Protein native-state stabilization by placing aromatic side chains in N-glycosylated reverse turns.
N-glycosylation of eukaryotic proteins helps them fold and traverse the cellular secretory pathway and can increase their stability, although the molecular basis for stabilization is poorly understood. Glycosylation of proteins at naïve sites (ones that normally are not glycosylated) could be useful for therapeutic and research applications but currently results in unpredictable changes to protein stability. We show that placing a phenylalanine residue two or three positions before a glycosylated asparagine in distinct reverse turns facilitates stabilizing interactions between the aromatic side chain and the first N-acetylglucosamine of the glycan. Glycosylating this portable structural module, an enhanced aromatic sequon, in three different proteins stabilizes their native states by -0.7 to -2.0 kilocalories per mole and increases cellular glycosylation efficiency.


Estimation efficiency and statistical power in arterial spin labeling fMRI.
Arterial spin labeling (ASL) data are typically differenced, sometimes after interpolation, as part of preprocessing before statistical analysis in fMRI. While this process can reduce the number of time points by half, it simplifies the subsequent signal and noise models (i.e., smoothed box-car predictors and white noise). In this paper, we argue that ASL data are best viewed in the same data analytic framework as BOLD fMRI data, in that all scans are modeled and colored noise is accommodated. The data are not differenced, but the control/label effect is implicitly built into the model. While the models using differenced data may seem easier to implement, we show that differencing models fit with ordinary least squares either produce biased estimates of the standard errors or suffer from a loss in efficiency. The main disadvantage to our approach is that non-white noise must be modeled in order to yield accurate standard errors, however, this is a standard problem that has been solved for BOLD data, and the very same software can be used to account for such autocorrelated noise.


Bcl9/Bcl9l are critical for Wnt-mediated regulation of stem cell traits in colon epithelium and adenocarcinomas.
Canonical Wnt signaling plays a critical role in stem cell maintenance in epithelial homeostasis and carcinogenesis. Here, we show that in the mouse this role is critically mediated by Bcl9/Bcl9l, the mammalian homologues of Legless, which in Drosophila is required for Armadillo/beta-catenin signaling. Conditional ablation of Bcl9/Bcl9l in the intestinal epithelium, where the essential role of Wnt signaling in epithelial homeostasis and stem cell maintenance is well documented, resulted in decreased expression of intestinal stem cell markers and impaired regeneration of ulcerated colon epithelium. Adenocarcinomas with aberrant Wnt signaling arose with similar incidence in wild-type and mutant mice. However, transcriptional profiles were vastly different: Whereas wild-type tumors displayed characteristics of epithelial-mesenchymal transition (EMT) and stem cell-like properties, these properties were largely abrogated in mutant tumors. These findings reveal an essential role for Bcl9/Bcl9l in regulating a subset of Wnt target genes involved in controlling EMT and stem cell-related features and suggest that targeting the Bcl9/Bcl9l arm of Wnt signaling in Wnt-activated cancers might attenuate these traits, which are associated with tumor invasion, metastasis, and resistance to therapy.


Metallo-regulation of the bimolecular triplex formation of a peptide nucleic acid.
Peptide nucleic acid (PNA) conjugates incorporating a bipyridine unit were prepared. The bipyridine was built into the loop moiety of PNAs that were designed to specifically form a hairpin and a PNA/DNA bimolecular triplex. While the thermal stability of the hairpin structure was only minimally affected by Cu(2+) addition, the PNA/DNA bimolecular triplex structure was significantly destabilized by complexation with Cu(2+). The melting temperature of the bimolecular triplex decreased by 17.4 °C in the presence of Cu(2+). This corresponds to more than a 1000 fold decrease in the binding constant for bimolecular triplex formation. Upon complexation, the bipyridine unit underwent a drastic conformational change which accounts for the observed differences in the thermal stabilities of the triplex upon binding. The bipyridine-PNA conjugate may be useful as an allosteric DNA carrier that releases the DNA in response to a certain metal ion concentration.


Effect of osteoarthritis on the repeatability of patella tendon angle measurement in dogs.
To evaluate the influence of osteoarthritis on the measurement of patella tendon angle (PTA) and determine intraobserver and interobserver variability. Retrospective clinical study. Eighty-seven mediolateral radiographs that were obtained prior to tibial tuberosity advancement. Radiographic osteoarthritis was scored by 2 observers using guidelines derived from the International Elbow Working Group Protocol. Patella tendon angle was measured by 3 observers on 3 occasions, with at least 7 days between measurements. The data were statistically analyzed via weighted κ and Kruskal-Wallis testing. A fair strength of agreement was found among observers scoring osteoarthritis, with the same grades in 48% of radiographs. The intraobserver average bias between PTA measurements 1 and 3 ranged from -0.38° to -0.94°. Interobserver bias in angle measurement ranged from -0.92° to -2.00°. Observer 1 had the narrowest range of PTA differences (12.1°), and observer 3 had the highest range of PTA differences (23.5°). Observer 2 had the lowest mean bias (-0.38°). The mean bias was lowest between observers 1 and 2 (-0.92°) and highest between observers 1 and 3 (-2.0°). The mean intraobserver standard deviation of the PTA measurement differences was 2.90°, and interobserver standard deviation of the PTA measurement differences was 2.26°. The degree of osteoarthritis did not influence PTA measurements or their variability. The current study did not find evidence of an influence of osteoarthritis on PTA or on the repeatability of measurements. Our findings suggest that osteoarthritis should not affect the radiographic planning for tibial tuberosity advancement surgery. The high variances in PTA measurement in less experienced observers may influence the clinical outcome of surgery.


[Efficacy of virtual reality on balance and gait in multiple sclerosis. Systematic review of randomized controlled trials].
Multiple sclerosis (MS) is a neurodegenerative disease that causes gait abnormalities and a deficit in balance control in the vast majority of people affected by it. Virtual reality has been proposed as a complementary approach to conventional physiotherapeutic treatment as a way of improving these variables. To assess the real efficacy of this approach compared to other neurorehabilitation therapies, or no intervention, in MS. A systematic review of randomized controlled trials was conducted. Studies of the last five years that compare virtual reality with conventional treatment or no intervention, on balance and/or gait, in adults with MS, were included. PEDro scale was used to assess methodological quality and the Oxford scale to determine the level of evidence and grades of recommendations. Eight studies met the eligibility criteria. For balance, the efficacy of virtual reality is, at least, comparable as conventional training. For gait, virtual reality seems not to be superior in improving the speed, compared with the other types of interventions assessed. Methodological quality of studies was low-moderate. Virtual reality is as effective as conventional training for improving balance in people with MS. No data suggests that virtual reality is superior to other interventions in improving gait speed. For other gait parameters, virtual reality's efficacy remains unknown.


A pore residue of the KCNQ3 potassium M-channel subunit controls surface expression.
KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3) are the principal subunits underlying the potassium M-current, which exerts a strong control on neuronal excitability. KCNQ3 subunits coassemble with KCNQ2 to form functional heteromeric channels that are specifically transported to the axonal initial segment and nodes of Ranvier. In contrast, there is no evidence for functional homomeric KCNQ3 channels in neurons, and it appears that these are inefficiently trafficked to the plasma membrane. Among eukaryotic potassium channels, the KCNQ3 subunit is unusual because it has an alanine in place of a threonine at the pore inner vestibule, three residues upstream of the GYG signature sequence of the selectivity filter. This residue is critical for the potentiation of the current after heteromerization, but the mechanism is unknown. We report that the presence of this uncommon residue at position 315 has a strong impact on the stability of the homotetramers and on channel trafficking. Wild-type KCNQ3 expressed alone is retained within the endoplasmic reticulum, and this mechanism is overcome by the substitution of threonine for Ala315. KCNQ3 subunits require assembly with KCNQ2 to exit this compartment, whereas KCNQ3-A315T is no longer dependent on KCNQ2 to form channels that are efficiently trafficked to the plasma membrane. The presence of this alanine, therefore, plays an important role in regulating the subunit composition of functional M-channels expressed at the surface of neurons.


Compositional heterogeneity in the bottom 1000 kilometers of Earth's mantle: toward a hybrid convection model
Tomographic imaging indicates that slabs of subducted lithosphere can sink deep into Earth's lower mantle. The view that convective flow is stratified at 660-kilometer depth and preserves a relatively pristine lower mantle is therefore not tenable. However, a range of geophysical evidence indicates that compositionally distinct, hence convectively isolated, mantle domains may exist in the bottom 1000 kilometers of the mantle. Survival of these domains, which are perhaps related to local iron enrichment and silicate-to-oxide transformations, implies that mantle convection is more complex than envisaged by conventional end-member flow models.


Approximate Boolean Operations on Large Polyhedral Solids with Partial Mesh Reconstruction.
We present a new approach to compute the approximate Boolean operations of two freeform polygonal mesh solids efficiently with the help of Layered Depth Images (LDIs). After applying the LDI sampling-based membership classification, the most challenging part, a trimmed adaptive contouring algorithm, is developed to reconstruct the mesh surface from the LDI samples near the intersected regions and stitch it to the boundary of the retained surfaces. Our method of approximate Boolean operations holds the advantage of numerical robustness as the approach uses volumetric representation. However, unlike other methods based on volumetric representation, we do not damage the facets in nonintersected regions, thus preserving geometric details much better and speeding up the computation as well. We show that the proposed method can successfully compute the Boolean operations of free-form solids with a massive number of polygons in a few seconds.


Codon-optimized glucoamylase sGAI of Aspergillus awamori improves starch utilization in an industrial yeast.
The development of a yeast that converts raw starch to ethanol in one step (called consolidated bioprocessing) could yield large cost reductions in the bioethanol industry. The aim of this study was to develop an efficient amylolytic Saccharomyces cerevisiae strain suitable for industrial bioethanol production. A native and codon-optimized variant of the Aspergillus awamori glucoamylase gene were expressed in the S. cerevisiae Y294 laboratory strain. Codon optimization resulted to be effective and the synthetic sequence sGAI was then δ-integrated into a S. cerevisiae strain with promising industrial fermentative traits. The mitotically stable recombinant strains showed high enzymatic capabilities both on soluble and raw starch (2425 and 1140 nkat/g dry cell weight, respectively). On raw corn starch, the engineered yeasts exhibited improved fermentative performance with an ethanol yield of 0.42 (g/g), corresponding to 75 % of the theoretical maximum yield.


A COVID-19 Pandemic Artificial Intelligence-Based System With Deep Learning Forecasting and Automatic Statistical Data Acquisition: Development and Implementation Study.
More than 79.2 million confirmed COVID-19 cases and 1.7 million deaths were caused by SARS-CoV-2; the disease was named COVID-19 by the World Health Organization. Control of the COVID-19 epidemic has become a crucial issue around the globe, but there are limited studies that investigate the global trend of the COVID-19 pandemic together with each country's policy measures. We aimed to develop an online artificial intelligence (AI) system to analyze the dynamic trend of the COVID-19 pandemic, facilitate forecasting and predictive modeling, and produce a heat map visualization of policy measures in 171 countries. The COVID-19 Pandemic AI System (CPAIS) integrated two data sets: the data set from the Oxford COVID-19 Government Response Tracker from the Blavatnik School of Government, which is maintained by the University of Oxford, and the data set from the COVID-19 Data Repository, which was established by the Johns Hopkins University Center for Systems Science and Engineering. This study utilized four statistical and deep learning techniques for forecasting: autoregressive integrated moving average (ARIMA), feedforward neural network (FNN), multilayer perceptron (MLP) neural network, and long short-term memory (LSTM). With regard to 1-year records (ie, whole time series data), records from the last 14 days served as the validation set to evaluate the performance of the forecast, whereas earlier records served as the training set. A total of 171 countries that featured in both databases were included in the online system. The CPAIS was developed to explore variations, trends, and forecasts related to the COVID-19 pandemic across several counties. For instance, the number of confirmed monthly cases in the United States reached a local peak in July 2020 and another peak of 6,368,591 in December 2020. A dynamic heat map with policy measures depicts changes in COVID-19 measures for each country. A total of 19 measures were embedded within the three sections presented on the website, and only 4 of the 19 measures were continuous measures related to financial support or investment. Deep learning models were used to enable COVID-19 forecasting; the performances of ARIMA, FNN, and the MLP neural network were not stable because their forecast accuracy was only better than LSTM for a few countries. LSTM demonstrated the best forecast accuracy for Canada, as the root mean square error (RMSE), mean absolute error (MAE), and mean absolute percentage error (MAPE) were 2272.551, 1501.248, and 0.2723075, respectively. ARIMA (RMSE=317.53169; MAPE=0.4641688) and FNN (RMSE=181.29894; MAPE=0.2708482) demonstrated better performance for South Korea. The CPAIS collects and summarizes information about the COVID-19 pandemic and offers data visualization and deep learning-based prediction. It might be a useful reference for predicting a serious outbreak or epidemic. Moreover, the system undergoes daily updates and includes the latest information on vaccination, which may change the dynamics of the pandemic.


The evolutionary dynamics of functional modules and the extraordinary plasticity of regulons: the Escherichia coli perspective.
Using profiles of phylogenetic profiles (P-cubic) we compared the evolutionary dynamics of different kinds of functional associations. Ordered from most to least evolutionarily stable, these associations were genes in the same operons, genes whose products participate in the same biochemical pathway, genes coding for physically interacting proteins and genes in the same regulons. Regulons showed the most plastic functional interactions with evolutionary stabilities barely better than those of unrelated genes. Further regulon analyses showed that global regulators contain less evolutionarily stable associations than local regulators. Genes co-repressed by global regulators had a higher evolutionary conservation than genes co-activated by global regulators. However, the reverse was true for genes co-repressed and co-activated by local regulators. Of all the regulon-related associations, the relationship between regulators and their target genes showed the most evolutionary stability. Different negative data sets built to contrast against each of the analysed kinds of modules also differed in evolutionary conservation revealing further underlying genome organization. Applying P-cubic analyses to other genomes might help visualize genome organization, understand the evolutionary importance and plasticity of functional associations and compare the quality of data sets expected to reflect functional interactions, such as those coming from high-throughput experiments.


Contralateral Eyebrow Approach for Unilateral Suprasellar Meningioma.
Unilateral suprasellar meningiomas have distinct features compared to other midline tumors, as they may produce severe visual symptoms even if small due to an early involvement of the optic canal. Surgical treatment of these tumors from an ipsilateral approach is challenging, as the tumor is covered by the optic nerve that needs to be mobilized to access the optic canal extension. A contralateral approach allows a direct line of sight to the tumor despite a longer working distance. We report the case of a 49-year-old patient presenting with unilateral visual loss related to a left suprasellar meningioma extending to the left optic canal and displacing the optic nerve laterally. Through a right eyebrow approach, a 2.5/2 cm supraorbital bone flap was raised and the orbital floor was thoroughly flattened. After dural opening, the carotid cistern was opened and CSF evacuated allowing a surgery without fixed retractors. The intracranial part of the tumor was removed, but the optic nerve seemed to be still displaced by the intracanalicular part. Under copious irrigation, the medial part of the optic canal was drilled, the dura incised, and the tumor removed. Postoperative course was favorable and the patient made a complete visual recovery. Postoperative MRI showed complete removal of the tumor. We present different surgical steps and discuss the nuances of the procedure. The contralateral eyebrow approach is an interesting addition to the surgical armamentarium and should be discussed for unilateral suprasellar tumors. The link to the video can be found at: https://youtu.be/2LTEOaGoKzo .


The role of coalitions in drug policy. Some theoretical and observational considerations.
Democratically organised societies have to find ways how to proceed when in need of a reformulation of strategies in face of new societal and technological developments, especially in dealing with controversial preferences and interests. The area of drug policy change presents an excellent example for discussing the problem and the process of coalition building for finding acceptable answers to new challenges. Modern sociological theory has developed concepts and tools for a description and analysis of such processes. Some concrete case studies from Swiss cities are available as a basis for advanced discussion of theoretical concepts. The observational description of the coalition building in the city of Zurich helps to illustrate the inherent elements, problems and outcomes; a more detailed process analysis focuses on the initial phases and further development of the various formal and informal coalitions, introducing the importance of shared objectives for action and the need for concerted activities. A clear policy concept and a consistent action plan were not available at first, but they proved to be an important step in the consolidation of what was a non-systematic beginning. What started at local level and led to a new national policy was not so much a continued clash between two ideologies - harm reduction versus strict prohibition -, but was the beginning of a new thinking about how the various policy elements could successfully work together in the pursuit of a shared concrete objective. These observations may be considered in further theory development and policy considerations.


Influence of Complications and Revision Surgery on Fulfillment of Expectations in Foot and Ankle Surgery.
Fulfillment of patients' expectations following foot and ankle surgery has been previously studied, and shown to be an effective modality in assessing patient-reported outcomes (PROs). Although this assessment has been shown to correlate well with patient satisfaction and other validated PROs, the impact of postoperative complications on fulfillment of expectations is unknown. The aim of this study is to therefore investigate the impact of postoperative complications on fulfillment of patients' expectations. Preoperatively, patients completed a validated Foot and Ankle Expectations Survey consisting of 23 questions encompassing domains including pain, ambulation, daily function, exercise, and shoe wear. At 2 years postoperatively, patients answered how much improvement they received for each item cited preoperatively. A fulfillment proportion (FP) was calculated as the amount of improvement received versus the amount of improvement expected. Chart review was performed to identify patient demographics, comorbidities, pain management, and postoperative complications, which were classified as minor (infection requiring antibiotics) or major (return to operating room for revision, deep infection). FP in patients with a complication was compared to patients who did not experience a complication. In addition, the Foot and Ankle Outcomes Score (FAOS), satisfaction, and Delighted-Terrible scale (how they would feel if asked to spend the rest of their life with their current foot/ankle symptom) were collected at final follow-up. Of the 271 patients (mean age 55.4 years, 65% female), 31 (11.4%, mean age 53.6, 58% female) had a postoperative complication: 25 major (19 revisions, 6 deep infections requiring irrigation and debridement), 4 minor (4 superficial infections requiring antibiotics), and 2 major and minor (revision and superficial infection). Average time from complication to completion of fulfillment survey was 15 (±3.6) months. The groups were similar in diagnoses. Complications were associated with significantly worse FP (0.69 ± 0.45 vs 0.86 ± 0.40, P = .02). Having a complication significantly correlated with worse satisfaction, Delighted-Terrible scale, and FP (P < .001). FAOS domains were similar between groups preoperatively; postoperatively, patients without complications had significantly higher Activities of Daily Living and Quality of Life scores (P < .05). Demographically, there was no difference in age, sex, body mass index, Charlson Comorbidity Index, depression/anxiety, or pain management between the 2 groups. Our data suggests that postoperative complications following foot and ankle surgery were associated with worse patient-reported fulfillment of their operative expectations even after recovery from the initial surgery and complication. This finding is independent of preoperative expectations, and correlates with patient satisfaction with their procedure. Therefore, while patient-perceived fulfillment following foot and ankle surgery is multifactorial, the incidence of a postoperative complication negatively impacts fulfillment as well as satisfaction following surgery. Level II, prospective comparative series.


Predictors of suicide and suicide attempt in subway stations: a population-based ecological study.
Suicidal behavior on the subway often involves young people and has a considerable impact on public life, but little is known about factors associated with suicides and suicide attempts in specific subway stations. Between 1979 and 2009, 185 suicides and 107 suicide attempts occurred on the subway in Vienna, Austria. Station-specific suicide and suicide attempt rates (defined as the frequency of suicidal incidents per time period) were modeled as the outcome variables in bivariate and multivariate Poisson regression models. Structural station characteristics (presence of a surveillance unit, train types used, and construction on street level versus other construction), contextual station characteristics (neighborhood to historical sites, size of the catchment area, and in operation during time period of extensive media reporting on subway suicides), and passenger-based characteristics (number of passengers getting on the trains per day, use as meeting point by drug users, and socioeconomic status of the population in the catchment area) were used as the explanatory variables. In the multivariate analyses, subway suicides increased when stations were served by the faster train type. Subway suicide attempts increased with the daily number of passengers getting on the trains and with the stations' use as meeting points by drug users. The findings indicate that there are some differences between subway suicides and suicide attempts. Completed suicides seem to vary most with train type used. Suicide attempts seem to depend mostly on passenger-based characteristics, specifically on the station's crowdedness and on its use as meeting point by drug users. Suicide-preventive interventions should concentrate on crowded stations and on stations frequented by risk groups.


Nonadiabatic dynamics simulation of keto isocytosine: a comparison of dynamical performance of different electronic-structure methods.
The nonadiabatic dynamics of keto isocytosine in the gas phase has been investigated using the on-the-fly trajectory surface hopping method based on two electronic-structure methods: SA-CASSCF and ADC(2). The results estimate an excited-state lifetime of around 1000 fs at the SA-CASSCF level, while a much shorter lifetime of 250-350 fs is obtained at the ADC(2) level. Although three conical intersections (CIs) (Ethyl. I, Ethyl. II and C[double bond, length as m-dash]O stretching) are relevant to the nonadiabatic decay of keto isocytosine, their contributions to the nonadiabatic decay are highly dependent on the electronic-structure methods employed in the dynamics simulation. The Ethyl. II CI is the main channel in the dynamics simulations at the SA-CASSCF level, while the C[double bond, length as m-dash]O stretching CI becomes dominant at the ADC(2) levels. Other high-level electronic-structure methods (MR-CISD and MS-CASPT2) are involved to benchmark our dynamics results. Through the analysis of the reaction pathways from the ground state minimum to the relevant CIs, we expect that the excited-state dynamical features obtained at the MR-CISD and MS-CASPT2 levels should be very similar to those at the SA-CASSCF level. The comparison of results obtained using different excited-state electronic-structure methods could provide guidance for further studies of similar systems.


TRPV1 and TRPA1 antagonists prevent the transition of acute to chronic inflammation and pain in chronic pancreatitis.
Visceral afferents expressing transient receptor potential (TRP) channels TRPV1 and TRPA1 are thought to be required for neurogenic inflammation and development of inflammatory hyperalgesia. Using a mouse model of chronic pancreatitis (CP) produced by repeated episodes (twice weekly) of caerulein-induced AP (AP), we studied the involvement of these TRP channels in pancreatic inflammation and pain-related behaviors. Antagonists of the two TRP channels were administered at different times to block the neurogenic component of AP. Six bouts of AP (over 3 wks) increased pancreatic inflammation and pain-related behaviors, produced fibrosis and sprouting of pancreatic nerve fibers, and increased TRPV1 and TRPA1 gene transcripts and a nociceptive marker, pERK, in pancreas afferent somata. Treatment with TRP antagonists, when initiated before week 3, decreased pancreatic inflammation and pain-related behaviors and also blocked the development of histopathological changes in the pancreas and upregulation of TRPV1, TRPA1, and pERK in pancreatic afferents. Continued treatment with TRP antagonists blocked the development of CP and pain behaviors even when mice were challenged with seven more weeks of twice weekly caerulein. When started after week 3, however, treatment with TRP antagonists was ineffective in blocking the transition from AP to CP and the emergence of pain behaviors. These results suggest: (1) an important role for neurogenic inflammation in pancreatitis and pain-related behaviors, (2) that there is a transition from AP to CP, after which TRP channel antagonism is ineffective, and thus (3) that early intervention with TRP channel antagonists may attenuate the transition to and development of CP effectively.


Improved survival with neoadjuvant therapy and resection for adenocarcinoma of the esophagus.
This study sought to determine the impact of preoperative chemotherapy and radiation therapy (neoadjuvant therapy) followed by resection in patients with adenocarcinoma of the esophagus. Long-term survival in patients with carcinoma of the esophagus has been poor. An increase in the incidence of adenocarcinoma of the esophagus has been reported recently. Fifty-eight patients with biopsy-proven adenocarcinoma of the esophagus treated at this institution from January 1951 through February 1993 were studied. Since 1989, 24 patients were entered prospectively into a multimodality treatment protocol consisting of preoperative cisplatin, 5-fluorouracil (5-FU), and leucovorin with or without etoposide, and concomitant mediastinal radiation (30 Gy). Patients were re-evaluated and offered resection. There were no deaths related to neoadjuvant therapy and toxicity was minimal. Before multimodality therapy was used, the operative mortality rate was 19% (3 of 16 patients). With multimodality therapy, there have been no operative deaths (0 of 23 patients). The median survival time in patients treated before multimodality therapy was 8 months and has yet to be reached for those treated with the neoadjuvant regimen (> 26 months, p < 0.0001). The actuarial survival rate at 24 months was 15% before multimodality therapy and 76% with multimodality therapy. No difference in survival was noted in neoadjuvant protocols with or without etoposide (p = 0.827). Multimodality therapy with preoperative chemotherapy and radiation therapy followed by resection appears to offer a survival advantage to patients with adenocarcinoma of the esophagus.


Role of Education in HIV Clinical Outcomes in a Tuberculosis Endemic Setting.
This study evaluated how educational attainment impacts clinical outcomes of HIV-positive patients in Durban, South Africa. The authors conducted a prospective study of 466 adult HIV-positive patients initiating antiretroviral therapy (ART) at an urban TB-HIV clinic from October 2004 to June 2007. The level of educational attainment (highest grade completed) was assessed at ART initiation. The authors measured tuberculosis treatment outcomes as well as death, lost to follow-up, viral suppression (HIV RNA <400 copies/mL), and immunologic response (CD4 ≥200 cells/mm(3)) at 6, 12, and 24 months after ART initiation. After 24 months of ART initiation, there were 43 deaths; viral suppression and immunologic response were observed in 88% and 83% of the remaining patients, respectively. The authors found no association between level of educational attainment and mortality (P = .12), loss to follow-up (P = .85), virologic response (P = .51), or immunologic response (P = .63). Similar findings were observed at 6 and 12 months post-ART initiation.


How might health services capture patient-reported safety concerns in a hospital setting? An exploratory pilot study of three mechanisms.
Emergent evidence suggests that patients can identify and report safety issues while in hospital. However, little is known about the best method for collecting information from patients about safety concerns. This study presents an exploratory pilot of three mechanisms for collecting data on safety concerns from patients during their hospital stay. Three mechanisms for capturing safety concerns were coproduced with healthcare professionals and patients, before being tested in an exploratory trial using cluster randomisation at the ward level. Nine wards participated, with each mechanism being tested over a 3-month study period. Patients were asked to feed back safety concerns via the mechanism on their ward (interviewing at their bedside, paper-based form or patient safety 'hotline'). Safety concerns were subjected to a two-stage review process to identify those that would meet the definition of a patient safety incident. Differences between mechanisms on a range of outcomes were analysed using inferential statistics. Safety concerns were thematically analysed to develop reporting categories. 178 patients were recruited. Patients in the face-to-face interviewing condition provided significantly more safety concerns per patient (1.91) compared with the paper-based form (0.92) and the patient safety hotline (0.43). They were also significantly more likely to report one or more concerns, with 64% reporting via the face-to-face mechanism, compared with 41% via the paper-based form and 19% via the patient safety hotline. No mechanism differed significantly in the number of classified patient safety incidents or physician-rated preventability and severity. Interviewing at the patient's bedside is likely to be the most effective means of gathering safety concerns from inpatients, potentially providing an opportunity for health services to gather patient feedback about safety from their perspective.


Antiplatelet agents and anticoagulants increased the bleeding risk of bedside percutaneous dilational tracheostomy in critically ill patients.
The main objective of this study was to investigate the safety of bedside percutaneous dilational tracheostomy (PDT) by pulmonologists in critically ill patients, and the factors associated with complications resulting from PDT. We retrospectively enrolled critically ill patients who had undergone bedside PDT in the intensive care units (ICUs) and respiratory care center from February 2016 to December 2018. A total of 312 patients were included for analysis, with a mean age of 69.6 ± 17.7 years. Two hundred and eight of the patients were male (66.7%). The mean acute physiology and chronic health evaluation II score was 25.3 ± 6.3, and the mean body mass index was 22.4 ± 4.2. Most of the patients were intubated due to respiratory disorders (51.3%). Fifty-six patients (17.9%) received antiplatelet agents or an anticoagulant regularly prior to PDT. All enrolled patients were undergone bedside PDT successfully. The total complication rate of PDT was 14.4%. Patients who took antiplatelet agents or anticoagulants regularly before PDT had a higher risk of bleeding than patients who went without (26.8% versus 7.0%, adjusted odds ratio 4.93 [95% f 2.16-11.25], p < 0.001). Finally, a longer length of intubation resulted in a higher probability in the length of ICU stay being ≧28 days (adjusted odds ratio 1.11 [95% CI 1.08-1.14], p < 0.001). Our study demonstrated that it was feasible for pulmonologists to perform bedside PDT in critically ill patients. However, antiplatelet agents and anticoagulants use increased the risk of bleeding in PDT patients.


Genome privacy: challenges, technical approaches to mitigate risk, and ethical considerations in the United States.
Accessing and integrating human genomic data with phenotypes are important for biomedical research. Making genomic data accessible for research purposes, however, must be handled carefully to avoid leakage of sensitive individual information to unauthorized parties and improper use of data. In this article, we focus on data sharing within the scope of data accessibility for research. Current common practices to gain biomedical data access are strictly rule based, without a clear and quantitative measurement of the risk of privacy breaches. In addition, several types of studies require privacy-preserving linkage of genotype and phenotype information across different locations (e.g., genotypes stored in a sequencing facility and phenotypes stored in an electronic health record) to accelerate discoveries. The computer science community has developed a spectrum of techniques for data privacy and confidentiality protection, many of which have yet to be tested on real-world problems. In this article, we discuss clinical, technical, and ethical aspects of genome data privacy and confidentiality in the United States, as well as potential solutions for privacy-preserving genotype-phenotype linkage in biomedical research.


Development of a spectroscopic technique for continuous online monitoring of oxygen and site-specific nitrogen isotopic composition of atmospheric nitrous oxide.
Nitrous oxide is an important greenhouse gas and ozone-depleting-substance. Its sources are diffuse and poorly characterized, complicating efforts to understand anthropogenic impacts and develop mitigation policies. Online, spectroscopic analysis of N2O isotopic composition can provide continuous measurements at high time resolution, giving new insight into N2O sources, sinks, and chemistry. We present a new preconcentration unit, "Stheno II", coupled to a tunable infrared laser direct absorption spectroscopy (TILDAS) instrument, to measure ambient-level variations in (18)O and site-specific (15)N N2O isotopic composition at remote sites with a temporal resolution of <1 h. Trapping of N2O is quantitative up to a sample size of ∼4 L, with an optimal sample size of 1200-1800 mL at a sampling frequency of 28 min. Line shape variations with the partial pressure of the major matrix gases N2/O2 and CO2 are measured, and show that characterization of both pressure broadening and Dicke narrowing is necessary for an optimal spectral fit. Partial pressure variations of CO2 and bath gas result in a linear isotopic measurement offset of 2.6-6.0 ‰ mbar(-1). Comparison of IR MS and TILDAS measurements shows that the TILDAS technique is accurate and precise, and less susceptible to interferences than IR MS measurements. Two weeks of measurements of N2O isotopic composition from Cambridge, MA, in May 2013 are presented. The measurements show significant short-term variability in N2O isotopic composition larger than the measurement precision, in response to meteorological parameters such as atmospheric pressure and temperature.


Disposition of [Ring-U-(14)C]styrene in rats and mice exposed by recirculating nose-only inhalation.
The disposition of styrene was studied in a group of 12 Sprague Dawley rats and two groups of 30 CD1 mice exposed separately to 160 ppm [ring-U-(14)C]styrene of high specific radioactivity of 1.92 TBq x mol(-1) (52 Ci x mol(-1)) for 6 h. A nose-only exposure system was successfully adapted to (1) recirculate a portion of the flow to limit the amount of (14)C-styrene required, and (2) avoid any polymerization of the compound. The mean uptake of styrene in rats was 113 +/- 7 micromol x kg(-1) x h(-1) and stable over time. The mean uptake in mice was higher, 189 +/- 53 and 183 +/- 76 micromol x kg(-1) x h(-1), for the first and second mouse inhalation experiment, but decreased steadily over time. Some of the mice, but none of the rats, showed signs of overt toxicity. The overall excretion of styrene and its metabolites was quantitatively similar in rats and mice. Urinary excretion was the primary route of excretion while fecal excretion accounted for only a very small part of the radioactivity. There was, however, a significant difference between mice and rats in the exhalation of (14)CO(2), which must have resulted from opening and subsequent breakdown of the aromatic ring. In mice the exhalation of (14)CO(2) accounted for 6.4 +/- 1.0 and 8. 0 +/- 0.5% of the styrene retained during the first and second mouse inhalation experiment. In rats, exhalation of (14)CO(2) accounted for only 2.0 +/- 0.7% of the retained styrene. Together with the results from the quantitative whole-body autoradiography (showing significantly higher binding in mouse lung and nasal passages compared to rat) the larger production of (14)CO(2) might be indicative of the formation of reactive ring-opened metabolites in the mouse lung, which, in turn, might be related to the observed development of bronchioalveolar tumors and nasal effects in mice exposed to styrene.


Influence of seasoning on vegetable selection, liking and intent to purchase.
Low vegetable intake continues to be a health concern, and strategies to increase vegetable intake have resulted in only small increases. One strategy that has received less attention is the use of seasonings. This study's objective was to determine the impact of seasoning on vegetable selection, liking, and intent to purchase. We conducted a 3-week study in a public café on a university campus. Customers buying a main dish could select a vegetable side (seasoned [SS] or steamed [ST]) at no cost. Based on café data and power analysis (alpha 0.05, 80% power), 2 days per vegetable pair were conducted with carrot, broccoli, and green bean pairs randomized 3 days/week 1 and 3, with normal service week 2. Selection was greater for SS vs ST, n = 335 vs. 143 for all 3 vegetables combined; n = 97 vs 47 for carrots; n = 114 vs. 55 for broccoli; n = 124 vs. 41 for green beans (p < 0.001 Chi-Square). Liking responses were similar for SS vs ST and were high for all vegetables. Response distribution was not significantly different for SS vs ST vegetables when people were asked if they would purchase the vegetable that they selected. More customers chose the 'somewhat likely' and 'very likely' (n = 353) than the 'not likely' and 'definitely would not' (n = 121) purchase responses. Regression showed that people who did not often consume a vegetable with lunch while dining out were 1.59 times more likely to select the SS vegetables over the ST (p = 0.007). Given a choice, consumers were more likely to select a seasoned vegetable. With low vegetable consumption as a predictor of seasoned vegetable choice, offering seasoned vegetables may increase intake in those with poor vegetable intake in a café setting.


Direct calculation of ice homogeneous nucleation rate for a molecular model of water.
Ice formation is ubiquitous in nature, with important consequences in a variety of environments, including biological cells, soil, aircraft, transportation infrastructure, and atmospheric clouds. However, its intrinsic kinetics and microscopic mechanism are difficult to discern with current experiments. Molecular simulations of ice nucleation are also challenging, and direct rate calculations have only been performed for coarse-grained models of water. For molecular models, only indirect estimates have been obtained, e.g., by assuming the validity of classical nucleation theory. We use a path sampling approach to perform, to our knowledge, the first direct rate calculation of homogeneous nucleation of ice in a molecular model of water. We use TIP4P/Ice, the most accurate among existing molecular models for studying ice polymorphs. By using a novel topological approach to distinguish different polymorphs, we are able to identify a freezing mechanism that involves a competition between cubic and hexagonal ice in the early stages of nucleation. In this competition, the cubic polymorph takes over because the addition of new topological structural motifs consistent with cubic ice leads to the formation of more compact crystallites. This is not true for topological hexagonal motifs, which give rise to elongated crystallites that are not able to grow. This leads to transition states that are rich in cubic ice, and not the thermodynamically stable hexagonal polymorph. This mechanism provides a molecular explanation for the earlier experimental and computational observations of the preference for cubic ice in the literature.


Hydrocortisone administration was associated with improved survival in Japanese patients with cardiac arrest.
There are few reports on hydrocortisone administration after cardiac arrest, and those that have been published included few subjects. This study aimed to evaluate the effect of hydrocortisone administration on the outcomes of patients who experienced cardiac arrest. We investigated the survival discharge rates and the length of hospital stay from cardiac arrest to discharge, stratified by use of hydrocortisone, using a Japanese health-insurance claims dataset that covers approximately 2% of the Japanese population. The study included the data of 2233 subjects who experienced either in-hospital or out-of-hospital cardiac arrest between January 2005 and May 2014. These patients were divided into two groups, based on the administration of hydrocortisone. We adjusted the baseline characteristics, medical treatment, and drug administration data of the two groups using propensity scores obtained via the inverse probability of treatment weighted method. The hydrocortisone group had a significantly higher survival discharge rate (13/61 [21.1%] vs. 240/2172 [11.0%], adjusted odds ratio: 4.2, 95% CI: 1.60-10.98, p = 0.004). In addition, the administration of hydrocortisone was independent predictor of survival to discharge (hazard ratio: 4.6, p < 0.001). The results demonstrate a correlation between hydrocortisone administration and the high rates of survival to discharge.


Income inequality among American states and the incidence of major depression.
Although cross-sectional and ecological studies have shown that higher area-level income inequality is related to increased risk for depression, few longitudinal studies have been conducted. This investigation examines the relationship between state-level income inequality and major depression among adults participating in a population-based, representative longitudinal study. We used data from the National Epidemiologic Survey on Alcohol and Related Conditions (n=34 653). Respondents completed structured diagnostic interviews at baseline (2001-2002) and follow-up (2004-2005). Weighted multilevel modelling was used to determine if U.S. state-level income inequality (measured by the Gini coefficient) was a significant predictor of depression at baseline and at follow-up, while controlling for individual-level and state-level covariates. We also repeated the longitudinal analyses, excluding those who had a history of depression or at baseline, in order to test whether income inequality was related to incident depression. State-level inequality was associated with increased incidence of depression among women but not men. In comparison to women residing in states belonging to the lowest quintile of income inequality, women were at increased risk for depression in the second (OR=1.18, 95% CI 0.86 to 1.62), third (OR=1.22, 95% CI 0.91 to 1.62), fourth (OR=1.37, 95% CI 1.03 to 1.82) and fifth (OR=1.50, 95% CI 1.14 to 1.96) quintiles at follow-up (p<0.05 for the linear trend). Living in a state with higher income inequality increases the risk for the development of depression among women.


Molecular insights into Cassava brown streak virus susceptibility and resistance by profiling of the early host response.
Cassava brown streak virus (CBSV) and Ugandan cassava brown streak virus (UCBSV) are responsible for significant cassava yield losses in eastern sub-Saharan Africa. To study the possible mechanisms of plant resistance to CBSVs, we inoculated CBSV-susceptible and CBSV-resistant cassava varieties with a mixed infection of CBSVs using top-cleft grafting. Transcriptome profiling of the two cassava varieties was performed at the earliest time point of full infection (28 days after grafting) in the susceptible scions. The expression of genes encoding proteins in RNA silencing, salicylic acid pathways and callose deposition was altered in the susceptible cassava variety, but transcriptional changes were limited in the resistant variety. In total, the expression of 585 genes was altered in the resistant variety and 1292 in the susceptible variety. Transcriptional changes led to the activation of β-1,3-glucanase enzymatic activity and a reduction in callose deposition in the susceptible cassava variety. Time course analysis also showed that CBSV replication in susceptible cassava induced a strong up-regulation of RDR1, a gene previously reported to be a susceptibility factor in other potyvirus-host pathosystems. The differences in the transcriptional responses to CBSV infection indicated that susceptibility involves the restriction of callose deposition at plasmodesmata. Aniline blue staining of callose deposits also indicated that the resistant variety displays a moderate, but significant, increase in callose deposition at the plasmodesmata. Transcriptome data suggested that resistance does not involve typical antiviral defence responses (i.e. RNA silencing and salicylic acid). A meta-analysis of the current RNA-sequencing (RNA-seq) dataset and selected potyvirus-host and virus-cassava RNA-seq datasets revealed that the conservation of the host response across pathosystems is restricted to genes involved in developmental processes.


The Panel Study of Income Dynamics: Overview, Recent Innovations, and Potential for Life Course Research.
Spanning over four decades, the Panel Study of Income Dynamics (PSID) is the world's longest running household panel survey. The resulting data archive presents research opportunities for breakthroughs in understanding the connections between economic status, health and well-being across generations and over the life course. The long panel, genealogical design, and broad content of the data represent a unique opportunity for a multi-perspective study of life course evolution and change within families over multiple generations. Based on relational data structures and advanced web-based archiving and delivery tools, the PSID has a publicly available web-based facility for users worldwide to create customized data extracts and codebooks based on nearly 70,000 variables from over 70,000 individuals over 44 years. This paper provides an overview of the PSID and its supplemental studies, the Disability and Use of Time Supplement, the Child Development Supplement, and the Transition into Adulthood study, and describes features and recent enhancements that have increased the potential of the archive for studying life course development.


Parachuting from fixed objects: descriptive study of 106 fatal events in BASE jumping 1981-2006.
To analyse the characteristics of fatal incidents in fixed object sport parachuting (building, antenna, span, earth (BASE) jumping) and create a basis for prevention. Descriptive epidemiological study. Data on reported fatal injury events (n = 106) worldwide in 1981-2006 retrieved from the BASE fatality list. Human, equipment and environmental factors. Identification of typical fatal incident and injury mechanisms for each of the four fixed object types of BASE jumping (building, antenna, span, earth). Human factors included parachutist free fall instability (loss of body control before parachute deployment), free fall acrobatics and deployment failure by the parachutist. Equipment factors included pilot chute malfunction and parachute malfunction. In cliff jumping (BASE object type E), parachute opening towards the object jumped was the most frequent equipment factor. Environmental factors included poor visibility, strong or turbulent winds, cold and water. The overall annual fatality risk for all object types during the year 2002 was estimated at about one fatality per 60 participants. Participants in BASE jumping should target risk factors with training and technical interventions. The mechanisms described in this study should be used by rescue units to improve the management of incidents.


CCL5/RANTES is a key chemoattractant released by degenerative intervertebral discs in organ culture.
Release of chemotactic factors in response to tissue damage has been described for different musculoskeletal tissues, including the intervertebral disc (IVD). This study investigated the chemoattractants that are released by induced degenerative IVDs and may be involved in recruiting mesenchymal stem cells (MSCs). Bovine caudal discs were cultured within a bioreactor and loaded under conditions that mimicked physiological or degenerative settings. Between days 4-6, medium was replaced by PBS, which was subsequently used for proteomic, ELISA and immunoprecipitation analyses of secreted chemokines and cytokines. A Boyden chamber assay was used to observe human MSC migration towards native and chemokine depleted media. Gene expression levels of chemokine receptors in human MSCs were analysed, and CCL5 was localised in bovine and human IVD by immunohistochemistry. Proteomic analysis revealed the presence of CCL5 and CXCL6 within conditioned media. Higher concentrations of CCL5 were found in the degenerative media, and a relationship was found between interleukin-1β and CCL5 concentration. Chemokine immunoprecipitation showed that MSCs had a significantly reduced chemotactic migration towards CCL5-immunoprecipitated and CCL5/CXCL6 co-immunoprecipitated media, whilst CXCL6 depletion did not change MSC chemotaxis. MSCs showed a significant increase in mRNA expression of the CCL5 receptors, CCR1 and CCR4, upon culture in degenerative media. Furthermore, CCL5 was identified in bovine and human disc tissue by immunohistochemistry. Hence, CCL5 may be a key chemoattractant that is produced and released by the intervertebral disc cells. Therefore, these factors could be used to enhance stem/progenitor cell mobilisation in regenerative therapies for early stages of disc degeneration.


A comparison of oncogene-induced senescence and replicative senescence: implications for tumor suppression and aging.
Cellular senescence is a stable proliferation arrest associated with an altered secretory pathway, the senescence-associated secretory phenotype. However, cellular senescence is initiated by diverse molecular triggers, such as activated oncogenes and shortened telomeres, and is associated with varied and complex physiological endpoints, such as tumor suppression and tissue aging. The extent to which distinct triggers activate divergent modes of senescence that might be associated with different physiological endpoints is largely unknown. To begin to address this, we performed gene expression profiling to compare the senescence programs associated with two different modes of senescence, oncogene-induced senescence (OIS) and replicative senescence (RS [in part caused by shortened telomeres]). While both OIS and RS are associated with many common changes in gene expression compared to control proliferating cells, they also exhibit substantial differences. These results are discussed in light of potential physiological consequences, tumor suppression and aging.


Forecasting paediatric malaria admissions on the Kenya Coast using rainfall.
Malaria is a vector-borne disease which, despite recent scaled-up efforts to achieve control in Africa, continues to pose a major threat to child survival. The disease is caused by the protozoan parasite Plasmodium and requires mosquitoes and humans for transmission. Rainfall is a major factor in seasonal and secular patterns of malaria transmission along the East African coast. The goal of the study was to develop a model to reliably forecast incidences of paediatric malaria admissions to Kilifi District Hospital (KDH). In this article, we apply several statistical models to look at the temporal association between monthly paediatric malaria hospital admissions, rainfall, and Indian Ocean sea surface temperatures. Trend and seasonally adjusted, marginal and multivariate, time-series models for hospital admissions were applied to a unique data set to examine the role of climate, seasonality, and long-term anomalies in predicting malaria hospital admission rates and whether these might become more or less predictable with increasing vector control. The proportion of paediatric admissions to KDH that have malaria as a cause of admission can be forecast by a model which depends on the proportion of malaria admissions in the previous 2 months. This model is improved by incorporating either the previous month's Indian Ocean Dipole information or the previous 2 months' rainfall. Surveillance data can help build time-series prediction models which can be used to anticipate seasonal variations in clinical burdens of malaria in stable transmission areas and aid the timing of malaria vector control.


Quantification of the spread of SARS-CoV-2 variant B.1.1.7 in Switzerland.
In December 2020, the United Kingdom (UK) reported a SARS-CoV-2 Variant of Concern (VoC) which is now named B.1.1.7. Based on initial data from the UK and later data from other countries, this variant was estimated to have a transmission fitness advantage of around 40-80 % (Volz et al., 2021; Leung et al., 2021; Davies et al., 2021). This study aims to estimate the transmission fitness advantage and the effective reproductive number of B.1.1.7 through time based on data from Switzerland. We generated whole genome sequences from 11.8 % of all confirmed SARS-CoV-2 cases in Switzerland between 14 December 2020 and 11 March 2021. Based on these data, we determine the daily frequency of the B.1.1.7 variant and quantify the variant's transmission fitness advantage on a national and a regional scale. We estimate B.1.1.7 had a transmission fitness advantage of 43-52 % compared to the other variants circulating in Switzerland during the study period. Further, we estimate B.1.1.7 had a reproductive number above 1 from 01 January 2021 until the end of the study period, compared to below 1 for the other variants. Specifically, we estimate the reproductive number for B.1.1.7 was 1.24 [1.07-1.41] from 01 January until 17 January 2021 and 1.18 [1.06-1.30] from 18 January until 01 March 2021 based on the whole genome sequencing data. From 10 March to 16 March 2021, once B.1.1.7 was dominant, we estimate the reproductive number was 1.14 [1.00-1.26] based on all confirmed cases. For reference, Switzerland applied more non-pharmaceutical interventions to combat SARS-CoV-2 on 18 January 2021 and lifted some measures again on 01 March 2021. The observed increase in B.1.1.7 frequency in Switzerland during the study period is as expected based on observations in the UK. In absolute numbers, B.1.1.7 increased exponentially with an estimated doubling time of around 2-3.5 weeks. To monitor the ongoing spread of B.1.1.7, our plots are available online.


In vivo imaging of drug-induced mitochondrial outer membrane permeabilization at single-cell resolution.
Observing drug responses in the tumor microenvironment in vivo can be technically challenging. As a result, cellular responses to molecularly targeted cancer drugs are often studied in cell culture, which does not accurately represent the behavior of cancer cells growing in vivo. Using high-resolution microscopy and fluorescently labeled genetic reporters for apoptosis, we developed an approach to visualize drug-induced cell death at single-cell resolution in vivo. Stable expression of the mitochondrial intermembrane protein IMS-RP was established in human breast and pancreatic cancer cells. Image analysis was then used to quantify release of IMS-RP into the cytoplasm upon apoptosis and irreversible mitochondrial permeabilization. Both breast and pancreatic cancer cells showed higher basal apoptotic rates in vivo than in culture. To study drug-induced apoptosis, we exposed tumor cells to navitoclax (ABT-263), an inhibitor of Bcl-2, Bcl-xL, and Bcl-w, both in vitro and in vivo. Although the tumors responded to Bcl-2 inhibition in vivo, inducing apoptosis in around 20% of cancer cells, the observed response was much higher in cell culture. Together, our findings show an imaging technique that can be used to directly visualize cell death within the tumor microenvironment in response to drug treatment.


Investigating the pressure-reducing effect of wound dressings.
Currently, polyurethane foam dressings are commercially available from many manufacturers. However, the pressure-reducing effect is expected to differ by the formulation and combination of the main and secondary ingredients and by manufacturing method. In this study, we investigated the effects of pressure reduction using dressing materials with various structural characteristics, including polyurethane foam dressings based on the engineering point of view, focusing on the dry state. Pressure was measured in a model that simulated compression on the sacral region in a decubitus position. Pressure was measured for different dressings: ten products, consisting of five types of material (polyurethane foam, hydropolymeric, Hydrofiber, hydrocolloid, and low-adherent absorbent). All dressings used in this study showed significantly reduced pressure. ALLEVYN Non-Adhesive had the lowest pressure at 35.833 ± 1.155 mmHg, and DuoDERM Extra Thin CGF had the highest pressure at 66.867 ± 1.060 mmHg. The pressure of the control was 74.667 ± 1.405 mmHg. The other dressings were: ALLEVYN Adhesive: 44.233 ± 0.777 mmHg; ALLEVYN Gentle Border: 46.967 ± 1.537mmHg; Mepilex Border: 53.867 ± 0.231 mmHg; Biatain Silicone: 56.000 ± 0.520 mmHg; TIELLE: 57.267 ± 3.403 mmHg;Versiva XC: 65.900 ± 0.800 mmHg; DuoDERM CGF: 57.267 ± 1.007 mmHg; and Melolin: 53.433 ± 1.973 mmHg. The pressure-reducing effect of dressing differs not only by material type but also by product. That is, the pressure-reducing effect can differ even if the dressings are of the same material type, such as polyurethane foam. Our study investigated only the effect of materials and structural characteristics on the cushion of dressings in the dry state. Therefore, further investigation is needed to confirm the effect of pressure reduction by dressing to meet the conditions in the clinic.


How to define responders in osteoarthritis.
Osteoarthritis is a clinical syndrome of failure of the joint accompanied by varying degrees of joint pain, functional limitation, and reduced quality of life due to deterioration of articular cartilage and involvement of other joint structures. Regulatory agencies require relevant clinical benefit on symptoms and structure modification for registration of a new therapy as a disease-modifying osteoarthritis drug (DMOAD). An international Working Group of the European Society on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and International Osteoporosis Foundation was convened to explore the current burden of osteoarthritis, review current regulatory guidelines for the conduct of clinical trials, and examine the concept of responder analyses for improving drug evaluation in osteoarthritis. The ESCEO considers that the major challenges in DMOAD development are the absence of a precise definition of the disease, particularly in the early stages, and the lack of consensus on how to detect structural changes and link them to clinically meaningful endpoints. Responder criteria should help identify progression of disease and be clinically meaningful. The ideal criterion should be sensitive to change over time and should predict disease progression and outcomes such as joint replacement. The ESCEO considers that, for knee osteoarthritis, clinical trial data indicate that radiographic joint space narrowing >0.5 mm over 2 or 3 years might be a reliable surrogate measure for total joint replacement. On-going research using techniques such as magnetic resonance imaging and biochemical markers may allow the identification of these patients earlier in the disease process.


Alterations in Evoked Otoacoustic Emissions by the Use of Meglumine Antimoniate in American Tegumentary Leishmaniasis Patients.
Tegumentary Leishmaniasis (TL) is a neglected, non-contagious, infectious disease, caused by different protozoa species of the Leishmania genus that affects skin and mucous membranes. Meglumine Antimoniate (MA), the first drug of choice for TL treatment in Brazil, has already been associated with cochlear toxicity, which is defined as damages of the cochlea caused by exposure to chemical substances, resulting in reversible or irreversible hearing loss. Auditory monitoring for cochlear toxicity aims at the early detection of auditory disorders, enabling, when possible, hearing to be preserved or an early auditory rehabilitation. Although otoacoustic emissions (OAEs) are used in this monitoring, there is no consensus on the criteria that define cochlear toxicity by this examination. The objective of this study was to describe the characteristics of the OAEs in cochlear toxicity monitoring in TL patients using MA. Prospective and longitudinal study of auditory monitoring of 35 patients with parasitological diagnosis of TL, with liminal tonal audiometry, high frequency audiometry, immitanciometry, distortion product evoked otoacoustic emissions (DPEOAEs) and transient evoked otoacoustic emissions (TEOAEs) before treatment, at the end of treatment, one month after the end of treatment and two months after the end of treatment. 80% male, with median age of 44 years (IIQ: 22-59). In the pre-treatment evaluation: 11.4% complained of hearing loss and 20% of tinnitus, 48.6% presented auditory alterations in liminal tonal audiometry (LTA, 65.2% in high frequency audiometry (HFA), 26.6% in DPEOAE and 51.4% in TEOAE. No association was verified between genre and alterations in the EOAE examinations. We observed that patients that presented disorders in DPEOAE examinations were 17 years older than those without alterations and that patients that showed disorders in TEOAEO examinations were 34 years older than those without disorders. The presence of alterations in DPEOAE and TEOAE before beginning treatment was associated with each other and with the presence of alterations in LTA and HFA, and only DPEOAE was associated with hearing loss. We observed a significantly higher number of alterations of DPEOAE at the end of treatment than during pre-treatment and values of the ratio signal/noise significantly smaller at the end of treatment than during pre-treatment in the frequencies of 2 kHz (difference of 1.7dB; p = 0.016) and 4 kHz (difference of 2.45dB; p = 0.016) in DPEOAE and in the range 1.75/2.5 kHz in TEOAE (difference of 2.9dB; p = 0.039). The ototoxic signals observed in our study using EOAE indicated that both, DPEOAE and TEOAE are adequate and sensitive techniques for clinical monitoring of ototoxicity by MA. Their application is very simple, and their results help the physician to take the most adequate steps for each patient, thus avoiding permanent hearing damage.


Evaluation of the adsorption potential of eco-friendly activated carbon prepared from cherry kernels for the removal of Pb2+, Cd2+ and Ni2+ from aqueous wastes.
Development, characterization and evaluation of the efficiency of cost-effective medium for the removal of Pb2+, Cd2+ and Ni2+ from aqueous systems, as a novel, eco-friendly solution for wastewater remediation were done. The precursors for low-cost adsorbent were lignocellulosic raw materials (sweet/sour cherry kernels), as industrial byproducts and components of organic solid waste. Activated carbon synthesis was carried out by thermochemical conversion (H3PO4, 500 °C) in the complete absence of inert atmosphere. Characterization of the activated carbon was performed by elemental analysis, FTIR, SEM, EDX and BET. BET surface area corresponds to 657.1 m2 g-1. The evaluation also included the influence of pH, contact time, solute concentration and adsorbent dose on the separation efficiency in the batch operational mode. The equilibrium and kinetic studies of adsorption were done. The maximum adsorption capacity of the activated carbon for Cd2+ ions was calculated from the Langmuir isotherm and found to be 198.7 mg g-1. Adsorption of Pb2+ and Ni2+ were better suitable to Freundlich model with the maximum adsorption capacity of 180.3 mg g-1 and 76.27 mg g-1, respectively. The results indicate that the pseudo-second-order model best describes adsorption kinetic data. Based on desorption study results, activated carbon was successfully regenerated with HNO3 for 3 cycles. In order to provide the results for basic cost-effective analysis, competing ion-effects in a real sample have been evaluated.


Functional refolding of a recombinant C-type lectin-like domain containing intramolecular disulfide bonds.
The lectin-like oxidized low-density lipoprotein scavenger receptor (LOX-1) is a pro-inflammatory marker and Type II membrane protein expressed on vascular cells and tissues. The LOX-1 extracellular domain mediates recognition of oxidized low-density lipoprotein (oxLDL) particles that are implicated in the development of atherosclerotic plaques. To study the molecular basis for LOX-1-mediated ligand recognition, we have expressed, purified and refolded a recombinant LOX-1 protein and assayed for its biological activity using a novel fluorescence-based assay to monitor binding to lipid particles. Overexpression of a hexahistidine-tagged cysteine-rich LOX-1 extracellular domain in bacteria leads to the formation of aggregates that accumulated in bacterial inclusion bodies. The hexahistidine-tagged LOX-1 molecule was purified by affinity chromatography from solubilized inclusion bodies. A sequential dialysis procedure was used to refold the purified but inactive and denatured LOX-1 protein into a functionally active form that mediated recognition of oxLDL particles. This approach allowed slow LOX-1 refolding and assembly of correct intrachain disulfide bonds. Circular dichroism analysis of the refolded LOX-1 molecule demonstrated a folded state with substantial alpha-helical content. Using immobilized recombinant, refolded LOX-1 we demonstrated a 70-fold preferential recognition for oxLDL over native LDL particles. Thus, a protein domain containing intrachain disulfide bonds can be reconstituted into a functionally active state using a relatively simple dialysis-based technique.


Prognostic significance of supradiaphragmatic lymphadenopathy identified on preoperative computed tomography scan in patients undergoing primary cytoreduction for advanced epithelial ovarian cancer.
It has been hypothesized that the supradiaphragmatic lymph nodes serve as the principal nodes for lymphatic drainage of the entire peritoneal cavity. The purpose of this study was to determine the prognostic significance of enlarged supradiaphragmatic nodes noted on preoperative computed tomographic (CT) scan in patients undergoing primary cytoreduction for advanced epithelial ovarian cancer (EOC). We performed a retrospective chart review of all patients with stage III and IV EOC according to the International Federation of Gynecology and Obstetrics who had preoperative CT scans, including the supradiaphragmatic region, and had undergone primary cytoreductive surgery at our institution between January 1997 and June 2004. Scans were retrospectively reviewed by a radiologist. We defined supradiaphragmatic adenopathy as nodes measuring greater than 5 mm on the largest of 2 perpendicular measurements on the CT scan. The Fisher exact test was used to compare proportions. Kaplan-Meier curves and log-rank tests were used for the survival analyses. A total of 212 evaluable patients were identified. All underwent attempted primary cytoreduction followed by systemic chemotherapy. None had any supradiaphragmatic nodes removed at primary cytoreduction. With a median follow-up time of 52 months, median overall survival for the entire cohort was 48 months. Of 212 patients, 92 (43%) had supradiaphragmatic adenopathy. Median survival was 50 months for patients without adenopathy and 45 months for patients with adenopathy (P = 0.09). Of the 212 patients, 155 (73%) underwent optimal cytoreduction. In these patients, median survival was 55 months for the 91 without adenopathy and 50 months for the 64 patients with supradiaphragmatic adenopathy (P = 0.09). We observed a trend toward worse survival in patients with enlarged supradiaphragmatic nodes. The prognostic impact of supradiaphragmatic adenopathy remains uncertain and deserves further study.


Faecal immunochemical testing in bowel cancer screening: Estimating outcomes for different diagnostic policies.
The National Health Service Bowel Cancer Screening Programme (NHS BCSP) in England has replaced guaiac faecal occult blood testing by faecal immunochemical testing (FIT). There is interest in fully exploiting FIT measures to improve bowel cancer (CRC) screening strategies. In this paper, we estimate the relationship of the quantitative haemoglobin concentration provided by FIT in faecal samples with underlying pathology. From this we estimate thresholds required for given levels of sensitivity to CRC and high-risk adenomas (HRA). Data were collected from a pilot study of FIT in England in 2014, in which 27,238 participants completed a FIT. Those with a faecal haemoglobin concentration (f-Hb) of at least 20 µg/g were referred for further investigation, usually colonoscopy. Truncated regression models were used to explore the relationship between bowel pathology and FIT results. Regression results were applied to estimate sensitivity to different abnormalities for a number of thresholds. Participants with CRC and HRA had significantly higher f-Hb, and this remained unchanged after adjusting for age and sex. While a threshold of 20 μg/g was estimated to capture 82.2% of CRC and 64.0% of HRA, this would refer 7.8% of participants for colonoscopy. The current programme threshold used in England of 120 μg/g was estimated to identify 47.8% of CRC and 25.0% of HRA. Under the current diagnostic policy of dichotomising FIT results, a very low threshold would be required to achieve high sensitivity to CRC and HRA, which would place further strain on colonoscopy resources. The NHS BCSP in England might benefit from a diagnostic policy that makes greater use of the quantitative nature of FIT.


Preparation of high-quality next-generation sequencing libraries from picogram quantities of target DNA.
New sequencing technologies can address diverse biomedical questions but are limited by a minimum required DNA input of typically 1 μg. We describe how sequencing libraries can be reproducibly created from 20 pg of input DNA using a modified transpososome-mediated fragmentation technique. Resulting libraries incorporate in-line bar-coding, which facilitates sample multiplexes that can be sequenced using Illumina platforms with the manufacturer's sequencing primer. We demonstrate this technique by providing deep coverage sequence of the Escherichia coli K-12 genome that shows equivalent target coverage to a 1-μg input library prepared using standard Illumina methods. Reducing template quantity does, however, increase the proportion of duplicate reads and enriches coverage in low-GC regions. This finding was confirmed with exhaustive resequencing of a mouse library constructed from 20 pg of gDNA input (about seven haploid genomes) resulting in ∼0.4-fold statistical coverage of uniquely mapped fragments. This implies that a near-complete coverage of the mouse genome is obtainable with this approach using 20 genomes as input. Application of this new method now allows genomic studies from low mass samples and routine preparation of sequencing libraries from enrichment procedures.


Pathogenic mitochondrial DNA mutations and associated clinical features in Korean patients with Leber's hereditary optic neuropathy.
To identify the spectrum of pathogenic mitochondrial DNA (mtDNA) mutations and clinical features in Korean patients with genetically confirmed Leber's hereditary optic neuropathy (LHON). The medical records of 34 unrelated, genetically confirmed LHON patients were reviewed. Total genomic DNA was isolated from the peripheral blood leukocytes of the patients with suspected LHON, and primary or secondary mtDNA mutations were identified by direct sequencing. We analyzed the visual acuity (VA), color vision, RNFL thickness, and visual field (VF) at the final visit from 20 patients who were followed-up for more than 6 months after the onset of LHON. Among 34 patients, 21 (61.8%) had the homoplasmic primary mutation, 11 (32.4%) had the homoplasmic secondary mutation, and 2 (5.9%) had the heteroplasmic primary mutation along with the homoplasmic secondary mutation. Analysis of mtDNA sequences revealed six different types of LHON-associated mutations: two primary LHON-associated primary mutations, m.11778G>A (20 patients, 58.8%) and m.14484T>C (3 patients, 8.8%), and four secondary LHON-associated mutations, which were m.3394T>C (3 patients, 8.8%), m.3497C>T (4 patients, 11.8%), m.11696G>A (4 patients, 11.8%), and m.14502T>C (2 patients, 5.9%). Secondary mutation-carrying patients demonstrated a decreased in RNFL thickness, similar to those in primary mutation-carrying LHON patients. These patients had a higher female ratio (P = 0.019), better VA (P = 0.043) and color vision (P = 0.005), as well as better VF. In addition to common primary LHON-associated mutations, our study identified secondary mtDNA mutations, which should be considered when evaluating patients with optic atrophy.


Long-Term High Fat Diet Has a Profound Effect on Body Weight, Hormone Levels, and Estrous Cycle in Mice.
BACKGROUND Obesity causes several health complications along with disruption of the reproductive system. The aim of the current study was to determine how long-term intake of very high fat diet (VHFD) changes the hormonal milieu, affecting the cellular morphology and reproductive cycle in female mice. MATERIAL AND METHODS Mice were fed on normal diet (ND) and VHFD for 2 weeks, 12 weeks, and 25-27 weeks. We assessed changes in body weight, food consumption, energy intake, cellular and tissue morphology, hormonal levels (leptin, insulin, and estradiol), and vaginal smears were performed at various time points to determine the length and cellularity at each stage of the estrous cycle. RESULTS Mice fed on VHFD showed a significant increase in weight gain, reduction in food intake, and increase in energy intake compared to animals fed on ND, indicating that the caloric density of the diet is responsible for the differences in weight gain. Hormonal analysis showed hyperleptinemia, hyperinsulinemia, and increases in estrogen levels, along with increases in size of the islet of Langerhans and adipocytes. After 25-27 weeks, all animals fed on VHFD showed complete acyclicity; elongation of phases (e.g., diestrous), skipping of phases (e.g., metestrous), or a combination of both, indicating disruption in the reproductive cycle. Quantitative analysis showed that in the diestrous phase there was a 70% increase in cell count in VHFD compared to animals fed on ND. CONCLUSIONS The above results show that morphological and hormonal changes caused by VHFD probably act via negative feedback to the hypothalamic-pituitary axis to shut down reproduction, which has a direct effect on the estrous cycle, causing acyclicity in mice.


Stereoselective reduction of ethyl 4-chloro-3-oxobutanoate by Escherichia coli transformant cells coexpressing the aldehyde reductase and glucose dehydrogenase genes.
The asymmetric reduction of ethyl 4-chloro-3-oxobutanoate (COBE) to ethyl (R)-4-chloro-3-hydroxybutanoate [(R)-CHBE] using Escherichia coli cells, which coexpress both the aldehyde reductase gene from Sporobolomyces salmonicolor and the glucose dehydrogenase (GDH) gene from Bacillus megaterium as a catalyst was investigated. In an organic solvent-water two-phase system, (R)-CHBE formed in the organic phase amounted to 1610 mM (268 mg/ml), with a molar yield of 94.1% and an optical purity of 91.7% enantiomeric excess. The calculated turnover number of NADP+ to CHBE formed was 13,500 mol/mol. Since the use of E. coli JM109 cells harboring pKAR and pACGD as a catalyst is simple, and does not require the addition of GDH or the isolation of the enzymes, it is highly advantageous for the practical synthesis of (R)-CHBE.


Plasma IgG pool is not defended from urinary loss in nephrotic syndrome.
In the nephrotic syndrome, the plasma level of some proteins of hepatic origin is partially defended by an increase in their synthetic rate. The plasma levels of several liver-derived proteins, as well as immunoglobulin G (IgG) are increased in one condition where plasma albumin concentration and oncotic pressure (II) are reduced, i.e., hereditary analbuminemia. To determine whether the urinary loss of IgG, a protein derived from the immune system, is compensated for by an increased synthetic rate, we measured IgG synthesis in normal Sprague-Dawley rats (SD); two models of the nephrotic syndrome: Heymann nephritis (HN) and Adriamycin treatment; and in Nagase analbuminemic rats (NAR), a model of decreased II without urinary protein loss. Plasma IgG and total IgG mass were significantly reduced in both HN and Adriamycin, yet IgG synthesis was nearly identical in HN, Adriamycin, and SD. In contrast, plasma and total IgG and IgG synthesis were all markedly increased in NAR. We derived a pathogen-free colony of NAR by Caesarean section and found that plasma IgG was not increased in pathogen-free NAR, despite reduced II. Thus, unlike proteins of hepatic origin (e.g., albumin) where synthesis increases following urinary loss, no compensatory increase in IgG synthesis occurs. Increased plasma IgG as well as IgG synthesis in the NAR is not a compensatory response to the absence of albumin or reduction in II, but rather is due to subclinical infection. Profound hypogammaglobulinemia of nephrotic syndrome occurs in part because no compensatory synthetic mechanisms balance urinary loss, and alteration in plasma II does not modulate IgG synthesis.


Complication rate after cystectomy following pelvic radiotherapy: an international, multicenter, retrospective series of 682 cases.
Conflicting evidence exists on the complication rates after cystectomy following previous radiation (pRTC) with only a few available series. We aim to assess the complication rate of pRTC for abdominal-pelvic malignancies. Patients treated with radical cystectomy following any previous history of RT and with available information on complications for a minimum of 1 year were included. Univariable and multivariable logistic regression models were used to assess the relationship between the variable parameters and the risk of any complication. 682 patients underwent pRTC after a previous RT (80.5% EBRT) for prostate, bladder (BC), gynecological or other cancers in 49.1%, 27.4%, 9.8% and 12.9%, respectively. Overall, 512 (75.1%) had at least one post-surgical complication, classified as Clavien ≥ 3 in 29.6% and Clavien V in 2.9%. At least one surgical complication occurred in 350 (51.3%), including bowel leakage in 6.2% and ureteric stricture in 9.4%. A medical complication was observed in 359 (52.6%) patients, with UTI/pyelonephritis being the most common (19%), followed by renal failure (12%). The majority of patients (86%) received an incontinent urinary diversion. In multivariable analysis adjusted for age, gender and type of RT, patients treated with RT for bladder cancer had a 1.7 times increased relative risk of experiencing any complication after RC compared to those with RT for prostate cancer (p = 0.023). The type of diversion (continent vs non-continent) did not influence the risk of complications. pRTC carries a high rate of major complications that dramatically exceeds the rates reported in RT-naïve RCs.


Evaluation of stiffness changes in a high-rise building by measurements of lateral displacements using GPS technology.
The outrigger truss system is one of the most frequently used lateral load resisting structural systems. However, little research has been reported on the effect of installation of outrigger trusses on improvement of lateral stiffness of a high-rise building through full-scale measurements. In this paper, stiffness changes of a high-rise building due to installation of outrigger trusses have been evaluated by measuring lateral displacements using a global positioning system (GPS). To confirm the error range of the GPS measurement system used in the full-scale measurement tests, the GPS displacement monitoring system is investigated through a free vibration test of the experimental model. Then, for the evaluation of lateral stiffness of a high-rise building under construction, the GPS displacement monitoring system is applied to measurements of lateral displacements of a 66-story high-rise building before and after installation of outrigger truss. The stiffness improvement of the building before and after the installation is confirmed through the changes of the natural frequencies and the ratios of the base shear forces to the roof displacements.


Voltage-gated ion channels in the axon initial segment of human cortical pyramidal cells and their relationship with chandelier cells.
The axon initial segment (AIS) of pyramidal cells is a critical region for the generation of action potentials and for the control of pyramidal cell activity. Here we show that Na+ and K+ voltage-gated channels, together with other molecules involved in the localization of ion channels, are distributed asymmetrically in the AIS of pyramidal cells situated in the human temporal neocortex. There is a high density of Na+ channels distributed along the length of the AIS together with the associated proteins spectrin betaIV and ankyrin G. In contrast, Kv1.2 channels are associated with the adhesion molecule Caspr2, and they are mostly localized to the distal region of the AIS. In general, the distal region of the AIS is targeted by the GABAergic axon terminals of chandelier cells, whereas the proximal region is innervated, mostly by other types of GABAergic interneurons. We suggest that this molecular segregation and the consequent regional specialization of the GABAergic input to the AIS of pyramidal cells may have important functional implications for the control of pyramidal cell activity.


Bacterial repetitive extragenic palindromic sequences are DNA targets for Insertion Sequence elements.
Mobile elements are involved in genomic rearrangements and virulence acquisition, and hence, are important elements in bacterial genome evolution. The insertion of some specific Insertion Sequences had been associated with repetitive extragenic palindromic (REP) elements. Considering that there are a sufficient number of available genomes with described REPs, and exploiting the advantage of the traceability of transposition events in genomes, we decided to exhaustively analyze the relationship between REP sequences and mobile elements. This global multigenome study highlights the importance of repetitive extragenic palindromic elements as target sequences for transposases. The study is based on the analysis of the DNA regions surrounding the 981 instances of Insertion Sequence elements with respect to the positioning of REP sequences in the 19 available annotated microbial genomes corresponding to species of bacteria with reported REP sequences. This analysis has allowed the detection of the specific insertion into REP sequences for ISPsy8 in Pseudomonas syringae DC3000, ISPa11 in P. aeruginosa PA01, ISPpu9 and ISPpu10 in P. putida KT2440, and ISRm22 and ISRm19 in Sinorhizobium meliloti 1021 genome. Preference for insertion in extragenic spaces with REP sequences has also been detected for ISPsy7 in P. syringae DC3000, ISRm5 in S. meliloti and ISNm1106 in Neisseria meningitidis MC58 and Z2491 genomes. Probably, the association with REP elements that we have detected analyzing genomes is only the tip of the iceberg, and this association could be even more frequent in natural isolates. Our findings characterize REP elements as hot spots for transposition and reinforce the relationship between REP sequences and genomic plasticity mediated by mobile elements. In addition, this study defines a subset of REP-recognizer transposases with high target selectivity that can be useful in the development of new tools for genome manipulation.


Compliance with handwashing in a teaching hospital. Infection Control Program.
Transmission of microorganisms from the hands of health care workers is the main source of cross-infection in hospitals and can be prevented by handwashing. To identify predictors of noncompliance with handwashing during routine patient care. Observational study. Teaching hospital in Geneva, Switzerland. Nurses (66%), physicians (10%), nursing assistants (13%), and other health care workers (11%). Compliance with handwashing. In 2834 observed opportunities for handwashing, average compliance was 48%. In multivariate analysis, noncompliance was higher among physicians (odds ratio [OR], 2.8 [95% CI, 1.9 to 4.1]), nursing assistants (OR, 1.3 [CI, 1.0 to 1.6]), and other health care workers (OR, 2.1 [CI, 1.4 to 3.2]) than among nurses and was lowest on weekends (OR, 0.6 [CI, 0.4 to 0.8]). Noncompliance was higher in intensive care than in internal medicine units (OR, 2.0 [CI, 1.3 to 3.1]), during procedures that carry a high risk for contamination (OR, 1.8 [CI, 1.4 to 2.4]), and when intensity of patient care was high (compared with < or = 20 opportunities for handwashing per hour of care, 21 to 40 opportunities: OR, 1.3 [CI, 1.0 to 1.7]; 41 to 60 opportunities: OR, 2.1 [CI, 1.5 to 2.9]; and > 60 opportunities: OR, 2.1 [CI, 1.3 to 3.5]). Compliance with handwashing was moderate. Variation across hospital ward and type of health care worker suggests that targeted educational programs may be useful. Even though observational data cannot prove causality, the association between noncompliance and intensity of care suggests that understaffing may decrease quality of patient care.


Solving nursing shortages: a common priority.
This paper provides a context for this special edition. It highlights the scale of the challenge of nursing shortages, but also makes the point that there is a policy agenda that provides workable solutions. An overview of nurse:population ratios in different countries and regions of the world, highlighting considerable variations, with Africa and South East Asia having the lowest average ratios. The paper argues that the 'shortage' of nurses is not necessarily a shortage of individuals with nursing qualifications, it is a shortage of nurses willing to work in the present conditions. The causes of shortages are multi-faceted, and there is no single global measure of their extent and nature, there is growing evidence of the impact of relatively low staffing levels on health care delivery and outcomes. The main causes of nursing shortages are highlighted: inadequate workforce planning and allocation mechanisms, resource constrained undersupply of new staff, poor recruitment, retention and 'return' policies, and ineffective use of available nursing resources through inappropriate skill mix and utilisation, poor incentive structures and inadequate career support. What now faces policy makers in Japan, Europe and other developed countries is a policy agenda with a core of common themes. First, themes related to addressing supply side issues: getting, keeping and keeping in touch with relatively scarce nurses. Second, themes related to dealing with demand side challenges. The paper concludes that the main challenge for policy makers is to develop a co-ordinated package of policies that provide a long term and sustainable solution. This paper highlights the impact that nursing shortages has on clinical practice and in health service delivery. It outlines scope for addressing shortage problems and therefore for providing a more positive staffing environment in which clinical practice can be delivered.


The potential impact of the COVID-19 pandemic on child growth and development: a systematic review.
This was a systematic review of studies that examined the impact of epidemics or social restriction on mental and developmental health in parents and children/adolescents. The PubMed, WHO COVID-19, and SciELO databases were searched on March 15, 2020, and on April 25, 2020, filtering for children (0-18 years) and humans. The tools used to mitigate the threat of a pandemic such as COVID-19 may very well threaten child growth and development. These tools - such as social restrictions, shutdowns, and school closures - contribute to stress in parents and children and can become risk factors that threaten child growth and development and may compromise the Sustainable Development Goals. The studies reviewed suggest that epidemics can lead to high levels of stress in parents and children, which begin with concerns about children becoming infected. These studies describe several potential mental and emotional consequences of epidemics such as COVID-19, H1N1, AIDS, and Ebola: severe anxiety or depression among parents and acute stress disorder, post-traumatic stress, anxiety disorders, and depression among children. These data can be related to adverse childhood experiences and elevated risk of toxic stress. The more adverse experiences, the greater the risk of developmental delays and health problems in adulthood, such as cognitive impairment, substance abuse, depression, and non-communicable diseases. Information about the impact of epidemics on parents and children is relevant to policy makers to aid them in developing strategies to help families cope with epidemic/pandemic-driven adversity and ensure their children's healthy development.


Guidelines-based treatment of anaemic STEMI patients: practice patterns and effects on in-hospital mortality: a retrospective analysis from the NCDR.
Anaemia is associated with an increased risk for morbidity and mortality in ST-elevation myocardial infarction (STEMI) patients. While several physiological mechanisms have been proposed to explain this association, decreased receipt of guidelines-based care may also contribute. We examined the relationship between admission haemoglobin (Hgb) level, receipt of ACC/AHA guidelines-based treatments, and in-hospital outcomes among STEMI patients. We also evaluated whether administration of these treatments modified the association between anaemia and in-hospital mortality in this group. We analysed data from 92,686 patients diagnosed with STEMI included in the NCDR ACTION Registry-GWTG database from January 2007 to March 2011. Patients were stratified by initial Hgb value: 83.1% (n=77,035) were classified as non-anaemic (Hgb >13.0 g/dl for men, >12.0 g/dl for women), 11.6% (n=10,710) as mildly anaemic (11.1-13.0 g/dl for men, 11.1-12.0 g/dl for women), 4.4% (n=4059) as moderately anaemic (9.1-11.0 g/dl), and 1.0% (n=882) as severely anaemic (<9.0 g/dl). Anaemia was associated with a significantly increased prevalence of other baseline comorbidities and decreased odds of receiving several class I recommended pharmacological treatments (heparin, beta-blockers, and angiotensin-converting enzyme inhibitors, p<0.01). The overall use of reperfusion therapy (fibrinolytic therapy and/or percutaneous coronary intervention) was also lower in anaemic vs. non-anaemic patients (p<0.01). Anaemia was associated higher in-hospital mortality risk, which remained significant after adjustment for use of guidelines-recommended therapies and interventions (p<0.01). In a national sample of STEMI patients, anaemia on presentation was associated with decreased receipt of ACC/AHA guidelines-based care and higher in-hospital mortality. However, the higher mortality rates could not be fully explained by differences in in-hospital treatment.


A test for patency of the cystic duct in acute cholecystitis.
A procedure was devised to quickly and reliably determine the patency of the cystic duct in patients suspected of having acute cholecystitis. First the gallbladder was stimulated to empty by a cholecystokinin injection. Thirty minutes later a radiolabeled biliary marker, either 150 muCi 131-I rose bengal or 2 mCi 99-mTc dihydrothioctic acid, was injected, and the accumulation of radioactivity in the liver and gallbladder regions was monitored by external gamma emission imaging and recording devices. The images of diagnostic importance were obtained between 60 and 90 minutes after injection of the tracer. Thirty-nine patients with acute abdominal pain were studied. Ten patients who had acute cholecystitis failed to show gallbladder accumulation of radioactivity, reflecting the cystic duct obstruction that initiates this disease. Twenty-nine patients having a variety of other diseases all showed gallbladder accumulation of activity, indicating in each patient that the cystic duct was patent. No significant adverse effects were noted. We conclude that the procedure is a useful adjunct to the clinical and roentgenographic evaluation of patients with acute abdominal pain.


Myosin II Synergizes with F-Actin to Promote DNGR-1-Dependent Cross-Presentation of Dead Cell-Associated Antigens.
Conventional type 1 DCs (cDC1s) excel at cross-presentation of dead cell-associated antigens partly because they express DNGR-1, a receptor that recognizes exposed actin filaments on dead cells. In vitro polymerized F-actin can be used as a synthetic ligand for DNGR-1. However, cellular F-actin is decorated with actin-binding proteins, which could affect DNGR-1 recognition. Here, we demonstrate that myosin II, an F-actin-associated motor protein, greatly potentiates the binding of DNGR-1 to F-actin. Latex beads coated with F-actin and myosin II are taken up by DNGR-1+ cDC1s, and antigen associated with those beads is efficiently cross-presented to CD8+ T cells. Myosin II-deficient necrotic cells are impaired in their ability to stimulate DNGR-1 or to serve as substrates for cDC1 cross-presentation to CD8+ T cells. These results provide insights into the nature of the DNGR-1 ligand and have implications for understanding immune responses to cell-associated antigens and for vaccine design.