Coronary artery bypass grafting in patients with dialysis-dependent renal failure.
Myocardial infarction and other cardiovascular events constitute the leading causes of death in dialysis-dependent, end-stage renal disease patients. Due to growth in the elderly population, the number of uremic patients who need surgical revascularization is likely to increase. Whether or not coronary artery bypass grafting is safe for patients on long-term dialysis remains a great concern. We retrospectively reviewed all cases of elective or urgent isolated coronary artery bypass grafting in our hospital, from 1 January 1998 through 31 March 2003, and identified 23 consecutive patients with dialysis-dependent renal disease (Group D). Twenty-two of them were on hemodialysis, and 1 was on peritoneal dialysis; the mean duration of dialysis was 19.2 +/- 22.5 months. We chose 69 matched non-dialysis patients who underwent bypass grafting in 2001 to serve as our control group (ND). Preoperative, operative, and postoperative data on these patients were compared. Group D consisted of 14 men and 9 women with a mean age of 63.8 +/- 9.9 years, and the mean number of distal anastomoses was 3.5 +/- 1.2. There were no significant differences between the 2 groups in preoperative factors, intubation time, intensive care unit stay, major complications, and 30-day mortality. However, uremic patients had a greater tendency to bleed, longer postoperative hospital stays, and more late deaths. We conclude that under a well-prepared dialysis program and meticulous perioperative management, coronary artery bypass grafting can be performed in dialysis-dependent patients, with increased but acceptable perioperative morbidity and mortality risks.


Workforce unavailability in Parkinson's disease.
Individuals with Parkinson's disease (PD) become unavailable in the workforce earlier than comparable members of the general population. This may result in significant social insurance expenses, but as workforce participation can be a source for social interaction and a vital part of the personal identity, there are likely to be personal implications extending far beyond the economic aspects. This study aimed to identify aspects that may contribute to workforce unavailability in people with PD. This was a cross-sectional registry study using data from the Swedish national quality registry for PD and included persons with PD in Skåne County, Sweden who were younger than 65 years. Variables were selected from the registry based on earlier studies and clinical experience and were tested for association with unavailability in the workforce: first in a series of simple regression analyses and then in a multiple logistic regression analysis. A total of 99 persons with PD-of whom 59 were available and 40 were unavailable in the workforce-were included in the study. Age (OR per year: 1.47, 95% CI: 1.18-1.85; P < 0.01) and anxiety (OR: 6.81, 95% CI: 1.20-38.67; P = 0.03) were significant contributing factors for unavailability in the workforce. Based on the findings in this exploratory study, anxiety-a potentially modifiable factor-and age may be contributing factors for workforce unavailability in PD. However, prospective studies are warranted to confirm the findings and the causation of the association between anxiety and workforce unavailability needs to be clarified.


Anticipatory detection of turning in humans for intuitive control of robotic mobility assistance.
Many wearable lower-limb robots for walking assistance have been developed in recent years. However, it remains unclear how they can be commanded in an intuitive and efficient way by their user. In particular, providing robotic assistance to neurologically impaired individuals in turning remains a significant challenge. The control should be safe to the users and their environment, yet yield sufficient performance and enable natural human-machine interaction. Here, we propose using the head and trunk anticipatory behaviour in order to detect the intention to turn in a natural, non-intrusive way, and use it for triggering turning movement in a robot for walking assistance. We therefore study head and trunk orientation during locomotion of healthy adults, and investigate upper body anticipatory behaviour during turning. The collected walking and turning kinematics data are clustered using the k-means algorithm and cross-validation tests and k-nearest neighbours method are used to evaluate the performance of turning detection during locomotion. Tests with seven subjects exhibited accurate turning detection. Head anticipated turning by more than 400-500 ms in average across all subjects. Overall, the proposed method detected turning 300 ms after its initiation and 1230 ms before the turning movement was completed. Using head anticipatory behaviour enabled to detect turning faster by about 100 ms, compared to turning detection using only pelvis orientation measurements. Finally, it was demonstrated that the proposed turning detection can improve the quality of human-robot interaction by improving the control accuracy and transparency.


Global impact of somatic structural variation on the DNA methylome of human cancers.
Genomic rearrangements exert a heavy influence on the molecular landscape of cancer. New analytical approaches integrating somatic structural variants (SSVs) with altered gene features represent a framework by which we can assign global significance to a core set of genes, analogous to established methods that identify genes non-randomly targeted by somatic mutation or copy number alteration. While recent studies have defined broad patterns of association involving gene transcription and nearby SSV breakpoints, global alterations in DNA methylation in the context of SSVs remain largely unexplored. By data integration of whole genome sequencing, RNA sequencing, and DNA methylation arrays from more than 1400 human cancers, we identify hundreds of genes and associated CpG islands (CGIs) for which the nearby presence of a somatic structural variant (SSV) breakpoint is recurrently associated with altered expression or DNA methylation, respectively, independently of copy number alterations. CGIs with SSV-associated increased methylation are predominantly promoter-associated, while CGIs with SSV-associated decreased methylation are enriched for gene body CGIs. Rearrangement of genomic regions normally having higher or lower methylation is often involved in SSV-associated CGI methylation alterations. Across cancers, the overall structural variation burden is associated with a global decrease in methylation, increased expression in methyltransferase genes and DNA damage response genes, and decreased immune cell infiltration. Genomic rearrangement appears to have a major role in shaping the cancer DNA methylome, to be considered alongside commonly accepted mechanisms including histone modifications and disruption of DNA methyltransferases.


Zimbabwe's prison facilities: Preparedness for institutional COVID-19 outbreaks.
Covid-19 cases and death are on the rise in Zimbabwe and other Southern African countries. This increase poses a major risk of outbreaks in institutions such as prisons and detention centers. Zimbabwe has a total of 46 main prisons that are overcrowded and without adequate running water, hand sanitizers, and face masks for both prisoners and warden officers. Although the country has released some prisoners, it is still not enough to decongest the prisons and mitigate the Covid-19 risk. There is a need to further decongest the prisons, ensure facilities have adequate tap water, and consider the use of video and audio technology to minimize visitors to inmates.


Development and Initial Evaluation of the Psychometric Properties of the Dialectical Behavior Therapy Barriers to Implementation Scale (BTI-S).
We examined the psychometric properties of the Dialectical Behavior Therapy (DBT) Barriers to Implementation Scale (BTI-S). Participants were clinicians completing a bipartite training, separated by 6 months of self-study, to implement DBT. Exploratory factor analysis was conducted with data collected from the initial training period (N = 790), while confirmatory factor analysis was based on data from the final training period (N = 660). The final model included 26 items and 4 factors with overall acceptable fit, χ2 (293, N = 660) = 460.989, p < .001, comparative fit index = .909, Tucker-Lewis index = .899, root mean square root mean square error of approximation (90% confidence interval) = .015. The internal reliability of the scores was low (range = .56 to .72). The final model fits reasonably well and measures four domains considered important for implementation of DBT. However, the low reliability of the scores indicates that the BTI-S would be improved with further development.


Use of sevoflurane inhalation sedation for outpatient third molar surgery.
This study attempted to determine if sevoflurane in oxygen inhaled via a nasal hood as a sole sedative agent would provide an appropriate level of deep sedation for outpatient third molar surgery. Twenty-four patients scheduled for third molar removal were randomly assigned to receive either nasal hood inhalation sevoflurane or an intravenous deep sedation using midazolam and fentanyl followed by a propofol infusion. In addition to measuring patient, surgeon, and dentist anesthesiologist subjective satisfaction with the technique, physiological parameters, amnesia, and psychomotor recovery were also assessed. No statistically significant difference was found between the sevoflurane and midazolam-fentanyl-propofol sedative groups in physiological parameters, degree of amnesia, reported quality of sedation, or patient willingness to again undergo a similar deep sedation. A trend toward earlier recovery in the sevoflurane group was identified. Sevoflurane can be successfully employed as a deep sedative rather than a general anesthetic for extraction of third molars in healthy subjects.


Evidence-based, cost-effective risk stratification and management after myocardial infarction. California Cardiology Working Group on Post-MI Management.
Current management of patients after an acute myocardial infarction (AMI) reflects a variety of approaches ranging from conservative to aggressive. Although each method is appropriate in certain subgroups, their application frequently lacks a scientific basis. Current, clinically relevant, evidence-based practice guidelines are needed for secondary prevention for survivors after an AMI. To meet this need, the California Cardiology Working Group was assembled to evaluate the available data from clinical trials and other published studies and develop evidence-based, cost-effective guidelines for clinicians to use as a basis for patient management after an AMI. The group consisted of 18 members, including cardiologists from academic institutions and physicians working in cardiac intensive care, private practices, and managed care settings, representing a broad spectrum of expertise pertaining to patients who have had an AMI. The members had expertise in cardiac intensive care, interventional cardiology, nuclear cardiology, lipid disorders, echocardiography, and cardiac rehabilitation. The intended audience for these practice guidelines includes all physicians who treat survivors of MI. A literature review of all relevant clinical trials and other published data about the natural history after AMI and the effects of current therapeutic modalities are discussed herein. Case histories served as models for application of the literature-based data. The recommendations for management were reached by consensus vote based on the scientific evidence. When more than 1 management option applied, this was recognized in the recommendations. The recommendations accompany the text.


Blood-Based Biomarkers and Long-term Risk of Frailty-Experience From the Swedish AMORIS Cohort.
Frailty is associated with reduced quality of life, poor health outcomes, and death. Past studies have investigated how specific biomarkers are associated with frailty but understanding biomarkers in concert with each other and the associated risk of frailty is critical for clinical application. Using a sample aged ≥59 years at baseline from the Swedish AMORIS (Apolipoprotein MOrtality RISk) cohort (n = 19 341), with biomarkers measured at baseline (1985-1996), we conducted latent class analysis with 18 biomarkers and used Cox models to determine the association between class and frailty and all-cause mortality. Four classes were identified. Compared to the largest class, the Reference class (81.7%), all other classes were associated with increased risk of both frailty and mortality. The Anemia class (5.8%), characterized by comparatively lower iron markers and higher inflammatory markers, had hazard ratio (HR) = 1.54, 95% confidence interval (CI) 1.38, 1.73 for frailty and HR = 1.76, 95% CI 1.65, 1.87 for mortality. The Diabetes class (6.5%) was characterized by higher glucose and fructosamine, and had HR = 1.59, 95% CI 1.43, 1.77 for frailty and HR = 1.74, 95% CI 1.64, 1.85 for mortality. Finally, the Liver class (6.0%), characterized by higher liver enzyme levels, had HR = 1.15, 95% CI 1.01, 1.30 for frailty and HR = 1.40, 95% CI 1.31, 1.50 for mortality. Sex-stratified analyses did not show any substantial differences between men and women. Distinct sets of commonly available biomarkers were associated with development of frailty and monitoring these biomarkers in patients may allow for earlier detection and possible prevention of frailty, with the potential for improved quality of life.


Prognostic factors in a multicentre study of 247 atypical pulmonary carcinoids.
To analyse clinical and biomolecular prognostic factors associated with the surgical approach and the outcome of 247 patients affected by primary atypical carcinoids (ACs) of the lung in a multi-institutional experience. We retrospectively evaluated clinical data and pathological tissue samples collected from 247 patients of 10 Thoracic Surgery Units from different geographical areas of our country. All patients were divided into four groups according to surgical procedure: sub-lobar resections (SURG1), lobar resections (SURG2), tracheobronchoplastic procedures (SURG3) and pneumonectomies (SURG4). Overall survival analysis was performed using the Kaplan-Meier method and log-rank test. Survival was calculated from the date of surgery to the last date of follow-up or death. The parameters evaluated included age, gender, smoking habits, laterality, type of surgery, 7th edition of TNM staging, mitosis Ki-67 (MIB1), multifocal forms, tumourlets, type of lymphadenectomy and neo/adjuvant therapy. For multivariate analysis, a Cox regression model was used with a forward stepwise selection of covariates. Two hundred and forty-seven patients (124 females and 123 males; range 10-84, median 60 years) underwent surgical resection for AC in the last 30 years as follows: n = 38 patients in SURG1, 181 in SURG2, 15 in SURG3 and 14 in SURG4. A smoking history was present in 136 of 247 (55%) patients. The median follow-up period was 98.7 (range 11.2-369.9) months. The overall survival probability analysis of the AC was 86.7% at 5 years, 72.4% at 10 years, 64.4% at 15 years and 58.1% at 20 years. Neuroendocrine multicentric forms were detected in 12 of 247 patients (4.8%; 1 of 12 pts) during the follow-up (range 11.2-200.4, median 98.7 months) and 33.4% had recurrence of disease. There were no significant differences between gender, tumour location and type of surgery at the multivariate analysis. Age [P < 0.001, hazard ratio (HR) 0.60; confidence interval (CI) 0.32-1.12], smoking habits (P = 0.002; HR 0.43, 95% CI 0.23-0.80) and lymph nodal metastatic involvement (P = 0.008; HR 0.46, 95% CI 0.26-0.82) were all significant at multivariate analysis. ACs of the lung are malignant neuroendocrine tumours with a worst outcome in patients over 70 years and in smokers. With the exception of pneumonectomy, the extent of resection does not seem to affect survival and should be accompanied preferably by lymphadenectomy. Pathological staging, along with a mitotic index more than Ki-67 (MIB1), appears to be the most significant prognostic factor at the univariate analysis.


The use of glycoprotein IIb/IIIa inhibitor therapy in acute ST-segment elevation myocardial infarction: current practice and future trends.
The goal of therapy in acute myocardial infarction is complete and timely restoration of coronary blood flow. Current strategies for reperfusion fail to achieve ideal results and resolution of ischemia in all patients. The platelet plays a pivotal role in the pathophysiology of an acute myocardial infarction, and antiplatelet therapy has been shown to improve clinical outcomes. The final common pathway for platelet activation and aggregation in acute myocardial infarction is the activation of the glycoprotein (GP) IIb/IIIa receptor. Newer reperfusion strategies target the GP IIb/IIIa receptor, thereby preventing the prothrombotic effects of platelets in an acute myocardial infarction. In the past decade, several strategies targeting the use of GP IIb/IIIa inhibitors have been evaluated. GP IIb/IIIa inhibitors have been shown to improve angiographic Thrombolysis in Myocardial Infarction (TIMI) 3 flow rates when used as reperfusion therapy given with heparin and aspirin as compared with heparin and aspirin alone. When GP IIb/IIIa inhibitors are used with full-dose fibrinolytics, early studies have suggested a trend toward more rapid and more complete reperfusion in an acute myocardial infarction. Later trials have examined the use of GP IIb/IIIa inhibitors in conjunction with reduced-dose fibrinolytics. Results from TIMI 14 and Global Use of Strategies to Open occluded arteries-IV pilot trials support the use of combination therapy with reduced- dose fibrinolytics and the GP IIb/IIIa inhibitor abciximab. Given the promising role of GP IIb/IIIa inhibitor therapy in acute myocardial infarction, investigators questioned the need for concomitant antithrombin therapy. However, data from several investigations suggest that antithrombin therapy is required when GP IIb/IIIa inhibitors are used with fibrinolytics, although it appears that the dose of heparin may be reduced. Finally, recent investigations have addressed the safety and efficacy of facilitated early percutaneous intervention. In this strategy, patients presenting with an acute myocardial infarction are treated with reduced-dose fibrinolytics and GP IIb/IIIa inhibitors and are taken to the interventional cardiac catheterization laboratory within the first 60 minutes of therapy.


Surveillance of pneumococcal diseases in Central and Eastern Europe.
Pneumococcal infection is a major cause of morbidity and mortality worldwide. The burden of disease associated with S. pneumoniae is largely preventable through routine vaccination. Pneumococcal conjugate vaccines (e.g. PCV7, PCV13) provide protection from invasive pneumococcal disease as well as non-invasive infection (pneumonia, acute otitis media), and decrease vaccine-type nasopharyngeal colonisation, thus reducing transmission to unvaccinated individuals. PCVs have also been shown to reduce the incidence of antibiotic-resistant pneumococcal disease. Surveillance for pneumococcal disease is important to understand local epidemiology, serotype distribution and antibiotic resistance rates. Surveillance systems also help to inform policy development, including vaccine recommendations, and monitor the impact of pneumococcal vaccination. National pneumococcal surveillance systems exist in a number of countries in Central and Eastern Europe (such as Croatia, Czech Republic, Hungary, Poland, Romania and Slovakia), and some have introduced PCVs (Czech Republic, Hungary, Kazakhstan, Russia, Slovakia and Turkey). Those countries without established programs (such as Kazakhstan, Russia and Ukraine) may be able to learn from the experiences of those with national surveillance systems. The serotype distributions and impact of PCV13 on pediatric pneumococcal diseases are relatively similar in different parts of the world, suggesting that approaches to vaccination used elsewhere are also likely to be effective in Central and Eastern Europe. This article briefly reviews the epidemiology of pneumococcal disease, presents the latest surveillance data from Central and Eastern Europe, and discusses any similarities and differences in these data as well the potential implications for vaccination policies in the region.


Diagnostic utility of cholescintigraphy in emergency department patients with suspected acute cholecystitis: comparison with bedside RUQ ultrasonography.
Tc-99m-HIDA cholescintigraphy studies of gallbladder (GB) emptying are considered to be the most accurate method to diagnose acute cholecystitis (AC). With increasing use of bedside ultrasound (US) by emergency physicians for the evaluation of GB pathology, it is important to determine the role of cholescintigraphy as an adjunct to emergency ultrasound of the gallbladder. The objective of this study was to determine the utility of cholescintigraphy as an adjunct to bedside ultrasound in the evaluation of Emergency Department (ED) patients with suspected acute cholecystitis. We retrospectively reviewed US studies of 102 patients being evaluated for AC at a large community ED with a residency program. All patients over 18 years of age presenting to the ED over a 1-year period who received an ED US of the GB followed by a cholescintigraphy were enrolled. Bedside ultrasonography was performed after an initial physical examination by a hospital-credentialed emergency sonologist. Criteria used to diagnose AC include the finding of gallstones with a sonographic Murphy sign, significant wall thickening over 5 mm, pericholecystic fluid, impacted stone, or a combination of these. US reports were compared to cholescintigraphy results, final diagnosis, disposition, and pathology results when applicable. Statistical analysis included descriptive statistics calculated using StatsDirect software. A total of 102 patients fit criteria for this study over a 1-year period. Three patients were dropped from data analysis due to incomplete data. ED US and cholescintigraphy examinations agreed for presence or absence of AC in 76 of 99 patients (77%; 95% confidence interval [CI] 68-84%) resulting in a correlation value of rs = 0.74. A total of 38 of 99 (38%; 95% CI 30-49%) patients were diagnosed with AC on cholescintigraphy and ED US agreed in 20 patients. ED US diagnosed 25 (25%; 95% CI 18-34%) patients with AC and cholescintigraphy agreed in 20 patients. Of 99 patients enrolled, 63 were admitted to the hospital (63%; 95% CI 53-72%). Of the admitted patients, 36 (36%; 95% CI 27-46%) went to the operating room (OR) for presumed AC. Of the 31 (79%; 95% CI 64-89%) with AC on cholescintigraphy who went to the OR, only 13 (42%; 95% CI 26-59%) had pathology-based diagnosis of AC; 15 (48%; 95% CI 32-65%) had chronic inflammation only and 3 (10%; 95% CI 4-25%) had a diagnosis of cholelithiasis only. In 12 of 15 OR cases (80%; 95% CI 62-98%), where cholescintigraphy diagnosed AC but ED US did not, operative diagnosis agreed with US. Five patients with normal cholescintigraphy but ED US diagnosis of AC were taken to OR; pathology agreed with ultrasonography in all. Three other patients diagnosed with AC on cholescintigraphy, but not on ED US, never required operative intervention based on consulting surgeon evaluation. Our study demonstrates that the utility of cholescintigraphy in the evaluation of ED patients with suspected acute cholecysitis after a negative ultrasound examination is very limited.


Representation of Social History Factors Across Age Groups: A Topic Analysis of Free-Text Social Documentation.
As individuals age, there is potential for dramatic changes in the social and behavioral determinants that affect health status and outcomes. The importance of these determinants has been increasingly recognized in clinical decision-making. We sought to characterize how social and behavioral health determinants vary in different demographic groups using a previously established schema of 28 social history types through both manual analysis and automated topic analysis of social documentation in the electronic health record across the population of an entire integrated healthcare system. Our manual analysis generated 8,335 annotations over 1,400 documents, representing 24 (86%) social history types. In contrast, automated topic analysis generated 22 (79%) social history types. A comparative evaluation demonstrated both similarities and differences in coverage between the manual and topic analyses. Our findings validate the widespread nature of social and behavioral determinants that affect health status over populations of individuals over their lifespan.


Tuberculous osteomyelitis presenting as shoulder pain.
A case of tuberculous osteomyelitis of the proximal humerus is described. The relevant literature is reviewed with attention to epidemiologic data. Issues highlighted include the frequent presentation in a subacute course without systemic illness; the value of plain radiography and especially magnetic resonance imaging; the importance of obtaining a tissue diagnosis; and the high rate of cure with medical therapy. Although rare in Western countries, skeletal tuberculosis is not uncommon in endemic areas and in migrants from such areas. With the growing use of biologic therapies, rheumatologists must be familiar with the diagnosis and treatment of tuberculosis in all its forms.


Taking an integrated approach: managing women with phytoestrogens.
An integrated approach can be employed when counselling women about menopausal management options, where lifestyle, complementary therapies and hormone replacement therapy (HRT) are discussed. Women might opt to use an alternative approach to HRT for a variety of reasons, e.g. fear of side-effects and risks or contraindications to HRT. There are many choices of dietary and herbal approaches for menopausal symptoms, which essentially divide into food supplements and herbal medicines. The choice can often be overwhelming and confusing for the woman. Of concern, the evidence for efficacy and safety of some of these complementary therapies can be extremely limited or non-existent. In order to enable women to make a fully informed choice, it is important that, when a recommendation is made regarding a specific complementary therapy, it should focus on preparations for which a significant dataset exists for efficacy and safety and in which there is ongoing research and development. One of the most extensively studied food supplements has been the phytoestrogenic preparation containing red clover isoflavones. There have been six randomized trials thus far studying the impact on vasomotor symptoms, three of which have shown a significant benefit compared to placebo. There are also data from small randomized and observational trials showing positive outcomes for surrogate markers of osteoporosis and cardiovascular disease. A recent study using validated depression scales has shown that women using red clover isoflavones may also derive psychological benefits. Safety data are reassuring for the endometrium and breast, although further studies would be welcome, particularly in women with significant medical risks.


Principles of bone and joint disease control programs--osteoporosis.
During the past decade osteoporosis has emerged as a major public health problem. In societies with aging populations, an increasing number of persons are at risk of fracture, the most detrimental outcome of osteoporosis. Osteoporosis was initially identified as a problem of westernized countries, but a rising number of fractures are occurring in Asia and South America, and the global estimates show steep increases in these regions. Over the age of 70 years, only 31-36% of people are estimated to have normal bone mass. The lifetime risk for hip fracture for 50-year-old women is 18 to 25% and the risk for men 6 to 7%. Hip fractures affect the most aged, and are a contributing factor to death, with up to 20% of patients having died within the first year. Rehabilitation is needed, but only 30% regain pre-fracture function. The lifetime risk of vertebral fracture has been estimated to be 15.4% after age 45 years, but this most likely largely underestimates the true risk. The demand on the health care system is therefore increasing, as are costs for society. Prevention of osteoporosis and fracture must be considered particularly for the elderly at highest risk. Awareness is needed at all levels, including decision making bodies, in order to raise the priority of, and effectively implement, strategies to reduce the number of persons suffering. Interventions for prevention of fractures must be cost-effective; therefore strategies are needed to identify those who will benefit most from more costly secondary measures.


Anisometropic amblyopia in Macaca nemestrina monkeys produced by atropinization of one eye during development.
Two macaque monkeys were reared with daily administration of the cycloplegic drug, atropine, to one eye until 8 months after birth. Behavioral testing of contrast sensitivity functions in the atropinized eyes during the rearing period demonstrated that this rearing procedure caused the treated eyes to be chronically defocused. Measurement at the age of 6 or 8 months of contrast sensitivity while optically correcting the defocus demonstrated that an amblyopia had developed in the treated eyes. Furthermore, the relative magnitude of the amblyopia across spatial frequencies was similar to the relative magnitude of the defocus. Subsequently testing at 1 year of age demonstrated that the deficits persisted for several months after termination of the defocus rearing. This rearing procedure appears to provide a reasonable primate model with which to study anisometropic amblyopia in monkeys.


Application of a Customized Total Talar Prosthesis for Revision Total Ankle Arthroplasty.
The rate of revision surgery for total ankle arthroplasty (TAA) is higher than for hip and knee arthroplasties. Tibiotalocalcaneal arthrodesis is widely used; however, it requires a large allograft. Thus, the use of a customized total talar prosthesis in combination with the tibial component of TAA (combined TAA) may be an effective strategy for talar component subsidence. This study aimed to evaluate the clinical and radiographic effectiveness of the combined TAA in such revision cases. Between 2000 and 2015, 10 patients (10 women; 10 ankles) were treated using the combined TAA for revision after standard TAA or combined procedures that included the use of a talar body prosthesis. In 6 patients, the tibial component was concurrently replaced. The median follow-up period was 49 months (interquartile range [IQR], 24.5 to 90 months). The Japanese Society for Surgery of the Foot (JSSF) ankle-hindfoot scale score, a numerical rating scale (NRS) pain score, passive range of motion of the ankle, and the presence of osteophytes and degenerative changes in the adjacent joints were assessed preoperatively and at final postoperative follow-up. The median NRS pain score improved significantly, from 7 (IQR, 6.25 to 8.75) to 2 (IQR, 1 to 3). The median JSSF ankle-hindfoot scale total score improved significantly, from 64 (IQR, 56.25 to 71.5) to 88.5 (IQR, 79.75 to 96). In the subcategories of this scale, the median pain score improved from 20 (IQR, 20 to 27.5) to 35 (IQR, 30 to 40), and the median function score improved from 34 (IQR, 26.5 to 37) to 43.5 (IQR, 39.75 to 46). The median range of motion improved from 29° (IQR, 25.5° to 35°) to 35° (IQR, 31.25° to 43.75°). No significant difference in osteophyte formation was found. Degenerative changes in the adjacent joint were found only in the talonavicular joint. The combined TAA, used in revision for postoperative complications after standard TAA or combined procedures including the use of a talar body prosthesis, was associated with improved objective JSSF ankle-hindfoot scale scores, subjective pain assessment, and range of motion in the ankle. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


The Postprandial Calcium Absorption of a Milk-Derived Calcium Permeate - The Acute RENEW Double-Blinded Randomized Controlled Cross-Over Study.
Studies suggest that dairy-derived calcium supplements have additional beneficial properties compared with other calcium supplements in relation to bone health. We investigated the postprandial calcium absorption from a milk-derived calcium permeate (CP) compared with calcium carbonate (CC). In this randomized double-blinded cross-over study, 10 healthy postmenopausal females (age 50-65 y) received maltodextrin (placebo), 800 mg calcium from CP or from CC provided in 6 capsules on separate days. A fasting blood sample was collected at baseline, 60, 120, 240, and 360 min after ingestion. At baseline and 360 min, spot-urine samples were collected. Serum-ionized calcium, intact parathyroid hormone, phosphorus, and magnesium were analyzed, as were urinary calcium, phosphorus, and magnesium. A linear mixed model was applied. Serum-ionized calcium concentration after the CC supplement was higher at 240 min compared with the CP supplement [between-group difference; 95% confidence interval (CI): 0.039 mmol/L; 95% CI: 0.017-0.061; P = 0.00078]. Serum-ionized calcium concentration after the CC supplement was significantly higher than placebo at all postprandial time points except at 60 min. Urinary calcium concentration in 360 min spot urine was higher after intake of CC compared with CP [between-group difference; 95% CI: 2.47 mmol/L; 95% CI: 1.90-3.03; P = 0.0042]. Postprandial calcium absorption from CP was lower than that of CC, and concurrently, urinary concentration reflected increased serum appearance by CC compared with CP, highlighting different metabolic responses. The long-term and clinical implications should be studied further.


Long-term follow-up of thromboangiitis obliterans.
To date there have been no clinical studies providing data on which to base a long-term medical and social prognosis of thromboangiitis obliterans (TAO). Against this background a retrospective investigation of the longterm course of patients with TAO, who attended the vascular clinic in the medical department of the Klinikum Westend of the Freien Universität Berlin (Free University of Berlin) or the Franziskus Hospital in Berlin was carried out during the period between 1970 and 1990. The 69 patients making up the overall group included 53 males and 16 females whose average age at the time of initial manifestation of TAO was 34 years. The mean interval between the initial manifestation of the disease and the follow up investigation was 10.7 (range: 2-30) years. The assessment of the course over the long-term was based on a clinical follow-up survey or the data provided by a questionnaire. In 96% of the patients symptoms began in one of the lower limbs, predominantly in the forefoot. During the further course of the illness, 73% of the patients developed symptoms in at least one other limb, either upper or lower. Since the initial development of symptoms, the patients had experienced an average of 5.4 (range: 1-20) acute attacks, that is, episodes of more severe symptoms. The most common reason for hospitalisation was necrosis of the lower limbs, the usual site being the forefoot with primary involvement of the big toe in 57% of the cases. The mean duration of hospitalisation per hospital stay was 36.8 (range: 1-210) days. During the course of the disease 54 (78.2%) of the patients required an average of 3.7 (range: 1-17) operations, 40 (74%) undergoing one or more amputations. Most of the amputations were performed during the first five years after disease onset and the amputation rate was 26%. With the exception of a single lady, all the patients were smokers, and 40 (83.5%) of 48 smokers for whom the relevant information was available persisted with their habit after the onset of the disease. 8 (16.6%) of the 48 patients claimed to have stopped smoking during the course of their disease. Among the patients who continued to smoke, 65% required an amputation, which was almost twice that seen in those who stopped smoking. In terms of number of acute attacks, surgical procedures and smoking, no relationship was found between early age (< 35 years) at onset and progression of the disease. TAO had a pronounced influence on the working life of many of the patients. Twelve changed their jobs because of thromboangiitis obliterans, while 24 (34.8%) retired prematurely on a pension at the mean age of 42. The long-term investigation shows that TAO is associated with frequent hospitalisations and surgical procedures. Continued consumption of tobacco in particular was found to be associated with a multiplication of the amputation rate. An influence of patient age at disease onset on the progression of TAO was excluded. In 49 (71%) of the patients, the disease resulted in termination of the working life by either dismissal or premature retirement.


Melanoma: tumor microenvironment and new treatments.
In the recent past years, many discoveries in the tumor microenvironment have led to changes in the management of melanoma and it is rising up hopes, specially, to those in advanced stages. FDA approved seven new drugs from 2011 to 2014. They are: Vemurafenib, Dabrafenib and Trametinib, kinases inhibitors used for patients that have BRAFV600E mutation; Ipilimumab (anti-CTLA4), Pembrolizumab (anti-PD-1) and Nivolumab (anti-PD-1), monoclonal antibodies that stimulate the immune system; and Peginterferon alfa-2b, an anti-proliferative cytokine used as adjuvant therapy. In this article, we will review the molecular bases for these new metastatic melanoma therapeutic agents cited above and also analyze new molecular discoveries in melanoma study, as Cancer-Testis antigens (CT). They are capable of induce humoral and cellular immune responses in cancer patients and because of this immunogenicity and their restrict expression in normal tissues, they are considered an ideal candidate for vaccine development against cancer. Among CT antigens, NY-ESO-1 is the best characterized in terms of expression patterns and immunogenicity. It is expressed in 20-40% of all melanomas, more in metastatic lesions than in primary ones, and it is very heterogeneous inter and intratumoral. Breslow index is associate with NY-ESO-1 expression in primary cutaneous melanomas, but its relation to patient survival remains controversial.


Isolation, characterization, and molecular cloning of a protein (Abp2) that binds to a Schizosaccharomyces pombe origin of replication (ars3002).
The autonomously replicating sequence (ARS) element ars3002 is associated with the most active replication origin within a cluster of three closely spaced origins on chromosome III of Schizosaccharomyces pombe. A 361-bp portion of ars3002 containing detectable ARS activity includes multiple near matches to the S. pombe ARS consensus sequence previously reported by Maundrell et al. (K. Maundrell, A. Hutchison, and S. Shall, EMBO J. 7:2203-2209, 1988). Using a gel shift assay with a multimer of an oligonucleotide containing three overlapping matches to the Maundrell ARS consensus sequence, we have detected several proteins in S. pombe crude extracts that bind to the oligonucleotide and ars3002. One of these proteins, ARS binding protein 1, was previously described (Abpl [Y. Murakami, J. A. Huberman, and J. Hurwitz, Proc. Natl. Acad. Sci. USA 93:502-507, 1996]). In this report the isolation, characterization, and cloning of a second binding activity, designated ARS binding protein 2 (Abp2), are described. Purified Abp2 has an apparent molecular mass of 75 kDa. Footprinting analyses revealed that it binds preferentially to overlapping near matches to the Maundrell ARS consensus sequence. The gene abp2 was isolated, sequenced, and overexpressed in Escherichia coli. The DNA binding activity of overexpressed Abp2 was similar to that of native Abp2. The deduced amino acid sequence contains a region similar to a proline-rich motif (GRP) present in several proteins that bind A+T-rich DNA sequences. Replacement of amino acids within this motif with alanine either abolished or markedly reduced the DNA binding activity of the mutated Abp2 protein, indicating that this motif is essential for the DNA binding activity of Abp2. Disruption of the abp2 gene showed that the gene is not essential for cell viability. However, at elevated temperatures the null mutant was less viable than the wild type and exhibited changes in nuclear morphology. The null mutant entered mitosis with delayed kinetics when DNA replication was blocked with hydroxyurea, and advancement through mitosis led to the loss of cell viability and aberrant formation of septa. The null mutant was also sensitive to UV radiation, suggesting that Abp2 may play a role in regulating the cell cycle response to stress signals.


Applications of natural language processing at emergency department triage: A narrative review.
Natural language processing (NLP) uses various computational methods to analyse and understand human language, and has been applied to data acquired at Emergency Department (ED) triage to predict various outcomes. The objective of this scoping review is to evaluate how NLP has been applied to data acquired at ED triage, assess if NLP based models outperform humans or current risk stratification techniques when predicting outcomes, and assess if incorporating free-text improve predictive performance of models when compared to predictive models that use only structured data. All English language peer-reviewed research that applied an NLP technique to free-text obtained at ED triage was eligible for inclusion. We excluded studies focusing solely on disease surveillance, and studies that used information obtained after triage. We searched the electronic databases MEDLINE, Embase, Cochrane Database of Systematic Reviews, Web of Science, and Scopus for medical subject headings and text keywords related to NLP and triage. Databases were last searched on 01/01/2022. Risk of bias in studies was assessed using the Prediction model Risk of Bias Assessment Tool (PROBAST). Due to the high level of heterogeneity between studies and high risk of bias, a metanalysis was not conducted. Instead, a narrative synthesis is provided. In total, 3730 studies were screened, and 20 studies were included. The population size varied greatly between studies ranging from 1.8 million patients to 598 triage notes. The most common outcomes assessed were prediction of triage score, prediction of admission, and prediction of critical illness. NLP models achieved high accuracy in predicting need for admission, triage score, critical illness, and mapping free-text chief complaints to structured fields. Incorporating both structured data and free-text data improved results when compared to models that used only structured data. However, the majority of studies (80%) were assessed to have a high risk of bias, and only one study reported the deployment of an NLP model into clinical practice. Unstructured free-text triage notes have been used by NLP models to predict clinically relevant outcomes. However, the majority of studies have a high risk of bias, most research is retrospective, and there are few examples of implementation into clinical practice. Future work is needed to prospectively assess if applying NLP to data acquired at ED triage improves ED outcomes when compared to usual clinical practice.


From Hip Screening to Hip Surveillance: Transforming Care for Patients With Cerebral Palsy: An Analysis of a Single Institution.
Surveillance programs aimed at monitoring hip displacement in patients with cerebral palsy have been demonstrated to decrease the incidence of hip dislocations and properly time surgical intervention, ultimately improving patient outcomes. The objective of this study was to determine whether the implementation of a hip screening to surveillance program at a tertiary academic teaching hospital in 2017 increased the frequency of radiographic evaluations and changed the timing of surgical intervention. A total of 592 patients with cerebral palsy were identified, and 468 of these patients had initial radiograph date data available. In this analysis, 246 patients with initial radiograph dates after 2012 were included. The study population was divided into two groups based on the initial radiograph date, 2012 to 2016 versus 2017 to 2022. One hundred sixty patients (65%) were in the 2012 to 2016 group, and 86 (35%) were in the 2017 to 2022 group. Statistical analysis was conducted using various techniques, such as two-sample Student t-test, Mann-Whitney U test, chi square/Fisher exact test, and multivariable linear regression analysis. The average number of radiographs per year in the 2017 to 2022 group was 0.11 (95% CI: 0.02, 0.20, P = 0.017) higher than the 2012 to 2016 group. After adjusting for confounders using multivariable linear regression analysis, this difference was even larger (difference 0.16, 95% CI: 0.06, 0.25, P = 0.001). The surgical intervention rate was significantly lower in the 2017 to 2022 group compared with the 2012 to 2016 group (12.9% versus 40.6%, P < 0.001). The results of this study suggest that the implementation of a hip screening to surveillance program results in more frequent radiographic evaluations and possibly a reduced need for surgical intervention from 2017 to 2022. In the 2012 to 2016 group, more surgical interventions were performed likely because of the lack of any hip surveillance or screening program in place.


Disinfection of the skin with detergent preparations of Irgasan DP 300 and other antiseptics.
An evaluation of the relative effectiveness of 2% hexachlorophane and 0.75% Irgasan DP 300 bar soaps in disinfection of the hands showed that the former caused a significantly larger reduction in natural skin bacteria than the latter after one handwash and after six handwashings, three on each of two successive days. Repeated use of Irgasan DP 300 bar soap caused a significantly greater reduction in skin flora than repeated handwashings with unmedicated bar soap, but a single handwash gave no significant reduction in skin flora compared with a single use of the unmedicated soap.In a comparison of a 4% chlorhexidine detergent solution a 3% hexachlorophane detergent cream and a 2% Irgasan DP 300 detergent solution the 4% chlorhexidine detergent gave the largest mean reduction in skin bacteria after one handwash and after six handwashings and 2% Irgasan DP 300 a poor and erratic reduction after a single handwash. After six handwashings all three preparations gave large reductions in skin bacteria. The 2% Irgasan preparation showed some residual activity on the skin after handwashing though less than that with chlorhexidine and with hexachlorophane-chlorocresol detergent preparations.


The 30-kDa and 38-kDa antigens from Mycobacterium tuberculosis induce partial maturation of human dendritic cells shifting CD4(+) T cell responses towards IL-4 production.
Mycobacterium tuberculosis (Mtb) infections are still a major cause of death among all infectious diseases. Although 99% of individuals infected with Mtb develop a CD4(+) Th1 and CD8(+) T cell mediated immunity as measured by tuberculin skin test, this results only in partial protection and Mtb vaccines are not effective. Deviation of immune responses by pathogens towards a Th2 profile is a common mechanism of immune evasion, typically leading to the persistence of the microbes. Here we tested the stimulatory capacity of selective Mtb antigens on human monocyte-derived dendritic cell (DC) maturation and cytokine production. DC maturation markers CD80, CD86 and CD83 were readily upregulated by H37Ra- and H37Rv-associated antigens, the 30-kDa (from Ag85 B complex) and 38-KDa Mtb antigens only partially induced these markers. All Mtb antigens induced variable levels of IL-6 and low levels of IL-10, there was no release of IL-12p70 detectable. Substantial IL-12p40 production was restricted to LPS or H37Ra and H37Rv preparations. Although the proliferation levels of primary T cell responses were comparable using all the differentially stimulated DC, the 30-kDa and 38-kDa antigens showed a bias towards IL-4 secretion of polarized CD4(+) T cells after secondary stimulation as compared to H37Ra and H37Rv preparations. Together our data indicate that 30-kDa and 38-kDa Mtb antigens induced only partial DC maturation shifting immune responses towards a Th2 profile.


Molecular and statistical approaches to the delimitation of Eimeriidae species: a case of extreme polymorphism in eimerian oocysts from the plumbeous pigeon Patagioenas plumbea (Vieillot, 1818) (Columbiformes) in South America.
The current work aimed to analyze, morphologically, statistically, and molecularly, oocysts shed from plumbeous pigeons, Patagioenas plumbea (Vieillot, 1818), from a locality at 2197 m of altitude near the Agulhas Negras peak, the highest point of the State of Rio de Janeiro, southeastern Brazil. The oocysts were extremely polymorphic, being subspheroidal, ovoidal, or ellipsoidal, in addition to having the random presence/absence of characteristic features associated with the oocyst wall, such as micropyle, micropyle cap, lateral micropyle, and outer veil/rough wall. Linear regression confirmed the extreme polymorphism of oocysts, showing that if all combinations of taxonomic characters in oocysts (morphotypes) were overestimated, 19 different species could be identified/described. In contrast, the means comparison analysis between oocysts with the presence/absence of characteristic features and the histograms showed equivalences and regularity in the distribution in the classes of measures, which indicate the presence of a single species in the measured oocysts. Molecular analyses were performed from the isolation of individual oocysts of different morphotypes, which had their genetic material extracted, amplified, and sequenced in 4 non-overlapping loci in the cox1 and cox3 genes and fragments of the small and large subunit rDNA of mitochondrial DNA. The sequences were 100% identical between the morphotypes, with the exception of a very small divergence observed at the locus that partially covers the cox3 gene. The phylogenetic analysis was inconclusive for the locus within the cox1 gene traditionally used for eimeriid coccidians; however, the other loci should have a promising future for phylogenetic studies when more sequences for the same genic regions are deposited in GenBank. Finally, the multifactorial analysis of the current work supported that the polymorphic oocysts shed from P. plumbea are a single species, which was named Eimeria patagioenasae, making this the twenty-second eimerian description from Columbiformes.


A mixed-approach to investigate what motivates Belgian students to study medicine.
This article was migrated. The article was marked as recommended. Aims - Our main objective was to explore the motivations that led our third year Belgian students to study medicine. Method - We used a mixed method as we collected both quantitative and qualitative measures at the same time through online surveys. Chi-Square tests were used to examine differences in motivation between gender of the participants. A thematic content analysis was then conducted on the open-ended question using a qualitative approach. Results and conclusions - The final sample consists of 243 third-year students (87 men and 156 women). Chi-square analyses revealed gender differences in motivations to study medicine. The motivation most often reported by our students in both qualitative and quantitative analyses is "altruistic motivation". The qualitative analysis identified, within this category, sometimes unrealistic beliefs about the practice of medicine, leading to the conclusion that it is necessary to put medical students in contact with the reality of the field as soon as possible. Furthermore, the lack of focus on the relationship with the patient within the formal curriculum and subsequent medical practice could be the cause of a form of disillusionment among these students. We believe that more lessons on relational aspects should be offered to them. Perspectives - Finally, in addition to identifying and classifying the motivations present among medical students, we believe that some perspectives are the analysis of the interactions between these motivations in 1) the determination of the choice of study and 2) the attitudes and behaviours that will result from it.


Plasma protein regulation by thyroid hormone.
Thyroid hormones (THs) regulate growth, development, differentiation and metabolic processes by interacting and activating thyroid hormone receptors (TRs). Although much progress has been made in our understanding of the transcriptional regulation of many TR target genes, little is known of the regulation of plasma protein gene expression by TRs. To investigate the role of TRs in plasma protein expression we used human hepatocellular carcinoma cell lines and carried out cDNA microarray analysis. Our results indicate that several plasma proteins including transferrin, prothrombin, angiotensinogen, haptoglobin, alpha-2-HS-glycoprotein alpha and beta chain, complement, lipoproteins and fibrinogen are up-regulated by THs. Furthermore, clusterin, alpha-2-macroglobulin precursor, prothymosin alpha and alpha-fetoprotein were found to be down-regulated by THs.Transferrin, an iron-binding protein expressed in all mammals, and mainly synthesized in the liver, was investigated further. Immunoblot and Northern blot analyses revealed that exposure of HepG2-TRalpha1 sub-lines and HepG2-Neo cells to tri-iodothyronine (T(3)) induced time- and dose-dependent increases in the abundance of transferrin mRNA and protein, with the extent of these effects correlating with the level of expression of TRalpha1. Nuclear run-on experiments indicate that this induction is functioning at the transcriptional level. Moreover, cyclohexamide treatment did not eliminate the induction of transferrin by TH. Thus, our results suggest that the induction of transferrin by TH is direct and may in fact be mediated by an as yet unidentified response element in the promoter region.


Morphological and mechanical characterization of bone phenotypes in the Amish G610C murine model of osteogenesis imperfecta.
Osteogenesis imperfecta (OI) is a hereditary bone disease where gene mutations affect Type I collagen formation resulting in osteopenia and increased fracture risk. There are several established mouse models of OI, but some are severe and result in spontaneous fractures or early animal death. The Amish Col1a2G610C/+ (G610C) mouse model is a newer, moderate OI model that is currently being used in a variety of intervention studies, with differing background strains, sexes, ages, and bone endpoints. This study is a comprehensive mechanical and architectural characterization of bone in G610C mice bred on a C57BL/6 inbred strain and will provide a baseline for future treatment studies. Male and female wild-type (WT) and G610C mice were euthanized at 10 and 16 weeks (n = 13-16). Harvested tibiae, femora, and L4 vertebrae were scanned via micro-computed tomography and analyzed for cortical and trabecular architectural properties. Femora and tibiae were then mechanically tested to failure. G610C mice had less bone but more highly mineralized cortical and trabecular tissue than their sex- and age-matched WT counterparts, with cortical cross-sectional area, thickness, and mineral density, and trabecular bone volume, mineral density, spacing, and number all differing significantly as a function of genotype (2 Way ANOVA with main effects of sex and genotype at each age). In addition, mechanical yield force, ultimate force, displacement, strain, and toughness were all significantly lower in G610C vs. WT, highlighting a brittle phenotype. This characterization demonstrates that despite being a moderate OI model, the Amish G610C mouse model maintains a distinctly brittle phenotype and is well-suited for use in future intervention studies.


Separating habitat invasibility by alien plants from the actual level of invasion.
Habitats vary considerably in the level of invasion (number or proportion of alien plant species they contain), which depends on local habitat properties, propagule pressure, and climate. To determine the invasibility (susceptibility to invasions) of different habitats, it is necessary to factor out the effects of any confounding variables such as propagule pressure and climate on the level of invasion. We used 20 468 vegetation plots from 32 habitats in the Czech Republic to compare the invasibility of different habitats. Using regression trees, the proportion of alien plants, including archaeophytes (prehistoric to medieval invaders) and neophytes (recent invaders), was related to variables representing habitat properties, propagule pressure, and climate. The propagule pressure was expressed as the proportion of surrounding urban and industrial or agricultural land, human population density, distance from a river, and history of human colonization in the region. Urban and industrial land use had a positive effect on the proportion of both archaeophytes and neophytes. Agricultural land use, higher population density, and longer history of human impact positively affected the proportion of archaeophytes. Disturbed human-made habitats with herbaceous vegetation were most invaded by both groups of aliens. Neophytes were also relatively common in disturbed woody vegetation, such as broad-leaved plantations, forest clearings, and riverine scrub. These habitats also had the highest proportion of aliens after removing the effect of propagule pressure and climate, indicating that they are not only the most invaded, but also most invasible. These habitats experience recurrent disturbances and are rich, at least temporarily, in available nutrients, which supports the hypothesis that fluctuating resources are the major cause of habitat invasibility. The least invaded habitats were mires and alpine-subalpine grasslands and scrub. After removing the effect of propagule pressure and climate, some habitats actually invaded at an intermediate level had very low proportions of aliens. This indicates that these habitats (e.g., dry, wet, and saline grasslands, base-rich fens, and broad-leaved deciduous woodlands) are resistant to invasion.


Dearomatization of [2.2]Paracyclophane-Derived N-Sulfonylimines through Cyclopropanation with Sulfur Ylides.
An unprecedented dearomatization of [2.2]paracyclophane-derived cyclic N-sulfonylimines was conducted through cyclopropanation with sulfur ylides, giving a series of dearomative cyclopropanes with good yields. DFT calculations suggested that the dearomatization was attributed to the relatively weak aromaticity of [2.2]paracyclophane derivatives that resulted from the effect of the unique [2.2]paracyclophane skeleton and the electron-withdrawing N-sulfonyl group. Some downstream elaborations of the products were demonstrated.


Brain Tumor Segmentation Using Convolutional Neural Networks in MRI Images.
Among brain tumors, gliomas are the most common and aggressive, leading to a very short life expectancy in their highest grade. Thus, treatment planning is a key stage to improve the quality of life of oncological patients. Magnetic resonance imaging (MRI) is a widely used imaging technique to assess these tumors, but the large amount of data produced by MRI prevents manual segmentation in a reasonable time, limiting the use of precise quantitative measurements in the clinical practice. So, automatic and reliable segmentation methods are required; however, the large spatial and structural variability among brain tumors make automatic segmentation a challenging problem. In this paper, we propose an automatic segmentation method based on Convolutional Neural Networks (CNN), exploring small 3 ×3 kernels. The use of small kernels allows designing a deeper architecture, besides having a positive effect against overfitting, given the fewer number of weights in the network. We also investigated the use of intensity normalization as a pre-processing step, which though not common in CNN-based segmentation methods, proved together with data augmentation to be very effective for brain tumor segmentation in MRI images. Our proposal was validated in the Brain Tumor Segmentation Challenge 2013 database (BRATS 2013), obtaining simultaneously the first position for the complete, core, and enhancing regions in Dice Similarity Coefficient metric (0.88, 0.83, 0.77) for the Challenge data set. Also, it obtained the overall first position by the online evaluation platform. We also participated in the on-site BRATS 2015 Challenge using the same model, obtaining the second place, with Dice Similarity Coefficient metric of 0.78, 0.65, and 0.75 for the complete, core, and enhancing regions, respectively.


Linking Smads and transcriptional activation.
TGF-beta1 (transforming growth factor-beta1) is the prototypical member of a large family of pleiotropic cytokines that regulate diverse biological processes during development and adult tissue homoeostasis. TGF-beta signals via membrane bound serine/threonine kinase receptors which transmit their signals via the intracellular signalling molecules Smad2, Smad3 and Smad4. These Smads contain conserved MH1 and MH2 domains separated by a flexible linker domain. Smad2 and Smad3 act as kinase substrates for the receptors, and, following phosphorylation, they form complexes with Smad4 and translocate to the nucleus. These Smad complexes regulate gene expression and ultimately determine the biological response to TGF-beta. In this issue of the Biochemical Journal, Wang et al. have shown that, like Smad4, the linker domain of Smad3 contains a Smad transcriptional activation domain. This is capable of recruiting the p300 transcriptional co-activator and is required for Smad3-dependent transcriptional activation. This study raises interesting questions about the nature and regulation of Smad-regulated gene activation and elevates the status of the linker domain to rival that of the much-lauded MH1 and MH2 domains.


Implementing homo- and heterodecoupling in region-selective HSQMBC experiments.
An NMR method to enhance the sensitivity and resolution in band-selective long-range heteronuclear correlation spectra is proposed. The excellent in-phase nature of the selHSQMBC experiment allows that homonuclear and/or heteronuclear decoupling can be achieved in the detected dimension of a 2D multiple-bond correlation map, obtaining simplified cross-peaks without their characteristic fine J multiplet structure. The experimental result is a resolution improvement while the highest sensitivity is also achieved. Specifically, it is shown that the (1)H-homodecoupled band-selective (HOBS) HSQMBC experiment represents a new way to measure heteronuclear coupling constants from the simplified in-phase doublets generated along the detected dimension.


The contribution of microbially produced nanoparticles to sustainable development goals.
Nanoparticles (NPs), particles having one or more dimensions below 100 nm, are currently being synthesized through chemical and physical methods on an industrial scale. However, these methods for the synthesis of NPs do not fit with sustainable development goals. NP synthesis, through chemical and physical methods, requires high temperatures and/or pressures resulting in high energy consumption and the generation of large amounts of waste. In recent years, research into the synthesis of NPs has shifted to more green and biological methods, often using microorganisms. A biological approach has many advantages over chemical and physical methods. Reactions are catalysed in aqueous solutions at standard temperature and pressure (cost effective and low energy syntheses). This method does not require solvents or harmful chemicals, making NP biosynthesis a greener and more eco-friendly method. Furthermore, NP synthesis by microbes does not require the use of pure starting materials; thus it can simultaneously be used for the bioremediation of contaminated water, land and waste, and the biosynthesis of NPs. Therefore the biosynthesis of NPs contributes to the sustainable development goals, while the alternative physical and chemical methods exclusively utilize scarce and expensive resources for NP synthesis.


Desoximetasone--a new topical corticosteroid: short- and long-term experiences.
A new potent topical corticosteroid, desoximetasone, was clinically evaluated in several hundred patients with steroid-responsive dermatoses. Both short-term and long-term comparative studies showed desoximetasone emollient cream (0.25 percent) to be highly effective. Studies comparing betamethasone valerate cream C0. p1 percent) with desoximetasone emollient cream (0.25 percent) showed the new topical steroid to be clinically superior in the relief of moderate and severe inflammatory manifestations of psoriasis and atopic dermatitis. In addition, desoximetasone was found to be safe, well tolerated, and accepted by the patients.


Long-term outcomes of needlescopic surgery in patients with colon cancer: a retrospective cohort study.
Laparoscopic surgery is a minimally invasive and frequently performed surgical procedure that has become the standard surgery for colorectal cancer. Needlescopic surgery (NS) for colon cancer has also been performed and reported as a less invasive technique. In this study, we investigated the long-term outcomes of NS in comparison with those of conventional surgery (CS). The data of 1122 patients without distant metastasis who underwent laparoscopic surgery between 2011 and 2014 were retrospectively analyzed. In this study, NS was defined as a laparoscopic procedure performed with the use of 3-mm ports and forceps with one 5-mm port for an energy device, as well as with clips. One 12-mm port was placed in the umbilicus for specimen extraction from the abdominal cavity. A total of 241 patients underwent NS. There was no significant difference between the 5-year recurrence rate and the 5-year total mortality rate (NS: 10.0% and 5.4% vs. CS: 10.3% and 3.5%, p = 0.86/0.23). In the multivariate analysis, NS was not found to be an independent prognostic factor. In terms of the distribution of recurrence sites, there was no significant difference between the two groups. NS for colon cancer was not inferior to CS in terms of short-term and long-term outcomes.


Implementation and evaluation of a new surgical residency model.
The Accreditation Council for Graduate Medical Education (ACGME) duty-hour requirements prompted program directors to rethink the organizational structure of their residency programs. Many surgical educators have expressed concerns that duty-hour restrictions would negatively affect quality of resident education. This article summarizes evaluation research results collected to study the impact of our reengineered residency program designed to preserve important educational activities while meeting duty-hour accreditation requirements. The traditional residency structure was redesigned to include a mixture of apprenticeship, small team, and night-float models. Impact evaluation data were collected using operative case logs, standardized test scores, quality assurance data, resident perception surveys, a faculty survey, and process evaluation measures. PGY1s and PGY2s enjoyed a substantial increase in operative cases. Operative cases increased overall and no resident has failed to meet ACGME volume or distribution requirements. American Board of Surgery In-Training Examination performance improved for PGY1s and PGY2s. Patient outcomes measures, including monthly mortality and number of and charges for admissions, showed no changes. Anonymously completed rotation evaluation forms showed stable or improved resident perceptions of case load, continuity, operating room teaching, appropriate level of faculty involvement and supervision, encouragement to attend conferences, and general assessment of the learning environment. A quality-of-life survey completed by residents before and after implementation of the new program structure showed substantial improvements. Faculty surveys showed perceived increases in work hours and job dissatisfaction. New physician assistant and nurse positions directly attributed to duty-hour restrictions amounted to about 0.2 full-time equivalent per resident. Duty-hour restrictions produce new challenges and might require additional resources but need not cause a deterioration of surgical residents' educational experience.


Cation-induced speciation of port-size during mordenite zeolite synthesis.
Mordenite (MOR) zeolite, an important industrial catalyst exists in two, isostructural variants defined by their port-size, small and large-port. Here we show for the first time how a systematic, single-parameter variation influences the synthesis out-come on the final MOR material leading to distinctly different catalysts. The cation identity has a direct impact on the synthesis mechanism with potassium cations generating the more constrained, small-port MOR variant compared to the large-port obtained with sodium cations. This was expressed by different degrees of accessibility ascertained with a combination of toluene breakthrough and temperature programmed desorption (TPD), propylamine TPD, as well as sterically sensitive isobutane conversion. Rietveld refinement of the X-ray diffractograms elucidated the preferential siting of the smaller sodium cations in the constricted 8-ring, from which differences in Al distribution follow. Note, there are no organic structure directing agents utilized in this synthesis pointing at the important role of inorganic structure directing agents (ISDA).


Cytodiagnosis of bone tumors by fine needle aspiration.
A retrospective study was undertaken of bone lesions examined by preoperative fine needle aspiration (FNA) cytology in our hospital during the ten-year period from 1970 to 1979. The 430 cytologically examined lesions were classified into three groups: inflammatory lesions, tumorlike lesions and tumors. A total of 54 patients had undergone surgery, with most of the lesions in those cases proven to be tumors or tumorlike by histologic study. Correlation between the histologic and FNA cytologic findings showed complete compatibility in 76% of the cases, partial compatibility in 13% and incompatibility in 11%. It is concluded that FNA biopsy is appropriate for identifying bone tumors and tumorlike lesions if sufficient numbers of tumor cells are obtained for morphologic examination. Although aspiration cytodiagnosis can be of considerable value in the recognition of certain bone lesions, it cannot replace formal tissue biopsy in the diagnosis of primary bone neoplasms. The morphology of several common bone tumors is described in detail and their differential diagnosis is discussed.


Prevention of cerebral vasospasm in the rat by depletion or inhibition of substance P in conducting vessels.
Cisternal blood injection in the rat induces a biphasic angiographic vasospasm, with a maximal acute spasm at 10 minutes and a maximal late spasm at 2 days after the subarachnoid hemorrhage (SAH). Depletion of substance P-containing sensory nerves to the cerebral arteries with capsaicin prior to SAH prevents the development of both acute and late spasm. Intrathecal administration of the substance P antagonist spantide 2 hours prior to SAH also prevents the development of vasospasm, while spantide administration 1 hour before SAH only hinders the occurrence of late vasospasm. Intracisternal administration of spantide 2 hours post-SAH prevents the development of late vasospasm. This antagonist per se can induce a short-lasting dose-dependent angiographic vasoconstriction. Substance P-containing nerve fibers on the cerebral arteries could constitute the sensory link in a reflex arc system involved in the development of vasospasm in which the presence of blood in the subarachnoid space stimulates sensory substance P-containing nerve fibers on the cerebral arteries inducing a centripetal impulse to the A2-nucleus tractus solitarius setting into motion the events in the brain stem leading to acute and late vasospasm.


Tertiary centres have improved survival compared to other hospitals in the Copenhagen area after out-of-hospital cardiac arrest.
Out-of-hospital cardiac arrest (OHCA) has been reported to carry very varying morbidity and mortality. However, it remains unclear whether this is caused by intrinsic factors of the OHCA or due to the level of in-hospital care. The aim of this study is to compare 30-day and long-term mortality after OHCA at tertiary heart centres and non-tertiary university hospitals. Data from the Copenhagen OHCA registry from June 2002 through December 2010 included a total of 1218 consecutive patients treated by the same mobile emergency care unit (MECU) with either return of spontaneous circulation (ROSC) or on-going resuscitation (n=53) at hospital arrival. The MECU transported patients to the nearest hospital unless an ECG on scene suggested ST-segment elevation myocardial infarction, in which case patients were transported to the nearest tertiary centre for acute coronary angiography. Therefore, patients with ST-elevation myocardial infarction (n=198) were excluded from the analysis. 30-day mortality was 56% vs. 76% and long term (up to 8years) mortality was 78% vs. 94% for tertiary and non-tertiary hospitals, respectively, both p<0.001. Multivariate analysis showed that admission to a non-tertiary hospital was independently associated with increased risk of death (HR=1.32, 95% CI: 1.09-1.59, p=0.004). Exclusion of patients with on-going resuscitation at admission resulted in HR=1.34 (1.11-1.62), p=0.003. A matched pair propensity score analysis of 255 patients confirmed the results of the proportional hazard analysis (HR=1.35, 95% CI: 1.11-1.65 p=0.003). Admission to tertiary centres is associated with lower mortality rates after OHCA compared with non-tertiary hospitals.


Immunohistochemical detection of multidrug-resistant protein expression in retinoblastoma treated by primary enucleation.
To compare the expression of multidrug-resistant proteins in retinoblastoma tumors among eyes treated with primary enucleation. A group of 18 patients with unilateral retinoblastoma with advanced intraocular disease was selected for the study. All patients had undergone primary enucleation. A histologic specimen from each patient was retrieved from the pathology archives and a tissue gene microarray was constructed (0.6 x 3-4 mm). Standard immunohistochemical techniques were used to study the tissue microarrays for the expression of the ATP-binding cassette (ABC) transporters: breast cancer resistance protein (BCRP; ABCG2), multidrug-resistant protein 1/P-glycoprotein (MDR1/Pgp; ABCB1), multidrug-resistant-associated protein 1 (MRP1; ABCC1), MRP2 (ABCC2), and MRP4 (ABCC4). Of the 18 specimens retrieved, 16 had adequate tissue for study. MRP1 was expressed in 8 (50%) of 16 tumors, and MRP2 was expressed in 5 (31%) of 16 tumors. MDR1/Pgp was found in 2 (12%) of 16 retinoblastomas. MRP4 and BCRP were not detected in any of the tumors studied. The results show that multiple ABC transporters were present in a cohort of sporadic patients with unilateral retinoblastoma who underwent primary enucleation. Studies are planned of the expression of ABC transporters in eyes treated by chemotherapy and/or radiation as a comparison with this group.


MarRA, SoxSR, and Rob encode a signal dependent regulatory network in Escherichia coli.
When exposed to low concentrations of toxic chemicals, bacteria modulate the expression of a number of cellular processes. Typically, these processes include those related to porin production, dismutases, and metabolic fluxes. In Escherichia coli (E. coli), the expression of these systems is largely controlled by three homologous transcriptional regulators: MarA, SoxS, and Rob. Each of the three regulators responds to distinct chemical signals (salicylate for MarA; paraquat for SoxS; and bipyridyl for Rob) and controls the expression of an overlapping set of downstream targets. In addition, the three systems autoregulate their own expression, and cross-regulate each other's expression. Specifically, MarA is known to activate SoxS expression, and Rob is known to activate MarA expression. In addition, a number of conflicting regulatory interactions are known to exist between the three loci. Thus, the three systems encode a complex regulatory topology with multiple feedback loops, the precise nature of whose interactions or their significance in cellular physiology is not well understood currently. In this work, we focus on understanding the details of this crosstalk between the Mar-Sox-Rob systems in E. coli, and the resulting control and dynamics of the expression of cellular processes by studying gene expression at the population level and at single-cell resolution in wild type and mutants. Our results indicate that the regulatory architecture between MarA, SoxS, and Rob is dependent on the signal (inducer) present in the environment. The regulators, in response to an inducer, form a Feed Forward Loop (FFL), which leads to faster and stronger induction of target genes in the cell, consequently resulting in better cellular growth. Through the FFL, the cell is able to integrate qualitatively different signals in the network, and consequently, control cellular physiology. In addition, we present two intriguing dynamic features of the Mar-Sox-Rob regulon. First, in the presence of salicylate, the activation of target genes via MarA and Rob, at single-cell resolution, is qualitatively different. Second, we report the synergistic activation of target and Mar/Sox systems in the presence of both salicylate and paraquat. These results strongly indicate that there exists a complex control of gene regulation in the Mar-Sox-Rob regulon. Mechanistic details of this control are likely quite complex, and may involve additional regulators.


Fixation of nitrous oxide by mesoionic and carbanionic N-heterocyclic carbenes.
A ditopic carbanionic N-heterocyclic carbene was found to react with the inert gas nitrous oxide, resulting in a stable covalent adduct with two intact N2O groups attached to the heterocycle. Mesoionic N-heterocyclic carbenes derived from C2-arylated 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene are also able to form adducts with one or two N2O groups. Crystallographic analyses of all adducts reveal bent N2O groups, which can adopt a cis or trans configuration.


Complete nucleotide sequence of the gene for human heparin cofactor II and mapping to chromosomal band 22q11.
Heparin cofactor II (HCII) is a 66-kDa plasma glycoprotein that inhibits thrombin rapidly in the presence of dermatan sulfate or heparin. Clones comprising the entire HCII gene were isolated from a human leukocyte genomic library in EMBL-3 lambda phage. The sequence of the gene was determined on both strands of DNA (15,849 bp) and included 1749 bp of 5'-flanking sequence, five exons, four introns, and 476 bp of DNA 3' to the polyadenylation site. Ten complete and one partial Alu repeats were identified in the introns and 5'-flanking region. The HCII gene was regionally mapped on chromosome 22 using rodent-human somatic cell hybrids, carrying only parts of human chromosome 22, and the chronic myelogenous leukemia cell line K562. With the cDNA probe HCII7.2, containing the entire coding region of the gene, the HCII gene was shown to be amplified 10-20-fold in K562 cells by Southern analysis and in situ hybridization. From these data, we concluded that the HCII gene is localized on the chromosomal band 22q11 proximal to the breakpoint cluster region (BCR). Analysis by pulsed-field gel electrophoresis indicated that the amplified HCII gene in K562 cells maps at least 2 Mbp proximal to BCR-1. Furthermore, the HCII7.2 cDNA probe detected two frequent restriction fragment length polymorphisms with the restriction enzymes BamHI and HindIII.


Comprehensive survey of SNPs in the Affymetrix exon array using the 1000 Genomes dataset.
Microarray gene expression data has been used in genome-wide association studies to allow researchers to study gene regulation as well as other complex phenotypes including disease risks and drug response. To reach scientifically sound conclusions from these studies, however, it is necessary to get reliable summarization of gene expression intensities. Among various factors that could affect expression profiling using a microarray platform, single nucleotide polymorphisms (SNPs) in target mRNA may lead to reduced signal intensity measurements and result in spurious results. The recently released 1000 Genomes Project dataset provides an opportunity to evaluate the distribution of both known and novel SNPs in the International HapMap Project lymphoblastoid cell lines (LCLs). We mapped the 1000 Genomes Project genotypic data to the Affymetrix GeneChip Human Exon 1.0ST array (exon array), which had been used in our previous studies and for which gene expression data had been made publicly available. We also evaluated the potential impact of these SNPs on the differentially spliced probesets we had identified previously. Though the 1000 Genomes Project data allowed a comprehensive survey of the SNPs in this particular array, the same approach can certainly be applied to other microarray platforms. Furthermore, we present a detailed catalogue of SNP-containing probesets (exon-level) and transcript clusters (gene-level), which can be considered in evaluating findings using the exon array as well as benefit the design of follow-up experiments and data re-analysis.


Structural studies of chromosomally encoded outer surface lipoprotein BB0158 from Borrelia burgdorferi sensu stricto.
Lyme disease, or also known as Lyme borreliosis, is caused by the spirochetes belonging to the Borrelia burgdorferi sensu lato complex, which can enter the human body following the bite of an infected tick. Many membrane lipid-bound proteins, also known as lipoproteins, are located on the surface of B. burgdorferi sensu lato and play a crucial role in the spirochete to interact with its environment, whether in ticks or mammals. Since the spirochete needs to perform various tasks, such as resisting the host's immune system or spreading throughout the organism, it is not surprising that numerous surface proteins have been found to be essential for B. burgdorferi sensu lato complex bacteria in causing Lyme disease. In this study, we have determined (at 2.4 Å resolution) and characterized the 3D structure of BB0158, one of the few chromosomally encoded outer surface proteins from B. burgdorferi sensu stricto. BB0158 belongs to the paralogous gene family 44 (PFam44), consisting of four other members (BB0159, BBA04, BBE09 and BBK52). The characterization of BB0158, which appears to form a domain-swapped dimer, in conjunction with the characterization of the corresponding PFam44 members, certainly contribute to our understanding of B. burgdorferi sensu stricto proteins.


Water Fraction Dependence of the Aggregation Behavior of Hydrophobic Fluorescent Solutes in Water-Tetrahydrofuran.
This work investigates the water fraction dependence of the aggregation behavior of hydrophobic solutes in water-tetrahydrofuran (THF) and the elucidation of the role of THF using fluorescence microscopy, dynamic light scattering, neutron and X-ray scattering, and photoluminescence measurements. On the basis of the obtained results, the following model is proposed: hydrophobic molecules are molecularly dispersed in the low-water-content region (10-20 vol %), while they form mesoscopic particles upon increasing the water fraction to ∼30 vol %. This abrupt change is due to the composition fluctuation of the water-THF binary system to form hydrophobic areas in THF, followed by THF-rich droplets where hydrophobic solutes are incorporated and form loose aggregates. Further increasing the water content prompts the desolvation of THF, which decreases the particle size and generates tight aggregates of solute molecules. This model is consistent with the luminescence behavior of the solutes and will be helpful to control the aggregation state of hydrophobic solutes in various applications.


Belantamab Mafodotin to Treat Multiple Myeloma: A Comprehensive Review of Disease, Drug Efficacy and Side Effects.
Multiple myeloma (MM) is a hematologic malignancy characterized by excessive clonal proliferation of plasma cells. The treatment of multiple myeloma presents a variety of unique challenges due to the complex molecular pathophysiology and incurable status of the disease at this time. Given that MM is the second most common blood cancer with a characteristic and unavoidable relapse/refractory state during the course of the disease, the development of new therapeutic modalities is crucial. Belantamab mafodotin (belamaf, GSK2857916) is a first-in-class therapeutic, indicated for patients who have previously attempted four other treatments, including an anti-CD38 monoclonal antibody, a proteosome inhibitor, and an immunomodulatory agent. In November 2017, the FDA designated belamaf as a breakthrough therapy for heavily pretreated patients with relapsed/refractory multiple myeloma. In August 2020, the FDA granted accelerated approval as a monotherapy for relapsed or treatment-refractory multiple myeloma. The drug was also approved in the EU for this indication in late August 2020. Of note, belamaf is associated with the following adverse events: decreased platelets, corneal disease, decreased or blurred vision, anemia, infusion-related reactions, pyrexia, and fetal risk, among others. Further studies are necessary to evaluate efficacy in comparison to other standard treatment modalities and as future drugs in this class are developed.


Elimination of deleterious mutations in plastid genomes by gene conversion.
Asexual reproduction is believed to be detrimental, mainly because of the accumulation of deleterious mutations over time, a hypothesis known as Muller's ratchet. In seed plants, most asexually reproducing genetic systems are polyploid, with apomictic species (plants forming seeds without fertilization) as well as plastids and mitochondria providing prominent examples. Whether or not polyploidy helps asexual genetic systems to escape Muller's ratchet is unknown. Gene conversion, particularly when slightly biased, represents a potential mechanism that could allow asexual genetic systems to reduce their mutation load in a genome copy number-dependent manner. However, direct experimental evidence for the operation of gene conversion between genome molecules to correct mutations is largely lacking. Here we describe an experimental system based on transgenic tobacco chloroplasts that allows us to analyze gene conversion events in higher plant plastid genomes. We provide evidence for gene conversion acting as a highly efficient mechanism by which the polyploid plastid genetic system can correct deleterious mutations and make one good genome out of two bad ones. Our finding that gene conversion can be biased may provide a molecular link between asexual reproduction, high genome copy numbers and low mutation rates.


Ethics in public health: call for shared moral public health literacy.
Public Health (PH) in Europe has become much more vocal about its moral understandings since 1992. The rising awareness that PH issues were inseparable from issues of human rights and social justice almost self-evidently directed the agenda of EUPHA and the European Public Health (EPH)-conferences. Problems of cultural and behavioural change, and environmental issues on a global scale were also added. The Section Ethics in PH invited the EPH community to join in 'arm chair thinking': coming together at conferences not only to share the 'how' and 'what' of PH research, practices and policies but also the 'why'. Time has been reserved to genuinely discuss what moral values are at stake in the work of PH and to actively develop a moral language and framework for PH Ethics. The challenge for the next decades is to find ways to involve the general public in the cultivation of a shared moral PH literacy.


The aromatic amino acid hydroxylases.
The enzymes phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase constitute the family of pterin-dependent aromatic amino acid hydroxylases. Each enzyme catalyzes the hydroxylation of the aromatic side chain of its respective amino acid substrate using molecular oxygen and a tetrahydropterin as substrates. Recent advances have provided insights into the structures, mechanisms, and regulation of these enzymes. The eukaryotic enzymes are homotetramers comprised of homologous catalytic domains and discrete regulatory domains. The ligands to the active site iron atom as well as residues involved in substrate binding have been identified from a combination of structural studies and site-directed mutagenesis. Mechanistic studies with nonphysiological and isotopically substituted substrates have provided details of the mechanism of hydroxylation. While the complex regulatory properties of phenylalanine and tyrosine hydroxylase are still not fully understood, effects of regulation on key kinetic parameters have been identified. Phenylalanine hydroxylase is regulated by an interaction between phosphorylation and allosteric regulation by substrates. Tyrosine hydroxylase is regulated by phosphorylation and feedback inhibition by catecholamines.


Decreasing the thresholds for electroporation by sensitizing cells with local cationic anesthetics and substances that decrease the surface negative electric charge.
The recently described method of cell electroporation by flow of cell suspension through localized direct current electric fields (dcEFs) was applied to identify non-toxic substances that could sensitize cells to external electric fields. We found that local cationic anesthetics such as procaine, lidocaine and tetracaine greatly facilitated the electroporation of AT2 rat prostate carcinoma cells and human skin fibroblasts (HSF). This manifested as a 50% reduction in the strength of the electric field required to induce cell death by irreversible electroporation or to introduce fluorescent dyes such as calcein, carboxyfluorescein or Lucifer yellow into the cells. A similar decrease in the electric field thresholds for irreversible and reversible cell electroporation was observed when the cells were exposed to the electric field in the presence of the non-toxic cationic dyes 9-aminoacridine (9-AAA) or toluidine blue. Identifying non-toxic, reversibly acting cell sensitizers may facilitate cancer tissue ablation and help introduce therapeutic or diagnostic substances into the cells and tissues.


Liquid API Feeding in Pharmaceutical HME: Novel Options in Solid Dosage Manufacturing.
Hot melt extrusion (HME) is a common unit operation. It is broadly applicable in the pharmaceutical industry and can be implemented in a continuous manufacturing line. However, the conventional way of active pharmaceutical ingredient (API) feeding with a pre-blend consisting of a powdered API and a polymer does not allow the flexibility and agility to adjust the process parameters, which is generally an essential part of continuous manufacturing. In addition, this method of API feeding may result in the segregation of the individual powder components or agglomeration of highly cohesive materials, leading to an inhomogeneous API content in the extrudates, especially at low doses. In this study, the universal applicability of liquid side feeding in pharmaceutical HME was demonstrated using various APIs suspended or dissolved in water and fed as suspension or undersaturated, supersaturated, and highly concentrated solutions into anterior parts of the extruder. The extrudates were characterized in terms of their API content, residual moisture content, and solid-state of the API embedded in the polymer. The results show that a uniform API content without major deviations can be obtained via this method. Furthermore, the residual moisture content of the extrudates was low enough to have no significant influence on further processing of the final dosage form. In summary, this advanced way of feeding allows an accurate, flexible, and agile feeding of APIs, facilitating the production of personalized final dosage forms and a novel option to link the manufacturing of the drug substance and the drug product.


Interprofessional bedside rounds: Nurse-physician collaboration and perceived barriers in an Asian hospital.
Interprofessional bedside rounds by nurses and physicians provide valuable space and time for the discussion of patient care, which is essential for providing quality care. However, nurse-physician collaboration and barriers to attending these rounds are not well-examined. This study aimed to examine the collaboration of nurses and physicians and their perceived barriers to interprofessional bedside rounds. A cross-sectional survey was conducted on 371 medical ward-based nurses and physicians from an acute care tertiary hospital in Singapore, using a 27-item Nurse-Physician Collaboration Scale and a 21-item Perceived Barriers to Interprofessional Bedside Rounds questionnaire. The overall Nurse-Physician Collaboration scores indicated positive attitudes toward nurse-physician collaboration in bedside rounds, with no significant difference found between nurses and physicians. While the sharing of information was reported to be the most frequent collaborative activity, the cooperative relationship was rated to be the least frequent behavior. The highest ranked barriers were related to time-related issues. The nurses reported a significantly greater perceived barrier in attending bedside round than the physicians. To optimize nurse-physician collaboration, the study advocates healthcare leaders to foster cooperative relationships between nurses and physicians and to reorganize ward routines to provide designated time periods for nurses to attend rounds.


[The concept of the surgical treatment of ectrodactyly in children].
The author presents his view on the problem of treatment of ectrodactyly on the basis of his experience with treatment of 159 children with this complex pathology. 1211 plastic and reconstructive operations were made on these patients. Results of the treatment were followed up during 14 years. A critical analysis is given in the light of long-term results of using the methods of recovery of under-developed fingers. The succession of the elimination of the hand defects giving favorable results in most patients is considered. Attention is given to inexpedient operative treatment of certain malformations of toes not influencing the foot function.


Study of the role of the carbohydrate and protein moieties of soy soluble polysaccharides in their emulsifying properties.
The objective of this work was to investigate the role played by the protein fraction of soy soluble polysaccharide (SSPS) during its adsorption at oil/water interfaces. SSPS was separated in a high (HMF; 310 kDa) and low (LMF; 20 kDa) molecular weight fraction by gel filtration. SSPS/HMF consisted of 91.6% carbohydrate and 2.2% protein and showed better emulsifying properties than those of the whole SSPS, whereas SSPS/LMF seemed to affect negatively the adsorption behavior of SSPS. SDS-PAGE of the protein fraction obtained from SSPS/HMF showed a molecular mass of 50 kDa, was composed predominantly of proline (23.1%) and glutamic acid (15.2%), and still contained 8.8% of neutral sugar and 5.3% of uronic acid. Results indicated that not all of the protein material present in SSPS contributes to SSPS functionality but that only the material associated with HMF aids in the adsorption of SSPS onto oil/water interfaces.


Cost-effectiveness of tolvaptan for euvolemic or hypervolemic hyponatremia.
Tolvaptan is clinically effective in increasing serum sodium concentrations for patients with euvolemic or hypervolemic hyponatremia. Appropriate treatment of hyponatremia may reduce the risk of death, hospital resource utilization, and economic burden. The aim of this study was to estimate the cost-effectiveness of tolvaptan treatment in patients who need to be hospitalized for treatment and monitoring of euvolemic or hypervolemic hyponatremia. A decision-analytic model was constructed to assess the clinical and economic impact of tolvaptan compared with placebo during a 1-month treatment period. The probabilities, utility weights, resource utilization, and costs in the model were derived from clinical trials, survey research, and the Korean National Health Insurance database. Cost analysis was performed from the perspective of the South Korean health care setting in 2012 Korean won (KRW). The model outcome was the incremental cost per quality-adjusted life-year gained. In addition, subgroup analysis was performed to identify the cost-effectiveness in case of tolvaptan treatment only for patients with marked hyponatremia. Deterministic and probabilistic sensitivity analyses were performed on key model parameters and assumptions. The total cost per patient was KRW 1,826,771 for tolvaptan treatment and KRW 2,281,926 for placebo. The quality-adjusted life-years for treatment with and without tolvaptan were 0.0481 and 0.0446, respectively. The base-case analysis revealed that tolvaptan was a more effective and less expensive strategy compared with placebo. In the subgroup analysis, this trend was more apparent in case of tolvaptan treatment only for patients with marked hyponatremia. The robustness of the results was confirmed by using deterministic and probabilistic sensitivity analyses. This cost-effectiveness analysis found that the use of tolvaptan was less expensive and more effective than treatment without tolvaptan in patients with euvolemic or hypervolemic hyponatremia.


[Effect of a malic acid load on the blood and urine content in animals of the products of a malate dehydrogenase reaction and the correlation of reduced and oxidized forms of ascorbic acid].
Addition of 150 mg of malic acid per a day to food of rabbits caused an increase in content of reduced ascorbic acid and pyruvic acid in blood; at the same time the content of oxydized forms of ascorbic acid was decreased. Similar alterations were observed in urine of guinea-pigs, which received 100 mg of malic acid per a day. The data obtained suggest that under these conditions the increased reduction, of ascorbic acid was due to increased formation of NADP with H2 in the course of reaction, catalyzed by malate dehydrogenase.