Mycobacterium tuberculosis infection in pregnant and nonpregnant women infected with HIV in the Women and Infants Transmission Study.
Prevalence of Mycobacterium tuberculosis (TB) infection and anergy were evaluated in a cohort of pregnant and nonpregnant women infected with the human immunodeficiency virus who were enrolled in a prospective natural history study (the Women and Infants Transmission Study) conducted in New York, NY; Boston and Worcester, Mass; Chicago, Ill; and San Juan, Puerto Rico. One hundred eighty-three women (65 pregnant, 118 nonpregnant) were evaluated for TB. The TB history and risk factors were assessed by interview and medical record review. Intradermal skin testing with tuberculin, mumps, and tetanus antigens and CD4+ lymphocyte count were performed. Overall prevalence of TB infection or disease by documented medical history and/or a tuberculin skin test induration of 5 mm or more was 14% (26 of 183). History of TB infection or disease was documented in 11% of the women who were interviewed. Tuberculin and anergy skin test results were evaluable for 124 women; 6% (seven of 124) had tuberculin skin test induration of 5 mm or more, including 11% (five of 46) of the pregnant women who were tested. Induration between 2 and 5 mm was observed in four more women, three of whom were pregnant. Anergy was observed in 42% (52 of 124); prevalence of anergy was higher in nonpregnant women (38 [49%] of 78) than in pregnant women (14 [30%] of 46). While anergy was more common in women with a CD4+ cell count of 0.5 x 10(9)/L or less, 27% of those with a CD4+ cell count of more than 0.5 x 10(9)/L were also anergic. These data support current Public Health Service recommendations for tuberculin skin testing in persons infected with the human immunodeficiency virus, and emphasize that evaluation should include pregnant as well as nonpregnant women. The prevalence of anergy does not appear increased in pregnancy in women infected with the human immunodeficiency virus. Health care providers should include tuberculin and anergy skin testing as part of the standard prenatal care for women infected with the human immunodeficiency virus.


Tuning the HOMO energy levels of organic dyes for dye-sensitized solar cells based on Br-/Br3- electrolytes.
A series of novel metal-free organic dyes TC301-TC310 with relatively high HOMO levels were synthesized and applied in dye-sensitized solar cells (DSCs) based on electrolytes that contain Br(-)/Br(3)(-) and I(-)/I(3)(-). The effects of additive Li(+) ions and the HOMO levels of the dyes have an important influence on properties of the dyes and performance of DSCs. The addition of Li(+) ions in electrolytes can broaden the absorption spectra of the dyes on TiO(2) films and shift both the LUMO levels of the dyes and the conduction band of TiO(2), thus leading to the increase of J(sc) and the decrease of V(oc). Upon using Br(-)/Br(3)(-) instead of I(-)/I(3)(-), a large increase of V(oc) is attributed to the enlarged energy difference between the redox potentials of electrolyte and the Fermi level of TiO(2), as well as the suppressed electron recombination. Incident photon to current efficiency (IPCE) action spectra, electrochemical impedance spectra, and nanosecond laser transient absorption reveal that both the electron collection yields and the dye regeneration yields (Φ(r)) depend on the potential difference (the driving forces) between the oxidized dyes and the Br(-)/Br(3)(-) redox couple. For the dyes for which the HOMO levels are more positive than the redox potential of Br(-)/Br(3)(-) sufficient driving forces lead to the longer effective electron-diffusion lengths and almost the same efficient dye regenerations, whereas for the dyes for which the HOMO levels are similar to the redox potential of Br(-)/Br(3)(-), insufficient driving forces lead to shorter effective electron-diffusion lengths and inefficient dye regenerations.


Adaptive algorithm for blind separation from noisy time-varying mixtures.
This article addresses the problem of blind source separation from time-varying noisy mixtures using a state variable model and recursive estimation. An estimate of each source signal is produced real time at the arrival of new observed mixture vector. The goal is to perform the separation and attenuate noise simultaneously, as well as to adapt to changes that occur in the mixing system. The observed data are projected along the eigenvectors in signal subspace. The subspace is tracked real time. Source signals are modeled using low-order AR (autoregressive) models, and noise is attenuated by trading off between the model and the information provided by measurements. The type of zero-memory nonlinearity needed in separation is determined on-line. Predictor-corrector filter structures are proposed, and their performance is investigated in simulation using biomedical and communications signals at different noise levels and a time-varying mixing system. In quantitative comparison to other widely used methods, significant improvement in output signal-to-noise ratio is achieved.


Trends underlying employer-sponsored health insurance growth for Americans younger than age sixty-five.
Little is known about the trends in health care spending for the 156 million Americans who are younger than age sixty-five and enrolled in employer-sponsored health insurance. Using a new source of health insurance claims data, we estimated per capita spending, utilization, and prices for this population between 2007 and 2011. During this period per capita spending on employer-sponsored insurance grew at historically slow rates, but still faster than per capita national health expenditures. Total per capita spending for employer-sponsored insurance grew at an average annual rate of 4.9 percent, with prescription spending growing at 3.3 percent and medical spending growing at 5.3 percent. Out-of-pocket medical spending increased at an average annual rate of 8.0 percent, whereas out-of-pocket prescription drug spending growth was flat. Growth in the use of medical services and prescription drugs slowed. Medical price growth accelerated, and prescription price growth decelerated. As a result, changes in utilization contributed less than changes in price did to overall spending growth for those with employer-sponsored insurance.


The keys to governance and stakeholder engagement: the southeast michigan beacon community case study.
Community-based health information exchanges (HIEs) and efforts to consolidate and house data are growing, given the advent of Accountable Care Organizations (ACOs) under the Affordable Care Act and other similar population health focused initiatives. The Southeast Michigan Beacon Community (SEMBC) can be looked to as one case study that offers lessons learned, insights on challenges faced and accompanying workarounds related to governance and stakeholder engagement. The SEMBC case study employs an established Data Warehouse Governance Framework to identify and explain the necessary governance and stakeholder engagement components, particularly as they relate to community-wide data sharing and data warehouses or repositories. Perhaps the biggest lesson learned through the SEMBC experience is that community-based work is hard. It requires a great deal of community leadership, collaboration and resources. SEMBC found that organizational structure and guiding principles needed to be continually revisited and nurtured in order to build the relationships and trust needed among stakeholder organizations. SEMBC also found that risks and risk mitigation tactics presented challenges and opportunities at the outset and through the duration of the three year pilot period. Other communities across the country embarking on similar efforts need to consider realistic expectations about community data sharing infrastructures and the accompanying and necessary governance and stakeholder engagement fundamentals.


Unintended pregnancy, induced abortion and abortion care-seeking experiences among adolescents in Kinshasa, Democratic Republic of Congo: a cross-sectional study.
To estimate age-specific abortion incidence and unintended pregnancy in Kinshasa, Democratic Republic of Congo and compare care experiences between adolescents (15-19 years) and older women (20-49 years). We used the age-specific variant of the Abortion Incidence Complications Method to estimate abortion and unintended pregnancy, with data from three primary sources: Health Facility Survey (n=361) provided postabortion care (PAC) caseloads; Prospective Morbidity Survey (n=1031) provided the age distribution and characteristics of women presenting for PAC and Health Professional Survey (n=115) provided an estimate of the proportion of abortions resulting in facility-based treatment of complications. Bivariate (χ2, t-test) and multivariable (binary logistic regression, Cox proportional hazard) analyses were used to compare abortion care experiences. Health facilities proving PAC in Kinshasa. Women who presented to PAC facilities with abortion complications and their care providers. The primary measures were abortion incidence and proportion of pregnancies unintended. The secondary measures were the odd of reporting specific abortion care experiences. Adolescents had an estimated 27 590 induced abortions, constituting 18.8% of abortions in Kinshasa in 2016. Adolescents had the lowest abortion rate among women less than 35 years (55.2/1000 women) but the highest rate among ever sexually active women (138.4/1000) and recently sexually active women (167.2/1000). Also, adolescents had the highest abortion ratio (82.4/100 live births), proportion of pregnancies unintended (80%) and proportion of unintended pregnancies ending in abortion (49%). Compared with older women, adolescents had higher odds of reporting pregnancy unintendedness (adjusted OR, AOR 1.36, 95% CI 1.75 to 2.24), seeking abortion at later than first trimester (AOR 1.34, 95% CI 1.09 to 1.63) and from non-medical professionals (AOR 1.68, 95% CI 1.31 to 2.14), and not using contraceptives before pregnancy (AOR 2.23, 95% CI 2.77 to 3.43) or postabortion (AOR 2.46, 95% CI 1.87 to 3.29). Interventions are needed to reduce unintended pregnancy among adolescents in Kinshasa and improve their abortion care experiences.


Conductance histogram evolution of an EC-MCBJ fabricated Au atomic point contact.
This work presents a study of Au conductance quantization based on a combined electrochemical deposition and mechanically controllable break junction (MCBJ) method. We describe the microfabrication process and discuss improved features of our microchip structure compared to the previous one. The improved structure prolongs the available life of the microchip and also increases the success rate of the MCBJ experiment. Stepwise changes in the current were observed at the last stage of atomic point contact breakdown and conductance histograms were constructed. The evolution of 1G0 peak height in conductance histograms was used to investigate the probability of formation of an atomic point contact. It has been shown that the success rate in forming an atomic point contact can be improved by decreasing the stretching speed and the degree that the two electrodes are brought into contact. The repeated breakdown and formation over thousands of cycles led to a distinctive increase of 1G0 peak height in the conductance histograms, and this increased probability of forming a single atomic point contact is discussed.


Taxol-stabilized microtubules can position the cytokinetic furrow in mammalian cells.
How microtubules act to position the plane of cell division during cytokinesis is a topic of much debate. Recently, we showed that a subpopulation of stable microtubules extends past chromosomes and interacts with the cell cortex at the site of furrowing, suggesting that these stabilized microtubules may stimulate contractility. To test the hypothesis that stable microtubules can position furrows, we used taxol to rapidly suppress microtubule dynamics during various stages of mitosis in PtK1 cells. Cells with stabilized prometaphase or metaphase microtubule arrays were able to initiate furrowing when induced into anaphase by inhibition of the spindle checkpoint. In these cells, few microtubules contacted the cortex. Furrows formed later than usual, were often aberrant, and did not progress to completion. Images showed that furrowing correlated with the presence of one or a few stable spindle microtubule plus ends at the cortex. Actin, myosin II, and anillin were all concentrated in these furrows, demonstrating that components of the contractile ring can be localized by stable microtubules. Inner centromere protein (INCENP) was not found in these ingressions, confirming that INCENP is dispensable for furrow positioning. Taxol-stabilization of the numerous microtubule-cortex interactions after anaphase onset delayed furrow initiation but did not perturb furrow positioning. We conclude that taxol-stabilized microtubules can act to position the furrow and that loss of microtubule dynamics delays the timing of furrow onset and prevents completion. We discuss our findings relative to models for cleavage stimulation.


Negative elongation factor is required for the maintenance of proviral latency but does not induce promoter-proximal pausing of RNA polymerase II on the HIV long terminal repeat.
The role of the negative elongation factor (NELF) in maintaining HIV latency was investigated following small hairpin RNA (shRNA) knockdown of the NELF-E subunit, a condition that induced high levels of proviral transcription in latently infected Jurkat T cells. Chromatin immunoprecipitation (ChIP) assays showed that latent proviruses accumulate RNA polymerase II (RNAP II) on the 5' long terminal repeat (LTR) but not on the 3' LTR. NELF colocalizes with RNAP II, and its level increases following proviral induction. RNAP II pause sites on the HIV provirus were mapped to high resolution by ChIP with high-throughput sequencing (ChIP-Seq). Like cellular promoters, RNAP II accumulates at around position +30, but HIV also shows additional pausing at +90, which is immediately downstream of a transactivation response (TAR) element and other distal sites on the HIV LTR. Following NELF-E knockdown or tumor necrosis factor alpha (TNF-α) stimulation, promoter-proximal RNAP II levels increase up to 3-fold, and there is a dramatic increase in RNAP II levels within the HIV genome. These data support a kinetic model for proviral transcription based on continuous replacement of paused RNAP II during both latency and productive transcription. In contrast to most cellular genes, HIV is highly activated by the combined effects of NELF-E depletion and activation of initiation by TNF-α, suggesting that opportunities exist to selectively activate latent HIV proviruses.


Association of the DRD2 gene Taq1A polymorphism and smoking behavior: a meta-analysis and new data.
Many studies have investigated the association of the dopamine type-2 receptor (DRD2) Taq1A polymorphism with tobacco use and cigarette smoking behaviors, but findings remain equivocal. There is a biological basis for considering that this association differs by sex, and differences in subpopulations might explain some of the contradictory evidence. Our a priori hypothesis was that the association of the DRD2 Taq1A polymorphism with smoking behavior would be more prominent in females than males. We therefore investigated the strength of evidence for an association between the DRD2 Taq1A polymorphism and smoking behavior in a large sample of females and used meta-analytic techniques to synthesize existing published data and explore the role of sex in explaining any heterogeneity between studies. We did not observe any strong evidence of association between the DRD2 Taq1A polymorphism and smoking behavior, including smoking initiation, smoking persistence, and smoking rate, either in our female sample or in our meta-analysis of 29 studies, comprising 28 published studies and the data from the present study. Metaregression suggested an association between the proportion of male participants in a study and the individual study effect size, indicating a larger effect size with a greater proportion of male participants for smoking initiation and smoking persistence. This effect did not appear to be due to the inclusion of the data from the present study. Available evidence does not support an association between the DRD2 Taq1A polymorphism and smoking behavior. Contrary to our a priori hypothesis, we found evidence of a stronger association in males than in females.


Antimicrobial activity of five essential oils against origin strains of the Enterobacteriaceae family.
An in vitro assay measuring the antimicrobial activity of essential oils of Coridothymus capitatus (Spanish origanum), Satureja montana, Thymus mastichina (Spanish Origanum majorana), Thymus zygis (Spanish variety of Thymus vulgaris) and Origanum vulgare has been carried out against poultry origin strains of Escherichia coli, Salmonella enteritidis and Salmonella essen, and pig origin strains of enterotoxigenic E. coli (ETEC), Salmonella choleraesuis and Salmonella typhimurium. Using the broth microdilution method, all the essential oils showed an MIC > or = 2% (v/v) for the two strains of E. coli. The essential oil that showed the highest antimicrobial activity against the four strains of Salmonella was Origanum vulgare (MIC < or = 1% v/v), followed by Thymus zygis (MIC < or =2% v/v). Thymus mastichina inhibited all the microorganisms at the highest concentration, 4% (v/v), while the rest of the essential oils showed highly variable results. By chemotyping, higher inhibitory capacity was observed in the oils with a higher percentage of phenolic components (carvacrol and thymol) in comparison with oils containing the monoterpenic alcohol linalool. The results of this work confirm the antimicrobial activity of some essential oils, as well as their potential application in the treatment and prevention of poultry and pig diseases caused by salmonella.


The Protocol of Low-level Laser Therapy in Orthodontic Practice: A Scoping Review of Literature.
Low-level laser therapy (LLLT) has been widely investigated as an adjunct technique for orthodontic treatment due to photobiomodulation effect. LLLT appears to be supportive for an orthodontic practice in terms of tooth movement acceleration, pain relief, and root resorption management. The decrease in these adverse effects will enhance the compliance in orthodontic patients, which could positively impact treatment outcomes. However, there seemed to be inconsistency in the impact of LLLT as well as its laser and treatment parameters. This scoping review aimed to evaluate the impact of different irradiation parameters on tooth movement acceleration, pain relief, and root resorption as well as to construct a protocol of LLLT in orthodontic practice. The search was conducted across PubMed, Scopus, Web of Science, Embase, Google Scholar, and the reference lists of identified articles. The last search was conducted on October 10, 2021 to identify experiments in humans regarding the application of LLLT as noninvasive treatment in orthodontic practice published between 2010 and 2021. However, they were excluded if they were not clinical research, if they did not report the source of laser, or if they were not relevant to tooth movement, pain perception, and root resorption, or if they were not available in English or in full-text. Following the systematic search and selection process, 60 articles were included in this review. A majority of included articles were published in the past few years. The findings of this review supported the application of LLLT in orthodontic practice with purposes of tooth movement acceleration and pain reduction. The positive impact of LLLT on root resorption had not been clearly evident yet. As this review demonstrated heterogeneity of both laser and treatment parameters, further research should be required to ensure the effectiveness of its specific parameters in orthodontic practice.


Palliative care research in Africa: consensus building for a prioritized agenda.
Palliative care research in Africa is in its relative infancy, with dedicated financial support extremely limited. Therefore, setting research priorities to optimize use of limited resources is imperative. To develop a prioritized research agenda for palliative care in Africa. We used a two-stage process involving palliative care professionals and researchers: 1) generation of an initial topic list at a consultative workshop of experts and 2) prioritization of that list using a consensus development process, the nominal group technique. Phase 1: 41 topics were generated across five groups, with several topics nominated in more than one group. Phase 2: 16 topics and three broad thematic areas were identified. The two most prioritized topics within each of the three themes were the following: Theme 1: patient, family, and volunteers-1) care outcomes and the impact of palliative care as perceived by patients and caregivers and 2) palliative care needs of children; Theme 2: health providers-1) impact of palliative care training on care and practice and 2) integration of palliative care and antiretroviral therapy services; and Theme 3: health systems-1) palliative care needs assessments at the micro-, meso-, and macro-levels and 2) integration of palliative care into health systems and educational curricula. Consensus-based palliative care topics determined by the study can assist researchers in optimizing limited research capacities by focusing on these prioritized areas. Subsequent to the identification and publication of the research agenda, concrete steps will be undertaken by the African Palliative Care Research Network and other partners to help implement it.


MyD88- and TRIF-independent induction of type I interferon drives naive B cell accumulation but not loss of lymph node architecture in Lyme disease.
Rapidly after infection, live Borrelia burgdorferi, the causative agent of Lyme disease, is found within lymph nodes, causing rapid and strong tissue enlargement, a loss of demarcation between B cell follicles and T cell zones, and an unusually large accumulation of B cells. We sought to explore the mechanisms underlying these changes, as lymph tissue disruption could be detrimental for the development of robust Borrelia-specific immunity. A time course study demonstrated that the loss of the normal lymph node structure was a distinct process that preceded the strong increases in B cells at the site. The selective increases in B cell frequencies were due not to proliferation but rather to cytokine-mediated repositioning of B cells to the lymph nodes, as shown with various gene-targeted and bone marrow irradiation chimeras. These studies demonstrated that B. burgdorferi infection induced type I interferon receptor (IFNR) signaling in lymph nodes in a MyD88- and TRIF-independent manner and that type I IFNR indirect signaling was required for the excessive increases of naive B cells at those sites. It did not, however, drive the observed histopathological changes, which occurred independently also from major shifts in the lymphocyte-homing chemokines, CXCL12, CXCL13, and CCL19/21, as shown by quantitative reverse transcription-PCR (qRT-PCR), flow cytometry, and transwell migration experiments. Thus, B. burgdorferi infection drives the production of type I IFN in lymph nodes and in so doing strongly alters the cellular composition of the lymph nodes, with potential detrimental effects for the development of robust Borrelia-specific immunity.


Needles and Haystacks: Finding Funding for Medical Education Research.
Medical education research suffers from a significant and persistent lack of funding. Although adequate funding has been shown to improve the quality of research, there are a number of factors that continue to limit it. The competitive environment for medical education research funding makes it essential to understand strategies for improving the search for funding sources and the preparation of proposals. This article offers a number of resources, strategies, and suggestions for finding funding. Investigators must be able to frame their research in the context of significant issues and principles in education. They must set their proposed work in the context of prior work and demonstrate its potential for significant new contributions. Because there are few funding sources earmarked for medical education research, researchers much also be creative, flexible, and adaptive as they seek to present their ideas in ways that are appealing and relevant to the goals of funders. Above all, the search for funding requires persistence and perseverance.


Toward Complete Sequence Flexibility of Nucleic Acid Base Analogue FRET.
Förster resonance energy transfer (FRET) using fluorescent base analogues is a powerful means of obtaining high-resolution nucleic acid structure and dynamics information that favorably complements techniques such as NMR and X-ray crystallography. Here, we expand the base-base FRET repertoire with an adenine analogue FRET-pair. Phosphoramidite-protected quadracyclic 2'-deoxyadenosine analogues qAN1 (donor) and qAnitro (acceptor) were synthesized and incorporated into DNA by a generic, reliable, and high-yielding route, and both constitute excellent adenine analogues. The donor, qAN1, has quantum yields reaching 21% and 11% in single- and double-strands, respectively. To the best of our knowledge, this results in the highest average brightness of an adenine analogue inside DNA. Its potent emissive features overlap well with the absorption of qAnitro and thus enable accurate FRET-measurements over more than one turn of B-DNA. As we have shown previously for our cytosine analogue FRET-pair, FRET between qAN1 and qAnitro positioned at different base separations inside DNA results in efficiencies that are highly dependent on both distance and orientation. This facilitates significantly enhanced resolution in FRET structure determinations, demonstrated here in a study of conformational changes of DNA upon binding of the minor groove binder netropsin. Finally, we note that the donor and acceptor of our cytosine FRET-pair, tCO and tCnitro, can be conveniently combined with the acceptor and donor of our current adenine pair, respectively. Consequently, our base analogues can now measure base-base FRET between 3 of the 10 possible base combinations and, through base-complementarity, between all sequence positions in a duplex.


The ran decathlon: multiple roles of Ran.
The Ran GTPase system affects many cellular processes, including the regulation of cell cycle progression, nuclear envelope structure and function, and nucleocytoplasmic transport. The biochemical basis for the involvement of Ran in nuclear import and export has been well documented, but the direct targets of Ran in other cellular processes have not yet been identified. There is, however, mounting evidence that Ran directly affects at least some of these other cellular processes by mechanisms independent of its role in transport. In this Commentary we discuss evidence linking Ran to different aspects of cell function, and how these multiple facets of Ran's activity may relate to each other.


Haploids: Constraints and opportunities in plant breeding.
The discovery of haploids in higher plants led to the use of doubled haploid (DH) technology in plant breeding. This article provides the state of the art on DH technology including the induction and identification of haploids, what factors influence haploid induction, molecular basis of microspore embryogenesis, the genetics underpinnings of haploid induction and its use in plant breeding, particularly to fix traits and unlock genetic variation. Both in vitro and in vivo methods have been used to induce haploids that are thereafter chromosome doubled to produce DH. Various heritable factors contribute to the successful induction of haploids, whose genetics is that of a quantitative trait. Genomic regions associated with in vitro and in vivo DH production were noted in various crops with the aid of DNA markers. It seems that F2 plants are the most suitable for the induction of DH lines than F1 plants. Identifying putative haploids is a key issue in haploid breeding. DH technology in Brassicas and cereals, such as barley, maize, rice, rye and wheat, has been improved and used routinely in cultivar development, while in other food staples such as pulses and root crops the technology has not reached to the stage leading to its application in plant breeding. The centromere-mediated haploid induction system has been used in Arabidopsis, but not yet in crops. Most food staples are derived from genomic resources-rich crops, including those with sequenced reference genomes. The integration of genomic resources with DH technology provides new opportunities for the improving selection methods, maximizing selection gains and accelerate cultivar development. Marker-aided breeding and DH technology have been used to improve host plant resistance in barley, rice, and wheat. Multinational seed companies are using DH technology in large-scale production of inbred lines for further development of hybrid cultivars, particularly in maize. The public sector provides support to national programs or small-medium private seed for the exploitation of DH technology in plant breeding.


Metapopulation dynamics enable persistence of influenza A, including A/H5N1, in poultry.
Highly pathogenic influenza A/H5N1 has persistently but sporadically caused human illness and death since 1997. Yet it is still unclear how this pathogen is able to persist globally. While wild birds seem to be a genetic reservoir for influenza A, they do not seem to be the main source of human illness. Here, we highlight the role that domestic poultry may play in maintaining A/H5N1 globally, using theoretical models of spatial population structure in poultry populations. We find that a metapopulation of moderately sized poultry flocks can sustain the pathogen in a finite poultry population for over two years. Our results suggest that it is possible that moderately intensive backyard farms could sustain the pathogen indefinitely in real systems. This fits a pattern that has been observed from many empirical systems. Rather than just employing standard culling procedures to control the disease, our model suggests ways that poultry production systems may be modified.


Impact of early cART on HIV blood and semen compartments at the time of primary infection.
HIV-infected cells in semen facilitate viral transmission. We studied the establishment of HIV reservoirs in semen and blood during PHI, along with systemic immune activation and the impact of early cART. Patients in the ANRS-147-OPTIPRIM trial received two years of early cART. Nineteen patients of the trial were analyzed, out of which 8 had acute PHI (WB ≤1 Ab). We quantified total cell-associated (ca) HIV-DNA in blood and semen and HIV-RNA in blood and semen plasma samples, collected during PHI and at 24 months of treatment. At enrollment, HIV-RNA load was higher in blood than in semen (median 5.66 vs 4.22 log10 cp/mL, p<0.0001). Semen HIV-RNA load correlated strongly with blood HIV-RNA load (r = 0.81, p = 0.02, the CD4 cell count (r = -0.98, p<0.0001), and the CD4/CD8 ratio (r = -0.85, p<0.01) in acute infection but not in later stages of PHI. Median blood and seminal cellular HIV-DNA levels were 3.59 and 0.31 log10cp/106 cells, respectively. HIV-DNA load peaked in semen later than in blood and then correlated with blood IP10 level (r = 0.62, p = 0.04). HIV-RNA was undetectable in blood and semen after two years of effective cART. Semen HIV-DNA load declined similarly, except in one patient who had persistently high IP-10 and IL-6 levels and used recreational drugs. HIV reservoir cells are found in semen during PHI, with gradual compartmentalization. Its size was linked to the plasma IP-10 level. Early treatment purges both the virus and infected cells, reducing the high risk of transmission during PHI. NCT01033760.


Post-diagnosis weight gain and breast cancer recurrence in women with early stage breast cancer.
To examine whether weight gain after diagnosis of breast cancer affects the risk of breast cancer recurrence. Patients included 3215 women diagnosed with early stage breast cancer (Stage I >1 cm., II, and IIIA) who were enrolled either in an observational cohort of breast cancer survivors or were part of the comparison group of a dietary intervention trial to prevent breast cancer recurrence. We computed weight change from 1 year prior to diagnosis to study enrollment. Delayed entry Cox proportional hazards models were used to evaluate associations of categories of weight change with time to recurrence, controlling for known prognostic factors. Neither moderate (5-10%) nor large (> 10%) weight gain (HR 0.8, 95% CI, 0.6-1.1; HR 0.9, 95% CI, 0.7-1.2, respectively) after breast cancer diagnosis was associated with an increased risk of breast cancer recurrence in the early years post-diagnosis (median time of 73.7 months from diagnosis). Our research provides evidence that weight gain commonly seen in the first several years following a breast cancer diagnosis does not increase a woman's risk for breast cancer recurrence in the first 5-7 years post-diagnosis. However, this research does not address the effects of weight gain on overall survival or on the risk of other new cancers, other prognostic outcomes of concern to the breast cancer survivor.


Effect of psychological intervention on exercise adherence in type 2 diabetic subjects.
Previous research has pointed to the efficacy of physical activity in individuals suffering from type 2 diabetes mellitus (type 2 DM). However, as with other populations, adherence to exercise programs is often problematic. This study assessed the effectiveness of a combination of exercise and psychological interventions in type 2 diabetics in terms of disease management and exercise adherence. Forty newly diagnosed type 2 diabetic subjects (54 +/- 6.5 years) took part in the study. Subjects were allocated to an exercise-only intervention (EO) or a combined exercise and psychological adherence intervention (EP) group. Adherence to the program was also monitored at a 6-month follow-up. The results confirmed a significant improvement in physiological parameters (total mass, fat mass, grip strength, peak flow, flexibility, and VO2 max) after the 12-week program in both groups (P < 0.001). The EP group had significant changes in body fat, grip strength, and peak flow (P < 0.05) in comparison to the EO group. Components of the visual analog mood scale (VAMS) were positively influenced in both groups from the therapy program (P < 0.001). The directed psychological intervention had a significant influence on attendance to the 12-week program (P < 0.001). This also resulted in significantly better adherence 6 months later (P < 0.05). In conclusion, the results have demonstrated that psychological intervention is of paramount importance for ensuring high adherence rates during exercise therapy for type 2 diabetic subjects.


Predictive value of an early amplitude integrated electroencephalogram and neurologic examination.
To examine the predictive validity of the amplitude integrated electroencephalogram (aEEG) and stage of encephalopathy among infants with hypoxic-ischemic encephalopathy (HIE) eligible for therapeutic whole-body hypothermia. Neonates were eligible for this prospective study if moderate or severe HIE occurred at <6 hours and an aEEG was obtained at <9 hours of age. The primary outcome was death or moderate/severe disability at 18 months. There were 108 infants (71 with moderate HIE and 37 with severe HIE) enrolled in the study. aEEG findings were categorized as normal, with continuous normal voltage (n=12) or discontinuous normal voltage (n=12), or abnormal, with burst suppression (n=22), continuous low voltage (n=26), or flat tracing (n=36). At 18 months, 53 infants (49%) experienced death or disability. Severe HIE and an abnormal aEEG were related to the primary outcome with univariate analysis, whereas severe HIE alone was predictive of outcome with multivariate analysis. Addition of aEEG pattern to HIE stage did not add to the predictive value of the model; the area under the curve changed from 0.72 to 0.75 (P=.19). The aEEG background pattern did not significantly enhance the value of the stage of encephalopathy at study entry in predicting death and disability among infants with HIE.


Usability and Feasibility of an Innovative mLearning Approach for Nurses Providing Option B+ Services in Manica and Sofala Provinces, Mozambique.
The scaling of Option B+ services, whereby all pregnant women who test HIV positive are started on lifelong antiretroviral therapy upon diagnosis regardless of CD4 T-cell count, is ongoing in many high HIV burden, low-resource countries. We developed and evaluated a tablet-based mobile learning (mLearning) training approach to build Option B+ competencies in frontline nurses in central Mozambique. Its acceptability and impact on clinical skills were assessed in maternal child health nurses and managers at 20 intervention and 10 control clinics. Results show that skill and knowledge of nurses at intervention clinics improved threefold compared with control clinics (p = .04), nurse managers at intervention clinics demonstrated a 9- to 10-fold improvement, and nurses reported strong acceptance of this approach. "mLearning" is one viable modality to enhance nurses' clinical competencies in areas with limited health workforce and training budgets. This study's findings may guide future scaling and investments in commercially viable mLearning solutions.


Maximizing the Therapeutic Potential of HSP90 Inhibitors.
HSP90 is required for maintaining the stability and activity of a diverse group of client proteins, including protein kinases, transcription factors, and steroid hormone receptors involved in cell signaling, proliferation, survival, oncogenesis, and cancer progression. Inhibition of HSP90 alters the HSP90-client protein complex, leading to reduced activity, misfolding, ubiquitination, and, ultimately, proteasomal degradation of client proteins. HSP90 inhibitors have demonstrated significant antitumor activity in a wide variety of preclinical models, with evidence of selectivity for cancer versus normal cells. In the clinic, however, the efficacy of this class of therapeutic agents has been relatively limited to date, with promising responses mainly observed in breast and lung cancer, but no major activity seen in other tumor types. In addition, adverse events and some significant toxicities have been documented. Key to improving these clinical outcomes is a better understanding of the cellular consequences of inhibiting HSP90 that may underlie treatment response or resistance. This review considers the recent progress that has been made in the study of HSP90 and its inhibitors and highlights new opportunities to maximize their therapeutic potential.


Impact of a dengue outbreak experience in the preventive perceptions of the community from a temperate region: Madeira Island, Portugal.
The ability to effectively modify behaviours is increasingly relevant to attain and maintain a good health status. Current behaviour-change models and theories present two main approaches for (healthier) decision-making: one analytical/logical, and one experiential/emotional/intuitive. Therefore, to achieve an integral and dynamic understanding of the public perceptions both approaches should be considered: community surveys should measure cognitive understanding of health-risk contexts, and also explore how past experiences affect this understanding. In 2011, community perceptions regarding domestic source reduction were assessed in Madeira Island͘. After Madeira's first dengue outbreak (2012) a unique opportunity to compare perceptions before and after the outbreak-experience occurred. This was the aim of this study, which constituted the first report on the effect of an outbreak experience on community perceptions regarding a specific vector-borne disease. A cross-sectional survey was performed within female residents at the most aegypti-infested areas. Perceptions regarding domestic source reduction were assessed according to the Essential Perception (EP)-analysis tool. A matching process paired individuals from studies performed before and after the outbreak, ensuring homogeneity in six determinant variables. After the outbreak, there were more female residents who assimilated the concepts considered to be essential to understand the proposed behaviour. Nevertheless, no significant difference was observed in the number of female residents who achieved the defined 'minimal understanding''. Moreover, most of the population (95.5%) still believed at least in one of the identified myths. After the outbreak some myths disappeared and others appeared. The present study quantified and explored how the experience of an outbreak influenced the perception regarding a dengue-preventive behaviour. The outbreak experience surprisingly led to the appearance of new myths within the population, apart from the expected increase of relevant concepts' assimilation. Monitoring public perceptions is therefore crucial to make preventing dengue campaigns updated and worthy.


Dinitrogen functionalization with bis(cyclopentadienyl) complexes of zirconium and hafnium.
The rich chemistry of substituted bis(cyclopentadienyl)zirconium and hafnium complexes bearing side-on coordinated dinitrogen ligands is highlighted in this Perspective. Our studies in this area were initially motivated by the desire to understand side-on vs. end-on dinitrogen coordination in bimetallic zirconocene and hafnocene N2 compounds. In the cases where eta2,eta2-dinitrogen compounds were isolated, both structural and computational data have established significant imido character in the metal-nitrogen bonds. This additional bonding interaction, which is diminished in end-on complexes bearing both terminal and bridging N2 ligands, facilitates dinitrogen functionalization by non-polar reagents including dihydrogen, carbon-hydrogen bonds and weak Brønsted acids such as water and ethanol. In hafnocene chemistry, where unwanted side-on, end-on isomerization is suppressed, cycloaddition of phenylisocyanate to coordinated N2 has also been accomplished. For N-H bond forming reactions involving H2, kinetic measurements, in addition to isotopic labelling and computational studies, are consistent with dinitrogen functionalization by 1,2-addition involving a highly ordered, four-centred transition structure.


Optimal MEMS device for mobility and zeta potential measurements using DC electrophoresis.
We have developed a novel microchannel geometry that allows us to perform simple DC electrophoresis to measure the electrophoretic mobility and zeta potential of analytes and particles. In standard capillary geometries, mobility measurements using DC fields are difficult to perform. Specifically, measurements in open capillaries require knowledge of the hard to measure and often dynamic wall surface potential. Although measurements in closed capillaries eliminate this requirement, the measurements must be performed at infinitesimally small regions of zero flow where the pressure driven-flow completely cancels the electroosmotic flow (Komagata Planes). Furthermore, applied DC fields lead to electrode polarization, further questioning the reliability and accuracy of the measurement. In contrast, our geometry expands and moves the Komagata planes to where velocity gradients are at a minimum, and thus knowledge of the precise location of a Komagata plane is not necessary. Additionally, our microfluidic device prevents electrode polarization because of fluid recirculation around the electrodes. We fabricated our device using standard MEMS fabrication techniques and performed electrophoretic mobility measurements on 500 nm fluorescently tagged polystyrene particles at various buffer concentrations. Results are comparable to two different commercial dynamic light scattering based particle sizing instruments. We conclude with guidelines to further develop this robust electrophoretic tool that allows for facile and efficient particle characterization.


Preventing caries in young children of immigrant Bangladeshi families in New York: perspectives of mothers and paediatricians.
Childhood caries is common in South Asian immigrant families. Few children visit a dentist by 12 months, as recommended by current guidelines. The paediatric visit has important potential for linking children to preventive care. The aim of this study was to understand the barriers and facilitators to caries prevention for young children of immigrant Bangladeshi families in New York. Qualitative data were collected as a preliminary step in the development of an oral health counselling intervention for South Asian children. Qualitative interviews on child feeding and oral health prevention were conducted with Bangladeshi mothers. Qualitative interviews were conducted with paediatricians regarding their experiences with providing care. The data were analysed using standard qualitative approaches. Paediatric practices serving low income Bangladeshi immigrants in New York City. 26 mothers of children aged 6-24 months receiving services in five paediatric settings and 15 paediatricians providing care in these settings. Both mothers and their paediatricians described risky feeding practices, communication problems and a lack of compliance. Oral health for young children was a low priority for some mothers. Most, however, were concerned about childhood caries but lacked skills or resources to decrease caries risk. Results support our plan to develop an empowerment-based counselling intervention to address caries risk in children. Paediatric dentists should be aware of the barriers to caries prevention in this group.


Ionic Driven Embedment of Hyaluronic Acid Coated Liposomes in Polyelectrolyte Multilayer Films for Local Therapeutic Delivery.
The ability to control the spatial distribution and temporal release of a therapeutic remains a central challenge for biomedical research. Here, we report the development and optimization of a novel substrate mediated therapeutic delivery system comprising of hyaluronic acid covalently functionalized liposomes (HALNPs) embedded into polyelectrolyte multilayer (PEM) platform via ionic stabilization. The PEM platform was constructed from sequential deposition of Poly-L-Lysine (PLL) and Poly(Sodium styrene sulfonate) (SPS) "(PLL/SPS)4.5" followed by adsorption of anionic HALNPs. An adsorption affinity assay and saturation curve illustrated the preferential HALNP deposition density for precise therapeutic loading. (PLL/SPS)2.5 capping layer on top of the deposited HALNP monolayer further facilitated complete nanoparticle immobilization, cell adhesion, and provided nanoparticle confinement for controlled linear release profiles of the nanocarrier and encapsulated cargo. To our knowledge, this is the first study to demonstrate the successful embedment of a translatable lipid based nanocarrier into a substrate that allows for temporal and spatial release of both hydrophobic and hydrophilic drugs. Specifically, we have utilized our platform to deliver chemotherapeutic drug Doxorubicin from PEM confined HALNPs. Overall, we believe the development of our HALNP embedded PEM system is significant and will catalyze the usage of substrate mediated delivery platforms in biomedical applications.


Gradients of structure-function tethering across neocortex.
The white matter architecture of the brain imparts a distinct signature on neuronal coactivation patterns. Interregional projections promote synchrony among distant neuronal populations, giving rise to richly patterned functional networks. A variety of statistical, communication, and biophysical models have been proposed to study the relationship between brain structure and function, but the link is not yet known. In the present report we seek to relate the structural and functional connection profiles of individual brain areas. We apply a simple multilinear model that incorporates information about spatial proximity, routing, and diffusion between brain regions to predict their functional connectivity. We find that structure-function relationships vary markedly across the neocortex. Structure and function correspond closely in unimodal, primary sensory, and motor regions, but diverge in transmodal cortex, particularly the default mode and salience networks. The divergence between structure and function systematically follows functional and cytoarchitectonic hierarchies. Altogether, the present results demonstrate that structural and functional networks do not align uniformly across the brain, but gradually uncouple in higher-order polysensory areas.


Thermospermine enhances translation of SAC51 and SACL1 in Arabidopsis.
The excessive xylem phenotype of acaulis5 (acl5), an Arabidopsis mutant defective in the synthesis of thermospermine, indicates that thermospermine is required for negative regulation of xylem differentiation. SAC51 was identified from a dominant suppressor of acl5, sac51-d, and encodes a basic helix-loop-helix (bHLH) protein. sac51-d has a premature termination codon in one of upstream open-reading frames (uORFs) of the SAC51 mRNA that is conserved among the SAC51 family members. Thermospermine may act to bypass the inhibitory effect of the uORF on main ORF translation. Another suppressor, sac57-d, also has a mutation in the conserved uORF of SACL3, a member of the SAC51 family. On the other hand, the double knockout of SAC51 and SACL3 is insensitive to thermospermine, suggesting their key role in the response to thermospermine. However, we found that thermospermine enhances mRNA translation of SAC51 and SACL1 but not of SACL2 and SACL3. Taken together with recent findings from other groups, we propose a mechanism by which thermospermine diffused from xylem precursor cells acts non-cell-autonomously to restrict their proliferation.


Incidence of Presumed Silicone Oil Droplets in the Vitreous Cavity After Intravitreal Bevacizumab Injection With Insulin Syringes.
Intravitreal bevacizumab is a frequently used antivascular endothelial growth factor medication in the United States, but its off-label use is associated with risks associated with the compounding preparation. To determine the incidence of presumed silicone oil droplets after intravitreal bevacizumab was prepared in insulin syringes by a compounding pharmacy. A retrospective review was conducted of 60 patients who experienced intravitreal silicone oil droplets in the eye after intravitreal bevacizumab injections from a single specialist practice from October 1, 2015, to November 30, 2016. Bevacizumab, 1.25 mg/0.05 mL, was delivered in insulin syringes with a 31-gauge needle. Small, round clear spheres in vitreous on dilated biomicroscopic retinal examination. Over a 14-month period involving 6632 intravitreal bevacizumab injections, 60 cases (35 [58%] women) of intravitreal silicone droplets were identified. Mean [SD] age of the patients was 80 [12] years; the population comprised 48 white, 9 Asian, and 3 Hispanic patients. The incidence of silicone oil droplet injections was 0.03% (1 of 3230) from October 2015 to April 2016 and 1.7% (59 of 3402) from May to November 2016 (Fisher exact test, P < .001; odds ratio [OR], 57; 95% CI, 9.8-2260). From May to November 2016, nonpriming the syringe before the intravitreal injection had a higher risk of intravitreal silicone oil droplets compared with priming the syringe (6.4% [47 of 739] vs 0.5% [12 of 2627]; Fisher exact test, P < .001; OR, 15.1; 95% CI, 7.9-33.4). Among the 60 cases, 41 patients (68%) were symptomatic, and the main symptom was floaters with spots of light. Among the patients with floaters, 36 (88%) improved over time (range, 2-8 months) despite the silicone droplets still being present on ophthalmoscopic examination. An increase in intravitreal silicone oil associated with bevacizumab prepared with insulin syringes was documented. Priming the syringe before injection was associated with a lower frequency of this complication. These findings suggest that physicians should counsel their patients on the risk of floaters with intravitreal bevacizumab preloaded in insulin syringes.


Endometrial adenocarcinoma with trophoblastic differentiation.
To report a case of stage IIIc poorly differentiated endometrial adenocarcinoma with trophoblastic differentiation and to review previously reported cases. The clinical course and histopathology of the case were reviewed, and a literature search for other reported cases was performed. The tumor contained syncytiotrophoblast-like giant cells that stained positively for the beta subunit of human chorionic gonadotropin (beta-hCG), and the patient's serum beta-hCG level was elevated (95 mIU/ml), but became undetectable after treatment. Beta-hCG was used as a tumor marker during further therapy. At 16 months' survival, she remains without evidence of disease and with a beta-hCG (level < 5 mIU/ml). Nine other cases of trophoblastic differentiation in gynecologic nontrophoblastic tumors have been reported, five in endometrial carcinomas which we review. Trophoblastic differentiation in gynecologic nontrophoblastic tumors is rare. Beta-hCG may be useful as a tumor marker in these cases. The clinical behavior of these tumors has been aggressive, with advanced stages at diagnosis, early widespread metastases or recurrences and poor patient outcomes. The patient presented in this report, however, remains without evidence of disease 16 months following diagnosis and may be the longest survivor with this tumor reported to date.


Identifying Outcomes that Are Important to Living Kidney Donors: A Nominal Group Technique Study.
Living kidney donor candidates accept a range of risks and benefits when they decide to proceed with nephrectomy. Informed consent around this decision assumes they receive reliable data about outcomes they regard as critical to their decision making. We identified the outcomes most important to living kidney donors and described the reasons for their choices. Previous donors were purposively sampled from three transplant units in Australia (Sydney and Melbourne) and Canada (Vancouver). In focus groups using the nominal group technique, participants identified outcomes of donation, ranked them in order of importance, and discussed the reasons for their preferences. An importance score was calculated for each outcome. Qualitative data were analyzed thematically. Across 14 groups, 123 donors aged 27-78 years identified 35 outcomes. Across all participants, the ten highest ranked outcomes were kidney function (importance=0.40, scale 0-1), time to recovery (0.27), surgical complications (0.24), effect on family (0.22), donor-recipient relationship (0.21), life satisfaction (0.18), lifestyle restrictions (0.18), kidney failure (0.14), mortality (0.13), and acute pain/discomfort (0.12). Kidney function and kidney failure were more important to Canadian participants, compared with Australian donors. The themes identified included worthwhile sacrifice, insignificance of risks and harms, confidence and empowerment, unfulfilled expectations, and heightened susceptibility. Living kidney donors prioritized a range of outcomes, with the most important being kidney health and the surgical, lifestyle, functional, and psychosocial effects of donation. Donors also valued improvements to their family life and donor-recipient relationship. There were clear regional differences in the rankings.


Myocarditis in enteric fever.
1. Myocarditis in the course of enteric fever is a common occurrence. In a series of 100 bacteriologically or serologically proved enteric fever, we found 7 cases with clinical evidence of myocarditis and 46 cases with ECG evidence of myocarditis. 2. Commonest ECG abnormality was Q-Tc prolongation (29%) followed by ST-T changes (20%) bundle branch block (7%) first degree A-V Block (%) and arrhythmia (2%). 3. All the ECG changes were transient except bundle branch block which persisted in 3 cases. 4. Those with other systemic complications had a higher chance of having myocarditis (P < 0.01). 5. Autopsy evidence of myocarditis was found in 2 cases. With our results, it is obvious that ECT must be recorded in all cases of enteric fever. Those with ECG changes must be observed carefully for clinical evidence of myocarditis. All these patients must have absolute bed rest. Judicious use of corticosteroids is indicated in selected cases of selected cases of severe myocarditis. Diuretics are indicated in cases with evidence of congestive cardiac failure.


Nanomechanical properties of α-synuclein amyloid fibrils: a comparative study by nanoindentation, harmonic force microscopy, and Peakforce QNM.
We report on the use of three different atomic force spectroscopy modalities to determine the nanomechanical properties of amyloid fibrils of the human α-synuclein protein. α-Synuclein forms fibrillar nanostructures of approximately 10 nm diameter and lengths ranging from 100 nm to several microns, which have been associated with Parkinson's disease. Atomic force microscopy (AFM) has been used to image the morphology of these protein fibrils deposited on a flat surface. For nanomechanical measurements, we used single-point nanoindentation, in which the AFM tip as the indenter is moved vertically to the fibril surface and back while the force is being recorded. We also used two recently developed AFM surface property mapping techniques: Harmonic force microscopy (HarmoniX) and Peakforce QNM. These modalities allow extraction of mechanical parameters of the surface with a lateral resolution and speed comparable to tapping-mode AFM imaging. Based on this phenomenological study, the elastic moduli of the α-synuclein fibrils determined using these three different modalities are within the range 1.3-2.1 GPa. We discuss the relative merits of these three methods for the determination of the elastic properties of protein fibrils, particularly considering the differences and difficulties of each method.


The RCI revisited after 15 years: used, reinvented, modified, debated, and natural logged.
The purpose of this article is to review the status of the Root Caries Index (RCI) 15 years after it was first introduced in the dental literature as a method for the reporting of supragingival root lesions. This review focuses on the extent to which the RCI has been used by epidemiologic researchers, as well as on the issues concerning the RCI as a useful index that have been raised and debated in the literature by those epidemiologic researchers. The debated points are categorized into six issues, including whether: (1) the RCI underestimates the prevalence of root caries by omitting subgingival root caries lesions; (2) the RCI overestimates the prevalence of root caries by using too rigid a definition of when recession can be visualized; (3) the RCI makes the assumption that there is a linear relationship between root caries lesions and the occurrence of at-risk surfaces, i.e., surfaces with recession; (4) the RCI, by ignoring missing teeth, distorts the descriptive epidemiologic picture of root caries; (5) recession is a predictor of root caries versus merely being an antecedent state; and (6) the imprecision of diagnosing gingival recession renders the RCI useless. Given both the evidence from recent studies and the professional interest in subgingival root caries, as addressed in the first debated point, it seems reasonable to modify the RCI to include a separate reporting of subgingival root caries. Of the remaining debated points over the past 15 years, three of these (points #2, #4, and #5 above) seemingly serve to clarify specific aspects of the RCI that were intended as inherent elements of the RCI as originally presented. The question as to whether there is an assumption of a linear relationship between root caries lesions and the occurrence of at-risk surfaces (point #3) is answered in the negative. The final debated point (#6), while addressing a fundamental periodontal tissue measurement issue--namely the reliability of identifying gingival recession--and while theoretically interesting, should not undermine the current use, or utility, of the RCI, but rather suggests the need for improved periodontal diagnostic techniques for the condition of recession. After 15 years, the RCI appears to be one of the two most common methods of reporting root caries in the epidemiologic literature (along with DFS counts). In fact, the best overall descriptive picture of root caries is achieved when those two reporting methods are presented in the same study accompanied by descriptive presentations of missing teeth and at-risk surfaces. Of all the debated points in the literature, the suggested modification of including subgingival lesions in the RCI leads now to the recommendation to collect subgingival data, but to do so in a manner that allows for separate presentation of supra- and subgingival root caries findings.


Future response of global coastal wetlands to sea-level rise.
The response of coastal wetlands to sea-level rise during the twenty-first century remains uncertain. Global-scale projections suggest that between 20 and 90 per cent (for low and high sea-level rise scenarios, respectively) of the present-day coastal wetland area will be lost, which will in turn result in the loss of biodiversity and highly valued ecosystem services1-3. These projections do not necessarily take into account all essential geomorphological4-7 and socio-economic system feedbacks8. Here we present an integrated global modelling approach that considers both the ability of coastal wetlands to build up vertically by sediment accretion, and the accommodation space, namely, the vertical and lateral space available for fine sediments to accumulate and be colonized by wetland vegetation. We use this approach to assess global-scale changes in coastal wetland area in response to global sea-level rise and anthropogenic coastal occupation during the twenty-first century. On the basis of our simulations, we find that, globally, rather than losses, wetland gains of up to 60 per cent of the current area are possible, if more than 37 per cent (our upper estimate for current accommodation space) of coastal wetlands have sufficient accommodation space, and sediment supply remains at present levels. In contrast to previous studies1-3, we project that until 2100, the loss of global coastal wetland area will range between 0 and 30 per cent, assuming no further accommodation space in addition to current levels. Our simulations suggest that the resilience of global wetlands is primarily driven by the availability of accommodation space, which is strongly influenced by the building of anthropogenic infrastructure in the coastal zone and such infrastructure is expected to change over the twenty-first century. Rather than being an inevitable consequence of global sea-level rise, our findings indicate that large-scale loss of coastal wetlands might be avoidable, if sufficient additional accommodation space can be created through careful nature-based adaptation solutions to coastal management.


Heat flow and hydrothermal circulation in the cascade range, north-central Oregon.
In north-central Oregon a large area of near-zero near-surface conductive heat flow occurs in young volcanic rocks of the Cascade Range. Recent advective heat flux measurements and a heat-budget analysis suggest that ground-water circulation sweeps sufficient heat out of areas where rocks younger than 6 Ma (million years ago) are exposed to account for the anomalously high advective and conductive heat discharge measured in older rocks at lower elevations. Earlier workers have proposed that an extensive midcrustal magmatic heat source is responsible for this anomalously high heat flow. Instead, high heat flow in the older rocks may be a relatively shallow phenomenon caused by regional ground-water flow. Any deeper anomaly may be relatively narrow, spatially variable, and essentially confined to the Quaternary (less than 2 Ma) arc. Magmatic intrusion at a rate of 9 to 33 cubic kilometers per kilometer of arc length per million years can account for the total heat flow anomaly. Deep drilling in the areas of high heat flow in the older rocks could indicate which model is more appropriate for the near-surface heat flow data.


Simulation-based objective assessment discerns clinical proficiency in central line placement: a construct validation.
Central venous catheterization (CVC) is associated with patient risks known to be inversely related to clinician experience. We developed and evaluated a performance assessment tool for use in a simulation-based central line workshop. We hypothesized that instrument scores would discriminate between less experienced and more experienced clinicians. Participants included trainees enrolled in an institutionally mandated CVC workshop and a convenience sample of faculty attending physicians. The workshop integrated several experiential learning techniques, including practice on cadavers and part-task trainers. A group of clinical and education experts developed a 15-point CVC Proficiency Scale using national and institutional guidelines. After the workshop, participants completed a certification exercise in which they independently performed a CVC in a part-task trainer. Two authors reviewed videotapes of the certification exercise to rate performance using the CVC Proficiency Scale. Participants were grouped by self-reported CVC experience. One hundred and five participants (92 trainees and 13 attending physicians) participated. Interrater reliability on a subset of 40 videos was 0.71, and Cronbach a was 0.81. The CVC Proficiency Scale Composite score varied significantly by experience: mean of 85%, median of 87% (range 47%-100%) for low experience (0-1 CVCs in the last 2 years, n = 27); mean of 88%, median of 87% (range 60%-100%) for moderate experience (2-49 CVCs, n = 62); and mean of 94%, median of 93% (range 73%-100%) for high experience (> 49 CVCs, n = 16) (P = .02, comparing low and high experience). Evidence from multiple sources, including appropriate content, high interrater and internal consistency reliability, and confirmation of hypothesized relations to other variables, supports the validity of using scores from this 15-item scale for assessing trainee proficiency following a central line workshop.


Insulin-like growth factor-binding protein-1: serum levels, promoter polymorphism, and associations with components of the metabolic syndrome in short subjects born small for gestational age.
IGF binding protein (IGFBP)-1 is the only acute regulator of IGF-I bioavailability. Its production is suppressed by insulin, and low levels are associated with hyperinsulinemia and cardiovascular disease risk in adults. Data on IGFBP-1 levels in short, small for gestational age (SGA) subjects are scarce, and associations with IGFBP1 promoter single nucleotide polymorphisms have not been established. The aim of the study was to determine IGFBP-1 levels in short SGA subjects compared with those in controls, to assess genotype frequency of the -575 G/A single nucleotide polymorphism, and to determine its impact on IGFBP-1 levels. A total of 272 short subjects born SGA and 330 subjects with normal stature (245 children, 85 young adults) participated in the study. We measured fasting levels of IGFBP-1, IGF-I, insulin and lipid parameters, and body composition. IGFBP-1 sd score (SDS) was comparable to controls in lean, short, SGA children but significantly lower in short SGA adults with normal fat mass (P < 0.001). IGFBP-1 SDS correlated significantly with insulin levels, systolic blood pressure SDS, and various lipid parameters. Baseline IGFBP-1 SDS was lowest in SGA children with -575 GG genotype and significantly higher in SGA children with one or two copies of the A allele. In response to a given insulin level, children with the AA genotype had a significantly higher IGFBP-1 SDS compared to children with the GG genotype. Normal IGFBP-1 levels in lean, short, SGA children may reflect a normal metabolic state, despite reported hyperinsulinemia. IGFBP-1 is modulated by polymorphic variability and seems to be an additional player in the complex interaction between the IGF-IGFBP axis, glucose homeostasis, and lipid metabolism.


An age-old paradigm challenged: old baboons generate vigorous humoral immune responses to LcrV, a plague antigen.
Immune senescence in the elderly results in decreased immunity with a concomitant increase in susceptibility to infection and diminished efficacy of vaccination. Nonhuman primate models have proven critical for testing of vaccines and therapeutics in the general population, but a model using old animals has not been established. Toward that end, immunity to LcrV, a protective Ag from Yersinia pestis, was tested in young and old baboons. Surprisingly, there was no age-associated loss in immune competence; LcrV elicited high-titer, protective Ab responses in the older individuals. The primary responses in the younger baboons were lower, but they did show boosting upon secondary immunization to the levels achieved in the old animals. The LcrV Ag was also tested in mice and, as expected, age-associated loss of immunity was seen; older animals responded with lower-titer Abs and, as a result, were more susceptible to Yersinia challenge. Thus, although age-related loss in immune function has been observed in humans, rodents, and some nonhuman primates, baboons appear to be unusual; they age without losing immune competence.


The shared genetic architecture of modifiable risk for Alzheimer's disease: a genomic structural equation modelling study.
Targeting modifiable risk factors may help to prevent Alzheimer's disease (AD), but the pathways by which these risk factors influence AD risk remain incompletely understood. We identified genome-wide association studies for AD and its major modifiable risk factors. We calculated the genetic correlation among these traits and modelled this using genomic structural equation modelling. We identified complex networks of genetic overlap among AD risk factors, but AD itself was largely genetically distinct. The data were best explained by a bi-factor model, incorporating a Common Factor for AD risk, and 3 orthogonal sub-clusters of risk factors. Taken together, our findings suggest that there is extensive shared genetic architecture between AD modifiable risk factors, but this is largely independent of AD genetic pathways. Extensive genetic pleiotropy between risk factors may influence AD indirectly by decreasing cognitive reserve or increasing risk of multimorbidity, leading to poorer brain health. Further work to understand the biology reflected by this communality may provide novel mechanistic insights that could help to prioritise targets for dementia prevention.


Chemopreventive effect of kava on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone plus benzo[a]pyrene-induced lung tumorigenesis in A/J mice.
Lung cancer is the leading cause of cancer death, and chemoprevention is a potential strategy to help control this disease. Epidemiologic survey indicates that kava may be chemopreventive for lung cancer, but there is a concern about its potential hepatotoxicity. In this study, we evaluated whether oral kava could prevent 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) plus benzo[a]pyrene (B[a]P)-induced lung tumorigenesis in A/J mice. We also studied the effect of kava to liver. At a dose of 10 mg/g diet, 30-week kava treatment (8 weeks concurrent with NNK and B[a]P treatment followed by 22 weeks post-carcinogen treatment) effectively reduced lung tumor multiplicity by 56%. Kava also reduced lung tumor multiplicity by 47% when administered concurrently with NNK and B[a]P for 8 weeks. Perhaps most importantly, kava reduced lung tumor multiplicity by 49% when administered after the final NNK and B[a]P treatment. These results show for the first time the chemopreventive potential of kava against lung tumorigenesis. Mechanistically, kava inhibited proliferation and enhanced apoptosis in lung tumors, as shown by a reduction in proliferating cell nuclear antigen (PCNA), an increase in caspase-3, and cleavage of poly(ADP-ribose) polymerase (PARP). Kava treatment also inhibited the activation of nuclear factor kappaBNF-kappaB, a potential upstream mechanism of kava chemoprevention. Although not rigorously evaluated in this study, our preliminary data were not suggestive of hepatotoxicity. Based on these results, further studies are warranted to explore the chemopreventive potential and safety of kava.


Molecular mechanisms disrupting porin expression in ertapenem-resistant Klebsiella and Enterobacter spp. clinical isolates from the UK.
The aim of this study was to investigate relatedness and molecular mechanism(s) of ertapenem resistance in clinical isolates of Klebsiella spp. (n = 28) and Enterobacter spp. (n = 27) referred from multiple hospitals to the UK national reference laboratory. Investigations included genotyping by PFGE, resistance gene analysis by PCR and antimicrobial susceptibility testing with and without inhibitors of efflux and beta-lactamase activity. Outer membrane proteins (OMPs) were profiled by SDS-PAGE; porin genes were sequenced and their expression was examined by RT-PCR. The contribution of porin deficiency to resistance was investigated by restoring functional porin genes on plasmids. PFGE showed significant clonal diversity among ertapenem-resistant isolates, with only small clusters identified. SHV- and CTX-M-type extended-spectrum beta-lactamases were identified in the Klebsiella spp. isolates, whereas AmpC overexpression or KPC carbapenemase was detected in the Enterobacter cloacae isolates. SDS-PAGE showed that Klebsiella pneumoniae and Enterobacter aerogenes with high-level ertapenem resistance (MICs > or = 16 mg/L) consistently lacked both of the two major non-specific porins, whereas variable patterns of OmpC and OmpF were seen in E. cloacae with lower-level ertapenem resistance. Various point mutations or insertion sequences were identified as disrupting the porin-coding sequences, as well as mutations in the promoter region. Functional restoration of OmpK35 or OmpK36 in Klebsiella and OmpC or OmpF in Enterobacter spp. isolates significantly decreased the MICs of all carbapenems, but particularly of ertapenem. We found no evidence of efflux contributing to resistance. Ertapenem resistance was exclusively due to combinations of beta-lactamases with impermeability caused by loss of OMPs. Efflux was not implicated and there was no national spread of resistant clones.


Reduced CYP2D6 function is associated with gefitinib-induced rash in patients with non-small cell lung cancer.
Rash, liver dysfunction, and diarrhea are known major adverse events associated with erlotinib and gefitinib. However, clinical trials with gefitinib have reported different proportions of adverse events compared to trials with erlotinib. In an in vitro study, cytochrome P450 (CYP) 2D6 was shown to be involved in the metabolism of gefitinib but not erlotinib. It has been hypothesized that CYP2D6 phenotypes may be implicated in different adverse events associated with gefitinib and erlotinib therapies. The frequency of each adverse event was evaluated during the period in which the patients received gefitinib or erlotinib therapy. CYP2D6 phenotypes were determined by analysis of CYP2D6 genotypes using real-time polymerase chain reaction techniques, which can detect single-nucleotide polymorphisms. The CYP2D6 phenotypes were categorized into 2 groups according to functional or reduced metabolic levels. In addition, we evaluated the odds ratio (OR) of the adverse events associated with each factor, including CYP2D6 activities and treatment types. A total of 232 patients received gefitinib therapy, and 86 received erlotinib therapy. Reduced function of CYP2D6 was associated with an increased risk of rash of grade 2 or more (OR, 0.44; 95% confidence interval [CI], 0.21-0.94; *p = 0.03), but not diarrhea ≥ grade 2 (OR, 0.49; 95% CI, 0.17-1.51; *p = 0.20) or liver dysfunction ≥ grade 2 (OR, 1.08; 95% CI, 0.52-2.34; *p = 0.84) in the gefitinib cohort. No associations were observed between any adverse events in the erlotinib cohort and CYP2D6 phenotypes (rash: OR, 1.77; 95% CI, 0.54-6.41; *p = 0.35/diarrhea: OR, 1.08; 95% CI, 0.21-7.43; *p = 0.93/liver dysfunction: OR, 0.93; 95% CI, 0.20-5.07; *p = 0.93). The frequency of rash was significantly higher in patients with reduced CYP2D6 activity who treated with gefitinib compared to patients with functional CYP2D6. CYP2D6 phenotypes are a risk factor for the development of rash in response to gefitinib therapy.


The temporal structure of the inner retina at a single glance.
The retina decomposes visual stimuli into parallel channels that encode different features of the visual environment. Central to this computation is the synaptic processing in a dense layer of neuropil, the so-called inner plexiform layer (IPL). Here, different types of bipolar cells stratifying at distinct depths relay the excitatory feedforward drive from photoreceptors to amacrine and ganglion cells. Current experimental techniques for studying processing in the IPL do not allow imaging the entire IPL simultaneously in the intact tissue. Here, we extend a two-photon microscope with an electrically tunable lens allowing us to obtain optical vertical slices of the IPL, which provide a complete picture of the response diversity of bipolar cells at a "single glance". The nature of these axial recordings additionally allowed us to isolate and investigate batch effects, i.e. inter-experimental variations resulting in systematic differences in response speed. As a proof of principle, we developed a simple model that disentangles biological from experimental causes of variability and allowed us to recover the characteristic gradient of response speeds across the IPL with higher precision than before. Our new framework will make it possible to study the computations performed in the central synaptic layer of the retina more efficiently.


Abortion: time to clarify Australia's confusing laws.
Australian criminal law is a matter for states and territories. In relation to abortion, many laws are unclear and outdated, and are inconsistent between states and territories. Doctors practise under time constraints and on a case-by-case basis. Most current laws have grey areas that leave doctors vulnerable to accusations, negative publicity and career damage, especially in the case of late abortions. All jurisdictions should follow the Australian Capital Territory's lead in allowing women to access abortion without fear of criminal prosecution. Federal, state and territory governments should introduce a single clear national law on abortion, both in early and late pregnancy.


RP1 is required for the correct stacking of outer segment discs.
Mutations in RP1 are a common cause of dominant retinitis pigmentosa (RP), but the mechanism by which the identified mutations lead to photoreceptor cell death and blindness has not been determined. To investigate the function of the RP1 protein in photoreceptors and gain insight into the mechanism of disease, gene-targeting techniques were used to produce mice with a mutant Rp1 allele that mimics the truncation alleles found to cause disease. RT-PCR was used to amplify illegitimate RP1 transcripts from lymphoblasts. Gene targeting was used to create mice with a mutant Rp1-myc allele. Confocal immunofluorescence microscopy was used to identify the location of the mutant Rp1-myc protein in photoreceptors. The structure of the photoreceptors in the resultant Rp1-myc mice was studied by light and electron microscopy. The retinal function of the mutant mice was investigated using analysis of full-field ERGs. Wild-type and mutant RP1 mRNA were both detected in lymphoblasts from patients with RP1 disease. Rp1-myc mice produced a truncated version of the Rp1 protein, containing the N-terminal 662 amino acids, which localized correctly to the axoneme of the photoreceptor outer segments. Mice homozygous for the mutant Rp1-myc allele underwent a rapid-onset retinal degeneration characterized by incorrectly oriented outer segment discs that failed to stack properly into outer segments. In contrast, the photoreceptors of heterozygous mice remained relatively healthy. The presence of mutant RP1 mRNA in lymphoblasts from patients with RP1 disease implies that the mutant message can escape nonsense-mediated mRNA decay and that a truncated RP1 protein may be produced in the retina. The truncated Rp1-myc protein appears to be nonfunctional, and not to exert a dominant negative effect in the photoreceptors of heterozygous mice. Results from homozygous Rp1-myc mice indicate that RP1 is required for the correct orientation and higher order stacking of outer segment discs.


Misclassification of survey responses and black-white disparity in mammography use, Behavioral Risk Factor Surveillance System, 1995-2006.
The validity of self-reported data for mammography differ by race. We assessed the effect of racial differences in the validity of age-adjusted, self-reported mammography use estimates from the Behavioral Risk Factor Surveillance System (BRFSS) from 1995 through 2006 to determine whether misclassification (inaccurate survey question response) may have obscured actual racial disparities. We adjusted BRFSS mammography use data for age by using 2000 census estimates and for misclassification by using the following formula: (estimated prevalence - 1 + specificity) / (sensitivity + specificity - 1). We used values reported in the literature for the formula (sensitivity = 0.97 for both black and white women, specificity = 0.49 and 0.62, respectively, for black and white women). After adjustment for misclassification, the percentage of women aged 40 years or older in 1995 who reported receiving a mammogram during the previous 2 years was 54% among white women and 41% among black women, compared with 70% among both white and black women after adjustment for age only. In 2006, the percentage after adjustment for misclassification was 65% among white women and 59% among black women compared with 77% among white women and 78% among black women after adjustment for age only. Self-reported data overestimate mammography use - more so for black women than for white women. After adjustment for respondent misclassification, neither white women nor black women had attained the Healthy People 2010 objective (≥ 70%) by 2006, and a disparity between white and black women emerged.


Adverse drug reaction profile of oseltamivir in Indian population: A prospective observational study.
To analyze the pattern of adverse drug reactions (ADRs) of oseltamivir and its comparison with available data. Suspected or confirmed cases of H1N1 influenza A on therapeutic regimen and close contacts of cases H1N1 influenza A on prophylactic regimen of oseltamivir were included. Data were collected by personal interview after obtaining written informed consent. Causality, severity, and preventability assessments were done by using Naranjo's scale, modified Hartwig and Siegel's scale, and modified Schumock and Thornton Scale, respectively. Data were expressed in proportions. Frequency of ADRs in therapeutic and prophylactic groups were compared with phase III trial of oseltamivir by using Chi-square test. Total 294 patients were interviewed. In prophylactic group, 107 of 257 (41.63%) and in therapeutic, group 23 of 37 (62.16%) developed ADRs. ADRs reported in therapeutic group was significantly (P = 0.029) higher as compared with prophylactic group. Frequently observed ADRs in both the groups were gastritis, nausea, vomiting, diarrhea weakness, sedation, loneliness, sadness, headache, and abdominal pain. Naranjo's algorithm showed all ADRs in probable category in prophylactic group, 27.78% probable and 72.22% possible reactions in therapeutic group. Severity assessment showed 76% mild and 24% moderate reactions in therapeutic group, 89% mild and 11% moderate reactions in prophylactic group. Severity of ADRs was significantly higher in therapeutic group. Most of ADRs were in nonpreventable category, except gastritis, nausea and vomiting were in definitely preventable category. Oseltamivir is well tolerated in Indian population. Gastrointestinal side effects are most common and preventable.


Priority setting: what constitutes success? A conceptual framework for successful priority setting.
The sustainability of healthcare systems worldwide is threatened by a growing demand for services and expensive innovative technologies. Decision makers struggle in this environment to set priorities appropriately, particularly because they lack consensus about which values should guide their decisions. One way to approach this problem is to determine what all relevant stakeholders understand successful priority setting to mean. The goal of this research was to develop a conceptual framework for successful priority setting. Three separate empirical studies were completed using qualitative data collection methods (one-on-one interviews with healthcare decision makers from across Canada; focus groups with representation of patients, caregivers and policy makers; and Delphi study including scholars and decision makers from five countries). This paper synthesizes the findings from three studies into a framework of ten separate but interconnected elements germane to successful priority setting: stakeholder understanding, shifted priorities/reallocation of resources, decision making quality, stakeholder acceptance and satisfaction, positive externalities, stakeholder engagement, use of explicit process, information management, consideration of values and context, and revision or appeals mechanism. The ten elements specify both quantitative and qualitative dimensions of priority setting and relate to both process and outcome components. To our knowledge, this is the first framework that describes successful priority setting. The ten elements identified in this research provide guidance for decision makers and a common language to discuss priority setting success and work toward improving priority setting efforts.


Successful Imatinib Treatment of an Abdominal Compartment Syndrome due to Huge Gastrointestinal Stromal Tumour.
Gastrointestinal stromal tumours (GISTs) are the most common digestive mesenchymal tumours, whose prognosis has been revolutionised by targeted therapies such as oral imatinib. Abdomen compartment syndrome (ACS) is associated with mortality superior to 50% in adults. ACS has never been reported to date in patients with GIST. Specific anticancer treatment in critically ill patients in intensive care unit (ICU) remains a matter of debate given the high mortality rate. Here, we report the case of a 58-year-old woman with ACS related to a 40-cm huge GIST and multi-organ failure requiring mechanical ventilation, vasopressive support and haemodialysis. She was treated in emergency with imatinib via the naso-gastric tube (day 1), then at day 3 by decompressive laparotomy and "open abdomen" without any tumour removal. Imaging after 11 days imatinib showed objective tumour response. Because of improvement of multi-organ dysfunctions, the laparotomy was closed at day 14, and the resuscitation procedures were progressively stopped. After discharge from hospital, she survived nearly two years. This is the first case of successful treatment of cancer-associated ACS by targeted therapy and decompressive laparotomy. Imatinib in critically ill patients with GIST may be successful even in presence of multi-organ failure.


Hospitalisations with Hidradenitis Suppurativa: An Increasing Problem That Deserves Closer Attention.
Hidradenitis suppurativa (HS), a chronic inflammatory skin disease of the hair follicle, can lead to scarring and disability. With an estimated European prevalence of 1%, few epidemiological studies of HS have been performed, and none focused on hospitalisations. We aimed to study the time trends of HS hospitalisations and to evaluate the demographic characteristics, hospital incidence rate, readmissions, length of stay, comorbidities and risk factors of hospitalised HS patients. We performed a retrospective observational study using a national administrative database in Portugal, with discharges between 2000 and 2014. All the inpatients aged 5 years or more with a diagnosis of HS were included. Variables analysed were age, sex, admission and discharge date, discharge outcome and diagnoses. A total of 1,177 patients were hospitalised in this time period (48 were aged 18 years or younger) with a male-to-female ratio of 1:1.17. There was a hospital incidence rate of 0.83 patients with HS per 100,000 person-years (95% CI = 0.78-0.88). The age group with the highest incidence rate was 20-29 years among women and 40-49 years among men. We recorded an increasing trend in the number of new hospitalised patients and in the hospital incidence rate of HS. Tobacco was the most common comorbidity/risk factor. Eighty-three percent of our population underwent HS surgery. This hospital-based incidence study showed that admission for HS is increasing and that the majority of the HS inpatients were surgical cases. In the future, prospective studies will be important to assess risk factors for hospitalisations and complications.


Oncologists' Perceptions of Recurrent Ovarian Cancer Patients' Preference for Participation in Treatment Decision Making and Strategies for When and How to Involve Patients in This Process.
The treatment decision-making (TDM) process in the medical encounter in ovarian cancer (OC) is directed by oncologists. There is little information on oncologists' perceptions of this process. Our objectives were to explore oncologists' perceptions concerning (1) patients' preference for involvement in TDM, (2) factors that affect when to introduce this discussion, and (3) strategies used for engaging women in TDM. We adopted a qualitative descriptive approach. Individual in-person interviews were used to collect data; themes were identified. Fifteen gynecologic and 5 medical oncologists from Ontario, Canada, participated. We found that oncologists made the assumption that women with recurrent OC were interested in being involved in TDM but rarely reported attempting to validate this assumption. The oncologists timed the initiation of the TDM discussion based on their degree of certainty of recurrent OC and their perception of the patient's readiness to be involved in TDM. Oncologists reported using strategies to engage women such as getting the women to take ownership of the decision, verbalize their priorities, lead the discussions, and giving the opportunity to gather information. Oncologists need to listen to each patient rather than make assumptions about the person based on her disease.


Cerebrospinal Fluid Biomarkers in Relation to MRZ Reaction Status in Primary Progressive Multiple Sclerosis.
The MRZ reaction (MRZR) comprises the three antibody indices (AIs) against measles, rubella, and varicella zoster virus, reflecting an intrathecal polyspecific B cell response highly specific for multiple sclerosis (MS). Thus, MRZR can be used to confirm a diagnosis of primary progressive MS (PPMS) but its pathophysiological and wider clinical relevance is unclear. This study aimed to investigate whether PPMS patients with a positive MRZR (MRZR+) differ from those with a negative MRZR (MRZR-) according to cerebrospinal fluid (CSF) biomarkers of B cell activity, neuroaxonal damage or glial activity, and clinical features. (1) Methods: In a multicenter PPMS cohort (n = 81) with known MRZR status, we measured B cell-activating factor (BAFF), chemokine CXC ligand 13 (CXCL-13), soluble B cell maturation antigen (sBCMA), soluble transmembrane activator and CAML interactor (sTACI), and chitinase-3-like protein 1 (CHI3L1) in the CSF with enzyme-linked immunosorbent assays (ELISAs). Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were detected in serum and CSF using single molecule array (SIMOA) technology. (2) Results: MRZR+ patients (45.7% of all PPMS patients) revealed higher levels of NfL in CSF compared to MRZR- patients (54.3%). There were positive correlations between each of sBCMA, sTACI, and intrathecal immunoglobin G (IgG) synthesis. Additionally, NfL concentrations in serum positively correlated with those in CSF and those of GFAP in serum. However, MRZR+ and MRZR- patients did not differ concerning clinical features (e.g., age, disease duration, Expanded Disability Status Scale (EDSS) at diagnosis and follow-up); CSF routine parameters; CSF concentrations of BAFF, CXCL-13, sBCMA, sTACI, CHI3L1, and GFAP; or serum concentrations of GFAP and NfL. (3) Conclusions: In PPMS patients, MRZR positivity might indicate a more pronounced axonal damage. Higher levels of the soluble B cell receptors BCMA and transmembrane activator and CAML interactor (TACI) in CSF are associated with a stronger intrathecal IgG synthesis in PPMS.


Hyponatremia in cirrhosis: pathogenesis, clinical significance, and management.
Hyponatremia is a frequent complication of advanced cirrhosis related to an impairment in the renal capacity to eliminate solute-free water that causes a retention of water that is disproportionate to the retention of sodium, thus causing a reduction in serum sodium concentration and hypo-osmolality. The main pathogenic factor responsible for hyponatremia is a nonosmotic hypersecretion of arginine vasopressin (or antidiuretic hormone) from the neurohypophysis related to circulatory dysfunction. Hyponatremia in cirrhosis is associated with increased morbidity and mortality. There is evidence suggesting that hyponatremia may affect brain function and predispose to hepatic encephalopathy. Hyponatremia also represents a risk factor for liver transplantation as it is associated with increased frequency of complications and impaired short-term survival after transplantation. The current standard of care based on fluid restriction is unsatisfactory. Currently, a new family of drugs, known as vaptans, which act by antagonizing specifically the effects of arginine vasopressin on the V2 receptors located in the kidney tubules, is being evaluated for their role in the management of hyponatremia. The short-term treatment with vaptans is associated with a marked increase in renal solute-free water excretion and improvement of hyponatremia. Long-term administration of vaptans seems to be effective in maintaining the improvement of serum sodium concentration, but the available information is still limited. Treatment with vaptans represents a novel approach to improving serum sodium concentration in cirrhosis.


Perceived threat predictor of calcium-rich foods in the women of premenopausal age Isfahan - Iran in 2013-2014.
During women lives, frequently face the challenge of calcium reduction and absorption. Decreased calcium absorption followed by a decrease in estrogen at perimenopausal ages, low average per capita calcium intake among women, wrong nutritional behavior, household income reductions and make them more susceptible to osteoporosis and related complications. The aim of this study was to evaluate the relationship between the health belief model constructs and consuming calcium-rich foods in menopausal age women. This study was descriptive-correlation study. The questionnaires were completed by 210 menopausal women who had referred to health centers. The research data were analyzed using: Frequency distribution, mean score, Pearson correlation coefficients and multivariate regression. Significant level of P < 0/05 were considered. The mean and standard deviation of the scores for perceived susceptibility and severity of the threats of consumption and complications of inadequate intake were respectively: (62.1 and 38.9, and 60.2 and 39.9) and (59.6 and 37.9 and 56.3 and 36.5). The relationship between the number of units of calcium intake with perceived susceptibility and severity calcium intake and complications caused by the inadequate intake of calcium were (P < 0.001, r = 0.581, r = 0.651) and (P < 0.001, r = 0.634, r = 0.567). The obtained results indicate that perceived threat is the prognostic factor for the intake of calcium-rich foods and the increase of perceived threat in the health promotion programs may be associated with the increase in the consumption of calcium-rich foods in the women of premenopausal age.


Heritable susceptibility for colitis in mice induced by IL-10 deficiency.
Severity of inflammatory bowel disease in IL-10 gene-targeted mice is in part determined by genetic background. In the current study, a targeted IL-10 gene was transferred into the C3H/HeJBir substrain, known to exhibit high T-cell and B-cell responses to enteric flora, and to be highly sensitive to colitigenic stress. IL-10-deficient C3H/HeJBir mice developed early onset colitis in contrast to IL-10-deficient C57BL/6J congenic mice. Histopathologic analysis of disease in C3H/HeJBir.Il10-/- and C57BL/6J.Il10-/- mice showed significant differences at all ages studied. Hybrids of these congenic strains (F1.Il10-/-) were produced to study the mode of inheritance as well as subphenotypes that correlated with histopathology. Lesions in F1 mice were intermediate between parental strains. C3H-contributed subphenotypes that correlated best with histopathology were peripheral blood granulocyte percentage, serum amyloid A concentration, spleen weight/body weight ratio, and mesenteric lymph node weight/ body weight ratio. Neither enhanced humoral immunity (secretory IgA, anti-Escherichia coli cellular membrane Ig) characteristic of C3H/HeJBir, nor T-cell percentages in peripheral blood correlated as well. This study represents a necessary step in elucidating murine genetic modifiers controlling colitis sensitivity.