Stapled Peptides Based on Human Angiotensin-Converting Enzyme 2 (ACE2) Potently Inhibit SARS-CoV-2 Infection In Vitro.
SARS-CoV-2 uses human angiotensin-converting enzyme 2 (ACE2) as the primary receptor to enter host cells and initiate the infection. The critical binding region of ACE2 is an ∼30-amino-acid (aa)-long helix. Here, we report the design of four stapled peptides based on the ACE2 helix, which is expected to bind to SARS-CoV-2 and prevent the binding of the virus to the ACE2 receptor and disrupt the infection. All stapled peptides showed high helical contents (50 to 94% helicity). In contrast, the linear control peptide NYBSP-C showed no helicity (19%). We have evaluated the peptides in a pseudovirus-based single-cycle assay in HT1080/ACE2 cells and human lung cell line A549/ACE2, overexpressing ACE2. Three of the four stapled peptides showed potent antiviral activity in HT1080/ACE2 (50% inhibitory concentration [IC50]: 1.9 to 4.1 μM) and A549/ACE2 (IC50: 2.2 to 2.8 μM) cells. The linear peptide NYBSP-C and the double-stapled peptide StRIP16, used as controls, showed no antiviral activity. Most significantly, none of the stapled peptides show any cytotoxicity at the highest dose tested. We also evaluated the antiviral activity of the peptides by infecting Vero E6 cells with the replication-competent authentic SARS-CoV-2 (US_WA-1/2020). NYBSP-1 was the most efficient, preventing the complete formation of cytopathic effects (CPEs) at an IC100 of 17.2 μM. NYBSP-2 and NYBSP-4 also prevented the formation of the virus-induced CPE with an IC100 of about 33 μM. We determined the proteolytic stability of one of the most active stapled peptides, NYBSP-4, in human plasma, which showed a half-life (T1/2) of >289 min.IMPORTANCE SARS-CoV-2 is a novel virus with many unknowns. No vaccine or specific therapy is available yet to prevent and treat this deadly virus. Therefore, there is an urgent need to develop novel therapeutics. Structural studies revealed critical interactions between the binding site helix of the ACE2 receptor and SARS-CoV-2 receptor-binding domain (RBD). Therefore, targeting the entry pathway of SARS-CoV-2 is ideal for both prevention and treatment as it blocks the first step of the viral life cycle. We report the design of four double-stapled peptides, three of which showed potent antiviral activity in HT1080/ACE2 cells and human lung carcinoma cells, A549/ACE2. Most significantly, the active stapled peptides with antiviral activity against SARS-CoV-2 showed high α-helicity (60 to 94%). The most active stapled peptide, NYBSP-4, showed substantial resistance to degradation by proteolytic enzymes in human plasma. The lead stapled peptides are expected to pave the way for further optimization of a clinical candidate.


Stenotrophomonas goyi sp. nov., a novel bacterium associated with the alga Chlamydomonas reinhardtii.
Background: A culture of the green algae Chlamydomonas reinhardtii was accidentally contaminated with three different bacteria in our laboratory facilities. This contaminated alga culture showed increased algal biohydrogen production. These three bacteria were independently isolated. Methods: The chromosomic DNA of one of the isolated bacteria was extracted and sequenced using PacBio technology. Tentative genome annotation (RAST server) and phylogenetic trees analysis (TYGS server) were conducted. Diverse growth tests were assayed for the bacterium and for the alga-bacterium consortium. Results: Phylogenetic analysis indicates that the bacterium is a novel member of the Stenotrophomonas genus that has been termed in this work as S. goyi sp. nov. A fully sequenced genome (4,487,389 base pairs) and its tentative annotation (4,147 genes) are provided. The genome information suggests that S. goyi sp. nov. is unable to use sulfate and nitrate as sulfur and nitrogen sources, respectively. Growth tests have confirmed the dependence on the sulfur-containing amino acids methionine and cysteine. S. goyi sp. nov. and Chlamydomonas reinhardtii can establish a mutualistic relationship when cocultured together. Conclusions: S. goyi sp. nov. could be of interest for the design of biotechnological approaches based on the use of artificial microalgae-bacteria multispecies consortia that take advantage of the complementary metabolic capacities of their different microorganisms.


Dietary patterns of Brazilian adolescents: results of the Brazilian National School-Based Health Survey (PeNSE).
The objectives of this study were to identify dietary patterns in Brazilian adolescents, describe their distributions in Brazil's State capitals and Federal District, and analyze the correlations with the Municipal Human Development Index (HDI-M). The study analyzed a sample of 60,954 ninth-graders from public and private schools who participated in the National School-Based Health Survey (PeNSE) in 2009. Cluster analysis was used to characterize dietary patterns. Three patterns were identified: healthy (27.7%), unhealthy (34.6%), and mixed (37.7%). Adolescents in the country's Southeast, South, and Central West regions showed a higher proportion of the healthy eating pattern. HDI-M showed a positive correlation with the healthy pattern and a negative correlation with the mixed pattern. The identification of different dietary patterns within and between regions and according to HDI-M highlights the need for better knowledge of each local context in terms of both the magnitude of events and the examination of determinants within these different realities.


Genome-wide SNP identification and characterization in two soybean cultivars with contrasting Mungbean Yellow Mosaic India Virus disease resistance traits.
Mungbean yellow mosaic India virus (MYMIV) is a bipartite Geminivirus, which causes severe yield loss in soybean (Glycine max). Considering this, the present study was conducted to develop large-scale genome-wide single nucleotide polymorphism (SNP) markers and identify potential markers linked with known disease resistance loci for their effective use in genomics-assisted breeding to impart durable MYMIV tolerance. The whole-genome re-sequencing of MYMIV resistant cultivar 'UPSM-534' and susceptible Indian cultivar 'JS-335' was performed to identify high-quality SNPs and InDels (insertion and deletions). Approximately 234 and 255 million of 100-bp paired-end reads were generated from UPSM-534 and JS-335, respectively, which provided ~98% coverage of reference soybean genome. A total of 3083987 SNPs (1559556 in UPSM-534 and 1524431 in JS-335) and 562858 InDels (281958 in UPSM-534 and 280900 in JS-335) were identified. Of these, 1514 SNPs were found to be present in 564 candidate disease resistance genes. Among these, 829 non-synonymous and 671 synonymous SNPs were detected in 266 and 286 defence-related genes, respectively. Noteworthy, a non-synonymous SNP (in chromosome 18, named 18-1861613) at the 149th base-pair of LEUCINE-RICH REPEAT RECEPTOR-LIKE PROTEIN KINASE gene responsible for a G/C transversion [proline (CCC) to alanine(GCC)] was identified and validated in a set of 12 soybean cultivars. Taken together, the present study generated a large-scale genomic resource such as, SNPs and InDels at a genome-wide scale that will facilitate the dissection of various complex traits through construction of high-density linkage maps and fine mapping. In the present scenario, these markers can be effectively used to design high-density SNP arrays for their large-scale validation and high-throughput genotyping in diverse natural and mapping populations, which could accelerate genomics-assisted MYMIV disease resistance breeding in soybean.


9-Vinylanthracene Based Fluorogens: Synthesis, Structure-Property Relationships and Applications.
Fluorescent dyes with aggregation-induced emission (AIE) properties exhibit intensified emission upon aggregation. They are promising candidates to study biomolecules and cellular changes in aqueous environments when aggregation formation occurs. Here, we report a group of 9-position functionalized anthracene derivatives that were conveniently synthesized by the palladium-catalyzed Heck reaction. Using fluorometric analyses, these dyes were confirmed to show AIE behavior upon forming aggregates at high concentrations, in viscous solvents, and when poorly solubilized. Their photophysical properties were then further correlated with their structural features, using density functional theory (DFT) calculation. Finally, we demonstrated their potential applications in monitoring pH changes, quantifying globular proteins, as well as cell imaging with confocal microscopy.


Long wavelength pass filters designed for the management of color vision deficiencies.
This study reports on the effectiveness of long wavelength pass filters dispensed as tinted spectacles as an aid for individuals with congenital red-green color vision deficiencies. The effectiveness of the filters was evaluated by the performance on a series of clinical color vision tests and a questionnaire after the subjects had tried the lenses for 1 week. The lenses improved performance on color vision tests that required discrimination between large color differences, particularly between red and green hues. However, performance was degraded on tests which required fine color discrimination or used colors that were located parallel to the tritan confusion axis. The improved performance on certain tests was primarily based on brightness artificats induced by the filters, whereas the degraded performance on the other tests was due to the absorption of short- to midwavelength light by the filters. A slight majority (56%) of the subjects rated the filters as being moderate to highly effective in improving their color discrimination. Nevertheless, only 17% were interested in actually purchasing a pair. Common reasons for rejecting the filters were the color distortions produced by the red filters and fewer colors were actually perceived when wearing the filters.


Halorussus amylolyticus sp. nov., isolated from an inland salt lake.
A halophilic archaeal strain, YC93T, was isolated from Yuncheng salt lake in Shanxi Province, China. Cells were pleomorphic rods, stained Gram-negative and formed light-red-pigmented colonies on agar plates. Strain YC93T was able to grow at 25–50 °C (optimum 37 °C), with 1.4–4.8 M NaCl (optimum 2.0 M), with 0–1.0 M MgCl2 (optimum 0.05 M) and at pH 6.0–9.5 (optimum pH 7.0). Cells lysed in distilled water and the minimal NaCl concentration to prevent cell lysis was 8 % (w/v). 16S rRNA gene sequence analysis revealed that strain YC93T had two dissimilar 16S rRNA genes both of which were phylogenetically related to those of the two recognized members of the genus Halorussus (93.0–95.3 % similarity). The rpoB′ gene of strain YC93T was phylogenetically related to the corresponding gene of Halorussus rarus TBN4T (91.3 % similarity) and Halorussus ruber YC25T (90.5 %). The major polar lipids were phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester, phosphatidylglycerol sulfate and five glycolipids chromatographically identical to those of Halorussus rarus CGMCC 1.10122T. The DNA G+C content of strain YC93T was 64.6 mol%. The phenotypic, chemotaxonomic and phylogenetic properties suggested that strain YC93T represents a novel species of the genus Halorussus, for which the name Halorussus amylolyticus sp. nov. is proposed. The type strain is YC93T ( = CGMCC 1.12126T = JCM 18367T).


Compensation of phase-to-amplitude modulation conversion in a complete frequency conversion system with an all-fiber system.
We report on an experimental demonstration of linear precompensation of nonlinear phase and amplitude transfer functions. We show the effective compensation with a linear all-fiber system of phase-to-amplitude modulation conversion due to a complete frequency conversion system including plane gratings and a nonlinear crystal.


Variational Inference and Learning of Piecewise Linear Dynamical Systems.
Modeling the temporal behavior of data is of primordial importance in many scientific and engineering fields. Baseline methods assume that both the dynamic and observation equations follow linear-Gaussian models. However, there are many real-world processes that cannot be characterized by a single linear behavior. Alternatively, it is possible to consider a piecewise linear model which, combined with a switching mechanism, is well suited when several modes of behavior are needed. Nevertheless, switching dynamical systems are intractable because their computational complexity increases exponentially with time. In this article, we propose a variational approximation of piecewise linear dynamical systems. We provide full details of the derivation of two variational expectation-maximization algorithms: a filter and a smoother. We show that the model parameters can be split into two sets: static and dynamic parameters, and that the former parameters can be estimated offline together with the number of linear modes, or the number of states of the switching variable. We apply the proposed method to the head-pose tracking, and we thoroughly compare our algorithms with several state of the art trackers.


Effect of tumor burden and route of administration on the immunotherapeutic properties of polyinosinic-polycytidylic acid stabilized with poly-L-lysine in carboxymethyl cellulose [Poly(I,C)-LC].
We examined the immunomodulatory and therapeutic activities of poly(I,C)-LC. Mice received a subcutaneous (s.c.) injection of sufficient numbers of MBL-2 lymphoma cells to produce in 1 week either a high or low tumor burden. A week after tumor cell injection, poly(I,C)-LC treatment was initiated; the agent was administered intraperitoneally (i.p.) at 5 mg/kg twice a week or at 2.5 or 0.5 mg/kg every day or as an intravenous (i.v.) injection at 0.5, 0.05, or 0.005 mg/kg three times a week. Poly(I,C)-LC treatment significantly increased antitumor effector cell functions in a variety of organs (including spleen, lungs, and peritoneum), as shown by increased killing of MBL-2 cells in vitro and increased tumor cell killing by natural killer cells and macrophages. Furthermore, prolongation of survival correlated with peritoneal macrophage tumoricidal activity when poly(I,C)-LC was given i.p. and with pulmonary effector cell function (including natural killer, cytolytic T-lymphocyte and macrophage tumoricidal activity) when the agent was administered i.v.


Report of the National Consensus Conference on Family Presence During Pediatric Cardiopulmonary Resuscitation and Procedures.
Representatives from 18 national organizations were convened for a conference to develop recommendations regarding family presence (FP) during pediatric procedures and cardiopulmonary resuscitation. Before the conference, invitees were given a questionnaire and provided with current literature regarding FP. A modified Delphi process was used to develop consensus, including use of multiple questionnaires and breakouts for discussion of specific issues. Participants were encouraged to develop consensus recommendations based on the literature and discussions. Changes in attitude were tracked with repeat questionnaires. Results of the conference were circulated to participants for review and revision. Consensus recommendations include (1) consider FP as an option for families during pediatric procedures and cardiopulmonary resuscitation, (2) offer FP as an option after assessing factors that could adversely affect the interaction, (3) if family is not offered the option for FP, document the reasons why, (4) always consider the safety of the health care team, (5) develop in-hospital transport and transfer policies and procedures for FP, such as family member definition, preparation of the family, handling disagreements, and providing support for the staff, (6) obtain legal review of policies, (7) include education in FP in all core curricula and orientation for health care providers, (8) promote research into best methods for education; effects of FP on patients, family, and staff; best practices for FP; and legal issues regarding FP, among others. These recommendations were approved in concept by the American Academy of Pediatrics and the Ambulatory Pediatrics Association.


[Expression of P27(kip1) and cyclin G in patients with acute leukemia and its correlation].
This study was purposed to explore the expression of P27(kip1)and cyclin G in patients with acute leukemia (AL) and its correlation. The reverse polymerase chain reaction (RT-PCR) was used to analyse the expression of P27(kip1) and cyclin G mRNA in 89 AL patients and 10 normal persons; Western blot was used to analyze the expression of P27(kip1) and cyclin G protein in 39 AL patients and 10 normal persons. The results showed that the cyclin G mRNA and protein expressions in new diagnosed/relapsed cases of AL were significantly higher than those in patients with remission and normal controls (p < 0.05 and p < 0.01), but there was no difference between remission cases and normal controls (p > 0.05). The expression of P27(kip1) mRNA in newly diagnosed/relapsed patients with AL was not significantly different from patients with remission and normal controls (p > 0.05), while the P27(kip1) protein expression in remission cases of AL and normal controls was significantly higher than that in new diagnosed/relapsed cases (p < 0.05), but there was no difference between remission cases and normal controls (p > 0.05). The expression of P27(kip1) negatively and lowly correlated with the expression of cyclin G in patients with AL. It is concluded that the low expression of P27(kip1) and the high expression of cyclin G in patients with AL may have some correlation with genesis and development of AL and may be an indication for poor prognosis of AL.


[The role of bruxism in the appearance of temporomandibular joint disorders].
Bruxism is a parafunction observed both in young and adult populations. The mean prevalence is about 20% and is decreasing with age. Women appear to clench more frequently than men. Often, bruxism is understood as both clenching with occasional tooth contact or grinding. A correct and validated definition has only recently been suggested. Many symptoms are assigned to this process, although few symptoms scientifically can be used as specific diagnostic criteria. The symptoms most often associated with bruxism like muscle-stiffness and -pain, limitation of mouth opening. TMJ-internal derangements, toothwear, are also found in TMD-patients. Because the bruxism-process is not only a problem for the patient, who suffers from pain, dysfunction and possible toothwear, it concerns also the dentist. It is essential that those who treat the bruxist-patient, have an understanding of the etiology, diagnosis and management of bruxism, of the many described oral parafunctional behaviors (oromotor behavior). This literature-review could not find a causal etiological mechanism between the occurrence of TMD-symptoms and the bruxism although a relationship between those two conditions has been described.


Competition between alpha-cleavage and energy transfer in alpha-azidoacetophenones.
Molecular modeling demonstrates that the first excited state of the triplet ketone (T1K) in azide 1b has a (pi,pi*) configuration with an energy that is 66 kcal/mol above its ground state and its second excited state (T2K) is 10 kcal/mol higher in energy and has a (n,pi*) configuration. In comparison, T1K and T2K of azide 1a are almost degenerate at 74 and 77 kcal/mol above the ground state with a (n,pi*) and (pi,pi*) configuration, respectively. Laser flash photolysis (308 nm) of azide 1b in methanol yields a transient absorption (lambdamax=450 nm) due to formation of T1K, which decays with a rate of 2.1 x 105 s-1 to form triplet alkylnitrene 2b (lambdamax=320 nm). The lifetime of nitrene 2b was measured to be 16 ms. In contrast, laser flash photolysis (308 nm) of azide 1a produced transient absorption spectra due to formation of nitrene 2a (lambdamax=320 nm) and benzoyl radical 3a (lambdamax=370 nm). The decay of 3a is 2 x 105 s-1 in methanol, whereas nitrene 2a decays with a rate of approximately 91 s-1. Thus, T1K (pi,pi*) in azide 1b leads to energy transfer to form nitrene 2b; however, alpha-cleavage is not observed since the energy of T2K (n,pi*) is 10 kcal/mol higher in energy than T1K, and therefore, T2K is not populated. In azide 1a both alpha-cleavage and energy transfer are observed from T1K (n,pi*) and T2K (pi,pi*), respectively, since these triplet states are almost degenerate. Photolysis of azide 1a yields mainly product 4, which must arise from recombination of benzoyl radicals 3a with nitrenes 2a. However, products studies for azide 1b also yield 4b as the major product, even though laser flash photolysis of azide 1b does not indicate formation of benzoyl radical 3b. Thus, we hypothesize that benzoyl radicals 3 can also be formed from nitrenes 2. More specifically, nitrene 2 does undergo alpha-photocleavage to form benzoyl radicals and iminyl radicals. The secondary photolysis of nitrenes 2 is further supported with molecular modeling and product studies.


A pharmacist-led prospective antibiotic stewardship intervention improves compliance to community-acquired pneumonia guidelines in 39 public and private hospitals across South Africa.
Pharmacists in low-middle-income countries (LMIC) are few and lack antibiotic stewardship (AS) training. The ability was assessed of non-specialised pharmacists to implement stewardship interventions and improve adherence to the South African community-acquired pneumonia (CAP) guideline in public and private hospitals. This was a multicentre, prospective cohort study of adult CAP patients hospitalised between July 2017 and July 2018. A CAP bundle was developed of seven process measures (diagnostic and AS) that pharmacists used to audit compliance and provide feedback. CAP bundle compliance rates and change in outcome measures [mortality, length of stay (LOS) and infection-related (IR)-LOS] during pre- and post-implementation periods were compared. In total, 2464 patients in 39 hospitals were included in the final analysis. Post-implementation, overall CAP bundle compliance improved from 47·8% to 53·6% (confidence interval [CI] 4·1-7·5, p<0·0001), diagnostic stewardship compliance improved from 49·1% to 54·6% (CI 3·3-7·7, p<0·0001) and compliance with AS process measures from 45·3% to 51·6% (CI 4·0-8·6, p<0·0001). Improved compliance with process measures was significant for five (2 diagnostic, 3 AS) of seven components: radiology, laboratory, antibiotic choice, duration and intravenous to oral switch. There was no difference in mortality between the two phases, [4·4%(55/1247) vs. 3·9%(47/1217); p=0·54], median LOS or IR LOS 6·0 vs. 6·0 days (p=0·20) and 5·0 vs. 5·0 days (p=0·40). Non-specialised pharmacists in public and private hospitals implemented stewardship interventions and improved compliance to SA CAP guidelines. The methodology of upskilling and a shared learning stewardship model may benefit LMIC countries.


X-ray crystal structure of the antimalarial agent (-)-halofantrine hydrochloride supports stereospecificity for cardiotoxicity.
The crystal and molecular structures and absolute configuration of (-)-halofantrine hydrochloride were determined by X-ray diffraction. The absolute configuration of the single chiral center of (-)-halofantrine was established to be in the S configuration. Thus, (+)-halofantrine, the more cardiotoxic isomer, has the R configuration. The carbon atom adjacent to the aromatic ring has the same configuration in both (+)- halofantrine and quinidine, suggesting a stereospecific component to the cardiotoxicity produced by both agents. The intramolecular N ... O distance is 4.177 +/- 0.006 A (1 A = 0.1 nm), which is close to the N ... O distance found in the crystal structure of (+/-)-halofantrine hydrochloride, even though the N-H group points in opposite directions in racemic halofantrine and (-)-halofantrine. Both the hydroxyl group and the amine group form hydrogen bonds with the chloride anions. The crystallographic parameters for (-)-halofantrine hydrochloride were as follows: chemical formula, C26H31Cl2F6NO+. Cl-; Mr, 492.4; symmetry of unit cell, orthorhombic; space group, P2(1)2(1)2(1); parameters of unit cell, a was 6.290 +/- 0.001 A, b was 13.533 +/- 0.003 A, and c was 30.936 +/- 0.006 A; volume of the unit cell, 2,633.2 +/- 0.7 A(3); number of molecules per unit cell, 4; calculated density, 1.354 g cm(-3); source of radiation, Cu K(alpha) (lambda = 1.54178 A); mu (absorption coefficient), 3.50 mm(-1); F(000) (sum of atomic scattering factors at zero scattering angle), 1,120; room temperature was used; final R (residual index), 4.75% for 2,988 reflections, with absolute value of Fo > 3sigma(F), where Fo is the observed structure factor and F is the structure factor.


Pulmonary function tests in obese people candidate to bariatric surgery.
Obesity is considered one of the most serious public health problems of the modern world. Because it alters the relationship between the lungs, chest wall and diaphragm, it is to be expected that it impacts on the respiratory function. In Portugal, there is not much data about the relationship between obesity and pulmonary function. The aim of this study was to characterize respiratory function in morbidly obese patients and to evaluate whether weight loss in patients submitted to bariatric surgery affects pulmonary function tests (PFT). We conducted a retrospective study with 36 morbidly obese patients submitted to bariatric surgery, with a mean age of 40.6 years, 64% female and with a mean body mass index (BMI) of 49.7 kg/m². All patients were clinical and functionally evaluated before surgery and after their weight had stabilized following surgery. They underwent a complete pulmonary function testing with spirometry, lung volumes, carbon monoxide diffusing capacity (DLCO), maximum respiratory pressures and arterial blood gases analysis. Prior to surgery almost all the patients had functional respiratory changes, 34 had a decrease in functional residual capacity (FRC) 6 of whom a restrictive syndrome. Only 2 patients did not show any functional or arterial blood gas change. After bariatric surgery, BMI decreased to 34 kg/m² and there was a significant improvement in almost all functional parameters with resolution of restrictive disorders. Nevertheless, in 13 patients the FRC remained decreased. After weight loss, the only correlation found was between reduction of BMI and increased FRC (r = -0.371; p = 0.028). This study suggests a relationship between obesity and pulmonary restriction and a positive impact of bariatric surgery in PFT.


A toxic dipeptide from the defense glands of the colorado beetle.
The Colorado beetle is protected against predators by the secretions of defensive glands located on the pronotum and the elytra. The single major compound of the secretion was identified as gamma-L-glutamyl-L-2-amino-3(Z),5-hexadienoic acid by spectroscopic and chemical methods. This compound, which contains a nonprotein beta,gamma- unsaturated amino acid, is toxic to ants (Myrmica rubra) at a concentration 10(-2) molar, which is less than its estimated concentration in the secretion (1.8 x 10(-1) molar).


Imaging for Barrett's esophagus: state of the art.
Barrett's esophagus is the premalignant condition for esophageal cancer and the diagnosis of esophageal adenocarcinoma on index endoscopy is increasing. Many advanced endoscopic techniques are available and aim to identify Barrett's esophagus-associated neoplasia earlier, thereby preventing progression into malignancy. It is well established adherence to Seattle protocol increases dysplasia detection but leaves large portions of mucosa unsampled. Recent attention has been given to wide-area transepithelial sampling as an additional means of biopsy and shows increased dysplasia detection rates. Many endoscopic techniques aim to increase the success of diagnosis of Barrett's esophagus-associated neoplasia, including probe confocal endomicroscopy, volumetric laser endomicroscopy, and virtual chromoendoscopy. Interestingly, volumetric laser endomicroscopy may also be useful in delineating margins during endoscopic mucosal resection, leading to both diagnostic and therapeutic applications. Advanced endoscopic techniques are available to increase detection of Barrett's esophagus-associated neoplasia; however, these remain localized to academic centers of excellence. With recent advancements in both sampling techniques and the potential application of imaging to therapeutics, these techniques are becoming more accessible to community endoscopists.


Negative expectancies for the group's outcomes undermine normative collective action: conflict between Christian and Muslim groups in Lebanon.
In this extension of the social identity model of collective action (SIMCA; Van Zomeren, Postmes, & Spears, 2008), group expectancies are an intervening construct for the impact of group identification, perceived group inefficacy, and perceived group injustice on normative collective action. In addition to the SIMCA path from greater group identification to more action, Hypothesis 1 was that greater identification fosters less negative group expectancies, which, in turn, promote action. Hypothesis 2 was that the SIMCA path from greater perceived group inefficacy to less action is mediated by negative group expectancies. These hypotheses were for low- and high-status groups, as was the expectation for the SIMCA path from greater perceived group injustice to more action. For the low-status group, Hypothesis 3 was that perceived injustice also undermines action by fostering more negative group expectancies. During severe ethno-religious group conflict in Lebanon, university students reported on SIMCA factors and their group expectancies. Results were in line with SIMCA and Hypotheses 2 and 3, and partly with Hypothesis 1. Group expectancies are discussed in relation to likelihood of amelioration, perceived instability, and emotions. Types of expectancies are discussed, as is the relation of expectancies to normative and non-normative collective action.


A combined microbial and biogeochemical dataset from high-latitude ecosystems with respect to methane cycle.
High latitudes are experiencing intense ecosystem changes with climate warming. The underlying methane (CH4) cycling dynamics remain unresolved, despite its crucial climatic feedback. Atmospheric CH4 emissions are heterogeneous, resulting from local geochemical drivers, global climatic factors, and microbial production/consumption balance. Holistic studies are mandatory to capture CH4 cycling complexity. Here, we report a large set of integrated microbial and biogeochemical data from 387 samples, using a concerted sampling strategy and experimental protocols. The study followed international standards to ensure inter-comparisons of data amongst three high-latitude regions: Alaska, Siberia, and Patagonia. The dataset encompasses different representative environmental features (e.g. lake, wetland, tundra, forest soil) of these high-latitude sites and their respective heterogeneity (e.g. characteristic microtopographic patterns). The data included physicochemical parameters, greenhouse gas concentrations and emissions, organic matter characterization, trace elements and nutrients, isotopes, microbial quantification and composition. This dataset addresses the need for a robust physicochemical framework to conduct and contextualize future research on the interactions between climate change, biogeochemical cycles and microbial communities at high-latitudes.


System identification and closed-loop control of end-tidal CO2 in mechanically ventilated patients.
This paper presents a systematic approach to system identification and closed-loop control of end-tidal carbon dioxide partial pressure (PETCO2) in mechanically ventilated patients. An empirical model consisting of a linear dynamic system followed by an affine transform is proposed to derive a low-order and high-fidelity representation that can reproduce the positive and inversely proportional dynamic input-output relationship between PETCO2 and minute ventilation (MV) in mechanically ventilated patients. The predictive capability of the empirical model was evaluated using experimental respiratory data collected from eighteen mechanically ventilated human subjects. The model predicted PETCO2 response accurately with a root-mean-squared error (RMSE) of 0.22+/-0.16 mmHg and a coefficient of determination (r2) of 0.81+/-0.18 (mean+/-SD) when a second-order rational transfer function was used as its linear dynamic component. Using the proposed model, a closedloop control method for PETCO2 based on a proportionalintegral (PI) compensator was proposed by systematic analysis of the system root locus. For the eighteen mechanically ventilated patient models identified, the PI compensator exhibited acceptable closed-loop response with a settling time of 1.27+/- 0.20 min and a negligible overshoot (0.51+/-1.17%), in addition to zero steady-state PETCO2 set point tracking. The physiologic implication of the proposed empirical model was analyzed by comparing it with the traditional multi-compartmental model widely used in pharmacological modeling.


Chiral porphyrazine near-IR optical imaging agent exhibiting preferential tumor accumulation.
A chiral porphyrazine (pz), H(2)[pz(trans-A(2)B(2))] (247), has been prepared that exhibits preferential in vivo accumulation in the cells of tumors. Pz 247 exhibits near-infrared (NIR) emission with lambda > 700 nm in the required wavelength range for maximum tissue penetration. When MDA-MB-231 breast tumor cells are treated with 247, the agent shows strong intracellular fluorescence with an emission maximum, 704 nm, which indicates that it localizes within a hydrophobic microenvironment. Pz 247 is shown to associate with the lipophilic core of LDL and undergo cellular entry primarily through receptor-mediated endocytosis accumulating in lysosomes. Preliminary in vivo studies show that 247 exhibits preferential accumulation and retention in the cells of MDA-MB-231 tumors subcutaneously implanted in mice, thereby enabling NIR optical imaging with excellent contrast between tumor and surrounding tissue. The intensity of fluorescence from 247 within the tumor increases over time up to 48 h after injection presumably due to the sequestration of circulating 247/LDL complex by the tumor tissue. As the need for cholesterol, and thus LDL, is elevated in highly proliferative tumor cells over nontumorigenic cells, 247 has potential application for all such tumors.


Plasma free choline, betaine and cognitive performance: the Hordaland Health Study.
Choline and betaine are nutrients involved in one-carbon metabolism. Choline is essential for neurodevelopment and brain function. We studied the associations between cognitive function and plasma concentrations of free choline and betaine. In a cross-sectional study, 2195 subjects (55 % women), aged 70-74 years, underwent extensive cognitive testing including the Kendrick Object Learning Test (KOLT), Trail Making Test (part A, TMT-A), modified versions of the Digit Symbol Test (m-DST), Block Design (m-BD), Mini-Mental State Examination (m-MMSE) and Controlled Oral Word Association Test (COWAT). Compared with low concentrations, high choline (>8·4 μmol/l) was associated with better test scores in the TMT-A (56·0 v. 61·5, P=0·004), m-DST (10·5 v. 9·8, P=0·005) and m-MMSE (11·5 v. 11·4, P=0·01). A generalised additive regression model showed a positive dose-response relationship between the m-MMSE and choline (P=0·012 from a corresponding linear regression model). Betaine was associated with the KOLT, TMT-A and COWAT, but after adjustments for potential confounders, the associations lost significance. Risk ratios (RR) for poor test performance roughly tripled when low choline was combined with either low plasma vitamin B₁₂ (≤257 pmol/l) concentrations (RR(KOLT)=2·6, 95 % CI 1·1, 6·1; RR(m-MMSE)=2·7, 95 % CI 1·1, 6·6; RR(COWAT)=3·1, 95 % CI 1·4, 7·2) or high methylmalonic acid (MMA) (≥3·95 μmol/l) concentrations (RR(m-BD)=2·8, 95 % CI 1·3, 6·1). Low betaine (≤31·1 μmol/l) combined with high MMA was associated with elevated RR on KOLT (RR(KOLT)=2·5, 95 % CI 1·0, 6·2). Low plasma free choline concentrations are associated with poor cognitive performance. There were significant interactions between low choline or betaine and low vitamin B₁₂ or high MMA on cognitive performance.


Accelerating locomotor recovery after incomplete spinal injury.
A traumatic spinal injury can destroy cells, irreparably damage axons, and trigger a cascade of biochemical responses that increase the extent of injury. Although damaged central nervous system axons do not regrow well naturally, the distributed nature of the nervous system and its capacity to adapt provide opportunities for recovery of function. It is apparent that activity-dependent plasticity plays a role in this recovery and that the endogenous response to injury heightens the capacity for recovery for at least several weeks postinjury. To restore locomotor function, researchers have investigated the use of treadmill-based training, robots, and electrical stimulation to tap into adaptive activity-dependent processes. The current challenge is to maximize the degree of functional recovery. This manuscript reviews the endogenous neural system response to injury, and reviews data and presents novel analyses of these from a rat model of contusion injury that demonstrates how a targeted intervention can accelerate recovery, presumably by engaging processes that underlie activity-dependent plasticity.


Cytotoxicity, anti-angiogenic, apoptotic effects and transcript profiling of a naturally occurring naphthyl butenone, guieranone A.
Malignant diseases are responsible of approximately 13% of all deaths each year in the world. Natural products represent a valuable source for the development of novel anticancer drugs. The present study was aimed at evaluating the cytotoxicity of a naphtyl butanone isolated from the leaves of Guiera senegalensis, guieranone A (GA). The results indicated that GA was active on 91.67% of the 12 tested cancer cell lines, the IC50 values below 4 μg/ml being recorded on 83.33% of them. In addition, the IC50 values obtained on human lymphoblastic leukemia CCRF-CEM (0.73 μg/ml) and its resistant subline CEM/ADR5000 (1.01 μg/ml) and on lung adenocarcinoma A549 (0.72 μg/ml) cell lines were closer or lower than that of doxorubicin. Interestingly, low cytotoxicity to normal hepatocyte, AML12 cell line was observed. GA showed anti-angiogenic activity with up to 51.9% inhibition of the growth of blood capillaries on the chorioallantoic membrane of quail embryo. Its also induced apotosis and cell cycle arrest. Ingenuity Pathway Analysis identified several pathways in CCRF-CEM cells and functional group of genes regulated upon GA treatment (P < 0.05), the Cell Cycle: G2/M DNA Damage Checkpoint Regulation and ATM Signaling pathways being amongst the four most involved functional groups. The overall results of this work provide evidence of the cytotoxic potential of GA and supportive data for its possible use in cancer chemotherapy.


Inhibition of growth of two human pancreatic adenocarcinomas in vivo by somatostatin analog SMS 201-995.
Somatostatin inhibits hormone secretion from gastrointestinal endocrine tumors. The purpose of this study was to determine whether SMS 201-995, a long-acting analog, would inhibit the growth of pancreatic adenocarcinomas. Two human pancreatic cancers grown in nude mice were studied: SKI, which has cholecystokinin receptors, and CAV, which does not. Tumors were implanted in groups of six mice each. Treatment groups received SMS 201-995 (100 micrograms/kg three times daily) by intraperitoneal injections and control animals received saline solution. Tumor area was measured twice weekly. After 7 weeks, the tumors and mouse pancreases were excised, weighed, and analyzed for protein and RNA and DNA content. In a second set of experiments, treatment was begun 21 days after transplantation. Mean body weights between groups were not different in any experiment. With treatment beginning on the day of transplantation, the tumor areas of SKI and CAV cancers were reduced by the third and fifth weeks of treatment, respectively. Tumor doubling times were prolonged with treatment in both SKI tumors (5 days) and CAV tumors (6 days). In the SKI treatment groups, tumor weight (52 percent), RNA content (72 percent), and DNA content (60 percent) were decreased at sacrifice compared with those of the control groups. In the CAV treatment group, the mean tumor weight (55 percent) and protein (48 percent), RNA (67 percent) and DNA contents (60 percent) were decreased compared with the CAV control group. Tumor growth of SKI and CAV cancers was also inhibited when treatment was delayed 21 days after transplantation. We conclude that these effects are not mediated by inhibition of cholecystokinin, as seen by similar inhibitory effects on both tumors. Treatment with SMS 201-995 may be an effective hormonal therapy in patients with pancreatic cancers.


Heart failure therapy: the fifth card.
The 2021 European Society of Cardiology guidelines for the diagnosis and treatment of acute and chronic heart failure (HF) have abandoned the sequential approach for optimal drug therapy and propose four drug classes (enzyme inhibitors conversion agents, angiotensin receptor antagonists, beta-blockers, and sodium-glucose cotransporter inhibitors 2) to be initiated and titrated in all patients with an ejection fraction <35%. This new approach offers advantages such as rapid introduction and titration, better tolerability, and early instrumental re-evaluation. In the VICTORIA study, the molecule vericiguat, a soluble guanylate cyclase activator, was shown to reduce the composite outcome of death from cardiovascular causes and first hospitalization for HF in a high-risk population. An additional randomized clinical trial (VICTOR) is ongoing to evaluate the efficacy and safety of vericiguat in a population with HF on optimized therapy and with no recent episodes of stabilization.


GSK3beta promotes apoptosis after renal ischemic injury.
The mechanism by which the serine-threonine kinase glycogen synthase kinase-3beta (GSK3beta) affects survival of renal epithelial cells after acute stress is unknown. Using in vitro and in vivo models, we tested the hypothesis that GSK3beta promotes Bax-mediated apoptosis, contributing to tubular injury and organ dysfunction after acute renal ischemia. Exposure of renal epithelial cells to metabolic stress activated GSK3beta, Bax, and caspase 3 and induced apoptosis. Expression of a constitutively active GSK3beta mutant activated Bax and decreased cell survival after metabolic stress. In contrast, pharmacologic inhibition (4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione [TDZD-8]) or RNA interference-mediated knockdown of GSK3beta promoted cell survival. Furthermore, RNA interference-mediated knockdown of Bax abrogated the cell death induced by constitutively active GSK3beta. In a cell-free assay, TDZD-8 inhibited the phosphorylation of a peptide containing the Bax serine(163) site targeted by stress-activated GSK3beta. In rats, TDZD-8 inhibited ischemia-induced activation of GSK3beta, Bax, and caspase 3; ameliorated tubular and epithelial cell damage; and significantly protected renal function. Taken together, GSK3beta-mediated Bax activation induces apoptosis and tubular damage that contribute to acute ischemic kidney injury.


Inhibition of Nodal signalling by Lefty mediated through interaction with common receptors and efficient diffusion.
Two TGFbeta-related proteins, Nodal and Lefty, are implicated in early embryonic patterning of vertebrates. Genetic data suggest that Nodal is a signalling molecule, while Lefty is an antagonist of Nodal, but their precise function remains unknown. The signalling pathway of Nodal was investigated with the use of a Nodal-responsive assay system based on frog animal caps. Expression of dominant negative mutants of various receptors indicated that ALK4, and either ActRIIA or ActRIIB, function as type I and type II receptors for Nodal, respectively. A soluble form of Cripto lacking the COOH-terminal region interacted with Nodal but failed to mediate Nodal signalling, indicating that the native Cripto protein functions as a membrane-bound co-receptor for Nodal. Processed forms of Lefty proteins, both smaller and larger forms, inhibited Nodal signalling. Such Lefty-induced inhibition was rescued by excess ActRIIA or ActRIIB, suggesting that Lefty antagonizes Nodal signalling through competitive binding to the common receptor ActRIIA or ActRIIB. This idea was supported by the demonstration of a genetic interaction between lefty2 and ActRIIB in mouse. Behaviours of GFP-Nodal and GFP-Lefty2 proteins were also investigated in chick embryos. Both proteins could diffuse over a long distance, but the latter diffused faster than the former. Efficient inhibition of Nodal signals by Lefty may involve competitive binding of Lefty to the common receptors and faster diffusion of Lefty.


Diet and acculturation among Hispanic/Latino older adults in the United States: a review of literature and recommendations.
Among U.S. and foreign-born Hispanic/Latino older adults living in the United States, associations of dietary acculturation and health outcomes have yielded no consistent findings. The purpose of this review was to present current knowledge and research disparities on acculturation, dietary intake, and health outcomes among the fastest growing minority group in the United States. Fifteen peer-reviewed studies that measured dietary acculturation among Mexican, Puerto Rican, and Dominican older adults living in the United States were identified and examined. This literature review divulged contradictory associations between dietary acculturation and dietary intake, along with nutritional and general health outcomes. Conclusive evidence has yet to be attained due to use of cross-sectional study designs and numerous acculturation measures as well as unique cultural and dietary patterns across diverse Hispanic/Latino populations. Further research is needed to ascertain dietary acculturation among U.S. and foreign-born Hispanic/Latino older adults in the United States and should strive to develop instruments that consider the social, economic, and political environments that influence the dietary acculturation process. Furthermore, longitudinal study designs and qualitative methodologies are warranted.


Management of the multiple organ donor.
The need for cadaveric organs for transplantation is increasing. This article provides guidelines for the identification of potential organ donors and suggests suitable principles of management. The physiological changes after brain death are briefly reviewed.


Volatile, Sensory and Functional Properties of HydroSOS Pistachios.
Climate change, the increase in world population, and the intensification of urban and industrial activities, will cause a shortage of water for agriculture. This situation requires conscientious studies to manage water deficits without affecting the quality of the crops. In this study, regulated deficit irrigation (RDI) strategies and three rootstocks (P. atlantica, P. integerrima, and P. terebinthus) were applied to pistachio cultivation to study the quality of fruits obtained based on the morphological, functional, aroma, and their sensory properties. The results obtained demonstrated that RDI T1 (during phenological phase II of cultivation the stem water potential was maintained around -1.5 MPa) led to pistachios with same morphological properties, total polyphenol content, antioxidant activity, volatile composition, sensory properties, better profile of fatty acids, and being the favorite ones for international consumers, as compared to pistachios obtained under full irrigation treatments. On the other hand, when P. integerrima was used, pistachios obtained had the highest weight, the lowest content of sucrose and the best functional properties.


The role of bronchial biopsy and washing in the diagnosis of allergic bronchopulmonary aspergillosis.
The diagnosis of allergic bronchopulmonary aspergillosis (ABPA) is usually established on the basis of clinical, serologic, and radiologic criteria, of which eight are commonly cited. Although histologic abnormalities are not usually considered, a study of lobectomy/lung biopsy specimens provided evidence that the combination of mucoid impaction of bronchi with "allergic" mucin and fungal hyphae is diagnostic of ABPA. We attempted to explore the use of surgical specimens in the diagnosis of ABPA by examining endobronchial biopsy specimens and washings. Bronchial biopsy specimens obtained from 1990 to 1995 that contained fungal hyphae were reviewed and assessed for the presence of "allergic" mucin and bronchial wall abnormalities. We also reviewed cytologic specimens and clinical, serologic, and radiologic findings of the corresponding patients. Five biopsy specimens had fungal hyphae and associated "allergic" mucin. In some patients, the mucin was small in amount and contained degenerated eosinophils that resembled macrophages. None of the patients was thought to have ABPA clinically. All of the five had bronchial mucoid impaction at bronchoscopy. After additional investigation, only one patient fulfilled all of the eight traditional criteria for ABPA; one other patient fulfilled six criteria. Although some tests were not completed in the remaining three patients, follow-up and/or response to steroids was consistent with ABPA in all of the three. Four patients had bronchial washing performed at the time of biopsy. Cytologic examination showed one to be normal except for inflammatory cells that did not include eosinophils; three others showed mucus containing eosinophils intermixed with Charcot-Leyden crystals and scattered hyphae. We conclude that patients with ABPA might have atypical manifestations of disease and not meet standard diagnostic criteria. Bronchoscopy with bronchial biopsy and washing plays a role in detecting these patients. The presence of "allergic" mucin might be overlooked in the small biopsy fragments obtained by bronchoscopy.


Effect of HBB genotype on survival in a cohort of transfusion-dependent thalassemia patients in Cyprus.
Initiation of regular transfusion in transfusion-dependent thalassemia (TDT) is based on the assessment of clinical phenotype. Pathogenic HBB variants causing β-thalassemia are important determinants of phenotype and could be used to aid decision making. We investigated the association of HBB genotype with survival in a cohort study in the four thalassemia centres in Cyprus. HBB genotype was classified as severe (β0/β0 or β+/β0), moderate (β+/β+), or mild (β0/β++ or β+/β++). Risk factors for mortality were evaluated using multivariate Cox proportional-hazards regression. 537 subjects were followed for a total of 20,963 person years. 80.4% (95% CI 76.4-84.7) of individuals survived to 50 years of age with increasing rates of liver, infection and malignancy-related deaths observed during recent follow-up. We evaluated non-modifiable risk factors and found worse outcomes associated with male sex (Hazard ratio 1.9, 95% CI 1.1-3.0, p=0.01) and milder genotype (Hazard ratio 1.6, 95% CI 1.1-2.3, p=0.02). The effect of genotype was confirmed in a second model, which included treatment effects. Patients with a milder genotype initiated transfusion significantly later and had reduced blood requirements compared to those with moderate or severe genotypes, although pre-transfusion hemoglobin levels did not differ between genotypes. Our results suggest that early treatment decisions to delay transfusion and different long-term treatment strategies in milder genotypes have led to adverse long-term effects of under-treated thalassemia and worse survival. We propose that HBB genotype determination and use of this information to aid in decision making can improve long-term outcomes of thalassaemia patients.


Molecular characterization of a small heat shock/alpha-crystallin protein in encysted Artemia embryos.
Molecular chaperones protect cells during stress by limiting the denaturation/aggregation of proteins and facilitating their renaturation. In this context, brine shrimp embryos can endure a wide variety of stressful conditions, including temperature extremes, prolonged anoxia, and desiccation, thus encountering shortages of both energy (ATP) and water. How the embryos survive these stresses is the subject of continuing study, a situation true for other organisms facing similar physiological challenges. To approach this question we cloned and sequenced a cDNA for p26, a molecular chaperone specific to oviparous Artemia embryos. p26 is the first representative of the small heat shock/alpha-crystallin family from crustaceans to be sequenced, and it possesses the conserved alpha-crystallin domain characteristic of these proteins. The secondary structure of this domain was predicted to consist predominantly of beta-pleated sheet, and it appeared to lack regions of alpha-helix. Unique properties of the nonconserved amino terminus, which showed weak similarity to nucleolins and fibrillarins, are enrichments in both glycine and arginine. The carboxyl-terminal tail is the longest yet reported for a small heat shock/alpha-crystallin protein, and it is hydrophilic, a common attribute of this region. Site-specific differences between amino acids from p26 and other small heat shock/alpha-crystallin proteins bring into question the functions proposed for some of these residues. Probing of Southern blots disclosed a multi-gene family for p26, whereas two size classes of p26 mRNA at 0.7 and 1.9 kilobase pairs were seen on Northern blots, the larger probably representing nonprocessed transcripts. Examination of immunofluorescently stained samples with the confocal microscope revealed that a limited portion of intracellular p26 is found in the nuclei of encysted embryos and that it resides within discrete compartments of this organelle. The results in this paper demonstrate clearly that p26 is a novel member of the small heat shock/alpha-crystallin family of proteins. These data, in concert with its restriction to embryos undergoing oviparous development, suggest that p26 functions as a molecular chaperone during exposure to stress, perhaps able to limit protein degradation and thus ensure a ready supply of functional proteins when growth is reinitiated.


Proximal intentional neglect: a case study.
Although neglect has been demonstrated in the horizontal, vertical, and radial planes of space and has been attributed to sensory-attentional, motor-intentional, and representational deficits, motor intentional neglect in the radial plane has not been previously described. A patient who had a right parietal infarct was tested with a modified cancellation task that uses a fixed window, thereby controlling attentional demands and allowing one to dissociate between intentional and representational neglect. This patient showed proximal (radial) intentional neglect (a failure to move towards or in proximal space). Unlike controls whose search times decreased with increasing window size, our patient showed no change in search time as a function of window size. This pattern of behaviour suggests that the patient's search strategy does not incorporate factors such as the relation between a fixed target space and a variably sized aperture, but rather was based on the allocation of a certain amount of resources for a fixed period of time after which, regardless of performance, the patient would stop searching.


Phase Ia/II, two-arm, open-label, dose-escalation study of oral panobinostat administered via two dosing schedules in patients with advanced hematologic malignancies.
Panobinostat is a potent oral pandeacetylase inhibitor that leads to acetylation of intracellular proteins, inhibits cellular proliferation and induces apoptosis in leukemic cell lines. A phase Ia/II study was designed to determine the maximum-tolerated dose (MTD) of daily panobinostat, administered on two schedules: three times a week every week or every other week on a 28-day treatment cycle in patients with advanced hematologic malignancies. The criteria for hematologic dose-limiting toxicities differed between patients with indications associated with severe cytopenias at baseline (leukemia and myeloid disorders) and those less commonly associated with baseline cytopenias (lymphoma and myeloma). In patients with leukemia and myeloid disorders, 60 mg was the MTD for weekly as well as biweekly panobinostat. In patients with lymphoma and myeloma, 40 mg was the recommended dose for phase II evaluation (formal MTD not determined) of weekly panobinostat, and 60 mg was the MTD for biweekly panobinostat. Overall, panobinostat-related grade 3-4 adverse events included thrombocytopenia (41.5%), fatigue (21%) and neutropenia (21%). Single-agent activity was observed in several indications, including Hodgkin lymphoma and myelofibrosis. This phase Ia/II study provided a broad analysis of the safety profile and efficacy of single-agent panobinostat in patients with hematologic malignancies.


Rivaroxaban Plus Aspirin in Patients With Vascular Disease and Renal Dysfunction: From the COMPASS Trial.
Chronic kidney disease is associated with an increased risk of both bleeding and ischemic cardiovascular events. The purpose of this study was to determine the balance of risks and benefits from the dual pathway antithrombotic regimen (rivaroxaban 2.5 mg twice daily [bd] plus aspirin, compared with aspirin) in vascular patients with or without moderate renal dysfunction. This was a secondary analysis of the COMPASS (Cardiovascular OutcoMes for People using Anticoagulation StrategieS) trial involving 27,395 patients with chronic coronary or peripheral artery disease. In COMPASS, 21,111 patients had an estimated glomerular filtration rate (GFR) at baseline of ≥60 ml/min, 6,276 had a GRF of <60 ml/min. Both the primary efficacy outcome (cardiovascular death, myocardial infarction, or stroke) and major bleeding were more frequent in those with renal dysfunction, and the frequency of these outcome events was inversely related to GFR. However, the primary outcome was consistently reduced with rivaroxaban 2.5 mg bd plus aspirin, irrespective of GFR category (GFR ≥60 ml/min, 3.5% rivaroxaban plus aspirin, 4.5% aspirin alone, hazard ratio [HR]: 0.76, 95% confidence interval [CI]: 0.64 to 0.90; GFR <60 ml/min, 6.4% rivaroxaban plus aspirin, 8.4% aspirin alone, HR: 0.75; 95% CI: 0.60 to 0.94). Major bleeding was more frequent with rivaroxaban 2.5 mg plus aspirin versus aspirin alone in those with GFR ≥60 ml/min (2.9% rivaroxaban plus aspirin, 1.6% aspirin alone, HR: 1.81; 95% CI: 1.44 to 2.28) and similarly in those with GFR <60 ml/min (3.9% rivaroxaban plus aspirin, 2.7% aspirin alone, HR: 1.47, 95% CI: 1.05 to 2.07). The benefits of the dual pathway COMPASS regimen (rivaroxaban 2.5 mg bd plus aspirin), versus aspirin alone, are preserved in patients with moderate renal dysfunction without evidence of an excess hazard of bleeding.


Cystic lesions of the pancreas. A diagnostic and management dilemma.
Due to enhanced imaging modalities, pancreatic cysts are being increasingly detected, often as an incidental finding. They comprise a wide range of differing underlying pathologies from completely benign through premalignant to frankly malignant. The exact diagnostic and management pathway of these cysts remains problematic and this review attempts to provide an overview of the pathology underlying pancreatic cystic lesions and suggests appropriate methods of management. A search was undertaken with a Pubmed database to identify all English articles using the keywords 'pancreatic cysts', 'serous cystadenoma', 'intraductal papillary mucinous tumour', 'pseudocysts', 'mucinous cystic neoplasm' and 'solid pseudopapillary tumour'. The mainstay of assessment of pancreatic cysts is cross-sectional imaging incorporating CT and MRI. Fine-needle aspiration (FNA) (often with endoscopic ultrasound) may provide valuable additional information but can lack sensitivity. Symptomatic cysts, increasing age and multilocular cysts (with a solid component and thick walls) are predictors of malignancy. A raised cyst aspirate CEA, CA 19-9 and mucin content (including abnormal cytology), if present, can accurately distinguish premalignant and malignant cysts from benign ones. In summary, all patients with pancreatic cystic lesions, whether asymptomatic or symptomatic, must be thoroughly investigated to ascertain the underlying nature of the cyst. Small asymptomatic cysts (<3 cm) with no suspicious features on imaging or FNA may be safely followed up. Follow-up should continue for at least 4 years, with a repeat FNA if needed. An algorithm for the management of pancreatic cystic tumours is also suggested. and IAP.


Effect of nasopharyngeal carcinoma-derived exosomes on human regulatory T cells.
Regulatory T cells (Treg) and tumor-exosomes are thought to play a role in preventing the rejection of malignant cells in patients bearing nasopharyngeal carcinoma (NPC). Treg recruitment by exosomes derived from NPC cell lines (C15/C17-Exo), exosomes isolated from NPC patients' plasma (Patient-Exo), and CCL20 were tested in vitro using Boyden chamber assays and in vivo using a xenograft SCID mouse model (n = 5), both in the presence and absence of anti-CCL20 monoclonal antibodies (mAb). Impact of these NPC exosomes (NPC-Exo) on Treg phenotype and function was determined using adapted assays (FACS, Q-PCR, ELISA, and MLR). Experiments were performed in comparison with exosomes derived from plasma of healthy donors (HD-Exo). The Student's t test was used for group comparisons. All statistical tests were two-sided. CCL20 allowed the intratumoral recruitment of human Treg. NPC-Exo also facilitated Treg recruitment (3.30 ± 0.34 fold increase, P < .001), which was statistically significantly inhibited (P < .001) by an anti-CCL20 blocking mAb. NPC-Exo also recruited conventional CD4(+)CD25(-) T cells and mediated their conversion into inhibitory CD4(+)CD25(high) cells. Moreover, NPC-Exo enhanced (P = .0048) the expansion of human Treg, inducing the generation of Tim3(Low) Treg with increased expression of CD25 and FOXP3. Finally, NPC-Exo induced an overexpression of cell markers associated with Treg phenotype, properties and recruitment capacity. For example, GZMB mean fold change was 21.45 ± 1.75 (P < .001). These results were consistent with a stronger suppression of responder cells' proliferation and the secretion of immunosuppressive cytokines (IL10, TGFB1). Interactions between NPC-Exo and Treg represent a newly defined mechanism that may be involved in regulating peripheral tolerance by tumors and in supporting immune evasion in human NPC.


Effect of instruction on the ability to use a self-administered epinephrine injector.
Patients with allergy as well as their parents frequently fail to use the self-administered epinephrine injection (EpiPen) properly in cases of allergic emergencies. To determine the benefit of an instruction session with follow-up instruction. We evaluated 141 patients aged 1.9-23.4 years (median 5.8 years, 83% with food allergy) or their parents (for those aged < 12 years) who were trained in the use of the EpiPen during the first diagnostic visit to the allergy clinic during 2006-2009. At the next follow-up visit, the patients or their parents were asked to list the indications for epinephrine administration and to demonstrate the five steps involved in using the EpiPen. Each step was scored on a scale of 0-2. Fourteen participants (9.9%) had used self-injectable epinephrine in the past. Only 65 (46%) brought the device with them to the follow-up visit. The mean total score for the whole sample was 4.03 +/- 3. Fifty-three participants (38%) failed to remove the cap before trying to apply the device. Only 8 (5.6%) had a maximum score. The patients and their parents were reinstructed in the use of the device: 41 participants were reexamined at a subsequent follow-up visit after 1.02 +/- 0.56 years; their mean score improved from 4.71 +/- 3.04 to 6.73 +/- 3.18 (P < 0.001). Patients with severe allergic reactions, as well as their parents, are not sufficiently skilled in the use of the EpiPen after only one instruction session with a specialist. Repeated instruction may improve the results and we therefore recommend that the instructions be repeated at every follow-up visit.


Cost-effectiveness analysis of the implementation of a National Immunization Program for rotavirus vaccination in a country with a low rotavirus gastroenteritis-related mortality: A South Korean study.
Rotavirus is a leading cause of severe gastroenteritis among children younger than 5 years in South Korea. Two rotavirus vaccines (RVs), pentavalent human-bovine reassortant vaccine (Rotateq®; RV5) and attenuated human strain originated monovalent vaccine (Rotarix®; RV1), have been available for voluntary vaccination using out-of-pocket payment since 2007 and 2008, respectively. Yet, RVs are not included in the National Immunization Program (NIP), partly because of the low associated mortality rate. We assessed the cost-effectiveness of RVs to assist the evidence-based decision-making process for NIP implementation in South Korea. Using a transparent age-structured static cohort model, we simulated the experience of ten annual birth cohorts of South Korean children from 2018 to 2027. Model inputs included rotavirus gastroenteritis (RVGE) incidence and mortality rates, RVGE treatment costs, vaccine coverage and timeliness, and vaccine effectiveness and price. The incremental costs of including RVs in the NIP compared to no vaccination were 59,662,738 USD and 152,444,379 USD for RV1 and RV5, respectively. The introduction of RV1 and RV5 can prevent 4799 disability-adjusted life years (DALYs) and 5068 DALYs. From the societal perspective, the incremental cost-effectiveness ratios (ICERs) for adopting RV into the NIP versus no vaccination were 12,432 USD per DALY averted for RV1 and 30,081 USD per DALY averted for RV 5. The weighted average for the ICERs of the two vaccines computed using the market share of each vaccine in the current voluntary use as a weight, was 21,698 USD per DALY averted. The estimated ICER was below 1 × gross domestic product per capita (30,000 USD), which has been a commonly used willingness-to-pay threshold for health care technology assessment in South Korea, suggesting that introducing RVs into the NIP would be cost-effective.


Targeting Complement Pathways in Polytrauma- and Sepsis-Induced Multiple-Organ Dysfunction.
Exposure to traumatic or infectious insults results in a rapid activation of the complement cascade as major fluid defense system of innate immunity. The complement system acts as a master alarm system during the molecular danger response after trauma and significantly contributes to the clearance of DAMPs and PAMPs. However, depending on the origin and extent of the damaged macro- and micro -milieu, the complement system can also be either excessively activated or inhibited. In both cases, this can lead to a maladaptive immune response and subsequent multiple cellular and organ dysfunction. The arsenal of complement-specific drugs offers promising strategies for various critical conditions after trauma, hemorrhagic shock, sepsis, and multiple organ failure. The imbalanced immune response needs to be detected in a rational and real-time manner before the translational therapeutic potential of these drugs can be fully utilized. Overall, the temporal-spatial complement response after tissue trauma and during sepsis remains somewhat enigmatic and demands a clinical triad: reliable tissue damage assessment, complement activation monitoring, and potent complement targeting to highly specific rebalance the fluid phase innate immune response.


Response of a Maize Synthetic to Selection for Components of Partial Resistance to Exserohilum turcicum.
A synthetic population of maize (Zea mays) was created from five inbred lines of varying levels of partial resistance to northern leaf blight (NLB). This synthetic was subjected to three cycles of recurrent phenotypic selection with pollen control for either increased latent period or decreased lesion length. A selection intensity of ca. 10% was used in each selection cycle. The original synthetic and three advanced selection cycles for each of the two components of partial resistance were evaluated in field trials in the summers of 1999 and 2001, and in greenhouse trials. Selection for increased latent period was more effective in improving resistance to NLB (20 to 27% gain/cycle) (as measured by area under the disease progress curve [AUDPC]) than was selection for decreased lesion length (14 to 18% gain/cycle). Responses in AUDPC to selection for either component of resistance were linear in the 1999 field trial, but were quadratic (decreased response in advanced cycles) in the 2001 trial. Selection for increased latent period in the field resulted in a 0.6-day increase in latent period per selection cycle when measured in the greenhouse and a 2-day increase per selection cycle when measured in the field. Selection for decreased lesion length in the field did not significantly alter latent period in the greenhouse. These results support using selection for increased latent period as an effective means of improving partial resistance to NLB in maize populations. Decreased lesion length was more difficult to measure and selection based on this criterion was less effective in improving partial resistance.


The Clinical Implications of Reversions in Patients with Advanced Pancreatic Cancer and Pathogenic Variants in BRCA1, BRCA2, or PALB2 after Progression on Rucaparib.
PARP inhibitors (PARPi) provide an effective maintenance option for patients with BRCA- or PALB2-mutated pancreatic cancer. However, mechanisms of PARPi resistance and optimal post-PARPi therapeutic strategies are poorly characterized. We collected paired cell-free DNA samples and post-PARPi clinical data on 42 patients with advanced, platinum-sensitive pancreatic cancer who were treated with maintenance rucaparib on NCT03140670, of whom 32 developed progressive disease. Peripherally detected, acquired BRCA or PALB2 reversion variants were uncommon (5/30; 16.6%) in patients who progressed on rucaparib. Reversions were significantly associated with rapid resistance to PARPi treatment (median PFS, 3.7 vs. 12.5 months; P = 0.001) and poor overall survival (median OS, 6.2 vs. 23.0 months; P < 0.0001). All patients with reversions received rechallenge with platinum-based chemotherapy following PARPi progression and experienced faster progression on this therapy than those without reversion variants (real-world time-to-treatment discontinuation, 2.4 vs. 5.8 months; P = 0.004). Of the patients who progressed on PARPi and received further chemotherapy, the OS from initiation of second-line therapy was significantly lower in those with reversion variants than in those without (5.5 vs. 12.0 months, P = 0.002). Finally, high levels of tumor shedding were independently associated with poor outcomes in patients who received rucaparib. Acquired reversion variants were uncommon but detrimental in a population of patients with advanced BRCA- or PALB2-related pancreatic ductal adenocarcinoma who received maintenance rucaparib. Reversion variants led to rapid progression on PARPi, rapid failure of subsequent platinum-based treatment, and poor OS of patients. The identification of such variants in the blood may have both predictive and prognostic value. See related commentary by Tsang and Gallinger, p. 5005.


Comprehending the dynamism of B chromosomes in their journey towards becoming unselfish.
Investigated for more than a century now, B chromosomes (Bs) research has come a long way from Bs being considered parasitic or neutral to becoming unselfish and bringing benefits to their hosts. B chromosomes exist as accessory chromosomes along with the standard A chromosomes (As) across eukaryotic taxa. Represented singly or in multiple copies, B chromosomes are largely heterochromatic but also contain euchromatic and organellar segments. Although B chromosomes are derived entities, they follow their species-specific evolutionary pattern. B chromosomes fail to pair with the standard chromosomes during meiosis and vary in their number, size, composition and structure across taxa and ensure their successful transmission through non-mendelian mechanisms like mitotic, pre-meiotic, meiotic or post-meiotic drives, unique non-disjunction, self-pairing or even imparting benefits to the host when they lack drive. B chromosomes have been associated with cellular processes like sex determination, pathogenicity, resistance to pathogens, phenotypic effects, and differential gene expression. With the advancements in B-omics research, novel insights have been gleaned on their functions, some of which have been associated with the regulation of gene expression of A chromosomes through increased expression of miRNAs or differential expression of transposable elements located on them. The next-generation sequencing and emerging technologies will further likely unravel the cellular, molecular and functional behaviour of these enigmatic entities. Amidst the extensive fluidity shown by B chromosomes in their structural and functional attributes, we perceive that the existence and survival of B chromosomes in the populations most likely seem to be a trade-off between the drive efficiency and adaptive significance versus their adverse effects on reproduction.


Ionic liquid mediated micelle to vesicle transition of a cationic gemini surfactant: a spectroscopic investigation.
In this contribution, we have examined a composition dependent self aggregated structural modification of a catanionic mixture of the surface active ionic liquid (IL) 1-butyl-3-methylimidazolium octyl sulphate and a cationic gemini surfactant (14-5-14) in aqueous medium. We have observed that the hydrodynamic diameter of the aggregates increases with increasing IL concentration and microscopic evidence (HRTEM, FESEM, and LCSM) shows the formation of vesicle like aggregates (Dh ≈ 200 nm) at XIL = 0.5. The steady state fluorescence anisotropy of the membrane binding probe DPH shows a micelle to vesicle transition at this composition. The viscosity of the solution shows a peak at XIL = 0.3, indicating the formation of a worm like micelle as an intermediate of the micelle to vesicle transition. The rotational dynamics shows a stiffer surfactant packing in the vesicles compared to the micelles, whereas, the solvation dynamics measurements indicate a higher abundance of bound type water in the vascular medium compared to that for the micelle. The formed vesicles also show stability towards temperature and biomolecules, which can be used for respective applications.


Zinc ejection as a new rationale for the use of cystamine and related disulfide-containing antiviral agents in the treatment of AIDS.
The highly conserved and mutationally intolerant retroviral zinc finger motif of the HIV-1 nucleocapsid protein (NC) is an attractive target for drug therapy due to its participation in multiple stages of the viral replication cycle. A literature search identified cystamine, thiamine disulfide, and disulfiram as compounds that have been shown to inhibit HIV-1 replication by poorly defined mechanisms and that have electrophilic functional groups that might react with the metal-coordinating sulfur atoms of the retroviral zinc fingers and cause zinc ejection. 1H NMR studies reveal that these compounds readily eject zinc from synthetic peptides with sequences corresponding to the HIV-1 NC zinc fingers, as well as from the intact HIV-1 NC protein. In contrast, the reduced forms of disulfiram and cystamine, diethyl dithiocarbamate and cysteamine, respectively, were found to be ineffective at zinc ejection, although cysteamine formed a transient complex with the zinc fingers. Studies with HIV-1-infected human T-cells and monocyte/macrophage cultures revealed that cystamine and cysteamine possess significant antiviral properties at nontoxic concentrations, which warrant their consideration as therapeutically useful anti-HIV agents.


Age of autism diagnosis in Latin American and Caribbean countries.
An earlier diagnosis of autism spectrum disorder might lead to earlier intervention. However, people living in Latin American and Caribbean countries do not have much knowledge about autism spectrum disorder symptoms. It has been suggested that the older a child is when diagnosed, the fewer opportunities he or she will have to receive services. We asked 2520 caregivers of autistic children in six different Latin America and Caribbean Countries, the child's age when they noticed some developmental delays and their child's age when they received their first autism spectrum disorder diagnosis. Results indicate that, on average, caregivers were concerned about their child's development by 22 months of age; however, the diagnosis was received when the child was 46 months of age. In addition, older children with better language abilities and public health coverage (opposed to private health coverage) were diagnosed later. On the contrary, children with other medical problems and more severe behaviors received an earlier diagnosis. In our study, children were diagnosed around the time they entered formal schooling, delaying the access to early intervention programs. In summary, the characteristics of the autistic person and the type of health coverage influence the age of diagnosis in children living in Latin America and Caribbean Countries.


Steroid elimination 24 hours after liver transplantation using daclizumab, tacrolimus, and mycophenolate mofetil.
Corticosteroids have long been a cornerstone of orthotopic liver transplant (OLTx) immunosuppression. Newer, more potent, agents have successfully allowed for more rapid tapering and discontinuation of corticosteroids in OLTx recipients. We hypothesize that corticosteroids can be safely avoided after the first postoperative day (POD) using these newer agents. Thirty adult OLTx recipients were prospectively enrolled in a randomized open-label, institutional review board-approved protocol. Fifteen patients (group A) received our standard regimen of tacrolimus, mycophenolate mofetil, and corticosteroids, and 15 patients (group B) received daclizumab, 2 mg/kg on POD 0 and 14, with tacrolimus, mycophenolate mofetil, and corticosteroids on POD 0 and 1 and then discontinuation. In both groups, mycophenolate mofetil was tapered off between 3 and 4 months after OLTx. Bone mineral densitometry was performed at 1, 3, and 6 months after OLTx. Quantitative hepatitis C virus (HCV) polymerase chain reaction was obtained at days 0, 7, 14, 21, and 28. Retransplant recipients, patients with autoimmune hepatitis, or status 1 or 2A patients were excluded. Patient and graft survival rates were 93% (group A) and 100% (group B) with mean follow-up of 18 months. Patients in group B had more rejection diagnosed (25%) compared with group A (6.7%). Yet, the incidence of biopsy-proven acute rejection requiring steroid therapy was 6.7% in both groups. Hispanic race was common in groups A and B (87% and 74%). A total of six biopsies were performed in group B, with three patients having mild rejection responding to an increase in tacrolimus without the need for corticosteroids. One patient in group B was switched to cyclosporine for severe neurotoxicity and remains on monotherapy with normal graft function. No patient in either group developed a requirement for additional antihypertensive medication. Likewise, there were no patients with new-onset diabetes. The bone mineral densitometry was higher in group B at every time point but did not reach statistical significance. Serum cholesterol level was significantly (P=0.03) lower in group B at 6 months after OLTx. Serum triglycerides were also lower, but the difference was not significant. Quantitative polymerase chain reaction for HCV-positive patients (group A, n=7; group B, n=8) frequently increased after OLTx. There was no correlative decrease associated with daclizumab. At present, two patients in group A have documented HCV recurrence. Corticosteroids can be safely avoided after POD 1 with the current regimen. With early follow-up, there is no difference in hypertension or diabetes or bone density. Lipid panels tended to be lower in patients who were not on corticosteroids. Longer term follow-up will be needed to demonstrate the potential advantage of corticosteroid avoidance in regard to hypertension, diabetes, and possibly HCV recurrence.


Successful treatment of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis with HLH-94 protocol.
Hemophagocytic lymphohistiocytosis (HLH) is a rare, fatal disorder of children, affecting predominantly the mononuclear phagocytic system. Previous reports indicate that Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (EBV-HLH) can also be fatal in many cases, although the prognosis for EBV-HLH is better than for the familial form of hemophagocytic lymphohistiocytosis. We treated four patients with EBV-HLH using immunochemotherapy including steroid, etoposide (VP-16), and cyclosporin, according to the HLH-94 protocol. All patients experienced persistent fever, cytopenia, and hypertriglyceridemia. Serological testing for EBV showed reactivated EBV infections in all patients. EBV DNA detected by PCR and EBV-encoded small RNA measured by in situ hybridization were confirmed in the patients' bone marrow specimens. Hemophagocytosis was shown in bone marrow aspirates and liver biopsy specimen. Complete remission was achieved in all patients after induction and continuation therapy for 4-10 months (median, 7 months) and was maintained for 15-27 months (median, 19 months) without the need for bone marrow transplantation. These results suggest that EBV-HLH can be effectively controlled by immunochemotherapy using the HLH-94 protocol.


The great drug policy debate--what means this thing called decriminalization?
The contemporary debate over decriminalization mimics in almost every respect a debate that took place in the 1960s and early 1970s. In both the earlier challenges to the status quo and the current attack on the criminalization of drug use, critics have stressed the counterproductive consequences of the prohibitionist ethos. Although it is unlikely that America will move toward decriminalization in the near future, the current debate provides an opportunity to examine the underlying premises of the massive expenditure of resources on repressive measures.


Community-Based ART Service Delivery for Key Populations in Sub-Saharan Africa: Scoping Review of Outcomes Along the Continuum of HIV Care.
HIV positive key population (KP) often face health system and social barriers to HIV care. KP include sex workers, men who have sex with men, persons who inject drugs, transgender people, and people in prisons and other closed settings. Community-based ART service delivery (CBART) has the potential to increase access to antiretroviral treatment (ART) and enhance retention in care. This scoping review summarized the evidence on the effect of CBART along the continuum of HIV care among KP in sub-Saharan Africa. We searched Pubmed, Web of Science, Google scholar, and NGO websites for articles published between 2010 and April 2020. We synthesized the involvement of KP community members or lay providers in medical task provision, and outcomes along the continuum of HIV care. Of 3,330 records identified, 66 were eligible for full test screening, out of which 12 were included in the review. CBART for KP was provided through: (a) community drop-in-centres, (b) community drop-in-centres plus mobile team, or (c) community-based health centres. KP were engaged as peer educators and they provided services such as community mobilisation activities for HIV testing and ART, ART adherence counselling, and referral for ART initiation. Across the KP-CBART studies, outcomes in terms of ART uptake, adherence to ART, retention in care and viral suppression were at least as good as those obtained for KP attending facility-based care. KP-CBART was as effective as facility-based care. To achieve the UNAIDS 95-95-95 target in sub-Saharan Africa, national programmes should scale-up KP-CBART to complement facility-based care.


Wild-type Drosophila melanogaster as a model host to analyze nitrogen source dependent virulence of Candida albicans.
The fungal pathogen Candida albicans is a common cause of opportunistic infections in humans. We report that wild-type Drosophila melanogaster (OrR) flies are susceptible to virulent C. albicans infections and have established experimental conditions that enable OrR flies to serve as model hosts for studying C. albicans virulence. After injection into the thorax, wild-type C. albicans cells disseminate and invade tissues throughout the fly, leading to lethality. Similar to results obtained monitoring systemic infections in mice, well-characterized cph1Δ efg1Δ and csh3Δ fungal mutants exhibit attenuated virulence in flies. Using the OrR fly host model, we assessed the virulence of C. albicans strains individually lacking functional components of the SPS sensing pathway. In response to extracellular amino acids, the plasma membrane localized SPS-sensor (Ssy1, Ptr3, and Ssy5) activates two transcription factors (Stp1 and Stp2) to differentially control two distinct modes of nitrogen acquisition (host protein catabolism and amino acid uptake, respectively). Our results indicate that a functional SPS-sensor and Stp1 controlled genes required for host protein catabolism and utilization, including the major secreted aspartyl protease SAP2, are required to establish virulent infections. By contrast, Stp2, which activates genes required for amino acid uptake, is dispensable for virulence. These results indicate that nutrient availability within infected hosts directly influences C. albicans virulence.


Unmet mental health needs in the general population: perspectives of Belgian health and social care professionals.
An unmet mental health need exists when someone has a mental health problem but doesn't receive formal care, or when the care received is insufficient or inadequate. Epidemiological research has identified both structural and attitudinal barriers to care which lead to unmet mental health needs, but reviewed literature has shown gaps in qualitative research on unmet mental health needs. This study aimed to explore unmet mental health needs in the general population from the perspective of professionals working with vulnerable groups. Four focus group discussions and two interviews with 34 participants were conducted from October 2019 to January 2020. Participants' professional backgrounds encompassed social work, mental health care and primary care in one rural and one urban primary care zone in Antwerp, Belgium. A topic guide was used to prompt discussions about which groups have high unmet mental health needs and why. Transcripts were coded using thematic analysis. Five themes emerged, which are subdivided in several subthemes: (1) socio-demographic determinants and disorder characteristics associated with unmet mental health needs; (2) demand-side barriers; (3) supply-side barriers; (4) consequences of unmet mental health needs; and (5) suggested improvements for meeting unmet mental health needs. Findings of epidemiological research were largely corroborated. Some additional groups with high unmet needs were identified. Professionals argued that they are often confronted with cases which are too complex for regular psychiatric care and highlighted the problem of care avoidance. Important system-level factors include waiting times of subsidized services and cost of non-subsidized services. Feelings of burden and powerlessness are common among professionals who are often confronted with unmet needs. Professionals discussed future directions for an equitable mental health care provision, which should be accessible and targeted at those in the greatest need. Further research is needed to include the patients' perspective of unmet mental health needs.


Successful treatment of permethrin toxicosis in two cats with an intravenous lipid administration.
The present work describes successful treatment of permethrin toxicosis in two cats with a novel therapy of intravenous lipid administration. Two cats presented in lateral recumbency and with generalized tremor after they had been incidentally treated with permethrin for flea control by their owners. Initial therapy consisted of diazepam, propofol, bathing, and intravenous fluids. After an initial bolus of 2mg/kg BW pentobarbital a pentobarbital continuous rate infusion (CRI) was started. Both cats received an emulsion of 20% soybean oil and 80% olive oil, commonly used as fat component of total parenteral nutrition in humans, later in the course of therapy. A bolus of 2 ml/kg BW of the emulsion followed by a CRI of 4 ml/kg BW/h for 4 hours was administered via a jugular catheter as reported previously. One cat received two cycles of therapy with intravenous lipid whereas the other cat needed just one application. Both cats recovered completely without requiring any further treatment. In conclusion, administration of intravenous lipids for permethrin toxicosis in cats is a novel treatment approach which seems to be highly effective in shortening the recovery time for permethrin toxicosis and possibly other fat-soluble toxins.


The resurgence of mumps and pertussis.
Vaccines and extended vaccination programs have had an extensive impact on morbidity and mortality rates due to infectious diseases. Because of the continuous and extensive use of vaccines in industrialized countries, many infectious diseases such as poliomyelitis, diphtheria and measles have been reduced to near-extinction. However, in recent years, many countries including the United States of America, the United Kingdom and Belgium, have been confronted with a resurgence of mumps and pertussis, despite high vaccination coverage for both vaccines. In this commentary, possible causes of this resurgence will be discussed, such as the occurrence of adapted microbes, failure to vaccinate and primary and secondary vaccine failure. Additional research of the immunological mechanisms is clearly needed to support the development of possible new and more immunogenic vaccines against mumps and pertussis. Meanwhile, extensive vaccination campaigns with both vaccines remain necessary.


Substance P: binding properties and studies on cellular responses in guinea pig macrophages.
The neuropeptide Substance P (SP) has been recognized to modulate functional activities of inflammatory cells. We have previously shown that it mediates macrophage activation. In this study we examined binding characteristics of SP and searched for additional evidence of heightened metabolic activity of guinea pig peritoneal macrophages upon challenge with this peptide. Radioligand studies indicated the existence of a homogeneous class of specific binding sites with high affinity for SP on macrophages. Scatchard analysis yielded an apparent KD of 1.9 +/- 0.4 X 10(-8) M (range: 1.4 to 2.4 X 10(-8) M), which was confirmed by kinetic studies. Binding was dose related, saturable, reversible, and could be inhibited by the SP antagonist (D-Pro2,D-Phe7,D-Trp9)-SP. Examination of peptide structural requirements revealed that both the COOH- and NH2-terminus contribute to receptor-ligand interaction. Other members of the tachykinin group of peptides were devoid of stimulatory action on macrophages. Cellular responses after engagement of the receptor sites by SP included downregulation of the membrane-associated enzyme 5'-nucleotidase and stimulation of synthesis and release of arachidonic acid metabolites, as well as of the lysosomal enzyme ADGase. These actions were specific as evidenced by immunoabsorption experiments. Our findings demonstrate that macrophage activation afforded by SP is effected through a receptor-mediated mechanism. Liberation of proinflammatory and immunomodulating substances in response to SP may be relevant to the pathogenesis of neuroinflammatory disease.


Proton MR spectroscopy of brain abnormalities in neonates born to HIV-positive mothers.
To examine the sensitivity of proton MR spectroscopy for detecting early central nervous system abnormalities in neonates born to human immunodeficiency virus (HIV)-positive mothers. Asleep, unsedated, and continuously monitored by electrocardiography, 10 newborns, 5 with HIV-positive and 5 with HIV-negative mothers, were studied within the first 10 days of life in a 1.5-T scanner. After T1- and T2-weighted images were obtained, proton spectra were performed using voxels of interest (3.4 cm3) in the deep parietooccipital white matter. Peaks were identified as N-acetyl-aspartate (2.0 ppm), creatine and phosphocreatine (3.0 ppm), choline (3.2 ppm), and inositol (3.5 ppm). Peak areas were used to calculate metabolic ratios: N-acetyl-aspartate to creatine, inositol to creatine, and creatine to choline. All newborns of HIV-positive mothers had abnormal proton spectra compared with control infants; a nonspecific amino acid peak in the 2.1- to 2.6-ppm area was elevated, broad, and overlapping the N-acetyl-aspartate peak in all the HIV-exposed newborns and in only 1 of the 5 control newborns. The choline-to-creatine ratio was higher in HIV-exposed newborns at 2.3 +/- 0.4 (normal term, 0.9 +/- 0.3), as was the N-acetyl-aspartate-to-creatine ratio at 2.6 +/- 0.9 (for control subjects, 1.2 +/- 0.4). MR images from these brain regions were all considered normal. Because acquired immunodeficiency syndrome develops in only a small fraction of neonates born to HIV-seropositive mothers, the above spectral abnormalities found in all our subjects may result from indirect effects of HIV, such as intrauterine growth retardation. These findings indicate that proton MR spectroscopy might play an important role in detecting early central nervous system complications in newborns of HIV-seropositive mothers.


Integrating Patient-Generated Health Data Into Clinical Care Settings or Clinical Decision-Making: Lessons Learned From Project HealthDesign.
Patient-generated health data (PGHD) are health-related data created or recorded by patients to inform their self-care and understanding about their own health. PGHD is different from other patient-reported outcome data because the collection of data is patient-driven, not practice- or research-driven. Technical applications for assisting patients to collect PGHD supports self-management activities such as healthy eating and exercise and can be important for preventing and managing disease. Technological innovations (eg, activity trackers) are making it more common for people to collect PGHD, but little is known about how PGHD might be used in outpatient clinics. The objective of our study was to examine the experiences of health care professionals who use PGHD in outpatient clinics. We conducted an evaluation of Project HealthDesign Round 2 to synthesize findings from 5 studies funded to test tools designed to help patients collect PGHD and share these data with members of their health care team. We conducted semistructured interviews with 13 Project HealthDesign study team members and 12 health care professionals that participated in these studies. We used an immersion-crystallization approach to analyze data. Our findings provide important information related to health care professionals' attitudes toward and experiences with using PGHD in a clinical setting. Health care professionals identified 3 main benefits of PGHD accessibility in clinical settings: (1) deeper insight into a patient's condition; (2) more accurate patient information, particularly when of clinical relevance; and (3) insight into a patient's health between clinic visits, enabling revision of care plans for improved health goal achievement, while avoiding unnecessary clinic visits. Study participants also identified 3 areas of consideration when implementing collection and use of PGHD data in clinics: (1) developing practice workflows and protocols related to PGHD collection and use; (2) data storage, accessibility at the point of care, and privacy concerns; and (3) ease of using PGHD data. PGHD provides value to both patients and health care professionals. However, more research is needed to understand the benefit of using PGHD in clinical care and to identify the strategies and clinic workflow needs for optimizing these tools.


Measuring burstiness for finite event sequences.
Characterizing inhomogeneous temporal patterns in natural and social phenomena is important to understand underlying mechanisms behind such complex systems and, hence, even to predict and control them. Temporal inhomogeneities in event sequences have been described in terms of bursts that are rapidly occurring events in short time periods alternating with long inactive periods. The bursts can be quantified by a simple measure, called the burstiness parameter, which was introduced by Goh and Barabási [Europhys. Lett. 81, 48002 (2008)EULEEJ0295-507510.1209/0295-5075/81/48002]. The burstiness parameter has been widely used due to its simplicity, which, however, turns out to be strongly affected by the finite number of events in the time series. As the finite-size effects on burstiness parameter have been largely ignored, we analytically investigate the finite-size effects of the burstiness parameter. Then we suggest an alternative definition of burstiness that is free from finite-size effects and yet simple. Using our alternative burstiness measure, one can distinguish the finite-size effects from the intrinsic bursty properties in the time series. We also demonstrate the advantages of our burstiness measure by analyzing empirical data sets.