Negotiating vaccine acceptance in an era of reluctance.
Studies to better understand the determinants of vaccine acceptance have expanded to include more investigation into dynamics of individual decision-making as well as the influences of peers and social networks. Vaccine acceptance is determined by a range of factors, from structural issues of supply, costs and access to services, as well as the more demand-side determinants. The term vaccine hesitancy is increasingly used in the investigation of demand-side determinants, moving away from the more polarized framing of pro- and anti-vaccine groups to recognizing the importance of understanding and engaging those who are delaying vaccination, accepting only some vaccines, or who are yet undecided, but reluctant. As hesitancy is a state of indecision, it is difficult to measure, but the stage of indecision is a critical time to engage and support the decision-making process. This article suggests modes of investigating the determinants of vaccine confidence and levers of vaccine acceptance toward better engagement and dialogue early in the process of decision-making. Pressure to vaccinate can be counter-productive. Listening and dialog can support individual decision-making and more effectively inform the public health community of the issues and concerns influencing vaccine hesitancy.


Essential oil from Fructus Alpiniae zerumbet ameliorates vascular endothelial cell senescence in diabetes by regulating PPAR-γ signalling: A 4D label-free quantitative proteomics and network pharmacology study.
Vascular endothelial cell senescence is associated with cardiovascular complications in diabetes. Essential oil from Fructus Alpiniae zerumbet (Pers.) B.L.Burtt & R.M.Sm. (EOFAZ) has potentially beneficial and promising diabetes-related vascular endothelial cell senescence-mitigating effects; however, the underlying molecular mechanisms remain unclear. To investigate the molecular effects of EOFAZ on vascular endothelial cell senescence in diabetes. A diabetes mouse model was developed using a high-fat and high-glucose diet (HFD) combined with intraperitoneal injection of low-dose streptozotocin (STZ, 30 mg/kg) and oral treatment with EOFAZ. 4D label-free quantitative proteomics, network pharmacology, and molecular docking techniques were employed to explore the molecular mechanisms via which EOFAZ alleviates diabetes-related vascular endothelial cell senescence. A human aortic endothelial cells (HAECs) senescence model was developed using high palmitic acid and high glucose (PA/HG) concentrations in vitro. Western blotting, immunofluorescence, SA-β-galactosidase staining, cell cycle, reactive oxygen species (ROS), cell migration, and enzyme linked immunosorbent assays were performed to determine the protective role of EOFAZ against vascular endothelial cell senescence in diabetes. Moreover, the PPAR-γ agonist rosiglitazone, inhibitor GW9662, and siRNA were used to verify the underlying mechanism by which EOFAZ combats vascular endothelial cell senescence in diabetes. EOFAZ treatment ameliorated abnormal lipid metabolism, vascular histopathological damage, and vascular endothelial aging in diabetic mice. Proteomics and network pharmacology analysis revealed that the differentially expressed proteins (DEPs) and drug-disease targets were associated with the peroxisome proliferator-activated receptor gamma (PPAR-γ) signalling pathway, a key player in vascular endothelial cell senescence. Molecular docking indicated that the small-molecule compounds in EOFAZ had a high affinity for the PPAR-γ protein. Western blotting and immunofluorescence analyses confirmed the significance of DEPs and the involvement of the PPAR-γ signalling pathway. In vitro, EOFAZ and rosiglitazone treatment reversed the effects of PA/HG on the number of senescent endothelial cells, expression of senescence-related proteins, the proportion of cells in the G0/G1 phase, ROS levels, cell migration rate, and expression of pro-inflammatory factors. The protective effects of EOFAZ against vascular endothelial cell senescence in diabetes were aborted following treatment with GW9662 or PPAR-γ siRNA. EOFAZ ameliorates vascular endothelial cell senescence in diabetes by activating PPAR-γ signalling. The results of the present study highlight the potential beneficial and promising therapeutic effects of EOFAZ and provide a basis for its clinical application in diabetes-related vascular endothelial cell senescence.


Knowledge of menstruation and fertility among adults in rural Western Kenya: Gaps and opportunities for support.
An understanding of menstruation and its relationship to fertility can help women know the gestational age of any pregnancies, and thus identify preterm births. It can also help women avoid unintended pregnancies. However, little is known about women, and especially men's, menstruation and fertility knowledge, outside of research on adolescent girls and stigma, and in low and middle income countries (LMIC). Additionally, little is known about practices surrounding the tracking of menstruation and fertility, and how, if at all, women would like to be supported in this. This research is the first phase in adapting a support tool for women in a LMIC, using an implementation science approach to understand relevant cultural needs. We explored women and men's understanding of the relationship between menstruation and fertility, and their interest in support tools, through in-depth qualitative interviews in rural western Kenya. We interviewed 45 adult men, adult women and adolescent women all who had children in 2018. We found high levels of misinformation about menstruation and fertility, with most respondents not knowing the correct times when a woman could become pregnant. Common sources of knowledge included friends/family and school. Few women got information from health providers, even when they were at a facility already for care. There were mixed feelings from women about wanting support from male partners regarding tracking menstruation. While women were interested in a tool that could help them track their menstruation and pregnancies, they had privacy concerns about a mobile health app approach and preferred simpler calendar based tools. This study provides evidence for the high need for correct menstruation information among both men and women, and not only for adolescents. It also suggests that despite the international health community's enthusiasm for mobile health solutions, that approach might not be most appropriate for this topic and setting.


A new small karst-dwelling species of Cyrtodactylus (Reptilia: Squamata: Gekkonidae) from Java, Indonesia.
A new small karst-dwelling species of the genus Cyrtodactylus is described from East Java and Special Province of Yogyakarta, Indonesia. Cyrtodactylus semiadii sp. nov. is a small species (SVL to 47.1 mm in females, 42.1 mm in males) distinguished from all other congeners by unique characters combination: short, robust, cylindrical tail, indistinct ventrolateral folds, absence of precloacal groove, absence of enlarged femoral scales, absence of precloacal and femoral pores and lack of enlarged median subcaudal scales. It is the third member of the genus recorded from Java.


Educating undergraduate occupational therapy and physiotherapy students in motivational interviewing: the student perspective.
Motivational Interviewing (MI) is an evidenced based talking therapy designed to affect client Health Behaviour Change. Previous research indicates that Allied Health Professionals (AHP) can effectively use the approach and training at pre-registration level has been piloted. However, student experiences of training is underexplored. To explore Physiotherapy and Occupational Therapy students' experiences of training in and implementation of Motivational Interviewing. Four focus groups including 24 undergraduates (14 OT and 10 PT) were conducted at the completion of the training and a subsequent clinical placement. Transcribed texts were analysed thematically. Data were triangulated with student written post-it notes and open questions in a post training questionnaire. Two overarching themes were developed from the data. Learning different ways to interact and the challenge of transformation illuminates specific aspects of the training which enabled learning as well as areas of contention. Using the spirit of MI, but not every contact counts highlights the facilitators and challenges of implementation on placements. Motivational interviewing is a useful addition to training neophyte health students. Key skills were adopted and in some cases transferred into practice. The process of learning indicates areas of potential improvement to enhance relevance of practice scenarios. The transfer to practice is more complex illustrating a need to negotiate professional and institutional expectations which should be considered in training.


[Choice of renal replacement therapy in patients with complicated uremia].
Fourteen patients with complicated uremia and multiple organ dysfunction syndrome were treated by renal replacement therapy (RRT), by hemodialysis and hemodiafiltration. Control group consisted of 14 age-matched convalescents without clinical and laboratory signs of uremia and systemic inflammatory response syndrome. The potentialities of Integral Diagnostic Expert Analytical System (IDEAS) based on the spectrophotokinetic (SPK) technique (ECOTEST, Russia; Thermo Labsystems, Finland) were evaluated on the basis of objective evaluation of clinical condition of end-stage renal disease patients. SPK technology proved to be a highly informative method of automated diagnosis, which allows monitoring the dialysis efficiency, detecting combined diseases and poor system's biocompatibility, which, in turn, permits correction of the treatment and realization of a differentiated approach to the choice of RRT method.


An EmrB multidrug efflux pump in Burkholderia thailandensis with unexpected roles in antibiotic resistance.
The antibiotic trimethoprim is frequently used to manage Burkholderia infections, and members of the resistance-nodulation-division (RND) family of efflux pumps have been implicated in multidrug resistance of this species complex. We show here that a member of the distinct Escherichia coli multidrug resistance B (EmrB) family is a primary exporter of trimethoprim in Burkholderia thailandensis, as evidenced by increased trimethoprim sensitivity after inactivation of emrB, the gene that encodes EmrB. We also found that the emrB gene is up-regulated following the addition of gentamicin and that this up-regulation is due to repression of the gene encoding OstR, a member of the multiple antibiotic resistance regulator (MarR) family. The addition of the oxidants H2O2 and CuCl2 to B. thailandensis cultures resulted in OstR-dependent differential emrB expression, as determined by qRT-PCR analysis. Specifically, OstR functions as a rheostat that optimizes emrB expression under oxidizing conditions, and it senses oxidants by a unique mechanism involving two vicinal cysteines and one distant cysteine (Cys3, Cys4, and Cys169) per monomer. Paradoxically, emrB inactivation increased resistance of B. thailandensis to tetracycline, a phenomenon that correlated with up-regulation of an RND efflux pump. These observations highlight the intricate mechanisms by which expression of genes that encode efflux pumps is optimized depending on cellular concentrations of antibiotics and oxidants.


Vandetanib combined with a p38 MAPK inhibitor synergistically reduces glioblastoma cell survival.
The survival for patients with high-grade glioma is poor, and only a limited number of patients respond to the therapy. The aim of this study was to analyze the significance of using p38 MAPK phosphorylation as a prognostic marker in high-grade glioma patients and as a therapeutic target in combination chemotherapy with vandetanib. p38 MAPK phosphorylation was analyzed with immunohistochemistry in 90 high-grade glioma patients. Correlation between p38 MAPK phosphorylation and overall survival was analyzed with Mann-Whitney U test analysis. The effects on survival of glioblastoma cells of combining vandetanib with the p38 MAPK inhibitor SB 203580 were analyzed in vitro with the median-effect method with the fluorometric microculture cytotoxicity assay. Two patients had phosphorylated p38 MAPK in both the cytoplasm and nucleus, and these two presented with worse survival than patients with no detectable p38 MAPK phosphorylation or phosphorylated p38 MAPK only in the nucleus. This was true for both high-grade glioma patients (WHO grade III and IV, n = 90, difference in median survival: 6.1 months, 95 % CI [0.20, 23], p = 0.039) and for the subgroup with glioblastoma patients (WHO grade IV, n = 70, difference in median survival: 6.1 months, 95 % CI [0.066, 23], p = 0.043). The combination of vandetanib and the p38 MAPK inhibitor SB 203580 had synergistic effects on cell survival for glioblastoma-derived cells in vitro. In conclusion, p38 MAPK phosphorylation may be a prognostic marker for high-grade glioma patients, and vandetanib combined with a p38 MAPK inhibitor may be useful combination chemotherapy for glioma patients.


The potential of reducing AST testing in hospital settings.
Aspartate aminotransferase (AST) is regularly ordered with alanine aminotransferase (ALT) to assess liver integrity. In many situations, AST testing provides little or no added clinical value, since ALT is more specific and the both enzyme activities highly correlate. The objective of this study is to determine the potential reduction in AST testing, if not performed when ALT results are within reference intervals (RI). Results for patients >18 years of age for both AST and ALT from the same specimen were obtained for the period January 1, 2017 - December 31, 2017. We calculated frequency of AST and ALT results that had various combinations of results within and above the RI. We also investigated the clinical locations of origin for the samples. In total 87,704 paired samples with both AST and ALT test results were recovered. The total of 73.2% of AST tests for males and 66.9% for females would be eliminated if we performed AST testing only when ALT was increased. However, 7.4% of elevated AST tests would be missed for males and 3.8% for females due to ALT being within limits. Specifically in the outpatient clinics, 79% male and 73% females paired enzyme results were within RI. Only 4% of males and 3% of females had paired results where ALT was within RI while AST > RI. The rate of test results with increased AST while ALT is within the RI is low enough to recommend limiting AST testing only to cases where ALT is above the RI. Our recommendation for AST restriction is to begin with the hospitals outpatient clinics.


Medication therapy management services in West Virginia: pharmacists' perceptions of educational and training needs.
The Medicare Modernization Act of 2003 recognizes the challenges associated with drug therapy in elderly patients with multiple chronic diseases, and requires the development of medication therapy management services (MTMS) for such beneficiaries. To assess pharmacists' perception of educational and training needs necessary to implement MTMS in community pharmacies in West Virginia, USA. Self-administered mail surveys with an explanatory cover letter were mailed to the designated pharmacist-in-charge (PIC) of each licensed community pharmacy (506) in West Virginia. Main outcome measures included pharmacists' comfort level, perceptions of value to patients, barriers to provision of services, and pharmacists' interest in receiving education and training related to MTMS. Of the 503 surveys that were deliverable, 203 (40.4%) usable responses were received. Fifty-five (27.1%) PICs reported that MTMS are currently being provided in their pharmacy. Respondents were likely to use services that aid in the development of MTMS and disease-state management, felt relatively comfortable in providing MTMS, and had a favorable view of the value of services to patients, but reported that lack of time tended to be a barrier. PICs in West Virginia are interested in and open to their pharmacists receiving education and training for implementation of MTMS.


Seizure outcomes after temporal lobectomy in pediatric patients.
Temporal lobe epilepsy (TLE) is the most common form of epilepsy in adults and is responsible for 15%-20% of epilepsy cases in children. Class I evidence strongly supports the use of temporal lobectomy for intractable TLE in adults, but fewer studies have examined seizure outcomes and predictors of seizure freedom after temporal lobectomy in pediatric patients. The authors performed a systematic review and meta-analysis of studies including 10 or more pediatric patients (age ≤ 19 years) published over the last 20 years examining seizure outcomes after temporal lobectomy for TLE. Thirty-six studies met their inclusion criteria. These 36 studies included 1318 pediatric patients with a mean age (± SEM) of 10.7 ± 0.3 years. Overall, seizure freedom (Engel Class I outcome) was achieved in 1002 cases (76%); 316 patients (24%) continued to have seizures (Engel Class II-IV outcome). All patients had at least 1 year of follow-up. Statistically significant predictors of seizure freedom after surgery included lesional epilepsy etiology (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.02-1.15), abnormal findings on preoperative MRI (OR 1.27, 95% CI 1.16-1.40), and lack of generalized seizures (OR 1.36, 95% CI 1.20-1.56). Among lesional epilepsy cases, there was a trend toward better outcome with gross-total lesionectomy than with subtotal resection. Approximately three-fourths of pediatric patients with TLE attain seizure freedom after temporal lobectomy. Favorable outcomes may be predicted by lesional epilepsy etiology, abnormal MRI, and lack of generalized seizures. Pediatric patients with medically refractory TLE should be referred to a comprehensive pediatric epilepsy center for surgical evaluation.


[Lowering the cesarean section rate by exclusion of cardiotocographically suspected acidosis using fetal blood gas analysis].
In 871 deliveries out of a total of 3980 effected during 1980-1982 at the Winterthur Gynaecological Hospital, we found it necessary to perform one or several microanalyses of blood (blood gas analyses) sub partu. Among these, we found retrospectively that in 22 cases the microanalysis of the blood gas had prevented us from performing caesarean section which would have seemed necessary if we had relied on the cardiotocographical findings alone. Micro-analysis of blood gas made it possible to exclude the presence of pre-acidosis or acidosis which would have made Caesarean section imperative; in all these cases, normal delivery via the vagina was achieved, and in no case did this result in severe acidosis. All newborn had a 5-minute Apgar score of 7 and higher. We can conclude from these results, therefore, that the indication for an immediate termination of delivery via Caesarean section should not depend solely on a pathological cardiotocogram; the final decision should be arrived at only after micro-analyses of blood gas have confirmed the presence of foetal pre-acidosis or acidosis.


Distinctive Roles of 5-aza-2'-deoxycytidine in Anterior Agranular Insular and Basolateral Amygdala in Reconsolidation of Aversive Memory Associated with Morphine in Rats.
5-aza-2'-deoxycytidine (5-aza), an inhibitor of DNA methyltransferases (DNMTs), has been implicated in aversive memory and the function of brain region involved in processing emotion. However, little is known about the role of 5-aza in the reconsolidation of opiate withdrawal memory. In the present study, using the morphine-naloxone induced conditioned place aversion (CPA) model in rats, we injected 5-aza into agranular insular (AI), granular insular (GI), basolateral amygdala (BLA) and central amygdala (CeA) immediately after the memory retrieval and tested the behavioral consequences at 24 h, 7 and 14 days after retrieval test. We found that 5-aza injection into AI disrupted the reconsolidation of morphine-associated withdrawal memory, but 5-aza injection into GI had no impact on the reconsolidation. Meanwhile, 5-aza injection into BLA but not CeA attenuated the withdrawal memory trace 14 days later. However, 5-aza administration to rats, in the absence of memory reactivation, had no effect on morphine-associated withdrawal memory. These findings suggest that 5-aza interferes with the reconsolidation of opiate withdrawal memory, and the roles of insular and amygdala in reconsolidation are distinctive.


The Association of Combined GSTM1 and CYP2C9 Genotype Status with the Occurrence of Hemorrhagic Cystitis in Pediatric Patients Receiving Myeloablative Conditioning Regimen Prior to Allogeneic Hematopoietic Stem Cell Transplantation.
Hemorrhagic cystitis (HC) is one of the complications of busulfan-cyclophosphamide (BU-CY) conditioning regimen during allogeneic hematopoietic stem cell transplantation (HSCT) in children. Identifying children at high risk of developing HC in a HSCT setting could facilitate the evaluation and implementation of effective prophylactic measures. In this retrospective analysis genotyping of selected candidate gene variants was performed in 72 children and plasma Sulfolane (Su, water soluble metabolite of BU) levels were measured in 39 children following treatment with BU-CY regimen. The cytotoxic effects of Su and acrolein (Ac, water soluble metabolite of CY) were tested on human urothelial cells (HUCs). The effect of Su was also tested on cytochrome P 450 (CYP) function in HepaRG hepatic cells. Cumulative incidences of HC before day 30 post HSCT were estimated using Kaplan-Meier curves and log-rank test was used to compare the difference between groups in a univariate analysis. Multivariate Cox regression was used to estimate hazard ratios with 95% confidence intervals (CIs). Multivariate analysis included co-variables that were significantly associated with HC in a univariate analysis. Cumulative incidence of HC was 15.3%. In the univariate analysis, HC incidence was significantly (p < 0.05) higher in children older than 10 years (28.6 vs. 6.8%) or in children with higher Su levels (>40 vs. <11%) or in carriers of both functional GSTM1 and CYP2C9 (33.3 vs. 6.3%) compared to the other group. In a multivariate analysis, combined GSTM1 and CYP2C9 genotype status was associated with HC occurrence with a hazards ratio of 4.8 (95% CI: 1.3-18.4; p = 0.02). Ac was found to be toxic to HUC cells at lower concentrations (33 μM), Su was not toxic to HUC cells at concentrations below 1 mM and did not affect CYP function in HepaRG cells. Our observations suggest that pre-emptive genotyping of CYP2C9 and GSTM1 may aid in selection of more effective prophylaxis to reduce HC development in pediatric patients undergoing allogeneic HSCT. Article summary: (1) Children carrying functional alleles in GSTM1 and CYP2C9 are at high risk for developing hemorrhagic cystitis following treatment with busulfan and cyclophosphamide based conditioning regimen. (2) Identification of children at high risk for developing hemorrhagic cystitis in an allogeneic HSCT setting will enable us to evaluate and implement optimal strategies for its prevention. Trial registration: This study is a part of the trail "clinicaltrials.gov identifier: NCT01257854."


Total Disc Replacement in Lumbar Degenerative Disc Diseases.
More than 10 years have passed since lumbar total disc replacement (LTDR) was introduced for the first time to the world market for the surgical management of lumbar degenerative disc disease (DDD). It seems like the right time to sum up the relevant results in order to understand where LTDR stands on now, and is heading forward to. The pathogenesis of DDD has been currently settled, but diagnosis and managements are still controversial. Fusion is recognized as golden standard of surgical managements but has various kinds of shortcomings. Lately, LTDR has been expected to replace fusion surgery. A great deal of LTDR reports has come out. Among them, more than 5-year follow-up prospective randomized controlled studies including USA IDE trials were expected to elucidate whether for LTDR to have therapeutic benefit compared to fusion. The results of these studies revealed that LTDR was not inferior to fusion. Most of clinical studies dealing with LTDR revealed that there was no strong evidence for preventive effect of LTDR against symptomatic degenerative changes of adjacent segment disease. LTDR does not have shortcomings associated with fusion. However, it has a potentiality of the new complications to occur, which surgeons have never experienced in fusion surgeries. Consequently, longer follow-up should be necessary as yet to confirm the maintenance of improved surgical outcome and to observe any very late complications. LTDR still may get a chance to establish itself as a substitute of fusion both nominally and virtually if it eases the concerns listed above.


Where have all the fathers gone? An extensive microsatellite analysis of paternity in the grey seal (Halichoerus grypus).
Microsatellites were used to conduct an extensive analysis of paternity of grey seals from two Scottish breeding colonies at North Rona (n = 1189) and the Isle of May (n = 694), spanning more than a decade. A maximum of 46% of pups at North Rona and 29% of pups at the Isle of May could be allocated a father, even though the majority of candidate males for specific study sites within each colony were believed to have been sampled. Based on the paternities which could be assigned, both colonies showed evidence of reproductive skew, apparently due to the presence of approximately five males who were exceptionally successful. Some males were assigned paternities at least 10 years before, and colleagues 10 years after, being sampled, implying a reproductive lifespan of at least 10 years, and there are indications that the real maximum lies in the range 15-20 years. Male grey seals appear to have at least two breeding strategies they can adopt. On land, some males benefit from a traditionally polygynous system. However, between 50 and 70% of grey seal pups born at a particular colony are not fathered by males who are likely to be sampled by us, implying that these males seldom venture ashore here. We conclude that aquatic mating may play a much larger role in the grey seal than has previously been thought.


Proximal humerus fracture.
A thirty-five-year-old man who fell from a tree is admitted to the emergency department with the x-rays shown below. Physical examination reveals that the patient is neurologically intact and has good pulses. Management of this case is described in the following opinions.


Serum gamma-glutamyltransferase within its normal range predicts a chronic elevation of alanine aminotransferase: a four year follow-up study.
Previous epidemiological and experimental studies support the concept that serum gamma-glutamyltransferase (GGT) activity within its normal range is related to oxidative stress. Since oxidative stress plays a crucial role in the pathogenesis of various liver diseases, serum GGT may predict development of liver damage. A total of 6,523 healthy male workers with normal alanine aminotransferase (ALT, <35 U/l) in a steel manufacturing company were followed for four years. Liver damage was defined as a chronic elevation of serum ALT (both 2001 and 2002). After adjusting for age, body mass index, alcohol consumption, cigarette smoking, exercise, and baseline value of ALT, in comparison with the group whose GGT level was <10 U/l, the adjusted relative risks for elevated ALT level among those with GGT levels 10-19, 20-29, 30-39, and over 40 U/l was 1.0, 2.5, 4.7, 7.4, and 12.0, respectively (P for trend <0.01). More importantly, this association was similarly observed even among non-drinkers; the corresponding relative risks were 1.0, 1.8, 3.8, 5.6, and 6.2 (P for trend <0.01). However baseline ALT did not predict abnormal GGT level four years later. Serum GGT levels within normal range predict incidence of chronic elevation of ALT. Oxidative stress might explain this relationship.


Antimicrobial polymers prepared by ROMP with unprecedented selectivity: a molecular construction kit approach.
Synthetic Mimics of Antimicrobial Peptides (SMAMPs) imitate natural host-defense peptides, a vital component of the body's immune system. This work presents a molecular construction kit that allows the easy and versatile synthesis of a broad variety of facially amphiphilic oxanorbornene-derived monomers. Their ring-opening metathesis polymerization (ROMP) and deprotection provide several series of SMAMPs. Using amphiphilicity, monomer feed ratio, and molecular weight as parameters, polymers with 533 times higher selectivitiy (selecitviy = hemolytic concentration/minimum inhibitory concentration) for bacteria over mammalian cells were discovered. Some of these polymers were 50 times more selective for Gram-positive over Gram-negative bacteria while other polymers surprisingly showed the opposite preference. This kind of "double selectivity" (bacteria over mammalian and one bacterial type over another) is unprecedented in other polymer systems and is attributed to the monomer's facial amphiphilicity.


Biochemistry. Ubiquitination--more than two to tango.
The ubiquitin pathway in the cell is an elegant system for targeting unwanted proteins for degradation. Three enzymes, E1, E2, and E3, are responsible for attaching the ubiquitin tag to proteins destined to be chopped up. In their Perspective, Joazeiro and Hunter discuss new structural findings that reveal the part played by an E3 called c-Cbl in this ubiquitinating process.


Blood rheology and systemic oxygen transport.
The interrelationship between systemic oxygen transport and hematocrit, has been studied under various conditions, while the influence of plasma viscosity on oxygen transport and tissue oxygenation has not entirely been explored. In experiments in dogs the plasma viscosity was increased either by isovolemic hemodilution with 6% hydroxyethyl starch (HES) 200/0.62, or 6% dextran-70, or by infusion of dextran-500 in a volume equivalent to 4% of blood volume from baseline to 3 mPa.s. Cardiac output and regional blood flow were assessed by means of radioactive labelled microspheres and local tissue oxygenation by means of pO2 multiwire surface electrodes. In normotensive healthy animals elevated plasma viscosity did neither jeopardize systemic nor regional blood flow; local tissue oxygenation of skeletal muscle remained unchanged or was even improved. We conclude that among the rheological factors influencing oxygen transport, the hematocrit plays the predominant role, while plasma viscosity is of minor importance.


Paracrine/autocrine control of female reproduction.
Neuropeptides, growth factors and cytokines are expressed in reproductive organs and tissues, where they interact with afferent endocrine messages to modulate cell proliferation and differentiation, local hormone secretion and vascular function. These events regulate complex processes such as gonadotropin pulsatility, ovulation, implantation and parturition. During reproductive life, a number of neuropeptides produced within the hypothalamus play a modulatory role in the control of gonadotropin-releasing hormone (GnRH) release, hence characterizing a hypothalamic paracrine system. The pituitary gland is a source and target of inhibin-related proteins, and these typical 'gonadal' products, once secreted by the pituitary cells, acquire the function of paracrine modulators of follicle-stimulating hormone (FSH) secretion. In the ovary, the effect of gonadotropins is locally modulated by growth factors acting in an autocrine/paracrine manner, although their precise role in folliculogenesis remains uncertain. Numerous local factors are involved in the control of endometrial growth, differentiation, receptivity and menstruation. Alterations in the paracrine endometrial system may underlie pathological processes such as infertility or endometrial neoplasia. The human placenta and its related membranes produce cytokines, hormones and growth factors that participate in the control of gestational development as well as in the maternal-fetal adaptation to gestational diseases. There is increasing evidence that paracrine signaling plays a fundamental role in all spheres of female reproductive function, and future research will concentrate on clarifying which of these local mechanisms play a decisive role in both physiology and disease, thus giving rise to new therapeutic strategies.


Performance of dye-affinity beads for aluminium removal in magnetically stabilized fluidized bed.
BACKGROUND: Aluminum has recently been recognized as a causative agent in dialysis encephalopathy, osteodystrophy, and microcytic anemia occurring in patients with chronic renal failure who undergo long-term hemodialysis. Only a small amount of Al(III) in dialysis solutions may give rise to these disorders. METHODS: Magnetic poly(2-hydroxyethyl methacrylate) (mPHEMA) beads in the size range of 80-120 microm were produced by free radical co-polymerization of HEMA and ethylene dimethacrylate (EDMA) in the presence of magnetite particles (Fe3O4). Then, metal complexing ligand alizarin yellow was covalently attached onto mPHEMA beads. Alizarin yellow loading was 208 micromol/g. These beads were used for the removal of Al(III) ions from tap and dialysis water in a magnetically stabilized fluidized bed. RESULTS: Al(III) adsorption capacity of the beads decreased with an increase in the flow-rate. The maximum Al(III) adsorption was observed at pH 5.0. Comparison of batch and magnetically stabilized fluidized bed (MSFB) maximum capacities determined using Langmuir isotherms showed that dynamic capacity (17.5 mg/g) was somewhat higher than the batch capacity (11.8 mg/g). The dissociation constants for Al(III) were determined using the Langmuir isotherm equation to be 27.3 mM (MSFB) and 6.7 mM (batch system), indicating medium affinity, which was typical for pseudospecific affinity ligands. Al(III) ions could be repeatedly adsorbed and desorbed with these beads without noticeable loss in their Al(III) adsorption capacity. CONCLUSIONS: Adsorption of Al(III) demonstrate the affinity of magnetic dye-affinity beads. The MSFB experiments allowed us to conclude that this inexpensive sorbent system may be an important alternative to the existing adsorbents in the removal of aluminium.


Recurarization in the recovery room.
A case of recurarization in the recovery room is reported. Accumulation of atracurium in the intravenous line led to recurarization after flushing the line in the recovery room. A respiratory arrest with severe desaturation and bradycardia occurred. Circumstances leading to this event and the mechanisms enabling a neuromuscular blockade to occur, following the administration of a small dose of relaxant, are discussed.


NHA-oc/NHA2: a mitochondrial cation-proton antiporter selectively expressed in osteoclasts.
Bone resorption is regulated by a complex system of hormones and cytokines that cause osteoblasts/stromal cells and lymphocytes to produce factors including RANKL, that ultimately result in the differentiation and activation of osteoclasts, the bone resorbing cells. We used a microarray approach to identify genes upregulated in RANKL-stimulated osteoclast precursor cells. Osteoclast expression was confirmed by multiple tissue Northern and in situ hybridization analysis. Gene function studies were carried out by siRNA analysis. We identified a novel gene, which we termed nha-oc/NHA2, which is strongly upregulated during RANKL-induced osteoclast differentiation in vitro and in vivo. nha-oc/NHA2 encodes a novel cation-proton antiporter (CPA) and is the mouse orthologue of a human gene identified in a database search: HsNHA2. nha-oc/NHA2 is selectively expressed in osteoclasts. NHA-oc/NHA2 protein localizes to the mitochondria, where it mediates Na(+)-dependent changes in mitochondrial pH and Na(+) acetate induced mitochondrial passive swelling. RNA silencing of nha-oc/nha2 reduces osteoclast differentiation and resorption, suggesting a role for NHA-oc/NHA2 in these processes. nha-oc/NHA2 therefore is a novel member of the CPA family and is the first mitochondrial NHA characterized to date. nha-oc/NHA2 is also unique in that it is the first eukaryotic and tissue-specific CPA2 characterized to date. NHA-oc/NHA2 displays the expected activities of a bona fide CPA and plays a key role(s) in normal osteoclast differentiation and function.


Direct isosurface visualization of hex-based high-order geometry and attribute representations.
In this paper, we present a novel isosurface visualization technique that guarantees the accurate visualization of isosurfaces with complex attribute data defined on (un)structured (curvi)linear hexahedral grids. Isosurfaces of high-order hexahedral-based finite element solutions on both uniform grids (including MRI and CT scans) and more complex geometry representing a domain of interest that can be rendered using our algorithm. Additionally, our technique can be used to directly visualize solutions and attributes in isogeometric analysis, an area based on trivariate high-order NURBS (Non-Uniform Rational B-splines) geometry and attribute representations for the analysis. Furthermore, our technique can be used to visualize isosurfaces of algebraic functions. Our approach combines subdivision and numerical root finding to form a robust and efficient isosurface visualization algorithm that does not miss surface features, while finding all intersections between a view frustum and desired isosurfaces. This allows the use of view-independent transparency in the rendering process. We demonstrate our technique through a straightforward CPU implementation on both complex-structured and complex-unstructured geometries with high-order simulation solutions, isosurfaces of medical data sets, and isosurfaces of algebraic functions.


[Reliability and validity of the 3 Dimensional Sleep Scale (3DSS)--day workers version--in assessing sleep phase, quality, and quantity].
Most sleep scales assess sleep quantity (e.g., sleep duration and daytime sleepiness) or sleep quality (e.g., sleep latency and maintenance); the Pittsburgh Sleep Quality Index (PSQI) is an exceptional example. However, the prevalence of 24-hour operations presents the need for a scale that can also measure sleep phase (e.g., sleep onset and offset). Furthermore, we have to assess the phase, quality and quantity respectively to understand which of them has a problem. Thus, the 3 Dimensional Sleep Scale (3DSS) - day workers version - was developed to assess each of them related to sleep, and this study attempted to verify its reliability and validity. Subjects were 635 day workers (461 men, 174 women; average age = 40.5 years) from the manufacturing and service industries. A scale was created based on a pre-study and discussions with specialists. The scale consisted of 17 sleep-related items. The skew of the data was assessed, and the construct validity and reliability were verified using exploratory and confirmatory factor analysis and Cronbach's alpha, respectively. The scale was scored and G-P analysis was performed. The items measuring phase, quality, and quantity of sleep were selected from the PSQI and SDS, and their correlation with the three scales of 3DSS were measured to verify the convergent and discriminant validity. In addition, the total scores obtained on the PSQI were compared with each scale of the 3DSS. No skew was found in the data. Exploratory factor analysis revealed a three-factor structure--quality, quantity, and phase. Each factor consisted of five items, therefore two items were excluded. The fitness of the 15-item model was better than that of the 17-item model according to confirmatory factor analysis. Cronbach's alpha for phase, quality and quantity score were 0.685, 0.768 and 0.716, respectively. The hypothesis tests were almost accepted, therefore convergent and discriminant validity were sufficiently established. The present study established the reliability and validity of the 3DSS; however, further studies using larger samples are needed to standardize the test and to establish a cut-off value.


Carbonic anhydrase II deficiency.
Carbonic anhydrase (CA) isoenzyme II deficiency--formerly called the syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification--is an autosomal recessive "inborn error of metabolism" that has disclosed important insight concerning osteoclast function. Nearly 50 cases have been described, predominantly from the Middle East and Mediterranean region. It is discovered late in infancy or early in childhood through developmental delay, short stature, fracture, weakness, cranial nerve compression, dental malocclusion, and/or mental subnormality. Typical radiographic features of osteopetrosis are present, and histopathologic study of the iliac crest reveals unresorbed calcified primary spongiosa. The radiographic findings are unusual, however, in that cerebral calcification appears by early childhood and the osteosclerosis and skeletal modeling defects may gradually resolve by adulthood. Patients are usually not anemic. A hyperchloremic metabolic acidosis, sometimes with hypokalemia, is caused by renal tubular acidosis that may be a proximal, distal, or combined type. Several different mutations within the CA II gene have been identified. There is no established medical therapy, and the long-term outcome remains to be characterized. Prenatal diagnosis has not been reported. Delineation of CA II deficiency establishes an important role in humans for CA II. The pathogenesis of the mental subnormality and cerebral calcification is poorly understood; however, CA II deficiency provides significant insight concerning CA II in renal regulation of acid/base homeostasis and osteoclast-mediated bone resorption.


Evolutionary and biochemical analyses reveal conservation of the Brassicaceae telomerase ribonucleoprotein complex.
The telomerase ribonucleoprotein complex (RNP) is essential for genome stability and performs this role through the addition of repetitive DNA to the ends of chromosomes. The telomerase enzyme is composed of a reverse transcriptase (TERT), which utilizes a template domain in an RNA subunit (TER) to reiteratively add telomeric DNA at the ends of chromosomes. Multiple TERs have been identified in the model plant Arabidopsis thaliana. Here we combine a phylogenetic and biochemical approach to understand how the telomerase RNP has evolved in Brassicaceae, the family that includes A. thaliana. Because of the complex phylogenetic pattern of template domain loss and alteration at the previously characterized A. thaliana TER loci, TER1 and TER2, across the plant family Brassicaceae, we bred double mutants from plants with a template deletion at AtTER1 and T-DNA insertion at AtTER2. These double mutants exhibited no telomere length deficiency, a definitive indication that neither of these loci encode a functional telomerase RNA. Moreover, we determined that the telomerase components TERT, Dyskerin, and the KU heterodimer are under strong purifying selection, consistent with the idea that the TER with which they interact is also conserved. To test this hypothesis further, we analyzed the substrate specificity of telomerase from species across Brassicaceae and determined that telomerase from close relatives bind and extend substrates in a similar manner, supporting the idea that TERs in different species are highly similar to one another and are likely encoded from an orthologous locus. Lastly, TERT proteins from across Brassicaceae were able to complement loss of function tert mutants in vivo, indicating TERTs from other species have the ability to recognize the native TER of A. thaliana. Finally, we immunoprecipitated the telomerase complex and identified associated RNAs via RNA-seq. Using our evolutionary data we constrained our analyses to conserved RNAs within Brassicaceae that contained a template domain. These analyses revealed a highly expressed locus whose disruption by a T-DNA resulted in a telomeric phenotype similar to the loss of other telomerase core proteins, indicating that the RNA has an important function in telomere maintenance.


Healing from weight stigma in community: A thematic analysis of a group intervention for large-bodied individuals.
Discrimination against and negative beliefs about large-bodied individuals, known as weight stigma, is pervasive and harmful. While previous research has focused on the negative consequences of weight stigma, the present study aims to highlight the lived experience of large-bodied individuals while also exploring the process of healing from harmful experiences of weight stigma. Ten adult (9/10 White, 8/10 cisgender women), large-bodied individuals recruited via snowball sampling through a nonprofit, grassroots, eating disorder advocacy organization participated in a 10-week, counselor-facilitated support group with the shared goal of healing from the impact of weight stigma. Researchers used reflexive thematic analysis to analyze video recordings and transcripts of group sessions to answer the following question: how did participants make sense of their weight stigma experiences and engage with the process of healing in community? Four primary themes were generated: (a) Community is Essential, (b) Storying, (c) Deprogramming and Changing Mindset, and (d) Expansive Healing. These results underscore the impact of weight stigma in the lives of large-bodied individuals and provide insight into how clinicians might support such individuals engaging in collective healing from these painful experiences. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Copper-zinc superoxide dismutase is activated through a sulfenic acid intermediate at a copper ion entry site.
Metallochaperones are a diverse family of trafficking molecules that provide metal ions to protein targets for use as cofactors. The copper chaperone for superoxide dismutase (Ccs1) activates immature copper-zinc superoxide dismutase (Sod1) by delivering copper and facilitating the oxidation of the Sod1 intramolecular disulfide bond. Here, we present structural, spectroscopic, and cell-based data supporting a novel copper-induced mechanism for Sod1 activation. Ccs1 binding exposes an electropositive cavity and proposed "entry site" for copper ion delivery on immature Sod1. Copper-mediated sulfenylation leads to a sulfenic acid intermediate that eventually resolves to form the Sod1 disulfide bond with concomitant release of copper into the Sod1 active site. Sod1 is the predominant disulfide bond-requiring enzyme in the cytoplasm, and this copper-induced mechanism of disulfide bond formation obviates the need for a thiol/disulfide oxidoreductase in that compartment.


Colon polyps and cancer.
A number of recent publications dealing with colon polyps and cancer emphasize cost-effectiveness and the outcomes of screening and follow-up surveillance of high-risk groups. These groups include patients with either a past personal history or a family history of colorectal adenomas or cancer. Several papers address the effectiveness and compliance with different methods of screening of the asymptomatic, average-risk population for colorectal neoplasia. Other important publications deal with colorectal cancer prevention, the natural history of the adenoma-carcinoma sequence, diagnosis of polyps and cancer, colonoscopic polypectomy, management of the patient with a malignant polyp, and endoscopic treatment of obstructing cancer.


Comparison of retinal nerve fiber layer and macular thickness measurements with Stratus OCT and OPKO/OTI OCT devices in healthy subjects.
To compare retinal nerve fiber layer (RNFL) and macular thickness measurements obtained with the Stratus optical coherence tomography (OCT) and OPKO/OTI OCT devices. Included in the study were 59 eyes of 30 participants. All measurements for each eye were done on the same day with both devices. Student's paired t-tests were used to compare the central macular thickness and RNFL measurements of the Stratus OCT and OPKO/OTI OCT. Pearson correlation was used to assess the relationship between the devices. Coefficient of variation (COV) was calculated to assess intersession repeatability. Using both the Stratus OCT and OPKO/OTI OCT, respectively, the measured mean average RNFL thicknesses were 98.9±11.1 µm and 115.1±9.6 µm (P=0.001), and the measured mean central retinal thicknesses (CRT) were 196.2±18.8 µm and 204.5±21.1 µm (P<0.001). Measured by the two devices, the RNFL thickness values were correlated in all quadrants, as were the retinal thickness values except the inferior outer sector. COV for average RNFL and CRT thickness were 2.9% and 4.6% for Stratus OCT, and 2.1% and 4.2% for OPKO/OTI OCT, respectively. We found good reproducibility of RNFL and retina thickness measurements for both Stratus OCT and OPKO/OTI OCT devices. However, even though the two OCT systems provided statistically correlated results, the values for both RNFL and macular thickness were statistically different. RNFL and macular thickness measurements with the OPKO/OTI OCT were higher than that of the Stratus OCT; therefore, the two OCT systems cannot be used interchangeably for the measurements of RNFL and macular thickness.


The Effect of Differentiation Grade of Cutaneous Squamous Cell Carcinoma on Excision Margins, Local Recurrence, Metastasis, and Patient Survival: A Retrospective Follow-Up Study.
The incidence of cutaneous squamous cell carcinoma (SCC) is increasing worldwide. Despite a growing body of literature on prognostic factors, it remains unclear how tumor differentiation grade influences patient survival. The aim of this study was to investigate a possible correlation between cutaneous SCC differentiation, local recurrence, metastasis, and patient survival. All consecutive patients treated for cutaneous SCC between 2001 and 2008 were retrospectively analyzed. Univariate survival analysis was used to assess the association of different tumor characteristics with survival. One hundred thirty-one patients with 155 SCCs were included (median follow-up, 81 months; range, 27-125 months). Although no significant correlation between tumor differentiation grade and local recurrence could be found, it was an independent prognostic factor for metastatic disease and overall survival (OS). Metastasis-free survival at 5 years was significantly higher in well-differentiated tumors (70%) compared to moderately (51%) and poorly differentiated SCCs (26%; P = 0.012); identical percentages were found for OS (P = 0.005). Furthermore, patients with incomplete excision of the first tumor showed an increased relative risk of dying of SCC of 4.0 (95% confidence interval, 2.4-6.6; P < 0.001) compared to excision with clear margins. Studies that investigated the relationship between SCC differentiation grade and patient survival are scarce and inconsistent. The present study indicates tumor differentiation grade is an independent prognostic factor for OS. This finding suggests poor differentiation of cutaneous SCC alone is sufficient to upstage the primary tumor in the TNM classification system.


The effectiveness of breath carbon monoxide analyzer in screening for environmental tobacco smoke exposure in Saudi pregnant women.
Exposure to environmental tobacco smoke (ETS) has harmful effects on the pregnancy outcomes similar to those observed in actively smoking pregnant women. The aim of this study was to estimate the sensitivity and specificity of the breath carbon monoxide (BCO) analysis in the assessment of smoking status among Saudi pregnant women, including ETS exposure compared to self-reported tobacco smoke exposure. A cross-sectional design was used during January 2012, 560 pregnant women, irrespective of their gestational age, agreed to undergo BCO testing and completed the data collection sheet for the study. Sensitivity, specificity, positive and negative predictive values were calculated to compare the BCO test with self-reported exposure to ETS. Of the study population 151 (27%) women self-reported ETS exposure during the index pregnancy, 409 (73%) self-reported non-exposure. Sensitivity of the test was 32.5% (95% CI; 25.2-40.3%), the Specificity was much higher at 69.2% (95% CI; 64.4-73.5%), the positive predictive value was 28% (95% CI, 21.9-35.1%), and the negative predictive value was 73.5% (95% CI; 68.9-77.7%). The BCO test is an ineffective tool to detect the level of ETS exposure among Saudi pregnant women.


Reliability of two functional clinical tests to evaluate trunk and lumbopelvic neuromuscular control and proprioception in a healthy population.
The need to accurately assess trunk and lumbopelvic proprioception and neuromuscular control is widely accepted. However, based on current literature, there is a lack of reliable clinical tests to evaluate these aspects in clinical practice. The objective of this study is to investigate intra- and inter-tester reliability of the lateral step down test and the lumbopelvic position-reposition test in a healthy population. Protocol and scoring methods were developed for the lateral step down test and lumbopelvic position-reposition test, used to assess trunk and lumbopelvic neuromuscular control and proprioception respectively. Each test was performed once by thirty participants and video analysis for test scoring was performed. Three items on the lateral step down test were scored to evaluate neuromuscular control and, four items on the lumbopelvic position-reposition test were scored to evaluate proprioception. Aggregate scores for each test were calculated based on the separate item scores. Intraclass correlation coefficients and linear weighted kappa coefficients were determined for intra- and inter-tester reliability. Based on the aggregate score, excellent intra- and inter-tester reliability (ICC (2,1)=0.73-0.88) was found for both tests. Moderate/almost perfect intra-and inter-tester agreement (K=0.62-0.91) was found for the separate items of the lateral step down test and fair/substantial agreement (K=0.25-0.76) for the items of the lumbopelvic position-reposition test. Current testing protocol and scoring method for the lateral step down test is reliable. Adjustments for the scoring method of the lumbopelvic position-reposition test are warranted to improve reliability.


The impact of passive heat maintenance strategies between an active warm-up and performance: a systematic review and meta-analysis.
Prior to exercise, a warm-up routine has been suggested to be an imperative factor in task readiness with the anticipation that it will enhance performance. One of the key benefits of a warm-up is the increase in muscle and core temperature, which can be achieved in a variety of ways. An effective way to achieve improvements in core and muscle temperature is by performing an active warm-up. However, lengthy transition periods between an active warm-up and exercise performance are known to cause a decline in core and muscle temperature, thereby reducing performance capability. As such, methods are needed to assist athletes during transition periods, to maintain the benefits of a warm-up with the aim of optimising performance. Accordingly, the purpose of this review is to systematically analyse the evidence base that has investigated the use of passive heating to aide sporting performance when a transition period is experienced. A systematic review and meta-analysis were undertaken following relevant studies being identified using PubMed, Web of Science, and EBSCO. Studies investigating the effects of passive heating strategies during the transition period between an active warm-up and exercise performance were included. The quality of the included studies were assessed by two independent reviewers using a modified version of the Physiotherapy Evidence Database scale. Seven studies, all high quality (mean = 7.6), reported sufficient data (quality score > 5) on the effects of passive heating strategies on exercise performance, these studies consisted of 85 well-trained athletes (78 male and 7 female). Passive heating strategies used between an active warm-up and exercise, significantly increased peak power output in all studies (ES = 0.54 [95% CI 0.17 to 0.91]). However, only a favourable trend was evident for exercise performance (ES = 1.07 [95% CI - 0.64 to 0.09]). Based upon a limited number of well-conducted, randomised, controlled trials, it appears that passive heating strategies used between an active warm-up and exercise have a positive impact on peak power output. Although, additional research is necessary to determine the optimum procedure for passive warm-up strategies.


Analysis and network representation of hotspots in protein interfaces using minimum cut trees.
We propose a novel approach to analyze and visualize residue contact networks of protein interfaces by graph-based algorithms using a minimum cut tree (mincut tree). Edges in the network are weighted according to an energy function derived from knowledge-based potentials. The mincut tree, which is constructed from the weighted residue network, simplifies and summarizes the complex structure of the contact network by an efficient and informative representation. This representation offers a comprehensible view of critical residues and facilitates the inspection of their organization. We observed, on a nonredundant data set of 38 protein complexes with experimental hotspots that the highest degree node in the mincut tree usually corresponds to an experimental hotspot. Further, hotspots are found in a few paths in the mincut tree. In addition, we examine the organization of hotspots (hot regions) using an iterative clustering algorithm on two different case studies. We find that distinct hot regions are located on specific sites of the mincut tree and some critical residues hold these clusters together. Clustering of the interface residues provides information about the relation of hot regions with each other. Our new approach is useful at the molecular level for both identification of critical paths in the protein interfaces and extraction of hot regions by clustering of the interface residues.


SVM-HUSTLE--an iterative semi-supervised machine learning approach for pairwise protein remote homology detection.
As the amount of biological sequence data continues to grow exponentially we face the increasing challenge of assigning function to this enormous molecular 'parts list'. The most popular approaches to this challenge make use of the simplifying assumption that similar functional molecules, or proteins, sometimes have similar composition, or sequence. However, these algorithms often fail to identify remote homologs (proteins with similar function but dissimilar sequence) which often are a significant fraction of the total homolog collection for a given sequence. We introduce a Support Vector Machine (SVM)-based tool to detect homology using semi-supervised iterative learning (SVM-HUSTLE) that identifies significantly more remote homologs than current state-of-the-art sequence or cluster-based methods. As opposed to building profiles or position specific scoring matrices, SVM-HUSTLE builds an SVM classifier for a query sequence by training on a collection of representative high-confidence training sets, recruits additional sequences and assigns a statistical measure of homology between a pair of sequences. SVM-HUSTLE combines principles of semi-supervised learning theory with statistical sampling to create many concurrent classifiers to iteratively detect and refine, on-the-fly, patterns indicating homology. When compared against existing methods for identifying protein homologs (BLAST, PSI-BLAST, COMPASS, PROF_SIM, RANKPROP and their variants) on two different benchmark datasets SVM-HUSTLE significantly outperforms each of the above methods using the most stringent ROC(1) statistic with P-values less than 1e-20. SVM-HUSTLE also yields results comparable to HHSearch but at a substantially reduced computational cost since we do not require the construction of HMMs. The software executable to run SVM-HUSTLE can be downloaded from http://www.sysbio.org/sysbio/networkbio/svm_hustle


Some recent advance in thoracic surgery.
In this brief presentation of some recent advances in thoracic surgery a number of miscellaneous topics which deserve consideration at this time are discussed. Among these are acidosis during anesthesia for thoracic operations, the problem of esophagitis in relation to surgery, recent improvements and reorientations in pulmonary operations, and some comments on operations upon the heart and great vessels.


Knowledge of congenital cytomegalovirus (cCMV) among physical and occupational therapists in the United States.
Congenital cytomegalovirus (cCMV) infections cause more children to have permanent disabilities than Down Syndrome, Fetal Alcohol Syndrome, Spina Bifida, and pediatric HIV/AIDS combined. The risk of infection during pregnancy can be significantly decreased using universal precautions, such as thorough handwashing and cleansing of surfaces and objects that have come into contact with infected body fluids. Children under 3 years of age are commonly asymptomatic excretors of CMV, with the highest viral loads present in saliva. Pediatric therapists have regular close contact with young children, and are thus likely at elevated occupational risk of acquiring CMV. Our objective was to evaluate therapist knowledge of cCMV and its transmission. We recruited American Occupational Therapy Association (AOTA) and American Physical Therapy Association (APTA) members via electronic newsletters and printed flyers from April to September 2015. Participants completed an online, anonymous 24-question survey using Survey Monkey. We compared responses between groups and previously published CMV awareness data using binomial tests of difference of proportions and multiple logistic regression. Our study identified both a low level of therapist awareness and poor demonstrated understanding of cCMV. Self-reported cCMV awareness amongst therapists was greater than awareness in the general population, and equivalent to awareness amongst health care professionals. Whereas 52% of participants self-reported awareness of cCMV, only 18% demonstrated understanding of the behavioral modes of CMV transmission. Fewer therapists reported awareness of cCMV than other, less prevalent conditions. Higher levels of health risk knowledge were associated with greater contact with children. Most participants reported learning about cCMV from the workplace. The knowledge gaps between self-reported awareness of cCMV and demonstrated understanding of modes of transmission described by our results emphasize the need for additional training of therapists. cCMV is preventable, and accurate knowledge of modes of transmission is crucial for the health of practitioners and clients.


Treatment of Patients with Low Back Pain: A Comparison of Physical Therapy and Chiropractic Manipulation.
Low back pain (LBP) is a pandemic and costly musculoskeletal condition in the United States (U.S.). Patients with LBP may endure surgery, injections, and expensive visits to emergency departments. Some suggest that using physical therapy (PT) or chiropractic in the earlier stage of LBP reduces the utilization of expensive health services and lowers the treatment costs. Given that there are costs and benefits with each of these treatments, the remaining question is in a short period of time which of these treatments is optimal. The purpose of this study was to investigate the cost-effectiveness of chiropractic versus PT in the U.S. A decision tree analytic model was used for estimating the economic outcomes. The findings showed that the total average cost in the chiropractic group was $48.56 lower than the PT group. The findings also showed that the daily adjusted life years (DALY) in the chiropractic group was 0.0043 higher than the PT group. Chiropractic care was shown to be a cost-effective alternative compared with PT for adults with at least three weeks of LBP over six months.


Reduction in hospital mortality over time in a hospital without a pediatric medical emergency team: limitations of before-and-after study designs.
To determine whether hospital mortality has decreased over time in a hospital that has not introduced a pediatric medical emergency team (PMET). Retrospective observational study. Quaternary children's hospital. All pediatric inpatient separations (defined as any discharge, including death) during 10 fiscal years. We searched our hospital administrative database to determine the number of pediatric inpatient separations and deaths, and we searched the hospital switchboard and pediatric intensive care databases to determine ward code and cardiopulmonary arrest rates. Relative risks (RRs) with 95% confidence intervals (CIs) and logistic regression compared results over time. During the periods of the 2 PMET studies showing a reduction in hospital mortality, we found a decrease in hospital mortality: for 1999-2002 vs 2002-2006, 212 deaths among 14 161 patients (1.50%) vs 219 of 26 767 (0.82%), RR, 0.55 (95% CI, 0.44-0.69); for 2000-2005 vs 2005-2007, 300 deaths among 29 497 patients (1.02%) vs 98 of 14 005 (0.70%), RR, 0.69 (95% CI, 0.55-0.86). During the periods of the 3 PMET studies showing no change in or not examining hospital mortality, we found no significant change in hospital mortality. The annual odds ratio for survival was 1.13 (95% CI, 1.09-1.16). There were no changes in ward code and cardiopulmonary arrest rates over time. We found a reduction in hospital mortality over time in a children's hospital without a PMET. This demonstrates the limitation of before-and-after study designs, and we hypothesize that multiple co-interventions account for the decrease in mortality. Whether a PMET could have reduced mortality further is unknown.


Management of an integrated project (Sens-it-iv) to develop in vitro tests to assess sensitisation.
Sens-it-iv is an integrated project, funded by European Commission Framework Programme 6, the overall objective of which is to develop in vitro tests and test strategies to be used by the chemical, cosmetic and pharmaceutical industries to assess the risk for potential contact and respiratory sensitisers. Such tests, once formally validated and accepted, will permit the evaluation of the sensitising potential of existing and new chemical entities and the products of the European industries for classification and labelling, as required by the new EU REACH legislation on chemicals, or for the purpose of risk assessment as required by the 7th Amendment to the EU Cosmetics Directive. Sens-it-iv involves 28 partners, representing industries, universities and regulatory bodies, including various institutes in the EU Member States and different competencies, all with the common aim of achieving a final deliverable - increasing the safety of consumer products, whilst reducing animal experimentation. This paper provides an overview of the structure of the project and a detailed description of the organisation of its management.


[Science on the front page: an analysis of the covers of three Brazilian newspapers].
Many studies have tried to understand how the media covers topics related to science and technology (S&T) but few have examined the presence of these topics on the front pages of newspapers. This study analyzes the content of front-page leads about S&T in 2006, focusing on one elite national paper (Folha de S.Paulo) and two regional papers (Jornal do Commercio, from Pernambuco, and Zero Hora, from Rio Grande do Sul). It was noted that all three papers devoted front-page space to S&T, although to differing degrees. Folha de S.Paulo featured the topic more often, while Zero Hora highlighted it the most on its front pages.


Mapping the domains on the phosphoprotein of bovine respiratory syncytial virus required for N-P interaction using a two-hybrid system.
Specific interactions between the nucleocapsid protein (N) and the phosphoprotein (P) of bovine respiratory syncytial virus (BRSV) have been investigated using a yeast-based two-hybrid system. Plasmids encoding the yeast GAL4 DNA binding domain fused with the N gene and GAL4 activation domain fused with the P gene were cotransfected into competent yeast cells. The ability of the N and P proteins to interact in vivo was measured by activation of the lacZ reporter gene by the GAL4 transactivation region. Results indicated that the N and P proteins interact very strongly in vivo. When interactions between N and various deletion mutants of the P protein were examined, an internal region (aa 132-168) and the highly acidic C-terminal region (aa 236-241) of the P protein were found to be essential for N-P interaction. In addition, the highly basic N-terminal region (amino acids 1-40) was found to be involved in N-P interaction to a lesser extent.


Artificial Selection for Pathogenicity Mutations in Staphylococcus aureus Identifies Novel Factors Relevant to Chronic Infection.
Adaptation of Staphylococcus aureus to host microenvironments during chronic infection involves spontaneous mutations, yet changes underlying adaptive phenotypes remain incompletely explored. Here, we employed artificial selection and whole-genome sequencing to better characterize spontaneous chromosomal mutations that alter two pathogenicity phenotypes relevant to chronic infection in S. aureus: intracellular invasiveness and intracellular cytotoxicity. We identified 23 genes whose alteration coincided with enhanced virulence, 11 that were previously known and 12 (52%) that had no previously described role in S. aureus pathogenicity. Using precision genome editing, transposon mutants, and gene complementation, we empirically assessed the contributions of individual genes to the two virulence phenotypes. We functionally validated 14 of 21 genes tested as measurably influencing invasion and/or cytotoxicity, including 8 newly implicated by this study. We identified inactivating mutations (murA, ndhC, and a hypothetical membrane protein) and gain-of-function mutations (aroE Thr182Ile, yhcF Thr74Ile, and Asp486Glu in a hypothetical peptidase) in previously unrecognized S. aureus virulence genes that enhance pathogenesis when introduced into a clean genetic background, as well as a novel activating mutation in the known virulence regulator gene saeS (Ala106Thr). Investigation of potentially epistatic interactions identified a tufA mutation (Ala271Val) that enhances virulence only in the context of purine operon repressor gene (purR) inactivation. This project reveals a functionally diverse range of genes affected by gain- or loss-of-function mutations that contribute to S. aureus adaptive virulence phenotypes. More generally, the work establishes artificial selection as a means to determine the genetic mechanisms underlying complex bacterial phenotypes relevant to adaptation during infection.


Redox Profiling Reveals Clear Differences between Molecular Patterns of Wound Fluids from Acute and Chronic Wounds.
Wound healing is a complex multiphase process which can be hampered by many factors including impaired local circulation, hypoxia, infection, malnutrition, immunosuppression, and metabolic dysregulation in diabetes. Redox dysregulation is a common feature of many skin diseases demonstrated by virtually all cell types in the skin with overproduction of reactive oxygen and nitrogen species. The objective of this study was to characterize the redox environment in wound fluids and sera from patients suffering from chronic leg ulcers (n = 19) and acute wounds (bulla fluids from second degree burns; n = 11) with serum data also compared to those from healthy volunteers (n = 7). Significantly higher concentrations of TNF-α, interleukine-8, vascular endothelial growth factor, and lactate dehydrogenase (measure of cell damage) were found in fluids from chronic wounds compared to acute ones. The extent of protein carbonylation (measure of protein oxidation), lipid peroxidation, and tyrosine nitration (indicator of peroxynitrite production) was similar in acute and chronic wound fluids, while radical scavenging activity and glutathione (GSH) levels were elevated in chronic wound fluids compared to acute wounds. Sera were also assessed for the same set of parameters with no significant differences detected. Nitrotyrosine (the footprint of the potent oxidant peroxynitrite) and poly(ADP-ribose) (the product of the DNA damage sensor enzyme PARP-1) could be detected in wound biopsies. Our data identify multiple signs of redox stress in chronic wounds with notable differences. In chronic wounds, elevations in antioxidant levels/activities may indicate compensatory mechanisms against inflammation. The presence of nitrotyrosine and poly(ADP-ribose) in tissues from venous leg ulcers indicate peroxynitrite production and PARP activation in chronic wounds.


[Estimate of the artery responsible for acute inferior myocardial infarct attack using arterial electrocardiograph tracings].
The aim of the study was to determine IRA (infarct-related artery) by analysis of the initial ECG (electrocardiogram) in patients with acute inferior wall myocardial infarction. Forty patients (36 male, 4 female) admitted to coronary care unit with the diagnosis of acute inferior wall myocardial infarction were included in the study. The mean age of patients was 62.2 year (29-85 years). The coronary angiography was performed in all patients at the first week of admission. To determine the relationship between IRA and R/S ratio, ST segment depression in lead aVL, statistical analysis was performed. IRA was the right coronary artery (RCA) in 20 cases, circumflex artery (Cx) in 15 cases, RCA + Cx in 5 cases. R/S ratio was bigger than one in patients with Cx lesion and R/S ratio was smaller than one in patients with RCA lesion. The degree of the ST segment depression was equal or smaller than 2 mm in patients with Cx lesion and greater than 2 mm in patients with RCA lesion (p < 0.05). There was no correlation between IRA and precordial reciprocal electrocardiographic changes. Diagnosis of right ventricular infarction was established in 75% of patients with RCA lesion, 26% of patients with Cx lesion and 100% of patients with RCA + Cx lesions. We concluded that it was possible to predict IRA after examining the initial ECG changes such as R/S ratio, ST segment depression. This prediction can shorten the time required to perform primary percutaneous transluminal coronary angioplasty. Non-invasive prediction of IRA was useful for suggestion of clinical course in patients with high complication risk, such as patients with RCA lesion.


Stimulation of Sigma-1 receptor by dehydroepiandrosterone ameliorates hypertension-induced kidney hypertrophy in ovariectomized rats.
The incidence of chronic renal disease in women increases with aging, especially after menopause, suggesting that loss of sex hormones contributes to the development and progression of renal diseases. Recent studies revealed that decreased dehydroepiandrosterone (DHEA) levels are associated with endothelial dysfunction, renal injury and increased cardiovascular mortality in postmenopausal women. We here investigate the role of DHEA, also known as Sigma-1 receptor (Sigma-1R) agonist, on kidney injury induced by pressure overload (PO) after ovariectomy (OVX) and defined mechanisms underlying its protective action. Wistar rats subjected to bilateral OVX were further treated with abdominal aortic stenosis between the right and left renal arteries. DHEA (15 and 30 mg/kg) was administered orally once a day for 14 days starting from two weeks after aortic banding. Time course study indicated that the right kidney (RK) weight-to-body weight (BW) ratio increases time-dependently from one to four weeks along with increased mean arterial blood pressure (MABP) after banding in the abdominal aorta with no change in the left kidney (LK) weight-to-BW ratio. Similarly, we found significant time-dependent decrease in Sigma-1R expression in the RK with no changes in the LK. Administration of the Sigma-1R agonist, DHEA, significantly inhibited hypertension-induced increases in the RKW-to-BW ratio and increased expression of Sigma-1R in the RK. DHEA also attenuated PO-induced disturbance of heart rate and MABP. DHEA administration significantly restored PO-induced impaired endothelial nitric oxide synthase (eNOS) activity with concomitant increased phosphorylation of eNOS (Ser1179) and Akt activity with increased phosphorylation at Ser 473 and at Thr 308 in the RK. We here documented, for the first time, the potential role of Sigma-1R to protect the kidney from PO-induced injury in ovariectomized rats. DHEA administration protects hypertension-induced kidney injury via upregulation of Sigma-1R and stimulation of Akt-eNOS signaling in ovariectomized rats.


Surface functional properties of native, acid-treated, and reduced soy glycinin. 2. Emulsifying properties.
Emulsifying properties of native and chemically modified soy glycinins were studied. The influence of ionic strength, protein sample composition and concentration, and assay conditions on the flocculation-creaming process and coalescence resistance was analyzed. Differences in these emulsifying properties were exhibited by native glycinins, which have a variable content of 4S, 11S, and 15S forms. Structure and functionality of native glycinin were modified by means of combined treatments: mild acidic treatments without heating or with heating at variable time and with or without disulfide bonds reduction. Modified glycinins presented different degrees of deamidation, surface hydrophobicity, and molecular mass. A slight enhancement of emulsifying stability at moderated deamidation degrees was observed. In different protein samples, a positive relationship between the flocculation-creaming rate constant and equilibrium oil volume fraction of emulsions with surface hydrophobicity was detected. A remarkable difference was observed between reduced and nonreduced samples, mainly with respect to behavior at low or high ionic strength.


[A fundamental and clinical study of ferritin 'Eiken' radioimmunoassay kit].
We have measured serum ferritin level using double antibody radioimmunoassay kit (Eiken ICL) and evaluated the characteristics of the kit and clinical usefulness. Satisfactory results were observed in standard curve, reproducibility, dilution and recovery test. In clinical evaluation, we have measured in normal subjects and patients with various diseases. The range in normal males and females were 13.0-158.7 ng/ml and 7.3-73.0 ng/ml, respectively. Serum ferritin level was elevated in patients with hepatoma, biliary cancer, lung cancer and other malignant diseases. Measurement of serum ferritin value would be useful in the monitoring of cancer patients.


[Socioeconomic status, eating patterns, and heavy metals exposure in women of childbearing age in Cali, Colombia].
Global increase in food and water pollution is associated with health risk, which depends on the concentration, the dose, and the exposure time. This has raised concerns about the possible long-term effects of chronic exposure to low concentrations of heavy metals, such as lead, cadmium and mercury. To explore the relationship among socioeconomic status, eating patterns, and exposure to heavy metals among a population of women in Cali, Colombia. A total of 233 non-pregnant women of childbearing age living in the Aguablanca district of Cali, Colombia, were enrolled in the study. We gathered sociodemographic data, as well as information on housing conditions, exposure to heavy metals, frequency of food intake, and anthropometric measurements. Samples of lettuce, cabbage and fish (tilapia and butterfish) were collected to determine lead, cadmium, and mercury concentrations. Descriptive and multiple correspondence analyses were performed to establish eating patterns. Fish was served in each of the three main meals of the day, with a bigger serving at lunch time. Cadmium was found in three samples of butterfish at levels below the acceptable. Of those who ate fish more than once a week, 11.1% bought the product at a cadmium-positive store. The multiple correspondence analysis showed a positive relationship between being black and consuming butterfish and tilapia more than once per week. The findings showed that the studied population had access to heavy metal-contaminated food, which combined with the women's cultural eating patterns, socioeconomic status, and metabolic characteristics led to a greater vulnerability to the effects of heavy metals exposure.


Effect of structural and conformation modifications, including backbone cyclization, of hydrophilic hexapeptides on their intestinal permeability and enzymatic stability.
A library of 18 hexapeptide analogs was synthesized, including sub-libraries of N- or C-methylation of the parent hexapeptide Phe-Gly-Gly-Gly-Gly-Phe, as well as backbone cyclized analogs of each linear analog with various ring sizes. N- or C-methylation as well as cyclization (but not backbone cyclization) have been suggested to improve intestinal permeability and metabolic stability of peptides in general. Here we aimed to assess their applicability to hydrophilic peptides. The intestinal permeability (Papp) of the 18-peptide library was in the range of 0.2-6.8 x 10-6 cm/sec. Based on several tests, we concluded that the absorption mechanism of all tested analogs is paracellular, regardless of the structural or conformational modifications. In all cases, backbone cyclization increased Papp (5-fold) in comparison to the linear analogs due to the smaller 3D size and also dramatically decreased peptide proteolysis by brush border enzymes. N- or C-methylation did not enhance the permeability of the linear analogs in this series.


Thalamic lesions in a patient with Menkes kinky-hair disease.
The thalamus in a patient with Menkes kinky-hair disease showed lesions involving the large association and specific sensory relay nuclei and sparing the nonspecific sensory relay nuclei. The results confirm the findings of Iwata et al. [1979] but add the notion of a relative sparing of the microneurons which represent 40-50% of the normal neuronal population in the medialis formation and 35-40% in the posterior formation [Dom 1976]. Although axonal and/or cortical neuronal damage has contributed some retrograde lesions, a primary thalamic degeneration probably represents the most important pathogenetic factor. Whether this degeneration results specifically from the deficiency of enzymes operative in copper metabolism in some thalamic nuclei only remains purely speculative. Its clinical significance within the syndrome dominated by a severe psychomotor retardation cannot be evaluated.


Hough transform from the radon transform.
An appropriate special case of a transform developed by J. Radon in 1917 is shown to have the major properties of the Hough transform which is useful for finding line segments in digital pictures. Such an observation may be useful in further efforts to generalize the Hough transform. Techniques for applying the Radon transform to lines and pixels are developed through examples, and the appropriate generalization to arbitrary curves is discussed.


Long-term tolerance of healthy human subjects to high amounts of xylitol and fructose: general and biochemical findings.
Three groups of volunteers, totalling 125, lived for two years on strict diets so that comparisons might be made with regard to the sweeteners: fructose (F), sucrose (S), and xylitol (X). The sizes of the test groups were: S, 35; F, 38; X, 52. The average monthly amounts of the sugars consumed in a varied assortment of foods were: S, 2.2 kg; F, 2.1 kg; X, 1.5 kg. The highest daily doses of fructose and xylitol were 200 - 400 g (maximum 430 g xylitol). Serum samples were analyzed for several chemical parameters. The dietary regimens did not result in clinically significant changes between the sugar groups. The ability of X to produce osmotic diarrhoea and flatulence was found to depend on the individual physiological responses of each volunteer. In many cases no symptoms were found although high amounts (200 - 400 g) of X were consumed. All pregnancies and deliveries in the F and X groups were normal. Practically all the volunteers accepted the F and X foods (almost 100 varities) and adhered to the dietary regimen for two years. This was due in the main to the fact that most F and X products were comparable to those containing sucrose.


Unilateral Pedicle Screw Fixation is Associated with Reduced Cost and Similar Outcomes in Selected Patients Undergoing Minimally Invasive Transforaminal Lumbar Interbody Fusion for L4-5 Degenerative Spondylolisthesis.
Retrospective study of 24 patients who underwent either a bilateral or unilateral TLIF procedure for the treatment of degenerative spondylolisthesis. To analyze differences in cost and outcome between patients undergoing minimally invasive transforaminal lumbar interbody fusion (mi-TLIF) with unilateral or bilateral pedicle screw fixation for L4-5 degenerative spondylolisthesis. Lumbar fusion surgeries, including the TLIF procedure, have been shown to be an effective treatment for leg and low back pain caused by degenerative spondylolisthesis. Some studies have shown TLIF surgeries to be cost-effective, but there is still a paucity of data and no consensus. Unilateral TLIFs can provide the same benefits as bilateral TLIFs, but come with additional benefits of a less invasive surgery. We retrospectively analyzed a consecutive series of patients with L4-5 degenerative stenosis and spondylolisthesis who either received a unilateral or bilateral mi-TLIF, paying particular attention to hospital cost and clinical outcome. Of the 33 patients eligible for analysis, we were able to obtain appropriate clinical and radiographic follow-up data on 24 patients (72.7%), 14 patients who underwent unilateral fixation, and 10 patients who underwent bilateral fixation. The cohorts were similar with regard to age, comorbidities, and demographics. Most patients reported good or excellent results, and there were no significant differences between the cohorts with regard to clinical outcome. There was one interbody graft extrusion in the unilateral cohort that required explantation, but no other hardware failures. Hospital cost was significantly lower in the unilateral cohort, and hardware savings accounted for only part of the difference. Unilateral pedicle screw fixation is an acceptable surgical strategy in patients with stable L4-5 degenerative spondylolisthesis undergoing mi-TLIF. In our series, unilateral fixation led to significant hospital cost savings without compromising clinical or radiographic outcomes.


MED12 overexpression is a frequent event in castration-resistant prostate cancer.
In a recent effort to unravel the molecular basis of prostate cancer (PCa), Barbieri and colleagues using whole-exome sequencing identified a novel recurrently mutated gene, MED12, in 5.4% of primary PCa. MED12, encoding a subunit of the Mediator complex, is a transducer of Wnt/β-catenin signaling, linked to modulation of hedgehog signaling and to the regulation of transforming growth factor beta (TGFβ)-receptor signaling. Therefore, these studies prompted us to investigate the relevance of MED12 in PCa. Expression of MED12, SMAD3 phosphorylation, and proliferation markers was assessed by immunohistochemistry on tissue microarrays from 633 patients. siRNA-mediated knockdown of MED12 was carried out on PCa cell lines followed by cellular proliferation assays, cell cycle analysis, apoptosis assays, and treatments with recombinant TGFβ3. We found nuclear overexpression of MED12 in 40% (28/70) of distant metastatic castration-resistant prostate cancer (CRPC(MET)) and 21% (19/90) of local-recurrent CRPC (CRPC(LOC)) in comparison with frequencies of less than 11% in androgen-sensitive PCa, and no overexpression in benign prostatic tissues. MED12 expression was significantly correlated with high proliferative activity in PCa tissues, whereas knockdown of MED12 decreased proliferation, reduced G1- to S-phase transition, and increased the expression of the cell cycle inhibitor p27. TGFβ signaling activation associates with MED12 nuclear overexpression in tissues and results in a strong increase in MED12 nuclear expression in cell lines. Furthermore, MED12 knockdown reduced the expression of the TGFβ target gene vimentin. Our findings show that MED12 nuclear overexpression is a frequent event in CRPC in comparison with androgen-sensitive PCa and is directly implicated in TGFβ signaling.


Role of β-blockers in the cardiovascular disease continuum: a collaborative Delphi survey-based consensus from Asia-Pacific.
This Delphi method of consensus was designed to develop scientific statements for β-blockers in the continuum of cardiovascular diseases with a special focus on the role of bisoprolol. Eleven experienced cardiologists from across the Asia-Pacific countries participated in two rounds of the survey. In the first round, experts were asked to rate agreement/disagreement with 35 statements across seven domains regarding the use of β-blockers for treating hypertension, heart failure, coronary artery diseases, co-morbidities, as well as their safety profile, usage pattern, and pharmacokinetic variability. A consensus for a statement could be reached with >70% agreement. Except for seven statements, all attained consensus in the first round. In the second round that was conducted virtually, the experts re-appraised their ratings for the seven statements along with a critical appraisal of two additional statements that were suggested by experts in the preceding round. At the end of the second round, the final version included 36 statements (34 original statements, two statements suggested by experts, and the omission of one statement that did not attain consensus). The final version of statements in the second round was disseminated among experts for their approval followed by manuscript development. Attainment of consensus for almost all statements reconfirms the clinical benefits of β-blockers, particularly β1-selective blockers for the entire spectrum of cardiovascular diseases.


A feasibility study of a leaky waveguide aptasensor for thrombin.
This proof-of-principle study demonstrates the feasibility of a leaky waveguide (LW) aptasensor, where aptamers were immobilised in a mesoporous chitosan waveguiding film for the detection of thrombin. This work has demonstrated that aptamers immobilised in hydrogels retain their affinity and selectivity towards their target and thus can be used as bioreceptors. The use of antibodies as bioreceptors for sensing thrombin is not viable because it is a serine protease, which will cleave the antibodies. Currently used assays based on clotting time and chromogenic/fluorogenic substrates have limited potential for thrombin measurement in whole blood. Using the initial binding rate over the first 5 min, the limit of detection of our LW aptasensor for thrombin was ∼22 nM. The sensor was tested with spiked serum samples, giving a reading of 46.1 ± 4.6 nM for a sample containing 50 nM thrombin. Our proposed sensor combines the robustness and low cost of aptamers as molecular recognition elements with the simple fabrication process of the chitosan-based leaky waveguide, making LW aptasensors highly attractive for applications in point-of-care diagnostics and healthcare monitoring.


Detecting Opioid-Related Aberrant Behavior using Natural Language Processing.
The United States is in the midst of a prescription opioid epidemic, with the number of yearly opioid-related overdose deaths increasing almost fourfold since 20001. To more effectively prevent unintentional opioid overdoses, the medical profession requires robust surveillance tools that can effectively identify at-risk patients. Drug-related aberrant behaviors observed in the clinical context may be important indicators of patients at risk for or actively abusing opioids. In this paper, we describe a natural language processing (NLP) method for automatic surveillance of aberrant behavior in medical notes relying only on the text of the notes. This allows for a robust and generalizable system that can be used for high volume analysis of electronic medical records for potential predictors of opioid abuse.


ATM/ATR Phosphorylation of CtIP on Its Conserved Sae2-like Domain Is Required for Genotoxin-Induced DNA Resection but Dispensable for Animal Development.
Homology-directed repair (HDR) of double-strand DNA breaks (DSBs) is dependent on enzymatic resection of DNA ends by the Mre11/Rad50/Nbs1 complex. DNA resection is triggered by the CtIP/Sae2 protein, which allosterically promotes Mre11-mediated endonuclease DNA cleavage at a position internal to the DSB. Although the mechanics of resection, including the initial endonucleolytic step, are largely conserved in eucaryotes, CtIP and its functional counterpart in Saccharomyces cerevisiae (Sae2) share only a modest stretch of amino acid homology. Nonetheless, this stretch contains two highly conserved phosphorylation sites for cyclin-dependent kinases (T843 in mouse) and the damage-induced ATM/ATR kinases (T855 in mouse), both of which are required for DNA resection. To explore the function of ATM/ATR phosphorylation at Ctip-T855, we generated and analyzed mice expressing the Ctip-T855A mutant. Surprisingly, unlike Ctip-null mice and Ctip-T843A-expressing mice, both of which undergo embryonic lethality, homozygous CtipT855A/T855A mice develop normally. Nonetheless, they are hypersensitive to ionizing radiation, and CtipT855A/T855A mouse embryo fibroblasts from these mice display marked defects in DNA resection, chromosomal stability, and HDR-mediated repair of DSBs. Thus, although ATM/ATR phosphorylation of CtIP-T855 is not required for normal animal development, it enhances CtIP-mediated DNA resection in response to acute stress, such as genotoxin exposure.


Small-cell carcinoma of the vagina. A clinicopathologic study.
We report a case of small-cell carcinoma of the vagina in a women whose entire uterus, cervix, both fallopian tubes, and both ovaries had been removed 22 years previously. She presented with diffuse submucosal disease of the distal vagina with a possible soft-tissue component extending beyond the end of the vaginal vault. Extensive microscopic and immunohistochemical assessment established the diagnosis; treatment was initiated with chemotherapy, followed by local radiotherapy. To our knowledge, this is the first fully characterized case of its kind. We discuss the aggressive local behavior and the characteristics of gynecologic small-cell tumors in general.


Reverse Triage to Increase the Hospital Surge Capacity in Disaster Response.
Successful and effective management of large-scale disasters and epidemics requires pre-established systematic plans to minimize the damage and control the situation. With an increasing number of people in need of urgent medical care, hospitals must improve their response capacity, being at the forefront of responding to disasters and incidents. One way to develop the hospital capacity in disaster response is by reverse triage (RT). The current study was conducted to investigate the role of RT to create additional hospital surge capacity in one of the major referral academic hospitals of Isfahan, Iran. This cross-sectional study was conducted in 2015 at Al-Zahra Subspecialty Hospital, Isfahan, Iran. The ten most common diseases leading to hospitalization in each ward of the hospital in 2014 were reviewed and, based on the prevalence, sorted and listed. Academic instructions for making a decision and possibility of early discharge was written and approved by an expert panel. On a day that was not set previously, the pre-selected in-charge person of each department was asked to run the RT following the instructions, and the number and percentage of those who were eligible for discharge via RT were determined. The total BOR in Al-Zahra Hospital in 2014 was about 80%, so it was estimated that almost 140 out of 700 beds are vacant. The results showed that by using RT, 108 (20%) hospitalized cases could be discharged, and considering the bed occupancy rate of about 80% and 140 vacant beds, a total of 248 beds could be provided following RT. Running RT in 41 wards and units of Isfahan Al-Zahra Hospital, on average, added 108 beds to the hospital capacity. This increment is not the same in all wards, as the role of intensive care units in RT for surge capacity is insignificant.


Diabetes mellitus: the first visit.
Diabetes mellitus is an 'insulin problem' as the maintenance of normoglycaemia is affected by either reduced pancreatic insulin production or cellular insulin resistance. During a patient's first visit for type 2 diabetes mellitus, there are several consultation tasks that the doctor should consider. First, the doctor has to disclose the diagnosis. Second, there is a need to correct any myths and misconceptions that the patient may have on the disease. Next, to allow the doctor to provide patient-specific disease education and advice on lifestyle modifications and goal setting, the biopsychosocial impact of the disease on the patient should be assessed, and relevant lifestyle information gathered. Lastly, screening for the complications of diabetes mellitus and its associated medical conditions should be planned.