A new arterial mechanical property indicator reflecting differences in invasive stimulus intensity induced by alteration of remifentanil concentration during laryngoscopy.
Reliable analgesia monitoring is not available for general anaesthesia cases. In 2003, we introduced a method to characterise arterial mechanical properties, which we termed arterial stiffness (K). However, it is unclear whether differences in K actually indicate changes in the intensity of a noxious stimulus. Thus, we examined the relationship between stress intensity and the value of K. Thirty patients under general anesthesia were randomly divided into two remifentanil concentration groups (2 and 6 ng/mL). After a steady concentration of remifentanil was achieved for at least 3 minutes, laryngoscopy was performed. After completion of laryngoscopy, once the K value returned to near-baseline, laryngoscopy with endotracheal intubation was performed, and the value of K after the procedure was recorded and analyzed. In total, data were obtained for 28 of 30 patients. The values of K before the laryngoscopy were not significantly different between the groups (2 ng/mL group: 13.1 [8.5-33.1] mmHg/%; 6 ng/mL group: 11.6 [4.3-31.4] mmHg/%; P=0.53). After laryngoscopy, K was approximately 2 times greater in the 2 ng/mL group than in the 6 ng/mL group (39.0 [13.6-115.9] mmHg/% vs. 19.0 [5.5-85.1] mmHg/%, P=0.02). After intubation also, K was approximately 2 times greater in the 2 ng/mL group (52.0 [27.7-122.0] mmHg/% vs. 24.3 [7.2-94.9] mmHg/%, P=0.04). The value for arterial stiffness (K) non-proportionally changes in response to stimulus intensity; therefore, it has the potential to be used as an indicator of nociceptive stimulation intensity.


Human inositol 1,4,5-trisphosphate 3-kinase isoform B (IP3KB) is a nucleocytoplasmic shuttling protein specifically enriched at cortical actin filaments and at invaginations of the nuclear envelope.
Recent studies have shown that inositol 1,4,5-trisphosphate 3-kinase isoform B (IP3KB) possesses important roles in the development of immune cells. IP3KB can be targeted to multiple cellular compartments, among them nuclear localization and binding in close proximity to the plasma membrane. The B isoform is the only IP3K that is almost ubiquitously expressed in mammalian cells. Detailed mechanisms of its targeting regulation will be important in understanding the role of Ins(1,4,5)P(3) phosphorylation on subcellular calcium signaling and compartment-specific initiation of pathways leading to regulatory active higher phosphorylated inositol phosphates. Here, we identified an exportin 1-dependent nuclear export signal ((134)LQRELQNVQV) and characterized the amino acids responsible for nuclear localization of IP3KB ((129)RKLR). These two targeting domains regulate the amount of nuclear IP3KB in cells. We also demonstrated that the localization of IP3KB at the plasma membrane is due to its binding to cortical actin structures. Intriguingly, all three of these targeting activities reside in one small polypeptide segment (amino acids 104-165), which acts as a multitargeting domain (MTD). Finally, a hitherto unknown subnuclear localization of IP3KB could be demonstrated in rapidly growing H1299 cells. IP3KB is specifically enriched at nuclear invaginations extending perpendicular between the apical and basal surface of the nucleus of these flat cells. Such nuclear invaginations are known to be involved in Ins(1,4,5)P(3)-mediated Ca(2+) signaling of the nucleus. Our findings indicate that IP3KB not only regulates cytoplasmic Ca(2+) signals by phosphorylation of subplasmalemmal and cytoplasmic Ins(1,4,5)P(3) but may also be involved in modulating nuclear Ca(2+) signals generated from these nuclear envelope invaginations.


Identification of candidate genes associated with triple negative breast cancer.
When triple negative breast cancer (TNBC) are analyzed by gene expression profiling different subclasses are identified, at least one characterized by genes related to immune signaling mechanisms supporting the role of these genes in the cancers. In an earlier study we observed differences in TNBC cell lines with respect to their expression of the cytokine IL32. Our analyses showed that certain cell lines expressed higher levels of the cytokine compared to others. Because TNBC are heterogeneous and immune-related genes appear to play a pivotal role in these cancers, we chose to examine the transcriptomes of the different cell lines based on IL32 expression. We performed group analyses of TNBC cell lines demonstrating high IL32 compared to low IL32 levels and identified IL32, GATA3, MYBL1, ETS1, PTX3 and TMEM158 as differentially associated with a subpopulation of TNBC. The six candidate genes were validated experimental and in different patient datasets. The genes distinguished a subset of TNBC from other TNBC, and TNBC from normal, luminal A, luminal B, and HER2 patient samples. The current project serves as a preliminary study in which we outline the discovery and validation of our list of six candidate genes.


Overcoming innate immune barriers that impede AAV gene therapy vectors.
The field of gene therapy has made considerable progress over the past several years. Adeno-associated virus (AAV) vectors have emerged as promising and attractive tools for in vivo gene therapy. Despite the recent clinical successes achieved with recombinant AAVs (rAAVs) for therapeutics, host immune responses against the vector and transgene product have been observed in numerous preclinical and clinical studies. These outcomes have hampered the advancement of AAV gene therapies, preventing them from becoming fully viable and safe medicines. The human immune system is multidimensional and complex. Both the innate and adaptive arms of the immune system seem to play a concerted role in the response against rAAVs. While most efforts have been focused on the role of adaptive immunity and developing ways to overcome it, the innate immune system has also been found to have a critical function. Innate immunity not only mediates the initial response to the vector, but also primes the adaptive immune system to launch a more deleterious attack against the foreign vector. This Review highlights what is known about innate immune responses against rAAVs and discusses potential strategies to circumvent these pathways.


The persistence of drug-induced fever by teicoplanin--a case report.
It was reported that the drug-induced fever of teicoplanin tended to persist after cessation of treatment. It is considered that the long half-life of teicoplanin causes the phenomenon. However there was no detailed report regarding plasma concentration of teicoplanin during onset of drug induced-fever. Therefore we investigated the relation between persistence of drug-induced fever and plasma concentration of teicoplanin. A 38-year-old male patient on the Left Ventricular Assist System (LVAS) was treated with teicoplanin for methicillin-resistant Staphylococcus aureus (MRSA) and he experienced drug-induced fever. Plasma concentrations of teicoplanin were measured not only during the treatment with the drug but also after it was discontinued. As such, plasma concentration was measured even when the fever had subsided. On Day 9 of treatment, the dose was increased from 400 to 600 mg, but the patient had a fever of about 38 - 39 °C. When the treatment was discontinued, it took 9 days for the fever to subside to a temperature of about 37 °C. The half-life of elimination of teicoplanin in the elimination phase is about 108 h, which is long. The fever persisted until the plasma concentration decreased to below 10 µg/ml, which is the effective trough concentration, and subsided when the estimated blood concentration was 7.5 µg/ml. We suggest that there is the possibility that the drug-induced fever due to teicoplanin persisted until the plasma concentration had decreased adequately. Close monitoring of plasma concentration is necessary, particularly when teicoplanin clearance is decreased such as in patients with renal dysfunction.


Effect of the anchoring strength on the phase behaviour of discotic liquid crystals under face-on confinement.
In this study we have performed molecular dynamics simulations to study a Gay-Berne discotic fluid confined in a slab geometry for a fixed confinement length. Four different anchoring strengths with a homeotropic (face-on) configuration were studied. We found that changing the anchoring strength changes the normal component of the stress tensor, which in turn changes the density of the system's bulk. This phenomenon leads to a shift in the isotropic-nematic transition temperature. We observe that the temperature regions where the nematic phase is present diminishes as the anchoring strength increases. The anchoring strength also affects the nematic-columnar coexistence temperature-region: it spans over more temperatures at higher anchoring strengths.


How Does Family Communication Relate to Adolescent Dating Violence and Externalizing Behaviors? The Role of Parent-Adolescent Risk Communication and Attitudes toward Violence in a Nicaraguan Sample.
Family plays a critical role for adolescent socialization. Parents in particular can promote either adolescent prosocial or problem behaviors. The purpose of the present study is two-fold. The first is to investigate the main and interaction effects of family communication (i.e., verbal hostility and expressiveness) on adolescent risk behaviors (i.e., dating violence and externalizing behaviors). The second is to test whether family communication is indirectly associated with adolescent risk behaviors through parent-adolescent risk communication and adolescent attitudes toward violence. Nicaraguan 7th and 8th graders were recruited to participate in paper-pencil surveys (N = 1,651). Path analysis identified significant main effects of verbal hostility for adolescent dating violence and externalizing behaviors. Although expressiveness did not show a significant main effect, interaction effects with verbal hostility were identified for both dating violence and externalizing behaviors. When verbal hostility was low, expressiveness was negatively related to adolescent dating violence and externalizing behaviors whereas when verbal hostility was high, expressiveness was positively associated with these behaviors. Significant indirect effects were detected only via adolescent attitudes toward violence. Prevention efforts that promote positive family environments and especially that eliminate verbal hostility are suggested.


Failure properties of passive human aortic tissue. II--Biaxial tension tests.
Descending mid-thoracic aortas were obtained from 16 autopsies and biaxial inflation tests performed on the tissue at dynamic (approximately 20 s-1) and quasi-static (approximately 0.01 s-1) strain rates. A bubble inflation technique was developed for this purpose. Extension histories of the specimens were recorded photographically and values of ultimate stresses and extension ratios in biaxial stretch have been calculated. Under conditions of uniform biaxial stretch the tissue consistently failed in a direction perpendicular to the long axis of the aorta and pressure values at failure were greater by a factor of two in the dynamic tests than those in the quasi-static tests.


Inhibition by brefeldin A of the specific B cell antigen presentation to MHC class II-restricted T cells.
We have shown previously that specific Ag presentation is prevented by the inhibition of protein synthesis but nonspecific presentation is not. In the present paper, Ag presentation by Ag-specific B cells was examined for sensitivity to brefeldin A (BFA), which blocks protein export from the endoplasmic reticulum. A20-HL B lymphoma expressing surface receptors specific for TNP was used as a B cell, and TNP-OVA was used as a specific Ag. The presence of BFA during pulsing of A20-HL cells with TNP-OVA inhibited the ability of the pulsed cells to stimulate 42-6A T cell clone, specific for OVA323-339 and Iad. The inhibition was not due to nonspecific toxicity of BFA, because the presence of BFA during pulsing of A20-HL cells with OVA323-339 did not affect their APC function. Ag binding to the receptor on A20-HL cells and internalization by the cells were observed in the presence of BFA. Thus, BFA might inhibit intracellular processing of specific Ag or intracellular complex formation of antigenic peptide from specific Ag with MHC class II molecules. Nonspecific Ag presentation by A20-HL cells, however, was resistant to BFA. A20-HL cells pulsed with OVA in the presence of BFA, even after fixation, could stimulate 42-6A cells to produce IL-2, although the IL-2 production was lower than that induced by A20-HL cells pulsed in the absence of BFA. These results suggest that the processing pathways for specific Ag and nonspecific Ag are different from each other, at least partly, in A20-HL cells.


Disparity between High Satisfaction and Severe Pain in Patients after Caesarean Section: A Prospective Observational-Controlled Investigation.
Recent advances in the treatment of postoperative pain (POP) have increased the quality of life in surgical patients. The aim of this study was to examine the quality of POP management in patients after CS in comparison with patients after comparable surgical procedures. This was a prospective observational analysis in patients after CS in comparison with the patients of the same age, who underwent comparable abdominal gynaecological surgeries (GS group) at the university hospital. A standardised questionnaire including pain intensity on the Verbal Rating Scale (VRS-11), incidence of analgesia-related side effects, and incidence of pain interference with the items of quality of life and patients' satisfaction with the treatment of POP was used. Sixty-four patients after CS reported more pain on movement than the patients after GS (N=63): mean 6.1 versus 3.6 (VRS-11; P < 0.001). The patients after CS reported less nausea (8 versus 41%) and vomiting (3 versus 21%; P < 0.001) and demonstrated better satisfaction with POP treatment than the patients after GS: 1.4 (0.7) versus 1.7 (0.7) (mean (SD); VRS-5; P=0.02). The disparity between the high level of pain and excellent satisfaction with POP treatment raises the ethical and biomedical considerations of restrictive pharmacological therapy of post-CS pain.


Ceramic thin-film formation on functionalized interfaces through biomimetic processing.
Processing routes have been developed for the production of thin ceramic films through precipitation from aqueous solutions. The techniques are based on crystal nucleation and growth onto functionalized interfaces. Surface functionalization routes have been developed by the mimicking of schemes used by organisms to produce complex ceramic composites such as teeth, bones, and shells. High-quality, dense polycrystalline films of oxides, hydroxides, and sulfides have now been prepared from "biomimetic" synthesis techniques. Ceramic films can be synthesized on plastics and other materials at temperatures below 100 degrees C. As a low-temperature process in which water rather than organic solvents is used, this synthesis is environmentally benign. Nanocrystalline ceramics can be produced, sometimes with preferred crystallite orientation. The direct deposition of high-resolution patterned films has also been demonstrated. The process is well suited to the production of organic-inorganic composites.


Relativistic Asymmetric Magnetic Reconnection.
We derive basic scaling equations for relativistic magnetic reconnection in the general case of asymmetric inflow conditions and obtain predictions for the outflow Lorentz factor and the reconnection rate. Kinetic particle-in-cell simulations show that the outflow speeds as well as the nonthermal spectral index are constrained by the inflowing plasma with the weaker magnetic energy per particle, in agreement with the scaling predictions. These results are significant for understanding nonthermal emission from reconnection in magnetically dominated astrophysical systems, many of which may be asymmetric in nature. The results provide a quantitative approach for including asymmetry on reconnection in the relativistic regime.


Effect of parasympathetic impairment on the haemodynamic response to handgrip in Chagas's heart disease.
Haemodynamic responses to sustained isometric exercise (handgrip at 30% of maximum voluntary capacity) were studied in 10 patients with Chagas's cardiopathy without previous or current heart failure. Five of the patients (group 1) had profound impairment of parasympathetic control of heart rate. They had no tachycardia in response to intravenous administration of atropine and no bradycardia during phase IV of the Valsalva manoeuvre. The other five (group 2) showed normal vagal regulation of heart rate, as judged by chronotropic responses to these tests. The heart rate change (mean (SD] elicited by the handgrip test was significantly lower in group 1 (from 93.0 (14.1) to 95.0 (16.7) beats/min) than in group 2 (from 78.2 (15.8) to 92.8 (18.1) beats/min). Pressor responses to handgrip were of similar magnitude (from 91.6 (7.8) to 109.0 (8.0) mm Hg in group 1 and from 88.6 (11.9) to 106.8 (20.9) mm Hg in group 2). In both groups no significant change in stroke index was detected during handgrip. Cardiac index increased during handgrip from 4.0 (1.2) to 4.8 (1.3) 1/min/m2 in group 2, but there was no significant change in group 1 (from 4.9 (0.7) to 4.8 (1.1) 1/min/m2). Changes in calculated systemic vascular resistance were significantly higher in group 1 (from 934 (175) to 1176 (383) dyn s cm-5) than in group 2 (from 1109 (404) to 1112 (424). This study shows that parasympathetic impairment adversely influences the haemodynamic pattern of response to isometric exercise in patients with Chagas's heart disease. In such conditions, the pressor response to handgrip is predominantly mediated by an increase in systemic vascular resistance rather than an increase in cardiac output.


An automatic sleep spindle detector based on wavelets and the teager energy operator.
Sleep spindles are one of the most important short-lasting rhythmic events occurring in the EEG during Non-Rapid Eye Movement sleep. Their accurate identification in a polysomnographic signal is essential for sleep professionals to help them mark Stage 2 sleep. Visual spindle scoring however is a tedious workload, as there are often a thousand spindles in an all-night recording. In this paper a novel approach for the automatic detection of sleep spindles based upon the Teager Energy Operator and wavelet packets has been presented. The Teager operator was found to accurately enhance periodic activity in epochs of the EEG containing spindles. The wavelet packet transform proved effective in accurately locating spindles in the time-frequency domain. The autocorrelation function of the resultant Teager signal and the wavelet packet energy ratio were used to identify epochs with spindles. These two features were integrated into a spindle detection algorithm which achieved an accuracy of 93.7%.


Downregulation of GLYAT Facilitates Tumor Growth and Metastasis and Poor Clinical Outcomes Through the PI3K/AKT/Snail Pathway in Human Breast Cancer.
The Glycine N-acyltransferase (GLYAT) gene encodes a protein that catalyzes the transfer of acyl groups from acyl CoA to glycine, resulting in acyl glycine and coenzyme A. Aberrant GLYAT expression is associated with several malignant tumors, but its clinical importance in human breast cancer (BC), has yet to be fully addressed. This study aims to evaluate the clinical function of GLYAT in BC patients. GLYAT expression was determined by immune blot and immunohistochemistry in three BC cell lines and primary cancer tissues. The MDA-MB 231 cell line was used for GLYAT gene knockdown experiments while the MCF7 cell line for overexpression experiments. Colony formation experiments, soft agar experiments, and transwell assays were utilized for further inspection of cell proliferation and migration capabilities. Immunofluorescence and western blot were used to detect markers of the epithelial-mesenchymal transition (EMT) and changes in the PI3K/AKT/Snail pathway. The role of GLYAT in tumor growth and metastasis was also assessed in nude mice in vivo. Also, a correlation analysis was performed between clinicopathological features and GLYAT expression in BC patients. GLYAT was decreased in human BC tissues and cell lines. Functional analysis showed that knockdown of GLYAT augmented BC cell proliferation in vitro and in vivo. However, this phenomenon was reversed when GLYAT was overexpressed in the transfected cells. Moreover, downregulation of GLYAT promoted the migratory properties of BC cells, likely through the activation of PI3K/AKT/Snail signaling, which subsequently induced the EMT. IHC analysis indicated that GLYAT was decreased in human BC tissues and lower GLYAT expression was correlated with histological grade, tumor TNM stage, Ki-67 status, and poorer survival in BC patients. Furthermore, lower GLYAT expression seemed as an independent risk factor related to poor prognosis in BC patients based on Cox regression analyses. Our findings demonstrate that downregulation of GLYAT expression in human breast cancer is correlated with EMT via the PI3K/AKT/Snail pathway and is also associated with histological grade, tumor TNM stage, Ki-67 status, and poor survival in breast cancer patients.


Rapid qPCR-based quantitative immune cell phenotyping in mouse tissues.
The immune microenvironment plays an important role in the regulation of diseases. The characterization of the cellular composition of immune cell infiltrates in diseases and respective models is a major task in pathogenesis research and diagnostics. For the assessment of immune cell populations in tissues, fluorescence-activated cell sorting (FACS) or immunohistochemistry (IHC) are the two most common techniques presently applied, but they are cost intensive, laborious, and sometimes limited by the availability of suitable antibodies. Complementary rapid qPCR-based approaches exist for the human situation but are lacking for experimental mouse models. Accordingly, we developed a robust, rapid RT-qPCR-based approach to determine and quantify the abundance of prominent immune cell populations such as T cells, helper T (Th) cells, cytotoxic T cells, Th1 cells, B cells, and macrophages in mouse tissues. The results were independently validated by the gold standards IHC and FACS in corresponding tissues and showed high concordance.


Islet transplantation under the kidney capsule corrects the defects in glycogen metabolism in both liver and muscle of streptozocin-diabetic rats.
Insulin-deficient rats are characterized by multiple defects in the pathway of glycogen synthesis and breakdown in both liver and skeletal muscle. The aim of this study was to clarify whether islet transplantation under the kidney capsule, which is associated with delivery of insulin into the peripheral circulation, is able to normalize glycogen metabolism in liver and muscle of streptozotocin-diabetic rats. Three groups of male Lewis rats were studied under fasting condition: controls, untreated diabetics, and islet transplanted diabetics. Glycogen content, glucose-6-phosphate concentration, and glycogen synthase activity were measured in both liver and skeletal muscle. Untreated diabetic rats were characterized by an increase in glycogen content of 178% and a reduction of glucose-6-phosphate level of 50%. Both glycogen and glucose-6-phosphate contents were restored to normal in transplanted diabetic rats. Active glycogen synthase (0.35 +/- 0.1 nmol/min/mg) and activity ratio (0.22 +/- 0.04) were significantly impaired compared with controls (0.99 +/- 0.2 nmol/min/mg and 0.43 +/- 0.06, respectively) and were normalized by islet transplantation. In the skeletal muscle, glycogen content was similar in the three groups of animals, whereas muscle glucose-6-phosphate level was reduced by 28% and glycogen synthase was in a less active state in the untreated diabetic rats. Both the glucose-6-phosphate concentration and the kinetic profile of glycogen synthase were normalized by islet transplantation. In conclusion, islet transplantation under the kidney capsule corrects the diabetes-induced abnormalities in glycogen and glucose-6-phosphate content and glycogen synthase activity in both liver and skeletal muscle.


Community-Acquired Methicillin-Resistant Staphylococcus aureus Prostatic Abscess Presenting as Acute Urinary Retention: A Case Report and Review of the Literature.
Background. Community-associated MRSA (CA-MRSA) strains have emerged as a substantial cause of infection in individuals without exposure to the healthcare system. Prostatic abscess is an uncommon disease. To date, there are only 6 published reports of a prostatic abscess secondary to CA-MRSA. Case Description. A 52-year-old diabetic Caucasian presented to the emergency department with severe lower abdominal pain of few hours duration, urinary frequency, and dribbling over the last 3 weeks. Physical examination was remarkable for an enlarged nontender prostate. A urine analysis showed pyuria while urine cultures grew CA-MRSA. Computed tomography of the abdomen and pelvis showed multiple prostate abscesses and a thickened urinary bladder wall. A TURP was performed by the urology team and pathology showed severe acute and chronic prostatitis with abscess formation and necrotic tissue. Our treatment regimen included IV vancomycin followed by oral trimethoprim/sulfamethoxazole and rifampin. Eradication of CA-MRSA was confirmed by follow-up cultures 2 months following discharge. Conclusion. This case illustrates the successful identification, diagnosis, and prompt treatment of a prostatic abscess secondary to CA-MRSA in a diabetic patient without recent hospitalization. Early treatment with antibiotics and transurethral resection of the prostate abscess led to a shortened hospital stay and decreased morbidity.


Oral nicotine marketing claims in direct-mail advertising.
Little is known regarding how oral nicotine products (eg, nicotine pouches, lozenges) are marketed to consumers, including whether potential implicit reduced harm claims are used. In the current study, we explored the marketing claims present in a sample of direct-mail oral nicotine advertisements sent to US consumers (March 2018-August 2020). Direct-mail ads (n=50) were acquired from Mintel and dual-coded for the following claims: alternative to other tobacco products, ability to use anywhere, spit-free, smoke-free and product does not contain tobacco leaf. We merged the coded data with Mintel's volume estimate (number of mail pieces sent to consumers) and calculated the proportion of oral nicotine advertisements containing claims by category. Of the 38 million pieces of oral nicotine direct-mail sent to US consumers, most featured claims that the product could be used anywhere (84%, 31.8 million pieces); was an alternative to other tobacco products (69%, 26.1 million pieces); and did not contain tobacco leaf (eg, 'tobacco leaf-free', 'simple' approach of extracting nicotine from tobacco; 55%, 20.7 million pieces). A slightly smaller proportion contained claims that oral nicotine was 'spit-free' (52%, 19.8 million pieces) or 'smoke-free' (31%, 11.7 million pieces). Our results provide an early indication of marketing claims used to promote oral nicotine. The strategies documented, particularly the use of language to highlight oral nicotine is tobacco-free, may covey these products as lower-risk to consumers despite the lack of evidence or proper federal authorisation that oral nicotine products are a modified-risk tobacco product. Future research is needed to examine consumer perceptions of such claims.


Induction of suppressor cells specific for AChR in experimental autoimmune myasthenia gravis.
Suppressor cells specific for acetylcholine receptor (AChR) were induced in a population of lymphocytes previously sensitized to AChR, obtained from rats with experimental autoimmune myasthenia gravis (EAMG). The lymphocytes were cultured with the immunosuppressive drug cyclosporin A plus purified AChR for 7 days. These cells, when mixed with lymphocytes from rats with EAMG in vitro, strongly suppressed the antibody response to AChR. They did not inhibit antibody responses to an unrelated antigen, an indication that suppression was specific for AChR. This approach should be a useful way to induce specific suppressor cells from sensitized populations of lymphocytes and may be applicable in the treatment of autoimmune diseases such as myasthenia gravis.


Off-label use of vaccines.
This article reviews the off-label recommendations and use of vaccines, and focuses on the differences between the labelled instructions on how to use the vaccine as approved by the regulatory authorities (or "label"1), and the recommendations for use issued by public health advisory bodies at national and international levels. Differences between public health recommendations and the product label regarding the vaccine use can lead to confusion at the level of vaccinators and vaccinees and possibly result in lower compliance with national vaccination schedules. In particular, in many countries, the label may contain regulatory restrictions and warnings against vaccination of specific population groups (e.g. pregnant women) due to a lack of evidence of safety from controlled trials at the time of initial licensure of the vaccine, while public health authorities may recommend the same vaccine for that group, based on additional post-marketing data and benefit risk analyses. We provide an overview of the different responsibilities between regulatory authorities and public health advisory bodies, and the rationale for off-label use2 of vaccines, the challenges involved based on the impact of off-label use in real-life. We propose to reduce off-label use of vaccines by requiring the manufacturer to regularly adapt the label as much as possible to the public health needs as supported by new evidence. This would require manufacturers to collect and report post-marketing data, communicate them to all stakeholders and regulators to extrapolate existing evidence (when acceptable) to other groups or to other brands of a vaccine (class effect3). Regulatory authorities have a key role to play by requesting additional post-marketing data, e.g. in specific target groups. When public health recommendations for vaccine use that are outside labelled indications are considered necessary, good communication between regulatory bodies, public health authorities, companies and health care providers or vaccinators is crucial. Recommendations as well as labels and label changes should be evidence-based. The rationale for the discrepancy and the recommended off-label use of a vaccine should be communicated to providers.


Preconception counselling for low health literate women: an exploration of determinants in the Netherlands.
Women from lower socioeconomic groups tend to be at greater risk of adverse perinatal outcomes, but are less likely to participate in preconception counselling compared to higher socioeconomic groups. This could be partly because of their limited skills to assess, understand and use health related information in ways that promote and maintain good health (health literacy skills). In this study we explored determinants of participation in preconception counselling among women with low health literacy in The Netherlands. Potential determinants of participation in preconception counselling were derived from the literature, and mapped onto a theoretical framework, which was tested for perceived relevance and completeness in an expert review (n = 20). The framework was used to prepare face-to-face interviews with women with low health literacy and a wish to conceive (n = 139). In the interviews we explored preconception counselling awareness, knowledge, considerations, subjective norms, self-efficacy, attitude, and intention. Linear regression analyses were used to test associations with intention to participate in preconception counselling. Most women (75%) were unaware of the concept of preconception counselling and the provision of counselling, even if they lived in areas where written invitations had been disseminated. Common considerations for participation were: preparation for pregnancy; perceived lack of information; and problems in a previous pregnancy. Considerations not to participate were mostly related to perceived sufficient knowledge and perceived low risk of perinatal problems. Respondents generally had a positive attitude towards participation in preconception counselling for themselves, and 41% reported that they would participate in preconception counselling. Women with low health literacy were generally unaware of the concept and provision of preconception counselling, but seemed to be interested in participation. Further research should investigate how to effectively reach and inform this group about preconception counselling. This knowledge is essential for evidence-based development of interventions to increase the accessibility and understanding of preconception counselling.


Appendectomy in South African inter-ethnic school pupils.
In 1984-1985, prevalences of appendectomy in inter-ethnic series of South African school pupils of 16-18 yr were: rural blacks, 0.5%; urban blacks, 1.0%; Indians, 2.6%; coloreds (Eur-African-Malay), 2.2%; Afrikaans whites, 13.4%; and English whites, 9.9%. Corresponding respective annual incidences per 1000 pupils of 10-19 yr were: 0.3, 0.6, 1.9, 1.7, 9.8, and 7.8. Thus, appendectomy is rare or infrequent in all except the white populations. Peak occurrence was postpubertal. There was no consistent sex bias. Dietarily, mean daily fiber intake was relatively low in all groups, 17.9-26.1 g. While the percentage of energy from fat intake was low in blacks, 16.3-22.3%, it was much higher in the other populations, 32.7-39.5%. Clearly, factors other than diet are involved in regulating frequency of appendectomy. While mortality is negligible and morbidity slight, elucidation of causation and prevention of the disease is desirable since subsequently appendectomy patients are at greater than average risk to certain cancers.


Genomewide association study of reproductive efficiency in female cattle.
Reproductive efficiency is of economic importance in commercial beef cattle production, as failure to achieve pregnancy reduces the number of calves marketed per cow exposed. Identification of genetic markers with predictive merit for reproductive success would facilitate early selection of sires with daughters having improved reproductive rate without increasing generation intervals. To identify regions of the genome harboring variation affecting reproductive success, we applied a genomewide association study (GWAS) approach based on the >700,000 SNP marker assay, using a procedure based on genotyping multianimal pools of DNA to increase the number of animals that could be genotyped with available resources. Cows from several populations were classified according to reproductive efficiency, and DNA was pooled within population and phenotype prior to genotyping. Populations evaluated included a research population at the U.S. Meat Animal Research Center, 2 large commercial ranch populations, and a number of smaller populations (<100 head) across the United States. We detected 2 SNP with significant genomewide association (P ≤ 1.49 × 10(-7)), on BTA21 and BTA29, 3 SNP with suggestive associations (P ≤ 2.91 × 10(-6)) on BTA5, and 1 SNP with suggestive association each on BTA1 and BTA25. In addition to our novel findings, we confirmed previously published associations for SNP on BTA-X and all autosomes except 3 (BTA21, BTA22, and BTA28) encompassing substantial breed diversity including Bos indicus and Bos taurus breeds. The study identified regions of the genome associated with reproductive efficiency, which are being targeted for further analysis to develop robust marker systems, and demonstrated that DNA pooling can be used to substantially reduce the cost of GWAS in cattle.


Neuromelanin magnetic resonance imaging in Parkinson's disease and multiple system atrophy.
Pigmented neurons in the substantia nigra pars compacta (SNc) and locus coeruleus (LC) show decreased numbers differentially in Parkinson's disease (PD) and multiple system atrophy (MSA). Recent reports have described that fast spin-echo T1-weighted magnetic resonance imaging (MRI) by a 3-tesla machine can visualize neuromelanin-related contrast of the noradrenergic and dopaminergic neurons respectively in the LC and the SNc. Using neuromelanin MRI at 3 T, we investigated possible alterations of these catecholaminergic neurons in 32 PD and 9 MSA patients, and compared the results with those of 23 normal volunteers. The contrast ratio of the LC and SNc was decreased in MSA and PD patients, most prominently in the LC in MSA patients. The contrast ratio of the SNc was correlated with the Hoehn-Yahr stage of PD and the severity of neuroradiological abnormalities in MSA. These results indicate a potential diagnostic value of neuromelanin MRI to distinguish MSA patients from normal and PD patients.


Improving American Healthcare Through "Clinical Lab 2.0": A Project Santa Fe Report.
Project Santa Fe was established both to provide thought leadership and to help develop the evidence base for the valuation of clinical laboratory services in the next era of American healthcare. The participants in Project Santa Fe represent major regional health systems that can operationalize laboratory-driven innovations and test their valuation in diverse regional marketplaces in the United States. We provide recommendations from the inaugural March 2016 meeting of Project Santa Fe. Specifically, in the transition from volume-based to value-based health care, clinical laboratories are called upon to provide programmatic leadership in reducing total cost of care through optimization of time-to-diagnosis and time-to-effective therapeutics, optimization of care coordination, and programmatic support of wellness care, screening, and monitoring. This call to action is more than working with industry stakeholders on the basis of our expertise; it is providing leadership in creating the programs that accomplish these objectives. In so doing, clinical laboratories can be effectors in identifying patients at risk for escalation in care, closing gaps in care, and optimizing outcomes of health care innovation. We also hope that, through such activities, the evidence base will be created for the new value propositions of integrated laboratory networks. In the very simplest sense, this effort to create "Clinical Lab 2.0" will establish the impact of laboratory diagnostics on the full 100% spend in American healthcare, not just the 2.5% spend attributed to in vitro diagnostics. In so doing, our aim is to empower regional and local laboratories to thrive under new models of payment in the next era of American health care delivery.


Simultaneous alignment and folding of protein sequences.
Accurate comparative analysis tools for low-homology proteins remains a difficult challenge in computational biology, especially sequence alignment and consensus folding problems. We present partiFold-Align, the first algorithm for simultaneous alignment and consensus folding of unaligned protein sequences; the algorithm's complexity is polynomial in time and space. Algorithmically, partiFold-Align exploits sparsity in the set of super-secondary structure pairings and alignment candidates to achieve an effectively cubic running time for simultaneous pairwise alignment and folding. We demonstrate the efficacy of these techniques on transmembrane β-barrel proteins, an important yet difficult class of proteins with few known three-dimensional structures. Testing against structurally derived sequence alignments, partiFold-Align significantly outperforms state-of-the-art pairwise and multiple sequence alignment tools in the most difficult low-sequence homology case. It also improves secondary structure prediction where current approaches fail. Importantly, partiFold-Align requires no prior training. These general techniques are widely applicable to many more protein families (partiFold-Align is available at http://partifold.csail.mit.edu/ ).


Identifying unmet needs from the General Medical Council Gateways to the Professions guidance.
This article was migrated. The article was marked as recommended. The General Medical Council (GMC) commissioned The RTK Ltd to conduct a research project to inform a revision of the Gateways to the Professions guidance (The Guidance). The Guidance supports medical education providers to ensure that disabled students and doctors in training (disabled learners) do not face unnecessary barriers to successful medical careers. The researchers consulted with medical schools, HEE Local Teams, deaneries and employers on their use of the current guidance and good practice. They also interviewed medical students to better understand their experiences of admissions procedures and the support they were able to access during their period of study. It was evident that the provision for disabled learners is varied; the research found no single established model of support. However, the interviews revealed some key principles of good practice and innovative suggestions for future provision. Medical education providers perceived a need for a revised version of The Guidance to reflect good practice and provide more specific advice to them as well as to leaners.


Multiplication of human rotavirus in cultured cells: an electron microscopic study.
Human rotaviruses were capable of efficient multiplication in LLC-MK2 cells when the inoculum was pre-treated with trypsin, centrifuged on to the cell monolayer and the infected cells maintained in a medium containing trypsin. However, not all of the human rotavirus isolates used to infect cells resulted in efficient virus production. The ability of human isolates to multiply in cultured cells was studied by direct observation of virus in the electron microscope, by radioactive labelling with 3H-uridine of the newly synthesized virus and by electron microscopic examination of thin sectioned infected cells. With one of the specimens used (F-617) only 5 to 10% of the cells showed evidence of virus multiplication, with the great majority of the infected cells showing numerous complete (double-capsid) virus particles scattered in the cytoplasm. When cells were inoculated with another human specimen (SIB-I), infected cells were more abundant, reaching a maximum of 60%; however, a variety of particle types, probably representing different subviral structures or different steps of rotavirus morphogenesis, were commonly observed. The presence of these aberrant or incomplete virus structures may represent a manifestation of the defectiveness of this virus and may explain the difficulties encountered in its serial passage.


Cryosurgical treatment of lentigo maligna.
Between the years 1973 and 1980, 20 patients with lentigo maligna were treated with cryosurgery. The tumors ranged in size from 1.0 to 7.0 cm (average size, 2.7 cm). The recurrence rate for all 20 patients was 10%. The mean average period for follow-up evaluation was 42.6 months. In selected cases (in particular, for patients of advanced age and with lesions of less than 4 cm), cryosurgery is of distinct value in the treatment of lentigo maligna. These tumors, small or large, warrant the use of temperature monitoring or the measurement of electrical current flow within the neoplasm during freezing. A longer follow-up period (for these patients and others) will determine the overall usefulness of cryosurgery in the treatment of lentigo maligna.


The Antioxidant Content of Coffee and Its In Vitro Activity as an Effect of Its Production Method and Roasting and Brewing Time.
Coffee is one of the most popular beverages in the world. The high production and health properties of coffee make it one of the best among daily drinks. Coffee is wrongly identified as only a stimulant because of its caffeine content. On the other hand, coffee is one of the best sources of other bioactive compounds, such as flavonoids and phenolic acids. Organic coffee is produced without artificial fertilizers and pesticides. Not only the high quality of beans but also roasting and brewing times guarantee the best taste and quality of coffee beverages. The aim of the present experiment was to determine the best level of roasting and brewing time for organic and conventional coffee. The experiment was carried out with Peru coffee beans from organic and conventional farms. The contents of caffeine and bioactive compounds were measured in different roasted and brewed coffee drinks. The obtained results showed that the conventional coffee contained significantly more caffeine, total flavonoids, and quercetin derivatives than the organic coffee. On the other hand, the organic coffee was characterized by a higher level of almost all bioactive compounds. The best level of roasting was determined to be medium, and the optimal brewing time was 3 minutes.


How effective are expressive writing interventions for adolescents? A meta-analytic review.
This meta-analysis evaluated the effects of the expressive writing intervention (EW; Pennebaker & Beall, 1986) among adolescents. Twenty-one independent studies that assessed the efficacy of expressive writing on youth samples aged 10-18 ears were collected and analyzed. Results indicated an overall mean g-effect size that was positive in direction but relatively small (0.127), as well as significant g-effect sizes ranging from 0.107 to 0.246 for the outcome domains of Emotional Distress, Problem Behavior, Social Adjustment, and School Participation. Few significant effects were found within specific outcome domains for putative moderator variables that included characteristics of the participants, intervention instructions, or research design. Studies involving adolescents with high levels of emotional problems at baseline reported larger effects on school performance. Studies that implemented a higher dosage intervention (i.e., greater number and, to some extent, greater spacing of sessions) reported larger effects on somatic complaints. Overall, the findings suggest that expressive writing tends to produce small yet significant improvements on adolescents' well-being. The findings highlight the importance of modifying the traditional expressive writing protocol to enhance its efficacy and reduce potential detrimental effects. At this stage of research the evidence on expressive writing as a viable intervention for adolescents is promising but not decisive.


Improved mean estimation and its application to diagonal discriminant analysis.
High-dimensional data such as microarrays have created new challenges to traditional statistical methods. One such example is on class prediction with high-dimension, low-sample size data. Due to the small sample size, the sample mean estimates are usually unreliable. As a consequence, the performance of the class prediction methods using the sample mean may also be unsatisfactory. To obtain more accurate estimation of parameters some statistical methods, such as regularizations through shrinkage, are often desired. In this article, we investigate the family of shrinkage estimators for the mean value under the quadratic loss function. The optimal shrinkage parameter is proposed under the scenario when the sample size is fixed and the dimension is large. We then construct a shrinkage-based diagonal discriminant rule by replacing the sample mean by the proposed shrinkage mean. Finally, we demonstrate via simulation studies and real data analysis that the proposed shrinkage-based rule outperforms its original competitor in a wide range of settings.


Improved accuracy of the exercise electrocardiogram: identification of three-vessel coronary disease in stable angina pectoris by analysis of peak rate-related changes in ST segments.
Exercise electrocardiography has relatively poor specificity and predictive accuracy for 3-vessel coronary artery disease (CAD) when conventional diagnostic criteria are used. However, electrocardiographic evaluation using linear regression analysis of the heart-rate (HR)-related change in ST-segment depression (ST/HR slope) is reported to accurately distinguish patients with from those without CAD, and to accurately separate patients with 1-, 2- and 3-vessel CAD. To assess the applicability of this method and to compare it with conventional interpretation, retrospective evaluation of 50 patients in whom exercise electrocardiography and coronary cineangiography had been performed for suspected CAD was conducted using a modified ST/HR slope analysis limited to leads V5, V6 and aVF. Eighteen patients had 3-vessel, 22 had 2-vessel, 6 had 1-vessel and 4 had no CAD. Standard electrocardiographic criteria (1 mm or more of horizontal or downsloping ST depression) identified 3-vessel CAD with a sensitivity of 78%, specificity of 56% and positive predictive value of only 50%. Peak ST/HR slope criteria (greater than or equal to 6.0 microV/beat/min) identified 3-vessel CAD with a sensitivity of 78%, specificity of 97% and positive predictive value of 93%. The overall test accuracy using measured peak ST/HR slope was 90%, compared with 64% for standard ST-depression criteria. In conclusion, analysis of the peak ST/HR slope can greatly improve the diagnostic accuracy of exercise electrocardiography, and further prospective study of this method is indicated.


Effectiveness of bacteriophages in the sputum of cystic fibrosis patients.
Bacteriophages have been shown to be effective for treating acute infections of the respiratory tract caused by antibiotic-resistant bacteria in animal models, but no evidence has yet been presented of their activity against pathogens in complex biological samples from chronically infected patients. We assessed the efficacy of a cocktail of ten bacteriophages infecting Pseudomonas aeruginosa following its addition to 58 sputum samples from cystic fibrosis (CF) patients collected at three different hospitals. Ten samples that did not contain P. aeruginosa were not analysed further. In the remaining 48 samples, the addition of bacteriophages led to a significant decrease in the levels of P. aeruginosa strains, as shown by comparison with controls, taking two variables (time and bacteriophages) into account (p = 0.024). In 45.8% of these samples, this decrease was accompanied by an increase in the number of bacteriophages. We also tested each of the ten bacteriophages individually against 20 colonies from each of these 48 samples and detected bacteriophage-susceptible bacteria in 64.6% of the samples. An analysis of the clinical data revealed no correlation between patient age, sex, duration of P. aeruginosa colonization, antibiotic treatment, FEV1 (forced expiratory volume in the first second) and the efficacy of bacteriophages. The demonstration that bacteriophages infect their bacterial hosts in the sputum environment, regardless of the clinical characteristics of the patients, represents a major step towards the development of bacteriophage therapy to treat chronic lung infections.


Bacillus brevis Migula 1900 taxonomy: reassociation and base composition of DNA.
Of 87 strains previously identified as Bacillus brevis Migula 1900, 58 had G + C contents of 47.0 to 51.9 mol%, a range that included the G + C content (48.7 mol%) of the type strain. The G + C contents for three other groups consisting of 5, 7, and 17 strains were 37.0 to 41.9, 42.0 to 46.9, and 52.0 mol% or higher, respectively. DNA reassociation studies showed that 25 of the 58 strains with G + C contents of 47.0 to 51.9 mol% were closely related genetically to the type strain and to each other. For the most part, this genetically related group was phenotypically homogeneous; variations in the fermentation of mannitol and mannose were observed. My results strongly suggest that many of the strains were misclassified as B. brevis. Consequently, much of the phenotypic heterogeneity of the species B. brevis Migula 1900 is not due to variations exhibited by genetically related organisms, but is the result of variability introduced by the presence of genetically unrelated strains.


Wanted DEAD/H or Alive: Helicases Winding Up in Cancers.
Cancer is one of the most studied areas of human biology over the past century. Despite having attracted much attention, hype, and investments, the search to find a cure for cancer remains an uphill battle. Recent discoveries that challenged the central dogma of molecular biology not only further increase the complexity but also demonstrate how various types of noncoding RNAs such as microRNA and long noncoding RNA, as well as their related processes such as RNA editing, are important in regulating gene expression. Parallel to this aspect, an increasing number of reports have focused on a family of proteins known as DEAD/H-box helicases involved in RNA metabolism, regulation of long and short noncoding RNAs, and novel roles as "editing helicases" and their association with cancers. This review summarizes recent findings on the roles of RNA helicases in various cancers, which are broadly classified into adult solid tumors, childhood solid tumors, leukemia, and cancer stem cells. The potential small molecule inhibitors of helicases and their therapeutic value are also discussed. In addition, analyzing next-generation sequencing data obtained from public portals and reviewing existing literature, we provide new insights on the potential of DEAD/H-box helicases to act as pharmacological drug targets in cancers.


A Pulmonary Trunk Banding Model of Pressure Overload Induced Right Ventricular Hypertrophy and Failure.
Right ventricular (RV) failure induced by sustained pressure overload is a major contributor to morbidity and mortality in several cardiopulmonary disorders. Reliable and reproducible animal models of RV failure are therefore warranted in order to investigate disease mechanisms and effects of potential therapeutic strategies. Banding of the pulmonary trunk is a common method to induce isolated RV hypertrophy but in general, previously described models have not succeeded in creating a stable model of RV hypertrophy and failure. We present a rat model of pressure overload induced RV hypertrophy caused by pulmonary trunk banding (PTB) that enables different phenotypes of RV hypertrophy with and without RV failure. We use a modified ligating clip applier to compress a titanium clip around the pulmonary trunk to a pre-set inner diameter. We use different clip diameters to induce different stages of disease progression from mild RV hypertrophy to decompensated RV failure. RV hypertrophy develops consistently in rats subjected to the PTB procedure and depending on the diameter of the applied banding clip, we can accurately reproduce different disease severities ranging from compensated hypertrophy to severe decompensated RV failure with extra-cardiac manifestations. The presented PTB model is a valid and robust model of pressure overload induced RV hypertrophy and failure that has several advantages to other banding models including high reproducibility and the possibility of inducing severe and decompensated RV failure.


Central retinal artery occlusion with an irido-embolus following carotid endarterectomy.
Endarterectomy is often the treatment of choice in carotid artery disease displaying significant stenosis of the internal carotid artery. This procedure is not without its complications, the most visually devastating being central retinal artery occlusion and secondary neovascularization. Such a case is presented here along with the interesting finding of a cholesterol irido-embolus, apparently the first citation in the ophthalmic literature to date.


The 1,2,3,4 phenomenon. Atrioventricular nodal gap in the dog.
This study confirms the facility with which the so-called 1,2,3,4 phenomenon can be reproduced in intact dog hearts. When a series of three atrial premature beats (A2, A3, A4) were delivered following a constant A1-A1 drive, we demonstrated a narrow zone of A1-A3 and A1-A4 intervals in which A4 conducted to the ventricles in the presence of A3 but not in its absence. We used His bundle and multiple atrial electrograms to produce the phenomenon in nine of 16 dogs. Facilitation of conduction of A4 (1) occurred above the His bundle, (2) occurred within narrow ranges of A1-A3 and A1-A4 intervals, (3) required penetration of A3 into the atrioventricular (AV) node, (4) required critically long A2-H2 intervals, (5) always was associated with prolonged A4-H4 intervals, and (6) was limited by atrial refractoriness. An apparent or pseudo-1,2,3,4 phenomenon demostrated in five of 16 dogs occurred with (1) latency between S4 and A4, (2) a sinus nodal or atrial reentry beat, or (3) an atrial escape beat. In the absence of A3, A4 could be made to conduct by preexciting the ventricle in advance of V2. We found no evidence for dual AV nodal pathways. Our results suggest that the underlying mechanism for the 1,2,3,4 phenomenon is analogous to the phenomenon of the gap in AV conduction.


Resources utilisation and economic burden of percutaneous vertebroplasty or percutaneous kyphoplasty for treatment of osteoporotic vertebral compression fractures in China: a retrospective claim database study.
Osteoporotic vertebral compression fractures (OVCF) is a common and often debilitating complication of osteoporosis, leading to significant morbidity and increased mortality. Percutaneous vertebroplasty (PVP) and Percutaneous kyphoplasty (PKP) are recommendable surgical treatments for OVCF. To evaluate PVP/PKP utilisation and their related direct medical costs for OVCF treatment in China from the payer perspective. A population-based medical claims database of a metropolitan city in China was analysed from the payer perspective, which included all inpatient claims from 01/01/2015 to 31/12/2017. All vertebral fractures patients that met the eligibility criteria (aged ≥50 years old, having vertebral fracture diagnosis, without unrelated diseases diagnoses such as tumour and scoliosis, received PVP/PKP) were deemed as OVCF patients. Baseline characteristics, surgery rate, length of stay in hospital, time to re-surgery, and costs (including costs per hospitalisation and annual costs) were described. Survival analysis function was used to estimate the re-surgery rate. Of the 50,686 patients with OVCF identified, 14,527 (28.66%) received a total number of 15,599 records of PVP/PKP surgeries from 2015 to 2017. Mean age was 75 at the first surgery captured in the database analysis period; females accounted for 79.54% of all cases. The median length of surgery stay was 9 days. Cumulative re-surgery rates were 1.22% in 30 days, 2.58% in 90 days, 3.61% in 183 days, 5.42% in 1 year, and 7.95% in 2 years. There was no significant difference in re-surgery rate between PVP and PKP (p = 0.3897). The median time to the re-surgery was 139 days. Mean costs per PVP/PKP-related hospitalisation were 35,906 CNY/5122 USD (34,195 CNY/4878USD for PVP, 44,414 CNY/6336 USD for PKP, p < 0.01). The overall costs of hospitalisation averaged 186.61 million CNY (26.62 million USD) per year in this metropolitan city. From 2015 to 2017, nearly one-third of OVCF inpatients received PVP/PKP and the re-surgery rate was 7.95%. PVP/PKP procedures for OVCF place a high economic burden for both the healthcare system and patients. Early detection and treatment of patients with osteoporosis are critical in China.


Efficacy and safety of entacapone in Parkinson's disease patients with suboptimal levodopa response: a 6-month randomized placebo-controlled double-blind study in Germany and Austria (Celomen study).
To determine the efficacy and safety of the catechol-O-methyltransferase (COMT) inhibitor entacapone, used as an adjunct to levodopa, in Parkinson's disease (PD) patients. In this parallel group, randomized, double-blind study, 301 PD patients, the majority with motor fluctuations, received entacapone (200 mg) or placebo with each daily dose of standard or controlled-release (CR) levodopa. The 24-week treatment period was followed by 2 weeks of entacapone withdrawal. Efficacy was determined by home diaries ('on' and 'off' times), Unified Parkinson's Disease Rating Scale (UPDRS) and changes in levodopa dosage, and safety by adverse-event inquiry, vital signs, electro cardiography (ECG) and laboratory tests. In the total population, the UPDRS activities of daily living and motor scores were significantly improved (P < 0.05) by entacapone vs placebo. In fluctuating patients, 'on' time increased (1.7 h) and 'off' time decreased (1.5 h) significantly more with entacapone than with placebo (0.5 and 0.6 h, respectively; P < 0.05), and the daily levodopa dose was reduced by 54 mg with entacapone and increased by 27 mg with placebo (P < 0.05). Entacapone benefit was lost on withdrawal. Entacapone efficacy was comparable between patients using CR and standard levodopa preparations. Increased dyskinesias (entacapone 34%, placebo 26%) and nausea (10 and 5%, respectively), mostly occurring shortly after treatment initiation, were generally managed by reducing the levodopa dose. Diarrhoea (entacapone 8%, placebo 4%) was seldom severe. There were no differences in vital signs, ECG or laboratory results. Entacapone is an effective and safe levodopa extender and enhancer, improving the symptomatic efficacy of levodopa in PD and adding to the patients' benefit.


Paracetamol voltammetric microsensors based on electrocopolymerized-molecularly imprinted film modified carbon fiber microelectrodes.
A molecularly imprinted polymer is presented as a carbon fiber microelectrode coating for determining the presence of paracetamol. The polymeric film was obtained by electrocopolymerization of o-phenylenediamine and aniline in the presence of the template molecule, through the use of cyclic voltammetry. After removing the template, the signals of the microsensor were converted into physical ones by a voltammetric transductor using square wave voltammetry. Various parameters influencing the electropolymerization and voltammetric determination processes were examined and optimized. The response of the imprinted microsensor to paracetamol was linearly proportional to its concentration over the range 6.5 x 10(-6) to 2.0 x 10(-3) mol l(-1), with good stability and reproducibility (RSD < 5.6%). The detection limit was 1.5 microM. Under the experimental conditions used the voltammetric microsensor was able to differentiate between paracetamol and other closely structurally-related compounds present in biological fluids, such as certain catecholamines.


Considerations in glaucoma therapy: fixed combinations versus their component medications.
Fixed combinations of medications that lower intraocular pressure (IOP) are increasingly used in the treatment of glaucoma and ocular hypertension and offer several potential advantages over combined use of the separate component medications including enhanced convenience, improved adherence, reduced exposure to preservatives, and possible cost savings. This review aims to examine the current role of IOP-lowering fixed combinations in disease management. The results of studies that compared the efficacy and safety of IOP-lowering fixed combinations with their component medications are summarized, including those fixed combinations that consist of a prostaglandin analog and timolol. The fixed combinations currently available for use in the United States are fixed-combination dorzolamide/timolol (FCDT) and fixed-combination brimonidine/timolol (FCBT). Both of these fixed combinations reduce IOP more effectively than their component medications used separately as monotherapy. FCBT therapy also demonstrates a more favorable safety profile and reduced ocular allergy compared to monotherapy with brimonidine, a component medication. Few studies have directly compared the efficacy and safety of FCDT and FCBT, but available evidence suggests that FCBT is at least as effective as FCDT in lowering IOP and is more comfortable and better tolerated. Additional studies are needed to further evaluate the comparative efficacy and tolerability of FCDT and FCBT in the management of glaucoma and ocular hypertension.


Total synthesis of (±)-mersicarpine following a 6-exo-trig radical cyclization.
Described is a total synthesis of racemic mersicarpine from diethyl 4-oxopimelate. The synthetic route takes advantage of a 2-indolyl radical cyclization to construct the pyrido[1,2-a]indole scaffold bearing the all-carbon quaternary stereocenter.


Generation and Characterization of a meta-Aryne on Cu and NaCl Surfaces.
We describe the generation of a meta-aryne at low temperature (T = 5 K) using atomic manipulation on Cu(111) and on bilayer NaCl on Cu(111). We observe different voltage thresholds for dehalogenation of the precursor and different reaction products depending on the substrate surface. The chemical structure is resolved by atomic force microscopy with CO-terminated tips, revealing the radical positions and confirming a diradical rather than an anti-Bredt olefin structure for this meta-aryne on NaCl.


The association between HIV and antituberculosis drug resistance.
In the UK, HIV is considered to be a risk factor for antituberculosis drug resistance. Evidence of the association is, however, inconclusive and there are few population-level data. The present study investigated the association in England and Wales during the period 1999-2005. National tuberculosis surveillance data for adults were matched to HIV/AIDS reports. Unmatched cases were assumed to be HIV-negative. Separate analyses were conducted on new tuberculosis cases and those with a previous diagnosis. Logistic regression was used for univariable and multivariable analyses. There were 1,657 previously diagnosed cases (80 HIV-positive) and 18,130 new cases (1,156 HIV-positive). Isoniazid resistance was found in 8.1% of previously diagnosed cases and 6.6% of new cases, and multidrug resistance in 2.8% and 0.7%, respectively. There was no evidence of an association between HIV and antituberculosis drug resistance among previously diagnosed cases. Among new cases, there was no overall association between HIV and isoniazid or multidrug resistance after adjusting for confounding factors. White HIV-positive patients were more likely to have multidrug resistance, but numbers were small. In contrast to some previous studies, this large, up-to-date study provides little evidence that HIV co-infected tuberculosis patients in England and Wales are at increased risk of firstline antituberculosis drug resistance.


Psychological interventions targeting partners of cancer patients: A systematic review.
Cancer patients' intimate partners often experience levels of psychological burden that are comparable to or even exceed that of the patients, making it imperative that they too be provided with appropriate psychological support. This review aimed to present the content and the effects of interventions delivered to caregiving partners of cancer patients on both partners and patients. Furthermore, we provide information about the acceptability of the interventions and study quality. An initial search in Web of Science, PsycINFO, and PubMed databases was conducted. We included RCTs as well as pre-post studies that focused on enhancing partners' wellbeing or diminishing partners' distress. To be included, interventions had to have been offered to partners either only or predominantly. We included studies published until December 2017. The methodological quality of the trials was assessed with the EPHPP assessment tool. Nine studies met the inclusion criteria. Intervention topics included social support, short-term problem solving, the marital relationship quality, role expectations, emotional resilience, and coping strategies. Positive intervention effects were found with regard to social support, emotional distress, improved communication, posttraumatic growth, self-efficacy, and coping. Despite considerably low response rates, the interventions were generally well accepted. Most of the studies suffer limitations because of methodological flaws, the lack of randomization, and small sample sizes. Interventions delivered to partners of cancer patients may have positive effects on both partners and patients. We derive several implications for future research: Intervention programs should be tailored to the specific needs of caregiving partners with regard to the cancer trajectory and gender. Effort has to be made to increase sample sizes as well as to include particularly burdened individuals. Selected measurement instruments should be sensitive to specific intervention effects. Finally, information on both statistical as well as clinical relevance of research findings should be provided.


Comparison of albuterol and isoproterenol aerosols in bronchial asthma.
Albuterol and isoproterenol aerosols were compared with placebo in a double-blind manner in 18 patients with bronchial asthma. Both drugs elicited significant improvement in flow rates and vital capacity. Duration of action was longer with albuterol than with isoproterenol. Neither was associated with significant increases in heart rate or blood pressure.


Negative affect, relapse, and Alcoholics Anonymous (AA): does AA work by reducing anger?
Anger and other indices of negative affect have been implicated in a stress-induced pathway to relapse. The Alcoholics Anonymous (AA) literature states that reduction of anger is critical to recovery, yet this proposed mechanism has rarely been investigated. Using lagged, controlled hierarchical linear modeling analyses, this study investigated whether AA attendance mobilized changes in anger and whether such changes explained AA-related benefit. Alcohol-dependent adults (N = 1,706) receiving treatment as part of a clinical trial were assessed at intake and at 3, 6, 9, 12, and 15 months. Findings revealed substantially elevated levels of anger compared with the general population (98th percentile) that decreased over 15-month follow-up but remained high (89th percentile). AA attendance was associated with better drinking outcomes, and higher levels of anger were associated with heavier drinking. However, AA attendance was unrelated to changes in anger. Although support was not found for anger as a mediator, there was strong convergence between AA's explicit emphasis on anger and the present findings: Anger appears to be a serious, enduring problem related to relapse and heavy alcohol consumption. Methodological factors may have contributed to the lack of association between AA and anger, but results suggest that AA attendance alone may be insufficient to alleviate the suffering and alcohol-related risks specifically associated with anger.


In vitro evidence of tissue susceptibility rhythms. I. Temporal variation in effect of potassium chloride and phenylephrine on rat aorta.
In this study, time-dependent variations in the in vitro sensitivity of rat thoracic aorta rings to potassium chloride (KCl) and phenylephrine (Phe) were investigated. Animals were synchronized with a 12h light and 12h darkness (lights on 08:00-20:00) schedule, and thoracic aortas were obtained at six different times of the day (1, 5, 9, 13, 17, and 21 hours after lights on). In order to avoid endothelial influence, all experiments were performed in endothelium-denuded preparations. Responses to KCI showed time-dependent variations in all the concentrations used. Phe-induced contractions also exhibited time-dependent differences. The rhythmic pattern of Phe responses did not change with the presence of the alpha1-adrenergic antagonist prazosin. In addition, both the EC50 values of KCl and Phe, and also the K(B) values of prazosin, displayed rhythmicity. In conclusion, time of obtaining tissues is an important factor for experimental standardization in, at least, vascular smooth muscle preparations.


Chamber-confined silicon-carbon nanofiber composites for prolonged cycling life of Li-ion batteries.
Silicon is a promising high capacity (4200 mA h g(-1)) anode material for lithium ion batteries but the significant volume change (over 300%) of silicon during lithiation/delithiation remains a challenge in terms of silicon pulverization and solid-electrolyte-interphase (SEI) accumulation in the silicon composite electrode. To alleviate the volumetric change of silicon, we built a flexible and self-supporting carbon-enhanced carbon nanofiber (CNF) structure with vacant chamber to encapsulate Si nanoparticles (vacant Si@CNF@C). This composite was tested directly without any polymer and current collector. The confined vacant chamber allowed the increasing volume of silicon and SEI accumulates to be well retained for a long cycle life. This chamber-confined silicon-carbon nanofiber composite exhibited an improved performance in terms of good cycling performance (620 mA h g(-1)), high coulombic efficiency (99%), and good capacity retention (80%) after 200 cycles. This self-supported silicon-carbon nanofiber structure showed high flexibility and good electrochemical performance for the potential as flexible electrode for lithium-ion batteries.


The International Classification of Functioning, Disability and Health (ICF) Core Sets for rheumatoid arthritis: a way to specify functioning.
Today, patients' functioning is a central issue in medicine. Concepts, classifications, and measurements of functioning and health, such as the International Classification of Functioning, Disability and Health (ICF) are of prime importance in clinical practice, teaching, and research. This report compares the contents of three of the most widely used health status measures in rheumatoid arthritis (RA), namely the Health Assessment Questionnaire disability index (HAQ), the Arthritis Impact Measurement Scales 2 (AIMS2), and the Short Form health survey (SF-36) based on the ICF. In addition, their content is compared to the Comprehensive ICF Core Set for RA. The comparisons illustrate that the different health status measures cover different components, and that they cover the different components with different level of precision. Using the ICF as a reference framework allows a researcher or a recommending instance to see which domains are covered in a specific instrument and, therefore, whether it is necessary to complement the study with other measures. Nevertheless, which specific health status measures to recommend still remains a challenge. If enough care is taken to define "what should be measured", it could form the basis for a solid and stable recommendation, adhered to for many years.


Direct and uninterrupted RNA amplification of enteroviruses with colorimetric microwell detection.
Enteroviruses (EV) cause a broad spectrum of human diseases, of which aseptic meningitis is among the most common and most clinically vexing. While the clinical symptoms of meningitis caused by bacteria, fungi and viruses are similar, the diagnosis, therapy and outcome of disease caused by these agents vary greatly. In order to appropriately manage meningitis patients, rapid and reliable diagnosis of EV meningitis impacts significantly on patient management. To develop a direct and uninterrupted RNA amplification of enteroviruses using rTth DNA polymerase. Purified coxsackievirus B6 RNA of various concentrations was amplified by rTth DNA polymerase-mediated amplification to determine analytic sensitivity. The specificity of the EV amplification was examined with a panel of nucleic acids from 36 EV serotypes, 15 non-EV pathogens and 10 coded clinical specimens of cerebrospinal fluid (CSF). All EV serotypes tested were detected successfully by this method at a sensitivity of 1 TCID(50) with the exception of echoviruses 1, 5, 22 and 23. Echovirus 5 was detected at 10 TCID(50), and echovirus 1 was detected at 100 TCID(50). Echoviruses 22 and 23 were not detectable at 100 TCID(50). Cross-reactivity of EV RT-PCR assay with 15 known non-EV meningitis pathogens has not been observed. Results of 10 CSF tested with this system correlated well with tissue culture. We have developed an EV amplification assay which has several important advantages over previously reported methods. This assay employs rTth DNA polymerase which possesses both reverse transcriptase and DNA polymerase activities, simplifying RNA reverse transcription and DNA amplification to an uninterrupted reaction. Additionally, potential carryover contamination and enhanced amplification specificity is provided by substituting dUTP for dTTP and adding uracil N-glycosylase (UNG) in the amplification reaction. Finally, the detection of amplified product is via a colorimetric, microwell format permitting the use of readily available instrumentation.


The multiplicity of combinations of myosin light chains and heavy chains in histochemically typed single fibres. Rabbit tibialis anterior muscle.
1. Combined histochemical and biochemical single-fibre analyses [Staron & Pette (1987) Biochem. J. 243, 687-693], were used to investigate the rabbit tibialis-anterior fibre population. 2. This muscle is composed of four histochemically defined fibre types (I, IIC, IIA and IIB). 3. Type I fibres contain slow myosin light chains LC1s and LC2 and the slow myosin heavy chain HCI, and types IIA and IIB contain the fast myosin light chains LC1f, LC2f and LC3f and the fast heavy chains HCIIa and HCIIb respectively. 4. A small fraction of fibres (IIAB), histochemically intermediate between types IIA and IIB, contain the fast light myosin chains but display a coexistence of HCIIa and HCIIb. 5. Similarly to the soleus muscle, C fibres in the tibialis anterior muscle contain both fast and slow myosin light chains and heavy chains. The IIC fibres show a predominance of the fast forms and the IC fibres (histochemically intermediate between types I and IIC) a predominance of the slow forms. 6. A total of 60 theoretical isomyosins can be derived from these findings on the distribution of fast and slow myosin light and heavy chains in the fibres of rabbit tibialis anterior muscle.


Can the use of probiotics in association with isoflavone improve the symptoms of genitourinary syndrome of menopause? Results from a randomized controlled trial.
To evaluate the effect of isoflavone administration, either in conjunction with probiotic use or not, on the symptoms of genitourinary syndrome of menopause, and compare the effects with those of hormone therapy. A randomized clinical trial was conducted on 60 postmenopausal women aged 40 to 60 years, randomly assigned to receive oral isoflavone (150 mg dry extract of glycine max) alone or isoflavone plus probiotic (Lactobacillus acidophilus, Lactobacillus casei, Lactococcus lactis, Bifidobacterium bifidum, and Bifidobacterium lactis) or hormone therapy (1 mg estradiol and 0.5 mg norethisterone acetate). The urogenital symptom subscale of the Menopause Rating Scale and International Consultation on Incontinence Questionnaire-Short Form were used to assess genitourinary symptoms. Vaginal maturation value, pH, vaginal health score, and vaginal flora were used to evaluate vaginal atrophy. Equol, equol intermediate, O-dimethylangolensin, and aglycones were measured using gas chromatography coupled to mass spectrometry. After 16 weeks of treatment, the urogenital symptoms, mainly vaginal dryness and sexual problem complaints, improved significantly in the hormone therapy group. There was a significant increase in the daidzein, glycitein, equol intermediate, and O-dimethylangolensin contents after 16 weeks in the isoflavone plus probiotic group. The maturation value, vaginal pH, and vaginal flora improved in the hormone therapy group. The vaginal health score increased in the isoflavone and hormone therapy groups. Probiotics improved the metabolism of isoflavones after 16 weeks of treatment. However, the increase in the contents of isoflavones and their metabolites failed to yield an estrogenic effect on the urogenital tract and relieve the vulvovaginal symptoms.


Effect of calcium electroporation in combination with metformin in vivo and correlation between viability and intracellular ATP level after calcium electroporation in vitro.
Calcium electroporation is a new experimental anti-cancer treatment where calcium is internalized into cells by application of short, high voltage pulses. Calcium electroporation has been shown to induce tumor necrosis associated with ATP depletion while the effect on normal fibroblasts was limited when investigated in a 3D in vitro spheroid model. We aimed to investigate the effect of calcium electroporation in combination with metformin, a drug that affects intracellular ATP level. We also aimed to study the relationship between the viability and intracellular ATP levels after calcium electroporation in vitro. In this study, we investigated the effect of calcium electroporation with metformin on NMRI-Foxn1nu mice in vivo on tumor size, survival, and intracellular ATP. We further investigated viability and intracellular ATP level in vitro after calcium electroporation in two human cancer cell lines: Breast (MDA-MB231) and colon (HT29), and in normal human fibroblasts (HDF-n), as well as investigating viability in human bladder cancer cells (SW780) and human small cell lung cancer cells (H69) where we have previously published intracellular ATP levels. Calcium electroporation significantly reduced the size and ATP level of bladder cancer tumors treated in vivo but no increased effect of metformin combined with calcium electroporation was shown on neither tumor size, survival, nor ATP level. Calcium electroporation in vitro significantly decreased viability compared with calcium alone (p<0.0001 for calcium concentrations from 0.5 mM for H69, HDF-n, and MDA-MB231; p<0.0001 for calcium concentrations from 1 mM for HT29 and SW780). Intracellular ATP levels decreased significantly after calcium electroporation (p<0.05), however no correlation between intracellular ATP level and viability after treatment was observed. Calcium electroporation caused reduced tumor size, increased survival, and acute ATP depletion in vivo. This effect was not augmented by metformin. Calcium electroporation is a possible novel anti-cancer treatment that has been shown to cause cell death associated with acute ATP depletion in vitro and in vivo.


Treating Cryptosporidium parvum infection in calves.
The present study evaluated the therapeutic efficacy of azithromycin, co-trimoxazole and kalvangi (Nigella sativa, also known as Black Cumin) against Cryptosporidium parvum infection in calves under field conditions. The experimental calves were treated with azithromycin (group A) at 1500 mg/calf/day, co-trimoxazole (group B) at 30 mg Kg-1 and kalvangi seeds powder (group C) at 750 mg Kg-1 BW orally for 7 days. Calves in the group D were naturally infected with C. parvum , untreated animals (positive control) while the calves in the group E were uninfected negative control animals. A significant decrease (p < 0.05) in oocyst counts for calves in groups A, B and C was observed compared to group D. When the oocyst counts amongst the treatment groups A, B and C were compared, a significant decrease (p < 0.05) was observed in group A. On day 21 post-treatment, the efficacy of azithromycin, co-trimoxazole and kalvangi in calves was 88.2% (95% C.I. ± 15.4), 45% (95% C.I. ± 21.8) and 27.8% (95% C.I. ± 20.7), respectively. This study confirmed previous reports of azithromycin efficacy against C. parvum infection, but found co-trimoxazole and kalvangi to be ineffective for this infection under these treatment regimens.


[Continuing care of patients with cardiovascular risk in general practice: patients with hypertension and their care].
Hypertension is an independent cardiovascular risk factor, therefore continuing care of patients with hypertension is an important task in cardiovascular prevention. This study was aimed to investigate continuing care of hypertension in general practices. Method of the study was a questionnaire survey, and 830 adult patients were involved. Forms contained information about duration of continuing care, associated risk factors, therapy, damages of target organs, and blood pressure values attained. Blood pressure measurement and hypertension grading were performed by the recommendation of the Hungarian Hypertension Society. Ratios of men and women participated in the study were 39.8% and 60.2%, respectively. Duration of hypertension care was 10.7 +/- 8.3 year. The care was initiated because of moderate and serious hypertension in 51.4% and 32.7%, respectively. Frequencies of cardiovascular, cerebrovascular and peripheral vascular problems were parallelly increased with severity of hypertension. Frequency of all types of antihypertensive drugs used were also increased with the hypertension grades. The most frequently used drugs were ACE-inhibitors. The target blood pressure of 140/90 Hgmm was reached in 46.4%, and according to blood pressure measured during the last year of continuing care, patients had mild hypertension in 41.5%, moderate in 7.6%, and serious one in 0.9%. Effectiveness of the hypertension care, based on decrease in blood pressure, was associated with severity of hypertension at the time of its diagnosis, the patients' age, but not with their gender. Summarizing, our results prove that there is a need for intensification of early detection, treatment and continuing care of hypertension.


New, ultrasensitive enzyme immunoassay for detecting vaccine- and disease-induced hepatitis A virus-specific immunoglobulin G in saliva.
Although detection of disease-induced hepatitis A virus (HAV)-specific antibodies in saliva has been successfully utilized in a few epidemiological studies, available assays fail to detect lower salivary anti-HAV levels associated with vaccine-induced immunity. We present a new capture enzyme immunoassay which employs a three-layer antibody recognition system. Evaluation of paired saliva-serum specimens from 1,025 international travellers, 134 other volunteers, and 91 hepatitis A vaccine recipients demonstrated 99.6% (95% confidence interval, 98.4 to 99.9) specificity and 98.7% (95% confidence interval, 97.7 to 99.4) sensitivity of this salivary assay in differentiating between immune and susceptible individuals, compared with serum-based methods. We conclude that this assay is sufficiently sensitive for reliable detection of both vaccine- and infection-induced HAV-specific immunoglobulin G in saliva, even when corresponding anti-HAV levels in serum are very low (< 1 IU/ml).


[Recommendation for validation and routine monitoring of sterilization processes with ethylene oxide for medical devices].
The European Medical Device Directives specifically address sterilization issues in a number of instances. The European Standards for sterilization of medical devices, especially EN 550, EN 554, EN 556 regulate the manufacture, installation and operation of sterilizers as well as the validation of sterilization processes, on using ethylene oxide (EN 550) or moist heat (EN 554) for sterilization. This recommendation is intended as a source of information for conducting validation according to EN 550 and concomitantly for ensuring that the medical devices reprocessed (cleaned, disinfected, packed, sterilized, stored) in the hospital setting or in other healthcare establishments are endowed with the same level of safety with respect to sterility as that of industrially produced and marketed sterile medical devices.


Design of random and sparse metalens with matrix pencil method.
We propose a matrix pencil method for designing one- or two- dimensional (1D or 2D) metalenses with randomly distributed meta-atoms. In contrast to the standard random synthesis algorithm that only randomizes the position of the meta-atoms, the proposed method designs both the position and phase of each meta-atom rigorously. Several all-dielectric random metalenses, in both 1D and 2D operating at 220 GHz, are presented by using our proposed algorithm. Minimum reduction of focusing efficiency can be achieved with respect to a standard metalens with periodically arranged meta-atoms. In contrast to previously reported random metalenses, our random metalenses achieve much higher efficiency, while staying polarization-independent. This synthesis method will pave a way for future random-metasurface-based device designs, which could have more degrees of freedom to information multiplexing.


Cardiac arrest in pregnancy and perimortem cesarean delivery: case report and discussion.
Cardiac arrest in pregnancy is a rare occurrence, particularly in the emergency department setting. The resuscitation of a pregnant patient in cardiac arrest is unique in a number of ways. Early identification and treatment of possible etiologies, appropriate response to the physiologic changes present in pregnancy, relief of potential vena cava obstruction by the gravid uterus, and expeditious preparation for possible cesarean delivery are important considerations for a successful resuscitation. We report and discuss the case of a pregnant patient with pulmonary edema and cardiac dysfunction who presented with severe hypoxemia and subsequent cardiac arrest and underwent a perimortem cesarean delivery and simultaneous fetal and maternal resuscitation in the emergency department.


The Adoption of Roles by Primary Care Providers during Implementation of the New Chronic Disease Guidelines in Urban Mongolia: A Qualitative Study.
(1) BACKGROUND: In 2011, new chronic disease guidelines were introduced across Mongolia. No formal advice was provided regarding role delineation. This study aimed to analyse the roles that different primary care providers adopted, and the variations in these, in the implementation of the guidelines in urban Mongolia; (2) METHODS: Ten group interviews with nurses and ten individual interviews each with practice doctors and practice directors were conducted. Data was analysed using a thematic approach based on the identified themes relevant to role delineation; (3) RESULTS: There was some variability and flexibility in role delineation. Factors involving teamwork, task rotation and practice flexibility facilitated well the guideline implementation. However, factors including expectations and decision making, nursing shortage, and training gaps adversely influenced in the roles and responsibilities. Some role confusion and dissatisfaction was identified, often associated with a lack of training or staff turnover; (4) CONCLUSIONS: Findings suggest that adequate ongoing training is required to maximize the range of roles particular provider types, especially primary care nurses, are competent to perform. Ensuring that role delineation is specified in guidelines could remove confusion and enhance implementation of such guidelines.


[Effect of protein content and thyroid hormone on body composition in growing rats].
The effects of an isocaloric control diet of high-protein and low-protein diets (in which protein amounted to 16, 62 and 2% of total calorie content, respectively) with and without simultaneous administration of Thyreotom or methylthiouracil on total body composition have been studied in growing male Wistar rats. In spite of higher average Kcal intake (per day and 100 g of body weight), the rats on the high-protein diet were weighing less than the control animals at the end of the experiment. As compared to the control animals, the rats on the high-protein diet as well as those on the low-protein diet showed a greater relative weight of the thyroid gland. The protein percentage of the body was not significantly increased by an increase in protein supply; likewise, it was not significantly reduced by a decrease in protein supply. The body fat content was by 2/3 lower in the rats on the lowprotein diet than in the control animals. This difference was statistically significant. Thyroid hormones (1 mug liothyronine + 4 mug levothyroxine/100 g body weight, administered orally for 3 weeks) produced a slight increase of body protein in the rats on the high-protein diet; they increased it significantly in the rats on the low-protein diet. Body fat was correspondingly reduced. Methylthiouracil reduces the body fat content in the control animals and in the rats on the high-protein diet; it increased the body fat content in the rats on the low-protein diet. Our results confirm the partial findings of human pathology and demonstrate clearly that nutritional diseases, especially protein deficiency, worsen considerably in case of concomitant disorders of thyroid hormone metabolism.


Persistence and Adherence to Psychostimulants, and Psychological Well-Being Up to 3 Years After Specialized Treatment of Adult Attention-Deficit/Hyperactivity Disorder: A Naturalistic Follow-Up Study.
Little is known about the long-term persistence and adherence of psychostimulant use in adults with attention-deficit/hyperactivity disorder (ADHD) and its relationship to their psychological well-being. The persistence and adherence to psychostimulants and psychological well-being were examined in adults with ADHD in a naturalistic follow-up, starting directly after discharge from their specialized treatment of ADHD at an outpatient ADHD clinic. Ninety-six patients were included at the time of discharge, who were interviewed by telephone at 6 months, 1 year, and 3 years after discharge. At the time of discharge, 78% used a psychostimulant prescribed by a psychiatrist. Of those on psychostimulants at the time of discharge, approximately half still used any of these psychostimulants 3 years after discharge. However, adherence rates were good for those who persisted to use psychostimulants. The female sex and middle educational level (relative to a higher educational level) were near-significantly related to nonpersistence, and having a higher educational level and the combined ADHD subtype were related to nonadherence. In turn, nonadherence was related to worse general functioning, lower mood, and poorer sleep quality. The importance of adherence should be discussed at the time of discharge, especially with female ADHD patients, those with a higher educational level, and those with a combined ADHD subtype, because nonadherence is associated with poorer outcomes.


Improving the peer review process in orthopaedic journals.
The peer review process for the evaluation of manuscripts for publication needs to be better understood by the orthopaedic community. Improving the degree of transparency surrounding the review process and educating orthopaedic surgeons on how to improve their manuscripts for submission will help improve both the review procedure and resultant feedback, with an increase in the quality of the subsequent publications. This article seeks to clarify the peer review process and suggest simple ways in which the quality of submissions can be improved to maximise publication success. Cite this article: Bone Joint Res 2013;2:245-7.


Median intradialytic blood pressure can track changes evoked by probing dry-weight.
Median BP obtained over a single dialysis treatment can diagnose hypertension among hemodialysis patients. Whether median BP is as useful to track change in BP is unknown. Among patients participating in the dry-weight reduction in hypertensive hemodialysis patients (DRIP) trial, interdialytic ambulatory BP was recorded at baseline, 4 weeks, and 8 weeks. The mean interdialytic ambulatory BP was compared to the following recordings: predialysis on one dialysis treatment (Pre1), predialysis averaged over 2 weeks of dialysis treatment (Pre6), postdialysis on one dialysis treatment (Post1), postdialysis averaged over 2 weeks of dialysis treatment (Post6), and median intradialytic BP over one treatment. Pre1 was unable to detect change in ambulatory BP. Although Pre6 was able to detect change, it overestimated the ambulatory BP. On average, the magnitude of reduction in Post1 in response to probing dry-weight was nearly twice that obtained by ambulatory BP monitoring. Even Post6 overestimated the magnitude of reduction in BP at 8 weeks. Median systolic BP was responsive to probing dry-weight and neither overestimated nor underestimated the interdialytic ambulatory systolic BP at baseline or over time. However, the SD of the differences between median systolic BP and interdialytic ambulatory systolic BP varied from 16 to 20 mmHg. Median intradialytic BP recordings can detect change in ambulatory BP evoked by reduction in dry-weight at the population level. Because of wide agreement limits between intradialytic and interdialytic BP, the individual prediction of ambulatory BP from median intradialytic BP can be misleading.


Laying hen behavior. 1. Effects of cage type and startle stimuli.
The well-being of commercial laying hens plays an important role in egg production. Behaviors such as pacing, displaced preening, increased aggression, and redirected activities have been associated with stress in poultry. This study was conducted to determine whether two strains of commercial layers, reported to differ in level of excitability, behave differently in two types of commercial cages. DeKalb Delta and Hy-Line W36 hens, 40 to 45 wk of age, were housed six to eight per cage in open or solid-sided cages, at an equal density between cages. For each strain, there were six cages per cage type for a total of 24 cages. In the first five experiments, behavioral data were obtained at a distance of 1 m by instantaneous or scan sampling. These experiments included hen behavior in both types of cages with and without the presence of frustrating or startle conditions. Some significant differences in behavior existed within experiments but not consistently among all experiments. Sampling method did not affect reliability of data collection. Two trials were then conducted to determine whether the length of time to return to normal activity after a startle stimulus is influenced by the cage type or strain. In the first startle experiment, DeKalb hens returned to normal activity more quickly than did Hy-Line hens (P = 0.07); this strain difference was not found when the experiment was repeated. Cage type did not appear to affect the behavior of birds adversely, although neither cage type appeared to confer an advantage. No clear differences were found in behavior by strain or by strain within cage.