The effects of clomiphene citrate upon ovulation and endocrinology when administered to patients with unexplained infertility.
Twenty-four couples with unexplained infertility were studied in a spontaneous cycle followed by a clomiphene citrate (CC) cycle (150 mg, days 5-9). All spontaneous cycles were ovulatory, as defined by follicular collapse determined by transvaginal sonography. In CC cycles, 6/24 (25%) cycles demonstrated luteinized unruptured follicles (LUF). In 2/6 LUF cycles there was no apparent luteinizing hormone (LH) surge. LUF cycles had significantly elevated LH levels in the follicular phase compared to ovulatory CC cycles. There was no apparent difference in serum oestradiol. In CC cycles multifollicular development occurred in 87.5% of cycles, with significantly elevated serum oestradiol. Luteinizing hormone and follicle-stimulating hormone were elevated in the follicular phase compared to spontaneous cycles. This study suggests a high incidence of LUF when CC is administered to ovulatory patients, and its use in patients with ovulatory infertility is questioned.


The Determination of Immunomodulation and Its Impact on Survival of Rectal Cancer Patients Depends on the Area Comprising a Tissue Microarray.
T cell density in colorectal cancer (CRC) has proven to be of high prognostic importance. Here, we evaluated the influence of a hyperfractionated preoperative short-term radiation protocol (25 Gy) on immune cell density in tumor samples of rectal cancer (RC) patients and on patient survival. In addition, we assessed spatial tumor heterogeneity by comparison of analogue T cell quantification on full tissue sections with digital T cell quantification on a virtually established tissue microarray (TMA). A total of 75 RC patients (60 irradiated, 15 treatment-naïve) were defined for retrospective analysis. RC samples were processed for immunohistochemistry (CD3, CD8, PD-1, PD-L1). Analogue (score 0-3) as well as digital quantification (TMA: 2 cores vs. 6 cores, mean T cell count) of marker expression in 2 areas (central tumor, CT; invasive margin, IM) was performed. Survival was estimated on the basis of analogue as well as digital marker densities calculated from 2 cores (Immunoscore: CD3/CD8 ratio) and 6 cores per tumor area. Irradiated RC samples showed a significant decrease in CD3 and CD8 positive T cells, independent of quantification mode. T cell densities of 6 virtual cores approximated to T cell densities of full tissue sections, independent of individual core density or location. Survival analysis based on full tissue section quantification demonstrated that CD3 and CD8 positive T cells as well as PD-1 positive tumor infiltrating leucocytes (TILs) in the CT and the IM had a significant impact on disease-free survival (DFS) as well as overall survival (OS). In addition, CD3 and CD8 positive T cells as well as PD-1 positive TILs in the IM proved as independent prognostic factors for DFS and OS; in the CT, PD-1 positive TILs predicted DFS and CD3 and CD8 positive T cells as well as PD-1 positive TILs predicted OS. Survival analysis based on virtual TMA showed no impact on DFS or OS. Spatial tumor heterogeneity might result in inadequate quantification of immune marker expression; however, if using a TMA, 6 cores per tumor area and patient sample represent comparable amounts of T cell densities to those quantified on full tissue sections. Consistently, the tissue area used for immune marker quantification represents a crucial factor for the evaluation of prognostic and predictive biomarker potential.


Dual format course design: neuroanatomy and neurophysiology for adult learners.
Adult learners require alternative learning opportunities to enable them to work and still be able to upgrade their education. This dual format course, combining online and face-to-face components, was developed to meet the need of students to complete a prerequisite undergraduate level neuroanatomy and neurophysiology course while attending a program that included fly-in weekends (seven) and online instruction (15 weeks). A combination of online lectures and on-campus lectures were used to teach pre-requisite neuroanatomy and neurophysiology course topics. The article presents the teaching material division between online and on-campus lectures and presentation of data collected. Survey data collected included student preferred: online media presentation, online activities developed to facilitate learning of the online material, online case study discussion, and testing formats. Students also were asked to comment on whether the class should move to a 100% online format and what their concerns would be moving to an all online format. Additional qualitative data on student input related to the course, adult learning and the learning environment will be presented. Blackboard data include: student daily access patterns, media and documents access and download patterns, and case study participation. Additionally, descriptive statistics from in class quizzes versus online quizzes includes: student patterns of test taking in an unlimited retake environment, scores on retakes and final scores (highest of retakes), in-class quiz scores, and comparison of comprehensive final exam scores from online versus face-to-face lecture material and testing. Findings provide valuable information for online course formatting, revisions and additional course development.


The impact of involuntary exit from employment in later life on the risk of major depression and being prescribed anti-depressant medication.
Involuntary employment exit in later life has been shown to be a risk factor for poor physical and mental health. This study aims to examine the relationship between involuntary employment exit in later life and subsequent risk of reporting major depression or being prescribed anti-depressant medication (ADM). Data were drawn from four waves of the Swedish Longitudinal Occupational Survey of Health (SLOSH). This is a nationally representative longitudinal cohort survey of persons employed in Sweden in 2003 and 2005. The sample was restricted to respondents who had exited the labour market aged 50+ years between 2006 and 2012 (N = 1433). Major depression was measured using the Symptom Checklist Core Depression Scale (SCL-CD6). Prescription ADM redeemed from a pharmacy was based on the National Prescribed Drug Register. After controlling for socio-demographic variables, health, health behaviours, and baseline depression, involuntary employment exit was associated with an increased risk of reporting major depression (OR 3.16; CI 1.32-7.61) and becoming newly prescribed ADM (HR 2.08; CI 1.03-4.21) compared to voluntary employment exit. Involuntary employment exit represents a risk for subsequent depression in later life. Mental health and social services ought to consider identifying these individuals for possible intervention programs to reduce the burden of depression in later life.


Evaluation of a new assessment tool in problem-based learning tutorials in dental education.
The Harvard School of Dental Medicine (HSDM) uses a hybrid problem-based learning (PBL) approach to teaching in the D.M.D. curriculum. Each tutorial group at HSDM is made up of eight to ten students. The objective of this study was to examine the performance of the students in the tutorial sessions as assessed by the tutor. A total of ten tutorial blocks led by twenty-four tutorial leaders were completed at HSDM between summer 2008 and fall 2009. All of the tutors were calibrated to a new assessment system that was developed for student assessment in the tutorials. The students were assessed on three major domains: knowledge acquisition, problem-solving and analytical thinking skills, and personal and interpersonal development. The tutors evaluated the students assigned to their group after the end of each block. Students also filled out a self-assessment form. Simple descriptive statistics were used to summarize the evaluations of the tutors. A total of 290 student evaluations from ten tutorial blocks were available for analysis. Tutors reported that 64 percent of the students preferred to communicate verbally without prompting and 68 percent of students submitted written reports to the groups during tutorial sessions. Tutors reported that a majority of students brought new information to each tutorial session (86.5 percent), brought information that facilitated others' learning (88.7 percent), integrated newly acquired knowledge with previous knowledge (92.7 percent), applied knowledge from self-study to explain issues during case discussions (91.7 percent), asked appropriate questions to stimulate discussions (87.3 percent), generated hypotheses to explain problems under discussion (83.8 percent), evaluated the hypotheses in light of available evidence (85.5 percent), defined and took responsibility for learning goals and objectives (89.3 percent), responded well to criticism (91.7 percent), took a leadership role (74.5 percent), and demonstrated sensitivity to psychosocial issues (88.6 percent). Student communication that tended to take over the group process in a non-contributory manner was reported in only 2 percent of the evaluations. Overall, students participating in PBL tutorial sessions appear to exhibit problem-solving and analytical thinking skills and personal and interpersonal attributes.


Selective short- and long-term effects of serotonin, small cardioactive peptide, and tetanic stimulation on sensorimotor synapses of Aplysia in culture.
Synapses between the sensory and motor cells of Aplysia can be enhanced by heterosynaptic or homosynaptic stimulation. We have used the isolated sensorimotor synapse of Aplysia in cell culture to explore short- and long-term heterosynaptic facilitation produced by 2 facilitatory transmitters and compared these to homosynaptic facilitation produced by posttetanic potentiation. We found that brief application of 5-HT or small cardioactive peptide (SCP) evokes comparable short-lasting enhancement of nondepressed sensorimotor synapses. The effect evoked by SCP diverges from that of 5-HT when the sensorimotor synapse is first depressed by low-frequency homosynaptic stimulation. Whereas 5-HT facilitates sensorimotor synapses whether or not they are depressed, SCP has little or no effect on synapses that have been depressed by more than 75%. The 2 transmitters also differ in producing long-term facilitation. Whereas repeated applications of 5-HT evoke long-term facilitation of the synapses, SCP applications do not. To determine whether these failures to facilitate could be overcome by increasing levels of cAMP, we applied SCP in the presence of phosphodiesterase inhibitors, which resulted in SCP evoking both short- and long-term changes comparable to that of 5-HT. Homosynaptic facilitation by post-tetanic potentiation differed from heterosynaptic facilitation in that tetanic stimulation failed to evoke long-lasting changes in the synapse. These results support recent findings that 5-HT is a critical neuromodulator in behavioral sensitization and dishabituation and suggest that critical levels of cAMP may be required for long- and short-term facilitation of depressed synapses.(ABSTRACT TRUNCATED AT 250 WORDS)


Reinforcing the staple line with Surgicel® Nu-knit® in Roux-en-Y gastric bypass: comparison with bovine pericardial strips.
In the literature, staple line leak rate is reported to be 1-6 %, and hemorrhage rate is 2-5 % in laparoscopic Roux-en-Y gastric bypass (LRYGB). Various buttress materials are available in an attempt to reduce perioperative complications. The aims of our study are to evaluate the effect of using absorbable hemostat (SNK) as buttress material and compare its usage with bovine pericardial strips (PSD). Between January 2006 to May 2007 and from October 2007 to December 2009, a total of 1,074 patients underwent LRYGB at our institution. Of these 1,074 patients, PSD was used in 443 (41.2 %) patients, and SNK was used in 631 (58.8 %) patients. A retrospective review of a prospectively collected database was performed for all LRYGB patients, noting the outcomes and complications of the procedure. Five (1.1 %) patients required transfusion of packed red blood cells (PRBC) during early postoperative period (postoperative 1-3 days) in the PSD group, while two (0.3 %) patients required transfusion in the SNK group. SNK patients received significantly lower mean units of PRBC (1.0 unit) when compared to that of PSD patients (5.0 units). One (0.2 %) anastomotic leak was found in the PSD group on postoperative day (POD) 10. One (0.2 %) patient in the SNK group also showed an anastomotic leak on POD 2. Additionally, the cost of SNK per procedure was significantly less than that of PSD. The use of absorbable hemostat as buttress material may be effective in reducing acute postoperative bleeding in LRYGB at a significantly lower cost.


Somatic hypermutation in 5' flanking regions of heavy chain antibody variable regions.
The aim of this study has been to determine the distribution of somatic mutations in the 5' flanking regions of rearranged immunoglobulin heavy chain variable region genes (VDJ). We sequenced the 5' flanking region in 12 secondary immune response antibodies produced in C57BL/6j mice against the hapten (4-hydroxy-3-nitrophenyl)acetyl (NP) coupled to chicken-gamma-globulin. In these and previously published sequences, almost 97% of the mutations occurred in the transcribed region of the gene, and only a minority of genes (5/29) contained mutations upstream of the transcription start (cap) site. No potential germ-line donor was found for a cluster of five base changes previously found in a single heavy chain gene, 3B62. However, the uniqueness of this mutational cluster and its distance from the normally mutated region suggests that the nucleotide changes may not be due to the normal mutator mechanism. Thus, as this was the only instance of somatic mutations that far upstream of the promoter/cap site region, the reverse transcriptase model for somatic hypermutation is still a possibility. The data are consistent with a mutational mechanism that requires transcription of the rearranged target V(D)J gene which appears to result in the generation of a positively skewed asymmetrical distribution of somatic mutations. A single mode is centered near the V(D)J and a long tail extends into the 3' non-translated region of the J-C intron. Two classes of model could explain this mutation distribution pattern: those where transcription products (RNA, cDNA) are the direct mutational substrates, or those that postulate local unfolding of the chromatin around a V(D)J rearrangement directly exposing the DNA of the transcribed region to specific mutational enzymes.


Osteoarthritis induction leads to early and temporal subchondral plate porosity in the tibial plateau of mice: an in vivo microfocal computed tomography study.
In osteoarthritis (OA), changes occur in both cartilage and subchondral bone. The subchondral bone plate facilitates normal cross-talk between articular cartilage and trabecular subchondral bone, and adaptive changes in the plate due to OA may therefore disturb cross-talk homeostasis. To investigate these changes over time, we examined the cartilage-subchondral bone interface using a combined approach of histologic analysis and in vivo microfocal computed tomography. Sixteen-week-old male C57BL/6 mice (n=32) received intraarticular injections of collagenase in 1 joint to induce instability-related OA and received saline injections in the contralateral knee joint (control joint). At 2, 4, 6, 10, and 14 weeks after injection, changes in the tibial subchondral bone plate and subchondral trabeculae were analyzed. Two weeks after injection, collagenase-injected joints had significantly more cartilage damage and osteophytosis than did control joints. Osteoclast activity directly underneath the subchondral bone plate was significantly elevated in collagenase-injected joints compared to control joints (mean±SEM osteoclast surface/bone surface 11.07±0.79% versus 7.60±0.81%), causing the plate to become thinner and creating a large increase in subchondral bone plate porosity (mean±SEM cumulative porosity volume 0.05±0.04×10(-3) mm3 in control joints versus 2.52±0.69×10(-3) mm3 in collagenase-injected joints). Four weeks after injection, the previously formed perforations disappeared, coinciding with a significant rise in osteoblast activity in the subchondral trabecular bone in collagenase-injected joints compared to control joints (mean ± SEM bone formation rate/bone surface 0.62±0.13 μm3/μm2 per day versus 0.30±0.03 μm3/μm2 per day). The current study is the first to provide quantitative longitudinal data on the dynamic changes in the subchondral bone plate after OA induction. The development of plate perforations may enhance mutual interaction between subchondral trabeculae, bone marrow cells, and the articular cartilage in OA.


Risk Stratification of Thyroid Nodules With Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance (AUS/FLUS) Cytology Using Ultrasonography Patterns Defined by the 2015 ATA Guidelines.
The purpose of this study was to evaluate the predictive value of ultrasonography (US) patterns based on the 2015 American Thyroid Association (ATA) guidelines for malignancy in atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) nodules. From January 2014 to August 2015, 133 thyroid nodules that were initially diagnosed as AUS/FLUS on fine needle aspiration (FNA) were included in this study. Each nodule was assigned a category with US patterns defined by the ATA guidelines. Clinical characteristics and US patterns were compared between the benign and malignant nodules, and malignancy rates were calculated according to the ATA guidelines. The malignancy rate in the very low suspicion group was 0.0% in AUS/FLUS nodules. When applying the ATA guidelines, significant differences existed for US patterns between the benign and malignant nodules in the AUS group ( P = .032) but not the FLUS group ( P = .168). Ultrasonography patterns by the 2015 ATA guidelines can provide risk stratification for nodules with AUS cytology but not for ones with FLUS cytology. For nodules with AUS/FLUS cytology with the very low suspicion pattern of the ATA guidelines, follow-up US might be recommended instead of repeat FNA.


Cognitive-behavioral therapy for women with lifelong vaginismus: a randomized waiting-list controlled trial of efficacy.
Women with lifelong vaginismus (N=117) were randomly assigned to cognitive-behavioral group therapy, cognitive-behavioral bibliotherapy, or a waiting list. Manualized treatment comprised sexual education, relaxation exercises, gradual exposure, cognitive therapy, and sensate focus therapy. Group therapy consisted of ten 2-hr sessions with 6 to 9 participants per group. Assistance with minimal-contact bibliotherapy consisted of 6 biweekly, 15-min telephone contacts. Twenty-one percent of the participants left the study before posttreatment assessment. Intent-to-treat analysis revealed that successful intercourse at posttreatment was reported by 14% of the treated participants compared with none of the participants in the control condition. At the 12-month follow-up 21% of the group therapy participants and 15% of the bibliotherapy participants, respectively, reported successful intercourse. Cognitive-behavioral treatment of lifelong vaginismus was thus found to be efficacious, but the small effect size of the treatment warrants future efforts to improve the treatment.


InnovationInsights: A Visual Analytics Approach for Understanding the Dual Frontiers of Science and Technology.
Science has long been viewed as a key driver of economic growth and rising standards of living. Knowledge about how scientific advances support marketplace inventions is therefore essential for understanding the role of science in propelling real-world applications and technological progress. The increasing availability of large-scale datasets tracing scientific publications and patented inventions and the complex interactions among them offers us new opportunities to explore the evolving dual frontiers of science and technology at an unprecedented level of scale and detail. However, we lack suitable visual analytics approaches to analyze such complex interactions effectively. Here we introduce InnovationInsights, an interactive visual analysis system for researchers, research institutions, and policymakers to explore the complex linkages between science and technology, and to identify critical innovations, inventors, and potential partners. The system first identifies important associations between scientific papers and patented inventions through a set of statistical measures introduced by our experts from the field of the Science of Science. A series of visualization views are then used to present these associations in the data context. In particular, we introduce the Interplay Graph to visualize patterns and insights derived from the data, helping users effectively navigate citation relationships between papers and patents. This visualization thereby helps them identify the origins of technical inventions and the impact of scientific research. We evaluate the system through two case studies with experts followed by expert interviews. We further engage a premier research institution to test-run the system, helping its institution leaders to extract new insights for innovation. Through both the case studies and the engagement project, we find that our system not only meets our original goals of design, allowing users to better identify the sources of technical inventions and to understand the broad impact of scientific research; it also goes beyond these purposes to enable an array of new applications for researchers and research institutions, ranging from identifying untapped innovation potential within an institution to forging new collaboration opportunities between science and industry.


Evaluation of the effect of sample suspension concentration and viral load on the outcome of the rabies tissue culture infection test.
In this study, we examined various brain suspension concentrations and viral loads in Neuro-2a cell cultures using 20 rabies-positive bovine samples. The reproducibility of results varied: 65% showed consistent outcomes across all concentrations, while 35% disagreed in at least one. Viral titers ranged from less than 25 × 101 to 25 × 103.50 TCID50/mL, with 20% below 25 × 101 TCID50/mL. Concentrations between 5% and 20% yielded over 90% agreement in positive results, but at 30%, agreement dropped from 85% to 50%. Cell confluence was successfully maintained at 5%, 10%, and 20%, while concentrations of 30% and above led to confluence loss. Low viral loads also negatively impacted reproducibility. These results suggest that sample concentration has a direct influence on preservation of cell confluence and that low viral loads may influence the reproducibility of the rabies tissue culture infection test (RTCIT).


WDR81 regulates adult hippocampal neurogenesis through endosomal SARA-TGFβ signaling.
Adult hippocampal neurogenesis, a process considered important for hippocampal function, is regulated at multiple molecular levels. Mutations in the gene encoding the WD40 repeat-containing protein WDR81 are associated with neurological disorders, including cerebellar ataxia, mental retardation, quadrupedal locomotion syndrome (CAMRQ2), and microcephaly. In this study, we show that ablation of WDR81 in adult neural progenitor cells (aNPCs) markedly reduced adult hippocampal neurogenesis and impaired hippocampus-dependent learning. WDR81 suppresses endosomal PtdIns3P synthesis, likely by inhibiting the assembly of the PI3K-III complex. In the absence of WDR81, endosomal PtdIns3P levels are greatly elevated, leading to endosomal persistence of the PtdIns3P-binding protein SARA and consequently hyperactivation of SARA-dependent TGFβ signaling. Inhibition of PI3K-III activity or suppression of SARA-dependent TGFβ signaling markedly ameliorated the defective adult neurogenesis in WDR81-deficient mice. Taken together, these findings not only uncover the requirement for the WDR81-SARA-TGFβ axis in adult hippocampal neurogenesis, but also suggest that defective adult hippocampal neurogenesis contributes to the etiology of WDR81-related neurological diseases.


Accurate dosimetry in 131I radionuclide therapy using patient-specific, 3-dimensional methods for SPECT reconstruction and absorbed dose calculation.
(131)I radionuclide therapy studies have not shown a strong relationship between tumor absorbed dose and response, possibly due to inaccuracies in activity quantification and dose estimation. The goal of this work was to establish the accuracy of (131)I activity quantification and absorbed dose estimation when patient-specific, 3-dimensional (3D) methods are used for SPECT reconstruction and for absorbed dose calculation. Clinically realistic voxel-phantom simulations were used in the evaluation of activity quantification and dosimetry. SPECT reconstruction was performed using an ordered-subsets expectation maximization (OSEM) algorithm with compensation for scatter, attenuation, and 3D detector response. Based on the SPECT image and a patient-specific density map derived from CT, 3D dosimetry was performed using a newly implemented Monte Carlo code. Dosimetry was evaluated by comparing mean absorbed dose estimates calculated directly from the defined phantom activity map with those calculated from the SPECT image of the phantom. Finally, the 3D methods were applied to a radioimmunotherapy patient, and the mean tumor absorbed dose from the new calculation was compared with that from conventional dosimetry obtained from conjugate-view imaging. Overall, the accuracy of the SPECT-based absorbed dose estimates in the phantom was >12% for targets down to 16 mL and up to 35% for the smallest 7-mL tumor. To improve accuracy in the smallest tumor, more OSEM iterations may be needed. The relative SD from multiple realizations was <3% for all targets except for the smallest tumor. For the patient, the mean tumor absorbed dose estimate from the new Monte Carlo calculation was 7% higher than that from conventional dosimetry. For target sizes down to 16 mL, highly accurate and precise dosimetry can be obtained with 3D methods for SPECT reconstruction and absorbed dose estimation. In the future, these methods can be applied to patients to potentially establish correlations between tumor regression and the absorbed dose statistics from 3D dosimetry.


The effects of amine-modified single-walled carbon nanotubes on the mouse microbiota.
Amine-modified carbon nanotubes are drug delivery platforms with great potential that have not yet been applied in human clinical trials. Although modified nanotube vectors have the ability to carry multiple effectors, targeting agents, and even wrapped RNA, reports on unmodified, insoluble carbon nanotubes have highlighted inflammation in organs, including the intestine, with disruption of its resident microbiota. Disruption of the microbiota may allow for colonization by pathogenic bacteria, such as Clostridoidies difficile, stimulate immunoinfiltrates into the lamina propria or alter the absorption of therapeutics. Most proposed nanotube drugs are soluble, modified structures that are administered parenterally, and the majority of these soluble macromolecules are renally excreted; however, some are released into the bile, gaining access to the gastrointestinal tract. Using environmentally isolated BALB/C mice in oral and intraperitoneal dosing models, high dose (3.80 or 4.25 mg/week), we administered amine-modified, soluble carbon nanotubes for 7 or 8 weeks. The general health and weight of the mice were monitored weekly, and upon killing, the diversity and content of their colonic, cecal, and ileal microbiota were assessed using shotgun 16S DNA sequencing. We show that while oral administration at suprapharmacological doses modestly altered the α- and β-diversity of the mouse microbiome, these changes did not result in observed changes in clinical end points. Intraperitoneally-dosed mice exhibited none of the toxicities assessed.


Resolving the chemical identity of H2SO4 derived anions on Pt(111) electrodes: they're sulfate.
Understanding how electrolyte composition controls electrocatalytic reactions requires molecular-level insight into electrode/electrolyte interaction. Perhaps the most basic aspect of this interaction, the speciation of the interfacial ion, is often controversial for even relatively simple systems. For example, for Pt(111) in 0.5 M H2SO4 it has long been debated whether the adsorbed anion is SO42-, HSO4- or an H3O+SO42- ion pair. Here we apply interface-specific vibrational sum frequency (VSF) spectroscopy and theory to this problem and perform an isotope exchange study: we collect VSF spectra of Pt(111) in H2SO4(H2O) and D2SO4(D2O) as a function of bias and show that at all potentials they are identical. This is the most direct spectroscopic evidence to date that SO42- is the dominant adsorbate, despite the fact that at 0.5 M H2SO4 bulk solution is dominated by HSO4-. This approach is based on the unique selection rule of the VSF spectroscopy and thus offers a new way of accessing general electrode/electrolyte interaction in electrocatalysis.


Surgical management of severe acute pancreatitis.
The substantial morbidity and mortality associated with severe acute pancreatitis has led to a variety of therapeutic approaches. We reviewed the records of 40 patients who had undergone the "triple-tube" procedure (gastrostomy, cholecystostomy, and jejunostomy) with drainage of the lesser sac and retroperitoneum. Cardiovascular, respiratory, renal, and hepatic dysfunction were common, and reoperation was required in 35% (14) of the cases. Gastrostomies and jejunostomies were associated with numerous complications, and cholecystostomies were rarely of benefit except when biliary tract disease was present. Debridement and drainage of necrotic pancreatic and retroperitoneal tissue afforded a higher survival rate in the small population in which they were employed. The overall mortality was 55% (22), reflecting and severity of the disease at the time of surgery. Early recognition and limited surgical debridement may be beneficial in this high-risk group.


[The use of the stapedius reflex in the fitting of hearing aids (author transl)].
The authors made experiments concerning the stapedius reflex without and with an hearing aid; there is a relation between this reflex and the discomfort threshold for the selection. The stimulus is given on a loudspeaker and the stapedius reflex permits in some cases to know the gain of the hearing aid and also the limit of discomfort. This method very useful particulary for children is objective.


[Transformations and continuities in Canadian social welfare programs].
Poor mothers and their families constitute a core dilemma for a social welfare system that aims primarily to encourage and keep workers in the labor force. Public income transfers to these and other marginalized groups may be viewed as disincentives to seek paid work and have been characterized in Canada by stinginess and contradictions since the beginning of the XX century. This paper discusses recent transformations in these programs and their effects on families and individuals. Focusing specifically on poor mothers raising children alone, it argues that many gradual cuts and reshaping these programs have changed the character of the social welfare state in Canada, blocking escape routes from poverty for marginalized groups.


Reimagining Alzheimer's disease--an age-based hypothesis.
The historical roots of Alzheimer's disease provide a sound conceptual basis for linking the behavioral and neurological symptoms of the disease with the frequently associated pathology of amyloid plaques and neurofibrillary tangles. Out of these roots has grown the "amyloid cascade hypothesis"--a vision of the etiology of Alzheimer's that has spurred the discovery of many important insights into the neurobiology of the disease. Despite these successes, the wealth of new data now available to biomedical researchers urges a full review of the origins of Alzheimer's, and such a reconsideration is offered here. It begins with the most widely accepted risk factor for developing Alzheimer's disease: age. Then, for an individual to progress from normal age-appropriate cognitive function to a condition where the full palette of clinical symptoms is expressed, three key steps are envisioned: (1) an initiating injury, (2) a chronic neuroinflammatory response, and (3) a discontinuous cellular change of state involving most, if not all, of the cell types of the brain. The amyloid cascade is integrated into this sequence, but reconfigured as an amyloid deposition cycle. In this way, the pathology of amyloid plaques is envisioned as highly correlated with, but mechanistically distinct from, the three obligatory steps leading to Alzheimer's disease. The implications of this new model are discussed with respect to our current diagnostic criteria, and suggestions are put forward for expanding our future research efforts.


Pedobacter yonginense sp. nov., isolated from a mesotrophic artificial Lake in Korea.
A non-motile red-pigmented bacterium, designated strain HMD1002(T), was isolated from an artificial lake located on the campus of Hankuk University of Foreign Studies, South Korea. The major fatty acids were iso-C(15:0) (29.6%), Summed Feature 3 (comprising C(16:1) omega7c and/or iso-C(15:0) 2-OH; 17.5%) and iso-C(17:0) 3-OH (12.5%). The major isoprenoid quinone was menaquinone-7 (MK-7). The DNA G+C content was 41.0 mol%. A phylogenetic tree based on 16S rRNA gene sequences showed that strain HMD1002(T) formed a lineage in the genus Pedobacer and was closely related to Pedobacer terrae (96.3%) and Pedobacer suwonensis (95.8%) in sequence similarity. On the basis of the evidence presented in this study, strain HMD1002(T) represents a novel species of the genus Pedobacter, for which the name Pedobacter yonginense sp.nov. is proposed. The type strain is HMD1002(T) (=KCTC 22721(T) = CEC(T) 7544(T)).


Nonrandom chromosomal changes in retinoblastomas.
The analysis of the karyotype in 76 retinoblastomas (24 our cases and 52 described in the literature) has revealed nonrandom changes of Iq, 6p, 13, 16 and the sex chromosomes. Complete or partial trisomy Iq was observed in 44 out of 76 tumours. Tetra-or trisomy 6p was found in 35 and 6 cases respectively. Chromosome 13 monosomy or its long arm deletion was described in 11 tumours. Monosomy 16 and loss of the X or Y--in 18 and 12 cases. The specific feature of retinoblastoma karyotype is presence (along with two normal homologues of the pair 6) of the marker chromosome i (6p). Possible causes of unexpectedly rare abnormalities of chromosome 13 in retinoblastoma cells were discussed in the light of well known data on predisposing role of constitutional deletion 13q14, and recent molecular genetic studies showing the significance of recessive tumour genes in carcinogenesis. The cytological signs of gene amplification (HSRs, DMs) were revealed in few retinoblastomas. However, the recent data on N-myc gene amplification and its elevated expression in several retinoblastomas indicate that amplification of the oncogene(s) might be involved in the genesis of this tumour. Further studies are needed to understand the correlative role of specific chromosome rearrangements, gene(s) amplification and action of recessive rb gene, located at 13q14 in initiation and progression of retinoblastoma.


Photochemical and microbial alterations of DOM spectroscopic properties in the estuarine system Ria de Aveiro.
The influence of photochemical transformations of chromophoric dissolved organic matter (CDOM) on microbial communities was evaluated in the estuarine system Ria de Aveiro. Two sites, representative of the marine and brackish water zones of the estuary, were surveyed regularly in order to determine seasonal and vertical profiles of variation of CDOM properties. Optical parameters of CDOM indicative of aromaticity and molecular weight were used to establish CDOM sources, and microbial abundance and activity was characterized. Additionally, microcosm experiments were performed in order to simulate photochemical reactions of CDOM and to evaluate microbial responses to light-induced changes in CDOM composition. The CDOM of the two estuarine zones showed different spectral characteristics, with significantly higher values of the specific ultra-violet absorbance at 254 nm (SUVA254) (5.5 times) and of the absorption coefficient at 350 nm (a350) (12 times) and lower SR (S275-295/S350-400) ratio at brackish water compared with the marine zone, reflecting the different amounts and prevailing sources of organic matter, as well as distinct riverine and oceanic influences. At the marine zone, the abundance of bacteria and the activity of Leu-AMPase correlated with a350 and a254, suggesting a microbial contribution to the HMW CDOM pool. The irradiation of DOM resulted in a decrease of the values of a254 and a350 and an increase of the slope S275-295 and of the ratios E2 : E3 (a250/a365) and SR, which in turn increase its bioavailability. However, the extent of photoinduced transformations and microbial responses was dependent on the initial optical characteristics of CDOM. In Ria de Aveiro both photochemical and microbial processes yielded optical changes in CDOM and the overall results of these combined processes determine the fate of CDOM in the estuarine system and have an influence on local productivity and in adjacent coastal areas.


The Arabidopsis malectin-like leucine-rich repeat receptor-like kinase IOS1 associates with the pattern recognition receptors FLS2 and EFR and is critical for priming of pattern-triggered immunity.
Plasma membrane-localized pattern recognition receptors such as FLAGELLIN SENSING2 (FLS2) and EF-TU RECEPTOR (EFR) recognize microbe-associated molecular patterns (MAMPs) to activate the first layer of plant immunity termed pattern-triggered immunity (PTI). A reverse genetics approach with genes responsive to the priming agent β-aminobutyric acid (BABA) revealed IMPAIRED OOMYCETE SUSCEPTIBILITY1 (IOS1) as a critical PTI player. Arabidopsis thaliana ios1 mutants were hypersusceptible to Pseudomonas syringae bacteria. Accordingly, ios1 mutants demonstrated defective PTI responses, notably delayed upregulation of PTI marker genes, lower callose deposition, and mitogen-activated protein kinase activities upon bacterial infection or MAMP treatment. Moreover, Arabidopsis lines overexpressing IOS1 were more resistant to P. syringae and demonstrated a primed PTI response. In vitro pull-down, bimolecular fluorescence complementation, coimmunoprecipitation, and mass spectrometry analyses supported the existence of complexes between the membrane-localized IOS1 and FLS2 and EFR. IOS1 also associated with BRASSINOSTEROID INSENSITIVE1-ASSOCIATED KINASE1 (BAK1) in a ligand-independent manner and positively regulated FLS2/BAK1 complex formation upon MAMP treatment. Finally, ios1 mutants were defective in BABA-induced resistance and priming. This work reveals IOS1 as a regulatory protein of FLS2- and EFR-mediated signaling that primes PTI activation upon bacterial elicitation.


Resilience: Building immunity in psychiatry.
The challenges in our personal, professional, financial, and emotional world are on rise, more so in developing countries and people will be longing for mental wellness for achieving complete health in their life. Resilience stands for one's capacity to recover from extremes of trauma and stress. Resilience in a person reflects a dynamic union of factors that encourages positive adaptation despite exposure to adverse life experiences. One needs to have a three-dimensional construct for understanding resilience as a state (what is it and how does one identify it?), a condition (what can be done about it?), and a practice (how does one get there?). Evaluating the level of resilience requires the measurement of internal (personal) and external (environmental) factors, taking into account that family and social environment variables of resilience play very important roles in an individual's resilience. Protection factors seem to be more important in the development of resilience than risk factors. Resilience is a process that lasts a lifetime, with periods of acquisition and maintenance, and reduction and loss for assessment. Overall, currently available data on resilience suggest the presence of a neurobiological substrate, based largely on genetics, which correlates with personality traits, some of which are configured via social learning. The major questions about resilience revolve around properly defining the concept, identifying the factors involved in its development and recognizing whether it is actually possible to immunize mental health against adversities. In the clinical field, it may be possible to identify predisposing factors or risk factors for psychopathologies and to develop new intervention strategies, both preventive and therapeutic, based on the concept of resilience. The preferred environments for application of resilience are health, education, and social policy and the right approach in integrating; it can be developed only with more research and analysis with focus on resilience. Be it patient or family member or caregiver, advocating resilience will empower psychiatrists in India.


Forensic psychiatry patients, services, and legislation in Nunavut and Greenland.
Circumpolar regions face unique challenges in establishing and maintaining mental health care systems, including forensic psychiatry services. The scarcity of data and lack of evidence concerning the forensic psychiatry patient (FPP) populations of Nunavut and Greenland exacerbates the challenges of informing best practices and healthcare planning. By comparing the prevalence of forensic psychiatry patients, the mental health care services, and the legislation in these two relatively similar but unique regions, insight may be gained that can help inform healthcare planning. This cross-sectional study includes all forensic psychiatry in- and outpatients in one year from Nunavut (2018) and on February 29, 2020, in Greenland. The Greenland sample (n = 93) was nearly four times larger than the Nunavut sample (n = 15) at the population level. Despite considerable differences in forensic legislation and service supply, the forensic psychiatry patients in the two areas share several similarities. A total of 87% (n = 13) in the Nunavut sample were diagnosed with a DSM-5 schizophrenia spectrum disorder or other psychotic disorder. In Greenland, 82% (n = 76) were diagnosed with an ICD-10 F2 diagnosis (schizophrenia, schizotypal and delusional disorders). Approximately 2/3 of the patients in both populations were diagnosed with substance use disorder, and 60% of the Nunavut FPP received long-acting antipsychotic injections versus 62% in Greenland. Nearly half of the FPPs in both populations had never been convicted prior to entering the forensic psychiatry system; Nunavut 45% versus Greenland 47%. A substantial proportion of Greenlandic FPPs were outpatients compared to Nunavut (83% versus 47%). This study is an essential first step toward describing a Model of Care for forensic psychiatry patients in circumpolar regions; furthermore, the clinical similarities between the two populations provide support for future joint Arctic research and the inclusion of artic forensic patients in international studies.


Improved quality of life over one year is associated with improved adherence in patients with schizophrenia.
Quality of life (QoL) is increasingly considered an important outcome in health research. We wished to explore the determinants of change in QoL in patients with schizophrenia over the course of a one-year RCT. Predictors of change in observer-rated QoL (Quality of Life Scale: QLS) were assessed in 363 patients with schizophrenia during the CUtLASS clinical trial. Change in QLS score over the course of a year correlated with change in psychotic and depressive symptoms and treatment adherence. Linear regression showed that improvement in QoL was predicted by reduction in negative and depressive symptoms and improvement in adherence rating. These three change scores together explained 38% of the variance in QLS change. Exploration of the direction of any possible causal effect, using TETRAD, indicated that improved adherence leads to improved QoL, and that change in depression also leads to QoL change. The relationship between QoL and negative symptoms suggests that greater social activity (reflected as better QoL scores) improves negative symptoms. Such a direct relationship between treatment adherence and QoL has not been reported before. Improving adherence to medication would appear to be a key approach to improving measured quality of life in people with schizophrenia.


SigH stress response mediates killing of Mycobacterium tuberculosis by activating nitronaphthofuran prodrugs via induction of Mrx2 expression.
The emergence of drug-resistant Mycobacterium tuberculosis strains highlights the need to discover anti-tuberculosis drugs with novel mechanisms of action. Here we discovered a mycobactericidal strategy based on the prodrug activation of selected chemical derivatives classified as nitronaphthofurans (nNFs) mediated by the coordinated action of the sigH and mrx2 genes. The transcription factor SigH is a key regulator of an extensive transcriptional network that responds to oxidative, nitrosative, and heat stresses in M. tuberculosis. The nNF action induced the SigH stress response which in turn induced the mrx2 overexpression. The nitroreductase Mrx2 was found to activate nNF prodrugs, killing replicating, non-replicating and intracellular forms of M. tuberculosis. Analysis of SigH DNA sequences obtained from spontaneous nNF-resistant M. tuberculosis mutants suggests disruption of SigH binding to the mrx2 promoter site and/or RNA polymerase core, likely promoting the observed loss of transcriptional control over Mrx2. Mutations found in mrx2 lead to structural defects in the thioredoxin fold of the Mrx2 protein, significantly impairing the activity of the Mrx2 enzyme against nNFs. Altogether, our work brings out the SigH/Mrx2 stress response pathway as a promising target for future drug discovery programs.


A classification tree approach for cardiac ischemia detection using spatiotemporal information from three standard ECG leads.
The accurate noninvasive diagnosis of cardiac ischemia remains a great challenge. To this end, the ECG is the main source of information, and personal health systems may now embed intelligence for enabling any citizen to self-record an ECG anywhere at any time. Our objective is to find a decision-support approach that makes best use of these resources. A new classification tree based on conditions combinations competition (T-3C) is proposed for building a multibranch tree of combined decision rules, and its performance is compared to usual methods based either on discriminant analysis or on classification trees. Moreover, we assessed with these methods, the diagnosis content for ischemia detection of the spatiotemporal ECG information that can be retrieved either from the standard 12-lead ECG or from only the three orthogonal leads subset (I, II, and V2), easy to set-up in self-care. The diagnostic accuracy of 14 decision-making strategies was compared for ischemia detection induced by angioplasty on a test set from a study population of 90 patients. The best performance is obtained with the T-3C algorithm on three-lead ECG, reaching 98% of sensitivity and of specificity, thus exceeding 23% of the diagnostic accuracy of the recommended and currently used standard ECG criteria.


[Myelin-like structures as a possible source of the smooth endoplasmic reticulum in early amphibian oocytes].
A comparative study of amphibian oocyte ultrastructural organization has shown a significant accumulation of elements of the smooth endoplasmic reticulum in the oocyte cytoplasm at the third stage of development. The analysis of oocytes of two frog species, Xenopus laevis and Rana temporaria, at the first and second stages of their development enabled us to recognize in the cytoplasm of the oocyte some myelin-like structures (MLs) made of 30-40 densely packaged membranous layers and shaped as dense bodies. MLs are also present in the adjacent follicular cells and in the intercellular space. In the oocyte cytoplasm these structures are located near the nuclear envelope and other intracellular organelles. At the third stage of oogenesis, which is characterized by a high functional activity of the cells, MLs are seen to unwrap sequentially into double-layer membranes similar to the smooth endoplasmic reticulum cisternae. Intermediate steps of this process being also observed. It is supposed that MLs may play the role of membrane stocks to be used eventually for the formation of nascent endoplasmic membranes in the amphibian oocytes.


The ventilator-assisted child: a case for empowerment.
Families are the most valuable resource available to ventilator assisted children. Enabling and empowering families is a nursing intervention that maximizes family strengths and functioning.


Inactive S. aureus Cas9 downregulates alpha-synuclein and reduces mtDNA damage and oxidative stress levels in human stem cell model of Parkinson's disease.
Parkinson's disease (PD) is one of the most common neurodegenerative diseases, but no disease modifying therapies have been successful in clinical translation presenting a major unmet medical need. A promising target is alpha-synuclein or its aggregated form, which accumulates in the brain of PD patients as Lewy bodies. While it is not entirely clear which alpha-synuclein protein species is disease relevant, mere overexpression of alpha-synuclein in hereditary forms leads to neurodegeneration. To specifically address gene regulation of alpha-synuclein, we developed a CRISPR interference (CRISPRi) system based on the nuclease dead S. aureus Cas9 (SadCas9) fused with the transcriptional repressor domain Krueppel-associated box to controllably repress alpha-synuclein expression at the transcriptional level. We screened single guide (sg)RNAs across the SNCA promoter and identified several sgRNAs that mediate downregulation of alpha-synuclein at varying levels. CRISPRi downregulation of alpha-synuclein in iPSC-derived neuronal cultures from a patient with an SNCA genomic triplication showed functional recovery by reduction of oxidative stress and mitochondrial DNA damage. Our results are proof-of-concept in vitro for precision medicine by targeting the SNCA gene promoter. The SNCA CRISPRi approach presents a new model to understand safe levels of alpha-synuclein downregulation and a novel therapeutic strategy for PD and related alpha-synucleinopathies.


Multiresistant Bacteria Isolated from Activated Sludge in Austria.
Wastewater contains different kinds of contaminants, including antibiotics and bacterial isolates with human-generated antibiotic resistances. In industrialized countries most of the wastewater is processed in wastewater treatment plants which do not only include commercial wastewater, but also wastewater from hospitals. Three multiresistant pathogens-extended spectrum β-lactamase (ESBL)-harbouring Enterobacteriaceae (Gram negative bacilli), methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococci (VRE)-were chosen for screening in a state of the art wastewater treatment plant in Austria. Over an investigation period of six months all three multiresistant pathogens could be isolated from activated sludge. ESBL was the most common resistance mechanism, which was found in different species of Enterobacteriaceae, and in one Aeromonas spp. Sequencing of ESBL genes revealed the dominance of genes encoding members of CTX-M β-lactamases family and a gene encoding for PER-1 ESBL was detected for the first time in Austria. MRSA and VRE could be isolated sporadically, including one EMRSA-15 isolate. Whereas ESBL is well documented as a surface water contaminant, reports of MRSA and VRE are rare. The results of this study show that these three multiresistant phenotypes were present in activated sludge, as well as species and genes which were not reported before in the region. The ESBL-harbouring Gram negative bacilli were most common.


Mu-Tau Neutrinos: Influencing Fast Flavor Conversions in Supernovae.
Neutrinos in a core-collapse supernova can undergo fast flavor conversions with a possible impact on the explosion mechanism and nucleosynthesis. We perform the first nonlinear simulations of fast conversions in the presence of three neutrino flavors. The recent supernova simulations with muon production call for such an analysis, as they relax the standard ν_{μ,τ}=ν[over ¯]_{μ,τ} (two-flavor) assumption. Our results show the significance of muon and tau lepton number angular distributions, together with the traditional electron lepton number ones. Indeed, our three-flavor results are potentially very different from two-flavor ones. These results strengthen the need to further investigate the occurrence of fast conversions in supernova simulation data, including the degeneracy breaking of mu and tau neutrinos.


Energy and water flux during terrestrial estivation and overland movement in a freshwater turtle.
The doubly labeled water (DLW) method for studying energy and water balance in field-active animals is not feasible for freshwater animals during aquatic activities, but several species of nominally aquatic reptiles leave wetlands for several critical and extended behaviors, where they face challenges to their energy and water balance. Using DLW, we studied energy and water relations during terrestrial estivation and movements in the eastern long-necked turtle (Chelodina longicollis), a species that inhabits temporary wetlands in southeastern Australia. Water efflux rates of 14.3-19.3 mL (kg d)(-1 ) during estivation were nearly offset by influx, indicating that turtles did not maintain water balance while terrestrial, though dehydration was slow. Estivation energy expenditure declined over time to 20.0-24.6 kJ (kg d)(-1) but did not indicate substantial physiological specializations. Energy reserves are predicted to limit survival in estivation to an estimated 49-261 d (depending on body fat), which is in close agreement with observed bouts of natural estivation in this population. The energy cost and water flux rates associated with overland movement behavior ranged from 46 to 99 kJ (kg d)(-1 ) and from 21.6 to 40.6 mL (kg d)(-1), respectively, for turtles moving 23-34 m d(-1). When a wetland dries, a turtle that forgoes movement to other wetlands can save sufficient energy to fuel up to 134 d in estivation. The increasing time in estivation with travel distance gained in this energy "trade-off" fits our previous observations that more turtles estivate when longer distances must be traveled to the nearest permanent lake, whereas emigration is nearly universal when only short distances must be traversed. The DLW method shows promise for addressing questions regarding the behavioral ecology and physiology of freshwater turtles in terrestrial situations, though validation studies are needed.


Direct peritoneal resuscitation from hemorrhagic shock: effect of time delay in therapy initiation.
After conventional resuscitation from hemorrhagic shock, splanchnic microvessels progressively constrict, leading to impairment of blood flow. This occurs despite restoration and maintenance of central hemodynamics. The authors' recent studies have demonstrated that topical and continuous ex vivo exposure of the gut microvasculature to a glucose-based clinical peritoneal dialysis solution (Delflex), as a technique of direct peritoneal resuscitation (DPR), can prevent these postresuscitation events when initiated simultaneously with conventional resuscitation. This study aimed to determine whether DPR applied after conventional resuscitation reverses the established postresuscitation intestinal vasoconstriction and hypoperfusion. Male Sprague-Dawley rats were bled to 50% of baseline mean arterial pressure and resuscitated intravenously over 30 minutes with the shed blood returned plus two times the shed blood volume of saline. Initiation of ex vivo, topical DPR was delayed to 2 hours (group 1, n = 8), or to 4 hours (group 2, n = 8), respectively, after conventional resuscitation. Intravital microscopy and Doppler velocimetry were used to measure terminal ileal microvascular diameters of inflow A1 and premucosal A3 (proximal pA3, distal dA3) arterioles and blood flow in the A1 arteriole, respectively. Maximum arteriolar dilation capacity was obtained from the topical application, in the tissue bath, of the endothelium-independent nitric oxide-donor sodium nitroprusside (10M). Hemorrhagic shock caused a selective vasoconstriction of A1 (-24.1% +/- 2.15%) arterioles from baseline, which was not seen in A3 vessels. This caused A1 blood flow to drop by -68.6% of the prehemorrhage value. Conventional resuscitation restored and maintained hemodynamics in all the animals without additional fluid therapy. In contrast, there was a generalized and progressive postresuscitation vasoconstriction of A1 (-21.7%), pA3 (-18.5%), and dA3 (-18.7%) vessels. The average postresuscitation A1 blood flow was -49.5% of the prehemorrhage value, indicating a persistent postresuscitation hypoperfusion. Direct peritoneal resuscitation reversed the postresuscitation vasoconstriction by 40.9% and enhanced A1 blood flow by 112.9% of the respective postresuscitation values. Delayed DPR reverses the gut postresuscitation vasoconstriction and hypoperfusion regardless of the initiation time. This occurs without adverse effects on hemodynamics. Direct peritoneal resuscitation-mediated enhancement of tissue perfusion results from the local effects from the vasoactive components of the Delflex solution, which are hyperosmolality, lactate buffer anion, and, to a lesser extent, low pH. The molecular mechanism of this vasodilation effect needs further investigation.


ATP-binding cassette transporters and neurodegenerative diseases.
ATP-binding cassette (ABC) transporters are one of the largest groups of transporter families in humans. ABC transporters mediate the translocation of a diverse range of substrates across cellular membranes, including amino acids, nucleosides, lipids, sugars and xenobiotics. Neurodegenerative diseases are a group of brain diseases that detrimentally affect neurons and other brain cells and are usually associated with deposits of pathogenic proteins in the brain. Major neurodegenerative diseases include Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. ABC transporters are highly expressed in the brain and have been implicated in a number of pathological processes underlying neurodegenerative diseases. This review outlines the current understanding of the role of ABC transporters in neurodegenerative diseases, focusing on some of the most important pathways, and also suggests future directions for research in this field.


Usefulness of combined risk stratification with heart rate and systolic blood pressure in the management of chronic heart failure. A report from the CHART-2 study.
The appropriate target ranges of heart rate (HR) and systolic blood pressure (SBP) for the management of chronic heart failure (CHF) patients remain to be elucidated in a large-scale cohort study. We examined 3,029 consecutive CHF patients with sinus rhythm (SR) (mean age, 67.9 years) registered in the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 Study (CHART-2; NCT00418041). There were 357 deaths (11.8%) during the median follow-up of 3.1 years. We first performed the classification and regression tree analysis for mortality, identifying SBP <89 mmHg, HR >70 beats/min and SBP <115 mmHg as the primary, secondary and tertiary discriminators, respectively. According to these, we divided the patients into low- (n=1,131), middle- (n=1,624) and high-risk (n=274) groups with mortality risk <10%, 10-20% and >20%, respectively. The low-risk group was characterized by SBP >115 mmHg and HR <70 beats/min and the high-risk group by SBP <89 mmHg regardless of HR values or SBP 89-115 mmHg and HR >76 beats/min. Multivariate Cox regression analysis revealed that the hazard ratio of all-cause death for low-, middle- and high-risk groups was 1.00 (reference), 1.48 (95% confidence interval (CI): 1.10-1.99, P=0.009) and 2.44 (95% CI 1.66-3.58, P<0.001), respectively. Subgroup analysis revealed that age ≥70 years, diabetes, or reduced left ventricular function had higher hazard ratios in the high-risk group. The results demonstrate the usefulness of combined risk stratification of HR and SBP in CHF patients with SR.


Non-Hodgkin's lymphomas in Asia.
The relative frequencies of the various histopathologic types of lymphomas are generally similar among Asian countries. Hodgkin's disease and follicular lymphomas are relatively rare in Asia. Among NHL, the Asians have a higher rate of aggressive NHL, as compared with the NCI data. Immunologic analysis revealed that PTCL is common in Asia. The relative frequency of PTCL is comparable among Chinese in Taiwan, the east coast of China, and Hong Kong, as well as in adult T-cell leukemia/lymphoma (ATLL) nonendemic areas in Japan. The increased rate of T-cell lymphomas in Asia is attributed to the low incidence of follicular lymphomas. The similar patterns of distribution in histopathologic and immunologic subtypes of NHL in Asia suggest that a common ethnic or geographic factor exists. To elucidate it, further detailed epidemiologic studies are needed. Primary extranodal NHL is slightly more prevalent in Asia than in the United States; the most frequent primary site is Waldeyer's ring in Japanese patients and the GI tract in Chinese patients. Primary small intestinal lymphoma in Asia showed the pattern of the Western type. Primary cutaneous lymphomas are rare in Asia. The clinical features of PTCL in Asia are comparable with those described in the United States, except for a predilection for the nasal/paranasal region. In Asia, outside Japan, ATLL has been reported only in Taiwan. The seroepidemiologic survey of carriers of ATLL showed the rate of seropositivity for HTLV-I in Taiwan was similar to that in nonendemic areas in Japan. The clinicopathologic features of ATLL in Taiwan and Japan are essentially identical. In children in Japan and Taiwan, Hodgkin's disease is much less frequent than in the West. However, the relative frequencies of the histopathologic and immunologic subtypes of childhood NHL in Japan and Taiwan do not differ significantly from those of the West. Although Burkitt's lymphoma in Japan and Taiwan is of nonendemic type, in India it may comprise both endemic and nonendemic types in almost equal number.


One-by-one coupling of single defect centers in nanodiamonds to high-Q modes of an optical microresonator.
In this letter, we present the on-demand coupling of single NV(-) defect centers in nanodiamonds to a polystyrene microspherical resonator. From an ensemble on a coverslip, we select single nanodiamonds containing a single defect proven by a pronounced antibunching dip. With the help of a scanning near-field probe, we can attach these nanodiamonds to a microsphere resonator one-by-one. A clearly modulated fluorescence spectrum demonstrates coupling of the single defect centers to high-Q whispering-gallery modes. Our experiments establish a toolbox to assemble complex systems consisting of single quantum emitters and (coupled) microresonators.


Investigation of low-temperature electroluminescence of InGaN/GaN based nanorod light emitting arrays.
For InGaN/GaN based nanorod devices using a top-down etching process, the optical output power is affected by non-radiative recombination due to sidewall defects (which decrease light output efficiency) and the mitigated quantum confined Stark effect (QCSE) due to strain relaxation (which increases internal quantum efficiency). Therefore, the exploration of low-temperature optical behaviors of nanorod light emitting diodes (LEDs) will help identify the correlation between these two factors. In this work, low-temperature electroluminescent (EL) spectra of InGaN/GaN nanorod arrays were explored and compared with those of planar LEDs. The nanorod LED exhibits a much higher optical output percentage increase when the temperature decreases. The increase is mainly attributed to the increased carriers in the quantum wells for radiative recombination. Also, due to a better spatial overlap of electrons and holes in the quantum wells, the increased number of carriers can be more efficiently recombined in the nanorod device. Next, while the nanorod array shows nearly constant peak energy in the EL spectra at various injection currents at the temperature of 300 K, a blue shift has been observed at 190 K. The results suggest that with less non-radiative recombination and thus more carriers in the quantum wells, carrier screening and band filling still prevail in the partially strain relaxed nanorods. Moreover, when the temperature drops to 77 K, the blue shift of both nanorod and planar devices disappears and the optical output power decreases since there are fewer carriers in the quantum wells for radiative recombination.


Calcium-deficient hydroxyapatite-PLGA composites: mechanical and microstructural investigation.
The microstructural and mechanical properties of composites composed of calcium deficient hydroxyapatite (CDHAp) and poly(lactide-co-glycolide) (PLGA) have been investigated. The composites were formed by hydrolysis of alpha-tricalcium phosphate (alpha-TCP) to CDHAp in pressed precomposite compacts of alpha-TCP-PLGA-NaCl. The differences in hydrolysis of alpha-TCP-PLGA-NaCl for two compositions of 80:10:10 wt % and 60:20:20 wt %. were monitored by isothermal calorimetry and X-ray diffraction. The microstructural evolution and variance in final composite microstructure after hydrolysis at 37 degrees C, 45 degrees C, and 56 degrees C were examined by scanning electron microscopy. HAp-PLGA composite formed from the alpha-TCP-PLGA-NaCl (80:10:10) precomposites at 37 degrees C developed a tensile strength of 13.3 +/- 0.9 MPa, a flexural strength of 24.8 +/- 1.7 MPa, and Young's modulus of 2.8 +/- 0.3 GPa. These values were 12.00 +/- 0.2 MPa, 36.1 +/- 2.1 MPa, and 5.5 +/- 0.8 GPa for the precomposite composition 60:20:20. All these mechanical properties showed a variation with hydrolysis temperature and composition. The differences in mechanical properties were related to the final microstructures of the composites, which are governed by the morphological changes in the polymer structure at its glass transition temperature and the extent of cement-type formation of CDHAp by hydrolysis of alpha-TCP.


Exome analysis of HIV patients submitted to dendritic cells therapeutic vaccine reveals an association of CNOT1 gene with response to the treatment.
With the aim of searching genetic factors associated with the response to an immune treatment based on autologous monocyte-derived dendritic cells pulsed with autologous inactivated HIV, we performed exome analysis by screening more than 240,000 putative functional exonic variants in 18 HIV-positive Brazilian patients that underwent the immune treatment. Exome analysis has been performed using the ILLUMINA Infinium HumanExome BeadChip. zCall algorithm allowed us to recall rare variants. Quality control and SNP-centred analysis were done with GenABEL R package. An in-house implementation of the Wang method permitted gene-centred analysis. CCR4-NOT transcription complex, subunit 1 (CNOT1) gene (16q21), showed the strongest association with the modification of the response to the therapeutic vaccine (p=0.00075). CNOT1 SNP rs7188697 A/G was significantly associated with DC treatment response. The presence of a G allele indicated poor response to the therapeutic vaccine (p=0.0031; OR=33.00; CI=1.74-624.66), and the SNP behaved in a dominant model (A/A vs. A/G+G/G p=0.0009; OR=107.66; 95% CI=3.85-3013.31), being the A/G genotype present only in weak/transient responders, conferring susceptibility to poor response to the immune treatment. CNOT1 is known to be involved in the control of mRNA deadenylation and mRNA decay. Moreover, CNOT1 has been recently described as being involved in the regulation of inflammatory processes mediated by tristetraprolin (TTP). The TTP-CCR4-NOT complex (CNOT1 in the CCR4-NOT complex is the binding site for TTP) has been reported as interfering with HIV replication, through post-transcriptional control. Therefore, we can hypothesize that genetic variation occurring in the CNOT1 gene could impair the TTP-CCR4-NOT complex, thus interfering with HIV replication and/or host immune response. Being aware that our findings are exclusive to the 18 patients studied with a need for replication, and that the genetic variant of CNOT1 gene, localized at intron 3, has no known functional effect, we propose a novel potential candidate locus for the modulation of the response to the immune treatment, and open a discussion on the necessity to consider the host genome as another potential variant to be evaluated when designing an immune therapy study.


Genistein at maximal physiologic serum levels induces G0/G1 arrest in MCF-7 and HB4a cells, but not apoptosis.
Several studies have demonstrated that a balanced diet can contribute to better human health. For this reason, soy-based food and pure isoflavones (pills) are one of the most consumed. The association of this consumption and lower risks of chronic diseases and cancer is well established for the Asian population and has been attracting the attention of people worldwide, especially women at menopause who seek to alleviate the symptoms associated with the lack of estrogen. Despite positive epidemiological data, concerns still exist because of conflicting results found in scientific literature with relation to the role of isoflavones in breast and hormone-related cancers. The aim of our study was to investigate the cytotoxicity, induction of apoptosis, and changes in apoptosis-related genes of maximal physiological serum levels of the isoflavone genistein (Gen) in MCF-7 tumoral cells and in HB4a non-tumoral cells. In addition, induction of cell cycle arrest was also investigated. Only supraphysiological levels of Gen (50 and 100 μM) were cytotoxic to these cell lines. Concentrations of 10 and 25 μM did not induce apoptosis and significant changes in expression of the studied genes. Positive results were found only in cell cycle analysis: G0/G1 delay of MCF-7 cells in both concentrations of Gen and at 25 μM in HB4a cells. It is the first study investigating effects of Gen in the HB4a cell line. Thus, despite the lack of apoptosis induction (generally found with high concentrations), Gen at physiologically relevant serum levels still exerts chemopreventive effects through the modulation of cell cycle.


Synchronously pumped CdSe optical parametric oscillator in the 9-10 microm region.
Continuous mode-locked operation of a singly resonant, synchronously pumped optical parametric oscillator (SPOPO) based on CdSe has produced idler output tuned over the range of 9.1-9.7 microm, the longest wavelength generated so far to our knowledge from a SPOPO. Average idler powers as high as approximately 70 mW are generated in the crystal. Tandem pumping with a diffraction-grating-tuned parametric oscillator in periodically poled lithium niobate provides a convenient and agile means of tuning the noncritically phase-matched CdSe device. The absence of any detrimental thermal effects in the CdSe crystal suggests that significant further power scaling should be possible, with idler tuning ranges extendable to cover 8-12 microm.


An evidence-based guideline for introducing oral feeding to healthy preterm infants.
The ability of a preterm infant to make the transition from gavage to oral nipple feeding depends on the infant's neurodevelopment in relation to behavioral organization, to a rhythmic suck-swallow-breathe pattern, and to cardiorespiratory regulation. Research-based knowledge about infant neurodevelopment in these three areas has led to the creation of a semidemand feeding method to aid in this transition. The method combines the use of nonnutritive sucking to promote awake behavior for feeding, use of behavioral assessment to identify readiness for feeding, and systematic observation of and response to infant behavior cues to regulate frequency, length, and volume of oral feedings. Semidemand feeding may be individualized for healthy preterm infants. This article discusses both the relevant knowledge about neurodevelopment and the semidemand feeding method itself.


Three-dimensional structure of the water-insoluble protein crambin in dodecylphosphocholine micelles and its minimal solvent-exposed surface.
We chose crambin, a hydrophobic and water-insoluble protein originally isolated from the seeds of the plant Crambe abyssinica, as a model for NMR investigations of membrane-associated proteins. We produced isotopically labeled crambin(P22,L25) (variant of crambin containing Pro22 and Leu25) as a cleavable fusion with staphylococcal nuclease and refolded the protein by an approach that has proved successful for the production of proteins with multiple disulfide bonds. We used NMR spectroscopy to determine the three-dimensional structure of the protein in two membrane-mimetic environments: in a mixed aqueous-organic solvent (75%/25%, acetone/water) and in DPC micelles. With the sample in the mixed solvent, it was possible to determine (>NH...OC<) hydrogen bonds directly by the detection of (h3)J(NC)' couplings. H-bonds determined in this manner were utilized in the refinement of the NMR-derived protein structures. With the protein in DPC (dodecylphosphocholine) micelles, we used manganous ion as an aqueous paramagnetic probe to determine the surface of crambin that is shielded by the detergent. With the exception of the aqueous solvent exposed loop containing residues 20 and 21, the protein surface was protected by DPC. This suggests that the protein may be similarly embedded in physiological membranes. The strategy described here for the expression and structure determination of crambin should be applicable to structural and functional studies of membrane active toxins and small membrane proteins.


Cranial melioidosis presenting as a mass lesion or osteomyelitis.
Melioidosis is caused by Burkholderia pseudomallei and causes multiple abscesses in different organs of the body. Cranial melioidosis, although uncommon, is sometimes confused with tuberculosis and is therefore under-recognized. The authors report on 6 cases of cranial infections caused by Burkholderia pseudomallei, presenting as mass lesions or cranial osteomyelitis, and review the literature. The authors performed a retrospective review of the records of patients with cranial melioidosis treated at their institution between 1998 and 2005 to determine the presentation, management, and outcome of patients with this infection. Of the 6 patients diagnosed with cranial melioidosis during this period, 4 had brain abscesses and 2 had cranial osteomyelitis. All patients were treated surgically, and a diagnosis was made on the basis of histopathological studies. All patients were started on antibiotic therapy following surgery and this was continued for 6 months. One patient died soon after stereotactic aspiration of a brain abscess, and the other 5 patients had good outcomes. Cranial melioidosis is probably more prevalent than has been previously reported. A high index of suspicion, early diagnosis, initiation of appropriate antibiotic therapy and treatment for an adequate period are essential for assuring good outcome in patients with cranial melioidosis. The authors recommend surgery followed by intravenous ceftazidime treatment for 6 weeks and oral cotrimoxazole for 6 months thereafter in patients with cranial melioidosis.


[Identification of nuclear polyhedrosis viruses by restriction analysis].
The restriction endonucleases Bam HI, Pst I, Sla I were used to study DNA of nuclear polyhedrosis virus (NPV) of bollworm, two NPV isolates of cabbage moth, NPV of black arches moth isolated from a natural population of caterpillars. The mean molecular sizes of virus genomes were calculated. Genotypic differences between two isolates of cabbage moth NPV were demonstrated. Heterogeneity of a natural isolate of black arches moth NPV was established.


Villonodular synovitis (PVNS) of the spine.
To describe the imaging features of spinal pigmented villonodular synovitis (PVNS). We retrospectively reviewed 15 cases of pathologically proven spinal PVNS. Patient demographics and clinical presentation were reviewed. Radiologic studies were evaluated by consensus of two musculoskeletal radiologists for spinal location, spinal segments affected, lesion center, detection of facet origin and intrinsic characteristics on radiography (n=11), myelography (n=7), CT (n=6) and MR imaging (n=6). Women (64%) were more commonly affected than men (36%) with an average age of 28 years. Clinical symptoms were pain (45%), neurologic (9%) or both (36%). Lesions most frequently affected the cervical spine (53%) followed by the thoracic (27%) and lumbar regions (20%). The majority of lesions (93%) were centered in the posterior elements with frequent involvement of the pedicle (67%), neural foramina (73%), lamina (67%) and facets (93%). No lesions showed calcification. Determination of a facet origin by imaging was dependent on imaging modality and lesion size. A facet origin could be determined in 45% of cases by radiography vs 67% of patients by CT (n=6) and MR (n=6). Large lesions (greater than 3 cm in at least one dimension) obscured the facet origin in all cases with CT and/or MR imaging (44%,n=4). Small lesions (less than 3 cm in any dimension) demonstrated an obvious facet origin in all cases by CT and/or MR imaging (56%,n=5). Low-to-intermediate signal intensity was seen in all cases on T2-weighted MR images resulting from hemosiderin deposition with "blooming effect" in one case with gradient echo MR images. PVNS of the spine is rare. Large lesions obscure the facet origin and simulate an aggressive intraosseous neoplasm. Patient age, a solitary noncystic lesion centered in the posterior elements, lack of mineralization and low-to-intermediate signal intensity on all MR pulse sequences may suggest the diagnosis in these cases. Small lesions demonstrate a facet origin on CT or MR imaging. This limits differential considerations to synovial-based lesions and additional features of a solitary focus, lack of underlying disease or systemic arthropathy, no calcification as well as low-to-intermediate signal intensity on all MR images should allow spinal PVNS to be suggested as the likely diagnosis.


Optimizing capacity utilization by large scale 3000 L perfusion in seed train bioreactors.
Increasing capacity utilization and lowering manufacturing costs are critical for pharmaceutical companies to improve their competitiveness in a challenging environment. Development of next generation cell lines, improved media formulations, application of mature technologies and innovative operational strategies have been deployed to improve yields and capacity utilization. This article describes a large-scale perfusion strategy for the N-1 seed train bioreactor that was successfully applied to achieve higher inoculation cell densities in the production culture. The N-1 perfusion at 3,000-L scale, utilizing a inclined settler, achieved cell densities of up to 158 × 10(5) cell mL(-1) at perfusion rates of 2950 L day(-1) and a retention efficiency of >85%. This approach increased inoculation cell densities and decreased cultivation times by ~20% in a CHO-based, fed-batch antibody manufacturing process while providing comparable culture performance, productivity, and product quality. The strategy therefore yielded significant increase in capacity utilization and concomitant cost improvement in a large scale cGMP facility. Details of the strategy, the cell retention device, and the cell culture performance are described in this article.


[Pregnancy in adolescence. A review of 840 clinical cases].
Pregnancy during adolescence is a medical problem and a social phenomenon of increasing importance. Opportune medical care may resolve pregnancy risk, but the lacks of this stage of life, and the lack of resources of certain communities, may frustrate the mother's desires, in such a way, that pregnancy in adolescence, will mean more a social problem than a medical one.


Generating sparse and selective third-order responses in the olfactory system of the fly.
In the antennal lobe of Drosophila, information about odors is transferred from olfactory receptor neurons (ORNs) to projection neurons (PNs), which then send axons to neurons in the lateral horn of the protocerebrum (LHNs) and to Kenyon cells (KCs) in the mushroom body. The transformation from ORN to PN responses can be described by a normalization model similar to what has been used in modeling visually responsive neurons. We study the implications of this transformation for the generation of LHN and KC responses under the hypothesis that LHN responses are highly selective and therefore suitable for driving innate behaviors, whereas KCs provide a more general sparse representation of odors suitable for forming learned behavioral associations. Our results indicate that the transformation from ORN to PN firing rates in the antennal lobe equalizes the magnitudes of and decorrelates responses to different odors through feedforward nonlinearities and lateral suppression within the circuitry of the antennal lobe, and we study how these two components affect LHN and KC responses.


Potent and selective double-headed thiophene-2-carboximidamide inhibitors of neuronal nitric oxide synthase for the treatment of melanoma.
Selective inhibitors of neuronal nitric oxide synthase (nNOS) are regarded as valuable and powerful agents with therapeutic potential for the treatment of chronic neurodegenerative pathologies and human melanoma. Here, we describe a novel hybrid strategy that combines the pharmacokinetically promising thiophene-2-carboximidamide fragment and structural features of our previously reported potent and selective aminopyridine inhibitors. Two inhibitors, 13 and 14, show low nanomolar inhibitory potency (Ki = 5 nM for nNOS) and good isoform selectivities (nNOS over eNOS [440- and 540-fold, respectively] and over iNOS [260- and 340-fold, respectively]). The crystal structures of these nNOS-inhibitor complexes reveal a new hot spot that explains the selectivity of 14 and why converting the secondary to tertiary amine leads to enhanced selectivity. More importantly, these compounds are the first highly potent and selective nNOS inhibitory agents that exhibit excellent in vitro efficacy in melanoma cell lines.


Mechanistic modeling of anti-microRNA-155 therapy combinations in lung cancer.
To improve treatment outcomes in non-small cell lung cancer (NSCLC), it is crucial to identify treatment strategies with the potential to exhibit drug synergism. This can lower the required effective dose, reducing exposure to drugs and associated toxicities, while improving treatment efficacy. In previous studies, drugs targeting the microRNA-155 or PD-L1 have been promising in restraining NSCLC tumor growth. We have developed a mathematical model that simulates the in vivo pharmacokinetics and pharmacodynamics of the novel nanoparticle-delivered anti-microRNA-155 for potential use with standard-of-care drug atezolizumab for NSCLC. Through modeling and simulation, we identified possible drug synergism between the two drugs that holds promise to improve tumor response at reduced drug exposure.Clinical Relevance-Identifying the possibility of drug synergism for an anti-microRNA-155 based nanotherapeutic with standard-of-care immunotherapy to improve lung cancer treatment outcomes.


A systems perspective of host-pathogen interactions: predicting disease outcome in tuberculosis.
The complex web of interactions between the host immune system and the pathogen determines the outcome of any infection. A computational model of this interaction network, which encodes complex interplay among host and bacterial components, forms a useful basis for improving the understanding of pathogenesis, in filling knowledge gaps and consequently to identify strategies to counter the disease. We have built an extensive model of the Mycobacterium tuberculosis host-pathogen interactome, consisting of 75 nodes corresponding to host and pathogen molecules, cells, cellular states or processes. Vaccination effects, clearance efficiencies due to drugs and growth rates have also been encoded in the model. The system is modelled as a Boolean network. Virtual deletion experiments, multiple parameter scans and analysis of the system's response to perturbations, indicate that disabling processes such as phagocytosis and phagolysosome fusion or cytokines such as TNF-alpha and IFN-gamma, greatly impaired bacterial clearance, while removing cytokines such as IL-10 alongside bacterial defence proteins such as SapM greatly favour clearance. Simulations indicate a high propensity of the pathogen to persist under different conditions.


Transcriptome pyrosequencing of the Antarctic brittle star Ophionotus victoriae.
Brittle stars are included within a whole range of species, which contribute to knowledge in the medically important area of tissue regeneration. All brittle stars regenerate lose limbs, but the rate at which this occurs is highly variable and species-specific. One of the slowest rates of arm regeneration reported so far is that of the Antarctic Ophionotus victoriae. Additionally, O. victoriae also has an unusual delay in the onset of regeneration of about 5months. Both processes are of interest for the areas of regeneration biology and adaptation to cold environments. One method of understanding the details of regeneration events in brittle stars is to characterise the genes involved. In the largest transcriptome study of any ophiuroid to date, we describe the results of mRNA pyrosequencing from pooled samples of regenerating arms of O. victoriae. The sequencing reads resulted in 18,000 assembled contiguous sequences of which 19% were putatively annotated by blast sequence similarity searching. We focus on the identification of major gene families and pathways with potential relevance to the regenerative processes including the Wnt/β-catenin pathway, Hox genes, the SOX gene family and the TGF beta signalling pathways. These data significantly increase the amount of ophiuroid sequences publicly available and provide candidate transcripts for the further investigation of the unusual regenerative process in this Antarctic ophiuroid.


Hematopoietic stem cells from different sources: biological and technical aspects.
Hematopoietic stem cell (HSC) enumeration is crucial to predict the engraftment potential of a given HSC collection, and currently involves the surrogate count of nucleated cells, CFU or CD34+ cells. However, there is raising evidence that CFU are HSC involved in short-term but not in long-term reconstitution, and that only a small fraction of all CD34+ cells have long term multilineage engraftment potential. In this regard, there is evidence that cord blood (CB), bone marrow (BM) and peripheral blood (PB) derived HSC are highly heterogeneous for a number of antigens useful for HSC enumeration by flow cytometry. Moreover, there is a raising evidence that a CD34 human HSC might exist. The CD34 HSC has been already described in animals and in human Hoechst 33342 negative HSC. This notwithstanding, clinical data have clearly demonstrated that purified allogeneic CD34+ cells can reconstitute the myeloid and the lymphoid lineages in myeloablated recipients. In the lack of a suitable marker for CD34 HSC enumeration, it is hard to predict the role of CD34 HSC in hematopoietic reconstitution after transplantation. On the other hand, these cells might be a better target for HSC expansion and gene transfer.


Readmission after seizure discharge in a nationally representative sample.
To determine the 30-day readmission rate after seizure-related discharge in a nationally representative sample, as well as patient, clinical, and hospital characteristics associated with readmission. Retrospective cohort study of adults discharged alive from a nonelective hospitalization for epilepsy or seizure, sampled from the Healthcare Cost and Utilization Project's 2014 Nationwide Readmissions Database. Descriptive statistics and logistic regression models were built to quantify and characterize nonelective readmission within 30 days. A total of 139,800 admissions met inclusion criteria, of which 15,094 (10.8%) were readmitted within 30 days. Patient characteristics associated with readmission included comorbid disease burden (Elixhauser score 2: adjusted odds ratio [AOR] [95% confidence interval (CI)] 1.38 [1.21-1.57]; Elixhauser score 3: AOR 1.52 [1.34-1.73]; Elixhauser score >4: AOR 2.28 [2.01-2.58] as compared to 1) and participation in public insurance programs (Medicare: AOR 1.39 [1.26-1.54]; Medicaid: AOR 1.39 [1.26-1.54] as compared to private insurance). Adverse events (AOR 1.17 [1.05-1.30]) and prolonged length of stay, as well as nonroutine discharge (AOR 1.32 [1.23-1.42]), were also associated with increased adjusted odds of readmission. The most common primary reason for readmission was epilepsy or convulsion (17%). Patients hospitalized with seizure are frequently readmitted. While readmitted patients are more likely to have multiple medical comorbidities, our study demonstrated that inpatient adverse events were also significantly associated with readmission. The most common reason for readmission was seizure or epilepsy. Together, these 2 findings suggest that a proportion of readmissions are related to modifiable care process factors and may therefore be avoidable. Further study into understanding preventable drivers of readmission in this population presents an opportunity to improve patient outcomes and health.


Modeling trajectories of perceived leg exertion during maximal cycle ergometer exercise in children and adolescents.
Borg developed scales for rating pain and perceived exertion in adults that have also been used in pediatric populations. Models describing functional relationships between perceived exertion and work capacity have not been studied in children. We compared different models and their fits to individual trajectories and assessed the variability in these trajectories. Ratings of perceived exertion (RPE) were collected from 79 children. Progressive cycle ergonometric testing was performed to maximal work capacity with test duration ranging from 6- 12 minutes. Ratings were obtained during each 1-minute increment. Work was normalized to individual maximal work capacity (Wmax). A delay was defined as the fraction of Wmax at which point an increase in ratings of leg fatigue occurred. Such a delay term allows the characterization of trajectories for children whose ratings were initially constant with increasing work. Two models were considered, a delay model and a power model that is commonly used to analyze Borg ratings. Individual model fit was assessed with root mean squared error (RMSE). Functional clustering algorithms were used to identify patterns. Leg tiredness developed quickly for some children while for others there was a delay before an in- creased ratings of leg exertion occurred with increasing work. Models for individual trajectories with the smallest RMSE included a delay and a quadratic term (quadratic-delay model), or a power function and a delay term (power-delay model) compared to a simple power function. The median delay was 40% Wmax (interquartile range (IQR): 26-49%) in a quadratic-delay model, while the median exponent was 1.03 (IQR: 0.83-1.78) in a power-delay model. Nine clusters were identified showing linear or quadratic patterns with or without a delay. Cluster membership did not depend on age, gender or diagnosis. Children and adolescents vary widely in their capacity to rate their perceptions and exhibit different functional relationships between ratings of perceived exertion and work capacity normalized across individuals. Models including a delay term, a linear component, or a power function can describe these individual trajectories of perceived leg exertion during incremental exercise to voluntary exhaustion.


Characterisation of the range of neutrophil stimulating mediators in cystic fibrosis sputum.
Most patients with cystic fibrosis (CF) die of respiratory failure due to chronic infection and destructive neutrophilic inflammation. To identify potential therapeutic targets by characterising the neutrophil stimulating mediators in the CF airway. Spontaneously expectorated CF sputum was extracted in phosphate buffered saline for assays of neutrophil chemotaxis, intracellular calcium mobilisation and cell shape change. Mediators were purified by ion exchange, C(18) reversed phase and size exclusion chromatography. A pool of CF sputum contained considerable neutrophil stimulating activity but neutralisation of interleukin (IL)8/CXCL8 had little inhibitory effect on neutrophil chemotactic (10149 (2023) migrating cells vs 8661 (2597) at 62 mg sputum/ml; NS) or shape change (% forward scatter increase 46 (8) vs 38 (5) at 19 mg sputum/ml; p<0.05) responses. Furthermore, the CF sputum pool induced an elevation in intracellular calcium ions even after desensitisation of the neutrophils to IL8. Chromatography identified contributions to the neutrophil shape change inducing activity from IL8, other CXC chemokines, leukotriene (LT) B(4) and two formyl peptides. There was also suggestive evidence for contributions from platelet activating factor (PAF) and C5a. Using non-chromatographed individual sputum samples, anti-IL8 alone did have an inhibitory effect on neutrophil chemotaxis (median inhibition 41%; p = 0.0002). However, even in this experiment, there were clearly significantly important, non-IL8 mediated, effects of CF sputum on neutrophils, and an inhibitor cocktail of anti-IL8 plus CXCR2, LTB(4), formyl peptide, PAF and C5a receptor antagonists inhibited chemotaxis by a median of 97% (p = 0.0002). Many chemoattractants contribute to the neutrophil stimulating activity in CF sputum although the relative contribution of these mediators differs in different patients. Selective blockade of single mediators may not be sufficient to control neutrophil recruitment and activation in the CF airway.


Prehospital Medicine and the Future Will ECMO Ever Play a Role?
Due to the hybrid warfare currently experienced by multiple NATO coalition and NATO partner nations, the tactical combat casualty care (TCCC) paradigm is greatly challenged. One of the major challenges to TCCC is the ad hoc extension phase in resource-poor environments, referred to as prolonged field care (PFC) and forward resuscitative care (FRC). The nuanced clinical skills with limited resources required by warfighters and auxiliary health care professionals to mitigate death on the battlefield and prevent morbidity and mortality in the PFC phase represent a balance that is still under review. The aim of our article is to describe the connection between extracorporeal membrane oxygenation (ECMO) or the extracorporeal life support (ECLS) treatment and its possible improvement in prehospital trauma care, at a Role 1 or 2 facility and, more provocatively, in the PFC phase of care in the future through innovative technology and how it connects with FRC. We report and describe here the primary components of ECMO/ECLS and present the main concept of a human extracorporeal circulation cocoon as a transitional living form for the cardiopulmonary stabilization of wounded combatants on the battlefield and their transportation to higher echelons of care and treatment facilities (to include damage control resuscitation [DCR] and damage control surgery [DCS]). As clinical governance, these matters would fall within the remit of the Committee on Surgical Combat Casualty Care (CoSCCC) and the Committee on Enroute Combat Casualty Care (CoERCCC), and it is within this framework that we propose this concept piece of ECMO in the prehospital space. We caution that this report is a proposed innovation to TCCC but also serves to push the envelope of the PFC and FRC paradigm. What we propose will not change the practice this year, but as ECMO technology progresses, it may change our practice within the next decade. We conclude with proposed novel future research to save life on the battlefield with ECMO as a major challenge and one worth the focus of further research. Medicine is controversial and constantly changing; for those who work in prehospital and battlefield medicine, change is the only constant on which we rely, and without provocative discussion that makes our systems and practice more robust, we will fail.


Deleterious effects of cypermethrin on rat liver and kidney: protective role of sesame oil.
The involvement of reactive oxygen species (ROS) has been implicated in the toxicity of various pesticides. Our study was designed to investigate the induction of oxidative stress by cypermethrin; a Type II pyrethroid in rat liver and kidney. In addition, the protective role of sesame oil against the toxicity of cypermethrin was investigated. Animals were divided into four equal groups; the first group used as control while groups 2, 3 and 4 were treated with sesame oil (5 mL/kg b.w), cypermethrin (12 mg/kg b.w) and the combination of both sesame oil (5 mL/kg b.w) plus cypermethrin (12 mg/kg b.w), respectively. Rats were daily administered with their respective doses for 30 days by gavage. Repeated oral administration of cypermethrin was found to reduce the level of glutathione (GSH) and the activities of the antioxidant enzymes. While, the level of TBARS was elevated indicating the presence of oxidative stress. The activities of LDH, AST and ALT were decreased in the liver extract while increased in the plasma of the cypermethrin-treated group. Also, the levels of urea and creatinine were significantly increased after treatment with cypermethrin. Liver and kidney injury was confirmed by the histological changes. In conclusion, the administration of sesame oil provided significant protection against cypermethrin-induced oxidative stress, biochemical changes, histopathological damage and genomic DNA fragmentation.