Multiple concurrent predictions inform prediction error in the human auditory pathway.
The key assumption of the predictive coding framework is that internal representations are used to generate predictions on how the sensory input will look like in the immediate future. These predictions are tested against the actual input by the so-called prediction error units, which encode the residuals of the predictions. What happens to prediction errors, however, if predictions drawn by different stages of the sensory hierarchy contradict each other? To answer this question, we conducted two fMRI experiments while male and female human participants listened to sequences of sounds: pure tones in the first experiment, frequency-modulated sweeps in the second experiment. In both experiments we used repetition to induce predictions based on stimulus statistics (stats-informed predictions) and abstract rules disclosed in the task instructions to induce an orthogonal set of (task-informed) predictions. We tested three alternative scenarios: neural responses in the auditory sensory pathway encode prediction error with respect to 1) the stats-informed predictions, 2) the task-informed predictions, or 3) a combination of both. Results showed that neural populations in all recorded regions (bilateral inferior colliculus, medial geniculate body, and primary and secondary auditory cortices) encode prediction error with respect to a combination of the two orthogonal sets of predictions. The findings suggest that predictive coding exploits the non-linear architecture of the auditory pathway for the transmission of predictions. Such non-linear transmission of predictions might be crucial for the predictive coding of complex auditory signals like speech.Significance Statement Sensory systems exploit our subjective expectations to make sense of an overwhelming influx of sensory signals. It is still unclear how expectations at each stage of the processing pipeline are used to predict the representations at the other stages. The current view is that this transmission is hierarchical and linear. Here we measured fMRI responses in auditory cortex, thalamus and midbrain while we induced two sets of mutually-inconsistent expectations on the sensory input, each putatively encoded at a different stage. We show that responses at all stages are concurrently shaped by both sets of expectations. The results challenge the hypothesis that expectations are transmitted linearly and provide for a normative explanation of the non-linear physiology of the corticofugal sensory system.


Seamless vascularized large-diameter tubular collagen scaffolds reinforced with polymer knittings for esophageal regenerative medicine.
A clinical demand exists for alternatives to repair the esophagus in case of congenital defects, cancer, or trauma. A seamless biocompatible off-the-shelf large-diameter tubular scaffold, which is accessible for vascularization, could set the stage for regenerative medicine of the esophagus. The use of seamless scaffolds eliminates the error-prone tubularization step, which is necessary when emanating from flat scaffolds. In this study, we developed and characterized three different types of seamless tubular scaffolds, and evaluated in vivo tissue compatibility, including vascularization by omental wrapping. Scaffolds (luminal Ø ∼ 1.5 cm) were constructed using freezing, lyophilizing, and cross-linking techniques and included (1) single-layered porous collagen scaffold, (2) dual-layered (porous+dense) collagen scaffold, and (3) hybrid scaffold (collagen+incorporated polycaprolacton knitting). The latter had an ultimate tensile strength comparable to a porcine esophagus. To induce rapid vascularization, scaffolds were implanted in the omentum of sheep using a wrapping technique. After 6 weeks of biocompatibility, vascularization, calcification, and hypoxia were evaluated using immunohistochemistry. Scaffolds were biocompatible, and cellular influx and ingrowth of blood vessels were observed throughout the whole scaffold. No calcification was observed, and slight hypoxic conditions were detected only in the direct vicinity of the polymer knitting. It is concluded that seamless large-diameter tubular collagen-based scaffolds can be constructed and vascularized in vivo. Such scaffolds provide novel tools for esophageal reconstruction.


Evaluation of the Efficacy of Computed Tomographic Coronary Angiography in Assessing Coronary Artery Morphology and Physiology: Rationale and Study Design.
Computed tomographic coronary angiography (CTCA) is a non-invasive imaging modality, which allows plaque burden and composition assessment and detection of plaque characteristics associated with increased vulnerability. In addition, CTCA-based coronary artery reconstruction enables local haemodynamic forces assessment, which regulate plaque formation and vascular inflammation and prediction of lesions that are prone to progress and cause events. However, the use of CTCA for vulnerable plaque detection in the clinical arena remains limited. To unlock the full potential of CTCA and enable its broad use, further work is needed to develop user-friendly processing tools that will allow fast and accurate analysis of CTCA, computational fluid dynamic modelling, and evaluation of the local haemodynamic forces. The present study aims to develop a seamless platform that will overcome the limitations of CTCA and enable fast and accurate evaluation of plaque morphology and physiology. We will analyse imaging data from 70 patients with coronary artery disease who will undergo state-of-the-art CTCA and near-infrared spectroscopy-intravascular ultrasound imaging and develop and train algorithms that will take advantage of the intravascular imaging data to optimise vessel segmentation and plaque characterisation. Furthermore, we will design an advanced module that will enable reconstruction of coronary artery anatomy from CTCA, blood flow simulation, shear stress estimation, and comprehensive visualisation of vessel pathophysiology. These advances are expected to facilitate the broad use of CTCA, not only for risk stratification but also for the evaluation of the effect of emerging therapies on plaque evolution.


Is treatment with a high flow nasal cannula effective in acute viral bronchiolitis? A physiologic study.
The high flow nasal cannula (HFNC) has recently been proposed to support infants with respiratory syncytial virus (RSV)-related respiratory distress. However, in this disease, no physiologic data are currently available on the effects of this device. We assessed the capacity of HFNC to generate positive airway pressure, as well as the resulting effects on breathing pattern and respiratory effort. Twenty-one infants less than 6 months old with acute RSV bronchiolitis were studied prospectively in the pediatric intensive care unit of a university hospital. Pharyngeal pressure (PP) and esophageal pressure (Pes) were measured simultaneously at four increasing flows of 1, 4, 6 and 7 L/min delivered through HFNC. The PP was correlated with flow rate (r = 0.65, p ≤ 0.0001), reaching mean and end-expiratory values of, respectively, 4 (95% CI 3-5) cmH₂O and 6.5 (95% CI 5-8) cmH2O at 7 L/min. A flow ≥2 L/kg/min was associated with the generation of a mean pharyngeal pressure ≥4 cmH₂O with a sensitivity of 67 %, a specificity of 96 %, a positive predictive value of 75 %, and a negative predictive value of 94.5%. Only flows ≥6 L/min provided positive PP throughout the respiratory cycle. From baseline to maximal flow rate, breathing frequency (p < 0.01), T i/T tot (p < 0.05), Pes swing (p < 0.05) and PTPesinsp/min (p < 0.01), an index of respiratory effort, were reduced. HFNC with a flow rate equal to or above 2 L/kg/min generated a clinically relevant PP, with improved breathing pattern and rapid unloading of respiratory muscles, in young infants with acute RSV bronchiolitis.


Hospital Dermatology: Review of Research in 2022-2023.
In the inpatient setting, dermatology consultants help reduce mortality, shorten length of stay, and reduce hospital readmissions. Recent research underscores the contributions of dermatology hospitalists, including phenotyping known and new severe cutaneous adverse drug reactions; showing improved progression-free and overall survival among those receiving dermatologic care for cutaneous reactions to immune checkpoint inhibitors; highlighting the role of dermatologists in reducing emergency department and hospital utilization by those with inflammatory skin diseases; and demonstrating ways in which dermatologists can effectively diagnose common and severe cutaneous diseases using asynchronous teledermatology, meeting the growing demand for inpatient dermatology services. This review covers selected highlights from the 2022-2023 inpatient dermatology literature.


Glass Microneedles: A Case Study for Regulatory Approval Using a Quality by Design Approach.
In this paper, a roadmap is provided for the regulatory approval of one of the exciting and dynamic drug delivery fields, microneedles, by using a Quality by Design approach to pharmaceutical product development. In this regard, a quality target product profile (QTPP) and the critical quality attributes (CQA) of microneedles are identified. A case study of the recently patented method of fabricating glass microneedles entirely from a therapeutic agent, thus eliminating the requirement for additional excipients is discussed. The glass microneedle, ArrayPatch, is a propriety wearable device with platform potential consisting of an array of sharp, but painless, dissolvable microneedles manufactured with 100% drug. The microneedles penetrate the skin on application and dissolve to deliver a locally effective dose. The in vitro characterization of the microneedle CQAs under WHO-guided stability conditions will be described to assess the manufacturing readiness of ArrayPatch. A live technical video is also provided, presenting a unique procedure of jugular vein cannulation through the ear vein of a pig animal model to study the in vivo pharmacokinetics of ArrayPatch compared to standard-of-care marketed products.


Combining cross-crystal averaging and MRSAD to phase a 4354-amino-acid structure.
The B and C proteins from the ABC toxin complex of Yersinia entomophaga form a large heterodimer that cleaves and encapsulates the C-terminal toxin domain of the C protein. Determining the structure of the complex formed by B and the N-terminal region of C was challenging owing to its large size, the non-isomorphism of different crystals and their sensitivity to radiation damage. A native data set was collected to 2.5 Å resolution and a non-isomorphous Ta6Br12-derivative data set was collected that showed strong anomalous signal at low resolution. The tantalum-cluster sites could be found, but the anomalous signal did not extend to a high enough resolution to allow model building. Selenomethionine (SeMet)-derivatized protein crystals were produced, but the high number (60) of SeMet sites and the sensitivity of the crystals to radiation damage made phasing using the SAD or MAD methods difficult. Multiple SeMet data sets were combined to provide 30-fold multiplicity, and the low-resolution phase information from the Ta6Br12 data set was transferred to this combined data set by cross-crystal averaging. This allowed the Se atoms to be located in an anomalous difference Fourier map; they were then used in Auto-Rickshaw for multiple rounds of autobuilding and MRSAD.


Description and comparison of pharmacy technician training programs in the United States.
To describe pharmacy technician training programs in the United States and to compare pharmacy technician program characteristics between programs with and without a pharmacist on faculty and between programs with different accreditation status. Descriptive, cross-sectional study. Not applicable. United States pharmacy technician programs. Not applicable. Student class size, faculty credentials, coursework components, program length, tuition rates, and admission criteria. Currently, there are more than 698 pharmacy technician programs across 1114 campuses, with complete data available for 216 programs. Programs varied widely in terms of class sizes, faculty credentials, and admission criteria. Programs with pharmacists on faculty were significantly less expensive than were those without pharmacists (P = 0.009). Accreditation had no impact on tuition prices. This is the first study of its kind to describe and characterize pharmacy technician training programs. There is relatively little control of technician training by the profession of pharmacy. The quality of these programs in terms of student outcomes is unknown, and it should be explored. Rigorous debate and discussion is needed regarding the future of pharmacy technician roles and the training required for those roles.


Dissecting the role of the myofilament in diaphragm dysfunction during the development of heart failure in mice.
Dyspnea and reduced exercise capacity, caused, in part, by respiratory muscle dysfunction, are common symptoms in patients with heart failure (HF). However, the etiology of diaphragmatic dysfunction has not been identified. To investigate the effects of HF on diaphragmatic function, models of HF were surgically induced in CD-1 mice by transverse aortic constriction (TAC) and acute myocardial infarction (AMI), respectively. Assessment of myocardial function, isolated diaphragmatic strip function, myofilament force-pCa relationship, and phosphorylation status of myofilament proteins was performed at either 2 or 18 wk postsurgery. Echocardiography and invasive hemodynamics revealed development of HF by 18 wk postsurgery in both models. In vitro diaphragmatic force production was preserved in all groups while morphometric analysis revealed diaphragmatic atrophy and fibrosis in 18 wk TAC and AMI groups. Isometric force-pCa measurements of myofilament preparations revealed reduced Ca(2+) sensitivity of force generation and force generation at half-maximum and maximum Ca(2+) activation in 18 wk TAC. The rate of force redevelopment (ktr) was reduced in all HF groups at high levels of Ca(2+) activation. Finally, there were significant changes in the myofilament phosphorylation status of the 18 wk TAC group. This includes a decrease in the phosphorylation of troponin T, desmin, myosin light chain (MLC) 1, and MLC 2 as well as a shift in myosin isoforms. These results indicate that there are multiple changes in diaphragmatic myofilament function, which are specific to the type and stage of HF and occur before overt impairment of in vitro force production.


One enzyme makes a fungal pathogen, but not a saprophyte, virulent on a new host plant.
Certain genes of Nectria haematococca, a fingal pathogen of pea (Pisum sativum), encode pisatin demethylase (pda), a cytochrome P-450 monoxygenase that detoxifies the phytoalexin pisatin. Because pda is required by N.haematococca for pathogenicity on pea, pisatin helps defend pea against N. haematococca. The possibility that pisatin is a general defense factormicrothat is, that pda can confer pathogenicity to fungi not normally pathogenic on peamicrowas investigated. Genes encoding pda were transformed into and highly expressed in Cochliobolus heterostrophus, a fungal pathogen of maize but not of pea, and in Aspergillus nidulans, a saprophytic fungus, neither of which produces a significant amount of pda. Transformants contained at least as much pda as did wild-type N. haematococca. Recombinant C. heterostrophus was normally virulent on maize, but it also caused symptoms on pea, whereas recombinant A. nidulans did not affect pea. Thus, phytoalexins can function in nonspecific resistance of plants to microbes; saprophytes appear to lack genes for basic pathogenicity.


F-information measures in medical image registration.
A measure for registration of medical images that currently draws much attention is mutual information. The measure originates from information theory, but has been shown to be successful for image registration as well. Information theory, however, offers many more measures that may be suitable for image registration. These all measure the divergence of the joint distribution of the images' grey values from the joint distribution that would have been found had the images been completely independent. This paper compares the performance of mutual information as a registration measure with that of other F-information measures. The measures are applied to rigid registration of positron emission tomography (PET)/magnetic resonance (MR) and MR/computed tomography (CT) images, for 35 and 41 image pairs, respectively. An accurate gold standard transformation is available for the images, based on implanted markers. The registration performance, robustness and accuracy of the measures are studied. Some of the measures are shown to perform poorly on all aspects. The majority of measures produces results similar to those of mutual information. An important finding, however, is that several measures, although slightly more difficult to optimize, can potentially yield significantly more accurate results than mutual information.


Phospholipase C signaling via the parathyroid hormone (PTH)/PTH-related peptide receptor is essential for normal bone responses to PTH.
We have previously shown that differentiation of hypertrophic chondrocytes is delayed in mice expressing a mutated PTH/PTHrP receptor (PTHR) (called DSEL here) that stimulates adenylyl cyclase normally but fails to activate phospholipase C (PLC). To better understand the role of PLC signaling via the PTHR in skeletal and mineral homeostasis, we examined these mice fed a normal or calcium-deficient diet. On a standard diet, DSEL mice displayed a modest decrease in bone mass. Remarkably, when fed a low-calcium diet or infused with PTH, DSEL mice exhibited strikingly curtailed peritrabecular stromal cell responses and attenuated new bone formation when compared with Wt mice. Attenuated in vitro colony formation was also observed in bone marrow cells derived from DSEL mice fed a low-calcium diet. Furthermore, PTH stimulated proliferation and increased mRNAs encoding cyclin D1 in primary osteoblasts derived from Wt but not from DSEL mice. Our data indicate that PLC signaling through the PTHR is required for skeletal homeostasis.


Structure of a single whisker representation in layer 2 of mouse somatosensory cortex.
Layer (L)2 is a major output of primary sensory cortex that exhibits very sparse spiking, but the structure of sensory representation in L2 is not well understood. We combined two-photon calcium imaging with deflection of many whiskers to map whisker receptive fields, characterize sparse coding, and quantitatively define the point representation in L2 of mouse somatosensory cortex. Neurons within a column-sized imaging field showed surprisingly heterogeneous, salt-and-pepper tuning to many different whiskers. Single whisker deflection elicited low-probability spikes in highly distributed, shifting neural ensembles spanning multiple cortical columns. Whisker-evoked response probability correlated strongly with spontaneous firing rate, but weakly with tuning properties, indicating a spectrum of inherent responsiveness across pyramidal cells. L2 neurons projecting to motor and secondary somatosensory cortex differed in whisker tuning and responsiveness, and carried different amounts of information about columnar whisker deflection. From these data, we derive a quantitative, fine-scale picture of the distributed point representation in L2.


Prediction of aerobic and anaerobic capacities of elite cyclists from changes in lactate during isocapnic buffering phase.
This study predicted aerobic and anaerobic capacities using relative changes of arterial blood lactate during the isocapnic buffering phase (relative [La]ISBP). Fourteen male professional cyclists (sprint-trained [n = 6] and endurance [n = 8]) performed 2 exercise sessions to exhaustion on a cycle ergometer; 1 incremental standard test to determine the isocapnic buffering phase, buffering capacities, and relative [La]ISBP and 1 supramaximal exercise test to determine maximal accumulated oxygen deficit (MAOD). The time between Lactate threshold (LT) and respiratory compensatory threshold (RCT) was considered to be the isocapnic buffering phase. Total buffering capacity was calculated as Δ[La]·ΔpH. Bicarbonate buffering was calculated as Δ[HCO3]·ΔpH, and the difference between -Δ[La]·ΔpH and Δ[HCO3]·ΔpH was considered as nonbicarbonate buffering. The lactate concentration for LT (p ≤ 0.05) and RCT (p ≤ 0.05), and relative [La]ISBP (p < 0.01) were significantly lower for endurance cyclists than for sprint-trained cyclists. A significant difference was found for bicarbonate buffering capacity between groups (p < 0.01). A significant correlation was found between relative [La]ISBP with (Equation is included in full-text article.)(r = -0.71, p ≤ 0.05) and MAOD (r = 0.73, p < 0.01). Relative [La]ISBP was useful for predicting aerobic power (R = 51%) and anaerobic capacity (R = 53%). These results demonstrated that relative [La]ISBP is an important variable in intermediary metabolism and in addition to (Equation is included in full-text article.)and LT is recommended for better evaluation of performance of athletes who show nearly equal contributions from the aerobic and anaerobic energy systems during exercise.


Host defense peptides in the oral cavity and the lung: similarities and differences.
Peptides with broad-spectrum antimicrobial activity are found in the mucosal surfaces at many sites in the body, including the airway, the oral cavity, and the digestive tract. Based on their in vitro antimicrobial and other immunomodulatory activities, these host defense peptides have been proposed to play an important role in the innate defense against pathogenic microbial colonization. The genes that encode these peptides are up-regulated by pathogens, further supporting their role in innate immune defense. However, the differences in the local microbial environments between the generally sterile airway and the highly colonized oral cavity suggest a more complex role for these peptides in innate immunity. For example, beta-defensin genes are induced in the airway by all bacteria and Toll-like receptor (TLR) agonists primarily through an NF-kappaB-mediated pathway. In contrast, the same genes are induced in the gingival epithelium by only a subset of bacteria and TLR ligands, via different pathways. Furthermore, the environments into which the peptides are secreted--specifically saliva, gingival crevicular fluid, and airway surface fluid--differ greatly and can effect their respective activities in host defense. In this review, we examine the differences and similarities between host defense peptides in the oral cavity and the airway, to gain a better understanding of their contributions to immunity.


Co-operation of the 5' and 3' untranslated regions of ornithine decarboxylase mRNA and inhibitory role of its 3' untranslated region in regulating the translational efficiency of hybrid RNA species via cellular factor.
The 5' untranslated region (UTR) has an inhibitory role in the translatability of ornithine decarboxylase (ODC) mRNA and of hybrid mRNA species, whereas the ODC 3' UTR causes a partial release of this inhibition. We designed experiments to explore whether the co-operation between ODC 5' UTR and 3' UTR in the translational regulation is due to a direct interaction of those sequences or whether it is mediated by their interaction with cellular factor(s). We stably transfected Chinese hamster ovary (CHO)-K1 cells and transiently transfected COS-1 cells with expression vectors carrying different chimaeric DNAs having the luciferase (LUC) coding sequence as reporter gene, the ODC 5' UTR or the ODC 3' UTR, or both, in the appropriate positions. We compared the results obtained by assaying the LUC activities of both transfected cell lines with each chimaeric DNA with those observed by translating the hybrid RNAs in a translation system in vitro. When the ODC 3' UTR was present, we observed a partial release of the translation inhibition owing to the ODC 5' UTR only in vivo. The releasing effect was restored in vitro by the addition of cytoplasmic extracts from wild-type CHO-K1 or COS-1 cells, prepared 2 and 8 h after their release from serum starvation. We also observed a partial inhibition of the translatability of the hybrid RNA owing to the presence of the ODC 3' UTR itself; the translational efficiency could be rescued by cell extract from 8 h serum-stimulated cells. The co-operation between the ODC-UTRs might be mediated by factors expressed by cells during particular phases of the cell cycle. Excess copies of the ODC-UTRs, expressed in trans, could compete in binding limited amounts of such regulatory factors and remove them from interaction with the endogenous ODC mRNA. This phenomenon should be reflected by modifications of the kinetics of ODC and/or LUC activities during serum stimulation. The overexpression of the ODC 3' UTR determined an increase in both endogenous ODC activity and LUC activity. Moreover, in the transfectants expressing the hybrid RNA species bearing the ODC 3' UTR the basal ODC activity is higher than that observed in control cells. We suggest that excess copies of the ODC 3' UTR mis-regulate the endogenous ODC translatability, probably by tying up regulatory molecules expressed by cells in limited amounts and sequestering them from the ODC mRNA species they should interact with.


Seasonal variability of diet and trophic level of the gelatinous predator Pelagia noctiluca (Scyphozoa).
Jellyfish populations apparently have increased in some places around the world and human problems with them also have increased. However, effects of jellyfish outbreaks in the ecosystems remain poorly understood and little or no information is available on their dietary preferences - in relation to the seasonal shifts of prey abundance - and on the potential variability of their impact on marine food webs. The mauve stinger Pelagia noctiluca (Forsskål, 1775) is by far the most common outbreak-forming scyphozoan jellyfish in the Western Mediterranean. By use of a combination of stomach contents, stable isotope (SI) and fatty acid (FA) analyses, we tested the hypothesis that changes in the seasonal dietary sources of P. noctiluca parallel changes in the FA and SI composition. Stomach content and biomarker analyses suggested that P. noctiluca is not a selective predator, cyclically shifting between carnivory and omnivory depending on the seasonality of accessible prey. The combination of SI and FA analyses highlighted the importance of microzooplankton as prey. Specific FA biomarkers showed that the diet of P. noctiluca changed seasonally depending on the availability of living plankton or suspended detritus. This study also revealed significant biochemical differences between jellyfish somatic and gonadal tissues, with total fatty acid concentration in the gonads up to ten times higher than in the somatic tissues.


Iterative variational mode decomposition based automated detection of glaucoma using fundus images.
Glaucoma is one of the leading causes of permanent vision loss. It is an ocular disorder caused by increased fluid pressure within the eye. The clinical methods available for the diagnosis of glaucoma require skilled supervision. They are manual, time consuming, and out of reach of common people. Hence, there is a need for an automated glaucoma diagnosis system for mass screening. In this paper, we present a novel method for an automated diagnosis of glaucoma using digital fundus images. Variational mode decomposition (VMD) method is used in an iterative manner for image decomposition. Various features namely, Kapoor entropy, Renyi entropy, Yager entropy, and fractal dimensions are extracted from VMD components. ReliefF algorithm is used to select the discriminatory features and these features are then fed to the least squares support vector machine (LS-SVM) for classification. Our proposed method achieved classification accuracies of 95.19% and 94.79% using three-fold and ten-fold cross-validation strategies, respectively. This system can aid the ophthalmologists in confirming their manual reading of classes (glaucoma or normal) using fundus images.


Probing excitation-contraction coupling in trachealis smooth muscle with the mycotoxin cyclopiazonic acid.
1. Muscarinic stimulation-induced tonic contraction of airway smooth muscle is independent of membrane potential. This contraction is not sensitive to inhibition by voltage-operated Ca2+ channel blockers or by K+ channel openers. 2. Cyclopiazonic acid (CPA) inhibits Ca2+ loading of internal stores but does not affect maximal tonic contraction induced by acetylcholine (ACh) in steady state conditions. 3. After depletion of internal Ca2+ stores with CPA, ACh-induced tonic contraction becomes dependent upon values of membrane potential. The contraction is then sensitive to voltage-operated Ca2+ channel blockers and to K+ channel openers. 4. Treatment of trachealis muscle with CPA potentiates the M2-mediated component of ACh stimulation, but this potentiation is not entirely responsible for the switch in excitation-contraction (E-C) coupling. 5. It is proposed that depletion of internal Ca2+ stores with CPA and promotion of M2-stimulation can lead to a switch in E-C coupling in trachealis smooth muscle from pharmaco- to electromechanical mode, perhaps by targeting a plasma membrane K+ channel.


Neurologic manifestations associated with an outbreak of typhoid fever, Malawi--Mozambique, 2009: an epidemiologic investigation.
The bacterium Salmonella enterica serovar Typhi causes typhoid fever, which is typically associated with fever and abdominal pain. An outbreak of typhoid fever in Malawi-Mozambique in 2009 was notable for a high proportion of neurologic illness. Describe neurologic features complicating typhoid fever during an outbreak in Malawi-Mozambique Persons meeting a clinical case definition were identified through surveillance, with laboratory confirmation of typhoid by antibody testing or blood/stool culture. We gathered demographic and clinical information, examined patients, and evaluated a subset of patients 11 months after onset. A sample of persons with and without neurologic signs was tested for vitamin B6 and B12 levels and urinary thiocyanate. Between March - November 2009, 303 cases of typhoid fever were identified. Forty (13%) persons had objective neurologic findings, including 14 confirmed by culture/serology; 27 (68%) were hospitalized, and 5 (13%) died. Seventeen (43%) had a constellation of upper motor neuron findings, including hyperreflexia, spasticity, or sustained ankle clonus. Other neurologic features included ataxia (22, 55%), parkinsonism (8, 20%), and tremors (4, 10%). Brain MRI of 3 (ages 5, 7, and 18 years) demonstrated cerebral atrophy but no other abnormalities. Of 13 patients re-evaluated 11 months later, 11 recovered completely, and 2 had persistent hyperreflexia and ataxia. Vitamin B6 levels were markedly low in typhoid fever patients both with and without neurologic signs. Neurologic signs may complicate typhoid fever, and the diagnosis should be considered in persons with acute febrile neurologic illness in endemic areas.


A prodrug of green tea polyphenol (-)-epigallocatechin-3-gallate (Pro-EGCG) serves as a novel angiogenesis inhibitor in endometrial cancer.
Anti-angiogenesis effect of a prodrug of green tea polyphenol (-)-epigallocatechin-3-gallate (Pro-EGCG) in malignant tumors is not well studied. Here, we investigated how the treatment with Pro-EGCG inhibited tumor angiogenesis in endometrial cancer. Tumor xenografts of human endometrial cancer were established and subjected to microarray analysis after Pro-EGCG treatment. First, we showed Pro-EGCG inhibited tumor angiogenesis in xenograft models through down-regulation of vascular endothelial growth factor A (VEGFA) and hypoxia inducible factor 1 alpha (HIF1α) in tumor cells and chemokine (C-X-C motif) ligand 12 (CXCL12) in host stroma by immunohistochemical staining. Next, we investigated how HIF1α/VEGFA was down-regulated and how the reduction of CXCL12 inhibited tumor angiogenesis. We found that VEGFA secretion from endometrial cancer cells was decreased by Pro-EGCG treatment through inhibiting PI3K/AKT/mTOR/HIF1α pathway. Furthermore, the down-regulation of CXCL12 in stromal cells by Pro-EGCG treatment restricted migration and differentiation of macrophages thereby inhibited infiltration of VEGFA-expressing tumor-associated macrophages (TAMs). Taken together, we demonstrated that treatment with Pro-EGCG not only decreases cancer cell-secreted VEGFA but also inhibits TAM-secreted VEGFA in endometrial cancer. These findings demonstrate that Pro-EGCG is a novel angiogenesis inhibitor for endometrial cancer.


Cytokine influence on simian immunodeficiency virus replication within primary macrophages. TNF-alpha, but not GMCSF, enhances viral replication on a per-cell basis.
The control of HIV-1 or SIV replication within macrophages is probably influenced by a variety of viral and cellular factors. Of the cellular factors, the authors have studied cytokine influence on SIV replication in vitro utilizing simian alveolar macrophages and uncloned SIVmacMTV, a macrophage-tropic variant. The approach allowed quantification of viral replication on a per-cell basis. As reported for HIV-1 replication in macrophages, TNF-alpha significantly increased SIV production in these macrophage cultures. GMCSF also resulted in marked increases in SIV gag protein in culture supernatants. However, after correcting for differences in total cell numbers and numbers of gag-containing cells in the treated and untreated cultures, GMCSF did not upregulate SIV production on a per-cell basis. IL-6 increased SIV replication little if at all but induced significantly greater cytopathic changes in the treated cultures compared with infected, untreated cultures. In contrast, IFN-gamma greatly decreased replication. Our results for GMCSF, IFN-gamma, and IL-6 are in contrast to previously published reports of cytokine control of HIV-1 growth in target cells, and they stress the importance of cell number analyses and the use of primary cultures in the study of lentiviral replication kinetics in macrophages.


Thiamine prescribing practices within university-affiliated hospitals: a multicenter retrospective review.
Patients with suspected thiamine deficiency should receive treatment with parenteral thiamine to achieve the high serum thiamine levels necessary to reverse the effects of deficiency and to circumvent problems with absorption common in the medically ill. To quantify rates of parenteral administration of thiamine across university-affiliated hospitals and to identify factors associated with higher rates of parenteral prescribing. Multicenter, retrospective observational study of thiamine prescriptions. Prescriptions for thiamine were captured from computerized pharmacy information systems across participating centers, providing information concerning dose, route, frequency, and duration of thiamine prescribed from January 2010 to December 2011. Fourteen university-affiliated tertiary care hospitals geographically distributed across Canada, including 48,806 prescriptions for thiamine provided to 32,213 hospitalized patients. Parenteral thiamine accounted for a statistically significant majority of thiamine prescriptions (57.6%, P < 0.001); however, oral thiamine constituted a significant majority of the total doses prescribed (68.4%, z = 168.9; P < 0.001). Protocols prioritizing parenteral administration were associated with higher rates of parenteral prescribing (61.3% with protocol, 45.8% without protocol; P < 0.001). Patients admitted under psychiatry services were significantly more likely to be prescribed oral thiamine (P < 0.001). Although parenteral thiamine accounted for a statistically significant majority of prescriptions, oral thiamine was commonly prescribed within academic hospitals. Additional strategies are needed to promote parenteral thiamine prescribing to patients with suspected thiamine deficiency.


CRMP-5 neuronal autoantibody: marker of lung cancer and thymoma-related autoimmunity.
We have defined a new paraneoplastic immunoglobulin G (IgG) autoantibody specific for CRMP-5, a previously unknown 62-kd neuronal cytoplasmic protein of the collapsin response-mediator family. CRMP-5 is in adult central and peripheral neurons, including synapses, and in small-cell lung carcinomas. Since 1993, our Clinical Neuroimmunology Laboratory has detected CRMP-5-IgG in 121 patients among approximately 68,000 whose sera were submitted for standardized immunofluorescence screening because a subacute neurological presentation was suspected to be paraneoplastic. This makes CRMP-5 autoantibody as frequent as PCA-1 (anti-Yo) autoantibody, second only to ANNA-1 (anti-Hu). Clinical information, obtained for 116 patients, revealed multifocal neurological signs. Most remarkable were the high frequencies of chorea (11%) and cranial neuropathy (17%, including 10% loss of olfaction/taste, 7% optic neuropathy). Other common signs were peripheral neuropathy (47%), autonomic neuropathy (31%), cerebellar ataxia (26%), subacute dementia (25%), and neuromuscular junction disorders (12%). Spinal fluid was inflammatory in 86%, and CRMP-5-IgG in 37% equaled or significantly exceeded serum titers. Lung carcinoma (mostly limited small-cell) was found in 77% of patients; thymoma was in 6%. Half of those remaining had miscellaneous neoplasms; all but two were smokers. Serum IgG in all cases bound to recombinant CRMP-5 (predominantly N-terminal epitopes), but not to human CRMP-2 or CRMP-3.


Pediatric basic and advanced life support: an update on practice and education.
This review aims to summarize the major changes in the 2010 Heart and Stroke foundation of Canada (HSFC) and the American Heart Association (AHA) Pediatric Basic and Advanced Life Support Guidelines. The Guidelines were based on the International Liaison Committee on Resuscitation's (ILCOR) comprehensive, evidence-based review of the resuscitation literature. The key recommendations from the Guidelines include: the removal of "look, listen and feel" and a de-emphasis on the use of the pulse check by healthcare providers to diagnose cardiac arrest; a change in the sequence of resuscitation for patients in cardiac arrest from the previously well-known "A-B-C" i.e. Airway, Breathing, and Chest Compressions to "C-A-B" i.e. Chest Compressions first; modification to the appropriate depth of compression (at least 1/3 of the anterior-posterior depth of the chest wall or about 4 cm in infants and 5 cm in children); end-tidal CO(2) monitoring (in intubated patients) to assess the quality of chest compressions and optimize cardiopulmonary resuscitation (CPR); and titrating Fi0O2 once "Return of Spontaneous Circulation" (ROSC) is achieved to maintain an oxygen saturation between 94-99%. Overall, pediatricians, family and community physicians who may care for acutely ill children should be aware of these updated guidelines in order to provide the best possible care to their patients.


The Cumulative Probability of Arrest by Age 28 Years in the United States by Disability Status, Race/Ethnicity, and Gender.
To estimate the cumulative probability (c) of arrest by age 28 years in the United States by disability status, race/ethnicity, and gender. I estimated cumulative probabilities through birth cohort life tables with data from the National Longitudinal Survey of Youth, 1997. Estimates demonstrated that those with disabilities have a higher cumulative probability of arrest (c = 42.65) than those without (c = 29.68). The risk was disproportionately spread across races/ethnicities, with Blacks with disabilities experiencing the highest cumulative probability of arrest (c = 55.17) and Whites without disabilities experiencing the lowest (c = 27.55). Racial/ethnic differences existed by gender as well. There was a similar distribution of disability types across race/ethnicity, suggesting that the racial/ethnic differences in arrest may stem from racial/ethnic inequalities as opposed to differential distribution of disability types. The experience of arrest for those with disabilities was higher than expected. Police officers should understand how disabilities may affect compliance and other behaviors, and likewise how implicit bias and structural racism may affect reactions and actions of officers and the systems they work within in ways that create inequities.


Impact of the new European respiratory (ERS)/American Thoracic Society (ATS) pulmonary function test interpretation guidelines 2021 on the interpretation of bronchodilator responsiveness in subjects with airway obstruction.
The impact of the new 2021 European Respiratory Society (ERS)/American Thoracic Society (ATS) pulmonary function test interpretation guidelines on the interpretation of bronchodilator responsiveness (BDR) in subjects with airway obstruction is still required. Therefore, the objective of this study was to explore the agreement between the 2005 and 2021 ERS/ATS criteria regarding the interpretation of the BDR. Moreover, we explore the factors that influenced the discordance of positive bronchodilator responsiveness (BDR+) between these two criteria. The agreement regarding the interpretation of BDR + between the two criteria was assessed using kappa (κ). The percentage of agreement in the interpretation of BDR + between the two criteria was calculated. The factors that influenced the discordance of BDR + between these two criteria were also analyzed. A total of 500 subjects with a mean age of 60.5 ± 15.6 years, 62.2% male were included. The study observed a good level of agreement in the interpretation of BDR + between the two criteria with kappa values = 0.782. The percentages of agreement on the interpretation of BDR + between the two criteria were high, with values = 90.6%. Male sex was the only factor that influenced the discordance of BDR + between these two criteria. A good level of agreement was observed in the interpretation of BDR + between the 2005 and 2021 criteria. Therefore, the 2005 and 2021 ERS/ATS criteria for BDR can be used interchangeably. However, the discordance of BDR + between these two criteria could be affected by sex.


Isometric endurance, body and skin temperature and limb and skin blood flow during the menstrual cycle.
Limb blood flow and skin and deep tissue temperature change during the menstrual cycle. However, the impact of these changes on isometric exercise performance has not been investigated. Isometric endurance was assessed at contraction tensions of 20, 40 and 60% of the maximal voluntary contraction strength (MVC) of the handgrip muscles in 8 women every other day throughout their menstrual cycles (MC). For any MC, contractions were only accomplished at one of the three tensions. For contractions at 40% MVC, an additional two MC were studied during which the circulation to the forearm was occluded during the contractions in one cycle and muscle temperature stabilized and occluded in another cycle. The results of these experiments showed a small variation in endurance during the MC for contractions at 60% MVC. This effect increased at 40% and was greatest for contractions at 20% MVC. When circulation was occluded, the response was changed in both magnitude and timing during the MC showing that there was variation in muscle performance due to the menstrual cycle not due to changes in blood flow. Further, when muscle temperature was stabilized and flow occluded, there was still lower endurance at the end of the Follicular phase showing an effect of the menstrual cycle on endurance absent changes in muscle temperature and blood flow. The results show that the MC alters isometric endurance due to 1) a cyclic variation in muscle temperature, 2) direct effects of the menstrual cycle on circulation and 3) Direct effects of the MC on muscle.


NOTES: a review of the technical problems encountered and their solutions.
Natural orifice translumenal endoscopic surgery (NOTES) is currently investigated and developed worldwide. In the past few years, multiple groups have confronted this challenge. Many technical problems are encountered in this technique due to the currently available tools for this approach. Some of the unique technical problems in NOTES include: blindly performed primary incisions; uncontrolled pneumoperitoneal pressure; no support for the endoscope in the abdominal cavity; inadequate vision; insufficient illumination; limited retraction and exposure; and the complexity of suturing and performing a safe anastomosis. In this paper, we review the problems encountered in NOTES and provide possible temporary solutions. Acute and survival studies were performed on 15 farm pigs. The hybrid technique approach (i.e., endoscopic surgery with the aid of laparoscopic vision) was performed in all cases. Procedures performed included liver biopsies, bilateral tubal ligation, oophprectomy, cholecystectomy, splenectomy and small bowel resection, and anastomosis. All attempted procedures were successfully performed. New methods and techniques were developed to overcome the technical problems. Closure of the gastrotomy was achieved by T-bar sutures and by stapler closure of the stomach incision. Small bowel anastomosis was achieved by the dual-lumen NOTES technique. The hybrid technique serves as a temporary approach to aid in developing the NOTES technique. A rectal or vaginal port of entry enables and facilitates gastrointestinal NOTES by using available laparoscopic instruments. The common operations performed today in the laparoscopic fashion could be probably performed in the NOTES approach. The safety of these procedures, however, is yet to be determined.


Phase I/II trial of a COX-2 inhibitor with limited field radiation for intermediate prognosis patients who have locally advanced non-small-cell lung cancer: radiation therapy oncology group 0213.
Treatment of patients who have locally advanced non-small-cell lung cancer and compromised performance status or weight loss (WL) is challenging. This study was conducted to test a low toxicity treatment regimen in this cohort. Patients were treated with concurrent celecoxib and thoracic radiation therapy to 45 Gy in 15 fractions or 60 to 66 Gy in 30 to 33 fractions. Eligible patients had inoperable or unresectable stage IIB, IIIA/B NSCLC, performance status 2 and/or greater than 5% WL. In the phase I portion of the study, the starting dose of celecoxib was 200 mg twice daily with one dose escalation to 400 mg twice daily. Celecoxib was continued for 2 years or until progression. The phase I component accrued eight patients each at 200 mg twice daily and 400 mg twice daily. Twice daily 400 mg was chosen for the phase II component, which enrolled five patients and was closed early because of poor accrual. We were able to analyze 18 patients. Performance status ratings were 0, 1, and 2 in 7, 7, and 4 patients, respectively. Median age was 72 years. WL of greater than 5% was noted in 10 patients (56%). Four of 10 had WL greater than or equal to 20%. Median follow-up and survival was 10 months. Overall survival rates at 1 and 2 years were 44.4% [95% confidence interval (CI), 21.6%-65.1%] and 22.2% (95% CI, 6.9%-42.9%), respectively. Progression-free survival at 1 year was 33.3% (95% CI, 13.7%-54.5%). Toxicities matched those expected with thoracic radiotherapy alone. Concurrent thoracic radiation therapy and celecoxib was well tolerated. The sample size was too small to draw conclusions regarding efficacy.


Does the duration of cardiopulmonary bypass or aortic cross-clamp, in the absence of blood and/or blood product administration, influence the IL-6 response to cardiac surgery?
Cardiopulmonary bypass (CPB) induces a systemic inflammatory response characterized by release of proinflammatory cytokines, including interleukin 6 (IL-6). Recent reports suggest that plasma IL-6 is increased after CPB. Previous studies evaluating the influence of duration of CPB and/or aortic cross-clamp time on the release of IL-6 are conflicting. Infusion of blood and blood products during these studies may have influenced plasma concentrations of proinflammatory cytokines by inducing host cell (monocyte) activation and IL-6 release. The purpose of our investigation was to determine, in an environment free from blood and/or blood product administration, the influence of duration of CPB and/or aortic cross-clamp on the magnitude of the IL-6 response in patients undergoing cardiac surgery. We prospectively evaluated plasma IL-6 levels preinduction (T0) and at sternal closure in 16 patients undergoing CPB (coronary artery bypass grafting, n = 9; valvular cardiac surgery, n = 7) to determine whether there is a correlation between the absolute increase in IL-6 and the duration of CPB or aortic cross-clamp time. None of the patients received blood and/or blood products during the study to control for the introduction of additional activated cells and soluble mediators, including IL-6. The results demonstrate that the magnitude of the IL-6 response to CPB is positively correlated with the duration of CPB but not with duration of aortic cross-clamp. It seems that induction of IL-6 release is part of a normal response to CPB and does not depend on activation of host cells during prolonged aortic cross-clamp. The activation or presence of inflammatory cytokines associated with administration of blood and/or blood products could have influenced previously published investigations relating the influence of duration of CPB and/or aortic cross-clamp time to the magnitude of the IL-6 response. This study found a positive correlation between the magnitude of the interleukin 6 response to cardiopulmonary bypass and duration of cardiopulmonary bypass (but not duration of aortic cross-clamp) when measurements were made in the absence of blood/blood product transfusion. Future studies evaluating strategies to reduce cytokine responses to cardiopulmonary bypass should therefore control for cardiopulmonary bypass duration.


Identification of an ancestral haplotype in the mitochondrial phylogeny of the ovine haplogroup B.
European mouflon (Ovis orientalis musimon) has been reintroduced in mainland Europe since the 18th-century sourcing from the Sardinian and Corsican autochthonous mouflon populations. The European mouflon is currently considered the feral descendent of the Asian mouflon (O. orientalis), and the result of first wave of sheep domestication occurred 11,000 years ago in the Fertile Crescent, and brought to Corsica and Sardinia ca. 6,000 years ago, where they still live as autochthonous populations. However, this phylogeny is based on mitogenome sequences of European mouflon individuals exclusively. We sequenced the first complete mtDNA of the long-time isolated Sardinian mouflon and compared it with several ovine homologous sequences, including mouflon from mainland Europe and samples representative of the five known mitochondrial domestic sheep haplogroups. We applied Bayesian inference, Maximum Likelihood and Integer Neighbour-Joining network methods and provided a robust, fully-resolved phylogeny with strong statistical support for all nodes. We identified an early split (110,000 years ago) of the Sardinian mouflon haplotype from both sheep and mainland European mouflon belonging to haplogroup B, the latter two sharing a more recent common ancestor (80,000 years ago). Further, the Sardinian mouflon sequence we generated had the largest genetic distance from domestic sheep haplogroups (0.0136 ± 0.004) among mouflon species. Our results suggest the Sardinian mouflon haplotype as the most ancestral in the HPG-B lineage, hence partially redrawing the known phylogeny of the genus Ovis.


Antioxidant and free radical scavenging activities of an exopolysaccharide from a probiotic bacterium.
Probiotic bacteria synthesize extracellular polysaccharides (EPSs) with commercially significant physiological and therapeutic activities. This important class of biomolecules is also characterized by their ability to remove reactive oxygen species (ROS) that are formed in the intestine by various metabolic reactions; hence, they exhibit antioxidant activities. Our probiotic bacterium, Bacillus coagulans RK-02, produces an EPS during the exponential and stationary growth phases when grown in a glucose mineral salts medium. The time course of EPS synthesis was studied with respect to biomass growth. The antioxidant and free radical scavenging potential of isolated EPS were studied by various methods, including the beta-carotene-linoleic acid model system, a superoxide radical scavenging assay using the PMS-NADH-nitroblue tetrazolium system, the 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity, a hydroxyl radical scavenging assay using the ascorbic acid-Cu(2+)-cytochrome c system and an in vitro microsome peroxidation inhibition study using a thiobarbituric acid assay. The antioxidant activities were compared to known antioxidants vitamin C and E, which were used as reference standards. The results showed that the EPS, which is a heteropolymer composed of four monosaccharides, produced by B. coagulans RK-02 had significant antioxidant and free radical scavenging activities.


Development of the control system for electron cyclotron resonance heating on J-TEXT tokamak.
A 105 GHz/500 kW/1 s electron cyclotron resonance heating (ECRH) system has been developed on J-TEXT tokamak since 2017. The core component of the ECRH system is a gyrotron manufactured by Gyrotron Complexes Ltd. (GYCOM Ltd.), which generates microwaves of a certain frequency and power. To guarantee safe and stable operation, it is necessary to design a specialized control system. The control system is expected to perform time sequence trigger, protection, signal monitoring, communication, and data acquisition. The hardware is built with real-time processors and data acquisition modules from National Instruments. The control program is realized by LabVIEW. Test results indicate that the control system can commit stable and safe operation of the gyrotron, which guarantees the integrated commissioning tests of the whole ECRH system and ECRH related physics experiments. Under the operation of this control system, the gyrotron can generate microwaves as expected, and the ECRH system is well protected when a fault takes place.


Bovine infectious abortion: a systematic review and meta-analysis.
The aim of the present systematic review and meta-analysis was to identify the main infectious agents related to bovine abortion worldwide in the period between 2000 and 2022. First, we investigated the global prevalence of infectious agents related to bovine abortion. For this analysis, only 27 articles detected of a wide panel of agents were included. The random effects model revealed that the estimated prevalence of the abortifacient agents in bovine abortion was 45.7%. The heterogeneity among studies was high, but Egger's test showed that there was no publication bias, even though the total number of samples analyzed in these articles was variable. There was no significant effect of the year of the study publication on the estimated prevalence, although an increasing trend was observed over time, possibly due to the implementation of new diagnostic techniques. Then, we analyzed the prevalence of the main transmissible agents in bovine abortion. For this analysis, 76 studies that analyzed 19,070 cases were included. Some infectious agent was detected in 7,319 specimens, and a final diagnosis was reached in 3,977 of these, when both the infectious agent and compatible histopathological changes were detected. We found that Neospora caninum was the most detected agent (22.2%), followed by opportunistic bacteria (21.4%), Chlamydiaceae family (10.9%) and Coxiella burnetii (9.5%). Regarding viral agents, bovine herpes virus type 1 and bovine viral diarrhea displayed similar prevalence rates (approximately 5%). After considering the description of specific histopathological changes, our analyzes showed that N. caninum was a confirmed cause of abortion in 16.7% of the analyzed cases, followed by opportunistic bacteria (12.6%) and Chlamydia spp. (6.8%); however, C. burnetii was only confirmed as a cause of abortion in 1.1% of the cases. For all agents, the heterogeneity among studies was high, and the subgroup analyzes discarded the diagnostic method as the cause of such heterogeneity. This study provides knowledge about the global prevalence of the different infectious agents related to bovine abortion, the most coming of which is N. caninum. In addition, this review reveals the existing deficiencies in the diagnosis of bovine abortion that must be addressed in the future.


Corrosion of electronic materials and devices.
Electronic materials and devices corrode in the same ways as automobiles, bridges, and pipelines, but their typically small dimensions make them orders of magnitude more susceptible to corrosion failure. As elsewhere, the corrosion involves interactions with the environment. Under control, these interactions can be put to use, as in the formation of protective and functional oxide films for superconducting devices. Otherwise, they cause damage, as in the electrolytic dissolution of conductors, even gold, in the presence of humidity and ionic contamination from atmospheric particles and gases. Preventing corrosion entails identifying the damaging interactions and excluding species that allow them to occur.


Tackling Vaccine Hesitancy and Increasing Vaccine Willingness Among Parents of Unvaccinated Children in Austria.
Objectives: In autumn 2021, there was a surge of COVID-19 infections in Austria, and vaccination coverage stagnated at a below-average level compared to the rest of Europe. Surveys showed that both children and adolescents were the main drivers of the rising infection rates and that vaccination numbers were particularly low in this age group. This was due to widespread vaccination skepticism and hesitancy among parents of unvaccinated children and adolescents. Methods: Here, we describe a novel intervention concept that allowed us to efficiently tackle parental vaccine hesitancy. We designed an intervention series that followed a reproducible format based on online face-to-face seminars in groups of a maximum of twenty people. Each seminar included an anonymous online questionnaire for internal quality control. Moreover, we assessed the motives of parental vaccine hesitancy and asked participants to rate subjective vaccine willingness for their children on a scale of zero to ten. Results: Within 8 weeks, more than 580 people participated in the seminar series. We found that concerns about the side effects of the vaccine were the predominant motive of vaccination hesitancy among the study population. Overall, the intervention could successfully increase the median parental vaccination willingness of participants from a score of five to eight. We identified tree hesitancy motives (distrust towards the pharmaceutical industry, the government, or feelings of restriction from personal freedom) that were associated with below-average vaccination willingness and significant lower increase. Conclusion: With this study we analyzed motives driving COVID-19 vaccination hesitancy among parents of unvaccinated children and reasons of parents to restrain their children from getting vaccinated. The intervention method described here, could effectively address individual concerns on a personal level while at the same time reach a large number of people across geographical and language barriers. Thereby we could significantly increase subjective vaccination willingness of the participants. Our approach is easy to apply, highly cost-effective, and can be used to tackle any kind of medical misinformation.


Receptor specificity of retinoid-induced epidermal hyperplasia: effect of RXR-selective agonists and correlation with topical irritation.
Retinoid induction of epidermal hyperplasia was investigated in hairless mice with synthetic ligands for the retinoic acid (RAR) and retinoid X (RXR) nuclear receptors. Induction of hyperplasia by all-trans retinoic acid and the RAR-specific retinoids TTNPB, tazarotene and AGN 190121 varied over a wide range (ED50 = 0.2-100 nmol/animal in three daily applications). Potency of induction was not directly correlated to receptor-binding affinity, but specificity of action could be demonstrated by inhibition with the high-affinity antagonist of the RARs, AGN 193109. Although RAR is functionally complexed with RXR in vivo, RXR-selective compounds have only weak potency in induction of hyperplasia. The ED50 value of the RXR-selective AGN 191701 was 600 nmol/animal compared with an ED50 value of 0.2 nmol for the structurally similar RAR-selective TTNPB. SR11237 and SR11217, also RXR-selective, each have an ED50 value of >1000 nmol. Unlike RAR-specific retinoids, RXR-selective retinoids cause only very mild skin flaking at high doses. Relative potencies for cumulative topical irritation (flaking and abrasion) of both RAR and RXR ligands were well correlated with epidermal hyperplasia. These data are consistent with RXR as a silent partner in the RAR-RXR heterodimer in skin.


Heterogeneous nuclear ribonucleoprotein B1 as early cancer biomarker for occult cancer of human lungs and bronchial dysplasia.
Heterogeneous nuclear ribonucleoprotein (hnRNP) B1 is a RNA-binding protein of Mr 37,000. We previously reported that hnRNP B1 was specifically overexpressed in the nuclei of human lung cancer cells, particularly in squamous cell carcinoma (E. Sueoka et al., Cancer Res., 59: 1404-1407, 1999). We extended this study to determine whether hnRNP BL was overexpressed in roentgenographically occult cancers of the lungs and premalignant lesions of squamous cell carcinomas, such as bronchial dysplasia. The additional object of our study was to examine the usefulness of hnRNP B1 as a potential diagnostic marker for squamous cell carcinoma of various organs, such as the oral cavity and esophagus in humans. Surgically resected specimens of bronchial dysplasia, lung cancers, and various human squamous cell carcinomas, collected at two hospitals in Japan, were subjected to immunohistochemical staining with anti-hnRNP B1 antibody. Overexpression of hnRNP B1 protein was observed in 100% of stage I lung cancer tissues, but it was not found in normal bronchial epithelium. Squamous cell carcinoma of the lungs showed stronger staining than other histological types, and elevation of hnRNP B1 was found in both roentgenographically occult lung cancers and bronchial dysplasia. Furthermore, cytological examination with anti-hnRNP B1 antibody detected cancer cells in sputum, suggesting the potential of hnRNP B1 protein as a new biomarker for the very early stage of lung cancer in humans. Because strong staining of hnRNP B1 was also observed in various squamous cell carcinomas of oral and esophageal tissues as shown in our recent reports, overexpression of hnRNP B1 seems to be a common event in the carcinogenic processes of squamous cell carcinoma. These results suggest that hnRNP B1 protein could be a useful diagnostic biomarker for both the very early stages of lung cancer and various squamous cell carcinomas in humans.


A phase diagram for energy flow-limited reactivity.
Intramolecular energy flow (also known as intramolecular vibrational redistribution or IVR) is often assumed in Rice-Ramsperger-Kassel-Marcus, transition state, collisional energy transfer, and other rate calculations not to be an impediment to reaction. In contrast, experimental spectroscopy, computational results, and models based on Anderson localization have shown that ergodicity is achieved rather slowly during molecular energy flow. The statistical assumption in rate theories might easily fail due to quantum localization. Here, we develop a simple model for the interplay of IVR and energy transfer and simulate the model with near-exact quantum dynamics for a 10-degree of freedom system composed of two five-mode molecular fragments. The calculations are facilitated by applying the van Vleck transformation to local random matrix models of the vibrational Hamiltonian. We find that there is a rather sharp "phase transition" as a function of molecular anharmonicity "a" between a region of facile energy transfer and a region limited by IVR and incomplete accessibility of the state space (classically, the phase space). The very narrow transition range of the order parameter a happens to lie right in the middle of the range expected for molecular torsion, bending, and stretching vibrations, thus demonstrating that reactive energy transfer dynamics several kBT above the thermal energy occurs not far from the localization boundary, with implications for controllability of reactions.


[Normative needs for care of schizophrenics: a useful concept for community psychiatric planning?].
One step in a public health research project focuses on the analysis of the individual (expert-based) normative needs for mental health care of chronic schizophrenic patients (n = 115) in the Dresden Region during the first year post hospital release and the extent to which this can be met by the current established level of complementary care. It is an exemplary contribution to the evaluation of community psychiatry as restructured in the Free State of Saxony following German reunification. The results of the study can be condensed to the following interpreting essential statements. Schizophrenics' normative needs for care are not a statistical issue. The single case analysis corroborates a high rate of relevant fluctuations, above all within the clinical sector (e.g. concerning "dyskinesias and other side effects"), that pose a particular challenge to the flexibility of a system of community psychiatry. This includes that the consequence for the practice of care implies then that when diagnosing course, attention must be paid to shifts in the content of the needs for mental health care (e.g. increasing importance of factors, which contain impairments of basic social competences) in order to orient to them any health care measures already initiated.--With the aid of the used research instrument (Needs for Care Assessment) deficits in meeting the needs for care can be identified. In the Dresden Region considerable deficits persist apparently in the subsections recreational activities and occupational and communication skills, which can be ascribed to the lack of appropriate institutions of care in the area.--The normative needs for care of schizophrenic patients cannot be determined simply on the basis of a few, quickly identifiable markers. Rather it demands individualized analysis incorporating variables pertaining to psychopathology, subjective coping, social competence and the course of the disorder. The development of the needs for care over the period of one year can apparently be predicted by trends in the social sector that are already visible within the first months. With regard to aspects of care planning this finding illustrates the limited ability of cross-section surveys to make definitive statements, as well as the predominance of social disabilities over the entire spectrum of the normative needs for psychiatric care.


Genetic polymorphism of cytochrome P450s, CYP2C19, and CYP2C9 in a Japanese population.
Genotypings of two mutations (*2 and *3) in CYP2C19 and the amino acid variants (Arg144/Cys, Tyr358/Cys, Ile359/Leu, and Gly417/Asp) in CYP2C9 were carried out in 140 unrelated Japanese subjects. Thirty-three subjects (23.6%) were genotypically identified as poor metabolizers of CYP2C19, and the allele frequencies of the CYP2C19*2 and CYP2C19*3 were 0.35 and 0.11, respectively. The authors' findings are in agreement with the 18% to 23% prevalence of poor metabolizers in the Japanese populations previously phenotyped. In CYP2C9, all subjects were homozygous (CYP2C9*1) for Arg144, Tyr358, Ile359, and Gly417, except for five subjects (3.6%) who were heterozygous for the Leu359 (CYP2C9*3). The frequencies of Arg144, Tyr358, Ile359, Leu359, and Gly417 variants were 1.0, 1.0, 0.982, 0.018, and 1.0, respectively. The low frequency of the Cys144 allele (CYP2C9*2) in the Japanese population is different from the frequency recently found in British subjects (allele frequency, 0.125 to 0.192). The results suggest that the known interindividual variations in the CYP2C9 sequence among Japanese subjects is small, and that Ile359/Leu is one possible site showing interracial polymorphism.


Chemical Chaperones as Novel Drugs for Parkinson's Disease.
Parkinson's disease (PD) is characterized by progressive loss of dopaminergic neurons and the accumulation of deposits of α-synuclein (α-syn) in the brain. The pivotal role of α-syn aggregation in PD makes it an attractive target for potential disease-modifying therapies. However, the disordered nature of the protein, its multistep aggregation mechanism, and the lack of structural information on intermediate species complicate the discovery of modulators of α-syn amyloid deposition. Despite these difficulties, small molecules have been shown to block the misfolding and aggregation of α-syn, and can even disentangle mature α-syn amyloid fibrils. In this review we provide an updated overview of these leading small compounds and discuss how these chemical chaperones hold great promise to alter the course of PD progression.


Clinical decision support alert appropriateness: a review and proposal for improvement.
Many healthcare providers are adopting clinical decision support (CDS) systems to improve patient safety and meet meaningful use requirements. Computerized alerts that prompt clinicians about drug-allergy, drug-drug, and drug-disease warnings or provide dosing guidance are most commonly implemented. Alert overrides, which occur when clinicians do not follow the guidance presented by the alert, can hinder improved patient outcomes. We present a review of CDS alerts and describe a proposal to develop novel methods for evaluating and improving CDS alerts that builds upon traditional informatics approaches. Our proposal incorporates previously described models for predicting alert overrides that utilize retrospective chart review to determine which alerts are clinically relevant and which overrides are justifiable. Despite increasing implementations of CDS alerts, detailed evaluations rarely occur because of the extensive labor involved in manual chart reviews to determine alert and response appropriateness. Further, most studies have solely evaluated alert overrides that are appropriate or justifiable. Our proposal expands the use of web-based monitoring tools with an interactive dashboard for evaluating CDS alert and response appropriateness that incorporates the predictive models. The dashboard provides 2 views, an alert detail view and a patient detail view, to provide a full history of alerts and help put the patient's events in context. The proposed research introduces several innovations to address the challenges and gaps in alert evaluations. This research can transform alert evaluation processes across healthcare settings, leading to improved CDS, reduced alert fatigue, and increased patient safety.


Botanicals and Hepatotoxicity.
The use of botanicals, often in the form of multi-ingredient herbal dietary supplements (HDS), has grown tremendously in the past three decades despite their unproven efficacy. This is paralleled by an increase in dietary supplement-related health complications, notably hepatotoxicity. This article reviews the demographics and motivations of dietary supplement (DS) consumers and the regulatory framework for DS in the US and other developed countries. It examines in detail three groups of multi-ingredient HDS associated with hepatotoxicity: OxyElite Pro (two formulations), green tea extract-based DS, and "designer anabolic steroids." These examples illustrate the difficulties in identifying and adjudicating causality of suspect compound(s) of multi-ingredient HDS-associated liver injury in the clinical setting. The article outlines future directions for further study of HDS-associated hepatotoxicity as well as measures to safeguard the consumer against it.


[Phagocytosis during mitotic and endomitotic chromosome replication in the trophoblast of the grey vole].
Phagocytosis was studied in three populations of trophoblast cells of the grey vole: primary and secondary giant cells, and spongiotrophoblast. In the two former, the cell growth is accomplished by endomitotic polyploidization only, whereas the spongiotrophoblast cells divide mitotically for a long time. The phagocytosis of these differs from that in giant cells. No more than 1--2 erythrocytes were phagocyted by the spongioblast diploid cells, while giant cells were able to phagocyte over several dozens of erythrocytes. The spongioblast cells are haemophagous and phagocyte only anucleate blood cells -- erythrocytes; unlike, giant cells, when ingrowing within the uterus mucose, are capable of taking up and digesting, in addition to erythrocytes, leukocytes, decidual and endothelial cells.


A skeletal randomization strategy for high-performance quinoidal-aromatic polymers.
Enhancing the solution-processability of conjugated polymers (CPs) without diminishing their thin-film crystallinity is crucial for optimizing charge transport in organic field-effect transistors (OFETs). However, this presents a classic "Goldilocks zone" dilemma, as conventional solubility-tuning methods for CPs typically yield an inverse correlation between solubility and crystallinity. To address this fundamental issue, a straightforward skeletal randomization strategy is implemented to construct a quinoid-donor conjugated polymer, PA4T-Ra, that contains para-azaquinodimethane (p-AQM) and oligothiophenes as repeat units. A systematic study is conducted to contrast its properties against polymer homologues constructed following conventional solubility-tuning strategies. An unusually concurrent improvement of solubility and crystallinity is realized in the random polymer PA4T-Ra, which shows moderate polymer chain aggregation, the highest crystallinity and the least lattice disorder. Consequently, PA4T-Ra-based OFETs, fabricated under ambient air conditions, deliver an excellent hole mobility of 3.11 cm2 V-1 s-1, which is about 30 times higher than that of the other homologues and ranks among the highest for quinoidal CPs. These findings debunk the prevalent assumption that a random polymer backbone sequence results in decreased crystallinity. The considerable advantages of the skeletal randomization strategy illuminate new possibilities for the control of polymer aggregation and future design of high-performance CPs, potentially accelerating the development and commercialization of organic electronics.


HB-EGF orchestrates the complex signals involved in triple-negative and trastuzumab-resistant breast cancer.
A number of therapeutic strategies targeting epidermal growth factor receptor (EGFR) have not always led to success in the present state of breast cancer therapy. Notably, there is currently no way to treat trastuzumab-resistant and triple-negative breast cancer (TNBC). Here, we found that heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of the EGFR ligands, was predominantly expressed in breast cancer and that treatment with crossreacting material 197 (CRM197), a specific inhibitor of HB-EGF, blocked ERK as well as AKT activation via complexes of EGFR and unknown growth factor receptors in TNBC or through complexes of EGFR and human epidermal growth factor receptor-2 in trastuzumab-resistant breast cancer, caused significant cell apoptosis and inhibited tumor growth. Accordingly, we can provide a novel concept that a certain EGFR ligand is recognized as a rational target against breast cancer. In addition, it is plausible that CRM197 could be an effective anticancer agent for molecularly targeted therapies.


Factors Associated with Pain Level in Patients Receiving Intravitreal Injection.
To identify the factors associated with the pain level in patients receiving intravitreal injection. A total of 120 patients were prospectively evaluated, and 104 were included in the study. Patients were asked to rate their pain intensity from 0 to 10 on the visual analog scale. Factors that were possibly associated with pain level were evaluated using a sociodemographic data form, state anxiety inventory, and the hospital anxiety and depression scale. Of the participants, 54 (51.9%) were female, and 50 (48.1%) were male, with a mean age of 65 ± 9.01 years. There was a positive correlation between pain level and state anxiety scores (r = 0.30; P < 0.001) and a negative correlation between hospital anxiety score (r = -0.23; P = 0.02) and hospital depression score (r = -0.27; P = 0.01). The correlation between pain score and education level was significantly higher in primary and secondary school graduates (P < 0.01). Smokers were observed to have higher pain scores (6.50 ± 2.21 in smokers and 4.87 ± 2.50 in nonsmokers; P = 0.01). Among diagnostic groups, pain scores were found to be significantly lower in the diabetic retinopathy (DR) group (6.82 ± 1.99 in age-related macular degeneration, 5.94 ± 2.27 in retinal vein occlusion, and 3.58 ± 1.97 in DR; P < 0.001). When pain scores were evaluated according to the drug injected, the group receiving bevacizumab injection was observed to have higher pain scores (7.32 ± 1.81 in bevacizumab, 4.00 ± 2.08 in aflibercept, and 3.92 ± 1.96 in ranibizumab; P < 0.001). Based on the multiple regression analysis, the state anxiety score, hospital anxiety score, hospital depression score, and smoking status were observed not to be significant predictors. The level of education, diagnosis, and active substance were found to have a statistically significant effect on pain perception. In this study, pain levels have been found to be high in smokers, those with a low educational level, individuals receiving bevacizumab for intravitreal injection, and those having a higher level of state anxiety, whereas patients with DR have lower pain scores.


Geometrical-optics code for computing the optical properties of large dielectric spheres.
Absorption of electromagnetic radiation by absorptive dielectric spheres such as snow grains in the near-infrared part of the solar spectrum cannot be neglected when radiative properties of snow are computed. Thus a new, to our knowledge, geometrical-optics code is developed to compute scattering and absorption cross sections of large dielectric particles of arbitrary complex refractive index. The number of internal reflections and transmissions are truncated on the basis of the ratio of the irradiance incident at the nth interface to the irradiance incident at the first interface for a specific optical ray. Thus the truncation number is a function of the angle of incidence. Phase functions for both near- and far-field absorption and scattering of electromagnetic radiation are calculated directly at any desired scattering angle by using a hybrid algorithm based on the bisection and Newton-Raphson methods. With these methods a large sphere's absorption and scattering properties of light can be calculated for any wavelength from the ultraviolet to the microwave regions. Assuming that large snow meltclusters (1-cm order), observed ubiquitously in the snow cover during summer, can be characterized as spheres, one may compute absorption and scattering efficiencies and the scattering phase function on the basis of this geometrical-optics method. A geometrical-optics method for sphere (GOMsphere) code is developed and tested against Wiscombe's Mie scattering code (MIE0) and a Monte Carlo code for a range of size parameters. GOMsphere can be combined with MIE0 to calculate the single-scattering properties of dielectric spheres of any size.


Isolated growth hormone deficiency (GHD) in childhood and adolescence: recent advances.
The diagnosis of GH deficiency (GHD) in childhood is a multistep process involving clinical history, examination with detailed auxology, biochemical testing, and pituitary imaging, with an increasing contribution from genetics in patients with congenital GHD. Our increasing understanding of the factors involved in the development of somatotropes and the dynamic function of the somatotrope network may explain, at least in part, the development and progression of childhood GHD in different age groups. With respect to the genetic etiology of isolated GHD (IGHD), mutations in known genes such as those encoding GH (GH1), GHRH receptor (GHRHR), or transcription factors involved in pituitary development, are identified in a relatively small percentage of patients suggesting the involvement of other, yet unidentified, factors. Genome-wide association studies point toward an increasing number of genes involved in the control of growth, but their role in the etiology of IGHD remains unknown. Despite the many years of research in the area of GHD, there are still controversies on the etiology, diagnosis, and management of IGHD in children. Recent data suggest that childhood IGHD may have a wider impact on the health and neurodevelopment of children, but it is yet unknown to what extent treatment with recombinant human GH can reverse this effect. Finally, the safety of recombinant human GH is currently the subject of much debate and research, and it is clear that long-term controlled studies are needed to clarify the consequences of childhood IGHD and the long-term safety of its treatment.


Particle tracking in drug and gene delivery research: State-of-the-art applications and methods.
Particle tracking is a powerful microscopy technique to quantify the motion of individual particles at high spatial and temporal resolution in complex fluids and biological specimens. Particle tracking's applications and impact in drug and gene delivery research have greatly increased during the last decade. Thanks to advances in hardware and software, this technique is now more accessible than ever, and can be reliably automated to enable rapid processing of large data sets, thereby further enhancing the role that particle tracking will play in drug and gene delivery studies in the future. We begin this review by discussing particle tracking-based advances in characterizing extracellular and cellular barriers to therapeutic nanoparticles and in characterizing nanoparticle size and stability. To facilitate wider adoption of the technique, we then present a user-friendly review of state-of-the-art automated particle tracking algorithms and methods of analysis. We conclude by reviewing technological developments for next-generation particle tracking methods, and we survey future research directions in drug and gene delivery where particle tracking may be useful.


Who is willing to pay for long-term care insurance in Catalonia?
Both public and private insurance for long-term care (LTC) in European countries employed is underdeveloped. However, limited evidence is gathered on the behavioural demand responses to the introduction of insurance schemes expanding insurance coverage. This paper aims at empirically examining the determinants of the ex ante demand for LTC coverage drawing upon an insurance-based WTP referendum approach format. Data is collected from a representative population sample of Catalonia (Spain), before a countrywide funding system was developed. Our findings suggest that (based on our questionnaire format) only one-fifth of the population is willing to pay for LTC coverage though it is a highly elastic product. Ex ante demand for LTC coverage is driven by individual's perceptions of old age disability risk (private information asymmetry) and housing tenure (giving rise to self-insurance), the latter reduces the probability of insurance coverage demand.


Water transport activity of the plasma membrane aquaporin PM28A is regulated by phosphorylation.
PM28A is a major intrinsic protein of the spinach leaf plasma membrane and the major phosphoprotein. Phosphorylation of PM28A is dependent in vivo on the apoplastic water potential and in vitro on submicromolar concentrations of Ca2+. Here, we demonstrate that PM28A is an aquaporin and that its water channel activity is regulated by phosphorylation. Wild-type and mutant forms of PM28A, in which putative phosphorylation sites had been knocked out, were expressed in Xenopus oocytes, and the resulting increase in osmotic water permeability was measured in the presence or absence of an inhibitor of protein kinases (K252a) or of an inhibitor of protein phosphatases (okadaic acid). The results indicate that the water channel activity of PM28A is regulated by phosphorylation of two serine residues, Ser-115 in the first cytoplasmic loop and Ser-274 in the C-terminal region. Labeling of spinach leaves with 32P-orthophosphate and subsequent sequencing of PM28A-derived peptides demonstrated that Ser-274 is phosphorylated in vivo, whereas phosphorylation of Ser-115, a residue conserved among all plant plasma membrane aquaporins, could not be demonstrated. This identifies Ser-274 of PM28A as the amino acid residue being phosphorylated in vivo in response to increasing apoplastic water potential and dephosphorylated in response to decreasing water potential. Taken together, our results suggest an active role for PM28A in maintaining cellular water balance.


The dose related effect of steroids on blast reduction rate and event free survival in children with acute lymphoblastic leukemia.
We examined the effect of high-dose methylprednisolone (HDMP) on blast reduction rate and compared it to conventional dose steroid treatment, administered during the first 7+ days of the induction remission period in patients with acute lymphoblastic leukemia (ALL). In our previous randomized study, the event free survival (EFS) was found to be higher in patients treated with HDMP (Group B) than in patients treated with a conventional dose of steroids (Group A). We used the chemotherapy protocol for ALL patients according to the St Jude Total XI study group. Medical records of all 194 patients who achieved complete remission were reviewed to determine the absolute blast count (ABC) in peripheral blood smears from day 0 of treatment until day 8. A target response of 1,000 blast/mm3 was employed. The time in which ABC remained > or = 1,000/mm3 and the EFS rates were assessed in group A (n = 44) and B (n = 51) of high risk patients. Group A and B patients were branched to chemotherapy schedules (A1, B1: steroid + vincristine + daunorubicine + intrathecal + 3 doses L-asparaginase; A2, B2: steroid + vincristine + daunorubicine + intrathecal; A3, B3: only steroid monotherapy). Number of patients from whom the ABC remained > or = 1,000/mm3 during all 7 days of induction treatment and the median number of days for blasts to reach the target level were significantly lower in group B1 than A1 (p < 0.05), concordantly the 8-year EFS was higher in group B1 (p = 0.01). In comparison of the subgroups, results of A2 and A3 were worse than of group B2 and B3. These findings strongly suggest that the effects of HDMP on blast cytoreduction and EFS are more potent than conventional dose steroids.


Minimum hematocrit for normothermic cardiopulmonary bypass in dogs.
The purpose of this study was to determine the minimum hematocrit supporting cerebral oxygenation during normothermic cardiopulmonary bypass (CPB) in dogs. The effect of hemodilution on cerebral blood flow (CBF), cerebral metabolic rate (CMRO2), and cerebral oxygen delivery (CDO2) was determined over a range of hematocrits. Measurements were obtained during 37.5 degrees C CPB with progressive normovolemic hemodilution (hematocrit 0.39 to 0.9) in eight anesthetized animals. Dextran 70 (6%) was used as a diluent. CBF was measured using the sagittal sinus outflow technique. CMRO2 and CDO2 were calculated using standard formula. Hemodilution was associated with a reciprocal rise in CBF. CBF at a hematocrit of 0.09 was 240% of the CBF when the hematocrit was 0.39. Increases in CBF compensated for decreased arterial oxygen content and CDO2 was maintained to a mean hematocrit of 0.14+/-0.02. At a hematocrit of 0.09+/-0.02, CDO2 and CMRO2 declined. Intracranial pressure remained stable throughout. Thus, the critical hematocrit for brain (the hematocrit at which metabolism becomes delivery-dependent) was between 0.09 and 0.14 during normothermic CPB in dogs. This is the first systematic attempt to determine the critical hematocrit supporting cerebral oxygenation during warm CPB. The curve describing the relationship between hematocrit and cerebral oxygen balance has a broad plateau and a genu near a hematocrit value of 0.15. While we do not advocate hemodilution to a hematocrit of 15% during "warm" CPB, these data provide a physiological foundation for our hemodilution practice and offer an explanation why low hematocrits are tolerated in certain patient populations.


Using formative research to lay the foundation for community level HIV prevention efforts: an example from the AIDS Community Demonstration Projects.
The AIDS Community Demonstration Projects provided community-level HIV prevention interventions to historically hard-to-reach groups at high risk for HIV infection. The projects operated under a common research protocol which encompassed formative research, intervention delivery, process evaluation, and outcome evaluation. A formative research process specifically focusing on intervention development was devised to assist project staff in identifying, prioritizing, accessing, and understanding the intervention target groups. This process was central to the creation of interventions that were acceptable and unique to the target populations. Intended to be rapid, the process took 6 months to complete. Drawn from the disciplines of anthropology, community psychology, sociology, and public health, the formative research process followed distinct steps which included (a) defining the populations at high-risk for HIV; (b) gathering information about these populations through interviews with persons who were outside of, but who had contact with, the target groups (such as staff from the health department and alcohol and drug treatment facilities, as well as persons who interacted in an informal manner with the target groups, such as clerks in neighborhood grocery stores and bartenders); (c) interviewing people with access to the target populations (gatekeepers), and conducting observations in areas where these high-risk groups were reported to gather (from previous interviews); (d) interviewing members of these groups at high risk for HIV infection or transmission; and (e) systematically integrating information throughout the process. Semistructured interview schedules were used for all data collection in this process. This standardized systematic method yielded valuable information about the focal groups in each demonstration project site. The method, if adopted by others, would assist community intervention specialists in developing interventions that are culturally appropriate and meaningful to their respective target populations.


Attachment of Staphylococcus aureus to polymethylmethacrylate increases its resistance to phagocytosis in foreign body infection.
The mechanisms responsible for the development of a pyogenic infection (most commonly due to staphylococci) in the vicinity of an implanted foreign body have been studied recently by several investigators. Thus, we have been able to demonstrate that the phagocytic function of residential polymorphonuclear leukocytes (PMN) is deficient in the presence of a foreign body. Others have shown that in the presence of foreign surfaces, microorganisms produce extracellular amorphous material, the pathogenic role of which is still to be defined. In the present study we use a novel assay system to demonstrate that Staphylococcus aureus Wood 46, after attachment to polymethylmethacrylate (PMMA), shows increased resistance to the phagocytic-bactericidal action of normal PMN. The first step of this assay involves the reproducible attachment of [3H]thymidine-labeled bacteria to PMMA cover slips. During the second step, attached bacteria were exposed to guinea pig peritoneal exudate PMN. In the third and final step, attached S. aureus cells were removed from the cover slips using a procedure harmless to the bacteria. The extent of bacterial detachment was estimated by radioactive counts and their viability by standard colony counts. Whereas bacteria that were attached artificially and rapidly by centrifugation and immediately exposed to PMN were killed in the phagocytic assay, bacteria adhering spontaneously to the cover slips for a prolonged period of time were more resistant to the killing action of the phagocytes. The spontaneous adherence of S. aureus to PMMA renders it poorly susceptible to the killing action of PMN.


Nijmegen paediatric CDG rating scale: a novel tool to assess disease progression.
Congenital disorders of glycosylation (CDG) are a group of clinically heterogeneous inborn errors of metabolism. At present, treatment is available for only one CDG, but potential treatments for the other CDG are on the horizon. It will be vitally important in clinical trials of such agents to have a clear understanding of both the natural history of CDG and the corresponding burden of disability suffered by patients. To date, no multicentre studies have attempted to document the natural history of CDG. This is in part due to the lack of a reliable assessment tool to score CDG's diverse clinical spectrum. Based on our earlier experience evaluating disease progression in disorders of oxidative phosphorylation, we developed a practical and semi-quantitative rating scale for children with CDG. The Nijmegen Paediatric CDG Rating Scale (NPCRS) has been validated in 12 children, offering a tool to objectively monitor disease progression. We undertook a successful trial of the NPCRS with a collaboration of nine experienced physicians, using video records of physical and neurological examination of patients. The use of NPCRS can facilitate both longitudinal and natural history studies that will be essential for future interventions.


Nonresponse and dropout rates in outcome studies on PTSD: review and methodological considerations.
Post-traumatic stress disorder (PTSD) represents a frequent consequence of a variety of extreme psychological stressors. Lists of empirically supported treatments for PTSD usually include cognitive behavioral therapy (CBT) and eye movement desensitization and reprocessing (EMDR), but nonresponse and dropout rates in these treatments often are high. We review the treatment dropout and nonresponse rates in 55 studies of empirically supported treatments for PTSD, review the literature for predictors of dropout and nonresponse, discuss methodological inconsistencies in the literature that make comparisons across studies difficult, and outline future directions for research. Dropout rates ranged widely and may have depended, at least in part, on the nature of the study population. It was not uncommon to find nonresponse rates as high as 50%. Standard methods of reporting dropout and nonresponse rates are needed for reporting outcomes. We suggest guidelines for collecting data to help identify characteristics and predictors of dropouts and nonresponders.


ECSMP: A dataset on emotion, cognition, sleep, and multi-model physiological signals.
This paper described the collection of multi-modal physiological signals, which include electroencephalography, electrocardiograph (ECG), photoplethysmography, electrodermal activity, temperature, and accelerometer data, recorded from 89 healthy college students during resting state, the emotion induction and recovery, and a set of cognitive function assessment tasks. Emotion, sleep, cognition, depression, mood, and other factors were evaluated through different methods, and were included in this dataset. Six emotions (neutral, fear, sad, happy, anger, and disgust) were induced by movie clips. The cognitive functions such as sustained attention, response inhibition, working memory, and strategy use, were quantitatively measured by Cambridge neuropsychological test automatic battery. The sleep ECG was collected the night before the emotion-induction experiment, and the sleep quality was analysed based on the sleep ECG. After the experiment, the participants were required to fill in questionnaires to evaluate the emotion regulation strategies, depression score, recent mood, and sleep quality index. The database can not only be directly used for the research of emotion recognition on multi-modal physiological signals, but also can further explore the interactions between emotion, cognition, and sleep.