Incidence and characteristics of adverse events in paediatric inpatient care: a systematic review and meta-analysis.
Adverse events (AEs) cause suffering for hospitalised children, a fragile patient group where the delivery of adequate timely care is of great importance. To report the incidence and characteristics of AEs, in paediatric inpatient care, as detected with the Global Trigger Tool (GTT), the Trigger Tool (TT) or the Harvard Medical Practice Study (HMPS) method. MEDLINE, Embase, Web of Science and Google Scholar were searched from inception to June 2021, without language restrictions. Studies using manual record review were included if paediatric data were reported separately. We excluded studies reporting: AEs for a specific disease/diagnosis/treatment/procedure, or deceased patients; study protocols with no AE outcomes; conference abstracts, editorials and systematic reviews; clinical incident reports as the primary data source; and studies focusing on specific AEs only. Methodological risk of bias was assessed using a tool based on the Quality Assessment Tool for Diagnostic Accuracy Studies 2. Primary outcome was the percentage of admissions with ≥1 AEs. All statistical analyses were stratified by record review methodology (GTT/TT or HMPS) and by type of population. Meta-analyses, applying random-effects models, were carried out. The variability of the pooled estimates was characterised by 95% prediction intervals (PIs). We included 32 studies from 44 publications, conducted in 15 countries totalling 33 873 paediatric admissions. The total number of AEs identified was 8577. The most common types of AEs were nosocomial infections (range, 6.8%-59.6%) for the general care population and pulmonary-related (10.5%-36.7%) for intensive care. The reported incidence rates were highly heterogeneous. The PIs for the primary outcome were 3.8%-53.8% and 6.9%-91.6% for GTT/TT studies (general and intensive care population). The equivalent PI was 0.3%-33.7% for HMPS studies (general care). The PIs for preventable AEs were 7.4%-96.2% and 4.5%-98.9% for GTT/TT studies (general and intensive care population) and 10.4%-91.8% for HMPS studies (general care). The quality assessment indicated several methodological concerns regarding the included studies. The reported incidence of AEs is highly variable in paediatric inpatient care research, and it is not possible to estimate a reliable single rate. Poor reporting standards and methodological differences hinder the comparison of study results.


HOXB7 promotes tumor progression via bFGF-induced activation of MAPK/ERK pathway and indicated poor prognosis in hepatocellular carcinoma.
The homeobox-containing gene HOXB7 plays an important role in the pathogenesis and progression of many cancers, yet its role in hepatocellular carcinoma (HCC) remains unclear. This study comprehensively analyzed the expression and clinical significance of HOXB7 in HCC and explored its potential mechanism in tumor progression. We found HOXB7 was highly expressed in HCC cell lines with highly metastatic potential and cancerous tissues from patients with tumor recurrence. The abilities of proliferation, migration, and invasion were notably decreased by depletion of HOXB7, and were enhanced by its enforced expression in vitro. HOXB7 expression was positively correlated with tumor progression and lung metastasis in vivo. The gene microarray data implied that HOXB7 affects biological functions of HCC cells through MAPK/ERK pathway activation. Further study confirmed that the effect of HOXB7 in activating MAPK/ERK pathway via induction of basic fibroblast growth factor (bFGF) secretion, and the inhibition of bFGF secretion could abolish MAPK/ERK pathway activation after ectopic expression of HOXB7. Chromatin immunoprecipitation experiments and luciferase reporter assays confirmed that HOXB7 promoted bFGF secretion via binding its promoter directly. Furthermore, the clinical significance of HOXB7 expression was confirmed using tissue microarrays containing 394 HCC tissue specimens. Patients with high HOXB7 expression showed shorter survival times and higher recurrence rates, and HOXB7 was an independent indicator for survival and recurrence. Overall, HOXB7 promotes HCC cell proliferation, migration, and invasion through the bFGF-induced MAPK/ERK pathway activation. It might be a novel prognostic factor in HCC and a promising therapeutic target for tumor metastasis and recurrence.


Multiligand Metal-Phenolic Assembly from Green Tea Infusions.
The synthesis of hybrid functional materials using the coordination-driven assembly of metal-phenolic networks (MPNs) is of interest in diverse areas of materials science. To date, MPN assembly has been explored as monoligand systems (i.e., containing a single type of phenolic ligand) where the phenolic components are primarily obtained from natural sources via extraction, isolation, and purification processes. Herein, we demonstrate the fabrication of MPNs from a readily available, crude phenolic source-green tea (GT) infusions. We employ our recently introduced rust-mediated continuous assembly strategy to prepare these GT MPN systems. The resulting hollow MPN capsules contain multiple phenolic ligands and have a shell thickness that can be controlled through the reaction time. These multiligand MPN systems have different properties compared to the analogous MPN systems reported previously. For example, the Young's modulus (as determined using colloidal-probe atomic force microscopy) of the GT MPN system presented herein is less than half that of MPN systems prepared using tannic acid and iron salt solutions, and the disassembly kinetics are faster (∼50%) than other, comparable MPN systems under identical disassembly conditions. Additionally, the use of rust-mediated assembly enables the formation of stable capsules under conditions where the conventional approach (i.e., using iron salt solutions) results in colloidally unstable dispersions. These differences highlight how the choice of phenolic ligand and its source, as well as the assembly protocol (e.g., using solution-based or solid-state iron sources), can be used to tune the properties of MPNs. The strategy presented herein expands the toolbox of MPN assembly while also providing new insights into the nature and robustness of metal-phenolic interfacial assembly when using solution-based or solid-state metal sources.


Stable α/δ phase junction of formamidinium lead iodide perovskites for enhanced near-infrared emission.
Although formamidinium lead iodide (FAPbI3) perovskite has shown great promise in the field of perovskite-based optoelectronic devices, it suffers the complications of a structural phase transition from a black perovskite phase (α-FAPbI3) to a yellow non-perovskite phase (δ-FAPbI3). Generally, it is pivotal to avoid δ-FAPbI3 since only α-FAPbI3 is desirable for photoelectric conversion and near-infrared (NIR) emission. However, herein, we firstly exploited the undesirable δ-FAPbI3 to enable structurally stable, pure FAPbI3 films with a controllable α/δ phase junction at low annealing temperature (60 °C) through stoichiometrically modified precursors (FAI/PbI2 = 1.1-1.5). The α/δ phase junction contributes to a striking stabilization of the perovskite phase of FAPbI3 at low temperature and significantly enhanced NIR emission at 780 nm, which is markedly different from pure α-FAPbI3 (815 nm). In particular, the optimal α/δ phase junction with FAI/PbI2 = 1.2 exhibited preferable long-term stability against humidity and high PLQY of 6.9%, nearly 10-fold higher than that of pure α-FAPbI3 (0.7%). The present study opens a new approach to realize highly stable and efficient emitting perovskite materials by utilizing the phase junctions.


Feeding and Development of Emerald Ash Borer (Coleoptera: Buprestidae) on Cultivated Olive, Olea europaea.
We examined the suitability of cultivated olive, Olea europaea L., as a host for emerald ash borer, Agrilus planipennis Fairmaire. In a bioassay using cut stems from a field-grown olive tree (cv. 'Manzanilla') we found that 45% of larvae that had emerged from eggs used to inoculate stems, were recovered alive, many as larvae or prepupae, during periodic debarking of a subset of stems. Three intact stems that 19 larvae successfully entered were exposed to a simulated overwintering treatment. Four live adults emerged afterwards, and an additional pupa and several prepupae were discovered after debarking these stems. Cultivated olive joins white fringetree as one of the two species outside of the genus Fraxinus capable of supporting the development of emerald ash borer from neonate to adult.


Estimating the malaria transmission over the Indian subcontinent in a warming environment using a dynamical malaria model.
Malaria is a major public health problem in India. The malaria transmission is sensitive to climatic parameters. The regional population-related factors also influence malaria transmission. To take into account temperature and rainfall variability and associated population-related effects (in a changing climate) on the malaria transmission over India, a regional dynamical malaria model, namely VECTRI (vector-borne disease community model) is used. The daily temperature and rainfall data derived from the historical (years 1961-2005) and representative concentration pathway (years 2006-2050) runs of the Coupled Model Intercomparison Project Phase 5 models have been used for the analysis. The model results of the historical run are compared with the observational data. The spatio-temporal changes (region-specific as well as seasonal changes) in the malaria transmission as a result of climate change are quantified over the India. The parameters related to the breeding cycle of malaria as well as those which estimate the malaria cases are analyzed in the global warming scenario.


Development and validation of a prediction algorithm for the onset of common mental disorders in a working population.
Common mental disorders are the most common reason for long-term sickness absence in most developed countries. Prediction algorithms for the onset of common mental disorders may help target indicated work-based prevention interventions. We aimed to develop and validate a risk algorithm to predict the onset of common mental disorders at 12 months in a working population. We conducted a secondary analysis of the Household, Income and Labour Dynamics in Australia Survey, a longitudinal, nationally representative household panel in Australia. Data from the 6189 working participants who did not meet the criteria for a common mental disorders at baseline were non-randomly split into training and validation databases, based on state of residence. Common mental disorders were assessed with the mental component score of 36-Item Short Form Health Survey questionnaire (score ⩽45). Risk algorithms were constructed following recommendations made by the Transparent Reporting of a multivariable prediction model for Prevention Or Diagnosis statement. Different risk factors were identified among women and men for the final risk algorithms. In the training data, the model for women had a C-index of 0.73 and effect size (Hedges' g) of 0.91. In men, the C-index was 0.76 and the effect size was 1.06. In the validation data, the C-index was 0.66 for women and 0.73 for men, with positive predictive values of 0.28 and 0.26, respectively Conclusion: It is possible to develop an algorithm with good discrimination for the onset identifying overall and modifiable risks of common mental disorders among working men. Such models have the potential to change the way that prevention of common mental disorders at the workplace is conducted, but different models may be required for women.


Revealing the structure-property relationship of covalent organic frameworks for CO₂ capture from postcombustion gas: a multi-scale computational study.
With the aid of multi-scale computational methods, a diverse set of 46 covalent organic frameworks (COFs), covering the most typical COFs synthesized to date, were collected to study the structure-property relationship of COFs for CO2 capture. For this purpose, CO2 capture from postcombustion gas (CO2-N2 mixture) under industrial vacuum swing adsorption (VSA) conditions was considered as an example. This work shows that adsorption selectivity, CO2 working capacity and the sorbent selection parameter of COFs all exhibit strong correlation with the difference in the adsorbility of adsorbates (ΔAD), highlighting that realization of large ΔAD can be regarded as an important starting point for designing COFs with improved separation performance. Furthermore, it was revealed that the separation performance of 2D-layered COFs can be greatly enhanced by generating "splint effects", which can be achieved through structural realignment to form slit-like pores with suitable size in the structures. Such "splint effects" in 2D-COFs can find their similar counterpart of "catenation effects" in 3D-COFs or MOFs. On the basis of these observations, a new design strategy was proposed to strengthen the separation performance of COFs. It could be expected that the information obtained in this work not only will enrich the knowledge of the structure-property relationship of COFs for separation, but also will largely facilitate their future applications to the fields related to energy and environmental science, such as natural gas purification, CO2, NO(x) and SO(x) capture, etc.


Gastrocystoplasty in children.
We report our experience of gastrocystoplasty in 8 children (mean age 10.1 years) with compromised renal function (mean creatinine 186 mmol/l, mean glomerular filtration rate 39 ml/min/1.73 m2). Current follow-up ranges from 11 to 35 months (mean 21). The physiological outcome of the procedure has been excellent, with improved biochemical and urodynamic parameters in all cases. Six patients are off H2-receptor blockers and are asymptomatic. In 2 children we have encountered significant symptoms related to acid secretion in the bladder. Detailed investigations suggest that the excess aciduria is related to the size of the gastric patch in 1 patient. The second child underwent renal transplantation 5 months after gastrocystoplasty and it is postulated that his immunosuppressive regimen (which includes prednisolone) may be responsible for the increased acid secretion. It is concluded that gastrocystoplasty is a very satisfactory alternative to intestinal segment bladder enhancement in children with compromised renal function, but the size of the gastric patch is critical in determining the resultant acid secretion. Post-transplantation immunosuppressive therapy may increase acid production from the gastric patch; since the children most suitable for gastrocystoplasty are also those likley to require transplantation, this aspect requires further study.


MLN4924 is an efficient inhibitor of NEDD8 conjugation in plants.
The conjugation of the ubiquitin-like modifier NEURAL PRECURSOR CELL-EXPRESSED DEVELOPMENTALLY DOWN-REGULATED PROTEIN8/RELATED TO UBIQUITIN1 (NEDD8/RUB1; neddylation) is best known as an important posttranslational modification of the cullin subunits of cullin-RING-type E3 ubiquitin ligases (CRLs). MLN4924 has recently been described as an inhibitor of NEDD8-ACTIVATING ENZYME1 (NAE1) in human. Here, we show that MLN4924 is also an effective and specific inhibitor of NAE1 enzymes from Arabidopsis (Arabidopsis thaliana) and other plant species. We found that MLN4924-treated wild-type seedlings have phenotypes that are highly similar to phenotypes of mutants with a partial defect in neddylation and that such neddylation-defective mutants are hypersensitive to MLN4924 treatment. We further found that MLN4924 efficiently blocks the neddylation of cullins in Arabidopsis and that MLN4924 thereby interferes with the degradation of CRL substrates and their downstream responses. MLN4924 treatments also induce characteristic phenotypes in tomato (Solanum lycopersicum), Cardamine hirsuta, and Brachypodium distachyon. Interestingly, MLN4924 also blocks the neddylation of a number of other NEDD8-modified proteins. In summary, we show that MLN4924 is a versatile and specific neddylation inhibitor that will be a useful tool to examine the role of NEDD8- and CRL-dependent processes in a wide range of plant species.


A shock flash breaking out of a dusty red supergiant.
Shock-breakout emission is light that arises when a shockwave, generated by the core-collapse explosion of a massive star, passes through its outer envelope. Hitherto, the earliest detection of such a signal was at several hours after the explosion1, although a few others had been reported2-7. The temporal evolution of early light curves should provide insights into the shock propagation, including explosion asymmetry and environment in the vicinity, but this has been hampered by the lack of multiwavelength observations. Here we report the instant multiband observations of a type II supernova (SN 2023ixf) in the galaxy M101 (at a distance of 6.85 ± 0.15 Mpc; ref. 8), beginning at about 1.4 h after the explosion. The exploding star was a red supergiant with a radius of about 440 solar radii. The light curves evolved rapidly, on timescales of 1-2 h, and appeared unusually fainter and redder than predicted by the models9-11 within the first few hours, which we attribute to an optically thick dust shell before it was disrupted by the shockwave. We infer that the breakout and perhaps the distribution of the surrounding dust were not spherically symmetric.


Prevalence of diabetes and pre-diabetes in a cohort of Italian young adults with Williams syndrome.
Williams syndrome (WS) is a rare, multisystemic genomic disorder showing a high prevalence of impaired glucose metabolism in adulthood. The reason for this association is unknown, though hemizygosity for genes mapping to the WS chromosome region has been implicated. Twenty-two Italian young adults with WS (13 females, 9 males) were studied. A 75 g oral glucose tolerance test (OGTT) was performed and β-cell function was estimated with Homeostasis Model Assessment (HOMA)-B%, Insulinogenic Index, and corrected insulin response whereas insulin sensitivity was assessed with HOMA-Insulin Resistance Index, Quantitative Insulin Check Index, and composite Insulin Sensitivity Index. One patient had known diabetes mellitus (DM), whereas impaired glucose tolerance (IGT) was diagnosed in 12 patients and DM in one (63.6% prevalence of impaired glucose metabolism). IGT patients were more insulin resistant than those with normal glucose tolerance (NGT), whereas β-cell function was unchanged or increased. Islet autoimmunity was absent. Logistic regression showed that impaired glucose metabolism was not associated with age, body mass index (BMI), or family history of DM. β-cell function, insulin sensitivity, and post-load insulin levels did not differ between WS patients with NGT and healthy controls comparable for gender, age, and BMI, though WS-NGT patients had higher post-load glucose values. These data confirm the high prevalence of impaired glucose metabolism in WS young adults, thus suggesting the need for screening these patients with OGTT. IGT is associated with reduced insulin sensitivity, but not with impaired β-cell function, islet autoimmunity, and traditional risk factors for type 2 DM.


Morphologic investigations on the rebound phenomenon after corticosteroid-induced atrophy in human skin.
Cutaneous atrophy was induced on the forearms of 4 volunteers by continuous occlusive application of clobetasol-17-propionate for 6 weeks, after which time the steroid was discontinued. Epidermal and dermal changes during the subsequent rebound "flare" were monitored for 2 weeks by light and transmission electron microscopy. An exuberant hyperplasia characterized the epidermal response. Within 2 days poststeroid, most basal cells displayed fine structural features typical of highly proliferating cells. "Dark"-staining keratinocytes appeared in large numbers 4 days poststeroid, preceding a 4-fold maximal increase of viable epidermal thickness which occurred at 7 days. The stratum corneum, initially very thin, increased markedly in thickness and displayed the typical basket-weave appearance. By 14 days, Langerhans cells, which were absent immediately poststeroid, were again present. At this time, the epidermis returned to a nearly normal state. Dermal restitution was similarly rapid. Initially, fibroblasts appeared very active as evidenced by widely dilated endoplasmic reticulum filled with flocculent material. Ground substance increased continuously, reaching normal levels by 14 days. An increase in postcapillary venules was noted during the rebound flare. Swift epidermal and dermal changes are evidence that topical corticosteroids are rapidly cleared from the skin. The vigorous epidermal hyperplasia reflects repair of the atrophic, suppressed epidermis as well as a response to desiccation consequent to the loss of the stratum corneum.


Veterans Justice Programs: Assessing Population Risks for Suicide Deaths and Attempts.
Understanding suicide risks among Veteran subpopulations is a national priority. This study assessed risks of suicide, suicide attempts, and other-cause mortality among recipients of Veterans Health Administration (VHA) Veterans Justice Program services as compared to other Veteran VHA users. Per VHA records, the cohort included 5,401,192 Veterans alive as of January 1, 2013 and with VHA utilization in 2012. Receipt of Veterans Justice Outreach (VJO) or Health Care for Reentry Veterans (HCRV) services in 2012 was assessed using encounter codes. Multivariable proportional hazards regression assessed risks of suicide (per National Death Index search results from the VA/DoD Mortality Data Repository) and attempts (per diagnoses and site reports) in 2013-2016, adjusting for demographic and clinical indicators. Compared to other patients, Veterans with VJO encounters had greater risk of suicide (unadjusted HR = 2.80, 95% confidence interval [CI] = 2.30-3.40; adjusted HR = 1.25, 95% CI = 1.02-1.53) and attempts (unadjusted HR = 8.88, 95% CI = 8.45-9.35; adjusted HR = 1.06, 95% CI = 1.00-1.11). Veterans with HCRV encounters had elevated risk of suicide attempts (unadjusted HR = 4.56, 95% CI = 4.00-5.20; adjusted HR = 1.42, 95% CI = 1.24-1.62). Risks were also elevated for other external causes of mortality. Findings document increased risk of suicidal behavior among Veterans Justice Program recipients. These results have informed VHA suicide prevention activities.


Adiabatic coarse-graining and simulations of stochastic biochemical networks.
We propose a universal approach for analysis and fast simulations of stiff stochastic biochemical networks, which rests on elimination of fast chemical species without a loss of information about mesoscopic, non-Poissonian fluctuations of the slow ones. Our approach is similar to the Born-Oppenheimer approximation in quantum mechanics and follows from the stochastic path integral representation of the cumulant generating function of reaction events. In applications with a small number of chemical reactions, it produces analytical expressions for cumulants of chemical fluxes between the slow variables. This allows for a low-dimensional, interpretable representation and can be used for high-accuracy, low-complexity coarse-grained numerical simulations. As an example, we derive the coarse-grained description for a chain of biochemical reactions and show that the coarse-grained and the microscopic simulations agree, but the former is 3 orders of magnitude faster.


Occupational exposure to whole body vibration-train drivers.
Whole body vibration exposure of the train drivers working for State Railway Lines is assessed by referring to ISO standard 2631 -1 and EU directive 2002/44/EC. The vibration measurements were done in the cabins of suburban and intercity train drivers. Suburban train driver performs his job usually in standing posture. Whereas intercity train driver works generally in seated (bending forward) posture and exposed to longer periods of continuous vibration, compared to suburban train drivers. The mean accelerations, a, along lateral, y, and vertical, z, directions measured on the driver seat (on the cabin floor) of the intercity (suburban) train were 1.4a (y) = 0.55 (0.28) m/s(2) and a (z) = 0.65 (0.23) m/s(2). Daily exposure action values suggested in EU directive are exceeded in case of intercity train drivers and their exposure falls within the health caution zone of ISO 2631-1. Intercity train drivers are therefore under the risk of having spinal disorders. A health surveillance plan requiring every five years the reassessment of the state of the spinal system of train drivers is suggested. As an early preventive measure, extended work day or more than one shift in a day is advised to be discouraged.


Effect of control strategies on prevalence, incidence and re-infection of clonorchiasis in endemic areas of China.
A pilot clonorchiasis control project was implemented to evaluate the efficacies of various chemotherapy strategies on prevalence, incidence and re-infection in Heilongjiang Province, China. Seven intervention groups (14,139 residents, about 2000 in each group) in heavily or moderately endemic areas were subjected to repeated praziquantel administration from 2001 to 2004. In the selective chemotherapy groups, residents were examined for fecal eggs, and those who tested positive were treated with three doses of 25 mg/kg praziquantel at 5-hour-intervals in one day. However, all residents were treated in the mass chemotherapy groups. In heavily endemic areas, two mass treatments of all residents in 2001 and 2003 reduced the prevalence from 69.5% to 18.8%, while four annual mass treatments reduced the prevalence from 48.0% in 2001 to 8.4% in 2004. Selective annual treatments for egg-positive subjects reduced the egg-positive rates from 54.9% in 2001 to 15.0% in 2004 or from 73.2% in 2001 to 12.3% in 2004. Selective treatments every 6 months significantly reduced the prevalence from 59.5% in 2001 to 7.5% in 2004. All of the repeated treatments reduced EPG (eggs per gram of feces) significantly. The annual mass treatment and selective treatment every 6 months produced lower prevalence and re-infection rates and higher egg reduction rate than annual selective treatments did. In the moderate endemic areas, egg positive rates were 24.8% and 29.7% in 2001 but were 1.9% and 1.3% after 2 or 3 selective treatments. The prevalence, incidence, re-infection rates in a moderately endemic area were significantly lower than those of heavy endemic areas. Repeated mass treatment or selective treatment with praziquantel every 6 to 12 months is highly effective for clonorchiasis control in heavily endemic areas. In contrast, one or two selective treatments with health education is effective in moderately endemic areas.


Vaccinia virus: a selectable eukaryotic cloning and expression vector.
Foreign DNA was inserted into two nonessential regions of the vaccinia virus genome by homologous recombination in cells infected with virus and transfected with plasmids containing the foreign DNA elements flanked by vaccinia virus DNA. Thymidine kinase-negative (TK-) recombinants were selected after inserting foreign DNA into the coding region of the TK gene of wild-type vaccinia virus; TK+ recombinants were selected after inserting the herpesvirus TK gene into TK- mutants of vaccinia virus. For TK+ expression, it was necessary to insert a 275-base-pair DNA fragment containing the initiation site and sequences upstream of an early vaccinia virus transcript next to the coding sequences of the herpesvirus gene. The unique ability of the herpesvirus TK to phosphorylate 125I-labeled deoxycytidine provided independent confirmation of gene expression. These studies demonstrate the use of vaccinia virus as a selectable cloning and expression vector, confirm the map location of the vaccinia virus TK gene, and provide initial information regarding the location of vaccinia virus transcriptional regulatory sequences.


Women's rights at work worth fighting for. Part 1.
The ACTU campaign to replace the WorkChoices legislation with fair labour laws is also a campaign for women workers. In almost every regard, the harsh impact of the Governments' new IR laws will be felt most keenly by women, because they exaggerate the disadvantage that many women face in the labour market. Women employed in jobs requiring lower skills, and those working unsocial or irregular hours of work or in 'atypical' employment will be particularly hard hit.


Localization and sub-cellular shuttling of HTLV-1 tax with the miRNA machinery.
The innate ability of the human cell to silence endogenous retroviruses through RNA sequences encoding microRNAs, suggests that the cellular RNAi machinery is a major means by which the host mounts a defense response against present day retroviruses. Indeed, cellular miRNAs target and hybridize to specific sequences of both HTLV-1 and HIV-1 viral transcripts. However, much like the variety of host immune responses to retroviral infection, the virus itself contains mechanisms that assist in the evasion of viral inhibition through control of the cellular RNAi pathway. Retroviruses can hijack both the enzymatic and catalytic components of the RNAi pathway, in some cases to produce novel viral miRNAs that can either assist in active viral infection or promote a latent state. Here, we show that HTLV-1 Tax contributes to the dysregulation of the RNAi pathway by altering the expression of key components of this pathway. A survey of uninfected and HTLV-1 infected cells revealed that Drosha protein is present at lower levels in all HTLV-1 infected cell lines and in infected primary cells, while other components such as DGCR8 were not dramatically altered. We show colocalization of Tax and Drosha in the nucleus in vitro as well as coimmunoprecipitation in the presence of proteasome inhibitors, indicating that Tax interacts with Drosha and may target it to specific areas of the cell, namely, the proteasome. In the presence of Tax we observed a prevention of primary miRNA cleavage by Drosha. Finally, the changes in cellular miRNA expression in HTLV-1 infected cells can be mimicked by the add back of Drosha or the addition of antagomiRs against the cellular miRNAs which are downregulated by the virus.


Considerations for patients with psoriasis travelling under immunosuppression.
With the establishment of modern systemic therapies for psoriasis, comprehensive consultation is required for travelling with immune modulation. Logistic aspects regarding transport and storage, climatic peculiarities of the country of travel and drug dependent risks regarding infections must be considered. Vaccinations and preventive measures are emphasized. Depending on the current national recommendations, special features of vaccinations while under immunosuppression must be taken into account.


Secreted Neutrophil Gelatinase-Associated Lipocalin Shows Stronger Ability to Inhibit Cyst Enlargement of ADPKD Cells Compared with Nonsecreted Form.
Polycystic kidney disease (PKD) is one of the most common inherited diseases and is characterized by the development of fluid-filled cysts along multiple segments of the nephron. Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of PKD, which is caused by mutations in either PKD1 or PKD2 genes that encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. As ADPKD progresses, cysts enlarge and disrupt normal kidney architecture, eventually leading to kidney failure. Our previous study showed that overexpression of exogenous kidney-specific neutrophil gelatinase-associated lipocalin (NGAL) reduced cyst progression and prolonged the lifespan of ADPKD mice (Pkd1L3/L3, 2L3 for short). In this study, we attempted to explore the underlying mechanism of reduced cyst progression in the presence of NGAL using immortalized 2L3 cells. The results of MTT and BrdU incorporation assays showed that recombinant mouse NGAL (mNGAL) protein significantly decreased the viability and proliferation of 2L3 cells. Flow cytometry and western blot analyses showed that mNGAL inhibited activation of the ERK and AKT pathways and induced apoptosis and autophagy in 2L3 cells. In addition, a 3D cell culture platform was established to identify cyst progression in 2L3 cells and showed that mNGAL significantly inhibited cyst enlargement in 2L3 cells. Overexpression of secreted mNGAL (pN + LS) and nonsecreted mNGAL (pN - LS) repressed cell proliferation and cyst enlargement in 2L3 cells and had effects on markers involved in proliferation, apoptosis, and autophagy. However, secreted mNGAL had a more pronounced and consistent effect than that of nonsecreted form. These results reveal that secreted mNGAL has stronger ability to inhibit cyst enlargement of ADPKD cells than that of nonsecreted form. These findings could help to identify strategies for the future clinical treatment of ADPKD.


[The relation of the activity of postheparin lipoprotein lipase with the CBC parameters in patients with acute coronary syndrome].
The aim of presented investigation was to study of the relation of the activity of postheparin lipoprotein lipase (LPL) with the blood test parameters in patients with acute coronary syndrome(ACS) during first 6-12 hours after appearance of acute anginous pain. 47 patients with the disease of coronary arteries (DCA) have been investigated. Acute form of ACS was revealed in 27 patients (mean age--62.9+/-11.7 years), chronic form--in 20 patients (mean age 67.9+/-14.0 years). The study was carried out in the first 6-12 hours after appearance of acute anginous pain. Control group consisted of 23 healthy subjects (mean age--37.5+/-8.9 years). Postheparin activity of LPL has been determined in whole cohort by potentiometric method. Blood test was carried out by standard method. The acute coronary syndrome was confirmed by electrocardiographic findings. In ACS group the activity of LPL significantly correlated inversely with the value of leukocytes (r=-0.4022, p=0.038), stab (r=-0.4808, p=0.011) and segmental leukocytes (r=-0.5853, p=0.001), erythrocyte sedimentation rate (r=-0.4188, p=0.030). Corning to the comparative analysis of chronic and acute forms of DCA, the activity of LPL was significantly lower in patients with chronic form compared to the acute form (p=0.043). Therefore, based on the obtained data it should be concluded that in 6-12 hours after development of acute coronary syndrome during worsening the inflammatory reaction (which reflected on the parameters of blood test) together with endothelial dysfunction it is expressed the decrease of the activity of endothelial enzyme LPL.


[Profile of effective donors from organ and tissue procurement services].
To characterize the profile of effective organ and tissue donors and to understand which organs and tissues were donated for transplantation. This was a quantitative, descriptive, exploratory, retrospective study that analyzed clinical data from 305 donors between January 2006 to December 2010. The data were then analyzed using descriptive analyses, generating frequency tables, measures of position (mean, minimum and maximum) and measures of dispersion (standard deviation) for data that was social and clinical in nature. There was an overall predominance of white (72%) and male (55%) individuals between the ages of 41 and 60 years (44%). The primary cause of brain death was cerebrovascular accident (55%). In the patient history, 31% of the patients were classified as overweight, 27% as hypertensive and only 4.3% as having diabetes mellitus. Vasoactive drugs were used in 92.7% of the donors, and the main drug of choice was noradrenaline (81.6%). Hyperglycemia and hypernatremia were diagnosed in 78% and 71% of the donors, respectively. Significant hemodynamic changes were found, and the results indicate that the use of vasoactive drugs was the main strategy used to control these changes. Furthermore, most donors presented with hyperglycemia and hypernatremia, which were frequently reported in association with brain death. The persistent nature of these findings suggests that the organ donors were inadequately maintained.


Thermodynamic and Transport Properties of LiF and FLiBe Molten Salts with Deep Learning Potentials.
Molten salts have attracted interest as potential heat carriers and/or fuel solvents in the development of new Gen IV nuclear reactor designs, high-temperature batteries, and thermal energy storage. In nuclear engineering, salts containing lithium fluoride-based compounds are of particular interest due to their ability to lower the melting points of mixtures and their compatibility with alloys. A machine learning potential (MLP) combined with a molecular dynamics study is performed on two popular molten salts, namely, LiF (50% Li) and FLiBe (66% LiF and 33% BeF2), to predict the thermodynamic and transport properties, such as density, diffusion coefficients, thermal conductivity, electrical conductivity, and shear viscosity. Due to the large possibilities of atomic environments, we employ training using Deep Potential Smooth Edition (DPSE) neural networks to learn from large datasets of 141,278 structures with 70 atoms for LiF and 238,610 structures with 91 atoms for FLiBe molten salts. These networks are then deployed in fast molecular dynamics to predict the thermodynamic and transport properties that are only accessible at longer time scales and are otherwise difficult to calculate with classical potentials, ab initio molecular dynamics, or experiments. The prospect of this work is to provide guidance for future works to develop general MLPs for high-throughput thermophysical database generation for a wide spectrum of molten salts.


RB stabilizes XPC and promotes cellular NER.
It has long been thought that the G(1)/S cell cycle checkpoint allows time for DNA repair by delaying S-phase entry. The p53 tumor suppressor pathway regulates the G(1)/S checkpoint by regulating the cyclin-dependent kinase inhibitor p21(Waf1/Cip1), but p53 also regulates the nucleotide excision DNA repair protein XPC. Here, using p53-null cell lines we show that additional mechanisms stabilize XPC protein and promote nucleotide excision repair (NER) in concert with the G(1)/S checkpoint. At least one mechanism to stabilize and destabilize XPC involves ubiquitin-mediated degradation of XPC, as the ubiquitin ligase inhibitor MG-132 blocked XPC degradation. The retinoblastoma protein RB, in its unphosphorylated form actually stabilized XPC and promoted NER as measured by host cell reactivation experiments. The data suggest that XPC protein and XPC-mediated NER are tightly linked to the G(1)/S checkpoint, even in cells lacking functional p53.


Multiple mechanisms for transcriptional regulation of the myc gene family in small-cell lung cancer.
The molecular mechanisms reported to regulate the expression of myc family genes are multiple and complex and include gene amplification, transcriptional activation, transcriptional attenuation, and mRNA stability. We have investigated which of these mechanisms are responsible for the extreme variation in myc gene family mRNA levels observed in human small-cell lung cancer cell lines. In addition to gene amplification, a block to nascent mRNA chain elongation, causing attenuation of transcription, is an important regulatory mechanism controlling the steady-state levels of c-myc and L-myc mRNA. The loss of transcriptional attenuation is correlated with overexpression of these two genes in cell lines which do not show gene amplification. Expression of c-myc mRNA appears to be dependent on promoter activity and attenuator function. In contrast, regulation of expression of the N-myc gene does not involve transcriptional attenuation; steady-state mRNA levels are correlated with promoter activity as well as gene amplification. We conclude that transcriptional regulation of each member of the myc gene family is accomplished by a different assortment of complex mechanisms, including gene copy number, promoter activation, and transcriptional attenuation. Interference at multiple points in this complex regulatory process appears to be an important mechanism by which small-cell lung cancer and other human tumors evade growth control.


Can a documentary increase help-seeking intentions in men? A randomised controlled trial.
We investigated whether a public health intervention-a three-part documentary called Man Up which explored the relationship between masculinity and mental health, well-being and suicidality-could increase men's intentions to seek help for personal and emotional problems. We recruited men aged 18 years or over who were not at risk of suicide to participate in a double-blind randomised controlled trial. Participants were randomly assigned (1:1) via computer randomisation to view Man Up (the intervention) or a control documentary. We hypothesised that 4 weeks after viewing Man Up participants would report higher levels of intention to seek help than those who viewed the control documentary. Our primary outcome was assessed using the General Help Seeking Questionnaire, and was analysed for all participants. The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12616001169437, Universal Trial Number: U1111-1186-1459) and was funded by the Movember Foundation. Three hundred and fifty-four men were assessed for eligibility for the trial and randomised to view Man Up or the control documentary. Of these, 337 completed all stages (nine participants were lost to follow-up in the intervention group and eight in the control group). Linear regression analysis showed a significant increase in intentions to seek help in the intervention group, but not in the control group (coef.=2.06, 95% CI 0.48 to 3.63, P=0.01). Our trial demonstrates the potential for men's health outcomes to be positively impacted by novel, media-based public health interventions that focus on traditional masculinity. ACTRN12616001169437, Results.


[Binding of NR1 plasmid DNA to membrane during replication in Escherichia coli mini-cells].
Studying the replication of NR1 plasmid in E. coli mini-cells it was shown that the character of bond between plasmid DNA and membrane depends on the stage of replication cycle of the plasmid. On initiation the DNA-membrane complex is sensitive to the action of ionic force. In the process of elongation the bond of DNA molecules with the membrane is unstable if exists at all, and can be broken even by the nonionic detergent. At the final stage of replication the newly synthesized molecules form a complex with the membrane structures which is unstable in the presence of 0,5 M NaCl. The destruction of the complex followed by the open cycle of plasmid DNA coming out of it takes place under the action of ionic detergent.


[Report on the ECR2003 (European Congress of Radiology): comparison of apparent diffusion coefficient (ADC) between different MRI scanners].
To analyze reproducibility of ADC measurements on different MRI scanners. Diffusion-weighted imaging (DWI) of a home-made phantom (gelatine of different concentration was enclosed in case of circle pillar shape) was performed with the following protocol; spin-echo type echo planar imaging; TR=7000 msec, TE=minimal, matrix=128 x 128, FOV=220 mm, slice thickness=5mm, NEX=1, b-factor=0, 500, and 1000 sec/mm(2) on four different 1.5T MR scanners [GE Signa Horizon (two of them), GE Signa Horizon Lx, and Siemens Magnetom Symphony]. Image analysis were performed on a workstation (GE Medical Systems) or on an operators console of Symphony (for data of Symphony). We used two-point method. Regions of interest (ROIs) were set on every part of ADC map of home-made phantom and ADCs were measured. A linear approximation graphs were also made with every MRI scanner and b-factor. A linear approximation was performed, formulas were y=-0.08x+2.32, r(2)=0.84(Lx), y=-0.09x+2.58, r(2)=0.89(Horizon-1) y=-0.11x+2.67, r(2)=0.95(Horizon-2), y=-0.08x+2.42, r(2)=0.97(Symphony) at b-factor of 500sec/mm(2). y=-0.08x+2.33, r(2)=0.91(Lx), y=-0.09x+2.43, r(2)=0.93(Horizon-1), y=-0.08x +2.48, r(2)=0.92(Horizon-2), y=-0.07x+2.39, r(2)=0.96(Symphony) at b-factor of 1000 sec/mm(2). ADC values measured at two MRI scanners (same model and older than the other scanners) are higher than other scanners on b-factor=500 sec/mm(2), but at b-factor=1000 sec/mm(2), a good relationship between every scanners was obtained. This result seems to depend on generation of the MRI scanners; newly scanners have good relations b-factor 500 and 1000 sec/mm(2). Pulse sequence design may be improved and optimized in newly scanners. When ADCs were used as quantitative value, a proper b-factor must be used.


Single-Cell RNA-seq Identifies Cell Subsets in Human Placenta That Highly Expresses Factors Driving Pathogenesis of SARS-CoV-2.
Infection by the Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) results in the novel coronavirus disease COVID-19, which has posed a serious threat globally. Infection of SARS-CoV-2 during pregnancy is associated with complications such as preterm labor and premature rupture of membranes, and a proportion of neonates born to infected mothers are also positive for the virus. During pregnancy, the placental barrier protects the fetus from pathogens and ensures healthy development. To predict if the placenta is permissive to SARS-CoV-2, we utilized publicly available single-cell RNA-seq data to identify if the placental cells express the necessary factors required for infection. SARS-CoV-2 binding receptor ACE2 and the S protein priming protease TMPRSS2 are co-expressed by a subset of syncytiotrophoblasts (STB) in the first trimester and extravillous trophoblasts (EVT) in the second trimester human placenta. In addition, the non-canonical receptor BSG/CD147 and other proteases (CTSL, CTSB, and FURIN) are detected in most of the placental cells. Other coronavirus family receptors (ANPEP and DPP4) were also expressed in the first and second trimester placental cells. Additionally, the term placenta of multiple species including humans expressed ACE2, DPP4, and ANPEP along with the viral S protein proteases. The ACE2- and TMPRSS2-positive (ACE2 + TMPRSS2 +) placental subsets expressed mRNA for proteins involved in viral budding and replication. These cells also had the mRNA for proteins that physically interact with SARS-CoV-2 in host cells. Further, we discovered unique signatures of genes in ACE2 + TMPRSS2 + STBs and EVTs. The ACE2 + TMPRSS2 + STBs are highly differentiated cells and express genes involving mitochondrial metabolism and glucose transport. The second trimester ACE2 + TMPRSS2 + EVTs are enriched for markers of endovascular trophoblasts. Both these subtypes abundantly expressed genes in the Toll-like receptor pathway. The second trimester EVTs are also enriched for components of the JAK-STAT pathway that drives inflammation. We carried out a systematic review and identified that in 12% of pregnant women with COVID-19, the placenta was infected with SARS-CoV-2, and the virus was detected in STBs. To conclude, herein we have uncovered the cellular targets for SARS-CoV-2 entry and have shown that these cells can potentially drive viremia in the developing human placenta. Our results provide a basic framework toward understanding the paraphernalia involved in SARS-CoV-2 infections in pregnancy.


Placental/umbilical cord blood transplantation.
In this article we summarize the clinical outcome of unrelated placental/umbilical cord blood (CB) transplantation, discuss the biological characteristics of CB hematopoietic progenitor/stem cells (HPC) and balance the relative advantages and disadvantages of this therapy as compared with transplantation of other HPC sources. Moreover, we discuss CB banking programs at local, national and international levels. The data reported by the investigators of the New York Placental/Umbilical Cord Blood Program and of the Eurocord group indicate that the clinical outcome of allogeneic unrelated CB transplantation is significantly related to cell dose, being more effective in children than in adults, and is highly dependent on disease stage at transplantation. Furthermore, both studies show lower graft-versus-host disease (GvHD) frequency and severity and prolonged time intervals for platelet engraftment as compared to those of bone marrow and mobilized peripheral blood recipients. Although the data from the New York Placental/Umbilical Cord Blood Program seem to support a negative effect of HLA differences, the latter were not significantly associated with survival in the Eurocord series. Additional observations are therefore necessary to collect conclusive evidence in this regard. Currently available data show that CB contains a higher proportion of primitive HPC and that CB-HPC possess higher proliferation and expansion potentials as compared to adult bone marrow. Furthermore, there is some evidence indicating that CB-HPC are more adequate than HPC from other sources for genetic manipulation and gene therapy. Despite the significant advances in the knowledge of the biology and in the clinical use of CB, a number of problems remain unsolved, including the standardization of banking procedures and unit quality and the development of suitable protocols for transplantation of adult patients.


Alpha(1) and alpha(2)-adrenoreceptor antagonists in streptozotocin- and vincristine-induced hyperalgesia.
The effect of alpha(1)- and alpha(2)-adrenoreceptor antagonists (prazosin and yohimbine, respectively) on streptozotocin (STZ)- and vincristine (VIN)-induced hyperalgesia in rats was studied. In two experimental models, yohimbine (1.0 mg/kg ip) completely abolished STZ and VIN-induced hyperalgesia. This effect was markedly prolonged in diabetic rats. Prazosin (0.3 mg/kg ip) attenuated and delayed development of STZ-induced hyperalgesia. In VIN-elicited neuropathy, the administration of prazosin not only delayed hyperalgesia but also produced antinociception. After cessation of drug administration, a significant decrease in nociceptive threshold was observed. The obtained results seem to indicate that both alpha(1)- and alpha(2)-adrenoreceptors are engaged in diabetic (STZ) and toxic (VIN) neuropathy.


Survival in acute myeloid leukemia is associated with NKp44 splice variants.
NKp44 is a receptor encoded by the NCR2 gene, which is expressed by cytokine-activated natural killer (NK) cells that are involved in anti-AML immunity. NKp44 has three splice variants corresponding to NKp44ITIM+ (NKp44-1) and NKp44ITIM- (NKp44-2, and NKp44-3) isoforms. RNAseq data of AML patients revealed similar survival of NKp46+NKp44+ and NKp46+NKp44- patients. However, if grouped according to the NKp44 splice variant profile, NKp44-1 expression was significantly associated with poor survival of AML patients. Moreover, activation of PBMC from healthy controls showed co-dominant expression of NKp44-1 and NKp44-3, while primary NK clones show more diverse NKp44 splice variant profiles. Cultured primary NK cells resulted in NKp44-1 dominance and impaired function associated with PCNA over-expression by target cells. This impaired functional phenotype could be rescued by blocking of NKp44 receptor. Human NK cell lines revealed co-dominant expression of NKp44-1 and NKp44-3 and showed a functional phenotype that was not inhibited by PCNA over-expression. Furthermore, transfection-based overexpression of NKp44-1, but not NKp44-2/NKp44-3, reversed the endogenous resistance of NK-92 cells to PCNA-mediated inhibition, and resulted in poor formation of stable lytic immune synapses. This research contributes to the understanding of AML prognosis by shedding new light on the functional implications of differential splicing of NKp44.


Turbinaric acid, a cytotoxic secosqualene carboxylic acid from the brown alga Turbinaria ornata.
A moderately cytotoxic secosqualene carboxylic acid designated turbinaric acid [1] has been isolated from the brown alga Turbinaria ornata, and it has been identified to be 4,8,13,17,21-pentamethyl-4,8,12,16,20-docosapentaenoic acid by means of spectral analysis and synthesis.


The revision of the 2014 European tobacco products directive: an analysis of the tobacco industry's attempts to 'break the health silo'.
The 2014 European Union (EU) Tobacco Products Directive (TPD) was negotiated in a changed policy context, following adoption of the EU's 'Smart Regulation' agenda, which transnational tobacco companies (TTCs) anticipated would increase their influence on health policy, and the WHO Framework Convention on Tobacco Control (FCTC), which sought to reduce it. This study aims to explore the scale and nature of the TTCs' lobby against the EU TPD and evaluate how these developments have affected their ability to exert influence. Analysis of 581 documents obtained through freedom of information requests, 28 leaked Philip Morris International (PMI) documents, 17 TTC documents from the Legacy Library, web content via Google alerts and searches of the EU institutions' websites, plus four stakeholder interviews. The lobby was massive. PMI alone employed over 160 lobbyists. Strategies mainly used third parties. Efforts to 'Push' (amend) or 'Delay' the proposal and block 'extreme policy options' were partially successful, with plain packaging and point of sales display ban removed during the 3-year delay in the Commission. The Smart Regulation mechanism contributed to changes and delays, facilitating meetings between TTC representatives (including ex-Commission employees) and senior Commission staff. Contrary to Article 5.3, these meetings were not disclosed. During the legislative process, Article 5.3 was not consistently applied by non-health Directorates of the European Commission, while the tools of the Smart Regulation appear to have facilitated TTC access to, and influence on, the 2014 TPD. The use of third parties undermines Article 5.3.


Endoscopic Endonasal Orbital Floor Fracture Repair With Mucosal Preservation to Reinforce the Fractured Bone.
Treatment of orbital floor fracture is often needed to cure diplopia and enophthalmos. However, the available surgical methods have many limitations. An endoscopic endonasal reduction is a familiar approach for otolaryngologists; however, reconstruction of the orbital floor may pose certain problems. Here, the authors developed the endoscopic endonasal orbital floor fracture repair with mucosal preservation procedure (mucosal preservation procedure). This study aims to evaluate outcomes after the mucosal preservation procedure. The authors analyzed 18 patients who had their orbital floor repaired using the mucosal preservation procedure. Pre- and post-operative ocular motility range was measured with a Hess screen test, and the percentage of Hess area ratio (HAR%) was used for all statistical comparisons. The distance between the fractured bone and orbital floor (DBFO) on computed tomography was measured before and four months after surgery. Overall, diplopia, and pain improved after surgery in all patients. Diplopia and pain completely disappeared in 17 patients, while only mild diplopia remained in one. HAR% increased significantly, whereas DBFO reduced significantly after the operation. In conclusion, the outcome of the mucosal preservation procedure was favorable without any major complications. Further studies with larger numbers of patients are needed to verify our technique.


[Transformation of frequency-modulated afferent activity by spinal motor neurons in the cat].
Transformation of the frequency-modulated afferent activity into postsynaptic shifts of the membrane potential in the spinal motoneurons and then into firing rates of evoked activity was studied in anesthetized cats. The phase of membrane potential oscillations evoked by activation of excitatory monosynaptic inputs practically coincided with the phase of a modulation signal in a wide frequency range. Phase lags of the oscillation were observed only at high frequencies, but even at 10.0 Hz the lag did not exceed 30-45 degrees. At the same time changes in the firing rates of the evoked activity always led the modulation signal. Transformation properties of the spinal motoneurons are discussed from the standpoint of nonlinear dynamic sensitivity of the central neurons.


Cheating and the effect of promises in Indian and German children.
Cheating is harmful to others and society at large. Promises have been shown to increase honesty in children, but their effectiveness has not been compared between different cultural contexts. In a study (2019) with 7- to 12-year-olds (N = 406, 48% female, middle-class), voluntary promises reduced cheating in Indian, but not in German children. Children in both contexts cheated, but cheating rates were lower in Germany than in India. In both contexts, cheating decreased with age in the (no-promise) control condition and was unaffected by age in the promise condition. These findings suggest that there may exist a threshold beyond which cheating cannot be further reduced by promises. This opens new research avenues on how children navigate honesty and promise norms.


[The use if Francisella tularensis lipopolysaccharide in the dot solid phase enzyme immunoassay].
To determine antitularemia antibodies in the sera of humans and animale, the possibility of using dot immunoassay with the use of F. tularensis lipopolysaccharide (LPS) as antigen-containing preparation was ascertained. Experiments demonstrated that this method made it possible to determine specific antitularemia antibodies in the sera of sick and immunized humans and animals. Investigetions carried out with the use of heterologous antisera to F. novicida, F. novicida-like and F. philomiragia, as well as Brucellf abortus, Vibrio cholerae and Yersinia enterocolitica, revealed that F. tularensis S-LPS was highly specific. The results obtained in this investigation are indicative of good prospects of using F. tularensis LPS in dot blotting for the laboratory diagnostics of tularemia in humans.


Leveraging auxiliary measures: a deep multi-task neural network for predictive modeling in clinical research.
Accurate predictive modeling in clinical research enables effective early intervention that patients are most likely to benefit from. However, due to the complex biological nature of disease progression, capturing the highly non-linear information from low-level input features is quite challenging. This requires predictive models with high-capacity. In practice, clinical datasets are often of limited size, bringing danger of overfitting for high-capacity models. To address these two challenges, we propose a deep multi-task neural network for predictive modeling. The proposed network leverages clinical measures as auxiliary targets that are related to the primary target. The predictions for the primary and auxiliary targets are made simultaneously by the neural network. Network structure is specifically designed to capture the clinical relevance by learning a shared feature representation between the primary and auxiliary targets. We apply the proposed model in a hypertension dataset and a breast cancer dataset, where the primary tasks are to predict the left ventricular mass indexed to body surface area and the time of recurrence of breast cancer. Moreover, we analyze the weights of the proposed neural network to rank input features for model interpretability. The experimental results indicate that the proposed model outperforms other different models, achieving the best predictive accuracy (mean squared error 199.76 for hypertension data, 860.62 for Wisconsin prognostic breast cancer data) with the ability to rank features according to their contributions to the targets. The ranking is supported by previous related research. We propose a novel effective method for clinical predictive modeling by combing the deep neural network and multi-task learning. By leveraging auxiliary measures clinically related to the primary target, our method improves the predictive accuracy. Based on featue ranking, our model is interpreted and shows consistency with previous studies on cardiovascular diseases and cancers.


Effectiveness of the Mediterranean diet: can it help delay or prevent Alzheimer's disease?
Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease characterized by cognitive and memory deterioration, with an increasing prevalence in the industrialized countries and an extraordinary cost of caring for patients. Due to the limited information available on the exact pathophysiology of the disease, over the last years there have been extensive efforts on the identification of possible risk factors, but no conclusive data have been obtained. Some risk factors have been identified but no clear evidence on what is clearly associated with the occurrence and progression of AD are available, and in particular no effective preventive strategies have been found. One of the most intriguing and appealing lines of investigation is the association between lifestyle habits such as diet and dietary compounds and the occurrence of AD. In this review, we focus on studies that investigated the association between nutrition and AD, paying particular attention to the role of a dietary pattern such as a Mediterranean-like diet on the occurrence of such disease. Studies in support of Mediterranean diet as an optimal diet for prevention of cardiovascular and major chronic diseases has rapidly evolved. A recent meta-analysis from our group, comprising prospective studies that investigated the association between adherence to Mediterranean diet and health status, showed a significant association between a greater adherence to Mediterranean diet and a reduced risk of major chronic degenerative diseases, including AD. Moreover, the Mediterranean diet has been extensively reported to be associated with a favorable health outcome and a better quality of life.


Cytoskeletal disruption activates the DLK/JNK pathway, which promotes axonal regeneration and mimics a preconditioning injury.
Nerve injury can lead to axonal regeneration, axonal degeneration, and/or neuronal cell death. Remarkably, the MAP3K dual leucine zipper kinase, DLK, promotes each of these responses, suggesting that DLK is a sensor of axon injury. In Drosophila, mutations in proteins that stabilize the actin and microtubule cytoskeletons activate the DLK pathway, suggesting that DLK may be activated by cytoskeletal disruption. Here we test this model in mammalian sensory neurons. We find that pharmacological agents designed to disrupt either the actin or microtubule cytoskeleton activate the DLK pathway, and that activation is independent of calcium influx or induction of the axon degeneration program. Moreover, activation of the DLK pathway by targeting the cytoskeleton induces a pro-regenerative state, enhancing axon regeneration in response to a subsequent injury in a process akin to preconditioning. This highlights the potential utility of activating the DLK pathway as a method to improve axon regeneration. Moreover, DLK is required for these responses to cytoskeletal perturbations, suggesting that DLK functions as a key neuronal sensor of cytoskeletal damage.


Combining maternal age and serum alpha-fetoprotein to predict the risk of Down syndrome.
Twenty-eight cases of Down syndrome with maternal serum alpha-fetoprotein (AFP) measured at second trimester were added to 137 previously reported cases. Seventy-eight percent of affected pregnancies had levels at or below the median AFP value, compared with 50% of unaffected pregnancies. Maternal age at delivery and serum AFP levels by multiples of the median were used to construct a table to determine the risk of Down syndrome. This was compared with the risk for a 35-year-old woman (one in 365). Similar risks were estimated for a 21-year-old with AFP below 0.4 multiples of the median, a 23-year-old below 0.5, a 26-year-old below 0.6, and a 29-year-old below 0.7 multiples of the median. This study provides guidelines for counseling pregnant women who have low serum AFP levels.


Bone morphogenetic protein-2 decorated silk fibroin films induce osteogenic differentiation of human bone marrow stromal cells.
Bone morphogenetic protein (BMP)-2 has a critical role in bone formation and regeneration. Therefore, the ability to immobilize this molecule in certain matrices may be crucial in bone tissue engineering. Using carbodiimide chemistry, BMP-2 was directly immobilized on silk fibroin films. Whereas human bone marrow stromal cells cultured on unmodified silk fibroin films in the presence of osteogenic stimulants exhibited little if any osteogenesis, the same cells cultured on BMP-2 decorated films in the presence of osteogenic stimulants differentiated into an osteoblastic lineage as assessed by their significantly elevated alkaline phosphatase activity, calcium deposition, and higher transcript levels of collagen type I, bone sialoprotein, osteopontin, osteocalcin, BMP-2, and cbfa1. Using cell culture inserts, it was demonstrated that differentiation was induced by the immobilized protein and not by protein released into the culture medium. Comparison with a similar amount of medium-supplemented BMP-2, where no additional protein was added with medium changes, showed that delivery of BMP-2 immobilized on the biomaterial surface was more efficient than soluble delivery. The results illustrate that BMP-2 covalently coupled on silk biomaterial matrices retains biological function in vitro based on the induction of osteogenic markers in seeded bone marrow stromal cells.


An in vitro model for the study of phagocytosis of damaged hepatocytes by rat Kupffer cells.
One function of Kupffer cells is the phagocytosis of nonviable hepatocytes. Our aims were to develop a model for phagocytosis of damaged hepatocytes by rat Kupffer cells in vitro, and to characterise prostaglandin E2 (PGE2), prostacyclin (PGI), and tumour necrosis factor-alpha (TNF) production in this model. Kupffer cells were incubated alone or with damaged hepatocytes for up to 18 h, then washed and cultured for up to 66 h. To compare mediator responses produced during inert particle phagocytosis, Kupffer cells were also incubated with latex beads. Phagocytic uptake of hepatocyte debris was confirmed in at least 50% of Kupffer cells. A dissociation between TNF and PGI responses was found for both latex beads and damaged hepatocytes, such that a TNF secretory response was not triggered by either stimulus whereas PGI production was increased for both. Although phagocytosis of beads increased PGE2 production, phagocytosis of hepatocytes did not. Phagocytosis of damaged hepatocytes by Kupffer cells results in the production of PGI but not PGE2 or TNF.


Prevalence of headache in Swedish schoolchildren, with a focus on tension-type headache.
To estimate the prevalence of tension-type headache, migraine and other headaches, 1850 schoolchildren, age 7-15 years, from the city of Uppsala, were invited to complete a questionnaire. The response rate was 74.1%. To validate the information from the questionnaires, 131 children and their parents were interviewed. Using the criteria of the International Headache Society, the 1-year prevalence of tension-type headache and migraine was 9.8 and 11.0%, respectively. However, these prevalence rates increased considerably, to 23.0 and 17.0%, respectively, when excluding the criteria defining the number of earlier episodes and duration of headache. The prevalence of headache increased with age, similarly in girls and boys up to 11 years, and thereafter only in girls. The preponderance in teenage girls was even more pronounced for tension-type headache than for migraine. Our results indicate an increase over time in headache prevalence when compared with findings in a study conducted in the same city in 1955.


DSM III in outreach emergency psychiatry.
As making a diagnosis in emergency psychiatry is often difficult, whether the systematic use of a diagnostic classification is worthwhile can be questioned. In the psychiatric emergency service in the Hague, The Netherlands, the use of a DSM III classification list was evaluated by comparing emergency service diagnoses during subsequent psychiatric treatments in 237 out of 300 consecutive contacts. For Organic Mental Disorders, Psychoactive Substance Use Disorders, Schizophrenia and Mood Disorders, the Kappa coefficient of agreement was found to lie between 0.5 and 0.6. The application of DSM III categories is considered to be suited to diagnostic classification in outreach emergency psychiatry.


Reduced Dicer expression in the cord blood of infants admitted with severe respiratory syncytial virus disease.
Respiratory syncytial virus (RSV) is one of the most important causes of pediatric hospital admissions in the developed world. The ribonuclease Dicer is an important regulator of gene expression and cellular function via RNA interference, and may also have anti-viral functions. A previous microarray analysis of the cord blood of 5 patients with RSV disease suggested downregulation of Dicer. In order to further investigate whether reduced Dicer expression can predispose newborns to RSV disease, we have analyzed the gene expression of Dicer in the cord blood of 37 infants with confirmed RSV disease. The cord blood of 2108 newborns was collected. 51 had a positive nasopharyngeal aspirate for RSV <1 year, and were grouped according to disease severity. 37 had sufficient cord blood RNA of good quality. Dicer gene expression was assessed by qPCR analysis of cord blood using a TaqMan low-density array and compared to control infants who did not present with RSV disease using the Mann-Whitney test. There was significant downregulation of Dicer in the severe disease group: relative quantity 0.69 (95% CI: 0.56 - 0.87), p = 0.002. There was no significant downregulation in the mild disease group. We demonstrate reduced Dicer expression in the cord blood of infants with severe RSV disease, prior to RSV exposure. We theorize that this may predispose to RSV disease by disruption of leukocyte gene regulation or direct anti-viral RNA interference mechanisms.


Trophic niche differentiation and utilisation of food resources in Collembola is altered by rainforest conversion to plantation systems.
Intensively managed monoculture plantations are increasingly replacing natural forests across the tropics resulting in changes in ecological niches of species and communities, and in ecosystem functioning. Collembola are among the most abundant arthropods inhabiting the belowground system sensitively responding to changes in vegetation and soil conditions. However, most studies on the response of Collembola to land-use change were conducted in temperate ecosystems and focused on shifts in community composition or morphological traits, while parameters more closely linked to ecosystem functioning, such as trophic niches, received little attention. Here, we used stable isotope analysis (13C and 15N) to investigate changes in the trophic structure and use of food resources by Collembola in Jambi province (Sumatra, Indonesia), a region that experienced strong deforestation in the last decades. Isotopic values of Collembola from 32 sites representing four land-use systems were analyzed (rainforest, rubber agroforest, rubber (Hevea brasiliansis) and oil palm (Elaeis guineensis) monoculture plantations). Across Collembola species Δ13C values were highest in rainforest suggesting more pronounced processing of litter resources by microorganisms and consumption of these microorganisms by Collembola in this system. Lower Δ13C values, but high Δ13C variation in Collembola in oil palm plantations indicated that Collembola shifted towards herbivory and used more variable resources in this system. Small range in Δ15N values in Collembola species in monoculture plantations in comparison to rainforest indicated that conversion of rainforest into plantations is associated with simplification in the trophic structure of Collembola communities. This was further confirmed by generally lower isotopic niche differentiation among species in plantations. Across the studied ecosystems, atmobiotic species (Symphypleona and Paronellidae) occupied the lowest, whereas euedaphic Collembola species occupied the highest trophic position, resembling patterns in temperate forests. Some species of Paronellidae in rainforest and jungle rubber had Δ15N values below those of leaf litter suggesting algivory (Salina sp.1, Callyntrura sp.1 and Lepidonella sp.1), while a dominant species, Pseudosinella sp.1, had the highest Δ15N values in most of the land-use systems suggesting that this species at least in part lives as predator or scavenger. Overall, the results suggest that rainforest conversion into plantation systems is associated with marked shifts in the structure of trophic niches in soil and litter Collembola with potential consequences for ecosystem functioning and food-web stability.


A comparison of minimally invasive transforaminal lumbar interbody fusion and decompression alone for degenerative lumbar spondylolisthesis.
OBJECTIVEThe optimal minimally invasive surgery (MIS) approach for grade 1 lumbar spondylolisthesis is not clearly elucidated. In this study, the authors compared the 24-month patient-reported outcomes (PROs) after MIS transforaminal lumbar interbody fusion (TLIF) and MIS decompression for degenerative lumbar spondylolisthesis.METHODSA total of 608 patients from 12 high-enrolling sites participating in the Quality Outcomes Database (QOD) lumbar spondylolisthesis module underwent single-level surgery for degenerative grade 1 lumbar spondylolisthesis, of whom 143 underwent MIS (72 MIS TLIF [50.3%] and 71 MIS decompression [49.7%]). Surgeries were classified as MIS if there was utilization of percutaneous screw fixation and placement of a Wiltse plane MIS intervertebral body graft (MIS TLIF) or if there was a tubular decompression (MIS decompression). Parameters obtained at baseline through at least 24 months of follow-up were collected. PROs included the Oswestry Disability Index (ODI), numeric rating scale (NRS) for back pain, NRS for leg pain, EuroQol-5D (EQ-5D) questionnaire, and North American Spine Society (NASS) satisfaction questionnaire. Multivariate models were constructed to adjust for patient characteristics, surgical variables, and baseline PRO values.RESULTSThe mean age of the MIS cohort was 67.1 ± 11.3 years (MIS TLIF 62.1 years vs MIS decompression 72.3 years) and consisted of 79 (55.2%) women (MIS TLIF 55.6% vs MIS decompression 54.9%). The proportion in each cohort reaching the 24-month follow-up did not differ significantly between the cohorts (MIS TLIF 83.3% and MIS decompression 84.5%, p = 0.85). MIS TLIF was associated with greater blood loss (mean 108.8 vs 33.0 ml, p < 0.001), longer operative time (mean 228.2 vs 101.8 minutes, p < 0.001), and longer length of hospitalization (mean 2.9 vs 0.7 days, p < 0.001). MIS TLIF was associated with a significantly lower reoperation rate (14.1% vs 1.4%, p = 0.004). Both cohorts demonstrated significant improvements in ODI, NRS back pain, NRS leg pain, and EQ-5D at 24 months (p < 0.001, all comparisons relative to baseline). In multivariate analyses, MIS TLIF-as opposed to MIS decompression alone-was associated with superior ODI change (β = -7.59, 95% CI -14.96 to -0.23; p = 0.04), NRS back pain change (β = -1.54, 95% CI -2.78 to -0.30; p = 0.02), and NASS satisfaction (OR 0.32, 95% CI 0.12-0.82; p = 0.02).CONCLUSIONSFor symptomatic, single-level degenerative spondylolisthesis, MIS TLIF was associated with a lower reoperation rate and superior outcomes for disability, back pain, and patient satisfaction compared with posterior MIS decompression alone. This finding may aid surgical decision-making when considering MIS for degenerative lumbar spondylolisthesis.


Health status and health behaviors among citizen endurance Nordic skiers in the United States.
More than two-thirds of Americans are overweight or obese (69%) placing them at high risk for a wide array of chronic diseases. Physical activity anchors most approaches to obesity prevention and weight management, but physical activity levels remain low in the general US population. As a group, citizen athletes who compete in Nordic skiing events such as the American Birkebeiner participate in fitness cultures that promote physical activity. During October-November 2014, we emailed a 48 question online survey to 23,611 individuals who had participated in the American Birkebeiner ski event, the largest citizen ski race in North America. Descriptive statistics were used to summarize data. Binomial and student t test were used to compare binary and continuous outcomes to health behaviors of the US population. 5433 individuals responded. Obesity prevalence (BMI ≥30) was 3% and average BMI was 24. Skiers reported very good health (88%), higher fitness than peers (99%), freedom from depression (93%) low levels of smoking (3%), high consumption of fruits and vegetables, moderate alcohol use, and high levels of physical activity. Fifteen percent practiced all 4 healthy living characteristics known to reduce cardiovascular event risk. As a group, citizen endurance Nordic skiers enjoy low levels of obesity, below average BMI, and report lifestyle behaviors known to decrease obesity, promote health, and reduce cardiovascular disease risk. Future research should explore hypotheses that explain how the fitness cultures surrounding citizen athletic events support weight loss, cardiovascular fitness, and healthy lifestyle habits.


Bridging conservation across the ex situ-in situ spectrum: Insights into the reproductive ecology of the threatened narrow-headed gartersnake (Thamnophis rufipunctatus).
Zoo-based (ex situ) conservation breeding programs provide invaluable opportunities to uncover enigmatic behaviors and traits of focal species under managed care, which can support research and conservation management efforts. A suite of factors and a limited range have yielded population declines in the threatened narrow-headed gartersnake (Thamnophis rufipunctatus). Better understanding its cryptic ecology and life history (e.g., reproductive ecology) offers conservation benefits. We analyzed data on courtship behavior, parity and litter size, offspring size, and neonatal growth from an ex situ T. rufipunctatus population at the Phoenix Zoo from 2009 to 2018. Courtship behavior and parturition phenology are likely linked with the North American monsoon season, yet the courtship window may be wider than realized. We document the first instances of interannual iteroparity and multigenerational rearing of successful breeders at the ex situ level. Litter sizes varied but were relative to maternal body mass, suggesting that fecundity may be driven by intrinsic condition (e.g., age and size) of breeding females. Mean offspring body masses were equivalent between sexes, and neonate growth trends were quadratic during their first 9 months. Sexual dimorphism became apparent around 4-5 months age. Much of these data are novel for T. rufipunctatus and provide insight into their reproductive ecology. Phenology of reproductive ecology and body size metrics can guide field surveillance, age estimations, and population ecology monitoring, as well as inform ex situ adaptive management practices. Strategies spanning the ex situ-in situ spectrum are applicable to other imperiled taxa to better inform conservation management decisions.


Simultaneous determination of docetaxel and ketoconazole in rat plasma by liquid chromatography/electrospray ionization tandem mass spectrometry.
A rapid and sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method has been developed and validated for simultaneous quantification of docetaxel and ketoconazole in rat plasma with paclitaxel as internal standard (IS). The analytes were extracted from rat plasma by using a liquid-liquid extraction technique with ethyl acetate and the LC separation was performed on a Cosmosil-C(18) analytical column (150 mm x 2.0 mm i.d., Nacalai Tesque Inc., Japan). The extracted samples were analyzed with LC/MS/MS, operating in selected reaction monitoring (SRM) mode. The SRM transitions of precursor ions to product ions were 830.3-->549.1 (m/z) for docetaxel, 531.2-->489.3 (m/z) for ketoconazole, and 876.7-->307.9 (m/z) for the IS. The calibration curves were linear over the range of 2-500 ng/mL for docetaxel and 50-20 000 ng/mL for ketoconazole, with coefficients of correlation above 0.999. The limits of quantification for docetaxel and ketoconazole were both 2 ng/mL. The limit of detection for each analyte was 1 ng/mL. The intra- and inter-day precision (CV) of analysis were within 7%, and the accuracy ranged from 95 to 110%. The overall recoveries for docetaxel and ketoconazole were about 89.0% and 91.1%, respectively. The total analysis time was only 9.0 min. This quantitation method was successfully applied to the simultaneous determination of docetaxel and ketoconazole in rat plasma and some potential interaction was found in the current coadministration pharmacokinetic study. This established method was also utilized in the in vitro and in vivo drug-drug interaction study of docetaxel and ketoconazole (to be published).


Printed titanium implants in UK craniomaxillofacial surgery. Part I: access to digital planning and perceived scope for use in common procedures.
This first part of a two-part study examines perceived applications for and barriers to using printed titanium in light of current caseloads, funding pathways, and use of digital planning. It aims to demonstrate the scope for printed titanium in modern practice and to guide industry about the needs of UK surgeons. A cross-sectional study over 14 weeks was performed electronically with support from the British Association of Oral and Maxillofacial Surgeons (BAOMS) and a national trainee-led recruitment team. Ethics approval was obtained at the lead centre. A total of 132 participants joined the study (70% consultants, 25% specialty registrars, and 5% other), approximating a 29% response rate from consultant/registrar BAOMS members throughout mainland UK. Eighty-eight per cent used CAD-CAM design, with highly variable funding/access, design/manufacturing workflows (in-house/outsourced). Eighty-eight per cent were involved with trauma, 61% with orthognathic, and 52% with oncology-reconstruction surgery. Favourite applications for printed titanium were orbital floor repair (89%) and free-flap jaw reconstruction (87%). Most participants also cited maxillary/zygomatic osteotomies and cranioplasty (range 61%-73%). Although a popular application (78%), the evidence base in temporomandibular joint surgery is limited. Those performing orthognathic surgery perceived more indications than those who did not (p=0.013). Key barriers included cost, turnaround time and logistics, and the need to be trained in traditional techniques. Printed titanium was useful for both common and niche procedures, but was specifically limited in emergency trauma. Most surgeons had experience in CAD-CAM surgery but technical understanding appeared unclear. Limiting factors included variable funding and production pathways, perceived costs, and logistics, but in-house design can minimise them. In part II, we quantify perceived benefits and limitations and whether surgeons' understanding and knowledge are sufficient to rationalise them.


An energy costly architecture of neuromodulators for human brain evolution and cognition.
In comparison to other species, the human brain exhibits one of the highest energy demands relative to body metabolism. It remains unclear whether this heightened energy demand uniformly supports an enlarged brain or if specific signaling mechanisms necessitate greater energy. We hypothesized that the regional distribution of energy demands will reveal signaling strategies that have contributed to human cognitive development. We measured the energy distribution within the brain functional connectome using multimodal brain imaging and found that signaling pathways in evolutionarily expanded regions have up to 67% higher energetic costs than those in sensory-motor regions. Additionally, histology, transcriptomic data, and molecular imaging independently reveal an up-regulation of signaling at G-protein-coupled receptors in energy-demanding regions. Our findings indicate that neuromodulator activity is predominantly involved in cognitive functions, such as reading or memory processing. This study suggests that an up-regulation of neuromodulator activity, alongside increased brain size, is a crucial aspect of human brain evolution.


Fluorescence Guided Surgery.
Fluorescence guided surgery (FGS) is an imaging technique that allows the surgeon to visualise different structures and types of tissue during a surgical procedure that may not be as visible under white light conditions. Due to the many potential advantages of fluorescence guided surgery compared to more traditional clinical imaging techniques such as its higher contrast and sensitivity, less subjective use, and ease of instrument operation, the research interest in fluorescence guided surgery continues to grow over various key aspects such as fluorescent probe development and surgical system development as well as its potential clinical applications. This review looks to summarise some of the emerging opportunities and developments that have already been made in fluorescence guided surgery in recent years while highlighting its advantages as well as limitations that need to be overcome in order to utilise the full potential of fluorescence within the surgical environment.


Coarse-grained molecular dynamics of ligands binding into protein: The case of HIV-1 protease inhibitors.
Binding dynamics and pathways of ligands or inhibitors to target proteins are challenging both experimental and theoretical biologists. A dynamics understanding of inhibitors interacting with protein is essential for the design of novel potent drugs. In this work we applied a coarse-grained molecular dynamics method for simulating inhibitors entering the binding cavity of human immunodeficiency virus type 1 protease (PR). It shows that the coarse-grained dynamics, consistent with the experimental results, can capture the essential molecular dynamics of various inhibitors binding into PR. The primary driving force for the binding processes is the nonbond interaction between inhibitors and PR. The size and topology of inhibitors and the interacting strength between inhibitors and PR have great influence on the binding mode and processes. The interaction strength between the PR and various inhibitors is also analyzed by atomistic molecular mechanics and Poisson-Boltzmann solvation area method.


Differential use of image enhancement techniques by experienced and inexperienced observers.
Full-field digital mammography (FFDM) systems are currently being used to acquire mammograms in digital format, but digital displays are less than ideal compared to traditional film-screen display. Certain physical properties of softcopy displays [e.g., modulation transfer function (MTF)] are less than optimal compared to film. We developed methods to compensate for some of these softcopy display deficiencies, based on careful physical characterization of the displays and image-processing software. A series of 100 FFDM and 60 digitized images was shown to six observers-half experienced (mammographers) and half inexperienced (radiology residents). The observers had to decide if a mass or microcalcification cluster was present and classify it as benign or malignant. A window could be activated that brought the image detail within the window to full resolution and corrected for the nonisotropic MTF of the Cathode Ray Tube (CRT) display. Experienced readers had better diagnostic performance and took less time to view the images. Experienced readers used window/level more than inexperienced readers, but inexperienced readers used magnification and the MTF compensation tool more often. Use of the magnification and the MTF tool increased reader decision confidence. Experienced and inexperienced readers use image-processing tools differently, with certain tools increasing reader confidence. Understanding how observers use image-processing tools may help in the development of better and more automated user interfaces.


Medical society in the early 1900s.
The Archives Section of the Hawaii Medical Library contains bound volumes of printed transactions of the Hawaii Territorial Medical Society Annual Meetings beginning in 1904, and minutes of the monthly meetings of the Society from December 2, 1905. During the monthly meetings, papers were read, cases presented, specimens shown, and business conducted. The latter often concerned problems or ideas that have continued to reappear and stimulate and/or frustrate members to this day.


Immunoradiometric assay of endotoxin in serum.
We describe an immunoradiometric assay for the specific detection and quantitation of endotoxin from Escherichia coli 026, with use of 125I-labeled antibody. The sensitivty of this assay is 1 microgram/L.E. coli 026 endotoxin was detected in serum of rats for as long as 24 h after intraperitoneal injection of 0.1 mg of endotoxin per 100 g body weight. The assay is specific for the O-polysaccharide portion of this endotoxin, as confirmed by results after protein digestion and oxidation of the endotoxin, as well as by failure to detect endotoxin in serum after similar injections of E. coli 0127 and Salmonella typhosa 0901 endotoxins.


Restricted replication of herpes simplex virus type 1 in murine embryonal carcinoma cells.
Herpes simplex virus type 1 (HSV-1) has a broad host range but the KOS strain of HSV-1 did not replicate efficiently in murine embryonal carcinoma (EC) cells. The yield of infectious HSV-1 from EC cells was 100- to 1000-fold lower than that from fibroblast cell lines of mouse, monkey or human origin. The thymidine kinase (TK) gene of HSV-1 is expressed early during the infectious cycle. The levels of TK mRNA and of TK activity in infected EC cells were only two- to threefold lower than levels from infected fibroblast cells. Infected EC cells supported replication of about half as much HSV-1 DNA as did fibroblast cells. The reduced yield of infectious virus was consistent with a paucity of virions in infected EC cells examined by electron microscopy, suggesting a major block late during the HSV-1 infectious cycle. We isolated a variant strain of HSV-1, called KOSEC, which replicated as efficiently in EC cells as in mouse fibroblasts. KOSEC infected EC and fibroblast cells, synthesized more TK mRNA, more TK enzyme, and more HSV-1 DNA than did the same cells infected with the KOS stain. Both HSV-1 strains induced similar levels of synthesis of gD, an early viral glycoprotein. By co-infection of EC cells with the KOS and KOSEC virus, both the elevated virus yield and the elevated TK synthesis seen in KOSEC-infected cells appeared to be recessive. Apparently a viral mutation that affects expression of some early viral functions can also overcome the EC cell restriction to HSV-1 replication.


Asperpyrone A attenuates RANKL-induced osteoclast formation through inhibiting NFATc1, Ca2+ signalling and oxidative stress.
Imbalance of osteoblast and osteoclast in adult leads to a variety of bone-related diseases, including osteoporosis. Thus, suppressing the activity of osteoclastic bone resorption becomes the main therapeutic strategy for osteoporosis. Asperpyrone A is a natural compound isolated from Aspergillus niger with various biological activities of antitumour, antimicrobial and antioxidant. The present study was designed to investigate the effects of Asperpyrone A on osteoclastogenesis and to explore its underlining mechanism. We found that Asperpyrone A inhibited RANKL-induced osteoclastogenesis in a dose-dependent manner when the concentration reached 1 µm, and with no cytotoxicity until the concentration reached to 10 µm. In addition, Asperpyrone A down-regulated the mRNA and protein expression of NFATc1, c-fos and V-ATPase-d2, as well as the mRNA expression of TRAcP and Ctsk. Furthermore, Asperpyrone A strongly attenuated the RNAKL-induced intracellular Ca2+ oscillations and ROS (reactive oxygen species) production in the process of osteoclastogenesis and suppressed the activation of MAPK and NF-κB signalling pathways. Collectively, Asperpyrone A attenuates RANKL-induced osteoclast formation via suppressing NFATc1, Ca2+ signalling and oxidative stress, as well as MAPK and NF-κB signalling pathways, indicating that this compound may become a potential candidate drug for the prevention or treatment of osteoporosis.


Reduced inflammation and altered innate response in neonates during paramyxoviral infection.
Human infants are frequently hospitalized due to infection with the paramyxovirus respiratory syncytial virus (RSV). However, very little is known about the neonatal response to paramyxoviral infection. Here, a neonatal model of paramyxoviral infection is developed using the mouse pathogen Sendai virus (SeV). Adult mice infected with SeV developed a predominantly neutrophilic inflammatory cell influx and a concomitant reduction in lung function, as determined by oxygen saturation. In contrast, neonates with SeV had significantly reduced inflammation and normal lung function. Surprisingly, infected neonates had similar viral loads as adult mice. A reduced neutrophil influx in the neonates may be due in part to reduced expression of both CXCL2 and intracellular adhesion molecule-1 (ICAM-1). Expression of IFN-γ and TNF-α increased in a dose-dependent manner in adult lungs, but neonates did not increase expression of either of these cytokines, even at the highest doses. Importantly, the expression of the RIG-I-like receptors (RLRs) was delayed in the neonatal mice, which might have contributed to their reduced inflammation and differential cytokine expression. Neonatal mice developed similar SeV titers and cleared the virus with similar efficiency despite developing a dramatically lower degree of pulmonary inflammation compared to adults. This suggests that inflammation in the lung may not be required to control viral replication. Future studies will be needed to determine any effect the reduced inflammation may have on the development of a protective memory response in neonates.


Extracorporeal lung perfusion.
The number of patients listed for lung transplantation largely exceeds the number of available transplantable organs because of both a shortage of organ donors and a low utilization rate of lungs from those donors due to injuries acquired during the process of brain death and intensive care unit (ICU) care. A novel strategy for donor lung preservation - ex-vivo lung perfusion (EVLP) - that keeps the organ at physiological protective conditions has shown great promise to increase lung utilization by reassessing, treating, and repairing injured donor lungs prior to transplantation. A first clinical trial using EVLP has shown the method to be safe and to allow for reassessment and improvement in function of lungs from high-risk donor lungs prior to transplantation. When these lungs were transplanted, low rates of primary graft dysfunction were achieved, and the early outcomes were similar to those with conventionally selected and transplanted lungs. Preclinical studies have shown a great potential of EVLP as a platform for the delivery of novel simple and advanced therapies to repair injured organs ex vivo and thus further increase the donor lung utilization rate. EVLP triggers a new era in lung transplantation. This method will allow for more and better organs to become available. Several experimental studies, clinical case reports, and a clinical trial have shown the safety of EVLP and the numerous potentials of EVLP.


Model-based target recognition in pulsed ladar imagery.
A pulsed ladar based object-recognition system with applications to automatic target recognition (ATR) is presented. The approach used is to fit the sensed range images to range templates extracted through a laser physics based simulation applied to geometric target models. A projection-based prescreener filters out more than 80% of candidate templates. For recognition, an M of N pixel matching scheme for internal shape matching is combined with a silhouette matching scheme. The system was trained on synthetic data obtained from the simulation, and has been blind tested on a data set containing real ladar images of military vehicles at various orientations and ranges. Successful blind testing on real imagery demonstrates the utility of synthetic imagery for training of recognizers operating on ladar imagery.


Implementation of a PMTCT programme in a high HIV prevalence setting in Johannesburg, South Africa: 2002-2015.
Great strides have been made in decreasing paediatric human immunodeficiency virus (HIV) infections, especially in sub-Saharan Africa. In South Africa, new paediatric HIV infections decreased by 84% between 2009 and 2015. This achievement is a result of a strong political will and the rapid evolution of the country's prevention of mother-to-child transmission (PMTCT) guidelines. In this paper we report on the implementation of a large PMTCT programme in Soweto, South Africa. We reviewed routinely collected PMTCT data from 13 healthcare facilities, for the period 2002-2015. Antiretroviral therapy (ART) coverage among pregnant women living with HIV (PWLHIV) and the mother-to-child transmission (MTCT) rate at early infant diagnosis were evaluated. In total, 360 751 pregnant women attended the facilities during the review period, and the HIV prevalence remained high throughout at around 30%. The proportion of PWLHIV presenting with a known HIV status increased from 14.3% in 2009 when the indicator was first collected to 45% in 2015, p < 0.001. In 2006, less than 10% of the PWLHIV were initiated on ART, increasing to 88% by 2011. The MTCT rate decreased from 6.9% in 2007 to under 1% from 2013 to 2015, p < 0.001. The achievements in decreasing paediatric HIV infections have been hailed as one of the greatest public health achievements of our times. While there are inherent limitations with using routinely collected aggregate data, the Soweto data reflect progress made in the implementation of PMTCT programmes in South Africa. Progress with PMTCT has, however, not been accompanied by a decline in HIV prevalence among pregnant women.