Tailoring Rituximab According to CD27-Positive B-Cell versus CD19-Positive B-Cell Monitoring in Neuromyelitis Optica Spectrum Disorder and MOG-Associated Disease: Results from a Single-Center Study.
B-cell-depleting agents have been widely used for neuromyelitis optica spectrum disorder (NMOSD) and MOG-associated diseases (MOGAD), but no consensus exists on the optimal dose and frequency of treatment administration. The aim of our study was to evaluate the effect of a Rituximab (RTX) personalized treatment approach based on CD27-positive B-cell monitoring on efficacy, safety, and infusion rates. This is a retrospective, uncontrolled, single-center study including patients with NMOSD and MOGAD treated with RTX at a tertiary multiple sclerosis center at the San Luigi University Hospital, Orbassano, Italy. All the patients were treated with RTX induction, followed by maintenance infusion at the dosage of 1000 mg according to cell repopulation: initially according to total CD19-positive B-cell monitoring (> 0.1% of lymphocytes), and subsequently according to CD27-positive B-cell repopulation (> 0.05% of lymphocytes for the first 2 years, and subsequently > 0.1%). NMOSD and MOGAD activity was assessed as clinical or MRI activity. All patients were screened of the occurrence of severe adverse events (AEs). A total of 19 patients were included in the analysis. Median follow-up was 7.64 years (range 3.09-16.25). The annualized relapse rate (ARR) 1 year before RTX start was 2.37 [Standard deviation (SD), 1.34] and decreased to 0.08 (SD 0.11) in the subsequent years after RTX initiation. ARR did not differ before and after start of CD27 monitoring. Median inter-dose time was 8.80 (range 5.78-14.23) before CD27 monitoring and 15.93 months (range 8.56-35.37) after CD27 monitoring (p < 0.001). We observed no AEs. Our findings suggest that in our cohort CD27-positive B-cell-based RTX reinfusion regimen was able to reduce the number of RTX reinfusions relative to CD19-positive B-cell monitoring, with comparable efficacy and safety profile. In order to achieve an even more individualized and effective treatment, the FCGR3A genetic polymorphisms could be evaluated when assessing RTX efficacy.


Assessment of environmental sustainability integration into higher education for future experts and leaders.
The environmental and climate crisis is gaining priority among critical human concerns; therefore, environmental knowledge and sustainable solutions play a significant role and gaining global popularity as an academic discipline. Additionally, United Nations Sustainable Development Goal no. 4 acknowledges education's role in promoting sustainable development, sustainable lifestyles, human rights, social responsibility, circular economy, and greening our economy and society. In this paper new conceptual framework that focuses on systematically analyzing environmental sustainability integration in study programs and subjects is developed. The main aim is to reflect the conceptual basis of education related to environmental sustainability topics such as sustainable development, social responsibility, circular economy, ecology, environmental protection, and greening to boost future environmental management practices in industry and services. Defining the level of integration of environmental and sustainability-related topics is divided by research field classification and study cycles (BSc, MSc, PhD). The specific added value of the developed conceptual framework is reflected by defining cross-sections and inter-and trans-disciplinary of sustainability topics integrated within specific programs and subjects. The conceptual framework was tested by assessing 1051 programs in progress in Slovenia. It was revealed that the highest share of study programs has an intermediate level of environmental sustainability with 2-3 subjects (392 study programs). These are represented mainly by integrating environmental protection, ecology, and "greening" but less with circular economy and social responsibility. Significant differences among specific study programs and study fields reflect that young intellectuals will not be equally educated and qualified for future managerial challenges. Master students gain the best insight into core sustainability and environmental topics needed for future environmental managers.


Voluntary and forced exposure to ethanol vapor produces similar escalation of alcohol drinking but differential recruitment of brain regions related to stress, habit, and reward in male rats.
A major limitation of the most widely used current animal models of alcohol dependence is that they use forced exposure to ethanol including ethanol-containing liquid diet and chronic intermittent ethanol (CIE) vapor to produce clinically relevant blood alcohol levels (BAL) and addiction-like behaviors. We recently developed a novel animal model of voluntary induction of alcohol dependence using ethanol vapor self-administration (EVSA). However, it is unknown whether EVSA leads to an escalation of alcohol drinking per se, and whether such escalation is associated with neuroadaptations in brain regions related to stress, reward, and habit. To address these issues, we compared the levels of alcohol drinking during withdrawal between rats passively exposed to alcohol (CIE) or voluntarily exposed to EVSA and measured the number of Fos+ neurons during acute withdrawal (16 h) in key brain regions important for stress, reward, and habit-related processes. CIE and EVSA rats exhibited similar BAL and similar escalation of alcohol drinking and motivation for alcohol during withdrawal. Acute withdrawal from EVSA and CIE recruited a similar number of Fos+ neurons in the Central Amygdala (CeA), however, acute withdrawal from EVSA recruited a higher number of Fos+ neurons in every other brain region analyzed compared to acute withdrawal from CIE. In summary, while the behavioral measures of alcohol dependence between the voluntary (EVSA) and passive (CIE) model were similar, the recruitment of neuronal ensembles during acute withdrawal was very different. The EVSA model may be particularly useful to unveil the neuronal networks and pharmacology responsible for the voluntary induction and maintenance of alcohol dependence and may improve translational studies by providing preclinical researchers with an animal model that highlights the volitional aspects of alcohol use disorder.


Nurses' spiritual attitudes and involvement-Validation of the Polish version of the Spiritual Attitude and Involvement List.
Spirituality is vital in the holistic approach to nursing care. The personal spirituality of nurses has been documented to have an impact on the spiritual nursing care they provide. To validate the Polish version of the Spiritual Attitude and Involvement List (SAIL) among nurses and to describe spiritual attitudes and involvement of nurses as measured with the tool. A cross-sectional, validation study was performed according to the STrengthening the Reporting of OBservational studies in Epidemiology guidelines. Study involving 163 nurses, with the use of four tools: (a) the SAIL; (b) the Self-Description Questionnaire; (c) the Scale of Spiritual Transcendence; and (d) the Brief Religious Coping questionnaire. The Explanatory Factor Analysis identified six factors and 25 items were retained explaining a total variance of 67.96%. In the Confirmative Factor Analysis, acceptable index fit values were obtained. Correlations were found between SAIL and the Brief Religious Coping questionnaire, the Self-Description Questionnaire, and the Spiritual Transcendence Scale. Nurses reported the highest scores on 'Meaningfulness' (= 4.95 out of 6.0, Standard Deviation [SD] 0.56) and the lowest on the 'Transcendent Experiences' factor (= 3.21 out of 6.0, SD 0.93). A strong correlation was found between 'Spiritual Activities' and the religious involvement of nurses (r = 0.506), and between 'Connectedness with nature' and the nurses' age and work experience (r = 0.315 and r = 0.321, respectively). The Polish version of SAIL shows acceptable psychometric properties and construct validity. With the validation of SAIL, future studies can be undertaken with the aim of measuring the personal spirituality of nurses in various settings (hospital vs. community), cultures, and countries, thus increasing the opportunity to compare findings. Moreover, more studies should be performed in order to assess whether there is any connection between personal spirituality and the spiritual nursing care provided to patients.


Epstein-Barr virus peptides derived from latent cycle proteins alter NKG2A + NK cell effector function.
Natural killer (NK) cells control viral infection through the interaction between inhibitory receptors and human leukocyte antigen (HLA) ligands and bound peptide. NK cells expressing the inhibitory receptor NKG2A/CD94 recognize and respond to autologous B cells latently infected with Epstein-Barr virus (EBV). The mechanism is not yet understood, thus we investigated peptides derived from seven latent proteins of EBV in the interaction of NKG2A and its ligand HLA-E. Functional analysis demonstrated that EBV peptides can bind to HLA-E and block inhibition of NK cell effector function. Moreover, analysis of DNA from 79 subjects showed sequence variations in the latent protein, LMP1, which alters NK responses to EBV. We provide evidence that peptides derived from EBV latent cycle proteins can impair the recognition of NKG2A despite being presented by HLA-E, resulting in NK cell activation.


Three-dimensional imaging through scattering media based on confocal diffuse tomography.
Optical imaging techniques, such as light detection and ranging (LiDAR), are essential tools in remote sensing, robotic vision, and autonomous driving. However, the presence of scattering places fundamental limits on our ability to image through fog, rain, dust, or the atmosphere. Conventional approaches for imaging through scattering media operate at microscopic scales or require a priori knowledge of the target location for 3D imaging. We introduce a technique that co-designs single-photon avalanche diodes, ultra-fast pulsed lasers, and a new inverse method to capture 3D shape through scattering media. We demonstrate acquisition of shape and position for objects hidden behind a thick diffuser (≈6 transport mean free paths) at macroscopic scales. Our technique, confocal diffuse tomography, may be of considerable value to the aforementioned applications.


A pure antiestrogen, ICI 182,780, stimulates the growth of tamoxifen-resistant KPL-1 human breast cancer cells in vivo but not in vitro.
The critical mechanisms responsible for antiestrogen resistance have not yet been elucidated. We previously established a breast cancer cell line, KPL-1, derived from a patient with recurrent disease which appeared under tamoxifenadministration. In a previous study, we suggested that this cell line is estrogen receptor (ER)-positive but tamoxifen-resistant. In the present study, the effects of a pure antiestrogen, ICI 182,780, on this cell line were investigated. Although tamoxifen inhibited neither cell growth nor estradiol-stimulated transcriptional activity in vitro, ICI 182,780, significantly inhibited both of them. Tamoxifen and ICI 182,780 were then administered to female nude mice bearing KPL-1 tumors. Tamoxifen had no effect on tumor growth, but ICI 182,780 unexpectedly stimulated it (p = 0.022). Estradiol tended to inhibit tumor growth (p = 0.198). Immunohistochemical analysis revealed that ICI 182,780 significantly increased the Ki6-labeling index (p<0.001) but estradiol decreased it (p = 0.035). To explore the possible mechanisms of these phenotypes, the mRNA levels of ER-alpha,ER-beta, transforming growth factor-beta1, fibroblast growth factor (FGF)-1 and FGF-4 in KPL-1 cells were compared with those in other ER-positive human breast cancer cell lines by reverse-transcription polymerase chain reaction. FGF-1 was overexpressed only in KPL-1 cells. This cell line is the first breast cancer cell line to be growth-stimulated by ICI 182,780 in vivo. Paracrine interaction between tumor cells and stromal cells mediated by growth factors, such as FGF-1, might be a key factor to explain the unique hormone responsiveness of KPL-1 cells.


Patch testing a patient with allergic contact hand dermatitis who is taking infliximab.
We report the case of a patient who developed allergic contact hand dermatitis while receiving infliximab infusions for psoriasis and psoriatic arthritis. Patch testing showed multiple positive allergens. To our knowledge, this is the first case report of successful patch testing in a patient receiving tumor necrosis factor-alpha (TNF-alpha) blockade therapy. TNF-alpha blockers do not necessarily suppress allergic contact hypersensitivity and are not an absolute contraindication to patch testing.


Intensified Nutrition Interventions in Antenatal Care Services Increased Consumption of Iron and Folic Acid Supplements and Early Breastfeeding Practices in Burkina Faso: Results of a Cluster-Randomized Program Evaluation.
Alive & Thrive supported the Government of Burkina Faso to strengthen the provision of iron and folic acid (IFA) supplementation and interpersonal counseling on maternal nutrition and breastfeeding through antenatal care (ANC) services and community-based contacts in 2 regions. We assessed the impacts of intensified nutrition interventions during ANC compared with standard ANC services on intervention coverage and maternal nutrition practices. A cluster-randomized evaluation compared 40 health center catchment areas in intervention areas with 40 in control areas. Repeated cross-sectional surveys in 2019 and 2021 (960 pregnant women and 1920 women with children 0-5 mo of age per survey round) provided data on impact indicators, intervention exposure, and other factors. We derived difference-in-difference (DID) effect estimates, adjusted for geographic clustering, for maternal dietary diversity, IFA consumption, and early breastfeeding practices. More women in intervention areas had 4+ ANC visits (DID: 8.3 percentage points [pps]) and started ANC during the first trimester (DID: 10.5 pp), compared with control areas. Improvements were achieved in exposure to nutrition counseling on dietary diversity (DID: 44.4 pp), food quantity (DID: 42.9 pp), adequate weight gain (DID: 35.1 pp), and breastfeeding (DID: 25.9 pp). Women in intervention areas consumed more IFA supplements during pregnancy (DID: 21 tablets). Early initiation of and exclusive breastfeeding also improved (DID: 17.0 and 8.3 pp, respectively). However, dietary diversity (4 out of 10 food groups) and mean probability of adequacy of micronutrient intake (14%) among pregnant women remained low in both areas. Strengthening maternal nutrition interventions delivered through government ANC services was feasible and effective in improving maternal nutrition practices. Continued efforts to strengthen the delivery and use of maternal nutrition services may be required for greater behavior changes, and to address family support, social norms, and other factors to improve women's diets during pregnancy.


[Socio-medical aspects of primary disability among those of working and over working age in Russian Federation].
According to the State Statistics a the indicators of primary disability in 2003-2015 years in Russia were studied, taking into account the population in working and over working age first time recognized as disabled persons. The necessity of medical organizations improvement during the medical and social expertise of patients in different ages was shown. The characteristics of social and medical features of the primary disability were presented that should be taken into consideration in the development of social protection programs, rehabilitation of disabled people and disability prevention, especially among elderly citizens.


Identification of two forms of the Ly-6.2 antigen showing differential expression.
A monoclonal antibody to the Ly-6.2 specificity, defined by strain and tissue distribution, was used to identify the cellular antigens of lymphocytes and tumor cell lines. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of immune precipitates demonstrated that the Ly-6.2 antigen on the surface of thymus and the T lymphoma EL-4 was a protein of 34 kd, whereas spleen cells showed two Ly-6.2 molecules of 34 kd and 56 kd. In vitro translation of EL-4 T-lymphoma poly A+ RNA followed by immunoprecipitation showed the synthesis of two Ly-6.2 precursor polypeptides. These two precursors were translated from separable mRNA molecules; the larger encoded a 54 kd polypeptide, while the second, smaller one translated a 36 kd polypeptide. Thus, the T lymphoma EL-4 contains two distinct mRNA, but only one is seen on the surface, while spleen cells contain and translate both mRNAs and both surface forms are detected. What determines the utilization of the two mRNAs and the surface expression of the two different proteins in the different tissues is not known. Whether the two mRNAs are the transcripts of one gene or arise by transcription of two separate but closely linked genes remains to be determined.


MIP-1alpha, MIP-1beta, RANTES, and ATAC/lymphotactin function together with IFN-gamma as type 1 cytokines.
We analyzed for the first time the expression of chemokines in subpopulations of the murine immune system at the single-cell level. We demonstrate in vitro and in a model of murine listeriosis that macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, regulated on activation normal T cell expressed and secreted (RANTES), and activation-induced, T cell-derived, and chemokine-related cytokine (ATAC)/lymphotactin are cosecreted to a high degree with IFN-gamma by activated individual natural killer (NK), CD8(+) T, and CD4(+) T helper 1 (Th1) cells. Functionally, ATAC and the CC chemokines cooperate with IFN-gamma in the up-regulation of CD40, IL-12, and tumor necrosis factor-alpha, molecules playing a central role in the effector phase of macrophages. Our data indicate that (i) MIP-1alpha, MIP-1beta, RANTES, and ATAC are not only chemoattractants but also coactivators of macrophages, (ii) MIP-1alpha, MIP-1beta, RANTES, and ATAC constitute together with IFN-gamma a group of "type 1 cytokines," and (iii) these cytokines act together as a functional unit that is used by NK cells in the innate phase and then "handed over" to CD8(+) T cells in the antigen-specific phase of the immune defense, thus bridging the two components of a Th1 immune reaction.


A theoretical investigation of the intercalative binding of 7-H pyrido[4.3C]carbazole chromophore into a d(CpG)2 minihelix.
Theoretical computations are performed of the intercalative binding to a model d(CpG)2 minihelix of 7-H pyrido[4.3C]carbazole, the precursor of the antitumor bisintercalating drug ditercalinium. The conformations of the intercalation site are generated by the AGNAS procedure (algorithm to generate nucleic acid structures) of Miller and co-workers. The ligand-nucleotide interactions and the nucleotide conformational energies are computed with the SIBFA procedures (sum of interactions between fragments ab initio computed), which use formulas of empirical origin that reproduce ab initio SCF (self-consistent field) computations. Among the candidate intercalation sites most favored energetically, one has a pattern of conformational angles related to the one determined crystallographically by Sobell et al. in a series of x-ray structural studies of small intercalator-dinucleotide monophosphate complexes. Optimal values of the unwinding angle, found in the range of -12 degrees to -14 degrees, are consistent with available experimental data on DNA.


Comparison of two serum bactericidal assays for Neisseria gonorrhoeae.
Pooled normal human serum killing of 14 strains of Neisseria gonorrhoeae was assessed by dilution plate and microtiter methods. In both assays, the strains presented a spectrum of sensitivity to the serum. In the dilution plate assay, results with two different concentrations of human serum were similar for most, but not all of the strains tested. When data for all of the strains were compared, no correlation was found between the dilution plate and microtiter bactericidal assays. Finally, we found that the bactericidal capacities of intact and complement-depleted human sera were very similar when assessed by microtiter methods, suggesting a non-complement-mediated serum killing mechanism.


Structure activity relationship studies on Amb639752: toward the identification of a common pharmacophoric structure for DGKα inhibitors.
A series of analogues of Amb639752, a novel diacylglycerol kinase (DGK) inhibitor recently discovered by us via virtual screening, have been tested. The compounds were evaluated as DGK inhibitors on α, θ, and ζ isoforms, and as antagonists on serotonin receptors. From these assays emerged two novel compounds, namely 11 and 20, which with an IC50 respectively of 1.6 and 1.8 µM are the most potent inhibitors of DGKα discovered to date. Both compounds demonstrated the ability to restore apoptosis in a cellular model of X-linked lymphoproliferative disease as well as the capacity to reduce the migration of cancer cells, suggesting their potential utility in preventing metastasis. Finally, relying on experimental biological data, molecular modelling studies allow us to set a three-point pharmacophore model for DGK inhibitors.


Colonial waterbirds provide persistent subsidies to swamp forests along an estuarine island food chain.
Birds are excellent vectors of allochthonous matter and energy due to their high mobility, with more intense flow when waterbirds congregate in breeding colonies, feeding in surrounding aquatic and terrestrial areas, and promoting nutritional pulses to nutrient-poor environments. In southern Brazil, a swamp forest on an estuarine island is used by waterbirds for breeding, providing an opportunity to investigate the potential effects of transport of matter between nutrient-rich environments. Soil, plants, invertebrates, and blood from terrestrial birds were collected and stable isotopes compared to similar organisms in a control site without heronries. Values of δ15N and δ13C from waterbirds were higher in the colony in comparison to the control site (spatial effect). The enrichment of 15N and 13C provided during the active colony period persisted after the breeding period, especially for δ15N, which was higher in all compartments (temporal effect). Moreover, the enrichment of 15N occurred along the entire trophic chain (vertical effect) in the colony environment, including different guilds of invertebrates and land birds. The enrichment in 13C seems to lose strength and was mostly explained by factors such as trophic guild rather than site, especially in birds. Bayesian mixture models with terrestrial vs. estuarine endpoints demonstrated that all organisms from both colony and control environments had assimilated estuarine matter. Finally, detritivorous invertebrates showed greater assimilation when compared to other guilds. This study demonstrates that adjacent nutrient-rich environments, such as palustrine forests and estuaries, are nutritionally enriched in several dimensions from nearby autochthonous subsidies that are maintained throughout the year.


Extended loneliness. When hyperconnectivity makes us feel alone.
In this paper, I analyse a specific kind of loneliness that can be experienced in the networked life, namely "extended loneliness". I claim that loneliness-conceived of as stemming from a lack of satisfying relationships to others-can arise from an abundance of connections in the online sphere. Extended loneliness, in these cases, does not result from a lack of connections to other people. On the contrary, it consists in the complex affective experience of both lacking and longing for meaningful relationships while being connected to many people online. The recursive interaction with a digital assistant in a smart flat is my key example for defining the contours of this specific kind of loneliness that emerges when hyperconnectivity becomes pervasive in the user's daily-life. Drawing on Sherry Turkle's work and employing the conceptual framework of the extended mind, I analyse the specific characteristics of extended loneliness and explore its phenomenology.


Accuracy and reproducibility of tablet-based applications for three-dimensional facial scanning: an in-vitro study.
An in-vitro study was performed to investigate the overall and regional accuracy and precision of digital three-dimensional facial scans obtained from four tablet-based applications (Bellus Dental Pro, Capture: 3D scan anything, Heges, and Scandy Pro 3D scanner) on an iPad Pro® (Apple Store, Cupertino, CA, USA), equipped with LiDAR and TrueDepth technology, compared to the validated manual measurements using a digital vernier caliper (DVC). The accuracy of the various applications was determined through multiple scans of a three-dimensional (3D) printed mannequin face using iPad Pro®. For precision evaluation, the mannequin's face was scanned five times with each application, and these models were compared using the coefficient of variation (CV). The descriptive statistics were done from SPSS version 23 (IBM Company, Chicago, USA). One-sample t-test was used to analyze the difference between the control and the various scans. While the applications Capture, Heges, and Scandy tended to overestimate the measured values compared to DVC, the Bellus application underestimated these values. Scandy showed the highest mean difference in the Go - Ch (R) measurement, with a value of 2.19 mm. All the others average differences were less than 1.60mm. The assessment of precision showed that the coefficient of variation ranged from 0.16% and 6.34%. The iPad Pro® (2020) showed good precision and reasonable reliability, and it appears to be an interesting and favorable technology for the acquisition of surface images of facial-like structures. Moreover, further clinical investigations should be conducted.


Cloning and in vitro expression of the cDNA encoding a putative nucleoside transporter from Arabidopsis thaliana.
Nucleoside transporters are integral membrane proteins involved in the uptake or release of nucleosides. Their function constitutes an essential step of the salvage pathway of nucleotide synthesis. In order to study the function of these proteins in higher plants, we cloned the cDNA corresponding to the AtENT1 gene that encodes a putative nucleoside transporter in Arabidopsis thaliana by RT-PCR. The amino acid sequence of the AtENT1 protein deduced from the cloned cDNA shared similarity to those of eukaryotic equilibrative nucleoside transporters. Structure prediction indicated that the deduced AtENT1 protein might possess eleven putative transmembrane domains. Southern hybridization revealed that AtENT1 had one homologue in the Arabidopsis genome. Northern blot analysis showed that AtENT1 might be constitutively expressed in most Arabidopsis organs and in plants at different developmental stages. Two AtENT1 fusion genes, AtENT1-His-tag and GFP-AtENT1-His-tag, were expressed in insect cells. Confocal microscopy demonstrated that the GFP-AtENT1-His-tag fusion protein was targeted specifically to the plasma membrane of insect cells.


Management of the parotid for high-risk cutaneous squamous cell carcinoma: A review from the salivary section of the American Head and Neck Society.
Metastases to the parotid nodal basin in patients with high-risk cutaneous squamous cell carcinoma (HRcSCC) impact disease specific survival (DSS) and overall survival (OS). A writing group convened by the Salivary Section of the American Head and Neck Society (AHNS) developed contemporary, evidence-based recommendations regarding management of the parotid nodal basin in HRcSCC based on available literature, expert consultation, and collective experience. The statements and recommendations were then submitted and approved by the AHNS Salivary Committee. These recommendations were developed given the wide variation of practitioners who treat HRcSCC in order to streamline management of the parotid nodal basin including indications for imaging, surgery, radiation, and systemic treatment options as well. This clinical update represents contemporary optimal management of the parotid nodal basin in HRcSCC and is endorsed by the Salivary Section of the AHNS.


Knee extension rate of velocity development affects walking performance differently in men and women.
Acceleration capacity affects physical function, but whether it differentially affects men versus women or weak versus strong individuals is less known. We investigated whether knee extension rate of velocity development (RVD, a measure of acceleration) is associated with walking performance independent of peak torque and whether the relationships differ in men versus women and in weak versus strong individuals. Relationships of RVD with walking performance were assessed in 326 women and 365 men aged 26-96 years enrolled in the Baltimore Longitudinal Study of Aging. Tests included knee extension peak torque and RVD assessed during a 180°·s-1 isokinetic strength test and four walking performance measures (usual-paced and fast-paced 6 m walks and 2.5 min usual-paced and 400 m fast-paced walks). Sex-stratified linear regression models were adjusted for age, race, height, appendicular lean mass, fat mass, peak torque, knee pain, and RVD*peak torque interaction. In men, RVD was not independently associated with any walking performance measure (p > 0.05), and, for the 6 m-usual walk only, there was a significant RVD*peak torque interaction (p < 0.0001). In women, RVD was independently associated with usual-paced walks (p < 0.05) and there were significant RVD ∗ peak torque interactions for all measures. Strength-specific analyses indicated that RVD was most associated with performance among weaker individuals. RVD is associated with walking performance in women, but less in men, and is most related to performance when strength is low. Strategies to accomplish motor tasks may be sex-specific. Future studies are needed to understand the mechanisms underlying such sex differences.


Haematological predictors of poor outcome among COVID-19 patients admitted to an intensive care unit of a tertiary hospital in South Africa.
Studies from Asia, Europe and the USA indicate that widely available haematological parameters could be used to determine the clinical severity of Coronavirus disease 2019 (COVID-19) and predict management outcome. There is limited data from Africa on their usefulness in patients admitted to Intensive Care Units (ICUs). We performed an evaluation of baseline haematological parameters as prognostic biomarkers in ICU COVID-19 patients. Demographic, clinical and laboratory data were collected prospectively on patients with confirmed COVID-19, admitted to the adult ICU in a tertiary hospital in Cape Town, South Africa, between March 2020 and February 2021. Robust Poisson regression methods and receiver operating characteristic (ROC) curves were used to explore the association of haematological parameters with COVID-19 severity and mortality. A total of 490 patients (median age 54.1 years) were included, of whom 237 (48%) were female. The median duration of ICU stay was 6 days and 309/490 (63%) patients died. Raised neutrophil count and neutrophil/lymphocyte ratio (NLR) were associated with worse outcome. Independent risk factors associated with mortality were age (ARR 1.01, 95%CI 1.0-1.02; p = 0.002); female sex (ARR 1.23, 95%CI 1.05-1.42; p = 0.008) and D-dimer levels (ARR 1.01, 95%CI 1.002-1.03; p = 0.016). Our study showed that raised neutrophil count, NLR and D-dimer at the time of ICU admission were associated with higher mortality. Contrary to what has previously been reported, our study revealed females admitted to the ICU had a higher risk of mortality.


Effect of envelope material on biosecurity during emergency bovine mortality composting.
The biosecurity of composting as an emergency disposal method for cattle mortalities caused by disease was evaluated by conducting full-scale field trials begun during three different seasons and using three different envelope materials. Process biosecurity was significantly affected by the envelope material used to construct the composting matrix. Internal temperatures met USEPA Class A time/temperature criteria for pathogen reduction in 89%, 67%, and 22%, respectively of seasonal test units constructed with corn silage, straw/manure, or ground cornstalks. In trials begun in the winter, survival times of vaccine strains of avian encephalomyelitis and Newcastle disease virus were noticeably shorter in silage test units than in the other two materials, but during summer/spring trials survival times in ground cornstalk and straw/manure test units were similar to those in test units constructed with silage.


Protective effects of quercetin against hydrogen peroxide-induced apoptosis in human neuronal SH-SY5Y cells.
Hydrogen peroxide (H(2)O(2)) is a major reactive oxygen species that has been implicated in various neurodegenerative diseases. Quercetin, one of the plant flavonoids, has been reported to harbor various physiological properties including antioxidant activity. In this study, we investigated the neuroprotective effects of quercetin against H(2)O(2)-induced apoptosis in human neuronal SH-SY5Y cells. H(2)O(2)-mediated cytotoxicity and lactate dehydrogenase release were suppressed in a quercetin concentration-dependent manner. In addition, quercetin repressed the expression of the pro-apoptotic Bax gene and enhanced that of the anti-apoptotic Bcl-2 gene in SH-SY5Y cells. Moreover, quercetin effectively inhibited the activation of the caspase cascade that leads to DNA fragmentation, a key feature of apoptosis, and subsequent cell death. These results indicate the importance of quercetin in protecting against H(2)O(2)-mediated neuronal cell death. Thus, quercetin might potentially serve as an agent for prevention of neurodegenerative diseases caused by oxidative stress and apoptosis.


Minimalist model for force-dependent DNA replication.
In experiments using optical or magnetic tweezers, investigators have monitored the rate at which polymerase enzymes catalyze DNA replication when the template strand is subjected to a stretching force. For T7, Klenow, and Sequenase polymerases, the replication rate increases modestly at low tension and then decreases markedly at higher tension. Molecular-dynamics (MD) simulations using x-ray structure data for the open and closed complexes of the Taq enzyme with DNA revealed that the dependence of replication rate on tension could be accounted for in terms of the induced enthalpy changes for the two DNA segments adjacent to the site of the added nucleotide. Here, we present a simple, minimalist two-segment local model (M2L) derived from some striking features seen in the MD simulations. The model predicts the tension dependence of the replication rate using only structural data and a critical tension, f(∗), without recourse to MD simulations. At f(∗), the outermost DNA segment undergoes a large angular reorientation in the open conformation of the enzyme. We give a generic plot for the M2L model, apply it to family A and B polymerases and HIV reverse transcriptase, and discuss factors that may govern the f(∗) flip parameter.


The owner's perspective.
Carole Sweeney attributed her pet cat's weight gain to his advancing age. But a trip to her local veterinary practice revealed complicated underlying causes - and gave her techniques to address them.


Ulcerative colitis in a Nigerian girl: a case report.
Ulcerative colitis (UC) is uncommon in the tropics and sub-tropics. We report a case of UC in a 7 year old girl whose parents were both Nigerians. This report is to alert healthcare professionals in sub-Saharan Africa that UC is not a rare health problem, especially in children. The patient presented with frequent passage of blood stained stool, abdominal pain and significant weight loss. The diagnosis was entertained after she was investigated for common causes of chronic diarrhea in our setting and the findings were negative. The patient symptoms abated after she was commenced on steroid therapy. Under-diagnosis and misdiagnosis may account for a dearth of information on UC in African children.


EGFR inhibition in NSCLC: New findings…. and opened questions?
The targeted inhibition of epidermal growth factor receptor (EGFR) has represented a milestone in the treatment of lung cancer. Several studies convincingly and consistently demonstrated a significant superiority of EGFR-TKIs over standard platinum-chemotherapy in EGFR-mutated NSCLC patients, leading to the sequential approval of gefitinib, erlotinib and afatinib as new standard first-line clinical treatment. To date we are witnessing a second revolution in the management of EGFR-positive NSCLC thanks to the development of new treatment strategies aiming to overcome acquired resistance to TKIs and ultimately improve patients' outcomes. In this review we summarize the most important recent findings regarding EGFR-inhibition in NSCLC, highlighting the current unsolved questions on the selection of the best TKI in first-line, which therapy can be combined with upfront EGFR-TKIs, how to overcome acquired resistance, and which are the clinical applications of liquid biopsy.


Prognostic Significance of Tumor-infiltrating Lymphocytes on Survival Outcomes of Patients With Resected Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-Analysis.
Tumor-infiltrating lymphocytes (TILs) play an important role in mediating treatment response in pancreatic cancer. This meta-analysis investigated the prognostic significance of TIL subsets on overall survival (OS) and disease-free survival (DFS) of patients with pancreatic cancer. Studies were gathered via search of PubMed, Google Scholar, and Cochrane Library databases up to August 1, 2019. Using Review Manager version 5.3.5, pooled hazard ratios and 95% confidence intervals (CIs) were calculated using random or fixed-effects models, depending on the heterogeneity of studies. A total of 11 studies comprising 1760 patients were included in the meta-analysis. Pooled analysis revealed that high CD8 TILs were associated with improved OS [hazard ratio (HR)=0.59, 95% CI=0.51-0.69, P<0.00001] and DFS (HR=0.60, 95% CI=0.50-0.73, P<0.00001). Similarly, high CD3 TILs correlated with better OS (HR=0.64, 95% CI=0.54-0.75, P<0.00001) and DFS (HR=0.53, 95% CI=0.31-0.92, P<0.0001). In contrast, high FoxP3 TILs were associated with worse OS (HR=1.39, 95% CI=1.03-1.88, P=0.03). Finally, high CD4 TILs showed significant improvement in OS (HR=0.74, 95% CI=0.63-0.86, P=0.0001). TILs are a promising prognostic biomarker in pancreatic cancer. Prospective studies evaluating TILs are recommended as well as the establishment of standards in the assessment of TILs.


Defining the educational needs of recent dental graduates preparing for the Membership of the Faculty of Dental Surgery examination.
On graduation, UK dentists wishing to advance their career enter two years of general professional training aimed at consolidating their undergraduate experience. The Membership of the Faculty of Dental Surgery examination (MFDS) attests to its successful completion and is a pre-requisite for entry into training programmes which lead to specialist status. Most MFDS candidates prepare for the examination on their own while in full-time employment and many reinforce this self-directed learning with participation in short revision courses or through distance learning. Here we seek to obtain data on the specific educational needs of these individuals. Questionnaires were used to interrogate 92 UK graduates attending short MFDS revision courses of up to 1 week's duration to identify which topic areas were perceived as particular areas of weakness. To gain greater insight into the responses obtained, 18/92 respondents were selected at random and followed up with semi-structured interviews informed by the questionnaires. Basic medical science, human diseases, law and ethics and health and safety regulations were the areas of weakness most frequently highlighted by the respondents. Most had undergone comprehensive courses in the first two topics; however, the interviews suggested that this was generally in the early stages of undergraduate training when they had difficulty in contextualising large quantities of new information. In the case of the latter two, teaching had been very varied and several interviewees felt that it had been inadequate. Recent graduates preparing for MFDS have clear educational needs. These data have begun to characterise the requirements of this group and may inform the planning of short revision courses designed to assist them.


The role of Irf6 in tooth epithelial invagination.
Thickening and the subsequent invagination of the epithelium are an important initial step in ectodermal organ development. Ikkα has been shown to play a critical role in controlling epithelial growth, since Ikkα mutant mice show protrusions (evaginations) of incisor tooth, whisker and hair follicle epithelium rather than invagination. We show here that mutation of the Interferon regulatory factor (Irf) family, Irf6 also results in evagination of incisor epithelium. In common with Ikkα mutants, Irf6 mutant evagination occurs in a NF-κB-independent manner and shows the same molecular changes as those in Ikkα mutants. Irf6 thus also plays a critical role in regulating epithelial invagination. In addition, we also found that canonical Wnt signaling is upregulated in evaginated incisor epithelium of both Ikkα and Irf6 mutant embryos.


SENP3 regulates high glucose-induced endothelial dysfunction via ROS dependent signaling.
The current study aimed to explore the role of SENP3 in endothelial cell dysfunction in a high-glucose setting. The gene and protein expressions of SENP3 in high-glucose cultured HAECs were examined using quantitative PCR and western blotting. The effects of SENP3 on HAEC viability, apoptosis, migration, and endothelial-monocyte adhesion were evaluated in vitro by knockdown. Moreover, a mouse streptozotocin-induced type I diabetes model was established for SENP3 expression assessment. In addition, the effects of SENP3 on ROS-related signaling pathways were investigated in high-glucose cultured HAECs. Significantly increased levels of SENP3 mRNA and protein were found in high-glucose cultured HAECs in a time-dependent manner. SENP3 knockdown reversed high glucose-induced HAEC viability, apoptosis, and migration reduction. SENP3 knockdown attenuated the high glucose-induced intercellular adhesion of THP-1 monocytic cells and HAECs via downregulation of ICAM-1 and VCAM-1 expression. Increased levels of SENP3, ICAM-1, and VCAM-1 expression were observed in the aorta tissue of mice with type I diabetes. Downregulation of SENP3 expression was observed in HAECs cultured with high glucose levels using the free radical scavenger N-acetyl-L-cysteine or NOX4 siRNA. SENP3 was involved in high glucose-induced endothelial dysfunction, and ROS-dependent signaling served as the mechanism.


The expression of Death Inducer-Obliterator (DIDO) variants in Myeloproliferative Neoplasms.
Chronic Myeloid Leukemia (CML), Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF) are Myeloproliferative Neoplasms (MPN) characterized by clonal myeloproliferation without cell maturation impairment. CML pathogenesis is associated with the Ph chromosome leading to BCR-ABL tyrosine-kinase constitutive expression. The Ph negative MPN (PV, ET and PMF) are characterized by the mutation JAK2(V617F) of the JAK2 protein in the auto-inhibitory JH2 domain, which is found in most PV patients and in approximately half of ET and PMF patients. Considerable effort is being made to understand the role of JAK2(V617F) at the MPN initiation and to clarify the pathogenesis and apoptosis resistance in CML, PV, ET and PMF patients. In the present investigation, we evaluated the Death Inducer-Obliterator (DIDO) (variants DIDO 1, 2 and 3) levels in CML, PV, ET and PMF patients. Our data reported the DIDO 1, 2 and 3 differential expressions in Myeloproliferative Neoplasms.


Expanded high-resolution genetic study of 109 Swedish families with Alzheimer's disease.
Alzheimer's disease (AD) is a neurodegenerative disease that affects approximately 20 million persons all over the world. There are both sporadic and familial forms of AD. We have previously reported a genome-wide linkage analysis on 71 Swedish AD families using 365 genotyped microsatellite markers. In this study, we increased the number of individuals included in the original 71 analysed families besides adding 38 new families. These 109 families were genotyped for 1100 novel microsatellite markers. The present study reports on the linkage data generated from the non-overlapping genotypes from the first genome scan and the genotypes of the present scan, which results in a total of 1289 successfully genotyped markers at an average density of 2.85 cM on 468 individuals from 109 AD families. Non-parametric linkage analysis yielded a significant multipoint LOD score in chromosome 19q13, the region harbouring the major susceptibility gene APOE, both for the whole set of families (LOD=5.0) and the APOE varepsilon4-positive subgroup made up of 63 families (LOD=5.3). Other suggestive linkage peaks that were observed in the original genome scan of 71 Swedish AD families were not detected in this extended analysis, and the previously reported linkage signals in chromosomes 9, 10 and 12 were not replicated.


Biodegradable stents with elastic memory.
This work reports, for the first time, the development of a fully biodegradable polymeric stent that can self-expand at body temperatures (approximately 37 degrees C), using the concept of elastic memory. This self-expansion is necessary in fully polymeric stents, to overcome the problem of elastic recoil following balloon expansion in a body vessel. Bi-layered biodegradable stent prototypes were produced from poly-L-lactic acid (PLLA) and poly glycolic acid (PLGA) polymers. Elastic memory was imparted to the stents by temperature conditioning. The thickness and composition of each layer in the stents are critical parameters that affect the rate of self-expansion at 37 degrees C, as well as the collapse strengths of the stents. The rate of self-expansion of the stents, as measured at 37 degrees C, exhibits a maximum with layer thickness. The Tg of the outer layer is another significant parameter that affects the overall rate of expansion.


Formation of directly mutagenic alpha-hydroxy-N-nitrosopiperidine phosphate ester by near-ultraviolet irradiation of N-nitrosopiperidine in phosphate buffer.
Previously we found that direct-acting mutagens can be formed from N-nitrosodialkylamines on exposure to near-ultraviolet light in the presence of phosphates. We have now isolated the mutagenic photoproduct formed from N-nitrosopiperidine and inorganic phosphate and identified its structure as the phosphate ester of alpha-hydroxy-N-nitrosopiperidine. This reaction represents a new, non-enzymatic activation of promutagenic N-nitrosodialkylamines.


Toxoplasmosis diagnostic techniques: Current developed methods and biosensors.
Toxoplasma gondii infection is a usual worldwide issue since a broad range of vertebrate hosts are infected by this famous parasite. However fetuses and immuno-compromised patients infected by parasite is of specific concern. Developing the easy-to-use, accurate, real time and selective methods for detection of toxoplasma infection has a key role in the treatment and management of patients. In this regard, rapid detection methods with reproducible outcomes during short period are highly interested. In this review, we discussed the recent developed molecular-based laboratory methods for detecting of Toxoplasma infection and also rapid diagnostic methods, especially optic and electrochemical based biosensors with point-of-care features.


Obstructed voiding in the female.
Bladder outlet obstruction in women is rare. The characteristics and aetiology of the condition in 163 females are discussed and their relation to treatment evaluated.


Prevention of transmission of Borrelia burgdorferi sensu lato and Anaplasma phagocytophilum by Ixodes spp. ticks to dogs treated with the Seresto® collar (imidacloprid 10% + flumethrin 4.5%).
The capability of imidacloprid 10% + flumethrin 4.5% (Seresto®) collars to prevent transmission of Borrelia burgdorferi sensu lato (Bbsl) and Anaplasma phagocytophilum (Ap) by naturally infected ticks was evaluated in two studies with 44 dogs. In each study, one group served as non-treated control, whereas the other groups were treated with the Seresto® collar. All dogs were exposed to naturally Bbsl- and Ap-infected hard ticks (Ixodes ricinus, Ixodes scapularis). In study 1, tick infestation was performed on study day (SD) 63 (2 months post-treatment [p.t.]); in study 2, it was performed on SD 32 (one month p.t.) respectively SD 219 (seven months p.t.). In situ tick counts were performed 2 days after infestation. Tick counts and removals followed 6 (study 1) or 5 days (study 2) later. Blood sampling was performed for the detection of specific Bbsl and Ap antibodies and, in study 1, for the documentation of Ap DNA by PCR. Skin biopsies were examined for Bbsl by PCR and culture (only study 1). The efficacy against Ixodes spp. was 100% at all time points. In study 1, two of six non-treated dogs became infected with Bbsl, and four of six tested positive for Ap; none of the treated dogs tested positive for Bbsl or Ap. In study 2, ten of ten non-treated dogs became infected with Bbsl and Ap; none of the treated dogs tested positive for Bbsl or Ap; 100% acaricidal efficacy was shown in both studies. Transmission of Bbsl and Ap was successfully blocked for up to 7 months.


Integrated Risk Assessment for WFD Ecological Status classification applied to Llobregat river basin (Spain). Part II - Evaluation process applied to five environmental Lines of Evidence.
Many indicators and indices related to a variety of biological, physico-chemical, chemical, and hydromorphological water conditions have been recently developed or adapted by scientists in order to support water managers in the Water Framework Directive (WFD) implementation. In this context, the achievement of a comprehensive and reliable Ecological Status classification of water bodies across Europe is hampered by the lack of harmonised procedures for selecting an appropriate set of indicators and integrating heterogeneous information in a flexible way. To this purpose, an Integrated Risk Assessment (IRA)(2) methodology was developed based on the Weight of Evidence approach. This method analyses and combines a set of environmental indicators grouped into five Lines of Evidence (LoE), i.e. Biology, Chemistry, Ecotoxicology, Physico-chemistry and Hydromorphology. The whole IRA methodology has been implemented as a specific module into a freeware GIS (Geographic Information System)-based Decision Support System, named MODELKEY DSS. This paper focuses on the evaluation of the four supporting LoE (i.e. Chemistry, Ecotoxicology, Physico-chemistry and Hydromorphology), and includes a procedure for a comparison of each indicator with proper thresholds and a subsequent integration process to combine the obtained output with the LoE Biology results in order to provide a single score expressing the Ecological Status classification. The approach supports the identification of the most prominent stressors, which are responsible for the observed alterations in the river basin under investigation. The results provided by the preliminary testing of the IRA methodology through application of the MODELKEY DSS to the Llobregat case study are finally reported and discussed.


The effects of a single bout of moderate-intensity aerobic exercise on visuomotor adaptation and its savings.
Performing exercise before or after motor skill learning is thought to have a positive impact on acquisition and retention of motor memories stored in our nervous system. It has been shown that performing 25 min of moderate-intensity aerobic exercise prior to visuomotor adaptation can enhance both visuomotor adaptation and its retention compared to 25 min of rest before the adaptation. To determine whether a single bout of aerobic exercise could actually facilitate the formation of a neural representation associated with a novel visuomotor condition, we examined aftereffects and savings associated with a visuomotor adaptation task following either an exercise or a rest condition. Sixteen healthy young individuals (18-35 years) first experienced 25 min of moderate-intensity cycling or rest, and then adapted to a 30-degree visuomotor rotation condition. Immediately following that, participants experienced a washout session, which was followed by a readaptation session. Results indicated that all subjects adapted to the visuomotor rotation completely, although no difference was found between the cycling and rest conditions. Aftereffects and savings were also observed in both conditions, but with no difference between the conditions. These findings suggest that compared to a short rest session, a single bout of moderate-intensity cycling may not have a greater impact for enhancing visuomotor adaptation and its retention. Further research is needed, in which the effects of certain factors such as exercise intensity, duration and timing are more systematically investigated.


Fatigue and health-related quality of life among patients with chronic obstructive pulmonary disease in China.
Fatigue is an important yet ignored symptom of chronic obstructive pulmonary disease (COPD). However, there is a paucity of literature from China on fatigue and its association with health-related quality of life (HRQoL) among COPD patients. The purpose of this study was to (a) evaluate fatigue of COPD inpatients in China and (b) explore the association between fatigue and HRQoL. This cross-sectional study recruited patients hospitalised for an acute exacerbation of COPD within one month from three general hospitals in central China. Disease severity, fatigue and HRQoL were assessed for all participants using COPD Assessment Test (CAT), 9-item Functional Assessment of Chronic Illness Therapy-Fatigue scale (FACIT-F) and 12-Item Short-Form Health Survey (SF-12v2). A total of 210 COPD patients participated in the study between April 2017 and January 2018, with an average age of 71.1 ± 12.2 years old. The overall prevalence of moderate to severe fatigue was 48.5%. A worse FACIT-F score was associated with worse CAT score (r = -0.74, P < 0.01; B = -0.70, P < 0.01) and worse SF-12v2 score (r = 0.77, P < 0.01; B = 0.66, P < 0.01). Almost half of the COPD patients experience moderate to severe fatigue. Patients with greater disease severity exhibited more severe fatigue and worse HRQoL. Fatigue symptom has a strongly negative effect on COPD patients' HRQoL, physical health and mental health. Health personnel is recommended to provide fatigue-related screening, counselling and health education, particularly for patients with moderate to severe COPD.


The effect of exercise on resting concentrations of peripheral brain-derived neurotrophic factor (BDNF) in major depressive disorder: A meta-analysis.
Exercise interventions have been shown to successfully improve depression in patients with major depressive disorder (MDD), but like other forms of antidepressant treatment, exercise is not effective in all patients and its mechanisms of action have not been fully elucidated. Brain-derived neurotrophic factor (BDNF), a key mediator of neurogenesis and neuronal survival, has been shown to be decreased in individuals with MDD. One potential mechanism by which exercise alleviates depression is through an increase in BDNF. In order to evaluate this hypothesis, we conducted a meta-analysis of studies that assessed the effects of a chronic (multi-week) exercise intervention on BDNF concentrations in MDD patients. MEDLINE, Embase, PsycINFO, SPORTDiscus, Rehabilitation & Sports Medicine Source, and CINAHL databases were searched for original, peer-reviewed reports of peripheral blood BDNF concentrations before and after a chronic exercise intervention in MDD patients. Standardized mean differences (SMDs) were generated from random effects models. Potential sources of heterogeneity were explored in meta-regression analyses. In six studies that met inclusion criteria, resting blood concentrations of BDNF were not significantly higher after a chronic exercise intervention (SMD = 0.43, 95% CI: -0.06-0.92, p = 0.09) in MDD patients. This meta-analysis did not find evidence that a chronic aerobic exercise intervention increases resting concentrations of BDNF in the blood of MDD patients; however, there is a lack of studies in this area making it difficult to reach a definitive conclusion. Future studies on this topic with larger sample sizes and longer durations are needed to draw more robust conclusions.


Continuous Monitoring of Essential Tremor: Standards and Challenges.
The value of continuous symptom monitoring in people with essential tremor is uncertain. To determine the relationship between tremor amplitude measured with wearable inertial sensors and clinician- and patient-rated measures. For 14 days, patients (1) wore inertial sensors on both wrists, (2) self-rated their tremor using a diary, (3) drew spirals, and (4) completed an activities of daily living scale once daily. Patients were also scored using The Essential Tremor Rating Scale (TETRAS) performance in the clinic by a clinician. We found strong correlations in patient-reported metrics of tremor, but weak correlations between these data and both the inertial sensor data and the in-clinic TETRAS scores. The patient experience of tremor during normal daily activities may differ from the transducer-based measures of tremor amplitude and rating scales of tremor severity. Future studies should consider how to record features of tremor that are important to patients.


Double immunocytochemical staining in the study of antibody-producing cells in vivo. Simultaneous detection of anti-hapten and anti-carrier antibody-producing cells in lymphoid tissue.
Mice were injected intravenously with 2 mg of a bovine gamma globulin-penicilloyl (BGG-Pen) conjugate. Cells producing specific antibodies against the protein carrier bovine gamma globulin (BGG) and cells producing specific antibodies against the hapten penicilloyl (Pen) could be distinguished simultaneously in the same spleen section using a combined peroxidase (HRP) and alkaline phosphatase (AP) immunocytochemical technique. AP-BGG conjugate was used for detection of anti-BGG-producing cells and HRP-human serum albumin (HSA)-Pen conjugate, prepared by coupling penicillin to HRP-HSA conjugate, was used for detection of anti-Pen-producing cells in the same spleen section. After performing both HRP and AP cytochemistry, cells with a blue-stained cytoplasm represent anti-BGG-producing cells and cells with a red-stained cytoplasm represent anti-Pen-producing cells.


The operative management of the difficult supracondylar fracture of the humerus in the child.
A series of supracondylar fractures of the humerus in children is presented. The majority was reduced by closed manipulation. The difficult fractures were defined as those in which adequate reduction either could not be achieved by manipulation or was not maintained, or those in which neurological or vascular complications occurred. Such cases were treated by open reduction and internal fixation. The results were assessed with regard to loss of elbow movement, deformity and symptoms. The results of the operative series were comparable with those achieved by closed manipulation in the easier cases. No secondary corrective procedures were necessary. It is concluded that closed manipulation should be used routinely as the method of treatment for supracondylar fractures of the humerus in children, except in the difficult case, for which operative treatment should be undertaken. Stiffness or deformity does not follow open reduction and internal fixation.


Isovolaemic hemodilution with gelatin and hydroxyethylstarch 130/0.42: effects on hemostasis in piglets.
Artificial colloids, frequently used to prevent hemorrhagic shock in children, impair blood coagulation. To determine the impact of acute isovolaemic hemodilution with artificial colloids on clot formation, we conducted an experimental study in a pediatric animal model. Fifteen piglets underwent hemorrhage by withdrawing 40 ml·kg(-1) of blood volume in steps of 10 ml·kg(-1) each within 1 hour. After each withdrawal, the blood loss was randomly compensated by administering 4% gelatin (GEL) or hydroxylethyl starch 130/0.42 (HES) in a ratio of 1 : 1, or isotonic crystalloid solution (ICS) in a ratio of 1 : 4 for isovolaemic hemodilution. Quality of clot formation and platelet function was measured using Thrombelastometry (ROTEM(®)) and Multiple electrode impedance aggregometry (Multiplate(®)) after 10, 20, and 40 ml·kg(-1) blood replacement. Moderate hemodilution (10-20 ml·kg(-1) blood replacement) caused no significant differences among groups (e.g. INTEM(®)-MCF after 20 ml·kg(-1) blood replacement (ICS vs GEL vs HES, P > 0.05). Profound hemodilution with 40 ml·kg(-1) blood replacement showed a significant difference between ICS and both colloids (P < 0.05), but no significant differences between GEL and HES. Impairment of clot formation by moderate isovolaemic hemodilution did not significantly differ between ICS, GEL, and HES. Profound hemodilution of more than 50% of the estimated blood volume with GEL and HES caused significant impairment of clot formation in comparison to ICS and has to be considered when using high amounts of these synthetic colloids.


Cognitive disorders in pediatric epilepsy.
Childhood epilepsy may cause cognitive disorders and the intellectual quotient is indeed not normally distributed in epileptic children, a fair proportion of whom show an IQ in the deficient range. Some epileptic syndromes happen during vulnerability periods of brain maturation and interfere with the development of specific cognitive functions. This is the case for the Landau-Kleffner syndrome, which generally appears during speech development and affects language. Similarly, West syndrome - or infantile spasms - is an epileptogenic encephalopathy appearing during the first years of life and induces a major delay in social and oculo-motor development. Specific impairments can also be identified in partial childhood epilepsies in relation with seizure focus localization. For instance, left temporal and frontal epilepsies are frequently associated with verbal impairments. Moreover, episodic memory disorders have been described in children suffering from temporal lobe epilepsy whereas executive deficits (planning, self-control, problem solving) have been reported in frontal lobe epilepsy. In most cases, including its mildest forms, childhood epilepsy induces attention deficits, which may affect academic achievement. These observations militate in favor of individual neuropsychological assessments as well as early interventions in order to provide the child with an optimal individualized treatment program.


LOX-1 deficiency increases ruptured abdominal aortic aneurysm via thinning of adventitial collagen.
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a key mediator of inflammation and plays an important role in the pathogenesis of atherosclerosis. Conversely, LOX-1 deficiency has been shown to decrease inflammation and atherosclerosis, both of which have been proposed to contribute to abdominal aortic aneurysm (AAA) pathogenesis. However, the role of LOX-1 in AAA pathogenesis remains unknown. Here, we investigated the effects of Olr1 (which encodes LOX-1) deletion on angiotensin II (Ang II)-induced AAA in apolipoprotein E knockout (ApoE KO) mice to determine whether LOX-1 deficiency mitigates AAA development. To accomplish this, we used serial, non-invasive ultrasound assessment, which revealed that the incidence and expansion rate of AAA were similar regardless of Olr1 deletion. However, Olr1 deletion significantly increased severe AAAs, including ruptured AAAs resulting in death. Oil Red O staining of the harvested aortas showed that the extent of atheroma burden localized in aneurysmal lesions did not differ between LOX-1-deficient and control mice, suggesting that Olr1 deletion did not decrease atheroma burden in the aneurysmal wall. Further histopathological analysis revealed that aneurysmal lesions in LOX-1-deficient mice had fewer fibroblasts and myofibroblasts, as well as thinner adventitial collagen, although the degree of elastin fragmentation or disruption was similar between LOX-1-deficient and control mice. An in vitro study confirmed that the proliferation of adventitial fibroblasts collected from LOX-1-deficient mice was significantly attenuated despite Ang II stimulation. In conclusion, Olr1 deletion may not mitigate aneurysm development but rather increases the vulnerability of rupture by suppressing adventitial fibroblast proliferation and collagen synthesis.


Advancements of in vitro transcribed mRNA (IVT mRNA) to enable translation into the clinics.
The accelerated progress and approval of two mRNA-based vaccines to address the SARS-CoV-2 virus were unprecedented. This record-setting feat was made possible through the solid foundation of research on in vitro transcribed mRNA (IVT mRNA) which could be utilized as a therapeutic modality. Through decades of thorough research to overcome barriers to implementation, mRNA-based vaccines or therapeutics offer many advantages to rapidly address a broad range of applications including infectious diseases, cancers, and gene editing. Here, we describe the advances that have supported the adoption of IVT mRNA in the clinics, including optimization of the IVT mRNA structural components, synthesis, and lastly concluding with different classes of IVT RNA. Continuing interest in driving IVT mRNA technology will enable a safer and more efficacious therapeutic modality to address emerging and existing diseases.


Evaluation of the effect of sildenafil and vascular endothelium growth factor combination treatment on skin flap survival in rats.
Distal ischemic necrosis of surgical flaps remains a challenging problem for the reconstructive surgeon. Recent studies have shown that either sildenafil or vascular endothelium growth factor (VEGF) treatment significantly improves ischemic skin flap viability. In this study, the effect of the combination of sildenafil and VEGF165 was evaluated on a rat skin flap model using orthogonal polarization spectral imaging and histologic analysis. Rats were assigned to either a sham (n = 31), vehicle (n = 24), sildenafil (n = 24), VEGF (n = 23), or sildenafil and VEGF combination treatment (n = 21) groups. Distances from the distal end of the flap to avascular, stasis, and normal capillary blood flow zones were determined using orthogonal polarization spectral imaging on a skin flap model. Vessel density assessment was done at 7 days post surgery. Imaging analysis showed significant reduction in avascular and stasis areas in sildenafil and VEGF combination-treated groups at 7 days post surgery (p < 0.05). The combination-treated group, however, was not significantly different when compared to the group treated with sildenafil only. The sildenafil-treated group showed a significant (p < 0.05) reduction in both areas at day 7 compared to the VEGF and control groups. Histologic analysis showed no significant differences in vessel density between the groups. The combination of sildenafil and VEGF decreases the extent of avascular and stasis zones in skin flaps. The skin flap improvement seen with the combination treatment was similar to the sildenafil treatment alone suggesting that enhanced flap survival was due solely to the effect of sildenafil.


TOPK promotes the growth of esophageal cancer in vitro and in vivo by enhancing YB1/eEF1A1 signal pathway.
T-LAK-originated protein kinase (TOPK), a dual specificity serine/threonine kinase, is up-regulated and related to poor prognosis in many types of cancers. Y-box binding protein 1 (YB1) is a DNA/RNA binding protein and serves important roles in multiple cellular processes. Here, we reported that TOPK and YB1 were both highly expressed in esophageal cancer (EC) and correlated with poor prognosis. TOPK knockout effectively suppressed EC cell proliferation and these effects were reversible by rescuing YB1 expression. Notably, TOPK phosphorylated YB1 at Thr 89 (T89) and Ser 209 (S209) amino acid residues, then the phosphorylated YB1 bound with the promoter of the eukaryotic translation elongation factor 1 alpha 1 (eEF1A1) to activate its transcription. Consequently, the AKT/mTOR signal pathway was activated by up-regulated eEF1A1 protein. Importantly, TOPK inhibitor HI-TOPK-032 suppressed the EC cell proliferation and tumor growth by TOPK/YB1/eEF1A1 signal pathway in vitro and in vivo. Taken together, our study reveals that TOPK and YB1 are essential for the growth of EC, and TOPK inhibitors may be applied to retard cell proliferation in EC. This study highlights the promising therapeutic potential of TOPK as a target for treatment of EC.


Tests with a new compound (Praziquantel) against Diphyllobothrium latum.
Praziquantel (Droncit) is a new anthelminthic agent with a strikingly wide therapeutic index. The efficiency of the drug against Diphyllobothrium latum was tested in vivo and in vitro. With a drug dose of 50 mg/kg, artificially infected hamsters were completely cured. The threshold value of the active dose was between 2-5 and 10-0 mg/kg. Clinical trials with Praziquantel against human diphyllobothriasis show great promise, all of ten patients treated with 25-0 mg/kg of the drug being cured. Praziquantel had little effect on larval or adult diphyllobothriids in vitro.


Ultrashort sleep-waking schedule. II. Relationship between ultradian rhythms in sleepability and the REM-non-REM cycles and effects of the circadian phase.
Eight subjects aged 20-30 years spent two 24 h periods in the sleep laboratory after having an adaptation night. At 16.00 h subjects began a strict 15 min waking-5 min sleeping schedule until 24.00 h. At 24.00 subjects retired for an uninterrupted monitored nocturnal sleep. Subjects were awakened after 6-7 h of sleep, either from REM sleep (in one experimental period) or 25 min after the end of a REM period (in the other experimental period) in a counterbalanced order, and a second 8 h 15 min waking-5 min sleeping schedule was initiated. There were no significant differences between the percentages of sleep stages 1 and 2 in the afternoon, evening and morning experiments. In each, stage 1 occurred in about 10 of the 24 'sleep attempts' and accounted for 15-19% of the total recording time; sleep stage 2 occurred in 2-5 sleep attempts and accounted for 3-8% of total recording time. Four of the 8 subjects showed REM sleep in 8 sleep 'attempts;' only one appeared during an evening period. Orthogonal spectral analysis revealed a dominant ultradian frequency of about 7.2 c/day during both experimental schedules. However, synchronizing the individual morning time series with the last nocturnal REM period resulted in the appearance of a single spectral peak at 14.4 c/day, which is the dominant ultradian frequency of the nocturnal REM-non-REM cycles.(ABSTRACT TRUNCATED AT 250 WORDS)


Cole-Cole modeling of real-time capacitance data for estimation of cell physiological properties in recombinant Escherichia coli cultivation.
Real-time estimation of physiological properties of the cell during recombinant protein production would ensure enhanced process monitoring. In this study, we explored the application of dielectric spectroscopy to track the fed-batch phase of recombinant Escherichia coli cultivation for estimating the physiological properties, namely, cell diameter and viable cell concentration (VCC). The scanning capacitance data from the dielectric spectroscopy were pre-processed using moving average. Later, it was modeled through a nonlinear theoretical Cole-Cole model and further solved using a global evolutionary genetic algorithm (GA). The parameters obtained from the GA were further applied for the estimation of the aforementioned physiological properties. The offline cell diameter and cell viability data were obtained from particle size analyzer and flow cytometry measurements to validate the Cole-Cole model. The offline VCC was calculated from the cell viability % from flow cytometry data and dry cell weight concentration. The Cole-Cole model predicted the cell diameter and VCC with an error of 1.03% and 7.72%, respectively. The proposed approach can enable the operator to take real-time process decisions to achieve desired productivity and product quality.


Perineuronal nets: past and present.
Golgi ranked the peripheral reticulum--which adheres intimately to nerve cell surfaces--alongside the intracellular reticulum, or Golgi apparatus,which immortalized his name. At first dismissed as an artefact of capricious staining techniques, this peripheral reticulum, or perineuronal net, is now recognized as a genuine entity in neurocytology. It represents a complex of extracellular matrix molecules interposed between the meshwork of glial processes, from which they are indistinguishable, and nerve-cell surfaces. In no other branch of neuroscience has the waxing and waning of interest in any morphological entity been so pronounced as in the case of the perineuronal net. This review traces the history of this enigmatic structure from its conception to the present time, brings to light the keen observational powers of morphologists at the turn of the century and reveals how their sagacious forethought anticipated current thinking on the role of perineuronal nets.


Neutral and acidic oligosaccharides supplementation does not increase the vaccine antibody response in preterm infants in a randomized clinical trial.
In preterm infants, a decreased immunological response and lower serological effectiveness are observed after immunizations due to ineffectiveness of both humoral and cellular immune mechanisms. To determine the effect of 80% neutral oligosaccharides [small-chain galacto-oligosaccharides/long-chain fructo-oligosaccharides (scGOS/lcFOS)] in combination with 20% pectin-derived acidic oligosaccharides (pAOS) on antibody concentrations after DTaP-IPV-Hib immunization in preterm infants. In this randomized clinical trial, preterm infants with gestational age <32 weeks and/or birth weight <1500 g received enteral supplementation with scGOS/lcFOS/pAOS or placebo (maltodextrin) between days 3 and 30 of life. Blood samples were collected at 5 and 12 months of age. In total, 113 infants were included. Baseline and nutritional characteristics were not different in both groups. Geometric mean titers were not different after prebiotic supplementation at 5 months, Ptx (37/44 EU/ml), FHA (78/96 EU/ml), Prn (78/80 EU/ml), Diphtheria (0.40/0.57 IU/ml), Tetanus (0.74/0.99 IU/ml) and Hib (0.35/0.63 µg/ml), and at 12 months Ptx (55/66 EU/ml), FHA (122/119 EU/ml), Prn (116/106 Eu/ml), Diphtheria (0.88/1.11 IU/ml), Tetanus (1.64/1.79 IU/ml) and Hib (2.91/2.55 µg/ml). Enteral supplementation of neutral (scGOS/lcFOS) and acidic oligosaccharides (pAOS) does not improve the immunization response in preterm infants. Controlled-Trials.com ISRCTN16211826 ISRCTN16211826.


Structural switching/polymorphism by sequential base substitution at quasi-palindromic SNP site (G → A) in LCR of human β-globin gene cluster.
The human β-globin gene Locus Control Region (LCR), a dominant regulator of globin gene expression contains five tissue-specific DNase I-hypersensitive sites (HSs). A single nucleotide polymorphism (SNP) (A → G) present in HS4 region of locus control region (LCR), have shown a notable association between the G allele and the occurrence of β-thalassemia. This SNP site exhibiting a hairpin - duplex equilibrium manifested in A → B like DNA transition has previously been reported from this laboratory. Since, DNA is a dynamic and adaptable molecule, so any change of a single base within a primary DNA sequence can produce major biological consequences commonly manifested in genetic disorders such as sickle cell anemia and β-thalassemia. Herein, the differential behavior of sequential single base substitutions G → A on the quasi-palindromic sequence (d-TGGGGGCCCCA; HPG11) has been explored. A combination of native gel electrophoresis, circular dichroism (CD), and UV-thermal denaturation (Tm) techniques have been used to investigate the structural polymorphism associated with various variants of HPG11 i.e. HPG11A2 to HPG11A5. The CD spectra confirmed that all the HPG11 variants exhibit a hairpin - duplex equilibrium. Oligomer concentration dependence on CD spectra has been correlated with A → B DNA conformational transition. However, as revealed in gel electrophoresis, HPG11A2 → A5 exhibit the formation of a tetramolecular structure (four-way junction) at higher oligomer concentration. UV-melting studies also supported the melting of hairpin, duplex and four-way junction structure. This polymorphism pattern may possibly be significant for DNA-protein recognition, in the process of regulation of LCR in the β-globin gene.


Cyto and genotoxicity of gold nanoparticles in human hepatocellular carcinoma and peripheral blood mononuclear cells.
Engineered nanomaterials have been extensively applied as active materials for technological applications. Since the impact of these nanomaterials on health and environment remains undefined, research on their possible toxic effects has attracted considerable attention. It is known that in humans, for example, the primary site of gold nanoparticles (AuNps) accumulation is the liver. The latter has motivated research regarding the use of AuNps for cancer therapy, since specific organs can be target upon appropriate functionalization of specific nanoparticles. In this study, we investigate the geno and cytotoxicity of two types of AuNps against human hepatocellular carcinoma cells (HepG2) and peripheral blood mononuclear cells (PBMC) from healthy human volunteers. The cells were incubated in the presence of different concentrations of AuNps capped with either sodium citrate or polyamidoamine dendrimers (PAMAM). Our results suggest that both types of AuNps interact with HepG2 cells and PBMC and may exhibit in vitro geno and cytotoxicity even at very low concentrations. In addition, the PBMC were less sensitive to DNA damage toxicity effects than cancer HepG2 cells upon exposure to AuNps.


Examining the role of the HIV-1 reverse transcriptase p51 subunit in positioning and hydrolysis of RNA/DNA hybrids.
Recent crystallographic analysis of p66/p51 human immunodeficiency virus (HIV) type 1 reverse transcriptase (RT) complexed with a non-polypurine tract RNA/DNA hybrid has illuminated novel and important contacts between structural elements at the C terminus of the noncatalytic p51 subunit and the nucleic acid duplex in the vicinity of the ribonuclease H (RNase H) active site. In particular, a short peptide spanning residues Phe-416-Pro-421 was shown to interact with the DNA strand, cross the minor groove of the helix, and then form Van der Waals contacts with the RNA strand adjacent to the scissile phosphate. At the base of the adjoining α-helix M', Tyr-427 forms a hydrogen bond with Asn-348, the latter of which, when mutated to Ile, is implicated in resistance to both nucleoside and non-nucleoside RT inhibitors. Based on our structural data, we analyzed the role of the p51 C terminus by evaluating selectively mutated p66/p51 heterodimers carrying (i) p51 truncations that encroach on α-M', (ii) alterations that interrupt the Asn-348-Tyr-427 interaction, and (iii) alanine substitutions throughout the region Phe-416-Pro-421. Collectively, our data support the notion that the p51 C terminus makes an important contribution toward hybrid binding and orienting the RNA strand for catalysis at the RNase H active site.


Structural and mechanical aspects of hypoeutectic Zn-Mg binary alloys for biodegradable vascular stent applications.
The study is concerned with the mechanical properties of Zn and three Zn-Mg double alloys with Mg concentrations: 0.5%, 1.0% and 1.5% in the form of rods with a diameter of 5 mm as potential materials for use in biodegradable medical implants, such as vascular stents. The materials were cast, next conventionally hot extruded at 250 °C and finally, hydrostatically extruded (HE) at ambient temperature. Occasionally HE process was carried at liquid nitrogen temperature or in combination with the ECAP process. After HE, the microstructure of the alloys was made up of fine-grained αZn of mean grain size ~1 μm in a 2-phase coat of 50-200 nm nano-grains of the fine αZn + Mg2Zn11 eutectic. The 3 to 4-fold reduction of grain size as a result of HE allowed an increase in yield strength from 100% to over 200%, elongation to fracture from 100% to thirty fold and hardness over 50% compared to the best literature results for similar alloys. Exceptions accounted for elongation to fracture in case of Zn-0.5 Mg alloy and hardness in case of Zn-1.5 Mg alloy, both of which fell by 20%. For the Zn-0.5 Mg and Zn-1Mg alloys, after immersion tests, no corrosive degradation of plasticity was observed. Achieving these properties was the result of generating large plastic deformations at ambient temperature due to the application of high pressure forming with the cumulative HE method. The results showed that Zn-Mg binary alloys after HE have mechanical and corrosive characteristics, qualifying them for applications in biodegradable implants, including vascular stents.


Student perceptions of faculty feedback following medication errors - A descriptive study.
Nursing students make medication errors as they progress through educational programs. It is important that faculty feedback is such that students feel comfortable reporting subsequent medication errors. The objectives of this study are to determine factors which increase the likelihood of nursing students reporting medication errors; to elicit nursing student perception of faculty feedback following a medication error, and determine how this faculty feedback impacts reporting of subsequent medication errors; and to develop recommendations regarding the most effective faculty approaches when providing feedback to nursing students following medication errors. This quantitative study uses a non-experimental, descriptive design. A convenience sample of 106 nursing students in one Canadian province completed a self-report questionnaire. The factors identified as increasing the likelihood of reporting medication errors for students who made a medication error were the same as for those who did not make an error. Group sizes were too small to determine if characteristics of faculty feedback had a significant impact on likelihood of reporting future errors. Students in both groups indicated intention to report errors based upon professional attitudes, behaviors and/or values. The researchers concluded that professional socialization, in combination with supportive learning environments, may increase student comfort in reporting medication errors.


Validity of the 28-item General Health Questionnaire in hospitalized gastroenterology patients.
The usefulness of the 28-item General Health Questionnaire (GHQ) in detecting psychiatric comorbidity in a sample of hospitalized gastroenterology patients was tested. Validity coefficients were determined by comparing the results of the GHQ with findings from a psychiatric interview. At the best discriminating score (8/9), the GHQ yielded a sensitivity of 77%, a specificity of 75%, a positive predictive value of 67%, and a misclassification rate of 24%. The GHQ did not accurately identify alcohol dependence and abuse and did not discriminate between patients with anxiety disorders and those with depressive disorders. Despite its limitations, the GHQ, if supplemented with specific questions about alcohol abuse, can effectively screen medical inpatients for psychiatric disorders.


Prognostic value of expanded liver transplantation criteria-the 5-5-500 rule-in patients with hepatic resection for intermediate-stage hepatocellular carcinoma.
This study aimed to evaluate the prognostic impact of the 5-5-500 rule in patients after hepatic resection for the intermediate stage of hepatocellular carcinoma (HCC; The Barcelona Clinic Liver Cancer classification [BCLC] B). 177 patients had hepatic resection for BCLC-B HCC. The 5-5-500 rule was defined by tumor size ≤5 cm in diameter, tumor number ≤5, and α-fetoprotein ≤500 ng/mL. The 3-, 5-, and 7-year recurrence-free survival rates were 22%, 14%, and 11% in patients within the 5-5-500 rule, and 16%, 10%, and 10% in patients beyond the 5-5-500 rule, respectively (P = .015). The 3-, 5-, and 7-year overall survival rates were 72%, 47%, and 34% in patients within the 5-5-500 rule, and 52%, 31%, and 25% in patients beyond the 5-5-500 rule, respectively (P = .035). Being beyond the 5-5-500 rule and liver cirrhosis were independent prognostic factors for recurrence-free survival. For overall survival, being beyond the 5-5-500 rule, age ≥65 years, Child-Pugh class B, and anti-hepatitis C antibody positive were identified as independent prognostic factors. The 5-5-500 rule could predict prognosis in BCLC-B patients with hepatic resection. Hepatic resection might provide survival benefit for selected patients with BCLC-B HCC within the 5-5-500 rule.


Bronchial rupture as a complication of response to combination chemotherapy in metastatic testicular carcinoma.
Chemotherapy for a metastatic germ cell tumor of the testis was complicated by a life-threatening bronchial rupture secondary to lysis of an endobronchial tumor. Subsequent chemotherapy was delayed because of this complication. Other pulmonary complications of chemotherapy-induced tumor lysis, including abscess formation, empyema and pneumothorax, are discussed.


Computed tomography of a thrombosed left anterior vena cava.
A case of transposed (left) inferior vena cava (IVC) with a normal suprarenal IVC visible on computed tomography (CT) is presented. There is concomitant recanalized thrombosis of the left IVC with venous collaterals present. Caval anomalies, differential diagnosis of a left IVC, and CT demonstration of thrombosis of major abdominal venous structures and associated venous collaterals are discussed.


[Suicides in the German prison system: frequency, risk factors, and prevention].
Prisoners have a high risk of dying by suicide and the highest suicide rates are recorded among prisoners on remand. A death by suicide is the most common single cause of death in German correctional institutions. This narrative overview first describes the prison population and its general healthcare needs by paying particular attention to psychiatric and substance use disorders. The main section attends to the prevalence, causes, and risk factors of prison suicide. Suicide prevention measures are presented.As in all parts of the world, the proportion of young men among prisoners in Germany is very high (94% in 2020). Most prisoners are young or middle-aged. The average annual suicide rates among men (105.8/100,000) and women (54.7/100,000) in German prisons are similar to those of most countries in the European Union (full census 2000-2011). Suicide rates among male German prisoners declined continuously from 2000-2013, regardless of age. In contrast, they increased among female prisoners; the reasons for this are not known. Evidence suggests that psychiatric disorders have not been identified.Important suicide prevention measures include shared accommodation and avoidance of solitary confinement, for example by offering work. In addition, validated German-language screening instruments are available to detect suicide risk at an early stage. For effective prison suicide prevention, identifying high-risk individuals, offering appropriate suicide prevention interventions, and developing team-based interventions among prison staff are required.


Retrobulbar anesthesia and retinal vascular obstruction.
The cases of three patients who developed combined central retinal artery/vein obstruction secondary to retrobulbar anesthesia are presented. In one case the obstruction was presumably present immediately after surgery, while in the other two it was observed to evolve over a period of several days. A dilated optic nerve sheath was demonstrated by contact B-scan ultrasonography in two cases and by computerized tomography in the third case, suggesting intravaginal sheath hemorrhage as a common underlying pathophysiologic process. Partial return of vision was evident in the latter case following orbitotomy with optic nerve sheath decompression.


The retention of titanium pins in high-copper amalgam and their influence on its fracture resistance.
The influence of titanium pins on the fracture resistance of amalgam and the retention of amalgam by titanium pins were compared to that of stainless-steel pins. The retention of stainless-steel pins embedded in amalgam to various depths was also evaluated. None of the pins had a significant influence on the compressive fracture resistance of amalgam. All pins embedded to standard depth in amalgam failed in tension, with titanium pins demonstrating the lowest resistance to tensile forces. Stainless-steel pins embedded 1.75 or 1.5 mm and loaded in tension caused failure in the amalgam, but at forces comparable to the retention of such pins in dentin.


BKV Related Hemorrhagic Cystitis-An Insight into Risk Factors and Later Complications-An Analysis on Behalf of Polish Adult Leukemia Group.
BK virus reactivation increases the likelihood of hemorrhagic cystitis (HC) after allogeneic hematopoietic stem cell transplant (HCT). In this study, we aimed to identify predictive and risk factors associated with the increased occurrence of this condition following HCT. On a group of 124 patients aged ≤71 years old (median 40 years) who underwent HCT, we analyzed sex, age, time from diagnosis to transplantation, type of conditioning, donor's relationship, age, and sex, the impact of immunosuppression with different drugs, and acute and chronic GVHD, BK viremia and viruria as potential factors increasing the risk of BK-related HC after HCT. HC occurred among 24 patients (24/124; 29.2%). A significant correlation was observed between HC incidences after HCT, BK viremia and viruria, and acute GVHD occurrence. Furthermore, the level of BKV DNA in serum at day +21 (>0.75 × 103) significantly impacted the patients' survival time. According to our results, the likelihood ratio of BKV-DNA on day +21 in serum is 6.25, indicating that this diagnostic test has the potential to be utilized in a clinical setting. These findings may be used as a voice in the discussion on implementing an optimal preemptive treatment in BKV reactivation after allogeneic HCT.


Recent applications of immunomodulatory biomaterials for disease immunotherapy.
Immunotherapy is used to regulate systemic hyperactivation or hypoactivation to treat various diseases. Biomaterial-based immunotherapy systems can improve therapeutic effects through targeted drug delivery, immunoengineering, etc. However, the immunomodulatory effects of biomaterials themselves cannot be neglected. In this review, we outline biomaterials with immunomodulatory functions discovered in recent years and their applications in disease treatment. These biomaterials can treat inflammation, tumors, or autoimmune diseases by regulating immune cell function, exerting enzyme-like activity, neutralizing cytokines, etc. The prospects and challenges of biomaterial-based modulation of immunotherapy are also discussed.


Measuring Quality in Barrett's Esophagus: Time to Embrace Quality Indicators.
Endoscopic eradication therapy is a safe and effective therapy that has revolutionized the management of patients with Barrett's esophagus (BE)-related neoplasia. Despite this, there remains significant heterogeneity in clinical practice with consequent variation in patient outcomes. The aim of this article was to align consensus statements based on the best available evidence and expert opinion from the United States and United Kingdom to develop robust and measurable quality indicators that help to ensure patients with BE-related neoplasia receive the highest possible quality of care uniformly.


Exposing the Underlying Relationship of Cancer Metastasis to Metabolism and Epithelial-Mesenchymal Transitions.
Cancer is a disease governed by the underlying gene regulatory networks. The hallmarks of cancer have been proposed to characterize the cancerization, e.g., abnormal metabolism, epithelial to mesenchymal transition (EMT), and cancer metastasis. We constructed a metabolism-EMT-metastasis regulatory network and quantified its underlying landscape. We identified four attractors, characterizing epithelial, abnormal metabolic, mesenchymal, and metastatic cell states, respectively. Importantly, we identified an abnormal metabolic state. Based on the transition path theory, we quantified the kinetic transition paths among these different cell states. Our results for landscape and paths indicate that metastasis is a sequential process: cells tend to first change their metabolism, then activate the EMT and eventually reach the metastatic state. This demonstrates the importance of the temporal order for different gene circuits switching on or off during metastatic progression of cancer cells and underlines the cascading regulation of metastasis through an abnormal metabolic intermediate state.


Clinical results in vitrectomy for diabetic traction retinal detachment.
A series of 75 eyes underwent pars plana vitrectomy for progressive diabetic traction retinal detachment of the macula. In all cases, the media was sufficiently clear to allow preoperative macular examination. The overall visual improvement was higher in phakic eyes (80%) than aphakic eyes (72%) and the rate of neovascular glaucoma was less in phakic eyes. The difference was not statistically significant, however. The final visual acuity corresponded to the degree of preoperative visual deterioration. Thus, surgery during the rapidly evolving proliferative and retracting process did not adversely affect the visual success rate when compared to previous reports on longstanding vitreous hemorrhage.


Negative emotional photographs are identified more slowly than positive photographs.
In three experiments, we investigated whether the emotional valence of a photograph influenced the amount of time required to initially identify the contents of the image. In Experiment 1, participants saw a slideshow consisting of positive, neutral, and negative photographs that were balanced for arousal. During the slideshow, presentation time was substantially limited (60 ms), and the images were followed by masks. Immediately following the slideshows, participants were given a recognition memory test. Memory performance was best for positive images and worst for negative images (Experiment 1). In Experiment 2, two simultaneous photographs were briefly presented and masked. On a trial-by-trial basis, participants indicated whether the two images were identical or not, thus removing the need for memory storage and retrieval. Again, performance was worst for negative images. The results of Experiment 3 suggested that these valence-based differences were not related attentional effects (Experiment 3). We argue that the valence of an image is detected rapidly and, in the case of negative images, interferes with processing the identity of the scene.


Immediate Lymphatic Reconstruction after Axillary Lymphadenectomy: A Single-Institution Early Experience.
Lymphedema is progressive arm swelling from lymphatic dysfunction which can occur in 30% patients undergoing axillary dissection/radiation for breast cancer. Immediate lymphatic reconstruction (ILR) is performed in an attempt decrease the risk of lymphedema in patients undergoing axillary lymph node dissection (ALND). The purpose of this study was to assess the efficacy of ILR in preventing lymphedema rates in ALND patients. An institutional review board-approved retrospective review was performed of all patients who underwent ILR from 2017 to 2019. Patient demographics, comorbidities, operative and pathologic findings, number of LVAs, limb measurements, complications, and follow-up were recorded and analyzed. Student's sample t-test, Fisher's exact test, and ANOVA were used to analyze data; significance was set at p < 0.05. Thirty-three patients were included in this analysis. Three patients (9.1%) developed persistent lymphedema, and two patients (6.1%) developed transient arm edema that resolved with compression and massage therapy. A significant effect was found for body mass index and the number of lymph nodes taken on the development of lymphedema (p < 0.01). The rate of lymphedema in this series was 9.1%, which is an improvement from historical rates of lymphedema. Our findings support ILR as a technique that potentially decreases the incidence of lymphedema after axillary lymphadenectomy. Obesity and number of lymph nodes removed were significant predictive variables for the development of lymphedema following LVA.