Distribution and abundance of insertion sequences among natural isolates of Escherichia coli.
A reference collection of 71 natural isolates of Escherichia coli (the ECOR collection) has been studied with respect to the distribution and abundance of transposable insertion sequences using DNA hybridization. The data include 1173 occurrences of six unrelated insertion sequences (IS1, IS2, IS3, IS4, IS5 and IS30). The number of insertion elements per strain, and the sizes of DNA restriction fragments containing them, is highly variable and can be used to discriminate even among closely related strains. The occurrence and abundance of pairs of unrelated insertion sequences are apparently statistically independent, but significant correlations result from stratifications in the reference collection. However, there is a highly significant positive association among the insertion sequences considered in the aggregate. Nine branching process models, which differ in assumptions regarding the regulation of transposition and the effect of copy number on fitness, have been evaluated with regard to their fit of the observed distributions. No single model fits all copy number distributions. The best models incorporate no regulation of transposition and a moderate to strong decrease in fitness with increasing copy number for IS1 and IS5, strong regulation of transposition and a negligible to weak decrease in fitness with increasing copy number for IS3, and less than strong regulation of transposition for IS2, IS4 and IS30.


Emerging role of extracellular vesicles in musculoskeletal diseases.
Research into the biology of extracellular vesicles (EVs), including exosomes and microvesicles, has expanded significantly with advances in EV isolation techniques, a better understanding of the surface markers that characterize exosomes and microvesicles, and greater information derived from -omics approaches on the proteins, lipids, mRNAs, and microRNAs (miRNAs) transported by EVs. We have recently discovered a role for exosome-derived miRNAs in age-related bone loss and osteoarthritis, two conditions that impose a significant public health burden on the aging global population. Previous work has also revealed multiple roles for EVs and their miRNAs in muscle regeneration and congenital myopathies. Thus, EVs appear to be involved in a number of degenerative conditions that impact the musculoskeletal system, indicating that the musculoskeletal system is an excellent model for investigating the role of EVs in tissue maintenance and repair. This review highlights the role of EVs in bone, skeletal muscle, and joint health, including both normal tissue metabolism as well as tissue injury repair and regeneration. A consistent theme that emerges from study of musculoskeletal EVs is that various miRNAs appear to mediate a number of key pathological processes. These findings point to a potential therapeutic opportunity to target EV-derived miRNAs as a strategy for improving musculoskeletal function.


Effect of Whole-Body-Vibration Training on Trunk-Muscle Strength and Physical Performance in Healthy Adults: Preliminary Results of a Randomized Controlled Trial.
Whole-body-vibration (WBV) stimulus equipment has been used as a new training method for health promotion. Its use in the clinic has expanded to the field of sports and rehabilitation for disabled patients. WBV training is rapidly gaining popularity in health and fitness centers as an alternative method for improving muscle performance. Acute positive effects of WBV have been shown on lower-extremity muscle power and vertical-jump ability; however, there have not been any studies focusing on the long-term effects of WBV for trunk muscle and dynamic balance. To investigate the effects of an 8-wk program of WBV in combination with trunk-muscle training on muscle performance in healthy, untrained adults. Laboratory-based, repeated-measures study. University laboratory. 20 healthy university men. Participants were randomly assigned to a WBV or non-WBV group. The WBV group performed a trunk-muscle-training program in combination with WBV; the non-WBV group performed the same muscle-training program without WBV for 8 wk. In the pre- and posttraining period, the participants were evaluated using the Functional Movement Screen (FMS), Y Balance Test (Y-test) (anterior, posteromedial, and posterolateral reach), trunk-muscle isometric strength (flexor, extensor, and flexor:extensor ratio), squat jump, and countermovement jump. The WBV group had greater improvement than the non-WBV group in both trunk-flexor muscle strength (P = .02) and the Y-test (anterior reach) (P = .004) between pre- and posttraining. Adding WBV to a trunk-muscle-strengthening program may improve trunk-flexor isometric strength and anterior reach during the Y-test more than training without WBV. The WBV protocol used in this study had no significant impact on FMS scores, squat jumping, countermovement jumping, trunk-extensor isometric strength, or trunk flexor:extensor ratio.


[Therapeutic Aggressiveness and Liquid Oncology].
Aggressiveness criteria proposed in the scientific literature a decade ago provide a quality judgment and are a reference in the care of patients with advanced cancer, but their use is not generalized in the evaluation of Oncology Services. In this paper we analyze the therapeutic aggressiveness, according to standard criteria, in 1.001 patients with advanced cancer who died in our Institution between 2010 and 2013. The results seem to show that aggressiveness at the end of life is present more frequently than experts recommend. About 25% of patients fulfill at least one criterion of aggressiveness. This result could be explained by a liquid Oncology which does not prioritize the patient as a moral subject in the clinical appointment. Medical care is oriented to necessities and must be articulated in a model focused on dignity and communication. Its implementation through Advanced Care Planning, consideration of patient's values and preferences, and Limitation of therapeutic effort are ways to reduce aggressiveness and improve clinical practice at the end of life. We need to encourage synergic and proactive attitudes, adding the best of cancer research with the best clinical care for the benefit of human being, moral subject and main goal of Medicine.


Compression? Yes, but for low or high frequencies, for low or high intensities, and with what response times?
Several rationales for using compression in hearing aids are outlined. These rationales comprise discomfort avoidance, loudness normalization, noise reduction, short term signal dynamic range reduction, empirically determined compression, and long-term signal dynamic range reduction. The compression systems needed to implement each of these differ greatly, and these differences can be viewed as differences in the frequency range undergoing most compression, the intensity range undergoing most compression, and the speed at which the compressor(s) operate. A classification system along these lines is introduced and examples of currently available hearing aids falling into each category are given. The effects of each type of compression on speech intelligibility is investigated via a review of published research. The results of this indicate that, for speech in quiet at a comfortable level, no compression scheme yet tested offers better intelligibility than individually selected linear amplification. If input level is then decreased and the aid wearer is prevented from adjusting the volume control, many types of compression provide intelligibility superior to that available from linear amplification. In broadband noise, only one system, containing wideband compression followed by fast acting high-frequency compression, has so far been shown to provide significant intelligibility advantages.


Structural and functional insight into serine hydroxymethyltransferase from Helicobacter pylori.
Serine hydroxymethyltransferase (SHMT), encoded by the glyA gene, is a ubiquitous pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the formation of glycine from serine. The thereby generated 5,10-methylene tetrahydrofolate (MTHF) is a major source of cellular one-carbon units and a key intermediate in thymidylate biosynthesis. While in virtually all eukaryotic and many bacterial systems thymidylate synthase ThyA, SHMT and dihydrofolate reductase (DHFR) are part of the thymidylate/folate cycle, the situation is different in organisms using flavin-dependent thymidylate synthase ThyX. Here the distinct catalytic reaction directly produces tetrahydrofolate (THF) and consequently in most ThyX-containing organisms, DHFR is absent. While the resulting influence on the folate metabolism of ThyX-containing bacteria is not fully understood, the presence of ThyX may provide growth benefits under conditions where the level of reduced folate derivatives is compromised. Interestingly, the third key enzyme implicated in generation of MTHF, serine hydroxymethyltransferase (SHMT), has a universal phylogenetic distribution, but remains understudied in ThyX-containg bacteria. To obtain functional insight into these ThyX-dependent thymidylate/folate cycles, we characterized the predicted SHMT from the ThyX-containing bacterium Helicobacter pylori. Serine hydroxymethyltransferase activity was confirmed by functional genetic complementation of a glyA-inactivated E. coli strain. A H. pylori ΔglyA strain was obtained, but exhibited markedly slowed growth and had lost the virulence factor CagA. Biochemical and spectroscopic evidence indicated formation of a characteristic enzyme-PLP-glycine-folate complex and revealed unexpectedly weak binding affinity of PLP. The three-dimensional structure of the H. pylori SHMT apoprotein was determined at 2.8Ǻ resolution, suggesting a structural basis for the low affinity of the enzyme for its cofactor. Stabilization of the proposed inactive configuration using small molecules has potential to provide a specific way for inhibiting HpSHMT.


Regional non-uniformity of left ventricular wall movement in man.
In order to assess the possible importance of regional non-uniformity of left ventricular function, angiograms of 42 normal subjects and 105 patients with coronary artery disease were digitised frame by frame. Regional curvature around the cavity was assessed, only positive curvature being compatible with ellipsoidal geometry. In normal subjects, positive curvature of the anterior wall was shown by all, but on the inferior wall was present in only 12 (28%) at end-diastole and five (12%) at end-systole. In patients with ischaemic heart disease, anterior wall curvature was again positive in all but four with apical aneurysm, but positive curvature of the inferior wall was present more frequently than normal, 47 (42%) at end-diastole and 39 (36%) at end-systole. In these patients, positive curvature at end-diastole was associated with reduced wall movement during ejection. Though the pattern of coronary artery involvement was random, there were conspicuous regional differences in the distribution of abnormal wall movement during isovolumic relaxation. Outward movement was found only on the anterior wall. Abnormal inward movement was five times as frequent on the inferior wall as on the anterior. An ellipsoidal cavity outline is not therefore characteristic of the normal left ventricle and, when present, this configuration is likely to be associated with a reduced amplitude of inferior wall movement. Regional differences of both structure and function can thus be shown in normal and abnormal hearts. They may arise from variation in local fibre architecture. Their presence must be taken into account in interpreting abnormalities of left ventricular function.


The nucleotide sequence of tobacco rattle virus RNA-2 (CAM strain).
The nucleotide sequence of the smaller genomic strand (RNA-2) of the bipartite tobacco rattle virus (CAM strain) has been determined. RNA-2 is capped at the 5' terminus and contains 1799 nucleotide residues. There is a single 223 codon long open reading frame extending from nucleotide 574 to 1242 which designates a protein of Mr 23,654. The derived amino acid composition, in percent, matches that previously determined for the virus capsid protein. The long open reading frame is flanked by 5' and 3' untranslated regions of 573 and 554 nucleotides, respectively. The 5' leader sequence contains two different sets of direct repeats, one of 119 nucleotides and the other of 76. It also contains 13 apparently unused AUG codons, four of which lie in the same frame as the capsid protein cistron. The 3' terminal sequence of RNA-2 is identical to that of the larger genomic strand (RNA-1) for 459 nucleotides.


CT-guided cervical selective nerve root block with a dorsal approach.
Cervical transforaminal blocks are frequently performed to treat cervical radicular pain. These blocks are performed mostly under fluoroscopy, but a CT-guided technique has also been described. The aim of this study was to review the results of CT-guided CSNRB by using a dorsal approach, to describe the contrast patterns achieved with this injection technique, and to estimate the degree of specificity and sensitivity. We used a CT-guided technique with a dorsal approach leading to a more extra-than transforaminal but a selective nerve root block as well. Of 53 blocks, we performed 38 for diagnostic and 15 for therapeutic indications. Pain relief was measured hourly on a VAS. The distribution of contrast and the angle of the trajectory of the injection needle were analyzed as well as the degree of pain relief. Contrast was found in the intraforaminal region in 8 (15%) blocks, extraforaminally in 40 (78%) blocks, and intraspinally in 3 (6%) blocks. The mean angle between the needle and the sagittal plane was 26.6° (range, from 1° to 50°). The mean distance between needle tip and nerve root was 4.43 mm (range, 0-20 mm). Twenty-six (68.4%) of the 38 diagnostic blocks led to a decrease in the pain rating of >50%. There were no complications or unintended side effects, apart from occasional local puncture pain. We conclude that CT-guided CSNRBs using a dorsal approach are feasible and that they are sensitive and specific.


Sumoylation of bZIP transcription factor NRL modulates target gene expression during photoreceptor differentiation.
Development of rod photoreceptors in the mammalian retina is critically dependent on the basic motif-leucine zipper transcription factor NRL (neural retina leucine zipper). In the absence of NRL, photoreceptor precursors in mouse retina produce only cones that primarily express S-opsin. Conversely, ectopic expression of NRL in post-mitotic precursors leads to a rod-only retina. To explore the role of signaling molecules in modulating NRL function, we identified putative sites of post-translational modification in the NRL protein by in silico analysis. Here, we demonstrate the sumoylation of NRL in vivo and in vitro, with two small ubiquitin-like modifier (SUMO) molecules attached to the Lys-20 residue. NRL-K20R and NRL-K20R/K24R sumoylation mutants show reduced transcriptional activation of Nr2e3 and rhodopsin promoters (two direct targets of NRL) in reporter assays when compared with wild-type NRL. Consistent with this, in vivo electroporation of the NRL-K20R/K24R mutant into newborn Nrl(-/-) mouse retina leads to reduced Nr2e3 activation and only a partial rescue of the Nrl(-/-) phenotype in contrast to the wild-type NRL that is able to convert cones to rod photoreceptors. Although PIAS3 (protein inhibitor of activated STAT3), an E3-SUMO ligase implicated in photoreceptor differentiation, can be immunoprecipitated with NRL, there appears to be redundancy in E3 ligases, and PIAS3 does not seem to be essential for NRL sumoylation. Our studies suggest an important role of sumoylation in fine-tuning the activity of NRL and thereby incorporating yet another layer of control in gene regulatory networks involved in photoreceptor development and homeostasis.


Risk of Seizure after Naloxone Therapy in Acute Tramadol Poisoning: A Systematic Review with Meta-Analysis.
Many studies have focused on the relationship between naloxone and seizure in tramadol poisoning but the results are in conflict. We performed a meta-analysis study to see whether naloxone prevents or increase the risk of seizure in tramadol poisoning. Bibliographic literature searches were conducted in the ISI Web of Science, Excerpta Medica Database (EMBASE), PubMed, and Cochrane from January 1990 to December 2017 for relevant articles. Pooled data were analyzed by calculating odds ratios (ORs) with 95% confidence intervals (CIs). The outcome includes seizure. To investigate the publication bias, Begg's and Egger's tests were used along with funnel plot as a graphical test. Seven studies met the inclusion criteria. The meta-analysis showed I 2, 27%, (P value, 0.23) indicating no significant heterogeneity. As a result, using the fixed effect, the OR was 1.14 (95% CI = 0.60-2.18, P value, 0.69) which was not significant, means naloxone did not increase the risk of seizure. Naloxone therapy did not increase the risk of seizure significantly in the treatment of acute tramadol poisoning. We suggest considering the risk/benefit when administration naloxone, especially for the seizure risk factors including previous history of seizure, tramadol misuse, and co-ingestion.


Using Microbial Aggregates to Entrap Aqueous Phosphorus.
The increasing use and associated loss of phosphorus to the environment pose risks to aquatic ecosystems. Technology for phosphorus removal based on microbial aggregates is a natural, ecologically widespread, and sustainable reclamation strategy. Two main processes dominate phosphorus removal by microbial aggregates: extra- and intra-cellular entrapment. Extracellular phosphorus entrapment relies on extracellular polymeric substances, while intracellular entrapment uses a wider variety of phosphorus-entrapping mechanisms. In microbial aggregates, microalgae-bacteria interactions, quorum sensing, and acclimation can enhance phosphorus removal. Based on these insights, we propose novel avenues for entrapping phosphorus using ecological and genetic engineering, manipulated interactions, and integrated processes to create phosphorus removal technology mediated by microbial aggregates.


Hydrogen-bonding induced cooperative effect on the energy transfer in helical polynorbornenes appended with porphyrin-containing amidic alanine linkers.
Polynorbornenes appended with porphyrins containing a range of different linkers are synthesized. The use of bisamidic chiral alanine linkers between the pending porphyrins and the polymeric backbone has been shown to bring the adjacent porphyrin chromophores to more suitable orientation for exciton coupling owing to hydrogen bonding between the adjacent linkers. The hydrogen bonding between the adjacent pendants in these polymers may induce a cooperative effect and therefore render single-handed helical structures for these polymers. Such a cooperative effect is reflected in the enhancement of FRET efficiencies between zinc-porphyrin and free base porphyrin in random copolymers.


CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants.
To expand the recent description of a new neurodevelopmental syndrome related to alterations in CDK19. Individuals were identified through international collaboration. Functional studies included autophosphorylation assays for CDK19 Gly28Arg and Tyr32His variants and in vivo zebrafish assays of the CDK19G28R and CDK19Y32H. We describe 11 unrelated individuals (age range: 9 months to 14 years) with de novo missense variants mapped to the kinase domain of CDK19, including two recurrent changes at residues Tyr32 and Gly28. In vitro autophosphorylation and substrate phosphorylation assays revealed that kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein. Injection of CDK19 messenger RNA (mRNA) with either the Tyr32His or the Gly28Arg variants using in vivo zebrafish model significantly increased fraction of embryos with morphological abnormalities. Overall, the phenotype of the now 14 individuals with CDK19-related disorder includes universal developmental delay and facial dysmorphism, hypotonia (79%), seizures (64%), ophthalmologic anomalies (64%), and autism/autistic traits (56%). CDK19 de novo missense variants are responsible for a novel neurodevelopmental disorder. Both kinase assay and zebrafish experiments showed that the pathogenetic mechanism may be more diverse than previously thought.


[Cellular restriction factors that inhibit human immunodeficiency virus replication: new strategies in antiretroviral therapy].
Human immunodeficiency virus requires receptors and cellular factors in target cells in order to complete a successful replication. Conversely, host cells express different proteins like TRIM5a, Tetherin BST-2, as well as cytidine deaminase proteins (APOBEC3) to suppress viral replication. These proteins, known as cellular restriction factors, provide an initial defense against infection as components of the innate immune response. The best characterized restriction factor is the cytidine deaminase APOBEC3G that has been shown to have an important role in HIV pathogenesis. Here, we review the current knowledge of host restriction factors, focusing on APOBEC3G, and possible therapeutic strategies against HIV infection.


The Peculiar Role of the Au3 Unit in Aum Clusters: σ-Aromaticity of the Au5Zn+ Ion.
The stability of small Aum (m = 4-7) clusters is investigated by analyzing their energetic, geometric, vibrational, magnetic, and electron density properties. Gold clusters can be constructed from stable cyclic 3-center-2-electron (3c-2e) Au3+ units (3-rings) with σ-aromaticity. The stabilization requires a flow of negative charge from internal 3-rings with electron-deficient bonding to peripheral 3-ring units with stronger Au-Au bonds. The valence-isoelectronic clusters Au6 and Au5Zn+ have similar electronic properties: Au5Zn+ is a strongly σ-aromatic molecule. An understanding of the structure of Aum clusters is obtained by deriving a Clar's Rule equivalent for polycyclic gold clusters: The structure with the larger number of rings with dominant 3c-2e character and a smaller degree of 3c-3e character occupies the global minimum of the Aum potential energy surface.


Connect to Protect Researcher-Community Partnerships: Assessing Change in Successful Collaboration Factors over Time.
Fifteen research sites within the Adolescent Medicine Trials Network for HIV/AIDS Interventions launched Connect to Protect community coalitions in urban areas across the United States and in Puerto Rico. Each coalition has the same overarching goal: Reducing local youth HIV rates by changing community structural elements such as programs, policies, and practices. These types of transformations can take significant amounts of time to achieve; thus, ongoing successful collaboration among coalition members is critical for success. As a first step toward building their coalitions, staff from each research site invited an initial group of community partners to take part in Connect to Protect activities. In this paper, we focus on these researcher-community partnerships and assess change in collaboration factors over the first year. Respondents completed the Wilder Collaboration Factors Inventory at five time points, approximately once every two to three months. Results across all fifteen coalitions show significant and positive shifts in ratings of process/structure (p<.05). This suggests that during the first year they worked together, Connect to Protect researcher-community partners strengthened their group infrastructures and operating procedures. The findings shed light on how collaboration factors evolve during coalition formation and highlight the need for future research to examine change throughout subsequent coalition phases.


Nebivolol reduces central blood pressure in stage I hypertensive patients: experimental single cohort study.
Assessment of central blood pressure (BP) has grown substantially over recent years because evidence has shown that central BP is more relevant to cardiovascular outcomes than peripheral BP. Thus, different classes of antihypertensive drugs have different effects on central BP despite similar reductions in brachial BP. The aim of this study was to investigate the effect of nebivolol, a β-blocker with vasodilator properties, on the biochemical and hemodynamic parameters of hypertensive patients. Experimental single cohort study conducted in the outpatient clinic of a university hospital. Twenty-six patients were recruited. All of them underwent biochemical and hemodynamic evaluation (BP, heart rate (HR), central BP and augmentation index) before and after 3 months of using nebivolol. 88.5% of the patients were male; their mean age was 49.7 ± 9.3 years and most of them were overweight (29.6 ± 3.1 kg/m2) with large abdominal waist (102.1 ± 7.2 cm). There were significant decreases in peripheral systolic BP (P = 0.0020), diastolic BP (P = 0.0049), HR (P < 0.0001) and central BP (129.9 ± 12.3 versus 122.3 ± 10.3 mmHg; P = 0.0083) after treatment, in comparison with the baseline values. There was no statistical difference in the augmentation index or in the biochemical parameters, from before to after the treatment. Nebivolol use seems to be associated with significant reduction of central BP in stage I hypertensive patients, in addition to reductions in brachial systolic and diastolic BP.


Unusual relationship between skin lesions and esophageal cancer: a case report and review of literature.
Esophageal cancer is a rare disease. In Spain, this tumor is the third most common gastrointestinal malignancy after colorectal and gastric cancer. Esophageal adenocarcinoma metastasizes to the skin with an incidence of 1 %, generally located in the neck, head and abdomen. It usually occurs in the overlying skin of the primary tumor, but may also appear in a distant site, the scalp being the most common place. Although the pathogenesis of esophageal adenocarcinoma is not well known, the existence of genetic alterations, such as the suppressor gene, has been proved and the involvement of oncogene c-erbB-2 amplified. Cytokeratin 20 and 7 are expressed in esophageal adenocarcinoma. Typically, cutaneous metastases from internal malignancy present as firm asymptomatic nodules. These nodules usually occur in multiple arrays on the skin adjacent to the primary tumor; however, they can occasionally become painful spontaneously. The main diagnostic test of esophageal cancer is the upper endoscopy, along with histopathology for confirmation of the tumor. The developments in surgery and the discovery of new cytotoxic agents have considerably decreased the locoregional recurrence. To date, the combination of these treatment modalities for advanced adenocarcinoma revealed that the recurrences mainly occur from hematic spread. Excision of the skin lesions produces pain palliation. In patients diagnosed with esophageal cancer who have responded satisfactorily to treatment with chemotherapy, radiation and surgery while having a long history of remission, and dermatology outpatient visits by the appearance of skin lesions, should make us think among the different differential diagnoses, the possibility of cutaneous metastases.


[Management solutions using digital technologies in the Healthy Moscow pavilions].
The digital transformation of healthcare is an integral part of the priorities in modern healthcare. A striking example of the practical implementation of compliance with the basic principles of digital healthcare is the Healthy Moscow project, which has been implemented since 2021, which has become a real breakthrough in Russia in ensuring accessibility and convenience in providing medical care to the population. The aim of the project is the early prevention of chronic non-communicable diseases, the formation of a healthy lifestyle and the improvement of the well-being of Moscow residents, as well as the development of a conscious attitude to taking care of their health. Pavilions in the park areas of Moscow are an integral part of the modern medical infrastructure, providing convenient conditions for obtaining medical advice and information. The article provides information on the types of digital technologies and basic equipment that the pavilions (large and small) are equipped with as part of the Healthy Moscow project, it is shown that the introduction of digital healthcare technologies is one of the key tasks of the national strategy of Russia, which contributes significantly contribution to the successful implementation of the Healthy Moscow project.


Obstetric interventions during labor and childbirth in Brazilian low-risk women.
This study evaluated the use of best practices (eating, movement, use of nonpharmacological methods for pain relief and partograph) and obstetric interventions in labor and delivery among low-risk women. Data from the hospital-based survey Birth in Brazil conducted between 2011 and 2012 was used. Best practices during labor occurred in less than 50% of women and prevalence of the use of these practices was lower in the North, Northeast and Central West Regions. The rate of use of oxytocin drips and amniotomy was 40%, and was higher among women admitted to public hospitals and in women with a low level of education. The uterine fundal pressure, episiotomy and lithotomy were used in 37%, 56% and 92% of women, respectively. Caesarean section rates were lower in women using the public health system, nonwhites, women with a low level of education and multiparous women. To improve the health of mothers and newborns and promote quality of life, a change of approach to labor and childbirth that focuses on evidence-based care is required in both the public and private health sectors.


Incompatible mechanical properties in compact bone.
The covariation of a number of mechanical of properties, and some physical characteristics, of compact bones from a wide range of bones were examined. Young's modulus was well predicted by a combination of mineral content and porosity. Increasing Young's modulus was associated with: increasing stress at yield, increasing bending strength, and a somewhat higher resilience, tensile strength and fatigue strength. Contrarily, in the post-yield region a higher Young's modulus (and more clearly, a higher mineral content) was associated with: a reduced work to fracture in tension, a reduced impact strength and an increased notch sensitivity in impact. Increasing porosity is associated with deleterious effects in the pre-yield region, but has little effect in the post-yield region. Bone, like many other materials, is unable to have good qualities in both the pre- and post-yield regions. Since an increase in mineral or Young's modulus is more potent, that is deleterious, in the post-yield than it is advantageous in the pre-yield region, it is likely that mineral content will be selected to be slightly lower than would be the case if it were equally potent in both regions. As is usual in biology, different adaptive extremes are incompatible.


JunB protects β-cells from lipotoxicity via the XBP1-AKT pathway.
Diets rich in saturated fats may contribute to the loss of pancreatic β-cells in type 2 diabetes. JunB, a member of the activating protein 1 (AP-1) transcription factor family, promotes β-cell survival and mediates part of the beneficial effects of GLP-1 agonists. In this study we interrogated the molecular mechanisms involved in JunB-mediated β-cell protection from lipotoxicity. The saturated fatty acid palmitate decreased JunB expression, and this loss may contribute to β-cell apoptosis, as overexpression of JunB protected cells from lipotoxicity. Array analysis of JunB-deficient β-cells identified a gene expression signature of a downregulated endoplasmic reticulum (ER) stress response and inhibited AKT signaling. JunB stimulates XBP1 expression via the transcription factor c/EBPδ during ER stress, and forced expression of XBP1s rescued the viability of JunB-deficient cells, constituting an important antiapoptotic mechanism. JunB silencing inhibited AKT activation and activated the proapoptotic Bcl-2 protein BAD via its dephosphorylation. BAD knockdown reversed lipotoxic β-cell death potentiated by JunB siRNA. Interestingly, XBP1s links JunB and AKT signaling as XBP1 knockdown also reduced AKT phosphorylation. GLP-1 agonists induced cAMP-dependent AKT phosphorylation leading to β-cell protection against palmitate-induced apoptosis. JunB and XBP1 knockdown or IRE1 inhibition decreased AKT activation by cAMP, leading to β-cell apoptosis. In conclusion, JunB modulates the β-cell ER stress response and AKT signaling via the induction of XBP1s. The activation of the JunB gene network and the crosstalk between the ER stress and AKT pathway constitute a crucial defense mechanism by which GLP-1 agonists protect against lipotoxic β-cell death. These findings elucidate novel β-cell-protective signal transduction in type 2 diabetes.


Monotypic Plasma Cell Proliferation of Uncertain Clinical Significance Mimicking Interstitial Cystitis: An Early Lesion of MALT Lymphoma?
We prospectively studied our institutional experience of bladder extranodal marginal zone (mucosa-associated lymphoid tissue [MALT]) lymphoma including bladder biopsies in which the possibility of MALT lymphoma was considered. We identified a subset of cases primary to the urinary bladder, presenting with prominent plasma cell infiltrates and symptoms mimicking bladder pain syndrome/interstitial cystitis. These proliferations were designated for this study as "monotypic plasma cell proliferation of uncertain clinical significance" (MPCP-US), as the features were insufficient for diagnosis of MALT lymphoma. We identified 33 patients, consisting of 22 cases of MPCP-US (6 of which were associated with amyloid deposition) and 11 cases of MALT lymphoma. MPCP-US was more prevalent in men (73%), a mass lesion was not identified at cystoscopy, and only 1 case had an accompanying urinary tract infection (4.5%). Histologically, MPCP-US presented as monotypic plasma cells arranged in a superficial band-like distribution in the lamina propria, predominantly kappa restricted (68%) and IgA+ or IgM+ (64% and 23%, respectively) and without a histologic mass of atypical B cells or plasma cells, not diagnostic for established MALT lymphoma or plasmacytoma. Secondary involvement of the bladder by other lymphoproliferative disorders was excluded and there was no evidence of progressive disease. MALT lymphomas are presented for comparison and our analysis demonstrated that MPCP-US represent a different clinicopathologic entity compared with classic MALT lymphoma. We present the first series of cases of MPCP-US. The recognition of this entity is fundamental to the development of management protocols to relieve intractable symptoms mimicking bladder pain syndrome/interstitial cystitis in these patients.


An enhanced diagnostic system for gear system monitoring.
The detection of the onset of damage in gear systems (e.g., gearboxes)is of great importance to a wide array of industries. In this paper, an enhanced diagnostic (ED) system is developed for real-time gear system condition monitoring. A neurofuzzy (NF) paradigm is adopted for pattern classification of the features from the energy, amplitude, and phase domains. The diagnostic reliability is enhanced by properly integrating predicted future machinery states that are forecast by recurrent NF predictors. An online training technique is proposed to improve the classifier's adaptive capability to accommodate different machinery conditions. The viability of this new monitoring system has been verified by experimental tests under different gear conditions. This proposed ED system has also been applied for real-time condition monitoring in multistage printing machines. The primary application has demonstrated its reliability as an effective monitoring tool for both production quality control and maintenance planning.


The impact of depression and pain catastrophization on initial presentation and treatment outcomes for atraumatic hand conditions.
Prior studies have suggested that patient-rated hand function is impacted by depression and pain catastrophization. We studied the impact that these comorbidities have on treatment outcomes. Two hundred and fifty-six patients presenting to an orthopaedic hand clinic were followed in this prospective cohort investigation. Patients who were prescribed treatment for atraumatic hand/wrist conditions were eligible for inclusion. At enrollment, all patients completed the Center for Epidemiologic Studies Depression (CES-D) scale, the Pain Catastrophizing Scale (PCS), and the Michigan Hand Outcomes Questionnaire (MHQ; scale of 0 to 100, with 100 indicating the best hand performance). One month and three months after treatment, patients again completed the MHQ. Participants' psychological comorbidity status was categorized as either affected (a CES-D score of ≥16, indicating depression, or a PCS score of ≥30, indicating catastrophization) or unaffected (a CES-D score of <16 and a PCS score of <30). Diagnoses and treatments for both the affected and unaffected groups were examined. The effect of time and patient status, and their interaction, on MHQ scores was evaluated by mixed modeling. Fifty patients were categorized as affected and 206 as unaffected. Diagnoses and treatments differed minimally between the two groups. At the time of enrollment, the mean MHQ score of the unaffected group (64.9; 95% confidence interval [CI], 62.5 to 67.3) was significantly higher than that of the affected group (48.1; 95% CI, 43.3 to 53.0). Both groups demonstrated similar significant absolute improvement over baseline at three months after treatment (an increase of 12.5 points [95% CI, 7.5 to 17.4] in the affected group and 12.8 points [95% CI, 10.4 to 15.3] in the unaffected group). Thus, at the time of final follow-up, the rating of hand function by the affected patients (60.6 [95% CI, 55.0 to 66.2]) was still significantly poorer than the rating by the unaffected patients (77.7 [95% CI, 75.0 to 80.5]). Although patients affected by depression and/or pain catastrophization reported worse self-rated hand function at baseline and at the time of follow-up, these patients showed similar absolute improvement in self-rated hand function following treatment compared with patients with unaffected status. Prognostic Level I. See Instructions for Authors for a complete description of levels of evidence.


Long-term effects of radioiodine on thyroid function, size and patient satisfaction in non-toxic diffuse goitre.
The long-term effects of (131)I-therapy in patients with symptomatic non-toxic diffuse goitre were evaluated. In a prospective open study, 34 patients (median age: 40 yrs, range: 27-68 yrs) were enrolled who suffered from a non-toxic goitre absent of nodules on clinical examination and on ultrasonography. Treatment indication was the presence of goitre giving rise to cervical compression and/or cosmetic discomfort. The median (131)I activity was 600 MBq (200-600 MBq) administered orally on an outpatient basis. The patients were investigated by clinical examination, thyroid ultrasonography and thyroid function tests at regular intervals and for at least 12 months after the (131)I-therapy. Yearly follow-up continued until the end of the study period or if permanent hypothyroidism ensued. The severity of symptoms was evaluated by a Visual Analogue Scale (VAS) (range: 0-10). The median follow-up time was 36 months (12-84). Goitre volume was reduced from 67.9+/-28.5 ml to 43.4+/-18.7 ml (mean+/-S.D.) (P<0.001) 3 months after the (131)I-therapy. After 3 years of follow-up, only 28.1+/-2.0% (mean+/-S.E.) remained of the initial goitre mass (P<0.001). Goitre was no longer present in 76% of the patients at the end of follow-up. An inverse correlation was found 1 year after therapy, but not after 3 years, between the initial goitre size and the percent reduction (r=-0.44, P=0.01). Thirty-six percent had become hypothyroid after three years. Median VAS scores were reduced from an initial 7.0 (cervical compression) and 5.5 (cosmetic discomfort) to 0.0 at the end of follow-up (P<0.001). Our data justify treatment of non-toxic diffuse goitre with (131)I because goitre reduction is pronounced, along with a very high degree of patient satisfaction and few side effects. We suggest that (131)I-therapy can be used as an alternative to L-T(4) suppressive therapy and thyroidectomy in this group of patients.


Hydrogen peroxide-induced renal injury. A protective role for pyruvate in vitro and in vivo.
Hydrogen peroxide (H2O2) contributes to renal cellular injury. alpha-Keto acids nonenzymatically reduce H2O2 to water while undergoing decarboxylation at the 1-carbon (1-C) position. We examined, in vitro and in vivo, the protective role of sodium pyruvate in H2O2-induced renal injury. Pyruvate effectively scavenged H2O2 in vitro, and suppressed H2O2-induced renal lipid peroxidation. Injury to LLC-PK1 cells induced by hydrogen peroxide was attenuated by pyruvate to an extent comparable to that seen with catalase. Studies utilizing [1-14C]pyruvate further demonstrated 1-C decarboxylation concurrent with cytoprotection by pyruvate from H2O2-induced injury. Pyruvate was also protective in vivo. Infusion of pyruvate before and during the intrarenal infusion of H2O2 attenuated H2O2-induced proteinuria. Systemic administration of pyruvate was also protective in the glycerol model of acute renal failure, a model also characterized by increased generation of H2O2. These findings indicate that pyruvate, a ubiquitous alpha-keto acid, scavenges H2O2 and protects renal tissue in vitro and in vivo from H2O2-mediated injury. These data suggest a potential therapeutic role for pyruvate in diseases in which increased generation of H2O2 is incriminated in renal damage.


Typologies of Suicide: A Critical Literature Review.
This review highlights proposed suicide typologies and identifies areas of future research. The current study is an illustrative, rather than exhaustive, qualitative review of theoretical and empirically derived typologies of suicide decedents. Theoretical and empirical typologies of suicide delineate between groups of suicide decedents based on individual, motivational, psychiatric, interpersonal, socio-demographic, and other variables. Certain core themes emerge across theoretical typologies including escape, aggression, intrapsychic pain, and relational concerns. Empirical typologies have identified unique patterns of life stressors, mental health history, health care utilization, and suicide method among suicide decedents. Future research should build on existing typological models of suicide to delineate when, and for whom, particular typologies of suicide may inform targeted prevention efforts. Researchers and clinicians should consider the characteristics and needs of particular high-risk groups when translating typological research into meaningful suicide prevention and intervention.


Whole animal matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry of ticks - Are spectra of Ixodes ricinus nymphs influenced by environmental, spatial, and temporal factors?
In the recent years matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) has become a useful tool to characterize arthropod species and their different stages of development. It was reported for sand flies and mosquitoes at immature stages and also assumed for ticks that geographic location can have a subtle influence on MALDI-TOF mass spectra which allows the discrimination of animals with specific local variations of the MALDI-TOF MS phenotype. It is so far uncertain, however, if these mass-spectrometric differences are based on genetic variation or on spectral features which depend on environmental or temporal features. The aim of this study was to analyze the influence of the geographic location, environmental factors and the season of the year on the MALDI-TOF mass spectra of Ixodes (I.) ricinus nymphs and if spectral variation would allow to draw conclusions with respect to the tick's provenience or conditions that influence the tick life cycle. Application of multivariate statistical models on spectra of ticks collected in different seasons and different habitats and locations within Germany showed that the impact of the location seemed to be small while season and habitat seemed to have stronger impact on the MALDI-TOF mass spectra. Possibilities and limitations of MALDI-TOF mass spectra to draw conclusions on the tick life cycle are discussed.


Adding oscillometry to spirometry in guidelines better identifies uncontrolled asthma, future exacerbations, and potential targeted therapy.
The objective of this review is to provide new advances in our understanding of the clinical importance of establishing peripheral airway impairment (PAI) by impulse oscillometry (IOS) and targeted therapy, which could result in better asthma outcomes. Data sources include PubMed and Google search, limited to English language and human disease, with key words IOS and asthma. Key findings include PAI being consistently associated with uncontrolled asthma across ethnicities, using IOS reference equations factoring Hispanic and White reference algorithms. It is noted that PAI is common even in patients considered well-controlled by asthma guidelines. In a large longitudinal analysis (Assessment of Small Airways Involved in Asthma or ATLANTIS study), a composite of R5-R20, AX, and X5 ordinal scores were independently predictive of asthma control and exacerbation in a multivariate analysis, but forced expiratory volume in 1 second was not significantly predictive of morbidities. However, combining forced expiratory volume in 1 second less than 80% with PAI resulted in greater odds of identifying uncontrolled asthma and exacerbations, than either alone. Applying an external validation method in children with asthma offers the clinician the IOS reference equations best fit for their own specific population. Several clinical phenotypes can also identify PAI with high probability, useful when IOS is not available. Poor asthma outcomes for obese patients with asthma are associated with dysanapsis and PAI, not obesity alone. Extrafine inhaled corticosteroids achieve better asthma control and improve peripheral airway function with fewer exacerbations at lower dosages than nonextrafine inhaled corticosteroid aerosols. In conclusion, these data support the benefit of adding IOS to spirometry in future asthma guidelines and suggest the potential benefit from targeted therapy.


Protein washdown as a defense mechanism against myocardial edema.
Myocardial edema occurs in many pathological conditions. We hypothesized that protein washdown at the myocardial microvascular exchange barrier would change the distribution of interstitial proteins from large to small molecules and diminish the effect of washdown on the colloid osmotic pressure (COP) of interstitial fluid and lymph. Dogs were instrumented with coronary sinus balloon-tipped catheters and myocardial lymphatic cannulas to manipulate myocardial lymph flow and to collect lymph. Myocardial venous pressure was elevated by balloon inflation to increase transmicrovascular fluid flux and myocardial lymph flow. COP of lymph was measured directly and was also calculated from protein concentration. Decreases occurred in both protein concentration and COP of lymph. The proportion of lymph protein accounted for by albumin increased significantly, whereas that accounted for by beta-lipoprotein decreased significantly. The change in the calculated plasma-to-lymph COP gradient was significantly greater than the change in the measured COP gradient. We conclude that the change in the distribution of interstitial fluid protein species decreases the effect of protein washdown on interstitial fluid COP and limits its effectiveness as a defense mechanism against myocardial edema formation.


Combining EPR spectroscopy and X-ray crystallography to elucidate the structure and dynamics of conformationally constrained spin labels in T4 lysozyme single crystals.
Electron paramagnetic resonance (EPR) spectroscopy in combination with site-directed spin labeling is used to investigate the structure and dynamics of conformationally constrained spin labels in T4 lysozyme single crystals. Within a single crystal, the oriented ensemble of spin bearing moieties results in a strong angle dependence of the EPR spectra. A quantitative description of the EPR spectra requires the determination of the unit cell orientation with respect to the sample tube and the orientation of the spin bearing moieties within the crystal lattice. Angle dependent EPR spectra were analyzed by line shape simulations using the stochastic Liouville equation approach developed by Freed and co-workers and an effective Hamiltonian approach. The gain in spectral information obtained from the EPR spectra of single crystalline samples taken at different frequencies, namely the X-band and Q-band, allows us to discriminate between motional models describing the spectra of isotropic solutions similarly well. In addition, it is shown that the angle dependent single crystal spectra allow us to identify two spin label rotamers with very similar side chain dynamics. These results demonstrate the utility of single crystal EPR spectroscopy in combination with spectral line shape simulation techniques to extract valuable dynamic information not readily available from the analysis of isotropic systems. In addition, it will be shown that the loss of electron density in high resolution diffraction experiments at room temperature does not allow us to conclude that there is significant structural disorder in the system.


Synthetic androgens as designer supplements.
Anabolic androgenic steroids (AAS) are some of the most common performance enhancing drugs (PED) among society. Despite the broad spectrum of adverse effects and legal consequences, AAS are illicitly marketed and distributed in many countries. To circumvent existing laws, the chemical structure of AAS is modified and these designer steroids are sold as nutritional supplements mainly over the Internet. Several side effects are linked with AAS abuse. Only little is known about the pharmacological effects and metabolism of unapproved steroids due to the absence of clinical studies. The large number of designer steroid findings in dietary supplements and the detection of new compounds combined with legal loopholes for their distribution in many countries show that stricter regulations and better information policy are needed.


3D-bioprinted, phototunable hydrogel models for studying adventitial fibroblast activation in pulmonary arterial hypertension.
Pulmonary arterial hypertension (PAH) is a progressive disease of the lung vasculature, characterized by elevated pulmonary blood pressure, remodeling of the pulmonary arteries, and ultimately right ventricular failure. Therapeutic interventions for PAH are limited in part by the lack ofin vitroscreening platforms that accurately reproduce dynamic arterial wall mechanical properties. Here we present a 3D-bioprinted model of the pulmonary arterial adventitia comprised of a phototunable poly(ethylene glycol) alpha methacrylate (PEG-αMA)-based hydrogel and primary human pulmonary artery adventitia fibroblasts (HPAAFs). This unique biomaterial emulates PAH pathogenesisin vitrothrough a two-step polymerization reaction. First, PEG-αMA macromer was crosslinked off-stoichiometry by 3D bioprinting an acidic bioink solution into a basic gelatin support bath initiating a base-catalyzed thiol-ene reaction with synthetic and biodegradable crosslinkers. Then, matrix stiffening was induced by photoinitiated homopolymerization of unreacted αMA end groups. A design of experiments approach produced a hydrogel platform that exhibited an initial elastic modulus (E) within the range of healthy pulmonary arterial tissue (E= 4.7 ± 0.09 kPa) that was stiffened to the pathologic range of hypertensive tissue (E= 12.8 ± 0.47 kPa) and supported cellular proliferation over time. A higher percentage of HPAAFs cultured in stiffened hydrogels expressed the fibrotic marker alpha-smooth muscle actin than cells in soft hydrogels (88 ± 2% versus 65 ± 4%). Likewise, a greater percentage of HPAAFs were positive for the proliferation marker 5-ethynyl-2'-deoxyuridine (EdU) in stiffened models (66 ± 6%) compared to soft (39 ± 6%). These results demonstrate that 3D-bioprinted, phototunable models of pulmonary artery adventitia are a tool that enable investigation of fibrotic pathogenesisin vitro.


Centralized red muscle in Odontaspis ferox and the prevalence of regional endothermy in sharks.
The order Lamniformes contains charismatic species such as the white shark Carcharodon carcharias and extinct megatooth shark Otodus megalodon, and is of particular interest given their influence on marine ecosystems, and because some members exhibit regional endothermy. However, there remains significant debate surrounding the prevalence and evolutionary origin of regional endothermy in the order, and therefore the development of phenomena such as gigantism and filter-feeding in sharks generally. Here we show a basal lamniform shark, the smalltooth sand tiger shark Odontaspis ferox, has centralized skeletal red muscle and a thick compact-walled ventricle; anatomical features generally consistent with regionally endothermy. This result, together with the recent discovery of probable red muscle endothermy in filter feeding basking sharks Cetorhinus maximus, suggests that this thermophysiology is more prevalent in the Lamniformes than previously thought, which in turn has implications for understanding the evolution of regional endothermy, gigantism, and extinction risk of warm-bodied shark species both past and present.


Enhancement of Localization Systems in NLOS Urban Scenario with Multipath Ray Tracing Fingerprints and Machine Learning.
A hybrid technique is proposed to enhance the localization performance of a time difference of arrival (TDOA) deployed in non-line-of-sight (NLOS) suburban scenario. The idea was to use Machine Learning framework on the dataset, produced by the ray tracing simulation, and the Channel Impulse Response estimation from the real signal received by each sensor. Conventional localization techniques mitigate errors trying to avoid NLOS measurements in processing emitter position, while the proposed method uses the multipath fingerprint information produced by ray tracing (RT) simulation together with calibration emitters to refine a Machine Learning engine, which gives an extra layer of information to improve the emitter position estimation. The ray-tracing fingerprints perform the target localization embedding all the reflection and diffraction in the propagation scenario. A validation campaign was performed and showed the feasibility of the proposed method, provided that the buildings can be appropriately included in the scenario description.


Effects of an Individualized mHealth-Based Intervention on Health Behavior Change and Cardiovascular Risk Among People With Metabolic Syndrome Based on the Behavior Change Wheel: Quasi-Experimental Study.
Metabolic syndrome (MetS) is a common public health challenge. Health-promoting behaviors such as diet and physical activity are central to preventing and controlling MetS. However, the adoption of diet and physical activity behaviors has always been challenging. An individualized mobile health (mHealth)-based intervention using the Behavior Change Wheel is promising in promoting health behavior change and reducing atherosclerotic cardiovascular disease (ASCVD) risk. However, the effects of this intervention are not well understood among people with MetS in mainland China. We aimed to evaluate the effects of the individualized mHealth-based intervention using the Behavior Change Wheel on behavior change and ASCVD risk in people with MetS. We conducted a quasi-experimental, nonrandomized study. Individuals with MetS were recruited from the health promotion center of a tertiary hospital in Zhejiang province, China. The study involved 138 adults with MetS, comprising a control group of 69 participants and an intervention group of 69 participants. All participants received health education regarding diet and physical activity. The intervention group additionally received a 12-week individualized intervention through a WeChat mini program and a telephone follow-up in the sixth week of the intervention. Primary outcomes included diet, physical activity behaviors, and ASCVD risk. Secondary outcomes included diet self-efficacy, physical activity self-efficacy, knowledge of MetS, quality of life, and the quality and efficiency of health management services. The Mann-Whitney U test and Wilcoxon signed rank test were primarily used for data analysis. Data analysis was conducted based on the intention-to-treat principle using SPSS (version 25.0; IBM Corp). Baseline characteristics did not differ between the 2 groups. Compared with the control group, participants in the intervention group showed statistically significant improvements in diet behavior, physical activity behavior, diet self-efficacy, physical activity self-efficacy, knowledge of MetS, physical health, and mental health after a 12-week intervention (P=.04, P=.001, P=.04, P=.04, P=.001, P=.04, P=.04, and P<.05). The intervention group demonstrated a statistically significant improvement in outcomes from pre- to postintervention evaluations (P<.001, P=.03, P<.001, P=.04, P<.001, P<.001, and P<.001). The intervention also led to enhanced health management services and quality. The individualized mHealth-based intervention using the Behavior Change Wheel was effective in promoting diet and physical activity behaviors in patients with MetS. Nurses and other health care professionals may incorporate the intervention into their health promotion programs.


Nutritional status seven years after Roux-en-Y gastric bypass surgery.
Nutritional deficiencies in patients after Roux-en-Y gastric bypass operations have been mainly attributed to dietary restriction. However, most of these studies have been performed during the period of greatest caloric restriction. Two hundred patients who were morbidly obese were followed for 6 to 8 years (mean, 6.7 years) after Roux-en-Y gastric bypass surgery. Each underwent a thorough physical examination and behavioral and nutritional assessments, including hemoglobin, red blood cell indices, serum iron content, iron binding capacity, and serum vitamin B12 and folic acid concentrations. Data obtained from blood tests disclosed a significant gradual decrease of the mean serum hemoglobin (p less than or equal to 0.0000), mean corpuscular volume (p less than 0.001), and iron saturation (p less than or equal to 0.0000). Mean vitamin B12 concentration improved during the last 3 years of follow-up. The mean values of iron saturation and vitamin B12 were not correlated with the patients' weight loss. Meat intolerance was observed in 51%, 60.3%, 59.5%, and 55.1% of the patients during the 0 to 12 months, 13 to 24 months, 25 to 72 months, and 73 to 96 months after surgery, respectively. A significant correlation was found between the eating habits and the laboratory values. The mean serum iron saturation, vitamin B12, and folic acid were significantly higher in patients who eat meat than in patients who do not eat meat (piron less than 0.0046, pB12 less than 0.0052, folate less than 0.01). In addition, oral vitamin and mineral supplements significantly improved the nutritional status of the patients. The patients had no caloric malnutrition or protein deficiency. Roux-en-Y gastric bypass induces long-term changes in eating habits, independent of caloric intake. Iron continuously declines 6 to 8 years after surgery, depending (significantly) on the eating behavior, but not on the caloric intake.


Provision of online eye movement and desensitisation therapy (EMDR) for people with post-traumatic stress disorder (PTSD): a multi-method service evaluation.
Background: The evidence for the effectiveness of online EMDR for PTSD is scarce.Objective: This service evaluation aimed to assess how online EMDR compared to in-person EMDR, in terms of its potential effectiveness and acceptability to therapists and patients.Method: The evaluation was carried out in the Cardiff and Vale University Health Board Traumatic Stress Service. We compared the outcome of therapy (PTSD scores at end of treatment), number of sessions, drop-out rate, and adverse events using linear/logistic regression in those receiving online EMDR over a 12-month period with those who had received in-person therapy in the year previous to that. Interviews with therapists and clients who had provided or undertaken online EMDR explored their views and experiences of treatment. Interviews were analysed thematically.Results: 33 people received in-person EMDR (15.3 sessions, SD = 1.4), and 45 received online EMDR (12.4 sessions, SD = 0.9). 24 individuals completed therapy in-person, and 32 online. There was no evidence of a difference in therapy completion, drop-out rates or adverse events between the two delivery modes. There was weak evidence that those who completed EMDR online and had available data (N = 29), had slightly lower PTSD scores at the end of therapy compared to those who received in-person EMDR (N = 24) (17.1 (SD = 3.2) versus 24.5 (SD = 3.0), mean difference = 7.8, 95% CI -0.3, 15.9, p = .06). However, groups were not randomised and only those who completed treatment were analysed, so estimates may be biased. 11 patients and five therapists were interviewed. Overall, both therapists and clients viewed online EMDR as safe and effective. Benefits mentioned by clients included feeling more in control and not having to travel. Clients' concerns related to lack of privacy and 'transition time/space' between therapy and their daily lives.Conclusion: Results suggest that online EMDR is an acceptable, safe and effective alternative to in-person EMDR for PTSD in this service.


Passive Radiative Cooling of Silicon Solar Modules with Photonic Silica Microcylinders.
Passive radiative cooling is a method to dissipate excess heat from a material by the spontaneous emission of infrared thermal radiation. For a solar cell, the challenge is to enhance PRC while retaining transparency for sunlight above the bandgap. Here, we design a hexagonal array of cylinders etched into the top surface of silica solar module glass to enhance passive radiative cooling. Multipolar Mie-like resonances in the cylinders are shown to cause antireflection effects in the infrared, which results in enhanced infrared emissivity. Using Fourier transform infrared spectrometry we measure the hemispherical reflectance of the fabricated structures and find the emissivity of the silica cylinder array in good correspondence with the simulated results. The microcylinder array increases the average emissivity between λ = 7.5-16 μm from 84.3% to 97.7%, without reducing visible light transmission.


Phenotype-environment association of the oxygen transport system in trimorphic European whitefish (Coregonus lavaretus) populations.
Replicated adaptive radiation events, typified by phenotypic divergence across resource axes, provide important insight into the eco-evolutionary dynamics that lead to the formation of new species. Here, we show that in trimorphic adaptive radiations of European whitefish (Coregonus lavaretus), divergence of the oxygen transport system has occurred across the pelagic/littoral (shallow)-profundal (deep) resource axis, and at multiple biological scales. Profundal whitefish exhibited significantly larger red blood cells (RBCs), a greater proportion of cathodic hemoglobin protein components, and higher hemoglobin transcript abundance in kidney compared to littoral and pelagic morphs. Hemoglobin transcript abundance in brain and gill, but not kidney, and anodic hemoglobin protein component diversity in blood were also linked to variation at an intronic single nucleotide polymorphism (SNP). As the whitefish morphs differ in population genetic structure at this SNP, hemoglobin transcript and protein divergence between profundal and pelagic/littoral morphs is likely being driven by genetic divergence. Our findings, along with our previous work on lake whitefish, highlight the importance of the oxygen transport system to the postglacial colonization of novel lacustrine environments by whitefish throughout the northern hemisphere.


Antibiotic prophylaxis to prevent post-abortal upper genital tract infection in women with bacterial vaginosis: randomised controlled trial.
To determine the prevalence of bacterial vaginosis in women undergoing first trimester suction termination of pregnancy and to evaluate the efficacy of metronidazole in reducing the risk of post abortal pelvic infection in women with bacterial vaginosis. Randomised double-blind placebo-controlled trial. Two teaching hospitals and one district general hospital. Two hundred and seventy-three women with bacterial vaginosis undergoing termination of pregnancy. Women with bacterial vaginosis, diagnosed using modified Spiegel's criteria, were individually randomised to receive either a 2 g metronidazole suppository or identical placebo per-operatively. Participants, doctors and investigators were blinded to treatment allocation. Participants were asked to complete a questionnaire about post-operative symptoms, visits to the general practitioner, antibiotic treatment, readmission to hospital, contraception and emotional response after one month. The prevalence of bacterial vaginosis was 29.3% (326/1,111). Intention-to-treat analysis showed that post-operative upper genital tract infection developed in 12/142 (8.5%) women allocated to metronidazole and 21/131 (16.0%) women randomised to placebo, a difference of 7.6% (95% confidence intervals -15.4 to +0.2%; relative risk 0.53. 0.27 to 1.03, P = 0.055). The effect of prophylaxis was similar when the analysis was restricted to women receiving the allocated treatment and with complete follow up. There was no difference in the risk of readmission to hospital and the frequencies of self reported symptoms in the two groups were similar. This randomised placebo-controlled trial among women with bacterial vaginosis provides weak evidence that metronidazole decreases the risk of upper genital tract infection after first trimester suction termination of pregnancy but a chance finding could not confidently be excluded. Large well-conducted randomised trials with long term outcome measures are now needed to determine the most effective antibiotic combinations and strategy for prevention of post-abortal pelvic infection.


The effect of systemic hydration on normal and impaired mucociliary function.
Whether systemic hydration enhances the clearance of lower airway secretions in normal lungs and in lungs during antigen-induced bronchial obstruction was studied. In five conscious allergic sheep, tracheal mucus velocity (TMV) as an index of lower airway mucociliary clearance was measured before and serially for 60 minutes following intravenous infusion of 5% dextrose solution at volumes ranging from 5 to 35 ml/kg. None of these fluid regimens had a significant effect on TMV, although there was a tendency toward a slowing of TMV at the higher volumes of 25 and 35 ml/kg. After producing an acute allergic airway response by inhalation challenge with specific antigen, there was a decrease in mean TMV by 27% and 15% before sham infusion and infusion of 35 ml/kg of dextrose solution, respectively. During the subsequent 60-minute observation period, mucociliary transport was further impaired by dextrose infusion, with mean TMV being lower after dextrose infusion than after sham infusion at all times of measurement (P less than 0.05). The lowest value was reached 30 minutes after dextrose infusion (45% of control). It was concluded that systemic hydration does not significantly alter airway mucociliary transport in the normal state but further impairs mucociliary transport during allergic mucociliary dysfunction. This raises questions regarding the therapeutic role of systemic hydration in the treatment of children and adults who have bronchial asthma.


CRISPR-Cas9 editing of non-coding genomic loci as a means of controlling gene expression in the sea urchin.
We seek to manipulate gene function here through CRISPR-Cas9 editing of cis-regulatory sequences, rather than the more typical mutation of coding regions. This approach would minimize secondary effects of cellular responses to nonsense mediated decay pathways or to mutant protein products by premature stops. This strategy also allows for reducing gene activity in cases where a complete gene knockout would result in lethality, and it can be applied to the rapid identification of key regulatory sites essential for gene expression. We tested this strategy here with genes of known function as a proof of concept, and then applied it to examine the upstream genomic region of the germline gene Nanos2 in the sea urchin, Strongylocentrotus purpuratus. We first used CRISPR-Cas9 to target established genomic cis-regulatory regions of the skeletogenic cell transcription factor, Alx1, and the TGF-β signaling ligand, Nodal, which produce obvious developmental defects when altered in sea urchin embryos. Importantly, mutation of cis-activator sites (Alx1) and cis-repressor sites (Nodal) result in the predicted decreased and increased transcriptional output, respectively. Upon identification of efficient gRNAs by genomic mutations, we then used the same validated gRNAs to target a deadCas9-VP64 transcriptional activator to increase Nodal transcription directly. Finally, we paired these new methodologies with a more traditional, GFP reporter construct approach to further our understanding of the transcriptional regulation of Nanos2, a key gene required for germ cell identity in S. purpuratus. With a series of reporter assays, upstream Cas9-promoter targeted mutagenesis, coupled with qPCR and in situ RNA hybridization, we concluded that the promoter of Nanos2 drives strong mRNA expression in the sea urchin embryo, indicating that its primordial germ cell (PGC)-specific restriction may rely instead on post-transcriptional regulation. Overall, we present a proof-of-principle tool-kit of Cas9-mediated manipulations of promoter regions that should be applicable in most cells and embryos for which CRISPR-Cas9 is employed.


[The Schmidt and Vernet classical syndrome. Alternating brain stem syndromes that do not exist?].
In contrast to the majority of classic brainstem syndromes, the interpretation of Schmidt's syndrome (ipsilateral palsy of the IX, X, XI, and XII cranial nerves with contralateral hemiparesis) and Vernet's syndrome (ipsilateral palsy of the IX, X, and XI nerves with contralateral hemiparesis) is controversial. They are sometimes addressed as crossed brainstem syndromes but also as syndromes due to multiple cranial nerve lesions without contralateral hemiparesis. In this study, the historic descriptions and recent publications about Schmidt's and Vernet's syndromes were reviewed and critically analysed. We conclude that historic descriptions and later publications describe exclusively patients with extracerebral lesions of multiple cranial nerves. "Central" syndromes of Schmidt and Vernet caused by brainstem lesion appear not to exist. An extremely extensive lesion explaining these hypothetical unilateral brainstem syndromes is theoretically possible but, however, was apparently never observed in any of the known unilateral brainstem diseases.


The repopulation of murine Langerhans cells after depletion by mild heat injury.
We have developed a model of focal Langerhans cell depletion by mild heat injury and used it to investigate the mechanisms of Langerhans cell repopulation in the injured epidermis. The possibility whether repopulation occurred by recruitment of precursor cells from the circulation or dermis or, alternatively, by migration from the surrounding normal epidermis into the injured area was considered. Repopulation was studied by evaluating the pattern of Langerhans cell reappearance and calculating the rate of change in the density. Heat injury followed by whole-body irradiation with shielding of the injured skin was used to assess repopulation in the absence of bone marrow precursors. Using tritiated thymidine autoradiography, we also investigated whether the newly arrived Langerhans cells (be they from circulating precursors or surrounding normal epidermis) actually divide. The results showed that heat injury completely eliminated the Langerhans cells within the area delineated by the injury. Two hours after injury, the Langerhans cells were fragmented and 2 days later, they could not be detected. Regeneration of the epidermis occurred 2 days after injury and Langerhans cells reappeared scattered somewhat sparsely in the centre of the lesion on day 3. These cells were small and slender, bearing one or two short dendrites. As the dendrites increased in number and in length, the cells became similar morphologically and phenotypically to normal Langerhans cells. The rate of repopulation increased dramatically between days 5 and 7 and reached normal density on day 11. The pattern of Langerhans cell repopulation in the injured area and the lack of repopulation in the irradiated animals indicated that repopulation occurs by immigration of precursors from the circulation or dermis. There was no indication of migration of Langerhans cells from surrounding normal epidermis. Lastly, the newly arrived Langerhans cells failed to divide at the site of injury.


Atopic Dermatitis and Hospitalization for Mental Health Disorders in the United States.
Little is known about mental health (MH) emergencies in atopic dermatitis (AD) and their financial burden. We sought to determine hospitalization rates and costs of MH disorders in AD patients. We analyzed data from the Nationwide Inpatient Sample from 2002 to 2012, containing a representative 20% sample of US hospitalizations. Overall, 835 AD (1.36%) and 2,434,703 non-AD (0.75%) patients had a primary admission for an MH disorder. Atopic dermatitis patients admitted for MH disorders were more likely to be younger, Asian, of black race, and in a higher income quartile and have an increasing number of chronic conditions. In multivariable logistic regression models adjusting for demographics, AD was associated with a primary admission for MH disorders in adults, including mood disorders, schizophrenia, and developmental disorders. Atopic dermatitis was not associated with a primary admission for an MH disorder in children. There were an estimated US $183,821,629 excess costs of care annually for MH disorders in inpatients with versus without AD. In conclusion, AD was associated with higher odds of hospitalization for all MH disorders and substantial excess costs of inpatient care.


Flanking sequence preference modulates de novo DNA methylation in the mouse genome.
Mammalian de novo DNA methyltransferases (DNMT) are responsible for the establishment of cell-type-specific DNA methylation in healthy and diseased tissues. Through genome-wide analysis of de novo methylation activity in murine stem cells we uncover that DNMT3A prefers to methylate CpGs followed by cytosines or thymines, while DNMT3B predominantly methylates CpGs followed by guanines or adenines. These signatures are further observed at non-CpG sites, resembling methylation context observed in specialised cell types, including neurons and oocytes. We further show that these preferences result from structural differences in the catalytic domains of the two de novo DNMTs and are not a consequence of differential recruitment to the genome. Molecular dynamics simulations suggest that, in case of human DNMT3A, the preference is due to favourable polar interactions between the flexible Arg836 side chain and the guanine that base-pairs with the cytosine following the CpG. By exchanging arginine to a lysine, the corresponding side chain in DNMT3B, the sequence preference is reversed, confirming the requirement for arginine at this position. This context-dependent enzymatic activity provides additional insights into the complex regulation of DNA methylation patterns.


Time Spent by Breast Imaging Radiologists to Perform Value-Added Activities at an Academic Cancer Center.
Health care reform in the United States has generated a paradigm shift in the practice of radiology aimed at increasing the degree of patient-centered care. We conducted a study to quantify the amount of time breast imaging radiologists spend on value-added activities at an academic comprehensive cancer center located in Miami, Florida, and accredited by the American College of Radiology as a Breast Imaging Center of Excellence. A prospective, observational study was conducted during a period of 20 consecutive workdays. Three participating breast imaging radiologists maintained a real-time log of each activity performed. A generalized linear model was used to perform a 1-way analysis of variance. An alpha level of .05 was used to determine statistical significance. The average daily time dedicated to these activities was 92.1 minutes (range, 56.4-132.2). The amount of time significantly differed among breast imaging radiologists and correlated with their assigned daily role (P < .001 for both) but was independent of their years of experience. The daily role that required the most time was the interpretation of diagnostic imaging studies, which is when most interactions with patients, their relatives, and referring physicians occurred. The specific activity that required the most time was preparing for and participating in tumor boards. Our findings suggest that the breast imaging radiologists who participated in this study dedicated a significant amount of their time to value-added activities to help improve patients' experience across the continuity of their care. We propose that similar studies be conducted at other institutions to better assess the magnitude of this finding across different breast imaging care settings.


Race matters in addressing homelessness: A scoping review and call for critical research.
Structural racism contributes to homelessness in the United States, as evidenced by the stark racial disparities in who experiences it. This paper reviews research at the intersections of race and homelessness to advance efforts to understand and address racial inequities. Part 1 offers a synthesis of homelessness research from the 1980s to 2015, where several scholars examined the role of race and racism despite mainstream efforts to present the issue as race-neutral. Part 2 presents the results of a systematic scoping review of research at the intersections of race and homelessness from 2016 to 2021. The 90 articles included demonstrate a growing, multidisciplinary body of literature that documents how needs and trajectories of people experiencing homelessness differ by race, examines how the racialized structuring of society contributes to homelessness risk, and explores how programs, policies, and grassroots action can address inequities. In addition to charting findings and implications, included studies are appraised against research principles developed by Critical Race Theory scholars, mapping the potential of existing research on race and homelessness to challenge racism.


Treatment with cyclophosphamide i.v. pulse therapy is an option for effective treatment of skin fibrosis in patients with early systemic sclerosis.
SSc is a autoimmune disease characterized by fibrosis of the skin and internal organs. There is a lack of evidence for the efficacy of i.v. CYC pulse therapy on skin thickening. We aimed to examine the response of i.v. CYC pulse therapy on skin thickening in our cohort of SSc patients and analysed factors that predict this response. We retrospectively evaluated the data for 143 patients with SSc from baseline to 12, 24 and 36 months. All patients were treated with at least 6 i.v. CYC pulses (750 mg/m2/month). We applied the modified Rodnan Skin Score (mRSS) to assess skin thickening. A clinically relevant response was defined as a decrease in mRSS of 5 points and 25% from baseline. Different baseline variables for predicting response on month 12 were tested in logistic regression analyses. Baseline characteristics of the patients with dcSSc and lcSSc were collected. Forty-three percent (n = 42) of dcSSc patients had a clinically relevant response on month 12. Non-responding on month 6 predicts non-response on month 12 (odds ratio 37.1; 95% CI 4.5, 306.4). We concluded that i.v. CYC pulse therapy should be considered as an effective treatment option for skin thickening in dcSSc patients, because 43% of this group of patients were found to have a clinically relevant response. Of the dcSSC patients who did not respond by month 6, only 29% had a response by month 12. This finding can help the physician and patient in shared decision making about whether or not to continue therapy.


OPA1 Regulates Lipid Metabolism and Cold-Induced Browning of White Adipose Tissue in Mice.
Mitochondria play a vital role in white adipose tissue (WAT) homeostasis including adipogenesis, fatty acid synthesis, and lipolysis. We recently reported that the mitochondrial fusion protein optic atrophy 1 (OPA1) is required for induction of fatty acid oxidation and thermogenic activation in brown adipocytes. In the current study we investigated the role of OPA1 in WAT function in vivo. We generated mice with constitutive or inducible knockout of OPA1 selectively in adipocytes. Studies were conducted under baseline conditions, at thermoneutrality, following high-fat feeding or during cold exposure. OPA1 deficiency reduced mitochondrial respiratory capacity in white adipocytes, impaired lipolytic signaling, repressed expression of de novo lipogenesis and triglyceride synthesis pathways, and promoted adipose tissue senescence and inflammation. Reduced WAT mass was associated with hepatic triglycerides accumulation and glucose intolerance. Moreover, mice deficient for OPA1 in adipocytes had impaired adaptive thermogenesis and reduced cold-induced browning of subcutaneous WAT and were completely resistant to diet-induced obesity. In conclusion, OPA1 expression and function in adipocytes are essential for adipose tissue expansion, lipid biosynthesis, and fatty acid mobilization of WAT and brown adipocytes and for thermogenic activation of brown and beige adipocytes.


The effect of mTOR inhibition on obstructive hydrocephalus in patients with tuberous sclerosis complex (TSC) related subependymal giant cell astrocytoma (SEGA).
Mammalian target of rapamycin inhibitors (mTORi) are known to effectively reduce the size of subependymal giant cell astrocytomas (SEGAs), which are benign brain lesions associated with Tuberous Sclerosis Complex (TSC) that commonly cause obstructive hydrocephalus (OH). This retrospective case series reviews an institutional experience of the effect of mTORi on OH in patients with TSC-related SEGA. Thirteen of 16 identified patients with TSC-related SEGA treated with mTORi from October 2007 to December 2018 were included. Serial magnetic resonance imaging (MRI) and clinical charts were reviewed to correlate symptoms and signs of increased intracranial pressure (iICP) with ventriculomegaly on MRI. A proposed ventriculomegaly scale was used: none (< 7 mm), mild (7-10 mm), moderate (11-30 mm), and severe (> 30 mm). OH was defined as moderate or severe ventriculomegaly, based on the largest measurement. Patients' median age at start of mTORi was 13 (6-17) years and five (38%) patients were female. Eight patients had OH at the time of mTORi initiation, five of whom were asymptomatic. Six patients had improvement of hydrocephalus on serial MRI imaging with mTORi therapy, while seven patients had no change based on the ventriculomegaly scale used. All three patients who presented with symptoms of iICP and had OH also had papilledema. None had worsening of hydrocephalus or required shunt placement. Out of five patients with symptoms of iICP, four avoided surgery. Most patients had asymptomatic OH at the time of diagnosis, and ventricular enlargement was not correlated with iICP symptoms. mTORi was successful for treatment of OH from TSC-related SEGA, even in the setting of acute symptoms of iICP.


Charybdotoxin selectively blocks small Ca-activated K channels in Aplysia neurons.
The action of charybdotoxin (ChTX), a peptide component isolated from the venom of the scorpion Leiurus quinquestriatus, was investigated on membrane currents of identified neurons from the marine mollusk, Aplysia californica. Macroscopic current recordings showed that the external application of ChTX blocks the Ca-activated K current in a dose- and voltage-dependent manner. The apparent dissociation constant is 30 nM at V = -30 mV and increases e-fold for a +50- to +70-mV change in membrane potential, which indicates that the toxin molecule is sensitive to approximately 35% of the transmembrane electric field. The toxin is bound to the receptor with a 1:1 stoichiometry and its effect is reversible after washout. The toxin also suppresses the membrane leakage conductance and a resting K conductance activated by internal Ca ions. The toxin has no significant effect on the inward Na or Ca currents, the transient K current, or the delayed rectifier K current. Records from Ca-activated K channels revealed a single channel conductance of 35 +/- 5 pS at V = 0 mV in asymmetrical K solution. The channel open probability increased with the internal Ca concentration and with membrane voltage. The K channels were blocked by submillimolar concentrations of tetraethylammonium ions and by nanomolar concentrations of ChTX, but were not blocked by 4-aminopyridine if applied externally on outside-out patches. From the effects of ChTX on K current and on bursting pacemaker activity, it is concluded that the termination of bursts is in part controlled by a Ca-activated K conductance.


[The health of the members of the Academy].
The present paper, analyses the health of the numerary members of the Academy since 1791 until 1998 as evaluated through mortality and supervivence registers from birth or until their entrance as members. A positive trend of 3.67 years in life expectancy appears as compared to male spaniards of their time. Finally, biasses of this work are discussed as well as possible factors that could have played a role in this life expectancy mirease.


A 5-year evaluation of two glass-ionomer cements used as fissure sealants.
To evaluate the retention and caries preventive effect of two glass ionomers used as fissure sealants: one resin modified glass ionomer (A) and one conventional glass-ionomer cement (B). The permanent first molars of 100 children, 6-8 years of age at the start of the study, were sealed. Material A was applied on one side (right side, upper, and lower) and material B was applied on the contralateral side (left side, upper, and lower) of the mouth. The control group was composed of 108 children who did not receive fissure sealant but received oral health education. After 5 years, 64.0% of the children of the experimental group and 73.0% of the children of the control group were available for reexamination. Material A was completely lost in 74.2% and material B in 89.0% (Wilcoxon matched pairs test, P < 0.05). Total retention rate was 1.6% for materials A and B. After 5 years, caries increment was 21.5% for the experimental group and 34.2% for the control group (chi2-test, P < 0.05). Sealing pits and fissures with glass-ionomer cements was effective in preventing caries.


What can plant autophagy do for an innate immune response?
Autophagy plays an established role in the execution of senescence, starvation, and stress responses in plants. More recently, an emerging role for autophagy has been discovered during the plant innate immune response. Recent papers have shown autophagy to restrict, and conversely, to also promote programmed cell death (PCD) at the site of pathogen infection. These initial studies have piqued our excitement, but they have also revealed gaps in our understanding of plant autophagy regulation, in our ability to monitor autophagy in plant cells, and in our ability to manipulate autophagic activity. In this review, we present the most pressing questions now facing the field of plant autophagy in general, with specific focus on autophagy as it occurs during a plant-pathogen interaction. To begin to answer these questions, we place recent findings in the context of studies of autophagy and immunity in other systems, and in the context of the mammalian immune response in particular.


Hospital readmission following transjugular intrahepatic portosystemic shunt: a 14-year single-center experience.
Placement of a transjugular intrahepatic portosystemic shunt (TIPS) is a relatively common procedure used to treat complications of portal hypertension. However, only limited data exist regarding the hospital-readmission rate after TIPS placement and no studies have addressed the causes of hospital readmission. We therefore sought to identify the 30-day hospital-readmission rate after TIPS placement at our institution and to determine potential causes and predictors of readmission. We reviewed our electronic medical-records system at our institution between 2004 and 2017 to identify patients who had undergone primary TIPS placement with polytetrafluoroethylene-covered stents and to determine the 30-day readmission rate among these patients. A series of univariable logistic-regression models were fit to assess potential predictors of 30-day readmission. A total of 566 patients were included in the analysis. The 30-day readmission rate after TIPS placement was 36%. The most common causes for readmission were confusion (48%), infection (15%), bleeding (11%), and fluid overload (7%). A higher Model for End-Stage Liver Disease (MELD) score corresponded with a higher rate of readmission (odds ratio associated with each 1-unit increase in MELD score: 1.06; 95% confidence interval: 1.02-1.09; P = 0.001). Other potential predictors, including indication for TIPS placement, were not significantly associated with a higher readmission rate. The 30-day readmission rate after TIPS placement with covered stents is high, with nearly half of these readmissions due to hepatic encephalopathy-a known complication of TIPS placement. Novel interventions to help reduce the TIPS readmission rate should be prioritized in future research.


Refinement within single yeast artificial chromosome clones of a minimal region commonly deleted on the short arm of chromosome 7 in Wilms tumours.
Cytogenetic and molecular data indicate an involvement of genes mapped to the proximal portion of the short arm of chromosome 7 (7p) in Wilms tumours (WTs). We have analysed 38 WTs using a panel of eight microsatellite markers mapped to proximal 7p. Loss of heterozygosity (LOH) in tumour, compared with matched constitutional DNA, was identified in eight cases. To define better the minimal region commonly deleted in these tumours, they were analysed with nine additional markers, mapped within the region of interest. One tumour (case 30) showed LOH for only one marker (D7S510), while maintaining heterozygosity for the two immediately flanking loci (D7S555 and D7S668). This result was confirmed by fluorescence in situ hybridisation analysis, which showed that in the majority (65%) of nuclei from tumour 30 hybridising with a bacterial artificial chromosome clone containing the D7S510 locus, only one signal was visible. Noticeably, both markers defining the limits of the observed deleted region are simultaneously present within two distinct overlapping yeast artificial chromosome (YAC) clones mapped to chromosome bands 7p13-p14. This suggests that the maximum length of the missing DNA fragment was approximately 1.3 Mb, corresponding to the length of the smaller of the two YAC clones. In all other cases that showed LOH, the deletion encompassed the 7p13-p14 region. For this reason, we speculate that the identified interval contains a gene whose inactivation is important for the development of at least a fraction of WTs.


rigor mortis encodes a novel nuclear receptor interacting protein required for ecdysone signaling during Drosophila larval development.
Pulses of the steroid hormone ecdysone trigger the major developmental transitions in Drosophila, including molting and puparium formation. The ecdysone signal is transduced by the EcR/USP nuclear receptor heterodimer that binds to specific response elements in the genome and directly regulates target gene transcription. We describe a novel nuclear receptor interacting protein encoded by rigor mortis (rig) that is required for ecdysone responses during larval development. rig mutants display defects in molting, delayed larval development, larval lethality, duplicated mouth parts, and defects in puparium formation--phenotypes that resemble those seen in EcR, usp, E75A and betaFTZ-F1 mutants. Although the expression of these nuclear receptor genes is essentially normal in rig mutant larvae, the ecdysone-triggered switch in E74 isoform expression is defective. rig encodes a protein with multiple WD-40 repeats and an LXXLL motif, sequences that act as specific protein-protein interaction domains. Consistent with the presence of these elements and the lethal phenotypes of rig mutants, Rig protein interacts with several Drosophila nuclear receptors in GST pull-down experiments, including EcR, USP, DHR3, SVP and betaFTZ-F1. The ligand binding domain of betaFTZ-F1 is sufficient for this interaction, which can occur in an AF-2-independent manner. Antibody stains reveal that Rig protein is present in the brain and imaginal discs of second and third instar larvae, where it is restricted to the cytoplasm. In larval salivary gland and midgut cells, however, Rig shuttles between the cytoplasm and nucleus in a spatially and temporally regulated manner, at times that correlate with the major lethal phase of rig mutants and major switches in ecdysone-regulated gene expression. Taken together, these data indicate that rig exerts essential functions during larval development through gene-specific effects on ecdysone-regulated transcription, most likely as a cofactor for one or more nuclear receptors. Furthermore, the dynamic intracellular redistribution of Rig protein suggests that it may act to refine spatial and temporal responses to ecdysone during development.


Antidepressant effect of ingested nicotine in female rats of Flinders resistant and sensitive lines.
Both major depression and depressive symptoms are associated with a high rate of nicotine dependence, and a history of major depression has an adverse impact on smoking cessation. The main objective of this study was to investigate whether continuous ingestion of nicotine affects indices of depressive behavior in the rat. We compared cholinergic- and serotonergic-hypersensitive Flinders Sensitive Line rats (FSL), a genetic animal model of depression, with their control counterparts, Flinders Resistant Line rats (FRL). Female rats of both lines were allowed access to a solution of nicotine bitartrate (100 microg/mL) in tap water for 14 days. Subsequent behavioral testing revealed striking effects of continuous ingestion of nicotine on depressive-like behavior of both lines. FSL and FRL rats that ingested nicotine for 14 days displayed less immobility in the 10-min forced-swim test (an index of depressive-like behavior) relative to the animals of both lines that were not exposed to nicotine or exposed to nicotine for shorter periods of time. This finding indicates that ingested nicotine has antidepressant properties that are independent of the genetic difference between FSL and FRL female rats. Animal studies on nicotine ingestion and withdrawal may become an important source of insights into the comorbidity of depression and nicotine self-administration.


Improving malignancy prediction through feature selection informed by nodule size ranges in NLST.
Computed tomography (CT) is widely used during diagnosis and treatment of Non-Small Cell Lung Cancer (NSCLC). Current computer-aided diagnosis (CAD) models, designed for the classification of malignant and benign nodules, use image features, selected by feature selectors, for making a decision. In this paper, we investigate automated selection of different image features informed by different nodule size ranges to increase the overall accuracy of the classification. The NLST dataset is one of the largest available datasets on CT screening for NSCLC. We used 261 cases as a training dataset and 237 cases as a test dataset. The nodule size, which may indicate biological variability, can vary substantially. For example, in the training set, there are nodules with a diameter of a couple millimeters up to a couple dozen millimeters. The premise is that benign and malignant nodules have different radiomic quantitative descriptors related to size. After splitting training and testing datasets into three subsets based on the longest nodule diameter (LD) parameter accuracy was improved from 74.68% to 81.01% and the AUC improved from 0.69 to 0.79. We show that if AUC is the main factor in choosing parameters then accuracy improved from 72.57% to 77.5% and AUC improved from 0.78 to 0.82. Additionally, we show the impact of an oversampling technique for the minority cancer class. In some particular cases from 0.82 to 0.87.


Ocular hazard from viewing the sun unprotected and through various windows and filters.
An optical source simulating the sun at the top of the atmosphere has been constructed and used to obtain retinal burn thresholds in the rhesus monkey for image diameters corresponding to that of the solar disk on the human retina. Powers incident on the cornea and retinal irradiances required to produce threshold lesions are given for exposure times ranging from 1 s to 3 min. The ocular hazards associated with viewing the sun through aircraft window systems are assessed in terms of these data. Also, radiation in the near infrared is shown to the retina.