Evaluating the negative or valuing the positive? Neural mechanisms supporting feedback-based learning across development.
How children learn from positive and negative performance feedback lies at the foundation of successful learning and is therefore of great importance for educational practice. In this study, we used functional magnetic resonance imaging (fMRI) to examine the neural developmental changes related to feedback-based learning when performing a rule search and application task. Behavioral results from three age groups (8-9, 11-13, and 18-25 years of age) demonstrated that, compared with adults, 8- to 9-year-old children performed disproportionally more inaccurately after receiving negative feedback relative to positive feedback. Additionally, imaging data pointed toward a qualitative difference in how children and adults use performance feedback. That is, dorsolateral prefrontal cortex and superior parietal cortex were more active after negative feedback for adults, but after positive feedback for children (8-9 years of age). For 11- to 13-year-olds, these regions did not show differential feedback sensitivity, suggesting that the transition occurs around this age. Pre-supplementary motor area/anterior cingulate cortex, in contrast, was more active after negative feedback in both 11- to 13-year-olds and adults, but not 8- to 9-year-olds. Together, the current data show that cognitive control areas are differentially engaged during feedback-based learning across development. Adults engage these regions after signals of response adjustment (i.e., negative feedback). Young children engage these regions after signals of response continuation (i.e., positive feedback). The neural activation patterns found in 11- to 13-year-olds indicate a transition around this age toward an increased influence of negative feedback on performance adjustment. This is the first developmental fMRI study to compare qualitative changes in brain activation during feedback learning across distinct stages of development.


Determination of the frequency of loss of heterozygosity in esophageal adenocarcinoma by cell sorting, whole genome amplification and microsatellite polymorphisms.
It is well established that the progression to human cancer is characterized by the evolution of clones of cells with accumulated genetic abnormalities. However, technical difficulties limit the ability to study this process in some premalignant and malignant conditions. For example, the progression to esophageal adenocarcinoma in the premalignant condition Barrett's esophagus is characterized by the evolution of genetic and cell cycle abnormalities, but it has been difficult to characterize this process completely because of the small size of biopsies and the relative abundance of genetically normal stromal cells in some esophageal adenocarcinomas and premalignant mucosa. We have combined flow cytometric cell sorting to obtain purified populations of neoplastic cells with whole genome amplification and analysis of microsatellite polymorphisms to determine the frequency of allelic loss on every nonacrocentric autosomal arm in 20 esophageal adenocarcinomas and two high-grade dysplasias. DNA samples of purified flow-sorted aneuploid and corresponding normal tissue were amplified with a degenerate 15mer primer. Aliquots of these reactions were then screened with forty-three highly polymorphic simple sequence repeat markers in PCR-based assays. Allelic losses were observed at polymorphic loci in 38 of the 40 chromosome arms that were analysed and the median fractional allelic loss (FAL) observed in the samples was 0.28. The background allelic loss frequency was estimated at 0.23 with the highest rates of loss observed at 17p (100%), 5q (80%), 9p (64%), 13q (43%), 18q (43%) and 1p (41%). These data represent the first comprehensive allelotype of esophageal adenocarcinoma and show the feasibility of multiloci analyses with small highly purified human biopsy material.


Elemental Substitution of Two-Dimensional Transition Metal Dichalcogenides (MoSe2 and MoTe2): Implications for Enhanced Gas Sensing.
The quest for a suitable material with the potential of capturing toxic nitrogen-containing gases (NH3, NO, and NO2) has motivated us to explore the structural, electronic, and gas-sensing properties of transition metal dichalcogenides (TMDs); MoSe2 and MoTe2. Spin-polarized density functional theory (DFT) calculations demonstrate weak binding of nitrogen-containing gases (NCGs) with the pristine TMDs, which limits the use of the latter as efficient sensing materials. However, suitable elemental substitutions improve the binding mechanism enormously. Our dispersion-corrected DFT calculations revealed that Se (Te) substitution with Ge (Sb) in MoSe2 (MoTe2) not only enhances the binding energies but also causes a significant variation in the electronic properties and work functions. A charge-transfer mechanism based on Bader analysis indicates that transfer of charges from MoSe2-Ge (MoTe2-Sb) to the NCGs is responsible for the improvement in the binding characteristics. Based on our findings, it is evident that 2.08% of elemental substitutional makes both MoSe2 and MoTe2 promising materials for NH3, NO, and NO2 gas sensing.


The role of complementary and alternative medicine (CAM) in Germany - a focus group study of GPs.
There has been a marked increase in the use of complementary and alternative medicine (CAM) in recent years worldwide. In Germany, apart from 'Heilpraktiker' (= state-licensed, non-medical CAM practitioners), some general practitioners (GPs) provide CAM in their practices. This paper aims to explore the attitudes of GPs about the role of CAM in Germany, in relation to the healthcare system, quality of care, medical education and research. Furthermore, experiences of GPs integrating CAM in their daily practice were explored. Using a qualitative methodological approach 3 focus groups with a convenience sample of 17 GPs were conducted. The discussions were transcribed verbatim and analysed using qualitative content analysis. The majority of the participating GPs had integrated one or more CAM therapies into their every-day practice. Four key themes were identified based on the topics covered in the focus groups: the role of CAM within the German healthcare system, quality of care, education and research. Within the theme 'role of CAM within the healthcare system' there were five categories: integration of CAM, CAM in the Statutory Health Insurance, modernisation of the Statutory Health Insurance Act, individual healthcare services and 'Heilpraktiker'. Regarding quality of care there were two broad groups of GPs: those who thought patients would benefit from standardizing CAM and those who feared that quality control would interfere with the individual approach of CAM. The main issues identified relating to research and education were the need for the development of alternative research strategies and the low quality of existing CAM education respectively. The majority of the participating GPs considered CAM as a reasonable complementary approach within primary care. The study increased our understanding of GPs attitudes about the role of CAM within the German healthcare system and the use of 'Heilpraktiker' as a competing CAM-provider. It seems to be a need for increased funding for research, better education and remuneration by the Statutory Health Insurance in order to improve access to 'Integrative medicine' in Germany.


Enhanced selectivity of target gas molecules through a minimal array of gas sensors based on nanoparticle-decorated SWCNTs.
An array of five sensors, based on carbon nanotubes (CNT) functionalized with nanoparticles of Au, TiO2, ITO, and Si has been fabricated and exposed to a selected series of target gas molecules (NH3, NO2, H2S, H2O, benzene, ethanol, acetone, 2-propanol, sodium hypochlorite, and several combinations of two gases). The results of principal component analysis (PCA) of the experimental data show that this array of sensors is able to detect different target gas and to discriminate each molecule in the 2D PCA parameters space. In particular, the possibility to include in the array a humidity sensor significantly increases the capability to discriminate the response to volatile organic compounds (VOCs), even though VOCs usually react with CNTs less than NO2 or NH3. This leads to an improvement in selectivity that could meet the requirements for gas detection applications in the field of environmental monitoring and breathomics, where sensors are exposed to a variety of different molecules and where the humidity can severely affect the overall response of the sensor. Finally, we demonstrate that the ability to test multiple sensors simultaneously can reveal a specific sensor sensitivity, addressing the best functionalization choice to improve the response of new sensors based on decorated CNT layers. In particular, our study shows the better capability of the ITO-decorated sensor to detect H2S and benzene.


Evolutionarily conserved long intergenic non-coding RNAs in the eye.
The discovery that the mammalian transcriptome encodes thousands of long intergenic non-coding (linc) RNA transcripts, together with recent evidence that lincRNAs can regulate protein-coding genes, has added a new level of complexity to cellular transcriptional/translational regulation. Indeed several reports now link mutations in lincRNAs to heritable human disorders. Here, we identified a subset of lincRNAs in terminally differentiated adult human retinal neurons based on their sequence conservation across species. RNA sequencing of eye tissue from several mammalian species with varied rod/cone photoreceptor content identified 18 lincRNAs that were highly conserved across these species. Sixteen of the 18 were conserved in human retinal tissue with 14 of these also conserved in the macular region. A subset of lincRNAs exhibited restricted tissue expression profiles in mice, with preferential expression in the retina. Mouse models with different populations of retinal cells as well as in situ hybridization provided evidence that these lincRNAs localized to specific retinal compartments, most notably to the photoreceptor neuronal layer. Computational genomic loci and promoter region analyses provided a basis for regulated expression of these conserved lincRNAs in retinal post-mitotic neurons. This combined approach identified several lincRNAs that could be critical for retinal and visual maintenance in adults.


A 3D iPSC-differentiation model identifies interleukin-3 as a regulator of early human hematopoietic specification.
Hematopoietic development is spatiotemporally tightly regulated by defined cell-intrinsic and extrinsic modifiers. The role of cytokines has been intensively studied in adult hematopoiesis; however, their role in embryonic hematopoietic specification remains largely unexplored. Here, we used induced pluripotent stem cell (iPSC) technology and established a 3-dimensional, organoid-like differentiation system (hemanoid) maintaining the structural cellular integrity to evaluate the effect of cytokines on embryonic hematopoietic development. We show, that defined stages of early human hematopoietic development were recapitulated within the generated hemanoids. We identified KDR+/CD34high/CD144+/CD43-/CD45- hemato-endothelial progenitor cells (HEPs) forming organized, vasculature-like structures and giving rise to CD34low/CD144-/CD43+/CD45+ hematopoietic progenitor cells. We demonstrate that the endothelial to hematopoietic transition of HEPs is dependent on the presence of interleukin 3 (IL-3). Inhibition of IL-3 signalling blocked hematopoietic differentiation and arrested the cells in the HEP stage. Thus, our data suggest an important role for IL-3 in early human hematopoiesis by supporting the endothelial to hematopoietic transition of hemato-endothelial progenitor cells and highlight the potential of a hemanoid-based model to study human hematopoietic development.


Resveratrol as a Bioenhancer to Improve Anti-Inflammatory Activities of Apigenin.
The aim of this study was to improve the anti-inflammatory activities of apigenin through co-treatment with resveratrol as a bioenhancer of apigenin. RAW 264.7 cells pretreated with hepatic metabolites formed by the co-metabolism of apigenin and resveratrol (ARMs) in HepG2 cells were stimulated with lipopolysaccharide (LPS). ARMs prominently inhibited (p < 0.05) the production of nitric oxide (NO), prostaglandin E₂ (PGE₂), interleukin (IL)-1β, IL-6 and TNF-α. Otherwise no such activity was observed by hepatic metabolites of apigenin alone (AMs). ARMs also effectively suppressed protein expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Co-administration of apigenin (50 mg/kg) and resveratrol (25 mg/kg) also showed a significant reduction of carrageenan-induced paw edema in mice (61.20% to 23.81%). Co-administration of apigenin and resveratrol led to a 2.39 fold increase in plasma apigenin levels compared to administration of apigenin alone, suggesting that co-administration of resveratrol could increase bioavailability of apigenin. When the action of resveratrol on the main apigenin metabolizing enzymes, UDP-glucuronosyltransferases (UGTs), was investigated, resveratrol mainly inhibited the formation of apigenin glucuronides by UGT1A9 in a non-competitive manner with a Ki value of 7.782 μM. These results suggested that resveratrol helps apigenin to bypass hepatic metabolism and maintain apigenin's anti-inflammatory activities in the body.


Fluid shear stress attenuates tumor necrosis factor-alpha-induced tissue factor expression in cultured human endothelial cells.
Hemodynamic forces modulate various endothelial cell functions under gene regulation. Previously, we have shown that fibrinolytic activity of endothelial cells is enhanced by the synergistic effects of shear stress and cytokines. In this study, we investigated the effect of shear stress on tumor necrosis factor (TNF)-alpha-induced tissue factor (TF) expression in cultured human umbilical vein endothelial cells (HUVECs), using a modified cone-plate viscometer. Shear stresses at physiological levels reduced TNF-alpha (100 U/mL)-induced TF expression at both mRNA and antigen levels, in a shear-intensity and exposure-time dependent manner, whereas shear stress itself did not induce TF expression in HUVECs. TF expressed on the cell surfaces measured by flow cytometry using an anti-TF monoclonal antibody (HTF-K180) was also decreased to one third by shear force applied at 18 dynes/cm2 for 15 hours before and 6 hours after TNF-alpha stimulation. Furthermore, functional activity of TF, as assessed by the activation of factor X in the presence of FVIIa and Ca2+, was also decreased by shear application. However, the stability of TF mRNA was not decreased in the presence of shear stress. These results suggest that shear force acts as an important regulator of TF expression in endothelium at the transcriptional level.


Identification of immunodominant Helicobacter pylori proteins with reactivity to H. pylori-specific egg-yolk immunoglobulin.
The importance of hens eggs as a source of specific antibodies (IgY) is well recognized. The protective effect of IgY obtained from hens immunized with Helicobacter pylori whole-cell lysate has been reported for the control of H. pylori infection. However, IgY produced by whole-cell lysates presents the possibility of cross-reactivity with other bacteria, including the normal human flora, and this could decrease the efficiency of IgY. In the present study, the immunodominant proteins of H. pylori with reactivity to H. pylori-specific IgY (IgY-Hp) were identified. IgY obtained from hens immunized with various fractions of H. pylori proteins was isolated and purified, titres of IgY-Hp against H. pylori were determined and cross-reactivity between IgY-Hp and normal human bacteria was examined by Western blot analysis. Finally, immunodominant H. pylori proteins were identified by LC/MS analysis. IgY obtained 2 months after immunization with H. pylori whole-cell lysate showed the highest antibody titre. Five immunodominant proteins were identified that were strongly reactive to IgY-Hp: urease beta-subunit (62 kDa), heat-shock protein 60 (60 kDa), urease alpha-subunit (26 kDa), probable peroxiredoxin (22 kDa) and probable thiol peroxidase (18 kDa). Immunization of hens with the immunodominant proteins identified would produce a more specific IgY against H. pylori.


Finding the Why, Changing the How: Improving the Mental Health of Medical Students, Residents, and Physicians.
The poor mental health of residents, characterized by high rates of burnout, depression, and suicidal ideation, is a growing concern in graduate medical education. Research is needed to gain a deeper understanding of the sources of distress as well as the sources of sustenance in residency training. The study by Mata and colleagues contributes significantly to this understanding. In addition to this line of research, however, studies are needed that assess the impact of interventions to help residents deal more effectively with the stress of training and find meaning in their work. Given the stresses of residency training, this approach may not make a dramatic difference in mental health outcomes. Efforts directed at changing the educational and clinical environments are also needed to reduce unnecessary stressors and create more positive settings for learning and clinical care. Since 2011, Saint Louis University School of Medicine has been pursuing a multipronged strategy to address these issues in the preclinical years. These efforts have led to dramatic decreases in depression and anxiety symptoms in students. An essential component of these interventions is the ongoing measurement of mental health outcomes across all four years of the curriculum. Leaders of residency programs, medical schools, and hospitals need to have the courage to measure these kinds of outcomes to spur change and track the efficacy of programs.


Demographic and epidemiological aspects of plastic surgery: profile of a supradistrict specialty.
The workload of plastic surgery is often poorly understood by the public and those responsible for financing health care. The authors have used linked statistical data to analyse demographic and epidemiological profiles of workload in plastic surgery in Oxfordshire. The analyses were constructed for residents of the district and for patients treated from other districts. The former provides a profile of workload generated for plastic surgery from a geographically-defined population. The latter complements this by adding information about 'imported' workload. Admission rates for plastic surgery were higher for children and elderly people than for other age groups; higher for males than females; and they increased during the 11 years of the study. Most of the increase represented an increase in people treated by the service, rather than an increase in readmissions, although there was a modest increase in the latter too. Lengths of stay per admission and total time spent in hospital per person declined considerably. The bulk of the workload in plastic surgery is concerned with the treatment of trauma (including burns), cancer and congenital malformations. The main clinical conditions treated by the specialty are documented distinguishing, for each condition, the extent to which the patients came from outside the authority in which the provider unit is cited.


Human-derived fusogenic peptides for the intracellular delivery of proteins.
The cytosolic delivery of therapeutic proteins (e.g., antibodies or enzymes) by cell-penetrating peptides (CPPs), such as a human immunodeficiency virus-derived TAT peptide, is facilitated by fusogenic peptides (FPs). For instance, we recently demonstrated that an FP, B18, which is derived from a sea urchin gamete fusion protein, promotes endosomal escape of an enhanced green fluorescent protein (eGFP)-TAT fusion protein directly conjugated to it. However, the potential clinical use of FPs raises concerns because all conventional FPs are non-human-derived. To solve this problem, we have attempted to identify novel human-derived FPs from two human proteins, including a human sperm protein, IZUMO1, which is involved in gamete recognition and fusion, and a human endogenous retroviral envelope protein, Syncytin1, which is involved in placental morphogenesis. Partial peptides from the core domains of the abovementioned proteins were chosen as candidates to generate human-derived FPs. We prepared fusion proteins of these peptides with eGFP and TAT in Escherichia coli and observed the localization of these fusion proteins in HeLa cells using confocal microscopy. Our results suggested that a 19-residues peptide of Syncytin1 (positions 322-340), named S19, possessed strong intracellular uptake activities with no detectable cytotoxicity. In addition, we estimated the number of molecules that escaped from endosomes using a nuclear localization signal, suggesting that the S19 peptide stimulated the intracellular delivery of TAT-fused eGFP by ~90-fold. Furthermore, we confirmed that S19 promoted the intracellular delivery of eGFP to various human cell lines, including HeLa, A431, HepG2, and SK-N-SH. In addition, we demonstrated that not only eGFP but also SNAP-tag and β-galactosidase were delivered efficiently and retained their activities.


Assessment of metal contents in spices and herbs from Saudi Arabia.
In the recent years, there has been a growing interest in monitoring heavy metal contamination of spices/herbs. Spices and herbs are sources of many bioactive compounds that can improve the tastes of food as well as influence digestion and metabolism processes. In the present study, the levels of some essential and toxic elements such as iron (Fe), zinc (Zn), copper (Cu), chromium (Cr), manganese (Mn), cobalt (Co), nickel (Ni), lead (Pb), and cadmium (Cd), present in common spices/herbs that were purchased from the local market in Saudi Arabia, were analyzed by atomic absorption spectroscopy after digestion with nitric acid/hydrogen peroxide mixture. Samples from the following spices/herbs were used: turmeric, cloves, black pepper, red pepper, cumin, legume, cinnamon, abazir, white pepper, ginger, and coriander. The concentration ranges for the studied elements were found as 48.8-231, 4.7-19.4, 2.5-10.5, below detection level (BDL)-1.0, 8.8-490, 1.0-2.6, and BDL-3.7 µg g(-1) for Fe, Zn, Cu, Cr, Mn, Ni, and Pb, respectively, while Cd and Co levels were below the detection limit. Consumers of these spices/herbs would not be exposed to any risk associated with the daily intake of 10 g of spices per day as far as metals Fe, Zn, Cu, Cr, Mn, Ni, and Pb are concerned.


Probiotics and their potential health claims.
Many studies have attempted to identify specific positive health effects of probiotics. One of the challenges in generalizing health effects of probiotics is that different strains exert disparate effects on human health. As a result, the efficacy of one strain or species cannot necessarily be inferred from another. The objective of this review is to examine the current scientific literature that could be used as the basis for potential health claims. More specifically, this paper will review existing evidence of different probiotic strains to prevent and treat diarrhea, treat irritable bowel syndrome (IBS), treat inflammatory bowel disease, and prevent colon cancer. The strongest evidence is related to the use of Lactobacillus rhamnosus GG in the prevention and treatment of rotavirus-associated diarrhea. Further examination of the literature also shows promise in the treatment of some forms of IBS with probiotics. Future studies that use consistent supplementation regimes will allow more definitive conclusions to be drawn on the effects of probiotics on IBS, inflammatory bowel disease, and colon cancer.


The role of linear and voltage-dependent ionic currents in the generation of slow wave oscillations.
Neuronal oscillatory activity is generated by a combination of ionic currents, including at least one inward regenerative current that brings the cell towards depolarized voltages and one outward current that repolarizes the cell. Such currents have traditionally been assumed to require voltage-dependence. Here we test the hypothesis that the voltage dependence of the regenerative inward current is not necessary for generating oscillations. Instead, a current I NL that is linear in the biological voltage range and has negative conductance is sufficient to produce regenerative activity. The current I NL can be considered a linear approximation to the negative-conductance region of the current-voltage relationship of a regenerative inward current. Using a simple conductance-based model, we show that I NL , in conjunction with a voltage-gated, non-inactivating outward current, can generate oscillatory activity. We use phase-plane and bifurcation analyses to uncover a rich variety of behaviors as the conductance of I NL is varied, and show that oscillations emerge as a result of destabilization of the resting state of the model neuron. The model shows the need for well-defined relationships between the inward and outward current conductances, as well as their reversal potentials, in order to produce stable oscillatory activity. Our analysis predicts that a hyperpolarization-activated inward current can play a role in stabilizing oscillatory activity by preventing swings to very negative voltages, which is consistent with what is recorded in biological neurons in general. We confirm this prediction of the model experimentally in neurons from the crab stomatogastric ganglion.


Magnetically induced nonlinear diagnostic features of fe-co-si-B metallic glasses.
We investigate the influence of an external magnetic field on optical photoinduced second-harmonic generation (PISHG) in Fe(18)Co(60)Si(9)B(13) metallic glass. A correlation between the output PISHG signal and degree of crystallinity (varied by thermoannealing) is observed. The applied magnetic field essentially suppresses the relaxation time of the PISHG. Strong angular dependence of the output PISHG signal reflects the peculiarities of phase synchronism conditions that exist in certain types of glass as a result of light scattering on grains. Saturation of the PISHG at magnetic fields higher then 0.75 T indicates correlation between the magnetically induced ordering and noncentrosymmetry electron-charge density appearance. Comparison of PISHG with x-ray diffraction results indicates that the PISHG results have higher sensitivity to hyperfine magnetic ordering. A possible origin of the observed phenomena is explained on the basis of phenomenological and microscopic approaches.


Atypical 3q26/MECOM rearrangements genocopy inv(3)/t(3;3) in acute myeloid leukemia.
Acute myeloid leukemia (AML) with inv(3)/t(3;3)(q21q26) is a distinct World Health Organization recognized entity, characterized by its aggressive course and poor prognosis. In this subtype of AML, the translocation of a GATA2 enhancer (3q21) to MECOM (3q26) results in overexpression of the MECOM isoform EVI1 and monoallelic expression of GATA2 from the unaffected allele. The full-length MECOM transcript, MDS1-EVI1, is not expressed as the result of the 3q26 rearrangement. Besides the classical inv(3)/t(3;3), a number of other 3q26/MECOM rearrangements with poor treatment response have been reported in AML. Here, we demonstrate, in a group of 33 AML patients with atypical 3q26 rearrangements, MECOM involvement with EVI1 overexpression but no or low MDS1-EVI1 levels. Moreover, the 3q26 translocations in these AML patients often involve superenhancers of genes active in myeloid development (eg, CD164, PROM1, CDK6, or MYC). In >50% of these cases, allele-specific GATA2 expression was observed, either by copy-number loss or by an unexplained allelic imbalance. Altogether, atypical 3q26 recapitulate the main leukemic mechanism of inv(3)/t(3;3) AML, namely EVI1 overexpression driven by enhancer hijacking, absent MDS1-EVI1 expression and potential GATA2 involvement. Therefore, we conclude that both atypical 3q26/MECOM and inv(3)/t(3;3) can be classified as a single entity of 3q26-rearranged AMLs. Routine analyses determining MECOM rearrangements and EVI1 and MDS1-EVI1 expression are required to recognize 3q-rearranged AML cases.


A Kernel-based Test of Independence for Cluster-correlated Data.
The Hilbert-Schmidt Independence Criterion (HSIC) is a powerful kernel-based statistic for assessing the generalized dependence between two multivariate variables. However, independence testing based on the HSIC is not directly possible for cluster-correlated data. Such a correlation pattern among the observations arises in many practical situations, e.g., family-based and longitudinal data, and requires proper accommodation. Therefore, we propose a novel HSIC-based independence test to evaluate the dependence between two multivariate variables based on cluster-correlated data. Using the previously proposed empirical HSIC as our test statistic, we derive its asymptotic distribution under the null hypothesis of independence between the two variables but in the presence of sample correlation. Based on both simulation studies and real data analysis, we show that, with clustered data, our approach effectively controls type I error and has a higher statistical power than competing methods.


Optimized photocatalytic degradation of caffeic acid by sol-gel TiO₂.
TiO₂anatase powder was prepared by means of the sol-gel method with titanium(IV) butoxide as precursor. The formation of a tetragonal crystal structure of TiO₂anatase at 500 °C was confirmed by X-ray powder diffraction. The characterization of the samples synthesized was complemented by scanning electron microscopy, diffuse reflectance infrared Fourier transform spectroscopy, nitrogen adsorption-desorption isotherms (Brunauer-Emmett-Teller) and diffuse reflectance spectroscopy. The photocatalytic activity of the TiO₂anatase powder was evaluated in the degradation of caffeic acid in aqueous solution under ultraviolet radiation. A central composite circumscribed design was used to assess the weight of the experimental variables, pH and amount of catalyst in the percentage of caffeic acid degraded and the optimal conditions. The optimized conditions were found to be pH = 5.2 and a load of TiO₂of 1.1 g L⁻¹. Under these conditions more than 90% of caffeic acid degradation was achieved after 30 min of lamp irradiation. At this time the mineralization reached was almost 60%.


Quantitative multi-color FRET measurements by Fourier lifetime excitation-emission matrix spectroscopy.
Förster resonant energy transfer (FRET) is extensively used to probe macromolecular interactions and conformation changes. The established FRET lifetime analysis method measures the FRET process through its effect on the donor lifetime. In this paper we present a method that directly probes the time-resolved FRET signal with frequency domain Fourier lifetime excitation-emission matrix (FLEEM) measurements. FLEEM separates fluorescent signals by their different phonon energy pathways from excitation to emission. The FRET process generates a unique signal channel that is initiated by donor excitation but ends with acceptor emission. Time-resolved analysis of the FRET EEM channel allows direct measurements on the FRET process, unaffected by free fluorophores that might be present in the sample. Together with time-resolved analysis on non-FRET channels, i.e. donor and acceptor EEM channels, time resolved EEM analysis allows precise quantification of FRET in the presence of free fluorophores. The method is extended to three-color FRET processes, where quantification with traditional methods remains challenging because of the significantly increased complexity in the three-way FRET interactions. We demonstrate the time-resolved EEM analysis method with quantification of three-color FRET in incompletely hybridized triple-labeled DNA oligonucleotides. Quantitative measurements of the three-color FRET process in triple-labeled dsDNA are obtained in the presence of free single-labeled ssDNA and double-labeled dsDNA. The results establish a quantification method for studying multi-color FRET between multiple macromolecules in biochemical equilibrium.


The Degree of Blood Supply and Infection Control Needed to Treat Diabetic Chronic Limb-Threatening Ischemia with Forefoot Osteomyelitis.
Diabetic foot ulcers combined with ischemia and infection can be difficult to treat. Few studies have quantified the level of blood supply and infection control required to treat such complex diabetic foot ulcers. We aimed to propose an index for ischemia and infection control in diabetic chronic limb-threatening ischemia (CLTI) with forefoot osteomyelitis. We retrospectively evaluated 30 patients with diabetic CLTI combined with forefoot osteomyelitis who were treated surgically from January 2009 to December 2016. After 44 surgeries, we compared patient background (age, sex, hemodialysis), infection status (preoperative and 1- and 2-week postoperative C-reactive protein [CRP] levels), surgical bone margin (with or without osteomyelitis), vascular supply (skin perfusion pressure), ulcer size (wound grade 0-3 using the Society for Vascular Surgery Wound, Ischemia, and foot Infection classification), and time to wound healing between patients with healing ulcers and those with nonhealing ulcers. Preoperative CRP levels and the ratio of ulcers classified as wound grade 3 were significantly lower and skin perfusion pressure was significantly higher in the healing group than in the nonhealing group (P < .05). No other significant differences were found between groups. This study demonstrates that debridement should be performed first to control infection if the preoperative CRP level is greater than 40 mg/L. Skin perfusion pressure of 55 mm Hg is strongly associated with successful treatment. We believe that this research could improve the likelihood of salvaging limbs in patients with diabetes with CLTI.


The Brunnsviken Brief Quality of Life Scale (BBQ): Development and Psychometric Evaluation.
Measurements of subjective quality of life (QoL) are an important complement to symptom ratings in clinical research and practice. Despite there being several established QoL self-rating scales, we identified a need for a freely accessible, easy-to-use inventory, validated for use with both clinical and non-clinical samples, based on the overall life satisfaction conceptualization of QoL. The Brunnsviken Brief Quality of life scale (BBQ) was designed to meet these requirements. Items were selected by performing a factor analysis on a large data-set of QoL ratings collected previously. Six life areas (Leisure time, View on life, Creativity, Learning, Friends and Friendship, and View of self) were identified as important for overall QoL and were included in the BBQ. A psychometric evaluation was performed using two independent samples: healthy undergraduate students (n = 163), and a sample seeking treatment for social anxiety disorder (n = 568). Results suggested a unifactorial structure, with good concurrent and convergent validity, high internal and test-retest reliability, and accurate classification ability. We conclude that the BBQ is a valid and reliable measure of subjective QoL for use in clinical and research settings. The BBQ is presently available in 31 languages and can be freely downloaded from www.bbqscale.com .


Sleep Patterns, Sleep Disturbances, and Associated Factors Among Chinese Urban Kindergarten Children.
This study aimed to characterize sleep patterns and disturbances among Chinese urban kindergarten children and examine potentially associated factors. Caregivers of 513 children (47.96% male) aged 3-6 years (mean age = 4.46, SD = 0.9) completed the Children's Sleep Habits Questionnaire (CSHQ) and the Strengths and Difficulties Questionnaire (SDQ). Almost 80% (78.8%) of the children scored above the original CSHQ cutoff point for global sleep disturbance. Regression analysis indicated that child's age, and the presence of emotional problems, hyperactivity and peer problems, cosleeping, and interparental inconsistency of attitudes toward child rearing accounted for significant variance in the CSHQ total score (R(2) = 22%). These findings indicate that there is an apparently high prevalence of sleep disturbances in Chinese urban kindergarten children; and sleep disturbances are associated with both child-related and parenting practice variables.


Peer review guidance: how do you write a good review?
Peer review is essential to the quality of scientific publications. As the volume of submissions to these journals increases, the need for an expanding cadre of trained reviewers also increases. Many reviewers do not receive formal training on conducting a peer review or education on the peer review process, however. The author presents an overview of the peer review process and provides guidance for conducting high-quality reviews of manuscripts submitted to The Journal of the American Osteopathic Association and other scientific journals.


A loaded self-managed exercise programme for patellofemoral pain: a mixed methods feasibility study.
A novel loaded self-managed exercise programme that includes pain education and self-management strategies may result in better outcomes for people with patellofemoral pain (PFP). However, establishing program feasibility is an essential first step before testing efficacy. The purpose of this study was to evaluate the feasibility and acceptability of conducting a definitive RCT which will evaluate the clinical and cost-effectiveness of a loaded self-managed exercise programme for people with PFP compared with usual physiotherapy. In a mixed methods, pragmatic, randomised controlled feasibility study, 60 participants with PFP (57% female; mean age 29 years) were recruited from a physiotherapy clinic within a large UK teaching hospital. They were randomly allocated to receive either a loaded self-managed exercise programme (n = 30) or usual physiotherapy (n = 30). Feasibility indicators of process, resources, and management were collected through follow-up of standardised questionnaires six months after recruitment and semi-structured interviews with 20 participants and physiotherapists. Recruitment rate was 5 participants per month; consent rate was 99%; adherence to intervention appointments was 87%; completeness of questionnaire data was 100%; and adherence to intervention delivery was 95%. Three exercise diaries were returned at six months (5%). At six months, 25 questionnaire booklets were returned (9 in the loaded self-managed group, 16 in the usual physiotherapy group), with a total retention rate of 42%. At six months, 56% (5/9) of respondents in the loaded self-managed group and 56% (9/16) in the usual physiotherapy group were classified as 'recovered'. Both groups demonstrated improvements in average pain (VAS), kinesiophobia, pain catastrophizing, general self-efficacy and EQ-5D-5 L from baseline to six months. The results of this feasibility study confirm that it is feasible and acceptable to deliver a loaded self-managed exercise programme to adults with PFP in an NHS physiotherapy outpatient setting. However, between group differences in lost to follow up and poor exercise diary completion mean we are uncertain on some feasibility aspects. These methodological issues need addressing prior to conducting a definitive RCT. ISRCTN 35272486 . Registered 19th December 2016.


Exploring People's Candidacy for Mobile Health-Supported HIV Testing and Care Services in Rural KwaZulu-Natal, South Africa: Qualitative Study.
The use of mobile communication technologies (mHealth: mobile health) in chronic disease management has grown significantly over the years. mHealth interventions have the potential to decentralize access to health care and make it convenient, particularly in resource-constrained settings. It is against this backdrop that we aimed to codevelop (with potential users) a new generation of mobile phone-connected HIV diagnostic tests and Web-based clinical care pathways needed for optimal delivery of decentralized HIV testing, prevention, and care in low- and middle-income countries. The aim of this study was to understand ways in which an mHealth intervention could be developed to overcome barriers to existing HIV testing and care services and promote HIV self-testing and linkage to prevention and care in a poor, HIV hyperendemic community in rural KwaZulu-Natal, South Africa. A total of 54 in-depth interviews and 9 focus group discussions were conducted with potential users (including health care providers) in 2 different communities. Theoretically informed by the candidacy framework, themes were identified from the interview transcripts, manually coded, and thematically analyzed. Participants reported barriers, such as fear of HIV identity, stigma, long waiting hours, clinic space, and health care workers' attitudes, as major impediments to effective uptake of HIV testing and care services. People continued to reassess their candidacy for HIV testing and care services on the basis of their experiences and how they or others were treated within the health systems. Despite the few concerns raised about new technology, mobile phone-linked HIV testing was broadly acceptable to potential users (particularly men and young people) and providers because of its privacy (individual control of HIV testing over health provider-initiated testing), convenience (individual time and place of choice for HIV testing versus clinic-based testing), and time saving. Mobile phone-connected HIV testing and Web-based clinical care and prevention pathways have the potential to support access to HIV prevention and care, particularly for young people and men. Although mHealth provides a way for individuals to test their candidacy for HIV services, the barriers that can make the service unattractive at the clinic level will also need to be addressed if potential demand is to turn into actual demand.


Comparative transcriptomics between species attributes reactogenicity pathways induced by the capsular group B meningococcal vaccine, 4CMenB, to the membrane-bound endotoxin of its outer membrane vesicle component.
The capsular group B meningococcal (MenB) four component vaccine (4CMenB) has been licensed for the prevention of invasive disease caused by MenB. The vaccine causes fever in infants, particularly when given in combination (concomitant) with other routinely-administered vaccines (routine), such as the standard diphtheria, tetanus, pertussis (DTP)-containing vaccine. To assess the suitability of a mouse immunisation model to study this phenomenon, we monitored temperature in mice after a second dose of routine vaccines, with or without 4CMenB, and compared the results with those in humans. Using this mouse model, we explored the reactogenicity of 4CMenB components by measuring changes in temperature, cytokines, and gene expression induced by 4CMenB, one of its components, wild-type or attenuated endotoxin outer membrane vesicles (OMVs), or lipopolysaccharide (LPS). A significant rise (p < 0.01) in temperature was observed in mice immunised with 4CMenB, wild-type OMVs, and LPS. RNA-sequencing of mouse whole blood revealed a gene signature shared by the 4CMenB, OMV, and LPS groups consisting of bacterial pattern recognition receptors and neutrophil activation marker genes. Sequencing of neutrophils isolated after concomitant 4CMenB identified cells expressing the OMV-associated genes Plek and Lcp1. Immunisation with 4CMenB or OMVs led to increased IL-6 in serum and significant upregulation (p < 0.0001) of prostaglandin-synthesising enzymes on brain tissue. These data demonstrate the suitability of a mouse model for assessing vaccine reactogenicity and strongly indicate that the fever following vaccination with 4CMenB in human infants is induced by endotoxin contained in the OMV component of the vaccine.


Treatment of Multisystem Inflammatory Syndrome in Children.
Evidence is urgently needed to support treatment decisions for children with multisystem inflammatory syndrome (MIS-C) associated with severe acute respiratory syndrome coronavirus 2. We performed an international observational cohort study of clinical and outcome data regarding suspected MIS-C that had been uploaded by physicians onto a Web-based database. We used inverse-probability weighting and generalized linear models to evaluate intravenous immune globulin (IVIG) as a reference, as compared with IVIG plus glucocorticoids and glucocorticoids alone. There were two primary outcomes: the first was a composite of inotropic support or mechanical ventilation by day 2 or later or death; the second was a reduction in disease severity on an ordinal scale by day 2. Secondary outcomes included treatment escalation and the time until a reduction in organ failure and inflammation. Data were available regarding the course of treatment for 614 children from 32 countries from June 2020 through February 2021; 490 met the World Health Organization criteria for MIS-C. Of the 614 children with suspected MIS-C, 246 received primary treatment with IVIG alone, 208 with IVIG plus glucocorticoids, and 99 with glucocorticoids alone; 22 children received other treatment combinations, including biologic agents, and 39 received no immunomodulatory therapy. Receipt of inotropic or ventilatory support or death occurred in 56 patients who received IVIG plus glucocorticoids (adjusted odds ratio for the comparison with IVIG alone, 0.77; 95% confidence interval [CI], 0.33 to 1.82) and in 17 patients who received glucocorticoids alone (adjusted odds ratio, 0.54; 95% CI, 0.22 to 1.33). The adjusted odds ratios for a reduction in disease severity were similar in the two groups, as compared with IVIG alone (0.90 for IVIG plus glucocorticoids and 0.93 for glucocorticoids alone). The time until a reduction in disease severity was similar in the three groups. We found no evidence that recovery from MIS-C differed after primary treatment with IVIG alone, IVIG plus glucocorticoids, or glucocorticoids alone, although significant differences may emerge as more data accrue. (Funded by the European Union's Horizon 2020 Program and others; BATS ISRCTN number, ISRCTN69546370.).


Prospective study of serum cysteine levels and oesophageal and gastric cancers in China.
Cancers of the upper gastrointestinal tract remain a significant cause of morbidity and mortality. Cysteine, known to be involved in a myriad of immuno-modulatory, anti-oxidant, and anti-carcinogenic pathways, has not been investigated in the aetiology of oesophageal or gastric cancers. To examine the relationship between serum cysteine concentration and risk of these cancers we conducted a nested case-cohort study within the General Population Nutrition Intervention Trial in Linxian, China. 498 oesophageal squamous cell carcinomas (OSCCs) and 255 gastric cardia adenocarcinomas (GCAs) were matched by age and sex to 947 individuals from the wider cohort. We calculated HRs and 95% CIs using the case-cohort estimator for the Cox proportional hazards models, stratified on age and sex, with adjustment for potential confounders. Higher concentrations of serum cysteine were significantly associated with a lower risk of both OSCC and GCA. For those in the highest quartile of serum cysteine, compared to those in the lowest, the multivariate HRs were 0.70 for OSCC (95% CI 0.51 to 0.98) and 0.59 for GCA (95% CI 0.38 to 0.91). These associations were dose dependent (p for trend=0.006 and 0.008, respectively). These inverse associations were not significantly modified by other risk factors, with the exception of age, where a stronger association was noted among persons in the older age strata. Higher serum concentrations of cysteine were associated with a significantly reduced risk of OSCC and GCA. Cysteine should be further investigated for its potential as a chemopreventive agent for upper gastrointestinal cancers.


Radio protective effects of the Ayurvedic medicinal plant Ocimum sanctum Linn. (Holy Basil): A memoir.
The use of compounds which can selectively protect normal tissues against radiation injury is of immense use because in addition to it protecting the normal tissue, will also permits use of higher doses of radiation to obtain better cancer control and possible cure. However, most of the radio protective compounds investigated possess inadequate clinical application principally due to their inherent systemic toxicity at their optimal protective concentrations. Plants commonly used as medicinal and dietary agents have recently been the focus of attention and studies have shown that Ocimum sanctum Linn. commonly known as the Holy Basil and its water soluble flavonoids, orientin and vicenin protects experimental animals against the radiation-induced sickness and mortality at nontoxic concentrations. Studies with tumor bearing mice have also shown that both Tulsi extract and its flavonoids selectively protect the normal tissues against the tumoricidal effects of radiation. Preclinical studies have also shown that the aqueous extract of the Tulsi leaves; its flavanoids orientin and vicenin, and eugenol, the principal nonpolar constituent present in Tulsi prevent radiation-induced clastogenesis. Mechanistic studies have indicated that free radical scavenging, antioxidant, metal chelating and anti-inflammatory effects may contribute toward the observed protection. In addition, clinical studies with a small number of patients have shown that Tulsi was effective as a radio protective agent. This review summarizes the results related to the radio protective properties of Tulsi and its phytochemicals and also emphasizes the aspects that warrant future research to establish its use as a radio protective agent.


Conceptual framework for estimating the social cost of drug abuse.
Drug abuse imposes costs on individuals and society. Researchers have produced several studies on a subset of tangible costs of drug abuse and other illnesses, but key tangible costs sometimes have been overlooked and, even when recognized, rarely have been estimated. An assortment of intangible costs also have received very little research attention. This study outlines a comprehensive conceptual framework for estimating the social cost of drug abuse. We address both the tangible and intangible costs for the drug-abusing and non-drug-abusing population. Our conceptual framework is based on critical reviews of new and traditional methods for estimating the costs of illness and disease including cost-of-illness methods, averting behavior methods, and utility valuation techniques. We show how the proposed methods can be combined with existing data to estimate the total social cost of drug abuse. Using social cost estimates will enable policymakers to more accurately assess the total burden of drug abuse and related problems on society.


Rapid ranging through evaluation of image distortion.
Distortion is an undesirable aberration found in optical imaging systems, necessitating numerical calibration. However, the fact that image distortion changes with observation distance can be used for ranging. This study developed a rapid, passive-ranging technique, which is simple, incurs low costs, results in minimal interference, and requires few parameters. After determining the location of reference points, the relationship between the normalized mean distortion of images and observation distance is described using two mathematical models, one of which is based on distortion theory and the other is derived from the curve fitting of the experimental results. Analyzing the instantaneous rate of image distortion can also assist in ranging. The proposed technique demonstrates high sensitivity at closer observation distances, but loses effectiveness as observation distances increase.


Evidence for an early gene duplication event in the evolution of the mitochondrial transcription factor B family and maintenance of rRNA methyltransferase activity in human mtTFB1 and mtTFB2.
Most metazoans have two nuclear genes encoding orthologues of the well-characterized Saccharomyces cerevisiae mitochondrial transcription factor B (sc-mtTFB). This class of transcription factors is homologous to the bacterial KsgA family of rRNA methyltransferases, which in Escherichia coli dimethylates adjacent adenine residues in a stem-loop of the 16S rRNA. This posttranscriptional modification is conserved in most metazoan cytoplasmic and mitochondrial rRNAs. Homo sapiens mitochondrial transcription factor B1 (h-mtTFB1) possesses this enzymatic activity, implicating it as a dual-function protein involved in mitochondrial transcription and translation. Here we demonstrate that h-mtTFB2 also has rRNA methyltransferase activity but is a less efficient enzyme than h-mtTFB1. In contrast, sc-mtTFB has no detectable rRNA methyltransferase activity, correlating with the lack of the corresponding modification in the mitochondrial rRNA of budding yeast. Based on these results, and reports that Drosophila melanogaster mtTFB1 and mtTFB2 do not have completely overlapping functions, we propose a model for human mtDNA regulation that takes into account h-mtTFB1 and h-mtTFB2 likely having partially redundant transcription factor and rRNA methyltransferase functions. Finally, phylogenetic analyses of this family of proteins strongly suggest that the presence of two mtTFB homologues in metazoans is the result of a gene duplication event that occurred early in eukaryotic evolution prior to the divergence of fungi and metazoans. This model suggests that, after the gene duplication event, differential selective pressures on the rRNA methyltransferase and transcription factor activities of mtTFB genes occurred, with extreme cases culminating in the loss of one of the paralogous genes in certain species.


CAD/CAM technology for implant abutments, crowns, and superstructures.
The aim of this systematic review was to compare implant prostheses fabricated by computer-assisted design and computer-assisted manufacturing (CAD/CAM) with conventionally fabricated implant prostheses when assessing esthetics, complications (biologic and mechanical), patient satisfaction, and economic factors. Electronic searches for clinical studies focusing on long-term follow-up were performed using the PubMed and Ovid search engines. Concentrating on the restorative aspect of the CAD/CAM technology applicable to implant dentistry, pertinent literature was divided into articles related to implant abutments, crowns, and frameworks. A total of 18 articles satisfied the inclusion criteria. Two articles reported on CAD/CAM crowns, six on abutments, and 10 on implant-supported CAD/CAM frameworks. The mean survival rate for CAD/CAM crowns was 98.85% and for CAD/CAM abutments 100%. The mean survival rate for CAD/CAM frameworks was 95.98%. Based on the current literature, CAD/CAM fabricated crowns, abutments, and frameworks demonstrate survival rates comparable to conventionally fabricated prostheses. Implant survival appears unaffected by fabrication technique. Since this technology encompasses several manufacturing variations, a new definition might be necessary to accurately define the processes under which the CAD/CAM restorations are fabricated. "Complete CAD/CAM product" where no or minimal manual intervention is employed could be a possible term.


Impact of respiratory motion on worst-case scenario optimized intensity modulated proton therapy for lung cancers.
We compared conventionally optimized intensity modulated proton therapy (IMPT) treatment plans against worst-case scenario optimized treatment plans for lung cancer. The comparison of the 2 IMPT optimization strategies focused on the resulting plans' ability to retain dose objectives under the influence of patient setup, inherent proton range uncertainty, and dose perturbation caused by respiratory motion. For each of the 9 lung cancer cases, 2 treatment plans were created that accounted for treatment uncertainties in 2 different ways. The first used the conventional method: delivery of prescribed dose to the planning target volume that is geometrically expanded from the internal target volume (ITV). The second used a worst-case scenario optimization scheme that addressed setup and range uncertainties through beamlet optimization. The plan optimality and plan robustness were calculated and compared. Furthermore, the effects on dose distributions of changes in patient anatomy attributable to respiratory motion were investigated for both strategies by comparing the corresponding plan evaluation metrics at the end-inspiration and end-expiration phase and absolute differences between these phases. The mean plan evaluation metrics of the 2 groups were compared with 2-sided paired Student t tests. Without respiratory motion considered, we affirmed that worst-case scenario optimization is superior to planning target volume-based conventional optimization in terms of plan robustness and optimality. With respiratory motion considered, worst-case scenario optimization still achieved more robust dose distributions to respiratory motion for targets and comparable or even better plan optimality (D95% ITV, 96.6% vs 96.1% [P = .26]; D5%- D95% ITV, 10.0% vs 12.3% [P = .082]; D1% spinal cord, 31.8% vs 36.5% [P = .035]). Worst-case scenario optimization led to superior solutions for lung IMPT. Despite the fact that worst-case scenario optimization did not explicitly account for respiratory motion, it produced motion-resistant treatment plans. However, further research is needed to incorporate respiratory motion into IMPT robust optimization.


Lymphocyte adhesion-dependent calcium signaling in human endothelial cells.
Vascular endothelial cells (ECs) can undergo dramatic phenotypic and functional alterations in response to humoral and cellular stimuli. These changes promote endothelial participation in the inflammatory response through active recruitment of immune effector cells, increased vascular permeability, and alteration in vascular tone. In an attempt to define early events in lymphocyte-mediated EC signaling, we investigated cytosolic-free calcium (Ca2+) changes in single, Fluo-3-labeled human umbilical vein ECs (HUVECs), using an ACAS interactive laser cytometer. Of all lymphocyte subsets tested, allogeneic CD3-, CD56+ natural killer (NK) cells uniquely elicited oscillatory EC Ca2+ signals in cytokine (interleukin [IL]-1- or tumor necrosis factor [TNF])-treated ECs. The induction of these signals required avid intercellular adhesion, consisted of both Ca2+ mobilization and extracellular influx, and was associated with EC inositol phosphate (IP) generation. Simultaneous recording of NK and EC Ca2+ signals using two-color fluorescence detection revealed that, upon adhesion, NK cells flux prior to EC. Lymphocyte Ca2+ buffering with 1,2-bis-5-methyl-amino-phenoxylethane-N,N,N'-tetra-acetoxymethyl acetate (MAPTAM) demonstrated that lymphocyte fluxes are, in fact, prerequisites for the adhesion-dependent EC signals. mAb studies indicate that the beta 2 integrin-intercellular adhesion molecule (ICAM)-1 adhesion pathway is critically involved. However, ICAM-1 antisense oligonucleotide inhibition of IL-1-mediated ICAM-1 hyperinduction had no effect on EC Ca2+ signaling in lymphocyte-EC conjugates, indicating that additional cytokine-induced EC alteration is required. These experiments combine features of lymphocyte-endothelial interactions, intercellular adhesion, EC cytokine activation and transmembrane signaling. The results implicate the IP/Ca2+ second messenger pathway in EC outside-in signaling induced by cytotoxic lymphocytes, and suggest that these signals may play a role in EC alteration by lymphocyte adhesion.


Acidic colonic microclimate--possible reason for false negative hydrogen breath tests.
About 5% of normal subjects fail to produce increased hydrogen breath concentration after ingestion of the non-digestible carbohydrate lactulose (low hydrogen producers). The existence of low hydrogen producers limits the diagnostic use of hydrogen (H2) breath tests. We studied the effects of lactulose and of magnesium sulphate (MgSO4) pretreatment on stool-pH and on hydrogen exhalation after oral loading with lactulose or lactose in 17 hydrogen producers and 12 low hydrogen producers. In seven hydrogen producers acidification of stool pH by lactulose pretreatment (20 g tid) decreased hydrogen exhalation and three of seven (43%) became low hydrogen producers. In contrast, after pretreatment of eight low hydrogen producers with magnesium sulphate (5 g twice daily) all eight produced hydrogen after a lactulose load. Similarly four lactose intolerant low hydrogen producers had abnormal lactose hydrogen breath tests after MgSO4 pretreatment. MgSO4 pretreatment neither resulted in false positive lactose hydrogen breath tests in five lactose tolerant hydrogen producers, nor increased the hydrogen exhalation in five additional hydrogen producing controls after ingestion of lactulose. The results of these studies confirm that hydrogen production from lactulose decreases when the colonic pH is lower (lactulose pretreatment), and increases when colonic pH is higher (MgSO4 pretreatment). In low hydrogen producers the lacking increase of H2 exhalation after ingestion of non-digestible carbohydrates can be overcome by MgSO4 pretreatment, thus increasing the sensitivity of the test by avoiding false negative hydrogen breath tests in low hydrogen producers with disaccharide malabsorption or maldigestion. The underlying mechanism of this remarkable effect of MgSO4 pretreatment warrants further investigation.


A CARE-compliant article: a case report of idiopathic brachial neuritis treated with ultrasound-guided electroacupuncture.
Electroacupuncture is commonly used for treating nerve injury. However, studies published in recent years have not described an appropriate method for accurately identifying the location and depth of injured nerves beneath the acupoints. A 26-year-old male patient had left shoulder pain and weakness after tetanus, diphtheria, and pertussis vaccination and was diagnosed with idiopathic brachial neuritis 24 months before this study. The patient had undergone prednisone and ibuprofen treatment in another hospital, but the therapeutic effect was poor and limited. The nerve conduction studies showed decreased amplitude over the left supraspinatus and deltoid muscles. Electromyography showed increased giant waves and polyphasic waves with reduced recruitments in the left deltoid muscle and increased giant waves with reduced recruitment in the left supraspinatus muscle. The condition was diagnosed with idiopathic brachial neuritis. Ultrasound was used to identify the location and depth of axillary and suprascapular nerves, and direct electroacupuncture was conducted at the quadrangular space and suprascapular notch to stimulate the nerves. Other needles were placed according to deltoid and supraspinatus muscles origins and insertions. The procedure was conducted once a week, and rehabilitation activities were conducted daily. The patient experienced significant improvements of left shoulder pain and muscle weakness after ultrasound-guided electroacupuncture treatment. The total shoulder pain and disability index score declined from 49.23% to 11.54%. The scores of both pain and disability domains improved and maintained stable declining after the intervention. The disability of the arm, shoulder; and hand scores declined from 60 to 23.3. According to amplitude data from nerve conduction studies, the injured axillary nerve showed remarkable improvement in the third month. Muscle strength improved to the normal state. The patient was generally satisfied with the ultrasound-guided electroacupuncture treatment. Ultrasound-guided electroacupuncture was based on anatomical correlations between nerves and muscles and on electrical stimulation theories. The results suggest that this intervention might be an alternative therapy for idiopathic brachial neuritis. Furthermore, in this study, it had minimal adverse effects. This therapy is demonstrated to be effective in future controlled studies.


Sustained Perceptual Deficits from Transient Sensory Deprivation.
Sensory pathways display heightened plasticity during development, yet the perceptual consequences of early experience are generally assessed in adulthood. This approach does not allow one to identify transient perceptual changes that may be linked to the central plasticity observed in juvenile animals. Here, we determined whether a brief period of bilateral auditory deprivation affects sound perception in developing and adult gerbils. Animals were reared with bilateral earplugs, either from postnatal day 11 (P11) to postnatal day 23 (P23) (a manipulation previously found to disrupt gerbil cortical properties), or from P23-P35. Fifteen days after earplug removal and restoration of normal thresholds, animals were tested on their ability to detect the presence of amplitude modulation (AM), a temporal cue that supports vocal communication. Animals reared with earplugs from P11-P23 displayed elevated AM detection thresholds, compared with age-matched controls. In contrast, an identical period of earplug rearing at a later age (P23-P35) did not impair auditory perception. Although the AM thresholds of earplug-reared juveniles improved during a week of repeated testing, a subset of juveniles continued to display a perceptual deficit. Furthermore, although the perceptual deficits induced by transient earplug rearing had resolved for most animals by adulthood, a subset of adults displayed impaired performance. Control experiments indicated that earplugging did not disrupt the integrity of the auditory periphery. Together, our results suggest that P11-P23 encompasses a critical period during which sensory deprivation disrupts central mechanisms that support auditory perceptual skills. Sensory systems are particularly malleable during development. This heightened degree of plasticity is beneficial because it enables the acquisition of complex skills, such as music or language. However, this plasticity comes with a cost: nervous system development displays an increased vulnerability to the sensory environment. Here, we identify a precise developmental window during which mild hearing loss affects the maturation of an auditory perceptual cue that is known to support animal communication, including human speech. Furthermore, animals reared with transient hearing loss display deficits in perceptual learning. Our results suggest that speech and language delays associated with transient or permanent childhood hearing loss may be accounted for, in part, by deficits in central auditory processing mechanisms.


Clinicopathological significance of Nup88 expression in patients with colorectal cancer.
The nucleoporin Nup88 is overexpressed in a series of human malignancies, however, its clinicopathological significance has not been studied. Our aims were to analyze Nup88 expression in normal mucosa, primary tumors and metastases from colorectal cancer patients and further to identify relationships of Nup88 expression with clinicopathological and other factors. Using immunohistochemistry, we investigated Nup88 expression in 198 primary colorectal tumors, 96 normal mucosa samples and 35 lymph node metastases. The results showed that the intensity of Nup88 expression increased from the normal mucosa to the primary tumors (p < 0.0001) and tended to increase from the primary tumors to the metastases (p = 0.15). Both primary tumors and metastases presented stronger expression in the invasive margin and vascular-invaded areas. Nup88 expression was positively related to distal tumor location (p = 0.01), infiltrative growth pattern (p = 0.04) and higher proliferative activity (p = 0.04) and reversely to the grade of differentiation (p = 0.02) and apoptosis (p = 0.049). Strong expression of Nup88 predicted a worse outcome in the patients with distal tumors during the follow-up period of up to 3 years (p = 0.02). It seems that overexpression of Nup88 was involved in the tumorigenesis and aggressiveness of colorectal cancers, and Nup88 may be used as a prognostic factor in patients with distal tumors.


Drinking Motives Moderate the Effect of the Social Environment on Alcohol Use: An Event-Level Study Among Young Adults.
The purpose of this study was to test (a) whether drinking motives predict event-level drinking on weekend evenings; (b) whether the number of friends present in social situations was associated with drinking on weekend evenings; and (c) whether drinking motives moderate the association between friends present and drinking. We linked individual-level drinking motives (measured at baseline) to event-level data assessed every Thursday, Friday, and Saturday evening over 5 weeks. The number of drinks and male and female friends present in the situation were assessed at 9 p.m., 10 p.m., 11 p.m., midnight, and 1 a.m. In total, 197 young adults (51.3% male) completed 11,516 event-level assessments. Multilevel models by gender revealed that higher enhancement motives predicted a greater number of drinks consumed in a given moment, but only among women. The higher the number of male and female friends present in a situation, the more drinks consumed by both genders. Last, drinking motives moderated the association between the number of friends present and the number of drinks. For women, higher enhancement motives predicted more drinks in situations with more male friends. For men, higher coping motives predicted more drinks in situations with no friends and in situations with more female friends. Lower coping motives predicted more drinks with more male friends. Higher conformity motives predicted fewer drinks with more female friends. Drinking motives appear to moderate event-level factors rather than directly predict drinking on weekend evenings. Depending on the motives for drinking, event-level factors (e.g., friends present in a situation) have a strong effect on an individual's drinking.


Prediction of the recurrence risk in patients with epilepsy after the withdrawal of antiepileptic drugs.
Many seizure-free patients who consider withdrawing from antiepileptic drugs (AEDs) hope to discontinue treatment to avoid adverse effects. However, withdrawal has certain risks that are difficult to predict. In this study, we performed a literature review, summarized the causes of significant variability in the risk of postwithdrawal recurrent seizures, and reviewed study data on the age at onset, cause, types of seizures, epilepsy syndrome, magnetic resonance imaging (MRI) abnormalities, epilepsy surgery, and withdrawal outcomes of patients with epilepsy. Many factors are associated with recurrent seizures after AED withdrawal. For patients who are seizure-free after treatment, the role of an electroencephalogram (EEG) alone in ensuring safe withdrawal is limited. A series of prediction models for the postwithdrawal recurrence risk have incorporated various potentially important factors in a comprehensive analysis. We focused on the populations of studies investigating five risk prediction models and analyzed the predictive variables and recommended applications of each model, aiming to provide a reference for personalized withdrawal for patients with epilepsy in clinical practice.


Proximity-compensated blazed transmission grating manufacture with direct-writing, electron-beam lithography.
Proximity-compensated, as well as uncompensated, blazed transmission gratings with periods of 4, 8, and 16 µm were manufactured with direct-writing, electron-beam lithography in positive resist. The compensated gratings performed better than the uncompensated ones. For the 4-µm compensated grating the measured diffraction efficiency was 67%. It was 35% for the uncompensated grating. The compensation was made by repeated convolutions in the spatial domain with the electron-beam point spread function. We determined this function by retrieving the phase from the measured diffraction pattern of the uncompensated gratings.


Current treatment approaches for Paget's Disease of Bone.
Paget's Disease of Bone (PDB) is the second most common metabolic bone disease following osteoporosis. PDB is characterized by an increase in bone resorption and bone deposition. For this reason antiresorptives were indicated as the ideal therapy for PDB. Recently, the availability of newer, more potent nitrogen-containing bisphosphonates has improved treatment outcomes, allowing a more convenient management of this disorder. However, no firm evidence exists to show that bisphosphonates can prevent the complications of PDB, and further work is needed to evaluate the influence of pharmacological therapy on long-term clinical outcomes, so that clinicians can make better-informed choices about the risks and benefits of treatment. This article will focus on the present status and future pharmacological developments in PDB.


Development of a novel therapeutic vaccine carrier that sustains high antibody titers against several targets simultaneously.
With the aim to improve the efficacy of therapeutic vaccines that target self-antigens, we have developed a novel fusion protein vaccine on the basis of the C-terminal multimerizing end of the variable lymphocyte receptor B (VLRB), the Ig equivalent in jawless fishes. Recombinant vaccines were produced in Escherichia coli by fusing the VLRB sequence to 4 different cancer-associated target molecules. The anti-self-immune response generated in mice that were vaccinated with VLRB vaccines was compared with the response in mice that received vaccines that contained bacterial thioredoxin (TRX), previously identified as an efficient carrier. The anti-self-Abs were analyzed with respect to titers, binding properties, and duration of response. VLRB-vaccinated mice displayed a 2- to 10-fold increase in anti-self-Ab titers and a substantial decrease in Abs against the foreign part of the fusion protein compared with the response in TRX-vaccinated mice (P < 0.01). VLRB-generated Ab response had duration similar to the corresponding TRX-generated Abs, but displayed a higher diversity in binding characteristics. Of importance, VLRB vaccines could sustain an immune response against several targets simultaneously. VLRB vaccines fulfill several key criteria for an efficient therapeutic vaccine that targets self-antigens as a result of its small size, its multimerizing capacity, and nonexposed foreign sequences in the fusion protein.-Saupe, F., Reichel, M., Huijbers, E. J. M., Femel, J., Markgren, P.-O., Andersson, C. E., Deindl, S., Danielson, U. H., Hellman, L. T., Olsson, A.-K. Development of a novel therapeutic vaccine carrier that sustains high antibody titers against several targets simultaneously.


Actin-based motility of pathogens: the Arp2/3 complex is a central player.
Bacterial actin-based motility has provided cell biologists with tools that led to the recent discovery that, in many forms of actin-based motilities, a key player is a protein complex named the Arp2/3 complex. The Arp2/3 complex is evolutionally conserved and made up of seven polypeptides involved in both actin filament nucleation and organization. Interestingly, this complex is inactive by itself and recent work has highlighted the fact that its activation is achieved differently in the different types of actin-based motilities, including the well-known examples of Listeria and Shigella motilities. Proteins of the WASP family and small G-proteins are involved in most cases. It is interesting that bacteria bypass or mimic some of the events occurring in eukaryotic systems. The Shigella protein IcsA recruits N-WASP and activates it in a Cdc42-like fashion. This activation leads to Arp2/3 complex recruitment, activation of the complex and ultimately actin polymerization and movement. The Listeria ActA protein activates Arp2/3 directly and, thus, seems to mimic proteins of the WASP family. A breakthrough in the field is the recent reconstitution of the actin-based motilities of Listeria and N-WASP-coated E. coli (IcsA) using a restricted number of purified cellular proteins including F-actin, the Arp2/3 complex, actin depolymerizing factor (ADF or cofilin) and capping protein. The movement was more effective upon addition of profilin, alpha-actinin and VASP (for Listeria). Bacterial actin-based motility is now one of the best-documented examples of the exploitation of mammalian cell machineries by bacterial pathogens.


A simple method to reconstruct the molar mass signal of respiratory gas to assess small airways with a double-tracer gas single-breath washout.
For the assessment of small airway diseases, a noninvasive double-tracer gas single-breath washout (DTG-SBW) with sulfur hexafluoride (SF6) and helium (He) as tracer components has been proposed. It is assumed that small airway diseases may produce typical ventilation inhomogeneities which can be detected within one single tidal breath, when using two tracer components. Characteristic parameters calculated from a relative molar mass (MM) signal of the airflow during the washout expiration phase are analyzed. The DTG-SBW signal is acquired by subtracting a reconstructed MM signal without tracer gas from the signal measured with an ultrasonic sensor during in- and exhalation of the double-tracer gas for one tidal breath. In this paper, a simple method to determine the reconstructed MM signal is presented. Measurements on subjects with and without obstructive lung diseases including the small airways have shown high reliability and reproducibility of this method.


Effect of Serum Ferritin on the Association Between Coffee Intake and Hyperuricemia Among American Women: The National Health and Nutrition Examination Survey.
Background Accruing evidence suggests an inverse relationship between coffee intake and serum uric acid. The mechanism(s) explaining this inverse relationship remains elusive. The aim of this study was to assess if the association between coffee intake and hyperuricemia is mediated via serum ferritin in women. Methods We pooled data from the 2003 to 2006 National Health and Nutrition Examination Survey (NHANES). We included women with complete information on all key variables. Coffee intake was classified as none, <1 cup/day, 1-3 cups/day, and ≥4 cups/day. Hyperuricemia was defined as serum uric acid >5.7 mg/dL. We assessed the association between coffee intake and hyperuricemia using logistic regression. Path analysis was used to examine whether serum ferritin mediated the effect of coffee on hyperuricemia. Results Among 2,139 women (mean age: 31.2 years [SD: 9.2]), mean serum uric acid was 4.4 mg/dL (SD: 1.0), and 227 (10.6%) had hyperuricemia. In multivariate logistic regression models, intake of ≥4 cups/day of coffee was associated with lower odds of hyperuricemia (OR 0.28 [95% CI: 0.09, 091], P=0.035). The total direct and indirect effect of coffee on hyperuricemia via serum ferritin was -0.16, P=0.009 and -8.1 × 10- 3, P=0.204, respectively. Conclusion Among women, moderate coffee consumption was inversely related to hyperuricemia by direct effect, rather than indirectly through the effects of serum ferritin. These findings suggest that serum ferritin does not mediate the inverse association between coffee and hyperuricemia in women.


Nosocomial infections in the ICU: Pens and spectacles as fomites.
Nosocomial infections are a major cause of morbidity and mortality. Non-medical objects known as fomites may have a role in their genesis. We investigated the significance of writing pens and spectacles as fomites. The study was conducted at Aga Khan University Hospital, Karachi, from July 2013 to September 2013. Cultures were taken from pens and/or spectacles of resident nurses, doctors and nursing assistants in intensive care unit (ICU). Organisms important in ICU nosocomial infections were targeted. Seven rounds of sampling over 3 weeks led to 55 pen and 5 spectacle samples. Growth was seen in 3(5.5%) pen samples and 1(20%) spectacle sample. Two (3.6%) pen cultures grew acinetobacter, 1)1.8%) grew candida and acinetobacter, and i spectacle culture grew vancomycin-resistant enterococcus faecium (VRE). Two out of the 4 (50%) personnel managing all ICU beds had growth. During the study, one or more ICU patients had infection with the same organisms. Pens and spectacles may be responsible for the spread of organisms like acinetobacter and VRE. Personnel managing multiple beds are more likely to carry contaminated fomites.


Polymer Materials for High-Performance Triboelectric Nanogenerators.
As an emerging branch of energy conversion technologies, the triboelectric nanogenerator (TENG) pioneers a brand-new path to effectively harness varieties of mechanical energies for the purpose of powering and/or sensing. Since its invention in 2012, the TENG has experienced a booming and revolutionary development in every respect, ranging from materials synthesis and modification, architecture design to performance optimization, power management, and application exploration. In comparison to the organic solar cell and organic light-emitting diodes, TENG is a unique technique that opens the venue of using polymer materials (PMs) for harvesting mechanical energy. So far, by virtue of superior charge transfer and capturing capabilities during friction, various kinds of PMs have been developed and used as triboelectric materials in order to achieve high-performance TENGs. Here, this work focuses on the utilization and development of PMs for the TENGs technology and first gives a summary of main PMs that are frequently adopted in currently reported energy-harvesting TENGs. Second, several kinds of PMs used lately in a few novel TENGs for special or specific energy-harvesting circumstances are introduced and highlighted. Finally, the perspectives on and challenges in developing high-performance PMs toward TENGs technology are conceived and expected to be instructive to future research.


Comparison between Long- and Short-Acting Erythropoiesis-Stimulating Agents in the Period Required for Haemoglobin Stabilisation in Treatment of Anaemia in Patients with Chronic Kidney Disease.
Comparative studies of the potency of long- and short-acting erythropoiesis-stimulating agents (L-ESAs and S-ESAs) on erythropoietic activity in patients with chronic kidney disease without dialysis have not been performed, although L-ESAs are used in many countries. We performed a retrospective analysis of non-dialysis (ND) patients who had received L-ESA or S-ESA. More days were needed for the S-ESA-treated group (368 d) to reach the haemoglobin (Hb) reference range than for the L-ESA-treated group (126 d). Therefore, we investigated risk factors that influence the period until the Hb level reaches the reference range. Patients were classified into two groups by the period until the Hb level was stabilised within the reference range: the short- and long-term group. Two risk factors for delayed Hb stabilisation were identified: age ≥60 years; and administration of an S-ESA for initial treatment. These findings suggest that the Hb level should be carefully monitored during ESA therapy in elderly ND patients, and that the ESA dose should be increased or L-ESA therapy should be utilised to treat renal anaemia.


Sequential healing at implants installed immediately into extraction sockets. An experimental study in dogs.
To compare the sequential healing at implants installed in a healed alveolar bony ridge or immediately after tooth extraction without functional load. In the mandible of 12 dogs, the mesial roots of the first molars were endodontically treated, the tooth hemisected, and the distal roots extracted. After 3 months, the mesial roots of the fourth premolars were endodontically treated, the tooth hemisected, and the distal roots extracted in one side of the mandible. Implants were placed immediately into extraction sockets (IPIES) of the fourth premolar and in the healed sites in the molar regions. Healing abutments were placed, and the flaps were sutured to allow a non-submerged healing. The time of surgery and of sacrifices were planned in such a way to obtain biopsies representing the healing after 1 and 2 weeks and 1 and 3 months, respectively. Ground sections were prepared for histological evaluation of tissues components on the implant surface and the coronal termination level of osseointegration (M-B). New bone apposition on the implant surface was slightly higher at the healed compared to the IPIES sites, being 7.4% and 4.1% after 1 week, and 67.3% and 65.3% after 3 months, respectively. Old bone was progressively resorbed, from 27.0% and 21.9% after 1 week, to 2.5% and 2.0% after 3 months, at healed and IPIES sites, respectively. M-B was 1.4 mm and 2.6 mm after 1 week, 1.2 mm and 1.2 mm after 3 months, at healed and IPIES sites, respectively. Similar patterns of sequential osseointegration were found at implants installed in healed alveolar bone or in alveolar sockets immediately after tooth extraction. The coronal termination level of osseointegration, that was different after 1 week, was found similar at the 3-month observation.


Disparities in access to neuro-oncologic care in the United States.
Race/ethnicity and social status influence admission to high-volume hospitals among patients who undergo craniotomy for tumor biopsy or resection. Retrospective analysis of the Nationwide Inpatient Sample (1988-2005), with additional factors from the Area Resource File. A 20% representative sample of all hospitals in 37 US states. A total of 76 436 patients 18 years or older who were admitted and underwent craniotomy for tumor biopsy or resection. Odds ratios (ORs) for the association of age, sex, race/ethnicity, insurance status, Charlson Comorbidity Index, and county-level characteristics with admission to high-volume hospitals (>50 craniotomies per year) or low-volume hospitals. A total of 25 481 patients (33.3%) were admitted to high-volume hospitals. Overall access to high-volume hospitals improved over time. However, racial/ethnic disparities in access to high-volume hospitals dramatically worsened for Hispanics (OR, 0.49) and African Americans (OR, 0.62) in recent years. Factors associated with better access to high-volume hospitals included years since 1988 (OR, 1.11), greater countywide neurosurgeon density (OR, 1.66), and higher countywide median household income (OR, 1.71). Factors associated with worse access to high-volume hospitals included older age (OR, 0.34 per year increase), increased countywide poverty rate (OR, 0.57), Hispanic race/ethnicity (OR, 0.68), and higher Charlson Comorbidity Index (OR, 0.96 per point increase). African Americans and Hispanics have disproportionately worse access to high-quality neuro-oncologic care over time compared with whites. Higher countywide median household income and decreased countywide poverty rate were associated with better access to high-volume hospitals, implicating socioeconomic factors in predicting admission to high-quality centers.


p53 expression in normal paraffin-embedded tissue using different antibodies and antigen retrieval buffer systems.
The study was undertaken to demonstrate wild-type p53 in normal paraffin-embedded tissues using two widely used antibodies, DO7 and 1801 and two different antigen retrieval buffer systems. Formalin-fixed paraffin-embedded normal tissue samples were obtained from the archives of the John Radcliffe Hospital, Oxford. Antigen retrieval was performed by microwaving using two different buffer systems: (i) the commercially available Dako target retrieval solution (Cat. no. 1699) (pH 9.8-9.9), (ii) freshly prepared buffer consisting of 0.1 m EDTA with 0.1% Tween pH 6.0, and (iii) freshly prepared buffer consisting of 0.1 m EDTA with 0.1% Tween pH 8.0. Staining was performed with DO7 and 1801 antibodies using the Dako Envision kit (peroxidase/DAB). DO7 antibody elicited strong nuclear staining in the mucosal cells of the small and large intestine, lymphoid cells, decidua, neurones such as Purkinje cells of the cerebellum, glandular epithelial cells and stromal cells of the prostate, cardiac myocytes and bronchial epithelial cells. Cytoplasmic staining was noted in Purkinje cells, glandular epithelium of prostate, exocrine pancreas and renal tubular epithelium. The 1801 antibody did not produce staining in any of these tissues. Our study demonstrates the presence of p53 in normal paraffin-embedded tissue with nuclear and/or cytoplasmic localization in some instances. In our view, DO7 appears to be better suited for such detection.


Accentuate the Positive: The Association Between Informal and Formal Supports and Caregiving Gains.
Background: To promote resilience among caregivers for persons living with dementia (PLWDs), we examine how formal and informal supports are linked to caregiving gains, and whether gender moderates the association between supports and gains. Method: Using the National Health and Aging Trends Study and associated National Study of Caregiving, sources of informal (emotional support, practical support, and help with the PLWD) and formal support (respite care, training program, support group) are considered as predictors of caregiving gains, with gender as a moderator of these associations. The sample included 707 caregivers for 502 PLWDs. Results: Greater caregiving gains were significantly associated with emotional support from friends/family (β = 0.14, SE = 0.09, p = .03). Furthermore, attending a caregiver training program was only associated with increased caregiving gains among men (β = 0.11, SE = 0.08, p = .02). Conclusion: Emotional support from family/friends appears particularly consequential for caregiving gains, and male caregivers may benefit most from programs that emphasize skill building.


Racial Segregation, Testing Site Access, and COVID-19 Incidence Rate in Massachusetts, USA.
The U.S. has merely 4% of the world population, but contains 25% of the world's COVID-19 cases. Since the COVID-19 outbreak in the U.S., Massachusetts has been leading other states in the total number of COVID-19 cases. Racial residential segregation is a fundamental cause of racial disparities in health. Moreover, disparities of access to health care have a large impact on COVID-19 cases. Thus, this study estimates racial segregation and disparities in testing site access and employs economic, demographic, and transportation variables at the city/town level in Massachusetts. Spatial regression models are applied to evaluate the relationships between COVID-19 incidence rate and related variables. This is the first study to apply spatial analysis methods across neighborhoods in the U.S. to examine the COVID-19 incidence rate. The findings are: (1) Residential segregations of Hispanic and Non-Hispanic Black/African Americans have a significantly positive association with COVID-19 incidence rate, indicating the higher susceptibility of COVID-19 infections among minority groups. (2) Non-Hispanic Black/African Americans have the shortest drive time to testing sites, followed by Hispanic, Non-Hispanic Asians, and Non-Hispanic Whites. The drive time to testing sites is significantly negatively associated with the COVID-19 incidence rate, implying the importance of the accessibility of testing sites by all populations. (3) Poverty rate and road density are significant explanatory variables. Importantly, overcrowding represented by more than one person per room is a significant variable found to be positively associated with COVID-19 incidence rate, suggesting the effectiveness of social distancing for reducing infection. (4) Different from the findings of previous studies, the elderly population rate is not statistically significantly correlated with the incidence rate because the elderly population in Massachusetts is less distributed in the hotspot regions of COVID-19 infections. The findings in this study provide useful insights for policymakers to propose new strategies to contain the COVID-19 transmissions in Massachusetts.


Bridging the healthcare gap: Building the case for epilepsy virtual clinics in the current healthcare environment.
Access to quality healthcare remains a challenge that is complicated by mounting pressures to control costs, and now, as we witness, the unprecedented strain placed on our healthcare delivery systems due to the COVID-19 pandemic. Challenges in healthcare access have driven a need for innovative approaches ensuring connectivity to health providers. Telehealth services and virtual clinics offer accessible disease management pathways for patients living in health resource limited areas or, as in the case of the COVID-19 pandemic, where there may be potential barriers to existing healthcare resources. Those suffering with serious chronic disorders often cannot be seen by a healthcare specialist due to their limited availability, or the lack of a specialist within a reasonable proximity. Epilepsy represents such a disorder where most of the world's population lacks the availability of necessary specialists. Virtual clinics allow for specialist care and an ability to perform necessary ambulatory electroencephalogram (EEG) monitoring by placing the technologies directly in patients' homes or at local clinics near the patients' homes. By moving the diagnostic process out of the hospital or epilepsy center, it becomes possible to overcome growing gaps in neurology services. Virtual clinics have the potential to expand access to high-quality, cost-effective care for the patient. The virtual clinic remotely connects those in need of medical support with specialists anywhere in the world, at any time of the day.


Improved heritability estimation from genome-wide SNPs.
Estimation of narrow-sense heritability, h(2), from genome-wide SNPs genotyped in unrelated individuals has recently attracted interest and offers several advantages over traditional pedigree-based methods. With the use of this approach, it has been estimated that over half the heritability of human height can be attributed to the ~300,000 SNPs on a genome-wide genotyping array. In comparison, only 5%-10% can be explained by SNPs reaching genome-wide significance. We investigated via simulation the validity of several key assumptions underpinning the mixed-model analysis used in SNP-based h(2) estimation. Although we found that the method is reasonably robust to violations of four key assumptions, it can be highly sensitive to uneven linkage disequilibrium (LD) between SNPs: contributions to h(2) are overestimated from causal variants in regions of high LD and are underestimated in regions of low LD. The overall direction of the bias can be up or down depending on the genetic architecture of the trait, but it can be substantial in realistic scenarios. We propose a modified kinship matrix in which SNPs are weighted according to local LD. We show that this correction greatly reduces the bias and increases the precision of h(2) estimates. We demonstrate the impact of our method on the first seven diseases studied by the Wellcome Trust Case Control Consortium. Our LD adjustment revises downward the h(2) estimate for immune-related diseases, as expected because of high LD in the major-histocompatibility region, but increases it for some nonimmune diseases. To calculate our revised kinship matrix, we developed LDAK, software for computing LD-adjusted kinships.


Coadministration of low-dose lipopolysaccharide and soluble tissue factor induces thrombosis after radiosurgery in an animal arteriovenous malformation model.
Radiosurgery for arteriovenous malformations is limited to small lesions and may take 3 years to produce total occlusion. It has recently been shown that coadministration of low-dose lipopolysaccharide (LPS) and soluble tissue factor (sTF) selectively induces thrombosis in murine tumor models, attributable perhaps to the prothrombotic phenotype of tumor vasculature. Radiosurgery may induce changes in endothelial prothrombotic molecules similar to those found in tumors. This study aimed to determine if a similar strategy could be used to stimulate thrombus formation in an animal arteriovenous malformation model. Seventeen rats underwent creation of a carotid-to-jugular anastomosis. Animals were intravenously injected with sTF, low-dose LPS, a combination of both, or placebo 24 hours after stereotactic irradiation of the anastomosis. Control animals received both agents after sham irradiation. Coadministration of sTF and LPS led to the formation of thrombi in up to 69% of small vessels and 39% of medium-sized vessels within the target region. The irradiated vasculature demonstrated intermediate rates of thrombosis after treatment with either sTF or LPS alone as did vessels within the fistula in the control group. Logistic regression analysis demonstrated significant associations between development of thrombi and treatment with radiation, sTF, or LPS (P < 0.005). There was no evidence of systemic thrombus formation or toxicity in any group. Treatment with sTF and LPS selectively induces thrombosis of irradiated vessels in a rat model of arteriovenous malformation. Stimulation of thrombosis may improve the efficacy of radiosurgery, increasing the treatable lesion size and reducing latency.


Fidelity of delivery of a physical activity intervention: predictors and consequences.
Assessing fidelity of behavioural interventions is important, but demanding and rarely done. This study assessed adherence to behaviour change techniques used in an intervention to increase physical activity among sedentary adults ( ProActive ; N = 365). Transcripts of 108 sessions with a sub-sample of 27 participants were assessed. An independent assessor coded adherence of four 'facilitators' who delivered the intervention to 208 protocol-specified facilitator behaviours (e.g. 'elicit perceived advantages of becoming more active') in four key sessions. Four raters classified the 208 behaviours under 14 techniques (e.g., goal setting, use of rewards) to enable calculation of adherence to techniques. Observed adherence to techniques across participants was modest (median 44%, IQR 35-62%), and lower than that reported by facilitators. Adherence differed between facilitators (range: 26-63%) and decreased across the four sessions (mean drop 9% per session, 95% confidence interval 7-11%). In this small sample facilitator adherence was unrelated to (change in) participants' physical activity or its cognitive predictors: Attitudes, subjective norm, perceived behavioural control and intention. Future research should investigate causal pathways between fidelity indicators and outcomes in larger samples and develop and test less intensive measures of fidelity.