A psychoeducational intervention reduces the need for anesthesia during radiotherapy for young childhood cancer patients.
Radiotherapy (RT) has become an important treatment modality in pediatric oncology, but its delivery to young children with cancer is challenging and general anesthesia is often needed. To evaluate whether a psychoeducational intervention might reduce the need for anesthesia, 223 consecutive pediatric cancer patients receiving 4141 RT fractions during 244 RT courses between February 1989 and January 2006 were studied. Whereas in 154 RT courses corresponding with 2580 RT fractions patients received no psychoeducational intervention (group A), 90 RT courses respectively 1561 RT fractions were accomplished by using psychoeducational intervention (group B). This tailored psychoeducational intervention in group B included a play program and interactive support by a trained nurse according to age to get familiar with staff, equipment and procedure of radiotherapy. Group A did not differ significantly from group B in age at RT, gender, diagnosis, localization of RT and positioning during RT. Whereas 33 (21.4%) patients in group A got anesthesia, only 8 (8.9%) patients in group B needed anesthesia. The median age of cooperating patients without anesthesia decreased from 3.2 to 2.7 years. In both uni- and multivariate analyses the psychoeducational intervention significantly and independently reduced the need for anesthesia. We conclude that a specifically tailored psychoeducational intervention is able to reduce the need for anesthesia in children undergoing RT for cancer. This results in lower costs and increased cooperation during RT.


A versatile synthesis of fumaquinone.
Fumaquinone, a novel prenylated naphthoquinone antibiotic, was synthetized from ethyl acetoacetate in three steps (58% overall yield). The key step of the synthesis is the construction of the naphthoquinone skeleton by a regioselective Diels-Alder reaction between a 2-alkyl 1,3-bis(trimethylsilyloxy)-1,3-diene derivative and a bromoquinone. This short and versatile approach confirms the structure of fumaquinone and allows the synthesis of derivatives at the C-6 position.


Hand hygiene in intensive care units: a matter of time?
Healthcare-associated infections are a frequent threat to patient safety and cause significant disease burden. The most important single preventive measure is hand hygiene (HH). Barriers to adherence with HH recommendations include structural aspects, knowledge gaps, and organizational issues, especially a lack of time in daily routine. To determine the number of hand hygiene opportunities (HHOs), compliance rates, and time spent on hand hygiene in intensive care units (ICUs). We conducted an observational study in two ICUs to determine the average number of HHOs per patient. Documentation was based on the World Health Organization concept of 'five moments for hand hygiene'. HHOs were collected in 12 patient rooms for 12h each. On average, 134 (internal ICU) and 182 (surgical ICU) HHOs per patient were observed during the 12h observation period. Overall HH compliance was 42.6%. Considering additional HHOs during the night shift, we estimated 218 (internal ICU) and 271 (surgical ICU) HHOs per patient-day. The average duration of hand disinfection was 7.6s. The time spent on HH was 8.3 (internal ICU) and 11.1 (surgical ICU) min during the day shift for each patient for all healthcare workers (nurses: 6.9min in the internal ICU and 8.3min in the surgical ICU). If nurses fully complied with guidelines, 58.2 (internal ICU) and 69.8 (surgical ICU) min would be spent on HH for each patient during the day shift. Complying with guidelines is time-consuming. Sufficient time for HH should be considered in staff planning.


Pulse characterization by THG d-scan in absorbing nonlinear media.
We report on few-cycle pulse characterization based on third harmonic generation dispersion scan (THG d-scan) measurements using thin films of different TiO(2)-SiO(2) compositions as nonlinear media. By changing the TiO(2) concentration in the thin film the band gap and therefore the position of the absorption edge were varied. The retrieved pulse durations from different nonlinear media agree within 5%, and the reconstructed pulse shapes prove to be immune against the absorption edges as well. The reason is the robust retrieval algorithm which takes the influence of wavelength dependent nonlinearity into account by a spectral weight function.


Do oral corticosteroids reduce the severity of acute lower respiratory tract illnesses in preschool children with recurrent wheezing?
Oral corticosteroids (OCSs) are recommended for severe wheezing episodes in children. However, limited evidence supports this intervention in preschool children with outpatient wheezing illnesses. We sought to investigate whether OCSs reduce symptom scores during acute lower respiratory tract illnesses (LRTIs) in preschool children with recurrent wheeze. We performed post hoc and replication analyses in 2 outpatient cohorts of children aged 1 to 5 years with episodic wheezing participating in clinical trials. We compared symptom scores during LRTIs that were or were not treated with OCSs, adjusting for differences in disease and episode severity covariates. We stratified episodes by severity by using a propensity model. The primary outcome was the area under the curve (AUC) of total symptom scores among the more severe episodes. Two hundred fifteen participants from the Acute Intervention Management Strategies trial experienced 798 acute LRTIs, 112 of which were defined as severe based on propensity scores. The AUCs of total symptom scores did not differ between the episodes that were (n = 70) and were not (n = 42) treated with OCSs (P = .46) nor was there an OCS treatment effect on individual symptom scores. Similar analyses of the Maintenance Versus Intermittent Inhaled Corticosteroids in Wheezing Toddlers trial, involving 278 participants with 133 severe LRTIs, confirmed the above findings (P = .46 for AUC of total symptoms score comparison). In 2 separate cohorts of preschool children with episodic wheezing, OCS treatment during clinically significant LRTIs did not reduce symptom severity during acute LRTIs, despite asthma controller medication use during most episodes. These findings need to be confirmed in a prospective randomized controlled trial.


Determinants in the place of death for people with different cancer types: a national population-based study.
Place of death has for the past decade increasingly come to be regarded as a robust indicator of how palliative care is organized and provided, and is also recognized as an important factor for well being at the end of life. Variations in place of cancer deaths have previously been reported in the context of country-specific healthcare organization, but without differentiating between cancer types and national regional variations. Our aim was to examine, at a population level, where people with cancer diseases die in Sweden, and to investigate associations of place of death and cancer type with individual, socioeconomic and geographical characteristics of the deceased. This population level study is based on death certificate data (sex; age; underlying cause of death and place of death) and population register data (educational attainment, marital status, living arrangements, area of residence, degree of urbanization, and healthcare region) of all 2012 cancer deaths in Sweden, with a registered place of death (hospital, nursing home, home, other places). Data were explored descriptively. To investigate associations between place of death and cancer types, and individual, socioeconomic and environmental characteristics, a series of multivariable logistic regression analyses were performed. The most frequent type of cancer death occurring at home was upper gastrointestinal cancer (25.6%) and the least frequent was hematological cancer (15.2%). Regional variations in cancer deaths occurring at home ranged from 17.1% to 28.4%. Factors associated with place of death by cancer type were age, educational attainment, marital status, healthcare regions and degree of urbanization. Large healthcare regional variations in place of death among different cancer types were found. The socioeconomic inequality previously demonstrated for screening, diagnostic and treatment processes, rehabilitation and survival thus also seems to be reflected in the place of death.


Coupling of Thalamocortical Sleep Oscillations Are Important for Memory Consolidation in Humans.
Sleep, specifically non-rapid eye movement (NREM) sleep, is thought to play a critical role in the consolidation of recent memories. Two main oscillatory activities observed during NREM, cortical slow oscillations (SO, 0.5-1.0 Hz) and thalamic spindles (12-15 Hz), have been shown to independently correlate with memory improvement. Yet, it is not known how these thalamocortical events interact, or the significance of this interaction, during the consolidation process. Here, we found that systemic administration of the GABAergic drug (zolpidem) increased both the phase-amplitude coupling between SO and spindles, and verbal memory improvement in humans. These results suggest that thalamic spindles that occur during transitions to the cortical SO Up state are optimal for memory consolidation. Our study predicts that the timely interactions between cortical and thalamic events during consolidation, contribute to memory improvement and is mediated by the level of inhibitory neurotransmission.


Feasibility of using single photon counting X-ray for lung tumor position estimation based on 4D-CT.
In stereotactic body radiation therapy of lung tumors, reliable position estimation of the tumor is necessary in order to minimize normal tissue complication rate. While kV X-ray imaging is frequently used, continuous application during radiotherapy sessions is often not possible due to concerns about the additional dose. Thus, ultra low-dose (ULD) kV X-ray imaging based on a single photon counting detector is suggested. This paper addresses the lower limit of photons to locate the tumor reliably with an accuracy in the range of state-of-the-art methods, i.e. a few millimeters. 18 patient cases with four dimensional CT (4D-CT), which serves as a-priori information, are included in the study. ULD cone beam projections are simulated from the 4D-CTs including Poisson noise. The projections from the breathing phases which correspond to different tumor positions are compared to the ULD projection by means of Poisson log-likelihood (PML) and correlation coefficient (CC), and template matching under these metrics. The results indicate that in full thorax imaging five photons per pixel suffice for a standard deviation in tumor positions of less than half a breathing phase. Around 50 photons per pixel are needed to achieve this accuracy with the field of view restricted to the tumor region. Compared to CC, PML tends to perform better for low photon counts and shifts in patient setup. Template matching only improves the position estimation in high photon counts. The quality of the reconstruction is independent of the projection angle. The accuracy of the proposed ULD single photon counting system is in the range of a few millimeters and therefore comparable to state-of-the-art tumor tracking methods. At the same time, a reduction in photons per pixel by three to four orders of magnitude relative to commercial systems with flatpanel detectors can be achieved. This enables continuous kV image-based position estimation during all fractions since the additional dose to the patient is negligible.


Quantification of the relative roles of niche and neutral processes in structuring gastrointestinal microbiomes.
The theoretical description of the forces that shape ecological communities focuses around two classes of models. In niche theory, deterministic interactions between species, individuals, and the environment are considered the dominant factor, whereas in neutral theory, stochastic forces, such as demographic noise, speciation, and immigration, are dominant. Species abundance distributions predicted by the two classes of theory are difficult to distinguish empirically, making it problematic to deduce ecological dynamics from typical measures of diversity and community structure. Here, we show that the fusion of species abundance data with genome-derived measures of evolutionary distance can provide a clear indication of ecological dynamics, capable of quantifying the relative roles played by niche and neutral forces. We apply this technique to six gastrointestinal microbiomes drawn from three different domesticated vertebrates, using high-resolution surveys of microbial species abundance obtained from carefully curated deep 16S rRNA hypervariable tag sequencing data. Although the species abundance patterns are seemingly well fit by the neutral theory of metacommunity assembly, we show that this theory cannot account for the evolutionary patterns in the genomic data; moreover, our analyses strongly suggest that these microbiomes have, in fact, been assembled through processes that involve a significant nonneutral (niche) contribution. Our results demonstrate that high-resolution genomics can remove the ambiguities of process inference inherent in classic ecological measures and permits quantification of the forces shaping complex microbial communities.


Increased expression of extracellular matrix proteins and decreased expression of matrix proteases after serial passage of glomerular mesangial cells.
The cellular events causing pathological extracellular matrix (ECM) accumulation in vivo are not well understood. Prolonged serial passage of several cell types in culture leads to increased production of extracellular matrix (ECM) proteins, but the mechanism for these putative fibrotic changes is not known. Here, human fetal glomerular mesangial cells were subjected to serial passage (P) in culture and the expression of ECM proteins, proteases and protease inhibitors was comprehensively evaluated. From P11 through P14, a series of phenotypic changes occurred. Steady-state expression of mRNA for alpha 1 chains of type III and type IV (but not type I) collagen, and for laminin beta 1 and gamma 1, increased 2- to 8-fold, while expression of mRNA for interstitial collagenase (MMP-1) and gelatinase A (MMP-2) virtually ceased. Expression of tissue-type plasminogen activator (tPA) mRNA also decreased markedly. Expression of mRNA for the tissue inhibitor of metalloproteinases (TIMP)-1, and of the smaller of two mRNA species for the PA inhibitor PAI-1, ceased by P14. There was a switch in expression of the two species of TIMP-2 mRNA: whereas the ratio of signal intensity comparing the 3.5 kb mRNA species to the 1.0 kb species was 5:1 up to P11, it was reversed (1:5) at P14 and later. Serial passage also led to changes in protein expression, with increased type IV collagen and laminin, but decreased interstitial collagenase and gelatinase A. The cells showed a progressive increase in staining for type IV collagen. These findings define the appearance of a matrix-accumulating phenotype in later-passage mesangial cells. Matrix expansion in vivo has been associated with increased transforming growth factor (TGF)-beta synthesis; the cells were found to show at least 5-fold increased expression of TGF-beta 1 mRNA from P8 to P16. However, treatment of P9 or P10 cells with graded doses of TGF-beta 1 increased expression of both collagen IV and gelatinase A mRNA and did not alter the ratio of signal intensity for TIMP-2 mRNA species. Thus, assumption of a matrix-accumulating phenotype by these cultured fetal glomerular mesangial cells is not accelerated by exogenous TGF-beta. These data describe an in vitro model of mesangial cell matrix turnover in which matrix accumulation could result from a concerted increase in ECM synthesis and decrease in ECM degradation.


Comparison of respiratory health-related quality of life in patients with intractable breathlessness due to advanced cancer or advanced COPD.
Breathlessness is common in patients with advanced cancer and almost universal in advanced chronic obstructive pulmonary disease (COPD), but studies suggest their experiences of breathlessness vary. This report builds on these studies by providing quantitative evidence of differences in respiratory health-related quality of life (HRQoL) between these groups. Further, it explores the validity of the Chronic Respiratory Questionnaire (CRQ) in patients with cancer. The CRQ-Original was completed within baseline interviews for a randomised controlled trial of a palliative intervention for intractable breathlessness due to advanced disease. Independent samples Mann-Whitney U tests were performed to identify significant differences in median scores for the four CRQ domains (mastery, dyspnoea, emotional function, fatigue) in patients with advanced COPD (n=73) or advanced cancer (n=67). The Minimally Clinically Important Difference of 0.5 was applied to determine clinical significance. Patients with advanced COPD scored lower across all four CRQ domains. This was statistically significant for dyspnoea, mastery and emotional function (p<0.05), and clinically significant for the latter two, suggesting poorer respiratory HRQoL. Patients with breathlessness due to advanced COPD have worse respiratory HRQoL than those with advanced cancer. This may result from greater burden of breathlessness in COPD due to condition longevity, lesser burden of breathlessness in cancer due to its episodic nature, or variance in palliative referral thresholds by disease group. Our results suggest that greater access to palliative care is needed in advanced COPD, and that formal psychometric testing of the CRQ may be warranted in cancer. NCT00678405.


CD28-B7 blockade after alloantigenic challenge in vivo inhibits Th1 cytokines but spares Th2.
Blocking the CD28-B7 T cell costimulatory pathway with the fusion protein CTLA4Ig inhibits alloimmune responses in vitro and in vivo and induces tolerance to cardiac allografts in mice and rats, but the mechanisms mediating the tolerant state in vivo are unknown. Here, we report the effects and potential mechanisms of CTLA4Ig in the rat renal allograft model. LEW rats were nephrectomized and received renal allografts from major histocompatibility complex-incompatible WF rats. While all untreated and control immunoglobulin (Ig)-treated animals acutely rejected their allografts and died, 86% of rats that received a single injection of CTLA4Ig on day 2 after transplantation had prolonged survival (> 60-100 days) with preserved renal function. By contrast, only 29% of animals that received CTLA4Ig on the day of engraftment had prolonged survival. Long-term survivors (> 100 days) exhibited donor-specific tolerance, accepting donor-matched WF but acutely rejecting third-party BN cardiac allografts. Immunohistological analysis of grafts sampled at 1 week after transplantation showed that both control and CTLA4Ig-treated animals had mononuclear cell infiltrates, with a higher percentage of CD4+ cells in the CTLA4Ig-treated group. However, while this was associated with vasculitis and tubulitis in control grafts, there was no evidence of tissue injury in CTLA4Ig-treated animals. The immune response leading to graft rejection in control animals was characterized by expression of the T helper (Th) type 1 cytokines interleukin (IL)-2 and interferon-gamma. In contrast, the persistent CD4+ infiltrate without graft rejection in CTLA4Ig-treated animals was associated with increased staining for the Th2-related cytokines IL-4 and IL-10. Furthermore, grafts from CTLA4Ig-treated animals had marked upregulation of intragraft staining for IgG1, but not IgG2a or IgG2b. Administration of rIL-2 to CTLA4Ig-treated animals restored allograft rejection in 50% of animals tested. These results confirm that blockade of the CD28-B7 pathway after alloantigenic challenge induces donor-specific acceptance of vascularized organ allografts, and indicates in this model that CTLA4Ig inhibits Th1 but spares Th2 cytokines in vivo.


Association of Digital Breast Tomosynthesis vs Digital Mammography With Cancer Detection and Recall Rates by Age and Breast Density.
Breast cancer screening examinations using digital breast tomosynthesis (DBT) has been shown to be associated with decreased false-positive test results and increased breast cancer detection compared with digital mammography (DM). Little is known regarding the size and stage of breast cancer types detected and their association with age and breast density. To determine whether screening examinations using DBT detect breast cancers that are associated with an improved prognosis and to compare the detection rates by patient age and breast density. This retrospective analysis of prospective cohort data from 3 research centers in the Population-based Research Optimizing Screening Through Personalized Regimens (PROSPR) consortium included data of women aged 40 to 74 years who underwent screening examinations using DM and DBT from January 1, 2011, through September 30, 2014. Statistical analysis was performed from November 8, 2017, to August 14, 2018. Use of DBT as a supplement to DM at breast cancer screening examination. Recall rate, cancer detection rate, positive predictive value, biopsy rate, and distribution of invasive cancer subtypes. Among 96 269 women (mean [SD] patient age for all examinations, 55.9 [9.0] years), patient age was 56.4 (9.0) years for DM and 54.6 (8.9) years for DBT. Of 180 340 breast cancer screening examinations, 129 369 examinations (71.7%) used DM and 50 971 examinations (28.3%) used DBT. Screening examination with DBT (73 of 99 women [73.7%]) was associated with the detection of smaller, more often node-negative, HER2-negative, invasive cancers compared with DM (276 of 422 women [65.4%]). Screening examination with DBT was also associated with lower recall (odds ratio, 0.64; 95% CI, 0.57-0.72; P < .001) and higher cancer detection (odds ratio, 1.41; 95% CI, 1.05-1.89; P = .02) compared with DM for all age groups even when stratified by breast density. The largest increase in cancer detection rate and the greatest shift toward smaller, node-negative invasive cancers detected with DBT was for women aged 40 to 49 years. For women aged 40 to 49 years with nondense breasts, the cancer detection rate for examinations using DBT was 1.70 per 1000 women higher compared with the rate using DM; for women with dense breasts, the cancer detection rate was 2.27 per 1000 women higher for DBT. For these younger women, screening with DBT was associated with only 7 of 28 breast cancers (25.0%) categorized as poor prognosis compared with 19 of 47 breast cancers (40.4%) when screening with DM. The findings suggest that screening with DBT is associated with increased specificity and an increased proportion of breast cancers detected with better prognosis compared with DM. In the subgroup of women aged 40 to 49 years, routine DBT screening may have a favorable risk-benefit ratio.


Bortezomib therapeutic effect is associated with expression and mutation of FGFR3 in human lymphoma cells.
Ectopically expressed and deregulated fibroblast growth factor receptor 3 (FGFR3) has been observed in many malignant cancer patients, including those with lymphoma. This study investigated whether the therapeutic effect of bortezomib in lymphoma is associated with FGFR3-expression. Cell proliferation and apoptosis assays were performed in minimal FGFR3 expressing U937 cells and compared to U937 cells overexpressing FGFR3 wild-type, or Y373C or K650E mutant FGFR3. Results from this study suggested the expression of FGFR3 protein is associated with the therapeutic effect of bortezomib. It was observed that bortezomib-induced apoptotic death is correlated with FGFR3 expression. U937 cells overexpression of wild-type FGFR3 demonstrated resistance to bortezomib treatment. U937 cells expressing Y373C mutated FGFR3 showed an almost equal resistance to bortezomib as U937 cells expressing wild-type FGFR3. U937 cells expressing mutated K650E FGFR3 showed more sensitivity to bortezomib than did the parental U937 cells. Furthermore, increased expression of Mcl-1 and decreased expression of NF-kappaB p65 suggested that bortezomib resistance associated with Y373C mutation and wild-type FGFR3 may be partly mediated through Bcl-2 and NF-kappaB signaling. Data from this study indicate that mutation status and the expression level of FGFR3 may be associated with bortezomib-related treatment resistance in lymphoma.


20 years of DNA-encoded chemical libraries.
The identification of specific binding molecules is a central problem in chemistry, biology and medicine. Therefore, technologies, which facilitate ligand discovery, may substantially contribute to a better understanding of biological processes and to drug discovery. DNA-encoded chemical libraries represent a new inexpensive tool for the fast and efficient identification of ligands to target proteins of choice. Such libraries consist of collections of organic molecules, covalently linked to a unique DNA tag serving as an amplifiable identification bar code. DNA-encoding enables the in vitro selection of ligands by affinity capture at sub-picomolar concentrations on virtually any target protein of interest, in analogy to established selection methodologies like antibody phage display. Multiple strategies have been investigated by several academic and industrial laboratories for the construction of DNA-encoded chemical libraries comprising up to millions of DNA-encoded compounds. The implementation of next generation high-throughput sequencing enabled the rapid identification of binding molecules from DNA-encoded libraries of unprecedented size. This article reviews the development of DNA-encoded library technology and its evolution into a novel drug discovery tool, commenting on challenges, perspectives and opportunities for the different experimental approaches.


Amino acids 257 to 288 of mouse p48 control the cooperation of polyomavirus large T antigen, replication protein A, and DNA polymerase alpha-primase to synthesize DNA in vitro.
Although p48 is the most conserved subunit of mammalian DNA polymerase alpha-primase (pol-prim), the polypeptide is the major species-specific factor for mouse polyomavirus (PyV) DNA replication. Human and murine p48 contain two regions (A and B) that show significantly lower homology than the rest of the protein. Chimerical human-murine p48 was prepared and coexpressed with three wild-type subunits of pol-prim, and four subunit protein complexes were purified. All enzyme complexes synthesized DNA on single-stranded (ss) DNA and replicated simian virus 40 DNA. Although the recombinant protein complexes physically interacted with PyV T antigen (Tag), we determined that the murine region A mediates the species specificity of PyV DNA replication in vitro. More precisely, the nonconserved phenylalanine 262 of mouse p48 is crucial for this activity, and pol-prim with mutant p48, h-S262F, supports PyV DNA replication in vitro. DNA synthesis on RPA-bound ssDNA revealed that amino acid (aa) 262, aa 266, and aa 273 to 288 are involved in the functional cooperation of RPA, pol-prim, and PyV Tag.


ETS2 and ERG promote megakaryopoiesis and synergize with alterations in GATA-1 to immortalize hematopoietic progenitor cells.
ETS2 and ERG are transcription factors, encoded on human chromosome 21 (Hsa21), that have been implicated in human cancer. People with Down syndrome (DS), who are trisomic for Hsa21, are predisposed to acute megakaryoblastic leukemia (AMKL). DS-AMKL blasts harbor a mutation in GATA1, which leads to loss of full-length protein but expression of the GATA-1s isoform. To assess the consequences of ETS protein misexpression on megakaryopoiesis, we expressed ETS2, ERG, and the related protein FLI-1 in wild-type and Gata1 mutant murine fetal liver progenitors. These studies revealed that ETS2, ERG, and FLI-1 facilitated the expansion of megakaryocytes from wild-type, Gata1-knockdown, and Gata1s knockin progenitors, but none of the genes could overcome the differentiation block characteristic of the Gata1-knockdown megakaryocytes. Although overexpression of ETS proteins increased the proportion of CD41(+) cells generated from Gata1s-knockin progenitors, their expression led to a significant reduction in the more mature CD42 fraction. Serial replating assays revealed that overexpression of ERG or FLI-1 immortalized Gata1-knockdown and Gata1s knockin, but not wild-type, fetal liver progenitors. Immortalization was accompanied by activation of the JAK/STAT pathway, commonly seen in megakaryocytic malignancies. These findings provide evidence for synergy between alterations in GATA-1 and overexpression of ETS proteins in aberrant megakaryopoiesis.


Transcatheter Laceration of Aortic Leaflets to Prevent Coronary Obstruction During Transcatheter Aortic Valve Replacement: Concept to First-in-Human.
This study sought to develop a novel technique called bioprosthetic or native aortic scallop intentional laceration to prevent coronary artery obstruction (BASILICA). Coronary artery obstruction is a rare but fatal complication of transcatheter aortic valve replacement (TAVR). We lacerated pericardial leaflets in vitro using catheter electrosurgery, and tested leaflet splaying after benchtop TAVR. The procedure was tested in swine. BASILICA was then offered to patients at high risk of coronary obstruction from TAVR and ineligible for surgical aortic valve replacement. BASILICA used marketed devices. Catheters directed an electrified guidewire to traverse and lacerate the aortic leaflet down the center line. TAVR was performed as usual. TAVR splayed lacerated bovine pericardial leaflets. BASILICA was successful in pigs, both to left and right cusps. Necropsy revealed full length lacerations with no collateral thermal injury. Seven patients underwent BASILICA on a compassionate basis. Six had failed bioprosthetic valves, both stented and stent-less. Two had severe aortic stenosis, including 1 patient with native disease, 3 had severe aortic regurgitation, and 2 had mixed aortic valve disease. One patient required laceration of both left and right coronary cusps. There was no hemodynamic compromise in any patient following BASILICA. All patients had successful TAVR, with no coronary obstruction, stroke, or any major complications. All patients survived to 30 days. BASILICA may durably prevent coronary obstruction from TAVR. The procedure was successful across a range of presentations, and requires further evaluation in a prospective trial. Its role in treatment of degenerated TAVR devices remains untested.


Patient compliance--whose responsibility?
This paper focuses on general practitioner and district nurse knowledge of prescribed drugs taken by their elderly patients, and the evaluation of a method of improving that knowledge by a patient held drug guide. Serious differences were identified in the knowledge of doctors, nurses and patients about drugs. The drug guide was associated with an improvement in patient knowledge of drugs as well as a reduction in disagreements between doctors and nurses. A key issue addressed is patient culpability in compliance. It is argued that this is a simplification which overlooks important factors such as inadequate communication and lack of knowledge on the part of doctors and nurses as well as the difficulties the patient may have with the regime.


Dynamics of aerosol size during inhalation: hygroscopic growth of commercial nebulizer formulations.
The size of aerosol particles prior to, and during, inhalation influences the site of deposition within the lung. As such, a detailed understanding of the hygroscopic growth of an aerosol during inhalation is necessary to accurately model the deposited dose. In the first part of this study, it is demonstrated that the aerosol produced by a nebulizer, depending on the airflows rates, may experience a (predictable) wide range of relative humidity prior to inhalation and undergo dramatic changes in both size and solute concentration. A series of sensitive single aerosol analysis techniques are then used to make measurements of the relative humidity dependent thermodynamic equilibrium properties of aerosol generated from four common nebulizer formulations. Measurements are also reported of the kinetics of mass transport during the evaporation or condensation of water from the aerosol. Combined, these measurements allow accurate prediction of the temporal response of the aerosol size prior to and during inhalation. Specifically, we compare aerosol composed of pure saline (150 mM sodium chloride solution in ultrapure water) with two commercially available nebulizer products containing relatively low compound doses: Breath®, consisting of a simple salbutamol sulfate solution (5 mg/2.5 mL; 1.7 mM) in saline, and Flixotide® Nebules, consisting of a more complex stabilized fluticasone propionate suspension (0.25 mg/mL; 0.5 mM in saline. A mimic of the commercial product Tobi© (60 mg/mL tobramycin and 2.25 mg/mL NaCl, pH 5.5-6.5) is also studied, which was prepared in house. In all cases, the presence of the pharmaceutical was shown to have a profound effect on the magnitude, and in some cases the rate, of the mass flux of water to and from the aerosol as compared to saline. These findings provide physical chemical evidence supporting observations from human inhalation studies, and suggest that using the growth dynamics of a pure saline aerosol in a lung inhalation model to represent nebulizer formulations may not be representative of the actual behavior of the aerosolized drug solutions.


Intra-Scleral Blue Nevus Arising within Oculodermal Melanocytosis: Melanoma or Not?
We report a 61-year-old female who presented to our service with recent growth of a thickened, pigmented, sub-conjunctival lesion within an area of ocular melanocytosis in her left eye. Lamellar sclerectomy was performed. Histopathological assessment revealed a localized melanocytic proliferation with features of blue nevus arising within the area of ocular melanocytosis. There was a small zone of cells showing cytological atypia and expansion of the scleral stroma. We believe this case to be the first report of intrascleral blue nevus arising within an area of ocular melanocytosis. Given the cytological atypia, the blue nevus may perhaps represent an intermediate stage within a progression from ocular melanocytosis towards melanoma. Patients with oculodermal melanocytosis merit regular long-term surveillance for early detection of melanoma, not only in the uvea, but also in the orbit and potentially the ocular surface.


What is asthma-COPD overlap syndrome? Towards a consensus definition from a round table discussion.
Patients with asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS) have been largely excluded from pivotal therapeutic trials and, as a result, its treatment remains poorly defined and lacking firm evidence. To date, there is no universally accepted definition of ACOS, which has made it difficult to understand its epidemiology or pathophysiology. Despite many uncertainties, there is emerging agreement that some of the key features of ACOS include persistent airflow limitation in symptomatic individuals 40 years of age and older, a well-documented history of asthma in childhood or early adulthood and a significant exposure history to cigarette or biomass smoke. In this perspective, we propose a case definition of ACOS that incorporates these key features in a parsimonious algorithm that may enable clinicians to better diagnose patients with ACOS and most importantly enable researchers to design therapeutic and clinical studies to elucidate its epidemiology and pathophysiology and to ascertain its optimal management strategies.


Prophylaxis with cationic liposome-DNA complexes protects hamsters from phleboviral disease: importance of liposomal delivery and CpG motifs.
Cationic liposome-DNA complexes (CLDC) are cationic/neutral lipid carriers complexed with plasmid DNA that when administered systemically results in a robust T(H)1 cytokine response. CLDC have been shown to be effective in prophylaxis and therapeutic treatment of animal models of viral disease. To determine the contribution of liposomal delivery and CpG content of the plasmid DNA to the efficacy of CLDC; plasmid, CpG-free plasmid DNA, or CpG-containing oligodeoxynucleotides (ODN) with and without liposomes, as well as poly(I:C(12)U), were evaluated for their ability to elicit protection against lethal Punta Toro virus (PTV, Bunyaviridae, phlebovirus) challenge in hamsters. CLDC-containing plasmid significantly improved survival, decreased systemic and liver viral loads, and reduced liver damage due to progression of viral infection. Mouse-reactive ODNs complexed with liposomes failed to protect hamsters, whereas ODNs known to cross-react with human and mouse (CpG 2006) or non-liposomal poly(I:C(12)U) showed survival benefit but did not limit liver injury. Liposomes complexed with a non-CpG motif-containing plasmid reduced liver viral load and tissue damage, but did not protect hamsters from death. To evaluate the mechanisms of the enhanced activity of CLDC, microarray experiments examined differences in the gene expression profile. The results suggest a broad T(H)1 response elicited by liposomal delivery of a diverse sequence containing CpG and non-CpG elements may be a more effective antiviral treatment than other nucleic acid based immunotherapeutics.


Risk of venous thromboembolism and the use of dienogest- and drospirenone-containing oral contraceptives: results from a German case-control study.
The primary objective of the study was to clarify whether the use of the oral contraceptive 2 mg dienogest/30 microg ethinylestradiol (DNG/EE) is associated with a higher risk of venous thromboembolism (VTE) than the use of other combined oral low-dose contraceptives (i.e. containing < or =30 microg EE), particularly oral contraceptives containing levonorgestrel (LNG). The secondary objective was to investigate the VTE risk associated with drospirenone/ethinylestradiol (DRSP/EE) in comparison to low-dose LNG/EE. This German community-based, case-control study recruited VTE cases from the primary care sector. Eligible cases were women aged 15-49 years with a VTE between January 2002 and February 2008. Four controls (women without a confirmed or potential VTE before the index date) were matched by age and region to each case. Medical information relevant for the assessment of VTE was abstracted from patient charts. Data on personal characteristics of the patients were collected via self-administered questionnaires. At the end of the study a blinded adjudication of the reported VTE was conducted. Conditional logistic regression techniques were used, adjusting for nine potential confounders, including personal history of VTE, family history of VTE, body mass index, duration of current combined oral contraceptive (COC) use and smoking. A total of 680 VTE cases and 2720 corresponding controls were analysed. The mean age of cases and controls was - as a result of matching - almost identical (36.1 years). A total of 35, 25, and 60 of the cases had used DNG-, DRSP- and LNG-containing low-dose COCs, respectively, at the time of the VTE diagnosis. The crude odds ratio (OR) for VTE associated with current COC use in comparison to women who had never used a COC before the index date was 1.9 (95% CI 1.5-2.5), the adjusted OR was 2.3 (95% CI 1.7-3.0). The point estimate of the crude OR of DNG/EE vs any other low-dose COCs was 0.9 (95% CI 0.6-1.3), the adjusted OR was 0.9 (95% CI 0.6-1.4). The crude ORs for DNG/EE and DRSP/EE vs low-dose LNG/EE were 1.1 (95% CI 0.7-1.8) and 1.0 (95% CI 0.6-1.6), respectively; the adjusted ORs were 1.1 (95% CI 0.7-1.9) and 1.0 (95% CI 0.6-1.8). The study confirms that COC use is associated with an increased risk of VTE. The VTE ORs (adjusted and crude) that compared DNG/EE and DRSP/EE with other low-dose COCs (including LNG/EE) were close to unity and do not indicate a higher risk for users of DNG/EE or DRSP/EE.


Treatment of neuroleptic-induced akathisia with the 5-HT2 antagonist mianserin. Double-blind, placebo-controlled study.
Serotonin (5-HT):dopamine imbalance may underlie neuroleptic-induced akathisia. To evaluate the efficacy of the 5-HT2 antagonist, mianserin in neuroleptic-induced akathisia. Thirty neuroleptic-treated patients with schizophrenia were randomly allocated in a double-blind design to receive either mianserin (15 mg/day) or placebo for five days. Patients were assessed at baseline and on Days 3 and 5 by the Barnes Akathisia Scale (BARS), as well as by other relevant clinical rating scales. Compared with the placebo group, the mianserin-treated patients showed a significant reduction in all four BARS subscales by Day 5, with mean reductions in the BARS global score of 9.9% and 52.2%, respectively (P = 0.006). Response to treatment (a reduction of at least two points on the BARS global subscale), was noted in six patients (40%) in the mianserin group and only one patient (9.1%) in the placebo group (P = 0.04, log odds ratio 2.23). Mianserin at a low dose may be a promising therapeutic option for patients with acute neuroleptic-induced akathisia.


[Leptin, ghrelin, and physical exercise].
Obesity is a major public health problem in the Western world resulting in serious social, physical and psychological damages. The genesis of obesity is complex involving a variety of factors such as genetic, psychological, metabolic and environmental factors. Progress in endocrinology and metabolism show that adipocyte is considered now as an endocrine tissue producing several substance including adiponectin, tumor necrosis factor-alpha, interleukin-6 and leptin. Specifically, leptin is the main peptide produced by the adipocyte and its serum concentration represents an important peripheral signal in the regulation of food intake and energy expenditure in mammals. In addition to leptin, a new peptide was discovered recently named ghrelin. Ghrelin, a peptide hormone identified in the stomach, is directly involved with the regulation of energy balance and obesity. Physical exercise has been used as a non-pharmacological tool in management of body weight and the effect of physical activity on weight control is an important issue for clinical studies in endocrinology field. Thus, this review will attempt to update the knowledge of leptin and ghrelin on the body weight regulation and the effect of exercise training on these peptide concentrations. It can be concluded that the relationship between physical exercise and the plasma concentration of these peptides is not clear. The reasons for that could be related to the differences in duration, intensity and frequency of the training program employed in each study. Indeed, most of the studies have not analyzed the intensity of training program by either plasma lactate concentration or maximum oxygen consumption. On the other hand, genetic basis could also explain the discrepancies found in some studies, since it has been shown that polymorphism for a variety of genes might be an important factor to determine the differences of cellular response to physical training.


Cigarette smoking as part of a syndemic among young men who have sex with men ages 13-29 in New York City.
The prevalence of cigarette smoking among young men who have sex with men (YMSM) is significantly higher than among their heterosexual peers. We undertook an analysis to examine cigarette smoking in relation to demographic factors and other risk behaviors among 580 YMSM, ages 13-29, in New York City. Cross-sectional data were collected as part of larger study of risk behaviors using palm devices and targeted active recruitment strategies across all five boroughs of the city. Multivariate modeling suggests that Asian or Pacific Islander and White YMSM are more likely to report cigarette smoking than other racial and ethnic groups, as are men reporting a middle class socioeconomic status. In addition, smoking was related to the likelihood of using a variety of illicit substances, as well as alcohol and pharmaceuticals without a prescription, during the period of assessment. YMSM who smoke cigarettes reported a greater number of casual sex partners and a greater number of transactional sex partners than non-smokers. Episodic analysis of sexual behaviors with casual partners indicated that smokers were more likely to engage in illicit drug and alcohol use immediately before or during sex than did non-smokers. These findings are understood as part of a larger syndemic among YMSM, and suggest that smoking prevention and cessation programs should be embedded as part of larger more holistic health and wellness programs targeting YMSM.


Structural covariance and cortical reorganisation in schizophrenia: a MRI-based morphometric study.
In patients with schizophrenia, distributed abnormalities are observed in grey matter volume. A recent hypothesis posits that these distributed changes are indicative of a plastic reorganisation process occurring in response to a functional defect in neuronal information transmission. We investigated the structural covariance across various brain regions in early-stage schizophrenia to determine if indeed the observed patterns of volumetric loss conform to a coordinated pattern of structural reorganisation. Structural magnetic resonance imaging scans were obtained from 40 healthy adults and 41 age, gender and parental socioeconomic status matched patients with schizophrenia. Volumes of grey matter tissue were estimated at the regional level across 90 atlas-based parcellations. Group-level structural covariance was studied using a graph theoretical framework. Patients had distributed reduction in grey matter volume, with high degree of localised covariance (clustering) compared with controls. Patients with schizophrenia had reduced centrality of anterior cingulate and insula but increased centrality of the fusiform cortex, compared with controls. Simulating targeted removal of highly central nodes resulted in significant loss of the overall covariance patterns in patients compared with controls. Regional volumetric deficits in schizophrenia are not a result of random, mutually independent processes. Our observations support the occurrence of a spatially interconnected reorganisation with the systematic de-escalation of conventional 'hub' regions. This raises the question of whether the morphological architecture in schizophrenia is primed for compensatory functions, albeit with a high risk of inefficiency.


Methods for quality adjustment of life years.
Several valuation techniques are in use for quality adjusting life years in cost utility analysis. The paper gives an overview of the variability in results. A close inspection of a number of instruments with respect to their theme, instructions, decision framing and the phrasing of questions make many of the observed differences in results understandable. When judging the validity of the different techniques, three points should be kept in mind. One is that statements about validity should be made with respect to concrete versions rather than broad categories like 'the rating scale', 'time trade-off' etc. Another point is that a valuation technique that is valid in clinical decision analysis may not be valid in health program evaluation, and vice versa. The third point is that quality weights for life years are empirically more meaningful, in the sense that they are more amenable to empirical testing, if they are interpreted simply as preference weights rather than measures of amounts of well life in the utilitarian tradition. Time trade-off with a moderate time horizon is recommended in clinical decision analysis, while a combination of time trade-off and a variant of person trade-off is recommended in health program evaluation.


Normothermic liver preservation: a new paradigm?
Despite increasing donor numbers, waiting lists and pre-transplant mortality continue to grow in many countries. The number of donor organs suitable for liver transplantation is restricted by cold preservation and ischemia-reperfusion injury (IRI). Transplantation of marginal donor organs has led to renewed interest in new techniques which have the potential to improve the quality of preservation, assess the quality of the organ and allow repair of the donor organ prior to transplantation. If successful, such techniques would not only improve the outcome of currently transplanted marginal livers, but also increase the donor pool. Experimental evidence suggests that preservation under near physiological conditions of temperature and oxygenation abrogates IRI. Normothermic perfusion maintains the organ in a physiological state, avoiding the depletion of cellular energy and the accumulation of waste products, which occurs with static cold storage. It enables viability assessment prior to transplantation thereby reducing the risk of transplanting inherently marginal organs. Here we review the use of normothermic machine perfusion as a means of organ preservation.


Evaluation of the Non-HDL Cholesterol to Apolipoprotein B Ratio as a Screening Test for Dysbetalipoproteinemia.
Familial dysbetalipoproteinemia is associated with the accumulation of remnant lipoproteins and premature cardiovascular disease. Identification of dysbetalipoproteinemia is important because family members may be affected. Diagnostic testing involves demonstration of β-lipoprotein in the VLDL fraction or characterization of apo E3. These investigations are complex and relatively expensive. The ratios of apo B to total cholesterol and triglycerides have been proposed as screening tests. However, the ratio of non-HDL cholesterol to apo B (NHDLC/apoB) could offer improved performance as the confounding effect of variations in HDL cholesterol is removed. We evaluated NHDLC/apoB as a screening test for dysbetalipoproteinemia, using β-quantification analysis as a reference standard. Data from 1637 patients referred over a 16-year period for β quantification were reviewed retrospectively. In 63 patients, diagnostic criteria for dysbetalipoproteinemia (VLDL cholesterol/triglyceride ratio ≥0.69 and presence of β-VLDL) were fulfilled, and 1574 patients had dysbetalipoproteinemia excluded. Mean NHDLC/apoB in patients with dysbetalipoproteinemia was 7.3 mmol/g (SD, 1.5 mmol/g) and with dysbetalipoproteinemia excluded was 4.0 mmol/g (SD, 0.5 mmol/g). The optimum cutoff of >4.91 mmol/g achieved a diagnostic sensitivity of 96.8% (95% CI, 89.0-99.6) and specificity of 95.0% (95% CI, 93.8-96.0). NHDLC/apoB offered improved performance compared to total cholesterol/apoB [diagnostic sensitivity 92.1% (95% CI, 82.4-97.4) and specificity 94.5% (95% CI, 93.2-95.6) with a cutoff of >6.55 mmol/g]. NHDL/apoB reference ranges were not sex-dependent, although there was a significant difference between men and women for total cholesterol/apoB. NHDLC/apoB offers a simple first-line test for dysbetalipoproteinemia in selecting patients with mixed hyperlipidemia for more complex investigations.


Determinants of cumulative fertility in Ghana.
The relatively few studies conducted on fertility differentials in Ghana have not controlled for the effect of important demographic variables, such as age at first marriage and current age of respondent. This paper attempts a multivariate analysis of the relationship between cumulative fertility and age at first marriage, level of education, religion, form of marriage and residence of husband. Data drawn from a census sample survey in 1971 include 72,816 currently married females aged 15-49 years. Age at first marriage was inversely related to cumulative fertility. The differentials were more pronounced for older women. Among the older women, the differentials were larger for rural than urban women. There were also significant fertility differentials associated with level of education, religion and form of marriage. Husband's residence was a poor predictor of cumulative fertility. As a policy measure, it is suggested that priority be given to providing young women with more education or employment opportunities as an alternative to early marriage.


Superenhancers: novel opportunities for nanowire optoelectronics.
Nanowires play a crucial role in the development of new generation optoelectronic devices ranging from photovoltaics to photodetectors, as these designs capitalize on the low material usage, utilize leaky-mode optical resonances and possess high conversion efficiencies associated with nanowire geometry. However, their current schemes lack sufficient absorption capacity demanded for their practical applicability, and more efficient materials cannot find widespread usage in these designs due to their rarity and cost. Here we suggest a novel and versatile nanoconcentrator scheme utilizing unique optical features of non-resonant Mie (NRM) scattering regime associated with low-index structures. The scattering regime is highly compatible with resonant Mie absorption effect taking place in nanowire absorbers. This technique in its optimized forms can provide up to 1500% total absorption enhancement, 400-fold material save and is suitable for large-area applications with significant area preservation compared to thin-film of same materials. Proposed superenhancer concept with its exceptional features such as broadband absorption enhancement, polarization immunity and material-independent manner paves the way for development of efficient nanowire photosensors or solar thermophotovoltaic devices and presents novel design opportunities for self-powered nanosystems.


Maternally-derived zinc transporters ZIP6 and ZIP10 drive the mammalian oocyte-to-egg transition.
Rapid cellular zinc influx regulates early mammalian development during the oocyte-to-egg transition through modulation of the meiotic cell cycle. Despite the physiological necessity of this zinc influx, the molecular mechanisms that govern such accumulation are unknown. Here we show that the fully grown mammalian oocyte does not employ a transcriptionally based mechanism of zinc regulation involving metal response element-binding transcription factor-1 (MTF-1), as demonstrated by a lack of MTF-1 responsiveness to environmental zinc manipulation. Instead, the mammalian oocyte controls zinc uptake through two maternally derived and cortically distributed zinc transporters, ZIP6 and ZIP10. Targeted disruption of these transporters using several approaches during meiotic maturation perturbs the intracellular zinc quota and results in a cell cycle arrest at a telophase I-like state. This arrest phenocopies established models of zinc insufficiency during the oocyte-to-egg transition, indicating the essential function of these maternally expressed transporters. Labile zinc localizes to punctate cytoplasmic structures in the human oocyte, and ZIP6 and ZIP10 are enriched in the cortex. Altogether, we demonstrate a mechanism of metal regulation required for female gamete development that may be evolutionarily conserved.


Hydronephrosis as a prognostic indicator in bladder cancer patients.
Pathological stage is the standard measure of prognosis in patients who have undergone radical cystectomy for bladder cancer. Despite the development of new imaging techniques, clinical staging for bladder cancer continues to be inaccurate. We investigated whether the presence of unilateral or bilateral upper tract obstruction could accurately predict advanced cancer stage (extravesical extension, stage greater than p3b or N+). A retrospective study of 415 patients diagnosed with transitional cell carcinoma of the bladder who were treated with radical cystectomy between 1983 and 1993 was conducted. All patients were followed for survival. The criteria for analysis included hydronephrosis status (no obstruction, unilateral, bilateral) as well as pathological stage of the tumor. Of 415 patients 72% presented with no, 22.7% unilateral and 5.3% bilateral obstruction. Our results showed a significant correlation between hydronephrosis and advanced cancer stage (p <0.0001), and decreased patient survival (p <0.0001). More than 90% of patients with bilateral obstruction had disease with extravesical extension. Of the patients with unilateral obstruction a third had disease confined to the bladder with a significant proportion confined to the bladder mucosa. The presence of unilateral or bilateral hydronephrosis is a clinical datum that is already available to help accurately stage bladder tumors. The presence of bilateral obstruction is an ominous sign, while a significant proportion of patients presenting with unilateral obstruction have disease confined to the bladder.


Transmission electron microtomography in soft materials.
This review summarizes the recent advances in three-dimensional (3D) imaging techniques and their application to polymer nanostructures, for example, microphase-separated structures of block copolymers. We place particular emphasis on the method of transmission electron microtomography (electron tomography for short; hereafter abbreviated as ET). As a result of recent developments in ET, truly quantitative 3D images of polymer nanostructures can now be obtained with subnanometer resolution. The introduction of scanning optics in ET has made it possible to obtain large amounts of 3D data from micrometer-thick polymer specimens by using conventional electron microscopes at a relatively low accelerating voltage, 200 kV. Thus, ET covers structures over a wide range of thicknesses, from a few nanometers to several hundred nanometers, which corresponds to quite an important spatial range for hierarchical polymer nanostructures. ET provides clear 3D images and a wide range of new structural information that cannot be obtained using other methods. Information traditionally derived from conventional microscopy or scattering methods can be directly acquired from 3D volume data. ET is a versatile technique that is not restricted to only polymer applications; it can also be used as a powerful characterization tool in energy applications such as fuel cells.


Industrial dental erosion: a cross-sectional, comparative study.
Occupational exposure to sulphuric acid mist (H2SO4) is a health hazard. The threshold limit value-time weighted average (TLV-TWA) of exposure to H2SO4 recommended by the American Conference of Governmental Industrial Hygienists (ACGIH, 1994-1996) is 1 mg/m3. This single-blind study conducted in an electro-winning facility in South Africa, compared dental erosion of anterior and premolar teeth of male workers exposed daily to H2SO4 in an exposed group (H2SO4 range: 0.3 mg/m3-1 mg/m3) and an unexposed group (H2SO4 range: 0.1 mg/m3-0.3 mg/m3). The exposed group comprised all workers at the facility exposed to the aforesaid range of H2SO4 (N = 103). A total of 102 unexposed subjects similar in composition with respect to age and length of service were randomly selected from the rest of the 700 workers at the facility. A questionnaire was administered to seek information on possible worker habits associated with dental erosion and to determine perceptions of oral function. Clinical examinations assessed prevalence and severity of dental erosion. The mean age of subjects was 31.4 years and mean length of service 4.2 years. In the exposed group 48% complained of pain and sensitivity on their teeth compared with the 31% of unexposed persons (P = 0.020). Dental erosion was present in exposed (96%) and unexposed (75%) subjects. Exposed subjects were more likely to develop erosion than unexposed subjects, the odds ratio being 5.531 within the confidence limits 2.167 < OR < 14.117. There was a significant difference in the severity of tooth surface loss between exposed and unexposed groups (P = 0.001). Dental erosion was most severe in the anterior teeth and occurred mostly on the labial and incisal surfaces.


SMRT sequencing data for Garcinia mangostana L. variety Mesta.
The "Queen of Fruits" mangosteen (Garcinia mangostana L.) produces commercially important fruits with desirable taste of flesh and pericarp rich in xanthones with medicinal properties. To date, only limited knowledge is available on the cytogenetics and genome sequences of a common variety of mangosteen (Abu Bakar et al., 2016 [1]). Here, we report the first single-molecule real-time (SMRT) sequencing data from whole genome sequencing of mangosteen of Mesta variety. Raw reads of the SMRT sequencing project can be obtained from SRA database with the accession numbers SRX2718652 until SRX2718659.


Electrocardiogram screening for aortic valve stenosis using artificial intelligence.
Early detection of aortic stenosis (AS) is becoming increasingly important with a better outcome after aortic valve replacement in asymptomatic severe AS patients and a poor outcome in moderate AS. We aimed to develop artificial intelligence-enabled electrocardiogram (AI-ECG) using a convolutional neural network to identify patients with moderate to severe AS. Between 1989 and 2019, 258 607 adults [mean age 63 ± 16.3 years; women 122 790 (48%)] with an echocardiography and an ECG performed within 180 days were identified from the Mayo Clinic database. Moderate to severe AS by echocardiography was present in 9723 (3.7%) patients. Artificial intelligence training was performed in 129 788 (50%), validation in 25 893 (10%), and testing in 102 926 (40%) randomly selected subjects. In the test group, the AI-ECG labelled 3833 (3.7%) patients as positive with the area under the curve (AUC) of 0.85. The sensitivity, specificity, and accuracy were 78%, 74%, and 74%, respectively. The sensitivity increased and the specificity decreased as age increased. Women had lower sensitivity but higher specificity compared with men at any age groups. The model performance increased when age and sex were added to the model (AUC 0.87), which further increased to 0.90 in patients without hypertension. Patients with false-positive AI-ECGs had twice the risk for developing moderate or severe AS in 15 years compared with true negative AI-ECGs (hazard ratio 2.18, 95% confidence interval 1.90-2.50). An AI-ECG can identify patients with moderate or severe AS and may serve as a powerful screening tool for AS in the community.


Characterization of the GPI-anchored endo β-1,3-glucanase Eng2 of Aspergillus fumigatus.
A GPI-anchored endo β-1,3-glucanase of Aspergillus fumigatus was characterized. The enzyme encoded by ENG2 (AFUA_2g14360) belongs to the glycoside hydrolase family 16 (GH16). The activity was characterized using a recombinant protein produced by Pichiapastoris. The recombinant enzyme preferentially acts on soluble β-1,3-glucans. Enzymatic analysis of the endoglucanase activity using Carboxymethyl-Curdlan-Remazol Brilliant Blue (CM-Curdlan-RBB) as a substrate revealed a wide temperature optimum of 24-40°C, a pH optimum of 5.0-6.5 and a K(m) of 0.8 mg ml(-1). HPAEC analysis of the products formed by Eng2 when acting on different oligo-β-1,3-glucans confirmed the predicted endoglucanase activity and also revealed a transferase activity for oligosaccharides of a low degree of polymerization. The growth phenotype of the Afeng2 mutant was identical to that of the wt strain.


A non-interpenetrating lead-organic framework with large channels based on 1D tube-shaped SBUs.
This work presents the construction of a porous lead-organic framework (UPC-10) with large channels of ∼24 Å. UPC-10 shows efficient adsorption of I2 and selective adsorption of some dyes containing the SO3- group. After the adsorption of dyes, UPC-10 exhibits a CO2 gas uptake ability. Furthermore, UPC-10 could be transformed into PbS in a H2S atmosphere, and the derived PbS manifests N2 and CO2 uptake abilities.


Effectiveness of Guideline-Recommended Cholecystectomy to Prevent Recurrent Pancreatitis.
Cholecystectomy during or within 4 weeks of hospitalization for acute biliary pancreatitis is recommended by guidelines. We examined adherence to the guidelines for incident mild-to-moderate acute biliary pancreatitis and the effectiveness of cholecystectomy to prevent recurrent episodes of pancreatitis. Individuals in the 2010-2013 MarketScan Commercial Claims & Encounters database with a hospitalization associated with International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes of 577.0 for acute pancreatitis and 574.x for gallstone disease were eligible. Guideline adherence was considered cholecystectomy within 30 days of the first/index hospitalization for biliary pancreatitis. Individuals with and without guideline-adherent cholecystectomy were compared for subsequent hospitalization for acute or chronic pancreatitis using a Cox proportional hazards model adjusted for age, sex, comorbidities, and length of index hospital stay. Of the 17,010 patients who met the inclusion criteria, 78% were adherent with the guidelines, including 10,918 who underwent cholecystectomy during the index hospitalization and 2,387 who underwent cholecystectomy within 30 days. Among 3,705 patients non-adherent with the guidelines, 1,213 had a cholecystectomy 1-6 months after the index hospitalization. Guideline-adherent cholecystectomy resulted in fewer subsequent hospitalizations for acute and chronic pancreatitis as compared with non-adherence to the guidelines (acute pancreatitis: 3% vs. 13%, P<0.001; chronic pancreatitis: 1% vs. 4%, P<0.001). Nearly four out of five patients underwent cholecystectomy for acute biliary pancreatitis in a timeframe, consistent with guidelines. Adherence resulted in a decrease in subsequent hospitalizations for both acute and chronic pancreatitis. However, the majority of non-adherent patients did not undergo a subsequent cholecystectomy. There may be factors that predict the need for immediate vs. delayed cholecystectomy.


Emerging ultra-narrow-band cyan-emitting phosphor for white LEDs with enhanced color rendition.
Phosphor-converted white LEDs rely on combining a blue-emitting InGaN chip with yellow and red-emitting luminescent materials. The discovery of cyan-emitting (470-500 nm) phosphors is a challenge to compensate for the spectral gap and produce full-spectrum white light. Na0.5K0.5Li3SiO4:Eu2+ (NKLSO:Eu2+) phosphor was developed with impressive properties, providing cyan emission at 486 nm with a narrow full width at half maximum (FWHM) of only 20.7 nm, and good thermal stability with an integrated emission loss of only 7% at 150 °C. The ultra-narrow-band cyan emission results from the high-symmetry cation sites, leading to almost ideal cubic coordination for UCr4C4-type compounds. NKLSO:Eu2+ phosphor allows the valley between the blue and yellow emission peaks in the white LED device to be filled, and the color-rendering index can be enhanced from 86 to 95.2, suggesting great applications in full-spectrum white LEDs.


Accuracy of diagnostic biopsy for cutaneous melanoma: implications for surgical oncologists.
While excisional biopsy is recommended to diagnose cutaneous melanoma, various biopsy techniques are used in practice. We undertook this study to identify how frequently final tumor stage and treatment recommendations changed from diagnostic biopsy to final histopathology after wide local excision (WLE). We compared the histopathology of the dermatopathologist-reviewed diagnostic biopsy and final WLE in 332 cutaneous melanoma patients. Tumor sites were extremity (51%), trunk (33%), and head/neck (16%). Initial biopsy types were excisional (56%), punch (21%), shave (18%), and incisional (5%). Most diagnostic biopsies were margin positive regardless of technique, and 36% of patients had residual melanoma on WLE. T-stage changed in 8% of patients, of whom 59% were diagnosed by punch biopsy, 15% by incisional biopsy, 15% by shave biopsy, and 11% by excisional biopsy (P < 0.0001). Treatment recommendations changed in 6%: 2% after excisional biopsy, 5% after shave biopsy, 18% after punch biopsy, and 18% after incisional biopsy (P < 0.0001). Although most biopsy margins were positive, T-stage and treatment changed for only a minority of melanoma patients. Our data provide valuable information to inform patient discussion regarding the likelihood of a change in prognosis and the need for secondary procedures after WLE. These data support the superiority of dermatopathologist-reviewed excisional biopsy when feasible.


Favorable Trisomies and ETV6-RUNX1 Predict Cure in Low-Risk B-Cell Acute Lymphoblastic Leukemia: Results From Children's Oncology Group Trial AALL0331.
Children's Oncology Group (COG) AALL0331 tested whether pegaspargase intensification on a low-intensity chemotherapy backbone would improve the continuous complete remission (CCR) rate in a low-risk subset of children with standard-risk B-acute lymphoblastic leukemia (ALL). AALL0331 enrolled 5,377 patients with National Cancer Institute standard-risk B-ALL (age 1-9 years, WBC < 50,000/μL) between 2005 and 2010. Following a common three-drug induction, a cohort of 1,857 eligible patients participated in the low-risk ALL random assignment. Low-risk criteria included no extramedullary disease, < 5% marrow blasts by day 15, end-induction marrow minimal residual disease < 0.1%, and favorable cytogenetics (ETV6-RUNX1 fusion or simultaneous trisomies of chromosomes 4, 10, and 17). Random assignment was to standard COG low-intensity therapy (including two pegaspargase doses, one each during induction and delayed intensification) with or without four additional pegaspargase doses at 3-week intervals during consolidation and interim maintenance. The study was powered to detect a 4% improvement in 6-year CCR rate from 92% to 96%. The 6-year CCR and overall survival (OS) rates for the entire low-risk cohort were 94.7% ± 0.6% and 98.7% ± 0.3%, respectively. The CCR rates were similar between arms (intensified pegaspargase 95.3% ± 0.8% v standard 94.0% ± 0.8%; P = .13) with no difference in OS (98.1% ± 0.5% v 99.2% ± 0.3%; P = .99). Compared to a subset of standard-risk study patients given identical therapy who had the same early response characteristics but did not have favorable or unfavorable cytogenetics, outcomes were significantly superior for low-risk patients (CCR hazard ratio 1.95; P = .0004; OS hazard ratio 5.42; P < .0001). Standard COG therapy without intensified pegaspargase, which can easily be given as an outpatient with limited toxicity, cures nearly all children with B-ALL identified as low-risk by clinical, early response, and favorable cytogenetic criteria.


Fetal alcohol-induced hyperactivity is reversed by treatment with the PPARα agonist fenofibrate in a rat model.
Exposure to alcohol in utero is linked to the development of a wide range of psychobehavioral changes, notably hyperactivity and attention deficit, with complex underlying pathological and functional mechanisms. Although the currently available treatments for hyperactivity have been studied in children exposed to alcohol in utero, the efficacy of these compounds is subject to debate and has prompted efforts to identify new pharmacological targets. In a rat model of early alcohol exposure (i.e., in utero and during lactation), we studied the effect of the lipid-lowering peroxisome proliferator-activated receptor (PPAR) alpha activator fenofibrate on psychobehavioral impairments. In the young rat, early exposure to alcohol perturbs locomotor behavior and induces prepubertal hyperactivity and postpubertal hypoactivity. The hyperactivity, usually observed at the end of the fifth week of life, was prevented by the administration of fenofibrate, which also had a beneficial effect on the accompanying attention deficit by reinforcing sustained attention. Our results with fenofibrate suggest that the pharmacological modulation of nuclear receptors such as PPAR-alpha may constitute a new therapeutic approach to managing the psychobehavioral disorders associated with early alcohol exposure.


Oxidation of F-actin controls the terminal steps of cytokinesis.
Cytokinetic abscission, the terminal step of cell division, crucially depends on the local constriction of ESCRT-III helices after cytoskeleton disassembly. While the microtubules of the intercellular bridge are cut by the ESCRT-associated enzyme Spastin, the mechanism that clears F-actin at the abscission site is unknown. Here we show that oxidation-mediated depolymerization of actin by the redox enzyme MICAL1 is key for ESCRT-III recruitment and successful abscission. MICAL1 is recruited to the abscission site by the Rab35 GTPase through a direct interaction with a flat three-helix domain found in MICAL1 C terminus. Mechanistically, in vitro assays on single actin filaments demonstrate that MICAL1 is activated by Rab35. Moreover, in our experimental conditions, MICAL1 does not act as a severing enzyme, as initially thought, but instead induces F-actin depolymerization from both ends. Our work reveals an unexpected role for oxidoreduction in triggering local actin depolymerization to control a fundamental step of cell division.


Interval timing as an emergent learning property.
Interval timing in operant conditioning is the learned covariation of a temporal dependent measure such as wait time with a temporal independent variable such as fixed-interval duration. The dominant theories of interval timing all incorporate an explicit internal clock, or "pacemaker," despite its lack of independent evidence. The authors propose an alternative, pacemaker-free view that demonstrates that temporal discrimination can be explained by using only 2 assumptions: (a) variation and selection of responses through competition between reinforced behavior and all other, elicited, behaviors and (b) modulation of the strength of response competition by the memory for recent reinforcement. The model departs radically from existing timing models: It shows that temporal learning can emerge from a simple dynamic process that lacks a periodic time reference such as a pacemaker.


A balanced scorecard for assessing a strategic plan in a clinical laboratory.
The Balanced Scorecard (BSC) is a tool for strategic management that is used in many companies and organizations worldwide, both in the public and private sector. With this purpose it has also been used in healthcare organizations and institutions but there are not many studies on the implementation of BSC methodology in the day-to-day clinical laboratory. This review shows the strategy for the development of a BSC, which includes theoretical perspective objectives, as well as some indicators and goals with which the monitoring and quantitative measurement of the achievements of a strategic plan in a clinical laboratory can be done. Moreover, the results of the indicators allow the prioritization of the initiatives to be implemented each year. The methodology for the development of the proposed BSC includes the following steps: definition of theoretical objectives of each of the perspectives most used in the management of a clinical laboratory (customers, financial, internal processes and learning) taking into account the vision and the organizational model of the laboratory; creation of a strategic map of perspective objectives; definition of the relevant indicators to follow up on the objectives in a quantitative manner and establishment of the goals. Whether or not the laboratory is a reference laboratory, in which specific and infrequent analysis and health population programs are performed, is another fact to take into account. In this review a BSC for a reference clinical laboratory of the Spanish public sector is shown.


Gelsolin levels in patients with bronchiolitis.
Hüsrevoğlu-Esen F. Altuner-Torun Y, Karakükçü Ç, Köse S, Şehriyaroğlu A, Kafadar D, Esen A, Köse M. Gelsolin levels in patients with bronchiolitis. Turk J Pediatr 2018; 60: 286-289. Bronchiolitis is the leading cause of hospitalization in infants. Biomarkers can show severity of the disease and help in clinical management. In this study, the aim was to determine the clinical predictiveness of plasma gelsolin levels (pGSN) in acute bronchiolitis. From December 2013 to May 2014, 52 patients with bronchiolitis (aged < 24 months) were included in this study. Baseline clinical characteristic, complete blood count, C-Reactive Protein, plasma gelsolin levels, chest X-rays were obtained in all patients. The patients were divided into three groups as mild, moderate and severe based on clinical findings. There was no significant difference in pGSN levels between the control group and 3 study groups according to their clinical scores such as mild, moderate and severe bronchiolitis (p > 0.05). Recent studies reported that pGSN levels can be used as a biomarker in sepsis, inflammation and injuries. In this study, we have demonstrated that pGSN level is not a predictive biomarker of bronchiolitis and its severity. Hence, we hypothesized that pGSN levels can be used in bacterial infections rather than viral infections as a biomarker.


Sine-wave electrical stimulation initiates a voltage-gated potassium channel-dependent soft tissue response characterized by induction of hemocyte recruitment and collagen deposition.
Soft tissue repair is a complex process that requires specific communication between multiple cell types to orchestrate effective restoration of physiological functions. Macrophages play a critical role in this wound healing process beginning at the onset of tissue injury. Understanding the signaling mechanisms involved in macrophage recruitment to the wound site is an essential step for developing more effective clinical therapies. Macrophages are known to respond to electrical fields, but the underlying cellular mechanisms mediating this response is unknown. This study demonstrated that low-amplitude sine-wave electrical stimulation (ES) initiates a soft tissue response in the absence of injury in Procambarus clarkii This cellular response was characterized by recruitment of macrophage-like hemocytes to the stimulation site indicated by increased hemocyte density at the site. ES also increased tissue collagen deposition compared to sham treatment (P < 0.05). Voltage-gated potassium (KV) channel inhibition with either 4-aminopyridine or astemizole decreased both hemocyte recruitment and collagen deposition compared to saline infusion (P < 0.05), whereas inhibition of calcium-permeable channels with ruthenium red did not affect either response to ES Thus, macrophage-like hemocytes in P. clarkii elicit a wound-like response to exogenous ES and this is accompanied by collagen deposition. This response is mediated by KV channels but independent of Ca(2+) channels. We propose a significant role for KV channels that extends beyond facilitating Ca(2+) transport via regulation of cellular membrane potentials during ES of soft tissue.


Pharmacologic and surgical therapies for patients with Meniere's disease: A systematic review and network meta-analysis.
Meniere's disease (MD) is a chronic condition of the inner ear consisting of symptoms that include vertigo attacks, fluctuating sensorineural hearing loss, tinnitus and aural fullness. Despite availability of various interventions, there is uncertainty surrounding their relative efficacy, thus making it difficult to select the appropriate treatments for MD. The objective of this systematic review was to assess the relative effects of the available pharmacologic and surgical interventions in patients with MD with regard to vertigo and other key patient outcomes based on data from randomized clinical trials (RCTs). Our published protocol registered with PROSPERO (CRD42019119129) provides details on eligibility criteria and methods. We searched various databases including MEDLINE, Embase and the Cochrane Library from inception to December 10th, 2018. Screening at citation and full-text levels and risk of bias assessment were performed by two independent reviewers in duplicate, with discrepancies resolved by consensus or third-party adjudication. Bayesian network meta-analyses (NMA) were performed for hearing change and vertigo control outcomes, along with pairwise meta-analyses for these and additional outcomes. We identified 2,889 unique citations, that yielded 23 relevant publications describing 18 unique RCTs (n = 1,231 patients). Overall, risk-of bias appraisal suggested the evidence base to be at unclear or high risk of bias. Amongst pharmacologics, we constructed treatment networks of five intervention groups that included placebo, intratympanic (IT) gentamicin, oral high-dose betahistine, IT steroid and IT steroid plus high-dose betahistine for NMAs of hearing change (improvement or deterioration) and complete vertigo control. IT steroid plus high-dose betahistine was associated with the largest difference in hearing improvement compared to placebo, followed by high-dose betahistine and IT steroid (though 95% credible intervals failed to rule out the possibility of no difference), while IT gentamicin was worse than IT steroid. The NMA of complete vertigo control suggested IT gentamicin was associated with the highest probability of achieving better complete vertigo control compared to placebo, followed by IT steroid plus high-dose betahistine. Only two studies related to surgical interventions were found, and data suggested no statistically significant difference in hearing changes between endolymphatic duct blockage (EDB) versus endolymphatic sac decompression (ESD), and ESD with or without steroid injection. One trial reported that 96.5% of patients in EDB group compared to 37.5% of the patients in ESD group achieved complete vertigo control 24 months after surgery (p = 0.002). To achieve both hearing preservation and vertigo control, the best treatment option among the pharmacologic interventions compared may be IT steroid plus high-dose betahistine, considering that IT gentamicin may have good performance to control vertigo but may be detrimental to hearing preservation with high cumulative dosage and short interval between injections. However, IT steroid plus high-dose betahistine has not been compared in head-to-head trials against other interventions except for IT steroid alone in one trial, thus future trials that compare it with other interventions will help establish comparative effectiveness with direct evidence.


Computational investigations into the structural and electronic properties of Cd n Te n (n = 1-17) quantum dots.
Size-tunability of the electronic and optical properties of semiconductor quantum dots and nanoclusters is due to the quantum size effect, which causes variations in the electronic excitations as the particle boundaries are changed. Recently, CdSe and CdTe quantum dots have been used in energy harvesting devices. Despite these promising practical applications, a complete understanding of the electronic transitions associated with the surfaces of the nanoparticles is currently lacking and is difficult to achieve experimentally. Computational methods could provide valuable insights and allow us to understand the electronic and optical properties of quantum dots and nanoclusters. Hollow cage and endohedral or core-shell cage structures for Cd n Te n clusters have been reported before. We have performed systematic density functional theory (DFT) studies on the structure and electronic properties of the Cd n Te n (n = 1-17) clusters. As the number of atoms increases in the Cd n Te n clusters, the predicted geometries change from simple planar structures to more complicated 3D-structures. Two classes of the most stable structures were elucidated for clusters with n = 10-17: (i) hollow cage structures with an empty center; and (ii) endohedral or core-shell cage structures with one or more atoms inside the cage. Noticeably higher highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) gaps were observed for the hollow cage isomers as compared to the core-shell structures. The highest occupied molecular orbitals of all of the clusters studied were shown to be localized on the surface of the cage for the hollow cage structures, while in the case of the core-shell structures, the HOMO electron densities were found to be distributed both on surface and the interior of the structures. Most of the small size clusters Cd n Te n (n = 2-9) showed minimal values for the dipole moments (close to zero) owing to the highly ordered and symmetric configurations of these structures. For isomers of the larger clusters (n = 10-17), it was observed that the core-shell structures have higher values for the dipole moments than the hollow cage species because of the highly symmetric structures of the hollow cages. Core-shell cage structures exhibited lower polarizability than the respective hollow cage structures.


Do the daily experiences of healthy men and women vary according to occupational prestige and work strain?
This study evaluated the influence of occupational prestige and work strain on mood, the occurrence of interpersonal conflict, and ambulatory blood pressure and heart rate. Participants were 50 men and 50 women matched for occupational prestige who were healthy and middle-aged and who completed measures of mood and conflict simultaneously with measures of ambulatory blood pressure and heart rate recorded every 30 minutes during waking hours of two workdays and one nonworkday; at the end of each day, overall ratings were made. Work strain was assessed by the Work Section of the Self-Evaluation and Social Support Interview Schedule. Multiple level random regression coefficients analyses were conducted. Men and women with low-prestige occupations experienced more interpersonal conflict, b = -0.03, p = .04, and higher ambulatory heart rate, b = -4.83, p = .004, throughout the three days of the study. Relative to those with low work strain, those reporting high work strain experienced negative emotion, b = -0.41, p < .0001, and boredom, b = -0.17, p < .0004. End of the day ratings of negative mood were more influenced by work strain among men than among women. No effects of occupational prestige or work strain were obtained for ambulatory blood pressure readings after adjustment for physical activity, posture, and location. Individuals in low-prestige occupations experience greater exposure to interpersonal conflict and arousal as indexed by heart rate, which might increase risk for stress-related illnesses often associated with social class. Individuals who report work strain experience negative mood and boredom, both at work and at home. The absence of work effects on ambulatory blood pressure may be due to the participants being healthy.


Difference in the structural features of streptococcal M proteins from nephritogenic and rheumatogenic serotypes.
The association of only certain M protein serotypes of group A streptococci with acute glomerulonephritis is very well recognized. Structural information on the M protein, a dimeric alpha-helical coiled-coil molecule, has come so far from three rheumatogenic serotypes, 5, 6, and 24. However, M proteins from the nephritogenic serotypes have not been well characterized. In the present study, we have isolated a biologically active 20,000 Mr pepsin fragment of type 49 M protein (PepM49), a nephritogenic serotype, and purified it to homogeneity using DEAE-Sephadex and gel filtration. The amino acid composition of PepM49 is similar to those of the rheumatogenic M protein serotypes PepM5, PepM6, and PepM24. However, the sequence of the NH2-terminal 60 residues of PepM49 shows little homology to any of these M protein serotypes, although the latter have significant homology among themselves. Nevertheless, PepM49 exhibits a strong heptad periodicity in its nonpolar residues, suggesting its overall conformational similarity with the other M molecules. During the course of the present studies, Moravek et al. (17) reported the NH2-terminal sequence of another M protein serotype, PepM1, which also does not exhibit much homology with the PepM5, PepM6, and PepM24 proteins. Our analysis of this sequence revealed that the PepM1 protein also exhibits a heptad periodicity of the nonpolar amino acids. A closer examination has revealed that the pattern of heptad periodicity in PepM49 and PepM1 proteins is more regular and more similar to each other than has been previously seen for the PepM5, PepM6, and PepM24 proteins. PepM1 is also a nephritogenic serotype. Taken together, these findings indicate an underlying conservation of the tertiary structure of the various M protein serotypes, despite the complexity in their antigenic variation and suggest that the nephritogenic M protein serotypes M1 and M49 may be further apart evolutionarily from the rheumatogenic serotypes 5, 6, and 24. The distinct differences in the structural features of the PepM1 and PepM49 proteins relative to the PepM5, PepM6, and PepM24 proteins are also suggestive of a correlation with the earlier broader classification of the group A streptococci into rheumatogenic and nephritogenic serotypes.


Association between sauna bathing and fatal cardiovascular and all-cause mortality events.
Sauna bathing is a health habit associated with better hemodynamic function; however, the association of sauna bathing with cardiovascular and all-cause mortality is not known. To investigate the association of frequency and duration of sauna bathing with the risk of sudden cardiac death (SCD), fatal coronary heart disease (CHD), fatal cardiovascular disease (CVD), and all-cause mortality. We performed a prospective cohort study (Finnish Kuopio Ischemic Heart Disease Risk Factor Study) of a population-based sample of 2315 middle-aged (age range, 42-60 years) men from Eastern Finland. Baseline examinations were conducted from March 1, 1984, through December 31, 1989. Frequency and duration of sauna bathing assessed at baseline. During a median follow-up of 20.7 years (interquartile range, 18.1-22.6 years), 190 SCDs, 281 fatal CHDs, 407 fatal CVDs, and 929 all-cause mortality events occurred. A total of 601, 1513, and 201 participants reported having a sauna bathing session 1 time per week, 2 to 3 times per week, and 4 to 7 times per week, respectively. The numbers (percentages) of SCDs were 61 (10.1%), 119 (7.8%), and 10 (5.0%) in the 3 groups of the frequency of sauna bathing. The respective numbers were 89 (14.9%), 175 (11.5%), and 17 (8.5%) for fatal CHDs; 134 (22.3%), 249 (16.4%), and 24 (12.0%) for fatal CVDs; and 295 (49.1%), 572 (37.8%), and 62 (30.8%) for all-cause mortality events. After adjustment for CVD risk factors, compared with men with 1 sauna bathing session per week, the hazard ratio of SCD was 0.78 (95% CI, 0.57-1.07) for 2 to 3 sauna bathing sessions per week and 0.37 (95% CI, 0.18-0.75) for 4 to 7 sauna bathing sessions per week (P for trend = .005). Similar associations were found with CHD, CVD, and all-cause mortality (P for trend ≤.005). Compared with men having a sauna bathing session of less than 11 minutes, the adjusted hazard ratio for SCD was 0.93 (95% CI, 0.67-1.28) for sauna bathing sessions of 11 to 19 minutes and 0.48 (95% CI, 0.31-0.75) for sessions lasting more than 19 minutes (P for trend = .002); significant inverse associations were also observed for fatal CHDs and fatal CVDs (P for trend ≤.03) but not for all-cause mortality events. Increased frequency of sauna bathing is associated with a reduced risk of SCD, CHD, CVD, and all-cause mortality. Further studies are warranted to establish the potential mechanism that links sauna bathing and cardiovascular health.


Cloning of a genetically unstable cytochrome P-450 gene cluster involved in degradation of the pollutant ethyl tert-butyl ether by Rhodococcus ruber.
Rhodococcus ruber (formerly Gordonia terrae) IFP 2001 is one of a few bacterial strains able to degrade ethyl tert-butyl ether (ETBE), which is a major pollutant from gasoline. This strain was found to undergo a spontaneous 14.3-kbp chromosomal deletion, which results in the loss of the ability to degrade ETBE. Sequence analysis of the region corresponding to the deletion revealed the presence of a gene cluster, ethABCD, encoding a ferredoxin reductase, a cytochrome P-450, a ferredoxin, and a 10-kDa protein of unknown function, respectively. The EthB and EthD proteins could be easily detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and were induced by ETBE in the wild-type strain. Upstream of ethABCD lies ethR, which codes for a putative positive transcriptional regulator of the AraC/XylS family. Transformation of the ETBE-negative mutant by a plasmid carrying the ethRABCD genes restored the ability to degrade ETBE. Complementation was abolished if the plasmid carried ethRABC only. The eth genes are located in a DNA fragment flanked by two identical direct repeats of 5.6 kbp. The ETBE-negative mutants carry a single copy of this 5.6-kbp repeat, suggesting that the 14.3-kbp chromosomal deletion resulted from a recombination between the two identical sequences. The 5.6-kbp repeat is a class II transposon carrying a TnpA transposase, a truncated form of the recombinase TnpR, and a terminal inverted repeat of 38 bp. The truncated TnpR is encoded by an IS3-interrupted tnpR gene.


Predictors of completed suicide in a cohort of 50,465 young men: role of personality and deviant behaviour.
Suicide seems to be increasing in young people in various countries and causes the greatest loss of years of life under the age of 65 in the Swedish population. Data from a national survey of 50,465 conscripts in Sweden were used in a prospective follow up study to assess personality and behavioural predictors of suicide in young men. Altogether 247 completed suicides occurred in the cohort during 13 years' follow up. Baseline data on social conditions, psychological assessments, and psychiatric diagnoses of the conscripts were entered into a Cox regression model with suicide as the outcome variable. Several early indicators of antisocial personality (poor emotional control, contact with a child welfare authority or the police, and lack of friends) were strongly predictive of suicide. None of the few conscripts who had a diagnosis of schizophrenia or affective psychosis committed suicide. A diagnosis of neurosis was associated with a twofold increase in the suicide rate and personality disorder with a threefold increase. Although the risk of suicide is difficult to assess in an unselected population owing to the low base rate of suicide, the predictors identified in the study may help to identify those at high risk in units where people with deviant behaviour and personality disorders cluster.


Armed and prohibited: characteristics of unlawful owners of legally purchased firearms.
A substantial proportion of individuals who lawfully purchase firearms later become unlawful owners ('prohibited firearm owners'), usually following events associated with an increased risk for future violence. This high-risk population has not previously been described. We aimed to characterise all individuals in California's Armed and Prohibited Persons System (APPS), a statewide programme for recovering firearms from individuals who legally purchased them and later became prohibited from ownership. We used univariate and bivariate statistics to describe and compare prohibited firearm owners in APPS with a random sample of non-prohibited firearm owners in relation to age, sex, race/ethnicity and type of firearms owned as of 1 February 2015. We also characterised the geographical distribution of prohibited firearm owners and described their prohibitions. Of the 18 976 prohibited firearm owners, most were men (93%), half were white (53%) and the mean age was 47 years. Prohibited firearm owners were more likely to be male and to be black or Hispanic people than non-prohibited owners. Both prohibited and non-prohibited firearm owners had an average of 2.6 firearms, mostly handguns. Nearly half (48%) of prohibited firearm owners had a felony conviction. Extrapolating from our findings, we estimated that there are approximately 100 000 persons in the USA who unlawfully maintained ownership of their firearms following a felony conviction. Retention of firearms among persons who become lawfully prohibited from possessing them is common in California. Given the nationwide dearth of a programme to recover such weapons, this is likely true in other states as well.


Use of a new cross-linked collagen membrane for the treatment of peri-implant dehiscence defects: a randomised controlled double-blinded clinical trial.
The aim of this randomised controlled double-blinded clinical trial was to determine the efficacy of a new cross-linked membrane (VN) in guided bone regeneration (GBR) around exposed dental implants compared to a native collagen membrane (BG). A total of 16 patients in need of implant treatment at two different sites with osseous defects were planned for this split-mouth study. After inserting the dental implants, peri-implant defects were treated according to the GBR technique using a VN membrane with prolonged resorption time in the randomised test site and a BG membrane in the control site. After a healing time of 6 months, mucoperiosteal flaps were elevated for the evaluation of the primary (vertical bone fill [ΔDL] and quality of newly formed tissue [QT]) and secondary outcome variables (infrabony defect height [DH], defect width [DW], defect depth [DD] and augmentation depth [AD]) and the sampling of biopsies apical to the implant shoulder. A total of 16 patients fulfilled the initial non-surgical inclusion and exclusion criteria. However, the study was discontinued early after 9 surgically treated patients because unacceptable safety issues arose and severe infection related to the VN membranes. The VN membrane revealed statistically significantly more soft tissue dehiscence than the BG membrane (56% and 11%, respectively, P = 0.0455). In 3 of these 9 patients the VN membrane had to be removed due to infection early after the first follow-up visit. For the statistical analyses these sites were designated as the value of the baseline. The mean ΔDL values were 1.8 ± 1.6 mm at the VN site and 4.7 ± 3.3 mm at the BG site. The ΔDD values were 0.6 ± 1.0 mm and 1.1 ± 1.2 mm, respectively, and reached statistical significance (P = 0.0208, CI 95% = -2.9 [-5.2;-0.6]). The corresponding linear defect fill (DF) values were 44% and 78%, respectively. The clinical assessment of QT showed comparable median values at sites treated with VN (3, interquartile range: 0; 3.5) and BG (3, interquartile range: 3; 4) without statistical significance. The histomorphometric analysis showed an average area density of 24.4% (SD 10.3, range 8-35%) newly formed bone at the test sites and of 35.0% (SD 20.6, range 8-60%) at the control sites. The histological data showed only some trends and did not reach statistical significance. In the present study, the VN membranes with prolonged resorption time demonstrated significantly more adverse events and insufficient bone regeneration compared to the native BG membranes and no advantages in favour of the VN membranes were detectable.