Longer-term efficiency and safety of increasing the frequency of whole blood donation (INTERVAL): extension study of a randomised trial of 20 757 blood donors.
The INTERVAL trial showed that, over a 2-year period, inter-donation intervals for whole blood donation can be safely reduced to meet blood shortages. We extended the INTERVAL trial for a further 2 years to evaluate the longer-term risks and benefits of varying inter-donation intervals, and to compare routine versus more intensive reminders to help donors keep appointments. The INTERVAL trial was a parallel group, pragmatic, randomised trial that recruited blood donors aged 18 years or older from 25 static donor centres of NHS Blood and Transplant across England, UK. Here we report on the prespecified analyses after 4 years of follow-up. Participants were whole blood donors who agreed to continue trial participation on their originally allocated inter-donation intervals (men: 12, 10, and 8 weeks; women: 16, 14, and 12 weeks). They were further block-randomised (1:1) to routine versus more intensive reminders using computer-generated random sequences. The prespecified primary outcome was units of blood collected per year analysed in the intention-to-treat population. Secondary outcomes related to safety were quality of life, self-reported symptoms potentially related to donation, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin and other factors. This trial is registered with ISRCTN, number ISRCTN24760606, and has completed. Between Oct 19, 2014, and May 3, 2016, 20 757 of the 38 035 invited blood donors (10 843 [58%] men, 9914 [51%] women) participated in the extension study. 10 378 (50%) were randomly assigned to routine reminders and 10 379 (50%) were randomly assigned to more intensive reminders. Median follow-up was 1·1 years (IQR 0·7-1·3). Compared with routine reminders, more intensive reminders increased blood collection by a mean of 0·11 units per year (95% CI 0·04-0·17; p=0·0003) in men and 0·06 units per year (0·01-0·11; p=0·0094) in women. During the extension study, each week shorter inter-donation interval increased blood collection by a mean of 0·23 units per year (0·21-0·25) in men and 0·14 units per year (0·12-0·15) in women (both p<0·0001). More frequent donation resulted in more deferrals for low haemoglobin (odds ratio per week shorter inter-donation interval 1·19 [95% CI 1·15-1·22] in men and 1·10 [1·06-1·14] in women), and lower mean haemoglobin (difference per week shorter inter-donation interval -0·84 g/L [95% CI -0·99 to -0·70] in men and -0·45 g/L [-0·59 to -0·31] in women) and ferritin concentrations (percentage difference per week shorter inter-donation interval -6·5% [95% CI -7·6 to -5·5] in men and -5·3% [-6·5 to -4·2] in women; all p<0·0001). No differences were observed in quality of life, serious adverse events, or self-reported symptoms (p>0.0001 for tests of linear trend by inter-donation intervals) other than a higher reported frequency of doctor-diagnosed low iron concentrations and prescription of iron supplements in men (p<0·0001). During a period of up to 4 years, shorter inter-donation intervals and more intensive reminders resulted in more blood being collected without a detectable effect on donors' mental and physical wellbeing. However, donors had decreased haemoglobin concentrations and more self-reported symptoms compared with the initial 2 years of the trial. Our findings suggest that blood collection services could safely use shorter donation intervals and more intensive reminders to meet shortages, for donors who maintain adequate haemoglobin concentrations and iron stores. NHS Blood and Transplant, UK National Institute for Health Research, UK Medical Research Council, and British Heart Foundation.


Amino acid sequence of the winged bean (Psophocarpus tetragonolobus) basic lectin. Adenine binding and identification of the active-site tryptophan residue.
The complete amino acid sequence of winged bean basic agglutinin (WBA I) was obtained by a combination of manual and gas-phase sequencing methods. Peptide fragments for sequence analyses were obtained by enzymatic cleavages using trypsin and Staphylococcus aureus V8 endoproteinase and by chemical cleavages using iodosobenzoic acid, hydroxylamine, and formic acid. COOH-terminal sequence analysis of WBA I and other peptides was performed using carboxypeptidase Y. The primary structure of WBA I was homologous to those of other legume lectins and more so to Erythrina corallodendron. Interestingly, the sequence shows remarkable identities in the regions involved in the association of the two monomers of E. corallodendron lectin. Other conserved regions are the double metal-binding site and residues contributing to the formation of the hydrophobic cavity and the carbohydrate-binding site. Chemical modification studies both in the presence and absence of N-acetylgalactosamine together with sequence analyses of tryptophan-containing tryptic peptides demonstrate that tryptophan 133 is involved in the binding of carbohydrate ligands by the lectin. The location of tryptophan 133 at the active center of WBA I for the first time subserves to explain a role for one of the most conserved residues in legume lectins.


Spatial modulation of repetition blindness and repetition deafness.
When two identical visual items are presented in rapid succession, people often fail to report the second instance when trying to recall both (e.g., Kanwisher, 1987). We investigated whether this temporal processing deficit is modulated by the spatial separation between the repeated stimuli within both audition and vision. In Experiment 1, lists of one to three digits were rapidly presented from loudspeaker cones arranged in a semicircle around the participant. Recall accuracy was lower when repeated digits were presented from different positions rather than from the same position, as compared to unrepeated control pairs, demonstrating that auditory repetition deafness (RD) is modulated by the spatial displacement between repeated items. A similar spatial modulation of visual repetition blindness (RB) was reported when pairs of masked letters were presented visually from either the same or different positions arranged on a semicircle around fixation (Experiment 2). These results cannot easily be accounted for by the token individuation hypothesis of RB (Kanwisher, 1987; Park & Kanwisher, 1994) and instead support a recognition failure account (Hochhaus & Johnston, 1996; Luo & Caramazza, 1995, 1996).


Dual Antibody-Conjugated Amyloid Nanorods to Promote Selective Cell-Cell Interactions.
Grafting biomolecules on nanostructures' surfaces is an increasingly used strategy to target pathogenic cells, with both diagnostic and therapeutic applications. However, nanomaterials monofunctionalized by conjugating a single type of ligand find limited uses in pathologies/therapies that require two or more targets/receptors to be targeted and/or activated with a single molecular entity simultaneously. Therefore, multivalent nanomaterials for dual- or multitargeting are attracting significant interest. This study provides a proof of concept of such nanostructures. We have recently developed a modular methodology that allows obtaining amyloid-based materials decorated with active globular domains. Here, this approach is exploited to generate functional amyloid fibrils displaying antibody capture moieties. A high antibody binding affinity and capacity for the resulting nanofibrils, whose size can be manipulated to obtain homogeneous nanorods with high biocompatibility, are demonstrated. These nanorods are then used for specific antibody-mediated targeting of different cell types. Simultaneous conjugation of these nanorods with different antibodies allows obtaining a mimic of a bispecific antibody that redirects T lymphocytes to tumoral cells, holding high potential for immunotherapy. Overall, the work illustrates a modular and straightforward strategy to obtain preparative quantities of multivalent antibody-functionalized nanomaterials with multitargeting properties without the need for covalent modification.


Impact of pediatric rehabilitation services on children's functional outcomes.
Relatively little is known about the treatment effectiveness and functional outcomes of pediatric rehabilitation therapies. This study was conducted to gain knowledge of the type and quantity of inpatient rehabilitation services provided to children who received acute inpatient rehabilitation and compare functional gains by age and diagnosis. A retrospective cohort design was used. Records of rehabilitation therapies and functional assessments of 814 pediatric patients who received inpatient rehabilitation during 1996, 1997, and 1998 were collected. The admission and discharge item ratings of the WeeFIM instrument were first transformed into interval-level measures of self-care, mobility, and cognition. Parametric analyses were used to compare functional gains across impairment groups and to examine the relationship between amount of treatment and functional gains. Occupational therapy and physical therapy were the primary rehabilitation services received by patients across impairment groups (98% and 99%, respectively). A large proportion of children with traumatic brain injuries also received speech therapy (97%) and psychology services (60%). Across domains (self-care, mobility, cognition), the largest gains were made by children who were older than 7 years and had traumatic injuries. Functional gains were significantly related to the amount of discipline-specific treatment received, after controlling for age, impairment, and functional status at admission. Rehabilitation therapy provision in pediatric inpatient rehabilitation varies greatly depending on children's age and the nature of the impairment. Systematic reporting of type and quantity of rehabilitation therapies along with functional assessments before and after hospitalization would allow researchers to track functional changes and study the determinants of functional improvement.


PAM50 breast cancer intrinsic subtypes and effect of gemcitabine in advanced breast cancer patients.
In vitro studies suggest basal breast cancers are more sensitive to gemcitabine relative to other intrinsic subtypes. The main objective of this study was to use specimens from a randomized clinical trial to evaluate whether the basal-like subtype identifies patients with advanced breast cancer who benefit from gemcitabine plus docetaxel (GD) compared to single agent docetaxel (D). From patients randomly assigned to GD or D, RNA was isolated from archival formalin-fixed, paraffin-embedded primary breast tumor tissue and used for PAM50 intrinsic subtyping by NanoString nCounter. Statistical analyses were prespecified as a formal prospective-retrospective clinical trial correlative study. Using time to progression (TTP) as primary endpoint, overall survival (OS) and response rate as secondary endpoints, relationships between subtypes and outcome after chemotherapy were analyzed by the Kaplan-Meier method, and Cox proportional hazards regression models. Data analysis was performed independently by the Danish Breast Cancer Cooperative Group (DBCG) statistical core and all statistical tests were two-sided. RNA from 270 patients was evaluable; 84 patients (31%) were classified as luminal A, 97 (36%) luminal B, 43 (16%) basal-like, and 46 (17%) as HER2-enriched. PAM50 intrinsic subtype was a significant independent prognostic factor for both TTP (p=0.014) and OS (p=0.0003). Response rate was not different by subtype, and PAM50 was not a predictor of TTP by treatment arm. PAM50 was however a highly significant predictor of OS following GD compared to D (pinteraction=0.0016). Patients with a basal-like subtype had a significant reduction in OS events [hazard ratio (HR)=0.29, 95% confidence interval (CI)=0.15-0.57; pinteraction=0.0006]. A significantly improved and clinically important prolongation of survival was seen from the addition of gemcitabine to docetaxel in advanced basal-like breast cancer patients.


Co-adaptive calibration to improve BCI efficiency.
All brain-computer interface (BCI) groups that have published results of studies involving a large number of users performing BCI control based on the voluntary modulation of sensorimotor rhythms (SMR) report that BCI control could not be achieved by a non-negligible number of subjects (estimated 20% to 25%). This failure of the BCI system to read the intention of the user is one of the greatest problems and challenges in BCI research. There are two main causes for this problem in SMR-based BCI systems: either no idle SMR is observed over motor areas of the user, or this idle rhythm is not modulated during motor imagery, resulting in a classification performance lower than 70% (criterion level) that renders the control of a BCI application (like a speller) difficult or impossible. Previously, we introduced the concept of machine learning based co-adaptive calibration, which provided substantially improved performance for a variety of users. Here, we use a similar approach and investigate to what extent co-adaptive learning enables significant BCI control for completely novice users, as well as for those who could not achieve control with a conventional SMR-based BCI.


Emerging protozoal pathogens in India: How prepared are we to face the threat?
Emerging protozoal pathogens have become a major threat to human health. The number of protozoal pathogens causing human disease has been on the rise since the last two to three decades. Significant increase in the number of immunocompromised people, increase in international travel, deforestation, and widespread urban dwellings are some of the factors contributing to this changing epidemiology of protozoal diseases. Apart from Naegleria and Acanthamoeba, other free-living amoebae like Balamuthia and Sappinia are being reported to cause meningoencephalitis in humans. Plasmodium knowlesi, a zoonotic malarial parasite, has become a major cause of human malaria in Southeast Asia. Trypanosoma evansi and Trypanosoma lewisi, which normally infect horses and rodents respectively, have been reported to cause human trypanosomiasis in India. Balantidium coli is emerging as an important cause of dysentery especially in the immunocompromised population. In India, where a significant proportion of population lives in close proximity to cattle and pigs, B. coli can emerge as a significant pathogen in cases of dysentery, especially in the immunocompromised population. Babesia microti has become an important cause of transfusion transmitted babesiosis (TTB) in countries like the United States. As Babesia can be misdiagnosed as Plasmodium and blood transfusion is becoming common in India, it is necessary to develop diagnostic tests to rule out this pathogen in blood donors. Increased awareness among clinicians, pathologists, and microbiologists along with other factors like constant surveillance, improved diagnostic tests, and a high index of suspicion are important to detect and properly treat such emerging protozoal pathogens in humans.


Liver Injury, Endotoxemia, and Their Relationship to Intestinal Microbiota Composition in Alcohol-Preferring Rats.
There is strong evidence that alcoholism leads to dysbiosis in both humans and animals. However, it is unclear how changes in the intestinal microbiota (IM) relate to ethanol (EtOH)-induced disruption of gut-liver homeostasis. We investigated this issue using selectively bred Sardinian alcohol-preferring (sP) rats, a validated animal model of excessive EtOH consumption. Independent groups of male adult sP rats were exposed to the standard, home-cage 2-bottle "EtOH (10% v/v) versus water" choice regimen with unlimited access for 24 h/d (Group Et) for 3 (T1), 6 (T2), and 12 (T3) consecutive months. Control groups (Group Ct) were composed of matched-age EtOH-naïve sP rats. We obtained samples from each rat at the end of each experimental time, and we used blood and colon tissues for intestinal barrier integrity and/or liver pathology assessments and used stool samples for IM analysis with 16S ribosomal RNA gene sequencing. Rats in Group Et developed hepatic steatosis and elevated serum transaminases and endotoxin/lipopolysaccharide (LPS) levels but no other liver pathological changes (i.e., necrosis/inflammation) or systemic inflammation. While we did not find any apparent alteration of the intestinal colonic mucosa, we found that rats in Group Et exhibited significant changes in IM composition compared to the rats in Group Ct. These changes were sustained throughout T1, T2, and T3. In particular, Ruminococcus, Coprococcus, and Streptococcus were the differentially abundant microbial genera at T3. The KEGG Ortholog profile revealed that IM functional modules, such as biosynthesis, transport, and export of LPS, were also enriched in Group Et rats at T3. We showed that chronic, voluntary EtOH consumption induced liver injury and endotoxemia together with dysbiotic changes in sP rats. This work sets the stage for improving our knowledge of the prevention and treatment of EtOH-related diseases.


Marine reserves can mitigate and promote adaptation to climate change.
Strong decreases in greenhouse gas emissions are required to meet the reduction trajectory resolved within the 2015 Paris Agreement. However, even these decreases will not avert serious stress and damage to life on Earth, and additional steps are needed to boost the resilience of ecosystems, safeguard their wildlife, and protect their capacity to supply vital goods and services. We discuss how well-managed marine reserves may help marine ecosystems and people adapt to five prominent impacts of climate change: acidification, sea-level rise, intensification of storms, shifts in species distribution, and decreased productivity and oxygen availability, as well as their cumulative effects. We explore the role of managed ecosystems in mitigating climate change by promoting carbon sequestration and storage and by buffering against uncertainty in management, environmental fluctuations, directional change, and extreme events. We highlight both strengths and limitations and conclude that marine reserves are a viable low-tech, cost-effective adaptation strategy that would yield multiple cobenefits from local to global scales, improving the outlook for the environment and people into the future.


Extracting concentrated guided light.
The maximum concentration of radiation is proportional to the square of the refractive index of the medium in which it propagates. A medium with a high refractive index can also serve as a lightguide for concentrated radiation. However, if concentrated radiation is extracted from one medium, with a high refractive index, to another, whose index is lower (e.g., from fused silica into air), part of the radiation may be lost because of the total internal reflection at the interface. We present polygonal shapes suitable for efficient extraction of the concentrated radiation in a controllable way, without increasing the cross-section area (or diameter) of the lightguide. It is shown analytically and experimentally that the use of a secondary concentrator, followed by such a light extractor, both having a high refractive index, can provide considerably more power to a solar receiver with a specific aperture.


A palladium complex immobilized onto a magnetic GO-MnFe2O4 surface as an effective and recyclable catalyst for the reduction of p-nitrophenol.
A magnetically separable palladium complex on a GO-MnFe2O4 surface has been synthesized by covalent immobilization of a palladium complex on the magnetic GO-MnFe2O4 surface functionalized with 3-aminopropyltriethoxysilane (APTES). In general, magnetic, iron based materials (MnFe2O4) are effective in many catalytic reactions and are advantageous compared with other metal oxides due to their magnetic recyclability. The catalytic activities of these nanohybrids have been studied in p-nitrophenol (p-Nip) reduction. Fourier transform infrared (FT-IR) spectroscopy, thermogravimetric analysis (TGA), inductively coupled plasma atomic emission spectrometry (ICP-AES), X-ray diffraction (XRD), energy dispersive X-ray analysis (EDAX) and transmission electron microscopy (TEM) were used to characterize the catalyst. The successful incorporation of the palladium complex onto GO-MnFe2O4 has been confirmed by FT-IR spectroscopy, thermogravimetric analysis and ICP-AES. The intact structure of GO-MnFe2O4 was verified by X-ray diffraction (XRD), energy dispersive X-ray analysis (EDAX) and TEM. The strong reduction of p-nitrophenol was shown by the palladium complex on GO-MnFe2O4. This magnetic heterogeneous catalyst was well recoverable with no significant loss of activity and selectivity after five successive runs.


Angiographic evaluation of the radial artery diameter in patients who underwent coronary angiography or coronary intervention.
The aim of this study was to determine the radial artery diameter of patients through angiography and evaluate the feasibility of using wider sheaths for radial interventions. In addition, any parameters that could affect the radial artery diameter were also evaluated. The radial artery is a suitable, beneficial route for coronary procedures and is considered a good alternative to transfemoral access. However, a small radial artery diameter may make complicated coronary and peripheral procedures even more difficult. Therefore, an evaluation of the radial artery diameter may help the interventional cardiologist to select the instruments and techniques that are the most appropriate for the patient. Radial artery diameters were calculated in 93 consecutive patients who underwent a transradial coronary procedure along with simultaneous radial angiography, and the anthropometric parameters that might affect the diameter and the association between vessel diameter and pain experienced by the patient during sheath removal were investigated. A total of 97 patients (69 males [71.1%]; 28 females [28.9%]) between 30-89 years of age (mean age, 59.0 ± 10.6 years) were included in the study. Four patients were excluded due to the failure of the radial procedure. The radial artery diameters were measured angiographically in the remaining 93 patients, and the procedural success rate was 95.8%. The mean radial artery diameters were 2.3 ± 0.38 mm in males, 2.1 ± 0.42 mm in females, and 2.3 ± 0.40 mm for the entire study population. Body weight and distal and proximal wrist diameters showed positive and significant correlations with the radial artery diameter (P=.025, P=.013, and P=.032, respectively). In this cross-sectional study, since the mean radial artery diameter was 2.3 ± 0.40 mm, the coronary procedures performed via the radial route can be deemed successful. Moreover, we found no independent predictors of radial artery diameter. Among the patients, 74% had coronary artery diameters of 6 Fr or larger. As long as the ulnar collateral circulation is sufficient, the transradial procedure can be safely performed without considering any other anthropometric parameters.


Treatment Regimens for Transplant-Ineligible Patients With Newly Diagnosed Multiple Myeloma: A Systematic Literature Review and Network Meta-analysis.
Many treatment regimens have been evaluated in transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM). The objective of this study was to compare the efficacy of relevant therapies for the treatment of TIE patients with NDMM. Progression-free survival (PFS) and overall survival (OS) from large randomised controlled trials (RCTs) evaluating different treatment options for TIE patients with NDMM were compared in a network meta-analysis (NMA). The NMA includes recent primary and long-term OS readouts from SWOG S0777, ENDURANCE, MAIA, and ALCYONE. Relevant trials were identified through a systematic literature review. Relative efficacy measures (i.e., hazard ratios [HRs] for PFS and OS) were extracted and synthesised in random-effects NMAs. A total of 122 publications describing 45 unique RCTs was identified. Continuous lenalidomide/dexamethasone (Rd) was selected as the referent comparator. Daratumumab-containing treatments (daratumumab/lenalidomide/dexamethasone [D-Rd], daratumumab/bortezomib/melphalan/prednisone [D-VMP]) and bortezomib/lenalidomide/dexamethasone (VRd) had the highest probabilities of being more effective than Rd continuous for PFS (HR: D-Rd, 0.53; D-VMP, 0.57, VRd, 0.77) and OS (HR: D-Rd, 0.68; VRd, 0.77, D-VMP, 0.78). D-Rd had the highest chance of being ranked as the most effective treatment with respect to PFS and OS. Results using a smaller network focusing on only those regimens that are relevant in Europe were consistent with the primary analysis. These comparative effectiveness data may help inform treatment selection in TIE patients with NDMM.


Consumption of Herbal Supplements or Homeopathic Remedies to Prevent COVID-19 and Intention of Vaccination for COVID-19 in Latin America and the Caribbean.
Users of complementary and alternative medicine (CAM) have a lower intention to receive vaccines. Furthermore, Latin America and the Caribbean (LAC) region are among the most affected areas by the COVID-19 pandemics and present a high proportion of CAM users. Therefore, this study evaluates the association between the consumption of herbal supplements or homeopathic remedies to prevent COVID-19 and the intention to vaccinate against COVID-19 in the LAC region. We conducted a secondary data analysis of a Massachusetts Institute of Technology (MIT) survey with Facebook to assess COVID-19 beliefs, behaviours, and norms. Crude and adjusted prevalence ratios (aPR) with their respective 95% confidence intervals (95% CI) were calculated using generalized linear models of the Poisson family with the log link function. The prevalence of the use of products to prevent COVID-19 was the following: consumption of herbal supplements (7.2%), use of homeopathic remedies (4.8%), and consumption of garlic, ginger, and lemon (11.8%). An association was found between using herbal supplements (19.0% vs. 12.8%; aPR = 1.44; 95% CI: 1.30-1.58), the use of homeopathic remedies (20.3% vs. 12.3%; aPR = 1.58; 95% CI: 1.25-1.98), and the consumption of garlic, ginger, and lemon (18.9% vs. 11.9%; aPR = 1.55; 95% CI: 1.50-1.61) and non-intention to vaccinate against COVID-19. In the LAC population, there is an association between using herbal supplements, using homeopathic remedies and consuming garlic, ginger, and lemon to prevent infection by COVID-19 and non-intention to vaccinate against this disease. Therefore, it is necessary to design targeted strategies for groups that consume these products as preventive measures against COVID-19 to increase vaccination coverage and expand the information regarding transmission and prevention strategies for SARS-CoV-2.


Cutaneous wound closure materials: an overview and update.
On a daily basis, dermasurgeons are faced with different kinds of wounds that have to be closed. With a plethora of skin closure materials currently available, choosing a solution that combines excellent and rapid cosmetic results with practicality and cost-effectiveness can be difficult, if not tricky. We aimed to review the available skin closure materials over the past 20 years and the scientific claims behind their effectiveness in repairing various kinds of wounds. The two authors independently searched and scrutinised the literature. The search was performed electronically using Pub Med, the Cochrane Database, Google Scholar and Ovid as search engines to find articles concerning skin closure materials written since 1990. Many factors are involved in the choice of skin closure material, including the type and place of the wound, available materials, physician expertise and preferences, and patient age and health. Evidence-based main uses of different skin closure materials are provided to help surgeons choose the appropriate material for different wounds.


Dynamics of Fat Oxidation from Sitting at Rest to Light Exercise in Inactive Young Humans.
Societal erosion of daily life low-level physical activity has had a great influence on the obesity epidemic. Given that low fat oxidation is also a risk factor for obesity, we investigated, in a repeated measures design, the dynamics of fat oxidation from a resting state to a light-intensity leg cycling exercise (0-50 watts) in inactive, healthy young adults. Using indirect calorimetry, energy expenditure and the respiratory quotient (RQ) were assessed in a sitting posture at rest and during a cycling exercise in 35 subjects (20 women). The rate of perceived exhaustion (RPE) was assessed using the Borg Scale. During graded leg cycling, the mean RPE did not exceed values corresponding to the exercise being perceived as 'light'. However, analysis of individual data at 50 watts revealed two distinct subgroups among the subjects: those having RPE values corresponding to the exercise being perceived as 'very light to light' and showing no increase in RQ relative to resting levels, as opposed to an increase in RQ in those who perceived the exercise as being 'somewhat hard to hard' (p < 0.001). Our study in inactive individuals showing that high fat oxidation was maintained during 'light-perceived' physical activity reinforced the potential importance of light physical activity in the prevention of obesity.


Economic arguments in migrant health policymaking: proposing a research agenda.
Welfare states around the world restrict access to public healthcare for some migrant groups. Formal restrictions on migrants' healthcare access are often justified with economic arguments; for example, as a means to prevent excess costs and safeguard scarce resources. However, existing studies on the economics of migrant health policies suggest that restrictive policies increase rather than decrease costs. This evidence has largely been ignored in migration debates. Amplifying the relationship between welfare state transformations and the production of inequalities, the Covid-19 pandemic may fuel exclusionary rhetoric and politics; or it may serve as an impetus to reconsider the costs that one group's exclusion from health can entail for all members of society.The public health community has a responsibility to promote evidence-informed health policies that are ethically and economically sound, and to counter anti-migrant and racial discrimination (whether overt or masked with economic reasoning). Toward this end, we propose a research agenda which includes 1) the generation of a comprehensive body of evidence on economic aspects of migrant health policies, 2) the clarification of the role of economic arguments in migration debates, 3) (self-)critical reflection on the ethics and politics of the production of economic evidence, 4) the introduction of evidence into migrant health policymaking processes, and 5) the endorsement of inter- and transdisciplinary approaches. With the Covid-19 pandemic and surrounding events rendering the suggested research agenda more topical than ever, we invite individuals and groups to join forces toward a (self-)critical examination of economic arguments in migration and health, and in public health generally.


Pathology-proven extradural ("distant") metastases of gliomas in adults in the Netherlands between 1971 and 2018: a systematic case series.
Diffuse gliomas are the most frequent primary tumors originating in the central nervous system parenchyma. Although the majority of these tumors are highly malignant, extradural metastases (EDM) are extremely rare. We aimed to perform a systematic review of patients with pathology-proven EDM of diffuse gliomas in the Netherlands. From the Nationwide Network and Registry of Histo- and Cytopathology in the Netherlands information on all cases with EDM between 1971 and October 2018 was retrieved. Patients aged < 18 years or with a diagnosis of ependymoma or continuous tumor growth from intradural to extradural were excluded. Demographics, initial tumor diagnosis, treatment characteristics, location of the EDM, and survival data were collected. IDH1 R132H immunohistochemistry was performed on cases in which a paraffin block of the metastatic tumor could be retrieved. Twenty-five patients with diffuse glioma and pathology-proven EDM were identified. Median age at diagnosis of glioma was 46 years (IQR: 35-59); 21 patients (84%) were male. Histopathologic diagnosis was glioblastoma in 17 patients (68%) and lower-grade tumor in eight patients. In 3 out of 12 patients of which a paraffin block could be retrieved immunohistochemistry revealed an IDH1-mutant glioma. Most frequent EDM locations were bone/bone marrow (14/25 patients; 56%), and lymph nodes (6/25 patients; 24%). EDM of diffuse glioma are rare. They occur most frequently in patients with glioblastoma, however, they can also originate from lower-grade, IDH-mutant gliomas. In daily practice, EDM of diffuse glioma should be considered in patients with tumefactive lesions of the bone or lymph nodes.


Structural analysis of bioinspired nano materials with synchrotron far IR spectroscopy.
Bioinspired fibres and hierarchical nano-materials are based on the self-assembly of organic building blocks such as polypeptides. Confirming the core structure of such materials is often challenging as they lack the long-range order required by crystallographic methods. Far-IR spectroscopy characterizes the vibrational modes of large molecular units. These vibrational modes are very sensitive to angle strain and second order interactions such as hydrogen bonding. As such, far-IR spectra hold information about the secondary structure and interactions of large biomolecules. Here we analyze the far-IR vibrational spectra of fibrous nano-materials based on three isomeric unnatural tripeptides, Ac-β(3)Leu-β(3)Ile-β(3)Ala, Ac-β(3)Ile-β(3)Ala-β(3)Leu, and Ac-β(3)Ala-β(3)Leu-β(3)Ile. These peptides have well described self-assembly characteristics, forming one-dimensional nanorods that impose tight conformational constraints on the constituent molecules. The synchrotron far-IR spectroscopic results were interpreted by using density functional theory (DFT) modelling based vibrational analysis. The sensitivity of the spectra to peptide conformation was assessed by comparing the experimental spectra with DFT predictions. In high dielectric implicit solvent, intramolecular hydrogen-bonding is inhibited and thus the energy minimized peptide structure remains close to the 14-helix folding characteristic of substituted β(3)-peptides, giving good agreement between the experimental and predicted vibration spectra. In contrast, energy minimization in vacuum alters the peptide conformation leading to intramolecular hydrogen bonds, and hence the predicted vibration spectra do not agree with the experimental data. Therefore, our results demonstrate the ability of far-IR spectroscopy to identify correct structural predictions and thus open the way for using far-IR spectroscopy for the characterization and structural analysis of bioinspired nano-materials and potentially their interactions with surfaces, ionic environments and other biomolecules. Far-IR structural analysis is particularly powerful in case of one- and two-dimensional materials such as fibres, hydrogels and thin layers where standard crystallographic analysis is not available.


Why Policies Fail: The Illusion of Services in the Opioid Epidemic.
Although New York State is a generous provider of substance-use treatment, people who ask for help have difficulty accessing services. If the laws are on the books, the agency is there to act, and the options are available, why is treatment so hard to get? The authors conducted 87 open-ended interviews and observed local task force meetings in Sullivan County, New York. They open coded data, identifying key topics and themes. Even though New York is a best-case scenario for treatment, people who seek help cannot always access it. The state sees the problem as a lack of beds or information about beds, but people on the ground face real barriers that make it difficult to get treatment, including the medical model of detoxification, admissions criteria, staff shortages, and other life complications. Contrary to the policy literature, this article shows that policies may fail not because they are poorly designed or implemented but because the policy itself does not address the actual underlying problem. Furthermore, in the case of opioids, it shows how misplaced solutions can hide evidence of the underlying problem, exacerbating the very issue that policy makers want to fix.


Social cues can push amphibious fish to their thermal limits.
Social context can impact how animals respond to changes in their physical environment. We used an aggressive, amphibious fish, the mangrove rivulus (Kryptolebias marmoratus) with environmentally determined sociality to test the hypothesis that social interactions would push fish to their thermal limits. We capitalized on the propensity of rivulus to emerge from warming water and demonstrated that social stimuli, produced by their reflection, increased emersion threshold without changing the critical thermal maximum, effectively diminishing thermal safety margins. When rivulus were denied air access, surface behaviours dramatically increased, supplanting social interactions. This suggests that assessing the terrestrial environment is crucially important. We conclude that social stimulation narrows the scope for survival in naturally stressful conditions.


Barriers to the Preclinical Development of Therapeutics that Target Aging Mechanisms.
Through the progress of basic science research, fundamental mechanisms that contribute to age-related decline are being described with increasing depth and detail. Although these efforts have identified new drug targets and compounds that extend life span in model organisms, clinical trials of therapeutics that target aging processes remain scarce. Progress in aging research is hindered by barriers associated with the translation of basic science discoveries into the clinic. This report summarizes discussions held at a 2014 Geroscience Network retreat focused on identifying hurdles that currently impede the preclinical development of drugs targeting fundamental aging processes. From these discussions, it was evident that aging researchers have varied perceptions of the ideal preclinical pipeline. To forge a clear and cohesive path forward, several areas of controversy must first be resolved and new tools developed. Here, we focus on five key issues in preclinical drug development (drug discovery, lead compound development, translational preclinical biomarkers, funding, and integration between researchers and clinicians), expanding upon discussions held at the Geroscience Retreat and suggesting areas for further research. By bringing these findings to the attention of the aging research community, we hope to lay the foundation for a concerted preclinical drug development pipeline.


Central nervous system activation by noise.
Connections between thalamic structures of the auditory system and subcortical areas (amygdala, hippocampus, hypothalamus) had been hypothesized to act as a fast reacting "memory chain" establishing and enhancing adverse excitations during noise exposure. Recent studies prove that the lateral amygdala is an important part of a second separate pathway to the telencephalic projections of the auditory system. This fast, monosynaptic thalamo-amygdala tract is responsible for full-blown "fear responses" evoked by auditory stimuli as shown by several conditioning experiments in animals: A fear memory system. The appertaining basic processes of plasticity in the amygdala are reductions of latencies of neuronal excitations and recruiting of more elements with shorter latency, long-term potentiation causing enhancement of auditory-evoked responses by repeated stimulation, as well as sharpening of primary broad tuning curves of elements. Very recently a study using Functional-Magnetic-Resonance-Imaging (fMRI) demonstrated that an amygdalar contribution to conditioned fear learning can be revealed in normal human subjects too. These findings were supported by Positron-Emission-Tomography (PET) studies in depressive persons showing that amygdala metabolic abnormality predicted the cortisol concentration in blood. Using connections via central amygdala, lateral and medial hypothalamus to parts named nuclei paraventriculares and regio arcuata, the sound evoked excitations reach two essential components of endocrine functioning: a) the well-known hypothalamic-pituitary-adrenal (HPA) system with a subsequent rise (via Corticotropin-Releasing Hormone: CRH) in Corticotropin (Adreno-CorticoTropin Hormone: ACTH) and the corticosterone levels; b) the synthesis of ACTH and beta-endorphine-like substances in the arcuate region being axonally transported to extrahypothalamic brain regions. Longer-lasting activation of the HPA-axis, especially abnormally increased or periodically elevated levels of cortisol and the widespread extrahypothalamically distributed CRF/ACTH may lead to disturbed hormonal balance and even to severe diseases.


Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects.
The adaptor protein-2 sigma subunit (AP2σ2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2σ2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca(2+) o) homeostasis. To elucidate the role of AP2σ2 in Ca(2+) o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2σ2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2σ2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype-phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2σ2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2σ2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2σ2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue.


Propagation of polychromatic Gaussian beams through thin lenses.
The transformation by a lens of a polychromatic laser beam composed of on-axis superposed monochromatic TEM00 Gaussian modes in the paraxial approximation is studied. The chromatic aberrations are described by allowing the waist position on the z axis and the Rayleigh range to depend on wavelength. The beam radius, the far-field divergence, the Rayleigh range, the beam product, the beam propagation factor, and the kurtosis parameter are calculated. The relationship between the fourth-order and the second-order moments of Hermite-Gaussian and Laguerre-Gaussian modes is obtained and is used for calculating kurtosis parameter. The results are generalized to polychromatic modes of higher orders. It is shown that the on-axis superposition of monochromatic TEM00 modes with no chromatic aberration is leptokurtic.


The rise of diversity in metabolic platforms across the Candidate Phyla Radiation.
A unifying feature of the bacterial Candidate Phyla Radiation (CPR) is a limited and highly variable repertoire of biosynthetic capabilities. However, the distribution of metabolic traits across the CPR and the evolutionary processes underlying them are incompletely resolved. Here, we selected ~ 1000 genomes of CPR bacteria from diverse environments to construct a robust internal phylogeny that was consistent across two unlinked marker sets. Mapping of glycolysis, the pentose phosphate pathway, and pyruvate metabolism onto the tree showed that some components of these pathways are sparsely distributed and that similarity between metabolic platforms is only partially predicted by phylogenetic relationships. To evaluate the extent to which gene loss and lateral gene transfer have shaped trait distribution, we analyzed the patchiness of gene presence in a phylogenetic context, examined the phylogenetic depth of clades with shared traits, and compared the reference tree topology with those of specific metabolic proteins. While the central glycolytic pathway in CPR is widely conserved and has likely been shaped primarily by vertical transmission, there is evidence for both gene loss and transfer especially in steps that convert glucose into fructose 1,6-bisphosphate and glycerate 3P into pyruvate. Additionally, the distribution of Group 3 and Group 4-related NiFe hydrogenases is patchy and suggests multiple events of ancient gene transfer. We infer that patterns of gene gain and loss in CPR, including acquisition of accessory traits in independent transfer events, could have been driven by shifts in host-derived resources and led to sparse but varied genetic inventories.


Cell type variation in responses to antimitotic drugs that target microtubules and kinesin-5.
To improve cancer chemotherapy, we need to understand the mechanisms that determine drug sensitivity in cancer and normal cells. Here, we investigate this question across a panel of 11 cell lines at a phenotypic and molecular level for three antimitotic drugs: paclitaxel, nocodazole, and an inhibitor of kinesin-5 (also known as KSP, Eg5, Kif11). Using automated microscopy with markers for mitosis and apoptosis (high content screening), we find that the mitotic arrest response shows relatively little variation between cell types, whereas the tendency to undergo apoptosis shows large variation. We found no correlation between levels of mitotic arrest and apoptosis. Apoptosis depended on entry into mitosis and occurred both from within mitosis and after exit. Response to the three drugs strongly correlated, although paclitaxel caused more apoptosis in some cell lines at similar levels of mitotic arrest. Molecular investigations showed that sensitivity to apoptosis correlated with loss of an antiapoptotic protein, XIAP, during the drug response, but not its preresponse levels, and to some extent also correlated with activation of the p38 and c-Jun NH(2) kinase pathways. We conclude that variation in sensitivity to antimitotic drugs in drug-naive cell lines is governed more by differences in apoptotic signaling than by differences in mitotic spindle or spindle assembly checkpoint proteins and that antimitotics with different mechanisms trigger very similar, but not identical, responses.


One-step fabrication of LSPR-tuneable reconfigurable assemblies of gold nanoparticles decorated with biotin-binding proteins.
Assemblies of gold nanoparticles with chain-like morphologies and new near-infrared (NIR) localized surface plasmon resonance (LSPR) are obtained by adding the biotin-binding proteins avidin, neutravidin or streptavidin to citrate-capped nanoparticles. The key idea behind this one-step fabrication method is to destabilize the colloids by adding positively charged proteins and/or by making their zeta potential less negative. The extent of assembly, and therefore the NIR LSPR, can be fine-tuned by varying the concentration of proteins as well as by changing the pH of the solution. The resulting nanoparticle clusters can also reconfigure into smaller assemblies that absorb less NIR light by adding thiolated molecules or by increasing the pH of the solution. This, along with the observation that the proteins retain their biotin-binding properties in the assemblies, makes the proposed method promising for the development of new biosensors and drug delivery platforms capable of self-regulating their optical properties as a function of chemical signals in their environment.


Advancing tools for human early lifecourse exposome research and translation (ATHLETE): Project overview.
Early life stages are vulnerable to environmental hazards and present important windows of opportunity for lifelong disease prevention. This makes early life a relevant starting point for exposome studies. The Advancing Tools for Human Early Lifecourse Exposome Research and Translation (ATHLETE) project aims to develop a toolbox of exposome tools and a Europe-wide exposome cohort that will be used to systematically quantify the effects of a wide range of community- and individual-level environmental risk factors on mental, cardiometabolic, and respiratory health outcomes and associated biological pathways, longitudinally from early pregnancy through to adolescence. Exposome tool and data development include as follows: (1) a findable, accessible, interoperable, reusable (FAIR) data infrastructure for early life exposome cohort data, including 16 prospective birth cohorts in 11 European countries; (2) targeted and nontargeted approaches to measure a wide range of environmental exposures (urban, chemical, physical, behavioral, social); (3) advanced statistical and toxicological strategies to analyze complex multidimensional exposome data; (4) estimation of associations between the exposome and early organ development, health trajectories, and biological (metagenomic, metabolomic, epigenetic, aging, and stress) pathways; (5) intervention strategies to improve early life urban and chemical exposomes, co-produced with local communities; and (6) child health impacts and associated costs related to the exposome. Data, tools, and results will be assembled in an openly accessible toolbox, which will provide great opportunities for researchers, policymakers, and other stakeholders, beyond the duration of the project. ATHLETE's results will help to better understand and prevent health damage from environmental exposures and their mixtures from the earliest parts of the life course onward.


Comparison of Wait Times for New Patients Between the Private Sector and United States Department of Veterans Affairs Medical Centers.
Concerns have been raised about the adequacy of health care access among patients cared for within the United States Department of Veterans Affairs (VA) health care system. To determine wait times for new patients receiving care at VA medical centers and compare wait times in the VA medical centers with wait times in the private sector (PS). A retrospective, repeated cross-sectional study was conducted of new appointment wait times for primary care, dermatology, cardiology, or orthopedics at VA medical centers in 15 major metropolitan areas in 2014 and 2017. Comparison data from the PS came from a published survey that used a secret shopper survey approach. Secondary analyses evaluated the change in overall and unique patients seen in the entire VA system and patient satisfaction survey measures of care access between 2014 and 2017. The outcome of interest was patient wait time. Wait times in the VA were determined directly from patient scheduling. Wait times in the PS were as reported in Merritt Hawkins surveys using the secret shopper method. Compared with the PS, overall mean VA wait times for new appointments in 2014 were similar (mean [SD] wait time, 18.7 [7.9] days PS vs 22.5 [7.3] days VA; P = .20). Department of Veterans Affairs wait times in 2014 were similar to those in the PS across specialties and regions. In 2017, overall wait times for new appointments in the VA were shorter than in the PS (mean [SD], 17.7 [5.9] vs 29.8 [16.6] days; P < .001). This was true in primary care (mean [SD], 20.0 [10.4] vs 40.7 [35.0] days; P = .005), dermatology (mean [SD], 15.6 [12.2] vs 32.6 [16.5] days; P < .001), and cardiology (mean [SD], 15.3 [12.6] vs 22.8 [10.1] days; P = .04). Wait times for orthopedics remained longer in the VA than the PS (mean [SD], 20.9 [13.3] vs 12.4 [5.5] days; P = .01), although wait time improved significantly between 2014 and 2017 in the VA for orthopedics while wait times in the PS did not change (change in mean wait times, increased 1.5 days vs decreased 5.4 days; P = .02). Secondary analysis demonstrated an increase in the number of unique patients seen and appointment encounters in the VA between 2014 and 2017 (4 996 564 to 5 118 446, and 16 476 461 to 17 331 538, respectively), and patient satisfaction measures of access also improved (satisfaction scores increased by 1.4%, 3.0%, and 4.0% for specialty care, routine primary care, and urgent primary care, P < .05). Although wait times in the VA and PS appeared to be similar in 2014, there have been interval improvements in VA wait times since then, while wait times in the PS appear to be static. These findings suggest that access to care within the VA has improved over time.


Effects of prolonged dark adaptation in patients with retinitis pigmentosa of Bothnia type: an electrophysiological study.
Bothnia dystrophy (BD) is a variant of recessive retinitis punctata albescens (RPA), caused by the missense mutation R233W in cellular retinaldehyde-binding protein (CRALBP), which is localized in the retinal pigment epithelium (RPE) and Müller cells of the retina. The purpose of this study was, by examining the electrophysiological responses of the retina, to evaluate the capacity of recovery of the whole retinal area and different cell types induced by extremely prolonged dark adaptation (DA) in BD disease and to gain further understanding of the pathogenesis of BD. Six young patients underwent bilateral full-field ERGs after 24 h of DA in one eye and standard DA in the fellow eye. The results were also compared with the effect of prolonged DA (10 h), previously studied in the same patients. After extremely prolonged DA (24 h) the rod b-wave and the mixed rod-cone a-wave responses reached normal though delayed amplitudes. An increase, up to normal level, in the oscillatory response was found. There was no obvious recovery of the cone response. We conclude that in young BD patients during extremely prolonged DA there is a significant additional capacity of recovery of rod function and also significant gain of activity in the inner retinal layer. A continuous but slow regeneration of rod photopigment seems to occur at least up to 24 h. The visual process in the RPE is retarded and CRALBP acts in this process; also, the Müller cells of the retina seem to be involved. The findings also support an extremely slow synthesis of photopigments and irreversibly disturbed cone function early in BD.


Evaluation of healthcare costs and utilization for patients with gout: a population-based matched cohort study.
To better understand the economic burden of gout patients in Taiwan, a nationwide retrospective study was conducted to compare the healthcare costs and utilization between gout and gout-free patients. The Longitudinal Health Insurance Database (LHID) 2010 was used to identify gout cases and matched gout-free controls. Gout cases were defined as having (1) at least three instances of diagnoses of gout on medical claims, or (2) one diagnosis of gout with at least one gout-related pharmacy claim in 2011. A control cohort was matched with cases at a 3:1 ratio by age, gender, residential area, and the Charlson Comorbidity Index. All medical utilization and costs per patient within the 365 days following the index date were compared between cases and controls. Out of 993,332 beneficiaries, a total of 21,376 matched gout patients met the gout inclusion criteria. Compared to controls, gout patients had more outpatient visits (mean = 31.2 vs 22.6), inpatient visits (mean = 1.7 vs 1.5), and ER visits (mean = 1.9 vs 1.7) (all p < .0001), as well as more outpatient costs (median = USD $634 vs $404), inpatient costs (median = USD $1330 vs $1254), and ER costs (median = USD $87 vs $89) (all p < .05). Gout patients had higher medical utilization and costs than gout-free patients. In gout patients, all-cause and gout-related utilization were mostly outpatient visits, whereas most of the all-cause and gout-related costs were due to hospitalization. The study findings could be useful for future economic evaluations and healthcare resource allocation.


Speciation, introgressive hybridization and nonlinear rate of molecular evolution in flycatchers.
Evolutionary history of Muscicapidae flycatchers is inferred from nuclear and mitochondrial DNA (mtDNA) sequence comparisons and population genetic analysis of nuclear and mtDNA markers. Phylogenetic reconstruction based on sequences from the two genomes yielded similar trees with respect to the order at which the species split off. However, the genetic distances fitted a nonlinear, polynomial model reflecting diminishing divergence rate of the mtDNA sequences compared to the nuclear DNA sequences. This could be explained by Haldane's rule because genetic isolation might evolve more rapidly on the mitochondrial rather than the nuclear genome in birds. This is because hybrid sterility of the heterogametic sex (females) would predate that of the homogametic sex (males), leading to sex biased introgression of nuclear genes. Analyses of present hybrid zones of pied (Ficedula hypoleuca) and collared flycatchers (F. albicollis) may indicate a slight sexual bias in rate of introgression, but the introgression rates were too low to allow proper statistical analyses. It is suggested, however, that the observed deviation from linearity can be explained by a more rapid mutational saturation of the mtDNA sequences than of the nuclear DNA sequences, as supported by analyses of third codon position transversions at two protein coding mtDNA genes. A phylogeographic scenario for the black and white flycatcher species is suggested based on interpretation of the genetic data obtained. Four species appear to have diverged from a common ancestor relatively simultaneously during the Pleistocene. After the last glaciation period, pied and collared flycatchers expanded their breeding ranges and eventually came into secondary contact in Central and Eastern Europe and on the Baltic Isles.


Asymptomatic spinal dural arteriovenous fistulas: pathomechanical considerations.
Spinal dural arteriovenous fistulas (SDAVFs) consist of a shunt with converging feeding vessels arising from radiculomeningeal arteries and draining retrogradely via a radicular vein into the perimedullary veins, thereby causing progressive myelopathy due to venous hypertension in the spinal cord. The purpose of this study was to evaluate the hypothesis that the obstruction of radicular venous outlets could be an additional factor inducing symptomatic venous hypertension due to a decreased outflow in SDAVFs. The authors compared the clinical and imaging findings in patients with asymptomatic SDAVFs identified incidentally at the upper thoracic region with the findings in symptomatic patients who harbored SDAVFs at the same level. All symptomatic patients presented with medullary dysfunction. The mean age of patients with asymptomatic SDAVF was 51.5 years, approximately 10 years younger than the patients with symptomatic SDAVF (64.1 years old). Despite the existence of dilated perimedullary vessels in the dorsal side of the spinal cord in all patients, the spinal cord edema seen in symptomatic patients was not detected on the MR images obtained in patients with asymptomatic SDAVF. The spinal angiograms of the asymptomatic patients distinctively demonstrated early radicular venous outflow from affected perimedullary veins to the extradural venous plexus as a potential alternate route for the venous hypertension to be released. Obstruction of the radicular venous outflow could be an important factor in inducing spinal congestive edema due to venous hypertension, as well as subsequent clinical symptoms of SDAVFs.


Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation.
The normally soluble TAR DNA-binding protein 43 (TDP-43) is found aggregated both in reversible stress granules and in irreversible pathogenic amyloid. In TDP-43, the low-complexity domain (LCD) is believed to be involved in both types of aggregation. To uncover the structural origins of these two modes of β-sheet-rich aggregation, we have determined ten structures of segments of the LCD of human TDP-43. Six of these segments form steric zippers characteristic of the spines of pathogenic amyloid fibrils; four others form LARKS, the labile amyloid-like interactions characteristic of protein hydrogels and proteins found in membraneless organelles, including stress granules. Supporting a hypothetical pathway from reversible to irreversible amyloid aggregation, we found that familial ALS variants of TDP-43 convert LARKS to irreversible aggregates. Our structures suggest how TDP-43 adopts both reversible and irreversible β-sheet aggregates and the role of mutation in the possible transition of reversible to irreversible pathogenic aggregation.


Enhanced maternal origin of the 22q11.2 deletion in velocardiofacial and DiGeorge syndromes.
Velocardiofacial and DiGeorge syndromes, also known as 22q11.2 deletion syndrome (22q11DS), are congenital-anomaly disorders caused by a de novo hemizygous 22q11.2 deletion mediated by meiotic nonallelic homologous recombination events between low-copy repeats, also known as segmental duplications. Although previous studies exist, each was of small size, and it remains to be determined whether there are parent-of-origin biases for the de novo 22q11.2 deletion. To address this question, we genotyped a total of 389 DNA samples from 22q11DS-affected families. A total of 219 (56%) individuals with 22q11DS had maternal origin and 170 (44%) had paternal origin of the de novo deletion, which represents a statistically significant bias for maternal origin (p = 0.0151). Combined with many smaller, previous studies, 465 (57%) individuals had maternal origin and 345 (43%) had paternal origin, amounting to a ratio of 1.35 or a 35% increase in maternal compared to paternal origin (p = 0.000028). Among 1,892 probands with the de novo 22q11.2 deletion, the average maternal age at time of conception was 29.5, and this is similar to data for the general population in individual countries. Of interest, the female recombination rate in the 22q11.2 region was about 1.6-1.7 times greater than that for males, suggesting that for this region in the genome, enhanced meiotic recombination rates, as well as other as-of-yet undefined 22q11.2-specific features, could be responsible for the observed excess in maternal origin.


Hemagglutinin-specific neutralization of subacute sclerosing panencephalitis viruses.
Subacute sclerosing panencephalitis (SSPE) is a progressive, lethal complication of measles caused by particular mutants of measles virus (MeV) that persist in the brain despite high levels of neutralizing antibodies. We addressed the hypothesis that antigenic drift is involved in the pathogenetic mechanism of SSPE by analyzing antigenic alterations in the MeV envelope hemagglutinin protein (MeV-H) found in patients with SSPE in relation to major circulating MeV genotypes. To this aim, we obtained cDNA for the MeV-H gene from tissue taken at brain autopsy from 3 deceased persons with SSPE who had short (3-4 months, SMa79), average (3.5 years, SMa84), and long (18 years, SMa94) disease courses. Recombinant MeVs with a substituted MeV-H gene were generated by a reverse genetic system. Virus neutralization assays with a panel of anti-MeV-H murine monoclonal antibodies (mAbs) or vaccine-immunized mouse anti-MeV-H polyclonal sera were performed to determine the antigenic relatedness. Functional and receptor-binding analysis of the SSPE MeV-H showed activity in a SLAM/nectin-4-dependent manner. Similar to our panel of wild-type viruses, our SSPE viruses showed an altered antigenic profile. Genotypes A, G3, and F (SSPE case SMa79) were the exception, with an intact antigenic structure. Genotypes D7 and F (SSPE SMa79) showed enhanced neutralization by mAbs targeting antigenic site IIa. Genotypes H1 and the recently reported D4.2 were the most antigenically altered genotypes. Epitope mapping of neutralizing mAbs BH015 and BH130 reveal a new antigenic site on MeV-H, which we designated Φ for its intermediate position between previously defined antigenic sites Ia and Ib. We conclude that SSPE-causing viruses show similar antigenic properties to currently circulating MeV genotypes. The absence of a direct correlation between antigenic changes and predisposition of a certain genotype to cause SSPE does not lend support to the proposed antigenic drift as a pathogenetic mechanism in SSPE.


Multigroup Confirmatory Factor Analysis of the Cognitive Dysfunction Questionnaire: instrument refinement and measurement invariance across age and sex.
The study adopted Confirmatory Factor Analysis (CFA) to investigate the factorial structure and reduce the number of items of the Cognitive Dysfunction Questionnaire (CDQ). The analyses were based on data for a total of 1,115 participants from population based samples (mean age: 63.0 ± 14.5 years, range: 25-95) randomly split into a refinement (N = 569) and a cross-validation (N = 546) sample. Equivalence of the measurement and structural portions of the refined model was demonstrated across the refinement and cross-validation samples. Among competing models the best fitting and parsimonious model had a hierarchical factor structure with five first-order and one second-order general factor. For the final version of the CDQ, 20 items within five domains were selected (Procedural actions, Semantic word knowledge, Face recognition, Temporal orientation, and Spatial navigation). Internal consistency reliabilities were adequate for the total scale and for the subscales. Multigroup CFAs indicated measurement invariance across age and sex up to the scalar level. Finally, higher levels of cognitive dysfunction as reflected by CDQ scores were predicted by advancing age, fewer years of education, and with deficits in general cognitive functioning as reflected by scores on the Mini-Mental State Examination. In conclusion, the CDQ appears to be psychometrically sound and shows the expected relationships with variables known to be associated with cognitive dysfunction and dementia. Future studies should apply it among clinical groups to further test its usefulness.


Mutant constructs of the beta-adrenergic receptor that are uncoupled from adenylyl cyclase retain functional activation of Na-H exchange.
beta-Adrenergic receptor (beta AR) agonists modulate a number of intracellular effectors; for example, they stimulate adenylyl cyclase and Ca2+ channels, inhibit Na+ channels and Mg2+ efflux, and activate Na-H exchange. Regulation of adenylyl cyclase, Ca2+, Na+, and Mg2+ by the beta AR is mediated through receptor coupling to the GTP-binding protein Gs. We have previously determined, however, that beta AR stimulation of Na-H exchange occurs independently of receptor coupling to Gs. In the present study, we analyzed mutant beta ARs containing deletions of amino acid residues within the third cytoplasmic domain, to determine whether there is a structural basis for the ability of the beta AR to couple divergently to the Gs-dependent stimulation of adenylyl cyclase and the Gs-independent activation of Na-H exchange. Receptor constructs with deletions of residues 222-229 and 258-270, which were previously shown to be defective in coupling to Gs and adenylyl cyclase, retained an isoproterenol-induced activation of Na-H exchange that was similar in time course and magnitude to that observed with the wild-type beta AR. These results confirm our previous findings that the beta AR activates Na-H exchange independently of Gs, and they further suggest that distinct molecular determinants of the receptor divergently stimulate adenylyl cyclase and Na-H exchange.


Geometric frustration and compatibility conditions for two-dimensional director fields.
Bent core (or banana shaped) liquid-crystal-forming-molecules locally favor an ordered state of zero splay and constant bend. Such a state, however, cannot be realized in the plane and the resulting liquid-crystalline phase is frustrated and must exhibit some compromise of these two mutually contradicting local intrinsic tendencies. This constitutes one of the most well-studied examples in which the intrinsic geometry of the constituents of a material gives rise to a geometrically frustrated assembly. Such geometric frustration is not only natural and ubiquitous but also leads to a striking variety of morphologies of ground states and exotic response properties. In this work we establish the necessary and sufficient conditions for two scalar functions, s and b to describe the splay and bend of a director field in the plane. We generalize these compatibility conditions for geometries with non-vanishing constant Gaussian curvature, and provide a reconstruction formula for the director field depending only on the splay and bend fields and their derivatives. Finally, we discuss optimal compromises for simple incompatible cases where the locally preferred values of the splay and bend cannot be simultaneously achieved.


From public health genomics to precision public health: a 20-year journey.
In this paper, we review the evolution of the field of public health genomics in the United States in the past two decades. Public health genomics focuses on effective and responsible translation of genomic science into population health benefits. We discuss the relationship of the field to the core public health functions and essential services, review its evidentiary foundation, and provide examples of current US public health priorities and applications. We cite examples of publications to illustrate how Genetics in Medicine reflected the evolution of the field. We also reflect on how public-health genomics is contributing to the emergence of "precision public health" with near-term opportunities offered by the US Precision Medicine (AllofUs) Initiative.


Efficacy and Safety of Degludec Compared to Glargine 300 Units/mL in Insulin-Experienced Patients With Type 2 Diabetes: Trial Protocol Amendment (NCT03078478).
A head-to-head trial (NCT03078478) between insulin degludec and insulin glargine U300 with the primary objective of comparing the risk of hypoglycemia is being conducted. During trial conduct, safety concerns related to the glycemic data collection system led to a postinitiation protocol amendment, described here. This randomized (1:1), open-label, treat-to-target, multinational trial was initiated in March 2017 with a planned treatment period of 52 weeks (16 weeks titration + 36 weeks maintenance). Overall, ~1600 insulin-experienced patients at risk of developing hypoglycemia based on predefined risk factors were included. The protocol amendment implemented in February 2018 resulted in assuring patient safety and an extension of the total treatment period up to 88 weeks (16 weeks titration + variable maintenance 1 + 36 weeks maintenance 2). The original glycemic data collection system (MyGlucoHealth blood glucose meter + electronic diary) was discontinued because of safety concerns and replaced with an Abbott blood glucose meter and paper diary to collect self-measured blood glucose and hypoglycemic episodes. The primary endpoint of number of severe or blood-glucose confirmed symptomatic hypoglycemic episodes will be evaluated with the same analysis duration and statistical methods as the original protocol. Only relevant changes were implemented to maintain patient safety while permitting evaluation of the scientific objectives of the trial. These observations highlight the importance of safety surveillance during trial conduct despite the use of currently marketed glucose monitoring devices. The prompt protocol amendment and ensuing actions ensured that the scientific integrity of the trial was not compromised.


Serotype 19A Is the most common serotype causing invasive pneumococcal infections in children.
The purpose of this study was to monitor the clinical and microbiologic features of invasive infections caused by Streptococcus pneumoniae among children before and after the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7). We conducted a 15-year prospective surveillance study of all invasive pneumococcal infections in children. The sample included infants and children at 8 children's hospitals in the United States with culture-proven invasive S pneumoniae infections. Since the implementation of routine PCV7 immunization in 2000, invasive infections have decreased yearly from 2001 through 2004, to a nadir of 151 infections; the rate then increased from 2005 through 2008. Compared with the pre-PCV7 era, a greater proportion of children with invasive pneumococcal infection had an underlying condition in the post-PCV7 period. Compared with the total number of annual admissions, the number of 19A isolates increased significantly from 2001 to 2008 (P < .00001). In 2007 and 2008, only 16 isolates (4%) were vaccine serotypes; 19A accounted for 46% (168 of 369) of the non-PCV7 serotypes. Thirty percent of the 19A isolates were multidrug resistant. Serotypes 1, 3, and 7F accounted for 22% of the non-PCV7 serotypes. Among children with invasive pneumococcal infections, the likelihood of a 19A serotype increased with the number of preceding PCV7 doses. Since 2005, the number of invasive pneumococcal infections in children has increased at 8 children's hospitals, primarily as a result of serotype 19A isolates, one third of which were resistant to multiple antibiotics in 2007 and 2008. Continued surveillance is necessary to detect emerging serotypes after the planned introduction of 13-valent or other pneumococcal vaccines.


Glucocorticoids inhibit the induction of nitric oxide synthase II by down-regulating cytokine-induced activity of transcription factor nuclear factor-kappa B.
Incubation of human A549/8 cells with human interleukin-1 beta (50 units/ml), interferon-gamma (100 units/ml), and tumor necrosis factor-alpha (10 ng/ml) (cytomix) resulted in a marked expression of the mRNA of the inducible nitric oxide synthase (NOS II). This induction was prevented by cycloheximide. Dexamethasone markedly reduced cytokine-induced NOS II mRNA concentrations; this reduction was prevented by RU 38486 (mifepristone). Pyrrolidine dithiocarbamate, an inhibitor of nuclear factor-kappa B (NF-kappa B) activation, also significantly decreased cytomix-induced NOS II mRNA levels. When A549/8 cells were transfected with a construct containing 1570-bp 5'-flanking sequence of the murine NOS II gene cloned before a reporter gene, the murine NOS II promoter was induced up to 20-fold with cytomix but not with bacterial lipopolysaccharide. Dexamethasone as well as pyrrolidine dithiocarbamate inhibited this induction. In electrophoretic mobility shift assays, nuclear protein extracts from cytomix-induced, but not from unstimulated cells, significantly slowed the migration of an oligonucleotide containing the NF-kappa B-binding site. This band shift was markedly reduced by dexamethasone. On the other hand, cytomix-induced nuclear protein content of NF-kappa B p65 and NF-kappa B p50 was not reduced by dexamethasone (as analyzed by Western blot). Dexamethasone also did not reduce cytomix-induced expression of NF-kappa B p65 mRNA or enhance the expression of NF-kappa B inhibitor mRNA. The human and murine NOS II promoters also contain consensus sequences for activating protein-1 (AP-1) binding. However, AP-1 binding activity of nuclear extracts of A549/8 cells was not enhanced by cytomix or inhibited by dexamethasone. These data suggest that the activated glucocorticoid receptor prevents (by a protein/protein interaction) the binding of transcription factor NF-kappa B, but not AP-1, to the NOS II promoter, thereby inhibiting the induction of NOS II transcription.


Non-pancreatic retroperitoneal pseudocyst: a benign disease with non-specific symptoms.
A 76-year-old man presented with abdominal pain and constipation for 1 month. The pain was dull aching in nature and over the right upper abdomen. He also reported decreased appetite. The patient had no previous attacks of acute pancreatitis or history of trauma. There was no history of fever or melena. On visual inspection of the abdomen, there was a mass effect protruding out of the right mid-abdomen. The mass was approximately measuring 15×15 cm, firm in consistency, non-tender, non-mobile and not moving with respiration. Haematological investigations were normal. Both amylase and lipase were within normal limits. A CT of the abdomen revealed a large well-defined thin-walled cystic lesion measuring 10.3×13.9×14.3 cm in the right lumbar and iliac region without calcification or haemorrhage. A diagnosis of retroperitoneal cyst was made and the patient was taken up for surgery. Histology of the cyst showed the absence of epithelia and was reported as pseudocyst.


Metabolic engineering of Yarrowia lipolytica to produce chemicals and fuels from xylose.
Yarrowia lipolytica is a biotechnological chassis for the production of a range of products, such as microbial oils and organic acids. However, it is unable to consume xylose, the major pentose in lignocellulosic hydrolysates, which are considered a preferred carbon source for bioprocesses due to their low cost, wide abundance and high sugar content. Here, we engineered Y. lipolytica to metabolize xylose to produce lipids or citric acid. The overexpression of xylose reductase and xylitol dehydrogenase from Scheffersomyces stipitis were necessary but not sufficient to permit growth. The additional overexpression of the endogenous xylulokinase enabled identical growth as the wild type strain in glucose. This mutant was able to produce up to 80g/L of citric acid from xylose. Transferring these modifications to a lipid-overproducing strain boosted the production of lipids from xylose. This is the first step towards a consolidated bioprocess to produce chemicals and fuels from lignocellulosic materials.


XactMice: humanizing mouse bone marrow enables microenvironment reconstitution in a patient-derived xenograft model of head and neck cancer.
The limitations of cancer cell lines have led to the development of direct patient-derived xenograft models. However, the interplay between the implanted human cancer cells and recruited mouse stromal and immune cells alters the tumor microenvironment and limits the value of these models. To overcome these constraints, we have developed a technique to expand human hematopoietic stem and progenitor cells (HSPCs) and use them to reconstitute the radiation-depleted bone marrow of a NOD/SCID/IL2rg(-/-) (NSG) mouse on which a patient's tumor is then transplanted (XactMice). The human HSPCs produce immune cells that home into the tumor and help replicate its natural microenvironment. Despite previous passage on nude mice, the expression of epithelial, stromal and immune genes in XactMice tumors aligns more closely to that of the patient tumor than to those grown in non-humanized mice-an effect partially facilitated by human cytokines expressed by both the HSPC progeny and the tumor cells. The human immune and stromal cells produced in the XactMice can help recapitulate the microenvironment of an implanted xenograft, reverse the initial genetic drift seen after passage on non-humanized mice and provide a more accurate tumor model to guide patient treatment.


Perfect for a Gin and Tonic: How Context Drives Consumption Within a Modified Bogus Taste Test.
To implement a modified bogus taste test (BTT) and to examine the interactive effects of environmental and social contexts on levels of 'alcohol' consumption. University students (Study 1 n = 38, Study 2 n = 80), recruited via opportunity sampling, completed a modified BTT under the pretence of assessing garnish preference for gin and tonic. All participants were tested alone or as part of an existing friendship group. In Study 1 participants were in a laboratory setting but were exposed to different contextual cues (alcohol-related or neutral) by way of posters displayed on the walls. In Study 2, participants assessed the drinks in either a pub or a library setting. In Study 1 participants tested in a group consumed significantly more when exposed to pub-related stimuli in contrast to those who were exposed to library-related stimuli. Participants who were alone and exposed to library-related cues consumed significantly more than those in a group and exposed to these cues. In Study 2, as in Study 1, participants tested in a group condition consumed significantly more of what they believed to be alcohol when in the pub compared to those who were tested in the library. Higher group consumption was also evident in the library condition, although the size of this difference was not as large as in the pub testing condition. In the absence of any pharmacological effects of alcohol, social and environmental context have an interactive impact on shaping consumption.


Experimental and computational evidence for an essential role of NaV1.6 in spike initiation at stretch-sensitive colorectal afferent endings.
Stretch-sensitive afferents comprise ∼33% of the pelvic nerve innervation of mouse colorectum, which are activated by colorectal distension and encode visceral nociception. Stretch-sensitive colorectal afferent endings respond tonically to stepped or ramped colorectal stretch, whereas dissociated colorectal dorsal root ganglion neurons generally fail to spike repetitively upon stepped current stimulation. The present study investigated this difference in the neural encoding characteristics between the soma and afferent ending using pharmacological approaches in an in vitro mouse colon-nerve preparation and complementary computational simulations. Immunohistological staining and Western blots revealed the presence of voltage-gated sodium channel (NaV) 1.6 and NaV1.7 at sensory neuronal endings in mouse colorectal tissue. Responses of stretch-sensitive colorectal afferent endings were significantly reduced by targeting NaV1.6 using selective antagonists (μ-conotoxin GIIIa and μ-conotoxin PIIIa) or tetrodotoxin. In contrast, neither selective NaV1.8 (A803467) nor NaV1.7 (ProTX-II) antagonists attenuated afferent responses to stretch. Computational simulation of a colorectal afferent ending that incorporated independent Markov models for NaV1.6 and NaV1.7, respectively, recapitulated the experimental findings, suggesting a necessary role for NaV1.6 in encoding tonic spiking by stretch-sensitive afferents. In addition, computational simulation of a dorsal root ganglion soma showed that, by adding a NaV1.6 conductance, a single-spiking neuron was converted into a tonic spiking one. These results suggest a mechanism/channel to explain the difference in neural encoding characteristics between afferent somata and sensory endings, likely caused by differential expression of ion channels (e.g., NaV1.6) at different parts of the neuron.


Papillary fibroelastoma of the tricuspid valve chordae with a review of the literature.
Endothelial papillary fibroelastomas represent a rare entity in cardiac pathology that at times may be associated with embolisation, angina, and sudden death. We report on a case of a 46-year-old woman with a papillary fibroelastoma originating on the chordae of the tricuspid valve. The tumour was discovered incidentally using transthoracic two-dimensional echocardiography. The patient had an uneventful recovery and remained free of symptoms after six months.


Observation of quantum-tunnelling-modulated spin texture in ultrathin topological insulator Bi2Se3 films.
Understanding the spin-texture behaviour of boundary modes in ultrathin topological insulator films is critically essential for the design and fabrication of functional nanodevices. Here, by using spin-resolved photoemission spectroscopy with p-polarized light in topological insulator Bi2Se3 thin films, we report tunnelling-dependent evolution of spin configuration in topological insulator thin films across the metal-to-insulator transition. We report a systematic binding energy- and wavevector-dependent spin polarization for the topological surface electrons in the ultrathin gapped-Dirac-cone limit. The polarization decreases significantly with enhanced tunnelling realized systematically in thin insulating films, whereas magnitude of the polarization saturates to the bulk limit faster at larger wavevectors in thicker metallic films. We present a theoretical model that captures this delicate relationship between quantum tunnelling and Fermi surface spin polarization. Our high-resolution spin-based spectroscopic results suggest that the polarization current can be tuned to zero in thin insulating films forming the basis for a future spin-switch nanodevice.


Identification of Atoxigenic Aspergillus flavus Isolates to Reduce Aflatoxin Contamination of Maize in Kenya.
Aspergillus flavus has two morphotypes, the S strain and the L strain, that differ in aflatoxin-producing ability and other characteristics. Fungal communities on maize dominated by the S strain of A. flavus have repeatedly been associated with acute aflatoxin poisonings in Kenya, where management tools to reduce aflatoxin levels in maize are needed urgently. A. flavus isolates (n = 290) originating from maize produced in Kenya and belonging to the L strain morphotype were tested for aflatoxin-producing potential. A total of 96 atoxigenic isolates was identified from four provinces sampled. The 96 atoxigenic isolates were placed into 53 vegetative compatibility groups (VCGs) through complementation of nitrate non-utilizing mutants. Isolates from each of 11 VCGs were obtained from more than one maize sample, isolates from 10 of the VCGs were detected in multiple districts, and isolates of four VCGs were found in multiple provinces. Atoxigenic isolates were tested for potential to reduce aflatoxin concentrations in viable maize kernels that were co-inoculated with highly toxigenic S strain isolates. The 12 most effective isolates reduced aflatoxin levels by >80%. Reductions in aflatoxin levels caused by the most effective Kenyan isolates were comparable with those achieved with a United States isolate (NRRL-21882) used commercially for aflatoxin management. This study identified atoxigenic isolates of A. flavus with potential value for biological control within highly toxic Aspergillus communities associated with maize production in Kenya. These atoxigenic isolates have potential value in mitigating aflatoxin outbreaks in Kenya, and should be evaluated under field conditions.


The microtensile bond test: a review.
The purpose of this review is to describe all of the various modifications of the microtensile bond test in one paper, so that investigators can select the modification that best suits their needs. The essence of the microtensile test is the division of resin-bonded teeth into slabs between 0.5 and 1.0 mm thick that are then trimmed in such a manner that tensile force will be concentrated on the bonded interface during testing. Among the many advantages of the technique are that each tooth produces multiple specimens. Further, there is no need for a matrix to limit the bonded surface area, since the area is determined by the dimensions of the trimmed specimens. The various modifications of the microtensile test have been used to measure differences in regional bond strength across occlusal dentin, down the external surface of teeth from crown through roots, down the internal surface of root canals from cervical to apical thirds, as well as to compare normal vs caries-affected occlusal dentin and normal vs sclerotic cervical dentin. The technique is ideal for evaluating the long-term durability of resin-hard-tissue bonds. The microtensile test methods offer versatility that cannot be achieved by conventional methods. It is more labor-intensive than conventional testing, but holds great potential for providing insight into the strength of adhesion of restorative materials to clinically relevant sites and substrates.


Deciphering the rhizosphere microbiome for disease-suppressive bacteria.
Disease-suppressive soils are exceptional ecosystems in which crop plants suffer less from specific soil-borne pathogens than expected owing to the activities of other soil microorganisms. For most disease-suppressive soils, the microbes and mechanisms involved in pathogen control are unknown. By coupling PhyloChip-based metagenomics of the rhizosphere microbiome with culture-dependent functional analyses, we identified key bacterial taxa and genes involved in suppression of a fungal root pathogen. More than 33,000 bacterial and archaeal species were detected, with Proteobacteria, Firmicutes, and Actinobacteria consistently associated with disease suppression. Members of the γ-Proteobacteria were shown to have disease-suppressive activity governed by nonribosomal peptide synthetases. Our data indicate that upon attack by a fungal root pathogen, plants can exploit microbial consortia from soil for protection against infections.


Packing conflicts in the Z' = 5 structure of CF(3)(CF(2))(3)(CH(2))(10)COOH.
Dimers of the partially fluorinated amphiphile 1-(perfluorobutyl)undecanoic acid, CF(3)(CF(2))(3)(CH(2))(10)COOH, crystallize in the same basic packing arrangement found for many n-alkyl carboxylic acids. The unit cell of the fluorinated compound, however, contains five independent molecules rather than the one found for most n-alkyl carboxylic acids including CH(3)(CH(2))(13)COOH. The structures of the two C(15) acids are compared. The structural modulations that lead to the large value of Z' can be understood as resulting from the conflict between the necessity of filling space densely and uniformly and the tendency of unlike groups to be segregated spatially. The few other known structures of compounds with both (CF(2))(n) and (CH(2))(m) regions show evidence of the same conflict.


Breast cancer leptomeningeal metastasis: propensity of breast cancer subtypes for leptomeninges and the analysis of factors influencing survival.
The aim of the study was to define biological subtypes of breast cancer that have the propensity to metastasize to the leptomeninges and to assess factors influencing survival from detection of leptomeningeal metastatis (LM). One hundred and eighteen consecutive breast cancer patients with LM were treated in one institution, between the years 1999 and 2009; 40.5 % of patients had triple-negative subtype, 37.5 % had luminal A subtype and 22 % had HER2-positive subtypes (luminal B and HER2). Of patients with LM, 35 % had lobular cancer. Median survival from the detection of LM was 18 weeks, and 1-year survival was 16 %. Cox multivariate analysis revealed that performance status and systemic treatment statistically significantly influenced survival of patients with LM. Triple-negative biological subtype and lobular histological type of breast cancer had the propensity to metastasize to the leptomeninges. Performance status and systemic treatment ordered after detection of LM statistically significantly influenced survival.


Sharing health research data - the role of funders in improving the impact.
Recent public health emergencies with outbreaks of influenza, Ebola and Zika revealed that the mechanisms for sharing research data are neither being used, or adequate for the purpose, particularly where data needs to be shared rapidly. A review of research papers, including completed clinical trials related to priority pathogens, found only 31% (98 out of 319 published papers, excluding case studies) provided access to all the data underlying the paper - 65% of these papers give no information on how to find or access the data. Only two clinical trials out of 58 on interventions for WHO priority pathogens provided any link in their registry entry to the background data. Interviews with researchers revealed a reluctance to share data included a lack of confidence in the utility of the data; an absence of academic-incentives for rapid dissemination that prevents subsequent publication and a disconnect between those who are collecting the data and those who wish to use it quickly. The role of the funders of research needs to change to address this. Funders need to engage early with the researchers and related stakeholders to understand their concerns and work harder to define the more explicitly the benefits to all stakeholders. Secondly, there needs to be a direct benefit to sharing data that is directly relevant to those people that collect and curate the data. Thirdly more work needs to be done to realise the intent of making data sharing resources more equitable, ethical and efficient. Finally, a checklist of the issues that need to be addressed when designing new or revising existing data sharing resources should be created. This checklist would highlight the technical, cultural and ethical issues that need to be considered and point to examples of emerging good practice that can be used to address them.


A comparison of the reliability of smartphone apps for opioid conversion.
Many medical professionals use smartphone applications (apps) on a daily basis to support clinical decision making. Opioid switching (conversion of one opioid to another at equianalgesic dose) is common in clinical practice and often challenging for doctors. Apps providing an opioid conversion tool can therefore be a useful resource. Despite rapid growth in the use of medical apps, the lack of robust regulation and peer review to ensure the accuracy and reliability of app content is currently an area of concern. We searched major online app stores for apps providing an opioid dose conversion tool. We assessed output variability between apps in the dose calculation of seven opioid switches, as well as assessing the level of professional medical involvement in the authorship, creation and design of the apps. Of 23 different apps identified, more than half (n = 12; 52 %) had no stated medical professional involvement and only 11 (48 %) apps provided direct references to primary sources for their opioid conversion ratios. Conversion of 1 mg of oral morphine to oral codeine demonstrated the largest conversion output range (median 6.67 mg, range 3.333-12 mg). Conversion of 1 mg of oral morphine to methadone ranged from 0.05-0.67 mg, with only 44 % of methadone-converting apps (n = 4) commenting that the conversion ratio changes with magnitude of methadone dose. Overall, 35 % of apps (n = 8) did not warn the user about the standard practice of dose reduction when opioid switching. There was a statistically significant difference in the mean conversion output for hydromorphone (oral) between apps with and without medical professional involvement (0.2256 vs 0.2536; p = 0.0377). There are significant concerns with regard to the reliability of information provided by apps offering opioid dose conversion, with lack of information regarding evidence-based content and peer review in many cases. It is crucial that better regulation of medical apps is instigated in order to ensure that patient safety is maintained.


Abdominal aortic calcification and surgical outcomes in patients with no known cardiovascular risk factors.
In the setting of cardiovascular (CV) risk evaluation before major elective surgery, current risk assessment tools are relatively poor for discriminating among patients. For example, patients with clinical CV risk factors can be clearly identified; but among those without appreciated clinical CV risk, there may be a subset with stigmata of CV disease noted during the preoperative radiographic evaluation. Our study evaluated the relationship between abdominal aortic (AA) calcification measured on preoperative computed tomography (CT) imaging and surgical complications in patients undergoing general elective and vascular surgery. We hypothesized that patients with no known CV risk factors but significant aortic calcification on preoperative imaging will have inferior surgical outcomes. The study group included 1180 patients from the Michigan Surgical Quality Collaborative (MSQC) database who underwent major general or vascular elective surgery between 2006 and 2009 and who had a CT scan of the abdomen specifically for preoperative planning. AA calcification was measured using novel analytic morphomic techniques and reported as a percentage of the total wall area containing calcification. Patients were divided into cohorts by clinical CV risk and extent of AA calcification. Univariate analysis was used to compare postoperative morbidity between patient cohorts. Multivariate logistic regression analysis was used to compare continuous AA calcification with overall morbidity in patients with no clinical CV risk factors. AA calcification was strongly skewed to the right (53.5% had no AA calcification) and was significantly correlated with age (ρ = 0.43, P < 0.001). Unadjusted univariate analysis of morbidity showed no significant differences in complication rates between patients in the clinical CV risk and significant AA calcification (no known CV risk factor) categories. The clinical CV risk (P < 0.001) and significant AA calcification without CV risk factors (P = 0.009) populations both had significantly more infectious and overall complications than patients with no AA calcification and no clinical CV risk. Multivariate logistic regression confirmed that AA calcification was a significant predictor of morbidity in patients with no clinical CV risk factors (odds ratio = 1.35, P = 0.017). This study suggests that AA calcification may be related to progression of CV disease and surgical outcomes. A better understanding of the complex interaction of patient physiology with overall ability to recover from major surgery, using novel approaches such as analytic morphomics, has great potential to improve risk stratification and patient selection.


The cross waveguide grating: proposal, theory and applications.
In this paper a novel grating-like integrated optics device is proposed, the Cross Waveguide Grating (XWG). The device is based upon a modified configuration of a traditional Arrayed Waveguide Grating (AWG). The Arrayed Waveguides part is changed, as detailed along this document, giving the device both the ability of multi/demultiplexing and power splitting/coupling. Design examples and transfer function simulations show good agreement with the presented theory. Finally, some of the envisaged applications are outlined.