Genomic screening for blood-borne viruses in transfusion settings.
The residual risk of post-transfusion human immunodeficiency virus (HIV) infection is low but slightly higher for hepatitis B virus (HBV) and hepatitis C virus (HCV), the main reason being viraemia during the window period preceding antibody or antigen detection by enzyme immunoassays. Immunosilent-infected individuals and carriers of distant viral variants also play an unquantifiable role. Multiple techniques, e.g. reverse transcription-polymerase chain reaction (RT-PCR), PCR, ligase-chain reaction, nucleic acid sequence-based amplification (NASBA) and transcription-mediated amplification (TMA) have been developed to amplify and detect viral genomes as single or multiplex assays. Equipment providing various degrees of automation has been adapted to these techniques. Applying nucleic acid amplification techniques (NAT) to blood screening, two main approaches have been advocated: plasma pool and single-donation testing. Pool testing presents the advantage of lower cost and readily available equipment although it is prone to false negative and positive reactions. The time required to identify infected donations is incompatible with blood component release, and may lead to product waste. Single-unit testing, although appealing, is not yet fully automated and potentially very costly unless a systematic multiplex approach is taken. Although technically feasible, NAT applied to the blood supply needs to be clinically evaluated and its cost efficiency assessed in the general public health context. However, pool NAT is currently implemented in continental Europe and the USA.


Abnormally abrupt transitions from sleep-to-wake in Huntington's disease sheep (Ovis aries) are revealed by automated analysis of sleep/wake transition dynamics.
Sleep disturbance is a common and disruptive symptom of neurodegenerative diseases such as Alzheimer's and Huntington's disease (HD). In HD patients, sleep fragmentation appears at an early stage of disease, although features of the earliest sleep abnormalities in presymptomatic HD are not fully established. Here we used novel automated analysis of quantitative electroencephalography to study transitions between wake and non-rapid eye movement sleep in a sheep model of presymptomatic HD. We found that while the number of transitions between sleep and wake were similar in normal and HD sheep, the dynamics of transitions from sleep-to-wake differed markedly between genotypes. Rather than the gradual changes in EEG power that occurs during transitioning from sleep-to-wake in normal sheep, transition into wake was abrupt in HD sheep. Furthermore, transitions to wake in normal sheep were preceded by a significant reduction in slow wave power, whereas in HD sheep this prior reduction in slow wave power was far less pronounced. This suggests an impaired ability to prepare for waking in HD sheep. The abruptness of awakenings may also have potential to disrupt sleep-dependent processes if they are interrupted in an untimely and disjointed manner. We propose that not only could these abnormal dynamics of sleep transitions be useful as an early biomarker of HD, but also that our novel methodology would be useful for studying transition dynamics in other sleep disorders.


Human resource management research in healthcare: a big data bibliometric study.
Human resource management (HRM) in healthcare is an important component in relation to the quality and efficiency of healthcare delivery. However, a comprehensive overview is lacking to assess and track the current status and trends of HRM research in healthcare. This study aims to describe the current situation and global trends in HRM research in healthcare as well as to indicate the frontiers and future directions of research. The research methodology is based on bibliometric mapping using scientific visualization software (VOSviewer). The data were collected from the Web of Science(WoS) core citation database. After applying the search criteria, we retrieved 833 publications, which have steadily increased over the last 30 years. In addition, 93 countries and regions have published relevant research. The United States and Australia have made significant contributions in this area. Current research articles focus on topics clustered into performance, hospital/COVID-19, job satisfaction, human resource management, occupational/mental health, and quality of care. The most frequently co-occurring keywords are human resource management, job satisfaction, nurses, hospitals, health services, quality of care, COVID-19, and nursing. There is limited research on compensation management and employee relations management, so the current HRM research field still has not been able to present a complete and systematic roadmap. We propose that our colleagues should consider focusing on these research gaps in the future.


Diagnosis and treatment of pre-insulin dependent diabetes.
The development of genetic and serological markers of autoimmune Type I diabetes has allowed us to begin to identify subjects at risk for the development of Type I diabetes. Assessment of these variables can assign risk to subjects and permit the implementation of immune intervention trials in an attempt to alter the course of pre-diabetes. This review discusses relevant aspects of the genetics and diagnosis of pre-diabetes, and both current and future clinical trials that are attempting to prevent the full expression of clinical diabetes in these individuals.


A forager-herder trade-off, from broad-spectrum hunting to sheep management at Aşıklı Höyük, Turkey.
Aşıklı Höyük is the earliest known preceramic Neolithic mound site in Central Anatolia. The oldest Levels, 4 and 5, spanning 8,200 to approximately 9,000 cal B.C., associate with round-house architecture and arguably represent the birth of the Pre-Pottery Neolithic in the region. Results from upper Level 4, reported here, indicate a broad meat diet that consisted of diverse wild ungulate and small animal species. The meat diet shifted gradually over just a few centuries to an exceptional emphasis on caprines (mainly sheep). Age-sex distributions of the caprines in upper Level 4 indicate selective manipulation by humans by or before 8,200 cal B.C. Primary dung accumulations between the structures demonstrate that ruminants were held captive inside the settlement at this time. Taken together, the zooarchaeological and geoarchaeological evidence demonstrate an emergent process of caprine management that was highly experimental in nature and oriented to quick returns. Stabling was one of the early mechanisms of caprine population isolation, a precondition to domestication.


Role of human herpesvirus 6 infection in young Brazilian children with rash illnesses.
Human herpesvirus type 6 (HHV-6) has been shown to infect almost all children by 4 years of age. Primary infection causes an undifferentiated febrile illness, with approximately 30% of children exhibiting the classic clinical manifestations of exanthem subitum. Even with typical clinical presentation, exanthem subitum is frequently misdiagnosed as measles or rubella. Our aim was to describe the frequency and clinical manifestations of HHV-6 infection in children less than 4 years of age enrolled in a study designed to define the etiology of rash diseases. The study was conducted between January 1998 and December 2006 at a general hospital and a large primary health care unit from Niterói, Rio de Janeiro, Brazil. Sera from 223 children, in whom measles, rubella, dengue fever, and parvovirus B19 infections were excluded, were studied for anti-HHV-6 antibodies using an indirect immunofluorescence test. Demographic and clinical data of those patients were described. Ninety-seven (43.5%) of the children had evidence of primary HHV-6 infection. The age of onset peaked at 6-11 months and 75% of the HHV-6 infection occurred in children between 6 and 17 months. Only 21% of the HHV-6 cases had a typical roseola-like illness and 73% and 46%, respectively, fulfilled the clinical criteria of measles and rubella suspected case. Our study confirms the importance of HHV-6 infection in young children and highlights the difficulties of diagnosing a rash illness on clinical grounds alone.


Structural insights into cis element recognition of non-polyadenylated RNAs by the Nab3-RRM.
Transcription termination of non-polyadenylated RNAs in Saccharomyces cerevisiae occurs through the action of the Nrd1-Nab3-Sen1 complex. Part of the decision to terminate via this pathway occurs via direct recognition of sequences within the nascent transcript by RNA recognition motifs (RRMs) within Nrd1 and Nab3. Here we present the 1.6 Å structure of Nab3-RRM bound to its UCUU recognition sequence. The crystal structure reveals clear density for a UCU trinucleotide and a fourth putative U binding site. Nab3-RRM establishes a clear preference for the central cytidine of the UCUU motif, which forms pseudo-base pairing interactions primarily through hydrogen bonds to main chain atoms and one serine hydroxyl group. Specificity for the flanking uridines is less defined; however, binding experiments confirm that these residues are also important for high affinity binding. Comparison of the Nab3-RRM to other structures of RRMs bound to polypyrimidine RNAs showed that this mode of recognition is similar to what is observed for the polypyrimidine-tract binding RRMs, and that the serine residue involved in pseudo-base pairing is only found in RRMs that bind to polypyrimidine RNAs that contain a cytosine base, suggesting a possible mechanism for discriminating between cytosine and uracil bases in RRMs that bind to polypyrimidine-containing RNA.


Annexins--new family of Ca2+-regulated-phospholipid binding protein.
Calcium and phospholipid binding proteins have been identified and localized by immunocytochemistry in a wide range of cells and tissues. Two of these proteins (calpactins) also bind F-actin and are substrates for tyrosine kinases. The similar membrane-binding properties of these molecules arise from conserved amino acid sequences and a model is proposed for the tertiary structure of a common calcium and phospholipid binding domain.


Adalimumab with or without methotrexate in juvenile rheumatoid arthritis.
Tumor necrosis factor (TNF) has a pathogenic role in juvenile rheumatoid arthritis. We evaluated the efficacy and safety of adalimumab, a fully human monoclonal anti-TNF antibody, in children with polyarticular-course juvenile rheumatoid arthritis. Patients 4 to 17 years of age with active juvenile rheumatoid arthritis who had previously received treatment with nonsteroidal antiinflammatory drugs underwent stratification according to methotrexate use and received 24 mg of adalimumab per square meter of body-surface area (maximum dose, 40 mg) subcutaneously every other week for 16 weeks. We randomly assigned patients with an American College of Rheumatology Pediatric 30% (ACR Pedi 30) response at week 16 to receive adalimumab or placebo in a double-blind fashion every other week for up to 32 weeks. Seventy-four percent of patients not receiving methotrexate (64 of 86) and 94% of those receiving methotrexate (80 of 85) had an ACR Pedi 30 response at week 16 and were eligible for double-blind treatment. Among patients not receiving methotrexate, disease flares (the primary outcome) occurred in 43% of those receiving adalimumab and 71% of those receiving placebo (P=0.03). Among patients receiving methotrexate, flares occurred in 37% of those receiving adalimumab and 65% of those receiving placebo (P=0.02). At 48 weeks, the percentages of patients treated with methotrexate who had ACR Pedi 30, 50, 70, or 90 responses were significantly greater for those receiving adalimumab than for those receiving placebo; the differences between patients not treated with methotrexate who received adalimumab and those who received placebo were not significant. Response rates were sustained after 104 weeks of treatment. Serious adverse events possibly related to adalimumab occurred in 14 patients. Adalimumab therapy seems to be an efficacious option for the treatment of children with juvenile rheumatoid arthritis. (ClinicalTrials.gov number, NCT00048542.)


Weekend/holiday versus weekday hospital discharge and guideline adherence (from the American Heart Association's Get with the Guidelines--Coronary Artery Disease database).
Most hospitals have reduced medical staff on weekends. Furthermore, a recent study on acute myocardial infarction suggested that weekend admissions were associated with higher mortality compared with weekday admissions. We sought to determine if compliance with guideline recommendations for acute coronary syndrome performance measures would be worse on weekends/holidays compared with weekdays. We utilized the American Heart Association's Get with the Guidelines (GWTG)--Coronary Artery Disease database. This study included 154,910 patients admitted to 515 various hospitals from January 14, 2000 to April 30, 2007 with acute coronary syndrome (ACS). Patients discharged on weekdays were older and were more likely to be women, have a history of atrial fibrillation, cerebral vascular accident/transient ischemic attack and chronic renal insufficiency, and present with unstable angina. Although patients discharged on the weekends/holidays were slightly less likely to receive angiotensin-converting enzyme inhibitors than those discharged on weekdays (68.3% vs 69.5%, p <0.0001), all other measures were similar, and a composite performance measure for 100% compliance was equal in both groups (81.5% vs 81.4%, p = 0.77). In conclusion, within GWTG participating hospitals, weekend/holiday staffing provides the same quality of care in ACS for discharge medications and counseling compared with full weekday staffing. However, there remain further opportunities to improve utilization of guideline-recommended therapies irrespective of discharge day.


Reliability and validity of non-invasive determined haemoglobin mass and blood volumes.
The carbon monoxide (CO) rebreathing method used for the determination of haemoglobin mass (Hbmass ) is associated with blood sample analysis (in this study: Radiometer ABL800). As an alternative hereto the aim of the present study was to evaluate the use of a portable and non-invasive CO pulse oximeter (Rad-57). With simultaneous determination of CO in the circulation by ABL800 (%HbCO) and Rad-57 (SpCO), Hbmass and blood volume (BV) were determined in duplicates in 24 volunteers. Percentage of typical errors (%TE) within methods and linear correlations between the two procedures were computed. Hbmass (Rad-57 = 798 ± 230 g; ABL800 = 781 ± 192 g) and BV (Rad-57 = 5700 ± 1373 ml; ABL800 = 5581 ± 1096 ml) were similar between methods. However, the %TE for Hbmass was higher (P<0·001) for Rad-57 (5·84 ± 5·29%) than for ABL800 (1·35 ± 1·13%). Similarly, the %TE for BV was higher (P<0·001) for Rad-57 (6·06 ± 5·76%) than for ABL800 (1·48 ± 1·25%). Lower (P<0·05) correlation coefficients between the methods were found when Hbmass > 905 g and BV > 6193 ml. Assessment of SpCO by Rad-57 resulted in considerably less precise determinations of Hbmass and BV, especially for high values. Thus, non-invasive assessment of Hbmass and BV cannot be recommended for scientific purposes, but may nonetheless be useful in clinical settings.


Efficacy of cognitive behavioural therapy for patients with chronic pain in Singapore.
The use of Cognitive Behavioural Therapy (CBT) techniques to manage chronic pain is relatively new and understudied in Singapore. Using data collected from group CBT programmes carried out at the Singapore General Hospital (SGH), we seek to explore the efficacy of the programme on pain intensity, self-efficacy, attitudes towards pain, and emotional factors. We also examined the efficacy of the longer 6- to 9-day group programme versus an abridged 2-day version called the Pacing Programme covering only some aspects of the full group programme. Twenty-nine adult patients underwent the intensive 6- to 9-day group programme while another 10 patients underwent the abridged 2-day group programme. The more extensive group programme encompassed teaching patients cognitive-behavioural methods of coping with pain, such as setting goals, pacing, cognitive restructuring by thinking in more positively, distraction, problem solving, sleep hygiene, communication skills, ability to cope with changes, and relaxation techniques. The abridged programme focused mainly on developing pacing skills. Patients were required to fill out questionnaires at the beginning of the programme, end of the programme, and at the 1-month and 6-month follow-ups to monitor progress. Preliminary results for the intensive 6- to 9-day group programme indicate decrease in pain and pain distress levels, improvements in management of pain, increased confidence to carry out activities despite pain, increased positive self-statements and decreased negative self-statements, decrease in fear of harm and pathophysiological beliefs, as well as decreases in the levels of depression, anxiety, and stress. The abridged 2-day programme yielded little change in pain and pain distress levels, but a slight increase in confidence to carry out activities despite pain. These preliminary results provide some evidence supporting the efficacy of CBT techniques in chronic pain management and contribute to the growing body of evidence for the effectiveness of psychological and behavioural techniques in the management of chronic pain.


Carcinoma in situ of the female breast. A clinico-pathological, immunohistological, and DNA ploidy study.
Carcinoma in situ of the breast (CIS) comprise a heterogenous group of lesions, covering a wide spectrum of clinical conditions and histopathological changes. With respect to biological behavior, CIS range from biologically aggressive lesions with a substantial risk of progression into invasive carcinoma (IC), to lesions with a very low malignant potential. Two main types of CIS are described--ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS). Previous studies of CIS indicate that approximately a third will subsequently develop IC. Autopsy studies indicate that CIS is frequently occurring and it was estimated that about 20% of all women will develop CIS during lifetime. Only a minor fraction is ever diagnosed, although the incidence of DCIS is increasing, especially related to mammography screening. The lack of knowledge about the biological significance of the histopathological subtypes was the background of the present study. In 1982, a nationwide, prospective study of CIS (protocol DBCG 82-IS) was initiated by the Danish Breast Cancer Cooperative Group (DBCG). From this protocol, the group of patients treated with breast conservation surgery (BCS) constituted the material for clinico-histological investigation. A total of 275 women were included in the period 1982-89. Follow-up studies showed that recurrence rate was significantly related to nuclear size of the primary lesion. Since nuclear changes might be related to DNA content and, furthermore, many invasive breast carcinomas were shown to be DNA aneuploid, flow cytometric (FCM) DNA ploidy analysis was performed in a series of DCIS lesions. More than 80% of these lesions were DNA aneuploid, with a distribution similar to that found in invasive carcinomas. This finding raised the hypothesis that the DNA pattern of an invasive carcinoma was already established at the preinvasive stage of DCIS. Therefore, FCM DNA analysis was performed on a series of ICs with predominance of DCIS. Partial or complete concordance in DNA ploidy between DCIS and IC within the individual case was found in most cases, except for the additional presence in the IC component of DNA hyperdiploid clones that might possibly be of importance for the process of invasion. In order to further characterize CIS lesions and, possibly, to discriminate biologically different groups, immunohistochemical markers were investigated in a consecutive series of CIS and IC with predominance of DCIS. The results were correlated to the histopathological and DNA ploidy findings. In DCIS, significant correlation was shown between large nuclear size and comedonecrosis, both of which showed also strong association to DNA aneuploidy, high proliferation activity, low steroid receptor content, and overexpression of c-erbB-2 and p53--factors that may indicate an aggressive behavior. Small nuclear CIS, whether LCIS or DCIS, on the contrary, were DNA diploid with low proliferation, and no cases showed overexpression of c-erbB-2 and p53. In IC, comparison of the DCIS and the invasive component showed similar patterns. No significant differences, in neither morphology, immunohistochemistry, nor DNA ploidy, were shown between DCIS without and with invasion. These findings may indicate that none of the parameters in question may on its own be essential for the decisive event of invasive growth.


Can increased atmospheric CO2 levels trigger a runaway greenhouse?
Recent one-dimensional (globally averaged) climate model calculations by Goldblatt et al. (2013) suggest that increased atmospheric CO(2) could conceivably trigger a runaway greenhouse on present Earth if CO(2) concentrations were approximately 100 times higher than they are today. The new prediction runs contrary to previous calculations by Kasting and Ackerman (1986), which indicated that CO(2) increases could not trigger a runaway, even at Venus-like CO(2) concentrations. Goldblatt et al. argued that this different behavior is a consequence of updated absorption coefficients for H(2)O that make a runaway more likely. Here, we use a 1-D climate model with similar, up-to-date absorption coefficients, but employ a different methodology, to show that the older result is probably still valid, although our model nearly runs away at ∼12 preindustrial atmospheric levels of CO(2) when we use the most alarmist assumptions possible. However, we argue that Earth's real climate is probably stable given more realistic assumptions, although 3-D climate models will be required to verify this result. Potential CO(2) increases from fossil fuel burning are somewhat smaller than this, 10-fold or less, but such increases could still cause sufficient warming to make much of the planet uninhabitable by humans.


Metagenomics analysis of cultured mucosal bacteria from colorectal cancer and adjacent normal mucosal tissues.
Introduction. Colorectal cancer (CRC) is one of the most common cancers worldwide. Multiple risk factors are involved in CRC development, including age, genetics, lifestyle, diet and environment. Of these, the role of the gut microbiota in cancer biology is increasingly recognized.Hypothesis/Gap Statement. Micro-organisms have been widely detected in stool samples, but few mucosal samples have been detected and sequenced in depth.Aim. Analysis of cultured mucosal bacteria from colorectal cancer and adjacent normal mucosal tissues with metagenomics sequencing.Methodology. Twenty-eight paired tumour and non-tumour tissues from 14 patients undergoing surgery for CRC were analysed. We removed the influence of eukaryotic cells via culture. The composition of mucosal microbiota in intestinal mucosa were detected and analysed with metagenomic sequencing.Results. Compared with non-cultured mucosal sample, 80 % bacteria species could be detected after culture. Moreover, after culture, additional 30 % bacteria could be detected, compared with non-cultured samples. Since after culture it was difficult to estimate the original abundance of microbiome, we focused on the identification of the CRC tissue-specific species. There were 298 bacterial species, which could only be cultured and detected in CRC tissues. Myroides odoratimimus and Cellulophaga baltica could be isolated from all the tumour samples of 14 CRC patients, suggesting that these species may be related to tumour occurrence and development. Further functional analysis indicated that bacteria from CRC tissues showed more active functions, including basic metabolism, signal transduction and survival activities.Conclusion. We used a new method based on culture to implement information on prokaryotic taxa, and related functions, which samples were from colorectal tissues. This method is suitable for removing eukaryotic contamination and detecting micro-organisms from other tissues.


[Renal physiology of urea transporters].
Urea transporters (UTs) are transmembrane urea-selective channel proteins that include two UT subfamilies, UT-A and UT-B. UT-A subfamily includes six members, UT-A1 to UT-A6, which are mainly expressed in kidney. UT-B subfamily has only one member that has a wide distribution in the body. UTs have been confirmed to play important roles in urinary concentration via the phenotypic analysis of 6 UT selective knockout mouse models. Experimental results suggest that UTs might be diuretic targets and that UT inhibitors might be developed as novel diuretics. This article reviews the physiological function and drug discovery of UT.


Efficacy and safety of intraurethral Erbium:YAG laser treatment in women with stress urinary incontinence following failed intravaginal laser therapy: a retrospective study.
Urinary incontinence (UI) is a prevalent condition affecting 25-45% of women and is linked to factors such as menopause, parity, high body mass index, and radical pelvic surgery. Among the three types of UI, stress incontinence (SUI) is the most common, accounting for almost 50% of cases, followed by urgency and overflow incontinence. UI has been found to be associated with reduced quality of life and mental stress. Non-invasive laser treatment is the safest and most effective option for managing SUI, with intraurethral Erbium SMOOTHTM laser treatment holding promise for patients experiencing SUI even after undergoing previous failed intravaginal Erbium:YAG laser treatment. The study recruited 93 female patients with mild to moderate SUI who had received two courses of intravaginal Erbium:YAG laser between January 2015 and June 2018. Of these, 22 patients (23%) who continued to experience SUI after a four-week interval for a second intravaginal Erbium:YAG laser were selected for intraurethral laser treatment in January 2019. The efficacy of the treatment was evaluated by comparing the pre- and post-treatment ICIQ-UI SF score. The urethral length was measured before the procedure. The main procedure involved delivering non-ablative laser energy using Erbium SMOOTHTM technology 2940 nm via a 4-mm cannula with personalized length and fluence was 1.5 J/cm. The 22 female patients with persistent SUI received intraurethral Erbium:YAG laser treatment. Their average age was 47.5 years, with an average of 2 parities and a mean body mass index of 20.97. All patients completed the ICIQ-SF questionnaire before and 3 months after the procedure. Of the patients, 77% reported improvement in symptoms, with 6 reporting strong improvement and 11 reporting improvement. The treatment was well-tolerated, with mild and transient adverse effects such as urinary infection in 1 patient (4.5%) and mild pain in 7 patients (31.8%). Intraurethral laser treatment may be helpful for Taiwanese women with persistent SUI after vaginal laser treatment. However, patients with prior pelvic surgery or pelvic organ prolapse history may limit the efficacy of intraurethral laser. Additional research is necessary to comprehensively investigate the advantages of intraurethral laser therapy. However, using intraurethral Erbium SMOOTHTM laser treatments to rejuvenate tissues and enhance structural support could be a promising avenue for managing stress urinary incontinence in Taiwanese women.


Dielectric RheoSANS - Simultaneous Interrogation of Impedance, Rheology and Small Angle Neutron Scattering of Complex Fluids.
A procedure for the operation of a new dielectric RheoSANS instrument capable of simultaneous interrogation of the electrical, mechanical and microstructural properties of complex fluids is presented. The instrument consists of a Couette geometry contained within a modified forced convection oven mounted on a commercial rheometer. This instrument is available for use on the small angle neutron scattering (SANS) beamlines at the National Institute of Standards and Technology (NIST) Center for Neutron Research (NCNR). The Couette geometry is machined to be transparent to neutrons and provides for measurement of the electrical properties and microstructural properties of a sample confined between titanium cylinders while the sample undergoes arbitrary deformation. Synchronization of these measurements is enabled through the use of a customizable program that monitors and controls the execution of predetermined experimental protocols. Described here is a protocol to perform a flow sweep experiment where the shear rate is logarithmically stepped from a maximum value to a minimum value holding at each step for a specified period of time while frequency dependent dielectric measurements are made. Representative results are shown from a sample consisting of a gel composed of carbon black aggregates dispersed in propylene carbonate. As the gel undergoes steady shear, the carbon black network is mechanically deformed, which causes an initial decrease in conductivity associated with the breaking of bonds comprising the carbon black network. However, at higher shear rates, the conductivity recovers associated with the onset of shear thickening. Overall, these results demonstrate the utility of the simultaneous measurement of the rheo-electro-microstructural properties of these suspensions using the dielectric RheoSANS geometry.


Iatrogenic Withdrawal Syndrome in the Pediatric Cardiac Intensive Care Unit: Incidence, Risk Factors and Outcome.
Critically ill children and neonates routinely receive opioids and benzodiazepines for analgesia and sedation in the pediatric intensive care unit (PICU). Prolonged opioid therapy often leads to tolerance and is associated with iatrogenic withdrawal syndrome (IWS) when opioids and benzodiazepines are weaned or discontinued. Our aim is to study the incidence, risk factors and outcome of IWS following use of a withdrawal protocol on pediatric patients after cardiac surgery. We prospectively included all postoperative pediatric patients who developed IWS after being assessed by the Withdrawal Assessment Tool (WAT-1) score (WAT-1 ≥3) over 9 months. Unit-based withdrawal management protocol was used. Patients' outcome was assessed by duration to be completely off opioids & benzodiazepines, duration of ICU and hospital stay. 432 patients were admitted during study period. Twenty-five patients (5.8%) developed IWS. The mean age and weight was 15.2 ± 31.4 months and 6.9 ± 7.7 kg respectively. 60% of the patients who developed withdrawal had previous ICU admissions with exposure to sedatives. In the IWS group the mean duration for use of fentanyl and midazolam infusions was 8.6 ± 5.1 & 9.6 ± 6 days respectively. The mean duration for completely stopping opioids and benzodiazepines was 17.2 ± 6.8 days with a mean duration of ventilation of 8.2 ± 6.8 days. The mean ICU and hospital stay for IWS patients was 26.5 ± 21.9 and 31.5 ± 21.1 days respectively. There was statistically significant difference in the mean age, and duration of use of sedatives between the patients who developed IWS and those who did not with P-value of 0.003 and < 0.0001, respectively. Withdrawal syndrome after pediatric cardiac surgery prolongs ICU and hospital stay. Our data shows that younger age and longer duration for use of sedatives seem to be risk factors for developing withdrawal syndrome.


The Association Between Lung Carcinoma and Tuberculosis.
The association between lung tuberculosis and lung carcinoma is still controversial. to describe the characteristics of patients with associated lung tuberculosis (TB) and lung carcinoma (LC) in patients treated in Clinic for pulmonary diseases and TB "Podhrastovi". This is the retrospective study of patients with LC associated with TB treated in Clinic for pulmonary diseases and TB "Podhrastovi" in five-year period -from 2012 to 2016. We analyzed sex and age of patients, whether TB preceded LC or LC preceded TB, a time period between the developments of these two diseases, activity of TB, the histopathological type of LC, localization of LC in lungs (bronchial, peripheral, cavern) according to histopathological type. In this period there were 2608 patients treated for LC. Among them there were 34 patients with diagnosed TB or 1.3%. All of them were smokers. No one had active TB. TB was the first diagnosis in all these patients. Each patient was previously treated for TB in hospital and had regular anti TB treatment. TB preceded LC in median time of 5 years (interquartile range 2 to 25 years). In 21 cases it was carcinoma of the drainage bronchus, in 11 cases it was peripheral lung carcinoma and 2 cases it was cavern carcinoma. patients with cured pulmonary tuberculosis represent a group at risk for developing lung carcinoma. Changes in the bronchial and alveolar mucosa which tuberculosis leaves behind in the lungs must be taken as a possible place of later malignant alteration. Patients with any form of pulmonary tuberculosis have to be controlled continuously.


Automatic Coronary Artery Plaque Quantification and CAD-RADS Prediction using Mesh Priors.
Coronary artery disease (CAD) remains the leading cause of death worldwide. Patients with suspected CAD undergo coronary CT angiography (CCTA) to evaluate the risk of cardiovascular events and determine the treatment. Clinical analysis of coronary arteries in CCTA comprises the identification of atherosclerotic plaque, as well as the grading of any coronary artery stenosis typically obtained through the CAD-Reporting and Data System (CAD-RADS). This requires analysis of the coronary lumen and plaque. While voxel-wise segmentation is a commonly used approach in various segmentation tasks, it does not guarantee topologically plausible shapes. To address this, in this work, we propose to directly infer surface meshes for coronary artery lumen and plaque based on a centerline prior and use it in the downstream task of CAD-RADS scoring. The method is developed and evaluated using a total of 2407 CCTA scans. Our method achieved lesion-wise volume intraclass correlation coefficients of 0.98, 0.79, and 0.85 for calcified, non-calcified, and total plaque volume respectively. Patient-level CAD-RADS categorization was evaluated on a representative hold-out test set of 300 scans, for which the achieved linearly weighted kappa (κ) was 0.75. CAD-RADS categorization on the set of 658 scans from another hospital and scanner led to a κ of 0.71. The results demonstrate that direct inference of coronary artery meshes for lumen and plaque is feasible, and allows for the automated prediction of routinely performed CAD-RADS categorization.


Characterizing and Optimizing Rater Performance for Internet-based Collaborative Labeling.
Labeling structures on medical images is crucial in determining clinically relevant correlations with morphometric and volumetric features. For the exploration of new structures and new imaging modalities, validated automated methods do not yet exist, and so researchers must rely on manually drawn landmarks. Voxel-by-voxel labeling can be extremely resource intensive, so large-scale studies are problematic. Recently, statistical approaches and software have been proposed to enable Internet-based collaborative labeling of medical images. While numerous labeling software tools have been created, the use of these packages as high-throughput labeling systems has yet to become entirely viable given training requirements. Herein, we explore two modifications to a typical mouse-based labeling system: (1) a platform independent overlay for recognition of mouse gestures and (2) an inexpensive touch-screen tracking device for non-mouse input. Through this study we characterize rater reliability in point, line, curve, and region placement. For the mouse input, we find a placement accuracy of 2.48±5.29 pixels (point), 0.630±1.81 pixels (curve), 1.234±6.99 pixels (line), and 0.058±0.027 (1 - Jaccard Index for region). The gesture software increased labeling speed by 27% overall and accuracy by approximately 30-50% on point and line tracing tasks, but the touch screen module lead to slower and more error prone labeling on all tasks, likely due to relatively poor sensitivity. In summary, the mouse gesture integration layer runs as a seamless operating system overlay and could potentially benefit any labeling software; yet, the inexpensive touch screen system requires improved usability optimization and calibration before it can provide an efficient labeling system.


Fluorinated tripodal receptors for potentiometric chloride detection in biological fluids.
Fluorinated tripodal compounds were recently reported to be efficient transmembrane transporters for a series of inorganic anions. In particular, this class of receptors has been shown to be suitable for the effective complexation of chloride, nitrate, bicarbonate and sulfate anions via hydrogen bonding. The potentiometric properties of urea and thiourea-based fluorinated tripodal receptors are explored here for the first time, in light of the need for reliable sensors for chloride monitoring in undiluted biological fluids. The ion selective electrode (ISE) membranes with tren-based tris-urea bis(CF3) tripodal compound (ionophore I) were found to exhibit the best selectivity for chloride over major lipophilic anions such as salicylate ( [Formula: see text] ) and thiocyanate ( [Formula: see text] ). Ionophore I-based ISEs were successfully applied for chloride determination in undiluted human serum as well as artificial serum sample, the slope of the linear calibration at the relevant background of interfering ions being close to Nernstian (49.8±1.7mV). The results of potentiometric measurements were confirmed by argentometric titration. Moreover, the ionophore I-based ISE membrane was shown to exhibit a very good long-term stability of potentiometric performance over the period of 10 weeks. Nuclear magnetic resonance (NMR) titrations, potentiometric sandwich membrane experiments and density functional theory (DFT) computational studies were performed to determine the binding constants and suggest 1:1 complexation stoichiometry for the ionophore I with chloride as well as salicylate.


Treatment of malarial acute renal failure by hemodialysis.
We studied 112 patients with malarial acute renal failure (ARF) during the period 1991-1997 at Bangkok Hospital for Tropical Diseases (Mahidol University, Bangkok, Thailand). Hemodialysis was performed in 101 (90.2%) of these patients. The mean number of times the patients were hemodialyzed was 6.5 (range = 1-27). Ninety-three (83.0%) patients were oliguric and the remainder were nonoliguric. Patients who had oliguric renal failure required more hemodialyses and had more complications than the nonoliguric patients. The oliguric patients had an eight-fold higher risk of requiring six or more hemodialyses (95% confidence interval = 1.2-53.9, P = 0.0008). The overall mortality rate was 10.7% (12 of 112). Eleven of the patients who died were jaundiced and eight of them had cerebral malaria with a Glasgow Coma Score < or = 8. We conclude that hemodialysis is a useful treatment for oliguric and nonoliguric ARF from severe malaria, particularly when initiated early in the course of the illness.


Non-Invasive Heart Rate Estimation From Ballistocardiograms Using Bidirectional LSTM Regression.
Non-invasive heart rate estimation is of great importance in daily monitoring of cardiovascular diseases. In this paper, a bidirectional long short term memory (bi-LSTM) regression network is developed for non-invasive heart rate estimation from the ballistocardiograms (BCG) signals. The proposed deep regression model provides an effective solution to the existing challenges in BCG heart rate estimation, such as the mismatch between the BCG signals and ground-truth reference, multi-sensor fusion and effective time series feature learning. Allowing label uncertainty in the estimation can reduce the manual cost of data annotation while further improving the heart rate estimation performance. Compared with the state-of-the-art BCG heart rate estimation methods, the strong fitting and generalization ability of the proposed deep regression model maintains better robustness to noise (e.g., sensor noise) and perturbations (e.g., body movements) in the BCG signals and provides a more reliable solution for long term heart rate monitoring.


Oscillatory activity of single units in a somatosensory cortex of an awake monkey and their possible role in texture analysis.
Neuronal activity was extracellularly recorded in the cortex of an awake monkey (Macaca fascicularis). Single units displaying oscillatory firing patterns were found in the upper bank of the lateral sulcus in a region where most of the neurons responded to somatosensory stimuli. The spectral energies of the oscillating activity were distributed in a trimodal fashion--0-15, 15-50, and 80-250 Hz--with the most common frequencies around 30 Hz. The oscillatory activity was not affected by anesthesia, but it was often reduced by tactile stimulation or self-initiated movements. Analysis of the spike trains suggests that the majority of oscillatory activity was intrinsically generated by the neurons. A neural model of texture analysis is offered based on a corticothalamic phase-locked loop. The newly identified oscillators play a key role in this model. The relevance of the model to physiological, anatomical, and psychophysical data, as well as testable predictions, are discussed.


Ion mobilities in diatomic gases: measurement versus prediction with non-specular scattering models.
Ion/electrical mobility measurements of nanoparticles and polyatomic ions are typically linked to particle/ion physical properties through either application of the Stokes-Millikan relationship or comparison to mobilities predicted from polyatomic models, which assume that gas molecules scatter specularly and elastically from rigid structural models. However, there is a discrepancy between these approaches; when specular, elastic scattering models (i.e., elastic-hard-sphere scattering, EHSS) are applied to polyatomic models of nanometer-scale ions with finite-sized impinging gas molecules, predictions are in substantial disagreement with the Stokes-Millikan equation. To rectify this discrepancy, we developed and tested a new approach for mobility calculations using polyatomic models in which non-specular (diffuse) and inelastic gas-molecule scattering is considered. Two distinct semiempirical models of gas-molecule scattering from particle surfaces were considered. In the first, which has been traditionally invoked in the study of aerosol nanoparticles, 91% of collisions are diffuse and thermally accommodating, and 9% are specular and elastic. In the second, all collisions are considered to be diffuse and accommodating, but the average speed of the gas molecules reemitted from a particle surface is 8% lower than the mean thermal speed at the particle temperature. Both scattering models attempt to mimic exchange between translational, vibrational, and rotational modes of energy during collision, as would be expected during collision between a nonmonoatomic gas molecule and a nonfrozen particle surface. The mobility calculation procedure was applied considering both hard-sphere potentials between gas molecules and the atoms within a particle and the long-range ion-induced dipole (polarization) potential. Predictions were compared to previous measurements in air near room temperature of multiply charged poly(ethylene glycol) (PEG) ions, which range in morphology from compact to highly linear, and singly charged tetraalkylammonium cations. It was found that both non-specular, inelastic scattering rules lead to excellent agreement between predictions and experimental mobility measurements (within 5% of each other) and that polarization potentials must be considered to make correct predictions for high-mobility particles/ions. Conversely, traditional specular, elastic scattering models were found to substantially overestimate the mobilities of both types of ions.


Population-based passive tick surveillance and detection of expanding foci of blacklegged ticks Ixodes scapularis and the Lyme disease agent Borrelia burgdorferi in Ontario, Canada.
We identified ticks submitted by the public from 2008 through 2012 in Ontario, Canada, and tested blacklegged ticks Ixodes scapularis for Borrelia burgdorferi and Anaplasma phagocytophilum. Among the 18 species of ticks identified, I. scapularis, Dermacentor variabilis, Ixodes cookei and Amblyomma americanum represented 98.1% of the 14,369 ticks submitted. Rates of blacklegged tick submission per 100,000 population were highest in Ontario's Eastern region; D. variabilis in Central West and Eastern regions; I. cookei in Eastern and South West regions; and A. americanum had a scattered distribution. Rates of blacklegged tick submission per 100,000 population were highest from children (0-9 years old) and older adults (55-74 years old). In two health units in the Eastern region (i.e., Leeds, Grenville & Lanark District and Kingston-Frontenac and Lennox & Addington), the rate of submission for engorged and B. burgdorferi-positive blacklegged ticks was 47× higher than the rest of Ontario. Rate of spread for blacklegged ticks was relatively faster and across a larger geographic area along the northern shore of Lake Ontario/St. Lawrence River, compared with slower spread from isolated populations along the northern shore of Lake Erie. The infection prevalence of B. burgdorferi in blacklegged ticks increased in Ontario over the study period from 8.4% in 2008 to 19.1% in 2012. The prevalence of B. burgdorferi-positive blacklegged ticks increased yearly during the surveillance period and, while increases were not uniform across all regions, increases were greatest in the Central West region, followed by Eastern and South West regions. The overall infection prevalence of A. phagocytophilum in blacklegged ticks was 0.3%. This study provides essential information on ticks of medical importance in Ontario, and identifies demographic and geographic areas for focused public education on the prevention of tick bites and tick-borne diseases.


Transcriptional responses to fluctuating thermal regimes underpinning differences in survival in the solitary bee Megachile rotundata.
The transcriptional responses of insects to long-term, ecologically relevant temperature stress are poorly understood. Long-term exposure to low temperatures, commonly referred to as chilling, can lead to physiological effects collectively known as chill injury. Periodically increasing temperatures during long-term chilling has been shown to increase survival in many insects. However, the transcripts responsible for this increase in survival have never been characterized. Here, we present the first transcriptome-level analysis of increased longevity under fluctuating temperatures during chilling. Overwintering post-diapause quiescent alfalfa leafcutting bees (Megachile rotundata) were exposed to a constant temperature of 6°C, or 6°C with a daily fluctuation to 20°C. RNA was collected at two different time points, before and after mortality rates began to diverge between temperature treatments. Expression analysis identified differentially regulated transcripts between pairwise comparisons of both treatments and time points. Transcripts functioning in ion homeostasis, metabolic pathways and oxidative stress response were up-regulated in individuals exposed to periodic temperature fluctuations during chilling. The differential expression of these transcripts provides support for the hypotheses that fluctuating temperatures protect against chill injury by reducing oxidative stress and returning ion concentrations and metabolic function to more favorable levels. Additionally, exposure to fluctuating temperatures leads to increased expression of transcripts functioning in the immune response and neurogenesis, providing evidence for additional mechanisms associated with increased survival during chilling in M. rotundata.


Characterization of cryptic rearrangements and variant translocations in acute promyelocytic leukemia.
Acute promyelocytic leukemia (APL) is typified by the reciprocal translocation, t(15; 17)(q22; q21), leading to the formation of PML-RARalpha and RARalpha-PML fusion genes. We have characterized 7 cases of morphologic APL found to lack the t(15; 17) on conventional cytogenetic assessment. In 6 of 7 cases, cryptic PML-RARalpha rearrangements were identified by reverse transcriptase-polymerase chain reaction and fluorescent in situ hybridization (FISH); whereas, in the remaining patient, APL was associated with the variant translocation, t(11; 17)(q23; q12-21), leading to the formation of PLZF-RARalpha and RARalpha-PLZF fusion genes. In each of the cases with cryptic PML-RARalpha rearrangements, PML-RARalpha transcripts were detected in the absence of RARalpha-PML, consistent with the concept that PML-RARalpha is the critical oncogenic fusion protein. In 4 of these cases with evaluable metaphase spreads, the occurrence of a nonreciprocal translocation was confirmed by FISH with sole formation of the PML-RARalpha fusion gene; in 3 cases with morphologically normal chromosomes 15 and 17, RARalpha was inserted into PML on 15q, whereas in the remaining patient the PML-RARalpha fusion arose due to insertion of 15q-derived material including PML into RARalpha on 17q. Immunofluorescence studies were performed using antibodies raised against PML and PIC 1, a ubiquitin-homology domain protein previously identified as an interaction partner of PML. In acute myeloid leukemia (AML) of subtypes other than M3, PIC 1 was localized to the nuclear membrane and colocalized with PML within discrete nuclear bodies. In APL cases with cryptic PML-RARalpha rearrangements, the characteristic microparticulate pattern of PML staining was detected with partial colocalization with PIC 1, indicative of disruption of the nuclear bodies; whereas in t(11; 17)-associated APL, PML and PIC 1 remained colocalized within discrete nuclear bodies, as observed in non-APL cases. Although deregulation of the putative growth suppressor PML and delocalization of other nuclear body constituents have been advocated to play a key role in the development of t(15; 17)-associated APL, the present study shows that disruption of PML nuclear bodies per se is not a prerequisite for the pathogenesis of APL.


Higher tactile sensitivity in preterm infants at term-equivalent age: A pilot study.
Despite a growing body of research on perinatal sensory abilities, data on the extent of tactile sensitivity and more particularly passive touch (i.e. sensitivity to a stimulation imposed on the skin) are relatively limited, and the development and processing of tactile function are still thus little known. This question is particularly of high importance for infants with atypical early development such as those born prematurely who are exposed to many sensory (including tactile) stimulations (being in a hospital setting) during a critical period of brain development and those born at early term whose birth occurs at the precise time of cortical reorganization, in particular in the sensory areas. Some parents and health-care providers have for instance reported that children born prematurely exhibit atypical (e.g. higher) sensitivity to "benign" tactile stimuli. In the present study, we hypothesized that preterm and early-term infants may show altered tactile sensitivity. We compared the behavioral responses around term-equivalent age of infants born either pre-term, early-term or at term to the application of a light (0.008 grams) mechanical stimulus. We found that almost all preterm infants perceive this tactile stimulus, contrarily to the two other groups of infants. This extreme tactile sensitivity may be due to experiential, maturational or more likely both processes. We also compared the tactile sensitivity of these infants to that of adults. We found that adults were irresponsive to the light mechanical stimulus. This finding opens not only new insights in understanding development of tactile processing, but also new lines of thought about the particular sensory world of premature and early-term infants and hence about the potential impact of early care practices.


Diagnosis and management of colovesical fistulas.
Diagnosis and management may present difficult problems in patients with colovesical fistulas. Symptoms in the urinary tract are most common, and cystoscopy, and cystography are the most valuable diagnostic procedures. It may not always be possible to demonstrate the fistula by diagnostic tests, and a high index of suspicion should be maintained in patients with inflammatory or neoplastic disease of the rectosigmoid area or bladder with recurrent cystitis. Definitive treatment should include resection of the fistula and diseased segment of the intestine. Both one stage and multistage procedures have their place in the treatment of this condition. There are specific criteria for success for a one stage procedure.


Intervention in alcohol use disorder in a general practice.
To report the outcome of intervention in 70 patients with alcohol use disorder in a general practice. Of the 84 patients age 18-69 years identified clinically or by a screening programme with alcohol use disorder, 70 who were available for at least 2 year follow up after diagnosis were included in the study group. The clinical notes of these patients were reviewed to determine evidence of sustained achievement of abstinence or controlled drinking and factors contributing to successful change in alcohol use. Sustained abstinence or controlled drinking was verified for 31 patients (44%) with a further 26 patients (37%) reporting reduction in alcohol use without evidence of sustained improvement. The mean interval from diagnosis to sustained improvement was 4 years. Only five patients accepted referral to specialist alcohol units. Successful change in the 31 patients achieving their drinking goal was directly related to intervention at the surgery for 9 patients. A motivational approach with focus on the patient's perception of the issues proved relatively successful in this practice. A prolonged period of change was required to achieve drinking goals. Other factors contributing to improvement are discussed.


Assessment of the Antioxidant and Anti-inflammatory Properties of Aqueous Extract of Rosa sempervirens Leaves.
The antioxidant and anti-inflammatory properties of an aqueous natural extract obtained from Rosa sempervirens leaves were assessed. The ability of the extract to scavenge DPPH, •OH, and H2O2 radicals, chelate ferrous ions, reduce ferric ions, and protect β-carotene-linoleic acid in emulsion from peroxidation was investigated in vitro. Furthermore, the anti-inflammatory activity of the extract was evaluated by measuring the stability of the membrane of human red blood cells against different hypotonic concentrations of NaCl and heat, as well as by inhibiting the denaturation of albumin. A high total phenolic content (278.38± 11.07 mg GAE/g) and flavonoid content (34.22± 0.12 mg QE /g) were found in the extract. The extract exhibited significant scavenging activity of DPPH (IC50 6.201 ± 0.126 µg/ ml), •OH (IC50 = 894.57 ± 21.18 µg/ml), and H2O2 (IC50= 107±09.58 µg/ml) radicals, and good antioxidant activity by chelating ferrous ions (IC50 = 2499.086 ± 28.267µg/ml), reducing ferric ions (IC50=141.33±2.34 µg/ml), exhibiting total antioxidant capacity (IC50 465.65 ± 9.71 μg/ml), and protecting β-carotene-linoleic acid against peroxidation (I% = 90.05 ± 1.65% at 1000µg/ml). R. sempervirens displayed anti-inflammatory activity in aqueous extract by inhibiting heat-induced albumin denaturation and stabilizing the membrane of human red blood cells. It was suggested from the results that R. sempervirens aqueous extract could help prevent oxidative and inflammatory processes due to its good antioxidant and anti-inflammatory properties.


Structural basis for the insensitivity of a serine enzyme (palmitoyl-protein thioesterase) to phenylmethylsulfonyl fluoride.
Palmitoyl-protein thioesterase-1 (PPT1) is a newly described lysosomal enzyme that hydrolyzes long chain fatty acids from lipid-modified cysteine residues in proteins. Deficiency in this enzyme results in a severe neurodegenerative storage disorder, infantile neuronal ceroid lipofuscinosis. Although the primary structure of PPT1 contains a serine lipase consensus sequence, the enzyme is insensitive to commonly used serine-modifying reagents phenylmethylsulfonyl fluoride (PMSF) and diisopropylfluorophosphate. In the current paper, we show that the active site serine in PPT1 is modified by a substrate analog of PMSF, hexadecylsulfonylfluoride (HDSF) in a specific and site-directed manner. The apparent K(i) of the inhibition was 125 micrometer (in the presence of 1.5 mm Triton X-100), and the catalytic rate constant for sulfonylation (k(2)) was 3.3/min, a value similar to previously described sulfonylation reactions. PPT1 was crystallized after inactivation with HDSF, and the structure of the inactive form was determined to 2.4 A resolution. The hexadecylsulfonyl was found to modify serine 115 and to snake through a narrow hydrophobic channel that would not accommodate an aromatic sulfonyl fluoride. Therefore, the geometry of the active site accounts for the reactivity of PPT1 with HDSF but not PMSF. These observations suggest a structural explanation as to why certain serine lipases are resistant to modification by commonly used serine-modifying reagents.


Human Genetic Variation Influences Enteric Fever Progression.
In the 21st century, enteric fever is still causing a significant number of mortalities, especially in high-risk regions of the world. Genetic studies involving the genome and transcriptome have revealed a broad set of candidate genetic polymorphisms associated with susceptibility to and the severity of enteric fever. This review attempted to explain and discuss the past and the most recent findings on human genetic variants affecting the progression of Salmonella typhoidal species infection, particularly toll-like receptor (TLR) 4, TLR5, interleukin (IL-) 4, natural resistance-associated macrophage protein 1 (NRAMP1), VAC14, PARK2/PACRG, cystic fibrosis transmembrane conductance regulator (CFTR), major-histocompatibility-complex (MHC) class II and class III. These polymorphisms on disease susceptibility or progression in patients could be related to multiple mechanisms in eliminating both intracellular and extracellular Salmonella typhoidal species. Here, we also highlighted the limitations in the studies reported, which led to inconclusive results in association studies. Nevertheless, the knowledge obtained through this review may shed some light on the development of risk prediction tools, novel therapies as well as strategies towards developing a personalised typhoid vaccine.


Phylogenetic Complexity of Morphologically Identified Anopheles squamosus in Southern Zambia.
Despite dramatic reductions in malaria cases in the catchment area of Macha Hospital, Choma District, Southern Province in Zambia, prevalence has remained near 1-2% by RDT for the past several years. To investigate residual malaria transmission in the area, this study focuses on the relative abundance, foraging behavior, and phylogenetic relationships of Anopheles squamosus specimens. In 2011, higher than expected rates of anthropophily were observed among "zoophilic" An. squamosus, a species that had sporadically been found to contain Plasmodium falciparum sporozoites. The importance of An. squamosus in the region was reaffirmed in 2016 when P. falciparum sporozoites were detected in numerous An. squamosus specimens. This study analyzed Centers for Disease Control (CDC) light trap collections of adult mosquitoes from two collection schemes: one performed as part of a reactive-test-and-treat program and the second performed along a geographical transect. Morphological identification, molecular verification of anopheline species, and blood meal source were determined on individual samples. Data from these collections supported earlier studies demonstrating An. squamosus to be primarily exophagic and zoophilic, allowing them to evade current control measures. The phylogenetic relationships generated from the specimens in this study illustrate the existence of well supported clade structure among An. squamosus specimens, which further emphasizes the importance of molecular identification of vectors. The primarily exophagic behavior of An. squamosus in these collections also highlights that indoor vector control strategies will not be sufficient for elimination of malaria in southern Zambia.


[Recuperation of ureteral peristalsis in the rat after denervation].
The paper presents the experimental work carried out on the influence of various surgical situations on ureteral peristalsis in the rat. It included 43 rats divided in three groups. Group I (n = 10) acted as control group and had only ureterolysis performed. In group II (n = 10), single section and subsequent anastomosis was performed. Group III (n = 23) included section at two levels, ureter extraction from the animal and subsequent autotransplantation of the ureter. The three groups were re-operated two months later to ratify peristalsis of the intervened ureter. Both in the first and second operations peristalsis, as well as the features and appearance of antiperistaltic waves were quantified. After 60 days, no changes were observed in group I, but groups II and III exhibited normal peristalsis to presence of antiperistaltic waves. Both groups had complications like stenosis, fistulas and hydronephrosis, but also normal functioning, histology and peristalsis.


Opiate-androgen interactions in drug-induced yawning and penile erections in the rat.
The effects of pretreatment with drugs on drug-induced yawning and penile erection in intact and chronically castrated rats were investigated. Naloxone partially blocked yawning in intact rats and in castrated rats pretreated with dihydro-testosterone propionate (DHTP) but not in control castrates. In contrast, naloxone potentiated apomorphine-induced penile erections in intact rats. Morphine, haloperidol and atropine blocked yawning and penile erections. Methyl naloxone, methyl atropine and domperidone at doses which are selectively peripheral-acting had no effect on drug-induced yawning or penile erection indicating that both effects are mediated centrally. Pretreatment with morphine did not change the naloxone effects in intact rats. The results indicate a naloxone-androgen interaction in drug-induced yawning but the results with morphine are not consistent with a role of opiates in this interaction. The penile erection data support a direct opiate-dopamine receptor interaction in this response. The haloperidol and atropine effects support a cholinergic-dopaminergic interaction in both yawning and penile erections.


Mechanisms involved in follistatin-induced hypertrophy and increased insulin action in skeletal muscle.
Skeletal muscle wasting is often associated with insulin resistance. A major regulator of muscle mass is the transforming growth factor β (TGF-β) superfamily, including activin A, which causes atrophy. TGF-β superfamily ligands also negatively regulate insulin-sensitive proteins, but whether this pathway contributes to insulin action remains to be determined. To elucidate if TGF-β superfamily ligands regulate insulin action, we used an adeno-associated virus gene editing approach to overexpress an activin A inhibitor, follistatin (Fst288), in mouse muscle of lean and diet-induced obese mice. We determined basal and insulin-stimulated 2-deoxy-glucose uptake using isotopic tracers in vivo. Furthermore, to evaluate whether circulating Fst and activin A concentrations are associated with obesity, insulin resistance, and weight loss in humans, we analysed serum from morbidly obese subjects before, 1 week, and 1 year after Roux-en-Y gastric bypass (RYGB). Fst288 muscle overexpression markedly increased in vivo insulin-stimulated (but not basal) glucose uptake (+75%, P < 0.05) and increased protein expression and intracellular insulin signalling of AKT, TBC1D4, PAK1, pyruvate dehydrogenase-E1α, and p70S6K, while decreasing TBC1D1 signaling (P < 0.05). Fst288 increased both basal and insulin-stimulated protein synthesis, but no correlation was observed between the Fst288-driven hypertrophy and the increase in insulin-stimulated glucose uptake. Importantly, Fst288 completely normalized muscle glucose uptake in insulin-resistant diet-induced obese mice. RYGB surgery doubled circulating Fst and reduced activin A (-24%, P < 0.05) concentration 1 week after surgery before any significant weight loss in morbidly obese normoglycemic patients, while major weight loss after 1 year did not further change the concentrations. We here present evidence that Fst is a potent regulator of insulin action in muscle, and in addition to AKT and p70S6K, we identify TBC1D1, TBC1D4, pyruvate dehydrogenase-E1α, and PAK1 as Fst targets. Circulating Fst more than doubled post-RYGB surgery, a treatment that markedly improved insulin sensitivity, suggesting a role for Fst in regulating glycaemic control. These findings demonstrate the therapeutic potential of inhibiting TGF-β superfamily ligands to improve insulin action and Fst's relevance to muscle wasting-associated insulin-resistant conditions in mice and humans.


DNA polymerase-catalyzed elongation of repetitive hexanucleotide sequences: application to creation of repetitive DNA libraries.
We demonstrate the elongation of various hexanucleotide sequences with thermophilic DNA polymerase, under isothermal or thermal cyclic reaction conditions. We prepared 10 types of double repeat hexanucleotide duplexes with various GC compositions containing between 0 and 6 GC nucleotides per repeat and incubated these duplexes with thermophilic Taq DNA polymerase and dNTPs at various temperatures. All of the model repetitive short duplexes were elongated under the isothermal incubation conditions, although there were some differences in the elongation efficiencies derived from the GC composition in the repetitive sequences. It was also found that all of the model repetitive duplexes were extended more effectively by a 3-step thermal cyclic reaction involving denaturation, annealing, and extension. On the basis of this technique, we prepared a glutamate-encoding short repetitive duplex and created long repetitive DNAs under isothermal and thermal cyclic reaction conditions. DNA sequencing analysis of the cloned repetitive DNA revealed that well-ordered long repetitive DNAs of various chain lengths were created by this DNA polymerase-catalyzed ligation method, and these were easily cloned into vectors by the TA-cloning method. This method could be useful for obtaining DNAs encoding arbitrary long repetitive amino acid sequences more effectively than the conventional T4 ligase-catalyzed ligation method.


Expression and proinflammatory role of proteinase-activated receptor 2 in rheumatoid synovium: ex vivo studies using a novel proteinase-activated receptor 2 antagonist.
Serine proteinases activate the G protein-coupled receptor, proteinase-activated receptor 2 (PAR-2), via cleavage and exposure of a tethered ligand. PAR-2 is known to exert proinflammatory actions in a murine model of arthritis, since PAR-2-deficient mice exhibit strikingly reduced articular inflammation. This study was undertaken to examine synovial PAR-2 expression and to determine the effect of a novel PAR-2 antagonist on synovial cytokine production, in order to investigate the hypothesis that PAR-2 plays a critical role in the pathogenesis of rheumatoid arthritis (RA). Using a monoclonal antibody to human PAR-2, expression in RA synovium and cultured synovial fibroblasts was characterized. The novel PAR-2 antagonist, ENMD-1068, was added to primary cultures of RA synovial tissue, from which spontaneous cytokine release was measured. PAR-2 was substantially up-regulated in RA synovium compared with control synovial tissue from patients with osteoarthritis or seronegative inflammatory arthritis, neither of which exhibited significant PAR-2 expression. Importantly, spontaneous release of tumor necrosis factor alpha and interleukin-1beta from RA synovium was substantially inhibited by ENMD-1068, in a dose-dependent manner. These findings identify PAR-2 as a novel upstream regulator of proinflammatory cytokine production in RA and indicate its potential as a novel therapeutic target in inflammatory arthritis.


Plasma cyclic nucleotides and plasma catecholamines before and after prolonged treatment with clonidine in hypertensive patients.
The effect of standing and physical exercise and catecholamines and cyclic nucleotides in plasma was measured in 8 patients with essential hypertension under standardized conditions before and after prolonged treatment with clonidine. Before clonidine medication noradrenaline, adrenaline and cyclic AMP (cAMP) increased in response to standing and bicycling for 20 min. No significant correlation was found between their absolute levels nor was the increase in cAMP following exercise correlated to the increase in noradrenaline. Standing and physical exercise were without effect on cyclic GMP (cGMP). Clonidine reduced the plasma noradrenaline concentration in supine position and the noradrenaline and the adrenaline response to standing and exercise. Plasma cAMP was uneffected by clonidine under basal conditions but the response to exercise was slightly reduced initially. During clonidine there was a positive correlation between the plasma levels of cAMP and noradrenaline following work. Clonidine produced an increase in plasma cGMP in supine position, immediately prior to bicycling and after 5 min of exercise.


Detection of Epstein-Barr virus DNA in sera from transplant recipients with lymphoproliferative disorders.
Early diagnosis of Epstein-Barr Virus (EBV)-associated posttransplant lymphoproliferative disease (PTLD) is important because many patients respond to reduction in immunosuppression, especially if PTLD is detected at an early stage. Previous studies have found elevated EBV DNA levels in blood from patients with PTLD, but these assays required isolation of cellular blood fractions and quantitation. We evaluated the presence of cell-free EBV DNA in serum from solid-organ transplant recipients as a marker for PTLD. Five of 6 transplant recipients with histopathologically documented PTLD had EBV DNA detected in serum at the time of diagnosis (sensitivity = 83%), compared with 0 of 16 matched transplant recipients without PTLD (specificity = 100%) (P < 0.001 [Fisher's exact test]). Furthermore, EBV DNA was detected in serum 8 and 52 months prior to the diagnosis of PTLD in two of three patients for whom stored sera were analyzed. Detection of EBV DNA in serum appears to be a useful marker for the early detection of PTLD in solid-organ transplant recipients. Further studies to define the role of such assays in evaluating solid-organ transplant patients at risk for PTLD are warranted.


IL-4 acts synergistically with IL-1 beta to promote lymphocyte adhesion to microvascular endothelium by induction of vascular cell adhesion molecule-1.
Adhesion of lymphocytes to endothelial cells (EC) is the requisite first element in the multistep process of transmigration from blood across the postcapillary venules. Selective expression of cell adhesion molecules (CM) by microvascular EC in lymphoid organs (e.g., lymph nodes) and during tissue inflammation modulates this traffic in a site-directed manner. CAM synthesis by EC is regulated in turn by cytokines released in the local microenvironment. Studies done largely with human umbilical vein EC have implicated IL-1, IFN-gamma, and TNF-alpha as cytokines which promote leukocyte adhesion to EC. In the work reported here, the responses of cultured microvascular EC derived from macaque lymph nodes to IL-1beta, IL-2, IFN-gamma, and IL-4 were examined. Increases in lymphocyte adhesion after preculture of microvascular EC in IL-1beta or IFN-gamma were typically 2-to 4-fold above controls and comparable to those reported for human umbilical vein EC. IL-2 had no effect. In contrast, IL-4 markedly enhanced adhesion to microvascular EC. IL-4-induced adhesion was observed as early as 4 h after induction, plateaued by 24 h, was stable through 72 h of culture, but decayed to basal levels within 72 h after removal of IL-4 from the cultures. IL-1beta, but not IL-2 or IFN-gamma, synergistically enhanced the action of IL-4 on cultured microvascular EC to promote lymphocyte binding. Adhesion triggered in this manner required de novo protein synthesis. However, the avidity of IL-4-activated microvascular EC for lymphocytes, and analyses of kinetics, cation and temperature dependence, and/or lack of blockade with mAb to endothelial leukocyte adhesion molecule-1, intra-cellular adhesion molecule-1, and MECA-79 indicated that these CAM were not central to the phenomenon. To aid identification of the relevant CAM, mAb specific to IL-4-induced microvascular EC were produced. One of these, 6G10, blocked up to 90% of lymphocyte adhesion to IL-4-induced microvascular EC, immunoprecipitated an IL-4-induced cell-surface molecule of 110-kDa molecular mass, and reacted specifically with Chinese hamster ovary cells transfected with human vascular cell adhesion molecule-1. Our results suggest that IL-4 may have potent effects on lymphocyte recirculation in vivo.


Effects of cement addition and briquetting of rock wool on its geomechanical stability in landfills.
Landfilling of mineral wool waste in big bags at separate landfill compartments is required in Austria. This results in enormous differences in the Young's moduli between common construction and demolition (C&D) waste compartments and mineral wool compartments, which causes severe accidents in terms of overturned vehicles due to sudden subsidence of the subsurface. Conditioning of mineral wool waste might be applied to adjust its geomechanical behaviour to that of common C&D waste but has never been investigated scientifically before. In this study we compare three scenarios for the conditioning of rock wool for landfilling: (A) loosely packing, (B) cutting comminution + cement addition and (C) cutting comminution + cement-supported briquetting. The performance of the different sample bodies under landfill conditions was simulated at the lab scale by cyclic loading (1223-3112 N, up to 160 cycles) using a 'Wille Geotechnik UL 300' press. The deformation was monitored during the experiment and Young's modulus was derived graphically, whereas the test execution was piston controlled. The Young's modulus increased during the experiments from 0.2 MPa to 4.6 MPa for scenario (A), from 0.6 MPa to 20.5 MPa for scenario (B) and from 7.5 MPa to 111.0 MPa for scenario (C). These results show that a combination of comminution and cement-supported briquetting significantly increases the geotechnical performance of mineral wool waste with respect to landfilling, which is still three orders of magnitude below that of common C&D waste, which is in the range of 30,000 MPa.


Evaluation of the immune response elicited by multi-antigenic DNA vaccine expressing SAG1, ROP2 and GRA2 against Toxoplasma gondii.
The parasite Toxoplasma gondii can infect most mammals and birds, sometimes causing severe pathology. Previous studies have reported that multi-antigenic vaccines were more effective than single-antigenic vaccine. It was also reported that the a single-gene vaccine with SAG1 or ROP2, GRA2 could only produce partial protection against T. gondii. In this study, we constructed a multi-antigenic DNA vaccine containing SAG1, ROP2 and GRA2, and evaluated its immune response. We used IL-12 as an adjuvant to enhance the immune response. We immunized BALB/c mice intramuscularly. After immunization, we evaluated the immune response using lymphocyte proliferation assay, cytokine and antibody measurements. The results showed that the group immunized with pcDNA3.1-SAG1-ROP2-GRA2 produced high Th1 immune response compared to other groups immunized with double-gene plasmid, empty plasmid or phosphate-buffered saline, respectively. Moreover, the co-immunization with IL-12 genes enhanced the immune response significantly and prolonged survival time. The current study showed that multi-antigenic DNA with IL-12 produced potent, effective and long-term protection against T. gondii challenge.


The confirmation of 9-carboxy-THC in urine by gas chromatography/mass spectrometry.
A mass spectral method for the identification of the urine metabolite of THC, 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid, has been developed. The metabolite is extracted from the urine, derivatized to the methyl ester, methyl ether, and analyzed on a gas chromatograph/mass spectrometer. Identification of the metabolite is based on the retention time of the derivatized compound and its electron impact (EI) or chemical ionization (CI) mass spectrum. The EI spectrum shows three characteristic ions at masses 313, 357, and 372 (the molecular ion). When methane is used as the reactant gas, the CI spectrum shows an ion at 341 and an M + 1 ion at mass 373.


Personality types in academic medicine.
Based on Swiss physician-scholar Carl G. Jung's theory of psychological types proposed in the 1920s, Kathleen Cook Briggs and her daughter Isabel Briggs Myers developed the Myers-Briggs Type Indicator (MBTI) three decades later. They applied Jung's dynamic theory to determine how persons take in information, make decisions, and communicate thoughts and feelings. Medical students were of special interest to their research and much has been written since then about the use of the MBTI in medicine. In this study, results of MBTIs administered to 1797 freshmen students at Louisiana State University School of Medicine--New Orleans from 1988 to 1998 are compared with those reported by the MBTI developers and others over the years and throughout the United States. Findings indicate some noteworthy shifts in the psychological profile of medical students over time and among schools that may be due to changes in the delivery of health care, the increase in technology in the practice of medicine, and the dramatic increase of women in medicine.


Video wireless capsule endoscopy: a diagnostic tool for early Crohn's disease.
Crohn's disease is a chronic immune-mediated disease that affects any or all segments of the gastrointestinal tract, but is mainly found in the small intestines or colon. Crohn's disease in the early stages present with symptoms such as chronic diarrhea, abdominal pain, and weight loss that may mimic other conditions and cause a delay in diagnosis. Many patients experience emotional difficulties related to this debilitating disease. Current procedures used to visualize the small bowel for diagnosis of Crohn's disease include small-bowel follow through, enteroclysis, and computerized tomography, but do not provide definition of the mucosal surface. Clinical research shows us the diagnostic yield of these tests are not as high as once thought. A new diagnostic tool, the M2A Video Capsule, can be used to visualize the small bowel mucosa. With the detailed photo images provided by the capsule, the physician now has the ability to detect subtle changes in the mucosal lining that may be consistent with early Crohn's disease that were previously not available or identifiable. Earlier disease treatment and management may decrease the inflammatory changes that lead to bowel thickening and stricturing and have a positive impact on the patient's total quality of life.


Molecular pharmacology of G protein-coupled receptors. Editorial.
G protein-coupled receptors are the largest group of membrane proteins and are the targets for approximately 30% of drugs currently used therapeutically. These 7-transmembrane-spanning proteins continue to provide new opportunities to develop therapeutics based on emerging knowledge of their structure, signalling properties and interactions with other proteins. This themed issue of the British Journal of Pharmacology contains a series of papers that cover these issues and identify approaches that may determine future directions. Many of these papers contain material that was presented at the 5th International Molecular Pharmacology of G Protein-Coupled Receptors meeting held in Sydney Australia in late 2008.


Genetics of schizophrenia and smoking: an approach to studying their comorbidity based on epidemiological findings.
The association between schizophrenia and tobacco smoking has been described in more than 1,000 articles, many with inadequate methodology. The studies on this association can focus on: (1) current smoking, ever smoking or smoking cessation; (2) non-psychiatric controls or controls with severe mental illness (e.g., bipolar disorder); and (3) higher smoking frequency or greater usage in smokers. The association with the most potential for genetic studies is that between ever daily smoking and schizophrenia; it may reflect a shared genetic vulnerability. To reduce the number of false-positive genes, we propose a three-stage approach derived from epidemiological knowledge. In the first stage, only genetic variations associated with ever daily smoking that are simultaneously significant within the non-psychiatric controls, the bipolar disorder controls and the schizophrenia cases will be selected. Only those genetic variations that are simultaneously significant in the three hypothesis tests will be tested in the second stage, where the prevalence of the genes must be significantly higher in schizophrenia than in bipolar disorder, and significantly higher in bipolar disorder than in controls. The genes simultaneously significant in the second stage will be included in a third stage where the gene variations must be significantly more frequent in schizophrenia patients who did not start smoking daily until their 20s (late start) versus those who had an early start. Any genetic approach to psychiatric disorders may fail if attention is not given to comorbidity and epidemiological studies that suggest which comorbidities are likely to be explained by genetics and which are not. Our approach, which examines the results of epidemiological studies on comorbidities and then looks for genes that simultaneously satisfy epidemiologically suggested sets of hypotheses, may also apply to the study of other major illnesses.


The influence of partner-specific memory associations on language production: Evidence from picture naming.
In typical interactions, speakers frequently produce utterances that appear to reflect beliefs about the common ground shared with particular addressees. Horton and Gerrig (2005a) proposed that one important basis for audience design is the manner in which conversational partners serve as cues for the automatic retrieval of associated information from memory. This paper reports the results of two experiments demonstrating the influence of partner-specific memory associations on language production. Following an initial task designed to establish associations between specific words (Experiment 1) or object categories (Experiment 2) and each of two partners, participants named a series of pictures in the context of the same two individuals. Naming latencies were shortest for responses associated with the current partner, and were not significantly correlated with explicit recall of partner-item associations. Such partner-driven memory retrieval may constrain the information accessible to speakers as they produce utterances for particular addressees.


Comparison of quinazoline and benzoylpyrazoline chemotypes targeting the CaVα-β interaction as antagonists of the N-type CaV2.2 channel.
Structural studies with an α subunit fragment of voltage-gated calcium (CaV) channels in complex with the CaVβ subunits revealed a high homology between the various CaVα-β subunits, predicting that targeting of this interface would result in nonselective compounds. Despite this likelihood, my laboratory initiated a rational structure-based screening campaign focusing on "hot spots" on the alpha interacting domain (AID) of the CaVβ2a subunits and identified the small molecule 2-(3,5-dimethylisoxazol-4-yl)-N-((4-((3-phenylpropyl)amino)quinazolin-2-yl)methyl)acetamide ( IPPQ ) which selectively targeted the interface between the N-type calcium (CaV2.2) channel and CaVβ. IPPQ (i) specifically bound to CaVβ2a; (ii) inhibited CaVβ2 's interaction with CaV.2-AID; (iii) inhibited CaV2.2 currents in sensory neurons; (iv) inhibited pre-synaptic localization of CaV2.2 in vivo; and (v) inhibited spinal neurotransmission, which resulted in decreased neurotransmitter release. IPPQ was anti-nociceptive in naïve rats and reversed mechanical allodynia and thermal hyperalgesia in rodent models of acute, neuropathic, and genetic pain. In structure-activity relationship (SAR) studies focused on improving binding affinity of IPPQ , another compound (BTT-369), a benzoyl-3,4-dihydro-1'H,2 H-3,4'-bipyrazole class of compounds, was reported by Chen and colleagues, based on work conducted in my laboratory beginning in 2008. BTT-369 contains tetraaryldihydrobipyrazole scaffold - a chemotype featuring phenyl groups known to be significantly metabolized, lower the systemic half-life, and increase the potential for toxicity. Furthermore, the benzoylpyrazoline skeleton in BTT-369 is patented across multiple therapeutic indications. Prior to embarking on an extensive optimization campaign of IPPQ , we performed a head-to-head comparison of the two compounds. We conclude that IPPQ is superior to BTT-369 for on-target efficacy, setting the stage for SAR studies to improve on IPPQ for the development of novel pain therapeutics.


[Analysis of efficacy of prevention and antioxidant therapy in premature infants].
282 (564 eyes) premature infants born at mean 27 +/- 2,5 weeks of gestation with birth weight 914+/- 247g were enrolled in the study. Comparative study showed preventive treatment with histochrome in infants with risk of retinopathy of prematurity (RP) to decrease the incidence of RP compared to infants treated with emoxipine and no antioxidant therapy. Incidence of RP in infants preventively treated with combination antioxidant agents (dicynon and emoxipine) was significantly lower compared to the group without preventive antioxidant treatment. Use of histochrome in treatment of RP via periocular injections and forced instillations promoted more favorable outcome of the disease.


Control of Acoustic Cavitation for Efficient Sonoporation with Phase-Shift Nanoemulsions.
Acoustic cavitation can be used to temporarily disrupt cell membranes for intracellular delivery of large biomolecules. Termed sonoporation, the ability of this technique for efficient intracellular delivery (i.e., >50% of initial cell population showing uptake) while maintaining cell viability (i.e., >50% of initial cell population viable) has proven to be very difficult. Here, we report that phase-shift nanoemulsions (PSNEs) function as inertial cavitation nuclei for improvement of sonoporation efficiency. The interplay between ultrasound frequency, resultant microbubble dynamics and sonoporation efficiency was investigated experimentally. Acoustic emissions from individual microbubbles nucleated from PSNEs were captured using a broadband passive cavitation detector during and after acoustic droplet vaporization with short pulses of ultrasound at 1, 2.5 and 5 MHz. Time domain features of the passive cavitation detector signals were analyzed to estimate the maximum size (Rmax) of the microbubbles using the Rayleigh collapse model. These results were then applied to sonoporation experiments to test if uptake efficiency is dependent on maximum microbubble size before inertial collapse. Results indicated that at the acoustic droplet vaporization threshold, Rmax was approximately 61.7 ± 5.2, 24.9 ± 2.8, and 12.4 ± 2.1 μm at 1, 2.5 and 5 MHz, respectively. Sonoporation efficiency increased at higher frequencies, with efficiencies of 39.5 ± 13.7%, 46.6 ± 3.28% and 66.8 ± 5.5% at 1, 2.5 and 5 MHz, respectively. Excessive cellular damage was seen at lower frequencies because of the erosive effects of highly energetic inertial cavitation. These results highlight the importance of acoustic cavitation control in determining the outcome of sonoporation experiments. In addition, PSNEs may serve as tailorable inertial cavitation nuclei for other therapeutic ultrasound applications.


The effect on lower spine muscle activation of walking on a narrow beam in virtual reality.
To what extent do people behave in immersive virtual environments as they would in similar situations in a physical environment? There are many ways to address this question, ranging from questionnaires, behavioral studies, and the use of physiological measures. Here, we compare the onsets of muscle activity using surface electromyography (EMG) while participants were walking under three different conditions: on a normal floor surface, on a narrow ribbon along the floor, and on a narrow platform raised off the floor. The same situation was rendered in an immersive virtual environment (IVE) Cave-like system, and 12 participants did the three types of walking in a counter-balanced within-groups design. The mean number of EMG activity onsets per unit time followed the same pattern in the virtual environment as in the physical environment-significantly higher for walking on the platform compared to walking on the floor. Even though participants knew that they were in fact really walking at floor level in the virtual environment condition, the visual illusion of walking on a raised platform was sufficient to influence their behavior in a measurable way. This opens up the door for this technique to be used in gait and posture related scenarios including rehabilitation.


[Severe osteoporosis in a young female patient with Crohn's disease].
Increasing pain in the region of the lumbar vertebrae occurred in a 23-year-old woman known for the past 6 1/2 years to have Crohn's disease affecting the ileocolon. Radiology revealed marked osteopenia with collapse and deformation of the vertebral bodies. The only pointer to a bone disease was a markedly lowered serum level of 25-OH-vitamin D (less than 10 ng/ml). Biopsy from the ileal crest revealed pure osteoporosis without osteomalacia. Decisive pathogenetic factors were, in the main, glucocorticoid medication, malnutrition and the long duration of Crohn's disease. During treatment with monofluorophosphate, 152 g daily, in fixed combination with 600 mg calcium as well as calcitonin (initially 100 I.U. daily subcutaneously for two weeks, then 100 I.U. every other day s.c.) and vitamin D (3 x 1,000 I.U. daily by mouth) she became free of symptoms, and she has remained so for 9 months.


Prediction model of postoperative pain exacerbation using an intravenous patient-controlled analgesia device and a wearable electrocardiogram sensor.
There is a need to develop objective and real-time postoperative pain assessment methods in perioperative medicine. Few studies have evaluated the relationship between pain severity and temporal changes of physiological signals in actual postoperative patients. In this study, we developed a machine learning model which was trained from intravenous patient-controlled analgesia (IV-PCA) records and electrocardiogram (ECG) of postoperative patients to predict pain exacerbation. A self-attentive autoencoder (SA-AE) model achieved 54% of sensitivity and a 1.76 times/h of false positive rate.Clinical relevance- We proposed a novel method for evaluating postoperative pain in real time and demonstrated the possibility of predicting pain exacerbation. The proposed method would realize the automatic administration of analgesics and the optimization of opioid doses.


(1E,4E)-1,5-Bis[4-(di-ethyl-amino)-phen-yl]penta-1,4-dien-3-one.
There are two crystallograpically independent mol-ecules in the asymmetric unit of the title bis-chalcone derivative, C25H32N2O. Both mol-ecules are twisted with a dihedral angle between the two substituted benzene rings of 11.19 (16)° in one mol-ecule and 14.40 (15)° in the other. The central penta-1,4-dien-3-one fragments make dihedral angles of 8.49 (17) and 4.26 (17)° with the two adjacent benzene rings in one mol-ecule, whereas the corresponding values are 8.42 (16) and 6.18 (16)° in the other. In the crystal, mol-ecules are arranged into chains along the c-axis direction. Adjacent chains are inter-linked by weak inter-molecular C-H⋯O inter-actions. The crystal is further stabilized by C-H⋯π inter-actions.


Interoperative radiotherapy of seventy-two cases of early breast cancer patients during breast-conserving surgery.
To evaluate interoperative radiotherapy after breast conservative surgery in early breast cancer patients in terms of postoperative complications, cosmetic outcome and recurrence events. From June 2007 to Dec 2011, 143 early breast cancer patients received breast conservative surgery. Seventy-two (study group) received interoperative radiotherapy, compared with 71 patients (control group) given routine radiotherapy. Postoperative complications were evaluated 1 month after surgery; cosmetic outcome was evaluated 1 year postoperatively; recurrence and death events were followed up. The average wound healing time was 13~22 d in the study group and 9~14 d in the control group. In the study group, 2 patients developed lyponecrosis, 16 patients showed wound edema while no such side effects were found in the control group. No infection or hematomas were found in either group. In the study group (59 cases), overall cosmetic outcome in 53 patients was graded as excellent or good, and in 6 as fair or poor. Meanwhile in the control group (56 cases), 42 patients were graded as excellent or good, and 14 as fair or poor (P=0.032). After a follow-up from 3 to 54 months (median: 32 months), two patients (2.78%) in study group developed local relapses, one of them (1.39%) died, 2 patients (2.78%) developed bone metastases. In control group, one patient (1.41%) developed local relapse, 2 patients (2.82%) developed bone metastases, and no one died. Intraoperative radiotherapy is safe and reliable with good cosmetic outcome.


A Machine Learning Model to Predict Patients' Adherence Behavior and a Decision Support System for Patients With Metastatic Breast Cancer: Protocol for a Randomized Controlled Trial.
Adherence to oral anticancer treatments is critical in the disease trajectory of patients with breast cancer. Given the impact of nonadherence on clinical outcomes and the associated economic burden for the health care system, finding ways to increase treatment adherence is particularly relevant. The primary end point is to evaluate the effectiveness of a decision support system (DSS) and a machine learning web application in promoting adherence to oral anticancer treatments among patients with metastatic breast cancer. The secondary end point is to collect a set of new physical, psychological, social, behavioral, and quality of life predictive variables that could be used to refine the preliminary version of the machine learning model to predict patients' adherence behavior. This prospective, randomized controlled study is nested in a large-scale international project named "Enhancing therapy adherence among metastatic breast cancer patients" (Pfizer 65080791), aimed to develop a predictive model of nonadherence and associated DSS and guidelines to foster patients' engagement and therapy adherence. A web-based DSS named TREAT (treatment adherence support) was developed using a patient-driven approach, with 4 sections, that is, Section A: Metastatic Breast Cancer; Section B: Adherence to Cancer Therapies; Section C: Promoting Adherence; and Section D: My Adherence Diary. Moreover, a machine learning-based web application was developed to predict patients' risk factors of adherence to anticancer treatment, specifically pertaining to physical status and comorbid conditions, as well as short and long-term side effects. Overall, 100 patients consecutively admitted at the European Institute of Oncology (IEO) at the Division of Medical Senology will be enrolled; 50 patients with metastatic breast cancer will be exposed to the DSS and machine learning web application for 3 months (experimental group), and 50 patients will not be exposed to the intervention (control group). Each participant will fill a weekly medication diary and a set of standardized self-reports evaluating psychological and quality of life variables (Adherence Attitude Inventory, Beck Depression Inventory-II, Brief Pain Inventory, 13-item Sense of Coherence scale, Brief Italian version of Cancer Behavior Inventory, European Organization for Research and Treatment of Cancer Quality of Life 23-item Breast Cancer-specific Questionnaire, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, 8-item Morisky Medication Adherence Scale, State-Trait Anxiety Inventory forms I and II, Big Five Inventory, and visual analogue scales evaluating risk perception). The 3 assessment time points are T0 (baseline), T1 (1 month), T2 (2 months), and T3 (3 months). This study was approved by the IEO ethics committee (R1786/22-IEO 1907). The recruitment process started in May 2023 and is expected to conclude on December 2023. The contribution of machine learning techniques through risk-predictive models integrated into DSS will enable medication adherence by patients with cancer. ClinicalTrials.gov NCT06161181; https://clinicaltrials.gov/study/NCT06161181. DERR1-10.2196/48852.