Influenza vaccine coverage in age-related risk groups in Poland, 2004-2007.
Routine vaccination of certain groups of persons, including children and the elderly might provide additional protection to persons at risk for influenza complications and reduce the overall influenza burden. The aim of the paper was to estimate the influenza vaccine coverage in persons aged 0-4 years and > 65 years in Poland in 2004-2007. Official data collected by National Institute of Hygiene, National Institute of Public Health and Central Statistical Office were analyzed. Among vaccinations performed in all persons, the percentage of vaccinations performed in children aged 0-4 years varied from 1.6% to 2.0%. The estimated vaccination coverage in this age group of population was < 2%. Among persons aged > 65 years the influenza vaccine coverage increased from 7% in 2004 to 14% in 2007. Subjects aged > 65 years represented 25-36% of all vaccinated individuals. The influenza vaccination rates among age-related risk groups in Poland remain low. No or very low increase in a total vaccination coverage rates, as demonstrated in our paper, indicates that meeting the WHO targets concerning influenza vaccination coverage will be very difficult, if no further action is taken concerning vaccine uptake.


The occipital and sacral pressures experienced by healthy volunteers under spinal immobilization: a trial of three surfaces.
The development of a pressure ulcer is of great significance to the life-long rehabilitative management of the person with a spinal cord injury, and may indeed delay and repeatedly interfere with that process. That the period preceding admission to the specialized spinal injury unit is crucial with regard to pressure ulcer development is evident in the professional literature. Both anecdotal and empirical evidence indicates that a significant number of pressure ulcers occur as a result of management provided prior to admission, and that such ulcers are more likely to occur in those patients who have undergone a transfer process from a hospital distal to the specialist unit on a hard spinal board. In consideration of this and of the fact that, in Ireland, the interhospital transfer of spinal injured patients has usually involved the employment of such spinal boards to achieve immobilization, this study sought to identify whether or not the pressure experienced by individuals at two anatomical locations was dependent on the support surface employed. Pressure under the occiput and sacrum of three healthy volunteers immobilized on three support surfaces was measured using air-filled pressure-measuring sacks. The surfaces employed were an uncovered spinal board; a spinal board with inflatable raft devise; and a full-body vacuum splint. Marked reductions in pressure were measured when using the inflatable raft and the vacuum mattress. The results of this study will provide a basis for a larger study and, through that, the formulation of recommendations for standardized practice along a national care pathway.


Ubiquitin C-terminal hydrolase-L3 promotes interferon antiviral activity by stabilizing type I-interferon receptor.
Type-I interferons (IFN-I) are important antiviral drugs which are widely used in clinical therapy of diverse viral infections. However, understanding the detailed mechanisms for IFN-I antiviral signaling remains a major challenge, and may provide novel targets for IFN-based antiviral therapy. So far, the roles of deubiquitinases (DUBs) in regulating IFN-I antiviral activity are still largely unexplored. Here, we find that Ubiquitin C-terminal hydrolase-L3 (UCHL3) plays an important role in regulating type I-interferon (IFN-I) mediated antiviral response. Interestingly, we find that UCHL3 regulates COPS5-dependent deneddylation of Cullin1, which is an essential component of SCFβ-TrCP complex and associated with SCFβ-TrCP activities. Furthermore, we reveal that UCHL3 physically interacts with COPS5, and determines the level and protein stability of cellular COPS5 by deubiquitinating COPS5. We further demonstrate that UCHL3 upregulates the levels of SCFβ-TrCP substrates including IFN-I receptor IFNAR1, which enhances IFN-I mediated signaling pathway and antiviral activity. These findings identify COPS5 as a novel in vivo substrate of UCHL3, and uncover the deubiquitination-deneddylation mediated regulation for IFN-I signaling and antiviral function, which may provide a novel strategy for improving IFN-based antiviral therapy.


MR imaging findings in the follow-up of patients with different stages of knee osteoarthritis and the correlation with clinical symptoms.
To assess the rate of cartilage loss, the change in bone marrow edema pattern and internal joint derangement at 1.5-T MRI in patients with knee osteoarthritis and to correlate these findings with the clinical Western Ontario and McMaster University Osteoarthitis (WOMAC) score. Forty subjects (mean age 57.7+/-15 years; 16 females and 24 males) were recruited: 6 healthy volunteers (OA0), 17 patients with mild osteoarthritis (OA1) and 17 with severe osteoarthritis (OA2) based on the Kellgren-Lawrence scale. MR scans, radiographs and WOMAC scores were obtained at baseline, first follow-up (1.4+/-0.67 years; n=40) and second follow-up (2.4+/-0.4 years; n=26). Cartilage morphology, bone marrow edema (BME), meniscal and ligamentous pathology were assessed on MR images and quantified by two radiologists in consensus. Full-thickness cartilage lesions were observed in 12/17 OA2 at baseline, in 13/17 at the first follow-up and in 7/10 at the second follow-up. Cartilage loss was found in eight patients at the first follow-up and five at the second follow-up. BME was observed in 23/40 patients at baseline, in 22/40 at the first follow-up and in 12/26 at the second follow-up. Changes in BME were visualized in 19/22 and 4/13 patients at the first and second follow-up, respectively. Changes in WOMAC scores over time did not correlate significantly with the amount of cartilage loss and the change in BME (P>0.05). MRI is well suited to monitor the progression of OA in the longitudinal follow-up since it shows cartilage defects, BME and internal joint derangement, pathologies that are not visualized by radiographs. The lack of significant correlation between MRI findings and clinical findings is not unexpected, has been previously described and may in part be due to the fact that patients get more accustomed to their pain as the knee progressively degenerates.


Studies on inhibitors of skin tumor promotion, XII. Rotenoids from Amorpha fruticosa.
As a part of screening studies for chemopreventive agents (anti-tumor-promoters), six North American plants belonging to the Amorpha genus were tested using an in vitro assay system. Of these plants, Amorpha fruticosa exhibited strong inhibitory effects on Epstein-Barr virus early antigen (EBA-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Also six rotenoids, amorphispironone [1], tephrosin [2], amorphigenin [3], 12a-hydroxyamorphigenin [4], 12a-hydroxydalpanol [5], and 6'-O-D-glucopyranosyldalpanol [6], were isolated from the leaves of A. fruticosa. Among these retenoids, 1 and 2 exhibited remarkable inhibitory effects of EBV-EA activation induced by TPA. Further, 1 and 2 exhibited significant anti-tumor-promotion effects on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test. These investigations suggested that these rotenoids might be valuable anti-tumor-promoters.


Facial growth after pharyngeal flap surgery in cleft palate patients: a five-year longitudinal study.
To assess the influence of a pharyngeal flap on facial morphology in patients with cleft lip and palate, we studied prospectively 20 consecutive patients with cleft lip and palate aged 4 to 9 years who needed a pharyngeal flap. We also studied a control group of 20 subjects matched with regard to age, sex, diagnosis, and method of primary treatment. Facial growth was followed for five years, beginning one year before operation. Before operation there was no significant difference between the operated group and the reference group as far as skeletal facial dimensions and angular measurements were concerned. The longitudinal comparison within each group showed that there was a change in mandibular growth direction backwards and downwards in the operated group. The changes in facial growth after pharyngeal flap operation were similar to those reported in patients with enlarged adenoids. Four years after operation, the change in the direction of mandibular growth did not result in any specific facial form that could be identified clinically.


Bilateral renal malakoplakia in infancy.
Two male infants aged 6 months presented with Escherichia coli septicaemia and urinary tract infection. Despite seemingly appropriate antibiotic therapy, a swinging fever, painful enlargement of both kidneys, sterile leukocyturia and renal failure persisted. Excretory urography, ultrasound scan, computerized tomography and magnetic resonance imaging showed diffuse infiltrative disease. 99mTc dimercaptosuccinic acid uptake was minimal, but a 67Ga-citrate scan showed striking diffuse uptake by both kidneys suggestive of inflammatory cell infiltration. Bilateral renal parenchymal malakoplakia was diagnosed on tissue examination. Bilateral parenchymal involvement of the kidneys by this chronic granulomatous disease has not previously been reported in infancy and is fatal if untreated. The lesion is believed infection-induced, due to defective bacterial activity of the macrophages, possibly related to an abnormally low cGMP/cAMP ratio. Treatment with intracellularly active trimethoprim-sulphamethoxazole, rifampicin and ascorbic acid resulted in complete recovery of the one infant so treated over a period of months.


Outcomes and patterns of failure for sinonasal undifferentiated carcinoma (SNUC): The Mayo Clinic Experience.
Sinonasal undifferentiated carcinoma (SNUC) is a rare aggressive disease arising in the nasal cavity and paranasal sinuses with poor prognosis and unclear optimal management. Forty patients were analyzed. Nasal cavity was the most common primary site. Most patients presented with T4 disease, received trimodality therapy, and were treated with intensity-modulated radiotherapy (IMRT). Median follow-up was 6.9 years. Sixteen patients (40%) experienced recurrent disease, 5 local (12.5%), 1 regional (2.5%), and 10 distant (25%). The 5-year overall survival (OS), recurrence-free survival (RFS), and locoreginal control (LRC) were 44%, 39%, and 71%, respectively. Patients treated with trimodality therapy had better outcomes compared to single modality therapy. Improved OS was noted with IMRT and with doses ≥60 Gy. The most common cause of death was distant metastasis. SNUC is an aggressive malignancy with a high tendency to metastasize. Better outcomes were obtained with a trimodality approach. Modern radiotherapy (RT) techniques and doses ≥ 60 Gy were associated with improved OS.


Targeting β Cells with Cathelicidin Nanomedicines Improves Insulin Function and Pancreas Regeneration in Type 1 Diabetic Rats.
Type 1 diabetes (T1D) is an incurable condition with an increasing incidence worldwide, in which the hallmark is the autoimmune destruction of pancreatic insulin-producing β cells. Cathelicidin-based peptides have been shown to improve β cell function and neogenesis and may thus be relevant while developing T1D therapeutics. In this work, a cathelicidin-derived peptide, LLKKK18, was loaded in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), surface-functionalized with exenatide toward a GLP-1 receptor, aiming the β cell-targeted delivery of the peptide. The NPs present a mean size of around 100 nm and showed long-term stability, narrow size distribution, and negative ζ-potential (-10 mV). The LLKKK18 association efficiency and loading were 62 and 2.9%, respectively, presenting slow and sustained in vitro release under simulated physiologic fluids. Glucose-stimulated insulin release in the INS-1E cell line was observed in the presence of the peptide. In addition, NPs showed a strong association with β cells from isolated rat islets. After administration to diabetic rats, NPs induced a significant reduction of the hyperglycemic state, an improvement in the pancreatic insulin content, and glucose tolerance. Also remarkable, a considerable increase in the β cell mass in the pancreas was observed. Overall, this novel and versatile nanomedicine showed glucoregulatory ability and can pave the way for the development of a new generation of therapeutic approaches for T1D treatment.


The historical question of acquired immunodeficiency syndrome in the 1960s in the Congo River basin area in relation to cryptococcal meningitis.
In Europe before the advent of the acquired immunodeficiency syndrome (AIDS), fatal cases of infection with Cryptococcus neoformans resembling acute meningitis were rarely described and never in young adults. However, rapidly fatal cryptococcal meningitis in young Africans has been known to exist in central Africa for at least 30 years, mainly in the lower area of the Congo River basin. Cases have been reported in this area since 1953, particularly in young patients during the 1950s. It is also known that central African AIDS patients frequently suffer from cryptococcosis, and there is a possibility that earlier clinical reports of encephalitis were actually fatal cases of AIDS in young Africans. It appears possible that the central part of the African continent is the area where human immunodeficiency virus originated.


[Multiple lncRNAs affect the incidence and development of melanoma].
To find the relationship between long non-coding RNA (lncRNA) based on data mining methods. Methods: We use a whole genome mRNA expression data set (GSE15605) from the gene expression ominibus database to find the lncRNAs which relate to melanoma. Results: Four lncRNAs (LINC01213, PGM5-AS1, LINC01133 and LOC284578) were significantly associated with the incidence and development of melanoma. Meanwhile, LINC01213, LINC01133 and LOC284578 were correlated with BRAF mutation, and PGM5-AS1 was related to NRAS mutation. Data mining study found that the model based on the expression values of these 4 lncRNAs can easily preferable classify the study samples. Conclusion: LncRNAs may play important roles in the incidence and development of melanoma.


Comparison of the hemodynamics and dynamics of fluid shift of Ringer's solution before surgery in children and adults.
The present study investigated the hemodynamics, vascular and extravascular volume expansion induced by infusion of lactated Ringer's solution in children and adults before surgery. This was a prospective randomized double-blind study. A total of 28 patients (14 children and 14 adult patients; American Society of Anesthesiology status I) scheduled for similar minor pelvic, anal rectal or lower limb surgery were recruited for the present study. All patients were administered with 10 ml/kg of lactated Ringer's solution at a constant rate over 20 min. After fluid infusion, plasma dilutions were calculated based on the concentration of hemoglobin. Heart rate (HR), mean arterial pressure (MAP) and urine output were measured before anesthesia was administered for surgery. Results demonstrated that the plasma dilution within 90 min of infusion initiation of lactated Ringer's solution was less pronounced in children compared with adult patients (0.07 vs. 0.16; P<0.001). Children also excreted more of the infused fluid through the kidney within 90 min of infusion initiation than the adults (55% vs. 24%; P=0.01). Following completion of fluid infusion, the volume expansion efficiency was higher in adults [0.82 (0.52-1.00)] than in children [0.46 (0.26-0.68)]. The relative changes in HR were significantly greater in children than in adults 15-60 min after infusion initiation (P<0.01). After 60 min, HRs were comparable between the groups; however, MAP declined significantly from 25-90 min after infusion initiation in children (P<0.05), yet remained nearly constant in adults (P>0.05). Simple regression analysis revealed a positive relationship between the relative changes in MAP and the plasma dilution, and the reduction in MAP in children was able to explain 47% of the variation in plasma dilution (R2=0.47; P=0.007). In conclusion, different hemodynamics and dynamics of fluid shift of Ringer's solution prior to surgery in children and adults may provide anesthesiologists with new information of how to administer fluid treatment for each patient.


Conceptual Knowledge Influences Decision Making Differently in Individuals with High or Low Cognitive Flexibility: An ERP Study.
Studies using the Iowa Gambling Task (IGT) have distinguished between good and bad decision makers and have provided an explanation for deficits in decision making. Previous studies have demonstrated a link between Wisconsin Card Sorting Test (WCST) performance and IGT performance, but the results were not consistent and failed to explain why WCST performance can predict IGT performance. The present study aimed to demonstrate that WCST performance can predict IGT performance and to identify the cognitive component of the WCST that affects IGT performance using event-related potentials (ERPs). In this study, 39 healthy subjects (5 subjects were excluded) were divided into a high group and a low group based on their global score on the WCST. A single-choice version of the IGT was used to eliminate the impact of retrieval strategies on the choice evaluation process and interference due to uncorrelated decks. Differences in the underlying neural mechanisms and explicit knowledge between the two groups during the three stages of the decision-making process were described. Based on the information processing perspective, we divided the decision-making process into three stages: choice evaluation, response selection, and feedback processing. The behavioral results showed that the highly cognitively flexible participants performed better on the IGT and acquired more knowledge of the task. The ERP results showed that during the choice evaluation stage, the P300 recorded from central and parietal regions when a bad deck appeared was larger in the high group participants than in the low group participants. During the response selection stage, the effect of choice type was significant only in the frontal region in the high group, with a larger effect for passing. During the feedback evaluation stage, a larger FRN was evoked for a loss than for a win in the high group, whereas the FRN effect was absent in the low group. Compared with the participants with low cognitive flexibility, the participants with high cognitive flexibility performed better on the IGT, acquired more knowledge of the task, and displayed more obvious somatic markers. The low group participants showed reduced working memory abilities during the choice evaluation stage. The appropriate somatic markers reflected by the DPN is formed only when conceptual knowledge is gained in the response selection stage. The absence of an FRN effect in the subjects who performed poorly on the WCST suggests a significant deficit in feedback learning and reward prediction.


The UCT Surgical Society - a society on the cutting edge.
The University of Cape Town Surgical Society is a student-run society established in 2006 and is affiliated with the Department of Surgery. The aims of the society are to supplement undergraduate training, to promote medical and surgical research, and to motivate students to pursue a career in surgery. Regular monthly lectures and surgical skills courses are offered, as well as weekly anatomy workshops. A recently launched Shadow Programme enables students to interact with practising surgeons in theatre, thereby gaining insight into the advantages and challenges involved in a future career in surgery.


Post-treatment of dextromethorphan on methamphetamine-induced drug-seeking and behavioral sensitization in rats.
In our previous study, we first demonstrated a significant effect of dextromethorphan (DM) on morphine-seeking behavior in morphine-dependent rats, when DM was given during morphine withdrawal. Using the same conditioned place preference (CPP) paradigm modified for measuring drug-seeking-related behavior, we further investigated the possible effect of DM on methamphetamine (MA)-seeking in MA-dependent rats. Our data showed that DM could also effectively suppress the drug-seeking behavior for MA, when administered during MA withdrawal. This suggests that DM may possess a pharmacological property to prevent drug-seeking behavior for addictive drugs in general. To examine the action sites of DM in the brain, DM was microinjected into the VTA or the NAc, and tested for its effect on MA-seeking during withdrawal. Both intra-VTA and intra-NAc injections of DM were able to block the MA-seeking, suggesting that DM has a dual action sites. In our neurochemical results, intra-NAc injection of DM showed a clear reduction of DA turnover rate at the NAc and the mPFC in response to MA challenge during withdrawal, which matched with the behavioral results. However, intra-VTA injection of DM reduced the DA turnover rate at the mPFC but did not have effect on the DA turnover rate at the NAc. Although further investigations may be needed to verify the connection between our neurochemical and behavioral results, the present study highlights the therapeutic potential of DM in antidrug-seeking behavior of MA and that the mechanism could be related to its effect on the mesolimbic and mesocortical dopaminergic pathways.


Impact of Phytoestrogens on Serum Lipids in Postmenopausal Women.
Objectives: The aim of the study was to assess the impact of soy- and red clover-derived isoflavones on serum lipid levels in postmenopausal women and to compare the effects to the lipid levels of healthy postmenopausal women without phytoestrogen supplementation. Materials and Methods: Blood levels of triglycerides, total cholesterol and cholesterol fractions were assessed. Measurements were performed before treatment and at 6-month intervals over a period of 18 months. The investigation included 74 healthy postmenopausal women randomized into three groups according to treatment. The first group of 23 patients received soy-derived isoflavones, the second group (26 patients) was given red clover-derived phytoestrogens, while the third control group (25 patients) received no supplements. Results: Mean triglyceride, cholesterol and LDL levels of patients in the control group were significantly higher than in both the soy and the red clover groups (p < 0.001) at all three time points, while mean values did not differ significantly between the soy and the red clover groups. The mean HDL levels of patients in the control group was significantly lower than in both the soy and the red clover groups (p < 0.001). Conclusions: Phytoestrogen supplementation had a positive metabolic effect on serum lipid levels in postmenopausal women. The impact on serum lipids levels was similar for soy and red clover.


Helicobacter pylori Empirical and Tailored Eradication Therapy and Factors Influencing Eradication Rate: a 4-Year Single-Center Study.
The Helicobacter pylori eradication rate with standard triple therapy (STT) is continuously decreasing due to clarithromycin resistance. This study aimed to investigate the eradication rate of empirical and tailored therapy and explore various factors affecting this eradication rate using clarithromycin resistance test data for the last 4 years at a single institution in Daegu. From August 2018 to July 2021, a total of 1,395 patients diagnosed with H. pylori infection based on rapid urea testing and histology at Keimyung University Dongsan Hospital were retrospectively examined. Participants were classified into the empirical and tailored therapy groups according to the results of the clarithromycin resistance test using the polymerase chain reaction. The overall eradication rate of empirical STT was 72.8%, and the eradication rate by year was 71.6% in 2018, 77.4% in 2019, 70.3% in 2020, and 70.6% in 2021; the differences were not statistically significant (p = 0.173). No significant difference was noted in the eradication rate according to gender, age, type of proton pump inhibitors, and use of probiotics. Significant differences were noted in the eradication rate according to the treat-ment period: 69.7% in the 7-day, 67.3% in the 10-day, and 81.4% in the 14-day group (p = 0.001). The eradication rate with STT was 87.4% in the non-resistant group. In the case of clarithromycin resistance, treatment was mainly with bismuth quadruple therapy (BQT), and the eradication rate was 86.1%. The eradication rate was higher with administration of BQT for 10 days or 14 days than for administration of BQT for 7 days, but with no statistical significance (p = 0.364). Extending the treatment period of STT helped in improving the eradication rate, and tailored therapy through clarithromycin resistance testing showed superior results when compared to empirical therapy.


Association of systemic diseases with retinal vein occlusive disease.
Retinal vein occlusion (RVO) is the second commonest vascular disease of the eye, second only to Diabetic Retinopathy. The association of the retinal vein occlusion with other systemic disease likes hypertension, diabetes mellitus and others has been well documented. With the increase in persons being affected from these disorders, patients with retinal vein obstruction are also increasing. Hence, a study was designed to evaluate all cases of RVO to find out its association with systemic disorders. A total of 100 patients (106 eyes) were enrolled in the study. Out of which, 66 cases reported to have Brach Retinal Vein Occlusion (BRVO) and rest 34 cases with Central Retinal Vein Occlusion (CRVO). Among the associated systemic diseases, hypertension and diabetes mellitus accounted for 84% cases. Isolated hypertension (54%) was most commonly seen followed by diabetes mellitus (8%). The prevalence of BRVO was almost twice as compared to CRVO. The high association of various systemic disorder especially Hypertension and diabetes further supports the need of early and periodic eye examination for those suffering from these disorders.


HYBRIDIZATION AND GEOGRAPHIC VARIATION IN TWO MEADOW KATYDID CONTACT ZONES.
In this study, previously unrecognized hybridization was documented between two meadow katydids in each of two disjunct contact zones, in the southeastern United States and along the Potomac River near Washington, DC. These two zones have very different histories and dynamics of interaction between the two taxa. Orchelimum nigripes and O. pulchellum (Tettigoniidae: Conocephalinae) are distributed west and east, respectively, of the Appalachian Mountains, from the Great Lakes to the Gulf Coast and along the Atlantic Coastal Plain from New York to the Florida Keys, but are not found in the Appalachians themselves. In addition, during this century O. nigripes has become established in a small area east of the Appalachians, in the Potomac River basin, where it has completely replaced O. pulchellum along the river corridor above Washington, DC. I sampled katydids from 40 sites across both hybrid zones and mapped geographic patterns of genetic variation (allele frequencies at two diagnostic loci) and variation in a morphometric index for males. Although the two taxa are quite distinct over most of their extensive distributions, there is clear evidence of introgression in both contact zones. In the Deep South, samples from a transect along the Gulf Coast define a broad hybrid zone of about 50-100 km, while samples from a transect 200 km to the north define a zone of about 150-250 km in width. Only one Deep South population shows a deviation from Hardy-Weinberg equilibrium at either locus, and there is no evidence of linkage disequilibrium in any Deep South population. In the Potomac region, there is a narrow upstream-downstream hybrid zone along the river. Within the Potomac River floodplains downriver from Washington, DC, as well as outside the floodplains throughout the region, O. pulchellum is present in abundance, but O. nigripes markers are virtually absent. Within the floodplains upriver from Washington, DC, O. nigripes is abundant, but O. pulch***ellum markers are virtually absent. All four mixed ancestry Potomac populations sampled show strong and highly significant linkage disequilibrium, although only one clearly deviates from single-locus Hardy-Weinberg equilibrium. The position of the Deep South hybrid zone is generally consistent with interspecific and intraspecific phylogeographic patterns previously reported for numerous taxa from the southeastern United States. The observed genetic and morphometric clines appear to be the result of neutral introgression over thousands of years. In the much younger Potomac hybrid zone, O. nigripes appears to be spreading downriver, interbreeding with O. pulchellum, and replacing it. The mechanism for this replacement remains uncertain, but may be clarified by ongoing behavioral, genetic, and breeding studies.


Doping dependence of heat transport in the iron-arsenide superconductor Ba(Fe(1-x)Co(x))2As2: from isotropic to a strongly k-dependent gap structure.
The temperature and magnetic field dependence of the in-plane thermal conductivity kappa of the iron-arsenide superconductor Ba(Fe(1-x)Co(x))2As2 was measured down to T approximately 50 mK and up to H = 15 T as a function of Co concentration x in the range 0.048 < or = x < or = 0.114. At H = 0, a negligible residual linear term in kappa/T as T-->0 at all x shows that the superconducting gap has no nodes in the ab plane anywhere in the phase diagram. However, while the slow H dependence of kappa(H) at T-->0 in the underdoped regime is consistent with a superconducting gap that is large everywhere on the Fermi surface, the rapid increase in kappa(H) observed in the overdoped regime shows that the gap acquires a deep minimum somewhere on the Fermi surface. Outside the antiferromagnetic-orthorhombic phase, the superconducting gap structure has a strongly k-dependent amplitude.


Analysis of correlated ROC areas in diagnostic testing.
This paper focuses on methods of analysis of areas under receiver operating characteristic (ROC) curves. Analysis of ROC areas should incorporate the correlation structure of repeated measurements taken on the same set of cases and the paucity of measurements per treatment resulting from an effective summarization of cases into a few area measures of diagnostic accuracy. The repeated nature of ROC data has been taken into consideration in the analysis methods previously suggested by Swets and Pickett (1982, Evaluation of Diagnostic Systems: Methods from Signal Detection Theory), Hanley and McNeil (1983, Radiology 148, 839-843), and DeLong, DeLong, and Clarke-Pearson (1988, Biometrics 44, 837-845). DeLong et al.'s procedure is extended to a Wald test for general situations of diagnostic testing. The method of analyzing jackknife pseudovalues by treating them as data is extremely useful when the number of area measures to be tested is quite small. The Wald test based on covariances of multivariate multisample U-statistics is compared with two approaches of analyzing pseudovalues, the univariate mixed-model analysis of variance (ANOVA) for repeated measurements and the three-way factorial ANOVA. Monte Carlo simulations demonstrate that the three tests give good approximation to the nominal size at the 5% levels for large sample sizes, but the paired t-test using ROC areas as data lacks the power of the other three tests and Hanley and McNeil's method is inappropriate for testing diagnostic accuracies. The Wald statistic performs better than the ANOVAs of pseudovalues. Jackknifing schemes of multiple deletion where different structures of normal and diseased distributions are accounted for appear to perform slightly better than simple multiple-deletion schemes but no appreciable power difference is apparent, and deletion of too many cases at a time may sacrifice power. These methods have important applications in diagnostic testing in ROC studies of radiology and of medicine in general.


CYP24A1 as a potential target for cancer therapy.
Increasing evidence has accumulated to suggest that vitamin D may reduce the risk of cancer through its biologically active metabolite, 1α,25(OH)2D3, which inhibits proliferation and angiogenesis, induces differentiation and apoptosis, and regulates many other cellular functions. Thus, it is plausible to assume that rapid clearance of 1α,25(OH)2D3 by highly expressed CYP24A1 could interrupt the normal physiology of cells and might be one cause of cancer initiation and progression. In fact, enhancement of CYP24A1 expression has been reported in literature for many cancers. Based on these findings, CYP24A1-specific inhibitors and vitamin D analogs which are resistant to CYP24A1-dependent catabolism might be useful for cancer treatment. CYP24A1-specific inhibitor VID400, which is an azole compound, markedly enhanced and prolonged the antiproliferative activity of 1α,25(OH)2D3 in the human keratinocytes. Likewise, CYP24A1-resistant analogs such as 2α-(3-hydroxypropoxy)-1α,25(OH)2D3 (O2C3) and its C2-epimer ED-71 (Eldecalcitol), and 19nor- 2α-(3-hydroxypropyl)-1α,25(OH)2D3 (MART-10) showed potent biological effects. Our in vivo studies using rats revealed that MART-10 had a low calcemic effect, which is a suitable property as an anticancer drug. Much lower affinity of MART-10 for vitamin D binding protein (DBP) as compared with 1α,25(OH)2D3 may be related to its more potent cellular activities. Based on these results, we conclude that (1) high affinity for VDR, (2) resistance to CYP24A1-dependent catabolism, (3) low affinity for DBP, and (4) low calcemic effect may be required for designing potent vitamin D analogs for cancer treatment.


A study about drug combination therapy of Schisandra sphenanthera extract and Rapamycin in healthy subjects.
To assess the effect of the drug combination of Schisandra sphenanthera extract (SchE) and Rapamycin (RAPA), 18 healthy subjects were given oral treatments of RAPA alone and with SchE. Pharmacokinetic investigations and indexes of hepatic and renal functions, as well as other indices of oral RAPA administration (2 mg), were performed both before and after the SchE treatment period. Whole-blood RAPA concentrations were determined by enzyme-linked immunosorbent assay. The research found that the mean whole-blood RAPA AUC(0-∞), C(max), and t(max) increased almost 2-, 2.1-, and 1.3-fold, respectively, and CL/F (-38.0%) decreased almost 1.6-fold in these subjects when RAPA was administered with SchE compared with oral RAPA administered alone. The results of this study proved that SchE can increase the oral bioavailability of RAPA and will add important information to the interaction area between drugs and herbal products.


Comparative studies of the phage T2 and T4 DNA (N6-adenine)methyltransferases: amino acid changes that affect catalytic activity.
The bacteriophage T2 and T4 dam genes code for a DNA (N6-adenine)methyltransferase (MTase). Nonglucosylated, hydroxymethylcytosine-containing T2gt- virion DNA has a higher level of methylation than T4gt- virion DNA does. To investigate the basis for this difference, we compared the intracellular enzyme levels following phage infection as well as the in vitro intrinsic methylation capabilities of purified T2 and T4 Dam MTases. Results from Western blotting (immunoblotting) showed that the same amounts of MTase protein were produced after infection with T2 and T4. Kinetic analyses with purified homogeneous enzymes showed that the two MTases had similar Km values for the methyl donor, S-adenosyl-L-methionine, and for substrate DNA. In contrast, they had different k(cat) values (twofold higher for T2 Dam MTase). We suggest that this difference can account for the ability of T2 Dam to methylate viral DNA in vivo to a higher level than does T4 Dam. Since the T2 and T4 MTases differ at only three amino acid residues (at positions 20 [T4, Ser; T2, Pro], 26 [T4, Asn; T2, Asp], and 188 [T4, Asp; T2, Glu]), we have produced hybrid proteins to determine which residue(s) is responsible for increased catalytic activity. The results of these analyses showed that the residues at positions 20 and 26 are responsible for the different k(cat) values of the two MTases for both canonical and noncanonical sites. Moreover, a single substitution of either residue 20 or 26 was sufficient to increase the k(cat) of T4 Dam.


Highest genetic diversity at the northern range limit of the rare orchid Isotria medeoloides.
Populations in previously glaciated regions are often genetically depauperate in comparison with populations at lower latitudes, due either to bottlenecks experienced in post-glacial colonization or to contemporary genetic drift in small, peripheral populations. Populations of the rare self-fertilizing North American orchid Isotria medeoloides are largest in the previously glaciated region near the northern range limit, allowing us to examine the role of historical versus contemporary processes in determining population genetic diversity and structure. If contemporary processes predominate, genetic diversity should increase with increasing census size. In contrast, if sequential bottlenecks associated with colonization are paramount, diversity should decrease with latitude and be relatively insensitive to census size. We genotyped 299 individuals from 20 populations at four variable microsatellite loci to contrast genetic diversity and structure for populations in previously glaciated regions versus previously unglaciated regions. Populations were highly inbred (F=0.95) and highly differentiated (R(ST)=0.485). Across all sampled populations, genetic diversity decreased and genetic differentiation increased with declining population size. Small southern populations were especially differentiated and genetically depauperate. In the glaciated part of the range, genetic diversity increased as populations approached the northern range limit, demonstrating the centrality of contemporary processes for this post-glacial colonist.


Transient changes in permeability in HeLa and L cells during detachment from a substrate.
The Na+ and K+ gradients of HeLa cells approach that of the medium during removal from a substrate with trypsin, but then recover during the next 15 min. The recovery is blocked by ouabain or the cold, but is unaffected by bumetanide. The effect is also obtained in cells which have no intercellular connexions, and in cells whose interior is made acid with CO2. Removal of cells with EDTA, pronase E and dispase has similar effects. It does not occur, or is greatly reduced, in cells already rounded up. Substances of molecular weight up to 5000 (e.g. inulin) also cross the cell membrane during this phase. We think that the effect is due to a transient increase in leakiness of the cell during rounding up, possibly due to the detachment of the 'feet' holding the cells onto the substrate. The transient increase in permeability of these cells may be a valuable method of introducing large molecules into them.


Effect of age, diet, and tissue type on PCr response to creatine supplementation.
Creatine/phosphorylcreatine (PCr) responses to creatine supplementation may be modulated by age, diet, and tissue, but studies assessing this possibility are lacking. Therefore we aimed to determine whether PCr responses vary as a function of age, diet, and tissue. Fifteen children, 17 omnivorous and 14 vegetarian adults, and 18 elderly individuals ("elderly") participated in this study. Participants were given placebo and subsequently creatine (0.3 g·kg-1·day-1) for 7 days in a single-blind fashion. PCr was measured through phosphorus magnetic resonance spectroscopy (31P-MRS) in muscle and brain. Creatine supplementation increased muscle PCr in children (P < 0.0003) and elderly (P < 0.001), whereas the increase in omnivores did not reach statistically significant difference (P = 0.3348). Elderly had greater PCr increases than children and omnivores (P < 0.0001 for both), whereas children experienced greater PCr increases than omnivores (P = 0.0022). In relation to diet, vegetarians (P < 0.0001), but not omnivores, had significant increases in muscle PCr content. Brain PCr content was not affected by creatine supplementation in any group, and delta changes in brain PCr (-0.7 to +3.9%) were inferior to those in muscle PCr content (+10.3 to +27.6%; P < 0.0001 for all comparisons). PCr responses to a standardized creatine protocol (0.3 g·kg-1·day-1 for 7 days) may be affected by age, diet, and tissue. Whereas creatine supplementation was able to increase muscle PCr in all groups, although to different extents, brain PCr was shown to be unresponsive overall. These findings demonstrate the need to tailor creatine protocols to optimize creatine/PCr accumulation both in muscle and in brain, enabling a better appreciation of the pleiotropic properties of creatine.NEW & NOTEWORTHY A standardized creatine supplementation protocol (0.3 g·kg-1·day-1 for 7 days) effectively increased muscle, but not brain, phosphorylcreatine. Older participants responded better than younger participants whereas vegetarians responded better than omnivores. Responses to supplementation are thus dependent on age, tissue, and diet. This suggests that a single "universal" protocol, originally designed for increasing muscle creatine in young individuals, may lead to heterogeneous muscle responses in different populations or even no responses in tissues other than skeletal muscle.


Mitochondrial Dysfunction Mediated by Poly(ADP-Ribose) Polymerase-1 Activation Contributes to Hippocampal Neuronal Damage Following Status Epilepticus.
Mitochondrial dysfunction plays a central role in the neuropathology associated with status epilepticus (SE) and is implicated in the development of epilepsy. While excitotoxic mechanisms are well-known mediators affecting mitochondrial health following SE, whether hyperactivation of poly(ADP-ribose) polymerase-1 (PARP-1) also contributes to SE-induced mitochondrial dysfunction remains to be examined. Here we first evaluated the temporal evolution of poly-ADP-ribosylated protein levels in hippocampus following kainic acid-induced SE as a marker for PARP-1 activity, and found that PARP-1 was hyperactive at 24 h following SE. We evaluated oxidative metabolism and found decreased NAD⁺ levels by enzymatic cycling, and impaired NAD⁺-dependent mitochondrial respiration as measured by polarography at 24 h following SE. Stereological estimation showed significant cell loss in the hippocampal CA₁ and CA₃ subregions 72 h following SE. PARP-1 inhibition using N-(6-Oxo-5,6-dihydro-phenanthridin-2-yl)- N,N-dimethylacetamide (PJ-34) in vivo administration was associated with preserved NAD⁺ levels and NAD⁺-dependent mitochondrial respiration, and improved CA₁ neuronal survival. These findings suggest that PARP-1 hyperactivation contributes to SE-associated mitochondrial dysfunction and CA₁ hippocampal damage. The deleterious effects of PARP-1 hyperactivation on mitochondrial respiration are in part mediated through intracellular NAD⁺ depletion. Therefore, modulating PARP-1 activity may represent a potential therapeutic target to preserve intracellular energetics and mitochondrial function following SE.


Consecutive stimulation of HBsAg promotes the viability of the human B lymphoblastoid cell line IM-9 through regulating the SIRT1-NF-κB pathway.
Patients with chronic HBV infection have been reported to suffer a significantly increased risk of NHL, but the underlying mechanisms remain to be clearly explained. The aim of the present study was to clarify the relationship between chronic HBV infection and NHL development. Fluorescence-activated cell sorting, Annexin V/7-aminoactinomycin D staining and MTS assay were used to analyze the rate of apoptosis and cell viability. In addition, western blotting was used to detect protein expression. The effects of the activator of SIRT1, SRT1720, and the inhibitor of SIRT1, nicotinamide, were also analyzed. The expression levels cytokines and chemokines were determined by multiplex assay. Hepatitis B surface antigen (HBsAg) was demonstrated to increase the viability of the human peripheral B lymphoblastoid cell line, IM-9, in a dose- and time-dependent manner. HBsAg also decreased histone H3 acetylation and p21 expression at the molecular level. HBsAg upregulated the expression of anti-apoptotic B-cell lymphoma-extra-large and B-cell lymphoma 2 proteins, and inactivated the intrinsic apoptosis pathway by reducing BCL2 associated X, apoptosis regulator expression and increasing the expression of sirtuin 1 (SIRT1) and nuclear factor-κB (NF-κB). HBsAg also altered the levels of certain chemokines and cytokines, including interleukin (IL)-4, -10 and -12, C-X-C motif chemokine 10 and C-C motif chemokine ligand 5. Inhibition of SIRT1 suppressed the effects induced by HBsAg. The anti-apoptotic effect of HBsAg in IM-9 cell lines occurred via the promotion of cell viability, inhibition of apoptosis, regulation of chemokines and cytokines, acetylation of histone H3 and alteration of SIRT1 and NF-κB expression. In conclusion, chronic stimulation with HBsAg promoted the viability of the human B lymphoblastoid cell line, IM-9, through regulation of the SIRT1-NF-κB pathway. This may be an underlying mechanism of HBV-associated NHL.


Functional Hypothalamic Amenorrhea: Recognition and Management of a Challenging Diagnosis.
Functional hypothalamic amenorrhea is responsible for approximately a third of the cases of secondary amenorrhea. The condition is a result of disturbances in gonadotropin-releasing hormone pulsatile secretion at the level of the hypothalamus, which in turn disrupts gonadotropin secretion. It is due to psychosocial stress, disordered eating, and/or excessive exercise. Often, however, it is a combination of more than one etiology, with a possible role for genetic or epigenetic predisposition. The dysfunctional gonadotropin-releasing hormone release leads to the cessation of ovarian function, resulting in amenorrhea, infertility, and a long-term impact on affected women's bone health, cardiovascular risk, cognition, and mental health. Functional hypothalamic amenorrhea is a diagnosis of exclusion, and treatment involves identifying and reversing the underlying cause(s). The aim of this concise review is to summarize the current knowledge of functional hypothalamic amenorrhea, review its pathophysiology and the adverse health consequences, and provide recommendations for diagnosis and management of this condition. Furthermore, this review will emphasize the gaps in research on this common condition impacting women of reproductive age all over the world.


Utility of hematuria testing in patients with suspected renal colic: correlation with unenhanced helical CT results.
To determine the utility of hematuria testing in a large series of patients with suspected renal colic using unenhanced helical computed tomography (CT) as the reference standard. A retrospective review of the CT reports of all patients who underwent unenhanced helical CT for suspected renal colic at one institution during a 3.5-year period and who also underwent a formal microscopic urinalysis within 24 hours of the CT study was conducted. The sensitivity, specificity, positive predictive value, and negative predictive value of the presence of any blood on the urinalysis for renal colic were calculated. Urolithiasis was present in 587 (62%) of the 950 patients, and 363 patients had negative examinations for renal colic, including 69 with significant alternative diagnoses in the latter group. Of the urinalyses, 492 were true-positive, 174 were true-negative, 189 were false-positive, and 95 were false-negative, yielding a sensitivity, specificity, positive predictive value, and negative predictive value of 84%, 48%, 72%, and 65%, respectively. Forty-six percent of the urinalysis results were negative for blood in the subset of patients with significant alternative diagnoses. The sensitivity of hematuria on microscopic urinalysis for renal colic using unenhanced CT as the reference standard was 84%, and the specificity and negative predictive value was low. The presence or absence of blood on urinalysis cannot be used to reliably determine which patients actually have ureteral stones.


Primary cardiac echinococcosis: report of two cases with review of the literature.
Two case reports of Saudi patients with primary cardiac hydatid cysts are presented. In the first case, a multilocular cyst was located in the wall of the left ventricle, whereas in the second case a cyst was located in the pericardial sac and another cyst in the left ventricular wall. The diagnosis was based on a history of animal contact, full clinical examination, serological tests and the use of plain radiography, including conventional tomogram, two-dimensional echocardiography, computed tomography and thallium perfusion isotope scan. This study has indicated that non-invasive radiological methods are sufficient to diagnose cardiac echinococcosis and could provide the same information as, or even more than if invasive techniques were used. Further screening of the two patients showed no involvement of other organs by hydatid cysts.


Contributions of extracellular-signal regulated kinase 1/2 activity to the memory trace.
The ability to learn from experience and consequently adapt our behavior is one of the most fundamental capacities enabled by complex and plastic nervous systems. Next to cellular and systems-level changes, learning and memory formation crucially depends on molecular signaling mechanisms. In particular, the extracellular-signal regulated kinase 1/2 (ERK), historically studied in the context of tumor growth and proliferation, has been shown to affect synaptic transmission, regulation of neuronal gene expression and protein synthesis leading to structural synaptic changes. However, to what extent the effects of ERK are specifically related to memory formation and stabilization, or merely the result of general neuronal activation, remains unknown. Here, we review the signals leading to ERK activation in the nervous system, the subcellular ERK targets associated with learning-related plasticity, and how neurons with activated ERK signaling may contribute to the formation of the memory trace.


Noninvasive Assessment of the Alloimmune Response in Kidney Transplantation.
Transplantation remains the optimal mode of kidney replacement therapy, but unfortunately long-term graft survival after 1 year remains suboptimal. The main mechanism of chronic allograft injury is alloimmune, and current clinical monitoring of kidney transplants includes measuring serum creatinine, proteinuria, and immunosuppressive drug levels. The most important biomarker routinely monitored is human leukocyte antigen (HLA) donor-specific antibodies (DSAs) with the frequency based on underlying immunologic risk. HLA-DSA should be measured if there is graft dysfunction, immunosuppression minimization, or nonadherence. Antibody strength is semiquantitatively estimated as mean fluorescence intensity, with titration studies for equivocal cases and for following response to treatment. Determination of in vitro C1q or C3d positivity or HLA-DSA IgG subclass analysis remains of uncertain significance, but we do not recommend these for routine use. Current evidence does not support routine monitoring of non-HLA antibodies except anti-angiotensin II type 1 receptor antibodies when the phenotype is appropriate. The monitoring of both donor-derived cell-free DNA in blood or gene expression profiling of serum and/or urine may detect subclinical rejection, although mainly as a supplement and not as a replacement for biopsy. The optimal frequency and cost-effectiveness of using these noninvasive assays remain to be determined. We review the available literature and make recommendations.


ST segment elevation myocardial infarction of a rare aetiology: an unexpected diagnosis.
A 43-year-old man presenting with acute coronary syndrome with ST segment elevation myocardial infarction underwent urgent coronary angiography. During the intervention, the patient was found to have several multiple filling defects with dynamic obstruction in the left coronary circulation. Thrombectomy was performed on distal left anterior descending artery and 2nd diagonal artery lesions with balloon angioplasty, which was unsuccessful. Considering the dynamic obstruction in the angiogram, immediate imaging was performed for structural evaluation of the heart. Cardiac CT revealed a circumferential groove on the heart, suggesting an external compression leading to dynamic obstruction of the coronary arteries on angiogram. Cardiac hernia, a very rare aetiology, was suspected to be the culprit for the ST segment elevation myocardial infarction. Thoracoscopy was performed, which revealed congenital cardiac hernia and a fibrous pericardial band encircling the apex. A left mini thoracotomy was performed to release the constriction imposed over the heart, with improvement in circulation.


Flavonol glycosides from Lysimachia capillipes.
Two new compounds, capilliposide I and capilliposide II, together with a known compound quercetin-3-O-(2,6-di-alpha-L-rhamnopyranosyl)-beta-D-galactopyranoside were isolated from the extracts of the whole herbs of Lysimachia capillipes. Their structures were established through their spectral data and chemical properties.


Self-assembled half-sandwich Ir, Rh-based organometallic molecular boxes for reversible trapping of halocarbon molecules.
Reactions of [Cp*MCl(mu-Cl)](2) (M = Ir or Rh) with 6,11-dihydroxy-5,12-naphthacenedione (H(2)DHNA) in the presence of base, gave the corresponding binuclear complexes [Cp*(2)M(2)(mu-DHNA)Cl(2)] (M = Ir (1a); M = Rh (1b)), respectively. Treatment of 1a or 1b with bidentate ligands (L) such as pyrazine, 4,4'-dipyridine (bpy), E-1,2-bis(4-pyridyl)ethene (bpe) or 2,5-bis(4-pyridyl)-1,3,5-oxadiazole (bpo) in the presence of AgOTf (OTf = CF(3)SO(3)) in CH(3)OH, gave the corresponding tetranuclear complexes, general formula [Cp*(4)M(4)(mu-DHNA)(2)(mu-L)(2)](OTf)(4) (3a, 4a, 5a, 6a: M = Ir; 3b, 4b, 5b, 6b: M = Rh), respectively. X-Ray analyses of 3a, 3b, 4a, 4b, 5a and 5b revealed that each of the half-sandwich metal centers was connected by pyridyl ligands and bis-bidentate bridging ligands to construct a rectangular cavity with different dimensions, and strong pi-pi interactions between independent molecules to form rectangular channels in the solid-state. Complexes 3a and 3b based on H(2)DHNA and pyrazine spacing ligands were found to exhibit selective and reversible small organic molecules adsorption properties. The example of C-H...Cl interactions served as a template by an interacted layer of monomeric complex for the creation of intercalated supramolecular arrays has been studied.


Theoretical rotation-torsion energies of HSOH.
The rotation-torsion energies in the electronic ground state of HSOH are obtained in variational calculations based on a newly computed ab initio CCSD(T)/aug-cc-pV(Q+d)Z potential energy surface. Using the concept of the reaction path Hamiltonian, as implemented in the program TROVE (theoretical rovibrational energies), the rotation-vibration Hamiltonian is expanded around geometries on the torsional minimum energy path of HSOH. The calculated values of the torsional splittings are in excellent agreement with experiment; the root-mean-square (rms) deviation is 0.0002 cm(-1) for all experimentally derived splittings (with J < or = 40 and K(a) < or = 4). The model provides reliable predictions for splittings not yet observed. The available experimentally derived torsion-rotation term values (with J < or = 40 and K(a) < or = 4) are reproduced ab initio with an rms deviation of 1.2 cm(-1) (0.7 cm(-1) for J < or = 20), which is improved to 1.0 cm(-1) (0.07 cm(-1) for J < or = 20) in an empirical adjustment of the bond lengths at the planar trans configuration. The theoretical torsional splittings of HSOH are analyzed in terms of an existing semiempirical model for the rotation-torsion motion. The analysis explains the irregular variation of the torsional splittings with K(a) that has been observed experimentally.


Effect of glucocorticoid hormone on nuclear matrix in cervical cancer cells in vitro.
Human papillomavirus (HPV) is one of the crucial factors in cervical carcinogenesis. High risk HPV16 prototype has been demonstrated in association with the nuclear matrix in a cervical carcinoma cell line(1,2). Nuclear matrix (NM) has been established as playing an important role in various nuclear activities as well as carcinogenic processes. Dexamethasone (DEX) (glucocorticoid hormone) inhibited the growth of CC2/CUHK2 cervical carcinoma cells with concurrent induction of epithelial cell differentiation. 2D- PAGE (IEF and NEPHGE) revealed alternations in NM protein composition. Further demonstration of changes in NM was evidenced by NuMA (a novel NM protein) labelling. The HPV16 E7 oncoprotein was shown to be reduced in total cellular protein as well as in NM protein fractions in response to DEX treatment, and this suppressed expression was confirmed by RT-PCR. Thus, it is suggested that dexamethasone can down-regulate the growth of cervical cancer cells and its induced changes in NM may be a cause of this suppression.


Improving Glucose Prediction Accuracy in Physically Active Adolescents With Type 1 Diabetes.
Physical activity presents a significant challenge for glycemic control in individuals with type 1 diabetes. As accurate glycemic predictions are key to successful automated decision-making systems (eg, artificial pancreas, AP), the inclusion of additional physiological variables in the estimation of the metabolic state may improve the glucose prediction accuracy during exercise. Predictor-based subspace identification is applied to a dynamic glucose prediction model including heart rate measurements along with variables representing the carbohydrate consumption and insulin boluses. To demonstrate the improvement in prediction ability due to the additional heart rate variable, the performance of the proposed modeling technique is evaluated with (SID-HR) and without heart rate (SID-2) as an additional input using experimental data involving adolescents at ski camp. Furthermore, the performance of the proposed approach is compared to that of the metabolic state observer (MSO) model currently used in the University of Virginia AP algorithm. The addition of heart rate in the subspace-based model (SID-HR) yields a statistically significant improvement in the root-mean-square error compared to the SID-2 model (P < .001) and the standard MSO (P < .001). Furthermore, the SID-HR model performed favorably in comparison to the SID-2 and MSO models after accounting for its increased complexity. Directly considering the effects of physical activity levels on glycemic dynamics through the inclusion of heart rate as an additional input variable in the glucose dynamics model improves the glucose prediction accuracy. The proposed methodology could improve exercise-informed model-based predictive control algorithms in artificial pancreas systems.


The relationship between theory of mind and sluggish cognitive tempo in school-age children with attention deficit and hyperactivity disorder.
Sluggish cognitive tempo (SCT) is considered as a cognitive-emotional style. Theory of mind (ToM) skills form the basis of human cognition and social behavior. The aim of this study is to contribute to SCT literature by examining the relationship between SCT and cognitive and affective ToM in school-age children with attention deficit and hyperactivity disorder (ADHD). Fifty school-age children with ADHD (43 boys and seven girls) and 40 typically developing children (34 boys and six girls) were assessed using Parent-rated Barkley Child Attention Scale and Child Behavior Checklist/6-18, cognitive (first- and second-order ToM) and affective ToM (Reading Mind in the Eyes Test and Unexpected Outcomes Test (UOT)) tests. Multiple linear regression analysis was performed to determine the variables that may predict SCT levels in children with ADHD. Attention deficit and hyperactivity disorder-inattention (Exp(B) = .334, p = .027), internalization (Exp(B) = .305, p = .006), and UOT scores (Exp(B) = .933, p = .015) significantly predicted SCT severity in children with ADHD. SCT severity was significantly associated with impaired cognitive ToM skills as measured by second-order ToM (Exp(B) = 1.933, p = .045). Our findings may indicate that affective ToM developing with age, and impaired cognitive ToM skills are associated with increasing SCT severity.


Accuracy of Computed Tomography in Diagnosis of Intra-abdominal Injuries in Stable Patients With Anterior Abdominal Stab Wounds: A Systematic Review and Meta-analysis.
Workup for patients presenting to the emergency department (ED) following an anterior abdominal stab wound (AASW) has been debated since the 1960s. Experts agree that patients with peritonitis, evisceration, or hemodynamic instability should undergo immediate laparotomy (LAP); however, workup of stable, asymptomatic or nonperitoneal patients is not clearly defined. The objective was to evaluate the accuracy of computed tomography of abdomen and pelvis (CTAP) for diagnosis of intraabdominal injuries requiring therapeutic laparotomy (THER-LAP) in ED patients with AASW. Is a negative CT scan without a period of observation sufficient to safely discharge a hemodynamically stable, asymptomatic AASW patient? We searched PubMed, Embase, and Scopus from their inception until May 2017 for studies on ED patients with AASW. We defined the reference standard test as LAP for patients who were managed surgically and inpatient observation in those who were managed nonoperatively. In those who underwent LAP, THER-LAP was considered as disease positive. We used the Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS-2) to evaluate the risk of bias and assess the applicability of the included studies. We attempted to compute the pooled sensitivity, specificity, positive likelihood ratio (LR+), and negative likelihood ratio (LR-) using a random-effects model with MetaDiSc software and calculate testing and treatment thresholds for CT scan applying the Pauker and Kassirer model. Seven studies were included encompassing 575 patients. The weighted prevalence of THER-LAP was 34.3% (95% confidence interval [CI] = 30.5%-38.2%). Studies had variable quality and the inclusion criteria were not uniform. The operating characteristics of CT scan were as follows: sensitivity = 50% to 100%, specificity = 39% to 97%, LR+ = 1.0 to 15.7, and LR- = 0.07 to 1.0. The high heterogeneity (I2 > 75%) of the operating characteristics of CT scan prevented pooling of the data and therefore the testing and treatment thresholds could not be estimated. The articles revealed a high prevalence (8.7%, 95% CI = 6.1%-12.2%) of injuries requiring THER-LAP in patients with a negative CT scan and almost half (47%, 95% CI = 30%-64%) of those injuries involved the small bowel. In stable AASW patients, a negative CT scan alone without an observation period is inadequate to exclude significant intraabdominal injuries.


Spectroscopic Characterization of the Product Ions Formed by Electron Ionization of Adamantane.
A structural characterization of the products formed in the dissociative electron ionization of adamantane (C10 H16 ) is presented. Molecular structures of product ions are suggested based on multiple-photon dissociation spectroscopy using the Free Electron Laser for Infrared eXperiments (FELIX) in combination with quantum-chemical calculations. Product ions are individually isolated in an ion trap tandem mass spectrometer and their action IR spectra are recorded. Atomic hydrogen loss from adamantane yields the 1-adamantyl isomer. The IR spectrum of the C8 H11 + product ion is best reproduced by computed spectra of 2- and 4-protonated meta-xylene and ortho- and para-protonated ethylbenzenes. The spectrum of the product ion at m/z 93 suggests that it is composed of a mixture of ortho-protonated toluene, para-protonated toluene and 1,2-dihydrotropylium, while the spectrum of the m/z 79 ion is consistent with the benzenium ion. This study thus suggests that adamantane is efficiently converted into aromatic species and astrophysical implications for the interstellar medium are highlighted.


Individualism and Egalitarianism Can Kill: How Cultural Values Predict Coronavirus Deaths Across the Globe.
While in some countries, many people have died due to the coronavirus (COVID-19), in other countries, only a few have died. Based on the cultural values theory, our first hypothesis was that in countries that are predominantly individualistic, the number of deaths will be high, whereas in countries with predominantly collectivist values, the number of deaths will be low. Our second hypothesis was that countries with high power distance and hierarchy will have fewer deaths compared to countries with low power distance and egalitarianism. The hypotheses were tested by referring to two different value studies (Hofstede's study of 76 countries and Schwartz's study of 75 countries) while also controlling for GDP per capita, Gini index, population density, median age per country, and BMI per country. Of the five control variables GDP and BMI significantly predicted coronavirus deaths. Taking into account GDP, Gini index, population density, median age, and BMI, hierarchical regression analyses confirmed the first hypothesis on individualism and the second hypothesis on egalitarianism. Therefore, in the case of this current pandemic, group-oriented and collectivist values and low egalitarianism values lead to specific health-related behaviors that ultimately keep more people alive.


Therapeutic approaches to problems of meaninglessness.
Paradigmatically, meaningful action, and by extension meaningful living, inhere in immersed participation in activities from which one derives substantial instrumental, intrinsic, and/or spiritual value. The greater the departure from this paradigm (the existentialist's "absurd" being the extreme case), the more meaningless will one's existence seem. Employing this paradigm case as a point of departure, the job of the psychotherapist becomes that of (a) diagnosing obstacles to clients securing such value in their behavior, and (b) assisting them in the removal or diminution of these obstacles. The empirically most common of these obstacles, as well as some therapeutic approaches to addressing them, have been discussed in this article.


Combined application of two Bacillus species enhance phytoremediation potential of Brassica napus in an industrial metal-contaminated soil.
This study aimed to assess the impact of individual as well as combined application of Lysinibacillus macroides and Bacillus safensis in phytoremediation potential of Brassica napus grown in soil contaminated by industrial effluents. In response to five metals; copper, chromium, nickel, lead, and cadmium, results revealed that germination percentage, fresh and dry weights, and photosynthetic pigments of B. napus decreased under contaminated soil. On the other hand, electrolyte leakage due to cellular injury, metabolites (proline and glycine betaine), antioxidant enzymes (superoxide dismutase, catalase, peroxidase, ascorbate peroxidase), accumulation of hydrogen peroxide and metals in plant's roots, shoots and leaves increased. Inoculation significantly reduced these effects as proved by the enhancement of germination percentage, fresh and dry biomass, and photosynthetic pigments. Simultaneously, the antioxidant enzymes, metabolites contents (proline and glycine betaine) and metal concentrations in plant's roots, shoots and leaves decreased. Combined application of both Bacilli strains was found more effective as compared to individual inoculation. It was concluded that metal resistant Bacillus species in combination had growth effects on B. napus and enhanced its phytoremediation efficiency in contaminated soil.Novelty statementBrassica napus; a hyper-accumulator of metals, loses phytoremediation potential with the passage of growth. Two Bacillus species (Lysinibacillus macroides and Bacillus safensis) having known bioremediation abilities were employed individually as well as in combination under metals contaminated soil to increase phytoremediation efficiency of B. napus. The metals containing soil used is a unique aspect in this study because selected soil, contaminated by industrial effluents, has not been evaluated or reported earlier. Combined application of Bacilli improved phytoremediation potential of B. napus more as compared to application of individual Bacillus strain which is yet another unique aspect of this investigation.


Imaging of vaporised sub-micron phase change contrast agents with high frame rate ultrasound and optics.
Phase-change ultrasound contrast agent (PCCA), or nanodroplet, shows promise as an alternative to the conventional microbubble agent over a wide range of diagnostic applications. Meanwhile, high-frame-rate (HFR) ultrasound imaging with microbubbles enables unprecedented temporal resolution compared to traditional contrast-enhanced ultrasound imaging. The combination of HFR ultrasound imaging and PCCAs can offer the opportunity to observe and better understand PCCA behaviour after vaporisation captures the fast phenomenon at a high temporal resolution. In this study, we utilised HFR ultrasound at frame rates in the kilohertz range (5-20 kHz) to image native and size-selected PCCA populations immediately after vaporisation in vitro within clinical acoustic parameters. The size-selected PCCAs through filtration are shown to preserve a sub-micron-sized (mean diameter < 200 nm) population without micron-sized outliers (>1 µm) that originate from native PCCA emulsion. The results demonstrate imaging signals with different amplitudes and temporal features compared to that of microbubbles. Compared with the microbubbles, both the B-mode and pulse-inversion (PI) signals from the vaporised PCCA populations were reduced significantly in the first tens of milliseconds, while only the B-mode signals from the PCCAs were recovered during the next 400 ms, suggesting significant changes to the size distribution of the PCCAs after vaporisation. It is also shown that such recovery in signal over time is not evident when using size-selective PCCAs. Furthermore, it was found that signals from the vaporised PCCA populations are affected by the amplitude and frame rate of the HFR ultrasound imaging. Using high-speed optical camera observation (30 kHz), we observed a change in particle size in the vaporised PCCA populations exposed to the HFR ultrasound imaging pulses. These findings can further the understanding of PCCA behaviour under HFR ultrasound imaging.


A late-emerging auditory deficit in autism.
Individuals with autism spectrum disorders (ASD) show enhanced perceptual and memory abilities in the domain of pitch, but also perceptual deficits in other auditory domains. The present study investigated their skills with respect to "echoic memory," a form of short-term sensory memory intimately tied to auditory perception, using a developmental perspective. We tested 23 high-functioning participants with ASD and 26 typically developing (TD) participants, distributed in two age groups (children vs. young adults; mean ages: ∼11 and ∼21 years). By means of an adaptive psychophysical procedure, we measured the longest period for which periodic (i.e., repeated) noise could be reliably discriminated from nonperiodic (i.e., plain random) noise. On each experimental trial, a single noise sample was presented to the participant, who had to classify this sound as periodic or nonperiodic. The TD adults performed, on average, much better than the other three groups, who performed similarly overall. As a function of practice, the measured thresholds improved for the TD participants, but did not change for the ASD participants. Thresholds were not correlated to performance in a test assessing verbal memory. The variance of the participants' response biases was larger among the ASD participants than among the TD participants. The results mainly suggest that echoic memory takes a long time to fully develop in TD humans, and that this development stops prematurely in persons with ASD.


Impacts of Size and Deformability of β-Lactoglobulin Microgels on the Colloidal Stability and Volatile Flavor Release of Microgel-Stabilized Emulsions.
Emulsions can be prepared from protein microgel particles as an alternative to traditional emulsifiers. Prior experiments have indicated that smaller and more deformable microgels would decrease both the physical destabilization of emulsions and the diffusion-based losses of entrapped volatile molecules. The microgels were prepared from β-lactoglobulin with an average diameter of 150 nm, 231 nm, or 266 nm; large microgels were cross-linked to decrease their deformability. Dilute emulsions of 15⁻50 μm diameter were prepared with microgels by high shear mixing. Light scattering and microscopy showed that the emulsions prepared with larger, untreated microgels possessed a larger initial droplet size, but were resistant to droplet growth during storage or after acidification, increased ionic strength, and exposure to surfactants. The emulsions prepared with cross-linked microgels emulsions were the least resistant to flocculation, creaming, and shrinkage. All emulsion droplets shrank as limonene was lost during storage, and the inability of microgels to desorb caused droplets to become non-spherical. The microgels were not displaced by Tween 20 but were displaced by excess sodium dodecyl sulfate. Hexanol diffusion and associated shrinkage of pendant droplets was not prevented by any of the microgels, yet the rate of shrinkage was reduced with the largest microgels.


Recommendations for managing a suboptimal response to biologics for moderate-to-severe psoriasis: A Belgian perspective.
Over the past decade, biologics have become the gold standard in the treatment of moderate-to-severe psoriasis for patients who have failed or who have contraindications to traditional systemic treatments. However, although practical recommendations on how to treat a suboptimal response to biologics exist in other chronic inflammatory diseases, they are only just beginning to emerge for psoriasis. This article aims to formulate recommendations in the case of a suboptimal response of psoriasis to biologics in the Belgian setting. A Belgian taskforce of psoriasis experts was convened to review the results of a literature search and formulate recommendations based on the available evidence and provide expert opinion to address gaps in the evidence. The taskforce has proposed a treatment algorithm for patients with a primary non-response or a secondary loss of response to help address an unmet need. Expert recommendations have been developed to address treatment strategies in case of a primary or secondary suboptimal response to biologics in the treatment of moderate-to-severe psoriasis in Belgium.


Burden of influenza in children: preliminary data from a pilot survey network on community diseases.
The burden of influenza and its clinical presentation are both poorly documented in French children. To measure the prevalence of acute respiratory infections over two winters (2000 to 2001 and 2001 to 2002), we performed a prospective community survey of 0- to 15-year-olds (n = 11 500 and 40 000, respectively) through a network [Grippe et Infections Respiratoires Aiguës Pédiatriques (GIRAP)] of general practitioners and pediatricians. Influenza viruses were detected by antigen detection and culture from nasopharyngeal swabs. Data on the clinical presentation of children infected with influenza A/H1N1, A/H3N2 or B viruses were derived from standardized forms. The prevalences of symptomatic acute respiratory infections were 28% and 27% for 2000 to 2001 and 2001 to 2002, respectively. In the winter of 2000 to 2001, a mild outbreak of influenza A/H1N1 affected 5.4% of the study population. The attack rates of influenza A/H1N1 were highest in children 5 to 15 years of age. In the winter of 2001 to 2002, influenza activity remained at a subepidemic level (5.9%; A/H3N2, 60%; B, 40%). The incidence of influenza A/H3N2 infections was highest in 2- to 4-year-old children, whereas influenza B strains were most frequently detected in children 4 to 10 years of age. Despite subepidemic levels of influenza, the GIRAP network was able to detect influenza A or B viruses in 35 to 60% of the samples during the peak of influenza epidemic. The frequency of influenza virus excretion in children with mild clinical symptoms indicates that children are an important reservoir and source of transmission of this virus.


Superior gluteal artery perforator flap salvaged via hyperbaric oxygen therapy.
The superior gluteal artery perforator (SGAP) flap can be challenging and in common with all flaps can develop venous and arterial insufficiency. Several prior studies have demonstrated the successful utility of hyperbaric oxygen therapy (HBOT) in the salvage of compromised flaps, mainly with deep inferior epigastric perforator, latissimus dorsi or transverse rectus abdominis myocutaneous flaps. SGAP flaps are autologous alternatives to abdominal-based flaps and provides adequate adipose tissue for breast reconstruction. We report a case of a woman in her 50s who underwent a delayed bilateral breast reconstruction using SGAP free flaps. Postoperatively, venous congestion of her right breast flap was noted for which she was referred for HBOT. An acceptable aesthetic result was achieved following 17 HBOT treatments. This is the first case we can find in the published literature of ischaemic SGAP free flap being salvaged by HBOT.


Ventilator-associated pneumonia: present understanding and ongoing debates.
Ventilator-associated pneumonia (VAP) is a common cause of nosocomial infection, and is related to significant utilization of health-care resources. In the past decade, new data have emerged about VAP epidemiology, diagnosis, treatment and prevention. Classifying VAP strictly based on time since hospitalization (early- and late-onset VAP) can potentially result in undertreatment of drug-resistant organisms in ICUs with a high rate of drug resistance, and overtreatment for patients not infected with resistant pathogens. A combined strategy incorporating diagnostic scoring systems, such as the Clinical Pulmonary Infection Score (CPIS), and either a quantitative or qualitative microbiological specimen, plus serial measurement of biomarkers, leads to responsible antimicrobial stewardship. The newly proposed ventilator-associated events (VAE) surveillance definition, endorsed by the Centers for Disease Control and Prevention, has low sensitivity and specificity for diagnosing VAP and the ability to prevent VAE is uncertain, making it a questionable surrogate for the quality of ICU care. The use of adjunctive aerosolized antibiotic treatment can provide high pulmonary concentrations of the drug and may facilitate shorter durations of therapy for multi-drug-resistant pathogens. A group of preventive strategies grouped as a 'ventilator bundle' can decrease VAP rates, but not to zero, and several recent studies show that there are potential barriers to implementation of these prevention strategies. The morbidity and mortality related to VAP remain high and, in the absence of a gold standard test for diagnosis, suspected VAP patients should be started on antibiotics based on recommendations per the 2005 ATS guidelines and knowledge of local antibiotic susceptibility patterns. Using a combination of clinical severity scores, biomarkers, and cultures might help with reducing the duration of therapy and achieving antibiotic de-escalation.


Sequential and simultaneous treatment approaches to cannabis use disorder and tobacco use.
Tobacco smoking among those seeking treatment for cannabis use disorder (CUD) is common and is a negative predictor of cannabis outcomes. Quitting tobacco may be beneficial for those seeking to quit cannabis use. This initial proof of concept, controlled trial was designed to compare a simultaneous versus sequential tobacco intervention among those seeking treatment for CUD. Sixty-seven adults received either a simultaneous (SIM) or sequential (SEQ) approach to tobacco cessation in the context of outpatient treatment for CUD. A tobacco intervention (TI) that combined web-based counseling with nicotine replacement therapy (NRT) was provided during weeks 1-12 for SIM and was delayed until weeks 13-24 for SEQ. During weeks 1-12, no between-condition significant differences were observed on treatment participation or cannabis use outcomes. The majority of SIM participants initiated TI counseling (62%), 50% made at least one quit attempt and 41% initiated NRT. Interestingly, 39% in SEQ made tobacco quit attempts and 18% initiated NRT on their own before the TI was offered to them. However, only 30% of those in SEQ continued treatment during weeks 13-24, which compromised between-condition comparisons following the TI, but illustrated a potential clinical concern with delaying the TI. Tobacco cessation outcomes generally were poor and did not differ between conditions. This initial controlled trial suggests that addressing tobacco use during CUD treatment is acceptable and generates action towards tobacco cessation. Additional trials testing more intensive TI models may be necessary to identify more efficacious interventions for co-use of cannabis and tobacco.


Scar flap for extension of the nasal and lip soft tissue shell in secondary cleft deformities: final aesthetic touches in clefts-part iii.
A scar flap is formed with the pedicle at the lateral part of the columella base at the cleft side, that is, in the center of the affected region. It enables flap placement according to individual need. A prospective evaluation was performed in a group of 76 patients with cleft lip and palate, all operated on by the same plastic surgeon. The flap was used to improve the height of the columella and the extent of nasal mucosa on the frontal septum and on the nostril base in the vestibule. In the lip, the flap raised its height and improved proportionality. The average area of flap used in a unilateral deformity was 42 mm. Both flaps in a bilateral deformity were 77 mm. The average follow-up was 22.4 months. Neither local nor general complications were noted apart from a recurrence of the deformity of the nasal septum in 7.9% of patients. The nasal passage was improved in 59.9% of patients and normalized in 19.6% upon follow-up rhinomanometry, but nevertheless, only one third of patients overcame their dynamic stereotype of breathing by the mouth. Anthropometric measurements showed an absence of statistically significant differences between patients after surgery and healthy individuals in crucial parameters (nasal tip projection, length of columella, nasolabial angle, nasal angle, and lip angle). The loss of the stigmatizing deformity is based on rotation of the nasolabial angle in relation to the aesthetic axis of the face. Direct examination proved aesthetic and functional improvement as statistically significant in 92.1% of patients.


Treatment of chronic idiopathic urticaria with topical preparations: controlled study of oxatomide gel versus dechlorpheniramine cream.
A controlled and completely randomized study was carried out with the aim of assessing the efficacy and safety of oxatomide gel in comparison with another preparation for topical use, dechlorpheniramine. Twenty-seven patients (sixteen F, eleven M) aged between 21 and 72 years (mean age 39) suffering from chronic idiopathic urticaria were treated for 15 days with oxatomide gel at 5% or dechlorpheniramine cream at 1%; 15 days of follow-up without therapy were then observed. Both the treatments allowed significant control of cutaneous symptoms. In particular, in the group treated with oxatomide there was a more marked reduction in itching and in the number of weals (p less than 0.01 between times), and in the dechlorpheniramine group in the severity of erythema (p less than 0.01 between times). During the follow-up period, a distinct flare-up of symptoms was observed only in the dechlorpheniramine group. Acceptability and safety, both clinical and biological, were good for both products.


A Simultaneously Antimicrobial, Protein-Repellent, and Cell-Compatible Polyzwitterion Network.
A simultaneously antimicrobial, protein-repellent, and cell-compatible surface-attached polymer network is reported, which reduces the growth of bacterial biofilms on surfaces through its multifunctionality. The coating was made from a poly(oxonorbornene)-based zwitterion (PZI), which was surface-attached and cross-linked in one step by simultaneous UV-activated CH insertion and thiol-ene reaction. The process was applicable to both laboratory surfaces like silicon, glass, and gold and real-life surfaces like polyurethane foam wound dressings. The chemical structure and physical properties of the PZI surface and the two reference surfaces SMAMP ("synthetic mimic of an antimicrobial peptide"), an antimicrobial but protein-adhesive polymer coating, and PSB (poly(sulfobetaine)), a protein-repellent but not antimicrobial polyzwitterion coating were characterized by Fourier transform infrared spectroscopy, ellipsometry, contact angle measurements, photoelectron spectroscopy, swellability measurements (using surface plasmon resonance spectroscopy, SPR), zeta potential measurements, and atomic force microscopy. The time-dependent antimicrobial activity assay (time-kill assay) confirmed the high antimicrobial activity of the PZI; SPR was used to demonstrate that it was also highly protein-repellent. Biofilm formation studies showed that the material effectively reduced the growth of Escherichia coli and Staphylococcus aureus biofilms. Additionally, it was shown that the PZI was highly compatible with immortalized human mucosal gingiva keratinocytes and human red blood cells using the Alamar Blue assay, the live-dead stain, and the hemolysis assay. PZI thus may be an attractive coating for biomedical applications, particularly for the fight against bacterial biofilms on medical devices and in other applications.


Stakeholders' perspectives and experiences of patient and public involvement (PPI) in clinical trials in maternal and neonatal healthcare: protocol for a qualitative evidence synthesis.
Patient and public involvement (PPI) has the potential to improve the relevance of trial outcomes and improve participant recruitment within clinical trials. However, the literature on PPI approaches, outcomes, and attitudes towards PPI in specific clinical research areas is limited. We are interested to know the current approaches to and views of PPI within maternal and neonatal clinical trials, from the perspective and experience of involved stakeholders. A qualitative evidence synthesis (QES) of stakeholders' perspectives and experiences of PPI will be conducted. Stakeholders will include any individual involved in maternal or neonatal clinical trials with experience of PPI in the area or who expresses their views on PPI. The electronic bibliographic databases CINAHL, MEDLINE, PsycINFO, EMBASE, Web of Science and the Maternity and Infant Care (OVID) will be searched from inception. Qualitative studies, mixed-methods studies where the qualitative data can be extracted independently, and surveys with open-ended qualitative questions, will be included. The QES seeks to explore stakeholders', including PPI contributors, trial participants and guardians, and trial researchers, perspectives and experiences of PPI in maternal and neonatal clinical trials. THE QES will provide an understanding of how PPI is understood, operationalised and experienced by stakeholders in maternal and neonatal clinical trials, with the aim of identifying good practice and areas for improvement. PROSPERO registration: CRD42023383878 (2 nd March 2023).


Tumor necrosis factor-α sensitizes breast cancer cells to natural products with proteasome-inhibitory activity leading to apoptosis.
The inflammatory microenvironment plays an important role in the process of tumor development. Tumor necrosis factor-α (TNF-α), a key pro-inflammatory cytokine, has a significant role in this process. Natural medicinal products such as Withaferin A (WA) and Celastrol (Cel) have shown anti-cancer and anti-inflammatory properties that can be attributed to multiple mechanisms including, but not limited to, apoptosis induction due to the inhibition of proteasomal activities. This study aimed to investigate the effects of TNF-α in combination with WA or Cel in vitro in MDA-MB-231 breast cancer cells. TNF-α, when combined with WA or Cel, activated caspase-3 and -9 and downregulated XIAP in a dose-dependent manner, leading to induction of apoptosis in MDA-MB-231 breast cancer cells. The combination also caused accumulation of the proteasomal target protein IκBα, resulting in inhibition of the nuclear translocation of nuclear factor-κB (NF-κB). Taken together, these results suggest that TNF-α could sensitize breast cancer cells MDA-MB-231 to WA and Cel, at least in part, through inhibiting the activation of NF-κB signaling, leading to XIAP inhibition with subsequent upregulation of caspase-3 and -9 activities. Thus, the anti-cancer activities of TNF-α are enhanced when combined with the natural proteasome inhibitors, WA or Cel.


Electronic structure of LaO based on frozen-core four-component relativistic multiconfigurational quasidegenerate perturbation theory.
The electronic structure of the LaO molecule is studied using frozen-core four-component multiconfigurational quasidegenerate perturbation theory. The ground state and nine experimentally observed excited states are examined. The ground state is (2)Sigma(1/2)(+) and its gross atomic orbital population is La(5p(5.76)6s(0.83)6p(0.14)p(*(0.21) )d(*(1.17) )f(*(0.26) )) O(2p(4.63)), where p*, d*, and f* are the polarization functions of La that form molecular spinors with O 2ps. We found that it is not necessary to consider the excitation from the O 2p electrons when analyzing the experimental spectra. This validates the foundation of the ligand field theory on diatomic molecules, including the La atom where only one electron is considered. The spectroscopic constants R(e), omega(e), and T(0) calculated for the ground state and low-lying excited states A'((2)Delta(3/2)), A'((2)Delta(5/2)) A((2)Pi(1/2)), and A((2)Pi(3/2)) are in good agreement with the experimental values.


Stochastic gene expression conditioned on large deviations.
The intrinsic stochasticity of gene expression can give rise to large fluctuations and rare events that drive phenotypic variation in a population of genetically identical cells. Characterizing the fluctuations that give rise to such rare events motivates the analysis of large deviations in stochastic models of gene expression. Recent developments in non-equilibrium statistical mechanics have led to a framework for analyzing Markovian processes conditioned on rare events and for representing such processes by conditioning-free driven Markovian processes. We use this framework, in combination with approaches based on queueing theory, to analyze a general class of stochastic models of gene expression. Modeling gene expression as a Batch Markovian Arrival Process (BMAP), we derive exact analytical results quantifying large deviations of time-integrated random variables such as promoter activity fluctuations. We find that the conditioning-free driven process can also be represented by a BMAP that has the same form as the original process, but with renormalized parameters. The results obtained can be used to quantify the likelihood of large deviations, to characterize system fluctuations conditional on rare events and to identify combinations of model parameters that can give rise to dynamical phase transitions in system dynamics.


Bovine herpesvirus 5 encodes a unique pattern of microRNAs compared with bovine herpesvirus 1.
Bovine herpesvirus type 5 (BoHV-5) and bovine herpesvirus 1 (BoHV-1) are two closely related viruses. However, BoHV-5 is responsible for fatal meningitis in calves, while BoHV-1 is associated with infectious rhinotracheitis in cattle, and the mechanism by which the two viruses cause different symptoms is not well understood. In this study, we identified 11 microRNA (miRNA) genes, encoded by the BoHV-5 genome, that were processed into 16 detectable mature miRNAs in productive infection as determined by deep sequencing. We found that 6 out of 16 miRNA genes were present as two copies in the internal repeat and terminal repeat regions, resulting in a total of 17 miRNA-encoding loci distributed in both DNA strands. Surprisingly, BoHV-5 shared only one conservative miRNA with BoHV-1, which was located upstream of the origin of replication. Furthermore, in contrast to BoHV-1, no miRNAs were detected in the unique short region and locus within or near the bovine infected-cell protein 0 and latency-related genes. Variations in both the 5' and 3' ends of the reference sequence were observed, resulting in more than one isoform for each miRNA. All of the 16 miRNAs were detectable by stem-loop reverse transcriptase-PCR. The miRNAs with high read numbers were subjected to Northern blot analysis, and all pre-miRNAs and one mature miRNA were detected. Collectively, the data suggest that BoHV-5 encodes a different pattern of miRNAs, which may regulate the life cycle of BoHV-5 and might account for the different pathogenesis of this virus compared with BoHV-1.


Multi-centre prospective internal and external evaluation of the Brompton Harefield Infection Score (BHIS).
Previously, we reported that the Brompton Harefield Infection Score (BHIS) accurately predicts surgical site infection (SSI) after coronary artery bypass grafting (CABG). The BHIS was developed using two-centre data and stratifies SSI risk into three groups based on female gender, diabetes or HbA1c > 7.5%, body mass index ≥ 35, left ventricular ejection fraction < 45% and emergency surgery. The purpose of this study was to prospectively evaluate BHIS internally as well as externally. Multi-centre prospective evaluation involving three tertiary centres took place between October 2012 and November 2015. SSI was classified using the Public Health England protocol. Receiver operating characteristic (ROC) curves assessed predictive accuracy. Across the four hospital sites, 168 of 4308 (3.9%) CABG patients had a SSI. Categorising the hospitals by BHIS score revealed that 65% of all patients were low risk (BHIS 0-1), 26% were medium risk (BHIS 2-3) and 8% were high risk (BHIS ≥ 4). The area under the ROC curve was in the range of 0.702-0.785. Overall area under the ROC curve was 0.709. BHIS provides a novel, internally and externally evaluated score for a patient's risk of SSI after CABG. It enables clinicians to focus on strategies to prospectively identify high-risk patients and improve outcomes.


Adsorption of phenthoate and acetochlor from water by clays and organoclays.
Adsorption of phenthoate and acetochlor onto kaolin, montmorillonite, bentonite clays and respective organoclays prepared by the exchange of quaternary ammonium as tetradecyltrimethyl ammonium bromide(TTAB), dodecyltrimethylammonium bromide (DTAB), and cetylpyridinium chloride (CPC) were studied. The adsorption equilibrium data points were fitted to Freundlich isotherm equations. The adsorption of phenthoate and acetochlor were significantly enhanced by surfactant treatment of the clays. The amount of both pesticides adsorbed per unit mass of organoclay followed the order of TTA-kaolin < TTA-montmorillonite < TTA-bentonite, which is inconsistent with the organic carbon content of the clays. The removal efficiency of organomontmorillonite to treat acetochlor is in the order of CP (C16)-montmorillonite > TTA (C14)-montmorillonite > DTA (C12)-montmorillonite. Phenthoate is adsorbed to greater extent than acetochlor by each adsorbent, which may be due to the higher hydrophobicity of phenthoate, indicating considerable hydrophobic interaction between adsorbent/adsorbate systems.


Woundoscopy: a new technique for examining deep, nonhealing wounds.
This article discusses a standard gastrointestinal procedure used to visualize sinus tracts in wounds. Sinus tracts have traditionally been visualized externally and probed internally. Because of this, the cause of the nonhealing wound was difficult to determine. Through a series of case studies performed at St. Francis Hospital Wound Care Institute, the authors documented the benefits to patients of a technique they call woundoscopy--endoscopy performed to gain additional information about wounds that have not healed by standard therapies. These benefits include early diagnosis and treatments less traumatic than traditional surgical incision and intervention. Although not a procedure to be used indiscriminately, woundoscopy resulted in positive outcomes. Further research seems warranted.


Crohn's disease of the larynx.
Extraintestinal involvement of Crohn's disease is becoming more readily identified. Laryngeal involvement by Crohn's disease, however, has been reported in only five cases in the medical literature. We present the sixth case as well as an analysis of the prior reports.


[Treatment of aphthosis with thalidomide and with colchicine].
Thalidomide alone (200-300 mg daily) or associated with colchicine (2-3 mg daily) was given orally to 25 patients with aphthosis: 8 patients with recurrent oral aphthae; 4 patients with recurrent mucocutaneous aphthosis, without visceral involvement, and 13 patients with Behçet's disease (Touraine's aphthosis). A major improvement was noted in all groups, with a rapid healing of mucous lesions and a rapid reduction of pain and burning as compared to prior spontaneous regressions. No new outbreaks were noted at a dose of 50-100 mg thalidomide and 1 mg colchicine daily. Under oral administration of the drugs, thrombophlebitis was noted in 1 case (third group) only. In the other patients with Behçet's disease, skin aphthae, ocular symptoms, arthritis, superficial nodular phlebitis quickly disappeared with treatment. The efficiency of the drugs is only temporary, since new lesions usually appeared a few weeks after the end of treatment. Due to the relatively small number of cases studied in each group, no conclusions can be drawn concerning the efficiency of thalidomide alone compared to the association of the two drugs. However, this open trial does support the usefulness of thalidomide, or thalidomide and colchicine, in recurrent mucocutaneous aphthae, aphthosis and Behçet's disease.