Bottom-up trait-mediated indirect effects decrease pathogen transmission in a tritrophic system.
A plant's induction of secondary defenses helps to decrease herbivore damage by changing resource quality. While these chemical or physical defenses may directly decrease herbivory, they can also have indirect consequences. In a tritrophic system consisting of a plant, an insect herbivore, and an insect pathogen, plant based trait-mediated indirect effects (TMIEs) can alter host-pathogen interactions and, thereby, indirectly affect disease transmission. In a series of field experiments, individual soybean plants (Glycine max) were sprayed with either a jasmonic acid (JA) solution to trigger induction of plant defenses or a similar control compound. Fall armyworm (Spodoptera frugiperda) larvae along with varying amounts of a lethal baculovirus were placed on the plants to measure transmission. Induction of plant defenses decreased viral transmission due to increased population heterogeneity arising from changes in individual susceptibility. The change in susceptibility via TMIEs was driven by a decrease in feeding rates and an increase viral dose needed to infect larvae. While the induction against herbivore attack may decrease herbivory, it can also decrease the efficacy of the herbivore's pathogen potentially to the plant's detriment. While TMIEs have been well-recognized for being driven by top-down forces, bottom-up interactions can dictate community dynamics and, here, epizootic severity.


Predictive value of circulating NMR metabolic biomarkers for type 2 diabetes risk in the UK Biobank study.
Effective targeted prevention of type 2 diabetes (T2D) depends on accurate prediction of disease risk. We assessed the role of metabolomic profiling in improving T2D risk prediction beyond conventional risk factors. Nuclear magnetic resonance (NMR) metabolomic profiling was undertaken on baseline plasma samples in 65,684 UK Biobank participants without diabetes and not taking lipid-lowering medication. Among a subset of 50,519 participants with data available on all relevant co-variates (sociodemographic characteristics, parental history of diabetes, lifestyle-including dietary-factors, anthropometric measures and fasting time), Cox regression yielded adjusted hazard ratios for the associations of 143 individual metabolic biomarkers (including lipids, lipoproteins, fatty acids, amino acids, ketone bodies and other low molecular weight metabolic biomarkers) and 11 metabolic biomarker principal components (PCs) (accounting for 90% of the total variance in individual biomarkers) with incident T2D. These 11 PCs were added to established models for T2D risk prediction among the full study population, and measures of risk discrimination (c-statistic) and reclassification (continuous net reclassification improvement [NRI], integrated discrimination index [IDI]) were assessed. During median 11.9 (IQR 11.1-12.6) years' follow-up, after accounting for multiple testing, 90 metabolic biomarkers showed independent associations with T2D risk among 50,519 participants (1211 incident T2D cases) and 76 showed associations after additional adjustment for HbA1c (false discovery rate controlled p < 0.01). Overall, 8 metabolic biomarker PCs were independently associated with T2D. Among the full study population of 65,684 participants, of whom 1719 developed T2D, addition of PCs to an established risk prediction model, including age, sex, parental history of diabetes, body mass index and HbA1c, improved T2D risk prediction as assessed by the c-statistic (increased from 0.802 [95% CI 0.791-0.812] to 0.830 [0.822-0.841]), continuous NRI (0.44 [0.38-0.49]) and relative (15.0% [10.5-20.4%]) and absolute (1.5 [1.0-1.9]) IDI. More modest improvements were observed when metabolic biomarker PCs were added to a more comprehensive established T2D risk prediction model additionally including waist circumference, blood pressure and plasma lipid concentrations (c-statistic, 0.829 [0.819-0.838] to 0.837 [0.831-0.848]; continuous NRI, 0.22 [0.17-0.28]; relative IDI, 6.3% [4.1-9.8%]; absolute IDI, 0.7 [0.4-1.1]). When added to conventional risk factors, circulating NMR-based metabolic biomarkers modestly enhanced T2D risk prediction.


Generation of 1.5 cycle pulses at 780 nm at oscillator repetition rates with stable carrier-envelope phase.
We demonstrate a spectral broadening and compression setup for carrier-envelope phase (CEP) stable sub-10-fs Ti:sapphire oscillator pulses resulting in 3.9 fs pulses spectrally centered at 780 nm. Pulses from the oscillator with 2 nJ energy are launched into a 1 mm long all-normal dispersive solid-core photonic crystal fiber and spectrally broadened to more than one octave. Subsequent pulse compression is achieved with a phase-only 4f pulse shaper. Second harmonic frequency resolved optical gating with a ptychographic reconstruction algorithm is used to obtain the spectral phase, which is fed back as a phase mask to the shaper display for pulse compression. The compressed pulses are CEP stable with a long term standard deviation of 0.23 rad for the CEP noise and 0.32 rad for the integrated rms phase jitter. The high total throughput of 15% results in a remaining pulse energy of about 300 pJ at 80 MHz repetition rate. With these parameters and the ability to tailor the spectral phase, the system is well suited for waveform sensitive photoemission experiments with needle tips or nanostructures and can be easily adapted to other sub-10 fs ultra-broadband Ti:sapphire oscillators.


Longitudinal study of soluble adhesion molecules in multiple sclerosis: correlation with gadolinium enhanced magnetic resonance imaging.
To assess whether serial serum levels of soluble forms of intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) are useful as surrogate markers of disease activity in multiple sclerosis (MS). Increased levels of sICAM-1 and sVCAM-1 have been described in cross-sectional, but not longitudinal, studies of patients with MS. Although they appear to correlate with clinical and MRI markers of disease activity, their role as potential surrogate markers remains undefined. Serial serum levels of sICAM-1 and sVCAM-1 were measured in patients with MS undergoing monthly gadolinium-enhanced MRI studies of the brain (462 gadolinium-enhanced MRI in 57 patients) and in 12 normal control subjects. Ten patients had primary progressive (PP), 22 relapsing remitting (RR), and 25 secondary progressive (SP) disease. Levels of sICAM-1 and sVCAM-1 were increased intermittently in patients with all subtypes of MS. Median levels of sICAM-1 were elevated in patients with MS compared with normal controls (normal controls median [interquartile range] = 176[119-209] compared with PP = 502[194-1768], RR = 419[158-481], and SP = 352[196-469] ng/mL; p = 0.04). After excluding patients with PP MS, patients with high sICAM-1 levels had a greater number of gadolinium-enhancing lesions per study (1.9[0.9-4.3]) than patients with normal levels (0.4[0-2.7], p = 0.03), and patients with MRI studies with no gadolinium-enhancing lesions had lower associated sICAM-1 levels (200 ng/mL[85-561]) than patients with only persistent (349 ng/mL[82-615]) or new enhancing lesions (497 ng/mL[108-667], p = 0.03). Patients with RR or SP disease that progressed clinically during the study had a greater number of gadolinium-enhancing lesions per MRI study (3.5[0.4-5.5]) than did patients in whom disease did not progress (1.2 [0.3-2.7], p = 0.03). The patients with progressive disease tended to have higher sICAM-1 levels (469 ng/mL [196-1019]) than patients in whom disease did not progress (353 ng/mL [171-469], p = 0.07). Although MS patients tended to have higher sVCAM-1 levels than did normal controls, this finding was not significant. No correlation could be found between levels of sVCAM-1 and gadolinium enhancement on MRI. Patients with MS have elevated levels of sICAM-1, which correlate with gadolinium enhancement on MRI and possibly short-term disease progression. Soluble ICAM-1, and not sVCAM-1, may therefore be suitable as a long-term surrogate marker of disease activity in MS.


Hospital admission and emergency care attendance risk for SARS-CoV-2 delta (B.1.617.2) compared with alpha (B.1.1.7) variants of concern: a cohort study.
The SARS-CoV-2 delta (B.1.617.2) variant was first detected in England in March, 2021. It has since rapidly become the predominant lineage, owing to high transmissibility. It is suspected that the delta variant is associated with more severe disease than the previously dominant alpha (B.1.1.7) variant. We aimed to characterise the severity of the delta variant compared with the alpha variant by determining the relative risk of hospital attendance outcomes. This cohort study was done among all patients with COVID-19 in England between March 29 and May 23, 2021, who were identified as being infected with either the alpha or delta SARS-CoV-2 variant through whole-genome sequencing. Individual-level data on these patients were linked to routine health-care datasets on vaccination, emergency care attendance, hospital admission, and mortality (data from Public Health England's Second Generation Surveillance System and COVID-19-associated deaths dataset; the National Immunisation Management System; and NHS Digital Secondary Uses Services and Emergency Care Data Set). The risk for hospital admission and emergency care attendance were compared between patients with sequencing-confirmed delta and alpha variants for the whole cohort and by vaccination status subgroups. Stratified Cox regression was used to adjust for age, sex, ethnicity, deprivation, recent international travel, area of residence, calendar week, and vaccination status. Individual-level data on 43 338 COVID-19-positive patients (8682 with the delta variant, 34 656 with the alpha variant; median age 31 years [IQR 17-43]) were included in our analysis. 196 (2·3%) patients with the delta variant versus 764 (2·2%) patients with the alpha variant were admitted to hospital within 14 days after the specimen was taken (adjusted hazard ratio [HR] 2·26 [95% CI 1·32-3·89]). 498 (5·7%) patients with the delta variant versus 1448 (4·2%) patients with the alpha variant were admitted to hospital or attended emergency care within 14 days (adjusted HR 1·45 [1·08-1·95]). Most patients were unvaccinated (32 078 [74·0%] across both groups). The HRs for vaccinated patients with the delta variant versus the alpha variant (adjusted HR for hospital admission 1·94 [95% CI 0·47-8·05] and for hospital admission or emergency care attendance 1·58 [0·69-3·61]) were similar to the HRs for unvaccinated patients (2·32 [1·29-4·16] and 1·43 [1·04-1·97]; p=0·82 for both) but the precision for the vaccinated subgroup was low. This large national study found a higher hospital admission or emergency care attendance risk for patients with COVID-19 infected with the delta variant compared with the alpha variant. Results suggest that outbreaks of the delta variant in unvaccinated populations might lead to a greater burden on health-care services than the alpha variant. Medical Research Council; UK Research and Innovation; Department of Health and Social Care; and National Institute for Health Research.


Wideband-adjustable reflection-suppressed rejection filters using chirped and tilted fiber gratings.
Wideband-adjustable band-rejection filters based on chirped and tilted fiber Bragg gratings (CTFBG) are proposed and experimentally demonstrated. The flexible chirp-rate and wide tilt-angle provide the gratings with broadband filtering functions over a large range of bandwidths (from 10 nm to 150 nm), together with a low insertion loss (less than 1 dB) and a negligible back-reflection (lower than -20 dB). The slope profile of CTFBG in transmission can be easily tailored by adjusting the tilt angle, grating irradiation time and chirp rate-grating factor, and it is insensitive to the polarization state of the input light, as well as to temperature, axial strain and surrounding refractive index. Furthermore, by coating the CTFBG with a suitable polymer (whose refractive index is close to that of the cladding glass), the cladding modes no longer form weakly discrete resonances and leave a smoothly varying attenuation spectrum for high-quality band-rejection filters, edge filters and gain equalizers.


Rapid changes in flowering time in British plants.
The average first flowering date of 385 British plant species has advanced by 4.5 days during the past decade compared with the previous four decades: 16% of species flowered significantly earlier in the 1990s than previously, with an average advancement of 15 days in a decade. Ten species (3%) flowered significantly later in the 1990s than previously. These data reveal the strongest biological signal yet of climatic change. Flowering is especially sensitive to the temperature in the previous month, and spring-flowering species are most responsive. However, large interspecific differences in this response will affect both the structure of plant communities and gene flow between species as climate warms. Annuals are more likely to flower early than congeneric perennials, and insect-pollinated species more than wind-pollinated ones.


Oldest known Eucalyptus macrofossils are from South America.
The evolutionary history of Eucalyptus and the eucalypts, the larger clade of seven genera including Eucalyptus that today have a natural distribution almost exclusively in Australasia, is poorly documented from the fossil record. Little physical evidence exists bearing on the ancient geographical distributions or morphologies of plants within the clade. Herein, we introduce fossil material of Eucalyptus from the early Eocene (ca. 51.9 Ma) Laguna del Hunco paleoflora of Chubut Province, Argentina; specimens include multiple leaves, infructescences, and dispersed capsules, several flower buds, and a single flower. Morphological similarities that relate the fossils to extant eucalypts include leaf shape, venation, and epidermal oil glands; infructescence structure; valvate capsulate fruits; and operculate flower buds. The presence of a staminophore scar on the fruits links them to Eucalyptus, and the presence of a transverse scar on the flower buds indicates a relationship to Eucalyptus subgenus Symphyomyrtus. Phylogenetic analyses of morphological data alone and combined with aligned sequence data from a prior study including 16 extant eucalypts, one outgroup, and a terminal representing the fossils indicate that the fossils are nested within Eucalyptus. These are the only illustrated Eucalyptus fossils that are definitively Eocene in age, and the only conclusively identified extant or fossil eucalypts naturally occurring outside of Australasia and adjacent Mindanao. Thus, these fossils indicate that the evolution of the eucalypt group is not constrained to a single region. Moreover, they strengthen the taxonomic connections between the Laguna del Hunco paleoflora and extant subtropical and tropical Australasia, one of the three major ecologic-geographic elements of the Laguna del Hunco paleoflora. The age and affinities of the fossils also indicate that Eucalyptus subgenus Symphyomyrtus is older than previously supposed. Paleoecological data indicate that the Patagonian Eucalyptus dominated volcanically disturbed areas adjacent to standing rainforest surrounding an Eocene caldera lake.


High affinity interactions of Pb2+ with synaptotagmin I.
Lead (Pb) is a potent neurotoxin that disrupts synaptic neurotransmission. We report that Synaptotagmin I (SytI), a key regulator of Ca2+-evoked neurotransmitter release, has two high-affinity Pb2+ binding sites that belong to its cytosolic C2A and C2B domains. The crystal structures of Pb2+-complexed C2 domains revealed that protein-bound Pb2+ ions have holodirected coordination geometries and all-oxygen coordination spheres. The on-rate constants of Pb2+ binding to the C2 domains of SytI are comparable to those of Ca2+ and are diffusion-limited. In contrast, the off-rate constants are at least two orders of magnitude smaller, indicating that Pb2+ can serve as both a thermodynamic and kinetic trap for the C2 domains. We demonstrate, using NMR spectroscopy, that population of these sites by Pb2+ ions inhibits further Ca2+ binding despite the existing coordination vacancies. Our work offers a unique insight into the bioinorganic chemistry of Pb(ii) and suggests a mechanism by which low concentrations of Pb2+ ions can interfere with the Ca2+-dependent function of SytI in the cell.


Management of Helicobacter pylori infection--the Maastricht IV/ Florence Consensus Report.
Management of Helicobacter pylori infection is evolving and in this 4th edition of the Maastricht consensus report aspects related to the clinical role of H pylori were looked at again in 2010. In the 4th Maastricht/Florence Consensus Conference 44 experts from 24 countries took active part and examined key clinical aspects in three subdivided workshops: (1) Indications and contraindications for diagnosis and treatment, focusing on dyspepsia, non-steroidal anti-inflammatory drugs or aspirin use, gastro-oesophageal reflux disease and extraintestinal manifestations of the infection. (2) Diagnostic tests and treatment of infection. (3) Prevention of gastric cancer and other complications. The results of the individual workshops were submitted to a final consensus voting to all participants. Recommendations are provided on the basis of the best current evidence and plausibility to guide doctors involved in the management of this infection associated with various clinical conditions.


Kidney GATA3+ regulatory T cells play roles in the convalescence stage after antibody-mediated renal injury.
FoxP3+ regulatory T cells (Tregs) play crucial roles in peripheral immune tolerance. In addition, Tregs that reside or accumulate in nonlymphoid tissues, called tissue Tregs, exhibit tissue-specific functions and contribute to the maintenance of tissue homeostasis and repair. In an experimental mouse model of crescentic glomerulonephritis induced by an anti-glomerular basement membrane antibody, Tregs started to accumulate in the kidney on day 10 of disease onset and remained at high levels (~30-35% of CD4+ T cells) during the late stage (days 21-90), which correlated with stable disease control. Treg depletion on day 21 resulted in the relapse of renal dysfunction and an increase in Th1 cells, suggesting that Tregs are essential for disease control during the convalescence stage. The Tregs that accumulated in the kidney showed tissue Treg phenotypes, including high expression of GATA3, ST2 (the IL33 receptor subunit), amphiregulin (Areg), and PPARγ. Although T-bet+ Tregs and RORγt+ Tregs were observed in the kidney, GATA3+ Tregs were predominant during the convalescence stage, and a PPARγ agonist enhanced the accumulation of GATA3+ Tregs in the kidney. To understand the function of specific genes in kidney Tregs, we developed a novel T cell transfer system to T cell-deficient mice. This experiment demonstrates that ST2, Areg, and CCR4 in Tregs play important roles in the accumulation of GATA3+ Tregs in the kidney and in the amelioration of renal injury. Our data suggest that GATA3 is important for the recruitment of Tregs into the kidney, which is necessary for convalescence after renal tissue destruction.


Atomic structures of wild-type and thermostable mutant recombinant human Cu,Zn superoxide dismutase.
Superoxide dismutase enzymes protect aerobic organisms from oxygen-mediated free-radical damage. Crystallographic structures of recombinant human Cu,Zn superoxide dismutase have been determined, refined, and analyzed at 2.5 A resolution for wild-type and a designed thermostable double-mutant enzyme (Cys-6----Ala, Cys-111----Ser). The 10 subunits (five dimers) in the crystallographic asymmetric unit form an unusual stable open lattice with 80-A-diameter channels. The 10 independently fit and refined subunits provide high accuracy, error analysis, and insights on loop conformations. There is a helix dipole interaction with the Zn site, and 14 residues form two or more structurally conserved side-chain to main-chain hydrogen bonds that appear critical to active-site architecture, loop conformation, and the increased stability resulting from the Cys-111----Ser mutation.


Nonlocal optical effects on the Goos-Hänchen shift at an interface of a composite material of metallic nanoparticles.
We present a theoretical study on the nonlocal optical effects on the Goos-Hänchen (GH) shift of reflected light from a composite material of metallic nanoparticles (MNPs). Using different nonlocal effective medium models, it is observed that such effects can be significant for small MNP of sizes down to a few nanometers. For small metallic volume fractions, the composite behaves like dielectric and the nonlocal effects lead to significant different Brewster angles, at which large negative GH shifts take place. For larger volume fractions or shorter wavelengths, the composite behaves more like metals and the nonlocal effects also lead to different Brewster angles but at values close to grazing incidence. These results will have significant implications in the application of different effective medium models for the characterization of these nanometallic composites when the MNPs are down to a few nanometers in size.


Expectations of barriers to psychosocial care: views of parents and adolescents in the community.
Parents with a child suffering from psychosocial problems frequently experience barriers to psychosocial care, which may hinder access. Expectations of barriers may have the same effect, but evidence is lacking. The aim of this study is to examine parents' and adolescents' expectations of barriers regarding psychosocial care for the child, along with associated child and family characteristics. We obtained data on an age-stratified random sample of school children/pupils aged 4-18 via questionnaires (N = 666; response rate 70.3 %). Expectations of barriers to psychosocial care were measured with the "Barriers to Treatment Participation Scale-Expectancies" questionnaire (BTPS-exp). Results showed that 64 % of the parents of children below age 12, 59 % of the parents of adolescents (age 12-18), and 84 % of the adolescents expected one or more barriers. Parents and adolescents expected barriers most frequently with respect to irrelevance of treatment. Mainly parents with low educational level and their adolescents expected barriers regarding treatment, and quite a few characteristics of parents of adolescents were associated with expecting multiple barriers regarding treatment demands and issues, for example, single parents, parents of lower educational level and of adolescent boys, and parents of adolescents with psychosocial problems. We conclude that adolescents especially, but also their parents and parents of younger children, expect major barriers to psychosocial care, which may greatly hinder appropriate care seeking. This evidence may support professionals and policymakers in their attempts to improve access to psychosocial care.


Which population level environmental factors are associated with asthma, rhinoconjunctivitis and eczema? Review of the ecological analyses of ISAAC Phase One.
The International Study of Asthma and Allergies in Childhood (ISAAC) Phase One showed large worldwide variations in the prevalence of symptoms of asthma, rhinoconjunctivitis and eczema, up to 10 to 20 fold between countries. Ecological analyses were undertaken with ISAAC Phase One data to explore factors that may have contributed to these variations, and are summarised and reviewed here.In ISAAC Phase One the prevalence of symptoms in the past 12 months of asthma, rhinoconjunctivitis and eczema were estimated from studies in 463,801 children aged 13 - 14 years in 155 centres in 56 countries, and in 257,800 children aged 6-7 years in 91 centres in 38 countries. Ecological analyses were undertaken between symptom prevalence and the following: Gross National Product per capita (GNP), food intake, immunisation rates, tuberculosis notifications, climatic factors, tobacco consumption, pollen, antibiotic sales, paracetamol sales, and outdoor air pollution.Symptom prevalence of all three conditions was positively associated with GNP, trans fatty acids, paracetamol, and women smoking, and inversely associated with food of plant origin, pollen, immunisations, tuberculosis notifications, air pollution, and men smoking. The magnitude of these associations was small, but consistent in direction between conditions. There were mixed associations of climate and antibiotic sales with symptom prevalence.The potential causality of these associations warrant further investigation. Factors which prevent the development of these conditions, or where there is an absence of a positive correlation at a population level may be as important from the policy viewpoint as a focus on the positive risk factors. Interventions based on small associations may have the potential for a large public health benefit.


Associations between gestational age at birth and infection-related hospital admission rates during childhood in England: Population-based record linkage study.
Children born preterm (<37 completed weeks' gestation) have a higher risk of infection-related morbidity than those born at term. However, few large, population-based studies have investigated the risk of infection in childhood across the full spectrum of gestational age. The objectives of this study were to explore the association between gestational age at birth and infection-related hospital admissions up to the age of 10 years, how infection-related hospital admission rates change throughout childhood, and whether being born small for gestational age (SGA) modifies this relationship. Using a population-based, record-linkage cohort study design, birth registrations, birth notifications and hospital admissions were linked using a deterministic algorithm. The study population included all live, singleton births occurring in NHS hospitals in England from January 2005 to December 2006 (n = 1,018,136). The primary outcome was all infection-related inpatient hospital admissions from birth to 10 years of age, death or study end (March 2015). The secondary outcome was the type of infection-related hospital admission, grouped into broad categories. Generalised estimating equations were used to estimate adjusted rate ratios (aRRs) with 95% confidence intervals (CIs) for each gestational age category (<28, 28-29, 30-31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 and 42 weeks) and the models were repeated by age at admission (<1, 1-2, 3-4, 5-6, and 7-10 years). An interaction term was included in the model to test whether SGA status modified the relationship between gestational age and infection-related hospital admissions. Gestational age was strongly associated with rates of infection-related hospital admissions throughout childhood. Whilst the relationship attenuated over time, at 7-10 years of age those born before 40 weeks gestation were still significantly higher in comparison to those born at 40 weeks. Children born <28 weeks had an aRR of 6.53 (5.91-7.22) during infancy, declining to 3.16 (2.50-3.99) at ages 7-10 years, in comparison to those born at 40 weeks; whilst in children born at 38 weeks, the aRRs were 1·24 (1.21-1.27) and 1·18 (1.13-1.23), during infancy and aged 7-10 years, respectively. SGA status modified the effect of gestational age (interaction P<0.0001), with the highest rate among the children born at <28 weeks and SGA. Finally, study findings indicated that the associations with gestational age varied by subgroup of infection. Whilst upper respiratory tract infections were the most common type of infection experienced by children in this cohort, lower respiratory tract infections (LRTIs) (<28 weeks, aRR = 10.61(9.55-11.79)) and invasive bacterial infections (<28 weeks, aRR = 6.02 (4.56-7.95)) were the most strongly associated with gestational age at birth. Of LRTIs experienced, bronchiolitis (<28 weeks, aRR = 11.86 (10.20-13.80)), and pneumonia (<28 weeks, aRR = 9.49 (7.95-11.32)) were the most common causes. Gestational age at birth was strongly associated with rates of infection-related hospital admissions during childhood and even children born a few weeks early remained at higher risk at 7-10 years of age. There was variation between clinical subgroups in the strength of relationships with gestational age. Effective infection prevention strategies should include focus on reducing the number and severity of LRTIs during early childhood.


Nasopharyngeal microbiota in infants and changes during viral upper respiratory tract infection and acute otitis media.
Interferences between pathogenic bacteria and specific commensals are known. We determined the interactions between nasopharyngeal microbial pathogens and commensals during viral upper respiratory tract infection (URI) and acute otitis media (AOM) in infants. We analyzed 971 specimens collected monthly and during URI and AOM episodes from 139 infants. The 16S rRNA V4 gene regions were sequenced on the Illumina MiSeq platform. Among the high abundant genus-level nasopharyngeal microbiota were Moraxella, Haemophilus, and Streptococcus (3 otopathogen genera), Corynebacterium, Dolosigranulum, Staphylococcus, Acinetobacter, Pseudomonas, and Bifidobacterium. Bacterial diversity was lower in culture-positive samples for Streptococcus pneumoniae, and Haemophilus influenzae, compared to cultured-negative samples. URI frequencies were positively associated with increasing trend in otopathogen colonization. AOM frequencies were associated with decreasing trend in Micrococcus colonization. During URI and AOM, there were increases in abundance of otopathogen genera and decreases in Pseudomonas, Myroides, Yersinia, and Sphingomonas. Otopathogen abundance was increased during symptomatic viral infection, but not during asymptomatic infection. The risk for AOM complicating URI was reduced by increased abundance of Staphylococcus and Sphingobium. Otopathogen genera played the key roles in URI and AOM occurrences. Staphylococcus counteracts otopathogens thus Staphylococcal colonization may be beneficial, rather than harmful. While Sphingobium may play a role in preventing AOM complicating URI, the commonly used probiotic Bifidobacterium did not play a significant role during URI or AOM. The role of less common commensals in counteracting the deleterious effects of otopathogens requires further studies.


Estimating the impact of somatic cell count on the value of milk utilising parameters obtained from the published literature.
The impact of mastitis on milk value per litre independent of the effect of mastitis on milk volume, was quantified for Ireland using a meta-analysis and a processing sector model. Changes in raw milk composition, cheese processing and composition associated with increased bulk milk somatic cell count (BMSCC) were incorporated into the model. Processing costs and market values were representative of current industry values. It was assumed that as BMSCC increased (i) milk fat and milk protein increased and milk lactose decreased, (ii) fat and protein recoveries decreased, (iii) cheese protein decreased and cheese moisture increased. Five BMSCC categories were examined from ⩽100 000 to >400 000 cells/ml. The analysis showed that as BMSCC increased the production quantities reduced. An increase in BMSCC from 100 000 to >400 000 cells/ml saw a reduction in net revenue of 3·2% per annum (€51·3 million) which corresponded to a reduction in the value of raw milk of €0·0096 cents/l.


Pathology associated with meningoencephalitis during bacterial kidney disease of salmonids.
The neural pathology associated with spontaneous cases of bacterial kidney disease (BKD), in five species of commercially reared salmonids, was investigated histopathologically and with immunofluorescence. Patterns of localisation of the causative organism of BKD within the central nervous system suggest that haematogenous spread to the meninges, particularly the tela choroidea posterior, the tela choroidea and vascularised capsule of the saccus dorsalis and epiphysis of the epithalamus, and the saccus vasculosus of the hypophysis, appears to be a frequent route by which the central nervous system becomes infected. Retrograde extension from the posterior uvea to the floor of the diencephalon along the epineurium and perineurium of the optic nerve also may be a mechanism of neural invasion. Extension appeared to occur from these sites into adjacent areas of the meninges, the neural parenchyma and ventricles. Demonstration of bacteria within salmonid ependymal cells, as well as the apparent ability of salmonid ependymal cells to respond metaplastically suggest a similarity to mammalian type III ependymal cells (tanycytes). Based on this study, it is apparent that teleosts can survive protracted severe brain damage. This, combined with the apparent similarities of neural response to infection between the salmonids used in this study and higher vertebrates, suggests that teleosts may be a useful lower vertebrate model for studying the pathogenesis and sequelae of bacterial meningitis.


Psychometric analysis of the Mental Health Recovery Measure in a sample of veterans with depression.
Using data from a sample of 398 veterans diagnosed with depression, the present study used principal components analysis to shorten the Mental Health Recovery Measure (MHRM) to a 10-item instrument. Results indicated the 10-item MHRM had excellent internal reliability. Construct validity for the 10-item MHRM was evidenced by correlations with measures of depression coping self-efficacy, social adjustment, hopelessness, and depression. The 10-item MHRM derived in the present study was compared with a 10-item version of the MHRM that was previously empirically derived in a sample of veterans with schizophrenia (Armstrong, Cohen, Hellemann, Reist, & Young, 2014). Results suggest that similar items represent the underlying construct of recovery for veterans with depression and veterans with schizophrenia. Veterans with depression reported lower average levels of recovery than veterans with schizophrenia. Study limitations, directions for future investigations, and the implications of routine assessment of mental health recovery in public mental health systems are discussed. (PsycINFO Database Record


Regions of the basal ganglia and primary olfactory system are most sensitive to neurodegeneration after extended sevoflurane anesthesia in the perinatal rat.
Extended general anesthesia early in life is neurotoxic in multiple species. However, little is known about the temporal progression of neurodegeneration after general anesthesia. It is also unknown if a reduction in natural cell death, or an increase in cell creation, occurs as a form of compensation after perinatal anesthesia exposure. The goal of this study was to evaluate markers of neurodegeneration and cellular division at 2, 24, or 72 h after sevoflurane (Sevo) exposure (6 h) in fully oxygenated postnatal day (PND) 7 rats. Neurodegeneration was observed in areas throughout the forebrain, while the largest changes (fold increase above vehicle) were observed in areas associated with either the primary olfactory learning pathways or the basal ganglia. These regions included the indusium griseum (IG, 25-fold), the posterior dorso medial hippocampal CA1 (17-fold), bed nucleus of the stria terminalis (Bed Nuclei STM, 5-fold), the shell of the nucleus accumbens (Acb, 5-fold), caudate/putamen (CPu, 5-fold), globus pallidus (GP, 9-fold) and associated thalamic (11-fold) and cortical regions (5-fold). Sevo neurodegeneration was minimal or undetectable in the ventral tegmentum, substantia nigra, and most of the hypothalamus and frontal cortex. In most brain regions where neurodegeneration was increased 2 h post Sevo exposure, the levels returned to <4-fold above control levels by 24 h. However, in the IG, CA1, GP, anterior thalamus, medial preoptic nucleus of the hypothalamus (MPO), anterior hypothalamic area (AHP), and the amygdaloid nuclei, neurodegeneration at 24 h was double or more than that at 2 h post exposure. Anesthesia exposure causes either a prolonged period of neurodegeneration in certain brain regions, or a distinct secondary degenerative event occurs after the initial insult. Moreover, regions most sensitive to Sevo neurodegeneration did not necessarily coincide with areas of new cell birth, and new cell birth was not consistently affected by Sevo. The profile of anesthesia related neurotoxicity changes with time, and multiple mechanisms of toxicity may exist in a time-dependent fashion.


The National Diabetes, Influenza, and Pneumococcal Campaign: an evaluation of campaign relevancy, partnerships, and media relations.
The Division of Diabetes Translation, Centers for Disease Control and Prevention, collaborated with its 59 Diabetes Prevention and Control Programs (DPCPs) to implement in 1998-1999 the National Diabetes Influenza and Pneumococcal Campaign. Postcampaign evaluation examined DPCPs' perceptions of the relevancy of the campaign in reaching the target population (adults aged 25-64 years with diabetes), establishing successful partnerships, and engaging the media. Most DPCPs stated the campaign reached their target population. DPCPs most commonly partnered with existing networks such as public health organizations or government agencies and direct health care providers. A majority of DPCPs did not find partnerships with direct health care providers to be effective in this campaign, but public health organizations, peer review organizations, and coalitions were described as successful partners. States in which DPCPs conducted follow-up calls to television stations regarding the airing of public service announcements generally had more announcements aired than states in which such calls were not made. Postcampaign evaluation findings also indicate that DPCPs who attempted to engage nontraditional partners (e.g., media outlets) achieved greater campaign success than those who did not. Future campaign efforts will likely benefit from relationships established with nontraditional partners, such as retailers, media outlets, local pharmacies, and faith-based organizations.


Discriminating precursors of common fragments for large-scale metabolite profiling by triple quadrupole mass spectrometry.
The goal of large-scale metabolite profiling is to compare the relative concentrations of as many metabolites extracted from biological samples as possible. This is typically accomplished by measuring the abundances of thousands of ions with high-resolution and high mass accuracy mass spectrometers. Although the data from these instruments provide a comprehensive fingerprint of each sample, identifying the structures of the thousands of detected ions is still challenging and time intensive. An alternative, less-comprehensive approach is to use triple quadrupole (QqQ) mass spectrometry to analyze predetermined sets of metabolites (typically fewer than several hundred). This is done using authentic standards to develop QqQ experiments that specifically detect only the targeted metabolites, with the advantage that the need for ion identification after profiling is eliminated. Here, we propose a framework to extend the application of QqQ mass spectrometers to large-scale metabolite profiling. We aim to provide a foundation for designing QqQ multiple reaction monitoring (MRM) experiments for each of the 82 696 metabolites in the METLIN metabolite database. First, we identify common fragmentation products from the experimental fragmentation data in METLIN. Then, we model the likelihoods of each precursor structure in METLIN producing each common fragmentation product. With these likelihood estimates, we select ensembles of common fragmentation products that minimize our uncertainty about metabolite identities. We demonstrate encouraging performance and, based on our results, we suggest how our method can be integrated with future work to develop large-scale MRM experiments. Our predictions, Supplementary results, and the code for estimating likelihoods and selecting ensembles of fragmentation reactions are made available on the lab website at http://pattilab.wustl.edu/FragPred.


Transcriptome analysis of ectopic chloroplast development in green curd cauliflower (Brassica oleracea L. var. botrytis).
Chloroplasts are the green plastids where photosynthesis takes place. The biogenesis of chloroplasts requires the coordinate expression of both nuclear and chloroplast genes and is regulated by developmental and environmental signals. Despite extensive studies of this process, the genetic basis and the regulatory control of chloroplast biogenesis and development remain to be elucidated. Green cauliflower mutant causes ectopic development of chloroplasts in the curd tissue of the plant, turning the otherwise white curd green. To investigate the transcriptional control of chloroplast development, we compared gene expression between green and white curds using the RNA-seq approach. Deep sequencing produced over 15 million reads with lengths of 86 base pairs from each cDNA library. A total of 7,155 genes were found to exhibit at least 3-fold changes in expression between green and white curds. These included light-regulated genes, genes encoding chloroplast constituents, and genes involved in chlorophyll biosynthesis. Moreover, we discovered that the cauliflower ELONGATED HYPOCOTYL5 (BoHY5) was expressed higher in green curds than white curds and that 2616 HY5-targeted genes, including 1600 up-regulated genes and 1016 down-regulated genes, were differently expressed in green in comparison to white curd tissue. All these 1600 up-regulated genes were HY5-targeted genes in the light. The genome-wide profiling of gene expression by RNA-seq in green curds led to the identification of large numbers of genes associated with chloroplast development, and suggested the role of regulatory genes in the high hierarchy of light signaling pathways in mediating the ectopic chloroplast development in the green curd cauliflower mutant.


Lymphocyte-endothelium interaction in systemic sclerosis and Raynaud's phenomenon.
To investigate interactions of immune cells with vascular endothelium in patients with systemic sclerosis (SSc) and in patients with idiopathic or autoimmune Raynaud's phenomenon (RP). Lymphocytes obtained from 11 patients with SSc, 9 with RP and 14 control subjects were pre-stimulated in vitro with alloantigens and cultured together with human umbilical vein endothelial cells (HUVECs). Lymphocyte adhesion and induction of endothelial HLA-class 11 molecules were measured by flow cytometry. Lymphocyte cytotoxicity against HUVECs was also evaluated. In some cases cells were cultured under experimental conditions of hypoxia and reoxygenation. Lymphocyte adhesion and induction of endothelial cell expression of HLA-DR molecules were similar in controls and SSc patients, but significantly lower in RP (p < 0.05 and p < 0.03, respectively). Cytotoxic activity of lymphoblasts against endothelial cells was negligible in all patient groups. Under experimental conditions of hypoxia and reoxygenation lymphocyte adhesion was significantly greater than in normoxic conditions in SSc patients, while it was similar to normoxia in control subjects and RP patients. These results suggest that in RP patients there may be regulatory mechanisms of lymphocyte response able to control the processes that lead to lymphocyte adhesion and endothelial HLA-DR molecule induction. These mechanisms could play an important role in RP, and might possibly be lost in clinically evident SSc.


Regulation of somatic cell reprogramming through inducible mir-302 expression.
Global demethylation is required for early zygote development to establish stem cell pluripotency, yet our findings reiterate this epigenetic reprogramming event in somatic cells through ectopic introduction of mir-302 function. Here, we report that induced mir-302 expression beyond 1.3-fold of the concentration in human embryonic stem (hES) H1 and H9 cells led to reprogramming of human hair follicle cells (hHFCs) to induced pluripotent stem (iPS) cells. This reprogramming mechanism functioned through mir-302-targeted co-suppression of four epigenetic regulators, AOF2 (also known as KDM1 or LSD1), AOF1, MECP1-p66 and MECP2. Silencing AOF2 also caused DNMT1 deficiency and further enhanced global demethylation during somatic cell reprogramming (SCR) of hHFCs. Re-supplementing AOF2 in iPS cells disrupted such global demethylation and induced cell differentiation. Given that both hES and iPS cells highly express mir-302, our findings suggest a novel link between zygotic reprogramming and SCR, providing a regulatory mechanism responsible for global demethylation in both events. As the mechanism of conventional iPS cell induction methods remains largely unknown, understanding this microRNA (miRNA)-mediated SCR mechanism may shed light on the improvements of iPS cell generation.


Isolation and analysis of a fur mutant of Neisseria gonorrhoeae.
The pathogenic Neisseria spp. produce a number of iron-regulated gene products that are thought to be important in virulence. Iron-responsive regulation of these gene products has been attributed to the presence in Neisseria spp. of the Fur (ferric uptake regulation) protein. Evidence for the role of Fur in neisserial iron regulation has been indirect because of the inability to make fur null mutations. To circumvent this problem, we used manganese selection to isolate missense mutations of Neisseria gonorrhoeae fur. We show that a mutation in gonococcal fur resulted in reduced modulation of expression of four well-studied iron-repressed genes and affected the iron regulation of a broad range of other genes as judged by two-dimensional polyacrylamide gel electrophoresis (PAGE). All 15 of the iron-repressed spots observed by two-dimensional PAGE were at least partially derepressed in the fur mutant, and 17 of the 45 iron-induced spots were affected by the fur mutation. Thus, Fur plays a central role in regulation of iron-repressed gonococcal genes and appears to be involved in regulation of many iron-induced genes. The size and complexity of the iron regulons in N. gonorrhoeae are much greater than previously recognized.


Agreement among Mediterranean Diet Pattern Adherence Indexes: MCC-Spain Study.
There are many different methods used to measure the degree of adherence to a Mediterranean diet (MD), limiting comparison and interpretation of their results. The concordance between different methodologies has been questioned and their evaluation recommended. The aim of this study was to evaluate the agreement among five indexes that measure adherence to a Mediterranean dietary pattern. The study population included healthy adults selected in the Multi-Case Control Spain (MCC-Spain) study recruited in 12 provinces. A total of 3640 controls were matched to cases by age and sex. To reach the aim, the following scores of adherence to a Mediterranean dietary pattern were calculated: Mediterranean diet score (MDS), alternative Mediterranean diet (aMED), relative Mediterranean diet (rMED), dietary score (DS) and literature-based adherence score (LBAS). The relative frequency of subjects with a high level of adherence to a MD varied from 22% (aMED index) to 37.2% (DS index). Similarly, a high variability was observed for the prevalence of a low level of MD: from 24% (rMED) to 38.4% (aMED). The correlation among MDS, aMED and rMED indexes was moderate, except for MDS and aMED with a high coefficient of correlation 0.75 (95% CI 0.74⁻0.77). The Cohen's Kappa coefficient among indexes showed a moderate⁻fair concordance, except for MDS and aMED with a 0.56 (95% CI 0.55⁻0.59) and 0.67 (95% CI 0.66⁻0.68) using linear and quadratic weighting, respectively. The existing MD adherence indexes measured the same, although they were based on different constructing algorithms and varied in the food groups included, leading to a different classification of subjects. Therefore, concordance between these indexes was moderate or low.


The evolution of Sex-linked barring alleles in chickens involves both regulatory and coding changes in CDKN2A.
Sex-linked barring is a fascinating plumage pattern in chickens recently shown to be associated with two non-coding and two missense mutations affecting the ARF transcript at the CDKN2A tumor suppressor locus. It however remained a mystery whether all four mutations are indeed causative and how they contribute to the barring phenotype. Here, we show that Sex-linked barring is genetically heterogeneous, and that the mutations form three functionally different variant alleles. The B0 allele carries only the two non-coding changes and is associated with the most dilute barring pattern, whereas the B1 and B2 alleles carry both the two non-coding changes and one each of the two missense mutations causing the Sex-linked barring and Sex-linked dilution phenotypes, respectively. The data are consistent with evolution of alleles where the non-coding changes occurred first followed by the two missense mutations that resulted in a phenotype more appealing to humans. We show that one or both of the non-coding changes are cis-regulatory mutations causing a higher CDKN2A expression, whereas the missense mutations reduce the ability of ARF to interact with MDM2. Caspase assays for all genotypes revealed no apoptotic events and our results are consistent with a recent study indicating that the loss of melanocyte progenitors in Sex-linked barring in chicken is caused by premature differentiation and not apoptosis. Our results show that CDKN2A is a major locus driving the differentiation of avian melanocytes in a temporal and spatial manner.


Quantification of clinical morbidity associated with schistosome infection in sub-Saharan Africa.
Health policy making in developing countries requires estimates of the (global) burden of disease. At present, most of the available data on schistosomiasis is limited to numbers of individuals harbouring the infection. We explored the relationship between the presence of schistosome infection and clinical morbidity, in order to estimate numbers of individuals with disease-specific morbidity for Schistosoma haematobium and Schistosoma mansoni infection in sub-Saharan Africa. We searched the literature for cross-sectional data from field studies reporting both schistosome infection and morbidity. This was used to derive a functional relationship between morbidity and infection. After standardisation for diagnostic method, the number of individuals with specific types of clinical morbidity or pathology was predicted. As only aggregated prevalences of infection were available for countries or areas, we adjusted for heterogeneity in infection levels within communities in those countries. In total, 70 million individuals out of 682 million (2000 estimate) in sub-Saharan Africa were estimated to experience haematuria in the last 2 weeks associated with S. haematobium infection, and 32 million dysuria. Ultrasound detected serious consequences of S. haematobium, major bladder wall pathology and major hydronephrosis, were predicted at 18 and 10 million, respectively. Infection with S. mansoni was estimated to cause diarrhoea in 0.78 million individuals, blood in stool in 4.4 million and hepatomegaly in 8.5 million. As the associations between prevalence of S. mansoni infection and prevalence of diarrhoea and blood in stool were not very clear, the resulting estimates may be underestimations. Using the very limited data available, we estimated the mortality rates due to non-functioning kidney (from S. haematobium) and haematemesis (from S. mansoni) at 150000 and 130000 per year. Given the overall high number of cases with schistosomiasis-related disease and associated death, we conclude that schistosomiasis remains an important public health problem in sub-Saharan Africa.


Direct Oral Anticoagulants vs Low-Molecular-Weight Heparin for Thromboprophylaxis in Nonoperative Pelvic Fractures.
Patients with pelvic fractures are prone to venous thromboembolic (VTE) complications. Recent literature shows superiority of direct oral anticoagulants (DOACs) over low-molecular-weight heparin (LMWH) for thromboprophylaxis in patients undergoing orthopaedic operations. The aim of our study was to compare in-hospital outcomes for DOACs vs LMWH in patients with nonoperative pelvic fractures. We performed a 2-year (2015 to 2016) analysis of the American College of Surgeons-Trauma Quality Improvement Program (ACS-TQIP) database. We included all adult patients with isolated blunt pelvic fractures who were managed nonoperatively and received thromboprophylaxis with either LMWH or DOACs (Factor-Xa inhibitor or direct thrombin inhibitor). Patients were divided into 2 groups based on receipt of DOACs vs LMWH and were propensity-score-matched in a 1:2 ratio to control for possible confounding factors. Primary outcomes were deep venous thrombosis (DVT) and/or pulmonary embolism (PE). Secondary outcomes were pRBC transfusions, intervention for hemorrhage control, and in-hospital mortality after initiation of thromboprophylaxis. We identified 20,692 patients with pelvic fractures. There were 7,312 patients with isolated pelvic fractures included, 852 of whom were matched (DOACs: 284; LMWH: 568). Mean age was 43.2 ± 15 years, median Injury Severity Score was 14 (range 10 to 18). Matched groups were similar in demographics, vital signs, injury parameters, and timing of initiation of thromboprophylaxis. Overall, 5.2% of patients had DVT, 1.4% PE, and 1.3% died. Patients who received DOACs were less likely to develop DVT (1.8% vs 6.9%, p < 0.01) compared with LMWH. There was no difference in PE (p = 0.85) or in-hospital mortality (p = 0.79) between the 2 groups. Similarly, there was no difference in post-prophylaxis blood transfusion, and post-prophylaxis intervention for hemorrhage control. In patients with nonoperative pelvic fractures, DOACs were associated with a reduced rate of DVT vs LMWH without increasing the risk of bleeding complications. No association was found between the type of thromboprophylactic agent and rates of PE or in-hospital mortality.


Antigenic heterogeneity of lipopolysaccharide among Burkholderia pseudomallei clinical isolates.
Burkholderia pseudomallei (BP) causes melioidosis, a potentially fatal human infection in the tropics. Clinical isolates from different geographical locations have similar morphological and biochemical characteristics. Although BP has been reported to possess 2 types of lipopolysaccharide (LPS) differing in the chemical structure of their O-polysaccharide (O-PS) component, earlier report demonstrated that the clinical strains exhibited identical LPS moieties. Recently, we reported antigenic similarity between the pathogenic (Ara-) and nonpathogenic (Ara+) biotypes. However, a few clinical isolates showed atypical SDS-PAGE profiles. In this study, LPS from 739 BP isolated from patients and animals in different geographical areas were extracted by proteinase K digestion method. Their SDS-PAGE profiles and their immunoreactivities with patients' sera and monoclonal antibody (MAb) to LPS were analyzed. The isolates showed 3 LPS patterns differing in the number and electrical mobility of bands in silver-stained gel. A majority of BP (711) isolates exhibited identical typical ladder pattern, 21 isolates showed atypical ladder pattern and 7 isolates did not exhibit ladder appearance. However, all LPS preparations exhibited similar endotoxic activity as determined by Limulus amebocyte lysate assay. On the other hand, there were no immunological cross reactivity between typical and atypical LPS, as judged from Western blot against homologous and heterologous sera from melioidosis patients from whom the typical and atypical LPS were isolated. Nevertheless, a Western blot profile of the typical LPS showed some variations when probed with MAb against BP LPS (9D5). Heat-killed bacteria from all LPS groups could similarly activate mouse macrophage cell line to produce nitric oxide (NO) and inducible NO synthase (iNOS).


Optimization of Cuprous Oxides Thin Films to be used as Thermoelectric Touch Detectors.
The electronic and optical properties of p-type copper oxides (CO) strongly depend on the production technique as it influences the obtained phases: cuprous oxide (Cu2O) or cupric oxide (CuO), the most common ones. Cu films deposited by thermal evaporation have been annealed in air atmosphere, with temperature between 225 and 375 °C and time between 1 and 4 h. The resultant CO films have been studied to understand the influence of processing parameters in the thermoelectric, electrical, optical, morphological, and structural properties. Films with a Cu2O single phase are formed when annealing at 225 °C, while CuO single phase films can be obtained at 375 °C. In between, both phases are obtained in proportions that depend on the film thickness and annealing time. The positive sign of the Seebeck coefficient (S), measured at room temperature (RT), confirms the p-type behavior of both oxides, showing values up to 1.2 mV·°C-1 and conductivity up to 2.9 (Ω·m)-1. A simple detector using Cu2O have been fabricated and tested with fast finger touch events.


Development of a framework for the implementation of synchronous e-mental health: a protocol for a realist synthesis of systematic reviews.
Background: During the COVID-19 pandemic, it has been necessary to deliver mental health care using technologies (e-mental health). But there have been difficulties in its application. Quantitative systematic reviews such as meta-analysis doesn't allow us to fully identify and properly describe this subject. Thus, our study has two main objectives: a) "to determine what evidence is available for synchronous e-mental health implementation"; and b) "to develop a framework informed by a realist analysis for the implementation of synchronous e-mental health". Methods: We will search MEDLINE, EBM Reviews, PsycINFO, EMBASE, SCOPUS, CINAHL Complete, and Web of Science databases from 1st January 2015 to September 2020, with no language restriction. A systematic review with a narrative description and a realist synthesis will be conducted. Primary studies relating to adults with common mental health problems using any type of mobile mental health intervention that includes a synchronic component and communication with a mental health professional will be included. For the analysis, we will make a realist synthesis of the systematic reviews, using a grounded theory approach with an emergent approach to synthesize the information, prioritizing the systematic reviews with a lower risk of bias in the AMSTAR-2 tool. The realist synthesis will be based on the interpretation, integration, and inference of the evaluated elements and the generation of hypotheses to better understand the implementation process of synchronous e-mental health. Finally, we will present the overall assessment in a Summary of Qualitative Findings table. Conclusion: Our results will allow a better understanding of the facilitator and limitations in implementing e-mental health.


Alternative Ultrasound Gel for a Sustainable Ultrasound Program: Application of Human Centered Design.
This paper describes design of a low cost, ultrasound gel from local products applying aspects of Human Centered Design methodology. A multidisciplinary team worked with clinicians who use ultrasound where commercial gel is cost prohibitive and scarce. The team followed the format outlined in the Ideo Took Kit. Research began by defining the challenge "how to create locally available alternative ultrasound gel for a low-resourced environment? The "End-Users," were identified as clinicians who use ultrasound in Democratic Republic of the Congo and Ethiopia. An expert group was identified and queried for possible alternatives to commercial gel. Responses included shampoo, oils, water and cornstarch. Cornstarch, while a reasonable solution, was either not available or too expensive. We then sought deeper knowledge of locally sources materials from local experts, market vendors, to develop a similar product. Suggested solutions gleaned from these interviews were collected and used to create ultrasound gel accounting for cost, image quality, manufacturing capability. Initial prototypes used cassava root flour from Great Lakes Region (DRC, Rwanda, Uganda, Tanzania) and West Africa, and bula from Ethiopia. Prototypes were tested in the field and resulting images evaluated by our user group. A final prototype was then selected. Cassava and bula at a 32 part water, 8 part flour and 4 part salt, heated, mixed then cooled was the product design of choice.


Shock-elicited pain and its reduction by concurrent tactile stimulation.
Human affective reactions to nociceptive electrical stimulation were attenuated by application of a tactile stimulus to the shocked site. No alteration was perceived when the same tactile stimulus was applied to a similar contralateral site. These results and a lack of alteration at sensation threshold demonstrate the effect to be more than simple masking and support the Melzack-Wall theory.


Modulation by substrates of the interaction between the HasR outer membrane receptor and its specific TonB-like protein, HasB.
TonB is a cytoplasmic membrane protein required for active transport of various essential substrates such as heme and iron siderophores through the outer membrane receptors of Gram-negative bacteria. This protein spans the periplasm, contacts outer membrane transporters by its C-terminal domain, and transduces energy from the protonmotive force to the transporters. The TonB box, a relatively conserved sequence localized on the periplasmic side of the transporters, has been shown to directly contact TonB. While Serratia marcescens TonB functions with various transporters, HasB, a TonB-like protein, is dedicated to the HasR transporter. HasR acquires heme either freely or via an extracellular heme carrier, the hemophore HasA, that binds to HasR and delivers heme to the transporter. Here, we study the interaction of HasR with a HasB C-terminal domain and compare it with that obtained with a TonB C-terminal fragment. Analysis of the thermodynamic parameters reveals that the interaction mode of HasR with HasB differs from that with TonB, the difference explaining the functional specificity of HasB for HasR. We also demonstrate that the presence of the substrate on the extracellular face of the transporter modifies, via enthalpy-entropy compensation, the interaction with HasB on the periplasmic face. The transmitted signal depends on the nature of the substrate. While the presence of heme on the transporter modifies only slightly the nature of interactions involved between HasR and HasB, hemophore binding on the transporter dramatically changes the interactions and seems to locally stabilize some structural motifs. In both cases, the HasR TonB box is the target for those modifications.


Vestibular evoked myogenic potentials in response to laterally directed skull taps.
In recent years it has been demonstrated that loud clicks generate short latency vestibular evoked myogenic potentials (VEMP). It has also been demonstrated that midline forehead skull tap stimulation evokes similar VEMP. In the present study, the influence of skull tap direction on VEMP was studied in 13 normal subjects and in five patients with unilateral vestibular loss. Gentle skull taps were delivered manually above each ear on the side of the skull. The muscular responses were recorded over both sternocleidomastoid muscles using skin electrodes. Among the normals, laterally directed skull taps evoked "coordinated contraction-relaxation responses", i.e. skull taps on one side evoked a negative-positive "inverted" VEMP on that side and a positive-negative "normal" VEMP on the other side. Among patients with unilateral vestibular function loss, skull taps above the lesioned ear evoked similar coordinated contraction-relaxation responses. However, skull taps above the healthy ear did not evoke that type of response. These findings suggest that laterally directed skull taps activate mainly the contralateral labyrinth.


Frequency distributions of helminths of wolves in Kazakhstan.
Between 2001 and 2008 a total of 41 wolves (Canis lupus) were necropsied in southern Kazakhstan and their intestinal parasite fauna evaluated. Of these animals 8 (19.5%) were infected with Echinococcus granulosus, 15 (36%) with Taenia spp, 13 (31.7%) with Dypilidium caninum, 5 (12.2%) with Mesocestoides lineatus, 15 (36.6%) with Toxocara canis, 16 (39%) with Toxascaris leonina, 8 (19.5%) with Trichuris vulpis, 9 (22%) with Macracanthorhynchus catulinus and 1 (2.4%) with Moniliformis moniliformis. All parasites had an aggregated distribution which followed a zero inflated or hurdle model. Although a small convenience sample of wolves, the results indicate a high prevalence of infection with E. granulosus. The mean abundance (1275 E. granulosus per wolf) was high with individual infected wolves carrying intensities of several thousand parasites. As wolves are common in Kazakhstan they may act as an important host in the transmission of this zoonotic parasite. The wolves were sampled from an area of Kazakhstan where there is a high prevalence of hydatid cysts in livestock and where echinococcosis has been observed in wild ungulates.


Dynamic Reorganization of Microtubule and Glioma Invasion.
Gliomas are characterized as highly diffuse infiltrating tumors, and currently available treatments such as surgery, radiation and chemotherapy are unfeasible or show limited efficacy against these tumors. Recent genetic and epigenetic analyses of glioma have revealed increasing evidence of the role of driver genetic alterations in glioma development and led to the identification of prognostic factors. Despite these findings, the survival rates of glioma patients remain low, and alternative treatments and novel targets are needed. Recent studies identified neural stem cells as the possible origin of gliomas, and some evidence has revealed shared functions and mechanisms between glioma cells and neurons, also supporting their similarity. The cytoskeleton plays important roles in the migration of normal cells as well as cancer cells. Recent reports have described a role for microtubules, a component of the cytoskeleton, in glioma invasion. Notably, several factors that regulate microtubule functions, such as microtubule-associated proteins, plus-end tracking proteins, or motor proteins, are upregulated in glioma tissues compared with normal tissue, and upregulation of these factors is associated with high invasiveness of glioma cells. In this review, we describe the mechanism of microtubules in glioma invasion and discuss the possibility of microtubule-targeted therapy to inhibit glioma invasion.


The relationship between social capital and quality management systems in European hospitals: a quantitative study.
Strategic leadership is an important organizational capability and is essential for quality improvement in hospital settings. Furthermore, the quality of leadership depends crucially on a common set of shared values and mutual trust between hospital management board members. According to the concept of social capital, these are essential requirements for successful cooperation and coordination within groups. We assume that social capital within hospital management boards is an important factor in the development of effective organizational systems for overseeing health care quality. We hypothesized that the degree of social capital within the hospital management board is associated with the effectiveness and maturity of the quality management system in European hospitals. We used a mixed-method approach to data collection and measurement in 188 hospitals in 7 European countries. For this analysis, we used responses from hospital managers. To test our hypothesis, we conducted a multilevel linear regression analysis of the association between social capital and the quality management system score at the hospital level, controlling for hospital ownership, teaching status, number of beds, number of board members, organizational culture, and country clustering. The average social capital score within a hospital management board was 3.3 (standard deviation: 0.5; range: 1-4) and the average hospital score for the quality management index was 19.2 (standard deviation: 4.5; range: 0-27). Higher social capital was associated with higher quality management system scores (regression coefficient: 1.41; standard error: 0.64, p=0.029). The results suggest that a higher degree of social capital exists in hospitals that exhibit higher maturity in their quality management systems. Although uncontrolled confounding and reverse causation cannot be completely ruled out, our new findings, along with the results of previous research, could have important implications for the work of hospital managers and the design and evaluation of hospital quality management systems.


Adipose Tissue in HIV Infection.
HIV infection and antiretroviral therapy (ART) treatment exert diverse effects on adipocytes and stromal-vascular fraction cells, leading to changes in adipose tissue quantity, distribution, and energy storage. A HIV-associated lipodystrophic condition was recognized early in the epidemic, characterized by clinically apparent changes in subcutaneous, visceral, and dorsocervical adipose depots. Underlying these changes is altered adipose tissue morphology and expression of genes central to adipocyte maturation, regulation, metabolism, and cytokine signaling. HIV viral proteins persist in circulation and locally within adipose tissue despite suppression of plasma viremia on ART, and exposure to these proteins impairs preadipocyte maturation and reduces adipocyte expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) and other genes involved in cell regulation. Several early nucleoside reverse transcriptase inhibitor and protease inhibitor antiretroviral drugs demonstrated substantial adipocyte toxicity, including reduced mitochondrial DNA content and respiratory chain enzymes, reduced PPAR-γ and other regulatory gene expression, and increased proinflammatory cytokine production. Newer-generation agents, such as integrase inhibitors, appear to have fewer adverse effects. HIV infection also alters the balance of CD4+ and CD8+ T cells in adipose tissue, with effects on macrophage activation and local inflammation, while the presence of latently infected CD4+ T cells in adipose tissue may constitute a protected viral reservoir. This review provides a synthesis of the literature on how HIV virus, ART treatment, and host characteristics interact to affect adipose tissue distribution, immunology, and contribution to metabolic health, and adipocyte maturation, cellular regulation, and energy storage. © 2017 American Physiological Society. Compr Physiol 7:1339-1357, 2017.


Diverse π-π stacking motifs modulate electrical conductivity in tetrathiafulvalene-based metal-organic frameworks.
We report three electrically conductive metal-organic frameworks (MOFs) based on a tetrathiafulvalene linker and La3+. Depending on the solvent ratios and temperatures used in their solvothermal synthesis, these MOFs crystallize with different topologies containing distinct π-π stacking sequences of the ligand. Notably, their transport properties correlate rationally with the stacking motifs: longer S···S contact distances between adjacent ligands coincide with lower electrical conductivities and higher activation energies. Diffuse reflectance spectroscopic measurements reveal ligand-based intervalence charge transfer bands in each phase, implicating charge delocalization among mixed-valent tetrathiafulvalene units as the dominant mode of transport. Overall, these frameworks demonstrate how tuning the intermolecular interactions in MOFs serves as a route towards controlling their physical properties.


DESM: portal for microbial knowledge exploration systems.
Microorganisms produce an enormous variety of chemical compounds. It is of general interest for microbiology and biotechnology researchers to have means to explore information about molecular and genetic basis of functioning of different microorganisms and their ability for bioproduction. To enable such exploration, we compiled 45 topic-specific knowledgebases (KBs) accessible through DESM portal (www.cbrc.kaust.edu.sa/desm). The KBs contain information derived through text-mining of PubMed information and complemented by information data-mined from various other resources (e.g. ChEBI, Entrez Gene, GO, KOBAS, KEGG, UniPathways, BioGrid). All PubMed records were indexed using 4,538,278 concepts from 29 dictionaries, with 1 638 986 records utilized in KBs. Concepts used are normalized whenever possible. Most of the KBs focus on a particular type of microbial activity, such as production of biocatalysts or nutraceuticals. Others are focused on specific categories of microorganisms, e.g. streptomyces or cyanobacteria. KBs are all structured in a uniform manner and have a standardized user interface. Information exploration is enabled through various searches. Users can explore statistically most significant concepts or pairs of concepts, generate hypotheses, create interactive networks of associated concepts and export results. We believe DESM will be a useful complement to the existing resources to benefit microbiology and biotechnology research.


MUSIC and aromatic residues: amino acid type-selective (1)H-(15)N correlations, III.
Amino acid type-selective experiments can help to remove ambiguities in automated assignment procedures for (15)N/(13)C-labeled proteins. Here we present five triple-resonance experiments that yield amino acid type-selective (1)H-(15)N correlations for aromatic amino acids. Four of the novel experiments are based on the MUSIC coherence transfer scheme that replaces the initial INEPT transfer and is selective for CH(2). The MUSIC sequence is combined with selective excitation pulses to create experiments for Trp (W-HSQC) as well as Phe, Tyr, and His (FYH-HSQC). In addition, an experiment selective for Trp H(epsilon1)-N(epsilon1) is presented. The new experiments are recorded as two-dimensional experiments and their performance is demonstrated with the application to a protein domain of 115 amino acids.


Structural rearrangement of SULT2A1: effects on dehydroepiandrosterone and raloxifene sulfation.
BACKGROUND: Human cytosoloic sulfotransferase (SULT) 2A1 is a major hepatic isoform and sulfates hydroxyl groups in structurally diverse sterols and xenobiotics. SULT2A1 crystal structures resolved in the presence and absence of 3',5'-diphosphoadenosine (PAP) or dehydropeiandrosterone (DHEA) suggest a significant rearrangement of the peptide that forms the surface of the active site in the presence of PAP. MATERIALS AND METHODS: Molecular modeling was used to examine the effects of the rearrangement in SULT2A1 associated with 3'-phosphoadenosine 5'-phosphosulfate (PAPS) binding on the binding of DHEA and raloxifene. The kinetics of DHEA and raloxifene sulfation was analyzed to investigate the effects of the rearrangement on SULT2A1 activity. RESULTS: Molecular models indicate that DHEA is able to bind to SULT2A1 in both conformations (open, without PAP; closed, with PAP) in a catalytic configuration, whereas raloxifene bound in a catalytic conformation only in the open structure. Raloxifene did not bind in the smaller, closed substrate binding pocket. Kinetic analysis of DHEA sulfation was consistent with a random Bi-Bi reaction mechanism, whereas raloxifene sulfation was more indicative of an ordered reaction mechanism with raloxifene binding first. Initial burst kinetics with DHEA yielded similar results after preincubation of SULT2A1 with DHEA or PAPS. Preincubation of SULT2A1 with raloxifene showed a burst of raloxifene sulfate formation with the addition of PAPS. In contrast, little raloxifene sulfate was formed if SULT2A1 was preincubated with PAPS and the reaction initiated with raloxifene. CONCLUSIONS: The structural rearrangements in SULT2A1 caused by PAPS binding can alter the sulfation mechanism and kinetics of different substrates.


Commonalities and Asymmetries in the Neurobiological Infrastructure for Language Production and Comprehension.
The neurobiology of sentence production has been largely understudied compared to the neurobiology of sentence comprehension, due to difficulties with experimental control and motion-related artifacts in neuroimaging. We studied the neural response to constituents of increasing size and specifically focused on the similarities and differences in the production and comprehension of the same stimuli. Participants had to either produce or listen to stimuli in a gradient of constituent size based on a visual prompt. Larger constituent sizes engaged the left inferior frontal gyrus (LIFG) and middle temporal gyrus (LMTG) extending to inferior parietal areas in both production and comprehension, confirming that the neural resources for syntactic encoding and decoding are largely overlapping. An ROI analysis in LIFG and LMTG also showed that production elicited larger responses to constituent size than comprehension and that the LMTG was more engaged in comprehension than production, while the LIFG was more engaged in production than comprehension. Finally, increasing constituent size was characterized by later BOLD peaks in comprehension but earlier peaks in production. These results show that syntactic encoding and parsing engage overlapping areas, but there are asymmetries in the engagement of the language network due to the specific requirements of production and comprehension.


Determining the optimal strategy for reopening schools, the impact of test and trace interventions, and the risk of occurrence of a second COVID-19 epidemic wave in the UK: a modelling study.
As lockdown measures to slow the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection begin to ease in the UK, it is important to assess the impact of any changes in policy, including school reopening and broader relaxation of physical distancing measures. We aimed to use an individual-based model to predict the impact of two possible strategies for reopening schools to all students in the UK from September, 2020, in combination with different assumptions about relaxation of physical distancing measures and the scale-up of testing. In this modelling study, we used Covasim, a stochastic individual-based model for transmission of SARS-CoV-2, calibrated to the UK epidemic. The model describes individuals' contact networks stratified into household, school, workplace, and community layers, and uses demographic and epidemiological data from the UK. We simulated six different scenarios, representing the combination of two school reopening strategies (full time and a part-time rota system with 50% of students attending school on alternate weeks) and three testing scenarios (68% contact tracing with no scale-up in testing, 68% contact tracing with sufficient testing to avoid a second COVID-19 wave, and 40% contact tracing with sufficient testing to avoid a second COVID-19 wave). We estimated the number of new infections, cases, and deaths, as well as the effective reproduction number (R) under different strategies. In a sensitivity analysis to account for uncertainties within the stochastic simulation, we also simulated infectiousness of children and young adults aged younger than 20 years at 50% relative to older ages (20 years and older). With increased levels of testing (between 59% and 87% of symptomatic people tested at some point during an active SARS-CoV-2 infection, depending on the scenario), and effective contact tracing and isolation, an epidemic rebound might be prevented. Assuming 68% of contacts could be traced, we estimate that 75% of individuals with symptomatic infection would need to be tested and positive cases isolated if schools return full-time in September, or 65% if a part-time rota system were used. If only 40% of contacts could be traced, these figures would increase to 87% and 75%, respectively. However, without these levels of testing and contact tracing, reopening of schools together with gradual relaxing of the lockdown measures are likely to induce a second wave that would peak in December, 2020, if schools open full-time in September, and in February, 2021, if a part-time rota system were adopted. In either case, the second wave would result in R rising above 1 and a resulting second wave of infections 2·0-2·3 times the size of the original COVID-19 wave. When infectiousness of children and young adults was varied from 100% to 50% of that of older ages, we still found that a comprehensive and effective test-trace-isolate strategy would be required to avoid a second COVID-19 wave. To prevent a second COVID-19 wave, relaxation of physical distancing, including reopening of schools, in the UK must be accompanied by large-scale, population-wide testing of symptomatic individuals and effective tracing of their contacts, followed by isolation of diagnosed individuals. None.


Rac1 and Scribble are targets for the arrest of neurite outgrowth by TBE virus NS5.
Tick-borne encephalitis virus (TBEV) causes extensive CNS disease in humans known as TBE, however, relatively little is known of the molecular mechanisms for its progress. Here, we now show that TBEV produces defects in neuronal development of PC12 cells through a function of the viral NS5 protein. The methyltransferase domain of NS5 is critical and sufficient for restriction of nerve growth factor induced neurite outgrowth. This effect is reversed by expression of NS5 mutants unable to bind Scribble and unexpectedly, in Scribble depleted cells with binding-competent NS5. Furthermore, we also demonstrate that the Rho GTPase Rac1 and the guanine nucleotide-exchange factor, betaPIX are outcompeted by NS5 for binding to Scribble, linking to effects on neurite outgrowth by TBEV. Together, these findings provide the first experimental evidence that Rac1 and betaPIX are indirect targets of NS5 acting through the multifunctional polarity protein Scribble to oppose neuronal differentiation. In conclusion, our results offer a potential mechanism by which TBEV alters neuronal circuitry and opens new avenues for therapeutic interventions.


Cancer Screening Among Women Prescribed Opioids: A National Study.
Prior work suggests that there are competing demands between addressing pain and other issues in primary care, potentially lessening delivery of evidence-based cancer screening. We assessed the association between opioid therapy and cancer screening among women in a nationally representative US sample. We conducted an observational analysis of the 2005-2015 Medical Expenditure Panel Surveys. We included all women aged ≥18 years without cancer and with opioid prescription and preventive care services data. Logistic regression analyses examined associations between receipt of opioid prescription (any vs none) and receipt of breast, cervical, and colorectal cancer screenings. Analyses were adjusted for sociodemographic characteristics, health status, health conditions, and usual source of care, as well as health care utilization. Of 53,982 participants, 15.8% reported ≥1 opioid prescription. Compared with women not prescribed opioids, those prescribed opioids were more likely to visit their doctor (median number of visits per year = 5, vs 1). Without adjustment for number of visits, women prescribed opioids were more likely to receive all 3 cancer screenings; the adjusted odds ratio for breast cancer screening was 1.26 (95% CI, 1.16-1.38), that for cervical cancer screening was 1.22 (95% CI, 1.13-1.33), and that for colorectal cancer screening was 1.22 (95% CI, 1.12-1.33). With adjustment for number of visits, adjusted odds ratios decreased (breast 1.07 [95% CI, 0.98-1.18]; cervical 1.01 [95% CI, 0.93-1.09]; colorectal 1.04 [95% CI, 0.95-1.14]). In a nationally representative sample, receipt of opioid prescriptions was not associated with less recommended cancer screenings. Rather, women receiving opioids had greater adjusted odds of receiving breast, cervical, and colorectal cancer screening, although the associations were attenuated by adjusting for their more frequent office visits relative to women not receiving opioids.


Chagas disease: control, elimination and eradication. Is it possible?
From an epidemiological point of view, Chagas disease and its reservoirs and vectors can present the following characteristics: (i) enzooty, maintained by wild animals and vectors, with broad occurrence from southern United States of America (USA) to southern Argentina and Chile (42ºN 49ºS), (ii) anthropozoonosis, when man invades the wild ecotope and becomes infected with Trypanosoma cruzi from wild animals or vectors or when the vectors and wild animals, especially marsupials, invade the human domicile and infect man, (iii) zoonosis-amphixenosis and exchanged infection between animals and humans by domestic vectors in endemic areas and (iv) zooanthroponosis, infection that is transmitted from man to animals, by means of domestic vectors, which is the rarest situation in areas endemic for Chagas disease. The characteristics of Chagas disease as an enzooty of wild animals and as an anthropozoonosis are seen most frequently in the Brazilian Amazon and in the Pan-Amazon region as a whole, where there are 33 species of six genera of wild animals: Marsupialia, Chiroptera, Rodentia, Edentata (Xenarthra), Carnivora and Primata and 27 species of triatomines, most of which infected with T. cruzi . These conditions place the resident populations of this area or its visitors - tourists, hunters, fishermen and especially the people whose livelihood involves plant extraction - at risk of being affected by Chagas disease. On the other hand, there has been an exponential increase in the acute cases of Chagas disease in that region through oral transmission of T. cruzi , causing outbreaks of the disease. In four seroepidemiological surveys that were carried out in areas of the microregion of the Negro River, state of Amazonas, in 1991, 1993, 1997 and 2010, we found large numbers of people who were serologically positive for T. cruzi infection. The majority of them and/or their relatives worked in piassava extraction and had come into contact with and were stung by wild triatomines in that area. Finally, a characteristic that is greatly in evidence currently is the migration of people with Chagas disease from endemic areas of Latin America to non-endemic countries. This has created a new dilemma for these countries: the risk of transmission through blood transfusion and the onus of controlling donors and treating migrants with the disease. As an enzooty of wild animals and vectors, and as an anthropozoonosis, Chagas disease cannot be eradicated, but it must be controlled by transmission elimination to man.


Structures of three HIV-1 HLA-B*5703-peptide complexes and identification of related HLAs potentially associated with long-term nonprogression.
Long-term nonprogression during acute HIV infection has been strongly associated with HLA-B*5701 or HLA-B*5703. In this study, we present the high resolution crystal structures of HLA-B*5703 complexes with three HIV-1 epitopes: ISPRTLNAW (ISP), KAFSPEVIPMF (KAF-11), and KAFSPEVI (KAF-8). These reveal peptide anchoring at position 2 and their C termini. The different peptide lengths and primary sequences are accommodated by variation in the specific contacts made to the HLA-B*5703, flexibility in water structure, and conformational adjustment of side chains within the peptide-binding groove. The peptides adopt markedly different conformations, and trap variable numbers of water molecules, near a cluster of tyrosine side chains located in the central region of the peptide-binding groove. The KAF-11 epitope completely encompasses the shorter KAF-8 epitope but the peptides are presented in different conformations; the KAF-11 peptide arches out of the peptide-binding groove, exposing a significant main chain surface area. Bioinformatic analysis of the MHC side chains observed to contribute to the peptide anchor specificity, and other specific peptide contacts, reveals HLA alleles associated with long-term nonprogression and a number of related HLA alleles that may share overlapping peptide repertoires with HLA-B*5703 and thus may display a similar capacity for efficient immune control of HIV-1 infection.


Infertility around the globe: new thinking on gender, reproductive technologies and global movements in the 21st century.
Infertility is estimated to affect as many as 186 million people worldwide. Although male infertility contributes to more than half of all cases of global childlessness, infertility remains a woman's social burden. Unfortunately, areas of the world with the highest rates of infertility are often those with poor access to assisted reproductive techniques (ARTs). In such settings, women may be abandoned to their childless destinies. However, emerging data suggest that making ART accessible and affordable is an important gender intervention. To that end, this article presents an overview of what we know about global infertility, ART and changing gender relations, posing five key questions: (i) why is infertility an ongoing global reproductive health problem? (ii) What are the gender effects of infertility, and are they changing over time? (iii) What do we know about the globalization of ART to resource-poor settings? (iv) How are new global initiatives attempting to improve access to IVF? (v) Finally, what can be done to overcome infertility, help the infertile and enhance low-cost IVF (LCIVF) activism? An exhaustive literature review using MEDLINE, Google Scholar and the keyword search function provided through the Yale University Library (i.e. which scans multiple databases simultaneously) identified 103 peer-reviewed journal articles and 37 monographs, chapters and reports from the years 2000-2014 in the areas of: (i) infertility demography, (ii) ART in low-resource settings, (iii) gender and infertility in low-resource settings and (iv) the rise of LCIVF initiatives. International Federation of Fertility Societies Surveillance reports were particularly helpful in identifying important global trends in IVF clinic distribution between 2002 and 2010. Additionally, a series of articles published by scholars who are tracking global cross-border reproductive care (CBRC) trends, as well as others who are involved in the growing LCIVF movement, were invaluable. Recent global demographic surveys indicate that infertility remains an ongoing reproductive problem, with six key demographic features. Despite the massive global expansion of ART services over the past decade (2005-2015), ART remains inaccessible in many parts of the world, particularly in sub-Saharan Africa, where IVF clinics are still absent in most countries. For women living in such ART-poor settings, the gender effects of infertility may be devastating. In contrast, in ART-rich regions such as the Middle East, the negative gender effects of infertility are diminishing over time, especially with state subsidization of ART. Furthermore, men are increasingly acknowledging their male infertility and seeking ICSI. Thus, access to ART may ameliorate gender discrimination, especially in the Global South. To that end, a number of clinician-led, LCIVF initiatives are in development to provide affordable ART, particularly in Africa. Without access to LCIVF, many infertile couples must incur catastrophic expenditures to fund their IVF, or engage in CBRC to seek lower-cost IVF elsewhere. Given the present realities, three future directions for research and intervention are suggested: (i) address the preventable causes of infertility, (ii) provide support and alternatives for the infertile and (iii) encourage new LCIVF initiatives to improve availability, affordability and acceptability of ART around the globe.


Communication disorders after stroke in Aboriginal Australians.
Limited research exists on acquired communication disorders (ACD) in Aboriginal Australians despite their high rates of stroke. Their uptake of rehabilitation services is low, and little information is available on functional consequences for this population. This pilot study explored consequences of ACD for Aboriginal Australians after stroke, including their experiences of services received. Semi-structured interviews were collected with 13 Aboriginal people with ACD, and family members, in Perth. Ages ranged from 30 to 78 years and time post stroke from 0.5 to 29 years. A qualitative, thematic analysis of interview transcripts was undertaken. The key themes which emerged were "getting on with life", coping with change, independence/interdependence, the importance of communication for maintaining family and community connection, role and identity issues and viewing the stroke consequences within the broader context of co-morbidities. While similar life disruptions were found to those previously reported in the general stroke population, this study highlighted differences, which reflect the particular context of ACD for Aboriginal people and which need to be considered when planning future services. While implications are limited due to small numbers, the findings emphasise the importance of a holistic approach, and integration of communication treatments into community-led social activities. Implications for Rehabilitation Aboriginal Australians frequently experience a range of concurrent and complex co-morbidities and demanding social or family circumstances at the same time as coping with communication disorders post-stroke. A holistic approach to post stroke rehabilitation may be appropriate with services that accommodate communication disorders, delivered in collaboration with Aboriginal organisations, emphasising positive attitudes and reintegration into community as fully as possible. Communication and yarning are important for maintaining family and community connection and identity, and family and community context should be incorporated into all assessment and treatment activities.


White matter microstructure alterations correlate with terminally differentiated CD8+ effector T cell depletion in the peripheral blood in mania: Combined DTI and immunological investigation in the different phases of bipolar disorder.
White matter (WM) microstructural abnormalities and, independently, signs of immunological activation were consistently demonstrated in bipolar disorder (BD). However, the relationship between WM and immunological alterations as well as their occurrence in the various phases of BD remain unclear. In 60 type I BD patients - 20 in manic, 20 in depressive, 20 in euthymic phases - and 20 controls we investigated: (i) diffusion tensor imaging (DTI)-derived fractional anisotropy (FA), radial diffusivity (RD) and axial diffusivity (AD) using a tract-based spatial statistics (TBSS) approach; (ii) circulating T cell subpopulations frequencies, as well as plasma levels of different cytokines; (iii) potential relationships between WM and immunological data. We found: (i) a significant widespread combined FA-RD alteration mainly in mania, with involvement of the body of corpus callosum (BCC) and superior corona radiata (SCR); (ii) significant increase in CD4+ T cells as well as significant decrease in CD8+ T cells and their subpopulations effector memory (CD8+ CD28-CD45RA-), terminal effector memory (CD8+ CD28-CD45RA+) and CD8+ IFNγ+ in mania; (iii) a significant relationship between WM and immunological alterations in the whole cohort, and a significant correlation of FA-RD abnormalities in the BCC and SCR with reduced frequencies of CD8+ terminal effector memory and CD8+ IFNγ+ T cells in mania only. Our data show a combined occurrence of WM and immunological alterations in mania. WM abnormalities highly correlated with reduction in circulating CD8+ T cell subpopulations that are terminally differentiated effector cells prone to tissue migration, suggesting that these T cells could play a role in WM alteration in BD.


Redistribution of cytoplasmic components during germinal vesicle breakdown in starfish oocytes.
The starfish oocyte is relatively clear optically, and its nucleus, termed the germinal vesicle, is large. These characteristics allowed studies by confocal microscopy of germinal vesicle breakdown during maturation in living oocytes. Three fluorescent probes for cytoplasmic components were used: fluorescein 70 kDa dextran, which does not cross the nuclear pore of immature oocytes and probably behaves in the same way as soluble cytosolic proteins, YOYO-1, which was used to localize ribosomes, and DiI which labels the nuclear envelope and endoplasmic reticulum. The first change observable by transmitted light microscopy during maturation is a wrinkling of the germinal vesicle envelope. Several minutes before the wrinkling, the 70 kDa dextran began to enter the germinal vesicle; the ribosomes did not enter during this period. The dextran is likely to be passing through nuclear pores whose size limit has increased but which still exclude ribosomes. At the time of the wrinkling of the germinal vesicle envelope, both 70 kDa dextran and ribosomes entered as a massive wave. The characteristics of this entry indicate that the permeability barrier of the nuclear envelope bilayer has been disrupted. The disruption of the permeability barrier occurred in a local region rather than around the entire periphery. Also, the disruption was observed more often on the animal pole side of the germinal vesicle (26/34 oocytes). The endoplasmic reticulum entered the nuclear region more slowly. Cytochalasin B inhibited this movement and also inhibited characteristic endoplasmic reticulum movements seen at high magnification. The effects of cytochalasin indicate that mixing of endoplasmic reticulum with nuclear space is an active process involving actin filaments.