Locus equations and coarticulation in three Australian languages.
Locus equations were applied to F2 data for bilabial, alveolar, retroflex, palatal, and velar plosives in three Australian languages. In addition, F2 variance at the vowel-consonant boundary, and, by extension, consonantal coarticulatory sensitivity, was measured. The locus equation slopes revealed that there were place-dependent differences in the magnitude of vowel-to-consonant coarticulation. As in previous studies, the non-coronal (bilabial and velar) consonants tended to be associated with the highest slopes, palatal consonants tended to be associated with the lowest slopes, and alveolar and retroflex slopes tended to be low to intermediate. Similarly, F2 variance measurements indicated that non-coronals displayed greater coarticulatory sensitivity to adjacent vowels than did coronals. Thus, both the magnitude of vowel-to-consonant coarticulation and the magnitude of consonantal coarticulatory sensitivity were seen to vary inversely with the magnitude of consonantal articulatory constraint. The findings indicated that, unlike results reported previously for European languages such as English, anticipatory vowel-to-consonant coarticulation tends to exceed carryover coarticulation in these Australian languages. Accordingly, on the F2 variance measure, consonants tended to be more sensitive to the coarticulatory effects of the following vowel. Prosodic prominence of vowels was a less significant factor in general, although certain language-specific patterns were observed.


[Bariatric surgery: part of a systematic approach to obesity].
Bariatric surgery is becoming popular as treatment of morbid obesity. With this popularity there is a danger that it surpasses or even replaces conservative medical therapy. Instead, bariatric surgery should be part of a systematic approach in the treatment of obesity. There is a new Dutch practice guideline on the treatment of morbid obesity in which conservative treatment is hardly covered. There is little evidence of the highest level to support the recommendations in this guideline.


High resolution coherent source location using transmit/receive arrays.
A general approach to super resolution imaging of point sources using active arrays of transmit/receive elements is presented. The usual techniques of high resolution imaging using single transmitters and passive receive arrays fail in the presence of sets of coherent point sources, which often arise due to coherent multipath. However, data obtained from transmit/receive arrays may be arranged into matrices to which eigenspace direction of arrival estimation may be successfully applied, even int he presence of coherent sources. Each such matrix may be thought of as corresponding to a different transmit/receive array; this may be either the actual transmit/receive array or a virtual transmit/receive array whose effect is synthesized. This approach provides great flexibility, since a large number of different synthetic or virtual arrays may be available for a given transmit/receive array, and each can provide a different tradeoff between the total number of resolvable targets and the largest number of mutually coherent targets which can be resolved.


Laser Doppler distance sensor using phase evaluation.
This paper presents a novel optical sensor which allows simultaneous measurements of axial position and tangential velocity of moving solid state objects. An extended laser Doppler velocimeter setup is used with two slightly tilted interference fringe systems. The distance to a solid state surface can be determined via a phase evaluation. The phase laser Doppler distance sensor offers a distance resolution of 150 nm and a total position uncertainty below 1 microm. Compared to conventional measurement techniques, such as triangulation, the distance resolution is independent of the lateral surface velocity. This advantage enables precise distance and shape measurements of fast rotating surfaces.


The Evolutionary Complexities of DNA Methylation in Animals: From Plasticity to Genetic Evolution.
The importance of DNA methylation in plastic responses to environmental change and evolutionary dynamics is increasingly recognized. Here, we provide a Perspective piece on the diverse roles of DNA methylation on broad evolutionary timescales, including (i) short-term transient acclimation, (ii) stable phenotypic evolution, and (iii) genomic evolution. We show that epigenetic responses vary along a continuum, ranging from short-term acclimatory responses in variable environments within a generation to long-term modifications in populations and species. DNA methylation thus unlocks additional potential for organisms to rapidly acclimate to their environment over short timeframes. If these changes affect fitness, they can circumvent the need for adaptive changes at the genome level. However, methylation has a complex reciprocal relationship with genetic variation as it can be genetically controlled, yet it can also induce point mutations and contribute to genomic evolution. When habitats remain constant over many generations, or populations are separated across habitats, initially plastic phenotypes can become hardwired through epigenetically facilitated mutagenesis. It remains unclear under what circumstances plasticity contributes to evolutionary outcomes, and when plastic changes will become permanently encoded into genotype. We highlight how studies investigating the evolution of epigenetic plasticity need to carefully consider how plasticity in methylation state could evolve among different evolutionary scenarios, the possible phenotypic outcomes, its effects on genomic evolution, and the proximate energetic and ultimate fitness costs of methylation. We argue that accumulating evidence suggests that DNA methylation can contribute toward evolution on various timescales, spanning a continuum from acclimatory plasticity to genomic evolution.


Synergy between CD28 and CD9 costimulation for naive T-cell activation.
Our previous study demonstrated that CD9 is expressed on most mature naive T-cells and delivers a potent costimulatory signal that functions independently of CD28. Here, we investigated whether this CD9-mediated signal is different from the CD28-mediated signal in the mode of costimulation and whether both signals function synergistically for T-cell activation. Anti-CD9 or anti-CD28 monoclonal antibody (mAb) increased [3H]TdR incorporation of naive T-cells in the absence of antigen-presenting cells (APC) when coimmobilized with submitogenic doses of anti-CD3 mAb. The levels of costimulation induced by ligation of CD9 and CD28 were comparable. However, the costimulatory effect differed between soluble anti-CD9 and CD28 mAb. A soluble form of anti-CD28 mAb could costimulate anti-CD3-triggered T-cells, whereas soluble anti-CD9 mAb failed to costimulate. Although anti-CD28 costimulated naive T-cells treated with phorbol myristate acetate (PMA) instead of anti-CD3 mAb, a combination of PMA plus anti-CD9 mAb could not induce T-cell activation. The combined costimulation of anti-CD3-triggered T-cells with anti-CD9 and anti-CD28 mAbs resulted in strikingly enhanced [3H]TdR uptake and lymphokine (IL-2 and IFN-gamma) production when compared to those induced by each costimulation. These results suggest that CD9 and CD28 induce T-cell costimulation using different signaling pathways, thereby inducing synergy in T-cell activation.


Statement No. 13: Timing differences pertaining to third-party payments. Healthcare Financial Management Association, Principles and Practices Board.
As this statement describes, institutional healthcare providers have recorded timing differences and continue to be confronted with circumstances warranting their recording. Medicare arrangements for paying for capital related cost are the most frequent basis of recording or changing previously recorded timing differences but other bases for recording or changing previously recorded timing differences are described in this statement. As this statement was being prepared for publication, another significant change in Medicare arrangements for paying for capital-related cost was under consideration. This statement is intended to describe the issue of timing differences generally and not to focus only on changes called for by a single legislative or regulatory action. Furthermore, the disposition of the currently proposed change is uncertain. Accordingly, the examples included in the appendices of this statement are the same as were included in the exposure draft of this statement released in 1990. HFMA has indicated its intent to prepare examples of the recording of changes in timing differences called for by legislation or regulations when the terms are sufficiently certain to warrant action. Those examples will be based on the conclusions included in this statement.


Extreme, but not moderate climate scenarios, impart sublethal effects on polyps of the Irukandji jellyfish, Carukia barnesi.
Ocean acidification and warming, fueled by excess atmospheric carbon dioxide, can impose stress on marine organisms. Most studies testing the effects of climate change on marine organisms, however, use extreme climate projection scenarios, despite moderate projections scenarios being most likely to occur. Here, we examined the interactive effects of warming and acidification on reproduction, respiration, mobility and metabolic composition of polyps of the Irukandji jellyfish, Carukia barnesi, to determine the responses of a cubozoan jellyfish to moderate and extreme climate scenarios in Queensland, Australia. The experiment consisted two orthogonal factors: temperature (current 25 °C and future 28 °C) and pH (current (8.0) moderate (7.9) and extreme (7.7)). All polyps survived in the experiment but fewer polyps were produced in the pH 7.7 treatment compared to pH 7.9 and pH 8.0. Respiration rates were elevated in the lowest pH treatment throughout most of the experiment and polyps were approximately half as mobile in this treatment compared to pH 7.9 and pH 8.0, regardless of temperature. We identified metabolites occurring at significantly lower relative abundance in the lowest pH (i.e. glutamate, acetate, betaine, methylguanidine, lysine, sarcosine, glycine) and elevated temperature (i.e. proline, trigonelline, creatinine, mannose, acetate, betaine, methylguanidine, lysine, sarcosine) treatments. Glycine was the only metabolite exhibiting an interactive effect between pH and temperature. Our results suggest that C. barnesi polyps are unaffected by the most optimistic climate scenario and may tolerate even extreme climate conditions to some extent.


University-Industry Interaction Patterns: Past models are analyzed, some recent experiments described, and recommendations for the future given.
The nation is entering a period when the R & D output must be increased, probably without major increases in resource allocation. Obviously, in this situation, either efficiency or productivity must be increased. Perhaps one of the most wasteful aspects of the national R & D system (and one that received little attention during the golden era of the 15 percent per year expansion) has been the very weak coupling between the university, on the one hand, and industry (or government), on the other. It is a serious error to allege about such coupling that "it has never worked," that the objectives and reward structures of the institutions are such that it cannot work, and so on. The fact is that coupling has never been tried seriously. History shows that the total dollar effort in research that required coupling or that had coupling as its main objective was on the order of $10 million per year (that is, much less than 0.1 percent of the research money spent on U.S. campuses). At the same time, there is little doubt that the experiments which must and will be tried in the immediate future call for innovations in management and changes in the attitude and structure of many universities. In conversations with administrators who have had experience with such programs, I have found strong suggestions of very mixed responses from the universities. In light of these responses, and if effectiveness is a goal, it would be better for those universities that are more wedded to disciplinary research, to single principal-investigator work, not to participate in these new efforts. We need much greater diversity in the styles of university life, and it would be healthy for the academic enterprise if some universities retained a greater degree of detachment from society, while others consciously decided to interact more with it, through the private sector, and made the changes necessary to do so. If initial funding is restricted to those universities that consider university-industry or university-government research a worthy objective and that have a proven track record and a favorable administrative and reward structure, the new programs may well establish a major new pattern of national R & D.


Circulating uromodulin inhibits systemic oxidative stress by inactivating the TRPM2 channel.
High serum concentrations of kidney-derived protein uromodulin [Tamm-Horsfall protein (THP)] have recently been shown to be independently associated with low mortality in both older adults and cardiac patients, but the underlying mechanism remains unclear. Here, we show that THP inhibits the generation of reactive oxygen species (ROS) both in the kidney and systemically. Consistent with this experimental data, the concentration of circulating THP in patients with surgery-induced acute kidney injury (AKI) correlated with systemic oxidative damage. THP in the serum dropped after AKI and was associated with an increase in systemic ROS. The increase in oxidant injury correlated with postsurgical mortality and need for dialysis. Mechanistically, THP inhibited the activation of the transient receptor potential cation channel, subfamily M, member 2 (TRPM2) channel. Furthermore, inhibition of TRPM2 in vivo in a mouse model mitigated the systemic increase in ROS during AKI and THP deficiency. Our results suggest that THP is a key regulator of systemic oxidative stress by suppressing TRPM2 activity, and our findings might help explain how circulating THP deficiency is linked with poor outcomes and increased mortality.


Resolution by deep sequencing of a dual hepatitis E virus infection transmitted via blood components.
Hepatitis E virus (HEV) is a zoonotic infection, with consumption of processed pork products thought to be the major route of transmission in England. The clinical features of HEV infection range from asymptomatic infection to mild hepatitis to fulminant liver failure. Persistent, chronic hepatitis is increasingly recognized in immunocompromised patients. Infection via HEV-containing blood components and organs has been reported and measures to reduce this transmission risk were introduced into the blood service in England in 2016. We report here the sequence and phylogenetic findings from investigations into a transmission event from an HEV-infected donor to two recipients. Phylogenetic analysis of HEV genome sequence fragments obtained by Sanger sequencing showed that, whilst most of the sequences from both recipients' samples grouped with the sequence from the blood donor sample, the relationship of five sequences from recipient 2 were unresolved. Analysis of Illumina short-read deep sequence data demonstrated the presence of two divergent viral populations in the donor's sample that were also present in samples from both recipients. A clear phylogenetic relationship was established, indicating a probable transmission of both populations from the donor to each of the immunocompromised recipients. This study demonstrates the value of the application of new sequencing technologies combined with bioinformatic data analysis when Sanger sequencing is not able to clarify a proper phylogenetic relationship in the investigation of transmission events.


Water supplies and sanitary facilities in rural Transkei.
Between October 1982 and September 1983, an outbreak of cholera occurred in Transkei. A total of 678 patients with clinical illness were reported in a review of positive laboratory results. Subsequent to each report, the health department personnel began a rigorous contact-tracing process during which data on the environment were collected. A total of 1,157 standardised forms listing 6,615 persons were returned to the Epidemiological Unit. Of these respondents, 87.2% reported having 'no sanitary facilities available' and 96.4% 'no refuse disposal site'. Rivers, wells, springs, streams, dams and stagnant pools were recorded as the main sources of water supply in the study area. Whether this situation will remain unchanged or improve can be determined only by continued surveillance.


Presence, flow, and narrative absorption: an interdisciplinary theoretical exploration with a new spatiotemporal integrated model based on predictive processing.
Presence, flow, narrative absorption, immersion, transportation, and similar subjective phenomena are studied in many different disciplines, mostly in relation to mediated experiences (books, film, VR, games). Moreover, since real, virtual, or fictional agents are often involved, concepts like identification and state empathy are often linked to engaging media use. Based on a scoping review that identified similarities in the wording of various questionnaire items conceived to measure different phenomena, we categorize items into the most relevant psychological aspects and use this categorization to propose an interdisciplinary systematization. Then, based on a framework of embodied predictive processing, we present a new cognitive model of presence-related phenomena for mediated and non-mediated experiences, integrating spatial and temporal aspects and also considering the role of fiction and media design. Key processes described within the model are: selective attention, enactment of intentions, and interoception. We claim that presence is the state of perceived successful agency of an embodied mind able to correctly enact its predictions. The difference between real-life and simulated experiences ("book problem," "paradox of fiction") lays in the different precision weighting of exteroceptive and interoceptive signals.


Smoking status, disease duration, and educational level in females, are related to asthma school participation.
Limited data is available on those who do not want to attend an asthma school. Two hundred and forty-five asthmatics aged 18-65 yrs with an FEV1 >50% predicted who had been seen at our outpatient asthma clinic within the last 3 yrs were invited to participate in an asthma school. The patients were contacted by phone by a nurse, offered a 2 day asthma school without personal costs. Altogether 78% of those contacted answered positively. In a logistic regression analysis including sex, age, smoking status, educational level, asthma duration and own opinion of the disease, the-adjusted odds ratio (OR) for nonsmokers wanting to participate versus smokers was 4.0 (95% confidence interval (CI): 1.8-8.3). The corresponding figure for patients with a recent asthma attack was 3.4 (95% CI: 1.5-7.6) compared to those without. For every 10 yr duration of disease the OR for wanting to take part in the asthma school increased by 1.6 (95% CI: 1.0-2.3). When analysing males and females separately, highly educated females were less willing to take part, while an opposite tendency was present in males. In conclusion those interested in taking part in an asthma school were characterized by highly motivated nonsmokers with long duration of disease and with a recent asthma attack, and not being highly educated females.


Behavioral outcomes of picky eating in childhood: a prospective study in the general population.
Picky eaters in the general population form a heterogeneous group. It is important to differentiate between children with transient picky eating (PE) and persistent PE behavior when adverse outcomes are studied. We analyzed four PE trajectories to determine the associations with child mental health prospectively. From a population-based cohort, 3,748 participants were assessed for PE at 1.5, 3, and 6 years of age using maternal reports. Four trajectories were defined: persistent (PE at all ages); remitting (PE before 6 years only); late-onset (PE at 6 years only); and never (no PE at any assessment). Child's problem behaviors were assessed with the Teacher's Report Form at 7 years of age. We examined associations between picky eating trajectories and emotional problems, behavioral problems and pervasive developmental problems using logistic regressions. Analyses were adjusted for child, parental, and socioeconomic confounders. We also adjusted for maternal-reported baseline problem behavior at age 1.5 years; the never picky eating group was used as reference. Persisting PE predicted pervasive developmental problems at age 7 years (OR = 2.00, 95% CI: 1.10-3.63). The association remained when adjusted for baseline pervasive developmental problems at 1.5 years (OR = 1.96, 95% CI: 1.10-3.51). Persistent PE was not associated with behavioral (OR = 0.92, 95% CI: 0.53-1.60) or emotional problems (OR = 1.24, 95% CI: 0.74-2.07). Other PE trajectories were not related to child behavioral or emotional problems. Persistent PE may be a symptom or sign of pervasive developmental problems, but is not predictive of other behavioral problems. Remitting PE was not associated with adverse mental health outcomes, which further indicates that it may be part of normal development.


EGFR and ERK activation resists flavonoid quercetin-induced anticancer activities in human cervical cancer cells in vitro.
In the present study, due to the complex and numerous targets of Sarcandrae Herb (also known as Zhong Jie Feng), network pharmacology was performed to analyze its therapeutic effect on 2 cervical cancer cell lines, which could assist with the development of novel therapies. The results suggested that the natural flavonoid quercetin (Que), the effective antitumor ingredient in SH, which is widely present in a variety of plants, may depend on the target, EGFR. Previous studies have shown that EGFR serves a crucial role in the occurrence and development of cervical cancer, but its downstream molecules and regulatory mechanisms remain unknown. The anti-cervical cancer cell properties of Que, which are present in ubiquitous plants, were examined in vitro to identify the association between Que and its underlying pathway using MTT assays, flow cytometry, western blot analysis and Transwell assays. It was found that Que reduced cervical cancer cell viability, promoted G2/M phase cell cycle arrest and cell apoptosis, as well as inhibited cell migration and invasion. The Tyr1068 phosphorylation site of EGFR and the corresponding ERK target were also examined and the 2 kinases were markedly activated by Que. Furthermore, the EGFR inhibitor, afatinib and the ERK inhibitor, U0126 blocked the increase of EGFR and ERK phosphorylation, and resulted in a notable enhancement of apoptosis and cell cycle arrest. Therefore, to the best of our knowledge, the current results provided the first evidence that EGFR and ERK activation induced by Que could resist Que-induced anticancer activities. On this basis, the present study determined the role of EGFR and the underlying signaling pathways involved in the anti-cervical cancer malignant behavior induced by Que and identified the negative regulatory association.


A comparative study of expression of Fc receptors in relation to the autoantibody-mediated immune response and neutrophil elastase expression in autoimmune blistering dermatoses.
Here we investigated the cutaneous CD32A and CD89 expression in relation to the neutrophil elastase (NE) expression and serum level of anti-desmoglein 1 and 3 (DSG1/DSG3) IgG in pemphigus, anti-BP180/BP230 IgG in bullous pemphigoid (BP), anti-gliadin nonapeptides (npG), tissue (tTG), and epidermal transglutaminases (eTG) IgA in dermatitis herpetiformis (DH). The examined material consisted of skin/mucosal tissues and sera. In total, 87 patients were studied. Immunohistochemistry on paraffin-embedded sections with quantitative digital morphometry was used to measure the intensity of CD32A/CD89/NE expressions. Levels of anti-DSG1/DSG3 IgG, anti-BP180/BP230 IgG, and anti-npG/tTG/eTG IgA were evaluated with ELISAs. CD32A was abundantly expressed in cutaneous lesions in pemphigus and BP. We found no statistically significant correlation between the CD32A/CD89 and NE expression intensities in pemphigus, BP, and DH. There was a significant correlation between CD89 expression and anti-npG IgA in DH. Our results revealed a lack of correlation between CD32A expressions and anti-DSG1/DSG3 IgG levels in pemphigus, anti-BP180/BP230 IgG in BP as well as CD89 expression and anti-tTG/eTG IgA in DH. CD89 seems to be linked with gluten intolerance in DH rather than with proteolytic destruction of dermal-epidermal junction. CD32A appears to play an important role in mediating skin injury in pemphigus and BP, but probably independently from specific autoantibodies.


Coenzyme Q10 prevents hepatic fibrosis, inflammation, and oxidative stress in a male rat model of poor maternal nutrition and accelerated postnatal growth.
It is well established that low birth weight and accelerated postnatal growth increase the risk of liver dysfunction in later life. However, molecular mechanisms underlying such developmental programming are not well characterized, and potential intervention strategies are poorly defined. We tested the hypotheses that poor maternal nutrition and accelerated postnatal growth would lead to increased hepatic fibrosis (a pathological marker of liver dysfunction) and that postnatal supplementation with the antioxidant coenzyme Q10 (CoQ10) would prevent this programmed phenotype. A rat model of maternal protein restriction was used to generate low-birth-weight offspring that underwent accelerated postnatal growth (termed "recuperated"). These were compared with control rats. Offspring were weaned onto standard feed pellets with or without dietary CoQ10 (1 mg/kg body weight per day) supplementation. At 12 mo, hepatic fibrosis, indexes of inflammation, oxidative stress, and insulin signaling were measured by histology, Western blot, ELISA, and reverse transcriptase-polymerase chain reaction. Hepatic collagen deposition (diameter of deposit) was greater in recuperated offspring (mean ± SEM: 12 ± 2 μm) than in controls (5 ± 0.5 μm) (P < 0.001). This was associated with greater inflammation (interleukin 6: 38% ± 24% increase; P < 0.05; tumor necrosis factor α: 64% ± 24% increase; P < 0.05), lipid peroxidation (4-hydroxynonenal, measured by ELISA: 0.30 ± 0.02 compared with 0.19 ± 0.05 μg/mL per μg protein; P < 0.05), and hyperinsulinemia (P < 0.05). CoQ10 supplementation increased (P < 0.01) hepatic CoQ10 concentrations and ameliorated liver fibrosis (P < 0.001), inflammation (P < 0.001), some measures of oxidative stress (P < 0.001), and hyperinsulinemia (P < 0.01). Suboptimal in utero nutrition combined with accelerated postnatal catch-up growth caused more hepatic fibrosis in adulthood, which was associated with higher indexes of oxidative stress and inflammation and hyperinsulinemia. CoQ10 supplementation prevented liver fibrosis accompanied by downregulation of oxidative stress, inflammation, and hyperinsulinemia.


Structural insights into the specificity of Xyn10B from Paenibacillus barcinonensis and its improved stability by forced protein evolution.
Paenibacillus barcinonensis is a soil bacterium bearing a complex set of enzymes for xylan degradation, including several secreted enzymes and Xyn10B, one of the few intracellular xylanases reported to date. The crystal structure of Xyn10B has been determined by x-ray analysis. The enzyme folds into the typical (beta/alpha)(8) barrel of family 10 glycosyl hydrolases (GH10), with additional secondary structure elements within the beta/alpha motifs. One of these loops -L7- located at the beta7 C terminus, was essential for xylanase activity as its partial deletion yielded an inactive enzyme. The loop contains residues His(249)-Glu(250), which shape a pocket opened to solvent in close proximity to the +2 subsite, which has not been described in other GH10 enzymes. This wide cavity at the +2 subsite, where methyl-2,4-pentanediol from the crystallization medium was found, is a noteworthy feature of Xyn10B, as compared with the narrow crevice described for other GH10 xylanases. Docking analysis showed that this open cavity can accommodate glucuronic acid decorations of xylo-oligosaccharides. Co-crystallization experiments with conduramine derivative inhibitors supported the importance of this open cavity at the +2 subsite for Xyn10B activity. Several mutant derivatives of Xyn10B with improved thermal stability were obtained by forced evolution. Among them, mutant xylanases S15L and M93V showed increased half-life, whereas the double mutant S15L/M93V exhibited a further increase in stability, showing a 20-fold higher heat resistance than the wild type xylanase. All the mutations obtained were located on the surface of Xyn10B. Replacement of a Ser by a Leu residue in mutant xylanase S15L can increase hydrophobic packing efficiency and fill a superficial indentation of the protein, giving rise to a more compact structure of the enzyme.


Are osteoclasts needed for the bone anabolic response to parathyroid hormone? A study of intermittent parathyroid hormone with denosumab or alendronate in knock-in mice expressing humanized RANKL.
PTH stimulates osteoblastic cells to form new bone and to produce osteoblast-osteoclast coupling factors such as RANKL. Whether osteoclasts or their activity are needed for PTH anabolism remains uncertain. We treated ovariectomized huRANKL knock-in mice with a human RANKL inhibitor denosumab (DMAb), alendronate (Aln), or vehicle for 4 weeks, followed by co-treatment with intermittent PTH for 4 weeks. Loss of bone mass and microarchitecture was prevented by Aln and further significantly improved by DMAb. PTH improved bone mass, microstructure, and strength, and was additive to Aln but not to DMAb. Aln inhibited biochemical and histomorphometrical indices of bone turnover,--i.e. osteocalcin and bone formation rate (BFR) on cancellous bone surfaces-, and Dmab inhibited them further. However Aln increased whereas Dmab suppressed osteoclast number and surfaces. PTH significantly increased osteocalcin and bone formation indices, in the absence or presence of either antiresorptive, although BFR remained lower in presence of Dmab. To further evaluate PTH effects in the complete absence of osteoclasts, high dose PTH was administered to RANK(-/-) mice. PTH increased osteocalcin similarly in RANK(-/-) and WT mice. It also increased BMD in RANK(-/-) mice, although less than in WT. These results further indicate that osteoclasts are not strictly required for PTH anabolism, which presumably still occurs via stimulation of modeling-based bone formation. However the magnitude of PTH anabolic effects on the skeleton, in particular its additive effects with antiresorptives, depends on the extent of the remodeling space, as determined by the number and activity of osteoclasts on bone surfaces.


Ultra-deep sequencing confirms immunohistochemistry as a highly sensitive and specific method for detecting BRAF V600E mutations in colorectal carcinoma.
The activating BRAF (V600) mutation is a well-established negative prognostic biomarker in metastatic colorectal carcinoma (CRC). A recently developed monoclonal mouse antibody (clone VE1) has been shown to detect reliably BRAF (V600E) mutated protein by immunohistochemistry (IHC). In this study, we aimed to compare the detection of BRAF (V600E) mutations by IHC, Sanger sequencing (SaS), and ultra-deep sequencing (UDS) in CRC. VE1-IHC was established in a cohort of 68 KRAS wild-type CRCs. The VE1-IHC was only positive in the three patients with a known BRAF (V600E) mutation as assessed by SaS and UDS. The test cohort consisted of 265 non-selected, consecutive CRC samples. Thirty-nine out of 265 cases (14.7%) were positive by VE1-IHC. SaS of 20 randomly selected IHC negative tumors showed BRAF wild-type (20/20). Twenty-four IHC-positive cases were confirmed by SaS (24/39; 61.5%) and 15 IHC-positive cases (15/39; 38.5%) showed a BRAF wild-type by SaS. UDS detected a BRAF (V600E) mutation in 13 of these 15 discordant cases. In one tumor, the mutation frequency was below our threshold for UDS positivity, while in another case, UDS could not be performed due to low DNA amount. Statistical analysis showed sensitivities of 100% and 63% and specificities of 95 and 100% for VE1-IHC and SaS, respectively, compared to combined results of SaS and UDS. Our data suggests that there is high concordance between UDS and IHC using the anti-BRAF(V600E) (VE1) antibody. Thus, VE1 immunohistochemistry is a highly sensitive and specific method in detecting BRAF (V600E) mutations in colorectal carcinoma.


The responsibilities of the state for the prevention and treatment of mental illness among prisoners.
There is mounting evidence that severe stress may produce profound psychophysiologic disturbances that can persist for many years. Imprisonment may be viewed as one such stress. The prison population has a high baseline incidence of mental illness, reflecting the societal groups from which most prisoners are drawn. The great stress of imprisonment may thus be a significant factor in the exacerbation of existing psychoses or in the precipitation of first psychotic episodes in certain prisoners. The responsibilities of the state in the prevention and treatment of mental illness among prisoners are not clear. United States Supreme Court rulings on sentencing procedures could be interpreted as requiring psychiatric evaluations of all prisoners. Furthermore, court rulings on the adequacy of medical care in prisons could be construed as requiring therapy for all prisoners suffering from major mental illnesses. Failure of the state to take reasonable steps to prevent and treat mental illness in the prison population may constitute cruel and unusual punishment under the Eighth Amendment of the Constitution.


C-Cbl protein in human cancer tissues is frequently tyrosine phosphorylated in a tumor-specific manner.
To search for the signaling pathway relevant to the tumorigenesis in human, we examined the expression and tyrosine phosphorylation of c-cbl proto-oncogene product, c-Cbl, in various human cancer cell lines and surgical specimens. In cells derived from human cancer, we found constitutive tyrosine phosphorylation of c-Cbl protein, whereas its phosphorylation was undetectable in control ECV304 cells. Expression and tyrosine phosphorylation of c-Cbl was also examined in various surgical specimens. Thirty-six surgical specimens obtained from human tumor tissues were studied: 9 gastric carcinomas, 10 colon carcinomas, 6 renal carcinomas, 2 hepatomas, 2 brain tumors, 2 uterus tumors, 1 breast carcinoma, 1 thyroid tumor, 1 bladder tumor and 2 lung carcinomas. We found tyrosine phosphorylation of c-Cbl protein in 12 cases (33%) of these tumor tissues in a tumor-specific manner. These results suggest the importance of c-Cbl signaling in tumorigenesis in human.


[Immunotherapies for drug addictions].
Immunotherapies in the form of vaccines (active immunization) or monoclonal antibodies (passive immunization) appear safe and a promising treatment approaches for some substance-related disorders. The mechanism of action of the antibody therapy is by preventing the rapid entry of drugs of abuse into the central nervous system. In theory, immunotherapies could have several clinical applications. Monoclonal antibodies may be useful to treat drug overdoses and prevent the neurotoxic effects of drugs by blocking the access of drugs to the brain. Vaccines may help to prevent the development of addiction, initiate drug abstinence in those already addicted to drugs, or prevent drug use relapse by reducing the pharmacological effects and rewarding properties of the drugs of abuse on the brain. Passive immunization with monoclonal antibodies has been investigated for cocaine, methamphetamine, nicotine, and phencyclidine (PCP). Active immunization with vaccines has been studied for cocaine, heroin, methamphetamine, and nicotine. These immunotherapies seem promising therapeutic tools and are at different stages in their development before they can be approved by regulatory agencies for the treatment of substance-related disorders. The purpose of this article is to review the current immunotherapy approaches with emphasis on the risks and benefits for the treatment of these disorders.


Progressive Increase Trend in HPV-Related Oropharyngeal Squamous Cell Carcinoma in Brazil.
Introduction The prevalence of oropharyngeal squamous cell carcinoma (OSCC) related to Human Papillomavirus (HPV) is rising in the whole world. Objective To access the prevalence and temporal trend of HPV infection in oropharyngeal cancer by analyzing the expression of the p16 protein. Methods We conducted a transversal study in a Brazilian reference oncology center. The sample consisted of 254 patients with OSCC. The analyzed period was from 2013 to 2017. All patients underwent p16 immunohistochemistry analysis. Results The overall prevalence of HPV-related OSCC was of 31.9%. During the analyzed period, we observed a trend of increasing rates of OSCC that marked positive for p16 immunohistochemistry. The annual prevalence of p16-positive cases was of 20.6% in 2013, 23.9% in 2014, 33.3% in 2015, 38.3% in 2016, and 34.2% in 2017. Most of the patients were stage III and IV (84%). Female patients (odds ratio [OR] = 2.43; 95% confidence interval [CI]: 1.003-5.888; p = 0.049) and younger patients (OR = 2.919; 95%CI: 1.682-5.067; p < 0.005) were associated with a higher risk of HPV-related OSCC. Tobacco consumption had a proportional lower risk of HPV-related OSCC (OR = 0.152; 95%CI: 0063-0.366; p < 0.005). Conclusion We observed an increasing prevalence of HPV-related OSCC in a specialized cancer hospital in Brazil.


Outcomes of surgical treatment of diabetic foot osteomyelitis: a series of 185 patients with histopathological confirmation of bone involvement.
We analysed the factors that determine the outcomes of surgical treatment of osteomyelitis of the foot in diabetic patients given early surgical treatment within 12 h of admission and treated with prioritisation of foot-sparing surgery and avoidance of amputation. A consecutive series of 185 diabetic patients with foot osteomyelitis and histopathological confirmation of bone involvement were followed until healing, amputation or death. Probing to bone was positive in 175 cases (94.5%) and radiological signs of osteomyelitis were found in 157 cases (84.8%). Staphylococcus aureus was the organism isolated in the majority of cultures (51.3%), and in 35 cases (36.8%) it proved to be methicillin-resistant. The surgical treatment performed included 91 conservative surgical procedures, which were defined as those where no amputation of any part of the foot was undertaken (49.1%). A total of 94 patients received some degree of amputation, consisting of 79 foot-level (minor) amputations (42.4%) and 15 major amputations (8%). Five patients died during the perioperative period (2.7%). Histopathological analysis revealed 94 cases (50.8%) of acute osteomyelitis, 43 cases (23.2%) of chronic osteomyelitis, 45 cases (24.3%) of acute exacerbation of chronic osteomyelitis and three remaining cases (1.6%) designated as 'other'. The risks of failure in the case of conservative surgery were exposed bone, the presence of ischaemia and necrotising soft tissue infection. Conservative surgery without local or high-level amputation is successful in almost half of the cases of diabetic foot osteomyelitis. Prospective trials should be undertaken to determine the relative roles of conservative surgery versus other approaches.


Acute otitis media and pneumococcal vaccination - an observational cross-sectional study of otitis media among vaccinated and unvaccinated children in Greenland.
Streptococcus pneumoniae is one of the main pathogens leading to otitis media. In 2010, the 13-valent pneumococcal conjugate vaccine (PCV13) was implemented in the Greenlandic childhood vaccination programme, but the effect of this change is not yet well documented. The objective of this study is to evaluate the effect of the implementation based on the number of episodes of acute otitis media (AOM). Data are obtained from medical records. We included all children born from 1 January 2015 to 30 September 2016, and thus eligible for the three doses of PCV13 including one year of follow-up time. Exclusion criteria were uncertain vaccination status and predefined comorbidities. The children were divided into two groups based on vaccination status: "Vaccinated" or "Incomplete/delayed". We included 1077 children in total, 742 children were allocated to the "Vaccinated" group and 335 children were allocated to the "Incomplete/delayed" group. There were significantly fewer episodes of AOM in the "Incomplete/delayed" group (p = 0.01). In conclusion Greenlandic children completely and timely vaccinated with PCV13 and born between January 2015 and September 2016 did not have fewer episodes of AOM compared to children who had incomplete or delayed vaccination status. Abbreviations: PCV13: 13-valent pneumococcal conjugate vaccine; OM: otitis media; AOM: acute otitis media; CSOM: chronic suppurative otitis media; WHO: World Health Organisation; NTHi: nontypeable Haemophilus influenzae.


Cdc42/N-WASP signaling links actin dynamics to pancreatic β cell delamination and differentiation.
Delamination plays a pivotal role during normal development and cancer. Previous work has demonstrated that delamination and epithelial cell movement within the plane of an epithelium are associated with a change in cellular phenotype. However, how this positional change is linked to differentiation remains unknown. Using the developing mouse pancreas as a model system, we show that β cell delamination and differentiation are two independent events, which are controlled by Cdc42/N-WASP signaling. Specifically, we show that expression of constitutively active Cdc42 in β cells inhibits β cell delamination and differentiation. These processes are normally associated with junctional actin and cell-cell junction disassembly and the expression of fate-determining transcription factors, such as Isl1 and MafA. Mechanistically, we demonstrate that genetic ablation of N-WASP in β cells expressing constitutively active Cdc42 partially restores both delamination and β cell differentiation. These findings elucidate how junctional actin dynamics via Cdc42/N-WASP signaling cell-autonomously control not only epithelial delamination but also cell differentiation during mammalian organogenesis.


A national study of obesity prevalence and trends by type of rural county.
Obesity is epidemic in the United States, but information on this trend by type of rural locale is limited. To estimate the prevalence of and recent trends in obesity among US adults residing in rural locations. Analysis of data from the Behavioral Risk Factor Surveillance System (BRFSS) for the years 1994-1996 (n = 342,055) and 2000-2001 (n = 385,384). The main outcome measure was obesity (body mass index [BMI] > or = 30), as determined by calculating BMI from respondents' self-reported height and weight. In 2000-2001, the prevalence of obesity was 23.0% (95% confidence interval [CI] 22.6%-23.4%) for rural adults and 20.5% (95% CI 20.2%-20.7%) for their urban counterparts, representing increases of 4.8% (95% CI 4.2%-5.3%) and 5.5% (95% CI 5.1%-5.9%), respectively, since 1994-1996. The highest obesity prevalence occurred in rural counties in Louisiana, Mississippi, and Texas; obesity prevalence increased for rural residents in all states but Florida over the study period. African Americans had the highest obesity prevalence of any group, up to 31.4% (95% CI 29.1%-33.6) in rural counties adjacent to urban counties. The largest difference in obesity prevalence between those with a college education compared with those without a high school diploma occurred in urban areas (18.4% [95% CI 17.9%-18.9%] vs 23.5% [95% CI 22.5%-24.5%], respectively); the smallest difference occurred in small, remote rural counties (20.3% [95% CI 18.7%-21.9%] versus 22.3% [95% CI 20.7%-24.0%], respectively). The prevalence of obesity is higher in rural counties than in urban counties; obesity affects some residents of rural counties disproportionately.


The kallikrein-kinin system in diabetic kidney disease.
Diabetic kidney disease (DKD) is one of the most common complications in diabetes mellitus and accounts for a large proportion of clinical nephrology practice. Studies have shown that the kallikrein-kinin system (KKS) may be involved in several pathogenic mechanisms that contribute to DKD, including oxidative stress, inflammatory cytokines, and profibrotic autacoids. This review focuses on recent research advance on the potential role of the KKS in the development of DKD and its clinical relevance. A number of recent studies support the idea that there is a protective role of the KKS in diabetes. For example, agents that activate the KKS have shown strong renal protective effects that might highlight its potential to change the clinical practice. In addition, diabetic mice lacking both bradykinin B2 and B1 receptors have worse kidney lesions as compared with wild-type diabetic mice. Current basic research has demonstrated that pharmacological activation of the KKS improves renal outcomes in diabetes. These findings suggest that this system may be a therapeutic target in preventing and treating DKD.


The importance of consumption of the epidermis in malignant melanoma and correlation with clinicopathological prognostic parameters.
The aim of the study was to investigate the importance of consumption of the epidermis as an additional diagnostic criteria for malignant melanoma and to evaluate its relationship to clinicopathological findings. The age, gender, localization of the lesion and the histopathological parameters such as tumor type, Breslow thickness, ulceration, Clark's level, mitosis/mm2, lymphocytic infiltration were noted in 40 malignant melanoma cases. Consumption of the epidermis was evaluated in tumor sections. Consumption of the epidermis (COE) due to thinning of the epidermis and loss of rete ridges was noted as (+) or (-). Furthermore, COE was compared with clinical and histopathological parameters. The Shapiro Wilk and Logistic Regression tests were used for statistical analysis. The results were accepted as significant if the p value was < 0.05. COE was detected in 60% (24/40) of malignant melanoma cases. A positive correlation was present between COE and head and neck localization (p = 0,698), superficial spreading melanoma (p = 0,341), ulceration (p = 0,097) and brisk lymphocytic infiltration (p = 0,200) but the results were not statistically significant. COE was frequently detected in males but the difference was not statistically significant (p = 0.796). There was no correlation or significant statistical association between COE and age, Breslow thickness, Clark's level or the mitotic index. The detection of COE in most of the patients suggests that COE could be a histopathological criterion in the diagnosis of malignant melanoma. The frequent association between COE and the presence of ulceration could also direct attention to COE as regards prognostic importance.


The role of zinc in the pathogenesis and treatment of central nervous system (CNS) diseases. Implications of zinc homeostasis for proper CNS function.
Zinc, the essential trace element, is known to play multiple biological functions in human organism. This metal is a component of many structural as well as regulatory and catalytic proteins. The precise regulation of zinc homeostasis is essential for central nervous system and for the whole organism. Zinc plays a significant role in the brain development and in the proper brain function at every stage of life. This article is a review of knowledge about the role of zinc in central nervous system (CNS) function. The influence of this biometal on etiopathogenesis, prevention and treatment of selected brain diseases and disorders was discussed. Zinc imbalance can result not only from insufficient dietary intake, but also from impaired activity of zinc transport proteins and zinc dependent regulation of metabolic pathways. It is known that some neurodegenerative processes are connected with zinc dyshomeostasis and it may influence the state of Alzheimer's disease, depression and ageing-connected loss of cognitive function. The exact role of zinc and zinc-binding proteins in CNS pathogenesis processes is being under intensive investigation. The appropriate zinc supplementation in brain diseases may help in the prevention as well as in the proper treatment of several brain dysfunctions.


The Relation between Migratory Activity of Pipistrellus Bats at Sea and Weather Conditions Offers Possibilities to Reduce Offshore Wind Farm Effects.
Bats undertaking seasonal migration between summer roosts and wintering areas can cross large areas of open sea. Given the known impact of onshore wind turbines on bats, concerns were raised on whether offshore wind farms pose risks to bats. Better comprehension of the phenology and weather conditions of offshore bat migration are considered as research priorities for bat conservation and provide a scientific basis for mitigating the impact of offshore wind turbines on bats. This study investigated the weather conditions linked to the migratory activity of Pipistrellus bats at multiple near- and offshore locations in the Belgian part of the North Sea. We found a positive relationship between migratory activity and ambient temperature and atmospheric pressure and a negative relationship with wind speed. The activity was highest with a wind direction between NE and SE, which may favor offshore migration towards the UK. Further, we found a clear negative relationship between the number of detections and the distance from the coast. At the nearshore survey location, the number of detections was up to 24 times higher compared to the offshore locations. Our results can support mitigation strategies to reduce offshore wind farm effects on bats and offer guidance in the siting process of new offshore wind farms.


Risk perception of sexually transmitted infections and HIV in Nigerian commercial sex workers living in Barcelona: a study protocol.
Sexually transmitted infections (STIs) and HIV are a serious global public health issue. These diseases are largely preventable, as they are directly and indirectly associated with potentially modifiable factors, including socioeconomic conditions. Sexual transmission is responsible for over 75% of new HIV infections worldwide. Moreover, commercial sex workers and their clients are two of the groups at the highest risk of acquiring and transmitting these infectious diseases, due to an extensive number of sexual encounters and the various factors related to commercial sex situations. This qualitative study aims to deepen the understanding of the risk perception of STIs and HIV and their associated factors in Nigerian commercial sex workers in the city of Barcelona. This is a qualitative, descriptive, interpretive study based on a social constructivist and phenomenological perspective conducted on a saturated sample of Nigerian commercial sex workers in the city of Barcelona. Data will be collected through semistructured individual and triangular group interviews. Information will be examined using a sociological discourse analysis, allowing us to understand the social and individual factors related to the risk perception of STIs and HIV in commercial sex workers. Qualitative studies are an important element in identifying individual, social and contextual factors directly or indirectly related to the health/disease process. This qualitative study will provide essential knowledge to improve health promotion, prevention strategies and effective management of STIs both for commercial sex workers and their clients. This study has been approved by the clinical research ethics committee (CEIC) of IDIAP Jordi Gol in Barcelona, 2012.


Validity of the top-down approach of inverse dynamics analysis in fast and large rotational trunk movements.
This study investigated the validity of the top-down approach of inverse dynamics analysis in fast and large rotational movements of the trunk about three orthogonal axes of the pelvis for nine male collegiate students. The maximum angles of the upper trunk relative to the pelvis were approximately 47°, 49°, 32°, and 55° for lateral bending, flexion, extension, and axial rotation, respectively, with maximum angular velocities of 209°/s, 201°/s, 145°/s, and 288°/s, respectively. The pelvic moments about the axes during the movements were determined using the top-down and bottom-up approaches of inverse dynamics and compared between the two approaches. Three body segment inertial parameter sets were estimated using anthropometric data sets (Ae et al., Biomechanism 11, 1992; De Leva, J Biomech, 1996; Dumas et al., J Biomech, 2007). The root-mean-square errors of the moments and the absolute errors of the peaks of the moments were generally smaller than 10 N·m. The results suggest that the pelvic moment in motions involving fast and large trunk movements can be determined with a certain level of validity using the top-down approach in which the trunk is modeled as two or three rigid-link segments.


Exploring the reliability and acceptability of cognitive tests for Indigenous Australians: a pilot study.
Reliable cognitive assessment for Indigenous Australians is difficult given that mainstream tests typically rely on Western concepts, content and values. A test's psychometric properties should therefore be assessed prior to use in other cultures. The aim of this pilot study was to examine the reliability and acceptability of four cognitive tests for Australian Aboriginal people. Participants were 40 male and 44 female (N = 84) Aboriginal patients from Alice Springs Hospital. Four tests were assessed for reliability and acceptability - Rowland Universal Dementia Assessment Screen (RUDAS) (n = 19), PEBL Corsi Blocks (Corsi) (n = 19), Story Memory Recall Test (SMRT) (n = 17) and a CogState battery (n = 18). Participants performed one to three of the tests with repeated assessment to determine test-retest reliability. Qualitative interviews were conducted and analysed based on an adapted phenomenological approach to explore test acceptability. An Indigenous Reference Group gave advice and guidance. Intra-class correlations (ICC) for test retest reliability ranged from r = 0.58 (CogState One Back accuracy) to 0.86 (RUDAS). Themes emerged relating to general impressions, impacts on understanding and performance, appropriateness, task preferences and suggested improvements. RUDAS, CogState Identification task, and SMRT showed the highest reliabilities. Overall the tests were viewed as a positive challenge and an opportunity to learn about the brain despite provoking some anxiety in the patients. Caveats for test acceptability included issues related to language, impacts of convalescence and cultural relevance.


Nivolumab for the treatment of bladder cancer.
The checkpoint inhibitor nivolumab has recently demonstrated effectiveness against metatstatic urothelial carcinoma. Nivolumab is a fully human monoclonal antibody blocking PD-1 and thereby enhancing antitumour immune mechanisms. Areas covered: In this review, the authors describe the treatment of metastatic bladder cancer with nivolumab against the background of the standard treatment with cisplatin-based chemotherapy which can prolong overall survival from 3-6 months in untreated cases to over one year. Different combinations of cisplatin-based chemotherapy can further prolong survival by only a few months. The authors highlight that cancer immunotherapy by checkpoint inhibition offers potential to further prolong patient survival with limited and well manageable toxicity although serious immune-related adverse events may occur. Expert opinion: The response rate to nivolumab and other checkpoint inhibitors after first line chemotherapy remains under 30%. Patients unfit for cisplatin may benefit from first-line cancer immunotherapy. It is unclear which patients will respond and PD-1/PD-L1 expression alone is not a sufficiently reliable response marker. Treatment costs are extreme and further trials will have to clarify which subset of patients in which context of management will have a substantial benefit.


Hunting for the elusive target antigen in gestational alloimmune liver disease (GALD).
The prevailing concept is that gestational alloimmune liver disease (GALD) is caused by maternal antibodies targeting a currently unknown antigen on the liver of the fetus. This leads to deposition of complement on the fetal hepatocytes and death of the fetal hepatocytes and extensive liver injury. In many cases, the newborn dies. In subsequent pregnancies early treatment of the woman with intravenous immunoglobulin can be instituted, and the prognosis for the fetus will be excellent. Without treatment the prognosis can be severe. Crucial improvements of diagnosis require identification of the target antigen. For this identification, this work was based on two hypotheses: 1. The GALD antigen is exclusively expressed in the fetal liver during normal fetal life in all pregnancies; 2. The GALD antigen is an alloantigen expressed in the fetal liver with the woman being homozygous for the minor allele and the father being, most frequently, homozygous for the major allele. We used three different experimental approaches to identify the liver target antigen of maternal antibodies from women who had given birth to a baby with the clinical GALD diagnosis: 1. Immunoprecipitation of antigens from either a human liver cell line or human fetal livers by immunoprecipitation with maternal antibodies followed by mass spectrometry analysis of captured antigens; 2. Construction of a cDNA expression library from human fetal liver mRNA and screening about 1.3 million recombinants in Escherichia coli using antibodies from mothers of babies diagnosed with GALD; 3. Exome/genome sequencing of DNA from 26 presumably unrelated women who had previously given birth to a child with GALD with husband controls and supplementary HLA typing. In conclusion, using the three experimental approaches we did not identify the GALD target antigen and the exome/genome sequencing results did not support the hypothesis that the GALD antigen is an alloantigen, but the results do not yield basis for excluding that the antigen is exclusively expressed during fetal life., which is the hypothesis we favor.


What Can a Urine Drug Screening Immunoassay Really Tell Us?
Urine drug screening has become standard of care in many medical practice settings to assess compliance, detect misuse, and/or to provide basis for medical or legal action. The antibody-based enzymatic immunoassays used for qualitative analysis of urine have significant drawbacks that clinicians are often not aware of. Recent literature suggests that there is a lack of understanding of the shortcomings of these assays by clinicians who are ordering and/or interpreting them. This article addresses the state of each of the individual immunoassays that are most commonly used today in order to help the reader become proficient in the interpretation and application of the results. Some literature already exists regarding sources of "false positives" and "false negatives," but none seem to present the material with the practicing clinician in mind. This review aims to avoid overwhelming the reader with structures and analytical chemistry. The reader will be presented relevant clinical knowledge that will facilitate appropriate interpretation of immunoassays regardless of practice settings. Using this review as a learning tool and a reference, clinicians will be able to interpret the results of commonly used immunoassays in an evidence-based, informed manner and minimize the negative impact that misinterpretation has on patient care.


An iron cycle cascade governs the response of equatorial Pacific ecosystems to climate change.
Earth System Models project that global climate change will reduce ocean net primary production (NPP), upper trophic level biota biomass and potential fisheries catches in the future, especially in the eastern equatorial Pacific. However, projections from Earth System Models are undermined by poorly constrained assumptions regarding the biological cycling of iron, which is the main limiting resource for NPP over large parts of the ocean. In this study, we show that the climate change trends in NPP and the biomass of upper trophic levels are strongly affected by modifying assumptions associated with phytoplankton iron uptake. Using a suite of model experiments, we find 21st century climate change impacts on regional NPP range from -12.3% to +2.4% under a high emissions climate change scenario. This wide range arises from variations in the efficiency of iron retention in the upper ocean in the eastern equatorial Pacific across different scenarios of biological iron uptake, which affect the strength of regional iron limitation. Those scenarios where nitrogen limitation replaced iron limitation showed the largest projected NPP declines, while those where iron limitation was more resilient displayed little future change. All model scenarios have similar skill in reproducing past inter-annual variations in regional ocean NPP, largely due to limited change in the historical period. Ultimately, projections of end of century upper trophic level biomass change are altered by 50%-80% across all plausible scenarios. Overall, we find that uncertainties in the biological iron cycle cascade through open ocean pelagic ecosystems, from plankton to fish, affecting their evolution under climate change. This highlights additional challenges to developing effective conservation and fisheries management policies under climate change.


Associations of stigma with negative health outcomes for people living with HIV in the Gambia: implications for key populations.
The HIV epidemic in the Gambia is concentrated among stigmatized key populations. This study explores the relationship between 3 types of HIV-related stigma and 3 health outcomes among people living with HIV (PLHIV) in the Gambia. Three hundred seventeen PLHIV from PLHIV support groups in the Gambia were surveyed using the PLHIV Stigma Index. Enacted stigma in health care settings was significantly associated with avoiding or delaying seeking care [adjusted odds ratio (aOR) = 3.03, 95% confidence interval (CI) = 1.24 to 7.89]; enacted stigma in the household or community (aOR = 1.21, 95% CI = 0.98 to 1.49) and internal stigma (aOR = 1.47, 95% CI = 0.96 to 2.22) were marginally associated. Enacted stigma in health care settings was significantly associated with non-use of antiretroviral therapy (aOR = 0.52, 95% CI = 0.31 to 0.88), whereas internal stigma and enacted stigma in the household or community were not. Enacted stigma in the household or community (aOR = 0.75, 95% CI = 0.64 to 0.87) and internal stigma (aOR = 0.69, 95% CI = 0.50 to 0.93) were significantly associated with poorer self-reported health status, whereas enacted stigma in health care settings was not. PLHIV in the Gambia face stigma regardless of identity as members of key populations, who may face dual stigma. Stigma mitigation represents a potentially important component of a comprehensive package of services to improve the HIV care continuum in the Gambia. Targeted interventions that address stigma with health care workers could facilitate antiretroviral therapy use and timely care seeking for PLHIV. Interventions to address internal stigma and enacted stigma in the household and community may yield additional dividends for the overall health of PLHIV. Examining only 1 domain of stigma may not be sufficient to understand the effect of stigma on a specific health outcome.


Fluorine teams up with water to restore inhibitor activity to mutant BPTI.
Introducing fluorine into molecules has a wide range of effects on their physicochemical properties, often desirable but in most cases unpredictable. The fluorine atom imparts the C-F bond with low polarizability and high polarity, and significantly affects the behavior of neighboring functional groups, in a covalent or noncovalent manner. Here, we report that fluorine, present in the form of a single fluoroalkyl amino acid side chain in the P1 position of the well-characterized serine-protease inhibitor BPTI, can fully restore inhibitor activity to a mutant that contains the corresponding hydrocarbon side chain at the same site. High resolution crystal structures were obtained for four BPTI variants in complex with bovine β-trypsin, revealing changes in the stoichiometry and dynamics of water molecules in the S1 subsite. These results demonstrate that the introduction of fluorine into a protein environment can result in "chemical complementation" that has a significantly favorable impact on protein-protein interactions.


Heterodetic bicyclic decapeptide cyclo (Glu1-Leu2-Pro3-Gly4-Ser5-Ile6-Pro7- Ala8) cyclo-(1 gamma-5 beta) Phe9-Gly10. Synthesis and 2-D NMR conformational analysis.
Bicyclic peptides are useful model molecules that can mimic the constrained local folding of a great number of natural peptides and proteins, such as ionophoric peptides, enzyme active site, and ligand-receptor active site. The synthesis of the bicyclic title compound with the liquid phase method is described with experimental details. Of particular interest is the heterodetic closure of the second ring. The peptide showed a complexing activity with metal cations like Ba2+, Ca2+, and Mg2+. The free bicyclic peptide conformation in solution has been studied by means of NMR spectroscopy and a plausible structure model worked out with model building on NMR constraints is proposed.


Success rate and complications of internal jugular vein catheterization with and without ultrasonography guide.
Central venous catheterization (CVC) is an important procedure in emergency departments (EDs). Despite existence of ultrasonography (US) devices in every ED, CVC is done using anatomical landmarks in many EDs in Iran. This study aimed to compare the traditional landmark method vs. US-guided method of CVC placement in terms of complications and success rate. In this randomized controlled trial, patients who were candidate for internal jugular vein catheterization, and referred to Baqiyatallah Hospital ED were randomly allocated into US-guided CVC and anatomical landmarks guided CVC groups. Central vein access time, number of attempts, success rate, and complications in each group were evaluated. Mann-Whitney U, chi-square and Fisher exact tests along with Pearson and Spearman correlation coefficients were used to analyze the data. Out of 100 patients, 56 were male and 44 were female. No significant differences were found between the US-guided and traditional landmark methods of CVC insertion in terms of age, gender, BMI, and site of catheter insertion. The mean access time was significantly lower in the US-guided group (37.12 ± 17.33 s vs. 63.42 ± 35.19 s, P < 0.001). The mean number of attempts was also significantly lower in the US-guided group (1.12 ± 0.3 vs. 1.58 ± 0.64 times, P < 0.001). Eighty-eight percent of patients in the US-guided group were catheterized in the first attempt, while 50% of patients in the traditional landmark group were catheterized in the second or more attempts (P < 0.001). The success rate was 100% in the US-guided group, while it was 88% in the landmark group (P = 0.013). Moreover, the rate of complications was significantly lower in the US-guided group (4% vs. 24%, P = 0.004). The US-guided method for CVC placement was superior to the traditional landmark method in terms of access time, number of attempts, success rate, and fewer complications.


An Assessment of a Socioeconomic Risk Screening Tool for Telemedicine Encounters in Pediatric Primary Care: A Pilot Study.
Socioeconomic adversity negatively affects child health. Telemedicine use in pediatrics is rapidly expanding. We piloted a socioeconomic risk screening tool within telemedicine visits. Using chart review, our primary aim was to assess the rates of screen completion, risk identification, and referral generation during telemedicine visits. Our secondary aim was to assess family satisfaction and barriers to connecting with referrals/interventions through follow-up telephone interviews. This study included 179 telemedicine encounters. The screening tool was completed in 63% of encounters and was positive in 5% of encounters. Of those who identified socioeconomic risks, 90% received a referral/intervention (social work consultation, food pantry, etc.). During follow-up calls, families expressed satisfaction with telemedicine, though 31% described difficulty connecting with the recommended services. High rates of socioeconomic risk screening resulting in interventions are achievable during telemedicine visits. Further work is needed to identify optimal socioeconomic risk screening questions and opportunities, and to ensure successful interventions.


Heterogeneous Enantioselective Catalysis with Chiral Encoded Mesoporous Pt-Ir Films Supported on Ni Foam.
The development of heterogeneous catalysts for asymmetric synthesis is one of the most challenging topics in chemistry, as it allows obtaining enantiomerically pure compounds. Recently, metal layers incorporating molecular chiral cavities, obtained by electroreduction of a metal source in the simultaneous presence of a non-ionic surfactant and asymmetric molecules, have been proposed for a wide range of applications, including enantioselective electroanalysis and electrosynthesis, as well as chiral separation. In contrast to this previous work, solely based on electrochemical phenomena, herein we designed and employed nanostructured chiral encoded Pt-Ir alloys, supported on high surface area nickel foams, as heterogeneous catalysts for the asymmetric hydrogenation of aromatic ketones. Fine-tuning the experimental conditions allows achieving very high enantioselectivity (>80%), combined with improved catalyst stability.


Characteristics of memory dysfunction in body dysmorphic disorder.
Although body dysmorphic disorder (BDD) is receiving increasing empirical attention, very little is known about neuropsychological deficits in this disorder. The current study investigated the nature of memory dysfunction in BDD, including the relationship between encoding strategies and verbal and nonverbal memory performance. We evaluated 17 patients with BDD and 17 healthy controls using the Rey-Osterrieth Complex Figure Test (RCFT) and the California Verbal Learning Test (CVLT). BDD patients differed significantly from healthy controls on verbal and nonverbal learning and memory indices. Multiple regression analyses revealed that group differences in free recall were statistically mediated by deficits in organizational strategies in the BDD cohort. These findings are similar to patterns previously observed in obsessive-compulsive disorder (OCD), suggesting a potential relationship between OCD and BDD. Studies in both groups have shown that verbal and nonverbal memory deficits are affected by impaired strategic processing.


Large-mode-area infrared guiding in ultrafast laser written waveguides in sulfur-based chalcogenide glasses.
Current demands in astrophotonics impose advancing optical functions in infrared domains within embedded refractive index designs. We demonstrate concepts for large-mode-area guiding in ultrafast laser photowritten waveguides in bulk Sulfur-based chalcogenide glasses. If positive index contrasts are weak in As2S3, Ge doping increases the matrix rigidity and allows for high contrast (10(-3)) positive refractive index changes. Guiding with variable mode diameter and large-mode-area light transport is demonstrated up to 10 μm spectral domain using transverse slit-shaped and evanescently-coupled multicore traces.


Interannual variability of atmospheric methane: possible effects of the el nino--southern oscillation.
Nearly continuous measurements at Cape Meares, Oregon, revealed that methane was increasing in the earth's atmosphere and that its concentration varied cyclically with the seasons. After 6 years of measurements, results show that the rate of increase in methane undergoes interannual variations; the most prominent of these coincided with the last major El Niño-Southern Oscillation, when methane concentrations fell far below expected levels. One of the consequences of the interannual variability is that the long-term rate of increase at Cape Meares is now about 16 parts per billion by volume per year, or about 1 percent annually, which is significantly less than that indicated by the earliest calculations.


Impact of chronic kidney disease and anemia on health-related quality of life and work productivity: analysis of multinational real-world data.
Reductions in health-related quality of life (HRQoL) in patients with chronic kidney disease (CKD) are thought to be exacerbated by the low hemoglobin (Hb) levels that define anemia, a common complication of CKD. The current analysis evaluated the impact of anemia on HRQoL and work productivity in patients with non-dialysis dependent and dialysis-dependent CKD using real-world data. Data were collected in France, Germany, Italy, Spain, the UK, the USA and China in 2012-2018 in the Adelphi Real World Disease Specific Programme™ for CKD, a large, cross-sectional, survey of physicians and their patients. Patients completed three patient-reported outcomes (PRO) instruments: the EuroQol 5-Dimension 3-level (EQ-5D-3 L), the Kidney Disease Quality of Life (KDQOL-36) instrument and the Work Productivity and Activity Impairment questionnaire. PROs were assessed by CKD stage and Hb levels, and regression analyses were performed with CKD stage and Hb level as independent variables and PROs as outcome variables, while adjusting for age, sex, CKD stage, comorbidities and cardiovascular risk. Overall, 5276 patients participated in the survey, including 28% stage 4 and 36% dialysis patients. Patients with lower Hb levels more often reported problems/issues on all EQ-5D-3 L domains (p < 0.0001). Regression analyses showed significant associations between lower Hb levels and the probability of low (< 0.8) EQ-5D-3 L utility scores (p < 0.0001) and low visual analog scale scores (p < 0.05), indicating poorer health status. Associations were seen even when adjusting for CKD stage and other potential confounding factors. Significant associations were observed between Hb level and the 12-Item Short-Form Health Survey (SF-12) Physical Component Summary, SF-12 Mental Component Summary and the three KDQOL-36 subscales (all p < 0.0001), and were confirmed using linear regression analyses adjusting for CKD stage and other potential confounders. Numerically greater work productivity losses and greater activity impairment were observed with lower Hb levels. Lower Hb levels worsen the impact of CKD on HRQoL, and are associated with lower work productivity in patients with CKD. Assessment and treatment of anemia should be recognized as a key component of integral CKD management throughout all stages of the disease.


[Prognostic factors for peritonitis in elderly patients. Multifactorial statistical analysis apropos of 216 cases].
The aim of this paper is to analyse retrospectively the data of our patients over 60 years old who had an acute peritonitis, localized or diffuse, to establish prognostic factors. They were 216 patients, who underwent surgical treatment between 1971 and 1990. We observed 243 variables and its significance using the chi 2 test. We divided our study in two stages: from 1.10.71 to 30.09.80 (group I = 93 patients) and from 1.10.80 to 31.01.90 (group II = 123 patients). Group I was composed by 51 men and 42 women with a mean age of 71.9 +/- 5.3 years. General mortality of this group was 36% (33 patients). Group II corresponded to 55 men and 68 women with a mean age of 74.26 +/- 7.1 years. Mortality was 23% (28 patients). Age, sex and associated clinical disorders were not significant on prognosis, meanwhile the clinical and biological form of presentation were not adequate to establish a severity index. The most common ethiologies were: biliar (24 patients = 26%) in group I and appendicular (41 patients = 32.2%) In group II. Significant factors on mortality rates in group II were: delay between onset of symptoms and surgical treatment (over 96 hs, p less than 0.05), generalized or purulent peritonitis operated after 96 hs from onset of the attack (p less than 0.05) and malignancy (p less than 0.01).


Peripapillary choroidal thickness in young Asians with high myopia.
To describe the topography and predictors of peripapillary choroidal thickness (PPCT) in highly myopic eyes of young, healthy, Asian subjects. A total of 870 young male subjects aged 21.63 ± 1.15 years were recruited from the Singapore military. Choroidal imaging was performed using enhanced depth imaging (EDI) spectral-domain optical coherence tomography (SD-OCT). Peripapillary choroidal thickness was manually measured at eight locations around the optic disc. We analyzed 448 subjects with high myopia (defined as spherical equivalent [SE] worse than -6.0 diopters [D]) and 116 with emmetropia (SE > -0.5 and < 0.5 D). The mean SE was -8.52 ± 1.20 D for the high-myopic group, and 0.11 ± 0.24 D for the emmetropic group. The mean peripapillary choroid was significantly thinner (142.62 ± 43.84 μm) in high myopes compared with emmetropes (181.90 ± 46.43 μm, P < 0.001). Likewise, PPCT showed further decrease with increase in degree of myopic refractive error. Distribution of PPCT showed a markedly different pattern in high-myopic eyes (thickest superiorly) and emmetropic eyes (thickest temporally). However, peripapillary choroid in both the groups was thinnest at the inferior location. Among the ocular factors studied, axial length, IOP, presence of posterior staphyloma, and chorioretinal atrophy were the factors significantly associated with PPCT. Highly myopic eyes have significantly thinner peripapillary choroid and showed different distribution of thickness, compared with emmetropes. Axial length, IOP, and presence of posterior staphyloma and chorioretinal atrophy significantly influence PPCT and should be taken into consideration during clinical interpretation of PPCT measurement.


Salience of Medical Concepts of Inside Clinical Texts and Outside Medical Records for Referred Cardiovascular Patients.
Outside medical records (OMRs) accompanying referred patients are frequently sent as faxes from external healthcare providers. Accessing useful and relevant information from these OMRs in a timely manner is a challenging task due to a combination of the presence of machine-illegible information and the limited system interoperability inherent in healthcare. Little research has been done on investigating information in OMRs. This paper evaluated overlapping and non-overlapping medical concepts captured from digitally faxed OMRs for patients transferring to the Department of Cardiovascular Medicine and from clinical consultant notes generated at the Mayo Clinic. We used optical character recognition (OCR) techniques to make faxed OMRs machine-readable and used natural language processing (NLP) techniques to capture clinical concepts from both machine-readable OMRs and Mayo clinical notes. We measured the level of overlap in medical concepts between OMRs and Mayo clinical narratives in the quantitative approaches and assessed the salience of concepts specific to Cardiovascular Medicine by calculating the ratio of those mentioned concepts relative to an independent clinical corpus. Among the concepts collected from the OMRs, 11.19% of those were also present in the Mayo clinical narratives that were generated within the 3 months after their initial encounter at the Mayo Clinic. For those common concepts, 73.97% were identified in initial consultant notes (ICNs) and 26.03% were captured over subsequent follow-up consultant notes (FCNs). These findings implied that information collected from the OMRs is potentially informative for patient care, but some valuable information (additionally identified in FCNs) collected from the OMRs is not fully used in an earlier stage of the care process. The concepts collected from the ICNs have the highest salience to Cardiovascular Medicine (0.112) compared to concepts in OMRs and concepts in FCNs. Additionally, unique concepts captured in ICNs (unseen in OMRs or FCNs) carried the most salient information (0.094), which demonstrated that ICNs provided the most informative concepts for the care of transferred patients.


Melanoma in children and the use of sentinel lymph node biopsy.
The rarity of pediatric melanoma prompted our review of sentinel lymph node biopsy (SLNB) and associated prognosis. A chart review from 1989 to 2004 revealed 12 cases of cutaneous melanoma. Variables analyzed included demographics, site, histology, tumor characteristics, nodal status, and distant metastasis (TMN status), SLNB and/or therapeutic lymph node dissection (TLND), adjuvant treatment, disease-free survival, and overall survival. Mean age at diagnosis was 8.5 years with 7 of 12 patients younger than 10 years (range, 0.3-17.9 years). Site distribution was the extremity (7), trunk (4), and head and neck (1). All patients had wide local excision and primary closure or skin graft. Breslow's thickness averaged 3.5 mm (range, 0.8-6 mm). Only patients diagnosed after 2000 with melanomas thicker than 1 mm were offered SLNB (extremity = 2, trunk = 1, head and neck = 1). Two patients had positive sentinel lymph node: one received TLND and interferon and one is followed closely (unclear pathology). Disease-free survival and overall survival by stage were stage I (n = 2, 3.9 years, 100%), stage II (n = 6, 7.7 years, 83%), stage III (n = 4, 2.6 years, 75%), and stage IV (n = 0). A stage II patient with negative SLNB, adjuvant chemotherapy, and interferon died 26 months after diagnosis, and a stage III patient with clinically and pathologically positive nodes after TLND died 15 months after diagnosis. Although a negative SLNB does not guarantee a favorable prognosis, its increasing use will further define its role in pediatric melanoma.


Temperature and Sugar Feeding Effects on the Activity of a Laboratory Strain of Aedes aegypti.
Aedes aegypti is an invasive mosquito species that is expected to expand its global distribution through climate change. As poikilotherms, mosquitoes are greatly affected by the temperature of the environment which can impact host-seeking, blood-feeding, and flight activity as well as survival and ability to transmit pathogens. However, an important aspect of mosquito biology on which the effect of temperature has not been investigated is water and sugar-feeding and how access to a sugar source might affect the insect's activity and survival under different thermal conditions. To close this knowledge gap, we relied on actometer experiments to study the activity of both female and male Ae. aegypti at 20 °C, 25 °C, and 30 °C, providing either water or 10% sucrose to the insects. We then measured the total carbohydrate contents of alive mosquitoes using the anthrone protocol. Survival was assessed and compared between all groups. Results from this study will inform on the thermal biology of Ae. aegypti mosquitoes and how access to sugar affects their activity.


Highly sensitive and uniform surface-enhanced Raman spectroscopy from grating-integrated plasmonic nanograss.
Surface-enhanced Raman scattering (SERS) spectroscopy has found a wide range of applications in biomedicine, food safety and environmental monitoring. However, to date, it is difficult for most SERS substrates to provide an extremely sensitive and highly uniform Raman response simultaneously. Here, we developed a sensitive and uniform SERS sensing strategy based on grating-integrated gold nanograsses (GIGNs), which can amplify the SERS signal up to 10-fold compared to the nanograss without grating (namely on the flat substrate) experimentally. Numerical simulation results show that such an improvement of SERS sensitivity arises from the enhanced hotspots relying on the strong coupling between the localized surface plasmon resonances of individual stripe-regulated gold nanorod assemblies and Wood's anomalies in air and dielectric grating. Importantly, these hotspots on the substrate can be flexibly tailored by adjusting the height and periodicity of the loaded grating. The SERS performances of the GIGNs have further been successfully demonstrated with the label-free detection of adenine and cytosine (DNA bases) molecules at the nanomolar level. Moreover, the GIGNs also presented the uniform spot-to-spot and sample-to-sample SERS signals of the analyte molecules (relative standard deviations down to ∼11% and 13%, respectively). These advantages suggest that our GIGN substrates are of great potential for SERS-related sensing.


Anion Engineering for Stabilizing Li Interstitial Sites in Halide Solid Electrolytes for All-Solid-State Li Batteries.
Halide solid electrolytes (SEs) have been highlighted for their high-voltage stability. Among the halide SEs, the ionic conductivity has been improved by aliovalent metal substitutions or choosing a ccp-like anion-arranged monoclinic structure (C2/m) over hcp- or bcc-like anion-arranged structures. Here, we present a new approach, hard-base substitution, and its underlying mechanism to increase the ionic conductivity of halide SEs. The oxygen substitution to Li2ZrCl6 (trigonal, hcp) increased the ionic conductivity from 0.33 to 1.3 mS cm-1 at Li3.1ZrCl4.9O1.1 (monoclinic, ccp), while the sulfur and fluorine substitutions were not effective. A systematic comparison study revealed that the energetic stabilization of interstitial sites for Li migration plays a key role in improving the ionic conductivity, and the ccp-like anion sublattice is not sufficient to achieve high ionic conductivity. We further examined the feasibility of the oxyhalide SE for practical and all-solid-state battery applications.


Assessing Patients With Altered Level of Consciousness.
Patients with alterations in level of consciousness are among the most difficult to assess, so knowledge of how to assess these patients is important for tracking trends and identifying changes. This article discusses methods used to assess patients admitted with an altered level of consciousness and describes the neurological assessment of and potential causes for altered level of consciousness. Identifying and understanding certain examination findings enable faster recognition and intervention for life-threatening neurological events, directly impacting outcomes for neurologically compromised individuals.


Clinical implications of pre-existing adenoma in endoscopically resected early gastric cancers.
Although gastric adenoma is widely accepted as a precursor of gastric cancer, pre-existing adenoma is not always detected in gastric cancer patients. To investigate the clinical characteristics of early gastric cancer (EGC) arising from adenoma, compared with those of EGC without pre-existing adenoma. Patients who underwent endoscopic resection for EGC at a single tertiary hospital were divided into two groups based on the presence (ex-adenoma group) or absence (de novo group) of pre-existing adenoma on pathologic specimens. Clinicopathologic characteristics, endoscopic features and long-term outcomes were analyzed. Of 1,509 patients, 236 (15.6%) were included in the ex-adenoma group. Mean age (P = 0.003) and Helicobacter pylori infection rate (P = 0.040) were significantly higher in the ex-adenoma than in the de novo group. Mean endoscopic size was significantly larger, elevated lesions were more prevalent (both P < 0.001), and carcinomas were more differentiated in the ex-adenoma group than in the de novo group (P = 0.037). The degree of atrophy (P = 0.025) or intestinal metaplasia (P < 0.001) was more advanced in the ex-adenoma group. Synchronous gastric neoplasia was significantly more prevalent in the ex-adenoma group (P < 0.001), whereas metachronous cancer recurrence rate was not significantly different between the two groups. EGCs with pre-existing adenoma show a greater association with H. pylori-related chronic inflammation than those without, which could explain the differences in the characteristics between groups. Potential differences in carcinogenic mechanisms between the groups were explored.


Outcomes of early, late, and no admission to the intensive care unit for patients hospitalized with community-acquired pneumonia.
The objective was to compare outcomes associated with early, late, and no admission to the intensive care unit (ICU) for patients hospitalized with community-acquired pneumonia (CAP). This was a post hoc analysis of the original data from the Emergency Department Community-Acquired Pneumonia (EDCAP) and Pneumocom-1 prospective multicenter cohort studies of adult patients hospitalized with CAP. Propensity score-adjusted analysis was used to compare 28-day mortality and hospital length of stay (LOS) for 199, 144, and 2,215 patients with early (i.e., ICU admission on the day of emergency department [ED] presentation), late, and no ICU admission. Unadjusted 28-day mortality rates were 13.1, 19.4, and 5.7% for early, late, and no ICU admissions, respectively (p < 0.001). After adjusting for quintile of propensity score, the odds of 28-day mortality were higher for late ICU admissions relative to early ICU admissions (odds ratio [OR] = 2.63; 95% confidence interval [CI] = 1.42 to 4.90), and no ICU admissions (OR = 3.40; 95% CI = 2.11 to 5.48), but did not differ between early and no ICU admissions (OR = 1.29; 95% CI = 0.79 to 2.09). The median hospital LOS was 10 days for early (interquartile range [IQR] = 7 to 18), 15 days for late (IQR 9 to 23), and 6 days (IQR 4 to 9) for no ICU admissions (p < 0.001). This study suggests that late but not early admission to the ICU is associated with higher 28-day mortality for patients hospitalized with CAP. Patients admitted to the ICU have longer hospital LOS in comparison to those managed on the wards, particularly if they are admitted late to the ICU.


Intracranial hypotension caused by leakage of cerebrospinal fluid from the thecal sac after lumboperitoneal shunt placement. Case report.
The authors describe a newly recognized complication of lumboperitoneal (LP) shunt placement, namely, intracranial hypotension from leakage of cerebrospinal fluid (CSF) through a defect in the lumbar dura created by the shunt catheter. They report on a 47-year-old obese woman with idiopathic intracranial hypertension who underwent routine placement of an LP shunt. Following surgery, her headache became worse. Two radionuclide shunt studies showed no anterograde tracer flow, suggesting either obstruction or a leak. After shunt reservoir manometry indicated low pressure, spinal magnetic resonance (MR) imaging was performed. The MR images revealed a CSF leak from the lumbar thecal sac. A computed tomography (CT) myelogram, performed by injection into the shunt reservoir, confirmed the presence of a leak by showing extravasation of contrast agent into the epidural space. The patient was treated by application of a CT-guided blood patch at the leak site. Catheter-associated CSF leak is an unusual cause of intracranial hypotension that can occur following LP shunt placement. This case report outlines the clinical features of this condition, documents the neuroradiological findings, and demonstrates successful treatment with a blood patch.


Changes in glycan branching and sialylation of the Thy-1 antigen during normal differentiation of mouse T-lymphocytes.
The glycans of the Thy-1 antigen present on thymocytes and lymph-node T-lymphocytes were investigated after external labelling of the cells. Neuraminidase, endoglycosidase H and endoglycosidase F were used in combination with sodium dodecyl sulphate/polyacrylamide-gel electrophoresis and isoelectric focusing in order to characterize the nature of the glycans on 125I-labelled and immunoprecipitated Thy-1. Glycopeptides were prepared from Thy-1 obtained from cells labelled by periodate/boro[3H]hydride treatment. The glycopeptides were separated by affinity chromatography on concanavalin A-Sepharose and analysed by gel filtration. The results show that both types of cells possess Thy-1 molecules with three N-linked carbohydrate chains, of which one is of 'high-mannose' type and the other two of triantennary and biantennary 'complex' type. The ratio of triantennary/biantennary chains was decreased on Thy-1 of mature cells compared with that of immature cells, but instead more sialic acid was present on these chains. Deglycosylated Thy-1 appeared to be of the same size regardless of origin, indicating that only the carbohydrate moiety differs between Thy-1 molecules of the two cell types.


[Combination use of an automatic anti-tachycardia pacemaker and an automatic implantable cardioverter-defibrillator in sustained recurrent ventricular tachycardia resistant to drugs].
We used the combination of an antitachycardia automatic ventricular pacemaker with the automatic implantable cardioverter-defibrillator in two patients with sustained, recurrent, drug-resistant ventricular tachycardias in whom a surgical ablation was not indicated. The indications for the combined use of the two systems were the possibility to control: a) the ventricular tachycardias with ventricular programmed stimulation; b) the arrhythmias which might eventually degenerate into ventricular flutter or fibrillation (as a result of anti-tachycardia pacing) with the defibrillator. To avoid any possible interference between the two systems we used the following protocol: a) endocardial bipolar pacing; b) the sensing electrodes of the defibrillator were placed as far as possible from the endocardial one; c) a suitable programming of the pacemaker output; d) a careful selection of the anti-tachycardia pacing programme (burst rate inferior to the cut-off rate of the cardioverter-defibrillator and/or a duration of the burst pacing inferior to the arrhythmia sensing time of the defibrillator); e) use of cardioverter-defibrillators with a high cut-off rate. We never observed, during the follow-up (11 and 4 months, respectively), interference between the two systems. Both patients had ventricular tachycardia recurrences (51 and 3 episodes, respectively). The arrhythmias were correctly detected and interrupted by the pacemaker without the intervention of the defibrillator. These data confirm the feasibility of the combined use of the two systems in patients with ventricular tachycardias and, in selected cases, this approach is preferable. The anti-tachycardia pacemaker counteracts some limitations of the defibrillators available at present. It offers a protection against bradyarrhythmias and allows a more precise storage of arrhythmic events. The anti-tachycardia pacemaker often controls ventricular tachycardias without the intervention of the defibrillator, thus giving the same a longer life-span and allowing patients to avoid the shock.


Placental grading by ultrasonography as an index of fetal maturity. Its application to the problem of elective caesarean section.
Ultrasonographic placental grading for estimation of fetal maturity before elective caesarean section was assessed at 38 weeks' gestation in 100 patients. It was impossible to grade the placenta in 5 cases, but in 95 it could be graded with confidence. In 90 cases the placenta was graded as II or III, and all the infants in these two groups had achieved lung maturity. Five patients had grade I placentas, and one of these patients had an immature baby. Amniocentesis for determination of the lecithin/sphingomyelin ratio and the presence of phosphatidyl glycerol was attempted in all cases. We failed to obtain liquor amnii from 6 of the 100 patients.


Ribosomal protein mutations induce autophagy through S6 kinase inhibition of the insulin pathway.
Mutations affecting the ribosome lead to several diseases known as ribosomopathies, with phenotypes that include growth defects, cytopenia, and bone marrow failure. Diamond-Blackfan anemia (DBA), for example, is a pure red cell aplasia linked to the mutation of ribosomal protein (RP) genes. Here we show the knock-down of the DBA-linked RPS19 gene induces the cellular self-digestion process of autophagy, a pathway critical for proper hematopoiesis. We also observe an increase of autophagy in cells derived from DBA patients, in CD34+ erythrocyte progenitor cells with RPS19 knock down, in the red blood cells of zebrafish embryos with RP-deficiency, and in cells from patients with Shwachman-Diamond syndrome (SDS). The loss of RPs in all these models results in a marked increase in S6 kinase phosphorylation that we find is triggered by an increase in reactive oxygen species (ROS). We show that this increase in S6 kinase phosphorylation inhibits the insulin pathway and AKT phosphorylation activity through a mechanism reminiscent of insulin resistance. While stimulating RP-deficient cells with insulin reduces autophagy, antioxidant treatment reduces S6 kinase phosphorylation, autophagy, and stabilization of the p53 tumor suppressor. Our data suggest that RP loss promotes the aberrant activation of both S6 kinase and p53 by increasing intracellular ROS levels. The deregulation of these signaling pathways is likely playing a major role in the pathophysiology of ribosomopathies.