Influence of thyrotropin releasing hormone (TRH) on drug-induced narcosis and hypothermia in rabbits.
Thyrotropin releasing hormone (TRH) administered via the intracerebroventricular (icv) route in doses ranging between 0.1 and 100 mug decreased the duration of pentobarbital-induced narcosis in rabbits. Antagonism of narcosis occurred whether TRH was administered before or after the barbiturate. TRH doses above 10 mug produced, in addition, behavioral excitation and hyperthermia. The antagonism of phenobarbital-induced narcosis was not as profound; animals were aroused only for a short period of time, after which the narcotized state returned. However, TRH exerted a prolonged antagonism or reversal of the phenobarbital-induced hypothermia. The central nervous system depression and analgesia produced by morphine were unaffected by TRH, but hypothermia and respiratory depression were reversed. TRH may represent an arousal factor in mammalian brain.


Anionic Bisoxazoline Ligands Enable Copper-Catalyzed Asymmetric Radical Azidation of Acrylamides.
Asymmetric radical azidation for the synthesis of chiral alkylazides remains a tremendous challenge in organic synthesis. We report here an unprecedented highly enantioselective radical azidation of acrylamides catalyzed by 1 mol % of a copper catalyst. The substrates were converted to the corresponding alkylazides in high yield with good-to-excellent enantioselectivity. Notably, employing an anionic cyano-bisoxazoline (CN-Box) ligand is crucial to generate a monomeric CuII azide species, rather than a dimeric CuII azide intermediate, for this highly enantioselective radical azidation.


Genetic analysis of the sugarcane (Saccharum spp.) cultivar 'LCP 85-384'. I. Linkage mapping using AFLP, SSR, and TRAP markers.
Sugarcane hybrids are complex aneu-polyploids (2n = 100-130) derived from inter-specific hybridization between ancestral polyploid species, namely S. officinarum L. and S. spontaneum L. Efforts to understand the sugarcane genome have recently been enhanced through the use of new molecular marker technologies. A framework genetic linkage map of Louisiana's popular cultivar LCP 85-384 was constructed using the selfed progeny and based on polymorphism derived from 64 AFLP, 19 SSR and 12 TRAP primer pairs. Of 1,111 polymorphic markers detected, 773 simplex (segregated in 3:1 ratio) and 182 duplex (segregate in 77:4 ratio) markers were used to construct the map using a LOD value of ≥ 4.0 and recombination threshold of 0.44. The genetic distances between pairs of markers linked in the coupling phase was computed using the Kosambi mapping function. Of the 955 markers, 718 simplex and 66 duplex markers were assigned to 108 co-segregation groups (CGs) with a cumulative map length of 5,617 cM and a density of 7.16 cM per marker. Fifty-five simplex and 116 duplex markers remained unlinked. With an estimated genome size of 12,313 cM for LCP 85-384, the map covered approximately 45.6% of the genome. Forty-four of the 108 CGs were assigned into 9 homo(eo)logous groups (HGs) based on information from locus-specific SSR and duplex markers, and repulsion phase linkages detected between CGs. Meiotic behavior of chromosomes in cytogenetic studies and repulsion phase linkage analysis between CGs in this study inferred the existence of strong preferential chromosome pairing behavior in LCP 85-384. This framework map marks an important beginning for future mapping of QTLs associated with important agronomic traits in the Louisiana sugarcane breeding programs.


Sub-Optimality of the Early Visual System Explained Through Biologically Plausible Plasticity.
The early visual cortex is the site of crucial pre-processing for more complex, biologically relevant computations that drive perception and, ultimately, behaviour. This pre-processing is often studied under the assumption that neural populations are optimised for the most efficient (in terms of energy, information, spikes, etc.) representation of natural statistics. Normative models such as Independent Component Analysis (ICA) and Sparse Coding (SC) consider the phenomenon as a generative, minimisation problem which they assume the early cortical populations have evolved to solve. However, measurements in monkey and cat suggest that receptive fields (RFs) in the primary visual cortex are often noisy, blobby, and symmetrical, making them sub-optimal for operations such as edge-detection. We propose that this suboptimality occurs because the RFs do not emerge through a global minimisation of generative error, but through locally operating biological mechanisms such as spike-timing dependent plasticity (STDP). Using a network endowed with an abstract, rank-based STDP rule, we show that the shape and orientation tuning of the converged units are remarkably close to single-cell measurements in the macaque primary visual cortex. We quantify this similarity using physiological parameters (frequency-normalised spread vectors), information theoretic measures [Kullback-Leibler (KL) divergence and Gini index], as well as simulations of a typical electrophysiology experiment designed to estimate orientation tuning curves. Taken together, our results suggest that compared to purely generative schemes, process-based biophysical models may offer a better description of the suboptimality observed in the early visual cortex.


Examining the association between cancer history in early life and dental care utilization.
This study aims to examine associations between cancer history in early life (diagnosed at 20 years of age or younger) and utilization of dental care. We analysed data of 10,185 participants, aged ≥20 years, from the National Health and Nutrition Examination Survey cycles 2015-2018. The main predictor was self-reported past history of any type of cancer diagnosed at 20 years of age or younger (yes/no). The outcome variables were having a dental visit within the past year, treatment or preventative visit, urgent need for care, and unmet dental need. Covariates included gender, age, race, marital status, education, and income. Bivariate and multiple logistic regression were conducted, accounting for the complex sampling design. There was no difference between early life cancer survivors in regards to dental visit within the past year (OR: 0.7; 95% CI: 0.3-1.6), visit for dental treatment (OR: 0.6; 95% CI: 0.3-1.6), urgent need for care (OR: 0.8; 95% CI: 0.3-2.0), or unmet dental need (OR: 0.6; 95% CI: 0.2-1.6) compared to cancer-free participants. Cancer history in early life doesn't impact dental care visits, type of last dental visit, dental care recommendation, or unmet dental need. Future cohort studies are needed to confirm this association.


Terror and disaster surgical care: training experienced trauma surgeons in decision making for a MASCAL situation with a tabletop simulation game.
Mass-casualty incidents, especially in connection with a terrorist attack, can quickly overwhelm the capacities of receiving hospitals. After a mass-casualty terrorist incident, patients often arrive at hospitals in an uncoordinated manner on account of the chaotic situation. Many patients leave the incident site and refer themselves to hospitals independently. Hospital decision makers must, therefore, be able to make quick decisions on diagnostic procedures and treatment for every individual patient and, at the same time, take into consideration available resources. They require decision criteria and aids to properly manage such scenarios. As part of the preparation of the Terror and Disaster Surgical Care (TDSC®) course, we developed a tabletop simulation game based on a comprehensive and structured review of the literature, the opinions of renowned experts, and the results of specialised conferences. This tabletop simulation game is played four times during each TDSC® course. Our analysis involved 264 of 465 course-participants from 2017 to 2019 and showed that the overall evaluation was very good and that participants grew more positive about the tabletop simulation game during the course. The tabletop simulation game received an average rating of 1.53 (1 = very good, 6 = insufficient). This rating remained consistently high over 19 courses. Hospital decision makers must respond to mass-casualty terrorist situations in a defined tactical and strategic approach. Rapid decisions must be made that take into account the special situation and available capacities and resources to maximise the number of survivors even though individual patients may have a poorer functional outcome. As part of the TDSC® course, the tabletop simulation game teaches high-level decision-making algorithms and prepares key hospital personnel for such situations.


PiSCES: Pi(scine) stream community estimation system.
The Piscine Stream Community Estimation System (PiSCES) provides users with a hypothesized fish community for any stream reach in the conterminous United States using information obtained from Nature Serve, the US Geological Survey (USGS), StreamCat, and the Peterson Field Guide to Freshwater Fishes of North America for over 1000 native and non-native freshwater fish species. PiSCES can filter HUC8-based fish assemblages based on species-specific occurrence models; create a community abundance/biomass distribution by relating relative abundance to mean body weight of each species; and allow users to query its database to see ancillary characteristics of each species (e.g., habitat preferences and maximum size). Future efforts will aim to improve the accuracy of the species distribution database and refine/augment increase the occurrence models. The PiSCES tool is accessible at the EPA's Quantitative Environmental Domain (QED) website at https://qed.epacdx.net/pisces/.


Four 5-hydroxytryptamine7 (5-HT7) receptor isoforms in human and rat produced by alternative splicing: species differences due to altered intron-exon organization.
The serotonin (5-HT) 5-HT7 receptor subtype is thought to mediate a number of physiological effects in mammalian brain and periphery. Previous studies suggested that alternative splicing might contribute to 5-HT7 receptor diversity as well. We now report that alternative splicing in human and rat tissues produces four 5-HT7 receptor isoforms that differ in their predicted C-terminal intracellular tails. Human and rat partial 5-HT7 cDNAs and intronic sequences were identified and compared. In rat tissues, three 5-HT7 isoforms, here called 5-HT7(a), 5-HT7(b), and 5-HT7(c), are found. Rat 5-HT7(a) [448-amino acid (aa)] and 5-HT7(b) (435-aa) forms arise from alternative splice donor sites. A third new isoform found in rat, 5-HT7(c) (470-aa), results from a retained exon cassette. Three 5-HT7 mRNA isoforms were also identified in human tissues, where only one isoform was previously described. Two human isoforms represent 5-HT7(a) and 5-HT7(b) forms (445- and 432-aa), but the third form does not correspond to 5-HT7(c). Instead, it constitutes a distinct isoform, 5-HT7(d) (479-aa), resulting from retention of a separate exon cassette. 5-HT7(d) transcripts are not present in rat because the 5-HT7(d)-specifying exon is absent from the rat 5-HT7 gene. A frame-shifting homologue of the rat 5-HT7(c)-Specifying exon is present in the human gene but is not used in the human tissues examined. Tissue-specific splicing differences are present in human between brain and spleen. These studies suggest that alternative splicing may contribute to diversity of 5-HT7 receptor action and that the human and rat repertoires of 5-HT7 splice variants are substantially different.


Kinematics of ACL and anterolateral ligament. Part II: anterolateral and anterior cruciate ligament reconstruction.
To quantify the influence of Single-Bundle with Lateral Plasty and Double-Bundle reconstruction on static and dynamic laxity in combined ACL- and ALL-deficient knees. The study included 10 fresh-frozen human knees. The joints were analyzed in the following conditions: ACL + ALL resection, Single-Bundle with Lateral Plasty (SBLP) reconstruction, Double-Bundle (DB) reconstruction. Testing parameters were: anterior displacement at 30° and 90° of flexion (AP30, AP90) applying a manual maximum load; internal rotation at 30° and 90° of flexion (INT30, INT90) applying a 5 Nm torque and acceleration and internal rotation Pivot-Shift (PS) test. Kinematics was acquired by a navigation system. Paired Student's t test was conducted to assess statistical difference (P < 0.05). At both 30° and 90° of knee flexion, both SBLP and DB surgical techniques showed a significant reduction (P < 0.01) of anterior-posterior tibial displacement compared to the resection of ACL + ALL. At 30° on knee flexion it is the SBLP that allows the greatest reduction of internal rotational laxity when compared to DB reconstruction. Concerning the PS test, only SBPL procedure had a significant laxity decrease considering the acceleration reached by the joint when compared with the ACL + ALL state (P < 0.01). Clinical relevance of this study is that the internal rotation and PS test were more efficiently controlled by the SBLP technique than by the DB one at both 30° and 90° of flexion in case of ACL + ALL lesions.


Better comparisons of antiepileptic drugs: what measures of efficacy?
With the licensing of new antiepileptic drugs there is an obvious need for the determination of the comparative efficacy, tolerability and overall effectiveness against standard (existing) antiepileptic drugs. Such data can only be determined within the context of well-designed randomised clinical trials (RCTs). Such comparative monotherapy studies may form a part of phase III drug development programmes for a new antiepileptic drug. They may be commenced once there is satisfactory evidence for efficacy and safety derived from placebo-controlled add-on studies in more refractory populations of patients. In this manuscript definitions of outcomes such as effectiveness, efficacy, and tolerability are given. Health-related quality of life measures are presented, and it can be argued that such measures should be a primary outcome variable. However, there is little evidence that any quality of life measures have sufficient validity and sensitivity to be a useful tool in the comparison of drug treatments for epilepsy. Different populations can be studied in 'withdrawal to monotherapy' designs. In such studies patients poorly controlled on their existing therapy are randomised to receive different monotherapy regimes with withdrawal of their existing antiepileptic drugs. This clinical trial design has not been used in genuine comparisons between antiepileptic drugs and the efficiency of this approach has yet to be determined. Experience from studies comparing monotherapy would suggest that differences in efficacy between antiepileptic drugs in the target populations may be difficult to detect. Differences likely exist between the incidence and profile of adverse effects between different drugs. The main benefit of new antiepileptic drugs may be in reducing the incidence and severity of adverse reactions compared to older drugs and in doing so they may prove to be more effective.


Low MFN2 expression related to ageing in granulosa cells is associated with assisted reproductive technology outcome.
Is low MFN2 expression associated with ageing in granulosa cells as well as assisted reproductive technology (ART) outcome, and what is the underlying mechanism of action of MFN2? In a prospective study, fresh granulosa cells were obtained from 161 women aged 20-40 years who underwent IVF with embryo transfer and who were divided into two groups: the diminished ovarian reserve (DOR) group (n = 51) and the control group (n = 110). Patient characteristics including age, infertility duration, body mass index, FSH, anti-Müllerian hormone (AMH), antral follicle count (AFC) and husband's semen parameters and granulosa cell MFN2 expression levels, cell apoptosis, mitochondrial membrane potential (ΔΨm) and ATP levels were analysed. There were no significant differences between the DOR and control groups in terms of age, infertility duration and husband'' semen parameters; however, significant (P< 0.05) changes were found between the two groups in FSH, AMH and AFC levels. MFN2 expression was remarkably lower in granulosa cells from the DOR group and decreased in both groups as age increased. Furthermore, among young patients, MFN2 levels significantly increased in patients with pregnancy. MFN2 protein levels and cell apoptosis were lower in the MFN2 knockdown (MFN2-siRNA) group than in the control (Cy3-siRNA) group. ΔΨm and ATP levels were reduced in the MFN2-siRNA group compared with the Cy3-siRNA group. Low MFN2 expression levels in granulosa cells were related to ageing, which may be involved in the clinical outcome of ART by promoting cell apoptosis and affecting mitochondrial function.


An evaluation of some factors affecting the detection of blood group antibodies by automated methods.
Some factors affecting the sensitivity of the automated methods for blood group antibody detection have been evaluated. The experiments revealed influencing differences between various albumin preparations. In the BMC method, one lot of albumin permitted no significant antibody detection. In the LISP technique, a plateau of maximum Polybrene activity was found. The beginning of this plateau depended on both the albumin preparation and the Polybrene lot. In the BMC method, methyl cellulose gave optimal sensitivity within a concentration range of 0.3 to 0.5 per cent. The stability of test cells stored in ACD at 4 C was studied. All test cells could be used safely up to two weeks. Cells from different donors showed variable reactivity after three weeks.


The spacing effect in young children's free recall: support for automatic-process explanations.
The effect of spacing repetitions on children's free recall was investigated in two experiments. In Experiment 1, both 4-year-old children and 7-year-old children exhibited a spacing effect in free recall, and the magnitude of the effect did not change with age. In Experiment 2, free recall was examined as a function of spacing, age (3 years old vs. 4 years old) and presentation rate (1 vs. 2 vs. 5 sec per stimulus). A spacing effect was obtained that did not differ as a function of age or presentation rate. Of particular interest was the fact that 3-year-olds exhibited a strong spacing effect even when stimuli were presented at a very rapid 1-sec rate. The results support the hypothesis that fundamental memory mechanisms that operate relatively automatically are sufficient to produce a spacing effect in free recall.


Infrared Responsive Choline Phosphate Lipids for Synergistic Cancer Therapy.
Choline phosphate lipids have been designed and developed as new-generation zwitterionic nanocarriers with excellent biocompatibility and bioorthogonality to provide a more programmable performance for cancer therapy. However, there is a lack of spatiotemporal and reversible control for drug release at target tumor cells, which can lead to severe adverse effects to normal tissue and discounted treatment outcome. Here, light-inducible Lip-cRGDfk/ICG/Dox liposomes were developed for synergistic cancer therapy. ICG can effectively convert light energy into selective heating in a local environment upon laser irradiation, thus inducing thermal ablation of tumor cells, and further reversibly trigger the spatiotemporal release of anticancer drugs (Dox) at tumor cells due to the conformation transformation of CP lipids to synergistically kill tumor cells. That Lip-cRGDfk/ICG/Dox exhibited a significant improvement for breast cancer therapy in vitro and in vivo is also demonstrated, thus it can serve as an efficient platform to noninvasively and spatiotemporally control the activation of cytotoxicity at tumor cells for precision cancer therapy.


The rate of re-endothelialization correlates inversely with the degree of the following intimal thickening in vein grafts. Electron microscopic and immunohistochemical studies.
The distribution of re-endothelialization and the development of intimal thickening were investigated electron microscopically and immunohistochemically using saphenous vein grafts implanted into the femoral artery in dogs. Animals were divided into two groups according to a difference of preparation of the venous grafts before implantation: group 1 without storage, and group 2 with storage for 1 h in 0.9% sodium chloride solution containing papaverine and heparin. In group 2 endothelial cells were almost totally denuded at 1 day, while endothelial islands were always left on the back of valves. In group 1 small islands of surviving endothelial cells were occasionally observed away from the valves. By 1 week, the re-endothelialization of group 1 and group 2 extended to 71 +/- 14.7% and 47 +/- 9% (mean +/- SD) of the total luminal surface area, respectively, and spread mainly from the valves but not from the adjacent artery. Immunohistochemical study using anti-dog fibrinogen IgG suggested that increased permeability of the graft wall continued for one month, in spite of the endothelial covering. Intimal thickening was most pronounced at 1 month, especially near the anastomosis, but was less in the middle of the grafts. These results indicate that intimal thickening of the venous grafts is a response to injury which intimately depends on the rate of re-endothelialization.


Carpal tunnel syndrome and acromegaly.
50 patients with acromegaly and carpal tunnel syndrome have been examined electrophysiologically before and after transnasal operation of the pituitary adenoma. 32 of the 50 patients (64%) had symptoms of carpal tunnel syndrome. 13 of them had neurological deficits. 28 of the examined patients had pathological neurographical findings only. About 1 week post-operatively DL was decreased in 43%; in 10 out of 13 patients with neurological deficits DL decreased. GH was normalized in 80% and reduced to 5-10 micrograms/l in a further 10%. The investigation did not show whether the carpal tunnel syndrome only depended on a GH increase or on other factors also such as e.g., on the duration of symptoms or tissue changes. None of the patients had the transversal carpal ligament operated on. The coincidence between acromegaly and carpal tunnel syndrome was 64%. In 3 cases the carpal tunnel syndrome was the leading sign to the diagnosis of acromegaly.


Degradation of bone matrix proteins by osteoclast cathepsins.
1. The degradation of the bone matrix proteins osteocalcin, osteonectin and alpha 2HS-glycoprotein by human cathepsins B and L and human osteoclastoma cathepsins has been investigated. 2. Intermediate degradation products (M(r) > 12 kDa) were not observed during the digestion of alpha 2HS-glycoprotein and osteonectin by cathepsins B and L although they were observed with some of the osteoclastoma cathepsins. Most of the osteoclastoma cathepsins were capable of degrading these two proteins to small peptides at comparable rates. 3. Each cathepsin produced a different pattern of osteocalcin degradation products. 4. The extensive range of non-collagenous proteins in bone matrix may necessitate the production by osteoclasts of cathepsins with different specificities during bone resorption.


The hScrib/Dlg apico-basal control complex is differentially targeted by HPV-16 and HPV-18 E6 proteins.
The E6 proteins of the high-risk Human papillomaviruses (HPV) types have a well-documented ability to target certain cellular proteins for ubiquitin-mediated degradation via the proteasome. Previous studies have shown that E6 proteins interact differently with different target proteins, and that the viral proteins, depending upon the target, may recruit diverse cellular ubiquitin-protein ligases. In this study, we have examined the abilities of E6 proteins from HPV-16 and HPV-18 to interact with and induce the degradation of two PDZ domain-containing targets, Dlg and hScrib. We have also mapped the binding site of E6 on hScrib and shown that the interaction of E6 with hScrib is distinct from its interactions with other PDZ domain-containing targets. This is reflected in the efficiency with which the two viral E6 proteins can inhibit hScrib's suppression of cell transformation.Dlg and hScrib have complementary activities in the control of epithelial cell polarity and the fact that both are targeted by high-risk HPV E6 proteins underlines their importance. Our finding that they are each targeted differently by HPV-16 and HPV-18 E 6 s suggests that the two viruses are subjected to somewhat different constraints and provides a possible explanation for the apparent redundancy in targeting both parts of this important control mechanism.


Application of ATR-far-infrared spectroscopy to the analysis of natural resins.
This study proposes FTIR spectroscopy in the far-infrared region (FarIR) as an alternative method for the characterisation of natural resins. To this purpose, standards of natural resins belonging to four different categories (sesquiterpenic, i.e. elemi, shellac; diterpenic, i.e. colophony, Venice turpentine; diterpenic with polymerised components, i.e. copal, sandarac; triterpenic, i.e. mastic and dammar) used as paint varnishes have been analysed by FarIR spectroscopy in ATR mode. Discrimination between spectral data and repeatability of measurements have been magnified and verified using principal component analysis, in order to verify the effectiveness of the method in distinguishing the four resin categories. The same samples were analysed in the MidIR range, but the spectral differences between the different categories were not evident. Moreover, the method has been tested on historical samples from the painting "La Battaglia di Cialdiran" (sixteenth century) and from a gilded leather (seventeenth century). In the first case, FarIR spectroscopy allowed confirmation of the results obtained by analytical pyrolysis. In the latter, FarIR spectroscopy proved successfully, effective in the identification of the superficial resin layer that could not be detected with the bulk chromatographic analyses.


Resting energy expenditure in cancer patients: Agreement between predictive equations and indirect calorimetry.
Disorders of energy metabolism is a common phenomenon in cancer patients. Changes in resting energy expenditure (REE) combined with inadequate nutrition support appear to be causes of nutritional depletion in cancer patients. In clinical practice, REE is typically calculated using predictive equations. The aim of this study was to determine the agreement between REE estimated by predictive equations and REE measured by IC in Portuguese cancer patients. Differences in measured REE between patients with different types of digestive cancers were also assessed. REE was measured by indirect calorimetry (IC) in 61 patients with cancer diagnosis (gastric cancer, cholangiocarcinoma, pancreatic cancer, liver cancer and colorectal cancer). Measured REE values were compared with those estimated by equations of Harris-Benedict, Schofield, Ireton-Jones, Mifflin-St.Jeor and Barcellos I and II. Mean Respiratory Quotient (RQ) was 0.77 ± 0.09, which indicates high lipids utilization as substrate. No statistically significant differences between REE or RQ from patients with different cancer types were observed. All equations underestimate REE: Harris-Benedict, mean difference -648 kcal (limits of agreement +627 to -1923 kcal); MifflinSt.Jeor, mean difference -694 kcal (limits of agreement +544 to -193 kcal); Schofield, mean difference -531 kcal (limits of agreement +662 to -1723 kcal); and Ireton-Jones, mean difference -556 kcal (limits of agreement +774 to -1887 kcal). Barcellos I and II showed lower mean difference when compared to measured REE, +59 and + 52 kcal, respectively, although presenting wide limits of agreement, +1542 to -1424 kcal and +1429 to -1326, respectively. Although Barcellos Equations underestimate less and enable more accurate average REE prediction in cancer patients, still present wide limits of agreement and therefore clinically important differences in REE estimation may be found at individual level. Our results support the appropriateness of measuring REE by IC to better adequate the nutrition support to cancer patients. Further research is needed to improve the current knowledge base of energy expenditure in cancer patients, and to improve the accuracy of existing predictive equations.


Revealing a gap in the clinical competence of nursing staff in nursing homes: a cross-sectional study with the Ms. Olsen test.
Nursing staff, caring for frail older people in long-term care, needs to have a certain level of clinical competence to identify diseases at an early stage and to assess and provide good nursing care. In Finland, nursing care is based on evidence-based and high-quality nursing care. However, earlier inspections by the National Supervisory Authority for Welfare and Health showed many discrepancies between the nursing staff's clinical competence and adequate and continuous education. This study aimed to explore nursing staff, i.e. the clinical competence and decision-making skills of registered and practical nurses in nursing homes for older people in Finland and to analyse the association between nurses' clinical competence and fundamental background factors. We conducted a cross-sectional study of 337 participants in 50 nursing homes in the western part of Finland, between December 2020 and January 2021. The instrument used was the validated Ms. Olsen test, an extraction of NOP-CET. Statistical analyses were conducted with descriptive statistics and correlations and a cut-off for clinical competence. This study with the Ms. Olsen test revealed that only one-fourth of the RNs and a third of the PNs passed the clinical competence test. In the self-evaluation, almost all participants evaluated themselves with good clinical competence. The Finnish Current Care Guidelines were used on a daily basis by 7.4% and weekly by 30%. Significant correlation was found between Swedish as a working language and mother tongue and the score for clinical competence. The clinical competence test, the Ms. Olsen test, was used in Finland for the first time to evaluate the nursing staffs´ clinical competence in nursing homes. We found gaps in the clinical competence in Finnish nursing homes, both for PNs and RNs. The result differed remarkably from their self-assessments and the staff did not use the national nursing guidelines as required to develop their nursing skills and knowledge. Gaps in the clinical competence have been identified and can be used to develop targeted continuous education.


Synthesis and antitumor activity of 1,2-dihydro-1-(2-deosy-beta-D-erythro-pentofuranosyl)-2-oxo-5-methylpyrazine 4-oxide, a structural analogue of thymidine.
1,2-Dihydro-1-(2-deoxy-beta-D-erythro-pentofuranosyl)-2-oxo-5-methylpyrazine 4-oxide was synthesized by condensation of the silylated pyrazine base with the blocked chloro sugar, followed by removal of the protecting groups. The compound inhibited the growth of leukemia L1210 cells in vitro by 50% at 2 x 10-7 M. At 400 mg/kg/day x 6 it increased the life-span of leukemia L1210 bearing mice by approximately 55%, without apparent toxicity to the host.


Explicit vs. implicit spatial processing in arrow vs. eye-gaze spatial congruency effects.
Arrows and gaze stimuli lead to opposite spatial congruency effects. While standard congruency effects are observed for arrows (faster responses for congruent conditions), responses are faster when eye-gaze stimuli are presented on the opposite side of the gazed-at location (incongruent trials), leading to a reversed congruency effect (RCE). Here, we explored the effects of implicit vs. explicit processing of arrows and eye-gaze direction. Participants were required to identify the direction (explicit task) or the colour (implicit task) of left or right looking/pointing gaze or arrows, presented to either the left or right of the fixation point. When participants responded to the direction of stimuli, standard congruency effects for arrows and RCE for eye-gaze stimuli were observed. However, when participants responded to the colour of stimuli, no congruency effects were observed. These results suggest that it is necessary to explicitly pay attention to the direction of eye-gaze and arrows for the congruency effect to occur. The same pattern of data was observed when participants responded either manually or verbally, demonstrating that manual motor components are not responsible for the results observed. These findings are not consistent with some hypotheses previously proposed to explain the RCE observed with eye-gaze stimuli and, therefore, call for an alternative plausible hypothesis.


In vivo evidence of global and focal brain alterations in anorexia nervosa.
Brain alterations are known to be associated with anorexia nervosa (AN) and tend to be distributed across brain structures, with only a few reports describing focal damage. Magnetic resonance images of 21 anorexic patients with different disease duration and 27 control subjects were acquired and compared using voxel-based morphometry (VBM). Patients had a significant reduction of total white matter (WM) volume and focal gray matter (GM) atrophy in cerebellum, hypothalamus, caudate nucleus and frontal, parietal and temporal areas. The cerebellum was more affected in patients with longer disease duration, whereas the hypothalamic alterations were more pronounced in patients with shorter food restriction. A correlation with body mass index (BMI) and GM was found in the hypothalamus. Our data demonstrate a diffuse reduction of WM together with focal areas of GM atrophy in AN. The finding of a hypothalamic focal atrophy points to hormonal dysfunction and opens the possibility for a central dysregulation of homeostasis. The involvement of temporoparietal areas could account for body image distortion. Finally, the cerebellar GM atrophy confirms previous findings and seems to be a late consequence of AN that could play a role in the chronic phase of the disease.


Quorum sensing of microalgae associated marine Ponticoccus sp. PD-2 and its algicidal function regulation.
Quorum sensing (QS) systems play important roles in regulating many physiological functions of microorganisms, such as biofilm formation, bioluminescence, and antibiotic production. One marine algicidal bacterium, Ponticoccus sp. PD-2, was isolated from the microalga Prorocentrum donghaiense, and its N-acyl-homoserine lactone (AHL)-mediated QS system was verified. In this study, we analyzed the AHLs profile of strain PD-2. Two AHLs, 3-oxo-C8-HSL and 3-oxo-C10-HSL, were detected using a biosensor overlay assay and GC-MS methods. Two complete AHL-QS systems (designated zlaI/R and zlbI/R) were identified in the genome of strain PD-2. When expressed in Escherichia coli, both zlaI and zlbI genes could each produce 3-oxo-C8-HSL and 3-oxo-C10-HSL. Algicidal activity was investigated by evaluating the inhibitory rate (IR) of microalgae growth by measuring the fluorescence of viable cells. We found that the metabolites of strain PD-2 had algicidal activity against its host P. donghaiense (IR 84.81%) and two other red tide microalgae, Phaeocystis globosa (IR 78.91%) and Alexandrium tamarense (IR 67.14%). β-cyclodextrin which binds to AHLs and inhibits the QS system reduced the algicidal activity more than 50%. This indicates that inhibiting the QS system may affect the algicidal metabolites production of strain PD-2. Our study indicated that a QS-regulated algicidal system may play a potential role in the process of red tides disintegration. QS might be a potential way to control red tides.


The dose-dependence of the split-dose response of marrow colony-forming units (CFU-S): similarity to other tissues.
The split-dose effect for survival of colony-forming units (CFU-S) in mouse bone-marrow increases with increasing total dose. This is compatible with the shape of the survival curve, since detailed measurements at doses lower than 200 rad show the presence of a marked initial slope, followed by a tendency towards an increased sensitivity at higher doses. The magnitude of the increase in the split-dose effect is quantitatively similar to values observed by others at comparable low doses in skin, intestine and lung, as deduced from multifraction experiments. It is concluded that these cells do not differ markedly, as has been generally believed, from many other cell types in the ability to demonstrate split-dose effects, when the doses used in the experiments are strictly comparable.


Long-term gait biomechanics in level, uphill, and downhill conditions following anterior cruciate ligament reconstruction.
Altered gait biomechanics have been linked to post-traumatic knee osteoarthritis development following anterior cruciate ligament reconstruction surgery, but the persistence of aberrant gait biomechanics after the first year post-surgery is inconsistent in the literature. Gait biomechanics are typically evaluated on a level surface, but this task may not elucidate discrepancies in individuals further removed from surgery due to the simplicity of the task. Graded surfaces are common in real-world ambulation and may exacerbate aberrant gait biomechanics due to greater mechanical demands. Forty-seven individuals post-anterior cruciate ligament reconstruction (4 ± 3 years post-surgery) and forty-seven uninjured controls completed gait analysis under level, uphill, and downhill conditions on an instrumented treadmill. Outcomes included knee flexion displacement and peak knee flexion angle, vertical ground reaction force, and knee extension and abduction moments. Knee extension moment and knee flexion displacement were lesser in the surgical limb compared to the contralateral during the downhill condition, with lesser knee flexion displacement also observed during the level condition. Additionally, knee extension moment was less symmetrical in the surgical group during both uphill and downhill conditions compared to controls. Knee flexion displacement was less symmetrical in the surgical group during both level and downhill conditions compared to controls. Graded surfaces elucidate aberrant gait biomechanics in individuals more than 1 year post-anterior cruciate ligament reconstruction that are not apparent during level walking. These findings suggest that gait assessment on level surfaces may mask existing deficiencies, and warrant emphasizing ambulation of graded surfaces during anterior cruciate ligament rehabilitation.


Long-term increases in BK potassium channel underlie increased action potential firing in dentate granule neurons following pilocarpine-induced status epilepticus in rats.
Temporal lobe epilepsy (TLE) is the most common form of acquired epilepsy in adult. Since dentate gyrus granule cells (GCs) play a critical role in hippocampal seizure generation, it is, therefore, important to understand changes in intrinsic properties of GCs in TLE. In this study, the electrophysiological properties of GCs obtained from epileptic rates were compared with the control group using whole cell patch-clamp recording. Results indicated a significant increase in the number of action potentials (APs) in depolarizing currents of 150 pA, 200 pA, and 250 pA. In addition, there was a significant decrease in AP half-width of GCs. The amplitude of fast afterhyperpolarization (fAHP) in epileptic group significantly decreased compared to control group. Blockade of large conductance calcium activated potassium channel (BK), channels with paxilline and iberiotoxin reversed pilocarpine-induced changes in electrophysiological properties of GCs in epileptic group. These results suggest that the BK channel blockers by reversing the firing properties of GCs might have beneficial preventative effects on pilocarpine-induced electrophysiological changes.


Surgical Approach and Hip Laterality Affect Accuracy of Acetabular Component Placement in Primary Total Hip Arthroplasty.
Controversy remains if the anterior approach improves acetabular component alignment, and many studies have compared approaches with different surgeons over different timeframes. The purpose of this study was to assess a single surgeon's experience over a one-year timeframe and radiographically compare acetabular component positioning with the direct anterior versus direct lateral approach. Secondarily, this study compares acetabular component position differences between right and left hips for a right-hand dominant surgeon. Postoperative radiographs of 289 primary total hip arthroplasties (THAs) performed by a single right-hand dominant surgeon in 2014 were reviewed for abduction, anteversion, and medial cup seating. Component position was compared to surgical approach with 152 direct anterior (DA) THAs (53%) and 137 direct lateral (DL) THAs (47%). The operative side was also compared to surgeon hand dominance. Surgeons target was 40° abduction, 20° anteversion ±5°, and seating to the teardrop ±5mm. Lewinnek target was also assessed. DA hips had a significantly lower abduction angle (p=0.04), less abduction target outliers (p<0.001), less abduction Lewinnek outliers (p<0.001), less target anteversion outliers (p<0.001), closer seating to teardrop (p<0.001), and less seating outliers (p<0.001). The combined target and Lewinnek safe zone were achieved more often in DA (p<0.001, p=0.042). Controlling for body mass index (BMI), the combined target achievement remained significantly better for DA (p=0.02), but combined Lewinnek was not significant (p=0.07). In the DA approach, right hips had a significantly lower abduction angle (p=0.03), less Lewinnek anteversion outliers (p=0.043), and less combined Lewinnek outliers (p=0.027). In the DL group, right hips had significantly higher anteversion angles (p=0.004) and Lewinnek anteversion outliers (p=0.033). The anterior approach improved target abduction, anteversion, and medialization compared to the direct lateral approach. Significant differences in component positioning were found in both approaches based on the surgeons dominant and non-dominant side.


Urinary tract stones: a complication of the Kock pouch continent urinary diversion.
Urinary tract stone disease has been found to be a later complication associated with the construction of the Kock pouch continent urinary diversion. Of 383 patients who underwent Kock pouch diversion between August 1982 and December 1986 stones developed in the pouch in 64 (16.7%), usually on exposed staples or eroded Marlex used to construct the nipple valves. Stones have recurred in 13 of the 64 patients (22%). Most stones were removed endoscopically with techniques similar to those used for percutaneous stone removal. Risk factors for stone formation include Marlex collar erosion and acute pyelonephritis. Changes in surgical techniques with elimination of the Marlex collar and a reduction in the number of staples have reduced the incidence of this later complication to 10%.


Changes in Prevalence of Mental Illness Among US Adults During Compared with Before the COVID-19 Pandemic.
The authors review trend and cohort surveys and administrative data comparing prevalence of mental disorders during, versus, and before the COVID-19 pandemic and changes in mental health disparities. Best evidence suggests clinically significant anxiety-depression point prevalence increased by relative-risk (RR) = 1.3 to 1.5 during the pandemic compared with before. This level of increase is much less than the implausibly high RR = 5.0 to 8.0 estimates reported in trend studies early in the pandemic based on less-appropriate comparisons. Changes in prevalence also occurred during the pandemic, but relative prevalence appears not to have changed substantially over this time.


Hospital-level high-risk antibiotic use in relation to hospital-associated Clostridioides difficile infections: Retrospective analysis of 2016-2017 data from US hospitals.
Antibiotics are widely used by all specialties in the hospital setting. We evaluated previously defined high-risk antibiotic use in relation to Clostridioides difficile infections (CDIs). We analyzed 2016-2017 data from 171 hospitals. High-risk antibiotics included second-, third-, and fourth-generation cephalosporins, fluoroquinolones, carbapenems, and lincosamides. A CDI case was a positive stool C. difficile toxin or molecular assay result from a patient without a positive result in the previous 8 weeks. Hospital-associated (HA) CDI cases included specimens collected >3 calendar days after admission or ≤3 calendar days from a patient with a prior same-hospital discharge within 28 days. We used the multivariable Poisson regression model to estimate the relative risk (RR) of high-risk antibiotic use on HA CDI, controlling for confounders. The median days of therapy for high-risk antibiotic use was 241.2 (interquartile range [IQR], 192.6-295.2) per 1,000 days present; the overall HA CDI rate was 33 (IQR, 24-43) per 10,000 admissions. The overall correlation of high-risk antibiotic use and HA CDI was 0.22 (P = .003), and higher correlation was observed in teaching hospitals (0.38; P = .002). For every 100-day (per 1,000 days present) increase in high-risk antibiotic therapy, there was a 12% increase in HA CDI (RR, 1.12; 95% CI, 1.04-1.21; P = .002) after adjusting for confounders. High-risk antibiotic use is an independent predictor of HA CDI. This assessment of poststewardship implementation in the United States highlights the importance of tracking trends of antimicrobial use over time as it relates to CDI.


En bloc resection of a T4B stage cancer of the hepatic flexure of the colon invading the liver, gall bladder, and pancreas/duodenum: A case report.
A T4B hepatic flexure of colon cancer that had invaded the liver, gall bladder, and pancreas/duodenum was removed through a D3 expanded right hemicolectomy + pancreaticoduodenectomy +sectional VI and VII hepatic segmentectomy.


Antagonism of the orexin receptors in the ventral tegmental area diminished the stress-induced analgesia in persistent inflammatory pain.
As a part of descending pain inhibitory system, orexin (OXs) in the ventral tegmental area (VTA) are implicated in nociceptive responses. The current study aimed to evaluate the role of OX receptors (OXRs) in the VTA in stress-induced analgesia in persistent inflammatory pain. Ninety-nine adult male Wistar rats underwent forced swim stress (FSS) following intra-VTA infusion of various doses of SB334867 or TCS OX2 29 (1, 3, 10, and 30 nmol/0.3 μL) as an OX1R or OX2R antagonist, respectively. The nociceptive threshold was evaluated using the formalin test as an animal model of persistent inflammatory pain. Current results demonstrated FSS as acute stress produced analgesic responses in the persistent inflammatory pain. Moreover, either OX1R or OX2R antagonist infusion in the VTA hindered the FSS-induced analgesia in both early and late phases. The inhibitory effect of SB334768 in the FSS-induced analgesia was stronger than TCS OX2 29 in both early and late phases of the formalin test. Neither SB334768 nor TCS OX2 29 alone affects pain-related behaviors in formalin tests. Intra-VTA microinjection of each treatment could not modify locomotion in rats. The findings suggest that OX1R and OX2R in the VTA are implicated in FSS-induced analgesia mechanisms.


Reinduction with certolizumab pegol in patients with relapsed Crohn's disease: results from the PRECiSE 4 Study.
We sought to determine the efficacy of certolizumab pegol reinduction in patients with active Crohn's disease who respond to induction therapy with certolizumab pegol and then relapse during continuous or interrupted maintenance therapy. In the Pegylated Antibody Fragment Evaluation in Crohn's Disease: Safety and Efficacy (PRECiSE) 2 trial, 428 patients who responded to induction therapy with certolizumab pegol at week 6 were randomized to continuous therapy with certolizumab pegol or placebo (drug interruption) during weeks 6 to 26. Patients who relapsed before week 26 could enter PRECiSE 4, an ongoing open-label extension trial in which patients on continuous therapy underwent recapture with a single extra 400-mg dose of certolizumab pegol, and patients who relapsed after drug interruption underwent reinduction with certolizumab pegol 400 mg at weeks 0, 2, and 4 followed by maintenance with certolizumab pegol 400 mg every 4 weeks. Disease activity was measured by the Harvey-Bradshaw Index. During PRECiSE 2, 124 patients had disease relapse and entered PRECiSE 4; 49 patients had received continuous therapy and 75 patients had drug interruption. At week 4 of PRECiSE 4, response rates were 63% in patients who relapsed on continuous therapy and 65% after drug interruption. Response was maintained in 55% and 59% of these responders, respectively, through week 52. Administration of 1 additional dose of certolizumab pegol to patients who relapsed on continuous maintenance therapy, and certolizumab pegol reinduction to those who relapsed after drug interruption, are effective strategies for treating patients who have relapsed after successful induction therapy with certolizumab pegol.


Overestimation of anticoagulant benefit in patients with atrial fibrillation and low life expectancy: evidence from 12 randomized trials.
Patients with atrial fibrillation (AF) have a high rate of all-cause mortality that is only partially attributable to vascular outcomes. While the competing risk of death may affect expected anticoagulant benefit, guidelines do not account for it. We sought to determine if using a competing risks framework materially affects the guideline-endorsed estimate of absolute risk reduction attributable to anticoagulants. We conducted a secondary analysis of 12 RCTs that randomized patients with AF to oral anticoagulants or either placebo or antiplatelets. For each participant, we estimated the absolute risk reduction (ARR) of anticoagulants to prevent stroke or systemic embolism using two methods. First, we estimated the ARR using a guideline-endorsed model (CHA 2 DS 2 -VASc) and then again using a Competing Risk Model that uses the same inputs as CHA 2 DS 2 -VASc but accounts for the competing risk of death and allows for non-linear growth in benefit over time. We compared the absolute and relative differences in estimated benefit and whether the differences in estimated benefit varied by life expectancy. 7933 participants had a median life expectancy of 8 years (IQR 6, 12), determined by comorbidity-adjusted life tables. 43% were randomized to oral anticoagulation (median age 73 years, 36% women). The guideline-endorsed CHA 2 DS 2 -VASc model estimated a larger ARR than the Competing Risk Model (median ARR at 3 years, 6.9% vs. 5.2%). ARR differences varied by life expectancies: for those with life expectancies in the highest decile, 3-year ARR difference (CHA 2 DS 2 -VASc model - Competing Risk Model 3-year risk) was -1.2% (42% relative underestimation); for those with life expectancies in the lowest decile, 3-year ARR difference was 5.9% (91% relative overestimation). Anticoagulants were exceptionally effective at reduced stroke risk. However, anticoagulant benefits were misestimated with CHA 2 DS 2 -VASc, which does not account for the competing risk of death nor decelerating treatment benefit over time. Overestimation was most pronounced in patients with the lowest life expectancy and when benefit was estimated over a multi-year horizon.


Influence of thyrotropin-releasing hormone on the postmenopausal female.
Daily blood samples were obtained from 5 postmenopausal patients for 21 days and analyzed for plasma follicle stimulating hormone (FSH), luteinizing hormone (LH), estrone, estradiol, progesterone, and serum T4. On days 8 through 14, oral thyrotropin-releasing hormone (TRH) was administered, 50 mg, 4 times a day. All patients showed asignificant T4 response. There was, however, no significant change in the plasma FSH, LH, estrone, estradiol, or progesterone. We conclude that oral administration ofTRH has no influence on the elevated circulating concentration of FSH and LH seen in the postmenopausal female.


Chondrosarcomas of the head and neck.
Chondrosarcomas of the head and neck are uncommon. Over a 35-year period (1950-1985) at our institution, 557 patients had an established diagnosis of chondrosarcoma. In 28 (5%) of these patients, the tumor was located in the head and neck region. A retrospective analysis was performed in an attempt to accurately define clinical characteristics, management, and outcome in these 28 patients. The patient population consisted of 15 males and 13 females whose ages ranged from 10 to 72 years, with a median of 38 years. Ten (36%) patients were untreated and 18 (64%) previously treated patients were referred for further management. The primary sites were maxilla (11), cervical vertebrae (7), mandible (3), skull (2), sphenoid and ethmoid sinuses (2), frontal sinus (1), nasal septum (1), and orbit (1). Lesions arising in the larynx were excluded from this study. The most common presenting symptom was a painless mass. Surgery was the definitive treatment in all patients. However, adjuvant radiation therapy or chemotherapy was utilized for residual disease in almost half of the cases (13 patients). Follow-up ranged from 5 to 35 years. Twelve (43%) of the 28 patients were known to be alive and free of disease more than 5 years after surgery. The most common cause of death was uncontrollable local disease (88%). However, only 3 of the 10 previously untreated patients developed local recurrence. For all patients, the median interval from time of first recurrence until death was 25 months (range 6 to 70 months). Positive margins in 8 of 12 patients resulted in local recurrence and eventual death.(ABSTRACT TRUNCATED AT 250 WORDS)


Ultra high-risk state for psychosis and non-transition: a systematic review.
Most effort in ultra high-risk (UHR) research has been directed at defining the clinical and neurobiological characteristics of those UHR subjects who go on to develop psychosis. The characteristics and outcome of the remaining UHR subjects have remained relatively unexplored. We performed a systematic review of clinical UHR studies to investigate whether information was available on the characteristics and outcome of UHR subjects who did not convert to psychosis. Of 2462 potentially relevant papers, 31 met inclusion criteria, i.e. 20 naturalistic and 11 intervention studies. On average 76% (range 46-92.6%) of the UHR patients made no transition to psychosis during follow-up (range 6 to 40 months). Nearly half of the studies provided no characteristics of those UHR subjects who did not develop psychosis. Six studies reported remission rates from initial UHR status (range 15.4% to 54.3%). Linear regression showed that more recent studies reported significantly lower transition rates as compared to earlier publications. An older mean age at baseline was associated with significant lower transition rates in publications with follow-ups exceeding 1 year. Our review illustrates that the long-term outcome of UHR subjects that do not develop psychosis is to date under-investigated. The studies reporting remission rates suggest that UHR criteria capture a non-negligible proportion of subjects that do not convert to psychosis.


Effects of synthetic progestagens on autonomic tone, neurohormones and C-reactive protein levels in young healthy females in reproductive age.
Heart rate variability and baroreceptor sensitivity are measures of autonomic control. While progestagen-containing replacement therapy in postmenopausal women adversely affects autonomic balance, the impact of hormonal contraceptives with synthetic progestagens on autonomic activity, neurohormones and C-reactive protein levels is not well characterized. We analyzed parameters of heart rate variability and baroreceptor sensitivity in young healthy females without (n = 27) or on oral contraceptives with synthetic progestagens (n = 31). Demographic characteristics were not different among the examined groups. Total power (controls: 5682+/-3618 vs. hormones: 4800+/-2957 ms2; NS), standard deviation of beat-to-beat intervals (SDNN; 66+/-24 vs. 63+/-20 ms; p = 0.74), other time- and frequency-dependent parameters of heart rate variability and baroreceptor sensitivity (6.0+/-3.2 vs. 6.5+/-2.7 ms/mm Hg; NS) were not significantly different among the groups. Total cholesterol and triglyceride as well as C-reactive protein (CRP) levels were significantly higher in users of hormonal contraceptives than in non-users (cholesterol: 187+/-37 vs. 166+/-28 mg/dL; p = 0.05; triglycerides: 110+/-35 vs. 68+/-30 mg/dL; p = 0.01; CRP: 2.7+/-2.1 vs. 1.0+/-1.4 mg/L; p < 0.001). Heart rate variability, baroreceptor sensitivity, lipid parameters and CRP levels were not affected during the ovarian cycle in non-users of hormonal contraception. The use of oral contraceptives containing synthetic progestagens was not associated with a modulation of autonomic tone, while lipid parameters and CRP levels were adversely affected. These data suggest that synthetic progestagens in modern oral contraceptives do not modulate the autonomic balance, but probably affect the atherogenic risk profile of young females in reproductive age.


First- and second-generation antipsychotic medication and cognitive processing in schizophrenia.
Schizophrenia has been consistently characterized by deficits in the cognitive domains of executive function, working memory, attention, and episodic memory. Although some cognitive abnormalities, such as motor slowing, may be associated with antipsychotic medication administration, generally the cognitive deficits shown by patients with schizophrenia can be attributed at least in part to the disease process. Modulation of the dopamine neurotransmitter system, notably through D2 receptor blockade, has been associated with psychotic symptom reduction and cognitive performance improvements in patients with schizophrenia. Although first-generation antipsychotic medication treatment initially was thought not to result in cognitive improvement, recent studies comparing second-generation antipsychotics to low doses of first-generation antipsychotic medication showed cognitive benefits for first-generation drugs, although perhaps not as great as that found after treatment with second-generation medication. Cognitive improvement associated with administration of antipsychotic medication may be a manifestation of improvement in general cortical information processing. Recent work has shown that specific genetic polymorphisms may interact with antipsychotic medication treatment to influence the degree to which cognitive abilities display improvement after treatment. In particular, the catechol-O-methyltransferase val108/158met polymorphism has been shown to predict working memory improvement after administration of antipsychotic medication to patients with schizophrenia.


Does delivering more dialysis improve clinical outcomes? What randomized controlled trials have shown.
Some randomized controlled trials (RCTs) have sought to determine whether different dialysis techniques, dialysis doses and frequencies of treatment are able to improve clinical outcomes in end-stage kidney disease (ESKD). Virtually all of these RCTs were enacted on the premise that 'more' haemodialysis might improve clinical outcomes compared to 'conventional' haemodialysis. Aim of the present narrative review was to analyse these landmark RCTs by posing the following question: were their intervention strategies (i.e., earlier dialysis start, higher haemodialysis dose, intensive haemodialysis, increase in convective transport, starting haemodialysis with three sessions per week) able to improve clinical outcomes? The answer is no. There are at least two main reasons why many RCTs have failed to demonstrate the expected benefits thus far: (1) in general, RCTs included relatively small cohorts and short follow-ups, thus producing low event rates and limited statistical power; (2) the designs of these studies did not take into account that ESKD does not result from a single disease entity: it is a collection of different diseases and subtypes of kidney dysfunction. Patients with advanced kidney failure requiring dialysis treatment differ on a multitude of levels including residual kidney function, biochemical parameters (e.g., acid base balance, serum electrolytes, mineral and bone disorder), and volume overload. In conclusion, the different intervention strategies of the RCTs herein reviewed were not able to improve clinical outcomes of ESKD patients. Higher quality studies are needed to guide patients and clinicians in the decision-making process. Future RCTs should account for the heterogeneity of patients when considering inclusion/exclusion criteria and study design, and should a priori consider subgroup analyses to highlight specific subgroups that can benefit most from a particular intervention.


Multidisciplinary approach and management of patients who seek medical advice for penile size concerns: a narrative review.
We aimed to provide an overview of the strategies available to manage patients concerned about their penile size and to provide useful surgical hints regarding the most common penile enlargement approaches, based on our surgical expertise in this field. A comprehensive research was carried out on MEDLINE/PubMed database to identify pertinent studies concerning penile enlargement issues. The search strategy included a range of keywords; e.g. penis, penile, enlargement, augmentation, lengthening, girth. Management of penile size-related concerns represents a real challenge for the urologist, especially when dealing with patients suffering from penile dysmorphophobic disorder (PDD). A multidisciplinary preoperative assessment, including a psychiatric/psychological evaluation, may help in discerning those patients who would benefit the most from counselling/conservative management from those who would benefit from surgery instead. Conservative approaches include the use of vacuum-based and penile-stretching devices, which have shown encouraging levels of efficacy and safety. Over the last decades, different surgical strategies have been developed, aimed at either increasing flaccid penile length or improving penile girth. Penile lengthening procedures are more established, and satisfactory results can be achieved by experienced, large referrals' volume, surgeons. To date, there is lack of consensus regarding the penile girth enhancing techniques, and therefore these should be regarded as experimental. A multidisciplinary approach is necessary to identify patients with PDD, who should not be offered surgical intervention and should be referred for psychiatric/psychological counselling instead. The surgical approach should be tailored to the subject's unique anatomy and underlying conditions.


Isolation of the polypeptide chains of prekeratin.
Stratum corneum alpha protein, the principal structural protein of the epidermis, and its precursor prekeratin have been studied. Both proteins have similar patterns on sodium dodecyl sulfate electrophoresis and consist of several polypeptide chains (designated A, A', B, B'). These subunits have been isolated by chromatography on diethylaminoethyl cellulose in 8 M urea and characterized. Immunological studies have shown that the four subunits could be grouped into two distinct immunological groups referred to as the A and B groups and analysis of the cyanogen bromide fragments of purified components appeared to support such a hypothesis. X-ray diffraction studies have shown that at least one A component and one B component are necessary for the production of a typical alpha X-ray diffraction pattern. Circular dichroism studies have shown that the polypeptide chains of either class have low ellipticity when compared to the intact molecule, indicating that both chains are necessary for the formation of an alpha-helical structure.


Effect of Bedside Compared With Outside the Room Patient Case Presentation on Patients' Knowledge About Their Medical Care : A Randomized, Controlled, Multicenter Trial.
Although bedside case presentation contributes to patient-centered care through active patient participation in medical discussions, the complexity of medical information and jargon-induced confusion may cause misunderstandings and patient discomfort. To compare bedside versus outside the room patient case presentation regarding patients' knowledge about their medical care. Randomized, controlled, parallel-group trial. (ClinicalTrials.gov: NCT03210987). 3 Swiss teaching hospitals. Adult medical patients who were hospitalized. Patients were randomly assigned to bedside or outside the room case presentation. The primary endpoint was patients' average knowledge of 3 dimensions of their medical care (each rated on a visual analogue scale from 0 to 100): understanding their disease, the therapeutic approach being used, and further plans for care. Compared with patients in the outside the room group (n = 443), those in the bedside presentation group (n = 476) reported similar knowledge about their medical care (mean, 79.5 points [SD, 21.6] vs. 79.4 points [SD, 19.8]; adjusted difference, 0.09 points [95% CI, -2.58 to 2.76 points]; P = 0.95). Also, an objective rating of patient knowledge by the study team was similar for the 2 groups, but the bedside presentation group had higher ratings of confusion about medical jargon and uncertainty caused by team discussions. Bedside ward rounds were more efficient (mean, 11.89 minutes per patient [SD, 4.92] vs. 14.14 minutes per patient [SD, 5.65]; adjusted difference, -2.31 minutes [CI, -2.98 to -1.63 minutes]; P < 0.001). Only Swiss hospitals and medical patients were included. Compared with outside the room case presentation, bedside case presentation was shorter and resulted in similar patient knowledge, but sensitive topics were more often avoided and patient confusion was higher. Physicians presenting at the bedside need to be skilled in the use of medical language to avoid confusion and misunderstandings. Swiss National Foundation (10531C_ 182422).


Tregs self-organize into a computing ecosystem and implement a sophisticated optimization algorithm for mediating immune response.
Regulatory T cells (Tregs) play a crucial role in mediating immune response. Yet an algorithmic understanding of the role of Tregs in adaptive immunity remains lacking. Here, we present a biophysically realistic model of Treg-mediated self-tolerance in which Tregs bind to self-antigens and locally inhibit the proliferation of nearby activated T cells. By exploiting a duality between ecological dynamics and constrained optimization, we show that Tregs tile the potential antigen space while simultaneously minimizing the overlap between Treg activation profiles. We find that for sufficiently high Treg diversity, Treg-mediated self-tolerance is robust to fluctuations in self-antigen concentrations but lowering the Treg diversity results in a sharp transition-related to the Gardner transition in perceptrons-to a regime where changes in self-antigen concentrations can result in an autoimmune response. We propose an experimental test of this transition in immune-deficient mice and discuss potential implications for autoimmune diseases.


Comparison of effects of volatile and intravenous anesthetics on pupillary function during general anesthesia in children: A prospective observational study.
The light reflex, which reflects central nervous system dysfunction, can also be affected by anesthetic agents. We evaluated whether these effects differed according to the anesthetic agent in pediatric patients. Twenty children aged 3-12 years who were scheduled to undergo elective surgery under general anesthesia were randomly allocated to propofol and sevoflurane groups and underwent pupillometric assessments at five points during anesthesia: T1, after confirming loss of consciousness; T2, after endotracheal intubation; T3, at the time of skin incision; T4, 1 h after skin incision; and T5, before endotracheal extubation. The primary outcome was the Neurological Pupil index at T4, and the secondary outcomes were other pupillometric parameters, including pupil diameter, percentage of change in pupil diameter, dilation velocity, and constriction velocity. At T4, the Neurological Pupil index was significantly lower in the sevoflurane group (median difference, 0.30; 95% CI, 0.00 to 0.70; p = .036). Furthermore, the Neurological Pupil index at all time points was lower in the sevoflurane group. The time-and-group interaction effects on constriction velocity and dilation velocity were significantly different [F(1, 4) = 16.68, p = .002; F(1, 4) = 14.78, p = .008, respectively] but were not different on the Neurological Pupil index, pupil diameter, and percentage of change in pupil diameter. No intergroup differences were observed in the baseline characteristics, the flow rate of remifentanil at each time point, and total infused remifentanil. The Neurological Pupil index value in pediatric patients under general anesthesia is affected by the anesthetic agent used; this factor requires consideration in evaluations of the Neurological Pupil index during general anesthesia.


Backscroll illusion: apparent motion in the background of locomotive objects.
Backscroll illusion is an apparent motion perceived in backgrounds of movie images that present locomotive objects such as people, animals, and vehicles. This illusion is from the visual system registering retinal motion signals in relation to high-level object motion signals. We confirmed this notion from psychophysical experiments that mainly presented a realistic human figure on a treadmill walking or running in front of a counterphase grating. The apparent grating motion was consistently induced in the direction opposite to the locomotion. The induction was tuned to a gait velocity. The time course showed that the illusion arose as if it was synchronized with gait recognition, and that it was sustained against several reversals of limb swings so that local motion accounts were denied. A weak but significant illusion was observed from a static figure that implied a gait. Thus, we concluded that the illusion was determined by the high-level recognition of biological motion. An additional experiment found a similar effect from a vehicle with rotating wheels but no induction from a rotating wheel per se. This result led us to hypothesize that the backscroll illusion is generalized to objects that have shapes implying their moving directions.


Double thumb sign in a case of epiglottitis.
Epiglottitis is a potentially life-threatening condition that requires quick and accurate diagnoses. The gold standard for diagnosis is for laryngoscopic visualisation of the epiglottis. However, this may not be well-tolerated in a patient with impending airway collapse, and lateral neck radiographs may support the diagnosis. The thumb sign is a recognized radiological feature of epiglottitis. We present a case of a 57-year-old gentleman with epiglottitis, whose lateral neck radiograph had the interesting feature of a double thumb sign. In spite of the significant airway oedema, he was conservatively managed with subsequent full recovery. The objective of this case report is to highlight the severity of airway narrowing with this radiological finding of double thumb sign, to alert the clinician to have closer monitoring or to consider artificial airway support.


Increased expression of pleiotrophin is a prognostic marker for patients with gastric cancer.
BACKGROUND/AIMs: Pleiotrophin (PTN) have been demonstrated to play an important role in the development of human gastric cancer. However, the prognostic value remains unclear. The aim of this study was to investigate whether expression of PTN has prognostic relevance in human gastric cancer. Immunohistochemistry was used to investigate the expression of PTN proteins in 178 patients with gastric cancer. The level of PTN mRNA in gastric cancer tissues and paratumor tissues were evaluated in 52 paired cases by quantitative real-time polymerase chainreaction(qRT-PCR). Survival analysis by the Kaplan-Meier method was performed to assess prognostic significance. The expression level of PTN in gastric cancer tissues was significantly higher (P<0.001) than those in paratumor tissues according to the immunohistochemistry analysis, which was confirmed by qRT-PCR analysis. Additionally, the overexpression of PTN was significantly associated with the tumor site (P=0.001), Lauren's classification (P<0.001),histologic differentiation(P=0.014),depth of invasion(P<0.001), TNM stage (P=0.003),and lymph node metastasis (P=0.002). Moreover, the Cox proportional- hazards regression analysis revealed that the increased expression of PTN was an independent prognostic factor for poor recurrence-free survival(RFS) and overall survival(OS)(both P<0.001). These findings indicated that the expression of PTN is significantly correlated with prognosis in gastric cancer patients, suggesting that the expression of PTN may be used as an independent prognostic marker.


Synaptic polarity and sign-balance prediction using gene expression data in the Caenorhabditis elegans chemical synapse neuronal connectome network.
Graph theoretical analyses of nervous systems usually omit the aspect of connection polarity, due to data insufficiency. The chemical synapse network of Caenorhabditis elegans is a well-reconstructed directed network, but the signs of its connections are yet to be elucidated. Here, we present the gene expression-based sign prediction of the ionotropic chemical synapse connectome of C. elegans (3,638 connections and 20,589 synapses total), incorporating available presynaptic neurotransmitter and postsynaptic receptor gene expression data for three major neurotransmitter systems. We made predictions for more than two-thirds of these chemical synapses and observed an excitatory-inhibitory (E:I) ratio close to 4:1 which was found similar to that observed in many real-world networks. Our open source tool (http://EleganSign.linkgroup.hu) is simple but efficient in predicting polarities by integrating neuronal connectome and gene expression data.


[The movement pattern during cleavage in artificially activated eggs ofPimpla turionellae (Hym.)].
The early embryonic development ofPimpla is characterized by a complicated temporal and spatial pattern of ooplasmic movements detected in time-lapse films made during cleavage. The modified movements observed after the architecture of oviposited eggs had been altered artificially by centrifugation indicated that there are different dynamic systems for ooplasmic streaming, contractions, and nuclear migration. The discovery that unlaid, explanted oocytes ofPimpla can be activated by mechanical deformation provided a new way of studying alterations of egg architecture, nucleocytoplasmic interactions, and the control of morphogenetic processes during cleavage and blastoderm formation. In this article, development and ooplasmic movements in explanted oocytes with and without articifial activation are described and compared with those observed in eggs after normal oviposition. Four categories of explanted "eggs" can be distinguished: 1. Inexplanted eggs which are not activated by mechanical deformation, no movement of egg plasm can be observed, and nuclear multiplication never takes place. Thus the completion of meiosis as well as the ooplasmic movements must be triggered by deformation of the egg in the ovipositor. 2. Inartificially activated eggs with diphasic blastoderm formation, the following deviations from normal development are registered. The mixing motion at the anterior end of the egg, the transfer flow, and the forward component of the fountain flow are all absent. Instead, a homogenizing movement is observed in the ooplasm of the anterior region of the egg. The energids in this region then migrate directly to the periphery, and in due time form the blastoderm (first phase of blastoderm formation). In the posterior 2/3 of the egg, blastoderm formation is slightly retarded. The so-called mixing motion, the unipolar flow and the caudal part of the fountain flow take place as in normal development, and the energids become distributed throughout a central plasm column before they migrate radially to initiate a second phase of blastoderm formation. There are marked ooplasmic contractions at the egg poles. 3. Forartificially activated eggs with successive blastoderm formation we recorded the same deviations from normal development as in the cephalic region of eggs of category 2. Blastoderm formation also occurs in due time. In the caudal region of the egg, a "dilated" unipolar flow is found. The fountain flow is reduced and greatly delayed. Energids migrating from the anterior egg region into the posterior may be carried to the posterior egg pole in a central plasm by the fountain flow. A peripheral, ring-shaped contraction moving in a posterior direction indicates the zone where the preblastoderm gradually forms. A marked antero-posterior time gradient is evident in blastoderm formation. Development of these eggs is greatly retarded up to hatching of the larvae. 4. Ineggs without blastoderm formation after activating treatment, no energids could be found apart from the meiotic nuclei. Nevertheless, the ooplasmic movement pattern and the histological aspect of these eggs sometimes resembled those of eggs oviposited by the female. Also, formation of pseudo-pole cells could be observed. These observations demonstrate that pseudocleavage takes place in such eggs. The streaming system is apparently able to achieve the pattern of ooplasmic movements independently of nuclear multiplication. Our observations demonstrate the autonomy of the streaming systems and of energid migration. The third dynamic system, ooplasmic contractions, occurs in artificially activated eggs combined with the streaming system and/or nuclear multiplication. It may possibly act independently in the very early contractions at the egg poles; these may be comparable to events at the elevation of a fertilization membrane. The discussion concerns exogeneous and endogeneous factors which may affect the pattern of movements, and the functions of mixing motion and unipolar flows in restricting the early nuclear migration to the central plasm. Also discussed are the significance of the anterior and posterior initial regions ("Initialbereiche") and ofsuccessive blastoderm formation with respect to the relation between long-germ and short-germ egg types.


Effects of Land-Use Type and Flooding on the Soil Microbial Community and Functional Genes in Reservoir Riparian Zones.
Ecological processes (e.g., nutrient cycling) in riparian zones are often affected by land-use type and flooding. The extent to which land-use types and flooding conditions affect soil microorganisms and their ecological functions in riparian zones is not well known. By using high-throughput sequencing and quantitative PCR (q-PCR), we tested the effects of three land-use types (i.e., forest, wetland, and grassland) and two flooding conditions (i.e., landward locations and waterward locations within the land-use types) on soil microbial communities and microbial functional genes in the riparian zones of a reservoir. Land-use type but not flooding significantly affected soil microbial community composition at the phylum level, while both land-use type and flooding significantly affected the orders Nitrosotaleales and Nitrososphaerales. Alpha diversity was higher in the wetland and forest regardless of flooding conditions. Functional gene abundance differed among the three land-use types. Archaeal amoA (AOA) and nirS genes were more abundant in the wetland than in the grassland or forest. Bacterial amoA (AOB), nirK, nirS, and nosZ genes were more abundant in the waterward location than in the landward location but only in the wetland. Soil pH, moisture, and concentrations of soil organic matter and total soil nitrogen were significantly associated with the composition of archaeal and bacterial communities as well as with their gene abundance. This study revealed that soil microorganisms putatively involved in nitrogen cycling in riparian zones were more affected by land-use type than flooding.


Iguratimod (T-614) attenuates severe acute pancreatitis by inhibiting the NLRP3 inflammasome and NF-κB pathway.
Severe acute pancreatitis (SAP) is an acute abdominal disease that can develop locally to the multiple organs. It is characterized by pancreatic tissue self-digestion, and the rapid release of inflammatory cytokines, which play a dominant role in local or even systemic inflammation. In this study, we investigate the protective effect of T-614 against SAP induced by cerulein plus LPS in mice. Biochemical markers associated with pancreatitis in serum such as inflammatory cytokines, amylase and lipase activities were measured. Related proteins of NLRP3 inflammasome and NF-κB signaling pathway were evaluated by western blotting. Hematoxylin-eosin staining (HE) and immunohistochemistry (IHC) were used to evaluate changes of inflammation in pancreatic tissue. T-614 significantly alleviated the elevation markers of pancreatitis and suppresses the pancreatic tissue damage, including histopathological and molecular manifestations. In conclusion, T-614 plays a protective role in experimental SAP mice model via anti-inflammatory effects.


Clinically occult presentation of comminuted intertrochanteric hip fractures.
Hip fractures in awake patients are rarely subtle in their clinical presentation. We report two cases of occult, comminuted, intertrochanteric hip fractures that occurred in awake, elderly patients who were brought to the emergency department for evaluation of other medical conditions. Neither patient complained of hip pain, and both were transported to the ED without spinal immobilization. Physical examination revealed no sign of hip fracture. Patient 1 was scheduled for admission and just prior to transfer out of the ED developed hip pain. Patient 2 was admitted for workup of possible transient ischemic attack and approximately 2.5 hours after admission complained of hip pain. Radiographs of both patients revealed comminuted intertrochanteric hip fractures. In an elderly, nonambulatory patient who may have fallen prior to evaluation, routine radiographs of the pelvis and hip should be performed followed by plain tomography, computed tomography, bone scan, or magnetic resonance imaging as indicated to rule out occult hip fracture. Even comminuted intertrochanteric hip fractures can present in an occult fashion; therefore, a high index of suspicion must be maintained for these injuries.


Dietary supplementation with monounsaturated and long-chain polyunsaturated fatty acids influences the liver structural recovery and hepatocyte binuclearity in female Wistar rats in experimental cirrhosis induced by thioacetamide.
Oral administration of 300 mg/l thioacetamide (TAA) for 4 months causes hepatic lesions comparable to those described in alcoholic liver cirrhosis in humans and associated protein-energy malnutrition. In this sense, direct supplementation with monounsaturated fatty acids (MUFAs) and/or polyunsaturated fatty acids (PUFAs) might provide an advantage in the correction of the fatty acid deficiency in these patients. PUFAs are essential components of cell membranes maintaining its fluidity and function, important energy sources, and precursors of eicosanoids. Moreover, these fatty acids also modulate gene transcription, mRNA stability, and cellular differentiation. Fifty-four female Wistar rats (Interfauna Ibérica, Barcelona, Spain) weighing 110-120 g were used in this study. The animals were divided into two groups: one group was treated with 300 mg/l TAA dissolved in drinking water during 4 months, and the other group, which served as a control, was given water without TAA. To evaluate the changes induced by the administration of TAA for 4 months, TAA-treated (n = 7) and control animals (n = 5) were killed. Then, the TAA treatment was stopped and the rest of the animals in both TAA and control groups were divided into three experimental groups and three control groups which received for 2 weeks different type of diets. Using the TAA-induced liver cirrhosis model in rats, we analysed the effects of dietary supplementation with MUFAs and PUFAs on binuclearity and ultrastructure of hepatocytes. After TAA-induced cirrhosis, we analysed whether dietary supplementation with fatty acids may restore the normal percentage of binucleated cells, as well as the ultrastructure, nuclear area, and nuclear/cytoplasm index of hepatocytes. Treatment with TAA causes cirrhosis characterized by the appearance of parenchyma nodules and fibrous septae, as well as qualitative and quantitative alterations in liver and plasma lipids. Our results indicate that dietary MUFAs support hepatocyte recovery regarding its ultrastructural and morphometric values. However, PUFAs-enriched diets (n-3 and n-3 + n-6) do not correct hepatomegaly, fibrosis or lipid accumulation. Thus, dietary PUFAs do not enhance hepatocyte recovery from morphological and ultrastructural alterations. In our experimental model of cirrhosis, dietary supplementation with a high proportion of long-chain PUFAs (n-3 or n-6) negatively influences liver recovery. This negative effect was likely due to the increased susceptibility of cell membranes to lipid peroxidation, together with an alteration in lipid metabolism.


Luteinizing hormone-releasing hormone gene expression differs in young and middle-aged females on the day of a steroid-induced LH surge.
LHRH mRNA levels were examined in young and middle-aged female rats at 4 times (10:00 h, 14:00 h, 18:00 h and 20:00 h) on the day of a steroid-induced LH surge by in situ hybridization with a digoxigenin-labeled riboprobe. Young, but not middle-aged females, exhibited dynamic temporal changes in the number of LHRH mRNA positive neurons detected in the organum vasculosum of the lamina terminalis-preoptic area (OVLT-POA) continuum. Specifically, fewer LHRH mRNA positive neurons were detected at 18:00 h compared with the number detected at 14:00 h and 20:00 h (P < 0.01) in the OVLT-POA of young females. All LHRH mRNA positive neurons present in 4 anatomically matched sections through the rostral POA of young and middle-aged animals were digitized for detailed computer-assisted analysis of the hybridization reaction product. The mean hybridization area (P < 0.00025) and integrated optical density per cell (P < 0.006) were reduced in middle-aged compared to young females consistent with a relative age-related decline in LHRH mRNA levels. Moreover, an age-related reduction in cellular and/or regional hybridization area was noted at each of the time points examined (P < 0.05-P < 0.001). These data confirm earlier reports of dynamic changes in LHRH mRNA levels on the day of an LH surge. Furthermore, they support a role for age-related alterations in LHRH gene expression in the disruption of regular estrous cyclicity in middle-aged females.


Surgical excision of intracardiac myxomas: a 20-year follow-up.
Since November 1968, 54 patients have undergone excision of an intracardiac myxoma, which was located in the left atrium in 46 (85%), in the right atrium in 6 (11%), and in the right ventricle in 2 (4%). There were 35 female and 19 male patients with a mean age of 48 +/- 14 years (range, 7 to 68 years). Four patients were asymptomatic; the others were seen mostly with exertional dyspnea, palpitation, signs of systemic illness, and syncopal episodes. Before operation, embolic episodes occurred in 13 patients with a left atrial myxoma. There were two early (3.7%) and two late deaths (3.8). Actuarial survival at 20 years is 91% +/- 4%, and most of the current survivors are asymptomatic at a mean follow-up of 6.5 +/- 5 years (range, 0.2 year to 20 years). Noninvasive reevaluation was performed with echocardiographic studies in 44 patients and 24-hour electrocardiographic monitoring in 34. No instances of tumor recurrence were observed, and there was a low incidence of major supraventricular arrhythmias late postoperatively. We conclude that excision of intracardiac myxomas is curative and long-term survival is excellent. The transseptal approach provides adequate exposure and allows complete removal of the tumor regardless of its location.


Synthesis, characterization, and evaluation of novel cell-penetrating peptides based on TD-34.
In this study, six N-1, N-2, or N-11 derivatives of TD-34 (a cationic cyclic cell-penetrating peptide [CPP], ACSSKKSKHCG) were designed and synthesized including both linear peptides and cyclic peptides, such as DL-1 (KWSSKKSKHCG), DLCC-1 (cyclopeptide, KWSSKKSKHCG), DL-2 (KWSSKKSKHCG-NH2 ), DLCC-2 (cyclopeptide, KWSSKKSKHCG-NH2 ), DL-3 (RWSSKKSKHCG), and DLCC-3 (cyclopeptide, RWSSKKSKHCG). The cyclic peptides were synthesized by disulfide bound linkages formed by N-2 and N-10 cysteine. In vitro penetration experiment was conducted to investigate the transdermal enhancement ability of these derivatives, using triptolide (TP) as model drug. The results display that at the presence of DLCC-2, the accumulative penetration amount of TP increased 1.71-fold (P < .05) within 12 hours, displaying better transdermal enhancing ability than TD-34. Meanwhile, DL-3 and DLCC-3 slightly decreased the transdermal delivery of TP, and the presence of DL-1 and DLCC-1 shows no obvious effect. In order to clarify the factors on the transdermal ability of peptides, the solubility of TP in phosphate buffer saline (PBS) at the presence of different peptides and the mechanism of transdermal delivery of CPPs was investigated. The result shows that most of these peptides have no significant effect on the solubility of TP except DLCC-3 (the solubility of TP slightly increased). And in order to investigate transdermal absorption route of DLCC-2, polyarginine linked to rhodamine b (Rh b) derivative is used. The result proved that the transdermal route of polyarginine is via hair follicle, which may change the transdermal route of its cargo molecule (TP). Our group previously proved that polyarginine and TD-34 have similar transdermal enhancing mechanism (changing the transdermal route of their cargo molecule); it is reasonably speculated that the transdermal route of DLCC-2 is the same as polyarginine and then changes the transdermal absorption route of TP. Furthermore, such results have laid a solid foundation for further investigation of CPPs and paved a way for both designing and synthesizing of new drug delivery system for therapy molecules.


The effect of spatial resolution on deep learning classification of lung cancer histopathology.
The microscopic analysis of biopsied lung nodules represents the gold-standard for definitive diagnosis of lung cancer. Deep learning has achieved pathologist-level classification of non-small cell lung cancer histopathology images at high resolutions (0.5-2 µm/px), and recent studies have revealed tomography-histology relationships at lower spatial resolutions. Thus, we tested whether patterns for histological classification of lung cancer could be detected at spatial resolutions such as those offered by ultra-high-resolution CT. We investigated the performance of a deep convolutional neural network (inception-v3) to classify lung histopathology images at lower spatial resolutions than that of typical pathology. Models were trained on 2167 histopathology slides from The Cancer Genome Atlas to differentiate between lung cancer tissues (adenocarcinoma (LUAD) and squamous-cell carcinoma (LUSC)), and normal dense tissue. Slides were accessed at 2.5 × magnification (4 µm/px) and reduced resolutions of 8, 16, 32, 64, and 128 µm/px were simulated by applying digital low-pass filters. The classifier achieved area under the curve ≥0.95 for all classes at spatial resolutions of 4-16 µm/px, and area under the curve ≥0.95 for differentiating normal tissue from the two cancer types at 128 µm/px. Features for tissue classification by deep learning exist at spatial resolutions below what is typically viewed by pathologists. We demonstrated that a deep convolutional network could differentiate normal and cancerous lung tissue at spatial resolutions as low as 128 µm/px and LUAD, LUSC, and normal tissue as low as 16 µm/px. Our data, and results of tomography-histology studies, indicate that these patterns should also be detectable within tomographic data at these resolutions.


Prolonged exposure therapy for PTSD in individuals with opioid use disorder: A randomized pilot study.
Nearly all individuals with opioid use disorder (OUD) report lifetime trauma exposure and one-third meet diagnostic criteria for posttraumatic stress disorder (PTSD). Although prolonged exposure (PE) therapy is a first-line treatment for PTSD, little is known about the effects of PE in individuals with co-occurring OUD. Furthermore, its efficacy is commonly undermined by poor therapy attendance. This pilot study evaluated the feasibility and initial efficacy of a novel PE protocol for improving PE attendance and PTSD symptoms among buprenorphine- or methadone-maintained adults with PTSD. Thirty participants with co-occurring PTSD and OUD were randomized to receive either: (a) continued medications for OUD (MOUD) treatment as usual (TAU), (b) Prolonged Exposure therapy (PE), or (c) PE with financial incentives delivered contingent upon PE session attendance (PE+). Primary outcomes included PE session attendance, PTSD symptom severity, and use of opioids other than prescribed MOUD. PE+ participants attended significantly more therapy sessions vs. PE (87% vs. 35%; p <.0001). PTSD symptom reductions were also significantly greater in the PE+ vs. TAU group (p =.046). Participants in the two PE conditions submitted significantly fewer urine samples that tested positive for opioids than TAU participants (0% vs. 22%; p =.007). These findings provide preliminary support for the efficacy of PE+ for improving PE attendance and PTSD symptoms without prompting opioid relapse in individuals with co-occurring PTSD and OUD. These promising results justify a larger scale randomized clinical trial to more rigorously evaluate this novel treatment approach.


Real-World Treatment Patterns and Clinical Outcomes in Patients With Stage III NSCLC: Results of KINDLE, a Multicountry Observational Study.
Stage III NSCLC is a heterogeneous disease requiring a multimodal management approach. We conducted a real-world, global study to characterize patients, treatment patterns, and their associated clinical outcomes for stage III NSCLC. KINDLE was a retrospective study in patients with stage III NSCLC (American Joint Committee on Cancer, seventh edition) diagnosed between January 2013 and December 2017, with at least 9 months of documented follow-up since index diagnosis. In addition to descriptive statistics, Kaplan-Meier methodology evaluated survival estimates; two-sided 95% confidence interval was computed. Cox proportional hazards model was used for univariate and multivariate analyses. A total of 3151 patients from more than 100 centers across 19 countries from Asia, Middle East, Africa, and Latin America were enrolled. Median age was 63.0 years (range: 21.0-92.0); 76.5% were males, 69.2% had a smoking history, 53.7% had adenocarcinoma, and 21.4% underwent curative resection. Of greater than 25 treatment regimens, concurrent chemoradiotherapy was the most common (29.4%). The overall median progression-free survival (95% confidence interval) and median overall survival (mOS) were 12.5 months (12.06-13.14) and 34.9 months (32.00-38.01), respectively. Significant associations (p < 0.05) were observed for median progression-free survival and mOS with respect to sex, region, smoking status, stage, histology, and Eastern Cooperative Oncology Group status. In univariate and multivariate analyses, younger age, stage IIIA, better Eastern Cooperative Oncology Group status, concurrent chemoradiotherapy, and surgery as initial therapy predicted better mOS. KINDLE reveals the diversity in treatment practices and outcomes in stage III NSCLC in a real-world setting in the preimmuno-oncology era. There is a high unmet medical need, necessitating novel approaches to optimize outcomes.


Fast repair of deoxythymidine radical anions by two polyphenols: rutin and quercetin.
The effects of rutin and quercetin on the repair of the deoxythemindine radical anion (dT*) were studied using the technique of pulse radiolysis. The radical anion of dT was formed by the reaction of hydrated electron with dT. After pulse irradiation of nitrogen-saturated aqueous solutions containing dT, 0.2M t-BuOH and either rutin or quercetin, the initially formed dT*(-), detected spectrophotometrically, rapidly decayed with the concurrent formation of the radical anion of rutin or quercetin. The results indicated that dT*(-) can be rapidly repaired by rutin or quercetin. The rate constants of the repair reactions were determined to be 3.1 and 4.1 x 10(9)M(-1)s(-1) for rutin and quercetin, respectively. With substitution by glycosyl groups at C(3)-OH bond being neighbor to C(4) keto group, which is the active site for electron transfer, rutin has a lower repair reaction rate constant toward dT*(-) than quercetin. Together with findings from our previous studies, the present results demonstrated that nonenzymatic fast repair may be a universal form of repair involving phenolic antioxidants.