regulation of the prostate physiology, particularly the glandular epithelium.


Pressure and temperature dependence of the chlorine NQR in caesium and sodium chlorates.
The (35)Cl nuclear quadrupole resonance (NQR) frequencies (nu(Q)) in caesium and sodium chlorates were measured as a function of temperature, from 77 to 300 K at different pressures up to 5.1 kbar, and the data were analysed to estimate the volume dependence of the electric field gradient (EFG), torsional frequency and also the contributions to the NQR frequency from static and dynamic effects. The variation of spin-lattice relaxation time with pressure at different temperatures was studied in the case of sodium chlorate and at room temperature in case of caesium chlorate. The pressure dependence of the spin-lattice relaxation time (T(1)) suggests that the relaxation is mainly due to the torsional motions.


Towards a high-performance anode for zinc metal batteries: A tri-functional nitrogen-defective graphitic carbon nitride material for anode protection.
As an important potential candidate for large-scale energy storage, rechargeable zinc metal batteries have become a research hotspot. Zn metal anodes are an extremely crucial component of rechargeable Zn metal batteries. However, the Zn dendrites, the evolution of hydrogen and side reactions on the surface of the Zn metal anodes severely hinder its commercial use. Here, we report a modified Zn metal anode with a layer of nitrogen-defective graphitic carbon nitride (NDCN) nanosheets coated onto a commercial Zn foil by a simple spraying method. The NDCN coating on the anode's surface not only provides zincophilic sites, but also drives the deposition of zinc with a particular crystallographic orientation. At the same time, the formation of zinc dendrites and the evolution of hydrogen were suppressed, which enhanced the reversibility of the anode. Thus, the symmetric cells with the NDCN-protected zinc foil (NDCN@Zn) electrodes remained stable for 2000 h at a current density of 5 mA cm-2. More importantly, the long-term cycling performance of the full cell tested at 1 A g-1 retained approximately 88 % of its capacity even after 2300 cycles. This simple but effective method will provide a reference for future studies on protecting the anodes of zinc metal batteries.


Five-factor personality measures in Chinese university students: effects of one-child policy?
Since the one-child policy was implemented in China in 1979, many investigators have studied the psychological consequences to children without siblings. Although the results are not conclusive, there is evidence that children who have siblings, rather than only children, have increased anxiety and depression. Whether the differences between students with and without siblings would continue when they reached university age is an interesting question. We used the Zuckerman-Kuhlman Personality Questionnaire to assess personality traits and the Plutchik-van Praag Depression Inventory to measure depressed mood in 134 university students with and 126 university students without siblings. Most students without siblings (93.7%) were reared in urban areas, while 90.3% of students with siblings came from rural areas. Parental professions were higher in social status and annual family incomes were higher in students without siblings. Increased neuroticism-anxiety, aggression-hostility, and depressed mood were found in students with siblings. Gender and annual family income were not significantly related to personality in the two groups, and birth-order position was not related to personality in the students with siblings. In contrast, the depression score was positively correlated with neuroticism-anxiety and aggression-hostility, but negatively correlated with parental occupation and annual family income. The greater competition to receive high education, reduced benefits from society, and lower level of social respect might nurture these personality traits in students with siblings. These findings might, in some limited aspects, indicate that the one-child policy affects personality traits and depressed mood in students with siblings.


Vasopressors in obstetrics.
Hypotension is a common, treatable side effect of neuraxial anesthesia, which has significant side effects for the mother and demonstrable biochemical effects in the fetus. It is clear that a shift in management of hypotension in the obstetric population is in order, but we can only speculate on the benefits for the compromised fetus due to the lack of available information in that patient population.


Structural characterization of SnS crystals formed by chemical vapour deposition.
The crystal and defect structure of SnS crystals grown using chemical vapour deposition for application in electronic devices are investigated. The structural analysis shows the presence of two distinct crystal morphologies, that is thin flakes with lateral sizes up to 50 μm and nanometer scale thickness, and much thicker but smaller crystallites. Both show similar Raman response associated with SnS. The structural analysis with transmission electron microscopy shows that the flakes are single crystals of α-SnS with [010] normal to the substrate. Parallel with the surface of the flakes, lamellae with varying thickness of a new SnS phase are observed. High-resolution transmission electron microscopy (TEM), scanning transmission electron microscopy (STEM), first-principles simulations (DFT) and nanobeam diffraction (NBD) techniques are employed to characterise this phase in detail. DFT results suggest that the phase is a strain stabilised β' one grown epitaxially on the α-SnS crystals. TEM analysis shows that the crystallites are also α-SnS with generally the [010] direction orthogonal to the substrate. Contrary to the flakes the crystallites consist of two to four grains which are tilted up to 15° relative to the substrate. The various grain boundary structures and twin relations are discussed. Under high-dose electron irradiation, the SnS structure is reduced and β-Sn formed. It is shown that this damage only occurs for SnS in direct contact with SiO2 .


Focus as a contextual priming mechanism in reading.
In two experiments, we found that readers are sensitive to manipulations of syntactically marked focus and that focus is an effective message level contextual priming mechanism. Changes in focus resulted in changes in sentence context effects on subsequent target word processing. This was demonstrated in latency to name the target word (Experiment 1) and in initial looking time on the target in silent reading (Experiment 2). Experiment 2 also revealed direct effects on the focused items, as readers made fewer regressions and spent less total time on a word that was focused than when it was not focused. However, no initial processing time effects were found on the focused word.


Centrifugal pulsing increases the recovery of viable spermatozoa.
Our purpose was to compare the number and quality of spermatozoa recover following the standard centrifugation method with those after pulsing the relative centrifugal field during centrifugation. A prospectively controlled in vitro study using ejaculates from 10 healthy sperm donors was undertaken. Number of sperm and sperm motility at 0, 3, and 24 hr post-incubation at 5 degrees C in TEST-yolk results determined the efficacy of the centrifugation techniques. The number of sperm and sperm motility at 0, 3, and 24 hr post-incubation at 5 degrees C in TEST-yolk were significantly higher for the sperm recovered following pulse centrifugation compared with those after standard centrifugation. Pulsing the relative centrifugal field during centrifugation yields a higher number of viable spermatozoa.


Thyrotropin-releasing hormone stimulates intestinal transit in young rats.
The effect of intracisternal injection of thyrotropin-releasing hormone (TRH) on small intestinal transit of a charcoal bolus was investigated in 14-, 21-, 28- and 35-day-old and adult rats. Intracisternal TRH (15 micrograms in 2 microliters) was administered, and transit (distance traveled by the charcoal) was measured 120 min later. In all age groups, intracisternal TRH increased charcoal transit significantly (P less than 0.05) as compared to saline-treated controls. This increase in transit was not mimicked by intravascular TRH, and it was blocked in all age groups by prior intraperitoneal injection of atropine (2 micrograms/g body weight). Vagotomy blocked TRH-induced increases in small intestine transit in rats of 28 days and older. Prior intraperitoneal injection of the antiserotonin compound, cyproheptadine (1 microgram/g body weight) reduced TRH-induced increases in small intestine transit in all age groups. These results demonstrate that centrally administered TRH stimulates small intestine transit through both cholinergic and serotonergic mechanisms in rats as early as 14 days of age.


Surveillance Focus; Causes of mortality in feral wild boar in the Forest of Dean.
This focus article has been prepared by Cat Man, veterinary lead of the APHA Wildlife Expert Group, and Susanna Williamson, veterinary lead of the APHA Pig Expert Group.


Lack of effects of Ca-acetyl homotaurinate on chronic and acute toxicities of ethanol in rats.
In a previous study, it was shown that in rats Ca-acetyl homotaurinate suppresses or eliminates the high oral intake of ethanol induced by earlier chronic ethanol administration, and to a lesser degree the spontaneous ethanol intake of ethanol-naive rats. The present study examines the effect of the drug on the chronic and acute toxicity of ethanol as a possible mechanism in its alteration of the reinforcing properties of ethanol intake. In the first experiment, it was demonstrated that chronic administration of the drug (45 mg/kg per day) for 15 days, alone or combined with chronic intragastric administration of high doses of ethanol, did not significantly alter subsequent ethanol intake. In two other experiments, it was shown that the drug did not interfere with acute ethanol toxicity as tested by ethanol-induced hypothermia, motor impairment and taste aversion in ethanol-naive rats. It is concluded that the acute activity of Ca-AOTA on CNS mechanisms presumably involved in the state of tolerance-dependence, other than those concerned in ethanol-induced hypothermia, motor impairment and taste aversion, may explain its action on the reinforcing property of ethanol intake.


Association of Unfavorable Social Determinants of Health With Stroke/Transient Ischemic Attack and Vascular Risk Factors in Hispanic/Latino Adults: Results From Hispanic Community Health Study/Study of Latinos.
Social determinants of health (SDOH) are non-medical factors that may contribute to the development of diseases, with a higher representation in underserved populations. Our objective is to determine the association of unfavorable SDOH with self-reported stroke/transient ischemic attack (TIA) and vascular risk factors (VRFs) among Hispanic/Latino adults living in the US. We used cross-sectional data from the Hispanic Community Health Study/Study of Latinos. SDOH and VRFs were assessed using questionnaires and validated scales and measurements. We investigated the association between the SDOH (individually and as count: ≤1, 2, 3, 4, or ≥5 SDOH), VRFs and stroke/TIA using regression analyses. For individuals with stroke/TIA (n=388), the mean age (58.9 years) differed from those without stroke/TIA (n=11,210; 46.8 years; P<0.0001). In bivariate analysis, income <$20,000, education less than high school, no health insurance, perceived discrimination, not currently employed, upper tertile for chronic stress, and lower tertiles for social support and language- and social-based acculturation were associated with stroke/TIA and retained further. A higher number of SDOH was directly associated with all individual VRFs investigated, except for at-risk alcohol, and with number of VRFs (β=0.11, 95% confidence interval [CI]=0.09-0.14). In the fully adjusted model, income, discrimination, social support, chronic stress, and employment status were individually associated with stroke/TIA; the odds of stroke/TIA were 2.3 times higher in individuals with 3 SDOH (95% CI 1.6-3.2) and 2.7 times (95% CI 1.9-3.7) for those with ≥5 versus ≤1 SDOH. Among Hispanic/Latino adults, a higher number of SDOH is associated with increased odds for stroke/TIA and VRFs. The association remained significant after adjustment for VRFs, suggesting involvement of non-vascular mechanisms.


Prediction of transport proteins from sequence information with the deep learning approach.
Transport proteins (TPs) are vital to the growth and life of all living things, especially in fields of microbial pathogenesis and drug resistance of tumor cells. Accurately identifying potential TPs remains an important challenge for the advancement of functional genomics. This study aimed to develop a tool for predicting TPs using the deep learning approach. Here, we proposed DeepTP, a convolutional neural network model that uses parallel subnetworks to extract features from protein sequences and uses fully connected layers for TP classification. To train and evaluate the performance of the developed model, datasets were collected from the UniProtKB/Swiss-Prot database. The test results revealed that the proposed model could successfully identify TPs with the AUCROC, accuracy, F-value, and Matthews correlation coefficient of 0.9719, 0.9513, 0.8982, and 0.8679, respectively. By further comparison, DeepTP achieved better performance than other commonly used methods. Analysis of the gradients of prediction score concerning input suggested that DeepTP makes predictions by recognizing the functional domains of TPs. We anticipate that DeepTP will serve as a useful tool for predicting TPs in large-scale genome projects, which will facilitate the discovery of novel TPs.


Growth of MTW9/PL2 estrogen-responsive rat mammary tumor cells in hormonally defined serum-free media.
Growth of the estrogen-responsive MTW9/PL2 rat mammary tumor cells was demonstrated in serum-free defined medium (designated DDM-1) formulated with F12-DME (1:1 vol/vol) supplemented with 15 mM HEPES pH 7.4, insulin 10 micrograms/ml, transferrin 10 micrograms/ml, sodium selenite 10 ng/ml, triiodo-L-thyronine 0.3 nM, phosphoethanolamine 5 microM, epidermal growth factor (20 ng/ml), 17 beta-estradiol 2 nM, and bovine serum albumin 20 micrograms/ml. In DDM-1, the growth rate was about one-half that seen in serum-containing medium. When ethanolamine (50 microM), glutathione (20 micrograms/ml), and linoleic acid/bovine serum albumin (150 micrograms/ml) were added (formulation DDM-2), the growth rate was 80% of serum-containing medium and not seed-density dependent. Deletion of estradiol from DDM-1 or DDM-2 had no effect on growth rate. Also, cells grown in steroid hormone deficient medium for 4 mo. continued to form estrogen-responsive tumors in rats as did cells cultured for the same period in 2 nM estradiol. To investigate autocrine growth factor secretion, a third medium (DDM-3) was prepared by deleting insulin, epidermal growth factor, phosphoethanolamine, estradiol, and both forms of bovine serum albumin from DDM-2. Growth in mitogen-free medium equaled 86% of the serum-stimulated rate and was seed-density dependent; phenol red deletion from DDM-3 had no effect on growth rate. Evidence presented suggests that autocrine factors stimulate growth of the MTW9/PL2 cells in DDM-3, and that this secretion may support the growth of estrogen-responsive cells in culture in the absence of steroid hormone.


Reflect and learn together - when two supervisors interact in the learning support process of nurse education.
To describe the importance of supervisors working together in supporting the learning process of nurse students through reflective caring science supervision. A supervision model has been developed in order to meet the need for interweaving theory and practice. The model is characterized by learning reflection in caring science. A unique aspect of the present project was that the student groups were led by a teacher and a nurse. Data were collected through interviews with the supervisors. The analysis was performed with a phenomenological approach. The results showed that theory and practice can be made more tangible and interwoven by using two supervisors in a dual supervision. The essential structure is built on the constituents 'Reflection as Learning Support', 'Interweaving Caring Science with the Patient's Narrative', 'The Student as a Learning Subject' and 'The Learning Environment of Supervision'. The study concludes that supervision in pairs provides unique possibilities for interweaving and developing theory and practice. The supervision model offers unique opportunities for cooperation, for the development of theory and practice and for the development of the professional roll of nurses and teachers.


Spectroscopic investigation of the interaction between copper (II) 2-oxo-propionic acid salicyloyl hydrazone complex and bovine serum albumin.
The interaction between copper (II) 2-oxo-propionic acid salicyloyl hydrazone (Cu(II)L) and bovine serum albumin (BSA) under physiological conditions was investigated by the methods of fluorescence spectroscopy, UV-Vis absorption, and circular dichroism spectroscopy. Fluorescence data showed that the fluorescence quenching of BSA by Cu(II)L was the result of the formation of the BSA-Cu(II)L complex. The apparent binding constants (K (a)) between Cu(II)L and BSA at four different temperatures were obtained according to the modified Stern-Volmer equation. The thermodynamic parameters, enthalpy change (DeltaH) and entropy change (DeltaS), for the reaction were calculated to be -80.79 kJ mol(-1) and -175.48 J mol(-1) K(-1) according to van't Hoff equation. The results indicated that van der Waals force and hydrogen bonds were the dominant intermolecular force in stabilizing the complex. The binding distance (r) between Cu(II)L and the tryptophan residue of BSA was obtained to be 4.1 nm according to Förster's nonradioactive energy transfer theory. The conformational investigation showed that the application of Cu(II)L increased the hydrophobicity of amino acid residues and decreased the alpha-helical content of BSA (from 62.71% to 37.31%), which confirmed some microenvironmental and conformational changes of BSA molecules.


Clonal spread of beta-lactamase-producing amoxicillin-clavulanate-resistant (BLPACR) strains of non-typeable Haemophilus influenzae among young children attending a day care in Japan.
Resistant strains of non-typeable Haemophilus influenzae (NTHi) are one of the principal causes of recurrent acute otitis media (otitis prone), rhinosinusitis, and pneumonia in young children. Beta-lactamase-nonproducing ampicillin-resistant (BLNAR) strains are particularly common in Japan, and beta-lactamase-producing amoxicillin-clavulanate resistant (BLPACR) strains are now emerging. We investigated the nasopharyngeal carriage status of these resistant strains among children attending a same day care center during a 10-year period. From 1999 to 2008, we obtained nasopharyngeal swab specimens from young children attending a same day care center and examined the incidence of resistant strains of NTHi. Antimicrobial resistance of NTHi was identified based on PCR analysis of mutation of the penicillin binding protein (PBP) genes. Pulsed-field gel electrophoresis (PFGE) was performed to examine the clonal relationship of each resistant strain. The prevalence of resistant strains of NTHi among the children attending this day care has significantly increased during the past 10 years and most of this day care children recently have resistant strains with PBP gene mutations in their nasopharynx. Genetically BLPACR (gBLPACR) strains have rapidly increased since 2007 and PFGE analysis demonstrated that all gBLPACR were clonally identical. This is the first report of apparent clonal dissemination of gBLPACR strains of NTHi occurring in a certain environment such as day care. The rapidly increasing prevalence of resistant strains, in particular gBLPACR, in this day care center may predict a high incidence of these resistant bacteria from clinical isolates in the near future and potential serious medical problems worldwide.


Longitudinal patient-reported outcomes and survival among early-stage non-small cell lung cancer patients receiving stereotactic body radiotherapy.
The study objective was to determine whether longitudinal changes in patient-reported outcomes (PROs) were associated with survival among early-stage, non-small cell lung cancer (NSCLC) patients undergoing stereotactic body radiation therapy (SBRT). Data were obtained from January 2015 through March 2020. We ran a joint probability model to assess the relationship between time-to-death, and longitudinal PRO measurements. PROs were measured through the Edmonton Symptom Assessment Scale (ESAS). We controlled for other covariates likely to affect symptom burden and survival including stage, tumor diameter, comorbidities, gender, race/ethnicity, relationship status, age, and smoking status. The sample included 510 early-stage NSCLC patients undergoing SBRT. The median age was 73.8 (range: 46.3-94.6). The survival component of the joint model demonstrates that longitudinal changes in ESAS scores are significantly associated with worse survival (HR: 1.04; 95% CI: 1.02-1.05). This finding suggests a one-unit increase in ESAS score increased probability of death by 4%. Other factors significantly associated with worse survival included older age (HR: 1.04; 95% CI: 1.03-1.05), larger tumor diameter (HR: 1.21; 95% CI: 1.01-1.46), male gender (HR: 1.87; 95% CI: 1.36-2.57), and current smoking status (HR: 2.39; 95% CI: 1.25-4.56). PROs are increasingly being collected as a part of routine care delivery to improve symptom management. Healthcare systems can integrate these data with other real-world data to predict patient outcomes, such as survival. Capturing longitudinal PROs-in addition to PROs at diagnosis-may add prognostic value for estimating survival among early-stage NSCLC patients undergoing SBRT.


Possible contribution of protein kinase C in the effects of histamine on the visceral nociceptor activities in vitro.
To clarify the possible contribution of protein kinase C activation in histamine-induced excitation and sensitization of the heat response of testicular polymodal receptors, the effects of staurosporine, a protein kinase C inhibitor, and phorbol 12,13-dibutyrate, a protein kinase C activating phorbol ester, were studied in visceral polymodal receptors. Single polymodal receptor activities were recorded in vitro from testis-spermatic nerve preparations obtained from deeply anesthetized dogs (pentobarbital sodium, 30 mg/kg, i.v.). Histamine (10 microM)-induced excitation and facilitation of the heat response of polymodal receptors were both suppressed by staurosporine (1 microM), suggesting that activation of protein kinase C is involved in both these effects of histamine. Application of phorbol 12,13-dibutyrate (0.1 microM) mixed with histamine increased the histamine-induced excitation, whereas a 5 min application of phorbol 12,13-dibutyrate before histamine suppressed it. These results suggest that phorbol 12,13-dibutyrate-activated protein kinase C has inactivation as well as activation effects on the intracellular cascade connected to histamine receptors, and that the former has a slower time course.


Arthroscopic washout of the ankle for septic arthritis in a three-month-old boy.
There is no report of athroscopic treatment for septic arthritis of the ankle in infants. We report a case of successful management of septic arthritis of the ankle in a three-month-old boy by arthroscopic washout. Arthroscopic washout may be a useful treatment for septic arthritis in young infants when performed early after onset.


Synthesis and evaluation of non-dimeric HCV NS5A inhibitors.
Based on the symmetrical bidentate structure of the NS5A inhibitor BMS-790052, a series of new monodentate molecules were designed. The synthesis of 36 new non-dimeric NS5A inhibitors is reported along with their ability to block HCV replication in an HCV 1b replicon system. Among them compound 5a showed picomolar range activity along with an excellent selectivity index (SI > 90,000).


Negative Multiparametric Magnetic Resonance Imaging of the Prostate Predicts Absence of Clinically Significant Prostate Cancer on 12-Core Template Prostate Biopsy.
To determine the negative predictive value of multiparametric magnetic resonance imaging (mpMRI), we evaluated the frequency of prostate cancer detection by 12-core template mapping biopsy in men whose mpMRI showed no suspicious regions. Six hundred seventy patients underwent mpMRI followed by transrectal ultrasound (TRUS)-guided systematic prostate biopsy from December 2012 to June 2016. Of this cohort, 100 patients had a negative mpMRI. mpMRI imaging sequences included T2-weighted and diffusion-weighted imaging, and dynamic contrast enhancement sequences. The mean age, prostate-specific antigen, and prostate volume of the 100 men included were 64.3 years, 7.2 ng/mL, and 71 mL, respectively. Overall cancer detection was 27% (27 of 100). Prostate cancer was detected in 26.3% (10 of 38) of patients who were biopsy-naïve, 12.1% (4 of 33) of patients who had a prior negative biopsy, and in 44.8% (13 of 29) of patients previously on active surveillance; Gleason grade ≥7 was detected in 3% of patients overall (3 of 100). The negative predictive value of a negative mpMRI was 73% for all prostate cancer and 97% for Gleason ≥7 prostate cancer. There is an approximately 3% chance of detecting clinically significant prostate cancer with systematic TRUS-guided biopsy in patients with no suspicious findings on mpMRI. This information should help guide recommendations to patients about undergoing systematic TRUS-guided biopsy when mpMRI is negative.


Gonadotrophin release in ovariectomized patients. I. Suppression by clomiphene or low doses of ethinyl oestradiol.
Administration of clomiphene citrate (150 mg/day) for 5 days to twenty-four ovariectomized patients and seven normal female patients evoked a significant release of FSH and LH in the normal control group and suppressed the gonadotrophin secretion in the castrated patients. A similar suppressive effect on gonadotrophin secretion was noted in eight ovariectomized patients treated for 10 days with low doses (50 microgram/day) of ethinyl oestradiol. It is suggested that in the ovariectomized hypoestrogenic patients, clomiphene acted as an oestrogen, suppressing by a negative feedback action gonadotrophin release in a way similar to ethinyl oestradiol. In the normal control group with an adequate steroid environment, clomiphene acted (probably at the hypothalamic level) as an oestrogen antagonist and stimulated gonadotrophin secretion. In view of our findings, it seems as if the ability of anovulatory patients to respond to clomiphene treatment by increased gonadotrophin secretion depends upon the absolute concentration of the compound in the different organs and by the quantitative relation of clomiphene to the endogenous oestrogens.


Returning coronary heart disease patients to work: a modified perspective.
A very large number of Americans die from Coronary heart disease (CHD); a large number survive. It is the goal of cardiac rehabilitation to restore the physical and economic status of individuals suffering from CHD. This paper reviews current CHD statistics, summarizes the factors that are known to cause CHD, traces the evolution of cardiac rehabilitation programs, and, finally, provides a new perspective for rehabilitating CHD patients based on job simulation.


Successful prenatal and perinatal management of a massive cervicofacial teratoma.
We report a fetus with a massive cervicofacial teratoma successfully managed in the prenatal and perinatal period. A 34-year-old woman was referred to our hospital at 16 weeks' gestation. Ultrasound examination revealed a left anterolateral fetal neck mass indicating typical findings of a teratoma. The tumor grew to tremendous size until occupying most of the uterine cavity causing severe discomfort for the patient. This necessitated ultrasound-guided removal of the intracystic fluid of the massive cervicofacial teratoma during pregnancy. Fetal MRI clearly demonstrated the mass extending from the orbit to the anterior chest wall without compression or deviation of the fetal airway. The entire mass increased to 18 cm in diameter at 37 weeks' gestation. Classical cesarean section was performed immediately after ultrasound-guided removal of the fluid from the cyst. A female infant weighing 3562 g was delivered. Resection of the tumor was accomplished on day 28 of life. The successful outcome in our case illustrates the value of accurate prenatal diagnosis of a giant cervicofacial teratoma using ultrasound and MRI, and careful management of the mother and fetus during the prenatal and perinatal period. It seems that ultrasound-guided removal of the intracystic fluid from the tumor during pregnancy should be considered to prevent preterm delivery.


BcNRT1, a plasma membrane-localized nitrate transporter from non-heading Chinese cabbage.
A nitrate transporter, BcNRT1, was isolated from non-heading Chinese cabbage (Brassica campestris ssp. chinensis Makino) cultivar 'Suzhouqing'. The full-length cDNA was obtained using the rapid amplification of cDNA ends technique and contains an open reading frame of 1,770 bp that predicts a protein of 589 acid residues that possesses 12 putative transmembrane domains. Using the GUS marker gene driven by the BcNRT1 promoter, we found BcNRT1 expression to be concentrated in primary and lateral root tips and in shoots of transgenic Arabidopsis plants. The YFP fused to BcNRT1 and transformed into cabbage protoplasts indicated that BcNRT1 was localized to the plasma membrane. The expression of BcNRT1 in roots was induced by exposure to 25 mM nitrate, and the BcNRT1 cRNA heterologously expressed in Xenopus laevis oocytes showed nitrate conductance when nitrate was included in the medium. Moreover, mutant chl1-5 plants harboring 35S::BcNRT1 showed sensitivity to chlorate treatment and exhibited restored nitrate uptake. In conclusion, the results indicate that BcNRT1 functions as a low affinity nitrate transporter in non-heading Chinese cabbage.


Outcomes of dexmedetomidine treatment in pediatric patients undergoing congenital heart disease surgery: a meta-analysis.
Dexmedetomidine decreases cardiac complications in adults undergoing cardiovascular surgery. This systematic review assessed whether perioperative dexmedetomidine improves congenital heart disease (CHD) surgery outcomes in children. The PubMed, Embase, and Cochrane Library databases were searched for randomized controlled trials (RCTs) or observational studies that were published until 16 April 2015 and compared dexmedetomidine with placebo or an alternative anesthetic agent during pediatric CHD surgery. The assessed outcomes included hemodynamics, ventilation length, intensive care unit (ICU) and hospital stays, blood glucose and serum cortisol levels, postoperative analgesia requirements, and postoperative delirium. Five RCTs and nine observational studies involving 2229 patients were included. In pooled analyses, dexmedetomidine was associated with shorter length of mechanical ventilation (mean difference: -93.36, 95% CI: -137.45, -49.27), lower postoperative fentanyl (mean difference: -24.11, 95% CI: -36.98, -11.24) and morphine (mean difference: -0.07, 95% CI: -0.14, 0.00) requirements, reduced stress response (i.e., lower blood glucose and serum cortisol levels), and lower risk of delirium (OR: 0.39, 95% CI: 0.21, 0.74). The hemodynamics of dexmedetomidine-treated patients appeared more stable, but there were no significant differences in the ICU or hospital stay durations. Dexmedetomidine may increase the bradycardia and hypotension risk (OR: 3.14, 95% CI: 1.47, 6.69). Current evidence indicates that dexmedetomidine improves outcomes in children undergoing CHD surgery. However, this finding largely relies on data from observational studies; high-quality RCTs are warranted because of the potential for subject selection bias.


Comparing the Approach to Radical Prostatectomy Using the Multiport da Vinci Xi and da Vinci SP Robots: A Propensity Score Analysis of Perioperative Outcomes.
Use of the single-port da Vinci SP robotic platform for various urological procedures has been described by several groups. However, the comparative performance of the SP robot in relation to earlier models such as the da Vinci Xi is still unclear. To compare intraoperative and short-term postoperative outcomes between the da Vinci Xi and SP robots for patients undergoing radical prostatectomy (RP) in a referral center. Data were prospectively collected for patients undergoing RP from June 2019 to April 2020 in a single center. The da Vinci SP was used for 71 patients and the da Vinci Xi for 875 patients. After propensity score (PS) matching, two groups of 71 patients were selected for the comparative study. RP via a transperitoneal approach using the same technique steps and anatomy access with both robot consoles. A PS analysis was performed using the covariates age, body mass index, Charlson comorbidity index, Sexual Health Inventory for Men score, American Urological Association symptom score, prostate size, prostate-specific antigen levels, Gleason score, D'Amico risk group, and degree of nerve-sparing. Intraoperative performance and short-term functional (continence and potency) and oncological outcomes were compared between the groups. Median follow-up was 4.4 mo (interquartile range [IQR] 1.6-7.2) for the SP group and 3.2 mo (IQR 1.6-4.8) for the Xi group (p = 0.2). The median total operative time and median console time were both significantly higher in the SP group, with median differences of 14 min (95% confidence interval [CI] 9-19) and 5 min (95% CI 0-5), respectively. The proportion of patients with blood loss of >100 ml was significantly lower in the SP group (difference of 27%, 95% CI 12-42%). No intra- or postoperative complications were reported in either group. There were no significant differences in pain scores at 6, 12, and 18 h or in positive surgical margin rates between the groups. The SP group had a significantly higher percentage of extraprostatic extension than the Xi group (difference of 16%, 95% CI 4.6-27%). None of the patients experienced biochemical recurrence during follow-up. The difference in continence rates at 45 d between the SP and Xi groups was 11% (95% CI -5.6% to 28%) and the difference in potency rates at 45 d was -7.3% (95% CI -21% to 6.2%). The short-term follow-up for comparison of functional and oncological outcomes is a limitation. Despite differences in trocar placement and technology between the two da Vinci consoles, the SP has satisfactory intraoperative performance compared to the Xi. SP surgery can be performed safely and effectively during the initial learning phase. However, longer-term follow-up is needed to provide further evidence on the impact of SP implementation on functional and oncological outcomes. We compared intraoperative and short-term postoperative outcomes for patients who underwent radical prostatectomy using two different robots, the da Vinci Xi and the single-port da Vinci SP. We found that operative time was longer for the Single Port console. Studies with long-term follow-up are needed to compare the functional and oncological outcomes.


Mercuric chloride induced enzymological changes in kidney and ovary of a teleost fish, Channa punctatus.
The effect of LC(50) (1.8 MG/L) and a sublethal concentration (0.03 mg/L) of in vivo mercuric chloride exposure on the activities of acid and alkaline phosphatases, glucose-6-phosphatase, lipase and urease in the kidneys and ovaries of a teleost fish, Channa punctatus has been studied after 96 hr and 30 days respectively. It has been observed that the activities of all the enzymes except acid phosphatase were significantly inhibited in both the tissues. However, treatment for 96 hr resulted in more marked inhibition than 30 days of treatment. Acid phosphatase showed elevation in activity in the kidney after 96 hr of treatment.


Incidence of subclinical ketosis in cows supplemented with a monensin controlled-release capsule in Holstein cattle, Florida, USA.
The objective of this study was to determine the effect of a monensin controlled-release capsule on the proportion of cows with subclinical ketosis (SK). During July to August 2001, 300 cows dried-off 50-70 days before expected parturition were randomly assigned to either a treatment (n = 150, oral capsule, 335 mg/d of monesin for 95 d) or control group (no capsule, n = 150). At 14 days postpartum, a milk sample was obtained and evaluated for beta-hydroxybutyrate (BHBA) using a semi-quantitative ketone test strip. In a sub-sample of 50 cows per group a blood sample was taken and analyzed for BHBA using an ELISA kit. Milk BHBA > or = 200 micromol/L was used as the cut-off value for diagnosis of SK. The incidence of SK based on the milk test was statistically different between groups (P < or = 0.05) with a value of 26.6% for control and 14.5% for cows treated with monensin, respectively. Cows treated with monensin were 0.68 times less likely to give a positive result for milk BHBA than non-treated cows (0.53-0.80; 95% CI). Serum BHBA concentrations did not differ between groups (0.81 +/- 0.09 mmol/L versus 0.70 +/- 0.07 mmol/L for controls and treated, respectively; P > 0.05). However, for each incremental increase in serum BHBA of 0.1 mmol/L occurrence of SK increased 52% (OR = 1.52; 1.21-1.91; 95% CI).


Neuropeptide Y in juvenile migraine and tension-type headache.
Neuropeptide Y (NPY) is widely distributed throughout sympathetic nerve endings where it is co-stored and co-secreted with noradrenaline. It is considered a marker of noradrenergic function. To determine the role of NPY in the pathogenesis of juvenile headache, we determined its plasma levels in two groups of young migraine patients (with and without aura), in a group of episodic tension-type headache patients and in a group of age and sex-matched healthy subjects. Significantly lower plasma levels of NPY were evident in the migraine patients with aura (P < 0.001) and, to a lesser extent, in the migraine patients without aura (P < 0.02), both assessed in the interictal period, with respect to the control group. Plasma NPY levels tended to significantly increase during attacks in migraine patients with aura (P < 0.0009). A less evident, though significant increase was also present during attacks in migraine patients without aura (P < 0.02). No significant variations were observed between headache-free periods and attacks in tension-type headache patients. Reduced NPY levels in the interictal period can be considered further evidence of the derangement of the sympathetic function in the course of migraine, particularly that with aura. The increase in NPY levels during migraine attacks could be an expression of sympathetic activation, even though the functional status of this system is less efficient.


Heritability of social anxiety-related concerns and personality characteristics: a twin study.
Negative evaluation fears figure prominently in the cognitive psychology of patients with social phobia. In this study, we examine the heritability of negative evaluation fears by using a twin sample. The authors also examine the relationships between negative evaluation fears and personality dimensions relevant to social phobia. Scores on the brief version of the Fear of Negative Evaluation Scale (BFNE) were examined in a sample of 437 (245 monozygotic and 192 dizygotic) twin pairs. Biometrical model fitting was conducted by using standard statistical methods. Genetic and environmental correlations with personality dimensions (from the Dimensional Assessment of Personality Pathology-Basic Questionnaire) were also calculated. Broad heritability estimate of the BFNE was 48%. Additive genetic effects and unique environmental effects emerged as the primary influences on negative evaluation fears. Genetic correlations between BFNE scores and the submissiveness, anxiousness, and social avoidance facets of the Dimensional Assessment of Personality Pathology-Basic Questionnaire were high (r(g) =.78 to.80). A cognitive dimension central to the phenomenology (and, perhaps, cause) of social phobia, the fear of being negatively evaluated, is moderately heritable. Moreover, the same genes that influence negative evaluation fears appear to influence a cluster of anxiety-related personality characteristics. Implications and limitations of these findings are discussed.


Cryptic Diversity of the European Blind Mole Rat Nannospalax leucodon Species Complex: Implications for Conservation.
We explored the cryptic speciation of the Nannospalax leucodon species complex, characterised by intense karyotype evolution and reduced phenotypic variability that has produced different lineages, out of which 25 are described as chromosomal forms (CFs), so many cryptic species remain unnoticed. Although some of them should be classified as threatened, they lack the official nomenclature necessary to be involved in conservation strategies. Reproductive isolation between seven CFs has previously been demonstrated. To investigate the amount and dynamics of genetic discrepancy that follows chromosomal changes, infer speciation levels, and obtain phylogenetic patterns, we analysed mitochondrial 16S rRNA and MT-CYTB nucleotide polymorphism among 17 CFs-the highest number studied so far. Phylogenetic trees delineated 11 CFs as separate clades. Evolutionary divergence values overlapped with acknowledged higher taxonomic categories, or sometimes exceeded them. The fact that CFs with higher 2n are evolutionary older corresponds to the fusion hypothesis of Nannospalax karyotype evolution. To participate in conservation strategies, N. leucodon classification should follow the biological species concept, and proposed cryptic species should be formally named, despite a lack of classical morphometric discrepancy. We draw attention towards the syrmiensis and montanosyrmiensis CFs, estimated to be endangered/critically endangered, and emphasise the need for detailed monitoring and population survey for other cryptic species.


Captopril and nifedipine interactions in the treatment of essential hypertensives: a crossover study.
In order to evaluate the antihypertensive effect and the tolerability of combination therapy with an angiotensin converting enzyme inhibitor (captopril) and a dihydropyridine calcium antagonist (nifedipine) compared with monotherapy and placebo, we studied 32 uncomplicated essential hypertensives. At the end of a 1-month placebo washout period, their diastolic blood pressure was greater than 105 and less than 120 mmHg. The subjects then received, according to a double-blind randomized crossover design, captopril (50 mg twice daily), nifedipine (20 mg twice daily), captopril plus nifedipine at the same doses and the corresponding placebo, each treatment being given for 1 month. Both captopril and nifedipine significantly reduced mean blood pressure, which was further and significantly reduced by the combination of the two drugs. The decreases in mean blood pressure induced by nifedipine were significantly greater than those induced by captopril, and those induced by the combined therapy were significantly greater than those induced by either drug on monotherapy. The heart rate was significantly increased only by nifedipine, and to a similar, but not significant, extent by the combination therapy. Plasma renin activity was similarly and significantly increased and urinary aldosterone tended to decrease to a similar extent under the three active treatments. Adverse effects were mild to moderate in intensity; their incidence under captopril was lower than that under placebo, while the incidence under nifedipine and combined therapy was greater than under placebo. Ankle oedema disappeared under the combined therapy in three out of four patients who developed this side effect under nifedipine, although one additional patient developed ankle oedema under combination therapy.(ABSTRACT TRUNCATED AT 250 WORDS)


Restoration of membrane excitability of squid giant axons by reagents activating tyrosine-tubulin ligase.
Using squid giant axon, an experimental survey was performed on restoration of the membrane excitability which had been partially suppressed. Among reagents examined, a combination of 400 mM KF, 50 micrometers tyrosine, 1 mM ATP, 1 mM Mg ions and 2 micrometers cAMP was found to induce the restoration of the excitability to a large extent. Further addition of a small amount of either porcine brain microtubule proteins or the squid axoplasm was found to support complete restoration. The experiments suggest that tubulin-tyrosine ligase contained in the porcine brain microtubule protein fraction or the squid axoplasm maintains the coupling between cytoskeletal structures and the plasma membrane.


Balancing the health benefits and environmental risks of pharmaceuticals: Diclofenac as an example.
Pharmaceuticals are designed to improve human and animal health, but even the most beneficial pharmaceuticals might raise some questions concerning the consequences of exposure to non-target organisms. To illustrate this situation and using diclofenac as a case-study, we analyze global consumption and occurrence data to identify hot spots of consumption without occurrence data, review the scientific literature on the harmful environmental effects to determine whether the observed concentrations in freshwater are of environmental concern, summarize the current pharmaceutical and environmental policies to highlight policy gaps, and suggest a series of research and policy recommendations, which can be summarized as follows: we need to improve the current knowledge on occurrence in freshwaters to properly implement environmental policies (i), diclofenac might pose a risk to non-target organisms in freshwater (ii); the harmful effects that some pharmaceuticals may have on the environment are not always addressed by environmental policies (iii).


Comparison of costs and complications of radical and partial nephrectomy for treatment of localized renal cell carcinoma.
To compare the complications and costs of radical and partial nephrectomy (PN) and to investigate the impact of increasing experience on costs and complications during a 7-year period. Nephron-sparing surgery has found increasing applications in the past decade. PN has achieved similar long-term results in localized renal cell carcinoma with respect to cancer control compared with radical nephrectomy (RN). However, data are limited on the direct comparison of complications and hospital costs between these two modalities. A retrospective case-matched study was performed comparing 60 RNs and 60 PNs during a 7-year period with respect to complications and hospital costs. A longitudinal comparison was also performed between the various periods to assess the impact of surgical experience on these parameters. The mean length of stay was 6.4 +/- 3 days in the RN group and 6.4 +/- 3.3 days in the PN group. The hospital costs were comparable between the two procedures during the observed interval. The mean operative time was 176.6 +/- 51.6 minutes for RN and 220.1 +/- 59.6 minutes for PN (P = 0.0001). This difference was accentuated during the observed period. No differences were found in the blood loss and transfusion rates between the groups. The complication rate was 3.3% and 10% for RN and PN, respectively (P = 0.2). Our data suggest that RN and PN can be performed with a similar rate of complications and comparable hospital costs. This is of practical importance when comparing these modalities as treatment options for localized renal cell carcinoma.


Amiodarone-induced pulmonary mass.
Amiodarone is an effective agent in the treatment of life-threatening ventricular arrhythmias. However, there are numerous side effects associated with this drug, including pulmonary toxicity. This report describes a pulmonary mass that developed in a patient receiving amiodarone and was initially thought to be a lung cancer. Complete resolution occurred after cessation of the drug.


Irinotecan combined with oxaliplatin and S-1 in patients with metastatic pancreatic adenocarcinoma: a single-arm, three-centre, prospective study.
To study the efficacy and toxicity of irinotecan combined with oxaliplatin and S-1 in patients with metastatic pancreatic adenocarcinoma. Previously untreated patients with cytologically or histologically confirmed metastatic pancreatic adenocarcinoma underwent a treatment regimen consisting of an intravenous infusion of irinotecan 165 mg/m2 and oxaliplatin 85 mg/m2 on day 1, and oral S-1 40 mg/m2 twice daily on days 1-14, repeating the regimen every 21 days until one of the following occurred: disease progression, intolerable toxicity, or patient death. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), response rate, toxicity, and quality of life. This ongoing study had been registered on ClinicalTrials.gov, NCT03726021. A total of 41 patients were enrolled in this study, 18 men and 23 women. The median PFS was 4.33 months [95% confidence interval (CI): 2.83-5.88] and the median OS was 11.00 months (95% CI: 9.16-12.84). There were no instances of a complete response; the partial response, stable disease, and disease progression rates were 39.02% (16/41), 29.27% (12/41), and 31.71% (13/41), respectively.The most common adverse side effects were mild to moderate nausea, vomiting, neutropenia, and thrombocytopenia. Grade 3 or 4 neutropenia and thrombocytopenia were observed in 29.27% (12/41) and 12.20% (5/41) of the patients, respectively. No treatment-related death was observed. Irinotecan combined with oxaliplatin and S-1 is a safe and effective treatment for metastatic pancreatic adenocarcinoma, and any toxicities are mild to moderate and tolerable. A larger study population is needed for further evaluation.


Optical coherence tomography findings in valsalva retinopathy.
To demonstrate the plane of premacular hemorrhage in Valsalva retinopathy with optical coherence tomography Observational case report Two young men with Valsalva stress-related premacular hemorrhage were evaluated by OCT scans, taken just above the level of sedimented blood. In both cases, OCT demonstrated two distinct membranes: a highly reflective band immediately above the premacular hemorrhage, corresponding to the internal limiting membrane, and an overlying patchy membrane with low optical reflectivity consistent with posterior hyaloid. OCT supported the clinical impression that the plane of premacular hemorrhage in Valsalva retinopathy is probably under ILM. Larger case studies are required to confirm this finding.


Single-Step Multiplex PCR Assay for Determining 92 Pneumococcal Serotypes.
For pneumococcal disease surveillance, simple and cost-effective methods capable of determining all serotypes are needed. Combining a single-tube multiplex PCR with fluorescently labeled primers followed by amplicon analysis using automated fluorescent capillary electrophoresis, each serotype of 92 reference isolates and 297 recently collected clinical isolates was successfully determined.


Synthesis, crystal structures and electrochemical properties of ferrocenyl imidazole derivatives.
Six ferrocenyl imidazole derivatives substituted with -Cl, -NO2 and -CH3 on the 2-position of the 1H-imidazole ring have been synthesized. Of the six compounds, the di-substituted ferrocenes, i.e. compounds 4 (1,1'-ferrocenylmethyl(2-chloroimidazole)), 5 (1,1'-ferrocenyl(2-nitroimidazole)), and 6 (1,1'-ferrocenylmethyl(2-methylimidazole)) are reported for the first time. The structure-property relationships of compounds 4, 5 and 6 were investigated by means of UV-visible, FTIR, 1H-NMR, 13C-NMR spectroscopy and electrochemical studies. UV-visible analysis in acetonitrile showed that the π -π* band of compounds 2 (1-ferrocenylmethyl(2-nitroimidazole)) and 5 appeared at longer wavelength compared to 1 (1-ferrocenylmethyl(2-chloroimidazole)), 3 (1-ferrocenylmethyl(2-methylimidazole)), 4 and 6. This phenomenon is due to the different electronics around the imidazole moieties. In cyclic voltammetry analysis, all compounds exhibited a quasi-reversible redox wave for the ferrocenyl and imidazole moieties. Density functional theoretical (DFT) calculations with the B3LYP/6-311+G(d) basis set were performed on compounds 1-6, and the calculated HUMO-LUMO band gap energies correlated with those obtained from electrochemical and spectroscopic data. The X-ray crystallographic analysis highlighted the effect of electron-withdrawing and electron-donating substituents on the conformation of the cyclopentadienyl rings attached to the ferrocenyl moiety.


New bifunctional metalloproteinase inhibitors: an integrated approach towards biological improvements and cancer therapy.
The key role of some matrix metalloproteinases (MMPs) on several pathological processes, including carcinogenesis and tumor growth, makes the development of MMP inhibitors (MMPIs) an attractive approach for cancer therapy. We present herein an integrated approach for the development of a new series of inhibitors of MMP2 and MMP14, two enzymes over-expressed by human ovarian cancer. As a first step, a new series of single model compounds bearing different zinc-binding groups (ZBGs), such as carboxylic, hydroxamic acid, hydrazide and sulfonylhydrazide groups, were studied and revealed reasonably good capacity for the Zn(II) chelation in solution and for the MMP inhibition. Aimed at further reinforcing the biological activity of these MMPIs as anti-cancer agents, a selection of those models was extra-functionalized with benzothiazole (BTA), a group with recognized antitumor activity. Analysis of the results obtained for these bifunctional compounds, in particular the inhibitory activity against MMP2 and MMP14 as well as the anti-proliferative activity on the A2780 ovarian cancer cell line, allowed to understand the activity dependence on the type of ZBG, as well as the relevance of the BTA moiety. Overall, the evidenced BTA-associated activity improvements on enzyme inhibition and cell antiproliferactivity, combined with the hydrolytic stability revealed by the hydrazide group, suggest that these new bifunctional BTA-hydrazide derivatives should be taken in consideration for the development of new generations of MMPIs with anti-cancer activity.


Temporomandibular articular disorders can be alleviated with surgery.
Medline, Embase and a variety of other sources were searched for English-language articles. Non-journal publications, conferences proceedings from professional organisations and from private and government agencies were screened. Bibliographies and reference lists from peer-reviewed and 'grey' literature were also reviewed. To meet the inclusion criteria articles must have reported studies of at least 10 patients, involve diagnoses of disc displacement with reduction (DDwR) or without reduction (DDw/oR) or degenerative joint disease (DJD) and include at least one of the following surgical techniques: arthrocentesis; arthroscopy; discectomy without replacement or disc repair/repositioning. The outcome measured was the proportion of patients who reported improvement after treatment. Study success rates were recalculated on an intent-to-treat basis. Meta-analyses were performed along with meta-regressions where heterogeneity was an issue. Three classes of meta-analyses were performed using different artificial, untreated, control groups assuming three levels of spontaneous improvement, namely 0, 37.5 and 75%. Twenty-two studies, comprising 30 patient groups and sample sizes of 11-237 patients, met the inclusion criteria. For studies of patients with DDwR, at the 0 and 37.5% rates of control group improvement, arthroscopy and disc repair/repositioning resulted in treatment effects significantly greater than zero, with no significant differences in the efficacy of these two surgical techniques. For studies of patients with DDw/OR, the proportion of patients who improved after arthroscopy or arthrocentesis was significantly greater than zero at all three levels of estimated control improvement. Disc repair effect size was not significant at the 75% rate. Surgical treatments appear to have some efficacy for people who have temporomandibular articular disorders that do not respond to nonsurgical therapies.


Therapeutic potential of resolvins in the prevention and treatment of inflammatory disorders.
Acute inflammation, the primary response to harmful infection and injury, can be successfully completed through effective resolution and tissue repair. Resolution of inflammation requires the elimination of key inflammatory cells and the downregulation of pro-inflammatory mediators in the inflamed sites. This coordinated process is actively regulated by biochemical mediators which possess anti-inflammatory and/or pro-resolving effects. Resolvins, endogenous lipid mediators generated from omega-3 fatty acids, have emerged as a novel class of potent molecules that counteract excessive inflammatory responses and stimulate pro-resolving mechanisms; regulating the trafficking of leukocytes and stimulating non-phlogistic phagocytosis of apoptotic neutrophils by macrophages.The disruption of these anti-inflammatory and pro-resolving mechanisms can not only cause the initiation of unnecessary inflammation, but also lead to the persistence of inflammation which contributes to the pathogenesis and progression of chronic inflammatory diseases. Since inflammation can have the beneficial effect on host defense, the timely resolution of inflammation is better to avoid chronic inflammatory situation, rather than merely blocking inflammation at the beginning. In this regards, understanding of the mechanism underlying resolution of inflammation provides a novel therapeutic approach to prevent and treat chronic inflammatory disorders. This review will address therapeutic potential of resolvins for the successful management of inflammatory ailments.


Hepatitis C treatment uptake among people who inject drugs in Oslo, Norway: A registry-based study.
Improving HCV treatment uptake among people who inject drugs (PWID) is crucial to achieving the WHO elimination targets. The aims were to evaluate HCV treatment uptake and HCV RNA prevalence in a large cohort of PWID in Norway. Registry-based observational study where all users of the City of Oslo's low-threshold social and health services for PWID between 2010-2016 (n = 5330) were linked to HCV notifications (1990-2019) and dispensions of HCV treatment, opioid agonist treatment (OAT) and benzodiazepines (2004-2019). Cases were weighted to account for spontaneous HCV clearance. Treatment rates were calculated using person-time of observation, and factors associated with treatment uptake were analysed using logistic regression. HCV RNA prevalence was estimated among individuals alive by the end of 2019. Among 2436 participants with chronic HCV infection (mean age 46.8 years, 30.7% female, 73.3% OAT), 1118 (45.9%) had received HCV treatment between 2010-2019 (88.7% DAA-based). Treatment rates increased from 1.4/100 PY (95% CI 1.1-1.8) in the pre-DAA period (2010-2013) to 3.5/100 PY (95% CI 3.0-4.0) in the early DAA period (2014-2016; fibrosis restrictions) and 18.4/100 PY (95% CI 17.2-19.7) in the late DAA period (2017-2019; no restrictions). Treatment rates for 2018 and 2019 exceeded a previously modelled elimination threshold of 50/1000 PWID. Treatment uptake was less likely among women (aOR 0.74; 95% CI 0.62-0.89) and those aged 40-49 years (aOR 0.74; 95% CI 0.56-0.97), and more likely among participants with current OAT (aOR 1.21; 95% CI 1.01-1.45). The estimated HCV RNA prevalence by the end of 2019 was 23.6% (95% CI 22.3-24.9). Although HCV treatment uptake among PWID increased, strategies to improve treatment among women and individuals not engaged in OAT should be addressed.