Prediction of osteoporosis in patients with rheumatoid arthritis using machine learning.
Osteoporosis is a serious health concern in patients with rheumatoid arthritis (RA). Machine learning (ML) models have been increasingly incorporated into various clinical practices, including disease classification, risk prediction, and treatment response. However, only a few studies have focused on predicting osteoporosis using ML in patients with RA. We aimed to develop an ML model to predict osteoporosis using a representative Korean RA cohort database. The KORean Observational study Network for Arthritis (KORONA) database, established by the Clinical Research Center for RA in Korea, was used in this study. Among the 5077 patients registered in KORONA, 2374 patients were included in this study. Four representative ML algorithms were used for the prediction: logistic regression (LR), random forest, XGBoost (XGB), and LightGBM. The accuracy, F1 score, and area under the curve (AUC) of each model were measured. The LR model achieved the highest AUC value at 0.750, while the XGB model achieved the highest accuracy at 0.682. Body mass index, age, menopause, waist and hip circumferences, RA surgery, and monthly income were risk factors of osteoporosis. In conclusion, ML algorithms are a useful option for screening for osteoporosis in patients with RA.


Recurrent NEDD4L Variant in Periventricular Nodular Heterotopia, Polymicrogyria and Syndactyly.
NEDD4L encodes an ubiquitin ligase which is expressed in the cortex and ventricular zone of the fetal brain. Missense variants in NEDD4L have been reported in nine patients with periventricular nodular heterotopia (PNH), polymicrogyria, cleft palate, and syndactyly. All reported variants are located in the HECT domain, causing deregulation of signaling pathways, including the AKT/mTOR pathway. Here we describe a first familial case with four affected members with a high degree of intra-familial phenotypic variability. Phenotypic features in the proband consisted of severe neurodevelopmental delay, refractory seizures, bilateral PNH, and perisylvian polymicrogyria. The other family members were less severely affected with mild developmental delay and isolated bilateral PNH. All family members had syndactyly. An unrelated patient presented with severe neurodevelopmental delay, seizures, and hypospadias, expanding the phenotypic spectrum. MRI revealed bilateral PNH and perisylvian polymicrogyria. All tested patients carry the recurrent variant c.623G > A, p.(Arg208Gln) in the WW domain of NEDD4L. The variant in the unrelated patient occurred de novo. This is the first report of a NEDD4L variant located in the WW domain which is probably involved in the recognition of substrates for ligation suggesting a loss of function variant.


Regulation of renal ammoniagenesis in the dog with chronic metabolic acidosis: effect of a glutamine load.
We recently emphasized that ATP is an obligatory product of renal glutamine metabolism and that all cells must remain in ATP balance. Based on this, we suggested that the maximum rate of renal ammoniagenesis in dogs with chronic metabolic acidosis may be limited by the rate of ATP utilization in the kidney. Since a large infusion of glutamine led to a twofold increase in renal ammoniagenesis in acidotic dogs, we wished to evaluate the renal metabolic changes that permitted this increment within the constraints of renal ATP balance. A large glutamine infusion did not lead to an augmented rate of ATP hydrolysis because renal oxygen consumption was not increased. Two major metabolic changes could explain this stimulation while maintaining ATP balance: first, ATP production from lactate by the kidney was decreased following the glutamine infusion; second, the metabolic fate of glutamine was changed so that more ammonium per ATP was synthesized (i.e., the rates of amino acid release into the renal vein were markedly enhanced, and gluconeogenesis was now a quantitatively significant process). 3-Mercaptopicolinate, an inhibitor of phosphoenolpyruvate carboxykinase, when infused with glutamine, apparently decreased the calculated rate of gluconeogenesis as expected; however, ammonium production did not decline, because the rate of amino acid release increased further, as did the rate of oxygen consumption. Therefore, a large glutamine infusion increased renal ammoniagenesis in dogs with chronic metabolic acidosis while maintaining ATP balance, because ATP production from other substrates was decreased and because the fate of glutamine metabolism was altered in that less ATP was formed per glutamine utilized.


Pervasive functional translation of noncanonical human open reading frames.
Ribosome profiling has revealed pervasive but largely uncharacterized translation outside of canonical coding sequences (CDSs). In this work, we exploit a systematic CRISPR-based screening strategy to identify hundreds of noncanonical CDSs that are essential for cellular growth and whose disruption elicits specific, robust transcriptomic and phenotypic changes in human cells. Functional characterization of the encoded microproteins reveals distinct cellular localizations, specific protein binding partners, and hundreds of microproteins that are presented by the human leukocyte antigen system. We find multiple microproteins encoded in upstream open reading frames, which form stable complexes with the main, canonical protein encoded on the same messenger RNA, thereby revealing the use of functional bicistronic operons in mammals. Together, our results point to a family of functional human microproteins that play critical and diverse cellular roles.


Anterior shoulder dislocation - seated versus traditional reduction technique.
Anterior dislocation of the shoulder joint is a common presentation to hospital emergency departments (EDs). To compare the requirement for sedation and length of ED stay utilising the author's seated shoulder reduction technique (SRT) with traditional shoulder reduction (TSR) techniques in the ED. A retrospective chart review of patients presenting to the ED between January 2005 and December 2007 was conducted. The review assessed technique, mean length of stay, sedation requirements and incidence of complications in patients who were treated with either the author's SRT or with TSR. A total of 486 patient charts were reviewed and 404 met inclusion criteria. Patients were categorised into the SRT group: 66 (16.3%) and TSR group: 338 (83.7%). Mean age of the groups was 30 years (SRT) vs. 29 years (TSR), with 80% being male. Mean length of stay in the SRT group was 1.5 hours (95% CI: 1.1-1.9) vs. TSR 2.9 hours (95% CI: 2.3-2.9; p<0.001). Sedation was not required in patients in the SRT group, but was required for all patients in the TSR group. No complications were reported in either group. In this study group, the author's technique was successful in reducing anterior shoulder dislocation, without the need for sedation, and reduced length of ED stay when compared to TSR techniques.


A separable median filter for image noise smoothing.
This paper investigates some properties of the separable filter resulting from successive applications of a one-dimensional median filter on the rows and columns of an image. Although the output of this separable filter is not identical to the corresponding nonseparable two-dimensional median filter with a square window, its performance in image noise smoothing is close. In particular, its effectiveness in smoothing noise and its behavior with edges are characterized and compared with those of the two-dimensional median filter. It is shown that the separable filter has a much simpler implementation in real-time hardware (at video rates, for example).


Orthopaedic Surgery Complications at a Tertiary Care Hospital in a Low- and Middle-Income Country: A National Surgical Quality Improvement Project Analysis.
Through a comparison of orthopaedic surgical procedures performed at a tertiary care hospital in Pakistan with other participating hospitals of National Surgical Quality Improvement Project (NSQIP), we aim to identify the areas of orthopaedic surgical care at our center that need improvement and also those which are at par with international standards. The study analyses orthopaedic surgeries at a tertiary care hospital in Pakistan using NSQIP registry to compare complication rates with other American College of Surgeons-NSQIP participant hospitals. Two reviewers collect data in different days every 8 days to reduce bias, and the results are reported in odds ratios using quarterly reports. This study included 584 eligible orthopaedic cases performed in 2021. Yearly institutional reports with odds ratios were also used to identify areas needing improvement and to implement changes to improve orthopaedic surgical outcomes at said institute. The quarterly reports suggest a relatively higher OR for certain indicators such as cardiac events, surgical site infection, mortality, and morbidity throughout. The renal failure rate was very high in the third and fourth quarters with odds ratios of 4.57 and 10.31, respectively. However, the official NSQIP annual institutional report for 2021 identified sepsis, surgical site infections, and cardiac complications as areas 'needing improvement'. It also indicated that the hospital performed exemplarily when it came to venous thromboembolism (VTE). As for the rest of the indicators, the hospital fell in the 'as expected' category of the NSQIP standards. This initial report helps the hospital's orthopaedic department in recognizing areas for improvement and making system-level changes to improve patient outcomes. The implementation of these interventions has yielded favorable outcomes, as evidenced by the findings in the NSQIP yearly report for 2022. Reinforcements and measures are needed to be taken to reduce the adverse events even further and to improve the patient outcomes and quality.


Investigating the safety of electroacupuncture with a Picoscope.
Our wish to know more about the paths taken by electrical currents in electroacupuncture (EA) with special reference to the heart, particularly in patients with an implanted pacemaker, prompted us to undertake this study. Using ourselves as subjects, we have developed a safe oscillographic method to detect, visualise and record the EA currents that avoids the use of equipment requiring mains electricity. After two trials with unsatisfactory equipment, we found that the newly developed model 3425 PicoScopeTM (Pico Technology Ltd), with a four channel differential amplifier input connected to a laptop PC operating in battery mode, satisfied our criteria. With this recording system, we carried out two sets of experiments in which EA was provided by a Cefar acus4TM stimulator. The results confirm that the placement of a pair of acupuncture needles for EA can be used to predict the paths taken by the stimulating currents, and thus their areas of likely influence. When the needles are placed in closely adjacent acupuncture points in a limb, there is little or no detectable spread of the currents along the limb or into the chest. By contrast, when the needles are placed far apart, the electrical currents spread widely. Thus, when each of a pair of needles is placed in a point on opposite arms, the electrical currents recorded in the area of the pectoral muscles is of an order that might trigger an abnormal cardiac rhythm in a susceptible heart or activate a cardiac pacemaker incorporating an intracardiac defibrillator (ICD). Our results confirm the guidelines for EA safe practice recommended by the British Medical Acupuncture Society (BMAS) to avoid adverse events, ie EA should not be applied such that the current is likely to traverse the heart. We can now be confident that electric fields generated by pairs of needles below the knee or elbow do not create detectable currents in the chest. It is likely that similar results would be obtained with the use of transcutaneous electrical nerve stimulation (TENS) but this remains to be established by additional experiments.


Training in the Era of EHR: Examining the Experience of Medical Student Documentation in the Ambulatory Care Setting.
This article was migrated. The article was marked as recommended. Purpose: Documenting clinical encounters in the electronic health record has become an important component of medical student training. Reflecting this trend, recent rule changes by the Centers for Medicare and Medicaid services now permit billing for medical student notes. We sought to investigate the educational value of student note-writing following implementation of these changes. Methods: We surveyed medical students at a private research university who participated in longitudinal ambulatory care experiences. Survey questions assessed the incorporation of student note-writing into clinic workflow, as well as the benefits and disadvantages of note-writing. Results: Thirty-six students completed the survey. A majority of students perceived benefits in regards to residency preparedness, engagement with the clinical team, and clinical reasoning ability as a result of writing notes in clinic. While some students reported seeing fewer patients as a result of note-writing, most felt that use of the electronic health record did not negatively impact patient interaction. Barriers cited included a lack of knowledge regarding billing requirements and preceptor apprehension toward student note-writing. Conclusion: The results of this study indicate that student note-writing continues to be a valuable part of medical training following recent billing changes. Our results also identify areas for improvement, including clarifying billing requirements and assuaging preceptor concerns.


Genes Regulating Epithelial Polarity Are Critical Suppressors of Esophageal Oncogenesis.
Esophageal cancer is an aggressive disease featured by early lymphatic and hematogenous dissemination, and is the sixth leading cause of cancer-related deaths worldwide. The proper formation of apicobasal polarity is essential for normal epithelium physiology and tissue homeostasis, while loss of polarity is a hallmark of cancer development including esophageal oncogenesis. In this review, we summarized the stages of esophageal cancer development associated with the loss or deregulation of epithelial cell apicobasal polarity. Loss of epithelial apicobasal polarity exerts an indispensable role in the initiation of esophageal oncogenesis, tumor progression, and the advancement of tumors from benign to malignant. In particular, we reviewed the involvement of several critical genes, including Lkb1, claudin-4, claudin-7, Par3, Lgl1, E-cadherin, and the Scnn1 gene family. Understanding the role of apicobasal regulators may lead to new paradigms for treatment of esophageal tumors, including improvement of prognostication, early diagnosis, and individually tailored therapeutic interventions in esophageal oncology.


Visfatin/Pre-B cell colony-enhancing factor in amniotic fluid in normal pregnancy, spontaneous labor at term, preterm labor and prelabor rupture of membranes: an association with subclinical intrauterine infection in preterm parturition.
Visfatin, a novel adipokine originally discovered as a pre-B-cell colony enhancing factor, is expressed by amniotic epithelium, cytotrophoblast, and decidua and is over-expressed when fetal membranes are exposed to mechanical stress and/or pro-inflammatory stimuli. Visfatin expression by fetal membranes is dramatically up-regulated after normal spontaneous labor. The aims of this study were to determine if visfatin is detectable in amniotic fluid (AF) and whether its concentration changes with gestational age, spontaneous labor, preterm prelabor rupture of membranes (preterm PROM) and in the presence of microbial invasion of the amniotic cavity (MIAC). In this cross-sectional study, visfatin concentration in AF was determined in patients in the following groups: 1) mid-trimester (n=75); 2) term not in labor (n=27); 3) term in spontaneous labor (n=51); 4) patients with preterm labor with intact membranes (PTL) without MIAC who delivered at term (n=35); 5) patients with PTL without MIAC who delivered preterm (n=52); 6) patients with PTL with MIAC (n=25); 7) women with preterm PROM without MIAC (n=26); and 8) women with preterm PROM with MIAC (n=26). Non-parametric statistics were used for analysis. 1) The median AF concentration of visfatin was significantly higher in patients at term than in mid-trimester; 2) Among women with PTL who delivered preterm, the median visfatin concentration was significantly higher in patients with MIAC than those without MIAC; 3) Similarly, patients with PTL and MIAC had a higher median AF visfatin concentration than those with PTL who delivered at term; 4) Among women with preterm PROM, the median AF visfatin concentration was significantly higher in patients with MIAC than those without MIAC. 1) Visfatin is a physiologic constituent of AF; 2) The concentration of AF visfatin increases with advancing gestational age; 3) AF visfatin concentration is elevated in patients with MIAC, regardless of the membrane status, suggesting that visfatin participates in the host response against infection.


Cloning and characterization of the Bacteroides fragilis metalloprotease toxin gene.
Strains of Bacteroides fragilis that produce a ca. 20-kDa heat-labile protein toxin (termed B. fragilis toxin [BFT]) have been associated with diarrheal disease of animals and humans. BFT alters the morphology of intestinal epithelial cells both in vitro and in vivo and stimulates secretion in ligated intestinal segments of rats, rabbits, and lambs. Previous genetic and biochemical data indicated that BFT was a metalloprotease which hydrolyzed G (monomeric) actin, gelatin, and azocoll in vitro. In this paper, the cloning and sequencing of the entire B. fragilis toxin gene (bft) from enterotoxigenic B. fragilis (ETBF) 86-5443-2-2 is reported. The bft gene from this ETBF strain consists of one open reading frame of 1,191 nucleotides encoding a predicted 397-residue holotoxin with a calculated molecular weight of 44,493. Comparison of the predicted BFT protein sequence with the N-terminal amino acid sequence of purified BFT indicates that BFT is most probably synthesized by ETBF strains as a preproprotein. These data predict that BFT is processed to yield a biologically active toxin of 186 residues with a molecular mass of 20.7 kDa which is secreted into the culture supernatant. Analysis of the holotoxin sequence predicts a 20-residue amphipathic region at the carboxy terminus of BFT. Thus, in addition to the metalloprotease activity of BFT, the prediction of an amphipathic domain suggests that oligomerization of BFT may permit membrane insertion of the toxin with creation of a transmembrane pore. Comparison of the sequences available for the bft genes from ETBF 86-5443-2-2 and VPI 13784 revealed two regions of reduced homology. Hybridization of oligonucleotide probes specific for each bft to toxigenic B.fragilis strains revealed that 51 and 49% of toxigenic strains contained the 86-5433-2-2 and VPI 13784 bft genes, respectively. No toxigenic strain hybridized with both probes. We propose that these two subtypes of bft be termed bft-1 (VPI 13784) and bft-2 (86-5433-2-2).


Sleep-wake disturbances after traumatic brain injury.
Sleep-wake disturbances are extremely common after a traumatic brain injury (TBI). The most common disturbances are insomnia (difficulties falling or staying asleep), increased sleep need, and excessive daytime sleepiness that can be due to the TBI or other sleep disorders associated with TBI, such as sleep-related breathing disorder or post-traumatic hypersomnia. Sleep-wake disturbances can have a major effect on functional outcomes and on the recovery process after TBI. These negative effects can exacerbate other common sequelae of TBI-such as fatigue, pain, cognitive impairments, and psychological disorders (eg, depression and anxiety). Sleep-wake disturbances associated with TBI warrant treatment. Although evidence specific to patients with TBI is still scarce, cognitive-behavioural therapy and medication could prove helpful to alleviate sleep-wake disturbances in patients with a TBI.


Selective elimination of long INterspersed element-1 expressing tumour cells by targeted expression of the HSV-TK suicide gene.
In gene therapy, effective and selective suicide gene expression is crucial. We exploited the endogenous Long INterspersed Element-1 (L1) machinery often reactivated in human cancers to integrate the Herpes Simplex Virus Thymidine Kinase (HSV-TK) suicide gene selectively into the genome of cancer cells. We developed a plasmid-based system directing HSV-TK expression only when reverse transcribed and integrated in the host genome via the endogenous L1 ORF1/2 proteins and an Alu element. Delivery of these new constructs into cells followed by Ganciclovir (GCV) treatment selectively induced mortality of L1 ORF1/2 protein expressing cancer cells, but had no effect on primary cells that do not express L1 ORF1/2. This novel strategy for selective targeting of tumour cells provides high tolerability as the HSV-TK gene cannot be expressed without reverse transcription and integration, and high selectivity as these processes take place only in cancer cells expressing high levels of functional L1 ORF1/2.


Allele-specific MMP-3 transcription under in vivo conditions.
A common matrix metalloproteinases-3 (MMP-3) -1612 5A/6A promoter polymorphism is associated with risk for cardiovascular disease, rheumatoid arthritis, and other diseases. Here we used the haplotype chromatin immunoprecipitation method to study allele-specific MMP-3 expression under in vivo conditions in heterozygous THP-1 cells. Pyrosequencing was used to analyse the ratio of 5A-allele to 6A-allele after chromatin immunoprecipitation using an antibody against phosphorylated active RNA polymerase II. There was no allele-specific difference in transcriptional activity during basal conditions, i.e., in unstimulated monocytic THP-1 cells. However, after stimulation of MMP-3 expression by monocyte differentiation or incubation with IL-1beta, the haplotype containing the 5A-allele was associated with higher transcriptional activity compared with the 6A-containing haplotype. Electromobility shift assay demonstrated increased binding of nuclear proteins to the 5A-allele after monocyte differentiation. In conclusion, the common MMP-3 5A/6A promoter polymorphism appears to be functional only during specific environmental conditions involving inflammation.


Effects of antenatal colonization with ureaplasma urealyticum on pulmonary disease in the immature baboon.
Current nonhuman models for bronchopulmonary dysplasia have not included perinatal infection. We studied the effects of antenatal Ureaplasma urealyticum (Uu) infection in the 125-d immature baboon. Ten 125-d gestation (term = 185 d) baboon dams were delivered after intra-amniotic inoculation with Uu. Serial blood and tracheal aspirate samples were analyzed for Uu colony-forming units, IL-6, IL-8, and cell counts. Physiologic parameters were serially recorded. Lung histology was examined after 14 d of ventilation and compared with unexposed controls. All Uu-exposed animals had >4 x 102 CFU in tracheal aspirate at 24 h. Four of nine Uu animals remained heavily colonized [(+) Uu] at necropsy (>6 x 103). Five animals had negative or low tracheal colony-forming units. All Uu animals had significant increases for white blood cells, IL-6, and IL-8 in amniotic and fetal lung fluid. Compared with controls, (+) Uu animals had significantly higher fraction of inspired oxygen, airway pressures, oxygenation index, and ventilation efficiency index between 48 and 240 h and had significantly elevated tracheal IL-6 and IL-8 concentrations between 72 and 240 h. Compared with controls (-) Uu animals had significantly better oxygenation index and ventilation efficiency index scores between 48 and 144 h. Lung histopathology in both Uu groups showed more severe bronchiolitis and interstitial pneumonitis compared with controls. Two patterns of disease were observed after Uu perinatal infection. Persistent colonization manifested a picture consistent with acute pneumonitis, worse lung function from 2 to 10 d, and prolonged elevated tracheal cytokines. Colonized animals that subsequently cleared Uu from the lung demonstrated early improved lung function compared with unexposed controls yet still manifested mixed bronchiolitis and interstitial pneumonitis at necropsy. Inherent immune system responses may determine outcome of perinatal Ureaplasma colonization.


Pregnancy Outcomes After Direct Uterine Myoma Thermal Ablation: Review of the Literature.
The objective of this review is to describe the reproductive outcomes of women after radiofrequency volumetric thermal ablation (RFVTA) of myomas or magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU). This is a literature review of the current case reports of reproductive outcomes after direct myoma thermal ablation at multiple academic and private centers throughout the world. A literature search was performed using PubMed and Medline. All publications that included data of women who underwent radiofrequency myoma ablation or MRgHIFU of myomas and subsequently conceived were included. There were 122 pregnancies after direct uterine myoma thermal ablation, and 20 pregnancies were reported after RFVTA. Of these cases, there was 1 spontaneous abortion and 7 elective terminations. The remaining 12 pregnancies went on to have live full-term deliveries, 9 (75%) by cesarean section and 3 (25%) by vaginal delivery. There were no reports of uterine abnormalities at delivery and 1 delayed postpartum hemorrhage with expulsion of a degenerated myoma. There are 102 reported pregnancies after MRgHIFU. There were 21 spontaneous abortions and 22 elective terminations, 48 deliveries, and 11 ongoing pregnancies at the time of report. There was 1 preterm delivery at 36 weeks due to placenta previa, and the remaining deliveries were full term. The complications reported included vaginal spotting (12.5%), delayed placental separation (4%), and placenta previa (4%). There were no cases of uterine rupture. In summary, RFVTA and MRgHIFU are new minimally invasive alternatives for the treatment of myomas. Further investigation into the reproductive outcomes after these myoma therapies is crucial to determine whether these are appropriate treatment options for women with symptomatic myomas who desire future fertility.


Expression of CD134 and CXCR4 mRNA in term placentas from FIV-infected and control cats.
Feline immunodeficiency virus (FIV) causes a natural infection of domestic cats that resembles HIV-1 in pathogenesis and disease progression. Feline AIDS is characterized by depression of the CD4+ T cell population and fatal opportunistic infections. Maternal-fetal transmission of FIV readily occurs under experimental conditions, resulting in infected viable kittens and resorbed or arrested fetal tissues. Although both FIV and HIV use the chemokine receptor CXCR4 as a co-receptor, FIV does not utilize CD4 as the primary receptor. Rather, CD134 (OX40), a T cell activation antigen and co-stimulatory molecule, is the primary receptor for FIV. We hypothesized that placental expression of CD134 and CXCR4 may render the placenta vulnerable to FIV infection, possibly facilitating efficient vertical transmission of FIV, and impact pregnancy outcome. The purpose of this project was to quantify the relative expression of CD134 and CXCR4 mRNA from the term placentas of three groups of cats: uninfected queens producing viable offspring, experimentally-infected queens producing only viable offspring, and experimentally-infected queens producing viable offspring among mostly non-viable fetuses. Total RNA was extracted from term placental tissues from all groups of cats. Real-time one-step reverse transcriptase-PCR was used to measure gene expression. The FIV receptors CD134 and CXCR4 were expressed in all late term feline placental tissues. Placentas from FIV-infected queens producing litters of only viable offspring expressed more CD134 and CXCR4 mRNA than those from uninfected queens, suggesting that infection may cause upregulation of the receptors. On the other hand, placentas from FIV-infected cats with non-successful pregnancies expressed similar levels of CD134 mRNA and slightly less CXCR4 mRNA than those from uninfected queens. Thus, it appears that cells expressing these receptors may play a role in pregnancy maintenance.


Empagliflozin Reduced Mortality and Hospitalization for Heart Failure Across the Spectrum of Cardiovascular Risk in the EMPA-REG OUTCOME Trial.
In the EMPA-REG OUTCOME trial (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) in patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease, in comparison with placebo, empagliflozin reduced the risks of 3-point major adverse cardiovascular events (3-point MACE), cardiovascular and all-cause death, and hospitalization for heart failure. We investigated whether these effects varied across the spectrum of baseline cardiovascular risk. Cardiovascular death, all-cause mortality, 3-point MACE, and hospitalization for heart failure in the pooled empagliflozin and placebo groups were analyzed in subgroups by prior myocardial infarction and stroke at baseline, and by estimated baseline cardiovascular risk based on the 10-point TIMI (Thrombolysis In Myocardial Infarction) Risk Score for Secondary Prevention. Of 7020 patients who received the study drug, 65% had a prior myocardial infarction or stroke, and 12%, 40%, 30%, and 18% were at low, intermediate, high, and highest estimated cardiovascular risk according to TIMI Risk Score for Secondary Prevention (≤2, 3, 4, and ≥5 points, respectively). In the placebo group, 3-point MACE occurred during the trial in 7.3%, 9.4%, 12.6%, and 20.6% of patients at low, intermediate, high, and highest estimated baseline risk, respectively. Relative reductions in risk of cardiovascular death, all-cause mortality, 3-point MACE and hospitalization for heart failure with empagliflozin versus placebo were consistent in patients with and without prior myocardial infarction and/or stroke and across subgroups by TIMI Risk Score for Secondary Prevention at baseline ( P>0.05 for randomized group-by-subgroup interactions). Despite all patients having atherosclerotic cardiovascular disease, patients in EMPA-REG OUTCOME demonstrated a broad risk spectrum for cardiovascular events. Reductions in key cardiovascular outcomes and mortality with empagliflozin versus placebo were consistent across the range of cardiovascular risk. URL: https://www.clinicaltrials.gov . Unique identifier: NCT01131676.


Physiologically based pharmacokinetic modeling of altered tizanidine systemic exposure by CYP1A2 modulation: Impact of drug-drug interactions and cigarette consumption.
Tizanidine is an alpha2-adrenergic agonist, used to treat spasticity associated with multiple sclerosis and spinal injury. Tizanidine is primarily metabolized by CYP1A2 and is considered a sensitive index substrate for this enzyme. The physiologically based pharmacokinetic (PBPK) modeling platform Simcyp® was used to evaluate the impact of CYP1A2 modulation on tizanidine exposure through drug-drug interactions (DDIs) and host-dependent habits (cigarette smoking). A PBPK model was developed to predict tizanidine disposition in healthy volunteers following oral administration. The model was verified based on agreement between model-simulated and clinically observed systemic exposure metrics (Cmax, AUC). The model was then used to carry-out DDI simulations to predict alterations in tizanidine systemic exposure when co-administered with various CYP1A2 perpetrators including competitive inhibitors (fluvoxamine, ciprofloxacin), a mechanism-based inhibitor (rofecoxib), and an inducer (rifampin). Additional simulations were performed to evaluate the impact of cigarette smoking on systemic exposure. Under each scenario, the PBPK model was able to capture the observed fold changes in tizanidine Cmax and AUC of tizanidine when coadministered with CYP1A2 inhibitors or inducers. These results add to the available research findings in the literature on PBPK predictions of drug-drug interactions and illustrate the potential application in drug development, specifically to support product labeling.


Construction of hierarchically porous metal-organic frameworks through linker labilization.
A major goal of metal-organic framework (MOF) research is the expansion of pore size and volume. Although many approaches have been attempted to increase the pore size of MOF materials, it is still a challenge to construct MOFs with precisely customized pore apertures for specific applications. Herein, we present a new method, namely linker labilization, to increase the MOF porosity and pore size, giving rise to hierarchical-pore architectures. Microporous MOFs with robust metal nodes and pro-labile linkers were initially synthesized. The mesopores were subsequently created as crystal defects through the splitting of a pro-labile-linker and the removal of the linker fragments by acid treatment. We demonstrate that linker labilization method can create controllable hierarchical porous structures in stable MOFs, which facilitates the diffusion and adsorption process of guest molecules to improve the performances of MOFs in adsorption and catalysis.


The nature and frequency of chimeras in eukaryotic metagenetic samples.
Pyrosequencing of an artificially assembled nematode community of known nematode species at known densities allowed us to characterize the potential extent of chimera problems in multi-template eukaryotic samples. Chimeras were confirmed to be very common, making up to 17% of all high quality pyrosequencing reads and exceeding 40% of all OCTUs (operationally clustered taxonomic units). Typically, chimeric OCTUs were made up of single or double reads, but very well covered OCTUs were also present. As expected, the majority of chimeras were formed between two DNA molecules of nematode origin, but a small proportion involved a nematode and a fragment of another eukaryote origin. In addition, examples of a combination of three or even four different template origins were observed. All chimeras were associated with the presence of conserved regions with 80% of all recombinants following a conserved region of about 25bp. While there was a positive influence of species abundance on the overall number of chimeras, the influence of specific-species identity was less apparent. We also suggest that the problem is not nematode exclusive, but instead applies to other eukaryotes typically accompanying nematodes (e.g. fungi, rotifers, tardigrades). An analysis of real environmental samples revealed the presence of chimeras for all eukaryotic taxa in patterns similar to that observed in artificial nematode communities. This information warrants caution for biodiversity studies utilizing a step of PCR amplification of complex DNA samples. When unrecognized, generated abundant chimeric sequences falsely overestimate eukaryotic biodiversity.


Interhemispheric vs. stimulus-response spatial compatibility effects in bimanual reaction times to lateralized visual stimuli.
In the present study, we tested right- and left-handed participants in a Poffenberger paradigm with bimanual responses and hands either in an anatomical or in a left-right inverted posture. We observed a significant positive crossed-uncrossed difference (CUD) in RTs for both manual dominance groups and both response postures. These results rule out an explanation of the CUD in terms of stimulus-response spatial compatibility (SRSC) and provide convincing evidence on the important role of interhemispheric callosal transfer in bimanual responding in right- as well as left-handed individuals.


TMDL implementation in agricultural landscapes: a communicative and systemic approach.
Increasingly, total maximum daily load (TMDL) limits are being defined for agricultural watersheds. Reductions in non-point source pollution are often needed to meet TMDL limits, and improvements in management of annual crops appear insufficient to achieve the necessary reductions. Increased adoption of perennial crops and other changes in agricultural land use also appear necessary, but face major barriers. We outline a novel strategy that aims to create new economic opportunities for land-owners and other stakeholders and thereby to attract their voluntary participation in land-use change needed to meet TMDLs. Our strategy has two key elements. First, focused efforts are needed to create new economic enterprises that capitalize on the productive potential of multifunctional agriculture (MFA). MFA seeks to produce a wide range of goods and ecosystem services by well-designed deployment of annual and perennial crops across agricultural landscapes and watersheds; new revenue from MFA may substantially finance land-use change needed to meet TMDLs. Second, efforts to capitalize on MFA should use a novel methodology, the Communicative/Systemic Approach (C/SA). C/SA uses an integrative GIS-based spatial modeling framework for systematically assessing tradeoffs and synergies in design and evaluation of multifunctional agricultural landscapes, closely linked to deliberation and design processes by which multiple stakeholders can collaboratively create appropriate and acceptable MFA landscape designs. We anticipate that application of C/SA will strongly accelerate TMDL implementation, by aligning the interests of multiple stakeholders whose active support is needed to change agricultural land use and thereby meet TMDL goals.


The Origin and Early Evolution of Life: Homochirality Emergence in Prebiotic Environments.
Homochirality is one of the signatures of life. Numerous geological and prebiotic chemistry studies have proved that disordered soups containing small organic molecules, gases, liquids, and minerals (such as those containing phosphorous) yielded racemic mixtures of building blocks for biomolecule assembly. Polymers obtained from these bricks should have been enantiopure with functional properties similar to modern biomolecules or heterochiral with some functions such as catalyzing a chemical transformation unspecifically. Up until now, no clues have been found as to how symmetry breaking occurred. In this review, we highlight the principal achievements regarding the emergence of homochirality during the prebiotic synthesis of building blocks. Furthermore, we tried to focus on approaches based on prebiotic systems chemistry (bottom-up) and laboratory scales to simulate plausible prebiotic messy environments for the emergence of life. We aim with this review to assemble, even partially, the puzzle pieces of the origin of life regarding the relevant phenomenon of homochiral symmetry breaking.


Consumption of Biscuits with a Beverage of Mulberry or Barley Leaves in the Afternoon Prevents Dinner-Induced High, but Not Low, Increases in Blood Glucose among Young Adults.
We examined the impact of consuming biscuits with a beverage of powdered mulberry or barley leaves in the afternoon on postprandial glucose levels at dinnertime among young adults. A total of 18 young adults participated in a partially double-blinded, randomized crossover trial over 2 weeks, consuming either: (1) no biscuits; (2) a biscuit; (3) a biscuit with a beverage of powdered mulberry leaves; or (4) a biscuit with a beverage of powdered barley leaves, as an afternoon snack followed by a standardized test dinner. Glucose levels were recorded after each meal. Results showed intake of biscuits with a beverage of mulberry and barley leaves significantly reduced postprandial rises in glucose after their immediate consumption and dinner, though there was no direct relationship between the glucose levels at the two meals. Compared to those with low glucose levels, participants with high glucose levels at dinner showed a stronger second meal effect, that was attributed to the mulberry or barley leaves, and were also more likely to have lean body weights and prefer evenings. Our findings indicate that eating snacks alongside mulberry or barley leaves is an effective way to suppress postprandial glucose levels in young adults with high glucose levels who prefer evenings.


Composite lymphoma. A clinicopathologic analysis of nine patients with Hodgkin's disease and B-cell non-Hodgkin's lymphoma.
Nine patients had composite lymphoma in which Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) involved the same anatomic site. Two of these patients had relapses of their tumors. In one, the initial biopsy specimen contained follicular and diffuse large cell NHL with unclassifiable HD, but the relapse showed diffuse large cell NHL with nodular sclerosis HD. In the other patient, both biopsy specimens showed follicular mixed NHL; the HD component in the initial biopsy specimen was nodular sclerosis, whereas, at relapse, it had the appearance of interfollicular HD. In the remaining seven patients, the HD component was subclassified as nodular sclerosis (three specimens) or mixed cellularity (three specimens), or it was unclassifiable (one specimen). The NHL component was categorized as diffuse large cell (two specimens), diffuse large cell immunoblastic (two specimens), follicular and diffuse large cell (one specimen), diffuse mixed small and large cell (one specimen), and lymphocytic lymphoma of intermediate differentiation (modified Rappaport classification) (one specimen). Paraffin section immunoperoxidase studies were done on the NHL component in eight patients (nine specimens) and on the HD component in six patients (seven specimens). In each of these, the NHL component was leukocyte common antigen (LCA) positive and Leu-M1 negative. In addition, the neoplastic cells were L26 positive and UCHL-1 negative, indicating a B-cell phenotype. In five of seven immunophenotyped cases, Reed-Sternberg (RS) and Hodgkin's (H) cells from the HD areas were Leu-M1 positive and LCA negative, reflecting an immunophenotype that is typical of non-lymphocyte-predominant HD. In two specimens, the malignant cells were negative for Leu-M1 and LCA (with positive internal controls). Composite lymphomas composed of HD and NHL are unusual, and cases of coexistent HD of the non-lymphocyte-predominant subtype and NHL are even less common. The results of the current study and a review of the literature indicate that this phenomenon usually involves a B-cell NHL that coexists with HD, perhaps further suggesting a close relationship between the malignant cells of HD (RS and H cells) and B lymphocytes.


Comparison of effectiveness of electrocautery and cryotherapy in partial matrixectomy after partial nail extraction in the treatment of ingrown nails.
To determine an effective mode of therapy of ingrown nail using two different methods. Patients with the diagnosis of stage 2 or 3 ingrown nails were included and divided into two groups. In the first group, partial matrixectomy was performed using electrocautery after partial nail extraction; in the second group, partial matrixectomy using cryotherapy was performed after partial nail extraction. The study included 53 patients with ingrown nails. Patient ages ranged from 11 to 79 years (median 31.8 ± 16.9). No relapse was observed in 96.2% of the patients after a follow-up period of 3-12 months (n = 51). Matrixectomy in 71.7% (n = 38) of patients was successful. Matrixectomy using electrocautery was successful in 18 of 29 patients. Matrixectomy using cryotherapy was successful in 20 of 24 patients. Matrixectomy should be added to the treatment of ingrown nails. There was no significant difference between electrocautery and cryotherapy in terms of relapse. In patients with advanced stages of ingrown nails, partial nail extraction combined with matrixectomy using cryotherapy is an effective method of treatment.


The Activated Clotting Time Paradox: Relationship Between Activated Clotting Time and Occlusion of the Radial Artery When Used as Vascular Access for Percutaneous Coronary Procedures.
Radial artery occlusion (RAO) is a thrombotic complication of transradial catheterization that can lead to permanent occlusion of the radial artery. Sheath-vessel diameter ratio, postprocedure compression time, occlusive hemostasis, and insufficient anticoagulation are all predictors of RAO. However, excessive anticoagulation can lead to longer time to achieve complete hemostasis and less patent hemostasis rate. This study was designed to assess the relationship among residual anticoagulation at the end of a percutaneous coronary procedure and the risk of RAO. Eight hundred thirty-seven patients undergoing transradial catheterization were enrolled. Activated clotting time (ACT) was measured before sheath removal. Patients were divided into 3 groups according to ACT values (ACT <150 s, ACT between 150 and 249 s, ACT >250 s), patent hemostasis with reverse Barbeau test was attempted in all patients, and compression device removed as soon as possible. Within 24 hours, patency of radial artery was checked by Doppler using reverse Barbeau technique. Incidence of RAO was higher for the extreme ACT values. Patent hemostasis were less frequently obtained and time to hemostasis significantly longer for increasing ACT values (P=0.004 for trend and <0.0001 for trend, respectively). At logistic regression analysis, ACT values <150 s were an independent predictor of RAO (odds ratio, 3.53; 95% IC, 1.677-7.43; P=0.001) while adjusted probability for RAO confirmed U-shaped relationship with ACT values. The level of anticoagulation is strongly related to incidence of RAO and should be measured objectively by ACT. URL: https://www.clinicaltrials.gov. Unique identifier: NCT02762344.


[Correlation between sanitation conditions and intestinal parasitosis in the population of Assis, State of São Paulo].
The distribution of the most frequent enteroparasites in the population of Assis, State of São Paulo, was studied from 1990 to 1992. A total of 18,366 medical examinations from six sanitary care centers in the neighbourhoods of Marialves, Progresso, city center, Xavier, Fiúza and Bonfim were analyzed. The general prevalence of enteroparasites was 23.3%. The most frequently found enteroparasites were: Giardia intestinalis (8.7%), Ascaris lumbricoides (5.5%), Trichuris trichiura (2.4%) and Hymenolepis nana (1.9%). In Marialves, a low income neighborhood, the prevalences were: 17%; 13.1%; 5.9% and 4.2%, respectively. The age group from 3 to 12 years showed the largest number of infected individuals. There was a correlation between basic sanitation conditions, expressed as the number of places connected to the city water and sewage systems, and the prevalence of parasites. There was also a decrease of parasite prevalence in all sanitary care centers from 1990 to 1992, which coincided with the increase in the number of new water and sewage systems in these neighborhoods.


Influence of refractive-index mismatch in high-resolution three-dimensional confocal microscopy.
The effects of the refractive-index mismatch in confocal laser scanning microscopy were extensively studied. The axial aberration induced in the case of fluorescent microspheres was measured. The data were used to take into account the mismatch-induced aberrations and to consider object-size influence. Then we focused on the effect of refractive-index mismatch on the effective system's point-spread function under different mismatch conditions and on depth of focusing. We experimentally verified that the peak of the point-spread function intensity profile decreases and the point-spread function itself progressively broadens as a function of the combined effect of the refractive-index mismatch and of the penetration depth, leading to a worsening of the system's overall performances. We also performed these same measurements by embedding subresolution beads in an oocyte's cytoplasm, which can be considered a turbid medium. We found evidence consistent with the previously developed theoretical model; in particular we found a strong dependence of the intensity peak on the focusing depth.


Comparison of a dietary survey and the duplicate plate method for determining dietary fluoride ingested by young children: a pilot study.
Investigators have attempted to establish the diet's contribution to the total body burden of fluoride in response to a reported trend towards an increase in fluoride intake. The aim of this study was to compare the suitability of two methods to collect dietary data for fluoride intake assessment. Assessments were made in 12 children using the duplicate plate and dietary diary methods following a randomized cross-over design. Foods and beverages were analysed for fluoride, and total fluoride intake per day was calculated. Results from each method were compared. Mean beverage fluoride intake was estimated at 316 +/- 120 and 422 +/- 195 microg/day utilizing the diary and duplicate plate methods, respectively. Mean food fluoride intake was estimated at 188 +/- 48 microg/day using the diary, whereas it was 130 +/- 41 microg using the duplicate plate method. Total fluoride intake was 504 +/- 138 and 552 +/- 192 microg/day utilizing the diary and duplicate methods. Large variations in daily fluoride intake from both beverages and food were observed between and within children. Both methods had inherent shortcomings and sources of error. The duplicate method was more labour intensive and costly; however, the diary method required a large number of assumptions. A combination of both methods seems to be most suitable to obtain reliable data.


Fabrication of a pH/Redox-Triggered Mesoporous Silica-Based Nanoparticle with Microfluidics for Anticancer Drugs Doxorubicin and Paclitaxel Codelivery.
A pH/redox-triggered mesoporous silica nanoparticle (MSN)-based nanoplatform has been fabricated for doxorubicin/paclitaxel (DOX/PTX) codelivery. In this drug-delivery system (DDS), PTX is covalently attached to the surface of DOX loaded MSN via a linker with disulfide bond. By directly attaching PTX to MSN, we can significantly enhance the PTX́s loading degree and achieve the optimum drug loading ratio to DOX, therefore, to generate the best synergistical effect. More importantly, PTX and the linker act as a redox-sensitive "gate" to precisely control the release profile of DOX and PTX. Subsequently, polystyrenesulfonate (PSS) is electrostatically coated to DOX loaded MSN-PTX in microfluidics to achieve acidic pH responsive, because the free amino group on MSN surface has a protonation state at acidic pH, and the electrostatic interaction will be destroyed at pH 5. In addition, PSS can also neutralize the surface zeta potential, thus reduce the nonspecific endocytosis of healthy cells. By evaluating cell viability in cancer cell BT549 and healthy breast cell MCF-10A, we observed that the nanoparticles can selectively release DOX and PTX and eliminate cancer cells, while they will have negligible effect on the healthy breast cells, due to the acidic and redox microenvironment in cancer cells. Overall, we have developed a nanoplatform for precise DOX/PTX combination therapy with high selectivity between cancer cells and healthy cells.


Relationship Between Brain Arterial Pathology and Neurocognitive Performance Among Individuals With Human Immunodeficiency Virus.
Human immunodeficiency virus-positive (HIV+) individuals have higher rates of cognitive impairment and cerebrovascular disease compared with uninfected populations. We hypothesize that cerebrovascular disease, specifically brain large artery disease, may play a role in HIV-associated neurocognitive disorders (HAND). Participants (N = 94) in the Manhattan HIV Brain Bank study were followed on average 32 ± 33 months with repeated neuropsychological examinations until death. We used five cognitive domains (motor, processing speed, working memory, verbal fluency, and executive functioning) to assess ante mortem performance. We quantified the diameter of the lumen and arterial wall thickness obtained during autopsy. The diagnoses of HAND were attributed using the American Academy of Neurology nosology. We used generalized linear mixed model to account for repeated measures, follow-up time, and codependence between arteries. Models were adjusted for demographics, viral loads, CD4 counts, history of opportunistic infections, and vascular risks. We included 94 HIV+ individuals (mean age 56 ± 8.3, 68% men, 54% African American). In adjusted models, there was an association between arterial wall thickness and global cognitive score (B = -0.176, P value = .03), processing speed (B = -0.175, P = .05), and verbal fluency (B = -0.253, P = .02). Participants with incident or worsening HAND had thicker brain arterial walls (B = 0.523 ± 0.234, P = .03) and smaller arterial lumen (B = -0.633 ± 0.252, P = .01). We report here a novel association between brain arterial wall thickening and poorer ante mortem cognitive performance and diagnosis of incident or worsening HAND at death. Strategies to preserve the arterial lumen or to prevent wall thickening may impact HAND.


Expression of RCAS1 and FasL in human trophoblasts and uterine glands during pregnancy: the possible role in immune privilege.
Pregnancy is an immunological balancing act. Trophoblasts do not express MHC class I or II, except HLA-C and G, but express Fas ligand (FasL), which confers immune privilege. RCAS1 (receptor-binding cancer antigen expressed on SiSo cells) has recently been recognized to play a role in immune evasion of the tumour cells. We therefore studied the involvement of RCAS1 and FasL in the infiltration of NK cells by examining the curettaged uterine contents of 20 cases of early stage of pregnancy. The cases were clinically divided into two groups; curettage was performed (A) due to the absence of foetal heart beats, and (B) due to spontaneous uterine bleeding and abortion. In group A, RCAS1 was expressed in the uterine glands and extravillous cytotrophoblasts, as was FasL. Infiltration of NK cells around the uterine glands was scarcely detected. In contrast, in group B, expression of both RCAS1 and FasL was strikingly decreased in both the level of expression and the numbers of RCAS1/FasL-positive cells and massive infiltration of NK cells was frequently detected around the uterine glands. These findings suggest that a reduction in RCAS1 and FasL expression seems to be closely associated with activation and infiltration of maternal NK cells and destruction of uterine glands, resulting in rejection of the foetus. Thus, expression of RCAS1 and FasL in the uterine glands and cytotrophoblasts may play a role in the downregulation of the maternal immune response, thereby maintaining pregnancy at early stage.


Behavior and parental expectations of child pedestrians.
Pedestrian injuries remain the most common cause of death from trauma for young school-age children. This study was based on the hypothesis that parents' abilities to accurately assess their children's street-crossing skills vary with the crossing test and age of the children, being less accurate for younger children. Children at three developmental levels (aged 5 through 6, 7 through 8, and 9 through 10 years) and their parents were evaluated on four street-crossing tests and a control vocabulary test. For each test, children's answers were compared to parents' estimates of their children's performance. Parents overestimated the abilities of their 5-through 6-year-olds on all four tests (P less than .01). Parents overestimated the abilities of 7- through 8-year-olds on two of the tests (P less than .05) and parents accurately assessed the abilities of the 9- through 10-year-olds. On the vocabulary test, parents overestimated their children's performance at all age levels (P less than .01). The results support the hypothesis and indicate that parents' expectations for their children's pedestrian skills are least accurate for 5- and 6-year-olds, with the mismatch decreasing as children get older. Inaccurate expectations of children's pedestrian skills may be fruitful target for injury prevention programs.


Association between parathyroid hormone levels and inflammatory markers among US adults.
High levels of parathyroid hormone (PTH) appear to be associated with an increased mortality. Previous studies concerning the relationship of inflammatory markers with hyperparathyroidism have yielded inconsistent results. This study investigated whether serum PTH concentrations were independently associated with several inflammatory markers among the US adults. Using data from the National Health and Nutrition Examination Survey, we examined the relation between serum PTH and C-reactive protein (CRP), red cell distribution width (RDW), and platelet-to-lymphocyte ratio (PLR) levels with weighted linear regression. Additionally, we examined the relation with increased modified Glasgow Prognostic Score (mGPS) by using weighted logistic regression. CRP, RDW, and PLR values increased with increasing serum PTH concentration. After extensively adjusting for covariates, CRP and RDW increased linearly and across PTH categories (all P < 0.001), while PLR marginally increased (P = 0.190 and P = 0.095 using PTH as a categorical and continuous variable, resp.). The odds ratio of increased mGPS was 1.11 and 1.31 across PTH categories and with increasing PTH levels continuously. These nationally representative data indicate that serum PTH levels are independently associated with several inflammatory markers in the US population. The casual relationship between PTH levels and inflammation remains to be elucidated.


Treatment of refractory myositis: a randomized crossover study of two new cytotoxic regimens.
To assess the clinical usefulness of 2 novel therapies for treatment-resistant myositis. Thirty patients with refractory myositis, of whom 25 had an inadequate or no response to previous cytotoxic therapy, were randomized to begin either a combination of weekly oral methotrexate and daily azathioprine (MTX/AZA) or intravenous methotrexate with leucovorin rescue (I.V. MTX) every 2 weeks for 6 months. Crossover to the alternate therapy occurred according to defined rules; evaluations of muscle strength and functional abilities were performed at the beginning, and after 3 and 6 months, of each treatment. Of the 15 patients initially randomized to oral MTX/AZA, 8 improved with oral therapy and 1 improved with I.V. MTX during the crossover period. Of the 15 patients initially randomized to I.V. MTX therapy, 3 improved with the I.V. therapy and 4 with the oral combination during the crossover period. Although the study lacked the power to directly compare both treatments, intention-to-treat analysis showed a trend in favor of those patients who first received oral combination therapy (P = 0.025). There were 0.09 adverse events per patient-month with oral combination therapy and 0.16 per patient-month with I.V. therapy (P = 0.09). Combination oral MTX/AZA may benefit patients with treatment-resistant myositis, including those who previously had inadequate responses to either MTX or AZA alone. I.V. MTX with leucovorin rescue may also benefit some patients with refractory myositis.


Short-Term Changes in Cardiorespiratory Fitness in Response to Exercise Training and the Association with Long-Term Cardiorespiratory Fitness Decline: The STRRIDE Reunion Study.
Background Substantial heterogeneity exists in the cardiorespiratory fitness (CRF) change in response to exercise training, and its long-term prognostic implication is not well understood. We evaluated the association between the short-term supervised training-related changes in CRF and CRF levels 10 years later. Methods and Results STRRIDE (Studies of a Targeted Risk Reduction Intervention Through Defined Exercise) trial participants who were originally randomized to exercise training for 8 months and participated in the 10-year follow-up visit were included. CRF levels were measured at baseline, after training (8 months), and at 10-year follow-up as peak oxygen uptake (vo2, mL/kg per min) using the maximal treadmill test. Participants were stratified into low, moderate, and high CRF response groups according to the training regimen-specific tertiles of CRF change. The study included 80 participants (age: 52 years; 35% female). At 10-year follow-up, the high-response CRF group had the least decline in CRF compared with the moderate- and low-response CRF groups (-0.35 versus -2.20 and -4.25 mL/kg per minute, respectively; P=0.02). This result was largely related to the differential age-related changes in peak oxygen pulse across the 3 groups (0.58, -0.23, and -0.86 mL/beat, respectively; P=0.03) with no difference in the peak heart rate change. In adjusted linear regression analysis, high response was significantly associated with greater CRF at follow-up independent of other baseline characteristics (high versus low [reference] CRF response: standard β=0.25; P=0.004). Conclusions Greater CRF improvement in response to short-term training is associated with higher CRF levels 10 years later. Lack of CRF improvements in response to short-term training may identify individuals at risk for exaggerated CRF decline with aging.


Polyps and diverticulosis of large bowel in autopsy population of Akita prefecture, compared with Miyagi. High risk for colorectal cancer in Japan.
A necropsy study of polypoid lesions and diverticula of the large bowel in the Japanese prefectures of Akita and Miyagi indicated that adenomatous polyps were more numerous in Akita (30%) than Miyagi (18.3%). They also were larger and showed more severe atypia in Akita. The sigmoid colon and rectum showed the most severe atypia in both prefectures. Hyperplastic polyps and diverticula were very uncommon in both prefectures. These results are discussed in relation to the different levels of risk to colorectal carcinoma in these prefectures and in Japanese migrants to Hawaii.


Occupational exposure to magnetic fields from transformer stations and electric enclosures in Turkey.
We aimed to provide a systematic evaluation of magnetic field (MF) exposure of staff working in the offices located above or close to transformer stations (TS) and electric enclosures (EE). Occupational short-term "spot" measurements with Narda EFA-300 and isotropic magnetic field probe were carried out in two National Banks and one Industrial Company having more than 500 employees. Extremely low-frequency (ELF) MFs up to several tens of μT were measured in the mentioned working environments. 25% of the measured MFs were found less than 0.3 μT, the background exposure level that staff receive at home, 75% were above 0.3 μT with the highest value of 6.8 μT. The mean and median personal exposures were calculated to be 1.19 μT and 0.56 μT, respectively. Most of the staff (83%) is under risk based on epidemiological studies that reported a statistically significant association between risk of leukemia and averaged magnetic fields of 0.2 μT or over. Results showed that risk evaluation should be considered to minimize the possibility of the workers being harmed due to exposure to work-related electromagnetic sources.


An integrated assay to probe endothelial glycocalyx-blood cell interactions under flow in mechanically and biochemically well-defined environments.
Cell-cell and cell-glycocalyx interactions under flow are important for the behaviour of circulating cells in blood and lymphatic vessels. However, such interactions are not well understood due in part to a lack of tools to study them in defined environments. Here, we develop a versatile in vitro platform for the study of cell-glycocalyx interactions in well-defined physical and chemical settings under flow. Our approach is demonstrated with the interaction between hyaluronan (HA, a key component of the endothelial glycocalyx) and its cell receptor CD44. We generate HA brushes in situ within a microfluidic device, and demonstrate the tuning of their physical (thickness and softness) and chemical (density of CD44 binding sites) properties using characterisation with reflection interference contrast microscopy (RICM) and application of polymer theory. We highlight the interactions of HA brushes with CD44-displaying beads and cells under flow. Observations of CD44+ beads on a HA brush with RICM enabled the 3-dimensional trajectories to be generated, and revealed interactions in the form of stop and go phases with reduced rolling velocity and reduced distance between the bead and the HA brush, compared to uncoated beads. Combined RICM and bright-field microscopy of CD44+ AKR1 T-lymphocytes revealed complementary information about the dynamics of cell rolling and cell morphology, and highlighted the formation of tethers and slings, as they interacted with a HA brush under flow. This platform can readily incorporate more complex models of the glycocalyx, and should permit the study of how mechanical and biochemical factors are orchestrated to enable highly selective blood cell-vessel wall interactions under flow.


Effective anticonvulsant therapy in a patient with limb shaking: a case report.
A case is described of a patient with limb shaking in whom anticonvulsant therapy was effective for inhibiting attacks. A 70 year old female developed rhythmical involuntary limb shaking of the right upper and lower limb in April 1986. She was diagnosed as having transient ischemic attacks and was followed up under treatment with an antiplatelet drug. Subsequently, anticonvulsant therapy was also initiated on an outpatient basis. In August 1991, she was admitted with shaking of the right upper and lower limbs. Low molecular dextran was ineffective for inhibiting limb shaking attacks, but intravenous injection of diazepam was effective. Phenytoin and phenobarbital was used in combination. No limb shaking attacks occurred thereafter. The involuntary movement was the same as that observed at the onset of the disease. Though no changes were observed in the pattern of the involuntary movement, anticonvulsant therapy was effective in preventing and inhibiting attacks. This finding is inconsistent with previous reports. It is possible that epileptic factors are involved in the development of this condition.


[Development of prefabricated flaps].
To sum up the experimental development and clinical application of prefabricated flap. The reported experimental results and clinical application of prefabricated flap extensively reviewed. Previous studies had proved that the revascularization of prefabricated flap mainly through anastomoses of implanted vessels and the original vessels of the flap, the implanted vessels slowly formed a new and complete blood vessel network, which could dominate the whole flap, three to four weeks later, the new vessels were mature and the flap could be transferred. Clinically, the superficial temporal vessels, gastroepiploic vessels, circumflex femoral vessels and thoracodorsalis vessels could be harvested for prefabricated flap with satisfactory results. Prefabricated flap provides a new method for the treatment of complicated defects.


What transcranial direct current stimulation intensity is best for cognitive enhancement?
In a recent study published in The Journal of Neurophysiology, Ehrardt et al. (Ehrhardt SE, Filmer HL, Wards Y, Mattingley JB, Dux PE. J Neurophysiol 125: 385-397, 2021) report that moderate intensity (1 mA/25 cm2) transcranial direct current stimulation (tDCS) is optimal for improving performance on a stimulus-response matching task, as opposed to a lower 0.7 mA/25 cm2 or higher 2 mA/25 cm2 dose. This result suggests that behavioral effects of tDCS do not follow a linear dose-response curve. Potential neurobiological and neurocognitive implications of these findings, as well as suggested directions for future research, are discussed.


[The use of orthotopic titanium designs for the elimination of mandibular defects].
The proposed titanium design offers new possibilities for primary and secondary mandibular bone repair. Operations using endoprostheses were performed in 31 patients, the esthetic and functional results are satisfactory.


Antioxidant Properties of Maqui Berry Extract (Aristotelia chilensis (Mol.) Stuntz) and Its Potential Photoprotective Role on Human Skin Fibroblasts.
Maqui berry (Aristotelia chilensis) is characterized by antioxidant and anti-inflammatory properties. The aim of this study was to evaluate the effect of maqui berry extracts on human skin fibroblasts (NHSFs) exposed to ultraviolet radiation (UVB). The photoprotective properties of the extracts were investigated via the determination of the total polyphenolic content (TPC) and antioxidant capacity (DPPH), and the chemical composition was assessed. The chemical purity of the extracts was studied via the evaluation of the toxic elements level. The water extract (MWE 57.75 ± 0.44 mg GAE/g) had the highest mean polyphenol content. The water (MWE) and ethanol (MEE70) extracts had the highest inhibitory activities against DPPH radical formation (283.63 ± 7.29 and 284.60 ± 4.31 mg Tx/L, respectively). The analyzed extracts were found to be safe in terms of toxic elements (arsenic, cadmium, lead). The tested extracts of maqui berry did not cause a cytotoxic effect on NHSF cells after 24, 48, and 72 h of incubation. When the NHSF cells were exposed to UVB radiation in the presence of maqui extracts, their viability was increased or maintained. The maqui berry extracts had a slightly protective effect against skin damage caused by UVB radiation. These were preliminary studies that require further research to determine which maqui compounds correspond with the photoprotective activity.


Organic cation transporters in psychiatric and substance use disorders.
Psychiatric and substance use disorders inflict major public health burdens worldwide. Their widespread burden is compounded by a dearth of effective treatments, underscoring a dire need to uncover novel therapeutic targets. In this review, we summarize the literature implicating organic cation transporters (OCTs), including three subtypes of OCTs (OCT1, OCT2, and OCT3) and the plasma membrane monoamine transporter (PMAT), in the neurobiology of psychiatric and substance use disorders with an emphasis on mood and anxiety disorders, alcohol use disorder, and psychostimulant use disorder. OCTs transport monoamines with a low affinity but high capacity, situating them to play a central role in regulating monoamine homeostasis. Preclinical evidence discussed here suggests that OCTs may serve as promising targets for treatment of psychiatric and substance use disorders and encourage future research into their therapeutic potential.


Kā-HOLO Project: a protocol for a randomized controlled trial of a native cultural dance program for cardiovascular disease prevention in Native Hawaiians.
As a major risk factor for cardiovascular and cerebrovascular disease (CVD), hypertension affects 33% of U.S. adults. Relative to other US races and ethnicities, Native Hawaiians have a high prevalence of hypertension and are 3 to 4 times more likely to have CVD. Effective, culturally-relevant interventions are needed to address CVD risk in this population. Investigators of the Kā-HOLO Project developed a study design to test the efficacy of an intervention that uses hula, a traditional Hawaiian dance, to increase physical activity and reduce CVD risk. A 2-arm randomized controlled trial with a wait-list control design will be implemented to test a 6-month intervention based on hula to manage blood pressure and reduce CVD risk in 250 adult Native Hawaiians with diagnosed hypertension. Half of the sample will be randomized to each arm, stratified across multiple study sites. Primary outcomes are reduction in systolic blood pressure and improvement in CVD risk as measured by the Framingham Risk Score. Other psychosocial and sociocultural measures will be included to determine mediators of intervention effects on primary outcomes. Assessments will be conducted at baseline, 3 months, and 6 months for all participants, and at 12 months for intervention participants only. This trial will elucidate the efficacy of a novel hypertension management program designed to reduce CVD risk in an indigenous population by using a cultural dance form as its physical activity component. The results of this culturally-based intervention will have implications for other indigenous populations globally and will offer a sustainable, culturally-relevant means of addressing CVD disparities. ClinicalTrials.gov: NCT02620709 , registration date November 23, 2015.


Long Noncoding RNA 3632454L22Rik Contributes to Corneal Epithelial Wound Healing by Sponging miR-181a-5p in Diabetic Mice.
This work explores the abnormal expression of long noncoding RNAs (lncRNAs), microRNAs (miRNAs) and messenger RNAs (mRNAs) in diabetic corneal epithelial cells (CECs) and constructs an associated competitive endogenous RNA (ceRNA) network. Moreover, we revealed that Rik may exert advantageous effects on diabetic corneal epithelial wound closure by sponging miR-181a-5p. We obtained the profiles of differentially expressed lncRNAs (DELs) of CECs of type 1 diabetic versus control corneas by microarray and summarized the differentially expressed miRNAs (DEmiRs) and differentially expressed genes (DEGs) data by published literature. Subsequently, the ceRNA network was constructed using bioinformatics analyses. The levels of lncRNA ENSMUST00000153610/3632454L22Rik (Rik) and miR-181a-5p were verified. The localization of Rik was identified with fluorescence in situ hybridization (FISH), and dual-luciferase assays proved the targeted relationship between Rik and miR-181a-5p. Furthermore, we validated the functional impact of Rik in vitro. Overall, 111 upregulated and 117 downregulated DELs were detected in diabetic versus control CECs. The level of Rik located in both the cytoplasm and the nucleus was clearly downregulated, whereas miR-181a-5p was upregulated in vitro and in vivo in the diabetic group versus the control group. Rik can act as a ceRNA to bind to miR-181a-5p, thus promoting diabetic corneal epithelial wound healing in vitro. This work investigated the expression profile of DELs and constructed ceRNA networks of diabetic CECs for the first time. Furthermore, we revealed that Rik may positively impact diabetic corneal epithelial wound healing by sponging miR-181a-5p, providing a novel potential therapeutic target of diabetic keratopathy (DK).


Comparing the Healing Abilities of Fluorapatite and Hydroxyapatite Ceramics in Regenerating Bone Tissue: An In Vivo Study.
Some reports in the literature show the advantages of fluoride-containing apatite ceramics over hydroxyapatite (HAP), at least in some aspects. While HAP has been used extensively in the treatment of bone defects, fluoridated apatite has hardly been tested in vivo. In order to verify the biological properties of fluoride-doped apatite and to assess its therapeutic potential, we synthesized fluorapatite (FAP) and applied it as a filling in bone defects of experimental animals (rabbits). The treatment effects were evaluated on extracted bones after 3 and 6 months from implantation using peripheral quantitative computed tomography (pQCT), dual-energy X-ray absorptiometry (DXA), radiography (X-ray) and histological staining. The study proved the integration between FAP and the bone tissue, thus indicating its stimulating effect on new bone formation and mineralization. The results achieved after 3 months of treatment were difficult to interpret unequivocally and suggested the transient delay in FAP integration of bone in comparison with HAP. The reasons for this phenomenon are unclear. Most likely, these differences between FAP and HAP resulted mainly from the different porosities, densities and ionic reactivity of the ceramics, which in our opinion affected their solubility, integration and degree of bone tissue resorption. However, it was shown that 6 months after implantation, similar level of bone defect regeneration was achieved for both FAP and HAP. In this article, we present our hypothesis concerning the basis of this phenomenon.


[Congenital bulbular urethral constrictures. Pathogenesis and treatment of diseases of the bladder neck and urogenital border regions(author's transl)].
This paper is a survey of the literature concerning diseases of the bladder neck, posterior urethra and the urogenital border region. Urethrographic, uroflowmetric and urethrocystoscopic examinations of more than 200 patients ranging in age from one day to over 70 years demonstrated a clear-cut bulbular urethral constricture in this broad-spectrum disease picture. Its a congenital appearance is explained embryologically. A case analysis allows for classification based on the functional value of the urethral constricture. Diseases of as yet unexplained etiology such as Marion's disease, bladder neck sclerosis, urethral valves and chronic prostatitis-prostatopathy are clarified, based on the demonstrated urodynamics.


Kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor confers resistance to the antiproliferative effect of interferon-alpha.
Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a 442 amino acid polypeptide-designated viral interferon regulatory factor (vIRF) that displays homology to members of the interferon regulatory factor (IRF) family that bind to consensus interferon sequences and transactivate cellular genes that can modulate growth inhibition. Studies were conducted to determine whether vIRF affects the growth suppression mediated by interferon-alpha (IFN-alpha) in a human B lymphocyte cell line. The human B lymphocyte cell line Daudi, which is sensitive to the antiproliferative effects of IFN-alpha, was stably transfected to express vIRF, and the proliferative response of vIRF expressing cells to IFN-alpha was compared with controls. The effect of vIRF on IRF- 1 transactivation was analyzed by co-transfection of an IFN-alpha-responsive chloramphenicol acetyltransferase reporter and expression plasmids encoding IRF-1 and vIRF. Electrophoretic mobility shift assays were conducted to determine whether vIRF interferes with the DNA binding activity of IRF-1. Daudi human B lymphocyte cells expressing vIRF were resistant to the antiproliferative effects of IFN-alpha, whereas wild-type Daudi or Daudi cells transformed with vector DNA were growth inhibited by IFN-alpha. The activation of an interferon-responsive reporter by IFN-alpha or IRF-1 was repressed by expression of vIRF. IRF-1 DNA binding activity was unaffected by vIRF, and vIRF alone did not bind to the interferon consensus sequence. These studies revealed that vIRF functions to inhibit interferon-mediated growth control of a human B lymphocyte cell line by targeting IRF-1 transactivation of interferon-inducible genes. Since KSHV is a B lymphotropic herpesvirus associated with two forms of B lymphocyte neoplasms, these effects of vIRF likely contribute to B cell oncogenesis associated with KSHV infection.


Fatal and non-fatal cardiovascular events in a general population prescribed sibutramine in New Zealand: a prospective cohort study.
The cardiovascular safety of sibutramine is currently under review by medicines regulatory authorities worldwide after the SCOUT (Sibutramine Cardiovascular Outcome Trial) showed an increased risk of cardiovascular events in patients taking sibutramine. Further data regarding the cardiovascular safety of sibutramine in a general population are now required. To quantify the risk of fatal and non-fatal cardiovascular adverse events in a general population prescribed sibutramine in postmarketing use. Observational prospective cohort study of patients dispensed sibutramine during a 3-year period (2001-4) and followed up for at least 1 year after their last prescription. The study included record-linkage to national mortality datasets to identify fatal events. Postmarketing 'real-life' use of sibutramine in a general population in New Zealand. All New Zealand patients dispensed a prescription for sibutramine in a 3-year period (for whom a National Health Identification number could be validated). 15 686 patients were included in the record linkage study for fatal events. A subgroup of 9471 patients was followed up by intensive methods for non-fatal events. (i) Rate of death from all causes and from cardiovascular events; and (ii) rates of non-fatal cardiovascular adverse events. Total exposure to sibutramine for 15 686 patients in the validated cohort was 5431 treatment-years. The rate of death from all causes in this cohort was 0.13 (95% CI 0.05, 0.27) per 100 treatment-years exposure. The rate of death from a cardiovascular event was 0.07 (95% CI 0.02, 0.19) per 100 treatment-years exposure. The most frequent non-fatal cardiovascular events in the intensively followed up cohort were hypertension, palpitations, hypotensive events and tachycardia. Risk of death from a cardiovascular event in this general population of patients prescribed sibutramine was lower than has been reported in other overweight/obese populations. The results of this study suggest that further evaluation of the benefit-risk profile of sibutramine is now required.


Directed evolution of the rRNA methylating enzyme Cfr reveals molecular basis of antibiotic resistance.
Alteration of antibiotic binding sites through modification of ribosomal RNA (rRNA) is a common form of resistance to ribosome-targeting antibiotics. The rRNA-modifying enzyme Cfr methylates an adenosine nucleotide within the peptidyl transferase center, resulting in the C-8 methylation of A2503 (m8A2503). Acquisition of cfr results in resistance to eight classes of ribosome-targeting antibiotics. Despite the prevalence of this resistance mechanism, it is poorly understood whether and how bacteria modulate Cfr methylation to adapt to antibiotic pressure. Moreover, direct evidence for how m8A2503 alters antibiotic binding sites within the ribosome is lacking. In this study, we performed directed evolution of Cfr under antibiotic selection to generate Cfr variants that confer increased resistance by enhancing methylation of A2503 in cells. Increased rRNA methylation is achieved by improved expression and stability of Cfr through transcriptional and post-transcriptional mechanisms, which may be exploited by pathogens under antibiotic stress as suggested by natural isolates. Using a variant that achieves near-stoichiometric methylation of rRNA, we determined a 2.2 Å cryo-electron microscopy structure of the Cfr-modified ribosome. Our structure reveals the molecular basis for broad resistance to antibiotics and will inform the design of new antibiotics that overcome resistance mediated by Cfr.


The mechanistic interplay between Nrf-2, NF-κB/MAPK, caspase-dependent apoptosis, and autophagy in the hepatoprotective effects of Sophorolipids produced by microbial conversion of banana peels using Saccharomyces cerevisiae against doxorubicin-induced hepatotoxicity in rats.
Doxorubicin (DOX) is a well-known chemotherapeutic agent which causes serious adverse effects due to multiple organ damage, including cardiotoxicity, nephrotoxicity, neurotoxicity, and hepatotoxicity. The mechanism of DOX-induced organ toxicity might be attributed to oxidative stress (OS) and, consequently, activation of inflammatory signaling pathways, apoptosis, and blockage of autophagy. Sophorolipids (SLs) as a glycolipid type of biosurfactants, are natural products that have unique properties and a wide range of applications attributed to their antioxidant and anti-inflammatory properties. Production of low-cost SLs from Saccharomyces cerevisiae grown on banana peels and investigating their possible protective effects against DOX-induced hepatotoxicity. The yeast was locally isolated and molecularly identified, then the yielded SLs were characterized by FTIR, 1H NMR and LC-MS/MS spectra. Posteriorly, thirty-two male Wistar rats were randomly divided into four groups; control (oral saline), SLs (200 mg/kg, p.o), DOX (10 mg/kg; i.p.), and SL + DOX (200 mg/kg p.o.,10 mg/kg; i.p., respectively). Liver function tests (LFTs), oxidative stress, inflammatory, apoptosis as well as autophagy markers were investigated. SLs were produced with a yield of 49.04% and treatment with SLs improved LFTs, enhanced Nrf2 and suppressed NF-κB, IL-6, IL-1β, p38, caspase 3 and Bax/Bcl2 ratio in addition to promotion of autophagy when compared to DOX group. Our results revealed a novel promising protective effect of SLs against DOX-induced hepatotoxicity in rats.


Molecular characterization of Salmonella weltevreden isolated from poultry: evidence of conjugal transfer of plasmid and antibiotic resistance.
Ten strains of Salmonella weltevreden isolated from poultry sources were examined and found to contain plasmid DNA ranging in size from 1.8 to 68.5 MD. All isolates were susceptible to carbenicillin, cephalothin, ceftriazone, gentamicin, kanamycin and nalidixic acid, but resistance to bacitracin (100%), penicillin G (100%), rifampicin (100%), sulphamethoxazole (100%), cefuroxime (80%) and tetracycline (60%) was recorded. The 55 MD plasmid of strain SW5 determined resistance to penicillin G and tetracycline, which was transmissible to the E. coli K12 recipient at a frequency of 3.52 x 10(-5) transconjugants per input donor cell. The results of arbitrarily primed polymerase chain reaction (AP-PCR), using two 10-mer oligonucleotides and PCR-ribotyping to differentiate between the ten strains of S. weltevreden were compared. The strains were separated into ten different genome types by AP-PCR but were indistinguishable by PCR-ribotyping. These results suggest that poultry may constitute a reservoir for disseminating antibiotic resistance and that AP-PCR may be a valuable tool for epidemiological studies.


Nasal allergies in the Asian-Pacific population: Results from the Allergies in Asia-Pacific Survey.
The Allergies in Asia-Pacific Survey describes the symptoms, impact, and treatment of allergic rhinitis (AR) across Australia, China, Hong Kong, Malaysia, Singapore, Taiwan, Vietnam, and the Philippines. The Allergies in Asia-Pacific Survey was undertaken to further clarify the prevalence of physician-diagnosed nasal allergies (NAs), impact on quality-of-life (QOL), existing treatment paradigms and gaps, and NA medications currently used in treatment. Thirty-three thousand three hundred seventy-eight households were screened for individuals, ≥4 years old, with a physician diagnosis of AR or NA and either symptoms or treatment in the past 12 months. Standardized questionnaires were used to make comparisons across regions. A total of 1043 adults and 192 children were included in the survey. Nine percent of participants were diagnosed with AR with two of three responding that their NAs were seasonal in nature. Nasal congestion was the most common and bothersome symptom of AR. Most participants reported that AR impacted their QOL with nearly one-half citing impairments in school/work performance/productivity. Sleep disturbances, secondary to AR, were also shown to be appreciable. Two-thirds of patients took medication for their AR. Less than one-quarter of survey respondents reported taking an intranasal corticosteroid and the satisfaction rate was similar to that of over-the-counter medications. The most common reasons cited for dissatisfaction were related to inadequate efficacy and bothersome side effects. AR appears to be extremely common across Asia-Pacific nations. Many individuals with AR suffer from symptoms that reduce QOL and treatment gaps exist with current therapies. Through identification of disease impact and highlighting treatment gaps, clinicians may better understand and treat AR, leading to improvements in overall patient satisfaction and QOL.


Surprise disrupts cognition via a fronto-basal ganglia suppressive mechanism.
Surprising events markedly affect behaviour and cognition, yet the underlying mechanism is unclear. Surprise recruits a brain mechanism that globally suppresses motor activity, ostensibly via the subthalamic nucleus (STN) of the basal ganglia. Here, we tested whether this suppressive mechanism extends beyond skeletomotor suppression and also affects cognition (here, verbal working memory, WM). We recorded scalp-EEG (electrophysiology) in healthy participants and STN local field potentials in Parkinson's patients during a task in which surprise disrupted WM. For scalp-EEG, surprising events engage the same independent neural signal component that indexes action stopping in a stop-signal task. Importantly, the degree of this recruitment mediates surprise-related WM decrements. Intracranially, STN activity is also increased post surprise, especially when WM is interrupted. These results suggest that surprise interrupts cognition via the same fronto-basal ganglia mechanism that interrupts action. This motivates a new neural theory of how cognition is interrupted, and how distraction arises after surprising events.


Low dose versus high dose stavudine for treating people with HIV infection.
Stavudine remains a component of combination antiretroviral therapy (ART) in resource-constrained countries due to its relatively low cost despite the WHO recommendation for its phasing out as a strategy to reduce stavudine associated toxicities. Where stavudine is still in use, it is recommended at a dose lower than the standard dose in order to reduce stavudine related toxicity. To compare the safety and virologic efficacy of low dose versus high dose stavudine for treating HIV-1 infection. The comprehensive search strategy developed by the Cochrane HIV/AIDS Review Group was used to identify randomised controlled trials that compared the use of low dose versus high dose stavudine. The last search was conducted in February 2014 and the searches covered the period 1996 to 2014. Randomised controlled trials comparing the use of low dose and high dose stavudine as part of ART combination therapy for treating adults. Two reviewers independently selected eligible trials, assessed methodological quality of the included studies and completed data extraction and analysis. The search identified 3952 abstracts which were scanned for relevance. Three trials met the inclusion criteria (Milinkovic 2007; McComsey 2008; Sanchez-Conde 2005). All three trials were conducted in developed countries, participants were ART experienced and all had sustained virologic suppression at baseline. A total of 157 participants were recruited to the trials. Sample sizes ranged from 24 to 92 and more than 79% of participants were male.The studies were at a high risk of selection, performance/detection and selective outcome reporting biases. Some baseline characteristics differed among the groups, including triglyceride levels in two studies and body mass index in one study. In light of variation in the design and follow-up of the study results, no meta-analysis was performed and the results of single studies are presented. There was no significant difference in virologic suppression in the included studies (Milinkovic 2007; McComsey 2008; Sanchez-Conde 2005); Risk Ratio (RR) 1.09 (95% CI: 0.93 to 1.28), 0.94 (95% CI:0.59 to 1.50) and 1.03 (95% CI: 0.90 to 1.18) respectively. Symptomatic hyperlactatemia was seen in the high dose arm of the Milinkovic 2007 study; RR 0.21 (95% CI: 0.01 to 4.66), in no participants in the McComsey 2008 trial and not reported on in the Sanchez-Conde 2005 trial. McComsey 2008 and Milinkovic 2007 demonstrated a reduction in bone mineral density (BMD), reduction in limb fat and an increase in triglycerides in the high dose arms. The studies did not indicate that any participants discontinued treatment due to adverse events. This systematic review identified only three small trials that evaluated virologic efficacy and safety of high dose versus low dose stavudine. All three trials were conducted in developed countries and none reported from developing countries yet stavudine remains a component of ART combination therapy in many developing countries. It was not possible to perform a meta-analysis on these trails. Individual results from the trials were imprecise and have not identified a clear advantage in virologic efficacy or safety between low and high dose stavudine. Furthermore, enrolled participants were treatment experienced with sustained virologic suppression and so existing data cannot be generalized to settings where stavudine is currently used in ART naive patients with high viral loads. Stavudine dose reduction trials in ART naive patients, in developing countries where stavudine is still being used are warranted as the phasing out of stavudine that is recommended by WHO may not be immediately universally feasible.


Transcatheter closure of post-myocardial infarction ventricular septal rupture.
Ventricular septal rupture (VSR) after acute myocardial infarction (AMI) is a potentially lethal mechanical complication of acute coronary syndromes. Given high surgical mortality, transcatheter closure has emerged as a potential strategy in selected cases. We report our single-center experience with double-umbrella device percutaneous closure of post-AMI VSR. In this single-center, retrospective, cohort study, patients who underwent transcatheter closure of post-AMI VSR between 1988 and 2008 at Boston Children's Hospital were included. Data were analysed according to whether the patients underwent direct percutaneous VSR closure or closure of a residual VSR after a previous surgical approach. Primary outcome was mortality rate at 30 days. Clinical predictors of primary outcome were investigated using univariate logistic regression. Thirty patients were included in the study (mean age, 67±8 years). A total of 40 closure devices were implanted. Major periprocedural complications occurred in 4 (13%) patients. Cardiogenic shock, increasing pulmonary/systemic flow ratio, and the use of the new generation (6-arm) STARFlex device all were associated with higher risk of mortality. The Model for End-Stage Liver Disease Excluding international normalized ratio (MELD-XI) score at the time of VSR closure seemed to be most strongly associated with death (odds ratio, 1.6; confidence interval, 1.1-2.2; P<0.001). Transcatheter closure of post-AMI VSR using CardioSEAL or STARFlex devices is feasible and effective. The MELD-XI score, a marker of multiorgan dysfunction, is a promising risk stratifier in this population of patients. Early closure of post-AMI VSR is advisable before establishment of multiorgan failure.


Synthetic chemical ligands and cognate antibodies for biorthogonal drug targeting and cell engineering.
A vast range of biomedical applications relies on the specificity of interactions between an antigen and its cognate receptor or antibody. This specificity can be highest when said antigen is a non-natural (synthetic) molecule introduced into a biological setting as a bio-orthogonal ligand. This review aims to present the development of this methodology from the early discovery of haptens a century ago to the recent clinical trials. We discuss such methodologies as antibody recruitment, artificial internalizing receptors and chemically induced dimerization, present the use of chimeric receptors and/or bispecific antibodies to achieve drug targeting and transcytosis, and illustrate how these platforms most impressively found use in the engineering of therapeutic cells such as the chimeric antigen receptor cells. This review aims to be of interest to a broad scientific audience and to spur the development of synthetic artificial ligands for biomedical applications.


Incidence of persistent postoperative pain after hepatectomies with 2 regimes of perioperative analgesia containing ketamine.
Studies designed to assess persistent postoperative pain (PPP) incidence after hepatectomies are lacking. Our aim was to assess PPP incidence 6 months after hepatectomies with intravenous (IV) or epidural (EPI) analgesia containing ketamine.Prospective observational comparative study between 2 cohorts of patients submitted to hepatectomy. Patients received 1 of 2 analgesic regimes containing ketamine: EPI group or IV group. Visual analog scale (VAS), Neuropathic Pain Symptom Inventory (NPSI), Pain Catastrophizing Scale (PCS), and quantitative sensorial testing (QST: to determine area of hyperalgesia/allodynia) were assessed preoperatively and postoperatively at 2 h, 24 h, 7 days, 1 month, and 6 months. VAS ≥ 1 at 1 and 6 months was considered indicative of PPP and VAS > 3 was considered as not controlled pain. Side effects and complications were registered.Forty-four patients were included: 23 in EPI group and 21 in IV group. Patients in IV group were older and had more comorbidities. No patient presented VAS > 3 at 1 or 6 months. VAS ≥ 1 at 1 and 6 months was 36.4% and 22.7%, respectively. No differences in VAS, NPSI, or PCS were found between groups. Allodynia/hyperalgesia area did not differ between groups and was infrequent and slight. Pain pressure threshold in the wound vertical component was significantly higher in EPI group after 7 days. IV group showed more cognitive side effects.Incidence of PPP at 6 months after open hepatectomies with EPI or IV analgesia containing ketamine was lower than previously reported for other abdominal surgeries.Ketamine influence on low PPP incidence and hyperalgesia cannot be discarded.