Cost-effectiveness of integrated treatment for hepatitis C virus (HCV) among people who inject drugs in Norway: An economic evaluation of the INTRO-HCV trial.
The INTRO-HCV randomized controlled trial conducted in Norway over 2017-2019 found that integrated treatment, compared with standard-of-care hospital treatment, for hepatitis C virus (HCV) with direct-acting antivirals (DAAs) improved treatment outcomes among people who inject drugs (PWID). We evaluated cost-effectiveness of the INTRO-HCV intervention. A Markov health state transition model of HCV disease progression and treatment with cost-effectiveness analysis from the health-provider perspective. Primary cost, utility, and health outcome data were derived from the trial. Costs and health benefits (quality-adjusted life-years, QALYs) were tracked over 50 years. Probabilistic and univariate sensitivity analyses investigated DAA price reductions and variations in HCV treatment and disease care cost assumptions, using costs from different countries (Norway, United Kingdom, United States, France, Australia). PWID attending community-based drug treatment centers for people with opioid dependence in Norway. Incremental cost-effectiveness ratio (ICER) in terms of cost per QALY gained, compared against a conventional (€70 000/QALY) willingness-to-pay threshold for Norway and lower (€20 000/QALY) threshold common among high-income countries. Integrated treatment resulted in an ICER of €13 300/QALY gained, with 99% and 71% probability of being cost-effective against conventional and lower willingness-to-pay thresholds, respectively. A 30% lower DAA price reduced the ICER to €6 900/QALY gained, with 91% probability of being cost-effective at the lower willingness-to-pay threshold. A 60% and 90% lower DAA price had 36% and >99% probability of being cost-saving, respectively. Sensitivity analyses suggest integrated treatment was cost-effective at the lower willingness-to-pay threshold (>60% probability) across different assumptions on HCV treatment and disease care costs with 30% DAA price reduction, and became cost-saving with 60%-90% price reductions. Integrated hepatitis C virus treatment for people who inject drugs in community settings is likely cost-effective compared with standard-of-care referral pathways in Norway and may be cost-saving in settings with particular characteristics.


An assessment of the current status of foot-and-mouth disease in Nigeria.
Foot-and-mouth disease has been widespread throughout the country in recent years. The disease occurs mainly in cattle though spillover of infections has been observed in sheep and pigs. Virus types A, SAT 2 and SAT 1 are the usual cause of outbreaks. The present field control method is a 6-monthly vaccination schedulae for animals in government ranches, the few semi-commercial ranches and piggeries as well as for other valuable animals and exotic animals of high production quality. Arrangements are under way to institute a strict and more comprehensive control programme against the disease in view of the envisaged expansion of livestock development projects and improved zoo-sanitary status projected for our 3rd National Livestock Development Plan. A national policy of a barrier and frontier vaccination programme supplemented with strategic vaccinations in vulnerable foci is here recommended and discussed on the basis of a survey on the present status of the disease.


Control of mammalian circadian rhythm by CKIepsilon-regulated proteasome-mediated PER2 degradation.
The mammalian circadian regulatory proteins PER1 and PER2 undergo a daily cycle of accumulation followed by phosphorylation and degradation. Although phosphorylation-regulated proteolysis of these inhibitors is postulated to be essential for the function of the clock, inhibition of this process has not yet been shown to alter mammalian circadian rhythm. We have developed a cell-based model of PER2 degradation. Murine PER2 (mPER2) hyperphosphorylation induced by the cell-permeable protein phosphatase inhibitor calyculin A is rapidly followed by ubiquitination and degradation by the 26S proteasome. Proteasome-mediated degradation is critically important in the circadian clock, as proteasome inhibitors cause a significant lengthening of the circadian period in Rat-1 cells. CKIepsilon (casein kinase Iepsilon) has been postulated to prime PER2 for degradation. Supporting this idea, CKIepsilon inhibition also causes a significant lengthening of circadian period in synchronized Rat-1 cells. CKIepsilon inhibition also slows the degradation of PER2 in cells. CKIepsilon-mediated phosphorylation of PER2 recruits the ubiquitin ligase adapter protein beta-TrCP to a specific site, and dominant negative beta-TrCP blocks phosphorylation-dependent degradation of mPER2. These results provide a biochemical mechanism and functional relevance for the observed phosphorylation-degradation cycle of mammalian PER2. Cell culture-based biochemical assays combined with measurement of cell-based rhythm complement genetic studies to elucidate basic mechanisms controlling the mammalian clock.


Erectile function recovery rate after radical prostatectomy: a meta-analysis.
Erectile function recovery (EFR) rates after radical prostatectomy (RP) vary greatly based on a number of factors, such as erectile dysfunction (ED) definition, data acquisition means, time-point postsurgery, and population studied. To conduct a meta-analysis of carefully selected reports from the available literature to define the EFR rate post-RP. EFR rate after RP. An EMBASE and MEDLINE search was conducted for the time range 1985-2007. Articles were assessed blindly by strict inclusion criteria: report of EFR data post-RP, study population >or=50 patients, >or=1 year follow-up, nerve-sparing status declared, no presurgery ED, and no other prostate cancer therapy. Meta-analysis was conducted to determine the EFR rate and relative risks (RR) for dichotomous subgroups. A total of 212 relevant studies were identified; only 22 (10%) met the inclusion criteria and were analyzed (9,965 RPs, EFR data: 4,983 subjects). Mean study population size: 226.5, standard deviation = 384.1 (range: 17-1,834). Overall EFR rate was 58%. Single center series publications (k = 19) reported a higher EFR rate compared with multicenter series publications (k = 3): 60% vs. 33%, RR = 1.82, P = 0.001. Studies reporting >or=18-month follow-up (k = 10) reported higher EFR rate vs. studies with <18-month follow-up (k = 12), 60% vs. 56%, RR = 1.07, P = 0.02. Open RP (k = 16) and laparoscopic RP (k = 4) had similar EFR (57% vs. 58%), while robot-assisted RP resulted in a higher EFR rate (k = 2), 73% compared with these other approaches, P = 0.001. Patients <60 years old had a higher EFR rate vs. patients >or=60 years, 77% vs. 61%, RR = 1.26, P = 0.001. These data indicate that most of the published literature does not meet strict criteria for reporting post-RP EFR. Single and multiple surgeon series have comparable EFR rates, but single center studies have a higher EFR. Younger men have higher EFR and no significant difference in EFR between ORP and LRP is evident.


Concordance between RT-PCR-based detection of respiratory viruses from nasal swabs collected for viral testing and nasopharyngeal swabs collected for bacterial testing.
Epidemiologic studies of respiratory infections frequently rely on separate sample collections for the detection of bacteria and viruses. The requirement for two specimens presents cost, logistical, and acceptability challenges. To determine the agreement in detection of respiratory viruses using RT-PCR between two different types of samples collected on the same day: nasal swabs preserved in viral transport medium (NS) and nasopharyngeal swabs preserved in skim milk-tryptone-glucose-glycerol [STGG] medium (NP), the current standard for pneumococcal colonization studies. Paired NS and NP samples were collected between May 2009 and September 2011 as part of the RESPIRA-PERU study, a large prospective cohort of Andean children <3 years of age. NS samples used polyester swabs and viral transport medium whereas NP samples used rayon wire-handled swabs and STGG medium. Samples were tested for influenza, human metapneumovirus (MPV), respiratory syncytial virus (RSV), human rhinovirus (HRV), parainfluenza virus 3 (PIV3) and adenovirus (ADV) using real-time RT-PCR. We calculated the agreement, and compared cycle thresholds (CT) between NP and NS samples. Among 226 paired NP-NS samples, we observed very high agreement with a Kappa statistic ranging from 0.71 for ADV to 0.97 for MPV. CT values were similar for both strategies. NP samples preserved in STGG provide a simple and reliable strategy for identification of both pneumococcus and respiratory viruses. This single specimen collection strategy could be used for epidemiologic studies, especially in resource-limited settings. Furthermore, archived NP-STGG specimens from previous studies could be reliably tested by RT-PCR for viruses.


The 13C urea breath test in the diagnosis of Helicobacter pylori infection.
The urea breath test (UBT) is one of the most important non-invasive methods for detecting Helicobacter pylori infection. The test exploits the hydrolysis of orally administered urea by the enzyme urease, which H pylori produces in large quantities. Urea is hydrolysed to ammonia and carbon dioxide, which diffuses into the blood and is excreted by the lungs. Isotopically labelled CO2 can be detected in breath using various methods. Labelling urea with 13C is becoming increasingly popular because this non-radioactive isotope is innocuous and can be safely used in children and women of childbearing age. Breath samples can also be sent by post or courier to remote analysis centres. The test is easy to perform and can be repeated as often as required in the same patient. A meal must be given to increase the contact time between the tracer and the H pylori urease inside the stomach. The test has been simplified to the point that two breath samples collected before and 30 minutes after the ingestion of urea in a liquid form suffice to provide reliable diagnostic information. The cost of producing 13C-urea is high, but it may be possible to reduce the dosage further by administering it in capsule form. An isotope ratio mass spectrometer (IRMS) is generally used to measure 13C enrichment in breath samples, but this machine is expensive. In order to reduce this cost, new and cheaper equipment based on non-dispersive, isotope selective, infrared spectroscopy (NDIRS) and laser assisted ratio analysis (LARA) have recently been developed. These are valid alternatives to IRMS although they cannot process the same large number of breath samples simultaneously. These promising advances will certainly promote the wider use of the 13C-UBT, which is especially useful for epidemiological studies in children and adults, for screening patients before endoscopy, and for assessing the efficacy of eradication regimens.


Scope-of-practice laws and expanded health services: the case of underserved women and advanced cervical cancer diagnoses.
Underserved women (rural, minority or poor) are disproportionally diagnosed with late-stage cervical cancer, indicative of inadequate access to, and use of, preventative healthcare. The Institute of Medicine (IOM) has proposed that nurse practitioners (NP) can address provider shortages among underserved populations, but to reduce shortages, scope-of-practice laws that restrict the delivery of care, must be revised. We examined the IOM recommendation of NP expanded scope-of-practice laws on reducing the disparity of underserved women diagnosed with late-stage cervical cancer. We examined the cohort of 10 673 women diagnosed with cervical cancer between 2010 and 2014 and reported to the Surveillance, Epidemiology and End Results cancer registry. We linked state-level laws regarding NP scope-of-practice to patients with cancer by their state of residence, diagnosis date and law enactment date. Hierarchical regression was used to explore NP full scope-of-practice law's impact on late-stage cancer diagnoses considering the moderating effect of women living in medically underserved areas. We adjusted for known confounders available in this population-based data set. Medically underserved women living in states with laws that restrict NP full scope-of-practice are twofold more likely to be diagnosed with late-stage cancer; adjusted OR and 95% CI (OR 2.08, 95% CI 1.4 to 3.1). These disparities were not observed among underserved women living in areas with NP full scope-of-practice laws (OR 0.95, 95% CI 0.7 to 1.3). NP full scope-of-practice laws could provide a pragmatic and cost-effective solution to healthcare provider shortages associated with late stage of cervical cancer diagnoses among underserved women.


The national sports safety in secondary schools benchmark (N4SB) study: defining athletic training practice characteristics.
Increased rates of sport participation and sport-related injury have led to greater emphasis on and attention to medical care of student-athletes in the secondary school setting. Access to athletic training services is seen as a critical factor for delivering adequate injury prevention and medical care to student-athletes. However, few data are available regarding practice characteristics of athletic trainers (ATs) in this setting. To characterize the practices of secondary school athletic trainers (ATs). Descriptive study. Web-based survey. A total of 17 558 ATs with current National Athletic Trainers' Association membership were identified for survey distribution. Of these, 4232 ATs indicated that they practiced in the secondary school setting, and 4045 completed some part of the survey. A Web-based survey was used to obtain demographic information about ATs and their secondary schools and characteristics of athletic training practice. Descriptive data regarding the athletic trainer's personal characteristics, secondary school characteristics, and practice patterns are reported as percentages and frequencies. Most respondents were in the early stages of their careers and relatively new to the secondary school practice setting. Nearly two-thirds (62.4%; n = 2522) of respondents had 10 or fewer years of experience as secondary school ATs, 52% (n = 2132) had been certified for 10 or fewer years, and 53.4% (n = 2164) had 10 or fewer years of experience in any practice setting. The majority of respondents (85%) worked in public schools with enrollment of 1000 to 1999 (35.5%) and with football (95.5%). More than half of respondents were employed directly by their school. Most respondents (50.6%) reported an athletic training budget of less than $4000. The majority of ATs performed evaluations (87.5%) on-site all of the time, with a smaller percentage providing treatments (73.3%) or rehabilitation (47.4%) services all of the time. This is the first study to describe secondary school athletic training that reflects national practice trends. To improve the quality of athletic training care and to support and improve current working conditions, the profession must examine how its members practice on a day-to-day basis.


Circulating miRNome detection analysis reveals 537 miRNAS in plasma, 625 in extracellular vesicles and a discriminant plasma signature of 19 miRNAs in children with retinoblastoma from which 14 are also detected in corresponding primary tumors.
miRNAs regulate post-transcriptional gene expression in metazoans, and thus are involved in many fundamental cellular biological processes. Extracellular miRNAs are also found in most human biofluids including plasma. These circulating miRNAs constitute a long distance inter cellular communication system and are potentially useful biomarkers. High throughput technologies like microarrays are able to scan a complete miRNome providing useful detection scores that are underexplored. We proposed to answer how many and which miRNAs are detectable in plasma or extracellular vesicles as these questions have not yet been answered. We set out to address this knowledge gap by analyzing the mirRNome in plasma and corresponding extracellular vesicles (EVs) from 12 children affected by retinoblastoma (Rb) a childhood intraocular malignant tumor, as well as from 12 healthy similarly aged controls. We calculated an average of 537 detectable miRNAs in plasma and 625 in EVs. The most miRNA enriched compartment were EVs from Rb cases with an average of 656 detectable elements. Using hierarchical clustering with the detection scores, we generated broad detection mirnome maps and identified a plasma signature of 19 miRNAs present in all Rb cases that is able to discriminate cases from controls. An additional 9 miRNAs were detected in all the samples; within this group, miRNA-5787 and miRNA-6732-5p were highly abundant and displayed very low variance across all the samples, suggesting both are good candidates to serve as plasma references or normalizers. Further exploration considering participant's sex, allowed discovering 5 miRNAs which corresponded only to females and 4 miRNAs corresponding only to males. Target and pathway analysis of these miRNAs revealed hormonal function including estrogen, thyroid signaling pathways and testosterone biosynthesis. This approach allows a comprehensive unbiased survey of a circulating miRNome landscape, creating the possibility to define normality in mirnomic profiles, and to locate where in these miRNome profiles promising and potentially useful circulating miRNA signatures can be found.


Preoperative stereotactic hookwire localization of nonpalpable breast lesions with and without the use of a further stereotactic check film.
A series of 394 women underwent 399 stereotactically guided preoperative hook-wire localization of non-palpable breast lesions. 250 lesions were localized without checking the position of the needle tip with a further stereo film. Later the position of the localization needle was checked by means of a further stereo film in 149 lesions. If the needle tip was beside the lesion (failed x- or y-coordinates), we took a new stereo film. Errors in needle depth (z-coordinate) produced particularly subtle signs. Therefore a polystyrene phantom and a metallic object was used to ascertain how to recognize needle depth error on the stereotactic film. In 51 lesions readjustment of the needle depth was necessary. Measured by our criteria, successful and acceptable localization procedures with or without a check stereo-image film showed no significant differences. Unsuccessful localizations without the check film were significantly higher (16.0%) than with the check film, without readjusting the needle depth (7.1%) or after readjusting the needle depth (9.8%). These unsuccessful localizations were mostly architectural distortions or microcalcifications. Our results suggest that success of the localization procedure is better by using the stereo check film as without it, even in lesions which are difficult to resolve and target on films. However, readjustment of the needle depth did not always lead to successful localization.


Divergent temporal courses for liking versus wanting in response to persuasion.
Liking and wanting are two foundational processes underlying the individual's reward system. Whereas the differences between liking and wanting have been studied extensively in the context of substance addiction, there have been few empirical studies of their manifestation in ordinary, nonaddictive contexts of behavior. In particular, previous research showed a temporal divergence of liking and wanting over repeated exposures to drugs; however, the temporal progression of liking versus wanting in response to ordinary stimuli remains less understood. This research tests the temporal divergence of liking versus wanting responses in a prevalent domain-namely, in response to persuasive messages-using a highly powered field experiment involving over 1,000 real-life stimuli and 100,000 subjects. Subjects were exposed to sequences of TV advertisements in random orderings and indicated how much they liked the persuasive messages and wanted the promoted items. We found, not surprisingly, an overall positive correlation whereby greater message liking was associated with greater wanting of the item. However, underlying the overall correlation, we found a sharp divergence with respect to the serial progression of liking versus wanting. Specifically, message liking was highest early in the sequence, whereas wanting of the promoted item was highest late in the sequence. We posit and provide evidence that this divergence is due to an appetizing effect for wanting, in contrast to a habituation and reference adaptation effect for liking. We discuss the implications of our results for theories of liking versus wanting for addictive as well as ordinary substances. (PsycINFO Database Record (c) 2020 APA, all rights reserved).


Clinical findings in obligate carriers of type I Usher syndrome.
Seventeen obligate carriers from nine families with autosomal recessive Usher syndrome type I underwent otological, audiological, vestibular, and ophthalmological examination in order to identify possible manifestations of heterozygosity. Linkage studies were performed and six families showed linkage to chromosome region 11q13.5 while 3 families have so far failed to show linkage to the candidate regions. Eight obligate carriers had an abnormal pure-tone audiogram. Two different audiometric patterns could be distinguished when hearing loss was corrected for age and sex. Four carriers (24%) had significant sensorineural hearing loss (SNHL) which increased at higher frequencies. The other 13 carriers had SNHL of about 10 dB at 0.25 and 0.5 kHz, but less at higher frequencies. Vestibular findings were generally normal. Electro-oculography demonstrated a significant lower mean light peak/dark trough ratio in Usher type I carriers compared to normal control individuals. The methods used in this study were found not to be specific enough to clinically identify carriers of Usher type I syndrome. Nevertheless it is remarkable that a number of obligate carriers showed significant audiological and ophthalmological abnormalities.


Efficacy of the EDP-M Scheme Plus Adjunctive Surgery in the Management of Patients with Advanced Adrenocortical Carcinoma: The Brescia Experience.
Etoposide, doxorubicin and cisplatin plus oral mitotane (EDP-M) comprise the reference regimen in the management of patients with adrenocortical carcinoma (ACC). In this paper, we described the outcome of 58 patients with advanced/metastatic ACC consecutively treated with EDP-M in a reference center for this rare disease in Italy. In this series, EDP-M obtained a partial response in 50% of patients; median progression free survival (PFS) and overall survival were 10.1 months (95% Confidence Interval [CI 95%] 8.1-12.8) and 18.7 months (95% CI: 14.6-22.8), respectively. EDP-M was not interrupted in five patients showing disease progression after two cycles without the appearance of new lesions and mitotane levels below the therapeutic range. In two of them, the disease remained stable at further imaging evaluations and the other three obtained a partial response. Twenty-six responding patients underwent surgery of residual disease and 13 of them became disease free. Surgery identified a pathological complete response (pCR) in four patients (7%) and Ki67 expression in post-chemotherapy tumor specimens, inferior to 15% (median value), was associated with better PFS and survival. In the present study, the EDP-M regimen is confirmed to have a limited efficacy. Early disease progression does not mean treatment inefficacy. Surgery of residual disease in partially responding patients allows for the detection of pCR in few of them and this condition is predictive of long-term survival. Ki67 expression of post-chemotherapy residual disease could be an additional prognostic factor that deserves to be studied further.


miRNA Polymorphisms and Risk of Cardio-Cerebrovascular Diseases: A Systematic Review and Meta-Analysis.
Recently extensive focus has been concentrated on the role of miRNAs in the initiation and progression of cardio-cerebrovascular diseases (CCDs) which constitute a range of conditions including cardiovascular diseases (CVDs, especially coronary artery disease (CAD)), congenital heart disease (CHD) and cerebrovascular diseases (CBVDs, especially the ischemic stroke (IS)). An increasing number of studies are evaluating the association between different miRNA polymorphisms and risk of CCDs, but results have been inconclusive. This study represents a comprehensive systematic review and meta-analysis of the association between miRNA polymorphisms and risk of CCDs. PubMed, Embase, Scopus, and Web of Science were queried to identify eligible articles. Odds ratios and 95% confidence intervals were used to assess the association of miRNA polymorphisms with CCD susceptibility. A total of 51 eligible articles evaluating the association of 31 miRNA polymorphisms were identified. Meta-analysis was performed for six miRNA polymorphisms. miR-146a rs2910164 (30 studies: 13,186 cases/14,497 controls), miR-149 rs2292832 (Nine studies: 4116 cases/3511 controls), miR-149 rs71428439 (Three studies: 1556 cases/1567 controls), miR-196a2 rs11614913 (20 studies: 10,144 cases/10,433 controls), miR-218 rs11134527 (Three studies: 2,322 cases/2,754 controls) were not associated with overall CCD. miR-499 rs3746444 was associated with CCD (20 studies: 9564 cases/8876 controls). In the subgroups, rs2910164 and rs3746444 were only associated with CVDs, especially CAD. In conclusion, the results support the existence of a role for miR-146a rs2910164 and miR-499 rs3746444 in determining susceptibility to CCDs, especially CAD.


The Utility of Magnetic Resonance Imaging for Detecting Unstable Cervical Spine Injuries in the Neurologically Intact Traumatized Patient Following Negative Computed Tomography Imaging.
Neurologically intact blunt trauma patients with persistent neck pain and negative computed tomography (CT) imaging frequently undergo magnetic resonance imaging (MRI) for evaluation of occult cervical spine injury. There is a paucity of data to support or refute this practice. This study was therefore performed to evaluate the utility of cervical spine MRI in neurologically intact blunt trauma patients with negative CT imaging. A retrospective review was performed of all neurologically intact blunt trauma patients presenting to a level 1 trauma center from 2005 to 2015 with persistent neck pain and negative CT imaging. The proportion of patients with positive MRI findings, subsequent treatment, and time required to obtain MRI results was evaluated. Of 223 patients meeting inclusion criteria, 11 had positive MRI findings; however, no patients were found to have unstable injuries requiring surgical treatment. The process for a complete evaluation of unstable cervical spine injury from the time of obtaining a CT scan was 19 hours and 43 minutes. Eleven patients had positive MRI findings, yet these findings did not alter treatment. In contrast, the time required to obtain MRI results may substantially delay patient care. IV (retrospective case series) CLINICAL RELEVANCE: Our results demonstrate that MRI has limited utility in neurologically intact blunt trauma patients with negative CT imaging.


VDAC1: from structure to cancer therapy.
Here, we review current evidence pointing to the function of VDAC1 in cell life and death, and highlight these functions in relation to cancer. Found at the outer mitochondrial membrane, VDAC1 assumes a crucial position in the cell, controlling the metabolic cross-talk between mitochondria and the rest of the cell. Moreover, its location at the boundary between the mitochondria and the cytosol enables VDAC1 to interact with proteins that mediate and regulate the integration of mitochondrial functions with other cellular activities. As a metabolite transporter, VDAC1 contributes to the metabolic phenotype of cancer cells. This is reflected by VDAC1 over-expression in many cancer types, and by inhibition of tumor development upon silencing VDAC1 expression. Along with regulating cellular energy production and metabolism, VDAC1 is also a key protein in mitochondria-mediated apoptosis, participating in the release of apoptotic proteins and interacting with anti-apoptotic proteins. The involvement of VDAC1 in the release of apoptotic proteins located in the inter-membranal space is discussed, as is VDAC1 oligomerization as an important step in apoptosis induction. VDAC also serves as an anchor point for mitochondria-interacting proteins, some of which are also highly expressed in many cancers, such as hexokinase (HK), Bcl2, and Bcl-xL. By binding to VDAC, HK provides both metabolic benefit and apoptosis-suppressive capacity that offers the cell a proliferative advantage and increases its resistance to chemotherapy. VDAC1-based peptides that bind specifically to HK, Bcl2, or Bcl-xL abolished the cell's abilities to bypass the apoptotic pathway. Moreover, these peptides promote cell death in a panel of genetically characterized cell lines derived from different human cancers. These and other functions point to VDAC1 as a rational target for the development of a new generation of therapeutics.


Cutaneous Injection of Resiniferatoxin Completely Alleviates and Prevents Nerve-Injury-Induced Neuropathic Pain.
Fifth lumbar (L5) nerve injury in rodent produces neuropathic manifestations in the corresponding hind paw. The aim of this study was to investigate the effect of cutaneous injection of resiniferatoxin (RTX), a TRPV1 receptor agonist, in the rat's hind paw on the neuropathic pain induced by L5 nerve injury. The results showed that intraplantar injection of RTX (0.002%, 100 µL) (1) completely reversed the development of chronic thermal and mechanical hypersensitivity; (2) completely prevented the development of nerve-injury-induced thermal and mechanical hypersensitivity when applied one week earlier; (3) caused downregulation of nociceptive pain markers, including TRPV1, IB4 and CGRP, and upregulation of VIP in the ipsilateral dorsal horn of spinal cord and dorsal root ganglion (DRG) immunohistochemically and a significant reduction in the expression of TRPV1 mRNA and protein in the ipsilateral DRG using Western blot and qRT-PCR techniques; (4) caused downregulation of PGP 9.5- and CGRP-immunoreactivity in the injected skin; (5) produced significant suppression of c-fos expression, as a neuronal activity marker, in the spinal neurons in response to a second intraplantar RTX injection two weeks later. This work identifies the ability of cutaneous injection of RTX to completely alleviate and prevent the development of different types of neuropathic pain in animals and humans.


Galectin-3 promotes chronic activation of K-Ras and differentiation block in malignant thyroid carcinomas.
Anaplastic thyroid carcinomas are deadly tumors that are highly invasive, particularly into the bones. Although oncogenic Ras can transform thyroid cells into a severely malignant phenotype, thyroid carcinomas do not usually harbor ras gene mutations. Therefore, it is not known whether chronically active Ras contributes to thyroid carcinoma cell proliferation, although galectin-3 (Gal-3), which is strongly expressed in thyroid carcinomas but not in benign tumors or normal glands, is known to act as a K-Ras chaperone that stabilizes and drives K-Ras.GTP nanoclustering and signal robustness. Here, we examined the possibility that thyroid carcinomas expressing high levels of Gal-3 exhibit chronically active K-Ras. Using cell lines representing three types of malignant thyroid tumors--papillary, follicular, and anaplastic--we investigated the possible correlation between Gal-3 expression and active Ras content, and then examined the therapeutic potential of the Ras inhibitor S-trans, trans-farnesylthiosalicylic acid (FTS; Salirasib) for thyroid carcinoma. Thyroid carcinoma cells strongly expressing Gal-3 showed high levels of K-Ras.GTP expression, and K-Ras.GTP transmitted strong signals to extracellular signal-regulated kinase. FTS disrupted interactions between Gal-3 and K.Ras, strongly reduced K-Ras.GTP and phospho-extracellular signal-regulated kinase expression, and enhanced the expression of the cell cycle inhibitor p21 as well as of the thyroid transcription factor 1, which is involved in thyroid cell differentiation. FTS also inhibited anaplastic thyroid carcinoma cell proliferation in vitro and tumor growth in nude mice. We conclude that wild-type K-Ras.GTP in association with Gal-3 contributes to thyroid carcinoma malignancy and that Ras inhibition might be a useful treatment strategy against these deadly tumors.


Self-calibrated pulse oximetry algorithm based on photon pathlength change and the application in human freedivers.
Pulse oximetry estimates the arterial oxygen saturation of hemoglobin (SaO2) based on relative changes in light intensity at the cardiac frequency. Commercial pulse oximeters require empirical calibration on healthy volunteers, resulting in limited accuracy at low oxygen levels. An accurate, self-calibrated method for estimating SaO2 is needed to improve patient monitoring and diagnosis. Given the challenges of calibration at low SaO2 levels, we pursued the creation of a self-calibrated algorithm that can effectively estimate SaO2 across its full range. Our primary objective was to design and validate our calibration-free method using data collected from human subjects. We developed an algorithm based on diffuse optical spectroscopy measurements of cardiac pulses and the modified Beer-Lambert law (mBLL). Recognizing that the photon mean pathlength (⟨L⟩) varies with SaO2 related absorption changes, our algorithm aligns/fits the normalized ⟨L⟩ (across wavelengths) obtained from optical measurements with its analytical representation. We tested the algorithm with human freedivers performing breath-hold dives. A continuous-wave near-infrared spectroscopy probe was attached to their foreheads, and an arterial cannula was inserted in the radial artery to collect arterial blood samples at different stages of the dive. These samples provided ground-truth SaO2 via a blood gas analyzer, enabling us to evaluate the accuracy of SaO2 estimation derived from the NIRS measurement using our self-calibrated algorithm. The self-calibrated algorithm significantly outperformed the conventional method (mBLL with a constant ⟨L⟩ ratio) for SaO2 estimation through the diving period. Analyzing 23 ground-truth SaO2 data points ranging from 41% to 100%, the average absolute difference between the estimated SaO2 and the ground truth SaO2 is 4.23%±5.16% for our algorithm, significantly lower than the 11.25%±13.74% observed with the conventional approach. By factoring in the variations in the spectral shape of ⟨L⟩ relative to SaO2, our self-calibrated algorithm enables accurate SaO2 estimation, even in subjects with low SaO2 levels.


Role of the pharmacist in pre-exposure chemoprophylaxis (PrEP) therapy for HIV prevention.
With a global estimate of 2.5 million new infections of HIV occurring yearly, discovering novel methods to help stem the spread of the virus is critical. The use of antiretroviral chemoprophylaxis for preventing HIV after accidental or occupational exposure and in maternal to fetal transmission has become a widely accepted method to combat HIV. Based on this success, pre-exposure chemoprophylaxis (PrEP) is being explored in at-risk patient populations such as injecting drug users, female sex workers and men who have sex with men. This off-label and unmonitored use has created a need for education and intervention by pharmacists and other healthcare professionals. Pharmacists should educate themselves on PrEP and be prepared to counsel patients about their means of obtaining it (e.g. borrowing or sharing medications and ordering from disreputable Internet pharmacies). They should also be proactive about medication therapy management in these patients due to clinically important drug interactions with PrEP medications. Only one trial exploring the safety and efficacy of tenofovir as PrEP has been completed thus far. However, five ongoing trials are in various stages and two additional studies are scheduled for the near future. Unfortunately, studies in this arena have met with many challenges that have threatened to derail progress. Ethical controversy surrounding post-trial care of participants who seroconvert during studies, as well as concerns over emerging viral resistance and logistical site problems, have already halted several PrEP trials. Information about these early trials has already filtered down to affected individuals who are experimenting with this unproven therapy as an "evening before pill". The potential for PrEP is promising; however, more extensive trials are necessary to establish its safety and efficacy. Pharmacists are well-positioned to play a key role in helping patients make choices about PrEP, managing their therapy, and developing policy with an eye towards the future.


Mean 20-year followup of Bernese periacetabular osteotomy.
The goal of the Bernese periacetabular osteotomy is to correct the deficient acetabular coverage in hips with developmental dysplasia to prevent secondary osteoarthrosis. We determined the 20-year survivorship of symptomatic patients treated with this procedure, determined the clinical and radiographic outcomes of the surviving hips, and identified factors predicting poor outcome. We retrospectively evaluated the first 63 patients (75 hips) who underwent periacetabular osteotomy at the institution where this technique was developed. The mean age of the patients at surgery was 29 years (range, 13-56 years), and preoperatively 24% presented with advanced grades of osteoarthritis. Four patients (five hips) were lost to followup and one patient (two hips) died. The remaining 58 patients (68 hips) were followed for a minimum of 19 years (mean, 20.4 years; range, 19-23 years) and 41 hips (60%) were preserved at last followup. The overall mean Merle d'Aubigné and Postel score decreased in comparison to the 10-year value and was similar to the preoperative score. We observed no major changes in any of the radiographic parameters during the 20-year postoperative period except the osteoarthritis score. We identified six factors predicting poor outcome: age at surgery, preoperative Merle d'Aubigné and Postel score, positive anterior impingement test, limp, osteoarthrosis grade, and the postoperative extrusion index. Periacetabular osteotomy is an effective technique for treating symptomatic developmental dysplasia of the hip and can maintain the natural hip at least 19 years in selected patients. Level III, prognostic study.


Improving Sensitivity to Detect Mild Cognitive Impairment: Cognitive Load Dual-Task Gait Speed Assessment.
Longitudinal research indicates that cognitive load dual-task gait assessment is predictive of cognitive decline and thus might provide a sensitive measure to screen for mild cognitive impairment (MCI). However, research among older adults being clinically evaluated for cognitive concerns, a defining feature of MCI, is lacking. The present study investigated the effect of performing a cognitive task on normal walking speed in patients presenting to a memory clinic with cognitive complaints. Sixty-one patients with a mean age of 68 years underwent comprehensive neuropsychological testing, clinical interview, and gait speed (simple- and dual-task conditions) assessments. Thirty-four of the 61 patients met criteria for MCI. Repeated measure analyses of covariance revealed that greater age and MCI both significantly associated with slower gait speed, ps<.05. Follow-up analysis indicated that the MCI group had significantly slower dual-task gait speed but did not differ in simple-gait speed. Multivariate linear regression across groups found that executive attention performance accounted for 27.4% of the variance in dual-task gait speed beyond relevant demographic and health risk factors. The present study increases the external validity of dual-task gait assessment of MCI. Differences in dual-task gait speed appears to be largely attributable to executive attention processes. These findings have clinical implications as they demonstrate expected patterns of gait-brain behavior relationships in response to a cognitive dual task within a clinically representative population. Cognitive load dual-task gait assessment may provide a cost efficient and sensitive measure to detect older adults at high risk of a dementia disorder. (JINS, 2017, 23, 493-501).


Mild traumatic brain injury. A primer for understanding its impact on employee return to work.
1. Mild head injuries are common occurrences in the United States. 2. If not properly understood and managed, mild head injuries can be unnecessarily costly in terms of lost work days, financial expenditures, and human suffering. 3. If properly understood and treated, most victims of mild head injuries can return to productive lifestyles. 4. Factors that place persons at high risk for more severe symptoms and/or more lengthy recovery periods are easy to conceptualize.


Alkalimonas collagenimarina sp. nov., a psychrotolerant, obligate alkaliphile isolated from deep-sea sediment.
A psychrotolerant, obligately alkaliphilic, collagenolytic enzyme-producing bacterium, strain AC40(T), was isolated from a deep-sea sediment off Torishima Island, Japan, at a depth of 4026 m. Phylogenetic analysis of 16S rRNA gene sequences indicated that this bacterium was closely related to members of the genus Alkalimonas, with highest sequence similarity (97.9 %) to Alkalimonas delamerensis 1E1(T). DNA-DNA hybridization experiments of strain AC40(T) with A. delamerensis 1E1(T) revealed a level of relatedness of less than 30 %. Cells of strain AC40(T) were strictly aerobic, rod-shaped, Gram-negative and motile by means of a single polar flagellum. The organism grew over a range of temperatures from 5 to 37 degrees C and at initial pH values between 7.0 and 10.5. Optimal growth was observed at 33 degrees C and at pH 8.5-10.0. Cellular fatty acids of strain AC40(T) were predominantly saturated and mono-unsaturated straight-chain components (C(16 : 0) and C(18 : 1)). The major isoprenoid quinone was Q-8. The G+C content of the DNA was 49.3 mol%. Phylogenetic characteristics, physiological properties and DNA-DNA hybridization data indicate that strain AC40(T) represents a novel species of the genus Alkalimonas, for which the name Alkalimonas collagenimarina sp. nov. is proposed. The type strain is AC40(T) (=JCM 14267(T)=NCIMB 14266(T)).


Near-room-temperature Chern insulator and Dirac spin-gapless semiconductor: nickel chloride monolayer.
A great obstacle for practical applications of the quantum anomalous Hall (QAH) effect is the lack of suitable QAH materials (Chern insulators) with a large non-trivial band gap, room-temperature magnetic order and high carrier mobility. Based on first-principles calculations it is shown here that a nickel chloride (NiCl3) monolayer has all these characteristics. Thus, the NiCl3 monolayer represents a new class of Dirac materials with Dirac spin-gapless semiconducting properties and high-temperature ferromagnetism (∼400 K). Taking into account the spin-orbit coupling, the NiCl3 monolayer becomes an intrinsic Chern insulator with a large non-trivial band gap of ∼24 meV, corresponding to an operating temperature as high as ∼280 K at which the quantum anomalous Hall effect could be observed. The calculated large non-trivial gap, high Curie temperature and single-spin Dirac states reported herein for the NiCl3 monolayer led us to propose that this material gives a great promise for potential realization of a near-room temperature QAH effect and potential applications in spintronics. Last but not least the calculated Fermi velocities of Dirac fermions of about 4 × 105 m s-1 indicate very high mobility in NiCl3 monolayers.


The Effects of Three Types of Sexual Orientation Victimization on HIV Sexual Risk Behavior Among Black South African Men Who Have Sex With Men (MSM).
The goal of this study is to examine the relations between histories of three types of sexual orientation victimization (childhood, personal, and institutional) and HIV sexual risk behavior among Black South African men who have sex with men (MSM). Secondarily, this study examines whether marijuana use and problem drinking mediate the relations. Participants were 125 Black MSM recruited from neighborhoods in Eastern Cape Province, South Africa. Questionnaires administered through audio computerized self-interviewing assessed sexual orientation victimizations, problem drinking and marijuana use, and unprotected anal sex with casual partners. Data were analyzed using multiple regression and multiple mediation modeling.Personal and institutional sexual victimizations were associated with condomless anal sex. Childhood sexual orientation victimization was positively associated with problem drinking. Neither problem drinking nor marijuana use mediated the relations between sexual orientation victimizations and having condomless anal sex with casual partners.


Deletion of the Plasmodium falciparum merozoite surface protein 7 gene impairs parasite invasion of erythrocytes.
Merozoite surface proteins have been implicated in the initial attachment to the host red blood cell membrane that begins the process of invasion, an important step in the life cycle of the malaria parasite. In Plasmodium falciparum, merozoite surface proteins include several glycosylphosphatidyl inositol-anchored proteins and peripheral proteins attached to the membrane through protein-protein interactions. The most abundant of these proteins is the merozoite surface protein 1 (MSP1) complex, encoded by at least three genes: msp1, msp6, and msp7. The msp7 gene is part of a six-member multigene family in Plasmodium falciparum. We have disrupted msp7 in the Plasmodium falciparum D10 parasite, as confirmed by Southern hybridization. Immunoblot and indirect immunofluorescence analyses confirmed the MSP7 null phenotype of D10DeltaMSP7 parasites. The synthesis, distribution, and processing of MSP1 were not affected in this parasite line. The level of expression and cellular distribution of the proteins MSP1, MSP3, MSP6, MSP9, and SERA5 remained comparable to those for the parental line. Furthermore, no significant change in the expression of MSP7-related proteins, except for that of MSRP5, was detected at the transcriptional level. The lack of MSP7 was not lethal at the asexual blood stage, but it did impair invasion of erythrocytes by merozoites to a significant degree. Despite this reduction in efficiency, D10DeltaMSP7 parasites did not show any obvious preference for alternate pathways of invasion.


The role of the autopsy in modern medical practice. A review.
The role of the autopsy in modern medical practice is reviewed in the light of waning clinical interest. After a historical introduction, the reasons for this lessening interest in the autopsy, its values and its limitations are discussed, and followed by consideration of the possible future pattern of postmortem investigation.


Prostaglandins: role in renin regulation and mediation of antihypertensive drug effects.
A role of prostaglandins in renin regulation has been recognized in animals and man. Indomethacin, a blocker of prostaglandin synthesis, lowers plasma renin activity, renal prostaglandin synthesis and causes sodium retention in man. It is shown that the sodium retaining effect of indomethacin can be separated from its effect on plasma renin activity. A more precise definition of the mechanisms whereby prostaglandins influence renin release is given showing that the baroreceptor and the macula densa mechanisms of renin release are affected by prostaglandins. Investigations aiming at the indentification of the prostaglandin responsible for cylooxygenase--dependent renin regulator reveal that PGI2 is a prominent prostaglandin biosynthesized in the renal cortex and causes renin release in vivo and in vitro. A hypothesis is presented which postulates that prostaglandin dependent renin release is mediated by prostacyclin. Various antihypertensive drug effects can be antagonized by blockers of prostaglandin biosynthesis. Possible mechanisms of such drug interactions between propranolol, hydralazine and diuretics on the one hand and indomethacin and aspirin on the other hand are discussed.


Genome-wide transcriptome analysis of toxigenic Fusarium verticillioides in response to variation of temperature and water activity on maize kernels.
Fusarium verticillioides is one of the important mycotoxigenic pathogens of maize since it causes severe yield losses and produces fumonisins (FBs) to threaten human and animal health. Previous studies showed that temperature and water activity (aw) are two pivotal environmental factors affecting F. verticillioides growth and FBs production during maize storage. However, the genome-wide transcriptome analysis of differentially expressed genes (DEGs) in F. verticillioides under the stress combinations of temperature and aw has not been studied in detail. In this study, DEGs of F. verticillioides and their related regulatory pathways were analyzed in response to the stress of temperature and aw combinations using RNA-Seq. The results showed that the optimal growth conditions for F. verticillioides were 0.98 aw and 25 °C, whereas the highest per-unit yield of the fumonisin B1 (FB1) was observed at 0.98 aw and 15 °C. The RNA-seq analysis showed that 9648 DEGs were affected by temperature regardless of aw levels, whereas only 218 DEGs were affected by aw regardless of temperature variations. Gene Ontology (GO) analysis revealed that a decrease in temperature at both aw levels led to a significant upregulation of genes associated with 24 biological processes, while three biological processes were downregulated. Furthermore, when aw was decreased at both temperatures, seven biological processes were significantly upregulated and four were downregulated. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that the genes, whose expression was upregulated when the temperature decreased, were predominantly associated with the proteasome pathway, whereas the genes, whose expression was downregulated when the aw decreased, were mainly linked to amino acid metabolism. For the FB1, except for the FUM15 gene, the other 15 biosynthetic-related genes were highly expressed at 0.98 aw and 15 °C. In addition, the expression pattern analysis of other biosynthetic genes involved in secondary metabolite production and regulation of fumonisins production was conducted to explore how this fungus responds to the stress combinations of temperature and aw. Overall, this study primarily examines the impact of temperature and aw on the growth of F. verticillioides and its production of FB1 using transcriptome data. The findings presented here have the potential to contribute to the development of novel strategies for managing fungal diseases and offer valuable insights for preventing fumonisin contamination in food and feed storage.


Calcium-dependent complex formation between PBP2 and lytic transglycosylase SltB1 of Pseudomonas aeruginosa.
In Gram-negative bacteria, the bacterial cell wall biosynthetic mechanism requires the coordinated action of enzymes and structural proteins located in the cytoplasm, within the membrane, and in the periplasm of the cell. Its main component, peptidoglycan (PG), is essential for cell division and wall elongation. Penicillin-binding proteins (PBPs) catalyze the last steps of PG biosynthesis, namely the polymerization of glycan chains and the cross-linking of stem peptides, and can be either monofunctional or bifunctional. Their action is coordinated with that of other enzymes essential for cell-wall biosynthesis, such as lytic transglycosylases (LT). Here, we have studied SltB1, an LT from Pseudomonas aeruginosa, and identified that it forms a complex with PBP2, a monofunctional enzyme, which requires the presence of Ca(2+). In addition, we have solved the structure of SltB1 to a high resolution, and identified that it harbors an EF-hand like motif containing a Ca(2+) ion displaying bipyramidal coordination. These studies provide initial structural details that shed light on the interactions between the PG biosynthesis enzymes in P. aeruginosa.


A Surgical Complexity Factor for Clefts of Primary and Secondary Palates.
The surgical treatment of patients with cleft lip and palate depends on the characteristics of the affected anatomical structures (palate, lip and nose). The objective of this work was to develop a quantified classification for these clefts, to represent their surgical complexity. This work was developed with the team of surgeons of the SUMA Cleft Leadership Center (CLC) Smile Train Mexico. The method of Multiple-Criteria Decision Analysis was applied using the Analytic Hierarchy Approach. A surgical complexity factor associated with each cleft was defined and it was validated in a sample of fifty patients treated at the SUMA-CLC.Clinical Relevance- A quantitative classification that represents the surgical complexity of clefts provides an objective unified criteria for planning the surgical treatment of patients, as well as having standardized procedures for the surgical treatment of patients.


A Comparison of Salivary Steroid Levels during Diagnostic Tests for Adrenal Insufficiency.
Numerous diagnostic tests are used to evaluate the hypothalamic-pituitary-adrenal axis (HPA axis). The gold standard is still considered the insulin tolerance test (ITT), but this test has many limitations. Current guidelines therefore recommend the Synacthen test first when an HPA axis insufficiency is suspected. However, the dose of Synacthen that is diagnostically most accurate and sensitive is still a matter of debate. We investigated 15 healthy men with mean/median age 27.4/26 (SD±4.8) years, and mean/median BMI (body mass index) 25.38/24.82 (SD±3.2) kg/m2. All subjects underwent 4 dynamic tests of the HPA axis, specifically 1 μg, 10 μg, and 250 μg Synacthen (ACTH) tests and an ITT. Salivary cortisol, cortisone, pregnenolone, and DHEA (dehydroepiandrosterone) were analysed using liquid chromatography-tandem mass spectrometry. During the ITT maximum salivary cortisol levels over 12.5 nmol/l were found at 60 minutes. Maximum cortisol levels in all of the Synacthen tests were higher than this; however, demonstrating that sufficient stimulation of the adrenal glands was achieved. Cortisone reacted similarly as cortisol, i.e. we did not find any change in the ratio of cortisol to cortisone. Pregnenolone and DHEA were higher during the ITT, and their peaks preceded the cortisol peak. There was no increase of pregnenolone or DHEA in any of the Synacthen tests. We demonstrate that the 10 μg Synacthen dose is sufficient stimulus for testing the HPA axis and is also a safe and cost-effective alternative. This dose also largely eliminates both false negative and false positive results.


Long-term prognosis of mild functional tricuspid regurgitation after mitral valve replacement.
Functional tricuspid regurgitation (FTR) is the most common type of tricuspid insufficiency and occurs approximately in 30% of patients with mitral valve disease. The major etiologic factor in the triggering of right ventricular dilation and thus causing functional tricuspid regurgitation, is pulmonary artery hypertension secondary to mitral valve disease. We aimed to analyze long-term outcomes of patients with mild tricuspid regurgitation at the time of mitral valve replacement. Sixty-six patients with mild tricuspid insufficiency who underwent mitral valve replacement were included in this observational retrospective study. Mean follow-up time was 8.3 ± 0.7 years. Patients whose tricuspid regurgitation remained unchanged or decreased following operation were enrolled to group 1 (n=32), patients whose tricuspid regurgitation increased were included to group 2 (n=34) and data were compared statistically with t-test, Mann-Whitney U, Chi-square and Fisher Exact test. Multiple regression analysis was performed to determine independent risk factors for FTR progression. REESULTS:Preoperatively female gender (p=0.02), body surface area (p=0.04), left atrium diameter (p=0.01), functional capacity (p=0.03), right ventricle diameter (p=0.04), and left ventricle mass index (p=0.04) were found to be statistically significant between groups. In the follow-up; functional capacity, grade of tricuspid insufficiency, pulmonary artery pressure, vena contracta width (p<0.001), TAPSE (tricuspid annular plane systolic excursion index) (p=0.04), annulus diameter (p=0.02), right ventricle diameter (p=0.01), left ventricle mass index (p=0.05), and ejection fraction (p=0.02) were found to be statistically different between groups. In multiple logistic regression analysis; preoperative LA diameter (OR=5.05; 95% CI:1.49-17.12; p=0.009) and female gender (OR=10.93; 95% CI:1.77-67.31; p=0.01) were found as independent risk factors for FTR progression. This study revealed that mild FTR might advance to moderate to severe grade in more than half of the patients in the follow-up. Thus, surgical approach to even mild FTR should be individualized based on patient's risk assessment.


Lactoferrin in acute necrotizing pancreatitis.
Lactoferrin, as measured in the pancreatic juice, has been thought to be of diagnostic value in chronic pancreatitis, but due to the hazards in cannulation of the pancreatic duct in the acute phase of pancreatitis the behavior of lactoferrin has remained obscure. In this study, lactoferrin levels were studied in pancreas tissue specimens obtained in ablative surgery for acute necrotizing pancreatitis (ANP) and in serum samples. A higher pancreatic lactoferrin content was found in ANP than in normal pancreas. Lactoferrin seemed not to leak from a necrotic pancreas in any considerable amounts into the circulation, as no differences were found in serum lactoferrin concentrations between ANP and controls. It remains an open question whether the lactoferrin increase is only an unspecific reaction in inflammation or is something specific for pancreatitis.


HuskinDB, a database for skin permeation of xenobiotics.
Skin permeation is an essential biological property of small organic compounds our body is exposed to, such as drugs in topic formulations, cosmetics, and environmental toxins. Despite the limited availability of experimental data, there is a lack of systematic analysis and structure. We present a novel resource on skin permeation data that collects all measurements available in the literature and systematically structures experimental conditions. Besides the skin permeation value kp, it includes experimental protocols such as skin source site, skin layer used, preparation technique, storage conditions, as well as test conditions such as temperature, pH as well as the type of donor and acceptor solution. It is important to include these parameters in the assessment of the skin permeation data. In addition, we provide an analysis of physicochemical properties and chemical space coverage, laying the basis for applicability domain determination of insights drawn from the collected data points. The database is freely accessible under https://huskindb.drug-design.de or https://doi.org/10.7303/syn21998881 .


Hospitalized acute patients with fever and severe infection have lower mortality than patients with hypo- or normothermia: a follow-up study.
Severe infection is a frequent cause of admission to an acute medical unit (AMU). However, not all infected patients present with fever. The aim was to assess differences in 30-day mortality among patients hospitalized with community-acquired severe infection presenting with hypothermia, normothermia or fever. A retrospective single-center follow-up at an AMU from August 1, 2009 to August 31, 2011. Patients were included the first time they presented with severe infection within the study period. Temperature was categorized into hypothermia (<36.0ºC), normothermia (36.0ºC-38.0ºC) and fever (>38.0ºC). Severe infection was defined as a discharge diagnosis indicating infection combined with organ failure within the first 24 h after arrival. Multivariable Cox regression analysis was computed to assess the association between temperature and 30-day mortality. A total of 2128 patients with severe infection were included. 3.0% (N = 64) were hypothermic, 57.1% (N = 1216) normothermic and 39.9% (N = 848) had fever at arrival. Crude 30-day mortality was 16.1% (N = 342, 95%CI 14.5-17.7%); 37.5% (N = 24, 95% CI 25.7-50.5%) for hypothermic patients, 18.3% (N = 223, 95%CI 16.2-20.6%) for normothermic patients and 11.2% (N = 95, 95%CI 9.2-13.5%) for patients with fever. Compared to normothermic patients, the adjusted hazard ratio of 30-day mortality among hypothermic patients was 1.62 (95%CI 1.06-2.49) and 0.74 (95%CI 0.58-0.94) among patients with fever. Over half of the patients admitted to an AMU with severe infection were normothermic at arrival. Hypothermia was associated with an increased risk of short-term mortality, whereas patients with fever were associated with a lower risk compared to those with normothermia.


IPH-2101, a fully human anti-NK-cell inhibitory receptor mAb for the potential treatment of hematological cancers.
NK-cell activity against tumor cells is regulated by a complex balance of inhibitory and activating signals, which are mediated by the binding of NK-cell receptors to activating and inhibitory ligands expressed on tumor cells. Thus, the disruption of the inhibitory cascade would shift the balance to activation. IPH-2101 (1-7F9), being developed by Innate Pharma, is a fully human IgG4 anti-killer immunoglobulin-like receptor (KIR) mAb for the treatment of hematological malignancies, such as acute myeloid leukemia (AML) and multiple myeloma (MM). In preclinical studies, IPH-2101 selectively bound to KIR2DL1, 2 and 3, and KIR2DS1 and 2, and exposure of KIR-transfected target cell lines to IPH-2101 led to an augmented NK-cell-mediated lysis. In phase I clinical trials in patients with AML and MM treated with IPH-2101, activation of NK cells was observed and IPH-2101 exhibited a good safety profile. At the time of publication, patients with MM had been recruited to phase II clinical trials to assess single-agent IPH-2101 or IPH-2101 in combination with lenalidomide. These and larger, randomized trials are warranted to clarify whether enhancing a patient's NK-cell activity by IPH-2101 will be a viable approach in the treatment of hematological malignancies.


Sore throat and antibiotics.
Sore throat is a common complaint among patients seeking treatment from primary care physicians and otolaryngologists. This article reviews the clinical syndromes which present with pharyngitis. An emphasis is placed on differential diagnosis and appropriate use of antibiotic therapy. The continued controversy regarding the treatment of streptococcal pharyngitis is also presented.


Feasibility study of semiconductor sequencing for noninvasive prenatal detection of fetal aneuploidy.
Noninvasive prenatal detection of common fetal aneuploidies with cell-free DNA from maternal plasma has been achieved with high-throughput next-generation sequencing platforms. Turnaround times for previously tested platforms are still unsatisfactory for clinical applications, however, because of the time spent on sequencing. The development of semiconductor sequencing technology has provided a way to shorten overall run times. We studied the feasibility of using semiconductor sequencing technology for the noninvasive detection of fetal aneuploidy. Maternal plasma DNA from 13 pregnant women, corresponding to 4 euploid, 6 trisomy 21 (T21), 2 trisomy 18 (T18), and 1 trisomy 13 (T13) pregnancies, were sequenced on the Ion Torrent Personal Genome Machine sequencer platform with 318 chips. The data were analyzed with the T statistic method after correcting for GC bias, and the T value was calculated as an indicator of fetal aneuploidy. We obtained a mean of 3 524 401 high-quality reads per sample, with an efficiency rate of 77.9%. All of the T21, T13, and T18 fetuses could be clearly distinguished from euploid fetuses, and the time spent on library preparation and sequencing was 24 h. Semiconductor sequencing represents a suitable technology for the noninvasive prenatal detection of fetal aneuploidy. With this platform, sequencing times can be substantially reduced; however, a further larger-scale study is needed to determine the imprecision of noninvasive fetal aneuploidy detection with this system.


Dissecting eukaryotic translation and its control by ribosome density mapping.
Translation of an mRNA is generally divided into three stages: initiation, elongation and termination. The relative rates of these steps determine both the number and position of ribosomes along the mRNA, but traditional velocity sedimentation assays for the translational status of mRNA determine only the number of bound ribosomes. We developed a procedure, termed Ribosome Density Mapping (RDM), that uses site-specific cleavage of polysomal mRNA followed by separation on a sucrose gradient and northern analysis, to determine the number of ribosomes associated with specified portions of a particular mRNA. This procedure allows us to test models for translation and its control, and to examine properties of individual steps of translation in vivo. We tested specific predictions from the current model for translational control of GCN4 expression in yeast and found that ribosomes were differentially associated with the uORFs elements and coding region under different growth conditions, consistent with this model. We also mapped ribosome density along the ORF of several mRNAs, to probe basic kinetic properties of translational steps in yeast. We found no detectable decline in ribosome density between the 5' and 3' ends of the ORFs, suggesting that the average processivity of elongation is very high. Conversely, there was no queue of ribosomes at the termination site, suggesting that termination is not very slow relative to elongation and initiation. Finally, the RDM results suggest that less frequent initiation of translation on mRNAs with longer ORFs is responsible for the inverse correlation between ORF length and ribosomal density that we observed in a global analysis of translation. These results provide new insights into eukaryotic translation in vivo.


Release of adenosine and cyclic AMP from coronary endothelium in isolated guinea pig hearts: relation to coronary flow.
The coronary efflux of radioactive 3',5'-cyclic adenosine monophosphate (cAMP) and adenosine from isolated guinea pig hearts was measured following selective prelabelling of coronary endothelial adenine nucleotides with 10 nM [2,8,5'-3H] adenosine. Intracoronary infusion of adenosine and its derivatives 5'-N-ethyl-carboxamide-adenosine (NECA), (-)-N6-(R-phenyl-isopropyl)-adenosine (R-PIA), and (+)-N6-(S-phenyl-isopropyl)-adenosine (S-PIA) caused dose-dependent parallel increases in both coronary flow and the coronary efflux of radioactive cAMP with a rank order of potency: NECA greater than R-PIA greater than adenosine greater than S-PIA. In contrast, adenosine receptor stimulation of isolated cardiomyocytes in primary culture decreased the cellular release of cAMP below control levels with a rank order of potency: R-PIA greater than NECA. Under control conditions, coronary efflux of adenosine and cAMP was 34.3 +/- 2.3 and 3.9 +/- 0.8 pmol/min (mean +/- SEM, n = 6), respectively. NECA (12 microM) caused an increase in cardiac cAMP release of 3.8 times and elevated the specific radioactivity of cAMP 5 times to 63.7 +/- 6.0 Ci/mol, a value 11 times greater than the specific radioactivity of tissue ATP. Based on these findings, it was concluded that the coronary endothelium possesses adenosine A2 receptors linked to adenylate cyclase, which are activated in parallel with increases in coronary flow and that cardiomyocyte adenosine receptors are predominantly of the A1 subtype. In addition, the contribution of the coronary endothelium to total cardiac adenosine release was calculated to be 14% using the specific radioactivities of adenosine and cAMP released into the effluent perfusate.


Nano/microparticles in conjunction with microalgae extract as novel insecticides against Mealworm beetles, Tenebrio molitor.
The intensive use of insecticides in global agricultural production has attracted much attention due to its many adverse effects on human health and the environment. In recent years, the utilization of nanotechnology has emerged as a tool to overcome these adverse effects. The aim of this work was to test different microparticles (zinc oxide (ZnO MPs) and silicon dioxide microparticles (SiO2 MPs)), and silver nanoparticles (Ag NPs) and to study their toxicity on a model organism, Tenebrio molitor. A comprehensive comparative study, which included more than a thousand mealworms divided into nine separate groups, was conducted. In addition to pure nano/microparticle solutions, the effect of particles mixed with the microalgae extract Chlamydomonas reinhardtii was also observed. Pure Ag NPs and SiO2 MPs resulted in larval mortality of more than 70% compared to that of pure ZnO MPs, in which the mortality rate was approximately 33%. A mixture of the algal extract with zinc oxide microparticles resulted in mortality that was double compared to that observed with pure ZnO MPs. In parallel, atomic absorption spectrometry (AAS) was used to determine the difference in the concentration of trace elements in the bodies of dead and live larvae.


Evolution of angiotensin II-mediated atherosclerosis in ApoE KO mice.
The dysregulation of renin-angiotensin system-signaling is a contributing factor to the development of atherosclerosis and cardiovascular disease. We studied the progression of angiotensin II (AngII)-induced arterial wall atherosclerosis after its induction. Atherosclerosis was accelerated in ApoE (-/-) C57B6 mice by 4 weeks of continuous osmotic pump administration of AngII (23 nmol/24 h). Changes in aortae were evaluated in these mice at 4 and 16 weeks after pump installation, as well as in control mice that were not administered AngII. In comparison to the non-AngII controls, AngII supplementation induced additional lesions in the aortic arch and its vessels 4 weeks after pump installation, indicating that AngII had an effect. These observations were grossly visible and were confirmed through histological analysis. Additionally, the AngII-mediated injuries continued to accelerate great vessel atherosclerosis after the discontinuation of AngII administration at 4 weeks. Atherosclerosis in the ApoE KO mice at 16 weeks post-AngII administration was increased by over 3-fold compared to the difference between lesion development in the ApoE KO mice at 4 weeks post-AngII and the age-matched control ApoE KO mice. While lesion size 12 weeks after cessation of AngII (16 week post-AngII group) increased 249% compared to the 4 week post-AngII group, differences between the rate of lesion formation in the 4 week post-AngII and non-AngII groups indicated a 70% increase and a linear relationship with time. Aortic dissections were present at 4 weeks post-AngII pump installation at high frequency compared to the unsupplemented controls, in which they were absent. Unexpectedly, aortic dissections were absent at 16 weeks post-AngII, indicating the presence of a healing process. The study suggests that excessive AngII initiates a cascade of pathological biochemical events and plaque evolution that does not cease even after AngII administration is discontinued.


Structural elucidation and biological significance of 2-hydroxy-1-naphthaldehyde derived sulfonamides and their first row d-transition metal chelates.
2-Hydroxy-1-naphthaldehyde derived sulfonamides and their first row d-transition metal chelates [cobalt (II), copper (II), nickel (II) and zinc (II)] have been synthesized and characterized. The nature of bonding and structure of all the compounds have been deduced from elemental analyses, infrared, 1H NMR, 13C NMR, mass spectrometry, electronic spectra, magnetic susceptibility and conductivity measurements. An octahedral geometry has been suggested for all the complexes. The metal complexes were screened for their antibacterial and antifungal activities on different species of pathogenic bacteria and fungi and their biopotency has been discussed. The results of these studies revealed that all compounds showed moderate to significant antibacterial activity against all bacterial strains and good antifungal activity against various fungal strains. In-vitro cytotoxic properties of all the compounds against Artemia salina was also studies by brine shrimp bioassay.


Dynamics of hepatitis C viremia following interferon-alpha administration.
Knowledge of the dynamics of hepatitis C virus (HCV) in vivo is important for elucidation of its pathogenesis and the establishment of therapeutic guidelines. The aim of this study was to obtain kinetic information about virus load following interferon-alpha (IFN-alpha) administration. Serial serum HCV core protein and HCV RNA levels were measured. IFN-alpha exponentially reduced serum HCV levels. The mean (+/-SD) viral half-life was 7.0 +/- 2.6 h in HCV core protein assay and 7.2 +/- 3.1 h in HCV RNA assay on the first day of therapy. This initial rapid decrease was followed by a slower decrease in serum HCV levels thereafter. Thus, the biphasic reduction in virus load during IFN-alpha therapy was demonstrated.


Extending Inferential Group Analysis in Type 2 Diabetic Patients with Multivariate GLM Implemented in SPM8.
Although voxel based morphometry studies are still the standard for analyzing brain structure, their dependence on massive univariate inferential methods is a limiting factor. A better understanding of brain pathologies can be achieved by applying inferential multivariate methods, which allow the study of multiple dependent variables, e.g. different imaging modalities of the same subject. Given the widespread use of SPM software in the brain imaging community, the main aim of this work is the implementation of massive multivariate inferential analysis as a toolbox in this software package. applied to the use of T1 and T2 structural data from diabetic patients and controls. This implementation was compared with the traditional ANCOVA in SPM and a similar multivariate GLM toolbox (MRM). We implemented the new toolbox and tested it by investigating brain alterations on a cohort of twenty-eight type 2 diabetes patients and twenty-six matched healthy controls, using information from both T1 and T2 weighted structural MRI scans, both separately - using standard univariate VBM - and simultaneously, with multivariate analyses. Univariate VBM replicated predominantly bilateral changes in basal ganglia and insular regions in type 2 diabetes patients. On the other hand, multivariate analyses replicated key findings of univariate results, while also revealing the thalami as additional foci of pathology. While the presented algorithm must be further optimized, the proposed toolbox is the first implementation of multivariate statistics in SPM8 as a user-friendly toolbox, which shows great potential and is ready to be validated in other clinical cohorts and modalities.


Effect of preemptive multimodal analgesia for arthroscopic knee ligament repair.
Administration of analgesic medication before surgery, rather than at the completion of the procedure, may reduce postoperative pain. Similarly, administration of multiple analgesics, with different mechanisms of action, may provide improved postoperative pain control and functional recovery. The purpose of our study was to compare pain scores and intravenous opioid consumption after outpatient anterior cruciate ligament (ACL) reconstruction in patients who received a multimodal drug combination (intravenous [IV] ketorolac, intra-articular morphine/ropivacaine/epinephrine, and femoral nerve block with ropivacaine) either before surgery or immediately at the completion of the surgical procedure. Forty patients presenting for same-day arthroscopic ACL repair using a semitendinosis tendon graft were included in this study. The patients were randomized to receive the following drugs either 15 minutes before skin incision or immediately after skin closure: (1) Ketorolac 30 mg IV. (2) Intra-articular injection of 20 mL ropivacaine 0.25% + morphine 2 mg and epinephrine 1:200,000. (3) Femoral nerve block with 20 mL ropivacaine 0.25%. Verbal pain scores were obtained in the postanesthesia care unit (PACU) and on postoperative days 1, 3, and 7. IV patient controlled analgesia (PCA) morphine consumption in the PACU was also recorded. Verbal pain rating scores were lower in group I (preemptive) for 2.0 hours after arrival in the PACU. There was no difference between groups in pain scores on postoperative days 1, 3, and 7. Mean IV PCA morphine consumption in the PACU was lower in group I (6.4 mg) versus group II (12.3 mg), P <.05. Preemptive, multimodal administration of our 3-component analgesic drug combination resulted in lower pain scores during the initial stay in the PACU unit and lower consumption of IV PCA morphine in the PACU. However, pain scores were similar in both groups on postoperative days 1, 3, and 7; thus, there was no measurable long-term advantage associated with preemptive multimodal drug administration.


Characterization of a 34-kDa soybean binding protein for the syringolide elicitors.
Syringolides are water-soluble, low-molecular-weight elicitors that trigger defense responses in soybean cultivars carrying the Rpg4 disease-resistance gene but not in rpg4 cultivars. 125I-syringolide 1 previously was shown to bind to a soluble protein(s) in extracts from soybean leaves. A 34-kDa protein that accounted for 125I-syringolide 1 binding activity was isolated with a syringolide affinity-gel column. Partial sequences of internal peptides of the 34-kDa protein were identical to P34, a previously described soybean seed allergen. In soybean seeds, P34 is processed from a 46-kDa precursor protein and was shown to have homology with thiol proteases. P34 is a moderately abundant protein in soybean seeds and cotyledons but its level in leaves is low. cDNAs encoding 46-, 34-, and 32-kDa forms of the soybean protein were cloned into the baculovirus vector, pVL1392, and expressed in insect cells. The resulting 32- and 34-kDa proteins, but not the 46-kDa protein, exhibited ligand-specific 125I-syringolide binding activity. These results suggest that P34 may be the receptor that mediates syringolide signaling.


Hybrid Iodide Perovskites of Divalent Alkaline Earth and Lanthanide Elements.
Hybrid halide perovskites AMIIX3 (A = ammonium cation, MII = divalent cation, X = Cl, Br, I) have been extensively studied but have only previously been reported for the divalent carbon group elements Ge, Sn, and Pb. While they have displayed an impressive range of optoelectronic properties, the instability of GeII and SnII and the toxicity of Pb have stimulated significant interest in finding alternatives to these carbon group-based perovskites. Here, we describe the low-temperature solid-state synthesis of five new hybrid iodide perovskites centered around divalent alkaline earth and lanthanide elements, with the general formula AMIII3 (A = methylammonium, MA; MII = Sr, Sm, Eu, and A = formamidinium, FA; MII = Sr, Eu). Structural, calorimetric, optical, photoluminescence, and magnetic properties of these materials are reported.


Approximate model for analyzing band structures of single-ring hollow-core anti-resonant fibers.
Precise knowledge of modal behavior is of essential importance for understanding light guidance, particularly in hollow-core fibers. Here we present a semi-analytical model that allows determination of bands formed in revolver-type anti-resonant hollow-core fibers. The approach is independent of the actual arrangement of the anti-resonant elements, does not enforce artificial lattice arrangements and allows determination of the effective indices of modes of preselected order. The simulations show two classes of modes: (i) low-order modes exhibiting effective indices with moderate slopes and (ii) a high number of high-order modes with very strong effective index dispersion, forming a quasi-continuum of modes. It is shown that the mode density scales with the square of the normalized frequency, being to some extent similar to the behavior of multimode fibers.


Testing adolescents for sexually transmitted infections in urban primary care practices: results from a baseline study.
Sexually active urban adolescents experience a high burden of sexually transmitted infections (STI). Adolescents often access medical care through general primary care providers; their time alone with a provider increases the likelihood that youth will disclose risky behavior, which may result in STI testing. Our goals were to assess the association (if any) between the provision of time alone and STI testing, and describe the rates of STI testing among sexually active adolescents in urban primary care. Youth (aged 12-19 years) presenting for care at 4 urban health centers were invited to complete post-visit surveys of their experience. Sexually transmitted infection screening rates were obtained from the clinical information systems (CIS); CIS data were linked to survey responses. We received 101 surveys. Surveyed youth experienced time alone in 69% of all visits. Time alone varied by age (older teens experienced more time alone), and it occurred more frequently in preventive visits (71%) versus nonpreventive visits (33%). It did not vary by gender. Forty-two of the 46 sexually active youth experienced time alone. Screening rates for sexually active females, either at the index visit or within 6 months prior to the index visit, were 17.9% for human immunodeficiency virus and 32.1% for gonorrhea/Chlamydia. No sexually active surveyed males were tested. Overall screening rates varied widely across practices (human immunodeficiency virus 0%-29%; gonorrhea/Chlamydia 7%-29%). There was no difference in screening rates among youth with and without time alone. STI testing for adolescents is being conducted in this primary care urban population, especially for sexually active females. However, clinicians in this setting are not screening females consistently enough and rarely screen males. We were unable to test our hypothesis that provision of time alone was associated with a higher rate of STI testing. Site differences suggest substantial variation in clinician practices that should be addressed in quality improvement interventions.


Myosin light chain phosphorylation in fast and slow skeletal muscles in situ.
The physiological properties of contraction-induced phosphate incorporation into the phosphorylatable light chain (P-light chain) of myosin were examined in fast-twitch white, fast-twitch red, and slow-twitch skeletal muscles in situ. Neural stimulation of rat gastrocnemius muscles between 0.5 and 100 Hz produced an increase in the phosphate content of the P-light chain from the white portion of the muscle, and the rate of P-light chain phosphorylation was frequency dependent. The extent of phosphorylation of P-light chain from the fast-twitch red portion of the gastrocnemius muscle was less. In contrast to fast-twitch skeletal muscle, only high-frequency stimulation (30-100 Hz) produced a small increase in the phosphate content of P-light chain from the slow-twitch soleus muscle. Fast white muscle contained 2.2 and 3.5 times more myosin light chain kinase activity than did the fast red and slow muscle, respectively. The rate of P-light chain dephosphorylation was four times faster in slow muscle than in fast white muscle. Thus the greater extent of phosphorylation of P-light chain in fast-twitch white skeletal muscle fibers may be due in part to the presence of more kinase and less phosphatase activities. Isometric twitch tension potentiation was correlated to the extent of phosphorylation of P-light chain from fast white muscle. The physiological consequences of P-light chain phosphorylation are likely to be of greatest importance in fast-twitch white muscle.


Clinical placements and nursing students' career planning: a qualitative exploration.
Many nursing students enter undergraduate programmes with preconceived ideas about their future nursing careers, and intend to practice in particular areas such as midwifery or paediatrics. Through clinical placements, students are exposed to different clinical areas and professional socialization is facilitated. However, little is known about the influence of clinical placements on students' career intentions. This paper reports nursing findings drawn from a large qualitative study conducted in Victoria, Australia that sought to explore the influence of health professional students' clinical placements on their future career intentions. Participants were invited to be involved in either face-to-face or focus group interviews depending upon their own preference. Thematic data analysis revealed three main themes: 're-affirming career choice', 'working in a particular area' and 'work location'. Findings from the study add to our understanding of factors influencing nursing students' planning for their future careers including the impact of clinical placements.


Workloads in genitourinary medicine clinics in England.
Work loads in venereal disease--sexually transmitted disease (STD)--genitourinary medicine (GUM) clinics have risen greatly in recent years. The increase in viral infections which are more difficult and time consuming to manage than those caused by bacteria and the higher expectations and demands of patients have combined to increase workloads more than the case figures indicate. This prompted the Department of Health and Social Security in 1988 to set up a survey of clinics in England with the following terms of reference: "To examine current and forecast workloads on GUM clinics, taking account of AIDS and other STDs, and to recommend any action which may need to be taken on manpower (including nursing manpower), training, resources and accommodation". The team concluded that the GUM service was ill equipped to meet the demands for its services, and made 36 recommendations. The priority recommendations included: the need to provide more resources; government ministers should give a lead in developing the service; all health districts should provide care for STD and HIV infection; all new patients should be seen on the day of presentation or failing that on the next occasion the clinic was open. Other recommendations included: location of all GUM clinics in the general outpatient department of general hospitals; accommodation of the same standard as other outpatient departments; review of the distribution of clinics; review of staffing levels and roles; and coordination of care of HIV infection. Many of these recommendations have already led to action including a lead from government ministers and provision of more funds. Many of the problems and recommendations will apply in other countries.


[Study on the LMCT band of zinc-bovine serum albumin].
The structure of metal centre in 1:1 zinc-bovine serum albumin complexes have been studied with UV spectrum. The data from literature is used to calculate the optical electronegativity of three pi orbits of histidyl imidazole. Using these data, we infer that two charge transition bands of complex of zinc ions and bovine serum albumin come from transition of pi 2, pi 3 electrons of histidyl imidazole to zinc ions.


Human pluripotent stem cell-derived kidney organoids for personalized congenital and idiopathic nephrotic syndrome modeling.
Nephrotic syndrome (NS) is characterized by severe proteinuria as a consequence of kidney glomerular injury due to podocyte damage. In vitro models mimicking in vivo podocyte characteristics are a prerequisite to resolve NS pathogenesis. The detailed characterization of organoid podocytes resulting from a hybrid culture protocol showed a podocyte population that resembles adult podocytes and was superior compared with 2D counterparts, based on single-cell RNA sequencing, super-resolution imaging and electron microscopy. In this study, these next-generation podocytes in kidney organoids enabled personalized idiopathic nephrotic syndrome modeling, as shown by activated slit diaphragm signaling and podocyte injury following protamine sulfate, puromycin aminonucleoside treatment and exposure to NS plasma containing pathogenic permeability factors. Organoids cultured from cells of a patient with heterozygous NPHS2 mutations showed poor NPHS2 expression and aberrant NPHS1 localization, which was reversible after genetic correction. Repaired organoids displayed increased VEGFA pathway activity and transcription factor activity known to be essential for podocyte physiology, as shown by RNA sequencing. This study shows that organoids are the preferred model of choice to study idiopathic and congenital podocytopathies.


Patients' complaints in a hospital emergency department in Singapore.
This study analysed the complaint rates, profile and trend, and complainant profile of patients' complaints received by the National University Hospital Emergency Medicine Department. An earlier ten-year study (1986-1995) was done on the complaint profile. Records of all patients' complaints, solicited and unsolicited, from January 2002 to December 2003, were retrieved from the Medical Affairs and Quality Improvement Unit files. Complaint profile analysed was reason, validity, and outcome of complaint and staff category involved. Complainant profile analysed was relationship of complainant to patient, ethnic group, gender and residence type of the complainant; and age group and triage category of the patient. Complaint case rate was 1.17 per 1,000 visits, with 1.27 complaints per complaint case. The complaints were organisation/logistics (49.0 percent), communication (26.0 percent), standard of care (22.9 percent) and other issues (1.3 percent). Most standard of care (76.0 percent) and half of organisation/logistics complaints (46.8 percent) were not valid. Most communication complaints were valid (73.7 percent) and involved all staff categories equally. Most complaints (82.8 percent) were resolved with an explanation/apology. Age group specific and triage-specific complaint rates were highest among adult patients and among priority 3 patients, respectively; ethnic group and gender-specific complaint rates were highest among Chinese patients and among female patients, respectively. Staff-patient communication and organisation/logistics must be continually improved to reduce complaints, while upholding a good standard of care. These would translate into cost savings for all parties. There must also be appropriate checks and balances particularly where complaints are not valid, so that doctors can practice cost-effective medicine.


Tumor cell pH detection based on CdSe quantum dots' fluorescence charateristics.
The incidence of cancers has increased year by year and the early diagnosis for cancer is important to prevent cancers. Due to abnormal metabolism of tumor cells, the acidification of extracellular environment is an important feature for cancer cells. To achieve efficient and accurate pH measurement, this paper proposes a new detection method based on the fluorescence characteristics of CdSe quantum dots detection, which uses CdSe QDs with unique optical properties as sensitive substances for pH detection. PBS buffer (0.2 mol/L) with different pH has been used to simulate cell metabolites at different pH values and use 365 nm laser source to excite mixture liquid. The emitted light was detected by a fluorescence detection device. A mathematical model between fluorescence intensity and pH was finally obtained. The experimental results show the method show better effectiveness than other pH detection methods and has a high resolution of 0.037 within a pH range of 6.1-7.8 and a measurement resolution of 0.037 pH units. This method has high temperature stability and short testing time, which shows high potential for pH detection. This method has its superiority in all the testing methods. It exhibits a new way of generalizing to pH detection.


Effects of sawdust pollution on the germination of fungal spores in Lagos Lagoon.
Four fungi, Aspergillus flavus, Aspergillus giganteus, Cladosporium oxysporum a and Trichoderma aureoviride, isolated from Lagos Lagoon, were tested for spore germination in aqueous sawdust extract of different hardwood species (Khaya ivorensis, Mitragyna ciliata and Triplochiton scleroxylon). Extracts of M. ciliata were inhibitory to spore germination especially at higher concentrations. Germ tubes of spores decreased in length with increase in extract concentration for C. oxysporum and T. aureoviride, while Aspergillus species showed increase in length up to a peak at 3% sawdust extract concentration, and thereafter germ tube lengths decreased with increasing concentration. Extracts of T. scleroxylon stimulated the spores and percentage germination increased at higher extract concentrations with no significant difference in germ tube length. Similarly, K. ivorensis had a stimulatory effect on spore germination and length of germ tube, especially at higher extract concentrations. Addition of soluble exogenous carbon and nitrogen sources to sawdust extract enhanced spore germination. Apart from A. flavus, which had only 9% germination, all the spores failed to germinate in lagoon water having 21% salinity. The spores were also inhibited by in lagoon water having 21 per thousand salinity. The spores were also inhibited by various inorganic salts, i.e. CaCl(2), KH(2)PO(4), MgSO(4) and NaCl, present in Lagos Lagoon. The results suggest that sawdust pollution causes enrichment of the lagoon, thereby enhancing spore germination.


Graves' hyperthyroidism-induced psychosis treated with aripiprazole--a case report.
Graves' disease is an autoimmune syndrome with symptoms such as tachycardia, atrial fibrillation, and psychiatric symptoms. Limited evidence exists for the treatment of Graves' hyperthyroidism-induced psychosis with atypical antipsychotics. A 47-year-old female with a psychiatric history of bipolar disorder presented for the first time to the psychiatric hospital. She was agitated and grossly psychotic with delusions. Electrocardiogram showed atrial fibrillation and tachycardia. Drug screen urinalysis was negative. Endocrine workup resulted in a diagnosis of Graves' disease (thyroid-stimulating hormone [TSH]: 0.005 μIU/mL, triiodothyronine [T3]: 537 ng/dL, thyroxine [T4]: 24 mcg/dL, free T4: 4.5 ng/dL, positive antithyroid peroxidase antibody, and antinuclear antibody). Aripiprazole 10 mg daily was initiated and titrated to 15 mg daily on day 4. On day 16, her suspicious behavior, judgment, and insight improved. Other medications given included aspirin 325 mg daily, metoprolol 25 mg twice daily, titrated to 12.5 mg twice daily, and methimazole 30 mg daily, titrated to 20 mg twice daily, and discontinued on day 29. The patient received radioiodine I-131 treatment 1 week later. We report the first known case on the use of aripriprazole to treat Graves' hyperthyroidism-induced psychosis. Further studies examining the long-term effects and appropriate dose and duration of aripiprazole in this patient population are needed.


Molecular analysis of the Coprinus cinereus mating type A factor demonstrates an unexpectedly complex structure.
We report here the molecular cloning of the A43 mating type factor from Coprinus cinereus, a basidiomycetous fungus. Our molecular analyses revealed an unexpected source of variation in the A factor. Though genetic studies have demonstrated that A has two subunits, alpha and beta, we located three nonoverlapping fragments in the A43 region that have A factor function following DNA-mediated transformation. The three fragments demonstrate no similarity to one another as judged by restriction enzyme maps and by hybridization on Southern blots. We conclude that the A43 factor is composed of at least three subunits. When strains carrying different A factors are examined by hybridization to the cloned subunits, extensive polymorphism is seen. Both intensity of hybridization and restriction fragment lengths vary between strains. Some strains fail to show any hybridization to a probe. In contrast, other strains from widely separated geographic locations apparently share very similar subunits. From comparative restriction enzyme mapping of A43 and a mutated A43 factor, we inferred that a 12-kb deletion in the A factor was responsible for the constitutive, dominant phenotype of the mutated A factor. The results of transformation experiments support an activator model for the activity of the A factor in regulating the A pathway.


Real-World Data on the Incidence of Stroke, Myocardial Infarction, and Mortality Among Nonvalvular Atrial Fibrillation Patients in Türkiye: New Oral Anticoagulants-TURKey Study.
Atrial fibrillation (AF) is strongly associated with an increased risk of ischemic events. Anticoagulation focuses on reducing the risk of embolism. Guideline recommended CHA2DS2-VASc scoring system is most widely used; however, different scoring systems do exist. Thus, we sought to assess the impact of anticoagulant treatment and different scoring systems on the development of stroke, myocardial infarction, and all-cause mortality in patients with nonvalvular AF. The present study was designed as a prospective cohort study. The enrollment of the patients was conducted between August 1, 2015, and January 1, 2016. The follow-up period was defined as the time from enrollment to the end of April 1, 2017, which also provided at least 12 months of prospective follow-up for each patient. A total of 1807 patients with AF were enrolled. During the follow-up, 2.7% (48) of patients had stroke, 0.8% (14) had myocardial infarction, and 7.5% (136) died. The anticoagulation and risk factors in AF (ATRIA) score had a better accuracy for the prediction of stroke compared to other scoring systems (0.729, 95% CI, 0.708-0.750, P <.05). Patients under low-dose rivaroxaban treatment had significantly worse survival (logrank P <.001). Age, CHA2DS2-VASc score, R2CHADS2 score, ATRIA score, chronic heart failure, prior stroke, and being under low-dose rivaroxaban treatment were independent predictors of clinical endpoint (P <.001). Low-dose rivaroxaban treatment was independently and strongly associated with the combined clinical endpoint. Furthermore, the ATRIA score proved to be a stronger predictor of stroke in the Turkish population.