Rising to the medication's requirements: The experience of elderly cancer patients receiving palliative chemotherapy in the elective oncogeriatrics field.
A new subfield of oncology has emerged in the last twenty years to raise awareness and address the specific needs of elderly cancer patients, a population that was long neglected in oncology. We sought to understand the individual experiences, as well as moral and social implications of considering elderly cancer patients as "treatable". Following an anthropological critical interpretative approach focusing on practical and symbolic effects of chemotherapy in a rapidly evolving medical field, we conducted 20 semi-structured interviews and observations of medicine storage places at home among elderly cancer patients aged 70 and over in a clearly incurable situation receiving palliative chemotherapy. We used photographs representing paths as triggers in interviews, and compared the patients' views with those of 12 health professionals in oncology during a brief open-ended interview. Elderly cancer patients consider themselves to be survivors and fighters. Their long trajectory is a result of their successful struggle and tolerance of the treatments allowing them to carry on. They continually observe their physical ability and test their resistance, they resist complaining and are grateful to have cancer at a late stage of life. By highlighting their active life rather than the treatment inconveniences, they show they are "young elderly" persons, capable of keeping active physically. They are treated precisely because they demonstrated that they had the physical and moral capacity to take the hit of the chemotherapy to their bodies and had the will to fight. The development of oncogeriatrics has enabled the treatment of the fittest cancer patients over 70, but the ethical debate to treat some elderly patients and not others, and decisions of therapeutic abstention facing frail elderly cancer patients remains an issue rarely discussed. This aspect should not be eluded by the important progress achieved in medicine facing cancer.


Identification of Subnanometric Ag Species, Their Interaction with Supports and Role in Catalytic CO Oxidation.
The nature and size of the real active species of nanoparticulated metal supported catalysts is still an unresolved question. The technique of choice to measure particle sizes at the nanoscale, HRTEM, has a practical limit of 1 nm. This work is aimed to identify the catalytic role of subnanometer species and methods to detect and characterize them. In this frame, we investigated the sensitivity to redox pretreatments of Ag/Fe/TiO₂, Ag/Mg/TiO₂ and Ag/Ce/TiO₂ catalysts in CO oxidation. The joint application of HRTEM, SR-XRD, DRS, XPS, EXAFS and XANES methods indicated that most of the silver in all samples is in the form of Ag species with size <1 nm. The differences in catalytic properties and sensitivity to pretreatments, observed for the studied Ag catalysts, could not be explained taking into account only the Ag particles whose size distribution is measured by HRTEM, but may be explained by the presence of the subnanometer Ag species, undetectable by HRTEM, and their interaction with supports. This result highlights their role as active species and the need to take them into account to understand integrally the catalysis by supported nanometals.


Onset of Osmotic Swelling in Highly Charged Clay Minerals.
Delamination by osmotic swelling of layered materials is generally thought to become increasingly difficult, if not impossible, with increasing layer charge density because of strong Coulomb interactions. Nevertheless, for the class of 2:1 layered silicates, very few examples of delaminating organo-vermiculites were reported in literature. We propose a mechanism for this repulsive osmotic swelling of highly charged vermiculites based on repulsive counterion translational entropy that dominates the interaction of adjacent layers above a certain threshold separation. Based on this mechanistic insight, we were able to identify several organic interlayer cations appropriate to delaminate highly charged, vermiculite-type clay minerals. These findings suggest that the osmotic swelling of highly charged organoclays is a generally applicable phenomenon rather than the odd exemption.


Validation of the CoRE Questionnaire for a Medical Journal Peer Review.
If a peer review instrument asks concrete questions (defined as items that can only generate disagreement if reviewers have different degrees of expertise), then questionnaires could become more meaningful in terms of resolving subjectivity thus leading to more reviewer agreement. A concrete item questionnaire with well-chosen questions can also help resolve disagreement when reviewers have the same level of expertise. We have recently created the core-item reviewer evaluation (CoRE) questionnaire for which decision-threshold score levels have been created, but which have not been validated. This prospective validation of these thresholds for the CoRE questionnaire demonstrated strong agreement between reviewer recommendations and their reported score levels when tested prospectively at Clinical Medicine and Research. We conclude that using the CoRE questionnaire will help reduce peer reviewer disagreement. More importantly, when reviewer expertise varies, editors can more easily detect this and decide which opinion reflects the greater expertise.


Arbovirological survey in Silica plateau area, Roznava District, Czechoslovakia.
The serosurveys conducted in the Silica plateau area of the Slovak karst region revealed the presence of specific neutralizing antibody against tick-borne encephalitis (TBE) virus in 18% of local inhabitants (33 examined, mostly goats and sheep farmers), 54% of goats (26 examined), 18% of sheep (120 examined) and 13% of cattle (60 examined), against Lipovník (LIP) virus in 30% of inhabitants, 88% of goats, 55% of sheep and 45% of cattle, and against Bhanja (BHA) virus in 27% of inhabitants, 46% of goats, 29% of sheep and 23% of cattle. The results of hemagglutination-inhibition tests with TBE and BHA antigens were analogous. A detailed analysis of these serologic data points to a recent enhancement of the circulation of LIP and BHA viruses and to a very low TBE virus activity in this natural focus of arboviral infections. The immunological surveys of the 32 former "Roznava disease" patients, conducted 25 years after an extensive epidemic of a TBE virus infection that originated in Roznava in 1951, revealed the presence of neutralizing (and also hemagglutination-inhibiting) antibodies against TBE virus in as many as 78% of cases. Antibodies against LIP and BHA viruses were also detectable in the sera of 16% and 9%, respectively, of these individuals. Populations of the ectoparasites examined for the presence of arbovirus comprised 231 Ixodes ricinus, 806 Dermacentor marginatus and 204 Haemaphysalis punctata ticks and 117 specimens of the louse-flies Melophagus ovinus. Two strains of arbivirus that were antigenically related to Lipovník and Tribec viruses belonging to a group of Kemerovo viruses were isolated from male and female I. ricinus ticks collected from cattle.


Immune Checkpoint Inhibitor-Related Myocarditis: Recognition, Surveillance, and Management.
Immune checkpoint inhibitor (ICI) therapy is an effective treatment for many patients. Although rare, immune-mediated cardiovascular adverse events can occur, including myocarditis. This article provides an overview of the incidence, proposed pathophysiology, and current surveillance for myocarditis in patients receiving ICI therapy. A literature search was conducted using PubMed®, CINAHL®, and Scopus® for articles published from 2016 through 2021 to evaluate current recognition, surveillance, and management protocols for ICI-related myocarditis. A case study illustrates the challenges in managing patients experiencing ICI-related cardiac adverse events. The incidence of myocarditis in patients treated with ICI therapy is 0.04%-1.14%, but it carries a high mortality rate of 25%-50%. A baseline cardiac evaluation and scheduled surveillance throughout therapy is recommended, particularly for patients with cardiovascular risk factors. Through continuing education and proper training, clinicians and nursing staff can recognize and promptly diagnose immune-related cardiac adverse events.


Molecular drivers of resistance to sulbactam-durlobactam in contemporary clinical isolates of Acinetobacter baumannii.
Acinetobacter baumannii-calcoaceticus complex (ABC) causes severe infections that are difficult to treat due to pre-existing antibiotic resistance. Sulbactam-durlobactam (SUL-DUR) is a targeted β-lactam/β-lactamase inhibitor combination antibiotic designed to treat serious infections caused by Acinetobacter, including multidrug- and carbapenem-resistant strains. In a recent global surveillance study of 5,032 ABC clinical isolates collected from 2016 to 2021, less than 2% of ABC isolates had SUL-DUR MIC values >4 µg/mL. Molecular characterization of these isolates confirmed the primary drivers of resistance are metallo-β-lactamases or penicillin-binding protein 3 (PBP3) mutations, as previously described. In addition, this study shows that certain common PBP3 variants, such as A515V, are insufficient to confer sulbactam resistance and that the efflux of durlobactam by AdeIJK is likely to play a role in a subset of strains.


Generating mobility networks with generative adversarial networks.
The increasingly crucial role of human displacements in complex societal phenomena, such as traffic congestion, segregation, and the diffusion of epidemics, is attracting the interest of scientists from several disciplines. In this article, we address mobility network generation, i.e., generating a city's entire mobility network, a weighted directed graph in which nodes are geographic locations and weighted edges represent people's movements between those locations, thus describing the entire mobility set flows within a city. Our solution is MoGAN, a model based on Generative Adversarial Networks (GANs) to generate realistic mobility networks. We conduct extensive experiments on public datasets of bike and taxi rides to show that MoGAN outperforms the classical Gravity and Radiation models regarding the realism of the generated networks. Our model can be used for data augmentation and performing simulations and what-if analysis.


Overcoming aromatase inhibitor resistance in breast cancer: possible mechanisms and clinical applications.
Estrogen plays crucial roles in the progression of hormone-dependent breast cancers through activation of nuclear estrogen receptor α (ER). Estrogen is produced locally from circulating inactive steroids and adrenal androgens in postmenopausal women. However, conversion by aromatase is a rate-limiting step in intratumoral estrogen production in breast cancer. Aromatase inhibitors (AIs) inhibit the growth of hormone-dependent breast cancers by blocking the conversion of adrenal androgens to estrogen and by unmasking the inhibitory effect of androgens, acting via the androgen receptor (AR). AIs are thus a standard treatment option for postmenopausal hormone-dependent breast cancer. However, although initial use of AIs provides substantial clinical benefit, some breast cancer patients relapse because of the acquisition of AI resistance. A better understanding of the mechanisms of AI resistance may contribute to the development of new therapeutic strategies and aid in the search for new therapeutic targets and agents. We have investigated AI-resistance mechanisms and established six AI-resistant cell lines. Some of them exhibit estrogen depletion-resistance properties via constitutive ER-activation or ER-independent growth signaling. We examined how breast cancer cells can adapt to estrogen depletion and androgen superabundance. Estrogen and estrogenic androgen produced independently from aromatase contributed to cell proliferation in some of these cell lines, while another showed AR-dependent cell proliferation. Based on these findings, currently proposed AI-resistance mechanisms include an aromatase-independent estrogen-producing pathway, estrogen-independent ER function, and ER-independent growth signaling. This review summarizes several hypotheses of AI-resistance mechanisms and discusses how existing or novel therapeutic agents may be applied to treat AI-resistant breast cancers.


A bio-inspired methodology of identifying influential nodes in complex networks.
How to identify influential nodes is a key issue in complex networks. The degree centrality is simple, but is incapable to reflect the global characteristics of networks. Betweenness centrality and closeness centrality do not consider the location of nodes in the networks, and semi-local centrality, leaderRank and pageRank approaches can be only applied in unweighted networks. In this paper, a bio-inspired centrality measure model is proposed, which combines the Physarum centrality with the K-shell index obtained by K-shell decomposition analysis, to identify influential nodes in weighted networks. Then, we use the Susceptible-Infected (SI) model to evaluate the performance. Examples and applications are given to demonstrate the adaptivity and efficiency of the proposed method. In addition, the results are compared with existing methods.


Solitary glandular papilloma of the peripheral lung: a report of two cases.
Solitary papilloma of the lung is thought to be a rare benign epithelial tumor, and complete surgical resection is currently the standard treatment for this pathology. However, some cases of papilloma have reportedly shown malignant potential. We report two cases of solitary glandular papilloma of the peripheral lung that were treated by thoracoscopic partial resection. The first patient presented with a nodular lesion in the lower lobe of the left lung that was detected on a follow-up chest computed tomography (CT) scan after treatment for laryngeal cancer. Partial lung resection was performed by video-assisted thoracoscopic surgery. In the second patient, a nodular lesion was incidentally identified in the lower lobe of the left lung during a health check-up. Partial lung resection was again performed by video-assisted thoracoscopic surgery. The postoperative course in both cases was uneventful, and no recurrences have been observed as of 44 months and 41 months postoperatively, respectively. To the best of our knowledge, malignant transformation has been reported both with the squamous type and the mixed type of solitary papilloma of the lung. The glandular variant has shown no tendency toward local recurrence after local excision and has no apparent malignant potential. Local excision is thus recommended for solitary glandular papilloma in order to preserve pulmonary function.


Imaging alpha-hemolysin with molecular dynamics: ionic conductance, osmotic permeability, and the electrostatic potential map.
alpha-Hemolysin of Staphylococcus aureus is a self-assembling toxin that forms a water-filled transmembrane channel upon oligomerization in a lipid membrane. Apart from being one of the best-studied toxins of bacterial origin, alpha-hemolysin is the principal component in several biotechnological applications, including systems for controlled delivery of small solutes across lipid membranes, stochastic sensors for small solutes, and an alternative to conventional technology for DNA sequencing. Through large-scale molecular dynamics simulations, we studied the permeability of the alpha-hemolysin/lipid bilayer complex for water and ions. The studied system, composed of approximately 300,000 atoms, included one copy of the protein, a patch of a DPPC lipid bilayer, and a 1 M water solution of KCl. Monitoring the fluctuations of the pore structure revealed an asymmetric, on average, cross section of the alpha-hemolysin stem. Applying external electrostatic fields produced a transmembrane ionic current; repeating simulations at several voltage biases yielded a current/voltage curve of alpha-hemolysin and a set of electrostatic potential maps. The selectivity of alpha-hemolysin to Cl(-) was found to depend on the direction and the magnitude of the applied voltage bias. The results of our simulations are in excellent quantitative agreement with available experimental data. Analyzing trajectories of all water molecule, we computed the alpha-hemolysin's osmotic permeability for water as well as its electroosmotic effect, and characterized the permeability of its seven side channels. The side channels were found to connect seven His-144 residues surrounding the stem of the protein to the bulk solution; the protonation of these residues was observed to affect the ion conductance, suggesting the seven His-144 to comprise the pH sensor that gates conductance of the alpha-hemolysin channel.


Language evolution: syntax before phonology?
Phonology and syntax represent two layers of sound combination central to language's expressive power. Comparative animal studies represent one approach to understand the origins of these combinatorial layers. Traditionally, phonology, where meaningless sounds form words, has been considered a simpler combination than syntax, and thus should be more common in animals. A linguistically informed review of animal call sequences demonstrates that phonology in animal vocal systems is rare, whereas syntax is more widespread. In the light of this and the absence of phonology in some languages, we hypothesize that syntax, present in all languages, evolved before phonology.


TNF directly stimulates glucose uptake and leucine oxidation and inhibits FFA flux in conscious dogs.
We tested the hypothesis that the metabolic changes in glucose, lipid, and protein metabolism seen during tumor necrosis factor (TNF) infusion were due to the increase in plasma glucagon concentration rather than to the direct effects of TNF. We employed a pancreatic clamp technique to keep plasma insulin and glucagon concentrations constant throughout a 4-h isotope infusion. Glucose, lipid, and protein kinetics were measured by means of the primed, constant infusion of [6,6-2H]glucose, [2H5]glycerol, [2H2]palmitic acid, and [1-13C]leucine. After a 2-h baseline period (period 1), TNF was infused as a primed, constant infusion (prime, 2.5 micrograms/kg; constant infusion, 62.5 ng.kg-1.min-1) for 2 h (period 2). Whereas plasma glucose concentration dropped significantly during TNF infusion, endogenous glucose production did not change. The decrease in glucose concentrations was due to a stimulation of glucose clearance (P < 0.05). The rate of lipolysis did not decrease significantly, but free fatty acid (FFA) flux and plasma FFA concentration significantly decreased during TNF infusion (P < 0.05). The rate of appearance of leucine was not affected by TNF infusion, but TNF caused a significant increase in 13CO2 excretion (P < 0.05) and leucine oxidation (P < 0.05). The calculated rates of whole body protein synthesis decreased. We concluded that TNF did not directly affect glucose production. Furthermore, changes in protein and lipid kinetics during TNF infusion were not mediated by changes in insulin or glucagon and may have reflected direct effects of TNF.


Evaluating the accuracy of a cataract surgery simulation video in depicting patient experiences under conscious anesthesia.
To evaluate the accuracy of a point-of-view cataract surgery simulation video in representing different subjective experiences of patients undergoing the procedure. One hundred consecutive post-cataract-surgery patients were shown a short simulation video of the surgery obtained through a porcine eye model during the first postoperative week. Patients then answered a multiple-choice questionnaire regarding their visual and tactile intraoperative experiences and how those experiences matched the simulation. Of the patients surveyed (n = 100), 78% (n = 78) recalled visual experiences during surgery, 11% recalled pain (n = 11), and 6.4% (n = 5) recalled frightening experiences. Thirty-six percent of patients (n = 36) were interviewed after their second cataract surgery; there was no statistically significant difference between anxiety scores reported before the first eye surgery and second eye surgery (p = 0.147). Among all patients who recalled visual experiences (n = 78), nearly half (47.4%) reported that the video was the same/similar to their experience. Forty-eight percent of the patients recommended future patients to watch the video before their procedures, and more than a third (36%) agreed that watching the video before surgery would have helped them to relax. Our model reflects the wide range of subjective patient experiences during and after surgery. The high percentage of patients who found the video accurate in different ways suggests that, with more development, point-of-view cataract simulation videos could prove useful for educational or clinical use. Further research may be done to confirm the simulation's utility, by screening the video for subjects before operations.


The clinical association between coagulation indexes, platelet-related parameters, and bone metastasis of newly diagnosed prostate cancer.
At present, much evidence shows that many cancers have a high risk of thrombosis. Several studies have shown the prognostic value of platelet-related parameters and coagulation indexes in prostate cancer (PCa). However, the association between platelet-related parameters, coagulation indexes and bone metastasis of Pca is unclear. A total of 234 pathologically diagnosed patients with Pca were consecutively collected and stratified into the bone metastasis group and non-bone metastasis group according to the results of the bone scan. ROC curve analysis was used to explore the auxiliary predictive value of single and combined parameters for bone metastasis in Pca patients. Univariate and multivariate Logistic regression analyses were used to determine the relationship between platelet-related parameters, coagulation indexes, and bone metastasis of Pca. Platelet count (PLT), fibrinogen (Fib), prostate-specific antigen (PSA), and D-dimer (DD) levels of the bone metastasis group were significantly higher than the non-bone metastasis group (P = 0.010, P < 0.001, P < 0.001, and P < 0.001, respectively). This study confirmed that PLT, PSA, DD and Fib have auxiliary predictive value for prostate cancer bone metastasis. After the combination of PLT, PSA, DD and Fib, the area under the curve, sensitivity and specificity increased significantly. The univariate logistic analysis demonstrated that PLT (OR: 1.008, P = 0.011), DD (OR: 2.690, P < 0.001), PSA (OR: 1.073, P < 0.001), Gleason score (OR: 7.060, P < 0.001), and Fib (OR: 2.082, P < 0.001) were significantly positively correlated with bone metastasis of Pca. Multivariate analysis showed that PSA (OR: 1.075, P < 0.001), DD (OR: 2.152, P < 0.001), Gleason score (OR: 2.904, P < 0.001), and Fib (OR: 1.706, P < 0.001) were independent risk factors for bone metastasis of Pca after adjusting for Age, BMI and other confounding factors. Higher platelet, D-dimer, prostate-specific antigen, Gleason score, and fibrinogen levels may predict a worse prognosis in patients with Pca. PLT, DD, and Fib, as readily available and relatively inexpensive indicators, help predict bone metastasis of Pca. It is suggested that PLT, DD and Fib may be helpful in the risk stratification of Pca.


Functional joint models for chronic kidney disease in kidney transplant recipients.
This functional joint model paper is motivated by a chronic kidney disease study post kidney transplantation. The available kidney organ is a scarce resource because millions of end-stage renal patients are on the waiting list for kidney transplantation. The life of the transplanted kidney can be extended if the progression of the chronic kidney disease stage can be slowed, and so a major research question is how to extend the transplanted kidney life to maximize the usage of the scarce organ resource. The glomerular filtration rate is the best test to monitor the progression of the kidney function, and it is a continuous longitudinal outcome with repeated measures. The patient's survival status is characterized by time-to-event outcomes including kidney transplant failure, death with kidney function, and death without kidney function. Few studies have been carried out to simultaneously investigate these multiple clinical outcomes in chronic kidney disease stage patients based on a joint model. Therefore, this paper proposes a new functional joint model from this clinical chronic kidney disease study. The proposed joint models include a longitudinal sub-model with a flexible basis function for subject-level trajectories and a competing-risks sub-model for multiple time-to event outcomes. The different association structures can be accomplished through a time-dependent function of shared random effects from the longitudinal process or the whole longitudinal history in the competing-risks sub-model. The proposed joint model that utilizes basis function and competing-risks sub-model is an extension of the standard linear joint models. The application results from the proposed joint model can supply some useful clinical references for chronic kidney disease study post kidney transplantation.


SITVITBovis-a publicly available database and mapping tool to get an improved overview of animal and human cases caused by Mycobacterium bovis.
Limited data are available for bovine tuberculosis and the infections it can cause in humans and other mammals. We therefore constructed a publicly accessible SITVITBovis database that incorporates genotyping and epidemiological data on Mycobacterium bovis. It also includes limited data on Mycobacterium caprae (previously synonymous with the name M. bovis subsp. Caprae) that can infect both animals and humans. SITVITBovis incorporates data on 25,741 isolates corresponding to 60 countries of origin (75 countries of isolation). It reports a total of 1000 spoligotype patterns: 537 spoligotype international types (SITs, containing 25 278 clinical isolates) and 463 orphan patterns, allowing a wide overview of the geographic distribution of various phylogenetical sublineages (BOV_1, BOV_2, BOV_3 and BOV_4-CAPRAE). The SIT identifiers of the SITVITBovis were compared to the SB numbers of the Mbovis.org database to facilitate crosscheck among databases. Note that SITVITBovis also contains limited information on mycobacterial interspersed repetitive units-variable number of tandem repeats when available. Significant differences were observed when comparing age/gender of human isolates as well as various hosts. The database includes information on the regions where a strain was isolated as well as hosts involved, making it possible to see geographic trends. SITVITBovis is publicly accessible at: http://www.pasteur-guadeloupe.fr:8081/SITVIT_Bovis. Finally, a future second version is currently in progress to allow query of associated whole-genome sequencing data. Database URLhttp://www.pasteur-guadeloupe.fr:8081/SITVIT_Bovis.


Farming on the Ocean via Desalination (FOOD).
Today, agricultural irrigation consumes the largest amount of freshwater globally, while humans are threatened by water scarcity. To eliminate the trade-off between hunger and thirst, here, we show off-grid maritime agriculture based on a floating solar-driven agro-desalination wooden dome. In this dome, part of the visible light is transmitted for photosynthesis, and the remaining solar energy drives solar desalination, providing enough water (>4 mm day-1) for irrigation. Based on this water-food synergy, the stages of germination and growth are demonstrated. This technology can, to a large extent, support food security and sustainable agriculture and, in principle, be used to create self-circulation systems at sea to help humans survive weather extremes such as floods and droughts.


"High-cost" employees in an occupational alcoholism program. A preliminary report.
In 1975 International Harvester Company established a Health Counseling Program for employees suffering from alcoholism. Eighty-three of 342 employees followed for at least one year were found to account for a major portion of medical and disability costs. These "high-cost" employees were further characterized in this study.


Environmental noise sources and interventions to minimize them: a tale of 2 hospitals.
Noise has been shown to interfere with the healing process and can disrupt the patient's experience. This study assessed patients' and staff's perceptions of noise levels and sources in the hospital environment and identified interventions to reduce the noise level. The interventions significantly reduced noise as perceived by patients and staff. Identification of a structured process to identify noise sources and standardization of noise measurement methods can improve the patient hospital experience.


Hypertriglyceridemia and its impact on mitotane monitoring in adrenocortical carcinoma.
Mitotane is used for treatment of advanced adrenocortical carcinoma. It is administered when the carcinoma is unresectable, metastasized, or at high-risk of recurrence after resection. In addition, mitotane is considered to have direct adrenolytic effects. Because of its narrow therapeutic-toxic range, therapeutic drug monitoring (TDM) is warranted. In 2020, a left-sided adrenal gland tumor was found (5.8 cm) in a 38-year-old man. Considering the size of this lesion and inability to exclude an adrenocortical carcinoma on imaging, a laparoscopic adrenalectomy was performed. Histopathologic examination determined presence of an adrenocortical carcinoma (pT2N0M0 ENSAT stadium II; ki67 10-15%). There was no evidence for residual or metastatic disease but given the high risk of recurrence, adjuvant therapy with mitotane was initiated. During TDM, a sudden and spuriously high level of mitotane was observed but without signs or symptoms of toxicity. After exploration, it was found that this high concentration was completely due to uncontrolled hypertriglyceridemia. After correction thereof, mitotane levels were again in the therapeutic range. This observation underscores the importance of TDM sampling in a fasting state with concurrent control of prevalent or incident dyslipidemia. TDM of mitotane is advocated to achieve therapeutic levels while avoiding toxicity. For correct TDM, sampling should be done at least 12 h after last intake of mitotane. Although sampling in fasting conditions in not explicitly mentioned in the guidelines, fasting state should be considered as elevated serum triglyceride levels might cause spuriously high mitotane levels. In patients undergoing treatment with mitotane and presenting with too high or unexplained fluctuating mitotane levels without signs or symptoms of toxicity, hypertriglyceridemia as a possible cause should be investigated. If dyslipidemia occurs in patients under mitotane treatment, other causes than mitotane (e.g. alcohol abuse and diabetes) should be considered and appropriate treatment should be initiated.


B-type natriuretic peptide signal peptide circulates in human blood: evaluation as a potential biomarker of cardiac ischemia.
The diagnosis of cardiac necrosis such as myocardial infarction can be difficult and relies on the use of circulating protein markers like troponin. However, there is a clear need to identify circulating, specific biomarkers that can detect cardiac ischemia without necrosis. Using specific immunoassay and tandem mass spectrometry, we show that a fragment derived from the signal peptide of B-type natriuretic peptide (BNPsp) not only is detectable in cytosolic extracts of explant human heart tissue but also is secreted from the heart into the circulation of healthy individuals. Furthermore, plasma levels of BNPsp in patients with documented acute ST-elevation myocardial infarction (n=25) rise to peak values ( approximately 3 times higher than the 99th percentile of the normal range) significantly earlier than the currently used biomarkers myoglobin, creatine kinase-MB, and troponin. Preliminary receiver-operating characteristic curve analysis comparing BNPsp concentrations in ST-elevation myocardial infarction patients and other patient groups was positive (area under the curve=0.97; P<0.001), suggesting that further, more rigorous studies in heterogeneous chest pain patient cohorts are warranted. Our results demonstrate for the first time that BNPsp exists as a distinct entity in the human circulation and could serve as a new class of circulating biomarker with the potential to accelerate the clinical diagnosis of cardiac ischemia and myocardial infarction. Clinical Trial Registration- URL: http://www.anzctr.org.au. Unique identifier: ACTRN12609000040268.


Spectrum of initial clinical presentations in Pakistani patients with systemic lupus erythematosus in the Arthritis Care Foundation lupus cohort.
The aim is to determine the pattern of initial clinical presentations of systemic lupus erythematous (SLE) in patients in a Pakistani lupus cohort. This is a multi-centric, retrospective, descriptive study that was done through the analysis of electronic records of patients registered with outdoor clinics of the Arthritis Care Foundation (ACF) from November 2021 to March 2023. Follow-up records of all patients diagnosed and labeled as SLE as per ACR/EULAR criteria 2019 were reviewed and only those patients whose initial presentation of SLE was documented at their incident visit (after verifying the signs and symptoms from record of their GP/referring physicians' visits) were included in the study. A total of 388 patients diagnosed with SLE were included in the study. Their data was then entered and analyzed by using SPSS 23. The qualitative data was expressed as percentages and numbers while the quantitative variables were expressed as mean and standard deviation. Data correlation was calculated by Chi-Square test, and a p-value of less than 0.05 was considered statistically significant. Of our 388 patients, 360 (92.8%) were females and 28 (7.2%) were males giving a female-to-male ratio of 12:1. The mean age of our patients was 32.8 + 9.8 years. Mucocutaneous manifestations were most commonly reported in our patient group by 336 (86.7%) patients. Musculoskeletal complaints were the next most common presenting feature reported by 246 (61.9%) patients followed by constitutional symptoms in 78 (20.1%) patients, and renal involvement in 42 (10.8%) patients. In our study, a majority of patients presented with mucocutaneous symptoms. It is therefore of paramount importance to suspect autoimmune diseases in patients with these system involvements.


2,5-Hexanedione-induced changes in the monomeric neurofilament protein content of rat spinal cord fractions.
Quantitative morphometric analyses have demonstrated that axon atrophy is the primary neuropathic feature in the CNS and PNS of rats intoxicated with 2,5-hexanedione (HD). Axon caliber is maintained by the exchange of mobile neurofilament (NF) subunits with the stationary polymer and, therefore, HD might produce atrophy by disrupting cytoskeletal turnover. To evaluate this possibility, groups of rats were exposed to HD at dosing schedules (175 mg/kg x 101 days or 400 mg/kg x 26 days) that produced moderate levels of neurological deficits and prevalent axon atrophy in spinal cord white matter tracts. Lumbar spinal cord regions from HD-intoxicated rats and their age-matched controls were Triton-extracted and separated by differential fractionation into a low-speed, insoluble pellet (P1) of NF polymer and a high-speed supernatant fraction (S2), which presumably contained mobile monomer. Cytoskeletal protein contents (NF-L, -M, -H, and beta-tubulin) in each fraction were determined by immunoblot analysis. Results show that regardless of HD dose-rate, the NF polymer in P1 remained unaffected, although soluble monomer in the S2 fraction was depleted significantly (60-80% reduction). Fractional beta-tubulin contents were inconsistently affected and abnormal higher-molecular-weight NF proteins were detected in the P1 fraction only. Studies with antibodies directed against phosphorylated (RT97) and nonphosphorylated (SMI32) epitopes on NF-H and measurements of corresponding isoelectric range suggested that alterations in phosphorylation were not involved. The selective depletion of Triton-soluble protein suggested that HD adduction of NFs interfered with the dynamic interactions of the polymeric and mobile monomeric pools.


Selecting Approaches for Hit Identification and Increasing Options by Building the Efficient Discovery of Actionable Chemical Matter from DNA-Encoded Libraries.
Over the past 20 years, the toolbox for discovering small-molecule therapeutic starting points has expanded considerably. Pharmaceutical researchers can now choose from technologies that, in addition to traditional high-throughput knowledge-based and diversity screening, now include the screening of fragment and fragment-like libraries, affinity selection mass spectrometry, and selection against DNA-encoded libraries (DELs). Each of these techniques has its own unique combination of advantages and limitations that makes them more, or less, suitable for different target classes or discovery objectives, such as desired mechanism of action. Layered on top of this are the constraints of the drug-hunters themselves, including budgets, timelines, and available platform capacity; each of these can play a part in dictating the hit identification strategy for a discovery program. In this article, we discuss some of the factors that we use to govern our building of a hit identification roadmap for a program and describe the increasing role that DELs are playing in our discovery strategy. Furthermore, we share our learning during our initial exploration of DEL and highlight the approaches we have evolved to maximize the value returned from DEL selections. Topics addressed include the optimization of library design and production, reagent validation, data analysis, and hit confirmation. We describe how our thinking in these areas has led us to build a DEL platform that has begun to deliver tractable matter to our global discovery portfolio.


The Impact of Medical Comorbidities on Patient Satisfaction in Chronic Rhinosinusitis.
Patient satisfaction has a significant bearing on medical therapy compliance and patient outcomes. The purpose of this study was to (1) describe patient satisfaction, as characterized by the Patient Satisfaction Questionnaire-18 (PSQ-18), in the care of patients with chronic rhinosinusitis (CRS) and (2) analyze the impact of comorbidities on satisfaction using the functional comorbidity index (FCI). Patient demographics, disease severity measures, and PSQ-18 scores for patients with CRS presenting to a tertiary rhinology clinic between November 2019 and April 2020 were collected and analyzed. FCI was calculated retrospectively using the electronic medical record; individual comorbidities were tabulated. Spearman's correlations followed by multivariate regression was used to assess the relationship between medical comorbidities and PSQ-18. Sixty-nine patients met criteria for analysis. There were no significant differences in age, gender, and Sinonasal Outcomes Test-22 scores between CRS patients with (CRSwNP) and without (CRSsNP) nasal polyps. There was no significant difference in the mean FCI for patients with CRSwNP versus CRSsNP (5.1 and 4.3, respectively) (P = .843). Similarly, there was no significant difference in the mean sum PSQ-18 score (78/100 in both) between these cohorts (P = .148). The mean sum PSQ-18 score was not significantly associated with anxiety (P = .728), depression (P = .624), or FCI (P = .282), but was significantly associated with hearing impairment (P < .001). Patient satisfaction in the care of CRS is generally high with a diagnosis of comorbid hearing impairment demonstrating a negative association with satisfaction in this cohort.


Efficient enrichment of glycopeptides using phenylboronic acid polymer brush modified silica microspheres.
For the development of rapid glycopeptide enrichment materials, conventional monolayer phenylboronic acid (PBA) based materials inevitably encounter many problems, such as low loading efficiency, long incubation time, and unsatisfactory selectivity. Extending the materials from a 1D monolayer to a 3D polymeric matrix will be one of the best candidates tackling these problems. In this work, a PBA-based polymer material (denoted as polyPBA@SiO2) was developed, in which flexible PBA polymer brushes were immobilized on the surface of silica microspheres, constructing an ideal platform for the efficient enrichment of glycopeptides. This material exhibits stronger interaction with glycopeptides in a higher concentration of organic solvent than in aqueous solution, resulting in the high binding capacity of 60 mg g-1. Moreover, higher selectivity for glycopeptides can be achieved with polyPBA@SiO2 than with both monolayer PBA modified silica and commercial PBA-agarose. These unique features of polyPBA@SiO2 could be attributed to the synergistic effect of polyvalent interactions provided by the polymer brush, specific interaction between PBA and glycopeptides and suppression of the non-specific binding of non-glycopeptides under high ACN concentration.


A Qualitative Study of Adult Hospitalized Patients With Difficult Venous Access Experiencing Short Peripheral Catheter Insertion in a Hospital Setting.
Hospitalized patients require venous access for procedures, treatments, or therapies. The short peripheral catheter (SPC) is one option for patients who need intravenous (IV) access for treatment. Patients with difficult vasculature sometimes require multiple attempts to obtain SPC access. The aim of this study was to gain an understanding of adult patients' experiences with SPC insertion, specifically those with difficult venous access. Ten participants were purposely sampled over a 2-month period for semistructured interviews from the medical, surgical, and telemetry units at an inner city, 750-bed trauma hospital in the southwestern United States. Four key themes developed from the interview data: skills and techniques of the clinicians, distress and the SPC insertion experience, physical and emotional pain, and patient/clinician communication. These themes provided ways that clinicians might improve the patient experience, including: ensuring experienced and confident inserters are available to insert SPCs, utilizing distraction and pain methods to decrease pain perception, communicating with patients regarding site selection and expectations during SPC insertion, and identifying patients with difficult vascular access to limit attempts per patient to preserve vascular sites.


In vitro reproductive toxicity of polychlorinated biphenyls: effects on oocyte maturation and developmental competence in cattle.
Polychlorinated biphenyls (PCBs) are one of the most persistent and widespread group of endocrine disrupting compounds in the ecosystem. High concentrations of these substances are known to be present in sewage sludge from industrial, agricultural, and domestic origin that is spread in increasing amounts on arable land and pasture as fertilizer and is found in water, representing an increasing risk for the reproductive health of farm animals. Objective of this study was to determine the impact of PCBs on maturation and developmental competence of cattle oocytes. Since PCBs are a family of 209 molecules present in the environment as a mixture, Aroclor-1254, a pool of more than 60 congeners, was used in these experiments as its composition is considered to be environmentally relevant. Cumulus-oocytes complexes were exposed during IVM to serial concentrations of Aroclor-1254 (between 1 microg/ml and 0.0001 microg/ml) and compared with control groups. Aroclor decreased the percentage of oocytes that reached metaphase II stage after 24 hr, at doses as low as 0.01 microg/ml. Groups treated with 0.001 microg/ml or above, showed an impaired fertilization rate and a dramatic increase of polyspermy. Moreover, exposure during maturation resulted in a reduced proportion of oocytes that cleaved and developed until blastocyst stage although no differences in embryo cell numbers were observed. The present study indicates that very low PCBs concentrations are sufficient to disrupt bovine oocyte maturation, its fertilization, and developmental competence. These results also provide a set of reference data for the assessment of the risk posed by these substances to animal reproductive health, though further work will be necessary to equate in vitro doses to in vivo exposures.


Brain Structural Abnormalities in a Group of Never-Medicated Patients With Long-Term Schizophrenia.
This study investigated brain morphometry in chronically ill but never-medicated schizophrenia patients and whether the relation of age to morphometric abnormalities differed from that in healthy subjects. In a cross-sectional design, high-resolution T1-weighted images were acquired from 25 schizophrenia patients with untreated chronic illness lasting 5 to 47 years and 33 matched healthy comparison subjects. Cortical thickness and gray matter volume were compared in the two groups. In regions with significant group differences, nonlinear modeling of age-related effects was used to test for accelerated decline in the patients. Schizophrenia patients had less cortical thickness in the bilateral ventromedial prefrontal cortices, left superior temporal gyrus, and right pars triangularis, relative to comparison subjects, and greater cortical thickness in the left superior parietal lobe. The relation of age to cortical thickness indicated faster age-related cortical thinning in the right ventromedial prefrontal cortex, left superior temporal gyrus, and right pars triangularis in patients than in comparison subjects, but slower thinning in the left superior parietal lobe. Gray matter volume was greater in the putamen bilaterally and smaller in the right middle temporal gyrus and right lingual gyrus of the patients, but age-related effects did not differ from those of the comparison subjects. The accelerated age-related decline in prefrontal and temporal cortical thickness in never-medicated schizophrenia patients suggests a neuroprogressive process in some brain regions. Slower age-related cortical thinning of the superior parietal cortex and striatal volumetric abnormalities unrelated to age suggest different pathological processes over time in these regions.


Spider, bee, and bird communities in cities are shaped by environmental control and high stochasticity.
Spatially organized distribution patterns of species and communities are shaped by both autogenic processes (neutral mechanism theory) and exogenous processes (niche theory). In the latter, environmental variables that are themselves spatially organized induce spatial structure in the response variables. The relative importance of these processes has not yet been investigated in urban habitats. We compared the variance explained by purely spatial, spatially structured environmental, and purely environmental components for the community composition of spiders (Araneae), bees (Apidae), and birds (Aves) at 96 locations in three Swiss cities. Environmental variables (topography, climate, land cover, urban green management) were measured on four different radii around sampling points (< 10 m, 50 m, 250 m, 1000 m), while Moran's eigenvector maps (MEMs) acted as spatial variables. All three taxonomic groups showed weak spatial structure. Spider communities reacted to very fine-scaled environmental changes of lawn and meadow management and climate. Bird community composition was determined by woody plants as well as solar radiation at all radii, the scale of the influence varying among species. Bee communities were weakly explained by isolated variables only. Our results suggest that the anthropogenic structuring of urban areas has disrupted the spatial organization of environmental variables and inhibited the development of biotic spatial processes. The near absence of spatial structure may therefore be a feature typical of urban species assemblages, resulting in urban community composition mainly influenced by local environmental variables. Urban environments represent a close-knit mosaic of habitats that are regularly disturbed. Species communities in urban areas are far from equilibrium. Our analysis also suggests that urban communities need to be considered as being in constant change to adapt to disturbances and changes imposed by human activities.


Functional Capacity Assessed by the Map Task in Individuals at Clinical High-Risk for Psychosis.
Recent studies have recognized that signs of functional disability in schizophrenia are evident in early phases of the disorder, and, as a result, can potentially serve as vulnerability markers of future illness. However, functional measures in the psychosis prodrome have focused exclusively on real-world achievements, rather than on the skills required to carry-out a particular real-world function (ie, capacity). Despite growing evidence that diminished capacity is critical to the etiology of the established disorder, virtually no attention has been directed towards assessing functional capacity in the pre-illness stages. In the present study, we introduce the Map task, a measure to assess functional capacity in adolescent and young-adult high-risk populations. The Map task was administered to 609 subjects at Clinical High-Risk (CHR) for psychosis and 242 Healthy Controls (HCs) participating in the North American Prodrome Longitudinal Study (NAPLS2). Subjects were required to efficiently complete a set of specified errands in a fictional town. CHR participants showed large impairments across major indices of the Map task, relative to the HCs. Most importantly, poor performance on the Map task significantly predicted conversion to psychosis, even after adjusting for age, IQ, clinical state, and other potential confounders. To the best of our knowledge, the Map task is one of the first laboratory-based measures to assess functional capacity in high-risk populations. Functional capacity deficits prior to the onset of psychosis may reflect a basic mechanism that underlies risk for psychosis. Early intervention targeting this domain may help to offset risk and independently improve long-term outcome.


Ectomycorrhizal fungi integrate nitrogen mobilisation and mineral weathering in boreal forest soil.
Tree growth in boreal forests is driven by ectomycorrhizal fungal mobilisation of organic nitrogen and mineral nutrients in soils with discrete organic and mineral horizons. However, there are no studies of how ectomycorrhizal mineral weathering and organic nitrogen mobilisation processes are integrated across the soil profile. We studied effects of organic matter (OM) availability on ectomycorrhizal functioning by altering the proportions of natural organic and mineral soil in reconstructed podzol profiles containing Pinus sylvestris plants, using 13 CO2 pulse labelling, patterns of naturally occurring stable isotopes (26 Mg and 15 N) and high-throughput DNA sequencing of fungal amplicons. Reduction in OM resulted in nitrogen limitation of plant growth and decreased allocation of photosynthetically derived carbon and mycelial growth in mineral horizons. Fractionation patterns of 26 Mg indicated that magnesium mobilisation and uptake occurred primarily in the deeper mineral horizon and was driven by carbon allocation to ectomycorrhizal mycelium. In this horizon, relative abundance of ectomycorrhizal fungi, carbon allocation and base cation mobilisation all increased with increased OM availability. Allocation of carbon through ectomycorrhizal fungi integrates organic nitrogen mobilisation and mineral weathering across soil horizons, improving the efficiency of plant nutrient acquisition. Our findings have fundamental implications for sustainable forest management and belowground carbon sequestration.


Efficacy of mesotherapy in facial rejuvenation: a histological and immunohistochemical evaluation.
Mesotherapy, commonly known as "biorejuvenation" or "biorevitalization", is a technique used to rejuvenate the skin by means of a transdermal injection of a multivitamin solution and natural plant extracts that are thought to improve the signs of skin aging. This prospective study aimed to evaluate the clinical effect of mesotherapy applied to periorbital wrinkles and to quantitatively evaluate histological changes in the skin occurring in response to the same treatment. Six volunteers with Fitzpatrick skin types III or IV and Glogau class I-III wrinkles were subjected to a three-month course of mesotherapy injections in the periocular area (six sessions administered at two-week intervals). Standard photographs and skin biopsies were obtained from the treatment area at baseline, at the end of treatment, and at three months post-treatment. Quantitative evaluation of collagen types I, III, and VII, newly synthesized collagen, total elastin, and tropoelastin was performed using a computerized morphometric analysis. The clinical evaluation of volunteers at baseline, end of treatment, and three months post-treatment revealed no significant differences. Histological and immunostaining analysis of collagen types I, III, and VII, newly synthesized collagen, total elastin, and tropoelastin showed no statistically significant changes (P > 0.05) after mesotherapy injection. The present study indicates that mesotherapy for skin rejuvenation does not result in statistically significant histological changes or clinical improvement.


Effects of hormone-replacement therapy on fibrinolysis in postmenopausal women.
Plasma levels of plasminogen-activator inhibitor type 1 (PAI-1), an essential inhibitor of fibrinolysis in humans, increase in women after menopause, and this may contribute to the risk of cardiovascular disease. We studied the effects of hormone-replacement therapy on PAI-1 levels. In a randomized, crossover study, we investigated the effects of oral conjugated estrogen (0.625 mg per day) in 30 postmenopausal women and transdermal estradiol (0.1 mg per day) in 20 postmenopausal women, either alone or in combination with medroxyprogesterone acetate (2.5 mg daily) for one month, on plasma PAI-1 antigen levels. Degradation products of cross-linked fibrin (D-dimer) were measured in serum as an index of fibrinolysis. PAI-1 levels were inversely associated with D-dimer levels at base line (r= -0.540, P=0.002). Conjugated estrogen, both alone and in combination with medroxyprogesterone acetate, reduced mean (+/-SD) plasma levels of PAI-1 from 32+/-34 ng per milliliter to 14+/-10 ng per milliliter (P<0.001) and from 31+/-29 ng per milliliter to 15+/-11 ng per milliliter (P=0.003), respectively; there was a significant inverse correlation between pretreatment PAI-1 levels and the degree of reduction in these levels during therapy (r= -0.631, P<0.001 for conjugated estrogen; r = -0.507, P=0.004 for combined therapy). The degree of reduction in PAI-1 levels was associated with increases in D-dimer levels both when conjugated estrogen was given alone (r= -0.572, P=0.001) and when combined hormone therapy was given (r= -0.541, P=0.002). Transdermal estradiol caused no significant changes in PAI-1 levels from base-line values. Conjugated estrogen, alone or combined with progestin therapy, reduced PAI-1 levels by approximately 50 percent in postmenopausal women and was associated with enhanced systemic fibrinolysis. These findings may partly explain the protective effect of hormone-replacement therapy with respect to coronary artery disease.


ACE I/D gene polymorphism can't predict the steroid responsiveness in Asian children with idiopathic nephrotic syndrome: a meta-analysis.
The results from the published studies on the association between angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism and the treatment response to steroid in Asian children with idiopathic nephrotic syndrome (INS) is still conflicting. This meta-analysis was performed to evaluate the relation between ACE I/D gene polymorphism and treatment response to steroid in Asian children and to explore whether ACE D allele or DD genotype could become a predictive marker for steroid responsiveness. Association studies were identified from the databases of PubMed, Embase, Cochrane Library and CBM-disc (China Biological Medicine Database) as of September 1, 2010, and eligible investigations were synthesized using meta-analysis method. Five investigations were identified for the analysis of association between ACE I/D gene polymorphism and steroid-resistant nephrotic syndrome (SRNS) risk in Asian children and seven studies were included to explore the relationship between ACE I/D gene polymorphism and steroid-sensitive nephrotic syndrome (SSNS) susceptibility. Five investigations were recruited to explore the difference of ACE I/D gene distribution between SRNS and SSNS. There was no a markedly association between D allele or DD genotype and SRNS susceptibility or SSNS risk, and the gene distribution differences of ACE between SRNS and SSNS were not statistically significant. II genotype might play a positive role against SRNS onset but not for SSNS (OR = 0.51, P = 0.02; OR = 0.95, P = 0.85; respectively), however, the result for the association of II genotype with SRNS risk was not stable. Our results indicate that D allele or DD homozygous can't become a significant genetic molecular marker to predict the treatment response to steroid in Asian children with INS.


Selective Etching of Metal-Organic Frameworks for Open Porous Structures: Mass-Efficient Catalysts with Enhanced Oxygen Reduction Reaction for Fuel Cells.
Fe-Nx-C-based single-atom (SA-Fe-N-C) catalysts have shown favorable oxygen reduction reaction (ORR) activity. However, their application in proton exchange membrane fuel cells is hindered by reduced performance owing to the thick catalyst layer, restricting mass transfer and the O2 supply. Metal-organic frameworks (MOFs) are a promising class of crystal materials, but their narrow pores exacerbate the sluggish mass-transport properties within the catalyst layer. This study developed an approach for constructing an open-pore structure in MOFs via chelation-assisted selective etching, resulting in atomically dispersed Fe atoms anchored on an N, S co-doped carbon framework. The open-pore structure reduces oxygen transport resistance in the membrane electrode assembly (MEA) with unprecedented ORR activity and stability, as evidenced by finite element simulations. In an acidic electrolyte, the OP-Fe-NC catalyst shows a half-wave potential of 0.89 V vs RHE, surpassing Pt/C by 20 mV, and a current density of 29 mA cm-2 at 0.9 ViR-free in the MEA. This study provides an effective structural strategy for fabricating electrocatalysts with high mass efficiency and atomic precision for energy storage and conversion devices.


Association of Velopharyngeal Insufficiency With Quality of Life and Patient-Reported Outcomes After Speech Surgery.
Patients with cleft palate and other causes of velopharyngeal insufficiency (VPI) suffer adverse effects on social interactions and communication. Measurement of these patient-reported outcomes is needed to help guide surgical and nonsurgical care. To further validate the VPI Effects on Life Outcomes (VELO) instrument, measure the change in quality of life (QOL) after speech surgery, and test the association of change in speech with change in QOL. Prospective descriptive cohort including children and young adults undergoing speech surgery for VPI in a tertiary academic center. Participants completed the validated VELO instrument before and after surgical treatment. The main outcome measures were preoperative and postoperative VELO scores and the perceptual speech assessment of speech intelligibility. The VELO scores are divided into subscale domains. Changes in VELO after surgery were analyzed using linear regression models. VELO scores were analyzed as a function of speech intelligibility adjusting for age and cleft type. The correlation between speech intelligibility rating and VELO scores was estimated using the polyserial correlation. Twenty-nine patients (13 males and 16 females) were included. Mean (SD) age was 7.9 (4.1) years (range, 4-20 years). Pharyngeal flap was used in 14 (48%) cases, Furlow palatoplasty in 12 (41%), and sphincter pharyngoplasty in 1 (3%). The mean (SD) preoperative speech intelligibility rating was 1.71 (1.08), which decreased postoperatively to 0.79 (0.93) in 24 patients who completed protocol (P < .01). The VELO scores improved after surgery (P<.001) as did most subscale scores. Caregiver impact did not change after surgery (P = .36). Speech Intelligibility was correlated with preoperative and postoperative total VELO score (P < .01) and to preoperative subscale domains (situational difficulty [VELO-SiD, P = .005] and perception by others [VELO-PO, P = .05]) and postoperative subscale domains (VELO-SiD [P = .03], VELO-PO [P = .003]). Neither the VELO total nor subscale score change after surgery was correlated with change in speech intelligibility. Speech surgery improves VPI-specific quality of life. We confirmed validation in a population of untreated patients with VPI and included pharyngeal flap surgery, which had not previously been included in validation studies. The VELO instrument provides patient-specific outcomes, which allows a broader understanding of the social, emotional, and physical effects of VPI. 2.


Creatine kinase B-subunit activity in human sera: temporal aspects of its sensitivity after myocardial infarction.
We assessed the changes in sensitivity and specificity of creatine kinase (CK) isoenzymes at various times after acute myocardial infarction. CK-B was measured by an immunoinhibition technique. CK-MB was measured both by column chromatography on Sephadex DEAE A-50 and by electrophoresis on agarose gel. For CK-B, the sensitivity in detecting infarct varied from 11% in the first 8 h after onset of symptoms to 80% at 32 h after the infarct. Sensitivities for CK-MB by column and by electrophoresis were 25 and 45% for the first 8-h period and 80 and 89% at the 32nd hour, respectively. Comparison of values for CK-B with values for CK-MB by column and by electrophoresis gave correlation coefficients of 0.935 and 0.896, respectively. Patients having macro CK-BB exhibit anomalously high values for CK-B with respect to total CK. Patients having a mild infarct may show no increase in CK-isoenzymes.


Changes in cognitive flexibility and hypothesis search across human life history from childhood to adolescence to adulthood.
How was the evolution of our unique biological life history related to distinctive human developments in cognition and culture? We suggest that the extended human childhood and adolescence allows a balance between exploration and exploitation, between wider and narrower hypothesis search, and between innovation and imitation in cultural learning. In particular, different developmental periods may be associated with different learning strategies. This relation between biology and culture was probably coevolutionary and bidirectional: life-history changes allowed changes in learning, which in turn both allowed and rewarded extended life histories. In two studies, we test how easily people learn an unusual physical or social causal relation from a pattern of evidence. We track the development of this ability from early childhood through adolescence and adulthood. In the physical domain, preschoolers, counterintuitively, perform better than school-aged children, who in turn perform better than adolescents and adults. As they grow older learners are less flexible: they are less likely to adopt an initially unfamiliar hypothesis that is consistent with new evidence. Instead, learners prefer a familiar hypothesis that is less consistent with the evidence. In the social domain, both preschoolers and adolescents are actually the most flexible learners, adopting an unusual hypothesis more easily than either 6-y-olds or adults. There may be important developmental transitions in flexibility at the entry into middle childhood and in adolescence, which differ across domains.


Use of Diffusion-Weighted Magnetic Resonance Imaging and Apparent Diffusion Coefficient in Gastric Cancer Staging.
The apparent diffusion coefficient (ADC), the quantitative parameter of diffusion-weighted magnetic resonance imaging (DW-MRI), is a measure for this restricted diffusion, and its role in gastric cancer (GC) including distinguishing malignant segments from healthy gastric wall, metastatic perigastric lymph nodes from benign nodes and evaluating response of GC to neoadjuvant chemotherapy has been investigated in previous studies. Evidence suggests that ADC may also be of help in assessment of aggressiveness and preoperative staging of gastric cancer, which needs to be explored in further studies. To investigate the role of DW-MRI and its quantitative parameter, ADC in staging of gastric cancer. Forty-six patients (28 male, 18 female, mean age 62 years) with non-metastatic biopsy- proven GC who underwent abdominal DW-MRI before surgery were included in this retrospective study. Tumor invasion depth (T-stage) and nodal involvement (N-stage) were evaluated using signal increase on DW-MRI, and tumor ADC was measured. Diagnostic performance of these results was assessed by comparing them with postsurgical histopathology based on 8th TNM classification. Sensitivity, specificity, and accuracy of DW-MRI in T-staging were 92.1%, 75%, 89.1% for ≤T2 vs. ≥T3; and 75%, 88.5%, 82.6% for ≤T3 vs. T4. However, sensitivity, specificity, and accuracy of DW-MRI in N-staging were 89.3%, 88.9%, 89.1% for ≤N1 vs. ≥N2; and 73.7%, 96.3%, 86.9% for ≤N2 vs. N3, respectively. Relative preoperative ADC values correlated with pT staging (r=-0.397, p=0.006). There was also a statistically significant difference of relative ADC values between ≤T3 and T4 stages, and a cut-off of 0.64 s/mm2 could differentiate these stages with an odds ratio of 7.714 (95% confidence interval, 1.479-40.243). The area under the receiver operating characteristic curve for differentiating ≤T3 and T4 stages was 0.725. DW-MRI may contribute to the clinical staging of non-metastatic GC. In particular, relative ADC of DW-MRI can distinguish T4 gastric cancer from less advanced T-stages.


Non-invasive wearables for remote monitoring of HbA1c and glucose variability: proof of concept.
Diabetes prevalence continues to grow and there remains a significant diagnostic gap in one-third of the US population that has pre-diabetes. Innovative, practical strategies to improve monitoring of glycemic health are desperately needed. In this proof-of-concept study, we explore the relationship between non-invasive wearables and glycemic metrics and demonstrate the feasibility of using non-invasive wearables to estimate glycemic metrics, including hemoglobin A1c (HbA1c) and glucose variability metrics. We recorded over 25 000 measurements from a continuous glucose monitor (CGM) with simultaneous wrist-worn wearable (skin temperature, electrodermal activity, heart rate, and accelerometry sensors) data over 8-10 days in 16 participants with normal glycemic state and pre-diabetes (HbA1c 5.2-6.4). We used data from the wearable to develop machine learning models to predict HbA1c recorded on day 0 and glucose variability calculated from the CGM. We tested the accuracy of the HbA1c model on a retrospective, external validation cohort of 10 additional participants and compared results against CGM-based HbA1c estimation models. A total of 250 days of data from 26 participants were collected. Out of the 27 models of glucose variability metrics that we developed using non-invasive wearables, 11 of the models achieved high accuracy (<10% mean average per cent error, MAPE). Our HbA1c estimation model using non-invasive wearables data achieved MAPE of 5.1% on an external validation cohort. The ranking of wearable sensor's importance in estimating HbA1c was skin temperature (33%), electrodermal activity (28%), accelerometry (25%), and heart rate (14%). This study demonstrates the feasibility of using non-invasive wearables to estimate glucose variability metrics and HbA1c for glycemic monitoring and investigates the relationship between non-invasive wearables and the glycemic metrics of glucose variability and HbA1c. The methods used in this study can be used to inform future studies confirming the results of this proof-of-concept study.


Medical Complications of Binge Eating Disorder.
Binge eating disorder (BED) is the most common eating disorder and is accompanied by multiple medical comorbidities, many of which are associated with obesity-related diseases. However, the BED itself is likely to confer additional risk factors. BED presents with medical symptoms in virtually every body system and can have devastating consequences on both quality and length of life. This review covers the major comorbidities of BED and highlights areas of ongoing research in this disorder.


Comparison of mortality in patients with acute myocardial infarction accidentally admitted to non-cardiology departments versus that in patients admitted to coronary care units.
The aim of this study was to prospectively investigate the clinical characteristics including symptoms and long-term mortality in patients with acute myocardial infarction (AMI) accidentally admitted to non-cardiology departments (NCDs). For comparison, similar observations in patients admitted to the coronary care unit (CCU) were collected. During a 1-year period, consecutive patients having cardiac troponin I measured at the Odense University Hospital were considered. The hospital has 27 clinical departments. Patients were classified as having an AMI if the diagnostic criteria of the universal definition were met. Follow-up was at least 1 year with mortality as the clinical end point. Of 3,762 consecutive patients, an AMI was diagnosed in 479, of whom 114 patients (24%) were hospitalized in NCDs and 365 (76%) in the CCU. Chest pain or chest discomfort more frequently occurred in patients from the CCU (83%) than in patients from the NCDs (45%, p <0.0001). At median follow-up of 2.1 years, 150 patients had died: 73 (64%) of patients from the NCDs and 77 (21%) of the patients from the CCU. In the multivariable Cox regression analysis, the adjusted hazard ratio of mortality for patients from the NCDs versus CCU was 2.0 (95% confidence interval 1.3 to 3.2). In conclusion, chest pain/discomfort was absent in more than half of the patients with AMI admitted to NCDs, and admission to NCDs was an independent predictor of a 2 times higher long-term mortality in comparison with admission to the CCU.


Relation of ordinal position signals to the expectation of reward and passage of time in four areas of the macaque frontal cortex.
Neurons in several areas of the monkey frontal cortex exhibit rank selectivity, firing differentially as a function of the stage attained during the performance of a serial order task. The activity of these neurons is commonly thought to represent ordinal position within the trial. However, they might also be sensitive to factors correlated with ordinal position including time elapsed during the trial (which is greater for each successive stage) and the degree of anticipation of reward (which probably increases at each successive stage). To compare the influences of these factors, we monitored neuronal activity in the supplementary motor area (SMA), presupplementary motor area (pre-SMA), supplementary eye field (SEF), and dorsolateral prefrontal cortex during the performance of a serial order task (requiring a series of saccades in three specified directions), a variable reward task (in which a cue displayed early in the trial indicated whether the reward received at the end of the trial would be large or small), and a long delay task (in which the monkey had simply to maintain fixation during a period of time approximating the duration of an average trial in the serial order task). We found that rank signals were partially correlated with sensitivity to elapsed time and anticipated reward. The connection to elapsed time was strongest in the pre-SMA. The connection to anticipated reward was most pronounced in the SMA and SEF. However, critically, these factors could not fully explain rank selectivity in any of the areas tested.


Evaluation of the value of attribution in the interpretation of adverse event data: a North Central Cancer Treatment Group and American College of Surgeons Oncology Group investigation.
In March 1998, Common Toxicity Criteria (CTC) version 2.0 introduced the collection of attribution of adverse events (AEs) to study drug. We investigate whether attribution adds value to the interpretation of AE data. Patients in the placebo arm of two phase III trials-North Central Cancer Treatment Group Trial 97-24-51 (carboxyamino-triazole v placebo in advanced non-small-cell lung cancer) and American College of Surgeons Oncology Group Trial Z9001 (imatinib mesylate v placebo after resection of primary gastrointestinal stromal tumors)-were studied. Attribution was categorized as unrelated (not related or unlikely) and related (possible, probable, or definite). In total, 398 patients (84 from Trial 97-24-51 and 314 from Trial Z9001) and 7,736 AEs were included; 47% and 50% of the placebo-arm AEs, respectively, were reported as related. When the same AE was reported in the same patient on multiple visits, the attribution category changed at least once 36% and 31% of the time. AE type and sex (Trial Z9001) and AE type and performance status (Trial 97-24-51) were associated with a higher likelihood of AEs being deemed related. Nearly 50% of AEs were reported as attributed to study drug on the placebo arm of two randomized clinical trials. These data provide strong evidence that AE attribution is difficult to determine, unreliable, and of questionable value in interpreting AE data in randomized clinical trials.


Lifestyle, quality of life, and health.
This study was performed in order to investigate the connection between lifestyle, quality of life, and health status by way of a questionnaire-based survey. The questionnaire was mailed in February 1993 to 2,460 persons aged between 18 and 88, randomly selected from the CPR (Danish Central Register), and 7,222 persons from the Copenhagen Perinatal Birth Cohort 1959-61. A total of 1,501 persons between the ages of 18 and 88 years and 4,626 persons between the ages of 31 and 33 years returned the questionnaire (response rates 61.0% and 64.1%, respectively). Variables investigated in this study were: alcohol consumption, tobacco consumption, type of diet, amount of exercise taken, quality of life, self-assessed health status, and number of medical complaints from which respondent suffered. The results showed that health has a stronger correlation to quality of life (r = 0.5, p < 0.0001) than it has to lifestyle (r = 0.2, p < 0.0001). It is concluded that preventable diseases could be more effectively handled through a concentrated effort to improve quality of life rather than through an approach that focuses solely on the factors that are traditionally seen to reflect an unhealthy lifestyle.


Low-dose exposure to Veratrum album in children causes mild effects--a case series.
White or false hellebore (Veratrum album) has a toxicological relevance because of the potential for misidentification of this plant as yellow gentian (Gentiana lutea). We report a retrospective case series of 11 children (8-12 years) with accidental intake of V. album at a youth camp where they had collected herbs for preparing fresh herb tea. Two children (18%) remained asymptomatic. Nine (82%) developed mild gastrointestinal symptoms, six (55%) presented neurological symptoms, and three (27%) showed bradycardia. All children recovered completely within 10 h of ingestion. The plant was identified at the emergency department; however, detection of veratridine and cevadine by means of high-performance liquid chromatography-Mass spectrometry from the blood of the child with the most severe symptoms was negative (limit 0.01 ng/mL). Veratrum species contain more than 200 different alkaloids, which are the principal toxins and are responsible for most clinical symptoms. There are likely multiple mechanisms of toxicity and some of them are only partially understood. The opening of voltage-gated sodium channels is probably one of the most relevant pathophysiological mechanisms. Veratrum album intoxication in children demonstrated the same clinical course as observed in adults. Accidental ingestion of a low dose of the plant had a favorable outcome with supportive care.


Proteomic analyses of a robust versus a poor chicken gastrointestinal colonizing isolate of Campylobacter jejuni.
Campylobacter spp. are a significant contributor to the bacterial etiology of acute gastroenteritis in humans. Epidemiological evidence implicates poultry as a major source of the organism for human illness. However, the factors involved in colonization of poultry with Campylobacter spp. remain unclear. Determining colonization-associated factors at the proteome level should facilitate our understanding of Campylobacter spp. contamination of poultry. Therefore, proteomic analyses were utilized to identify expression differences between two Campylobacter jejuni isolates, a robust colonizer A74/C and a poor colonizing strain of the chicken gastrointestinal system designated NCTC 11168-PMSRU. Proteomic analyses by two-dimensional gel electrophoresis revealed the specific expression of an outer membrane-fibronectin binding protein, serine protease, and a putative aminopeptidase in the soluble portion of the robust colonizer A74C. Several proteins including a cysteine synthase and aconitate hydratase were detected specifically in the poor colonizer C. jejuni NCTC 11168-PMSRU isolate. Variation in the amino acid sequences resulting in different isoelectric points and relative mobility of the flagellin and C. jejuni major outer membrane (MOMP) protein were also detected between the two isolates. Western blotting of the bacterial proteins revealed the presence of two flagellin proteins in the poor colonizer versus one in the robust colonizing isolate, but no differences in MOMP. The results demonstrated that proteomics is useful for characterizing phenotypic variation among Campylobacter spp. isolates. Interestingly, different gene products potentially involved in robust colonization of chickens by Campylobacter spp. appear to conform to recently identified expression patterns in Biofilm or agar-adapted isolates.


Barriers to non-HDL cholesterol goal attainment by providers.
Despite improvements in low-density lipoprotein cholesterol goal attainment, non-high-density lipoprotein cholesterol (non-HDL-C) goal attainment remains poor. This study assessed providers' knowledge of, attitude toward, and practice regarding non-HDL-C. Based on a conceptual model, we designed a questionnaire that was administered to internal medicine, family practice, cardiology, and endocrinology providers attending continuous medical education conferences. Responses were compared with those of providers attending a clinical lipidology conference. The response rate was 33.3% (354/1063). Among providers attending nonlipidology conferences, only 26% knew that non-HDL-C was a secondary treatment target, 34% knew non-HDL-C treatment goals, 56% could calculate non-HDL-C levels, and 66% knew that non-HDL-C levels could be calculated from a standard lipid panel. Compared with providers attending the lipidology conference, the other providers were less likely (P≤.01) to have read the Adult Treatment Panel III guidelines (46% vs 98%) or to use non-HDL-C (36% vs 91%). No differences were found between primary care and specialty providers. Lack of familiarity with Adult Treatment Panel III guidelines (34%) and of knowledge regarding non-HDL-C importance (21%) and calculation (22.7%) were the most common barriers identified. Major gaps remain in providers' awareness regarding non-HDL-C definition, calculation, and goals. System-level interventions are needed across specialties to address these gaps.


Retroviral sequences related to human T-lymphotropic virus type II in patients with chronic fatigue immune dysfunction syndrome.
Chronic fatigue immune dysfunction syndrome (CFIDS) is a recently recognized illness characterized by debilitating fatigue as well as immunological and neurological abnormalities [Straus, S.E. (1988) J. Inf. Dis. 157, 405-412]. Once thought to be caused by Epstein-Barr virus, it is now thought to have a different but unknown etiology. We evaluated 30 adult and pediatric CFIDS patients from six eastern states for the presence of human T-lymphotropic virus (HTLV) types I and II by Western immunoblotting, polymearse chain reaction, and in situ hybridization of blood samples. The majority of patients were positive for HTLV antibodies by Western blotting and for HTLV-II gag sequences by polymerase chain reaction and in situ hybridization. Twenty nonexposure healthy controls were negative in all assays. These data support an association between an HTLV-II-like virus and CFIDS.


Influence of palatal surface shape of dentures on food perception.
The purpose of this study was to clarify the influence of the palatal surface shape of dentures on food perception. Eighteen healthy dentulous subjects (mean age, 24 years) were investigated. Four types of experimental plate were used: (i) a tailor-made plate, (ii) an average-model plate, (iii) a smooth plate, and (iv) a wrinkle plate. Test foods consisted of Bavarian cream cubes containing one to three mustard seeds and six raw carrot pieces of different shapes. Bavarian cream cubes with three seeds were used for analysis. Other foods were used as dummy foods. Subjects were required to wear experimental plates and press test foods placed on the anterior area of the tongue against the experimental plates. We measured time required to perceive number of spherical bodies, rate of correct answers, and level of perception with each type of experimental plate using a 100-mm visual analogue scale. The results showed a significant difference in response time between the average-model plate and the other experimental plates, with response time longest for the average-model plate. On the other hand, no significant differences in rate of correct answers regarding number of spherical bodies or level of perception were found among the experimental plates. When incisive papilla, palatine suture and palatal rugae based on the standard Japanese shape were replicated on the palatal surface of the plates, the time required for food perception during ingestion was prolonged in comparison to plates with other palatal surface shapes.


[Exhausted literature. The emergence of the new in Samuel Beckett's novels and plays].
The article investigates literary subjectivity in some texts by Samuel Beckett. The article proceeds by relating the ways of how narration and speech acts constitute literary subjectivity to the problems of subjectivity that scientific investigations deal with. While successful self-regulation of the organism nourishes the roots of subjectivity, i.e., the habits, subjectivity decomposes in states of exhaustion, when self-regulation breaks down. As soon as a certain threshold is transgressed, fatigue sets in, alters the personality and eventually leads to exhaustion--a state, which psychiatrists compare to mental illness. Notwithstanding the different explanations given, scientists agreed about the effects of exhaustion. According to their investigations, the decomposition of personality by exhaustion generally does not involve apathy, withdrawal from activity or termination of movements, but rather mere action. Similarly, in Beckett's novels and plays exhaustion is much more than tiredness, as French philosopher Gilles Deleuze observed. For Beckett, exhaustion is rather the model for both literary innovation and a new concept of subjectivity, which he explores on the basis of a detailed knowledge of physiology, psychology, and psychiatry, but using his own literary means. The exhausted subject is beyond any calculus of activity. It will perform an activity even if he or she makes mistakes or loses control, and will thus act in an unpredictable way. This unpredictable action is not an exception in the continuation of the habits, but rather points to the moment when a new subjectivity emerges. Such new subjectivity suraces in Beckett's novels and plays in forms of literary innovation.


[Instructions for aggregated evidence: Systematic reviews and meta-analyses (part 1)].
High-quality, up-to-date, systematic reviews comprehensively summarize the evidence from clinical studies for a focused clinical question. A meta-analyses is a quantitative summary of results from individual studies and often part of a systematic review. Important features of a systematic review are a focused research question, a comprehensive, reproducible search for primary studies, selection of studies using clear and transparent eligibility criteria, and a standardized critical appraisal of the methodological quality of included studies.


Clinical features and virological analysis of a case of Middle East respiratory syndrome coronavirus infection.
The Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging virus involved in cases and case clusters of severe acute respiratory infection in the Arabian Peninsula, Tunisia, Morocco, France, Italy, Germany, and the UK. We provide a full description of a fatal case of MERS-CoV infection and associated phylogenetic analyses. We report data for a patient who was admitted to the Klinikum Schwabing (Munich, Germany) for severe acute respiratory infection. We did diagnostic RT-PCR and indirect immunofluorescence. From time of diagnosis, respiratory, faecal, and urine samples were obtained for virus quantification. We constructed a maximum likelihood tree of the five available complete MERS-CoV genomes. A 73-year-old man from Abu Dhabi, United Arab Emirates, was transferred to Klinikum Schwabing on March 19, 2013, on day 11 of illness. He had been diagnosed with multiple myeloma in 2008, and had received several lines of treatment. The patient died on day 18, due to septic shock. MERS-CoV was detected in two samples of bronchoalveolar fluid. Viral loads were highest in samples from the lower respiratory tract (up to 1·2 × 10(6) copies per mL). Maximum virus concentration in urine samples was 2691 RNA copies per mL on day 13; the virus was not present in the urine after renal failure on day 14. Stool samples obtained on days 12 and 16 contained the virus, with up to 1031 RNA copies per g (close to the lowest detection limit of the assay). One of two oronasal swabs obtained on day 16 were positive, but yielded little viral RNA (5370 copies per mL). No virus was detected in blood. The full virus genome was combined with four other available full genome sequences in a maximum likelihood phylogeny, correlating branch lengths with dates of isolation. The time of the common ancestor was halfway through 2011. Addition of novel genome data from an unlinked case treated 6 months previously in Essen, Germany, showed a clustering of viruses derived from Qatar and the United Arab Emirates. We have provided the first complete viral load profile in a case of MERS-CoV infection. MERS-CoV might have shedding patterns that are different from those of severe acute respiratory syndrome and so might need alternative diagnostic approaches. European Union; German Centre for Infection Research; German Research Council; and German Ministry for Education and Research.


Total RNA Analysis of Bacterial Community Structural and Functional Shifts Throughout Vertebrate Decomposition.
Multiple methods have been proposed to provide accurate time since death estimations, and recently, the discovery of bacterial community turnover during decomposition has shown itself to have predictable patterns that may prove useful. In this study, we demonstrate the use of metatranscriptomics from the postmortem microbiome to simultaneously obtain community structure and functional data across postmortem intervals (PMIs). We found that bacterial succession patterns reveal similar trends as detected through DNA analysis, such as increasing Clostridiaceae as decomposition occurs, strengthening the reliability of total RNA community analyses. We also provide one of the first analyses of RNA transcripts to characterize bacterial metabolic pathways during decomposition. We found distinct pathways, such as amino acid metabolism, to be strongly up-regulated with increasing PMIs. Elucidating the metabolic activity of postmortem microbial communities provides the first steps to discovering postmortem functional biomarkers since functional redundancy across bacteria may reduce host individual microbiome variability.


Differential Gene Expression Patterns in Blood and Cerebrospinal Fluid of Multiple Sclerosis and Neuro-Behçet Disease.
Inflammatory demyelinating disorders of the central nervous system are debilitating conditions of the young adult, here we focus on multiple sclerosis (MS) and neuro-Behçet disease (NBD). MS is an autoimmune disorder of the central nervous system. NBD, a neurological manifestation of an idiopathic chronic relapsing multisystem inflammatory disease, the behçet disease. The diagnosis of MS and NBD relies on clinical symptoms, magnetic resonance imaging and laboratory tests. At first onset, clinical and imaging similarities between the two disorders may occur, making differential diagnosis challenging and delaying appropriate management. Aiming to identify additional discriminating biomarker patterns, we measured and compared gene expression of a broad panel of selected genes in blood and cerebrospinal fluid (CSF) cells of patients suffering from NBD, MS and non inflammatory neurological disorders (NIND). To reach this aim, bivariate and multivariate analysis were applied. The Principal Analysis Component (PCA) highlighted distinct profiles between NBD, MS, and controls. Transcription factors foxp3 in the blood along with IL-4, IL-10, and IL-17 expressions were the parameters that are the main contributor to the segregation between MS and NBD clustering. Moreover, parameters related to cellular activation and inflammatory cytokines within the CSF clearly differentiate between the two inflammatory diseases and the controls. We proceeded to ROC analysis in order to identify the most distinctive parameters between both inflammatory neurological disorders. The latter analysis suggested that IL-17, CD73 in the blood as well as IL-1β and IL-10 in the CSF were the most discriminating parameters between MS and NBD. We conclude that combined multi-dimensional analysis in blood and CSF suggests distinct mechanisms governing the pathophysiology of these two neuro-inflammatory disorders.


Evidence-Based Management of Depression in Palliative Care: A Systematic Review.
Depression can be quite common in the palliative care population. The estimated prevalence ranges from 24% to 70%. Depression in this population leads to a decreased quality of life and may lead to a desire for an earlier death. We conducted a systematic review to establish a better understanding of the available treatment interventions, both pharmacological and nonpharmacological specific to the palliative population. PubMed, PsycINFO, and CINAHL databases were searched using the MeSH terms: Palliative Care, Palliative Medicine, Terminal Illness, End of Life Care, and Depression or Depressive Disorder, as well as the keywords palliative care, care palliative, and depression. We considered all published peer-reviewed articles written in English and pertaining to humans. Articles were hand searched from citations. The Mixed Methods Appraisal Tool was used for study quality appraisal. Thirty-nine eligible articles were found; 29 articles examined nonpharmacological options, while 10 focused on pharmacological options. The 29 articles discussing nonpharmacological methods discussed 22 interventions. Of the 22 interventions, 10 showed therapeutic benefit. Of the 10 studies focusing on pharmacological interventions, seven showed therapeutic benefit. This is the first systematic review that examined both nonpharmacological and pharmacological methods to treat depression in the palliative setting. There is evidence to indicate that methylphenidate and antidepressants can provide a therapeutic benefit for palliative care patients with depressive symptoms. This benefit may be enhanced when these medications are used in combination. The use of music therapy or future-focused psychotherapy may also be beneficial in the treatment of depression.


Efficacy of varicocelectomy in the treatment of hypogonadism in subfertile males with clinical varicocele: A meta-analysis.
To reassess the efficacy of varicocelectomy in the treatment of hypogonadism in subfertile males, we carried out a meta-analysis of clinical trials and retrospective studies that compared the pre-operative and postoperative serum testosterone. We searched Embase and PubMed (1980 to May 2016) for studies. Eight studies and 712 patients were included. The combined analysis of seven studies discovered that the mean serum testosterone of patients post-operation improved by 34.3 ng/dl (95% CI: 22.57-46.04, p < .00001, I² = 0.0%) compared with their pre-operative levels. In subgroup analysis, testosterone improvements in the hypogonadal treated subgroup were more significant (improved by 123 ng/dl, 95% CI: 114.61-131.35, p < .00001, I2 = 37%) than in the eugonadals, or the untreated controls. In an analysis of surgery versus untreated control (three studies included), results showed that mean testosterone among hypogonadals increased by 105.65 ng/dl (95% CI: 77.99-133.32), favouring varicocelectomy, as the differences were significant (p < .00001), However, there were insignificant differences in eugonadals (p = .36). In conclusion, varicocelectomy significantly improved testosterone in hypogonadal men with subfertility. Active surgical treatment of varicocele might have a benefit of maintaining healthy androgen levels in subfertile men.


[Adenine nucleotide metabolic characteristics in different forms of myocardial infarct].
The "adenosine" and "non-adenosine" mechanisms of adenine nucleotide (ATP, ADP, AMP KP) metabolism were studied in 58 patients with myocardial infarction. Predominant activation of the "adenosine" mechanism of metabolism was revealed in patients with acute myocardial infarction with a marked pain syndrome in the first 24 hours of the disease. In the painless form of myocardial infarction the "nonadenosine" nucleotide metabolism is activated while the "adenosine" type is inhibited. The determination and comparison of indices reflecting the condition of the "adenosine" and "nonadenosine" mechanisms of metabolism provide the possibility for evaluating the severity of the pathological process and, on this basis, elaborating a differentiated approach to the treatment of the patient.


TCF12 promotes the tumorigenesis and metastasis of hepatocellular carcinoma via upregulation of CXCR4 expression.
TCF12, which is known to be involved in the regulation of cell growth and differentiation, has been reported to function as an oncogene or a tumor suppressor gene in the progression of various malignant tumors. However, its function and molecular mechanism in hepatocellular carcinoma (HCC) remain unclear. Methods: Stable ectopic TCF12 expression or knockdown in HCC cell lines was established by lentiviral infection. Then, MTT, colony formation, migration, invasion and HUVECs tube formation assays as well as an orthotopic xenograft model were used to investigate the biologic function of TCF12 in HCC cells in vitro and in vivo. Subsequently, RNA-Seq analysis was utilized to explore the target genes regulated by TCF12. RT-qPCR, western blotting, a dual-luciferase reporter assay, Ch-IP, CHIP-Seq and functional rescue experiments were used to confirm the target gene regulated by TCF12. Finally, RT-qPCR, western blot and immunohistochemical (IHC) staining were performed to detect the expression level of TCF12 and to analyze the correlation of TCF12 with downstream genes as well as the clinical significance of TCF12 in human primary HCC. Results: Our functional studies revealed that stable overexpression of TCF12 in human HCC cells enhanced cell proliferation, migration and invasion in vitro and in vivo, whereas knockdown of TCF12 showed opposing effects. Mechanistically, CXCR4 was a downstream target of TCF12, and TCF12 directly bound to the CXCR4 promoter to regulate its expression. Moreover, CXCR4, with its ligand CXCL12, played a critical role in tumor progression induced by TCF12 via activation of the MAPK/ERK and PI3K/AKT signaling pathways. Clinically, IHC analysis revealed that TCF12 was significantly associated with poor survival of HCC patients and that TCF12 expression was closely correlated with CXCR4 expression in primary HCC tissues. Conclusion: Our findings are the first to indicate that TCF12 could promote the tumorigenesis and progression of HCC mainly by upregulating CXCR4 expression and is a prognostic indicator for patients with HCC.


Maximum-Likelihood Tree Estimation Using Codon Substitution Models with Multiple Partitions.
Many protein sequences have distinct domains that evolve with different rates, different selective pressures, or may differ in codon bias. Instead of modeling these differences by more and more complex models of molecular evolution, we present a multipartition approach that allows maximum-likelihood phylogeny inference using different codon models at predefined partitions in the data. Partition models can, but do not have to, share free parameters in the estimation process. We test this approach with simulated data as well as in a phylogenetic study of the origin of the leucin-rich repeat regions in the type III effector proteins of the pythopathogenic bacteria Ralstonia solanacearum. Our study does not only show that a simple two-partition model resolves the phylogeny better than a one-partition model but also gives more evidence supporting the hypothesis of lateral gene transfer events between the bacterial pathogens and its eukaryotic hosts.