Radiofrequency ablation planning beyond simulation.
It is a challenging task to plan a radiofrequency (RF) ablation therapy to achieve the best outcome of the treatment and avoid recurrences at the same time. A patient specific simulation in advance that takes the cooling effect of blood vessels into account is a helpful tool for radiologists, but this needs a very high accuracy and thus high computational costs. In this work, we present various methods, which improve and extend the planning of an RF ablation procedure. First, we discuss two extensions of the simulation model to obtain a higher accuracy, including the vaporization of the water in the tissue and identifying the model parameters and to analyze their uncertainty. Furthermore, we discuss an extension of the planning procedure namely the optimization of the probe placement, which optimizes the overlap of the tumor area with the estimated coagulation in order to avoid recurrences. Since the optimization is constrained by the model, we have to take into account the uncertainties in the model parameters for the optimization as well. Finally, applications of our methods to a real RF ablation case are presented.


Influence of tea consumption on acute myocardial infarction in China population: the INTERHEART China study.
We assessed the association between tea consumption and acute myocardial infarction (AMI) using INTERHEART China data. Cases (n = 2909) and controls (n = 2947) were randomly selected and frequency matched by age and sex. Participants who drank tea ≥4 cups/d had a significantly higher risk of AMI than tea nondrinkers; odds ratio (OR) was 1.29 (95% confidence interval [CI]: 1.03-1.61) compared with tea nondrinkers. A similar trend was found in green tea drinkers; OR was 1.52 (95% CI: 1.13-2.05) in the participants who drank 3 cups/d and 1.73 (95% CI: 1.35-2.22) in the participants who drank ≥4 cups/d compared with tea nondrinkers. We also found that green tea consumption had a greater effect on females; OR was 2.80 (95% CI: 1.43-5.50) in females. In conclusion, we found that the risk of AMI increases as tea consumption increases. Further studies are needed to confirm this association.


Clinical evaluation of the efficacy and safety of noberastine, a new H1 antagonist, in seasonal allergic rhinitis: a placebo-controlled, dose-response study.
Noberastine (NOB), a new histamine H1 antagonist, has potent and specific peripheral antihistaminic activity. To evaluate the efficacy and safety of NOB in ragweed seasonal allergic rhinitis, 250 eligible patients were randomized to one of four parallel, double-blind treatment groups: NOB, 10, 20, and 30 mg, or placebo, each administered once daily for 3 weeks. Rescue medication was prohibited. Efficacy parameters included global response rate (percentage of responders), physician visit, patient-diary symptom scores, and onset of action. Efficacy analyses used alpha = 0.0167 (adjusted for multiple comparisons). Efficacy parameters demonstrated universal superiority of NOB therapy over placebo therapy with statistical significance achieved frequently; no statistically or clinically significant separation was demonstrated among NOB-treated groups. Global-response rates for all active-treatment groups (range, 62.7% to 71.1%) were statistically significantly greater than rates for the placebo-treated group (39.6%). Median time to first relief of symptoms was within 2 to 4 hours for NOB-treated groups versus 72 hours for the placebo-treated group. No significant abnormalities in safety parameters were ascribed to NOB treatment. Incidence and severity of adverse experiences of NOB-treated groups were comparable in incidence and severity to placebo treatment. NOB treatment did not appear to cause weight gain or sedation. Once-daily NOB, 10, 20, and 30 mg, is equally and highly effective and safe in the symptomatic management of seasonal allergic rhinitis compared to placebo.


Patient's perception of a nurse-led Trastuzumab pathway.
This paper presents the development of a pathway at a cancer unit in Northern England. The pathway aimed to ensure that patients with early breast cancer who were receiving Trastuzumab did so in a safe manner. This was achieved by developing a multiprofessional pathway, which crossed traditional boundaries to ensure the patient received the best care available. This paper describes the patient's perception of the pathway obtained through a patient satisfaction survey and suggestions for its future direction.


Sorafenib: complexities of Raf-dependent and Raf-independent signaling are now unveiled.
Hepatocellular carcinoma (HCC) is the most common primary cancer worldwide. The only current drug available for clinical treatment of HCC is sorafenib, which inhibits multiple signaling kinases including Raf family members, platelet-derived growth factor receptor, vascular endothelial growth factor receptors 1 and 2, c-Kit, and Fms-like tyrosine kinase 3. Many studies have revealed that the mechanism underlying the antitumor effect of sorafenib is complex. Because sorafenib inhibits C-Raf more potently than B-Raf, the therapeutic efficacy of sorafenib is strongly influenced by the relative expression and activity of B-Raf and C-Raf and the complex interactions between these factors. Moreover, Rafindependent signaling mechanisms have recently emerged as important pathways of sorafenib-induced cell death. Basic research studies have suggested that using sorafenib as part of a combination therapy may improve its effect, although this has yet to be confirmed by clinical evidence. Further studies of the functional mechanism of sorafenib are required to advance the development of targeted therapy for HCC. To aid future work on sorafenib, we here review the current literature pertaining to sorafenib signaling and its clinical efficacy in both monotherapy and combination therapy.


Distinct epidermal stem cell compartments are maintained by independent niche microenvironments.
The mammalian epidermis is a stratified, multilayered epithelium, consisting of the interfollicular epidermis and associated appendages, which extend into the dermis and include hair follicles, sebaceous glands, and sweat glands. Stem cells are essential for the maintenance of this tissue and are also potential sources of multipotent adult precursor cells. Stem cell populations occupying specific locations or niches have been identified in the interfollicular epidermis, the hair follicle and the sebaceous gland. Recent research has focused on how the stem cell niches provide specific sites where stem cells can reside indefinitely and undergo self-renewal or differentiation into specific cell lineages, as required for epidermal replenishment or hair follicle growth.


Harvesting phosphorus-containing moieties for their antibacterial effects.
Clinically manifested resistance of bacteria to antibiotics has emerged as a global threat to society and there is an urgent need for the development of novel classes of antibacterial agents. Recently, the use of phosphorus in antibacterial agents has been explored in quite an unprecedent manner. In this comprehensive review, we summarize the use of phosphorus-containing moieties (phosphonates, phosphonamidates, phosphonopeptides, phosphates, phosphoramidates, phosphinates, phosphine oxides, and phosphoniums) in compounds with antibacterial effect, including their use as β-lactamase inhibitors and antibacterial disinfectants. We show that phosphorus-containing moieties can serve as novel pharmacophores, bioisosteres, and prodrugs to modify pharmacodynamic and pharmacokinetic properties. We further discuss the mechanisms of action, biological activities, clinical use and highlight possible future prospects.


Impact of sleep quality on functional capacity, peripheral muscle strength and quality of life in patients with chronic obstructive pulmonary disease.
The purpose of this study was to assess the impact of quality of sleep on functional capacity, peripheral muscle strength and quality of life in patients with chronic obstructive pulmonary disease (COPD). Forty patients with COPD (61.6 ± 8.28 years) were included in this study. Subjective sleep quality (Pittsburgh sleep quality index), quality of life (Nottingham health profile), quadriceps muscle strength (QMS) and functional capacity (6-min walk test) were assessed. Poor sleep quality (Pittsburgh sleep quality index total >5) was present in 57% of the patients. Patients with a poor sleep quality had significantly lower QMS and higher exercise heart rate (p < 0.05). The Pittsburgh sleep quality index total score was associated with QMS, Nottingham health profile physical mobility and sleep scores, exercise fatigue and dyspnea (p < 0.05). Sleep quality is affected in a majority of patients with COPD. It is related with symptoms, functional capacity, peripheral muscle strength and general quality of life.


gammadelta T cells of human early pregnancy decidua: evidence for cytotoxic potency.
The immune compromise in decidua allows a semiallogeneic fetus to survive without impairing the ability of the maternal immune system to fight infections. Cytotoxic mechanisms are likely to be important in this compromise. Using RT-PCR, immunoflow cytometry and immunoelectron microscopy, the cytotoxic potential of isolated human decidual gammadelta T cells was studied. mRNA for perforin (Pf), granzymes A and B, granulysin and Fas ligand (FasL) was simultaneously expressed in decidual gammadelta T cells. Pf and FasL were not expressed on the cell surface. However, the cells constitutively synthesized Pf and stored it in cytolytic granules. Within the granules Pf mainly resided in the granule core formed by Pf-containing microvesicles. Ultrastructurally, three groups of Pf-containing granules were distinguished. They probably represent different stages of granule maturation in a process where Pf-containing microvesicles first attach to the core cortex and then are translocated across the cortex into the core. Presynthesized FasL was also stored in the core and microvesicles of the cytolytic granules. Upon degranulation by ionomycin/Ca(2+) treatment, FasL was rapidly translocated to the cell surface, demonstrating that its surface expression was not controlled by de novo biosynthesis. Thus decidual gammadelta T cells appear to perform Pf- and FasL-mediated cytotoxicity utilizing a common secretory mechanism based on cytolytic granule exocytosis. The first cytochemical visualization of lipids in the cytolytic granules is provided. These intragranular lipids probably wrap up the core and participate in packaging of the cytotoxic proteins as well as in the killing process. An ultrastructural model of a cytolytic granule is presented.


Replicating through telomeres: a means to an end.
Proper replication of the telomeric DNA at chromosome ends is critical for preserving genome integrity. Yet, telomeres present challenges for the replication machinery, such as their repetitive and heterochromatic nature and their potential to form non-Watson-Crick structures as well as the fact that they are transcribed. Numerous telomere-bound proteins are required to facilitate progression of the replication fork throughout telomeric DNA. In particular, shelterin plays crucial functions in telomere length regulation, protection of telomeres from nuclease degradation, control of DNA damage response at telomeres, and the recruitment of associated factors required for telomere DNA processing and replication. In this review we discuss the recently uncovered functions of mammalian telomere-specific and telomere-associated proteins that facilitate proper telomere replication.


[Cutaneous tuberculosis yesterday and today].
Cutaneous tuberculosis were very frequent in Europe until the middle of the 20th. Century in which their incidence decreased drastically as a consequence of the specific treatments. On the other hand, the M. bovis caused infections which were previously very common have also been disappearing due to control of milk and the livestock produced for eating purposes. Cutaneous tuberculosis have classically been divided into two groups: typical tuberculosis, with follicular structure and demonstrated bacillus by culture or inoculation and atypical tuberculosis (tuberculids), in which there are no follicular structure and the bacillus is not isolated. Its relationship with tuberculosis is principally based on the personal and/or familial background and on the strong positivity of the Mantoux reaction. The concept of tuberculide has always been under debate. Above all in the second half of the 20th. Century, most of the authors were skeptical in regards to its tuberculous etiology. However, since the 1990's, determinations of bacillary DNA in the lesions by the PCR technique has made it possible to demonstrate the M. tuberculosis in them. At present, due to the probably re-emergence of tuberculosis in general as consequence of the immunodeficiency (AIDS), of the M. tuberculosis strains resistant to treatment, and of the cases imported by immigration, some increase in the incidence of cutaneous tuberculosis can be predicted in the future, although it need be feared that this will reach the amounts of other periods. On the other hand, immunodeficiences have made the anergic forms, such as tuberculosis cutis miliaris diseminata or tuberculous gumma, which were previously rare, less rare al present.


Iontophoresis of endothelin receptor antagonists in rats and men.
The treatment of scleroderma-related digital ulcers is challenging. The oral endothelin receptor antagonist (ERA) bosentan has been approved but it may induce liver toxicity. The objective of this study was to test whether ERAs bosentan and sitaxentan could be locally delivered using iontophoresis. Cathodal and anodal iontophoresis of bosentan and sitaxentan were performed on anaesthetized rat hindquarters without and during endothelin-1 infusion. Skin blood flow was quantified using laser-Doppler imaging and cutaneous tolerability was assessed. Iontophoresis of sitaxentan (20 min, 20 or 100 µA) was subsequently performed on the forearm skin of healthy men (n = 5). In rats neither bosentan nor sitaxentan increased skin blood flux compared to NaCl. When simultaneously infusing endothelin-1, cathodal iontophoresis of sitaxentan increased skin blood flux compared to NaCl (AUC(0-20) were 44032.2 ± 12277 and 14957.5 ± 23818.8 %BL.s, respectively; P = 0.01). In humans, sitaxentan did not significantly increase skin blood flux as compared to NaCl. Iontophoresis of ERAs was well tolerated both in animals and humans. This study shows that cathodal iontophoresis of sitaxentan but not bosentan partially reverses endothelin-induced skin vasoconstriction in rats, suggesting that sitaxentan diffuses into the dermis. However, sitaxentan does not influence basal skin microvascular tone in rats or in humans.


Mobilization of peripheral blood stem cells with paclitaxel and rhG-CSF in high-risk breast cancer patients.
Preclinical studies have demonstrated the rapid and efficient mobilization of hematopoietic peripheral blood stem cells (PBSC) in a mouse model using the combination of paclitaxel with recombinant human granulocyte colony-stimulating factor (rhG-CSF). On the basis of these results, a clinical trial was initiated using rhG-CSF with paclitaxel for PBSC mobilization in high-risk breast cancer patients. The mobilized PBSC were evaluated for CD34(+) cell number, mononuclear cell content, and clonogenic potential. One-hundred and seventeen breast cancer patients received paclitaxel (300 mg/m(2)) administered as a 24-h continuous intravenous infusion. Forty-eight hours after completing paclitaxel, rhG-CSF (5 microg/kg) was initiated and continued until completion of PBSC collection. Leukapheresis was initiated once the white blood cell count reached 1.0 x 10(9)/L. Each collection was evaluated for the numbers of mononuclear cells (MNC) and CD34(+) cells. Clonogenic potential was enumerated using colony-forming units-granulocyte-macrophage (CFU-GM) and burst-forming units-erythroid (BFU-E). Patients receiving paclitaxel with rhG-CSF mobilized a large number of mononuclear cells/apheresis (mean, 3.7 x 10(8); range, 3.3-4.1) and CD34(+) cells/apheresis (mean, 7.2 x 10(6); range, 6.1-8.4). The average number of leukophereses needed was 1.8 (mean, range 1.6-2.0). Colony growth was normal with 178.9 x 10(5) and 214.8 x 10(5) colonies counted in CFU-GM and BFU-E assays, respectively. Patients engrafted platelets and neutrophils on day 10 following transplantation. In conclusion, PBSC mobilization with paclitaxel and rhG-CSF results in a large number of mononuclear cells and CD34(+) cells with normal clonogenic potential. The cells engraft normally following high-dose chemotherapy and autologous stem cell transplantation in high-risk breast cancer patients. These results demonstrate that paclitaxel with rhG-CSF is an efficient mobilizing agent in high-risk breast cancer patients.


Energy intake, nonexercise physical activity, and weight loss in responders and nonresponders: The Midwest Exercise Trial 2.
To compare energy intake, total daily energy expenditure (TDEE), nonexercise energy expenditure (NEEx), resting metabolic rate (RMR), nonexercise physical activity (NEPA), and sedentary time between participants with weight loss <5% (nonresponders) vs. ≥5% (responders) in response to exercise. Adults (18-30 years) with overweight/obesity (BMI 25-40 kg/m(2) ) were randomized to exercise: 5 days/week, 400 or 600 kcal/session, 10 months. Of the participants, 40 responded and 34 did not respond to the exercise protocol. Nonresponder energy intake was higher vs. responders, significant only in men (P=0.034). TDEE increased only in responders (P=0.001). NEEx increased in responders and decreased in nonresponders, significant only in men (P=0.045). There were no within- or between-group differences for change in RMR. NEPA increased in responders and decreased in nonresponders (group-by-time interactions: total sample, P=0.049; men, P=0.016). Sedentary time decreased in both groups, significant only in men. Men who did not lose weight in response to exercise (<5%) had higher energy intake and lower NEEx when compared with men losing ≥5%. No significant differences in any parameters assessed were observed between women who lost <5% vs. those losing ≥5%. Factors associated with the weight loss response to exercise in women warrant additional investigation.


Do clinical features allow for accurate prediction of fungal pathogenesis in bloodstream infections? Potential implications of the increasing prevalence of non-albicans candidemia.
To describe the evolving epidemiology of fungal bloodstream infections in critically ill and noncritically ill patients and to identify predictors of infection with non-albicans yeast species. Retrospective case series. Two academic, tertiary care centers. All persons during a 4-yr period who developed fungemia. None. We initially compared subjects with Candida albicans vs. alternative yeast. In a sensitivity analysis, we compared persons with potentially fluconazole-resistant organisms (Candida glabrata and Candida krusei) to those with other fungi. We also repeated these analyses in the subgroup of persons in the intensive care unit when they developed fungemia. The study cohort included 245 patients (60% in the intensive care unit), and C. albicans accounted for 52% of infections, whereas C. glabrata represented 20% of cases. The distribution of isolates was similar in both intensive care unit patients and those on the wards. In the entire population, no variable, including both previous fluconazole exposure and severity of illness, correlated with the fungemia due to a non-albicans species. In our sensitivity analysis, no factor was independently associated with a potentially fluconazole-resistant yeast. For the subgroup of subjects whose fungemia was diagnosed while they were in the intensive care unit, no variable differentiated C. albicans from non-albicans isolates. Non-albicans yeast are common both in the intensive care unit and on the wards. Simple clinical factors do not allow the clinician to effectively identify patients likely infected with non-albicans pathogens or with possible fluconazole-resistant fungi.


Regulation of PI-2b Pilus Expression in Hypervirulent Streptococcus agalactiae ST-17 BM110.
The widely spread Streptococcus agalactiae (also known as Group B Streptococcus, GBS) "hypervirulent" ST17 clone is strongly associated with neonatal meningitis. The PI-2b locus is mainly found in ST17 strains but is also present in a few non ST17 human isolates such as the ST-7 prototype strain A909. Here, we analysed the expression of the PI-2b pilus in the ST17 strain BM110 as compared to the non ST17 A909. Comparative genome analyses revealed the presence of a 43-base pair (bp) hairpin-like structure in the upstream region of PI-2b operon in all 26 ST17 genomes, which was absent in the 8 non-ST17 strains carrying the PI-2b locus. Deletion of this 43-bp sequence in strain BM110 resulted in a 3- to 5-fold increased transcription of PI-2b. Characterization of PI-2b promoter region in A909 and BM110 strains was carried out by RNAseq, primer extension, qRT-PCR and transcriptional fusions with gfp as reporter gene. Our results indicate the presence of a single promoter (Ppi2b) with a transcriptional start site (TSS) mapped 37 bases upstream of the start codon of the first PI-2b gene. The large operon of 16 genes located upstream of PI-2b codes for the group B carbohydrate (also known as antigen B), a major constituent of the bacterial cell wall. We showed that the hairpin sequence located between antigen B and PI-2b operons is a transcriptional terminator. In A909, increased expression of PI-2b probably results from read-through transcription from antigen B operon. In addition, we showed that an extended 5' promoter region is required for maximal transcription of gfp as a reporter gene in S. agalactiae from Ppi2b promoter. Gene reporter assays performed in Lactococcus lactis strain NZ9000, a related non-pathogenic Gram-positive species, revealed that GBS-specific regulatory factors are required to drive PI-2b transcription. PI-2b expression is up-regulated in the BM110ΔcovR mutant as compared to the parental BM110 strain, but this effect is probably indirect. Collectively, our results indicate that PI-2b expression is regulated in GBS ST17 strains, which may confer a selective advantage in the human host either by reducing host immune responses and/or increasing their dissemination potential.


Covid-19 lockdowns, income distribution, and food security: An analysis for South Africa.
Absent vaccines and pharmaceutical interventions, the only tool available to mitigate its demographic effects is some measure of physical distancing, to reduce contagion by breaking social and economic contacts. Policy makers must balance the positive health effects of strong distancing measures, such as lockdowns, against their economic costs, especially the burdens imposed on low income and food insecure households. The distancing measures deployed by South Africa impose large economic costs and have negative implications for the factor distribution of income. Labor with low education levels are much more strongly affected than labor with secondary or tertiary education. As a result, households with low levels of educational attainment and high dependence on labor income would experience an enormous real income shock that would clearly jeopardize the food security of these households. However, in South Africa, total incomes for low income households are significantly insulated by government transfer payments. From public health, income distribution and food security perspectives, the remarkably rapid and severe shocks imposed because of Covid-19 illustrate the value of having in place transfer policies that support vulnerable households in the event of 'black swan' type shocks.


Endoscopic ultrasound in idiopathic acute pancreatitis.
The aim of this study was to determine the utility of endoscopic ultrasound (EUS) in patients with unexplained acute pancreatitis, and whether endoscopic retrograde cholangiopancreatography (ERCP) is subsequently needed. Subjects who underwent EUS for assessment of idiopathic acute pancreatitis were identified, their medical records were reviewed, and they were contacted for a follow-up telephone interview. EUS diagnosis was compared with the final diagnosis and outcome. EUS revealed a cause of pancreatitis in 21 of the 31 subjects (68%), including microlithiasis in five (16%), chronic pancreatitis in 14 (45%), pancreas divisum in two (6.5%), pancreatic cancer in one (3.2%), and was not diagnostic in 10 (32%). During a mean follow-up period of 16 months, diagnosis changed in four subjects (13%), and nine subjects (29%) had ERCP because of persistent symptoms or recurrent pancreatitis. EUS, a less invasive test than ERCP, demonstrated an etiology in two-thirds of patients with idiopathic acute pancreatitis. Most patients did not require ERCP during the follow-up period. EUS can be an alternative to ERCP in patients with unexplained acute pancreatitis.


Correlates of osteoprotegerin levels in women and men.
Osteoprotegerin (OPG) is a potent antiresorptive molecule that binds the final effector for osteoclastogenesis, receptor activator of NF-kappaB ligand (RANK-L). OPG production is regulated by a number of cytokines and hormones, including sex steroids, but there are few data on age and gender effects on circulating serum OPG levels, as well as possible relationships between OPG levels and bone turnover markers or bone mineral density (BMD). Thus, we measured serum OPG levels in an age-stratified, random sample of men (n = 346 age range, 23-90 years) and women (n = 304; age range 21-93 years) and related them to sex steroid levels, bone turnover markers and BMD. Serum OPG levels increased with age in both men (R = 0.39, p < 0.001) and women (R = 0.18, p < 0.01). Premenopausal women had higher OPG levels than men under age 50 years (171 +/- 6 pg/ml vs 134 +/- 6 pg/ml, respectively, p < 0.001), whereas serum OPG levels were no different in postmenopausal women compared with men = 50 years (195 +/- 7 pg/ml vs 188 +/- 7 pg/ml, respectively, p = 0.179). OPG levels correlated inversely with serum bioavailable testosterone levels in men = 50 years (R = -0.27, p < 0.001), but no associations were present with either estrogen or testosterone levels in the women. In the men, there was a trend for OPG levels to be associated positively with bone resorption markers and inversely with BMD. Collectively, the gender difference in OPG levels suggests that sex steroids may regulate OPG production in vivo, as has been found in vitro. Moreover, OPG production may also rise with increases in bone turnover, probably as a homeostatic mechanism to limit bone loss. Further studies directly testing these hypotheses should provide additional insights into the potential role of OPG in bone loss related to aging and sex steroid deficiency.


Management of atrial fibrillation in seven European countries after the publication of the 2010 ESC Guidelines on atrial fibrillation: primary results of the PREvention oF thromboemolic events--European Registry in Atrial Fibrillation (PREFER in AF).
We sought to describe the management of patients with atrial fibrillation (AF) in Europe after the release of the 2010 AF Guidelines of the European Society of Cardiology. The PREFER in AF registry enrolled consecutive patients with AF from January 2012 to January 2013 in 461 centres in seven European countries. Seven thousand two hundred and forty-three evaluable patients were enrolled, aged 71.5 ± 11 years, 60.1% male, CHA2DS2VASc score 3.4 ± 1.8 (mean ± standard deviation). Thirty per cent patients had paroxysmal, 24.0% had persistent, 7.2% had long-standing persistent, and 38.8% had permanent AF. Oral anticoagulation was used in the majority of patients: 4799 patients (66.3%) received a vitamin K antagonist (VKA) as mono-therapy, 720 patients a combination of VKA and antiplatelet agents (9.9%), 442 patients (6.1%) a new oral anticoagulant drugs (NOAC). Antiplatelet agents alone were given to 808 patients (11.2%), no antithrombotic therapy to 474 patients (6.5%). Of 7034 evaluable patients, 5530 (78.6%) patients were adequately rate controlled (mean heart rate 60-100 bpm). Half of the patients (50.7%) received rhythm control therapy by electrical cardioversion (18.1%), pharmacological cardioversion (19.5%), antiarrhythmic drugs (amiodarone 24.1%, flecainide or propafenone 13.5%, sotalol 5.5%, dronedarone 4.0%), and catheter ablation (5.0%). The management of AF patients in 2012 has adapted to recent evidence and guideline recommendations. Oral anticoagulant therapy with VKA (majority) or NOACs is given to over 80% of eligible patients, including those at risk for bleeding. Rate is often adequately controlled, and rhythm control therapy is widely used.


Visceral leishmaniasis relapse hazard is linked to reduced miltefosine exposure in patients from Eastern Africa: a population pharmacokinetic/pharmacodynamic study.
Low efficacy of miltefosine in the treatment of visceral leishmaniasis was recently observed in Eastern Africa. To describe the pharmacokinetics and establish a pharmacokinetic/pharmacodynamic relationship for miltefosine in Eastern African patients with visceral leishmaniasis, using a time-to-event approach to model relapse of disease. Miltefosine plasma concentrations from 95 patients (48 monotherapy versus 47 combination therapy) were included in the population pharmacokinetic model using non-linear mixed effects modelling. Subsequently a time-to-event model was developed to model the time of clinical relapse. Various summary pharmacokinetic parameters (various AUCs, Time > EC50, Time > EC90), normalized within each treatment arm to allow simultaneous analysis, were evaluated as relapse hazard-changing covariates. A two-compartment population model with first-order absorption fitted the miltefosine pharmacokinetic data adequately. Relative bioavailability was reduced (-74%, relative standard error 4.7%) during the first week of treatment of the monotherapy arm but only the first day of the shorter combination regimen. Time to the relapse of infection could be described using a constant baseline hazard (baseline 1.8 relapses/year, relative standard error 72.7%). Miltefosine Time > EC90 improved the model significantly when added in a maximum effect function on the baseline hazard (half maximal effect with Time > EC90 6.97 days for monotherapy). Miltefosine drug exposure was found to be decreased in Eastern African patients with visceral leishmaniasis, due to a (transient) initial lower bioavailability. Relapse hazard was inversely linked to miltefosine exposure. Significantly lower miltefosine exposure was observed in children compared with adults, further urging the need for implementation of dose adaptations for children.


What Is the Significance of Variant Histology in Urothelial Carcinoma?
Urothelial carcinoma can exhibit a wide range of variant morphologies. Many variants present diagnostic challenges and carry clinical implications that inform prognosis and treatment decisions. To provide an overview of the diagnostic, therapeutic, and prognostic significance of histological variants of urothelial carcinoma. A PubMed/MEDLINE-based literature search was conducted using the key terms "urothelial carcinoma", "variant histology", "nested", "micropapillary", "microcystic", "sarcomatoid", "squamous differentiation", "glandular differentiation", "clear cell", "plasmacytoid", "lymphoepithelioma-like carcinoma", "squamous cell carcinoma", "small cell carcinoma", "adenocarcinoma", "radiotherapy", "neoadjuvant chemotherapy", and "adjuvant chemotherapy". The incidence of variant histology is increasing due to improved recognition. Nonetheless, diagnosis can pose challenges due to sampling limitations and interobserver variability. Although associated with advanced disease at presentation, survival outcomes for most variants do not differ significantly compared with pure urothelial carcinoma of the same stage. Controversy exists regarding optimal management due to the low quality of available evidence. For most cases, radical cystectomy with pelvic lymph node dissection (with neoadjuvant chemotherapy when appropriate) represents the standard of care. Small cell carcinoma and lymphoepithelioma-like carcinoma appear to be particularly chemosensitive. Accurate identification of variant histological subtypes is an important part of risk stratification, as these variants exhibit aggressive biological behaviour. Variant histology tumours are associated with advanced disease at presentation, which must be considered when counselling patients regarding survival outcomes. Optimal management remains to be defined but in most cases; neoadjuvant chemotherapy and radical cystectomy with pelvic lymph node dissection remains the mainstay of treatment. It is important to recognise histological variants of urothelial carcinoma as they indicate aggressive disease. When compared with patients with pure urothelial carcinoma of the same disease stage, survival does not appear to be significantly worse. In most cases, patients with invasive variant histology should be treated with neoadjuvant chemotherapy and radical cystectomy. Take Home Messages Accurate identification of variant histology is important as it exhibits aggressive biological behaviour and affects treatment. Although associated with advanced disease at presentation, with appropriate treatment, survival outcomes are not significantly different compared with pure urothelial carcinoma of the same stage.


The edge of reason: reporting and inference near the detection limit.
Although the general concept of a detection limit as a lower practical operating limit for an analytical method is widely understood, the precise interpretation of results near the IUPAC limit of detection is rarely as well understood or implemented. It is important to distinguish between statements about the analytical result, which is known, and inferences about the true value, which are not known. It is also crucial to understand that there are at least two quite different limits involved and that the limit most commonly referred to as the 'limit of detection' is, surprisingly, not intended as the criterion for detection of an analyte. This Technical Brief describes the principal internationally recognised approach to decision and detection limits.


Influence of Structural Porosity and Martensite Evolution on Mechanical Characteristics of Nitinol via In-Silico Finite Element Approach.
Nitinol (NiTi) alloys are gaining extensive attention due to their excellent mechanical, superelasticity, and biocompatibility properties. It is difficult to model the complex mechanical behavior of NiTi alloys due to the solid-state diffusionless phase transformations, and the differing elasticity and plasticity presenting from these two phases. In this work, an Auricchio finite element (FE) model was used to model the mechanical behavior of superelastic NiTi and was validated with experimental data from literature. A Representative Volume Element (RVE) was used to simulate the NiTi microstructure, and a microscale study was performed to understand how the evolution of martensite phase from austenite affects the response of the material upon loading. Laser Powder Bed Fusion (L-PBF) is an effective way to build complex NiTi components. Porosity being one of the major defects in Laser Powder Bed Fusion (L-PBF) processes, the model was used to correlate the macroscale effect of porosity (1.4-83.4%) with structural stiffness, dissipated energy during phase transformations, and damping properties. The results collectively summarize the effectiveness of the Auricchio model and show that this model can aid engineers to plan NiTi processing and operational parameters, for example for heat pump, medical implant, actuator, and shock absorption applications.


Monitoring of p53 autoantibodies in lung cancer during therapy: relationship to response to treatment.
Alteration of the p53 gene is the most frequent genetic alteration in human cancer, and it leads to the accumulation of mutant p53 in the nucleus of tumor cells. In addition, it has been shown that patients with various types of neoplasias have p53 antibodies in their sera. ELISA was used to detect anti-p53 antibodies in their sera of 167 patients with lung cancer. Among these, 32 individuals (16 positive for p53 antibodies and 16 negative) were monitored over a period of 30 months for p53 antibodies. Twelve of 16 antibody positive patients had reduced titers during chemotherapy that led to partial or complete remissions of disease. The specificity of these antibodies was confirmed by two different ELISA procedures and by immunoprecipitation. The very rapid, specific decrease in these antibodies during therapy suggests that a constant level of tumoral cells with nuclear accumulating p53 protein is necessary for a detectable humoral anti-p53 response. The good correlation found between the specific evolution of the p53 antibody titer and the response to therapy suggests that p53 antibodies could represent a useful tool for checking the response to therapy and for monitoring some relapses before they are clinically detectable.


Generating autologous hematopoietic cells from human-induced pluripotent stem cells through ectopic expression of transcription factors.
Hematopoietic cell transplantation (HCT) is a successful treatment modality for patients with malignant and nonmalignant disorders, usually when no other treatment option is available. The cells supporting long-term reconstitution after HCT are the hematopoietic stem cells (HSCs), which can be limited in numbers. Moreover, finding an appropriate human leukocyte antigen-matched donor can be problematic. If HSCs can be stably produced in large numbers from autologous or allogeneic cell sources, it would benefit HCT. Induced pluripotent stem cells (iPSCs) established from patients' own somatic cells can be differentiated into hematopoietic cells in vitro. This review will highlight recent methods for regulating human (h) iPSC production of HSCs and more mature blood cells. Advancements in transcription factor-mediated regulation of the developmental stages of in-vivo hematopoietic lineage commitment have begun to provide an understanding of the molecular mechanism of hematopoiesis. Such studies involve not only directed differentiation in which transcription factors, specifically expressed in hematopoietic lineage-specific cells, are overexpressed in iPSCs, but also direct conversion in which transcription factors are introduced into patient-derived somatic cells which are dedifferentiated to hematopoietic cells. As iPSCs derived from patients suffering from genetically mutated diseases would express the same mutated genetic information, CRISPR-Cas9 gene editing has been utilized to differentiate genetically corrected iPSCs into normal hematopoietic cells. IPSCs provide a model for molecular understanding of disease, and also may function as a cell population for therapy. Efficient differentiation of patient-specific iPSCs into HSCs and progenitor cells is a potential means to overcome limitations of such cells for HCT, as well as for providing in-vitro drug screening templates as tissue-on-a-chip models.


Enamel Demineralization Resistance and Remineralization by Various Fluoride-Releasing Dental Restorative Materials.
The aim of this study is to investigate the resistance of various fluoride-releasing restorative materials against the demineralization and remineralization of enamel surfaces, including those that have been recently introduced to the market. Three different fluoride-releasing restorative materials were considered: glass ionomer (FI), resin-modified glass ionomer (RL), and an alkasite restorative material (CN). The acid neutralization ability was investigated using pH measurement, and the concentrations of released fluoride and calcium ions were measured. Finally, the demineralization resistance and remineralization effects of enamel were observed using a microhardness tester and SEM. CN showed an initial substantial increase in pH followed by a steady increase, with values higher than those of the other groups (p < 0.05). All three groups released fluoride ions, and the CN group released more calcium ions than the other groups (p < 0.05). In the acid resistance test, from the microhardness and SEM images, the CN group showed effective resistance to demineralization. In the remineralization test, the microhardness results showed that the FI and CN groups recovered the microhardness from the values of the demineralized enamel surface (p < 0.05). This was confirmed by the SEM images from remineralization tests; the CN group showed a recovered demineralized surface when immersed in artificial saliva for 7 days. In conclusion, alkasite restorative material can be an effective material when used in cariogenic environments.


A randomized clinical trial of topical treatments for mild and severe udder cleft dermatitis in Dutch dairy cows.
Udder cleft dermatitis (UCD) is a skin lesion in dairy cows affecting the anterior parts of the udder, with the lesions often needing a long time to heal. The lesions can be characterized as mild or severe. The etiology of UCD is not fully understood and studies on the effectiveness of topical treatments have not been published. The objective of this study, therefore, was to conduct a randomized clinical trial to investigate the effectiveness of 2 different topical treatments, one for mild and one for severe UCD lesions, compared with untreated control groups. The treatment and control groups were randomized within herd for mild and severe UCD. The treatments were applied for a maximum period of 12 wk on 8 Dutch dairy farms. Mild UCD lesions were treated once a d 3 times a week on fixed days with a non-sting barrier film. Severe UCD lesions were first stratified into class A (lesion length <5 cm) or class B (lesion length ≥5 cm) and then randomly allocated to treatment or control groups within herd. Both severe lesion classes were treated once per day every day with an enzyme alginogel. Every week, the lesions of affected animals were inspected and photographed by the investigator. These photographs were reviewed weekly by an external wound expert who classified the lesions as mild, severe class A, severe class B, or healed. Based on this classification, the investigator judged weekly whether the lesions had improved compared with their classification of the previous week. For mild UCD lesions, improvement was defined as occurring when lesions were healed. For severe UCD lesions, improvement was defined as a transition from class B to class A, transition from any severe UCD lesion (class A or B) to a mild UCD lesion, or when the lesion was defined as healed. Data were analyzed using a discrete time survival analysis with time to first improvement as dependent variable. In total, data from 214 animals were analyzed to estimate the effectiveness of treatment. Results showed that treatment of mild UCD lesions had no influence on improvement compared with untreated lesions. Treated severe lesions, however, showed 3.4 times more improvement compared with the untreated controls. Improvement varied between herds, and cows with a parity of 5 or higher showed significantly less improvement than first parity animals. Early identification of severe UCD lesions followed by prompt treatment with an enzyme alginogel supports the healing process.


Problems and solutions in longitudinal research: from theory to practice.
Longitudinal studies provide the only method for directly studying the natural course of human growth and development and are therefore invaluable, both to public health and clinical medicine. However, longitudinal studies are accompanied by specific problems. The purpose of this final paper is to discuss in two separate sections some of the methodological, analytical and practical issues regarding the relevance of the findings reported. Examples of such problems and their solutions are described. Methodological issues discussed concern statistical conclusion validity, internal validity and construct validity of longitudinal studies. Practical issues discussed concern the design of longitudinal studies, the recruitment and retention of subjects, and the methods used. Finally, examples of the significance of longitudinal research outcomes to public health and clinical medicine are given.


Role of cytokines in hyperoxia mediated inflammation in the developing lung.
The development of Chronic Lung Disease of Prematurity (CLD) has been associated with the use of hyperoxic conditions during ventilation. Inflammation has been demonstrated to contribute to the development of this disease, both on histological examination of diseased lungs, and by the use of bronchoalveolar lavage. Hyperoxia is believed to contribute to this inflammatory process by causing direct injury to epithelial and endothelial cells. The formation of reactive oxygen species is thought to result in production of cytokines. These act within a complex network, orchestrating an inflammatory response. Evidence for a role of cytokines in CLD has been inferred by studies in human infants showing increased concentrations of cytokines, growth factors and inflammatory cells at early stages in infants destined to develop CLD. These findings have been supported by the use of animal models of hyperoxic lung injury. The treatment of CLD is currently centered on the suppression of cytokine production. As understanding of this disease increases, more specific targets are being developed which aim to reduce the oxidative load on the lung, and prevent recruitment of inflammatory cells that are responsible for the tissue damage underlying this disease.


Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells.
Avoiding destruction by immune cells is a hallmark of cancer, yet how tumors ultimately evade control by natural killer (NK) cells remains incompletely defined. Using global transcriptomic and flow-cytometry analyses and genetically engineered mouse models, we identified the cytokine-TGF-β-signaling-dependent conversion of NK cells (CD49a-CD49b+Eomes+) into intermediate type 1 innate lymphoid cell (intILC1) (CD49a+CD49b+Eomes+) populations and ILC1 (CD49a+CD49b-Eomesint) populations in the tumor microenvironment. Strikingly, intILC1s and ILC1s were unable to control local tumor growth and metastasis, whereas NK cells favored tumor immunosurveillance. Experiments with an antibody that neutralizes the cytokine TNF suggested that escape from the innate immune system was partially mediated by TNF-producing ILC1s. Our findings provide new insight into the plasticity of group 1 ILCs in the tumor microenvironment and suggest that the TGF-β-driven conversion of NK cells into ILC1s is a previously unknown mechanism by which tumors escape surveillance by the innate immune system.


Structure of undecacarbonyl[tris(pentafluorophenyl)phosphine]-triangulo- triosmium, a substituted osmium cluster containing a fluorinated triphenylphosphine ligand.
[Os3(CO)11[P(C6F5)3]], Mr = 1410.87, monoclinic, P2(1)/n, a = 19.058 (1), b = 9.109 (1), c = 20.424 (2) A, beta = 105.53 (1) degree, V = 3416 (1) A3, Z = 4, Dm = 2.74 (2), Dx = 2.743 g cm-3, mu(Mo K alpha, lambda = 0.71073 A) = 113.3 cm-1, F(000) = 2560, T = 297 (1) K, RF = 0.022 for 3529 reflections. The Os atoms form an approximate isosceles triangle. Each Os atom exhibits a distorted octahedral coordination geometry. The carbonyl groups are all terminal and the bulky phosphine ligand is coordinated equatorially.


Distribution, behaviour, bioavailability and remediation of poly- and per-fluoroalkyl substances (PFAS) in solid biowastes and biowaste-treated soil.
Aqueous film-forming foam, used in firefighting, and biowastes, including biosolids, animal and poultry manures, and composts, provide a major source of poly- and perfluoroalkyl substances (PFAS) input to soil. Large amounts of biowastes are added to soil as a source of nutrients and carbon. They also are added as soil amendments to improve soil health and crop productivity. Plant uptake of PFAS through soil application of biowastes is a pathway for animal and human exposure to PFAS. The complexity of PFAS mixtures, and their chemical and thermal stability, make remediation of PFAS in both solid and aqueous matrices challenging. Remediation of PFAS in biowastes, as well as soils treated with these biowastes, can be achieved through preventing and decreasing the concentration of PFAS in biowaste sources (i.e., prevention through source control), mobilization of PFAS in contaminated soil and subsequent removal through leaching (i.e., soil washing) and plant uptake (i.e., phytoremediation), sorption of PFAS, thereby decreasing their mobility and bioavailability (i.e., immobilization), and complete removal through thermal and chemical oxidation (i.e., destruction). In this review, the distribution, bioavailability, and remediation of PFAS in soil receiving solid biowastes, which include biosolids, composts, and manure, are presented.


Correlation Between IL-20 and De Quervain's Disease Severity.
De Quervain's disease is a stenosing tenosynovitis of the first dorsal compartment of the wrist. Histopathological studies have reported that the thickening of the first dorsal retinaculum is characterized by degeneration rather than inflammation. However, significant infiltration of mast cells and macrophages was noted in a torn tendon study, which suggested that innate immune pathways are part of the mechanism that mediates early tendinopathy. Recently, Interleukin-20 (IL-20) has been reported to provoke potent inflammation and regulate angiogenesis and chemotaxis, which are important for the pathogenesis of inflammatory diseases. The main purpose of our study was to investigate the correlation between IL-20 and tumor necrosis factor (TNF-α) and clarify the potential predictor of tendinopathy progression. Hematoxylin and eosin (H & E) and immunohistochemistry (IHC) staining were used to score and analyze the clinical outcome. TNF-α, IL-20 and related inflammation cytokines were examined. Moreover, the tenocytes were cultured with a stimulator and were used to examine inflammatory cytokine secretions. A real-time polymerase chain reaction (Real-time PCR) was used to detect the gene expression profile. The IHC data showed that TNF-α is up-regulated in grade III de Quervain's. The analysis data showed that IL-20 is positively correlated with TNF-α and disease severity. The real-time PCR showed that the inflammation stimulator enhanced the expression of IL-20 mRNA expression. Inflammation cytokines such as TNF-alpha, transforming growth factor-β (TGF-β) and IL-1 have been used as predictors of de Quervain's; IL-20 is a new predictor based on this study. In the future, IL-20 expression's involvement in the molecular mechanism of the severity of de Quervain's should be further investigated.


Finding and recruiting the highest risk HIV-negative men who have sex with men.
This study compared the ability of different field and online recruitment venues to reach those at highest risk for HIV infection among HIV-negative men who have sex with men (MSM), given that some subgroups are difficult to reach, and venues vary in the demographic characteristics of the samples they yield. Compared to other venues, dating/hookup websites reached significantly higher-than-expected concentrations of White MSM aged 40 and above, including those who reported unprotected anal intercourse (UAI). Facebook was the most successful venue for the recruitment of MSM who used stimulants, including those who reported UAI. MSM who reported UAI were more likely to be recruited online. This study points to systematic variation in the samples obtained via different recruitment strategies, which should be taken into consideration when designing intervention/prevention programs targeting HIV-negative MSM.


Crowd-sourcing and automation facilitated the identification and classification of randomized controlled trials in a living review.
To evaluate an approach using automation and crowdsourcing to identify and classify randomized controlled trials (RCTs) for rheumatoid arthritis (RA) in a living systematic review (LSR). Records from a database search for RCTs in RA were screened first by machine learning and Cochrane Crowd to exclude non-RCTs, then by trainee reviewers using a Population, Intervention, Comparison, and Outcome (PICO) annotator platform to assess eligibility and classify the trial to the appropriate review. Disagreements were resolved by experts using a custom online tool. We evaluated the efficiency gains, sensitivity, accuracy, and interrater agreement (kappa scores) between reviewers. From 42,452 records, machine learning and Cochrane Crowd excluded 28,777 (68%), trainee reviewers excluded 4,529 (11%), and experts excluded 7,200 (17%). The 1,946 records eligible for our LSR represented 220 RCTs and included 148/149 (99.3%) of known eligible trials from prior reviews. Although excluded from our LSRs, 6,420 records were classified as other RCTs in RA to inform future reviews. False negative rates among trainees were highest for the RCT domain (12%), although only 1.1% of these were for the primary record. Kappa scores for two reviewers ranged from moderate to substantial agreement (0.40-0.69). A screening approach combining machine learning, crowdsourcing, and trainee participation substantially reduced the screening burden for expert reviewers and was highly sensitive.


Endoplasmic reticulum stress modulates liver inflammatory immune response in the pathogenesis of liver ischemia and reperfusion injury.
Although endoplasmic reticulum (ER) stress has been implicated in the pathophysiology of organ ischemia-reperfusion injury (IRI), the underlying mechanisms have yet to be fully elucidated. In particular, because tissue proinflammatory immune response is the key mediator of local IRI, how ER stress impacts liver immune cell activation cascade remains to be determined. In vitro, ER stress in macrophages and hepatocytes were induced by pharmacological agents. Macrophage Toll-like receptor 4 and hepatocyte tumor necrosis factor α responses were studied. In vivo, the induction of ER stress by ischemia-reperfusion and the impact of ER stress amelioration by a small molecule chaperon 4-phenylbutyric acid on liver immune response were studied in a murine partial liver warm ischemia model. ER-stressed macrophages generated a significantly enhanced proinflammatory immune response against Toll-like receptor 4 stimulation, whereas ER-stressed hepatocytes became more susceptible to tumor necrosis factor α-induced cell death. Ischemia-reperfusion resulted in up-regulations of spliced X-box binding protein 1 and activating transcription factor 6 levels in affected livers. Mice pretreated with 4-phenylbutyric acid were protected from liver IRI, in parallel with diminished local proinflammatory gene induction program. Our study documents a potential immune regulatory role of ER stress in the mechanism of liver IRI and provides a rationale for targeting stress response as a new therapeutic means to ameliorate tissue inflammation in organ transplant recipients.


Mandibulofacial dysostosis with microcephaly: An expansion of the phenotype via parental survey.
Mandibulofacial dysostosis with microcephaly (MFDM) is due to haploinsufficiency of spliceosomal GTPase EFTUD2. Features include microcephaly, craniofacial dysmorphology, developmental disability, and other anomalies. We surveyed parents of individuals with MFDM to expand knowledge about health, development, and parental concerns. Participants included attendees of the inaugural MFDM family conference in June 2019 and members of the MFDM online group. To explore MFDM variable expressivity, we offered targeted Sanger sequencing for untested parents. Forty-seven parents participated in the survey. 59% of individuals with MFDM were male, with mean age 6.4 years (range 8 months to 49 years). Similar to the literature (n = 123), common features include microcephaly, cleft palate, choanal stenosis, tracheoesophageal fistula, heart problems, and seizures. New information includes airway intervention details, age-based developmental outcomes, rate of vision refractive errors, and lower incidences of prematurity and IUGR. Family concerns focused on development, communication, and increased support. Targeted Sanger sequencing for families of seven individuals demonstrated de novo variants, for a total of 91.9% de novo EFTUD2 variants (n = 34/37). This study reports the largest single cohort of individuals with MFDM, expands phenotypic spectrum and inheritance patterns, improves understanding of developmental outcomes and care needs, and identifies development as the biggest concern for parents.


History of Coffee Consumption and Risk of Alzheimer's Disease: a Meta-epidemiological Study of Population-based Cohort Studies.
Four published quantitative systematic reviews showed conflicting results involving coffee consumption and the risk of Alzheimer's disease (AD). The aim of this meta-epidemiological meta-analysis (MEMA) was to evaluate the factors underlying the conflicting results and estimate the effect size and direction of the AD risk associated with coffee consumption in population-based cohort studies. The primary subjects of MEMA were derived from 3 cohort studies selected by the related systematic reviews. Additional studies involving the primary subjects were searched using citation discovery tools. Prospective cohort studies evaluating the association between coffee consumption and AD risk were selected. A fixed effects model was applied to estimate the summary relative risk (sRR) and its 95% confidence intervals (CIs). Subgroup analysis was conducted according to the level of coffee consumption. Egger's test was used to evaluate publication bias. Four cohort studies were finally selected. A total of 36,300 participants from Finland, Sweden, Germany, and the United States of America were selected. The sRR (and its 95% CI) (I-squared value) by highest-versus-lowest method was 0.98 (0.92-1.05) (0.0%). In addition, none of the results of subgroup analyses by the level of coffee consumption showed any statistical significance. This MEMA found that there was no association between coffee consumption and AD risk. Based on recent evidence suggesting that gene-environment interactions contribute to AD pathogenesis, it is necessary to conduct population-based cohort studies involving non-Caucasians.


Immunological abnormalities in juvenile myelomonocytic leukaemia.
Immunological studies were performed on 24 children suffering from juvenile myelomonocytic leukaemia. Strikingly high serum immunoglobulin levels with a frequent tendency towards homogeneity and light-chain imbalance were present, together with a high incidence of antinuclear antibodies (52%) and antihuman IgG antibodies (43%). Members of the families of 19 of the children were also studied. A few similar abnormalities were found in eight families, mostly clustered in four of them. The significance of the association of these immunological aberrations with juvenile myelomonocytic leukaemia is at present unknown. In view of the interrelation observed in experimental models between immunological abnormalities and oncogenic viruses the possibility of a common aetiological factor such as a viral infection during fetal life is suggested.


Growth promotion effects and plasma changes from feeding high dietary concentrations of zinc and copper to weanling pigs (regional study).
An experiment was conducted to determine the effect of high dietary intakes of Zn and Cu and their combination on growth performance of weanling pigs with diverse health status and management strategies. Twelve experiment stations cooperated and used a total of 1,356 pigs that averaged 6.55 kg BW and 22.2 d age at weaning. The four dietary treatments, all of which met or exceeded NRC requirements, were 1) control, 2) 3,000 ppm Zn (from Zn oxide), 3) 250 Cu ppm (from Cu sulfate), or 4) 3,000 ppm Zn and 250 ppm Cu. The diets were fed as a complex Phase I diet (1.4% lysine) for 7 d followed by a Phase II diet (1.2% lysine) for 21 d. Chlortetracycline (220 ppm) was added to all diets. Fecal color (1 = yellow to 5 = black) and consistency (1 = very firm to 5 = very watery) were scored daily for 3 wk. At the end of the 28-d study, 412 pigs were bled at five stations, and plasma Cu, Zn, and Fe concentrations were determined at one station with atomic absorption spectrophotometry. Average daily gain (375, 422, 409, 415 g/d), feed intake (637, 690, 671, 681 g/d), and gain/feed (586, 611, 611, 612 g/kg) were improved (P < .01) by the addition of Zn and(or) Cu. Significant Cu x Zn interactions imply that the responses to Zn and Cu were independent and not additive. There were significant (P < .01) Zn and Cu effects and a Zn x Cu interaction on fecal color (3.17, 3.24, 4.32, 3.57) and consistency (2.39, 2.14, 2.14, 2.13). Dietary additions of Cu and Zn resulted in elevated plasma concentrations of Cu and Zn, respectively. These data indicate that pharmacological additions of 3,000 ppm Zn (oxide) or 250 ppm Cu (sulfate) stimulate growth beyond that derived from intakes of Zn and Cu that meet nutrient requirements. However, the combination of Zn and Cu did not result in an additive growth response.


Official Websites Providing Information on COVID-19 Vaccination: Readability and Content Analysis.
Online information on COVID-19 vaccination may influence people's perception and willingness to be vaccinated. Official websites of vaccination programs have not been systematically assessed before. This study aims to assess and compare the readability and content quality of web-based information on COVID-19 vaccination posted on official/governmental websites. Furthermore, the relationship between evaluated website parameters and country vaccination rates were calculated. By referring to an open data set hosted at Our World in Data, the 58 countries/regions with the highest total vaccination count as of July 8, 2021, were identified. Together with the websites from the World Health Organization and European Union, a total of 60 vaccination campaign websites were targeted. The "frequently asked questions" or "questions and answers" section of the websites were evaluated in terms of readability (Flesch Reading Ease score and Flesch-Kincaid Grade Level), quality (Health On the Net Foundation code [HONcode] certification and Quality Evaluation Scoring Tool), and content stating vaccination duration of protection and potential side effects. In terms of readability, the Flesch Reading Ease score of the vaccination frequently asked questions websites ranged between 11.2 and 69.5, with a mean of 40.9 (SD 13.2). Meanwhile, the Flesch-Kincaid Grade Level ranged between 6.5 and 17.6, with a mean of 12.1 (SD 2.8). In terms of quality, only 2 websites were HONcode certified, and the Quality Evaluation Scoring Tool score of the websites ranged between 7 and 20, with a mean of 15.3 (SD 3.1). Half of the websites (25/50) did not present a publication date or date of the last update. Regarding the duration of protection offered by the vaccines, 46% (23/50) of the websites stated that they do not know, and another 40% (20/50) did not address it. Five side effects of the vaccinations were most frequently mentioned, namely, fever/chill (41/50, 82%), various injection site discomfort events (eg, swelling, redness, or pain; 39/50, 78%), headache (36/50, 72%), fatigue (33/50, 66%), and muscle/joint pain (31/50, 62%). In general, the content quality of most of the evaluated websites was good, but HONcode certification should be considered, content should be written in a more readable manner, and a publication date or date of the last update should be presented.


The National Veteran Sleep Disorder Study: Descriptive Epidemiology and Secular Trends, 2000-2010.
A large proportion of individuals affected by sleep disorders are untreated and susceptible to accidents, injuries, long-term sequelae (e.g., risk of cardiovascular disease, cancer, psychiatric disorders), and increased mortality risk. Few studies have examined the scope and magnitude of sleep disorder diagnoses in the United States (US) or factors influencing them. Veterans are particularly vulnerable to factors that elicit or exacerbate sleep disorders. This serial cross-sectional study characterized secular trends in diagnosed sleep disorders among veterans seeking care in US Veterans Health Administration facilities over an eleven-year span (FY2000-2010, n = 9,786,778). Electronic medical records from the national Veterans Administration Informatics and Computing Infrastructure database were accessed. Cases were defined using diagnostic codes specified by the American Academy of Sleep Medicine. Age-adjusted annual prevalence was summarized by sex, race, combat exposure, body mass index, and comorbid diagnoses (cardiovascular disease, cancer, mental disorders). Sleep apnea (47%) and insomnia (26%) were the most common diagnoses among patients with any sleep disorder. There was a six-fold relative increase in total sleep disorder prevalence over the study period. Posttraumatic stress disorder, which tripled over the same time period, was associated with the highest prevalence of sleep disorders (16%) among the comorbid conditions evaluated. The results indicate a growing need for integration of sleep disorder management with patient care and health care planning among US veterans. A commentary on this article appears in this issue on page 1331.


[The relevance of the inflammatory response in the injured brain].
Research efforts in recent years have defined traumatic brain injury (TBI) as a predominantly immunological and inflammatory disorder. This perception is based on the fact that the overwhelming neuroinflammatory response in the injured brain contributes to the development of posttraumatic edema and to neuropathological sequelae which are, in large part, responsible for the adverse outcome. While the "key" mediators of neuroinflammation, such as the cytokine cascade and the complement system, have been clearly defined by studies in experimental TBI models, their exact pathways of interaction and pathophysiological implications remain to be further elucidated. This lack of knowledge is partially due to the concept of a "dual role" of the neuroinflammatory response after TBI. This notion implies that specific inflammatory molecules may mediate diverse functions depending on their local concentration and kinetics of expression in the injured brain. The inflammation-induced effects range from beneficial aspects of neuroprotection to detrimental neurotoxicity. The lack of success in pushing anti-inflammatory therapeutic concepts from"bench to bedside" for patients with severe TBI strengthens the further need for advances in basic research on the molecular aspects of the neuroinflammatory network in the injured brain. The present review summarizes the current knowledge from experimental studies in this field of research and discusses potential future targets of investigation.


IR780-based light-responsive nanocomplexes combining phase transition for enhancing multimodal imaging-guided photothermal therapy.
Near-infrared (NIR) light-triggered photothermal therapy (PTT) has been widely applied for treating cancer. The combination of nanotechnology and NIR has shown great promise for promoting the efficacy of PTT. However, PTT alone could not completely ablate the tumors and easily causes tumor recurrence. To overcome this challenge, many studies have been performed to enhance PTT, including combining chemical therapy and radiotherapy, both of which have side effects on the body. To reduce the side effects and enhance PTT, a new infrared IR780-based nanocomplex combining liquid fluorocarbon perfluoropentane (PFP) has been synthesized for enhancing multimodal imaging-guided PTT. Under NIR irradiation, the size changes of PFP-loaded nanobubbles transforming into microbubbles allow ultrasound (US) imaging, showing boundaries and internal information of tumors. The breakup process and cascade reaction of phase transition can improve intratumoral permeation and retention of nanoparticles in nonmicrovascular tissue and damage the cell membranes of tumors, further enhancing PTT to kill tumor cells. The strong absorption in the NIR field of IR780-loaded NPs allows not only photoacoustic (PA) imaging but also NIR fluorescence (NIRF) imaging, which provides more anatomical information about tumors. This nanocomplex exhibits good biocompatibility and nontoxicity, strong PA/US/NIRF imaging contrast, excellent liquid-gas transition and a photothermal effect. This finding provides a new method to enhance multimodal imaging-guided cancer nanotheranostics.


Early onset Morganella morganii sepsis in a newborn infant with emergence of cephalosporin resistance caused by depression of AMPC beta-lactamase production..
A preterm infant with early onset Morganella morganii sepsis was treated with cefotaxime and gentamicin after confirmation of antimicrobial susceptibility. The infant developed persistent ventriculitis caused by the emergence of a cefotaxime-resistant Morganella variant with derepression of its AmpC beta-lactamase. When choosing antibiotic therapy, the risk of development of resistance to cephalosporins should be considered in infections caused by M. morganii and other Gram-negative organisms with inducible AmpC beta-lactamases.


Late epilepsy after aneurysm operations.
The risk of late epilepsy was analyzed in a consecutive series of 177 patients operated on for supratentorial aneurysms. Late seizures occurred in 25 patients (14%); the seizures were recurrent in 21 patients (12%). Most seizures were partial, secondary generalized, or generalized tonic-clonic (72%). The mean latency between the operation and seizures was 8.4 months (range, 1 to 24 months), and in only 2 patients was the interval more than 12 months. The most important risk factors were preoperative and postoperative complications. Only 2.5% of the 81 Grade I patients developed epilepsy, compared to 33% of the 42 Grade III-IV patients. Other risk factors were location of the aneurysm in the middle cerebral artery, the presence of a large intracerebral hematoma, postoperative spasm with late ischemic infarction, and shunt-dependent hydrocephalus. The timing of operation or intraventricular intracranial pressure monitoring did not change the risk of late epilepsy. The fact that only 2 patients had early epilepsy may have been due to routine treatment with prophylactic anticonvulsants. The value of prophylaxis in late epilepsy is unproven, but prophylactic treatment could be useful in patients with a high risk of epileptic seizures.


Physiological and subjective arousal to prospective mental imagery: A mechanism for behavioral change?
Emotional prospective mental imagery, in which we simulate possible future events within our minds, have a pronounced impact on behavior. For example, repeated engagement in positive prospective imagery can lead to behavioral activation, while negative prospective imagery can lead to catastrophizing and avoidance. Physiological arousal boosts memory consolidation, creating emotional memories. Thus, if emotional prospective imagery produces an arousal response, the memory consolidation of these simulations of the future may be boosted, offering a possible underlying mechanism for the impact of emotional prospective imagery on behavior. In order to examine the feasibility of arousal as a possible mechanism behind the impact of emotional prospective imagery on behavior, sixty participants produced autobiographical prospective imagery of 30 scenes (10 positive, 10 neutral, and 10 negative), during which arousal responses (skin conductance) were measured, and ratings for subjective arousal, valence, and imagery vividness were collected. Moreover, because vividness of prospective imagery has been related to anxiety and depression, the study examined this relation also for event-related autobiographical prospective imagery. The results showed that emotional prospective imagery were associated with higher subjective arousal ratings as compared to neutral imagery. Physiological arousal responses showed a similar pattern, but further data is needed for a firm conclusion. Nevertheless, arousal-boosted consolidation remains a possible contributing mechanism for the impact of emotional prospective imagery on behavior. Moreover, results suggest both anxiety and depression may entail a reduced ability to invent prospective life situations. However, only anxiety was associated with less vivid imaginations, unless the imaginations were of negative content. Hence, anxious individuals may experience negative prospective imagery more vividly than imagery with neutral and positive content.


A proposal to rationalize within-species plant virus nomenclature: benefits and implications of inaction.
Current approaches used to name within-species, plant virus phylogenetic groups are often misleading and illogical. They involve names based on biological properties, sequence differences and geographical, country or place-association designations, or any combination of these. This type of nomenclature is becoming increasingly unsustainable as numbers of sequences of the same virus from new host species and different parts of the world increase. Moreover, this increase is accelerating as world trade and agriculture expand, and climate change progresses. Serious consequences for virus research and disease management might arise from incorrect assumptions made when current within-species phylogenetic group names incorrectly identify properties of group members. This could result in development of molecular tools that incorrectly target dangerous virus strains, potentially leading to unjustified impediments to international trade or failure to prevent such strains being introduced to countries, regions or continents formerly free of them. Dangerous strains might be missed or misdiagnosed by diagnostic laboratories and monitoring programs, and new cultivars with incorrect strain-specific resistances released. Incorrect deductions are possible during phylogenetic analysis of plant virus sequences and errors from strain misidentification during molecular and biological virus research activities. A nomenclature system for within-species plant virus phylogenetic group names is needed which avoids such problems. We suggest replacing all other naming approaches with Latinized numerals, restricting biologically based names only to biological strains and removing geographically based names altogether. Our recommendations have implications for biosecurity authorities, diagnostic laboratories, disease-management programs, plant breeders and researchers.


Acute predictors of return to employment after traumatic brain injury: a longitudinal follow-up.
To investigate the relation between selected acute injury and patient characteristics and subsequent return to work 1 to 5 years postinjury. Longitudinal design with prospectively collected data. Data were collected on patients at the time of injury and each year postinjury for up to 5 years. Four medical centers in the federally sponsored Traumatic Brain Injury Model Systems project that provide emergency medical services, intensive and acute medical care, inpatient rehabilitation, and a spectrum of community rehabilitation services. Patients were selected from a national database of 538 rehabilitation inpatients admitted to acute care within 8 hours of traumatic brain injury (TBI) and seen at 1 to 5 years follow-up. Not applicable. Employment status (employed vs not employed) at 1 to 5 years postinjury. Logistic regression analyses were performed to determine the extent to which selected variables predicted employment status at years 1 to 5 postinjury. At year 1 postinjury, preinjury productivity, age, education, and rehabilitation length of stay were all significantly associated with postinjury employment. Preinjury employment and productivity and age significantly predicted employment at postinjury year 2. At year 3 postinjury, preinjury productivity, age, and FIMtrade mark instrument discharge score significantly predicted employment status. Age was significantly associated with employment status at year 4 postinjury. Preinjury employment and productivity and Disability Rating Scale discharge score were found to be significant predictors of postinjury employment at year 5 follow-up. The relationship between certain acute injury and patient variables (eg, age, preinjury productivity, education, discharge FIM) and subsequent return to work may provide rehabilitation professionals with useful information regarding the intensity and types of services needed for individuals in the vocational rehabilitation planning process.


A sterically encumbered photoredox catalyst enables the unified synthesis of the classical lignan family of natural products.
Herein, we detail a unified synthetic approach to the classical lignan family of natural products that hinges on divergence from a common intermediate that was strategically identified from nature's biosynthetic blueprints. Efforts toward accessing the common intermediate through a convergent and modular approach resulted in the discovery of a sterically encumbered photoredox catalyst that can selectively generate carbonyl ylides from electron-rich epoxides. These can undergo concerted [3 + 2] dipolar cycloadditions to afford tetrahydrofurans, which were advanced (2-4 steps) to at least one representative natural product or natural product scaffold within all six subtypes in classical lignans. The application of those synthetic blueprints to the synthesis of heterolignans bearing unnatural functionality was demonstrated, which establishes the potential of this strategy to accelerate structure-activity-relationship studies of these natural product frameworks and their rich biological activity.


Molecular mechanics and dynamics characterization of an in silico mutated protein: a stand-alone lab module or support activity for in vivo and in vitro analyses of targeted proteins.
Over the past 20 years, the biological sciences have increasingly incorporated chemistry, physics, computer science, and mathematics to aid in the development and use of mathematical models. Such combined approaches have been used to address problems from protein structure-function relationships to the workings of complex biological systems. Computer simulations of molecular events can now be accomplished quickly and with standard computer technology. Also, simulation software is freely available for most computing platforms, and online support for the novice user is ample. We have therefore created a molecular dynamics laboratory module to enhance undergraduate student understanding of molecular events underlying organismal phenotype. This module builds on a previously described project in which students use site-directed mutagenesis to investigate functions of conserved sequence features in members of a eukaryotic protein kinase family. In this report, we detail the laboratory activities of a MD module that provide a complement to phenotypic outcomes by providing a hypothesis-driven and quantifiable measure of predicted structural changes caused by targeted mutations. We also present examples of analyses students may perform. These laboratory activities can be integrated with genetics or biochemistry experiments as described, but could also be used independently in any course that would benefit from a quantitative approach to protein structure-function relationships.


[Characteristics of exercise ventilation and gas exchange in obese and extremely obese patients].
Objective: To evaluate the characteristics of exercise ventilation and gas exchange in obese and extremely obese patients by Cardiopulmonary exercise test (CPX). Methods: Restrospective anal-ysis of subjects who underwent CPET in Shengjing Hospital of China Medical University from June 2014 to June 2017. A total of 74 subjects were enrolled. According to the body mass index (BMI), 74 subjects were divided into control group(18.5 kg/m(2)≤BMI<23.9 kg/m(2)) (n=21), obese group (28.0 kg/m(2)≤BMI<40.0 kg/m(2)) (n=30) and extremely obese group(BMI≥40.0 kg/m(2))(n=23), respectively. V(O2max), V(O2max)/kg, anaerobic thresh-old(AT), oxygen pulse(V(O2)/HR), breath reserve(BR), inhale time (VTin), expiratory time(VTex) and ventilato-ry equivalent for CO(2)(EqCO(2))were measured by CPX and compared by using one-way ANOVA. Results: Compared to the control group (1 620±400) L/min, the maximal oxygen uptake(V(O2max)) in obese group(1 905±592) L/min and extremely obese group (2 131.09±541.86) L/min were significance higher (F=5.14, P<0.01). The V(O2max)/kg in obese group (19±5) L·min(-1)·kg(-1) and extremely obese groups (16±4) L·min(-1)·kg(-1) were sig-nificant lower than those in control group(27±5)L·min(-1)·kg(-1) (F=35.37,P<0.01). Compared to the control group (9.3±1.4)L·min(-1)·W(-1), the change of oxygen uptake required under certain exercise load (ΔV(O2)/ΔWR) in obese group(9.0±1.7) L·min(-1)·W(-1)and extremely obese group (8.7±2.2) L·min(-1)·W(-1) were no significant difference (F=0.67,P=0.51). The AT in obese group (1 114±391) L/min and extremely obese group (1 348±349) L/min were significant higher than those in control group (832±223) L/min (F=12.85,P<0.01). Com-pared to the control group(10±4) L·min(-1)·b(-1), V(O2)/HR in obese group (12±3) L·min(-1)·b(-1) and extremely obese group(14±3) L·min·b(-1) were significance higher (F=8.16, P<0.01). No significant difference was found between the three groups in BR, VTin, VTex and EqCO(2). Conclusion: obese and extremely obese individu-als have a decreased ablity to exercise when the body requires anaerobic metabolism to provide energy. As exercise power increases, the heart oxygen consumption per stroke and the amount of volume and oxygen re-quired for gax exchange does increase.


Voltage dependence of intramembrane charge movement and conductance activation of batrachotoxin-modified sodium channels in frog node of Ranvier.
Sodium current and sodium channel intramembrane gating charge movement (Q) were monitored in voltage-clamped frog node of Ranvier after modification of all sodium channels by batrachotoxin (BTX). BTX caused an approximately threefold increase in steepness of the Q vs. voltage relationship and a 50-mV negative shift in its midpoint. The maximum amount of intramembrane charge was virtually identical before and after BTX treatment. BTX treatment eliminated the charge immobilization observed in untreated nodes after relatively long depolarizing pulses and slowed the rate of OFF charge movement after a pulse. After BTX treatment, the voltage dependence of charge movement was the same as the steady-state voltage dependence of sodium conductance activation. The observations are consistent with the hypothesis that BTX induces an aggregation of the charged gating particles associated with each channel and causes them to move as a unit having approximately three times the average valence of the individual particles. Movement of this single aggregated unit would open the BTX-modified sodium channel.


Spinal radiographs in those with back pain-when are they appropriate to diagnose vertebral fractures?
The presence of an osteoporotic vertebral fracture improves fracture risk assessment and may change management, so it is vital for healthcare professionals to assess patients for the presence or absence of these fractures. This may be particularly important in the presence of back pain. However, the correlation between low back symptoms and spinal imaging results is poor and the pathophysiology of most low back pain is not known, leading to a common conclusion that spinal radiographs are not appropriate for the assessment of back pain. For individual patients with back pain, spinal radiographs should be considered if they have certain features in the history and examination. As well as the traditional risk factors for osteoporosis, self-reported descriptives of back pain and novel physical examination findings have been shown to make the presence of vertebral fractures more likely. Systematic approaches have the potential to improve bone health across the population but need to be targeted to be cost-effective. Spinal radiographs should be considered for individual older patients with back pain if they have certain additional features in the history and examination.


Multiple incremental decremental learning of support vector machines.
We propose a multiple incremental decremental algorithm of support vector machines (SVM). In online learning, we need to update the trained model when some new observations arrive and/or some observations become obsolete. If we want to add or remove single data point, conventional single incremental decremental algorithm can be used to update the model efficiently. However, to add and/or remove multiple data points, the computational cost of current update algorithm becomes inhibitive because we need to repeatedly apply it for each data point. In this paper, we develop an extension of incremental decremental algorithm which efficiently works for simultaneous update of multiple data points. Some analyses and experimental results show that the proposed algorithm can substantially reduce the computational cost. Our approach is especially useful for online SVM learning in which we need to remove old data points and add new data points in a short amount of time.


Integrative model of caregiving: how macro and micro factors affect caregivers of adults with severe and persistent mental illness.
The study tested an integrative model of caregiving by examining the effects of sociocultural characteristics, interpersonal relations, mental health service structure, consumers' symptoms, objective burden, and evaluation of service systems on the subjective experiences of caregivers. The sample consisted of 428 caregivers of adults with severe and persistent mental illness. Results from multiple regression analyses indicated that ethnicity was the most significant sociocultural factor on caregivers' worry, personal growth, and benefits. Caregivers enrolled in managed care plans worried more about their consumers' welfare and felt less gratified by their experiences than their counterparts from fee-for-service plans. Implications to and partnerships among caregivers and mental health service systems were discussed.


The Application of the Principles of Responsible AI on Social Media Marketing for Digital Health.
Social media enables medical professionals and authorities to share, disseminate, monitor, and manage health-related information digitally through online communities such as Twitter and Facebook. Simultaneously, artificial intelligence (AI) powered social media offers digital capabilities for organizations to select, screen, detect and predict problems with possible solutions through digital health data. Both the patients and healthcare professionals have benefited from such improvements. However, arising ethical concerns related to the use of AI raised by stakeholders need scrutiny which could help organizations obtain trust, minimize privacy invasion, and eventually facilitate the responsible success of AI-enabled social media operations. This paper examines the impact of responsible AI on businesses using insights from analysis of 25 in-depth interviews of health care professionals. The exploratory analysis conducted revealed that abiding by the responsible AI principles can allow healthcare businesses to better take advantage of the improved effectiveness of their social media marketing initiatives with their users. The analysis is further used to offer research propositions and conclusions, and the contributions and limitations of the study have been discussed.


BH3-only proteins: Orchestrators of apoptosis.
The BH3-only proteins of Bcl-2 family are essential initiators of apoptosis that propagate extrinsic and intrinsic cell death signals. The interaction of BH3-only proteins with other Bcl-2 family members is critical for understanding the core machinery that controls commitment to apoptosis by permeabilizing the mitochondrial outer membrane. BH3-only proteins promote apoptosis by both directly activating Bax and Bak and by suppressing the anti-apoptotic proteins at the mitochondria and the endoplasmic reticulum. To prevent constitutive cell death, BH3-only proteins are regulated by a variety of mechanisms including transcription and post-translational modifications that govern specific protein-protein interactions. Furthermore, BH3-only proteins also control the initiation of autophagy, another important pathway regulating cell survival and death. Emerging evidence indicates that the interaction of BH3-only proteins with membranes regulates binding to other Bcl-2 family members, thereby specifying function. Due to the important role of BH3-only proteins in the regulation of cell death, several promising BH3-mimetic drugs that are active in pre-clinical models are currently being tested as anti-cancer agents. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.


[Bacteremia in the elderly. Clinical features and prognostic factors].
The analysis of the most relevant characteristics and prognostic factors in elderly patients with bacteremia. For the period 1989-1993 a prospective study of all significant bacteremias in adult patients admitted to a General Hospital was performed. Patients were visited until their death or during at least 50 days. The most relevant findings in elderly patients (over 65 years old) are described. Overall survival probabilities were obtained by Kaplan-Merner analysis. Cox proportional models were used to examine hazards of dying. Of the 1,128 bacteremias studied, 603 (53.9%) were in elderly patients. In this group, the increasing age was related with higher frequency of urinary (p = 0.02) and biliary (p = 0.001) sources of infection and lower frequency of underlying neoplasia (p = 0.06), immunosuppression (p = 0.0000) and development of septic shock (p = 0.02). These differences are higher in patients over 85. Among older patients the survival probability in the day 21 after diagnosis was 0.71 (95% CI 0.66-0.74), significantly lower to the probability in younger patients (p = 0.0001). In the elderly patients, the worse prognestic was associated to shock (RR = 8; 95% CI 5.8-11), indeterminated source of infection (RR = 3.6; 95% CI 2.2-5.8), underlying neoplasia (RR = 1.7; 95% CI 1.3-2.4), neutropania (RR = 1.5; 95% CI 1.1-2.1) nosocomial acquisition (RR = 1.3; 95% CI 1.0-3.1) and inappropriate treatment (RR = 1.2; 95% CI 1.0-3.2), but age was not an independent contributor. We found differences between the clinical characteristics and the prognosis of bactermia in elderly and younger patients. Among elder patients, those over 85 years old constitute a particular group with well defined characteristics.


Video education provides effective wound care instruction pre- or post-mohs micrographic surgery.
The objective of this study was to determine if delivery of wound care instruction pre-Mohs micrographic surgery versus the typical, post-Mohs surgery would allow for greater patient retention. A non-blinded, randomized, controlled trial receiving institutional review board exemption from Michigan State University was conducted over a three-month period. Patients scheduled for Mohs surgery on 13 selected days were randomized into pre- versus post-procedure groups to receive wound care education. This study was conducted at a dermatology practice in Saint Joseph, Michigan. Fifty cognitive and literate patients greater than 18 years of age were evaluated in this study. PARTICIPANTS' ability to recall instructions delivered by a Mohs surgeon in the form of digital media was assessed by a 10-question, multiple-choice exam. Additional analyses were conducted on patient's disposition around medical professionals, past experience with Mohs surgery, preference for digital media versus human instruction, and desire for home access. Pre- (n=24; score=77±14%) versus post-(n=26; 83±11%) procedure education displayed no significant difference (p=0.13) in overall questionnaire performance. Seventy-four percent of participants preferred video delivery as opposed to provider instruction. Thirty-four percent reported being intimidated by healthcare workers. Participant performance showed no significant change (p=0.78) with previous exposure (79±19%) to Mohs surgery versus a first-time encounter (80±11%). Video education prior to or post-Mohs surgery serves as an effective mechanism for patient education and improvement of time management in clinical practice.


Fast Optical Investigation of Cardiac Electrophysiology by Parallel Detection in Multiwell Plates.
Current techniques for fast characterization of cardiac electrophysiology employ optical technologies to control and monitor action potential features of single cells or cellular monolayers placed in multiwell plates. High-speed investigation capacities are commonly achieved by serially analyzing well after well employing fully automated fluorescence microscopes. Here, we describe an alternative cost-effective optical approach (MULTIPLE) that exploits high-power LED arrays to globally illuminate a culture plate and an sCMOS sensor for parallel detection of the fluorescence coming from multiple wells. MULTIPLE combines optical detection of action potentials using a red-shifted voltage-sensitive fluorescent dye (di-4-ANBDQPQ) with optical stimulation, employing optogenetic actuators, to ensure excitation of cardiomyocytes at constant rates. MULTIPLE was first characterized in terms of interwell uniformity of the illumination intensity and optical detection performance. Then, it was applied for probing action potential features in HL-1 cells (i.e., mouse atrial myocyte-like cells) stably expressing the blue light-activatable cation channel CheRiff. Under proper stimulation conditions, we were able to accurately measure action potential dynamics across a 24-well plate with variability across the whole plate of the order of 10%. The capability of MULTIPLE to detect action potential changes across a 24-well plate was demonstrated employing the selective K v 11.1 channel blocker (E-4031), in a dose titration experiment. Finally, action potential recordings were performed in spontaneous beating human induced pluripotent stem cell derived cardiomyocytes following pharmacological manipulation of their beating frequency. We believe that the simplicity of the presented optical scheme represents a valid complement to sophisticated and expensive state-of-the-art optical systems for high-throughput cardiac electrophysiological investigations.


Characterization of three novel desaturases involved in the delta-6 desaturation pathways for polyunsaturated fatty acid biosynthesis from Phytophthora infestans.
Phytophthora infestans is the causative agent of potato blight that resulted in the great famine in Ireland in the nineteenth century. This microbe can release large amounts of the C20 very long-chain polyunsaturated fatty acids arachidonic acid (ARA; 20:4Δ(5, 8, 11, 14)) and eicosapentaenoic acid (EPA; 20:5Δ(5, 8, 11, 14, 17)) upon invasion that is known to elicit a hypersensitive response to their host plant. In order to identify enzymes responsible for the biosynthesis of these fatty acids, we blasted the recently fully sequenced P. infestans genome and identified three novel putatively encoding desaturase sequences. These were subsequently functionally characterized by expression in Saccharomyces cerevisiae and confirmed that they encode desaturases with Δ12, Δ6 and Δ5 activity, designated here as PinDes12, PinDes6 and PinDes5, respectively. This, together with the combined fatty acid profiles and a previously identified Δ6 elongase activity, implies that the ARA and EPA are biosynthesized predominantly via the Δ6 desaturation pathways in P. infestans. Elucidation of ARA and EPA biosynthetic mechanism may provide new routes to combating this potato blight microbe directly or by means of conferring resistance to important crops.


Nicergoline in the treatment of dizziness in elderly patients. A review.
In elderly patients, dizziness occurs very frequently with significant effects on the patient's life. Its frequency increases with age, and may arise from a variety of causes. Chronic dysequilibrium in elderly patients is most probably related to disturbances within the central nervous system, due either to altered neuronal functions or to an underlying vascular disease. Nicergoline, a drug used in the treatment of cognitive disturbances in geriatric patients, improves dizziness in elderly demented and non-demented patients. In a double blind,placebo controlled trial the drug improved (i) the severity of symptoms, measured by the dizziness assessment rating scale (DARS), (ii) the overall clinical conditions revealed by global impression scale, and (iii) the perceived quality of life estimated by the dizziness handicap inventory (DHI). These results indicate a possible positive effect also on posturographic measures. Moreover, the improvement occurred at no expense of the established strategy of postural control suggesting that the effect is mediated by a substitute compensatory mechanism allowing the patient to preserve consolidated postural strategies. The results of previous open clinical studies in about 3000 patients are in agreement with those findings. Overall, severity of symptoms decreased by 68 % (57 % in the control study). Globally, the results indicate a beneficial effect of nicergoline on symptoms related to balance disorders of central origin. Animal studies show that the drug displays a broad spectrum of actions on cellular and molecular mechanisms. Moreover, animal research specifically aimed at vestibular pathophysiology has revealed that nicergoline improves vestibular compensation in models of vestibular lesion. Chronic treatment with nicergoline improved the time-course of behavioral recovery in old rats after hemi-labyrinthectomy and counteracted the regulation of cholinergic receptors observed after lesion in old rats. Nicergoline interacts at several levels by various mechanisms, from the molecular level to cognitive function, probably enhancing spontaneous plasticity phenomena underlying the central vestibular compensation. This effect is not dependent from the interaction with a single-transmitter-identified neural pathway, but from anatomical, functional and neurochemical synergistic adjustments in several brain areas.