Chest imaging in iatrogenic respiratory disease.
Iatrogenic respiratory disease is an important cause of patient morbidity and mortality. Clinical and radiologic findings are nonspecific and diagnosis can be difficult. Therefore, it is important for physicians to be familiar with the iatrogenic diseases for which their patients are at risk, as well as their common radiologic appearances. Causes of iatrogenic respiratory disease include drugs, transplantation, radiation, transfusion, or other miscellaneous therapies.


Interkingdom signaling induces Streptococcus pneumoniae biofilm dispersion and transition from asymptomatic colonization to disease.
Streptococcus pneumoniae is a common human nasopharyngeal commensal colonizing 10% to 40% of healthy individuals, depending on age. Despite a low invasive disease rate, widespread carriage ensures that infection occurs often enough to make S. pneumoniae a leading bacterial cause of respiratory disease worldwide. However, the mechanisms behind transition from asymptomatic colonization to dissemination and disease in otherwise sterile sites remain poorly understood but are epidemiologically strongly linked to infection with respiratory viruses. In this report, we show that infection with influenza A virus and treatment with the resulting host signals (febrile-range temperatures, norepinephrine, extracytoplasmic ATP, and increased nutrient availability) induce the release of bacteria from biofilms in a newly developed biofilm model on live epithelial cells both in vitro and during in vivo colonization. These dispersed bacteria have distinct phenotypic properties different from those of both biofilm and broth-grown, planktonic bacteria, with the dispersed population showing differential virulence gene expression characteristics resulting in a significantly increased ability to disseminate and cause infection of otherwise sterile sites, such as the middle ear, lungs, and bloodstream. The results offer novel and important insights into the role of interkingdom signaling between microbe and host during biofilm dispersion and transition to acute disease. This report addresses the mechanisms involved in transition from pneumococcal asymptomatic colonization to disease. In this study, we determined that changes in the nasopharyngeal environment result in the release of bacteria from colonizing biofilms with a gene expression and virulence phenotype different not only from that of colonizing biofilm bacteria but also from that of the broth-grown planktonic bacteria commonly used for pathogenesis studies. The work importantly also identifies specific host factors responsible for the release of bacteria and their changed phenotype. We show that these interkingdom signals are recognized by bacteria and are induced by influenza virus infection, which is epidemiologically strongly associated with transition to secondary pneumococcal disease. As virus infection is a common inducer of transition to disease among species occupying the nasopharynx, the results of this study may provide a basis for better understanding of the signals involved in the transition from colonization to disease in the human nasopharynx.


Vegetation fire smoke, indigenous status and cardio-respiratory hospital admissions in Darwin, Australia, 1996-2005: a time-series study.
Air pollution in Darwin, Northern Australia, is dominated by smoke from seasonal fires in the surrounding savanna that burn during the dry season from April to November. Our aim was to study the association between particulate matter less than or equal to 10 microns diameter (PM10) and daily emergency hospital admissions for cardio-respiratory diseases for each fire season from 1996 to 2005. We also investigated whether the relationship differed in indigenous Australians; a disadvantaged population sub-group. Daily PM10 exposure levels were estimated for the population of the city from visibility data using a previously validated model. We used over-dispersed Poisson generalized linear models with parametric smoothing functions for time and meteorology to examine the association between admissions and PM10 up to three days prior. An interaction between indigenous status and PM10 was included to examine differences in the impact on indigenous people. We found both positive and negative associations and our estimates had wide confidence intervals. There were generally positive associations between respiratory disease and PM10 but not with cardiovascular disease. An increase of 10 microg/m3 in same-day estimated ambient PM10 was associated with a 4.81% (95%CI: -1.04%, 11.01%) increase in total respiratory admissions. When the interaction between indigenous status and PM10 was assessed a statistically different association was found between PM10 and admissions three days later for respiratory infections of indigenous people (15.02%; 95%CI: 3.73%, 27.54%) than for non-indigenous people (0.67%; 95%CI: -7.55%, 9.61%). There were generally negative estimates for cardiovascular conditions. For non-indigenous admissions the estimated association with total cardiovascular admissions for same day ambient PM10 and admissions was -3.43% (95%CI: -9.00%, 2.49%) and the estimate for indigenous admissions was -3.78% (95%CI: -13.4%, 6.91%), although ambient PM10 did have positive (non-significant) associations with cardiovascular admissions of indigenous people two and three days later. We observed positive associations between vegetation fire smoke and daily hospital admissions for respiratory diseases that were stronger in indigenous people. While this study was limited by the use of estimated rather than measured exposure data, the results are consistent with the currently small evidence base concerning this source of air pollution.


Prevalence, Severity, and Prognostic Effect of Hepatopulmonary Syndrome in Liver Transplant Candidates.
Hepatopulmonary syndrome (HPS) is commonly encountered in the setting of end-stage liver disease (ESLD). Past studies have reported conflicting results in terms of demonstrating an association between HPS and mortality. The aim of this study was to determine the prevalence of HPS in patients with ESLD referred for assessment of transplantation suitability. In addition, we investigated survival rates in the setting of HPS, with and without liver transplantation. The medical records of 524 consecutive patients with ESLD evaluated for potential liver transplantation were retrospectively reviewed. HPS was defined by a reduced partial pressure of oxygen or an elevated alveolar-arterial oxygen gradient and the presence of intrapulmonary vascular dilatation on contrast-enhanced echocardiography. In total, 57 subjects (12%) fulfilled the diagnostic criteria of HPS; 88% of these had mild to moderate HPS. For patients with HPS, the overall survival rates at 1 and 3 years were 95% and 92%, respectively. Liver transplants were received by 245 patients (53%), 26 of whom had HPS. For transplant recipients with HPS, the overall survival rates at 1 and 3 years were 96% and 91%, respectively, compared to 85% and 80% in subjects without HPS. Post-transplantation survival in patients with and without HPS did not differ significantly (HR=0.489, 95% CI: 0.153-1.564; p=0.228). This study demonstrated a high prevalence of IPVD and HPS among patients who were potential candidates for liver transplantation. HPS was mild to moderate in the majority of those affected and had no significant effect on overall survival.


Involvement of TRPC channels in lung cancer cell differentiation and the correlation analysis in human non-small cell lung cancer.
The canonical transient receptor potential (TRPC) channels are Ca(2+)-permeable cationic channels controlling the Ca(2+) influx evoked by G protein-coupled receptor activation and/or by Ca(2+) store depletion. Here we investigate the involvement of TRPCs in the cell differentiation of lung cancer. The expression of TRPCs and the correlation to cancer differentiation grade in non-small cell lung cancer (NSCLC) were analyzed by real-time PCR and immunostaining using tissue microarrays from 28 patient lung cancer samples. The association of TRPCs with cell differentiation was also investigated in the lung cancer cell line A549 by PCR and Western blotting. The channel activity was monitored by Ca(2+) imaging and patch recording after treatment with all-trans-retinoic acid (ATRA). The expression of TRPC1, 3, 4 and 6 was correlated to the differentiation grade of NSCLC in patients, but there was no correlation to age, sex, smoking history and lung cancer cell type. ATRA upregulated TRPC3, TRPC4 and TRPC6 expression and enhanced Ca(2+) influx in A549 cells, however, ATRA showed no direct effect on TRPC channels. Inhibition of TRPC channels by pore-blocking antibodies decreased the cell mitosis, which was counteracted by chronic treatment with ATRA. Blockade of TRPC channels inhibited A549 cell proliferation, while overexpression of TRPCs increased the proliferation. We conclude that TRPC expression correlates to lung cancer differentiation. TRPCs mediate the pharmacological effect of ATRA and play important roles in regulating lung cancer cell differentiation and proliferation, which gives a new understanding of lung cancer biology and potential anti-cancer therapy.


Elevated circulating levels of interferon-γ and interferon-γ-induced chemokines characterise patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis.
Interferon-γ (IFNγ) is the pivotal mediator in murine models of primary haemophagocytic lymphohistiocytosis (pHLH). Given the similarities between primary and secondary HLH (sec-HLH), including macrophage activation syndrome (MAS), we investigate the involvement of the IFNγ pathway in MAS by evaluating levels of IFNγ and of the induced chemokines, and their relation with laboratory parameters of MAS in systemic juvenile idiopathic arthritis (sJIA) patients with MAS and in a murine MAS model. The Luminex multiplexing assay was used to assess serum levels of interleukin (IL)-1β, IL-6, IFNγ and of the IFNγ-induced chemokines CXCL9, CXCL10 and CXCL11 in patients with sec-HLH (n=11) and in patients with sJIA (n=54), of whom 20 had active MAS at sampling. Expression of IFNγ-induced chemokines was assessed in IL-6 transgenic mice in which MAS is induced by TLR4 stimulation with lipopolysaccharide. Levels of IFNγ and of IFNγ-induced chemokines were markedly elevated during active MAS and sec-HLH and were significantly higher in patients with MAS compared with active sJIA without MAS. Levels in patients with active sJIA without MAS were comparable to those of patients with clinically inactive sJIA. During MAS, ferritin and alanine transferase levels and neutrophil and platelet counts were significantly correlated with serum levels of IFNγ and CXCL9. In murine MAS, serum levels of ferritin were significantly correlated with mRNA levels of Cxcl9 in liver and spleen. The high levels of IFNγ and of IFNγ-induced chemokines and their correlation with the severity of laboratory abnormalities of MAS suggest a pivotal role of IFNγ in MAS.


Network analysis of host-virus communities in bats and rodents reveals determinants of cross-species transmission.
Bats are natural reservoirs of several important emerging viruses. Cross-species transmission appears to be quite common among bats, which may contribute to their unique reservoir potential. Therefore, understanding the importance of bats as reservoirs requires examining them in a community context rather than concentrating on individual species. Here, we use a network approach to identify ecological and biological correlates of cross-species virus transmission in bats and rodents, another important host group. We show that given our current knowledge the bat viral sharing network is more connected than the rodent network, suggesting viruses may pass more easily between bat species. We identify host traits associated with important reservoir species: gregarious bats are more likely to share more viruses and bats which migrate regionally are important for spreading viruses through the network. We identify multiple communities of viral sharing within bats and rodents and highlight potential species traits that can help guide studies of novel pathogen emergence.


Are self-reports of breathing effort and breathing distress stable and valid measures among persons with asthma, persons with COPD, and healthy persons?
Breathing is a subjective experience that includes physical sensations, such as effort to breathe, and an affective element, such as breathing distress. The overall purpose of this investigation was to evaluate whether measurement of the physical sensations (breathing effort) and affective response to these sensations of breathing (breathing distress) are consistent and valid. A longitudinal repeated measures design was used to evaluate a 2-week daily breathing with a sub-sample (n = 43) who also recorded their daily breathing during 4 weeks. Age-matched, stable subjects (n = 92) with an average age of 62 were evaluated. The sample consisted of 32 subjects with chronic obstructive pulmonary disease, 27 subjects with asthma, and 33 healthy subjects. Visual Analogue Scales for breathing effort (VAS-E) and breathing distress (VAS-D) were scored daily. The VAS-E and VAS-D mean, highest, and lowest scores were found to be stable over time in the sub-sample and a significant difference (F = 2.56, P <.05) between VAS-E and VAS-D was found. Differences were found in mean and highest VAS-E and VAS-D by group, with the COPD group reporting the highest values. This investigation provided initial evidence of the stability and validity of daily VAS-E and VAS-D measures and preliminary support for the use of daily VAS logs to evaluate differences in breathing effort and breathing distress.


Apple Replant Disease: Causes and Mitigation Strategies.
After replanting apple (Malus domestica Borkh.) on the same site severe growth suppressions, and a decline in yield and fruit quality are observed in all apple producing areas worldwide. The causes of this complex phenomenon, called apple replant disease (ARD), are only poorly understood up to now which is in part due to inconsistencies in terms and methodologies. Therefore we suggest the following definition for ARD: ARD describes a harmfully disturbed physiological and morphological reaction of apple plants to soils that faced alterations in their (micro-) biome due to the previous apple cultures. The underlying interactions likely have multiple causes that extend beyond common analytical tools in microbial ecology. They are influenced by soil properties, faunal vectors, and trophic cascades, with genotype-specific effects on plant secondary metabolism, particularly phytoalexin biosynthesis. Yet, emerging tools allow to unravel the soil and rhizosphere (micro-) biome, to characterize alterations of habitat quality, and to decipher the plant reactions. Thereby, deep insights into the reactions taking place at the root rhizosphere interface will be gained. Counteractions are suggested, taking into account that culture management should emphasize on improving soil microbial and faunal diversity as well as habitat quality rather than focus on soil disinfection.


Supramolecular Assembly of Biobased Graphene Oxide Quantum Dots Controls the Morphology of and Induces Mineralization on Poly(ε-caprolactone) Films.
Biobased 2D graphene oxide quantum dots (GOQDs) were synthesized from waste paper via carbon nanosphere intermediates and evaluated as property-enhancing additives for poly(ε-caprolactone) (PCL). The morphology of PCL films was controlled by supramolecular assembly of the small, 2D GOQDs in the polymer matrix. Phase behavior studies of PCL-GOQD in the solid state indicated concentration-dependent self-association of GOQD sheets, which was confirmed by SEM observations. Depending on the GOQD concentration, the formation of, e.g., spheres and stacked sheets was observed. GOQDs also induced mineralization on the surface of the films. A calcium phosphate (CaP) mineralization test revealed that the density of growing CaP crystals was controlled by the type of GOQD aggregates formed. Thus, utilization of the aggregation behavior of small GOQD sheets in polymeric matrices paves the way for tuning the morphology and properties of nanocomposites.


[Usefulness of fluorodeoxyglucose-positron emission tomography in a case of pleural sarcoidosis].
Pleural sarcoidosis is not a rare disease, and some patients with sarcoidosis experience chest pain, although the cause is often unknown. Various studies have indicated that fluorodeoxyglucose-positron emission tomography (FDG-PET) is useful for diagnosing and monitoring sarcoidosis. A 62-year-old man noted left-side dominant chest and back pain, although chest computed tomography (CT) revealed no abnormalities. Two months later, chest and back pain rapidly increased in severity and blurred vision appeared. In addition to uveitis, renal dysfunction was observed and chest CT on admission revealed enlargement of bilateral hilar/mediastinal lymph nodes and diffuse small nodular opacities and subpleural nodules, mainly in the segment of the left upper lobe (S1+2). FDG-PET revealed intense FDG uptake in bilateral peripheral lung parenchyma, spread widely along the subpleura and right inguinal lymph nodes with high uptake in the hilar and mediastinal lymph nodes. Sarcoidosis was diagnosed by transbronchial lung biopsy and renal biopsy. Oral corticosteroid treatment was performed due to persistent chest and back pain and rapid progression of renal dysfunction. Chest and back pain immediately disappeared and renal function improved. Follow-up FDG-PET performed 2 months after corticosteroid treatment revealed no areas of intense FDG uptake.


Metavirome Sequencing to Evaluate Norovirus Diversity in Sewage and Related Bioaccumulated Oysters.
Metagenomic sequencing is a promising method to determine the virus diversity in environmental samples such as sewage or shellfish. However, to identify the short RNA genomes of human enteric viruses among the large diversity of nucleic acids present in such complex matrices, method optimization is still needed. This work presents methodological developments focused on norovirus, a small ssRNA non-enveloped virus known as the major cause of human gastroenteritis worldwide and frequently present in human excreta and sewage. Different elution protocols were applied and Illumina MiSeq technology were used to study norovirus diversity. A double approach, agnostic deep sequencing and a capture-based approach (VirCapSeq-VERT) was used to identify norovirus in environmental samples. Family-specific viral contigs were classified and sorted by SLIM and final norovirus contigs were genotyped using the online Norovirus genotyping tool v2.0. From sewage samples, 14 norovirus genogroup I sequences were identified of which six were complete genomes. For norovirus genogroup II, nine sequences were identified and three of them comprised more than half of the genome. In oyster samples bioaccumulated with these sewage samples, only the use of an enrichment step during library preparation allowed successful identification of nine different sequences of norovirus genogroup I and four for genogroup II (>500 bp). This study demonstrates the importance of method development to increase virus recovery, and the interest of a capture-based approach to be able to identify viruses present at low concentrations.


Comparison of Boer, Kiko, and Spanish meat goat does for stayability and cumulative reproductive output in the humid subtropical southeastern United States.
Longevity is the amount of time breeding females stay active in a herd by avoiding death or culling because of illness or reproductive failure. This is a trait of economic relevance in commercial small ruminant breeding herds as it affects lifetime reproductive output. The purpose of this study was to determine if breed of meat goat influences breeding doe survival rates and cumulative reproductive performance under semi-intensive management. Boer (n = 132), Kiko (n = 92) and Spanish (n = 79) does were evaluated for longevity trends and cumulative kid production. The herd was managed on humid subtropical pasture. Does had the chance to complete 2 to 6 production years. Survival curves were analyzed for 2 culling methods. The actual culling practice removed does after two failures to wean a kid. An alternative culling protocol removed doe records after the first failure to wean a kid. Kid production traits analyzed across herd life were the total number of kids weaned and cumulative kid weight weaned to the 2-, 3-, and 5-year stayability endpoints. Most (82%) doe exits were illness-related under the actual culling method. Reproductive failure represented 51% of doe exits under the alternative culling protocol. Boer does had greater survival declines (P < 0.01) from 2 to 6 years of herd life compared with Kiko and Spanish under both culling protocols. Boer does had lower stayability rates (P < 0.01) at each year endpoint for both culling protocols. Under the alternative protocol, over 50% of Boer does failed to complete 2 years, whereas over 50% of Kiko and Spanish does successfully completed 4 years. Boer does had lower (P < 0.01) total number of kids weaned and cumulative weight weaned through each stayability endpoint compared with Kiko and Spanish. Boer does had low stayability and cumulative kid production rates compared with Kiko and Spanish does. Poor health was the primary driver of does exiting the herd. Kiko and Spanish does did not differ for longevity and lifetime performance indicators.


Transcription factories, chromatin loops, and the dysregulation of gene expression in malignancy.
Pathologists recognize and classify cancers according to nuclear morphology, but there remains little scientific explanation of why malignant nuclei possess their characteristic features, or how those features are related to dysregulated function. This essay will discuss a basic structure-function axis that connects one central architectural motif in the nucleus-the chromatin loop-to the vital nuclear function of transcription. The loop is attached to a "transcription factory" through components of the transcription machinery (either polymerases or transcriptional activators/repressors), and the position of a gene within a loop determines how often that gene is transcribed. Then, dysregulated transcription is tightly coupled to alterations in structure, and vice versa. We also speculate on how the experimental approaches being used to analyze loops and factories might be applied to study the problems of tumour initiation and progression.


Centennial-scale Holocene climate variations amplified by Antarctic Ice Sheet discharge.
Proxy-based indicators of past climate change show that current global climate models systematically underestimate Holocene-epoch climate variability on centennial to multi-millennial timescales, with the mismatch increasing for longer periods. Proposed explanations for the discrepancy include ocean-atmosphere coupling that is too weak in models, insufficient energy cascades from smaller to larger spatial and temporal scales, or that global climate models do not consider slow climate feedbacks related to the carbon cycle or interactions between ice sheets and climate. Such interactions, however, are known to have strongly affected centennial- to orbital-scale climate variability during past glaciations, and are likely to be important in future climate change. Here we show that fluctuations in Antarctic Ice Sheet discharge caused by relatively small changes in subsurface ocean temperature can amplify multi-centennial climate variability regionally and globally, suggesting that a dynamic Antarctic Ice Sheet may have driven climate fluctuations during the Holocene. We analysed high-temporal-resolution records of iceberg-rafted debris derived from the Antarctic Ice Sheet, and performed both high-spatial-resolution ice-sheet modelling of the Antarctic Ice Sheet and multi-millennial global climate model simulations. Ice-sheet responses to decadal-scale ocean forcing appear to be less important, possibly indicating that the future response of the Antarctic Ice Sheet will be governed more by long-term anthropogenic warming combined with multi-centennial natural variability than by annual or decadal climate oscillations.


Lasting biological effects of early environmental influences. VII. Metabolism of adenosine in mice exposed to early environmental stress.
The metabolism of adenosine 3',5'-monophosphate (cyclic AMP) was studied in specific pathogen-free mice exposed to neonatal infection with mouse enterovirus or to malnutrition during early life. Metabolic activity was determined by measuring the turnover of cyclic AMP-8-(14)C to respiratory (14)CO(2), its incorporation into various organs and plasma, and the binding activity of synaptosome for cyclic AMP. Early malnutrition increased the catabolism of cyclic AMP as measured by expiration in respiratory CO(2). The level of cyclic AMP was lower in plasma and its incorporation into various tissues was decreased in infected and malnourished animals. Metabolic products of cyclic AMP were isolated from plasma by ion exchange chromatography. Cyclic AMP-8-(14)C had completely disappeared 9 hr after injection. Fewer metabolites of cyclic AMP were detected in infected or malnourished groups than in controls and the metabolic reaction from 5'-AMP to adenosine seemed to be slow in these animals. The ability to incorporate cyclic AMP to synaptosome was also impaired in the experimental groups. The concentrations of brain cyclic AMP were lower in infected or malnourished animals than in controls. Depression of accumulation of cyclic AMP probably resulted from excessive activity of phosphodiesterase, rather than from impairment of adenyl cyclase. Intraperitoneal administration of theophylline brought the activity level of phosphodiesterase to normal in infected or malnourished mice; this fact probably accounted for enhanced accumulation of brain cyclic AMP.


Transcultural adaptation of the Breast Cancer Awareness Measure.
To overcome the lack of a validated and robust Arabic instrument to measure breast cancer awareness. Currently, there is no validated Arabic instrument for measuring breast cancer awareness levels. We adapted, translated and validated the Breast Cancer Awareness Measure developed by Cancer Research UK. The instrument was translated into Arabic and back-translated for validation. Validation and reliability tests were conducted using purposively sampled 972 Arab women older than 20 years, living in Oman. The adapted content was validated by a panel of medical, linguistic and cultural experts, followed by cognitive interviews (n = 10), behavioural coding (n = 30) and criterion validation (n = 646). The instrument was tested for acceptability and its subscales for internal consistency. Inter-rater reliability was estimated between two similar groups (n = 144 and n = 142) to test homogeneity. The adapted and translated instrument had a high acceptability (98.7% completed). The validation process shaped the adaptation, and resulted in strong criterion validity (R = 0.58, P < 0.01). The instrument subscales for risk factors and warning signs had high internal consistency (Cronbach's alpha 0.856 and 0.890, respectively), with all floor and ceiling effects less than 15%. The correlation measure for inter-rater reliability was 0.97 (P < 0.01). Through the incorporation of contextual characteristics and prevalent beliefs among Arab populations, the adapted Best Cancer Awareness Measure is a robust Arabic instrument for the measurement of breast cancer awareness and early detection practices among Arab women. The purposively selected sample may not be representative of the population. Improvement of awareness and early detection of breast cancer can contribute towards reducing mortality from the disease. The adapted instrument has policy implications, since measurement of awareness levels is essential towards breast health promotion policies in Arab countries.


High prevalence of occult thrombosis in cases of mild/moderate COVID-19.
An increasing number of reports have observed thrombosis in severe cases of COVID-19. The aim of this study was to evaluate the incidence of thromboembolism in mild/moderate cases of COVID-19. All of the patients had normal coagulation tests and none had any overt thrombotic complications. Our findings indicate that it is important to screen the thrombotic status of cases with mild/moderate COVID-19. Between 11 June and 8 July 2020, 23 patients with mild/moderate COVID-19 pneumonia consented to having computed tomography pulmonary angiography (CPTA) and computed tomography venography (CTV) scans of the lungs and extremity veins. Doppler ultrasound (DUS) was also performed in all patients for screening. The incidence, clinical manifestations, laboratory examinations, imaging features, and prognosis, of patients with venous thromboembolism (VTE) were analyzed and compared with those of patients with COVID-19 pneumonia without VTE. Nineteen patients (82.6%) had VTE, mainly distal limb thrombosis. Only one of the VTE patients was positive when screened by DUS; the other VTE patients were negative by DUS. All of the mild/moderate patients with VTE were screened by CTPA + CTV. Blood tests for inflammatory, coagulation, and biochemical, parameters were all within the normal range, except for WBC and LDH. When using CTV screening for DVT, we found that the incidence of thrombosis in patients with mild/moderate COVID-19 markedly increased to 82.6% (19/23). Screening for thrombosis is therefore important in patients with COVID-19. CTV is more sensitive than DUS for the detection of thrombosis. More research is now needed to evaluate the significance of thrombosis in COVID-19 pneumonia.


Sleep symptoms and clinical markers of illness in patients with heart failure.
The purpose of this study was to survey patients with heart failure (HF) for sleep symptoms using a standardized questionnaire and correlate symptoms with conventional markers of clinical status. A self-report paper questionnaire was offered to patients presenting to a tertiary care HF clinic. Symptoms were grouped according to "risk" categories and correlated with routine clinical information. One hundred six (52.7% of 201 with all data) respondents had a high pretest probability for sleep apnea syndrome. Sixty three (31.3%) reported symptoms suggesting the presence of chronic insomnia; seven (3.5%) and eight (4%) reported symptoms of narcolepsy and restless legs syndrome, respectively. High-risk respondents for sleep apnea had a higher body mass index (p<0.001), were younger (p<0.05), and had a higher ejection fraction (p<0.05). The odds ratio (confidence interval) for paroxysmal nocturnal dyspnea (PND) to a complaint of sleepiness was 1.99 (1.1-3.6) and to a complaint of insomnia was 3.5 (1.8-6.5). In men, complaints of sleepiness in patients with PND were correlated, 4.47 (1.9-10.3), as was a correlation to high pretest probability for sleep apnea, 2.47 (1.1-5.5). There were no correlation of New York Heart Association status classification to high risk for sleep apnea, but a complaint of insomnia tended to occur with worsening functional status (p<0.05). There was only modest correlation of self-reported symptoms as elicited by a questionnaire and risk for sleep disorders with common clinical assessments for HF. Such collection of symptoms might be useful in establishing guidelines for routine sleep testing or as an adjunct to clinical trials.


Efficacies of plant phenolic compounds on sodium butyrate induced anti-tumour activity.
The ability of the differentiation inducing agent sodium butyrate (NaB) alone or combined with plant-derived phenolic compounds to produce growth inhibition in human erythroleukemic cells was investigated. As a single agent, curcumin produced a marked inhibition of proliferation indicated by its low concentration used. The effect of phenolics on the cell cycle could probably contribute to the augmented antiproliferative activity of NaB. The present data show that quercetin produced synergistic effect in terms of cell killing in association with NaB. Both curcumin and ferulic acid potentiated NaB-induced reduction of cell number. When NaB was added before exposure to graded doses of quercetin it did induce a greater inhibitory effect. The combination of NaB and quercetin seems less effective on S180 ascites tumour cells. As a single agent quercetin was found to be the most efficacious on S180 tumour model.


V3 variation in HIV-seropositive patients receiving a V3- targeted vaccine.
To analyze V3 loop sequences of HIV-1 in three seropositive individuals who exhibited declines in viremia while receiving a V3-targeted vaccine. Retrospective analysis of case series at an HIV Clinic, University of Tel Aviv. Three HIV-1-seropositive, PPD-DTHR-positive (PPD, Siebert purified protein derivative of tuberculin; DTHR, delayed type hypersensitivity reaction) individuals who had been inoculated with a mixture of PPD-cross-linked V3 peptides from five HIV strains and then exhibited declines in HIV-1 viremia during the course of vaccination in the absence of combination antiretroviral therapy and whose virus levels resurged once vaccine boosting was discontinued. Declines in viremia were observed even when the viral V3 sequences of the patients' HIV differed by at least one or two amino acid residues from those of the five peptides in the vaccine. Although viral mutants with amino acid substitutions within V3 appeared during vaccination, plasma virus loads remained at low levels for several months after these variants appeared. About a year after boosting was discontinued, anti-V3 peptide antibodies in the patients had declined and plasma virus returned to the prevaccination levels or higher. Compared with the isolates that predominated during the course of vaccination, the resurgent viruses contained zero to six amino acid residue differences in the V3 loop but few synonymous substitutions. Viruses with altered V3 sequences did emerge but did not result in increased viremia during the course of vaccination. In two individuals where V3 mutations were absent in the virus that re-emerged after vaccine boosting ceased, resurgence could not have been a consequence of V3 changes.


Bis- and mono(m-benzoic acid)-functionalized pillar[5]arenes.
Installation of m-benzoic acid functionalities on pillar[5]arene rims resulted in bis- and mono(m-benzoic acid)-functionalized pillar[5]arenes 1 and 2. Bis(m-benzoic acid)-functionalized pillar[5]arene 1 was able to self-assemble to form one-dimensional channels with DMF molecules residing in pillar[5]arene cavities. Esterification of two carboxylic acids in 1 with decane-1,10-diol did not afford a [1]catenane, but a bicyclic compound. Although 1-decanol esterification of mono(m-benzoic acid)-functionalized pillar[5]arene 2 did not form a self-included [1]pseudorotaxane-like structure, a mono(decyl m-benzoate)-functionalized pillar[5]arene bearing an ethyl acetate chain was found to form a self-included complex with the ethyl acetate moiety residing inside the pillar[5]arene cavity.


COVID-19 and coagulative axis: review of emerging aspects in a novel disease.
Latest evidences from literature suggest that SARS-CoV-2 disease 2019 (COVID-19) is commonly complicated with coagulopathy and that disseminated intravascular coagulation is present in the majority of deceased patients. Particularly, conventional coagulation parameters appear to be significantly altered in patients with poor prognosis. A wide-ranging cross- talk between coagulative haemostasis and inflammation, as well as the activation of coagulation cascade during viral infections, are well established. Another important evidence which may explain coagulation disorders in COVID-19 is the increase of thrombus formation under conditions of hypoxia. Despite the exact pathophysiological mechanism of coronavirus-induced thromboembolism needs to be further investigated, this finding suggests that it is good practice to assess the risk of thrombosis in COVID-19 patients to improvethe clinical management in terms of anticoagulation therapy. Anticoagulants, mainly low-molecular-weight heparin (LMWH), should be tailored in patients meeting sepsis induced coagulopathy (SIC) criteria or with markedly elevated D-dimer. In this context, further studies are needed to optimise the decision making in therapeutic approach.


The clinical impact of expert pathological review on lymphoma management: a regional experience.
The All Wales Lymphoma Panel (AWLP) was established in January 1998 to provide a central expert pathological review service for district general hospital pathologists. A discordance rate of 20% between the submitted and reviewed diagnosis has previously been identified. It has not been known whether this change in diagnosis affects clinical management. Ninety-nine patients whose diagnosis was changed as a result of central pathological review are presented. Between January 1998 and August 2000, 125 of 745 (17%) specimens submitted for AWLP review had a consequent change in pathological diagnosis. Of these 125 specimens, 99 (79%) complete case notes were recovered. In all 99 cases, a hypothetical management plan was generated using collected data, clinical protocols and the submitted pathological diagnosis. These plans were compared with the actual management patients received based on the reviewed diagnosis proffered by the AWLP. Forty-six of 99 (46%) cases had a change in management as a result of central pathological review. Overall, management was changed in 8% of cases referred for central pathological review. In conclusion, expert central pathological review has a direct effect on patient management.


Multidrug-Resistant Mycobacterium tuberculosis of the Latin American Mediterranean Lineage, Wrongly Identified as Mycobacterium pinnipedii (Spoligotype International Type 863 [SIT863]), Causing Active Tuberculosis in South Brazil.
We recently detected the spoligotype patterns of strains of Mycobacterium pinnipedii, a species of the Mycobacterium tuberculosis complex, in sputum samples from nine cases with pulmonary tuberculosis residing in Porto Alegre, South Brazil. Because this species is rarely encountered in humans, we further characterized these nine isolates by additional genotyping techniques, including 24-locus mycobacterial interspersed repetitive-unit-variable-number tandem-repeat (MIRU-VNTR) typing, verification of the loci TbD1, RD9, pks15/1, RD(Rio), and fbpC, the insertion of IS6110 at a site specific to the M. tuberculosis Latin American Mediterranean (LAM) lineage, and whole-genome sequencing. The combined analysis of these markers revealed that the isolates are in fact M. tuberculosis and more specifically belong to the LAM genotype. Most of these isolates (n8) were shown to be multidrug resistant (MDR), which prompted us to perform partial sequencing of the rpoA, rpoB, rpoC, katG, and inhA genes. Seven isolates (77.8%) carried the S315T mutation in katG, and one of these (11%) also presented the C((-17)T single-nucleotide polymorphism (SNP) in inhA. Interestingly, six of the MDR isolates also presented an undescribed insertion of 12 nucleotides (CCA GAA CAA CCC) in codon 516 of rpoB. No putative compensatory mutation was found in either rpoA or rpoC. This is the first report of an M. tuberculosis LAM family strain with a convergent M. pinnipedii spoligotype. These spoligotypes are observed in genotype databases at a modest frequency, highlighting that care must be taken when identifying isolates in the M. tuberculosis complex on the basis of single genetic markers.


Kv2.1: a voltage-gated k+ channel critical to dynamic control of neuronal excitability.
Neurons use a variety of mechanisms to dynamically control their own signaling capabilities. Regulation of voltage-dependent K+ channel localization and function has long been recognized as a major mechanism to achieve dynamic regulation of intrinsic neuronal excitability in a number of mammalian and non-mammalian neurons. Our recent evidence, together with compelling data from other laboratories, suggests that in mammalian neurons the Kv2.1 channel may play an especially prominent role in determining intrinsic neuronal excitability. Kv2.1 is widely expressed in brain and composes the majority of delayed rectifier K+ current in pyramidal neurons in cortex and hippocampus, and is also widely expressed in interneurons. Dynamic modulation of Kv2.1 localization and function by a mechanism involving activity-dependent Kv2.1 dephosphorylation dramatically impacts intrinsic excitability of neurons. Here we review previous studies of Kv2.1 localization and function in neurons, and summarize recent work regarding dynamic regulation of these characteristics. We also discuss possible roles of the Kv2.1 channel in neuronal and network excitability.


Trends in opioid analgesic use for headaches in US emergency departments.
Although not recommended as first line therapy by consensus guidelines, opioid analgesics are commonly used to treat headaches. This study evaluates trends in opioid use for headaches in US emergency departments (EDs). We performed a retrospective review of the National Hospital Ambulatory Medical Care Survey, 2001 through 2010. Adult headache-related visits were identified. Medications (opioid and nonopioid) used for the treatment of headache were categorized based on medication class. Trends in ED use of the most common opioids (codeine, hydrocodone, hydromorphone, morphine, and oxycodone) were explored. The proportion of visits for which each medication was used was tabulated, and trends were analyzed using survey-weighted logistic regression. Headache visits during which any opioid was used increased between 2001 (20.6%; 95% confidence interval [CI], 18.1-23.4) and 2010 (35.0%; 95% CI, 31.8-38.4; P < .001). Prescribing of hydromorphone, morphine, and oxycodone increased, with the largest relative increase (461.1%) in hydromorphone (2001, 1.8% [95% CI, 1.2-2.6]; 2010, 10.1% [95% CI, 8.2-12.4]). Codeine use declined, and hydrocodone use remained stable. Use of opioid alternatives, including acetaminophen, butalbital, and triptans did not change over the study period, whereas use of nonsteroidal anti-inflammatory drugs increased from 26.2% (95% CI, 23.0-29.7) to 31.4% (95% CI, 28.6-34.3). Prescribing of antiemetic agents decreased from 24.1% (95% CI, 19.6-29.2) to 23.5% (95% CI, 21.1-26.0). Intravenous fluid use increased from 20.0% (95% CI, 17.0-23.4) to 34.5% (95% CI, 31.0-38.2) of visits. Despite limited endorsement by consensus guidelines, there was increased use of opioid analgesics to treat headaches in US EDs over the past decade.


Insights into the regenerative property of plant cells and their receptivity to transgenesis: wheat as a research case study.
From a holistic perspective, the discovery of cellular plasticity, a very interesting property of totipotency, underlies many topical issues in biology with important medical applications, while transgenesis is a core research tool in biology. Partially known, some basic mechanisms involved in the regenerative property of cells and in their receptivity to transgenesis are common to plant and animal cells and highlight the principle of the unity of life. Transgenesis provides an important investigative instrument in plant physiology and is regarded as a valuable tool for crop improvement. The economic, social, cultural and scientific importance of cereals has led to a rich stream of research into their genetics, biology and evolution. Sustained efforts to achieve the results obtained in the fields of genetic engineering and applied biotechnology reflect this deep interest. Difficulties encountered in creating genetically modified cereals, especially wheat, highlighted the central notions of tissue culture regeneration and transformation competencies. From the perspective of combining or encountering these competencies in the same cell lineage, this reputedly recalcitrant species provides a stimulating biological system in which to explore the physiological and genetic complexity of both competencies. The former involves two phases, dedifferentiation and redifferentiation. Cells undergo development switches regulated by extrinsic and intrinsic factors. The re-entry into the cell division cycle progressively culminates in the development of organized structures. This is achieved by global chromatin reorganization associated with the reprogramming of the gene expression pattern. The latter is linked with surveillance mechanisms and DNA repair, aimed at maintaining genome integrity before cells move into mitosis, and with those mechanisms aimed at genome expression control and regulation. In order to clarify the biological basis of these two physiological properties and their interconnectedness, we look at both competencies at the core of defense/adaptive mechanisms and survival, between undifferentiated cell proliferation and organization, constituting a transition phase between two different dynamic regimes, a typical feature of critical dynamic systems. Opting for a candidate-gene strategy, several gene families could be proposed as relevant targets for investigating this hypothesis at the molecular level.


Doxorubicin cardiotoxicity may be caused by its metabolite, doxorubicinol.
Doxorubicin (former generic name, adriamycin), a highly effective anticancer drug, produces cardiotoxicity, which limits its therapeutic potential. The mechanism of this cardiotoxicity has remained elusive. Our data suggest that this toxicity could involve doxorubicinol, the primary circulating metabolite of doxorubicin. Doxorubicinol was markedly more potent than doxorubicin at compromising both systolic and diastolic cardiac function. Similarly, doxorubicinol was much more potent than doxorubicin at inhibiting the calcium pump of sarcoplasmic reticulum [ATP phosphohydrolase (Ca2+-transporting), EC 18.104.22.168], the Na+/K+ pump of sarcolemma [ATP phosphohydrolase (Na+/K+-transporting), EC 18.104.22.168], and the F0F1 proton pump of mitochondria [ATP phosphohydrolase (H+-transporting, EC 22.214.171.124]. Our finding that this highly toxic metabolite was produced by cardiac tissue exposed to doxorubicin suggests that doxorubicinol could accumulate in the heart and contribute significantly to the chronic cumulative cardiotoxicity of doxorubicin therapy. Our observation that doxorubicin was more potent than doxorubicinol in inhibiting tumor cell growth in vitro suggests that the cardiotoxicity of doxorubicin is dissociable from its anticancer activity.


Molecular targeting of BCL2 and BCLXL proteins by synthetic BCL2 homology 3 domain peptide enhances the efficacy of chemotherapy.
Chemotherapeutic agents are known to induce programmed cell death or apoptosis. The activation of cellular antiapoptotic defense that prevents the translation of drug-induced damage into cell death is the key factor in cellular antiapoptotic resistance that decreases the chemotherapeutic effectiveness of a broad spectrum of anticancer drugs. A novel proapoptotic anticancer drug delivery system (DDS) was designed to simultaneously induce apoptosis and suppress antiapoptotic cellular defense. The system includes three main components: 1) anticancer drug camptothecin (CPT) as an apoptosis inducer, 2) synthetic BCL2 homology 3 domain (BH3) peptide as a suppressor of cellular antiapoptotic defense, and 3) poly(ethylene glycol) (PEG) polymer as a carrier. The above DDS was studied in vitro using A2780 human ovarian carcinoma cells and in vivo on nude mice bearing xenografts of human ovarian tumor. The results obtained in both series of experiments corroborate each other. They show that the designed DDS provided intracellular delivery of active components and suppressed cellular antiapoptotic defense, leading to the more pronounced induction of caspase-dependent signaling pathway of apoptosis compared with CPT alone and simple CPT-PEG conjugate. Including BH3 peptide in complex DDS decreased apoptotic cellular defense, substantially increased toxicity of the whole complex, and provided high antitumor activity. Therefore, the proposed novel multicomponent proapoptotic anticancer drug delivery system has high potential to enhance the efficacy of chemotherapy.


Radioenvironmental survey of the Megalopolis lignite field basin.
The Megalopolis lignite field basin in southern Greece, with Megalopolis-A and B lignite-fired power plants in operation (total 900 MW), has been repeatedly investigated during the past 25 years by the Nuclear Engineering Section of the National Technical University of Athens (NES-NTUA). The present work aims at an integrated radioenvironmental approach leading to the dose assessment to the public and to the plants staff. This approach includes systematic sampling of lignite and barren at the local lignite mines feeding the power plants and sampling of lignite, fly-ash and bottom ash at the power plants for the determination of the activity of the natural radionuclides 226Ra, 232Th, 40K, 234Th and 210Pb. Furthermore, the following measurements and samplings were conducted in 25 selected sites within 10 km around the power plants: soil sampling for the determination of the above radionuclides, radon concentration and exhalation rate measurements, soil gas radon concentration measurements, dose measurements and calculations, determination of air-particulate matter concentration, etc. The results obtained allowed for the mapping of the parameters studied which lead to useful conclusions. Dosimetric calculations for the population living around the power plants and the plants staff were also performed based on the guidance of UNSCEAR (1982 report).


Spontaneous emission control in high-extraction efficiency plasmonic crystals.
We experimentally and theoretically investigate exciton-field coupling for the surface plasmon polariton (SPP) in waveguide-confined (WC) anti-symmetric modes of hexagonal plasmonic crystals in InP-TiOAu-TiO-Si heterostructures. The radiative decay time of the InP-based transverse magnetic (TM)-strained multi-quantum well (MQW) coupled to the SPP modes is observed to be 2.9-3.7 times shorter than that of a bare MQW wafer. Theoretically we find that 80 % of the enhanced photoluminescence (PL) is emitted into SPP modes, and 17 % of the enhanced PL is redirected into WC-anti-symmetric modes. In addition to the direct coupling of the excitons to the plasmonic modes, this demonstration is also useful for the development of high-temperature SPP lasers, the development of highly integrated photo-electrical devices, or miniaturized biosensors.


Effect of long-term fluoride exposure on lipid peroxidation and histology of testes in first- and second-generation rats.
This experiment was designed to investigate the histological and lipid peroxidation effects of chronic fluorosis on testes tissues of first- and second-generation rats. Sixteen virgin female Wistar rats were mated with eight males (2:1) for approximately 12 h to obtain first-generation rats. Pregnant rats were divided into two groups: controls and fluoride-given group, each of which containing five rats. Pregnant rats in the fluoride-given group were exposed to a total dose of 30 mg/l sodium fluoride (NaF) in commercial drinking water containing 0.07 mg/l of NaF throughout the gestation and lactation periods. After the lactation period, the young animals (first generation, F1) were exposed to the same dose of NaF in drinking water for 4 months. At the end of the 4 months of experimental period, nine randomly chosen male rats (F1) were killed and testes tissues were taken for histopathological and biochemical analysis. The remaining eight female rats were mated with four males (2:1) for approximately 12 h to obtain second-generation rats. Six female were identified as pregnant and treated with similarly throughout the gestation and the lactation periods. After the lactation period, the young male animals (second generation, F2) were also treated in the same way for 4 months. At the end of the 4 months of experimental period, nine randomly chosen male rats (F2) were killed and testes tissues were collected for histopathological and biochemical analysis. The rats in the control group were applied the same procedure without NaF administration. In biochemical analysis of the fluoride given F1 and F2 rats, it has been found that plasma fluoride levels and testes thiobarbituric acid reactive substance levels were significantly increased when compared with the control group. In F1 and F2 rats, similar histopathological changes were observed. In both groups, spermatogenesis was severely reduced. Spermatogonia and primary spermatocytes were normal, however, there was a widespread degeneration in other spermatogenic cell lines of the seminiferous epithelium. The histological structures of the Sertoli and interstitial Leydig cells were normally observed. It is concluded that chronic fluorosis exposure leads to a remarkable destruction in testes tissues of F1 and F2 rats via lipid peroxidation.


Geometric least squares means ratios for the analysis of Plasmodium falciparum in vitro susceptibility to antimalarial drugs.
The susceptibility of microbes such as Plasmodium falciparum to drugs is measured in vitro as the concentration of the drug achieving 50% of maximum effect (IC50); values from a population are summarized as geometric means. For antimalarial drugs, as well as for antibiotics, assessing changes in microbe susceptibility over time under drug pressure would help inform treatment policy decisions, but no standard statistical method exists as yet. A mixed model was generated on loge-transformed IC50 values and calculated geometric least squares means (GLSM) with 90% confidence intervals (CIs). In order to compare IC50s between years, GLSM ratios (GLSMR) with 90%CIs were calculated and, when both limits of the 90%CIs were below or above 100%, the difference was considered statistically significant. Results were compared to those obtained from ANOVA and a generalized linear model (GLM). GLSMRs were more conservative than ANOVA and resulted in lower levels of statistical significance. The GLSMRs approach allowed for random effect and adjustment for multiple comparisons. GLM was limited in the number of year-to-year comparisons by the need for a single reference year. The three analyses yielded generally consistent results. A robust analytical method can palliate inherent limitations of in vitro sensitivity testing. The random effects GLSMRs with adjustment for multiple comparisons and 90%CIs require only assumptions on the mixed model to be applied. Results are easy to display graphically and to interpret. The GLMSRs should be considered as an option for monitoring changes in drug susceptibility of P. falciparum malaria and other microbes.


Multicenter research into the quality of life of patients with advanced oropharyngeal carcinoma with long-term survival associated with human papilloma virus.
The treatment of advanced-stage oropharyngeal squamous cell carcinoma may utilize various modes, including combining surgery with chemoradiotherapy (CTRT), or primary CTRT followed by rescue surgery. In previous literature it has been revealed how patients treated with combined modes report a low quality of life (QoL) and severe consequences following surgery, radiotherapy and chemotherapy, in the short and in the long-term. The decrease in the QoL of patients treated with high-intensity multi-modal strategies highlights the necessity of modifying treatments, particularly for young HPV-positive patients, where an increased survival rate has already been reported. The modified treatment for HPV-positive tumors in the tonsils and at the base of the tongue is based on the deintensification of therapies aiming to reduce toxicity and thereby improve QoL in the long term, whilst still maintaining therapeutic effectiveness. The aim of the present study was to evaluate the QoL in patients with a long-term survival, who were treated with combined therapy for squamous cell tumors in the tonsils and at the base of the tongue, and to compare the results observed in HPV-positive and HPV-negative patients. According to statistical analysis, differences in the general QoL and in the single scales of the European Organization for the Research and Treatment of Cancer questionnaires were not correlated with the type of therapy selected for the particular patient. QoL considered the presence of HPV, the type of treatment, the subregion of the tonsils vs. the base of the tongue and the disease stage at the time of diagnosis, and was determined to be non-influential with regard to these specific variables.


Delayed linkage to care in one-third of HIV-positive individuals in the Netherlands.
To determine time to linkage to HIV care following diagnosis and to identify risk factors for delayed linkage. Patients newly diagnosed with HIV at sexually transmitted infections (STI) clinics in the Netherlands were followed until linkage to care. Data were collected at the time of diagnosis and at first consultation in care, including demographics, behavioural information, CD4+ counts and HIV viral load (VL) measurements. Delayed linkage to care was defined as >4 weeks between HIV diagnosis and first consultation. 310 participants were included; the majority (90%) being men who have sex with men (MSM). For 259 participants (84%), a date of first consultation in care was known; median time to linkage was 9 days (range 0-435). Overall, 95 (31%) of the participants were not linked within 4 weeks of diagnosis; among them, 44 were linked late, and 51 were not linked at all by the end of study follow-up. Being young (<25 years), having non-Western ethnicity or lacking health insurance were independently associated with delayed linkage to care as well as being referred to care indirectly. Baseline CD4+ count, VL, perceived social support and stigma at diagnosis were not associated with delayed linkage. Risk behaviour and CD4+ counts declined between diagnosis and linkage to care. Although most newly diagnosed patients with HIV were linked to care within 4 weeks, delay was observed for one-third, with over half of them not yet linked at the end of follow-up. Vulnerable subpopulations (young, uninsured, ethnic minority) were at risk for delayed linkage. Testing those at risk is not sufficient, timely linkage to care needs to be better assured as well.


Perceived barriers to computerised quality documentation during anaesthesia: a survey of anaesthesia staff.
Underreporting of intraoperative events in anaesthesia is well-known and compromises quality documentation. The reasons for such omissions remain unclear. We conducted a questionnaire-based survey of anaesthesia staff to explore perceived barriers to reliable documentation during anaesthesia. Participants anonymously completed a paper-based questionnaire. Predefined answers referred to potential barriers. Additional written comments were encouraged. Differences between physician and nurse anaesthetists were tested with t-tests and chi-square tests. Twenty-five physician and 30 nurse anaesthetists (81% of total staff) completed the survey. The reported problems referred to three main categories: (I) potential influences related to working conditions and practices of data collection, such as premature entry of the data (indicated by 85% of the respondents), competing duties (87%), and interfering interruptions or noise (67%); (II) problems referring to institutional management of the data, for example lacking feedback on the results (95%) and lacking knowledge about what the data are used for (75%); (III) problems related to specific attitudes, e.g., considering these data not useful for quality improvement (47%). Physicians were more sceptical than nurses regarding the relevance of these data for quality and patient safety. The common perceived difficulties reported by physician and nurse anaesthetists resemble established barriers to incident reporting and may similarly act as barriers to quality documentation during anaesthesia. Further studies should investigate if these perceived obstacles have a causal impact on quality reporting in anaesthesia. ClinicalTrials.gov identifier is NCT01524484. Registration date: January 21, 2012.


Older workers in the construction industry: results of a routine health examination and a five year follow up.
To describe the health status of older construction workers and the occurrence of early retirement due to disability or of mortality within a five year follow up. Firstly, a cross sectional study was performed among 4958 employees in the German construction industry, aged 40-64 years, who underwent standardised routine occupational health examinations in 1986-8. The study population included plumbers, carpenters, painters/varnishers, plasterers, unskilled workers, and white collar workers (control group). Job specific prevalence and age adjusted relative prevalence were calculated for hearing loss, abnormal findings at lung auscultation, reduced forced expiratory volume, increased diastolic blood pressure, abnormalities in the electrocardiogram, increased body mass index, hypercholesterolaemia, increased liver enzymes, abnormal findings in an examination of the musculoskeletal system, and abnormalities of the skin. Secondly, follow up for disability and all cause mortality was ascertained between 1992 and 1994 (mean follow up period = 4.5 y). Job specific crude rates were calculated for the occurrence of early retirement due to disability and for all cause mortality. With Cox's proportional hazards model, job specific relative risks, adjusted for age, nationality, and smoking were obtained. Compared with the white collar workers, a higher prevalence of hearing deficiencies, signs of obstructive lung diseases, increased body mass index, and musculoskeletal abnormalities were found among the construction workers at the baseline exam. During the follow up period, 141 men died and 341 men left the labour market due to disability. Compared with white collar workers, the construction workers showed a 3.5 to 8.4-fold increased rate of disability (P < 0.05 for all occupational groups) and a 1.2 to 2.1-fold increased all cause mortality (NS). This study shows the need and possibilities for further health promotion in workers employed in the construction industry, targeting both work related conditions and personal lifestyle factors. Rehabilitation measures should be enforced to limit the rate of disability among construction workers.


Undifferentiated connective tissue disease, fibromyalgia and the environmental factors.
The aim of this study was to discuss the role of environmental factors in the induction and perpetuation of autoimmunity, with particular focus on undifferentiated connective tissue disease (UCTD) and fibromyalgia. These two entities may share undefined clinical and laboratory features and recognize environmental exposures as triggering factors. From this particular point of view, both UCTD and fibromyalgia may resemble the picture of the 'Autoimmune/Inflammatory Syndrome Induced by Adjuvants' (ASIA). A case-control study on environmental exposures showed that patients with UCTD were significantly more exposed to several adjuvants (vaccines, metal implants, proximity to metal factories and foundries) than age and sex-matched healthy controls. UCTD exposed to major ASIA triggers (vaccines, silicone) displayed typical features of ASIA (general weakness, chronic fatigue, irritable bowel syndrome) in the context of a predisposing genetic background (familiarity for autoimmunity). The induction and perpetuation of autoimmunity is a complex process that requires the interaction between the individual genetic background and the environment. Environmental factors are gaining increasing attention since the description of ASIA, a syndrome that includes symptoms typically seen in patients with fibromyalgia and UCTD. A recent case-control study focusing on environmental exposures suggested that nearly half of patients with UCTD may fall within the ASIA spectrum.


Life-threatening complications of ibogaine: three case reports.
Ibogaine is a naturally occurring psychoactive alkaloid extracted from the roots of the Tabernanthe iboga plant, which in alternative medicine is used to treat drug dependency. However, this upcoming, online advocated therapy can be dangerous due to its potentially lethal adverse effects. We present three cases in which toxic side effects were noted. We used the Naranjo scale to estimate the probability of a causal relationship between these effects and ibogaine. Findings in these three cases are suggestive of a causal relationship between the use of ibogaine and serious respiratory and cardiac problems (including lengthening of the QT interval). In our opinion it is of great importance that clinicians are aware of these potentially serious side effects and realise that widespread online marketing practices will give many more people access to ibogaine.


Effect of fisetin supplementation on inflammatory factors and matrix metalloproteinase enzymes in colorectal cancer patients.
A growing body of evidence indicates that inflammation is associated with tumorigenesis, metastasis and chemotherapeutic resistance in patients with colorectal cancer (CRC). Natural flavonoids are promising agents for inflammation-related tumor progression in patients with CRC. This study aimed to assess the efficacy of flavonoid fisetin supplementation on the inflammatory status and matrix metalloproteinase (MMP) levels in these patients. In this double-blind, randomized placebo-controlled clinical trial, 37 CRC patients undergoing chemotherapy were assigned to receive either 100 mg fisetin (n = 18) or placebo (n = 19) for seven consecutive weeks. The supplementation began one week before chemotherapy and continued until the end of the second chemotherapy cycle. Levels of interleukin (IL)-8, IL-10, high-sensitivity C-reactive protein (hs-CRP), MMP-7, and MMP-9 were measured in plasma using ELISA, before and after the intervention. The trial was registered at http://www.irct.ir (code: IRCT2015110511288N9). The participants were 55.59 ± 15.46 years old with 62.16% being male. After the intervention, the plasma levels of IL-8 and hs-CRP reduced significantly in the fisetin group (p < 0.04 and p < 0.01, respectively). Additionally, fisetin supplementation suppressed the values of MMP-7 levels (p < 0.02). However, significant changes were observed only in IL-8 concentrations in the fisetin group when compared with the placebo group (p < 0.03). The changes in the levels of other metabolic factors were not statistically significant. According to the results, fisetin could improve the inflammatory status in CRC patients, suggesting it as a novel complementary antitumor agent for these patients and warranting further studies.


Bacterial complement evasion.
The human complement system is elemental to recognize bacteria, opsonize them for handling by phagocytes, or kill them by direct lysis. However, successful bacterial pathogens have in turn evolved ingenious strategies to overcome this part of the immune system. In this review we discuss the different stages of complement activation sequentially and illustrate the immune evasion strategies that various bacteria have developed to evade each subsequent step. The focus is on bacterial proteins, either surface-bound or excreted, that block complement activation. The underlying molecular mechanism of action and the possible role in pathophysiology of bacterial infections are discussed.


No association between Cholinergic Muscarinic Receptor 2 (CHRM2) genetic variation and cognitive abilities in three independent samples.
Cognitive ability has a substantial genetic component and more than 15 candidate genes have been identified over the past 8 years. One gene that has been associated with general cognitive ability is the cholinergic muscarinic 2 receptor (CHRM2). In an attempt to replicate this finding we typed marker rs8191992 (the originally reported CHRM2 SNP) in two population based cohorts-one Scottish aged over 50 years (N = 2,091) and the other English comprising non-demented elderly participants (N = 758)-and a family-based Australian adolescent sample (N = 1,537). An additional 29 SNPs in CHRM2 were typed in the Australian sample and a further seven in the English cohort. No significant association was found between CHRM2 and diverse measures of cognitive ability in any of the samples. In conclusion, this study does not support a role for CHRM2 in cognitive ability.


Occupational and environmental influences on scleroderma.
This article has reviewed available data on the environmental agents, including occupational factors, that might influence susceptibility to scleroderma. None of the exposures considered could act independently in causing the disease and individually would only be responsible for a small proportion of cases. Nonetheless, they do provide useful insight into the possible mechanisms of disease causation.


[Violence-related injuries in an urban environment-view from an accident and emergency department].
Violence is a growing problem worldwide. In Switzerland, interpersonal violence seems to be an increasing problem as well. The aim of the current study was to describe a comprehensive picture of violence in a swiss city with regard to medical and social aspects. A total of 1740 patients injured by violent crimes between April 2004 and January 2011 were enrolled into this study. Most of them were male. There were no relevant changes regarding the number of within the observation period. However, the proportion of affected females increased. Especially at the weekend, there is a need for preventive measures to reduce the high number of affected patients and the associated costs.


Different MHC class I alleles compete for presentation of overlapping viral epitopes.
We previously identified an HLA-B8+ donor, NW, whose lymphoblastoid cells failed to present a B8-restricted epitope from the influenza A nucleoprotein following viral infection, although added peptide could still be presented. The failure to present through HLA-B8 following viral infection appears to be specific for the NP epitope. Here, we report that donor NW makes an HLA-B2702-restricted influenza-specific CTL response to an epitope in the nucleoprotein that overlaps the B8-restricted epitope by 8 aa. Two mechanisms for the failure of this cell line to present the B8-restricted epitope following viral infection are investigated. One is that there is an antigen processing polymorphism specific to the NW cell line, so that there is either preferential generation or preferential transport of the B2702 epitope. The other is that B8 and B2702 compete for a common peptide fragment in the ER and this leads to suboptimal loading of HLA-B8.


Living systematic reviews: 4. Living guideline recommendations.
While it is important for the evidence supporting practice guidelines to be current, that is often not the case. The advent of living systematic reviews has made the concept of "living guidelines" realistic, with the promise to provide timely, up-to-date and high-quality guidance to target users. We define living guidelines as an optimization of the guideline development process to allow updating individual recommendations as soon as new relevant evidence becomes available. A major implication of that definition is that the unit of update is the individual recommendation and not the whole guideline. We then discuss when living guidelines are appropriate, the workflows required to support them, the collaboration between living systematic reviews and living guideline teams, the thresholds for changing recommendations, and potential approaches to publication and dissemination. The success and sustainability of the concept of living guideline will depend on those of its major pillar, the living systematic review. We conclude that guideline developers should both experiment with and research the process of living guidelines.


An unusual complication after shoulder hemiarthroplasty.
Hemiarthroplasty of the shoulder can be a safe and an effective treatment for pain in patients with rheumatoid arthritis. Many complications have been previously described in the literature; the most common of which are dislocation, loosening, periprosthetic fractures, and infection. We report a patient who presented with a discharging sinus over the tip of the acromium which was created by the displacement of the prosthesis and erosion of the AC joint and distal clavicle. The erosion of the distal clavicle and AC joint caused the remaining proximal clavicle to become mobile and displaced posteriorly; this spike of clavicle was then able to penetrate the trapezius muscle and eventually the skin causing an aseptic sinus. This was successfully treated with the exploration and excision of the distal 2 cm of the clavicle.


Trends in calving ages and calving intervals for dairy cattle breeds in the United States.
Trends since 1980 for calving age and calving interval, 2 factors that influence herd life, were examined by parity for 5 breeds of US dairy cattle. Calving data were from cows with records that passed edits for USDA genetic evaluations and were in herds that remained on Dairy Herd Improvement test. First-calf heifers calved at progressively younger ages over time, but the age decline was less for later parities because of longer calving intervals. Breed differences for calving age were evident for all parities; current mean age at first calving ranged from 24 mo for Jerseys to 28 mo for Ayrshires. Mean calving age across all parities declined over time for all breeds, primarily because of increased turnover rate, and ranged from 48 mo for Holsteins to 54 mo for Ayrshires. Across parity, annual increase in calving interval was reasonably consistent (0.90 to 1.07 d/yr) for all breeds except Jersey (0.49 d/yr). Within parity, regressions of calving interval on year were generally similar to overall breed trend. Breed means for first calving interval across time ranged from 390 d for Jerseys to 407 d for Brown Swiss.


Associations of Apolipoprotein E ε4 Genotype and Ball Heading With Verbal Memory in Amateur Soccer Players.
Emerging evidence suggests that long-term exposure to ball heading in soccer, the most popular sport in the world, confers risk for adverse cognitive outcomes. However, the extent to which the apolipoprotein E ε4 (APOE ε4) allele, a common risk factor for neurodegeneration, and ball heading are associated with cognition in soccer players remains unknown. To determine whether the APOE ε4 allele and 12-month ball heading exposure are associated with verbal memory in a cohort of adult amateur soccer players. A total of 379 amateur soccer players were enrolled in the longitudinal Einstein Soccer Study from November 11, 2013, through January 23, 2018. Selection criteria included participation in soccer for more than 5 years and for more than 6 months per year. Of the 379 individuals enrolled in the study, 355 were genotyped. Three players were excluded for reporting extreme levels of heading. Generalized estimating equation linear regression models were employed to combine data across visits for a cross-sectional analysis of the data. At each study visit every 3 to 6 months, players completed the HeadCount 12-Month Questionnaire, a validated, computer-based questionnaire to estimate 12-month heading exposure that was categorized as low (quartiles 1 and 2), moderate (quartile 3), and high (quartile 4). Verbal memory was assessed at each study visit using the International Shopping List Delayed Recall task from CogState. A total of 352 soccer players (256 men and 96 women; median age, 23 years [interquartile range, 21-28 years]) across a total of 1204 visits were analyzed. High levels of heading were associated with worse verbal memory performance (β = -0.59; 95% CI, -0.93 to -0.25; P = .001). There was no main association of APOE ε4 with verbal memory (β = 0.09; 95% CI, -0.24 to 0.42; P = .58). However, there was a significant association of APOE ε4 and heading with performance on the ISRL task (χ2 = 7.22; P = .03 for overall interaction). In APOE ε4-positive players, poorer verbal memory associated with high vs low heading exposure was 4.1-fold greater (APOE ε4 negative, β = -0.36; 95% CI, -0.75 to 0.03; APOE ε4 positive, β = -1.49; 95% CI, -2.05 to -0.93), and poorer verbal memory associated with high vs moderate heading exposure was 8.5-fold greater (APOE ε4 negative, β = -0.13; 95% CI, -0.54 to 0.29; APOE ε4 positive, β = -1.11, 95% CI, -1.70 to -0.53) compared with that in APOE ε4-negative players. This study suggests that the APOE ε4 allele is a risk factor for worse memory performance associated with higher heading exposure in the prior year, which highlights that assessing genetic risks may ultimately play a role in promoting safer soccer play.


Interleukin-27 acts as multifunctional antitumor agent in multiple myeloma.
Multiple myeloma (MM) derives from plasmablast/plasma cells that accumulate in the bone marrow. Different microenvironmental factors may promote metastatic dissemination especially to the skeleton, causing bone destruction. The balance between osteoclast and osteoblast activity represents a critical issue in bone remodeling. Thus, we investigated whether interluekin-27 (IL-27) may function as an antitumor agent by acting directly on MM cells and/or on osteoclasts/osteoblasts. The IL-27 direct antitumor activity on MM cells was investigated in terms of angiogenesis, proliferation, apoptosis, and chemotaxis. The IL-27 activity on osteoclast/osteoblast differentiation and function was also tested. In vivo studies were done using severe combined immunodeficient/nonobese diabetic mice injected with MM cell lines. Tumors from IL-27- and PBS-treated mice were analyzed by immunohistochemistry and PCR array. We showed that IL-27 (a) strongly inhibited tumor growth of primary MM cells and MM cell lines through inhibition of angiogenesis, (b) inhibited osteoclast differentiation and activity and induced osteoblast proliferation, and (c) damped in vivo tumorigenicity of human MM cell lines through inhibition of angiogenesis. These findings show that IL-27 may represent a novel therapeutic agent capable of inhibiting directly MM cell growth as well as osteoclast differentiation and activity.


The functional limits of the aneurysmal aortic root. A unique pressure testing apparatus.
The aortic root has unique embryological development and is a highly sophisticated and complex structure. In studies that report on the biomechanical characteristics of the thoracic aorta, distinction between the aortic root and ascending aorta regions is nonexistent. Our objective is to determine the maximal pressures at which dissection occurs or tissue failure occurs in the aortic root compared to that of the ascending aorta in the presence of aortic aneurysms. This may help guide preoperative monitoring, diagnosis and the decision for operative intervention for aortic root aneurysms in the normal and susceptible populations. We developed a simple aortic root and ascending aorta pressure testing unit in series. Ten fresh porcine hearts were obtained from the local abattoir (n = 5 aortic root and n = 5 ascending aorta for comparison). Using a saline filled needle and syringe, artificial fluid-filled aneurysms were created between the intima and medial layers of the aortic root. The aorta lumen was then progressively filled with saline solution. Pressure measurement was taken at time of loss of tissue integrity, obvious tissue dissection or aneurysm rupture, and the tissue structure was then visually examined. In the aortic root, mean maximal pressure (mmHg) at tissue failure was 208 mmHg. Macroscopic examination revealed luminal tears around the coronary ostia in 2/5 specimens, and in all specimens, there was propagation of the dissection in the aortic root in a circumferential direction. In all ascending aorta specimens, the maximal aortic pressures exceeded 300 mmHg without tissue failure or dissection, and eventual apparatus failure. Our results indicate that the aneurysmal aortic root tissues are at greater risk of rupture and dissection propagation at lower aortic pressure. With further analysis, this could guide clinical and surgical management.


Epigenomic landscape of human colorectal cancer unveils an aberrant core of pan-cancer enhancers orchestrated by YAP/TAZ.
Cancer is characterized by pervasive epigenetic alterations with enhancer dysfunction orchestrating the aberrant cancer transcriptional programs and transcriptional dependencies. Here, we epigenetically characterize human colorectal cancer (CRC) using de novo chromatin state discovery on a library of different patient-derived organoids. By exploring this resource, we unveil a tumor-specific deregulated enhancerome that is cancer cell-intrinsic and independent of interpatient heterogeneity. We show that the transcriptional coactivators YAP/TAZ act as key regulators of the conserved CRC gained enhancers. The same YAP/TAZ-bound enhancers display active chromatin profiles across diverse human tumors, highlighting a pan-cancer epigenetic rewiring which at single-cell level distinguishes malignant from normal cell populations. YAP/TAZ inhibition in established tumor organoids causes extensive cell death unveiling their essential role in tumor maintenance. This work indicates a common layer of YAP/TAZ-fueled enhancer reprogramming that is key for the cancer cell state and can be exploited for the development of improved therapeutic avenues.


Association Between Use of the 21-Gene Recurrence Score Assay and Receipt of Chemotherapy Among Medicare Beneficiaries With Early-Stage Breast Cancer, 2005-2009.
Guidelines recommend consideration of chemotherapy for most patients with early-stage, estrogen receptor-positive, invasive breast cancer in the absence of additional prognostic information. The 21-gene recurrence score (RS) assay has been shown in limited academic settings to reduce physician recommendations for adjuvant chemotherapy. Associations between the adoption of the assay and receipt of chemotherapy in the general population have not been examined. To examine whether adoption of the RS assay in a nationally representative sample of patients with early-stage breast cancer was associated with use of chemotherapy. Retrospective cohort study of Medicare beneficiaries who received a diagnosis of incident breast cancer between 2005 and 2009 using Surveillance, Epidemiology, and End Results data set with linked Medicare claims. Receipt of chemotherapy within 12 months after diagnosis. A total of 44,044 patients had low-risk (24.0%), intermediate-risk (51.3%), or high-risk disease (24.6%, lymph node positive) as defined by National Comprehensive Cancer Network (NCCN) guidelines and met the study criteria. We observed no overall association between receipt of the RS assay and chemotherapy (odds ratio [OR], 1.03 [99% CI, 0.88-1.19]). In multivariable analysis, there was a significant interaction between NCCN risk and use of the RS assay, with assay use associated with lower chemotherapy use in high-risk patients (OR, 0.36 [99% CI, 0.26-0.50]) and greater chemotherapy use in low-risk patients (OR, 3.71 [99% CI, 2.30-5.98]), compared with no receipt of the assay (P=.006 for the overall interaction). Results were similar in prespecified subgroup analyses of patients 70 years and younger, with the exception of a shift toward lower chemotherapy use during 2008 (OR, 0.90 [99% CI, 0.77-.1.05]; P=.09) and 2009 (OR, 0.81 [99% CI, 0.66-0.99]; P=.007). In unadjusted analyses, overall chemotherapy use decreased over time in patients 70 years or younger with high-risk disease and those receiving the assay. The impact of the adoption of the RS assay on receipt of chemotherapy was strongly population dependent and was associated with relatively lower chemotherapy use in groups with high-risk disease and relatively higher chemotherapy use in patients with low-risk disease. Overall use of chemotherapy decreased during the study period in patients who were most likely to receive chemotherapy.


Estimating the number of helminthic infections in the Republic of Cameroon from data on infection prevalence in schoolchildren.
The prevalence of infection with helminths is markedly dependent on age, yet estimates of the total number of infections are typically based on data only from school-aged children. Such estimates, although useful for advocacy, provide inadequate information for planning control programmes and for quantifying the burden of disease. Using readily available data on the prevalence of infection in schoolchildren, the relation between the prevalence of infection in school-aged children and prevalence in the wider community can be adequately described using species-specific models. This paper explores the reliability of this approach to predict the prevalence infection in the community and provides a model for estimating the total number of people infected in the Republic of Cameroon. Using data on the prevalence of helminthic infection in school-aged children in Cameroon, the prevalence of infection in pre-school children and adults was estimated from species-specific linear and logistic regression models developed previously. The model predictions were then used to estimate the number of people infected in each district in each age group in Cameroon. For Cameroon, if only the prevalence of infection in schoolchildren is used, the number of people infected with each helminthic species will be overestimated by up to 32% when compared with the estimates provided by the species-specific models. The calculation of confidence intervals supports the statistical reliability of the model since a narrow range of parameter estimates is evident. Furthermore, this work suggests that estimation of national prevalence of infection and the number infected will be enhanced if data are stratified by age; this model represents a useful planning tool for obtaining more accurate estimates. Estimates based on data aggregated from three geographical levels (district, regional, and national) show that summarizing prevalence data at the national level will result in biases of up to 19%. Such biases reflect differences in the geographical distribution for the prevalence of each species. Developing more accurate estimates requires a better understanding of the differences in the spatial heterogeneity of each species and also better methods of incorporating this information when making estimates.


Evaluation of Xpert MTB/RIF testing for rapid diagnosis of childhood pulmonary tuberculosis in children by Xpert MTB/RIF testing of stool samples in a low resource setting.
Children with tuberculosis (TB) remain underdiagnosed due to difficulty in testing for Mycobacterium tuberculosis (MTB) infection. We evaluated the Xpert MTB/RIF assay for respiratory and stool testing in children for pulmonary TB through a cross-sectional study at tertiary care facilities in Karachi, Pakistan. Fifty children aged 0-15 years screened by a modified Kenneth-Jones (KJ) score were included. Mycobacterial culture of respiratory samples was the microbiological standard against stool Xpert TB results. All positive TB cases were compared against a treatment response standard (TRS). Twelve study subjects were diagnosed by Xpert TB and nine by MTB culture. Compared with culture [gastric aspirates (GA)/sputum (spm)], stool Xpert TB had a sensitivity of 88.9% (95% CI 50.7-99.4) and a specificity of 95% (95% CI 81.8-99.1). Xpert TB stool versus GA/spm had sensitivity of 81.8% (95% CI 47.8-96.8) and specificity of 94.7% (95% CI 84.6-99.9). We found good agreement (kappa scores of >0.8) between stool Xpert, GA/spm Xpert and GA/spm culture. Stool Xpert PPV and NPV against TRS was 100 and 82.1% respectively. Stool Xpert TB is a relatively easy option for diagnosis for pulmonary childhood TB in a high burden low-resource setting.


[Quality of contraception services in El Alto, Bolivia].
The objective of this study was to evaluate the quality of contraception services in the city of El Alto, Bolivia. In the study design, four components were considered: 1) interpersonal relations between service providers and users, 2) the availability of various contraceptive methods, 3) conditions in the service centers, and 4) user satisfaction. The opinions of three groups were taken into account: service providers, service users, and nonusers. The service centers were classified as either governmental or nongovernmental, depending on the management of the institution to which the service center belonged. The study data came from a situation analysis of the services and from comments gathered from study participants in 1995. The study found that providers held a more favorable view than did service users of the interpersonal relations and personal treatment that physicians provided. Nonusers had an unfavorable perception of physicians' treatment of users. Users' perceptions of receiving egalitarian treatment correlated with their style of dress. With regard to the availability of contraceptive methods, 15 of the 36 centers surveyed did not have modern methods, despite there being a national policy to provide them to the public. The supply of contraception services for couples and for adolescents is limited, especially in the governmental institutions. The analysis of the conditions in the service centers demonstrated that some institutions had serious difficulties providing services of at least a minimum quality. Finally, the study describes how most of the service limitations in El Alto can be corrected through moderate-cost strategies.


Lessons from the experience of U.N. Convention on the Rights of Persons With Disabilities: addressing the democratic deficit in global health governance.
This article reviews the contributions of the UN Convention on the Rights of Persons with Disabilities (CRPD) to the progressive development of both international human rights law and global health law and governance. It provides a summary of the global situation of persons with disabilities and outlines the progressive development of international disability standards, noting the salience of the shift from a medical model of disability to a rights-based social model reflected in the CRPD. Thereafter, the article considers the Convention's structure and substantive content, and then analyzes in specific detail the particular contributions of the Convention to health and human rights law and global health governance. It concludes with an exploration of the potential implications of the CRPD's innovations for some of the most pressing issues in global health governance, including the Convention's contributions to the principle of participation in decision-making.


Organisational factors associated with hospital costs and patient mortality in the 365 days following hip fracture in England and Wales (REDUCE): a record-linkage cohort study.
Hip fracture care delivery varies between hospitals, which might explain variations in patient outcomes and health costs. The aim of this study was to identify hospital-level organisational factors associated with long-term patient outcomes and costs after hip fracture. REDUCE was a record-linkage cohort study in which national databases for all patients aged 60 years and older who sustained a hip fracture in England and Wales were linked with hospital metrics from 18 organisational data sources. Multilevel models identified organisational factors associated with the case-mix adjusted primary outcomes: cumulative all-cause mortality, days spent in hospital, and inpatient costs over 365 days after hip fracture. Between April 1, 2016, and March 31, 2019, 178 757 patients with an index hip fracture were identified from 172 hospitals in England and Wales. 126 278 (70·6%) were female, 52 479 (29·4%) were male, and median age was 84 years (IQR 77-89) in England and 83 years (77-89) in Wales. 365 days after hip fracture, 50 354 (28·2%) patients had died. Patients spent a median 21 days (IQR 11-41) in hospital, incurring costs of £14 642 (95% CI 14 600-14 683) per patient, ranging from £10 867 (SD 5880) to £23 188 (17 223) between hospitals. 11 organisational factors were independently associated with mortality, 24 with number of days in hospital, and 25 with inpatient costs. Having all patients assessed by an orthogeriatrician within 72 h of admission was associated with a mean cost saving of £529 (95% CI 148-910) per patient and a lower 365-day mortality (odds ratio 0·85 [95% CI 0·76-0·94]). Consultant orthogeriatrician attendance at clinical governance meetings was associated with cost savings of £356 (95% CI 188-525) and 1·47 fewer days (95% CI 0·89-2·05) in the hospital in the 365 days after hip fracture per patient. The provision of physiotherapy to patients on weekends was associated with a cost saving of £676 (95% CI 67-1285) per patient and with 2·32 fewer days (0·35-4·29) in hospital in the 365 days after hip fracture. Multiple, potentially modifiable hospital-level organisational factors associated with important clinical outcomes and inpatient costs were identified that should inform initiatives to improve the effectiveness and efficiency of hip fracture services. Versus Arthritis.


An overview of therapeutic approaches to brain tumor stem cells.
Primary and secondary malignant central nervous system (CNS) tumors are devastating invasive tumors able to give rise to many kinds of differentiated tumor cells. Glioblastoma multiform (GBM), is the most malignant brain tumor, in which its growth and persistence depend on cancer stem cells with enhanced DNA damage repair program that also induces recurrence and resists current chemo- and radiotherapies. Unlike non-tumor stem cells, tumor stem cells lack the normal mechanisms that regulate proliferation and differentiation, resulting in uncontrolled production and incomplete differentiation of tumor cells. In current paper recent developments and new researches in the field of brain tumor stem cells have been reviewed.


Effect of inosiplex on the humoral and cell-mediated immune responses to intradermal human diploid cell rabies vaccine.
Antigen-stimulated lymphocyte transformation was studied in recipients of intradermal human diploid cell rabies vaccine (HDCV). HDCV was administered intradermally at 8 different anatomical sites, 0.1 ml each, on day 0; followed by another 4-site injection on day 7. Rabies antigen-stimulated in vitro proliferative response was evident as early as 7 days after starting immunization. It reached a peak on day 14 and had declined by day 28. The cellular proliferative response preceded and roughly correlated with the antirabies antibody response. Simultaneous administration of inosiplex, an antiviral and immunopotentiating drug, during the first 10 days of intradermal HDCV immunization did not result in heightened antibody titres or cell-mediated immune response to the vaccine. The number of T cells and the lymphocyte proliferative response to phytohaemagglutinin in inosiplex-treated vaccinees were similarly not significantly different from untreated controls. Our results confirm other previous findings that a specific cell-mediated immune response can be consistently and rapidly induced by an intradermal regimen of HDCV immunization. The addition of inosiplex to this regimen did not enhance the humoral or cell-mediated immune responses to the vaccine. The apparent lack of immunostimulating effect of inosiplex in this setting may be the result of several factors such as the immunization schedule and the immunologic parameters examined.


The Characteristics and Trends in Adrenocortical Carcinoma: A United States Population Based Study.
Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis. Data on the incidence of ACC, however, are scarce and not recent. The purpose of this study was to characterize the tumor and the patients developing ACC over the last four decades using a large population based database. We identified all cases of ACC diagnosed between 1973 - 2014 from the Surveillance, Epidemiology, and End Results-18 registry. Descriptive analyses were used for all extracted demographic, clinical, pathological, therapeutic and survival data, and were compared between the four time periods of 1973 to 1984, 1985 to 1994, 1995 to 2004 and 2005 to 2014 using Chi-square tests for categorical variables and one-way analysis of variance for continuous variables. There were a total of 2,014 cases of ACC between 1973 and 2014 with an age-adjusted incidence of 1.02 per million populations. The median age at diagnosis was 55 years with the majority of them being females and whites. The proportion of cases by different genders, races and age at diagnosis had not changed significantly over time. These malignancies were mostly the only primary malignancy, unilateral and of high grades at diagnosis. Surgical resection of the tumor remained the mainstay of treatment. However, there was a significant increase in the use of adjuvant radiotherapy, adjuvant chemotherapy and chemotherapy alone in recent times. The median survival time was 17 months, but continues to decrease in recent time periods. ACC continues to be a rare malignancy in the United States. However, most cases continue to be diagnosed only in advanced stages and are associated with poor survival. These findings underline the need for specific diagnostics tools with new and more effective treatment options.