Optimizing positive end-expiratory pressure by oscillatory mechanics minimizes tidal recruitment and distension: an experimental study in a lavage model of lung injury.
It is well established that during mechanical ventilation of patients with acute respiratory distress syndrome cyclic recruitment/derecruitment and overdistension are potentially injurious for lung tissues. We evaluated whether the forced oscillation technique (FOT) could be used to guide the ventilator settings in order to minimize cyclic lung recruitment/derecruitment and cyclic mechanical stress in an experimental model of acute lung injury. We studied six pigs in which lung injury was induced by bronchoalveolar lavage. The animals were ventilated with a tidal volume of 6 ml/kg. Forced oscillations at 5 Hz were superimposed on the ventilation waveform. Pressure and flow were measured at the tip and at the inlet of the endotracheal tube respectively. Respiratory system reactance (Xrs) was computed from the pressure and flow signals and expressed in terms of oscillatory elastance (EX5). Positive end-expiratory pressure (PEEP) was increased from 0 to 24 cm H2O in steps of 4 cm H2O and subsequently decreased from 24 to 0 in steps of 2 cm H2O. At each PEEP step CT scans and EX5 were assessed at end-expiration and end-inspiration. During deflation the relationship between both end-expiratory and end-inspiratory EX5 and PEEP was a U-shaped curve with minimum values at PEEP = 13.4 ± 1.0 cm H2O (mean ± SD) and 13.0 ± 1.0 cm H2O respectively. EX5 was always higher at end-inspiration than at end-expiration, the difference between the average curves being minimal at 12 cm H2O. At this PEEP level, CT did not show any substantial sign of intra-tidal recruitment/derecruitment or expiratory lung collapse. Using FOT it was possible to measure EX5 both at end-expiration and at end-inspiration. The optimal PEEP strategy based on end-expiratory EX5 minimized intra-tidal recruitment/derecruitment as assessed by CT, and the concurrent attenuation of intra-tidal variations of EX5 suggests that it may also minimize tidal mechanical stress.


[Health impact assessment: a tool to incorporate health into non-sanitary interventions].
Interventions implemented by governments are very frequently related to the determinants of health. Health impact assessment (HIA) is used as a predictive tool to include health in nonhealth policymaking. This paper defines HIA, describes its methods, procedures and applications, and discusses opportunities and challenges associated with HIA. Doing a HIA implies studying the intervention, profiling the target population, and estimating its impacts on health by means of combining quantitative and qualitative evidence. HIA has been used in different kinds of policies (transports, urban regeneration, culture, energy development etc.), at different levels (local, national, European) and in many countries. Despite its scarce use in Spain, HIA allows to consider health in sectorial policymaking, taking into account social inequalities in health, so that healthier public policies can be designed. On the other hand, HIA is a tool under methodological development which use is hindered due to the existing narrow biomedical perspective on the determinants of health, and to the difficulties in working in public policy-making with multisectorial and participative perspectives.


Phytoceramide in vertebrate tissues: one step chromatography separation for molecular characterization of ceramide species.
Ceramide is a precursor for complex sphingolipids in vertebrates, while plants contain phytoceramide. By using a novel chromatography purification method we show that phytoceramide comprises a significant proportion of animal sphingolipids. Total ceramide including phytoceramide from mouse tissue (brain, heart, liver) lipid extracts and cell culture (mouse primary astrocytes, human oligodendroglioma cells) was eluted as a single homogenous fraction, and then analyzed by thin layer chromatography, and further characterized by gas chromatography-mass spectrometry (GC-MS). We detected a unique band that migrated between non-hydroxy fatty acyl ceramide and hydroxy fatty acyl ceramide, and identified it as phytoceramide. Using RT-PCR, we confirmed that mouse tissues expressed desaturase 2, an enzyme that has been reported to generate phytoceramide from dihydroceramide. Previously, only trace amounts of phytoceramide were reported in vertebrate intestine, kidney, and skin. While its function is still elusive, this is the first report of phytoceramide characterization in glial cells and vertebrate brain, heart, and liver.


The Greek A gamma beta+-HPFH observed in a large black family.
Several members of a Black family with a heterozygosity for an A gamma beta+-HPFH, shown in 1969 to have relatively low levels of Hb F and a low glycine to alanine ratio in the gamma chain of this Hb F, were reinvestigated. Thirteen of 30 available family members in two generations had the heterozygous form of this condition, which was characterized by a decreased level of Hb A2, an average Hb FAD value of 13.3%, an equal distribution of Hb F over the red cells, and normal hematological values. The gamma chain composition of isolated Hb F was determined by reversed phase high performance liquid chromatography for all 13 heterozygotes and showed an average A gamma value of 84.5%. Hybridization with synthetic oligonucleotides, specific for normal and mutant sequences at positions 111-129 5' to the A gamma globin gene, identified a G----A base substitution at position 117, similar to that seen in subjects with the Greek A gamma-HPFH. Our data support conclusions by others that this replacement is causative of the increased A gamma chain synthesis in this condition. Haplotype analysis supported the suggestion that the G----A substitution occurred as an independent event in this Black family.


Mapping of functional organization in human visual cortex: electrical cortical stimulation.
To investigate the pattern of functional organization in the human visual cortex through electrical cortical stimulation. Electrical cortical stimulation was applied to the occipital cortex and adjacent cortices using subdural grid electrodes in 23 epilepsy patients. Diverse visual responses were recorded. These responses were divided into different categories according to the specific response modalities, such as form, color, and motion. Form visual responses were further subdivided into simple, intermediate, and complex responses. The cortical localization of subdural electrodes was identified using MRI-CT coregistration. The cortical distribution of different visual responses was projected into three-dimensional surface renderings of the brain. The distribution and frequency of subdural electrodes showing different visual responses were quantified by calculating the percentage of the number of electrodes showing one specific type of visual response at the corresponding anatomic region to the total number of electrodes in all brain regions that produced the same response. Simple form responses were obtained mostly at the occipital pole and the inferior occipital gyrus (47.4%) and the striate cortex (42.4%). Intermediate form responses occurred mainly on the peristriate cortex (52.5%) and the lateral occipital (28.0%) and fusiform gyri (19.5%). Complex forms were produced by stimulation of the basal temporo-occipital region (57.6%) and the lateral temporal or lateral temporo-occipital junctional region (42.4%). Color responses occurred on the basal occipital area, mostly at the fusiform (40.0%) and lingual gyri (36.0%). Moving sensations were evoked by stimulation of the basal temporo-occipital (28.4%) and the mesial parieto-occipital or temporo-parieto-occipital junctional regions (23.9%). Different modalities of vision, such as form, color, and moving sensation, appeared to be distributed and organized in different areas of the human visual cortex.


Cognitive function and dementia in six areas of England and Wales: the distribution of MMSE and prevalence of GMS organicity level in the MRC CFA Study. The Medical Research Council Cognitive Function and Ageing Study (MRC CFAS).
This two-stage prevalence survey involved geographically delimited areas, four urban (Liverpool, Newcastle, Nottingham and Oxford) and two rural (Cambridgeshire and Gwynedd), including institutions. Stratified random population samples of people in their 65th year and above, from Family Health Service Authorities were studied. The sample was stratified (65-74 years and > or = 75) to provide equal numbers. In Liverpool equal numbers in 5 year age groups were taken. After an initial screening interview, approximately 20% were selected on the basis of age, AGECAT organicity confidence level and MMSE score to proceed to a detailed assessment interview from which the full AGECAT organicity confidence level could be derived. Major influences on MMSE were confirmed as age, sex, social class and educational level. Estimates of prevalence of AGECAT O3 and above for each centre and the entire sample according to age are given, based on 1991 Census population structure, and suggest that around half a million (543,400) people in England and Wales would be defined as case level by this method. The five centres employing the same methodology showed no heterogeneity in prevalence. Prevalence of cognitive impairment and dementia appear not to vary widely across the centres examined in this study, which provides stable estimates by age and sex for AGECAT O3 and above, and norms for MMSE. Using these estimates as an indication of the size of the population affected, around 550,000 individuals in England and Wales would be expected to be suffering from dementia of mild or greater severity.


Implementation of Novel Molecular Biomarkers for Non-small Cell Lung Cancer in the Netherlands: How to Deal With Increasing Complexity.
The diagnostic landscape of non-small cell lung cancer (NSCLC) is changing rapidly with the availability of novel treatments. Despite high-level healthcare in the Netherlands, not all patients with NSCLC are tested with the currently relevant predictive tumor markers that are necessary for optimal decision-making for today's available targeted or immunotherapy. An expert workshop on the molecular diagnosis of NSCLC involving pulmonary oncologists, clinical chemists, pathologists, and clinical scientists in molecular pathology was held in the Netherlands on December 10, 2018. The aims of the workshop were to facilitate cross-disciplinary discussions regarding standards of practice, and address recent developments and associated challenges that impact future practice. This paper presents a summary of the discussions and consensus opinions of the workshop participants on the initial challenges of harmonization of the detection and clinical use of predictive markers of NSCLC. A key theme identified was the need for broader and active participation of all stakeholders involved in molecular diagnostic services for NSCLC, including healthcare professionals across all disciplines, the hospitals and clinics involved in service delivery, healthcare insurers, and industry groups involved in diagnostic and treatment innovations. Such collaboration is essential to integrate different technologies into molecular diagnostics practice, to increase nationwide patient access to novel technologies, and to ensure consensus-preferred biomarkers are tested.


Big Data Usage Patterns in the Health Care Domain: A Use Case Driven Approach Applied to the Assessment of Vaccination Benefits and Risks. Contribution of the IMIA Primary Healthcare Working Group.
Generally benefits and risks of vaccines can be determined from studies carried out as part of regulatory compliance, followed by surveillance of routine data; however there are some rarer and more long term events that require new methods. Big data generated by increasingly affordable personalised computing, and from pervasive computing devices is rapidly growing and low cost, high volume, cloud computing makes the processing of these data inexpensive. To describe how big data and related analytical methods might be applied to assess the benefits and risks of vaccines. We reviewed the literature on the use of big data to improve health, applied to generic vaccine use cases, that illustrate benefits and risks of vaccination. We defined a use case as the interaction between a user and an information system to achieve a goal. We used flu vaccination and pre-school childhood immunisation as exemplars. We reviewed three big data use cases relevant to assessing vaccine benefits and risks: (i) Big data processing using crowdsourcing, distributed big data processing, and predictive analytics, (ii) Data integration from heterogeneous big data sources, e.g. the increasing range of devices in the "internet of things", and (iii) Real-time monitoring for the direct monitoring of epidemics as well as vaccine effects via social media and other data sources. Big data raises new ethical dilemmas, though its analysis methods can bring complementary real-time capabilities for monitoring epidemics and assessing vaccine benefit-risk balance.


The biodiversity of the Mediterranean Sea: estimates, patterns, and threats.
The Mediterranean Sea is a marine biodiversity hot spot. Here we combined an extensive literature analysis with expert opinions to update publicly available estimates of major taxa in this marine ecosystem and to revise and update several species lists. We also assessed overall spatial and temporal patterns of species diversity and identified major changes and threats. Our results listed approximately 17,000 marine species occurring in the Mediterranean Sea. However, our estimates of marine diversity are still incomplete as yet-undescribed species will be added in the future. Diversity for microbes is substantially underestimated, and the deep-sea areas and portions of the southern and eastern region are still poorly known. In addition, the invasion of alien species is a crucial factor that will continue to change the biodiversity of the Mediterranean, mainly in its eastern basin that can spread rapidly northwards and westwards due to the warming of the Mediterranean Sea. Spatial patterns showed a general decrease in biodiversity from northwestern to southeastern regions following a gradient of production, with some exceptions and caution due to gaps in our knowledge of the biota along the southern and eastern rims. Biodiversity was also generally higher in coastal areas and continental shelves, and decreases with depth. Temporal trends indicated that overexploitation and habitat loss have been the main human drivers of historical changes in biodiversity. At present, habitat loss and degradation, followed by fishing impacts, pollution, climate change, eutrophication, and the establishment of alien species are the most important threats and affect the greatest number of taxonomic groups. All these impacts are expected to grow in importance in the future, especially climate change and habitat degradation. The spatial identification of hot spots highlighted the ecological importance of most of the western Mediterranean shelves (and in particular, the Strait of Gibraltar and the adjacent Alboran Sea), western African coast, the Adriatic, and the Aegean Sea, which show high concentrations of endangered, threatened, or vulnerable species. The Levantine Basin, severely impacted by the invasion of species, is endangered as well. This abstract has been translated to other languages (File S1).


Development of SNP assays for hessian fly response genes, Hfr-1 and Hfr-2, for marker-assisted selection in wheat breeding.
The Hessian fly response genes, Hfr-1 and Hfr-2, have been reported to be significantly induced in a Hessian fly attack. Nothing is known about the allelic variants of these two genes in susceptible (S) and resistant (R) wheat cultivars. Basic local alignment search tool (BLAST) analysis of Hessian fly response genes have identified three alleles of Hessian fly response gene 1 (Hfr-1) on chromosome 4AL and 7DS, and 10 alleles of Hessian fly response gene 2 (Hfr-2) on chromosome 2BS, 2DL, 4BS, 4BL, 5AL and 5BL. Resequencing exons of Hfr-1 and Hfr-2 have identified a single nucleotide polymorphism (SNP) in the lectin domain of each gene that segregates some R sources from S cultivars. Two SNP assays have been developed. The SNP883_Hfr-1 assay characterizes a 'G/A' SNP in Hfr-1, which differentiates 14 Hessian fly R cultivars from S ones. The SNP1294_Hfr-2 assay differentiates 12 R cultivars from S ones. Each of the two SNPs identified in Hfr-1 and Hfr-2 is 'G/A' and resulted in an amino acid change from isoleucine to valine in the lectin domain of the proteins of the alleles in the R cultivars. In addition to the genotype profiles of Hfr-1 and Hfr-2, generated for a set of 249 wheat cultivars which included a set of 39 R cultivars, this study has genotyped the Hessian fly response gene, HfrDrd, and the H32 gene for the wheat germplasm. Resistant cultivars from different origins with one, two, three or four resistance (R) genes in various combinations/permutations have been identified. This study has identified allelic differences in two Hessian fly response genes, Hfr-1 and Hfr-2, between S and R cultivars and developed one SNP assay for each of the genes. These two SNP assays for Hfr-1 and Hfr-2, together with the published assays for HfrDrd and the H32 gene, can be used for the selection and incorporation of one or more of these 4 R genes identified in the different R sources in wheat breeding programs.


A re-evaluation of the role of host defence peptides in mammalian immunity.
Host defence peptides are found in all classes of life and are a fundamental component of the innate immune response. Initially it was believed that their sole role in innate immunity was to kill invading microorganisms, thus providing direct defence against infection. Evidence now suggests that these peptides play diverse and complex roles in the immune response and that, in higher animals, their functions are not restricted to the innate immune response. In in vitro experiments certain host defence peptides have been demonstrated to be potent antimicrobial agents at modest concentrations, although their antimicrobial activity is often strongly reduced or ablated in the presence of physiological concentrations of ions such as Na(+) and Mg(2+). In contrast, in experiments done in standard tissue culture media, the composition of which more accurately represents physiological levels of ions, mammalian host defence peptides have been demonstrated to have a number of immunomodulatory functions including altering host gene expression, acting as chemokines and/or inducing chemokine production, inhibiting lipopolysaccharide induced pro-inflammatory cytokine production, promoting wound healing, and modulating the responses of dendritic cells and cells of the adaptive immune response. Animal models indicate that host defence peptides are crucial for both prevention and clearance of infection. As interest in the in vivo functions of host defence peptides is increasing, it is important to consider whether in mammals the direct antimicrobial and immunomodulatory properties observed in vitro are physiologically relevant, especially since many of these activities are concentration dependent. In this review we summarize the concentrations of host defence peptides and ions reported throughout the body and compare that information with the concentrations of peptides that are known have antimicrobial or immunomodulatory functions in vitro.


Safety and preliminary findings with the intravascular contrast agent NC100150 injection for MR coronary angiography.
In this Phase I clinical study, a novel ultrasmall superparamagnetic iron oxide contrast agent, NC100150 Injection (Nycomed Imaging, Oslo, Norway, a part of Nycomed Amersham), was used in two-dimensional magnetic resonance coronary angiography (MRCA). Safety and imaging data were acquired from 18 healthy male volunteers at both 0.5 and 1.5 T, before and after the administration of NC100150 Injection. Through-plane and in-plane images of the right coronary artery were analyzed. The postcontrast imaging sequences used prepulses and a high flip angle, to introduce T1 weighting. At 1.5 T (TE 2.6 msec), the through-plane coronary artery signal-to-noise ratio (SNR) (P = 0.04), coronary artery-to-fat signal difference-to-noise ratio (SDNR) (P = 0.001), coronary artery-to-myocardium SDNR (P<0.001), and coronary artery delineation (P<0.001) were improved by the administration of NC100150 Injection. For in-plane imaging, coronary artery delineation improved, but there were no significant changes in the SNR and SDNR. At 0.5 T, with the longer TE (6.7 msec) imaging sequence used, there was a reduction in the SNR (P = 0.01), the fat SDNR (through-plane P = 0.02; in-plane P = 0.25), and the coronary artery diameter (P<0.01 in both imaging planes). There was a trend toward improvement in the myocardial SDNR and coronary artery delineation. In conclusion, NC 100150 Injection was given safely to 18 healthy subjects, with no major adverse reactions. Coronary artery delineation was improved in both imaging planes at 1.5 T, with a trend toward improvement at 0.5 T. At 1.5 T, with a short TE imaging sequence, the marked T1 shortening effects of NC100150 Injection were dominant, leading to an improvement in the quantitative parameters for the through-plane images. At 0.5 T, with a longer TE imaging sequence, the T2* effects of the contrast agent played a role in reducing the quantitative image parameters. With further optimization of imaging sequences, to take advantage of the long-lived intravascular T1 shortening effect of NC100150 Injection, further improvements in MRCA will be possible.


Informing Strategy to Ensure Detection: Perceptions of Coronavirus Testing in a Southeastern U.S. Urban Homeless Population.
Attitudes of those in the homeless population toward testing, particularly during a pandemic, are critical to understand, so that they and their communities may be safely triaged and protected. Homeless persons are more likely to be exposed during viral epidemics, and have greater vulnerability for more severe viral illness, due to greater medical comorbidities. The literature reflects a dearth of published papers describing the perceptions, interest, and motivations of homeless people to seek or receive viral testing, despite their status as a high-risk population. A quality improvement project consisting of a cross-sectional survey took place at 8 SARS-CoV-2 infection testing sites (local shelters and drop-in sites) within Duval County, Jacksonville, FL. The vast majority of homeless individuals approached for testing completed demographic data and a checklist of beliefs and attitudes about testing (N=764) and underwent COVID-19 nasopharyngeal swab testing (n=679). Mean age was 48; 66% were male, and the predominant race was Black (51%) with 89% of non-Hispanic ethnicity. Of the total participants, 59.2% wanted testing and 4.6% declined testing. Attitudes toward testing varied by site and by wanting vs. not wanting to be tested. Top reasons in those wanting testing included curiosity; a belief that faith would protect them from the virus; and having shelter encouragement to be tested. Top attitudes among those not wanting to be tested were: shelter encouraged me; curiosity; and receiving a gift card. For the total group of subjects, being offered a $10 gift card did not affect their desire to be tested. Those who were not faith-influenced were less likely to want testing. Findings from selected literature and this quality improvement study support the use of a variety of strategies to encourage participation in testing events with large numbers of homeless individuals, including education, gift cards, shelter staff encouragement, involvement of local faith leaders and more broad support by the community. An additional qualitative study would complement these findings, as populations appear to differ in beliefs and attitudes depending on their location and other demographics. Motivational strategies to influence testing rates can be fine-tuned if beliefs, perceptions and attitudes are better understood.


Impact of Cumulative Chemotherapy Dose on Survival With Adjuvant FEC-D Chemotherapy for Breast Cancer.
Reductions in adjuvant chemotherapy dose <85% for historical regimens (ie, cyclophosphamide/methotrexate/fluorouracil) are known to affect breast cancer survival. This threshold, in addition to early versus late dose reductions, are poorly defined for third-generation anthracycline/taxane-based chemotherapy. In patients with breast cancer receiving adjuvant 5-fluorouracil/epirubicin/cyclophosphamide followed by docetaxel (FEC-D), we evaluated the impact of chemotherapy total cumulative dose (TCD), and early (FEC) versus late (D only) dose reductions, on survival outcomes. Women with stage I-III, hormone receptor-positive/negative, HER2-negative breast cancer treated with adjuvant FEC-D chemotherapy from 2007 through 2014 in Alberta, Canada, were included. TCD for cycles 1 to 6 of <85% or ≥85% was calculated. Average cumulative dose was also calculated for early (cycles 1-3) and late (cycles 4-6) chemotherapy. Survival outcomes (disease-free survival [DFS] and overall survival [OS]) were estimated using Kaplan-Meier and multivariate analysis. Cohorts were evaluated for uniformity. Characteristics were reasonably balanced for all cohorts. Overall, 1,302 patients were evaluated for dose reductions, with 16% being reduced <85% (n=202) relative to ≥85% (n=1,100; 84%). Patients who received TCD ≥85% relative to <85% had superior 5-year DFS (P=.025) and OS (P<.001) according to Kaplan-Meier analysis, which remained significant on univariate and multivariate analyses. In stratified late and early dose reduction cohorts, DFS and OS showed a significant inferior survival trend for dose reduction early in treatment administration in 5-year Kaplan-Meier (P=.002 and P<.001, respectively) and multivariate analyses (hazard ratio [HR], 1.46; P=.073, and HR, 1.77; P=.011, respectively). Dose delays of <14 or ≥14 days and granulocyte colony-stimulating factor use did not affect outcomes. Chemotherapy TCD <85% for adjuvant FEC-D affects breast cancer survival. Late reductions (D only) were not shown to adversely affect DFS or OS. Conversely, early reductions (FEC±D) negatively affected patient outcomes.


An investigation of fingerstick blood collection for point-of-care HIV-1 viral load monitoring in South Africa.
Viral load (VL) quantification is an important tool in determining newly developed drug resistance or problems with adherence to antiretroviral therapy (ART) in HIV-positive patients. VL monitoring is becoming the standard of care in many resource-limited settings. Testing in resource-limited settings may require sampling by fingerstick because of general shortages of skilled phlebotomists and the expense of venepuncture supplies and problems with their distribution. To assess the feasibility and ease of collecting 150 µL capillary blood needed for the use of a novel collection device following a classic fingerstick puncture. Patients were recruited by the study nurse upon arrival for routine ART monitoring at the Themba Lethu Clinic in Johannesburg, South Africa. Each step of the fingerstick and blood collection protocol was observed, and their completion or omission was recorded. One hundred and three patients consented to the study, of whom three were excluded owing to the presence of callouses. From a total of 100 patients who consented and were enrolled, 98% of collection attempts were successful and 86% of participants required only one fingerstick to successfully collect 150 µL capillary blood. Study nurse adherence to the fingerstick protocol revealed omissions in several steps that may lower the success rate of capillary blood collection and reduce the performance of a subsequent VL assay. The findings of this study support the feasibility of collecting 150 µL of capillary blood via fingerstick for point-of-care HIV-1 VL testing in a resource-limited setting.


Distinct responses of neurons and astrocytes to TDP-43 proteinopathy in amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease caused by motor neuron loss, resulting in muscle wasting, paralysis and eventual death. A key pathological feature of ALS is cytoplasmically mislocalized and aggregated TDP-43 protein in >95% of cases, which is considered to have prion-like properties. Historical studies have predominantly focused on genetic forms of ALS, which represent ∼10% of cases, leaving the remaining 90% of sporadic ALS relatively understudied. Additionally, the role of astrocytes in ALS and their relationship with TDP-43 pathology is also not currently well understood. We have therefore used highly enriched human induced pluripotent stem cell (iPSC)-derived motor neurons and astrocytes to model early cell type-specific features of sporadic ALS. We first demonstrate seeded aggregation of TDP-43 by exposing human iPSC-derived motor neurons to serially passaged sporadic ALS post-mortem tissue (spALS) extracts. Next, we show that human iPSC-derived motor neurons are more vulnerable to TDP-43 aggregation and toxicity compared with their astrocyte counterparts. We demonstrate that these TDP-43 aggregates can more readily propagate from motor neurons into astrocytes in co-culture paradigms. We next found that astrocytes are neuroprotective to seeded aggregation within motor neurons by reducing (mislocalized) cytoplasmic TDP-43, TDP-43 aggregation and cell toxicity. Furthermore, we detected TDP-43 oligomers in these spALS spinal cord extracts, and as such demonstrated that highly purified recombinant TDP-43 oligomers can reproduce this observed cell-type specific toxicity, providing further support to a protein oligomer-mediated toxicity hypothesis in ALS. In summary, we have developed a human, clinically relevant, and cell-type specific modelling platform that recapitulates key aspects of sporadic ALS and uncovers both an initial neuroprotective role for astrocytes and the cell type-specific toxic effect of TDP-43 oligomers.


Identification of patients at risk of metastasis using a prognostic 31-gene expression profile in subpopulations of melanoma patients with favorable outcomes by standard criteria.
A substantial number of patients who relapse and die from cutaneous melanoma (CM) are categorized as being at low risk by traditional staging factors. The 31-gene expression profile (31-GEP) test independently stratifies metastatic risk of patients with CM as low (Class 1, with 1A indicating lowest risk) or high (Class 2,with 2B indicating highest risk). To assess risk prediction by the 31-GEP test within 3 low-risk (according to the American Joint Committee on Cancer) populations of patients with CM: those who are sentinel lymph node (SLN) negative, those with stage I to IIA tumors, and those with thin (≤1 mm [T1]) tumors. A total of 3 previous validation studies provided a nonoverlapping cohort of 690 patients with 31-GEP results, staging information, and survival outcomes. Kaplan-Meier and Cox regression analysis were performed. The results included the identification of 70% of SLN-negative patients who experienced metastasis as Class 2, the discovery of reduced recurrence-free survival for patients with thin tumors and Class 2B biology compared with that of those with Class 1A biology (P < .0001); and determination of the 31-GEP test as an independent predictor of risk compared with traditional staging factors in patients with stage I to IIA tumors. Diagnoses spanned multiple versions of pathologic staging criteria. The 31-GEP test identifies high-risk patients who are likely to experience recurrence or die of melanoma within low-risk groups of subpopulations of patients with CM who have SLN-negative disease, stage I to IIA tumors, and thin tumors.


Fetal head moulding: finite element analysis of a fetal skull subjected to uterine pressures during the first stage of labour.
Fetal head moulding is a phenomenon which may contribute to satisfactory progress during delivery as it allows the fetal head to accommodate to the geometry of the passage. In contrast, excessive head moulding may result in cranial birth injuries and thus affect the infant shortly or even long after birth. One group of researchers in the past investigated the biomechanics of fetal head moulding from an engineering point of view and limited themselves to a static, linear model of the parietal bones. In this paper, we present a non-linear model of the deformation of a complete fetal skull, when subjected to pressures exerted by the cervix, during the first stage of labour. The design of the model involves four main steps: shape recovery of the fetal skull, the generation of a valid and compatible mesh for finite element analysis (FEA), the specification of a physical model and the analysis of deformation. Results of the analysis show good agreement with those obtained from clinical experiments on the quantitative assessment of fetal head moulding. The model also displays shapes after moulding which have been reported in previous studies and which are generally known in the obstetric and paediatric communities.


Sex differences in outcome following community-based cardiopulmonary arrest.
To determine whether men and women suffering cardiopulmonary arrest differ in terms of survival and risk factors for survival. A prospective cohort study, using the Heartstart (Scotland) database, was undertaken on all 22 161 people suffering community-based cardiopulmonary arrest in Scotland between 1988 and 1997. The outcomes studied were death at the arrest scene, death before admission, death in hospital and death at any point up to discharge. Univariate analysis, using chi-square and Mann-Whitney U tests, was used to compare men and women in terms of patient characteristics, management and outcome. Multivariate logistic regression analysis was used to determine the association between sex and outcome after adjustment for case-mix. Sex differences in outcome varied over time. Women had a poorer risk profile than men. They were older (P<0.0001) and less likely to have shockable rhythms (P<0.0001). Despite this, they were more likely to survive to admission (P<0.0001). However, thereafter, women were more likely to die in hospital (P<0.01). There was no significant difference between the sexes in overall case-fatality rates to discharge. Women have a better early prognosis than men. However, this represents a postponement of death, rather than avoidance.


Comparison of First-Order Sorption Kinetics Using Concept of Two-Site Sorption Model.
We compared two different approaches available in the literature for first-order sorption kinetics, which constitutes the slow time-dependent part of the two-site sorption model commonly used for solute transport. One approach assumes that sorbed concentrations in the Type-1 site (S(1)) and the Type-2 site (S(2)) are directly associated with a solute concentration (C) in liquid phase by forming two-site sorption with a parallel interface; the other assumes that S(2) is associated with only S(1) at the Type-1 site, resulting in two-site sorption with a serial interface. Application of different kinetics to a batch system where solute mass is conserved resulted in an identical type of liquid and sorbed concentration versus time equation in the form of exponential decay. However, because of the different structure and components used to define the kinetic part (S(2)), some parameters estimated from observed kinetic sorption data deviated significantly from one another. For instance, the fraction (f) of the Type-1 site varied as much as twofold, which led to different transport behavior. This indicates that choice of the kinetic part in the two-site sorption model becomes important when attempting appropriate transport modeling on reactive solutes.


Cytoplasmic SQSTM1/ P62 Accumulation Predicates a Poor Prognosis in Patients with Malignant Tumor.
Aims: SQSTM1/p62, as an autophagy marker, is a key molecule involved in the autophagy process. Recent studies have demonstrated that p62 has a close relationship with tumorigenesis and progression, but the impact of p62 on patients' survival has not been comprehensively understood. Therefore, we conducted this study to assess the expression level of p62 in tumor cells and the prognostic role of p62 expression in various malignant tumors. Methods: We searched PubMed, PubMed Central (PMC), Embase, Ovid and Web of Science databases and identified 30 eligible studies containing 14,072 patients to include in the meta-analysis. The p62 mRNA and protein expression profiles in various tumor tissues and normal tissues were presented according to the Human Protein Atlas (HPA) and the Gene Expression Profiling Interactive Analysis (GEPIA). We also tested the association between p62 mRNA level and patients' survival based on the Cancer Genome Atlas (TCGA) and the Human Protein Atlas (HPA) databases. Results: The expression levels of p62 mRNA and protein varied in different tissues. The p62 proteins were elevated and mainly located in the cytoplasm in some types of tumor compared with the normal tissues. The pooled results indicated that p62 overexpression in tumor tissues was associated with a worse prognosis. In the subgroup analysis, a significant relationship was observed between cytoplasmic p62 accumulation and both overall survival (HR 1.53, 95% CI: 1.03-2.27, P < 0.05) and disease-specific survival (HR 1.60, 95% CI: 1.15-2.24, P < 0.01). The relationship between p62 and worse survival was more evident in early stage tumors. P62 mRNA expression had no significant effect on the patient's survival except of liver cancer. Conclusions: The findings of this meta-analysis highlight the role of p62 as a useful prognostic biomarker for some types of tumor according to different clinicopathologic features, which may contribute to the selection of effective treatment methods for different malignant tumors.


Virulence factors of Escherichia cofi from cellulitis or colisepticemia lesions in chickens.
This study was designed to compare virulence factors of cellulitis-derived Escherichia coli to colisepticemic E. coli in order to clarify whether E. coli associated with cellulitis comprise a unique subset of pathogenic E. coli. Isolates were tested for serotype, capsule, aerobactin production, colicin production, the presence of the iss gene, and serum resistance. Untypable isolates made up the greatest percentage of each group. Serotypes O2 and O78 were the most commonly identified among both groups of isolates. No statistical differences in the distribution of aerobactin or colicin production, capsule, or iss gene were observed between groups. Cluster analysis showed that 90% of the E. coli isolates had greater than 42% livability in serum-resistance tests. No separation of colisepticemic vs. cellulitis E. coli isolates was observed on the basis of SR. Colicin production by E. coli was highly correlated with serum resistance (P = 0.0029). These data suggest that cellulitis E. coli have virulence traits similar to those of colisepticemic E. coli.


Reference accuracy in spine surgery.
The references list is an important part of a scientific article that serves to confirm the accuracy of the authors' statements. The goal of this study was to evaluate the reference accuracy in the field of spine surgery. Four major peer-reviewed spine surgery journals were chosen for this study based on their subspecialty clinical impact factors. Sixty articles per journal were selected from 12 issues each of The Spine Journal, Spine, and Journal of Neurosurgery: Spine, and 40 articles were selected from 8 issues of Global Spine Journal, for a total of 220 articles. All the articles were published in 2019 and were selected using computer-generated numbers. From the references list of each article, one reference was again selected by using a computer-generated number and then checked for citation or quotation errors. The results indicate that 84.1% of articles have a minor citation error, 4.5% of articles have a major citation error, 9.5% of articles have a minor quotation error, and 9.1% of articles have a major quotation error. Journal of Neurosurgery: Spine had the fewest citation errors compared with the other journals evaluated in this study. Using chi-square analysis, no association was determined between the occurrence of errors and potential markers of reference mistakes. Still, statistical significance was found between the occurrence of citation errors and the spine journals tested. In order to advance medical treatment and patient care in spine surgery, detailed documentation and attention to detail are necessary. The results from this study illustrate that improved reference accuracy is required.


Minor stroke due to large artery occlusion. When is intravenous thrombolysis not enough? Results from the SITS International Stroke Thrombolysis Register.
Beyond intravenous thrombolysis, evidence is lacking on acute treatment of minor stroke caused by large artery occlusion. To identify candidates for additional endovascular therapy, we aimed to determine the frequency of non-haemorrhagic early neurological deterioration in patients with intravenous thrombolysis-treated minor stroke caused by occlusion of large proximal and distal cerebral arteries. Secondary aims were to establish risk factors for non-haemorrhagic early neurological deterioration and report three-month outcomes in patients with and without non-haemorrhagic early neurological deterioration. We analysed data from the SITS International Stroke Thrombolysis Register on 2553 patients with intravenous thrombolysis-treated minor stroke (NIH Stroke Scale scores 0-5) and available arterial occlusion data. Non-haemorrhagic early neurological deterioration was defined as an increase in NIH Stroke Scale score ≥4 at 24 h, without parenchymal hematoma on follow-up imaging within 22-36 h. The highest frequency of non-haemorrhagic early neurological deterioration was seen in 30% of patients with terminal internal carotid artery or tandem occlusions (internal carotid artery + middle cerebral artery) (adjusted odds ratio: 10.3 (95% CI 4.3-24.9), p < 0.001) and 17% in extracranial carotid occlusions (adjusted odds ratio 4.3 (2.5-7.7), p < 0.001) versus 3.1% in those with no occlusion. Proximal middle cerebral artery-M1 occlusions had non-haemorrhagic early neurological deterioration in 9% (adjusted odds ratio 2.1 (0.97-4.4), p = 0.06). Among patients with any occlusion and non-haemorrhagic early neurological deterioration, 77% were dead or dependent at three months. Patients with minor stroke caused by internal carotid artery occlusion, with or without tandem middle cerebral artery involvement, are at high risk of disabling deterioration, despite intravenous thrombolysis treatment. Acute vessel imaging contributes usefully even in minor stroke to identify and consider endovascular treatment, or intensive monitoring at a comprehensive stroke centre, for patients at high risk of neurological deterioration.


Commercial Use of Emotion Artificial Intelligence (AI): Implications for Psychiatry.
Emotion artificial intelligence (AI) is technology for emotion detection and recognition. Emotion AI is expanding rapidly in commercial and government settings outside of medicine, and will increasingly become a routine part of daily life. The goal of this narrative review is to increase awareness both of the widespread use of emotion AI, and of the concerns with commercial use of emotion AI in relation to people with mental illness. This paper discusses emotion AI fundamentals, a general overview of commercial emotion AI outside of medicine, and examples of the use of emotion AI in employee hiring and workplace monitoring. The successful re-integration of patients with mental illness into society must recognize the increasing commercial use of emotion AI. There are concerns that commercial use of emotion AI will increase stigma and discrimination, and have negative consequences in daily life for people with mental illness. Commercial emotion AI algorithm predictions about mental illness should not be treated as medical fact.


Genetic polymorphism in sex hormone metabolism and prostate cancer risk.
We compared single-nucleotide polymorphisms for point mutations in cytochrome P450 genes, including cytochrome P450c17α (CYP17), cytochrome P450 aromatase (CYP19), steroid-5-a-reductase (SRD5A2), and prostate-specific antigen (PSA) involved in androgen and estrogen production. Between January 2008 and January 2010, 90 patients were enrolled in the study. Of these patients, 28 were diagnosed with benign prostatic hyperplasia and 32 with prostate cancer, while 30 subjects were included as a control group. CYP19 1531 C>T, SRD5A2 gene V89L, CYP17 gene -34 T/C, PSA-158 (G/A) regions were evaluated for the association between polymorphisms and benign prostatic hyperplasia and prostate cancer in study population. Age, body mass index, peak urinary flow rate (Q max), voided urine volume, post-void residual urine volume, total PSA, free PSA, free/total PSA ratio, prostate weights measured by transrectal ultrasonography, erectile dysfunction score, and international prostate symptom score were compared between groups. No statistically significant difference in CYP19 1531 C>T, SRD5A2 V89L, and CYP17 -34T/C was observed in both groups when compared to the control group. The homozygote variant of PSA- 158 (G/A) was significantly lower for prostate cancer. Age, total PSA, free PSA, free/total PSA ratio, prostate weight, and Q max were evaluated using multi-variant analysis. Only Q max was significant for the homozygote variant. The probability of being homozygous was 5.8- fold higher in subjects with Q max >14 mL/s. In the Turkish population, the homozygote variant of PSA-158 (G/A) was significantly lower for prostate cancer.


National Beef Quality Audit-2016: Transportation, mobility, live cattle, and carcass assessments of targeted producer-related characteristics that affect value of market cows and bulls, their carcasses, and associated by-products.
The National Beef Quality Audit-2016 marks the fourth iteration in a series assessing the quality of live beef and dairy cows and bulls and their carcass counterparts. The objective was to determine the incidence of producer-related defects, and report cattle and carcass traits associated with producer management. Conducted from March through December of 2016, trailers (n = 154), live animals (n = 5,470), hide-on carcasses (n = 5,278), and hide-off hot carcasses (n = 5,510) were surveyed in 18 commercial packing facilities throughout the United States. Cattle were allowed 2.3 m2 of trailer space on average during transit indicating some haulers are adhering to industry handling guidelines for trailer space requirements. Of the mixed gender loads arriving at processing facilities, cows and bulls were not segregated on 64.4% of the trailers surveyed. When assessed for mobility, the greatest majority of cattle surveyed were sound. Since the inception of the quality audit series, beef cows have shown substantial improvements in muscle. Today over 90.0% of dairy cows are too light muscled. The mean body condition score for beef animals was 4.7 and for dairy cows and bulls was 2.6 and 3.3, respectively. Dairy cattle were lighter muscled, yet fatter than the dairy cattle surveyed in 2007. Of cattle surveyed, most did not have horns, nor any visible live animal defects. Unbranded hides were observed on 77.3% of cattle. Carcass bruising was seen on 64.1% of cow carcasses and 42.9% of bull carcasses. However, over half of all bruises were identified to only be minor in severity. Nearly all cattle (98.4%) were free of visible injection-site lesions. Current results suggest improvements have been made in cattle and meat quality in the cow and bull sector. Furthermore, the results provide guidance for continued educational and research efforts for improving market cow and bull beef quality.


Cryptic grain-scale heterogeneity of oxygen isotope ratios in metamorphic magnetite.
Oxygen isotope ratios measured by ion microprobe in magnetite from granulite-facies marble of the Adirondack Mountains, New York, range from +2 to +11 per mil (standard mean ocean water) across a single grain that measures 3 millimeters by 5 millimeters. Low values are concentrated in irregular domains near the grain boundary but also occur in the grain's interior. In contrast, grains 1 millimeter in diameter that are from a second nearby sample show no significant heterogeneity, except within 10 micrometers of the grain boundary. These data, including large gradients of up to 9 per mil per 10 micrometers, provide important new constraints on the nature and origins of intragrain isotopic heterogeneity and on oxygen isotope thermometry. The differences between these magnetite grains result from contrasting mechanisms of isotope exchange with fluids after the peak of regional metamorphism. Volume diffusion of oxygen through the crystal structure of magnetite contributed to isotope exchange in the rims of small grains, but larger grains are crosscut by healed cracks that are not readily detected and that short-circuited diffusion.


Transmission of the severe acute respiratory syndrome on aircraft.
The severe acute respiratory syndrome (SARS) spread rapidly around the world, largely because persons infected with the SARS-associated coronavirus (SARS-CoV) traveled on aircraft to distant cities. Although many infected persons traveled on commercial aircraft, the risk, if any, of in-flight transmission is unknown. We attempted to interview passengers and crew members at least 10 days after they had taken one of three flights that transported a patient or patients with SARS. All index patients met the criteria of the World Health Organization for a probable case of SARS, and index or secondary cases were confirmed to be positive for SARS-CoV on reverse-transcriptase polymerase chain reaction or serologic testing. After one flight carrying a symptomatic person and 119 other persons, laboratory-confirmed SARS developed in 16 persons, 2 others were given diagnoses of probable SARS, and 4 were reported to have SARS but could not be interviewed. Among the 22 persons with illness, the mean time from the flight to the onset of symptoms was four days (range, two to eight), and there were no recognized exposures to patients with SARS before or after the flight. Illness in passengers was related to the physical proximity to the index patient, with illness reported in 8 of the 23 persons who were seated in the three rows in front of the index patient, as compared with 10 of the 88 persons who were seated elsewhere (relative risk, 3.1; 95 percent confidence interval, 1.4 to 6.9). In contrast, another flight carrying four symptomatic persons resulted in transmission to at most one other person, and no illness was documented in passengers on the flight that carried a person who had presymptomatic SARS. Transmission of SARS may occur on an aircraft when infected persons fly during the symptomatic phase of illness. Measures to reduce the risk of transmission are warranted.


Measuring bioavailability of polychlorinated biphenyls in soil to earthworms using selective supercritical fluid extraction.
If the release mechanisms during selective chemical extraction of persistent organic pollutants (POP) mimic release mechanisms in natural systems during biological uptake, then a selective non-exhaustive extraction could give a quantitative measure of the bioavailable POP fraction. Supercritical fluid extraction (SFE) is suggested as a possible technique to estimate the amount of bioavailable polychlorinated biphenyls (PCBs) at contaminated sites and hence serve as a new tool in risk assessment. The uptake of PCBs by earthworm (Eisenia foetida) was investigated. PCB contaminated soil was pre-extracted with selective non-exhaustive SFE (50 degrees C, 350 bar, 1h), which removed on average 70% of the individual PCBs. Earthworms were placed in this pre-extracted soil, as well as in untreated soil. After 10 days, the PCB uptake by earthworms in the two systems was compared. The bioaccumulation factor (BAF) was 83% lower in the pre-extracted system than in the untreated system, demonstrating that SFE extracts primarily bioavailable contaminants. From the data, the bioavailable fraction could also be calculated to be 75%, which is very close to the 70% removed by SFE under the applied conditions. This suggests that the chemical methodology is capable of measuring the bioavailable fraction very accurately in this system.


AimB Is a Small Protein Regulator of Cell Size and MreB Assembly.
The MreB actin-like cytoskeleton assembles into dynamic polymers that coordinate cell shape in many bacteria. In contrast to most other cytoskeleton systems, few MreB-interacting proteins have been well characterized. Here, we identify a small protein from Caulobacter crescentus, an assembly inhibitor of MreB (AimB). AimB overexpression mimics inhibition of MreB polymerization, leading to increased cell width and MreB delocalization. Furthermore, aimB appears to be essential, and its depletion results in decreased cell width and increased resistance to A22, a small-molecule inhibitor of MreB assembly. Molecular dynamics simulations suggest that AimB binds MreB at its monomer-monomer protofilament interaction cleft and that this interaction is favored for C. crescentus MreB over Escherichia coli MreB because of a closer match in the degree of opening with AimB size, suggesting coevolution of AimB with MreB conformational dynamics in C. crescentus. We support this model through functional analysis of point mutants in both AimB and MreB, photo-cross-linking studies with site-specific unnatural amino acids, and species-specific activity of AimB. Together, our findings are consistent with AimB promoting MreB dynamics by inhibiting monomer-monomer assembly interactions, representing a new mechanism for regulating actin-like polymers and the first identification of a non-toxin MreB assembly inhibitor. Because AimB has only 104 amino acids and small proteins are often poorly characterized, our work suggests the possibility of more bacterial cytoskeletal regulators to be found in this class. Thus, like FtsZ and eukaryotic actin, MreB may have a rich repertoire of regulators to tune its precise assembly and dynamics.


Evaluation of Physicochemical Characteristics in Drinking Water Sources Emphasized on Fluoride: A Case Study of Yancheng, China.
In this study, the concentration of fluoride and the associated health risks for infants, children, and adults were analyzed and compared for three drinking water sources in Yancheng City, Jiangsu Province, China. To analyze the relationship between the water quality parameters of pH, fluoride (F-), sulfate (SO₄2-), chloride (Cl-), total dissolved solids (TDS), total alkalinity (TAlk), sodium (Na⁺), and potassium (K⁺), statistical analyses including correlation analysis, R-mode cluster analysis and factor analysis were performed based on monthly data from the year 2010 to 2015. The results indicated: (1) Fluoride concentrations in the drinking water sources ranged from 0.38 to 1.00 mg L-1 (mean = 0.57 mg L-1) following the order of Tongyu River > Yanlong Lake > Mangshe River; (2) fluoride concentrations in 22.93% of the collected samples were lower than 0.5 mg L-1, which has the risk of tooth cavities, especially for the Mangshe River; (3) the fluoride exposure levels of infants were higher than children and adults, and 3.2% of the fluoride exposure levels of infants were higher than the recommended toxicity reference value of 122 μg kg-1 d-1 as referenced by Health Canada, which might cause dental fluorosis issues; (4) the physico-chemical characteristics are classified the into four groups reflecting F-- TAlk, Na⁺-K⁺, SO₄2--Cl-, and pH-TDS, respectively, indicating that fluoride solubility in drinking water is TAlk dependent, which is also verified by R-mode cluster analysis and factor analysis. The results obtained supply useful information for the health department in Yancheng City, encouraging them to pay more attention to fluoride concentration and TAlk in drinking water sources.


Elegant Hermite-Laguerre-Gaussian beams.
A novel family of paraxial laser beams called elegant Hermite-Laguerre-Gaussian beams (EHLGBs) are presented. The EHLGBs, a unity of elegant Hermite-Gaussian beams (EHGBs) and elegant Laguerre-Gaussian beams (ELGBs), constitute the exact and continuous transition modes between EHGBs and ELGBs when an additional parameter continuously changes. The virtual source for generation of the EHLGBs is identified. From the spectral representation of the elegant Hermite-Lauguerre-Gaussian waves, we derive the first three orders of nonparaxial corrections for the corresponding paraxial EHLGBs.


Using Citizen Scientists to Gather, Analyze, and Disseminate Information About Neighborhood Features That Affect Active Living.
Many Latinos are insufficiently active, partly due to neighborhoods with little environmental support for physical activity. Multi-level approaches are needed to create health-promoting neighborhoods in disadvantaged communities. Participant "citizen scientists" were adolescent (n = 10, mean age = 12.8 ± 0.6 years) and older adult (n = 10, mean age = 71.3 ± 6.5 years), low income Latinos in North Fair Oaks, California. Citizen scientists conducted environmental assessments to document perceived barriers to active living using the Stanford Healthy Neighborhood Discovery Tool, which records GPS-tracked walking routes, photographs, audio narratives, and survey responses. Using a community-engaged approach, citizen scientists subsequently attended a community meeting to engage in advocacy training, review assessment data, prioritize issues to address and brainstorm potential solutions and partners. Citizen scientists each conducted a neighborhood environmental assessment and recorded 366 photographs and audio narratives. Adolescents (n = 4), older adults (n = 7) and community members (n = 4) collectively identified reducing trash and improving personal safety and sidewalk quality as the priority issues to address. Three adolescent and four older adult citizen scientists volunteered to present study findings to key stakeholders. This study demonstrated that with minimal training, low-income, Latino adolescent and older adult citizen scientists can: (1) use innovative technology to gather information about features of their neighborhood environment that influence active living, (2) analyze their information and identify potential solutions, and (3) engage with stakeholders to advocate for the development of healthier neighborhoods.


Fetoscopic laser treatment of twin-to-twintransfusion syndrome (TTTS).
The aim of this study was to report the results of the first 10 cases of fetoscopic laser surgery for twin-to-twin transfusion syndrome by the Rotunda Hospital Fetal Treatment Programme. All cases of severe TTTS managed by our team from 2006 to 2007 were included. All fetoscopic laser surgeries were performed by a single specialist in fetal medicine. All pregnancies were followed up to pregnancy completion and a minimum of six weeks neonatal life. Laser surgeries were performed with ultrasound guidance and percutaneously using local anaesthesia via a 2.8mm rigid fetoscope. Selective laser ablation of placental vessels was accomplished with a neodymium:YAG laser. The first 10 cases of severe TTTS managed by our team are reported. Laser ablation of placental vessels was accomplished successfully in all cases. Two pregnancies were complicated by preterm premature rupture of membranes before 22 weeks and both pregnancies were lost. Of the remaining 16 fetuses, one was diagnosed with significant ventriculomegaly postoperatively and underwent selective termination in the United Kingdom. The overall intact neonatal survival rate was 65%. Fetoscopic laser ablation of placental vessels for severe twin-to-twin transfusion syndrome is now available in Ireland, and our programme has delivered results that are in keeping with international best practices in this regard.


School-based human papillomavirus vaccination: An opportunity to increase knowledge about cervical cancer and improve uptake of screening.
Poor knowledge about cervical cancer plays a role in limiting screening uptake. HPV vaccination provides an untested platform to distribute information that could possibly improve knowledge and screening coverage. To measure changes in knowledge and screening uptake when information and screening opportunities were provided to mothers of adolescent HPV vaccine recipients. During an HPV vaccine implementation project in the Western Cape (WC) and Gauteng Province (GP), South Africa, information about cervical cancer was provided to parents during a lecture, written information was distributed, and mothers were then invited to either screen at their clinic (WC) or use a self-screening kit (GP). A structured questionnaire was used to test cervical cancer knowledge and screening practices, comparing these before and after the project and between the two screening groups. Complete data for both questionnaires were available for 777 of 906 recruited women. Initial knowledge was poor, but on retesting 6 months later, knowledge about symptoms (p<0.005), screening (p<0.005) and vaccination (p<0.05) improved significantly after the information session and school-based HPV vaccination. In the second questionnaire, women reported significantly more screening and the last reported screening test was more recent. This improvement was more favourable in GP than in the WC (41% v. 26% reporting screening in the past 12 months). These results demonstrate how adolescent HPV vaccine programmes can help to control cervical cancer among mothers by offering information and screening. It is important not to lose this opportunity to educate mothers and their daughters and offer effective methods to prevent cervical cancer in both generations.


Can Labor Market Policies Reduce Deaths of Despair?
Do minimum wages and the earned income tax credit (EITC) mitigate rising "deaths of despair?" We leverage state variation in these policies over time to estimate event study and difference-in-differences models of deaths due to drug overdose, suicide, and alcohol-related causes. Our causal models find no significant effects on drug or alcohol-related mortality, but do find significant reductions in non-drug suicides. A 10 percent minimum wage increase reduces non-drug suicides among low-educated adults by 2.7 percent, and the comparable EITC figure is 3.0 percent. Placebo tests and event-study models support our causal research design. Increasing both policies by 10 percent would likely prevent a combined total of more than 700 suicides each year.


From a crisis to an opportunity: Eight insights for doing science in the COVID-19 era and beyond.
The COVID-19 crisis has forced researchers in Ecology to change the way we work almost overnight. Nonetheless, the pandemic has provided us with several novel components for a new way of conducting science. In this perspective piece, we summarize eight central insights that are helping us, as early career researchers, navigate the uncertainties, fears, and challenges of advancing science during the COVID-19 pandemic. We highlight how innovative, collaborative, and often Open Science-driven developments that have arisen from this crisis can form a blueprint for a community reinvention in academia. Our insights include personal approaches to managing our new reality, maintaining capacity to focus and resilience in our projects, and a variety of tools that facilitate remote collaboration. We also highlight how, at a community level, we can take advantage of online communication platforms for gaining accessibility to conferences and meetings, and for maintaining research networks and community engagement while promoting a more diverse and inclusive community. Overall, we are confident that these practices can support a more inclusive and kinder scientific culture for the longer term.


Association between Common Etiologies and Precipitants of Acute Decompensated Heart Failure.
Acute decompensated heart failure (ADHF) comprises the etiology of heart failure and the precipitant of acute decompensation. Early identification of the precipitant of ADHF is important in management, but an association between the precipitant and etiology of ADHF has not been established. The objective of this study is to determine whether the precipitant of acute decompensation is associated with the etiology of heart failure. This was a prospective observational study conducted over 2 years. Patients with ADHF secondary to common etiologies such as hypertension and rheumatic heart diseases (RHD) were enrolled in the study. The demographics, precipitants, and relevant variables on echocardiography and electrocardiography were documented. The frequencies of the etiology and precipitants of heart failure were derived. The Chi-square test was used to determine an association between categorical variables, and independent t-test was used to compare the means of continuous variables. A value of P < 0.05 was considered statistically significant. There were a total of 190 participants. Hypertensive and RHD were 96 (50.5%) and 94 (49.5%), respectively. One hundred and three (54.2%) were females and males were 87 (45.8%). The precipitants were pneumonia 104 (54.7%), arrhythmias 47 (24.7%), urinary tract infection 36 (19.5%), and infective endocarditis 3 (1.6%). The association between these etiologies and precipitants of ADHF yielded a value of P = 0.597. There is no association between the precipitant and etiology of ADHF. Therefore, the precipitant of ADHF should be actively sought for in every case for optimal management and better outcomes.


Vision screening in a primary care setting. A missed opportunity?
To determine the effectiveness of vision screening in a primary care setting, we administered a questionnaire and a vision test to 458 patients from a general medical clinic. Subjects were referred for complete ophthalmologic evaluation if they failed the vision test or met other "high-risk" criteria based on information contained in the questionnaire. Patient-initiated requests for eye examinations were also honored. A total of 169 patients were scheduled for eye examinations, and 148 actually underwent ophthalmologic evaluation. One hundred one of those examined were referred on the basis of the study criteria. "Serious eye disease" (cataract, glaucoma, diabetic retinopathy, or age-related macular degeneration) was diagnosed in 96 (95%) of these patients. Prompt surgical intervention was recommended in 27 (27%), and medical treatment was begun in 21 (21%). Of those with serious eye disease, 59% met the criteria by failing the vision test, while 69% met the high-risk criteria determined by the questionnaire. Of the 148 subjects who received ophthalmologic evaluations, 47 requested them. Serious eye disease was diagnosed in 23 (50%) of the 47 patients. None of these individuals required immediate surgery, and medical treatment for glaucoma was begun in eight (17%). These data suggest that screening for serious eye disease in a primary care setting is an efficient mechanism to use for the identification of patients with undetected ocular disorders that require follow-up or treatment.


A Call to Action: Dismantling Racial Injustices in Preclinical Research and Clinical Care of Black Patients Living with Small Cell Lung Cancer.
Small cell lung cancer (SCLC) is an aggressive disease with dismal survival rates and limited therapeutic options. SCLC development is strongly associated with exposure to tobacco carcinogens. However, additional genetic and environmental risk factors that contribute to SCLC pathogenesis are beginning to emerge. Here, we specifically assess disparities pertaining to SCLC in Black populations. In contrast to non-small cell lung cancer, preliminary data suggest that Black individuals may actually be at a lower risk of developing SCLC relative to white individuals. This difference remains unexplained but urgently needs to be verified in larger data sets, because it could provide important new insights and approaches to understanding this recalcitrant tumor. Importantly, little biological information exists on SCLC in Black individuals, and few patient-derived preclinical SCLC models from diverse ancestries are available in the laboratory. Unfortunately, we note strikingly low numbers of Black participants in clinical trials testing new treatments for SCLC. Evidence further indicates that care for patients with SCLC may vary between communities with a large fraction of Black patients and those without. Together, these observations underscore the need to better investigate genetic, environmental, and socioeconomic factors associated with SCLC development, preclinical research, clinical care, and outcomes.


The integrin β1 subunit regulates paracellular permeability of kidney proximal tubule cells.
Epithelial cells lining the gastrointestinal tract and kidney have different abilities to facilitate paracellular and transcellular transport of water and solutes. In the kidney, the proximal tubule allows both transcellular and paracellular transport, while the collecting duct primarily facilitates transcellular transport. The claudins and E-cadherin are major structural and functional components regulating paracellular transport. In this study we present the novel finding that the transmembrane matrix receptors, integrins, play a role in regulating paracellular transport of renal proximal tubule cells. Deleting the integrin β1 subunit in these cells converts them from a "loose" epithelium, characterized by low expression of E-cadherin and claudin-7 and high expression of claudin-2, to a "tight" epithelium with increased E-cadherin and claudin-7 expression and decreased claudin-2 expression. This effect is mediated by the integrin β1 cytoplasmic tail and does not entail β1 heterodimerization with an α-subunit or its localization to the cell surface. In addition, we demonstrate that deleting the β1 subunit in the proximal tubule of the kidney results in a major urine-concentrating defect. Thus, the integrin β1 tail plays a key role in regulating the composition and function of tight and adherens junctions that define paracellular transport properties of terminally differentiated renal proximal tubule epithelial cells.


Long-term neurocognitive and educational outcomes of neonatal insults in Kilifi, Kenya.
There is little data on the long-term neurocognitive and educational outcomes among school-aged survivors of neonatal jaundice (NNJ) and hypoxic-ischemic encephalopathy (HIE) in Africa. This study investigates the long-term neurocognitive and educational outcomes and the correlates of these outcomes in school-aged survivors of NNJ or HIE in Kilifi, Kenya. We conducted a cross-sectional study on neurocognitive and educational outcomes among school-aged survivors (6-12 years) of NNJ (n = 134) and HIE (n = 107) and compared them to a community comparison group (n = 134). We assessed nonverbal intelligence, planning, working memory, attention, syntax, pragmatics, word-finding, memory, perceptual-motor, mathematical, and reading abilities. We also collected information on medical history, caregivers' mental health, and family environment. The survivors of NNJ had lower mean total scores in word-finding [F (1, 250) = 3.89, p = 0.050] and memory [F (1, 248) = 6.74, p = 0.010] than the comparison group. The survivors of HIE had lower mean scores in pragmatics [F (1, 230) = 6.61, p = 0.011] and higher scores higher scores in non-verbal reasoning [F (1, 225) =4.10, p = 0.044] than the comparison group. Stunted growth was associated with almost all the outcomes in HIE. Survivors of NNJ and HIE present with impairment in the multiple domains, which need to be taken into consideration in the planning of educational and rehabilitative services.


Dysmenorrhoea and coping strategies among secondary school adolescents in Ilala District, Tanzania.
Dysmenorrhoea is common problem among adolescents worldwide. Its prevalence varies greatly in different populations and ethnic groups. Adolescents with severe dysmenorrhoea may miss classes and other social activities. The aim of this study was to determine the prevalence and coping strategies for dysmenorrhoea among secondary school adolescents in Ilala municipal, Tanzania. A cross sectional study was conducted in eight public and private secondary schools in Ilala municipal. A total of 880 girls in form II and form III who had attained menarche were interviewed using a self administered questionnaire between August and October 2007. The mean age at menarche was 13.3 years with the youngest at nine years and the oldest at sixteen years. Six hundred fifty two (74.1%) girls had dysmenorrhoea. Backache, breast tenderness and non specific joint pains were significantly more common symtoms among adolescents with dysmenorrhoea than without dysmenorrhoea. Medication was used by 362 (55.5 %) girls to relieve dysmenorrhoea. Commonest medications used were paracetamol and diclofenac. Adolescents who missed school due to dysmenorrhoea were 154 (23.6%) and 140 (21.5%) missed social activities. High proportion of secondary school adolescents has dysmenorrhoea in Ilala municipal with a significant number missing school and social activities. Reproductive health education in primary and secondary schools should be enhanced to increase awareness and care seeking.


A signaling complex of Ca2+-calmodulin-dependent protein kinase IV and protein phosphatase 2A.
Stimulation of T lymphocytes results in a rapid increase in intracellular calcium concentration ([Ca2+]i) that parallels the activation of Ca2+-calmodulin-dependent protein kinase IV (CaMKIV), a nuclear enzyme that can phosphorylate and activate the cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB). However, inactivation of CaMKIV occurs despite the sustained increase in [Ca2+]i that is required for T cell activation. A stable and stoichiometric complex of CaMKIV with protein serine-threonine phosphatase 2A (PP2A) was identified in which PP2A dephosphorylates CaMKIV and functions as a negative regulator of CaMKIV signaling. In Jurkat T cells, inhibition of PP2A activity by small t antigen enhanced activation of CREB-mediated transcription by CaMKIV. These findings reveal an intracellular signaling mechanism whereby a protein serine-threonine kinase (CaMKIV) is regulated by a tightly associated protein serine-threonine phosphatase (PP2A).


Partridgeberry polyphenols protect rat primary cortical neurons from oxygen-glucose deprivation-reperfusion-induced injury via suppression of inflammatory adipokines and regulation of HIF-1α and PPARγ.
The aim of this study was to investigate the neuroprotective ability of partridgeberry polyphenols in rat primary cortical neurons against oxygen-glucose deprivation/reperfusion (OGD/R) injury in vitro and explore the underlying therapeutic mechanism(s). The OGD/R injury was induced in rat primary cortical neurons by incubation with deoxygenated glucose-free medium in a hypoxia chamber. The strongest activity in this regard was exhibited by partridgeberry-derived PPF2 and PPF3, i.e. the flavan-3-ol- and flavonol-rich polyphenol fractions of partridgeberry (P ≤ 0.05). Moreover, partridgeberry polyphenol pre-treatment reduced the membrane damage in primary neurons, as measured by the lactose dehydrogenase (LDH) release assay (P ≤ 0.05). Furthermore, PPF2 and PPF3 pre-treatment (100 µg ml(-1)) for 24 hours, before OGD/R, resulted in the strongest suppression of interleukin (IL)-6 and tumor necrosis factor-α induction by OGD/R injury, compared with the control group (P ≤ 0.05). Additionally, the protein levels of hypoxia-inducible factor (HIF-1α) and PPARγ, quantified by ELISA presented a significant modulation following PPFs treatment (100 µg ml(-1)), favorably toward neuroprotection, compared with the respective controls after OGD/R injury in vitro (P ≤ 0.05). In summary, partridgeberry polyphenols at concentrations of 1-100 µg ml(-1), significantly induced a decline in OGD/R injury-triggered apoptosis in vitro, suppressed the inflammatory biomarkers in primary neurons, and modulated the activity of HIF-1α and proliferator-activated receptor gamma (PPARγ) following hypoxic injury.


The acute effects of whole blood donation on cardiorespiratory and haematological factors in exercise: A systematic review.
This systematic review aimed to collect the relevant historical and current literature to produce an informed analysis of the acute effects on cardiorespiratory and haematological factors following whole blood donation (~ 470 ml) during exercise. Testing the hypothesises that blood donation produces either no changes (Null) or produces significant changes (alternate) in haematology, [Formula: see text], heart rate, exercising power and time. Four databases of medical and science orientations were searched with terms sensitive to connections regarding exercise, blood donation (400-500 ml)/haematology, [Formula: see text], heart rate, exercising power and time. The study retrieval process utilised the PRISMA approach and selection was via an adapted scoring method according to the Consensus based Standards for the selection of health Measurements Instruments (COSMIN). Systematic review focused on 24-48 hrs post donation. Details of the PRSIMA checklist can be found in the accompanying online document. Following scrutiny of 48 research papers by two independent assessors 8 experimental studies were included. Four studies showed a mean reduction for difference in [Formula: see text] (- 2.4 ± 1.4 ml∙kg-1∙min-1) and a medium effect size (-0.26). No statistical significance was present at the mean meta-analysis level, also the case for heart rate, time to exhaustion and power. A mean reduction was seen in haemoglobin (- 1.05 g.dL-1), haematocrit (- 3.71%) and red blood cells (- 0.44 Mio μL-1), very large effect size was observed (Cohen's d, -0.75, -1.16 and -4.23 respectively) and statistical significance (95% CI, -2.04, -0.54; -4.59, 2.28 and -4.37, -4.10 respectively). Although individual studies show that [Formula: see text] Is reduced from blood donation pooled results show that [Formula: see text] is indeed not significantly reduced from blood donation 24-48 hrs post donation. Additionally sub-maximally there isn't enough data to produce substantial comparatives. Furthermore, this systematic review demonstrates that there are not enough high-quality studies regarding cardiorespiratory outcomes following blood donation.


Toward a multi-level strategy to reduce stigma in global mental health: overview protocol of the Indigo Partnership to develop and test interventions in low- and middle-income countries.
There is increasing attention to the impacts of stigma and discrimination related to mental health on quality of life and access to and quality of healthcare. Effective strategies for stigma reduction exist, but most evidence comes from high-income settings. Recent reviews of stigma research have identified gaps in the field, including limited cultural and contextual adaptation of interventions, a lack of contextual psychometric information on evaluation tools, and, most notably, a lack of multi-level strategies for stigma reduction. The Indigo Partnership research programme will address these knowledge gaps through a multi-country, multi-site collaboration for anti-stigma interventions in low- and middle-income countries (LMICs) (China, Ethiopia, India, Nepal, and Tunisia). The Indigo Partnership aims to: (1) carry out research to strengthen the understanding of mechanisms of stigma processes and reduce stigma and discrimination against people with mental health conditions in LMICs; and (2) establish a strong collaborative research consortium through the conduct of this programme. Specifically, the Indigo Partnership involves developing and pilot testing anti-stigma interventions at the community, primary care, and mental health specialist care levels, with a systematic approach to cultural and contextual adaptation across the sites. This work also involves transcultural translation and adaptation of stigma and discrimination measurement tools. The Indigo Partnership operates with the key principle of partnering with people with lived experience of mental health conditions for the development and implementation of the pilot interventions, as well as capacity building and cross-site learning to actively develop a more globally representative and equitable mental health research community. This work is envisioned to have a long-lasting impact, both in terms of the capacity building provided to participating institutions and researchers, and the foundation it provides for future research to extend the evidence base of what works to reduce and ultimately end stigma and discrimination in mental health.


Production of hydrogen by electrocatalysis: making the H-H bond by combining protons and hydrides.
Generation of hydrogen by reduction of two protons by two electrons can be catalysed by molecular electrocatalysts. Determination of the thermodynamic driving force for elimination of H2 from molecular complexes is important for the rational design of molecular electrocatalysts, and allows the design of metal complexes of abundant, inexpensive metals rather than precious metals ("Cheap Metals for Noble Tasks"). The rate of H2 evolution can be dramatically accelerated by incorporating pendant amines into diphosphine ligands. These pendant amines in the second coordination sphere function as protons relays, accelerating intramolecular and intermolecular proton transfer reactions. The thermodynamics of hydride transfer from metal hydrides and the acidity of protonated pendant amines (pK(a) of N-H) contribute to the thermodynamics of elimination of H2; both of the hydricity and acidity can be systematically varied by changing the substituents on the ligands. A series of Ni(II) electrocatalysts with pendant amines have been developed. In addition to the thermochemical considerations, the catalytic rate is strongly influenced by the ability to deliver protons to the correct location of the pendant amine. Protonation of the amine endo to the metal leads to the N-H being positioned appropriately to favor rapid heterocoupling with the M-H. Designing ligands that include proton relays that are properly positioned and thermodynamically tuned is a key principle for molecular electrocatalysts for H2 production as well as for other multi-proton, multi-electron reactions important for energy conversions.


Abject pilgrimage and healing in Jaume Roig's Spill.
In the Spill o Llibre de les dones, the 15th century writer and physician from Valencia, Jaume Roig, uses the motif of pilgrimage to attack earthly women, particularly women healers. Roig undermines the salutary function of medieval pilgrimage in order to expose worldly women in their effort to harm male pilgrims. Since men cannot rely on earthly women, they must seek a healing encounter with the Virgin, whose salutary ministrations are always constant and efficacious. Roig's assault on women through pilgrimage relates to wider social attempts to marginalize traditional women healers from legitimate salutary practice, since he aims to dissuade male readers from seeking women's healing services in everyday society.


Acute effects of caffeine on choroidal thickness and ocular pulse amplitude.
To explore ocular changes in healthy people after caffeine consumption. This prospective observational study was carried out with students of the Turgut Özal University Medical Faculty from May 15 to 15 December 2014. Enrolled in the study were 17 healthy subjects (n = 17 eyes), with a median age of 24 (IQR 1), ranging between 21 and 26 years. The control group (6 females, 11 males) aged between 23 and 28 (median 25 years [IQR 4.75]). For study, one eye from each participant was randomly selected. To obviate the effect of diurnal variations, tests were performed at the same time of the day (10:00 a.m.-12:00 p.m.). Each subject was given an ophthalmologic examination before the study to exclude those with undiagnosed ocular disease. Version 6.0 Cirrus high-definition optical coherence tomography (HD-OCT) (Carl Zeiss Meditec, Dublin, CA) was used to measure CT at the fovea, and 1500 μm nasal and 1500 μm temporal to the fovea. After baseline OCT measurements, participants were asked to have 200 mg oral caffeine intake or a placebo capsule (200 mg lactose powder). Two further OCT measurements were applied at the first and fourth hours of caffeine intake. All participants also had intraocular pressure (IOP) and ocular pulse amplitude (OPA) measurements recorded before, first and fourth hours of caffeine intake. IOP and OPA were measured using the dynamic contour tonometry (DCT) (Swiss Micro Technology AG, Port, Switzerland). The groups showed no significant difference by means of age, gender, spherical refraction and axial length (p > 0.05). Baseline choroidal thickness measurements of the study and control group showed no significant difference. Oral caffeine intake caused a significant reduction in choroidal thickness compared with baseline, at all three measurement points, (p < 0.05). There were no significant changes in IOP and OPA measurements compared with the baseline values (p > 0.05). The choroidal thickness still continued to decrease for at least 4 h following caffeine intake; whereas, the difference between 1 and 4 h was not statistically significant (p > 0.05). However, choroidal thicknesses, IOP and OPA values of the control group revealed no significant difference at all points when comparing measurements at baseline with 1 and 4 h after placebo intake (p > 0.05). We found no significant change in IOP and OPA following oral 200 mg caffeine intake, while CT significantly decreased, for at least 4 h.


The complexity of integrating a behavioral medicine approach into physiotherapy clinical practice.
Introduction and Aim: The implementation of a behavioral medicine (BM) approach in physiotherapy is challenging, and studies regarding the determinants are sparse. Thus, the aim of this study was to explore determinants of applying a BM approach in physiotherapy for patients with persistent pain across the micro-, meso-, and macro-levels. Methods: A qualitative multiple-case study design was used. Data were collected from four cases through semi-structured interviews with physiotherapists (PTs), patients, and managers; observations of video-recorded treatment sessions; and reviews of local directives and regulations. Data were analyzed with inductive content analysis and cross-case analysis, followed by mapping to the domains of determinants at the micro-, meso-, and macro-levels within the Implementation of Change Model. Results: Similar determinants were found across the cases. At the micro-level, these determinants concerned the PTs' ambivalence toward a BM approach, a biomedical focus, embarrassment asking about psychosocial factors, BM knowledge, skills for applying the approach, and self-awareness. Others concerned the patients' role expectations of the PT, patients as active or passive agents in the treatment process, patients' focus on biomedical aspects, and confidence in the PT. At the meso-level, support from managers and peers, allocation of time, and expectations from the organization were identified as determinants. No determinants were identified at the macro-level. Conclusion: The complexity of integrating a BM approach into physiotherapy clinical practice arises from multiple determinants functioning as both facilitators and barriers. By selecting strategies to address these determinants, the implementation of a BM approach could be supported.


Neutral sphingomyelinase in physiological and measles virus induced T cell suppression.
T cell paralysis is a main feature of measles virus (MV) induced immunosuppression. MV contact mediated activation of sphingomyelinases was found to contribute to MV interference with T cell actin reorganization. The role of these enzymes in MV-induced inhibition of T cell activation remained equally undefined as their general role in regulating immune synapse (IS) activity which relies on spatiotemporal membrane patterning. Our study for the first time reveals that transient activation of the neutral sphingomyelinase 2 (NSM2) occurs in physiological co-stimulation of primary T cells where ceramide accumulation is confined to the lamellum (where also NSM2 can be detected) and excluded from IS areas of high actin turnover. Genetic ablation of the enzyme is associated with T cell hyper-responsiveness as revealed by actin dynamics, tyrosine phosphorylation, Ca2+-mobilization and expansion indicating that NSM2 acts to suppress overshooting T cell responses. In line with its suppressive activity, exaggerated, prolonged NSM2 activation as occurring in co-stimulated T cells following MV exposure was associated with aberrant compartmentalization of ceramides, loss of spreading responses, interference with accumulation of tyrosine phosphorylated protein species and expansion. Altogether, this study for the first time reveals a role of NSM2 in physiological T cell stimulation which is dampening and can be abused by a virus, which promotes enhanced and prolonged NSM2 activation to cause pathological T cell suppression.


What is a pilot or feasibility study? A review of current practice and editorial policy.
In 2004, a review of pilot studies published in seven major medical journals during 2000-01 recommended that the statistical analysis of such studies should be either mainly descriptive or focus on sample size estimation, while results from hypothesis testing must be interpreted with caution. We revisited these journals to see whether the subsequent recommendations have changed the practice of reporting pilot studies. We also conducted a survey to identify the methodological components in registered research studies which are described as 'pilot' or 'feasibility' studies. We extended this survey to grant-awarding bodies and editors of medical journals to discover their policies regarding the function and reporting of pilot studies. Papers from 2007-08 in seven medical journals were screened to retrieve published pilot studies. Reports of registered and completed studies on the UK Clinical Research Network (UKCRN) Portfolio database were retrieved and scrutinized. Guidance on the conduct and reporting of pilot studies was retrieved from the websites of three grant giving bodies and seven journal editors were canvassed. 54 pilot or feasibility studies published in 2007-8 were found, of which 26 (48%) were pilot studies of interventions and the remainder feasibility studies. The majority incorporated hypothesis-testing (81%), a control arm (69%) and a randomization procedure (62%). Most (81%) pointed towards the need for further research. Only 8 out of 90 pilot studies identified by the earlier review led to subsequent main studies. Twelve studies which were interventional pilot/feasibility studies and which included testing of some component of the research process were identified through the UKCRN Portfolio database. There was no clear distinction in use of the terms 'pilot' and 'feasibility'. Five journal editors replied to our entreaty. In general they were loathe to publish studies described as 'pilot'. Pilot studies are still poorly reported, with inappropriate emphasis on hypothesis-testing. Authors should be aware of the different requirements of pilot studies, feasibility studies and main studies and report them appropriately. Authors should be explicit as to the purpose of a pilot study. The definitions of feasibility and pilot studies vary and we make proposals here to clarify terminology.


Expression of various protection of telomeres 1 variants is associated with telomere length and radiosensitivity in colon and gastric adenocarcinoma cells in vitro.
Protection of telomeres 1 (POT1) is a telomere-binding protein, which binds to the single-stranded DNA extensions of telomeres and regulates telomere length. Different POT1 mRNA variants were examined and compared with telomere length and radiosensitivity in colon and gastric adenocarcinoma cells. POT1 production and telomere lengths were assessed using 10 human cancer cell lines by quantitative polymerase chain reaction (qPCR). POT1 mRNA levels, which were relatively stable, were significantly correlated with telomere length in gastric cancer cells and colon cancer cells, except for HT29 (P<0.01). POT1 v5 indexes were closely associated with radiosensitivity in colon cancer cells and gastric cancer cells (P<0.05). In conclusion, POT1 may be a good marker for the examination of cell-specific telomere length and radiosensitivity.


Neuroprotective effects of Brazilian green propolis and its main constituents against oxygen-glucose deprivation stress, with a gene-expression analysis.
Our purpose was to investigate the neuroprotective effects (and the underlying mechanism) exerted by water extract of Brazilian green propolis (WEP) and its main constituents against the neuronal damage induced by oxygen-glucose deprivation (OGD)/reoxygenation in retinal ganglion cells (RGC-5, a rat ganglion cell-line transformed using E1A virus). Cell damage was induced by OGD 4 h plus reoxygenation 18 h exposure. In RGC-5, and also in PC12 (rat pheochromocytoma, neuronal cells), WEP and some of its main constituents attenuated the cell damage. At the end of the period of OGD/reoxygenation, RNA was extracted and DNA microarray analysis was performed to examine the gene-expression profile in RGC-5. Expression of casein kinase 2 (CK2) was down-regulated and that of Bcl-2-related ovarian killer protein (Bok) was up-regulated following OGD stress, results that were confirmed by quantitative reverse transcriptase-PCR (qRT-PCR). These effects were normalized by WEP. Our findings indicate that WEP has neuroprotective effects against OGD/reoxygenation-induced cell damage and that certain constituents of WEP (caffeoylquinic acid derivatives, artepillin C, and p-coumaric acid) may be partly responsible for its neuroprotective effects. Furthermore, the protective mechanism may involve normalization of the expressions of antioxidant- and apoptosis-related genes (such as CK2 and Bok, respectively).


Advances in DNA-based techniques for the detection of seafood species substitution on the commercial market.
Increased worldwide trade and processing of seafood has increased the potential for species substitution on the commercial market. To detect and prevent species substitution, several deoxyribonucleic acid (DNA)-based methods have been developed that can be used to identify species in a variety of food types. For large-scale applications, such as regulatory screening, these methods must be rapid, cost-effective, reliable, and have high potential for automation. This review highlights recent technological advances in DNA-based identification methods, with a focus on seafood species identification in automated, high-throughput settings. Advances in DNA isolation methods include silica-based columns for use in high-throughput operations and magnetic bead particles for increased and targeted recovery of DNA. The three most widely used methods for seafood species identification (polymerase chain reaction [PCR] sequencing, PCR-restriction fragment length polymorphism, and species-specific PCR) will be discussed, with a focus on the incorporation of technologies such as rapid PCR cycling, microfluidic chips, and real-time PCR. Emerging methods, including DNA microarrays and next-generation sequencing will also be explored for their potential to identify seafood species on a large scale. Overall, many of the technological advances discussed here offer complementary properties that will enable species identification in a variety of settings and with a range of products.


Safety and efficacy of ambrisentan for the treatment of portopulmonary hypertension.
Ambrisentan is a selective endothelin-receptor antagonist that is approved by the US Food and Drug Administration for the treatment of pulmonary arterial hypertension. We describe hemodynamic responses and clinical outcomes of patients with portopulmonary hypertension (POPH) treated with ambrisentan. In this observational study, we prospectively identified and followed consecutive adult patients with POPH who received monotherapy with ambrisentan ≤ 10 mg daily from January 2007 until December 2009. Liver enzymes were assessed monthly. Pulmonary hemodynamic responses were assessed using echocardiograms and right-sided heart catheterizations. We identified 13 patients (seven men) with POPH and began monotherapy with ambrisentan. The median age was 57 (interquartile range [IQR], 52-60). Patients were followed for a median of 613 days (IQR, 385-1,011). The median model for end-stage liver disease score was 10 (IQR, 8.5-15); eight patients had Child-Turcotte-Pugh A classification. Median time on ambrisentan therapy was 390 days (IQR, 363-611). Two patients died, one of advanced hepatocellular carcinoma and one of septic shock following pneumonia. The mean pulmonary artery pressure decreased from a baseline median of 58 mm Hg (IQR, 37-63) to 41 mm Hg (IQR, 27-48) (P = .004). The pulmonary vascular resistance median was reduced from 445 dynes/s/cm(5) (IQR, 329-834) to 174 dynes/s/cm(5) (IQR, 121-361) (P = .008). There was no difference in the longitudinal analysis of liver function tests (aspartate aminotransferase, alanine aminotransferase, total bilirubin, and international normalized ratio) after 12 months of therapy. One patient underwent successful liver transplantation and normalized pulmonary hemodynamic responses after transplantation. In this small cohort of patients with moderate to severe pulmonary hypertension in the setting of POPH, we have shown that ambrisentan monotherapy can significantly improve pulmonary hemodynamic responses without adverse effect on hepatic function.