Parkinson's Disease Medication Administration During a Care Transition: The Impact of Interprofessional Team Simulation on Student Competency, Comfort, and Knowledge.
This study investigated the impact of an interprofessional mock code on students' comfort and competency related to Parkinson's disease (PD) medication administration during care transitions. Patients with PD are at increased risk for medication errors during hospitalization. Individualization of PD medication creates vulnerability during care transitions. Four interprofessional groups took part in this study: baccalaureate degree senior nursing students (n = 113), master's level nurse anesthesia students (n = 35), doctor of osteopathic medicine fourth-year students (n = 32), and doctor of clinical psychology fourth-year students (n = 22). Groups participated in an unfolding case study simulation involving a mock code with a focus on the omission of time-sensitive PD medication. Pre- and postsimulation test results were compared. Findings indicated an increased understanding among three of the four groups relating to medication timing during care transitions. All groups improved with respect to perceived comfort and competency.


Technical limitations and pitfalls of diffusion-weighted imaging in intraoperative high-field MRI.
Image quality in high-field intraoperative MRI (iMRI) is often influenced negatively by susceptibility artifacts. While routine sequences are rather robust, advanced imaging such as diffusion-weighted imaging (DWI) is very sensitive to susceptibility resulting in insufficient imaging data. This study aims to analyze intraoperatively acquired DWI to identify the main factors for susceptibility, to compare results with postoperative images and to identify technical aspects for improvement of intraoperative DWI. 100 patients with intraaxial lesions operated in a high-field iMRI were analyzed retrospectively for the quality of intraoperative DWI in comparison to the postoperative scan. General quality of the MR scan, individual diffusion restrictions, artifacts, and their causes were analyzed. Inclusion criteria were met in 78 patients, 124 diffusion restrictions were included in the comparative analysis. PPV and NPV for the detection of DWI changes intraoperatively were 0.94 and 0.56, respectively (SEN 0.94; SPE 0.56). Image quality was rated significantly (p < 0.0001) worse intraoperatively compared to the postoperative MRI. The main reasons for reduced image quality intraoperatively were air (64%) and artificial material (e.g., compress) (38%) in the resection cavity, as well as positioning of patient's head outside the MR's isocenter 37%. Analysis of surgical approaches showed that frontal craniotomies have the highest risk of limited image quality (40%), whereat better results (15% limited image quality) were seen for all other approaches (p = 0.059). Intraoperative DWI showed reliable results in this analysis. However, image-quality was limited severely in many cases leading to uncertainty in the interpretation. Susceptibility-causing factors might be prevented in many cases, if the surgical team is aware of them. The most important factors are good filling of the resection cavity with irrigation fluid, not placing artificial materials in the resection cavity and adequate positioning of patient's head according to the MR isocenter.


External validation of the HCM Risk-Kids model for predicting sudden cardiac death in childhood hypertrophic cardiomyopathy.
Sudden cardiac death (SCD) is the most common mode of death in childhood hypertrophic cardiomyopathy (HCM). The newly developed HCM Risk-Kids model provides clinicians with individualized estimates of risk. The aim of this study was to externally validate the model in a large independent, multi-centre patient cohort. A retrospective, longitudinal cohort of 421 patients diagnosed with HCM aged 1-16 years independent of the HCM Risk-Kids development and internal validation cohort was studied. Data on HCM Risk-Kids predictor variables (unexplained syncope, non-sustained ventricular tachycardia, maximal left ventricular wall thickness, left atrial diameter, and left ventricular outflow tract gradient) were collected from the time of baseline clinical evaluation. The performance of the HCM Risk-Kids model in predicting risk at 5 years was assessed. Twenty-three patients (5.4%) met the SCD end-point within 5 years, with an overall incidence rate of 2.03 per 100 patient-years [95% confidence interval (CI) 1.48-2.78]. Model validation showed a Harrell's C-index of 0.745 (95% CI 0.52-0.97) and Uno's C-index 0.714 (95% 0.58-0.85) with a calibration slope of 1.15 (95% 0.51-1.80). A 5-year predicted risk threshold of ≥6% identified 17 (73.9%) SCD events with a corresponding C-statistic of 0.702 (95% CI 0.60-0.81). This study reports the first external validation of the HCM Risk-Kids model in a large and geographically diverse patient population. A 5-year predicted risk of ≥6% identified over 70% of events, confirming that HCM Risk-Kids provides a method for individualized risk predictions and shared decision-making in children with HCM.


Periplocoside P affects synaptic transmission at the neuromuscular junction and reduces synaptic excitability in Drosophila melanogaster by inhibiting V-ATPase.
Periplocoside P (PSP) is a major component of Periploca sepium Bunge known for its potent insecticidal activity. V-Type adenosine triphosphatase (V-ATPase), which is widely distributed in the cytoplasmic membranes and organelles of eukaryotic cells, plays a crucial role in synaptic excitability conduction. Previous research has shown that PSP targets the apical membrane of goblet cells in the insect midgut. However, the effects of PSP on synaptic transmission at the neuromuscular junction are often overlooked. The bioassay revealed that Drosophila adults with different genetic backgrounds showed varying levels of susceptibility to PSP in the order: parats1 > parats1 ;DSC1-/- ≈ w1118 > DSC1-/- . Intracellular electrode recording demonstrated that PSP, similar to bafilomycin A1, had an impact on the amplitude of the excitatory junction potential (EJP) and accelerated excitability decay. Furthermore, the alteration in EJP amplitude is concentration-dependent. Another surprising discovery was that the knockout DSC1 channel showed insensitivity to PSP. Our findings confirm that PSP can influence synaptic transmission at the neuromuscular junction of Drosophila larvae by targeting V-ATPase. These results provide a basis for investigating the mechanism of action of PSP and its potential application in designing novel insecticides. © 2023 Society of Chemical Industry.


Designs for Evaluating the Community-Level Impact of Comprehensive Prevention Programs: Examples from the CDC Centers of Excellence in Youth Violence Prevention.
This article discusses the opportunities and challenges of developing research designs to evaluate the impact of community-level prevention efforts. To illustrate examples of evaluation designs, we describe six projects funded by the Centers for Disease Control and Prevention to evaluate multifaceted approaches to reduce youth violence in high-risk communities. Each of these projects was designed to evaluate the community-level impact of multiple intervention strategies to address individual and contextual factors that place youth at risk for violent behavior. Communities differed across projects in their setting, size, and how their boundaries were defined. Each project is using multiple approaches to compare outcomes in one or more intervention communities to those in comparison communities. Five of the projects are using comparative interrupted time-series designs to compare outcomes in an intervention community to matched comparison communities. A sixth project is using a multiple baseline design in which the order and timing of intervention activities is randomized across three communities. All six projects are also using regression point displacement designs to compare outcomes within intervention communities to those within broader sets of similar communities. Projects are using a variety of approaches to assess outcomes including archival records, surveys, and direct observations. We discuss the strengths and weaknesses of the designs of these projects and illustrate the challenges of designing high-quality evaluations of comprehensive prevention approaches implemented at the community level.


Influence of silibinin and β-β-dimethylacrylshikonin on chordoma cells.
Chordoma, slow growing bone tumours originating from remnants of the notochord, leave affected patients with a median survival of six years. The high recurrence rate of chordoma, together with limited treatment options and bad overall prognosis, make the development of new treatment options urgently necessary. In this study, the potential of two natural products, silibinin and β-β-dimethylacrylshikonin (DMAS), was tested on clival (MUG-CC1 and UM-Chor1) as well as sacral (MUG-Chor1 and U-CH2) chordoma cell lines. The treatment was administered both as single- and combined therapy. For investigation of cell viability, the Cell Titer 96 Aqueous Non-Radioactive Cell Proliferation Assay Kit was used. Apoptosis induction was studied by flow cytometry, (Annexin V/SYTOX Green, caspase-3) and RT-qPCR. Pathway analyses were performed by western blot. Both drugs were found to reduce cell viability alone as well as in combination in a dose dependent manner, with DMAS being more efficient than silibinin. The mode of cell death was mainly apoptosis in DMAS treated samples, while the combination therapy led to apoptosis as well as late-apoptosis/necrosis. Silibinin therapy alone, although reducing cell viability, did not lead to significant apoptotic effects in the performed assays. Focussing on the molecular mechanism of DMAS induced apoptosis, it was found that major genes of the mitochondrial apoptosis pathway, like NOXA and PUMA were overexpressed. Additionally, western blot experiments showed a decrease of ERK/pERK, STAT3/pSTAT3 (Tyr705) and AKT/pAKT expression/activation levels under DMAS treatment. DMAS is a promising new candidate for chordoma therapy, while silibinin or a combination of both is less favourable.


Intoxicating effects of three aliphatic alcohols and barbital on two rat strains genetically selected for their ethanol intake.
Intoxicating effects of ethanol, isopropanol, tert. butanol and barbital were studied by comparing performances on the tilted plane of ethanol preferring AA (Alko, Alcohol) and ethanol avoiding ANA (Alko, Non-Alcohol) rat strains raised by genetic selection for their voluntary ethanol intake. The motor coordination of AA rats was found to be less affected than that of ANA rats by all three alcohols and barbital. The results indicate a marked genetic difference in neural tolerance to the alcohols and barbital, and suggest that neural tolerance to alcohols plays a role in determining the ethanol preference of AA rats and ethanol aversion of ANA rats.


A review: Development and application of surface molecularly imprinted polymers toward amino acids, peptides, and proteins.
Molecularly imprinted polymers (MIPs) have received wide interests in the bioanalysis field as "artificial antibodies". They can mimic biological receptors by selectively recognizing and adsorbing target molecules owing to their specific affinity to the targets. Traditional MIPs obtained by bulk imprinting have some defects, including low adsorption capacity, poor site accessibility, restricted mass transfer, and irregular morphology, which limit their development. Surface molecularly imprinted polymers (SMIPs) show the features of large surface area, allow fast mass transfer, and have high adsorption capacity and efficiency. They have been intensively used in the research of amino acids, peptides, and proteins due to these advantages. In this review, we systematically summarize the preparation of SMIPs including components and polymerization strategies, and their applications focusing on amino acids, peptides, and proteins are discussed in detail. Finally, future trends and challenges for the design and development of SMIPs are described.


Discovery of small molecule β-catenin suppressors that enhance immunotherapy.
Small molecules directly downregulating β-catenin could potentially offer a more effective therapeutic approach for combating against cancer stem cells, as compared to targeting the downstream components of the Wnt/β-catenin pathway. The challenge, however, lies in the fact that very few β-catenin suppressors have proven clinically effective, leaving a significant gap in medical solutions. Given that E-cadherin has a natural affinity for β-catenin, it stands to reason that agents designed to increase E-cadherin expression might provide an alternative method of regulating β-catenin levels. In this study, we report our discovery of DSS-C12 and DSS-B8, specific ester-based drugs derived from Dan-Shen-Su (DSS) extracted from the herb Salvia miltiorrhiza. Remarkably, these compounds display a potent ability to downregulate β-catenin, while also improving overall survival in post-surgery mice. Additionally, when these drugs are used in combination with PD-L1 checkpoint blockade, they stimulate enhanced systemic immune responses leading to significant suppression of primary tumor growth. In-depth mechanistic studies revealed that DSS-B8 functions as a vitamin D receptor agonist without inducing hypercalcemic effects. Collectively, our findings indicate that DSS-derived small molecules have considerable potential as clinically viable therapeutic strategies for β-catenin deactivation.


First visualization of circulating neutrophil extracellular traps using cell fluorescence during human septic shock-induced disseminated intravascular coagulation.
Disseminated intravascular coagulation (DIC) is a severe complication of septic shock. Polymorphonuclear neutrophils (PMNs) may play a key role in septic shock-induced DIC via the release of neutrophils extracellular traps (NETs). NETs capture invading pathogens, but also act as a pro-coagulant surface at the interface between immunity and thrombosis. During septic shock-induced DIC, neutrophil activation may result in excessive NET formation. Herein, we originally report the presence of circulating NETs in human blood during septic shock-induced DIC. To investigate NET formation during shock-induced DIC neutrophils were isolated from patients in septic shock associated with (n = 3) or without (n = 3) DIC. Neutrophils from healthy donors (n = 3) were stimulated in vitro with ionomycin as NET formation positive controls. PMNs smears were stained with mouse anti-human FITC anti-myeloperoxidase antibody and the blue-fluorescent DAPI nucleic acid stain. NETs were identified as elongated extracellular DNA fibers associated to myeloperoxidase detected by immunofluorescence. NETs were unambiguously observed in PMNs from septic shock patients with DIC but not from patients without DIC. NETs features in DIC+ patients were undistinguishable from those observed in ionomycin-induced PMNs from healthy donors. Fluorescence images of NETs were associated to extracellular cytoplasmic expansions. Our data report for the first time the direct visualization of circulating NETs in patients with septic shock-induced DIC. The in vivo relevance of previously reported indirect markers of NETosis (neutrophil side fluorescence) is confirmed.


Mechanistic-enriched models: integrating transcription factor networks and metabolic deregulation in cancer.
In the present paper we will examine methodological frameworks to study complex genetic diseases (e.g. cancer) from the stand point of theoretical-computational biology combining both data-driven and hypothesis driven approaches. Our work focuses in the apparent counterpoint between two formal approaches to research in natural science: data- and hypothesis-driven inquiries. For a long time philosophers have recognized the mechanistic character of molecular biology explanations. On these grounds we suggest that hypothesis and data-driven approaches are not opposed to each other but that they may be integrated by the development of what we call enriched mechanistic models. We will elaborate around a case study from our laboratory that analyzed the relationship between transcriptional de-regulation of sets of genes that present both transcription factor and metabolic activity while at the same time have been associated with the presence of cancer. The way we do this is by analyzing structural, mechanistic and functional approaches to molecular level research in cancer biology. Emphasis will be given to data integration strategies to construct new explanations. Such analysis has led us to present a mechanistic-enriched model of the phenomenon. Such model pointed out to the way in which regulatory and thermodynamical behavior of gene regulation networks may be analyzed by means of gene expression data obtained from genome-wide analysis experiments in RNA from biopsy-captured tissue. The foundations of the model are given by the laws of thermodynamics and chemical physics and the approach is an enriched version of a mechanistic explanation. After analyzing the way we studied the coupling of metabolic and transcriptional deregulation in breast cancer, we have concluded that one plausible strategy to integrate data driven and hypothesis driven approaches is by means of resorting to fundamental and well established laws of physics and chemistry since these provide a solid ground for assessment.


A set of inhibitors for discrimination between the basic isozymes of glutathione transferase in rat liver.
A set of inhibitors including hematin, bromosulfophthalein, and triethyltin bromide was used for discrimination and identification of the major basic isozymes of glutathione transferase in rat liver cytosol. Six enzymes are formed as binary combinations of 4 protein subunits: A, B, C, and L. Discrimination between the transferases can be based on the differences of the subunits in susceptibility to the inhibitors. The identification of transferase subunits is further supported by the combined use of specific substrates and inhibitors.


Platelet-activating factor induces cell death in cultured astrocytes and oligodendrocytes: involvement of caspase-3.
The biologically active lipid metabolite, platelet-activating factor (PAF), is thought to contribute to inflammatory processes and tissue damage in a variety of central nervous system (CNS) injuries. In previous studies, we found that after contusion spinal cord injury, treatment with a PAF antagonist led to significantly increased white matter tissue sparing as well as decreased mRNA levels for pro-inflammatory cytokines. Some studies suggest that PAF can also have toxic effects on neurons in vitro. Few studies, however, have examined the effects of PAF on glial cells of the CNS. In the present study, the potential for PAF to act as a toxin to cultured astrocytes was examined. Also investigated were the effects of PAF on oligodendrocytes at two different stages of development. Treatment with 0.02-2 microM PAF for 72 h resulted in significant levels of cell death in both cell types (P < 0.05), an effect that was blocked by the PAF receptor antagonists, WEB 2170 and BN 52021. To investigate PAF-induced glial cell death further, we looked for activation of the enzyme, caspase-3, which can be indicative of apoptosis. Immunocytochemistry demonstrated that PAF at all concentrations caused activation of caspase-3 at 24, 48, and 72 h after treatment in both cell types. Caspase-3-dependent cell death was further confirmed using knockout mice (-/-) deficient in the caspase-3 gene. Toxicity was lost when astrocytes (-/-) were exposed to 0.02-2 microM PAF (P < 0.01). Oligodendrocytes (-/-) were not susceptible to toxicity at 2 microM PAF (P < 0.001). The results demonstrate that the pro-inflammatory molecule, PAF, induces cell death in cultured CNS glial cells and that this effect is, in part, dependent on caspase-3 activation.


Acid-assisted oil extraction directly from thraustochytrids fermentation broth and its energy assessment for docosahexaenoic acid-enriched oil production.
Thraustochytrids are the most prominent source of polyunsaturated fatty acids, specifically docosahexaenoic acid (DHA). Downstream processing constitutes a significant fraction of total production cost and thus needs judicious optimization. Currently, hazardous solvent-based extraction methods are used to extract oil from the dry or wet thraustochytrids cell mass. The process is also highly energy-intensive due to involvement of dewatering and drying as unit operations. Current work devised an energy-efficient acid-assisted extraction (AAE) methodology to overcome dry and wet biomass-based extraction limitations. AAE recovered 91 % of total oil with 35-40 % PUFA from the direct fermentation broth, eliminating the need for dewatering and drying of fermentation broth/cell biomass. The current work also presents an all-inclusive comparison of the energy assessment of oil extraction from dry and AAE method. AAE produced PUFA enriched oil with a total energy consumption of 210 MJ/kg, which was four times lower than that of conventional dry cell extraction methodology.


Lithium concentration in tap water, bottled mineral water, and Danube River water in Hungary.
Due to increased manufacture and recycling of lithium batteries across the world, we may anticipate a rise in lithium pollution in the aquatic environment and drinking water reservoirs. In order to investigate the current status regarding the lithium content in Hungarian tap waters, samples were collected from the public drinking water supply systems of 19 county seats in Hungary during seasonally selected times. Depending on the water sources, such as bank-filtrated river water, surface water from open reservoirs, and groundwater, the lithium concentrations varied between 0.90-4.23, 2.12-11.7 and 1.11-31.4 µg/L, respectively, while the median values were 3.52, 5.02 and 8.55 µg/L, respectively. The lithium concentration in the bottled Hungarian mineral waters was also determined since the daily intake of lithium can be influenced by the consumption of mineral waters. The concentrations ranged from 4.2 to 209 µg/L, while the median value was only 17.8 µg/L. Additionally, a correlation was only found between lithium and potassium concentrations. The lithium concentration was also assessed at ten sampling locations in the Hungarian segment of the Danube River since the Danube water is also a water source for additional drinking water utilities using bank filtration technology. The mean and median lithium concentrations were 2.78 and 2.64 µg/L, respectively.


Changes in the rate of laminin and entactin synthesis in F9 embryonal carcinoma cells treated with retinoic acid and cyclic amp.
The synthesis of laminin A and B chains, and of entactin, has been measured in murine F9 embryonal carcinoma cells differentiating in response to retinoic acid and cyclic AMP. Undifferentiated cells synthesis low levels of laminin, amounting to approximately 0.02% of the [35S]methionine incorporated into cytoplasmic protein during a 15-min pulse. After 6 days induction, laminin synthesis has increased 15- to 20-fold. Undifferentiated F9 cells synthesise more intracellular laminin B2 chains (Mr 225,000) than B1 chains (Mr 225,000), but the excess B2 chains are apparently not assembled into the secreted laminin molecule. Indirect immunofluorescence shows faint cytoplasmic staining and short fibrils of laminin between the undifferentiated F9 cells.


Extracellular vesicles in cancer immune responses: roles of purinergic receptors.
Extracellular vesicles (EVs) are nano- to micro-scale membrane-enclosed vesicles that are released from presumably all cell types. Tumor cells and immune cells are prodigious generators of EVs often with competing phenotypes in terms of immune suppression versus immune stimulation. Purinergic receptors, proteins that bind diverse purine nucleotides and nucleosides (ATP, ADP, AMP, adenosine), are widely expressed across tissues and cell types, and are prominent players in immune and tumor cell nucleotide metabolism. The effects of purinergic receptor stimulation or agonism tend to produce inflammatory responses that may aid immune stimulation but may also provoke various immune suppression mechanisms, particularly in the tumor microenvironment. EVs released by cells following receptor stimulation are frequently pro-inflammatory, but often also pro-thrombolytic; these EVs may generate an environment that favors tumor progression at the cost of an effective immune response. Purinergic signaling pathways are becoming more recognized as valuable targets in various therapeutic scenarios, including cancer. It is possible that some of those clinically relevant compounds might also impact EV secretion and/or phenotype, which would hopefully capitalize on the immune stimulatory properties of purinergic signaling while minimizing the immune suppressive consequences. This review covers a relatively understudied area in EV biology, but even so, focuses almost exclusively on the purinergic receptors in a very limited capacity. There is much more to evaluate and incorporate into our understanding of extracellular nucleotides in EV biology, and we hope this work prompts further discovery.


Identification of ALDH4 as a p53-inducible gene and its protective role in cellular stresses.
To identify additional targets of p53, we used a cDNA microarray system to examine gene-expression patterns in response to enforced expression of exogenous p53 in p53-deficient cancer cells, and identified the aldehyde dehydrogenase 4 ( ALDH4) gene as a direct target of p53. ALDH4 is a mitochondrial-matrix NAD+-dependent enzyme catalyzing the second step of the proline degradation pathway. Expression of ALDH4 mRNA was induced in HCT116 cells in response to DNA damage caused by adriamycin treatment, in a p53-dependent manner. ALDH4 contains a potential p53 binding sequence in intron1 and the interaction of p53 with the site was shown by EMSA and ChIP assays. We confirmed p53-dependent transcriptional activity of the binding site by means of a reporter assay. Inhibition of ALDH4 expression by antisense oligonucleotides was able to enhance cell death induced by infection with Ad-p53. H1299 cells transformed to over-express ALDH4 showed significantly lower intracellular reactive oxygen species (ROS) levels than parental or control cells after treatment with hydrogen peroxide or UV. Those cells were also resistant to cell damage caused by hydrogen peroxide. These results suggest that p53 might play a protective role against cell damage induced by generation of intracellular ROS, through transcriptional activation of ALDH4.


A world beyond P: policies, strategies, tactics and advice.
A short review of the changing approach to statistics' contribution to the conduct of physiological experiments, with suggestions for further changes and better practice.


Scintillation proximity assay: a sensitive and continuous isotopic method for monitoring ligand/receptor and antigen/antibody interactions.
Scintillation proximity assay (SPA) makes it possible to use radioisotopes for monitoring binding reactions continuously without the need to separate free from bound components. As a result SPA can be carried out more rapidly than most other methods used to monitor binding reactions. The methodology also lends itself to automation. The sensitivities already achieved with SPA procedures are comparable to the sensitivities of other procedures in use today. Another feature of SPA is that the key reagents (beads, 125I labeling) are relatively inexpensive. The principles of SPA, utilizing 125I-labeled molecules, are discussed and some applications to immunology, receptor binding, and measurement of potential across membranes are presented. SPA should also be applicable to monitoring interactions involving nucleic acids, lipids, and carbohydrates. Characteristics of some radionuclides, other than tritium and 125I, that may be used in SPA are presented.


Novel antimicrobial/antioxidant Eremurus luteus root gum coating containing rosemary essential oil nanoemulsions for extension of chicken meat shelf life.
Herein, the effect of incorporation of rosemary essential oil (REO) nanoemulsions with the smallest (98.14 nm) and largest (148.04 nm) droplets' sizes at different concentrations (0%, 2%, and 4% v/v) in Eremurus luteus root gum (ELRG) coating solution on microbial, chemical, and sensory qualities of chicken fillets during cold storage was investigated. The results demonstrated a significant reduction in pH and TBA value and total viable microbial count (TVC) of chicken meat samples after using an active ELRG coating compared with the uncoated sample. Moreover, the properties of active ELRG coatings were more affected by the concentration of REO nanoemulsions than the size of their droplets. More antimicrobial and antioxidant activities were observed in coated samples containing 4% (v/v) REO nanoemulsions (L-4 and S-4). The highest and lowest pHs at the end of storage belonged to uncoated (6.89) and S-4 coated (6.41) samples, respectively. Unlike the control sample (8th day), the microbial population in the active coated samples (>12th day) reached the threshold level (7 log CFU/g) later. The TBA value in the control and coated samples was 0.56 and 0.4-0.47 mg/kg after 12 days of cold storage, respectively. Increasing the REO nanoemulsion content from 2% to 4% (v/v) in the coating solution enhanced the score of sensory parameters such as odor, color, and total acceptance of the chicken meat, especially on the last day of cold storage. The obtained results suggested ELRG-REO coatings as an effective strategy to delay the chemical and microbial deterioration of chicken meat fillets.


Transitional care and clinical management of adolescents, young adults, and suspected new adult patients with congenital central hypoventilation syndrome.
With contemporaneous advances in congenital central hypoventilation syndrome (CCHS), recognition, confirmatory diagnostics with PHOX2B genetic testing, and conservative management to reduce the risk of early morbidity and mortality, the prevalence of identified adolescents and young adults with CCHS and later-onset (LO-) CCHS has increased. Accordingly, there is heightened awareness and need for transitional care of these patients from pediatric medicine into a multidisciplinary adult medical team. Hence, this review summarizes key clinical and management considerations for patients with CCHS and LO-CCHS and emphasizes topics of particular importance for this demographic. We performed a systematic review of literature on diagnostics, pathophysiology, and clinical management in CCHS and LO-CCHS, and supplemented the review with anecdotal but extensive experiences from large academic pediatric centers with expertise in CCHS. We summarized our findings topically for an overview of the medical care in CCHS and LO-CCHS specifically applicable to adolescents and adults. Care topics include genetic and embryologic basis of the disease, clinical presentation, management, variability in autonomic nervous system dysfunction, and clarity regarding transitional care with unique considerations such as living independently, family planning, exposure to anesthesia, and alcohol and drug use. While a lack of experience and evidence exists in the care of adults with CCHS and LO-CCHS, a review of the relevant literature and expert consensus provides guidance for transitional care areas.


Successful treatment of highly advanced immunoglobulin G4-related kidney disease presenting renal mass-like regions with end-stage kidney failure: a case study.
Immunoglobulin G4-related kidney disease characterized by immunoglobulin G4-positive plasma cell-rich tubulointerstitial nephritis has distinctive serological and radiological findings. Renal prognosis is good because of a good response to glucocorticoids. Here we report a case of successful treatment of highly advanced immunoglobulin G4-related kidney disease presenting renal mass-like regions with end-stage kidney failure. A 59-year-old Japanese man was referred to our hospital because of uremia with a creatinine level of 12.36 mg/dL. Urinalysis revealed mild proteinuria and hyperβ2microglobulinuria, and blood tests showed hyperglobulinemia with an IgG level of 3243 mg/dL and an IgG4 level of 621 mg/dL. Non-contrast computed tomography revealed renal mass-like regions. Based on the findings, immunoglobulin G4-related kidney disease was suspected, however, further radiological examination showed unexpected results. Ga-67 scintigraphy showed no kidney uptake. T2-weighted magnetic resonance imaging revealed high-intensity signals which corresponded to mass-like regions and multiple patchy low-intensity signals in kidney cortex. Finally, the patient was diagnosed with immunoglobulin G4-related kidney disease by renal pathology of severe immunoglobulin G4-positive plasma cell-rich tubulointerstitial nephritis and characteristic fibrosis. He received 50 mg oral prednisolone, which was tapered with a subsequent decrease of serum creatinine and IgG4 levels. One year after initiation of treatment, he achieved normalization of serum IgG4 level and proteinuria, and remained off dialysis with a creatinine level of 3.50 mg/dL. After treatment with steroids, repeat imaging suggested bilateral severe focal atrophy. However, mass-like regions did not show atrophic change although renal atrophy was evident in patchy low-intensity lesions on T2-weighted magnetic resonance imaging. These findings suggest that multiple patchy low-intensity signals and high-intensity mass-like regions were mildly atrophic lesions of immunoglobulin G4-related kidney disease due to severe fibrosis and normal parts of kidney, respectively. In immunoglobulin G4-related kidney disease with severe kidney failure, radiological findings should be carefully examined. In addition, renal prognosis may be good despite highly advanced tubulointerstitial nephritis and fibrosis.


Transgenic and knock-out models for studying DNA repair.
Transgenic animal technology, and especially the use of germ line manipulation for gene targeting, offers new strategies for in vivo analysis of the mechanisms of DNA repair and cell cycle control underlying their efficiency. In vivo risk assessment of genotoxic agents is already facilitated by using transgenic mice. Knock-out mice provide an opportunity to study the function of the disrupted gene, to model human diseases related to this inactivation, and to determine the consequences of loss of function after a genotoxic exposure. These models might also allow the development of new gene therapy strategies.


Equine platelets inhibit E. coli growth and can be activated by bacterial lipopolysaccharide and lipoteichoic acid although superoxide anion production does not occur and platelet activation is not associated with enhanced production by neutrophils.
Activated platelets can contribute to host defense through release of products with bactericidal actions such as antimicrobial peptides and reactive oxygen species (ROS), as well as by forming heterotypic aggregates with neutrophils and enhancing their antimicrobial properties. Whilst release of vasoactive mediators from equine platelets in response to stimuli including bacterial lipopolysaccharide (LPS) has been documented, neither ROS production, nor the effects of activated platelets on equine neutrophil ROS production, have been reported. This study first sought evidence that activated equine platelets inhibit bacterial growth. Platelet superoxide production in response to stimuli including Escherichia coli-derived LPS and lipoteichoic acid (LTA) from Staphylococcus aureus was then determined. The ability of LPS and LTA to up-regulate platelet P-selectin expression and induce platelet-neutrophil aggregate formation was investigated and the effect of co-incubating activated platelets with neutrophils on superoxide production measured. Growth of E. coli was inhibited in a time-dependent manner, and to a similar extent, by addition of platelet rich plasma (PRP) or platelet poor plasma (PPP) obtained by centrifugation of PRP. Activation of platelets in PRP by addition of thrombin led to a significant increase in the inhibitory action between 0.5 and 2h. Although phorbol myristate acetate (PMA) caused superoxide production by equine platelets in a protein kinase C-dependent manner, thrombin, platelet activating factor (PAF), LPS, LTA and formyl-methionyl-leucyl phenylalanine (FMLP) were without effect. LPS and LTA did induce platelet activation, measured as an increase in P-selectin expression (% positive cells: 17±3 (un-stimulated); 63±6 (1μg/ml LPS); 64±6 (1μg/ml LTA); n=5) but not platelet superoxide production or heterotypic aggregate formation. Co-incubation of activated platelets with neutrophils did not increase neutrophil superoxide production. This study has demonstrated for the first time that when activated, equine platelets, like those of other species, are capable of releasing ROS that could assist in bacterial killing. However, the findings suggest that neither superoxide production by platelets nor enhancement of production by neutrophils is likely to play a significant role. Nevertheless, as has been reported in man, equine PPP and PRP did inhibit E. coli growth in vitro, and addition of thrombin significantly increased the inhibitory effect of PRP. This suggests that products released from activated platelets could contribute to antimicrobial activity in the horse. The factors in equine plasma and released by activated platelets that are responsible for inhibiting bacterial growth have yet to be determined.


Molecular profiling of patient-derived breast cancer xenografts.
Identification of new therapeutic agents for breast cancer (BC) requires preclinical models that reproduce the molecular characteristics of their respective clinical tumors. In this work, we analyzed the genomic and gene expression profiles of human BC xenografts and the corresponding patient tumors. Eighteen BC xenografts were obtained by grafting tumor fragments from patients into Swiss nude mice. Molecular characterization of patient tumors and xenografts was performed by DNA copy number analysis and gene expression analysis using Affymetrix Microarrays. Comparison analysis showed that 14/18 pairs of tumors shared more than 56% of copy number alterations (CNA). Unsupervised hierarchical clustering analysis showed that 16/18 pairs segregated together, confirming the similarity between tumor pairs. Analysis of recurrent CNA changes between patient tumors and xenografts showed losses in 176 chromosomal regions and gains in 202 chromosomal regions. Gene expression profile analysis showed that less than 5% of genes had recurrent variations between patient tumors and their respective xenografts; these genes largely corresponded to human stromal compartment genes. Finally, analysis of different passages of the same tumor showed that sequential mouse-to-mouse tumor grafts did not affect genomic rearrangements or gene expression profiles, suggesting genetic stability of these models over time. This panel of human BC xenografts maintains the overall genomic and gene expression profile of the corresponding patient tumors and remains stable throughout sequential in vivo generations. The observed genomic profile and gene expression differences appear to be due to the loss of human stromal genes. These xenografts, therefore, represent a validated model for preclinical investigation of new therapeutic agents.


Response of stratified cultures of human keratinocytes to disruption of proteoglycan synthesis by p-nitrophenyl-beta-D-xylopyranoside.
Proteoglycans play a role in regulating proliferation and adhesion of cells to each other and to the basal lamina. Synthesis of proteoglycans is disrupted by beta-xylosides, which serve as alternate substrate sites for glycosaminoglycan chain attachment and therefore prevent glycosylation of the core protein. We have investigated the effects of p-nitrophenyl-beta-D-xylopyranoside (PNP-xyloside) on cultured human keratinocytes. Stratified cultures were incubated for 7 days with PNP-xyloside (0.05-2.0 mM). Concentrations as low as 0.05 mM increased the secretion of free chondroitin sulfate by 10-15-fold over untreated cultures. Cell-associated proteoglycan decreased as PNP-xyloside concentration increased. At 2 mM PNP-xyloside, heparan sulfate as well as chondroitin sulfate addition to core proteins was disrupted: the core protein of epican, a heparan sulfate form of CD44 found on keratinocytes, was detected immunologically but lacked heparan sulfate. 2.0 mM PNP-xyloside reduced the number of attached cells by 20-25% after 7 days, but had little effect on morphology or protein synthesis. These results indicate that intact proteoglycans are not critical for maintaining epidermal keratinocyte stratification, cell-cell adhesion, or growth.


An integrative approach to untangling species delimitation in the Cataglyphis bicolor desert ant complex in Israel.
Although extensive research has been carried out on the desert ants in the genus Cataglyphis in recent years, some of the specific intra- and interspecific relationships remain elusive. The present study disentangles the phylogenetic relationships among the C. bicolor complex in Israel using an integrative approach based on genetic markers, morphometric measurements, and chemical analyses (cuticular hydrocarbons). Several species delimitation approaches based on four nuclear, two mitochondrial, and eleven microsatellite markers, as well as 16 body measurements and 56 chemical variables, were employed to deciphering the occurrence of cryptic species in our data set. Our findings support the occurrence of at least four distinct species in the C. bicolor group in Israel, one of which may be a complex of three more recent species. The findings confirm the distinctiveness of C. isis and C. holgerseni. They attest the presence of a recently discovered species, C. israelensis, in the central mountain ridge and the occurrence of another clade distributed from the Negev to the Mediterranean coast, comprising the species C. niger, C. savignyi, and C. drusus. Although these three species are separated on the basis of mtDNA, this subgrouping was not supported by any of the nuclear sequence markers nor by the microsatellite analysis. This genetic structure may thus either reflect a possible recent speciation, or a geographical structuring of a single species. Overall, using these different sources of evidence we locate our samples within a global phylogeny of the bicolor group and discuss the processes that underlie speciation in this group.


Clinical characterization of int22h1/int22h2-mediated Xq28 duplication/deletion: new cases and literature review.
Int22h1/int22h2-mediated Xq28 duplication syndrome is caused by ~0.5 Mb chromosomal duplications mediated by nonallelic homologous recombination between intron 22 homologous region 1 (int22h1) and 2 (int22h2), which, in addition to int22h3, are also responsible for inversions disrupting the F8 gene in hemophilia A. This syndrome has recently been described in 9 males with cognitive impairment, behavioral problems, and distinctive facial features; and 6 females with milder phenotypes. The reciprocal deletion was previously reported in a mother and daughter. It was suggested that this deletion may not have phenotypic effects in females because of skewed chromosome X inactivation, but may be embryonic lethal in males. Array comparative genomic hybridization analyses were performed using oligonucleotide-based chromosomal microarray. Chromosome X inactivation studies were performed at the AR (androgen receptor) and FMR1 (fragile X mental retardation 1) loci. We present here 5 males and 6 females with int22h1/int22h2-mediated Xq28 duplication syndrome. The males manifested cognitive impairment, behavioral problems, and distinctive facial features. Two of the six females manifested mild cognitive impairment. This duplication was maternally inherited, and skewed chromosome X inactivation was observed in the majority of females carrying the duplication. We also report the reciprocal deletion in a mother and daughter with overweight, but normal cognition. In addition, we present the first case of a prenatally diagnosed de novo int22h1/int22h2-mediated deletion in a healthy female infant. We reviewed individuals previously reported with similar or overlapping rearrangements and evaluated the potential roles of genes in the rearrangement region. The similarity of clinical features among individuals with the int22h1/int22h2-mediated Xq28 duplication supports the notion that this duplication causes a recognizable syndrome that affects males with females exhibiting milder phenotypes. It is suggested that the observed cognitive impairment in this syndrome results from increased dosage of RAB39B gene located within the duplicated region. Increased dosage of CLIC2 may also contribute to the phenotype. The reciprocal deletion results in skewed chromosome X inactivation and no clinical phenotype in females. Review of overlapping deletions suggests that hemizygous loss of VBP1 may be the cause for the proposed male lethality associated with this deletion.


[Hypertrichosis].
Hypertrichosis denotes growth of hair on any part of the body in excess of the amount usually present in persons of the same age, race, and sex, excluding androgen-dependent hair growth. Hypertrichosis may be an isolated finding or associated with a syndrome, be associated with additional congenital anomalies or a marker for systemic disease. In order to diagnose it accurately, the age of onset, type, localization and pattern of hair growth, associated disorders, medications and perhaps associated anomalies and family history should be considered. Even though hypertrichosis usually has limited medical significance, it often causes cosmetic embarrassment, often resulting in a significant emotional burden. Treatment options are available, though limited in terms of efficacy and patient satisfaction. No single method of hair removal is appropriate for all body locations and patients, and the one adopted will depend on the type, area, and amount of excessive hair growth, as well as on the age, sex, and personal preference of the patient. Patients with hypertrichosis should be adequately advised of the treatment modalities. These include cosmetic procedures (bleaching, trimming, shaving, plucking, waxing, chemical epilatories, electrosurgical epilation), and hair removal using light sources and lasers.


[Assessment of fetal lung maturity by fluorescence polarization method: comparison with lecithin/sphingomyelin ratio, shake test and turbidometry (author's transl)].
Ninety seven amniotic fluid samples from 89 pregnant women ranging from 9 to 41 weeks of gestation were analyzed for fetal lung maturity by the fluorescence polarization (FP) method and the values were compared with three other methods; lecithin/sphingomyelin (L/S) ratio, shake test and optical density at 650 nm. Of 89 cases 14 were complicated pregnancies. Three respiratory distress syndrome (RDS) was predicted by FP method. FLuorescence polarization (FP) values of amniotic fluid samples declined abruptly from about 34 weeks of gestation in normal pregnancy. The data suggest that the lung maturity threshold of FP value is 0.333. The false negative and false positive results for the FP value were 1.4% and 0%, respectively. There was a significant correlation between FP value and L/S ration (r = 0.766). Among the four methods tested the FP method is more advantageous than the others in reliability, accuracy, reproducibility, operational simplicity and rapidity.


Effects of repeated wet and dry swallows in healthy adult females.
Understanding changes that may occur in the swallow with repetitive use in healthy individuals is a prerequisite to evaluate and treat persons with compromised swallowing. To determine any systematic effect of use on swallow function, we attempted to tax the swallow mechanism in a rigorous sequence of dry and liquid swallow conditions. Oropharyngeal temporal measures were assessed videofluoroscopically for 12 healthy females aged 20-29 during 42 wet and 5 dry swallows. No significant effects were found for any temporal measures over a series of 21 l-mL and 21 cup swallows plus 5 dry swallows, indicating swallow efficiency and safety do not appear to decline over 47 swallows in this young adult population. Additionally, no significant effects were found over the dry swallows or when 1-mL liquid swallows were compared with the dry, indicating dry swallows do not demonstrate significant change over a 5-swallow series due to reduced available saliva. Ability of subjects to perform consecutive dry swallows varied greatly. Results of this study provide normative data regarding multiple, consecutive, wet and dry swallowing in a healthy female population.


Intrinsic capacity of older people in the community using WHO Integrated Care for Older People (ICOPE) framework: a cross-sectional study.
The World Health Organization (WHO) published the Integrated Care for Older People (ICOPE) framework to guide assessing and promoting intrinsic capacity of older adults. This study, adopting the WHO ICOPE framework, assessed the intrinsic capacity impairment and investigated the relationship among intrinsic capacity, social engagement, and self-care capacity on performing activities of daily living. It also assessed the sensitivity of the initial brief screening and the detailed full assessment. This is a cross-sectional study conducted in 11 community centers in Hong Kong. Intrinsic capacity was assessed in two steps identical to WHO ICOPE handbook: using WHO ICOPE brief screening tool (step 1) and detailed full assessment (step 2) to assess the intrinsic capacity domains of locomotion, cognition, vitality, psychological well-being, and sensory capacity (hearing and vision). Structural equational modeling analysis was used to examine the relationship among intrinsic capacity, social engagement, and self-care capacity, and the mediating role of intrinsic capacity in the relationships. A total of 304 older adults with a mean age 76.73 (SD = 7.25) years participated in WHO ICOPE Step 1 brief screening, and 221 participants (72.7%) showed intrinsic capacity impairment. After completing Step 2 full assessment, 202 participants (66.4%) had one or more impaired intrinsic capacity domains. The overall sensitivity and specificity of the screening tool were 95% and 57.6% respectively, whereas the sensitivity of each domain ranged from 74.7% to 100%. The percentage of impairment in locomotion (117, 39.8%), cognition (75, 25.5%), psychological well-being (34, 11.6%), vision (75, 24.7%), hearing capacity (82, 27.9%), and vitality (8, 2.7%). People in younger old age (β = -0.29, p < 0.001), with more education (β = 0.26, p < 0.001), and absence of hypertension (β = -0.11, p < 0.05) were more likely to have better intrinsic capacity. Intrinsic capacity was positively associated with self-care capacity in performing activities of daily living (β = 0.21, p < 0.001) and social engagement (β = 0.31, p < 0.001). The ICOPE screening tool is a sensitive instrument to detect intrinsic capacity impairment among community-dwelling older adults and it does not demand substantial workforce; its use is worthy to be supported. The intrinsic capacity impairment in community-dwelling older adults are prevalent, in particular, in locomotor and cognitive capacity. Actions should be taken to slow or prevent the impairment, support self-care and social engagement in old age.


Psychoanalytic psychotherapy and its supervision via videoconference: experience, questions and dilemmas.
The patient lives in Berlin, the therapist in Lisbon and the supervisor in Budapest. Not long ago, continuous psychotherapy and supervision would have been impossible in such a setting. Nowadays, modern communication technologies via the Internet create new possibilities for patients, therapists, and supervisors. However, when we engage in psychoanalytic practice via modern means of telecommunication, we need to examine if the fundamental tenets of the psychoanalytic process are preserved. We need to think about initial assessment, about how we arrange the setting, how we work with transference and countertransference, what kinds of new forms of resistance we are facing and, indeed, how we can recognize new phenomena and handle inevitable problems. In this clinical paper, we tackle these questions in the context of three-times-a-week psychoanalytic psychotherapy.


The angiotensin II receptor antagonist telmisartan reduces urinary albumin excretion in patients with isolated systolic hypertension: results of a randomized, double-blind, placebo-controlled trial.
To examine the effect of telmisartan or hydrochlorothiazide on the control of urinary albumin excretion (UAE) in patients with isolated systolic hypertension (ISH) unselected for albuminuria in a pre-planned substudy of a large, multicentre, double-blind, placebo-controlled, randomized study. The Angiotensin II Receptor Antagonist Micardis in Isolated Systolic hypertension (ARAMIS) study compared the antihypertensive efficacy after 6 weeks of once-daily fixed doses of telmisartan 20, 40 or 80 mg versus hydrochlorothiazide 12.5 mg or placebo in patients (n = 1039, aged 35-84 years) with ISH (seated blood pressure 150-179/< 90 mmHg). The prospective substudy analysed UAE using spot morning samples. Urinary albumin (> 2.2-901.6 mg/l) was detected at baseline in 614 out of 918 patients who were included in the substudy analysis. In the telmisartan group (n = 354, all doses combined), a median reduction in UAE from a baseline of 14.1% [95% confidence interval (CI) 7.3, 21.8] was observed versus 1.1% (95% CI -13.5 to 16.0) and 2.7% (95% CI -0.9 to 19.9) in the hydrochlorothiazide (n = 140) and placebo (n = 120) groups, respectively. The difference between telmisartan and hydrochlorothiazide was significant (P = 0.017). Reductions in UAE with telmisartan were observed in patients with baseline normoalbuminuria, microalbuminuria or macroalbuminuria. Telmisartan and hydrochlorothiazide produced comparable reductions in systolic blood pressure in these patients. In patients with ISH unselected for baseline albuminuria, telmisartan 20-80 mg after 6 weeks' treatment afforded significantly greater lowering of UAE than hydrochlorothiazide 12.5 mg, irrespective of the baseline UAE, and despite comparable reductions in systolic blood pressure with both drugs.


Interpopulational variation in recovery time from chill coma along a geographic gradient: a study in the common woodlouse, Porcellio laevis.
Extreme temperatures restrict the performance of terrestrial arthropods and variations in low temperatures on a latitudinal scale influence physiological variables. Recovery time from chill coma is a measure of cold tolerance and it is a good index of climatic adaptation. We tested differences in recovery time of the common woodlouse (Porcellio laevis) exposed to different thermal conditions. Individuals were sampled from four different populations in Chile, spanning a latitudinal range of approximately 10 degrees . Significant differences were found in recovery time among experimental temperatures and among populations, but no interaction between these factors. The results of recovery time in P. laevis showed a positive increment with annual mean minimum temperature, indicating that there is geographical variation in recovery time. While body mass presented interpopulational variation, this variation was not associated with thermal variables or latitude. Overall, our results agree with previous studies in the sense that recovery time from chill coma decreases towards high latitudes, and it is independent of taxa, continent and hemisphere.


Seasonal and weekly patterns of occurrence of acute cardiovascular diseases: does a gender difference exist?
Cardiovascular (CV) disease is the leading cause of death in women. It is known that acute CV events exhibit temporal patterns of onset, that is, seasonal and weekly. We aimed to verify whether such patterns show differences by gender. We analyzed cumulative data from our previous studies dealing with hospital admissions for CV events, such as acute myocardial infarction (AMI), stroke, transient ischemic attack (TIA), aortic diseases (AD), and pulmonary embolism (PE), in the region Emilia-Romagna (RER) of Italy (ICDM9-CM codes, years 1998?2006). Total population and subgroups by gender (percentage of monthly and daily events) were tested for uniformity with the chi-square test, and a chronobiologic method was applied to monthly percentage of data for seasonal rhythmic analysis. Season: We considered 130,693 patients (45.1% women): 64,191 AMI, 43,642 TIA, 4,615 AD, 19,425 PE. The monthly and seasonal distribution showed respective peaks in January and in winter, with no differences by gender. Day-of-week: We considered 168,921 patients (45.6% women): 64,191 AMI, 56,453 stroke, 43,642 TIA, 4,615 AD. The weekly distribution showed a peak on Monday, with no differences by gender. A multivariate regression logistic analysis, including in the model either major CV risk factors (hypertension, dyslipidemia, diabetes mellitus) and subgroups by age, did not find any difference in the temporal distribution of events in women and men. The seasonal and day-of-week distribution of occurrence of CV events seems to be independent of gender.


The intra-aortic balloon pump as an adjunctive therapy for severe myocardial contusion.
The management of patients with post-traumatic myocardial contusion requires close electrocardiographic and hemodynamic monitoring. When complications such as cardiogenic shock occur, aggressive treatment using Swan-Ganz catheterization for monitoring of intravascular volume and cardiac inotropic support are necessary. Failure to restore hemodynamic stability using these measures is an indication for the use of intra-aortic balloon pump counterpulsation. A case of successful management of a patient with post-traumatic myocardial contusion complicated by refractory cardiogenic shock using intra-aortic balloon pump counterpulsation is presented. Use of the intra-aortic balloon pump improved cardiac output, eventually resulting in hemodynamic stabilization.


Folate receptor alpha (FRA) expression in breast cancer: identification of a new molecular subtype and association with triple negative disease.
Given that several targeted therapies directed towards folate receptor alpha (FRA) are in late stage clinical development, the sensitive and robust detection of FRA in tissues is of paramount importance relative to patient selection, prognosis and prediction. In the present study we undertook an immunohistochemical evaluation of expression of FRA in breast cancer samples using formalin-fixed, paraffin-embedded (FFPE) tissues, primarily invasive ductal carcinomas, using a newly described monoclonal antibody, 26B3. Samples assessed included both tissue microarrays (TMA) and whole tissue sections from archival tissue blocks. Normal breast shows a highly restricted expression of FRA to luminal membrane staining of secretory ductal cells, consistent with FRA secretion into milk. In early stage (stages I-III) invasive ductal carcinomas, FRA staining was observed in approximately 30% of all samples, independent of molecular subtype (estrogen receptor (ER)/progesterone receptor (PR)/human epidermal growth factor receptor type 2 (Her2)). However, FRA expression was shown to associate with ER/PR negative tumors relative to ER/PR positive tumors (p = 0.012) and perhaps more importantly, with triple negative breast cancers (TNBC; p < 0.0001). FRA immunoreactivity was also shown to be retained in stage IV metastatic breast cancer samples from diverse anatomic sites including lymph node and bone. In metastatic breast cancer, FRA was shown to be expressed in 86% of TNBC patients. Taken together, these data suggest that FRA expressing breast cancer represents a novel molecular subtype and, further, may represent a new therapeutic target for this devastating disease.


Effective and efficient neural networks for spike inference from in vivo calcium imaging.
Calcium imaging provides advantages in monitoring large populations of neuronal activities simultaneously. However, it lacks the signal quality provided by neural spike recording in traditional electrophysiology. To address this issue, we developed a supervised data-driven approach to extract spike information from calcium signals. We propose the ENS2 (effective and efficient neural networks for spike inference from calcium signals) system for spike-rate and spike-event predictions using ΔF/F0 calcium inputs based on a U-Net deep neural network. When testing on a large, ground-truth public database, it consistently outperformed state-of-the-art algorithms in both spike-rate and spike-event predictions with reduced computational load. We further demonstrated that ENS2 can be applied to analyses of orientation selectivity in primary visual cortex neurons. We conclude that it would be a versatile inference system that may benefit diverse neuroscience studies.


A randomized, double-masked, crossover comparison of the efficacy and safety of botulinum toxin type A produced from the original bulk toxin source and current bulk toxin source for the treatment of cervical dystonia.
In 1997, the US FDA approved a new bulk toxin source (now referred to as current) for the manufacture of botulinum toxin type A (BTX-A). The current BTX-A preparation has a lower neurotoxin complex protein load than the original BTX-A preparation, which may reduce antigenic potential. The present double-masked, multicenter study compared the efficacy and safety of BTX-A (BOTOX) produced from both original and current bulk toxin sources for the treatment of cervical dystonia. Patients (N = 133) were injected with BTX-A produced from original and current bulk toxin sources using a crossover design. Adverse events were assessed at each visit. Efficacy was assessed at 2 and 6 weeks post-injection using the severity and pain-disability subscales of the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). Mean BTX-A doses were comparable (original: 155 U, current: 156 U). Both BTX-A preparations produced similar, statistically significant reductions in TWSTRS severity and pain-disability scores at weeks 2 and 6 post-injection. The original and current BTX-A preparations showed no significant differences in adverse events, including both treatment-related (34%, 31%) and treatment-unrelated (27%, 32%), respectively. BTX-A produced from the original and current bulk toxin sources showed comparable efficacy and safety in the treatment of cervical dystonia; both significantly reduced dystonia severity and pain.


Review of Cutaneous Graft-vs-Host Disease.
Graft-vs-host disease (GVHD) is a multisystem disease that arises as a complication of allogeneic hematopoietic stem cell transplant. It is due to recognition of the recipient's tissues by immune cells from the donor. The skin and mucous membranes are the organs most commonly affected. GVHD is classified as acute or chronic depending on the pathophysiology and clinical presentation. Acute GVHD typically presents with the triad of rash, diarrhea, and hyperbilirubinemia, and treatment is based on systemic corticosteroid and immunosuppressant therapy. The cutaneous manifestations of chronic GVHD are divided into sclerodermiform and nonsclerodermiform, and the mucous membranes and skin appendages may also be affected. The diagnosis is mainly clinical, but skin biopsy can help in doubtful cases. Treatment can be topical, systemic, or physical, depending on the size, site, and depth of the lesions and the involvement of other organs.


Submarine groundwater discharge data at meter scale (223Ra, 224Ra, 226Ra, 228Ra and 222Rn) in Indian River Bay (Delaware, US).
Submarine groundwater discharge (SGD) was sampled at high-spatial resolution in Indian River Bay, DE, USA, in July 2016 to characterize the spatial variability of the activity of the radium and radon isotopes commonly used to estimate SGD. These data were part of an investigation into the methods and challenges of characterizing SGD rates and variability, especially in the coastal aquifer transition from freshwater to saltwater (Hydrogeological processes and near shore spatial variability of radium and radon isotopes for the characterization of submarine groundwater discharge (Duque et al., 2019)). Samples were collected with seepage meters and minipiezometers to obtain sufficient volumes for analytical characterization. Seepage meter samples (for 223Ra, 224Ra, 226Ra, and 228Ra) were collected at two-hour intervals over a semi-diurnal tidal cycle from 30 seepage meters. Samples for 222Rn characterization were collected with a minipiezometer from 25 cm below the bay bed at each seepage meter location. All samples were analyzed with standard and state of the art procedures.


Association of serum eosinophilia and total immunoglobulin E concentration with the risk of allergic symptoms and allergic sensitization, respectively: A 2-year follow-up study.
Serum eosinophil percentage (SEP), eosinophil cationic protein (ECP) concentration, and total IgE (TIgE) concentration are known to increase in patients with allergic disease; however, the relevance of these elevated markers in children with negative allergic test results remains unclear. Therefore, this 2-year follow-up study aimed to investigate whether SEP, ECP concentration, and TIgE concentration are associated with an increased risk for allergic sensitization and allergic symptoms. In 2012, SEP, ECP concentration, and TIgE concentration of third- and fourth-grade students from 6 elementary schools were measured. Skin prick test was performed, and the presence of allergic nasal symptoms was investigated using a questionnaire. In 2014, the same examinations were performed in the same set of students, who were then in the fifth and sixth grades, respectively, of the same schools. The cut-off value and usefulness of serologic markers (eosinophil count, ECP concentration, and TIgE concentration) were calculated using the receiver operating characteristic curve. Serum eosinophil percentage (cut-off value, 3.8%) was associated with the newly developed allergic nasal symptoms (sensitivity, 77.9; specificity, 41.8). A high serum TIgE concentration (cut-off value, 17.7 IU/mL) was also associated with the risk for allergic sensitization (sensitivity, 46.3; specificity, 85.3). SEP and TIgE concentration were associated with the development of allergic symptoms and allergic sensitization, respectively, 2 years after the first examination.


Quantifying the efficacy of overbite reduction in patients treated with clear aligners using optimized versus conventional attachments.
Deep overbite has been shown to be difficult to correct with clear aligners. Optimized deep bite attachments are reported to facilitate deep bite correction with aligners. The aim of this retrospective study was to quantify the efficacy of deep bite correction with aligners when using optimized versus conventional attachments. This was a retrospective cohort study. The pretreatment and post-treatment intraoral scans of patients with deep overbite treated with Invisalign clear aligners were accessed. Patients were divided into two groups: group A, patients treated with conventional attachments, and group B, patients treated with optimized attachments. Pre and post-treatment overbite and the planned overbite reduction were measured and compared between groups. Descriptive statistics were computed, and statistical significance was set at P < 0.05. Seventy-eight patients were included. There was no statistically significant difference in overbite reduction between patients who had conventional versus optimized attachments. The amount of overbite reduction observed post-treatment was found to be no more than 33-40% of the planned amount of overbite reduction across all patients and groups. Deep overbite correction with aligners remains difficult regardless of the type of attachment used. Optimized attachments are no more effective than using conventional attachments in reducing deep overbite. The amount of overbite reduction expected with clear aligners is significantly lower than the planned overbite reduction. When correcting deep bite with clear aligners, the attachment type does not improve the success rate. Clinicians should plan to overcorrect deep bite reduction to expect only 33% to 40% of their planned final overbite to be actually expressed.


Several genes in the extended human MHC contribute to predisposition to autoimmune diseases.
Autoimmune diseases, such as type 1 diabetes, rheumatoid arthritis, psoriasis and systemic lupus erythematosus, affect approximately 4% of the population in industrialized countries, and are characterized by an immune-mediated destruction of autologous cells and/or tissues. More knowledge is needed to prevent and treat this large group of diseases. Unravelling the genetic predisposing factors is important in this respect, and large research efforts have been initiated to reach this goal. The human MHC, also called the human leukocyte antigen (HLA) complex, is known to harbour major genetic determinants for autoimmune diseases. For several autoimmune diseases certain classical HLA class II and/or class I genes are strongly associated with disease. As a result of recent systematic screening studies additional genes and regions in the MHC, including the extended MHC, are now known to contribute to the predisposition.


Physiological mechanisms underlying children's circannual growth patterns and their contributions to the obesity epidemic in elementary school age children.
Several studies since the 1990s have demonstrated that children increase their body mass index at a faster rate during summer months compared with the school year, leading some to conclude that the out-of-school summer environment is responsible. Other studies, however, have suggested that seasonality may play a role in children's height and weight changes across the year. This article reviews evidence for seasonal differences in the rate of children's height and weight gain and proposes potential physiological mechanisms that may explain these seasonal variations.


Functional insights into aberrant brain responses and integration in patients with lifelong premature ejaculation.
Even though lifelong premature ejaculation (PE) is highly prevalent, few studies have investigated the neural mechanisms underlying PE. The extent and pattern of brain activation can be determined through a version of functional magnetic resonance imaging (fMRI) with erotic picture stimuli (task fMRI) and a resting-state fMRI (rs fMRI). We showed that the brain activity in the left inferior frontal gyrus and left insula was decreased both during the task and in the resting state, while there was higher activation in the right middle temporal gyrus during the task. Higher functional connectivity was found in PE between those three brain areas and the bilateral middle cingulate cortex, right middle frontal gyrus and supplementary motor area. Moreover, the brain activity had positive correlation with clinical rating scales, such as intravaginal ejaculatory latency time (IELT) and the Chinese Index of Premature Ejaculation (CIPE). These findings revealed that brain responses and functional integration in certain brain areas are impaired in cases of PE, which was consistently supported by multiple measurements obtained using a task and rs fMRI approach.


Variation in Brain Subcortical Network Topology Between Men With and Without PE: A Diffusion Tensor Imaging Study.
Premature ejaculation (PE) is a highly prevalent male sexual dysfunction. Previous studies have found abnormal activity in the sympathetic nervous system and penile sensory pathway of PE. Few studies have investigated the neural mechanisms underlying PE. The aim of this study was to examine whether the altered cortico-subcortical network topological properties of the brain white matter structural network could be used to differentiate patients with PE from healthy control (HC) subjects. Diffusion tensor images data were collected from 32 patients with PE and 35 HC participants. Then, brain white matter structural networks were reconstructed from image acquisition. Furthermore, nodal measures were calculated and hub regions were identified using the graph-theoretical methods. For cortical brain regions, increased strength, global efficiency, and decreased shortest path length were found in the right superior frontal gyrus (medial), and superior frontal gyrus (medial orbital) were found in patients with PE. In addition, patients with PE also showed decreased strength in the right rolandic operculum and decreased shortest path length, and increased global efficiency in the right inferior frontal gyrus (triangular part). For subcortical brain structures, patients with PE were associated with decreased shortest path length and increased global efficiency in the left insula and right caudate nucleus. Finally, the results showed that 9 PE-specific hub regions were identified in patients compared with HCs, including 7 cortical regions and 2 subcortical regions. Our results provide new understanding about the pathology of PE and enhances the understanding of PE pathology. Our results offer biological markers for understanding the physiopathology of PE. However, our study is a cross-sectional design, longitudinal design studies need to explore the causal relationships between aberrant topological characteristics and PE. Our results provide new insights into the neural mechanism of PE involving cortico-subcortical network changes, which could serve as a potential biomarker to differentiate individuals with PE from HCs. Chen J, Yang J, Huang X, et al. Variation in Brain Subcortical Network Topology Between Men With and Without PE: A Diffusion Tensor Imaging Study. J Sex Med 2020;17:48-59.


N-acetyl-cysteine in the treatment of Parkinson's disease. What are we waiting for?
Parkinson's disease is an age-related neurodegenerative disorder that is ameliorated with levodopa. However, long-term use of this drug is limited by motor complications, postural instability and dementia resulting in the progression of the disease. Insights into the organization of the basal ganglia and knowledge of the mechanisms responsible for cell death in Parkinson's disease has permitted the development of putative neuro-protective drugs that might slow the disease progression. Although no drug has yet been established to alter the rate of disease progression, recent publications have confirmed previous results and hypotheses about the probable role of thiolic antioxidants on Parkinson's disease, demonstrating a significant reduction of dopaminergic neuronal degeneration in α-synuclein over expressing mice treated with oral N-acetyl-cysteine. This thiolic antioxidant is a modified form of the natural amino acid cysteine, which is the precursor of the most potent intracellular antioxidant glutathione. Besides, increasing evidence has been accumulated in the last 10years about the beneficial effects of this thiolic antioxidant in experimental and pathologic states of the nervous system, including against neurotoxic substances. The present paper put forward the existing rationale evidence for the use of N-acetyl-cysteine alone or in combination with levodopa in the clinical management of this neurodegenerative disorder.


Evaluation of the ethanolic ultrasound-assisted extraction from clove (Syzygium aromaticum) leaves and chemical characterization of the extracts.
In this study, clove leaves (Syzygium aromaticum) were subjected to ultrasound-assisted extraction (UAE) with ethanol as the solvent, following a central composite design to evaluate the effects of time, amplitude, solvent/sample ratio, and temperature on the yield, eugenol content, and antioxidant capacity of the extracts. The results were compared with those obtained using the conventional method of maceration (ME). The optimum conditions for extract yield were achieved with an extraction time of 25 min,amplitude of 85%, solvent/sample ratio of 35 mL g-1, and temperature of 70 °C, and the result (14.63 wt%) was three times higher than that of conventional extraction. Eugenol was detected in the extracts obtained by both methods, with the highest yield of 2.94 g eugenol kg leaves-1obtained in the UAE method, while the ME method achieved 1.36 g eugenol kg leaves-1.In general, the extracts exhibited high antioxidant capacities.


A volume-dependent, chloride-sensitive component of taurine release stimulated by potassium from retina.
Chick retinas exposed to 56 mM KCl showed marked swelling of cells and synaptic structures, detected by morphological examination as well as by measurements of cell water content. Retinal cell swelling is prevented by omission of chloride. Potassium chloride, 56 mM, elicited the efflux of [3H]taurine by a process that is partly calcium-dependent, highly chloride-dependent (80%), and sensitive to furosemide. The release of [3H]dopamine under the same conditions is completely calcium-dependent and increases in the absence of chloride. The chloride-dependent component of [3H]taurine efflux seems related to increases in volume changes since it is markedly reduced when cell swelling is prevented either by maintaining constant the K X Cl product (Donnan equilibrium) or by making the solution hypertonic with mannitol. Omission of calcium and of chloride showed additive effects, practically suppressing the potassium-stimulated release of taurine. These results suggest that the potassium-stimulated efflux of [3H]taurine consists of a large component associated to changes in cell volume and a small component probably related to the depolarizing effects of potassium.


Generation of an isolable, monomeric manganese(V)-oxo complex from O2 and visible light.
The direct conversion of a Mn(III) complex [(TBP(8)Cz)Mn(III) (1)] to a Mn(V)-oxo complex [(TBP(8)Cz)Mn(V)(O) (2)] with O(2) and visible light is reported. Complex 1 is also shown to function as an active photocatalyst for the oxidation of PPh(3) to OPPh(3). Mechanistic studies indicate that the photogeneration of 2 does not involve singlet oxygen but rather likely occurs via a free-radical mechanism upon photoactivation of 1.


Trichinella britovi outbreak: Epidemiological, clinical, and biological features.
We aimed to describe the first cases of human trichinellosis due to Trichinella britovi in Serbia. A large trichinellosis outbreak due to the consumption of wild boar meat products took place during the 2015-2016 winter. In January 2016, the Department of Infectious Diseases in Uzice examined 111 individuals with clinical and biological signs of trichinellosis, of whom 19 were hospitalized. Trichinella species identification was performed by multiplex PCR. Serodiagnosis was performed using immunofluorescence antibody assay, indirect ELISA, and Western Blot as confirmatory tests. The main symptoms included myalgia (83%), weakness (82%), joint pain (80%), fever (77%), facial edema (74%), and diarrhea (23%). Eosinophil levels>500/μl were observed in 98% of patients. Elevated CPK levels were detected in 71% of patients and elevated LDH levels in 75%. Three patients had cardiac complications. Treatment included mebendazole, nonsteroidal anti-inflammatory drugs, and corticosteroids. Anti-Trichinella antibodies were observed in 89.7% of patients two months after disease onset, including all hospital-treated patients. Among them, serum positivity detected one year later was 100%. This outbreak highlighted communication failures, from hunters to consumers. Awareness should be raised on the relation between trichinellosis and game meat. Trichinella species detection is important for adequate outbreak recording and could contribute to better understanding the clinical and serological signs of T. britovi infection.


Retracted: Strategies of Ice and Snow Tourism to Optimize Ecological Environment and Economic Growth from the Perspective of Sustainable Development.
[This retracts the article DOI: 10.1155/2022/9577859.].


Cortisol levels in cats' hair in presence or absence of Microsporum canis infection.
The purpose of this work was to perform a preliminary screening in the domestic cat to assess the concentration of cortisol in hairs by radioimmunoassay technique (RIA) in presence or absence of Microsporum canis infections. A total of 245 cats (7 with cutaneous lesions referable to dermatophytosis and 238 apparently healthy) coming from 14 shelters were examined. M. canis was isolated in 126 (51.4%) cats. The cortisol levels were significantly higher in cats with lesions or without lesions but with a high number of colonies in the plates (≥ 10 CFU) than in cats negative or with a lower number of colonies. The results obtained seem to highlight that chronic high levels of cortisol in cats could possibly promote the dermatophytes infections. Furthermore, in High-CFU asymptomatic cats, it could be present a state of infectious, and they, therefore, represents not a simple mechanical carrier.


[The problem of surgical therapy of bone cysts at the coxal end of the femur (author's transl)].
The problem of the juvenile bone cyst in the region of the coxal end of the femur is described on the basis of the case histories and references. Surgery is always mandatory, whereas the type of surgery depends on the dimensions and shape of the juvenile bone cyst.


Transient ischemic attack after electromotive drug administration for chronic non-infectious cystitis: report of two similar cases.
Electromotive drug administration (EMDA) is a new and promising approach for the treatment of chronic non-infectious cystitis. In animal studies utilizing EMDA there was evidence for deep penetration of dyes into the muscular layers of the bladder wall. However, besides minor local irritation no systemic side effects have been reported after translation of EMDA into the clinical setting. This article reports for the first time systemic neurological alterations after EMDA for chronic non-infectious cystitis. Two male patients, aged 72 and 78 years, respectively, were readmitted to the emergency room within few hours after EMDA showing clinical signs of transient ischemic attacks (TIA). After clinical examination, both patients were observed. Under overnight observation without any specific therapy the symptoms vanished completely in both patients. In older patients (>70 years of age) undergoing EMDA, cardiac and neurologic function should be monitored. The time of treatment during the first EMDA session should be limited to 15 or 20 min.


Bioinformatic Analysis of Natively Paired VH:VL Antibody Repertoires for Antibody Discovery.
Next-generation DNA sequencing (NGS) of human antibody repertoires has been extensively implemented to discover novel antibody drugs, to analyze B-cell developmental features, and to investigate antibody responses to infectious diseases and vaccination. Because the antibody repertoire encoded by human B cells is highly diverse, NGS analyses of antibody genes have provided a new window into understanding antibody responses for basic immunology, biopharmaceutical drug discovery, and immunotherapy. However, many antibody discovery protocols analyze the heavy and light chains separately due to the short-read nature of most NGS technologies, whereas paired heavy and light chain data are required for complete antibody characterization. Here, we describe a computational workflow to process millions of paired antibody heavy and light chain DNA sequence reads using the Illumina MiSeq 2x300 NGS platform. In this workflow, we describe raw NGS read processing and initial quality filtering, the annotation and assembly of antibody clonotypes relating to paired heavy and light chain antibody lineages, and the generation of complete heavy+light consensus sequences for the downstream cloning and expression of human antibody proteins.


A comparative study of robotic and laparoscopic approaches to Heller myotomy.
Minimally invasive Heller myotomy for achalasia is commonly performed laparoscopically, but recently done with robotic assistance. We compare outcomes of the 2 approaches. From January 2010 to January 2020, 447 patients underwent Heller myotomy with anterior fundoplication (170 with robotic assistance and 277 laparoscopically). End points included short-term and longitudinal esophageal emptying according to timed barium esophagram, symptom relief according to Eckardt score, and time-related reintervention. Normal esophageal morphology, present in 328 patients, was defined as nonsigmoidal with width <5 cm. We performed a propensity score--matched analysis to evaluate outcomes among robotic and laparoscopic groups. Timed barium esophagrams showed complete emptying at 5 minutes in 58% (77/132) of the robotic group and 48% (115/241) of the laparoscopic group in the short term (within 6 months of surgery). In the propensity-matched patients with normal esophageal morphology, the robotic group had a higher longitudinal prevalence of complete emptying of barium at 5 minutes (54% vs 34% at 4 years; P = .05), better intermediate-term Eckardt scores (1.7% vs 10% > 3 at 4 years; P = .0008), and actuarially fewer reinterventions (1.2% vs 11% at 3 years; P = .04). Both robotically assisted and laparoscopic Heller myotomy had excellent outcomes in patients treated for achalasia. In a matched subgroup of patients with normal esophageal morphology within this heterogeneous disease, the robotic approach might be associated with greater esophageal emptying, palliation of symptoms, and freedom from reintervention in the intermediate term. Long-term analysis would be important to determine if this trend persists.


The relationship between the visual field and the optic nerve head in glaucomas.
In a retrospective study of 50 eyes with chronic open-angle glaucoma we compared the findings obtained using stereochronoscopy (Sc), papillometry (Pm) and visual-field measurements. We found relationship between the neuroretinal-rim area and the visual-field findings measured using the Octopus glaucoma program, G1. There was only a weak relationship between the Sc findings and the visual-field measurements. This suggests that Sc detects a type of damage that is not detectable either using Pm or by visual-field examinations. Our results also suggest that quantitative perimetry detects the same kind of damage as that revealed by Pm. The neuroretinal-rim area was best correlated with short-term fluctuation, but was also very significantly correlated with mean damage and corrected loss variance.


Collaborative practice trends in US physician office visits: an analysis of the National Ambulatory Medical Care Survey (NAMCS), 2007-2016.
Practice arrangements in physician offices were characterised by examining the share of visits that involved physician assistants (PAs) and nurse practitioners (NPs). The hypothesis was that collaborative practice (ie, care delivered by a dyad of physician-PA and/or physician-NP) was increasing. Temporal ecological study. Non-federal physician offices. Patient visits to a physician, PA or NP, spanning years 2007-2016. A stratified random sample of visits to office-based physicians was pooled through the National Ambulatory Medical Care Survey public use linkage file. Among 317 674 visits to physicians, PAs or NPs, solo and collaborative practices were described and compared over two timespans of 2007-2011 and 2012-2016. Weighted patient visits were aggregated in bivariate analyses to achieve nationally representative estimates. Survey statistics assessed patient demographic characteristics, reason for visit and visit specialty by provider type. Within years 2007-2011 and 2012-2016, there were 4.4 billion and 4.1 billion physician office visits (POVs), respectively. Comparing the two timespans, the rate of POVs with a solo PA (0.43% vs 0.21%) or NP (0.31% vs 0.17%) decreased. Rate of POVs with a collaborative physician-PA increased non-significantly. Rate of POVs with a collaborative physician-NP (0.49% vs 0.97%, p<0.01) increased. Overall, collaborative practice, in particular physician-NP, has increased in recent years (p<0.01), while visits handled by a solo PA or NP decreased (p<0.01). In models adjusted for patient age and chronic conditions, the odds of collaborative practice in years 2012-2016 compared with years 2007-2011 was 35% higher (95% CI 1.01 to 1.79). Furthermore, in 2012-2016, NPs provided more independent primary care, and PAs provided more independent care in a non-primary care medical specialty. Preventive visits declined among all providers. In non-federal physician offices, collaborative care with a physician-PA or physician-NP appears to be a growing part of office-based healthcare delivery.


Pharmacist-led counselling intervention to improve antiretroviral drug adherence in Pakistan: a randomized controlled trial.
Pakistan is facing a growing population of people living with human immunodeficiency (HIV). In this randomized controlled trial, we investigate if a pharmacist-led intervention can increase adherence to antiretroviral therapy (ART) for people living with HIV (PLWH). Adults with HIV, who have been taking ART for more than 3 months were randomly assigned to receive either a pharmacist-led intervention or their usual care. Measures of adherence were collected at 1) baseline 2) just prior to delivery of intervention and 3) 8 weeks later. The primary outcomes were CD4 cell count and self-reported adherence measured with the AIDS Clinical Trial Group (ACTG) questionnaire. Post-intervention, the intervention group showed a statistically significant increase in CD4 cell counts as compared to the usual care group (p = 0.0054). In addition, adherence improved in the intervention group, with participants being 5.96 times more likely to report having not missed their medication for longer periods of time (p = 0.0086) while participants in the intervention group were 7.74 times more likely to report missing their ART less frequently (p < 0.0001). The findings support the improvement in ART adherence and HIV management. The trial is registered with Australian New Zealand Clinical Trials Registry ( ACTRN12618001882213 ). Registered 20 November 2018.


Patients at elevated risk of melanoma: individual predictors of non-compliance to GP referral for a dermatologist consultation.
The aim of this study is to assess whether patients at elevated risk of melanoma attended a dermatologist consultation after a General Practitioner referral and to determine individual predictors of non-compliance. This survey included 1506 high-risk French patients (selected using the Self-Assessment Melanoma Risk Score) referred to a dermatologist between April and October 2011. Compliance was evaluated from January to April 2012, based on attendance at a dermatologist consultation (or scheduling an appointment). Demographic data and factors mapping the Health Belief Model were tested as correlates using a multivariate logistic regression. Compliance with referral was 58.4%. The top seven factors associated with non-compliance were as follows: GP advice to consult was unclear (OR=13.22; [7.66-23.56]); no previous participation in cancer screenings, including smear tests (OR=5.03; [2.23-11.83]) and prostate screening (OR=2.04; [1.06-3.97]); lack of knowledge that melanoma was a type of cancer (OR=1.94; [1.29-2.92]); and reporting no time to make an appointment (OR=2.08; [1.82-2.38]), forgetting to make an appointment (OR=1.26; [1.08-1.46]), long delays in accessing an appointment (OR=1.25; [1.12-1.41]), not being afraid of detecting something abnormal (OR=1.54; [1.35-1.78]), no need to consult a dermatologist to feel secure (OR=1.28; [1.09-1.51]). Physicians should be aware of the factors predicting patient compliance with referrals for dermatologist consultations; better General Practitioner counseling might enhance compliance in high-risk populations.


Elephants born in the high stress season have faster reproductive ageing.
Senescent declines in reproduction and survival are found across the tree of life, but little is known of the factors causing individual variation in reproductive ageing rates. One contributor may be variation in early developmental conditions, but only a few studies quantify the effects of early environment on reproductive ageing and none concern comparably long-lived species to humans. We determine the effects of 'stressful' birth conditions on lifetime reproduction in a large semi-captive population of Asian elephants (Elephas maximus). We categorise birth month into stressful vs. not-stressful periods based on longitudinal measures of glucocorticoid metabolites in reproductive-aged females, which peak during heavy workload and the start of the monsoon in June-August. Females born in these months exhibit faster reproductive senescence in adulthood and have significantly reduced lifetime reproductive success than their counterparts born at other times of year. Improving developmental conditions could therefore delay reproductive ageing in species as long-lived as humans.


Changes in the commercial brand of tacrolimus lead to subtherapeutic trough levels and acute rejection in renal transplant recipients.
The vigilance of tacrolimus (TAC) trough levels is an essential part of renal transplant follow up. Reduced TAC trough levels and high variability are related to adverse outcomes. The aim of this study was to evaluate the impact of brand changes on tacrolimus (TAC) subtherapeutic (SubT) trough levels, acute rejection (AR), and kidney function. This is a prospective, observational cohort study of renal transplant recipients, between January 2016 and October 2018. Tacrolimus trough levels and brand used by the patient were both registered at every consult. Tacrolimus values ≤3.5 ng/mL were considered SubT. 445 patients were included. The median number of TAC brand changes was 2 (IQR, 1-4). Patients were grouped according to the number of brand changes: Group 1 = 0 (n = 107), Group 2 = 1-4 (n = 236), and Group 3 = ≥5 (n = 102). Patients with the greatest number of brand changes had a greater proportion and number of SubT TAC trough levels (Group 1 = 36.4%, average 0.53; Group 2 = 39.8%, average 0.65, Group 3 = 59.8%, average 1.17, P < .001) and AR (Group 1 = 0.9%, Group 2 = 11%, Group 3 = 14.7%, P < .001). On multivariate analysis, SubT levels and the number of brand changes were related to AR. In Mexico, changes in TAC brand are associated with an elevated frequency of SubT levels. Brand changes and SubT levels are independently associated with acute rejection. The supply policies on TAC brands in Mexico require revision to avoid changing brands as much as possible.


Brain and systemic temperature in patients with severe subarachnoid hemorrhage.
The significance of brain temperature (BT) in patients with severe brain damage remains unclear. This study investigated the relationships between BT, systemic temperature (ST), and clinical outcome in patients with severe subarachnoid hemorrhage. Thirty-one comatose patients with severe subarachnoid hemorrhage underwent ventricular drainage immediately after admission. The ventricular catheter also allowed monitoring of BT. ST was continuously measured using a bladder catheter with thermistor probe. BT at the start of the monitoring was lower than ST in four patients, and all died of brain swelling. BT was higher than ST at first but later fell below ST ("temperature reversal") in 12 patients, who all died of acute brain swelling. BT was higher than ST throughout the monitoring in 15 patients. Five of these patients died of causes other than brain swelling such as rerupture of the cerebral aneurysm, multiple organ failure, or respiratory failure. The other 10 patients survived with various degrees of disability. Observation of BT and ST can predict the outcome of severe subarachnoid hemorrhage.


ReactomeGSA - Efficient Multi-Omics Comparative Pathway Analysis.
Pathway analyses are key methods to analyze 'omics experiments. Nevertheless, integrating data from different 'omics technologies and different species still requires considerable bioinformatics knowledge.Here we present the novel ReactomeGSA resource for comparative pathway analyses of multi-omics datasets. ReactomeGSA can be used through Reactome's existing web interface and the novel ReactomeGSA R Bioconductor package with explicit support for scRNA-seq data. Data from different species is automatically mapped to a common pathway space. Public data from ExpressionAtlas and Single Cell ExpressionAtlas can be directly integrated in the analysis. ReactomeGSA greatly reduces the technical barrier for multi-omics, cross-species, comparative pathway analyses.We used ReactomeGSA to characterize the role of B cells in anti-tumor immunity. We compared B cell rich and poor human cancer samples from five of the Cancer Genome Atlas (TCGA) transcriptomics and two of the Clinical Proteomic Tumor Analysis Consortium (CPTAC) proteomics studies. B cell-rich lung adenocarcinoma samples lacked the otherwise present activation through NFkappaB. This may be linked to the presence of a specific subset of tumor associated IgG+ plasma cells that lack NFkappaB activation in scRNA-seq data from human melanoma. This showcases how ReactomeGSA can derive novel biomedical insights by integrating large multi-omics datasets.