Reproductive intentions and outcomes among women on antiretroviral therapy in rural Uganda: a prospective cohort study.
Antiretroviral therapy (ART) may influence the biological, social and behavioral determinants of pregnancy in HIV-infected women. However, there are limited longitudinal data on the reproductive intentions and outcomes among women on ART in Africa. METHODOLOGY /PRINCIPAL FINDINGS: Using a prospective cohort design, we analyzed trends in desire for children and predictors of pregnancy among a cohort of 733 HIV-infected women in rural Uganda who initiated ART between May 2003 and May 2004 and were followed up in their homes until June 2006. Women answered in-depth social and behavioral questionnaires administered every quarter in year 1 after initiating ART, and every 6 to 12 months thereafter. Use of family planning methods was assessed at 18 and 24 months after starting ART. We tested for non-constant pregnancy incidence by using a shape parameter test from the Weibull distribution. We modeled repeated measurements of all variables related to the women's desire for children over time using a generalized estimating equation (GEE) extension to the logistic regression model. Risk factors for pregnancy were examined using Cox proportional hazards model. 711 women eligible for the study were followed-up for a median time of 2.4 years after starting ART. During this time, less than 7% of women reported wanting more children at any time point yet 120 (16.9%) women experienced 140 pregnancies and pregnancy incidence increased from 3.46 per 100 women-years (WY) in the first quarter to 9.5 per 100 WY at 24 months (p<0.0001). This was paralleled by an increase in the proportion of women reporting sexual activity in the past 3 months, from 24.4% at baseline to 32.5% over 24 months of follow-up (p = 0.001). Only 14% of women used permanent or semi-permanent family planning methods by their second year on ART. In the multivariate model, younger age (HR = 2.71 per 10-year decrease, 95% CI: 2.95-3.78), having a BMI>18.5 (HR = 1.09, CI: 1.01-1.18) and not having used condoms consistently in the last 3 months (HR = 1.79, CI: 1.02-3.13) were independently associated with pregnancy. Women on ART and their partners should be consistently counseled on the effects of ART in restoring fertility, and offered regularly free and comprehensive family planning services as part of their standard package of care.


LRRK1-phosphorylated CLIP-170 regulates EGFR trafficking by recruiting p150Glued to microtubule plus ends.
The binding of ligand to epidermal growth factor receptor (EGFR) causes the receptor to become activated and stimulates the endocytosis of EGFR. Early endosomes containing activated EGFR migrate along microtubules as they mature into late endosomes. We have recently shown that LRRK1, which is related to the familial Parkinsonism gene product Park8 (also known as LRRK2), regulates this EGFR transport in a manner dependent on LRRK1 kinase activity. However, the downstream targets of LRRK1 that might modulate this transport function have not been identified. Here, we identify CLIP-170 (also known as CLIP1), a microtubule plus-end protein, as a substrate of LRRK1. LRRK1 phosphorylates CLIP-170 at Thr1384, located in its C-terminal zinc knuckle motif, and this promotes the association of CLIP-170 with dynein-dynactin complexes. We find that LRRK1-mediated phosphorylation of CLIP-170 causes the accumulation of p150(Glued) (also known as DCTN1) a subunit of dynactin, at microtubule plus ends, thereby facilitating the migration of EGFR-containing endosomes. Thus, our findings provide new mechanistic insights into the dynein-driven transport of EGFR.


National prevalence of methicillin-resistant Staphylococcus aureus in inpatients at United States health care facilities, 2010.
Methicillin-resistant Staphylococcus aureus (MRSA) remains one of the most prevalent multidrug-resistant organisms causing health care-associated infections. Limited data are available about how the prevalence of MRSA has changed over the past several years and what MRSA prevention practices have been implemented since the 2006 Association for Professionals in Infection Control and Epidemiology, Inc, MRSA survey. We conducted a national prevalence survey of MRSA colonization or infection in inpatients at US health care facilities. The survey was developed, received institutional review board approval, and then was distributed to all US Association for Professionals in Infection Control and Epidemiology, Inc, members. Members were asked to complete the survey on 1 day during the period August 1 to December 30, 2010, reporting the number of inpatients with MRSA infection or colonization and facility- and patient-specific information. Personnel at 590 facilities indicated a state and responded to the survey. All states were represented, except for Alaska and Washington, DC (mean, 12 facilities per state; range, 1-38). Respondents reported 4,476 MRSA-colonized/infected patients in 67,412 inpatients; the overall MRSA prevalence rate was 66.4 per 1,000 inpatients (25.3 infections and 41.1 colonizations per 1,000 inpatients). Active surveillance testing was conducted by 75.7% of the respondents; 39.6% used nonselective media, 37.2% used selective media, and 23.3% used polymerase chain reaction. Detailed data were provided on 3,176 MRSA-colonized/infected patients. Of those in whom colonization/infection status was reported (1,908/3,086 [61.8%] were MRSA colonized and 1,778/3,086 [38.2%] were MRSA infected), most MRSA-colonized or infected patients (78.3%) were detected within 48 hours of admission; the most common site of infection was skin and soft tissue (42.9%); and, using the Centers for Disease Control and Prevention's definitions, approximately 50% would be classified as health care-associated infections. Our survey documents that the MRSA prevalence in 2010 is higher than that reported in our 2006 survey. However, the majority of facilities currently are performing active surveillance testing, and, compared with 2006, the rate of MRSA infection has decreased while the rate of MRSA colonization has increased. In addition, compared with 2006, the proportion of MRSA strains recovered from MRSA-colonized/infected patients that are health care-associated strains has deceased, and community-associated strains have increased.


Making medical care and research rational and affordable.
Expenditure on insurance, consultations, the multitude of tests ordered by the doctor, and very expensive drugs make the treatment of illness a great burden. Should the patient need admission to a hospital and, worse, an intensive care unit, the load becomes almost unbearable. Medical research has moved from the domain of the single keen observer to that of highly qualified experts working in laboratories containing costly equipment. The budget for these projects now runs into lakhs or crores of rupees.


Disruptions of neurological services, its causes and mitigation strategies during COVID-19: a global review.
The COVID-19 pandemic leads to disruptions of health services worldwide. To evaluate the particular impact on neurological services a rapid review was conducted. Studies reporting the provision of neurological services during the pandemic and/or adopted mitigation strategies were included in this review. PubMed and World Health Organization's (WHO) COVID-19 database were searched. Data extraction followed categories used by WHO COVID-19 pulse surveys and operational guidelines on maintaining essential health services during COVID-19. The search yielded 1101 articles, of which 369 fulfilled eligibility criteria, describing data from 210,419 participants, being adults (81%), children (11.4%) or both (7.3%). Included articles reported data from 105 countries and territories covering all WHO regions and World Bank income levels (low income: 1.9%, lower middle: 24.7%, upper middle: 29.5% and high income; 44.8%). Cross-sectoral services for neurological disorders were most frequently disrupted (62.9%), followed by emergency/acute care (47.1%). The degree of disruption was at least moderate for 75% of studies. Travel restrictions due to lockdowns (81.7%) and regulatory closure of services (65.4%) were the most commonly reported causes of disruption. Authors most frequently described telemedicine (82.1%) and novel dispensing approaches for medicines (51.8%) as mitigation strategies. Evidence for the effectiveness of these measures is largely missing. The COVID-19 pandemic affects all aspects of neurological care. Given the worldwide prevalence of neurological disorders and the potential long-term neurological consequences of COVID-19, service disruptions are devastating. Different strategies such as telemedicine might mitigate the negative effects of the pandemic, but their efficacy and acceptability remain to be seen.


Evolution of mosquito preference for humans linked to an odorant receptor.
Female mosquitoes are major vectors of human disease and the most dangerous are those that preferentially bite humans. A 'domestic' form of the mosquito Aedes aegypti has evolved to specialize in biting humans and is the main worldwide vector of dengue, yellow fever, and chikungunya viruses. The domestic form coexists with an ancestral, 'forest' form that prefers to bite non-human animals and is found along the coast of Kenya. We collected the two forms, established laboratory colonies, and document striking divergence in preference for human versus non-human animal odour. We further show that the evolution of preference for human odour in domestic mosquitoes is tightly linked to increases in the expression and ligand-sensitivity of the odorant receptor AaegOr4, which we found recognizes a compound present at high levels in human odour. Our results provide a rare example of a gene contributing to behavioural evolution and provide insight into how disease-vectoring mosquitoes came to specialize on humans.


Characterization of an ovarian cancer activating factor in ascites from ovarian cancer patients.
Ascites from ovarian cancer patients contain potent growth-promoting activity toward human ovarian cancer cells both in vitro and in vivo. This activity is associated with rapid increases in cytosolic free calcium ([Ca2+]i) as a consequence of phosphoinositide hydrolysis. In this study, we describe the purification, characterization, and identification of an ovarian cancer activating factor (OCAF) from ascites of ovarian cancer patients. We have isolated OCAF by a combination of solvent extraction, silica gel chromatography, and TLC. Mass spectral analysis, phospholipase sensitivity, and gas chromatographic behavior of purified OCAF indicate that OCAF is composed of various species of lysophosphatidic acid (LPA), including LPAs with polyunsaturated fatty acyl chains (linoleic, arachidonic, and docosahexaenoic acids). However, OCAF is more potent than sn-1 palmitoyl, oleoyl, or stearoyl LPA in increasing [Ca2+]i in ovarian cancer cells. The ability of OCAF to alter [Ca2+]i is sensitive to the effects of lipoxidase, whereas the activity of sn-1 oleoyl, stearoyl, or palmitoyl LPA is not, suggesting that polyunsaturated bonds in the fatty acyl chain of OCAF may account for its increased ability to activate ovarian cancer cells. Furthermore, a sn-2 linoleoyl LPA generated by phospholipase A1 treatment of synthetic phosphatidic acid is much more active than are sn-1 palmitoyl, stearoyl, or oleoyl LPA in increasing [Ca2+]i in ovarian cancer cells. Taken together, these data suggest that the ability of OCAF to increase cellular calcium may reside in the structure and/or location of the fatty acyl chain of LPA. Purified OCAF, at concentrations similar to those present in ascites from ovarian cancer patients, was sufficient to induce proliferation of ovarian cancer cells, as indicated by thymidine incorporation, reduction of 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide, or colony formation. However, even at optimal concentrations of OCAF, proliferation was lower than that induced by FCS or ascites from ovarian cancer patients, indicating that, although OCAF may be a major regulator of ovarian cancer cells in vivo, it is not the sole mediator present in ascites, and it likely functions in concert with other growth factor activities.


Traffic-related air pollution and spectacles use in schoolchildren.
To investigate the association between exposure to traffic-related air pollution and use of spectacles (as a surrogate measure for myopia) in schoolchildren. We analyzed the impact of exposure to NO2 and PM2.5 light absorbance at home (predicted by land-use regression models) and exposure to NO2 and black carbon (BC) at school (measured by monitoring campaigns) on the use of spectacles in a cohort of 2727 schoolchildren (7-10 years old) in Barcelona (2012-2015). We conducted cross-sectional analyses based on lifelong exposure to air pollution and prevalent cases of spectacles at baseline data collection campaign as well as longitudinal analyses based on incident cases of spectacles use and exposure to air pollution during the three-year period between the baseline and last data collection campaigns. Logistic regression models were developed to quantify the association between spectacles use and each of air pollutants adjusted for relevant covariates. An interquartile range increase in exposure to NO2 and PM2.5 absorbance at home was respectively associated with odds ratios (95% confidence intervals (CIs)) for spectacles use of 1.16 (1.03, 1.29) and 1.13 (0.99, 1.28) in cross-sectional analyses and 1.15 (1.00, 1.33) and 1.23 (1.03, 1.46) in longitudinal analyses. Similarly, odds ratio (95% CIs) of spectacles use associated with an interquartile range increase in exposures to NO2 and black carbon at school was respectively 1.32 (1.09, 1.59) and 1.13 (0.97, 1.32) in cross-sectional analyses and 1.12 (0.84, 1.50) and 1.27 (1.03, 1.56) in longitudinal analyses. These findings were robust to a range of sensitivity analyses that we conducted. We observed increased risk of spectacles use associated with exposure to traffic-related air pollution. These findings require further confirmation by future studies applying more refined outcome measures such as quantified visual acuity and separating different types of refractive errors.


Flexible and printable dielectric polymer composite with tunable permittivity and thermal stability.
Lightweight and printable polymer dielectrics are ubiquitous in flexible hybrid electronics, exhibiting high breakdown strength and mechanical reliability. However, their advanced electronic applications are limited due to their relatively low permittivity, compared to their ceramic counterparts. Here, we report flexible all organic percolative nanocomposites that contain in situ grown conductive polymer networks and dielectric polymer matrix, in which their dielectric properties can be designed and guided from the percolation theory. High dielectric constant of all organic percolative nanocomposites is shown over a broad frequency range under intensive bending cycles, while their thermal stability is attributed to thermally conductive 2D montmorillonite nanosheets. The printable polymer composites with high dielectric performance and thermal stability will find broader interest in flexible hybrid electronics and radio frequency devices.


Concerted O atom-proton transfer in the O-O bond forming step in water oxidation.
As the terminal step in photosystem II, and a potential half-reaction for artificial photosynthesis, water oxidation (2H(2)O --> O(2) + 4e(-) + 4H(+)) is key, but it imposes a significant mechanistic challenge with requirements for both 4e(-)/4H(+) loss and O-O bond formation. Significant progress in water oxidation catalysis has been achieved recently by use of single-site Ru metal complex catalysts such as [Ru(Mebimpy)(bpy)(OH(2))](2+) [Mebimpy = 2,6-bis(1-methylbenzimidazol-2-yl)pyridine; bpy = 2,2'-bipyridine]. When oxidized from to Ru(V) = O(3+), these complexes undergo O-O bond formation by O-atom attack on a H(2)O molecule, which is often the rate-limiting step. Microscopic details of O-O bond formation have been explored by quantum mechanical/molecular mechanical (QM/MM) simulations the results of which provide detailed insight into mechanism and a strategy for enhancing catalytic rates. It utilizes added bases as proton acceptors and concerted atom-proton transfer (APT) with O-atom transfer to the O atom of a water molecule in concert with proton transfer to the base (B). Base catalyzed APT reactivity in water oxidation is observed both in solution and on the surfaces of oxide electrodes derivatized by attached phosphonated metal complex catalysts. These results have important implications for catalytic, electrocatalytic, and photoelectrocatalytic water oxidation.


The role of echocardiography in transcatheter aortic valve implantation.
Transcatheter aortic valve implantation (TAVI) is an effective and less invasive treatment for the increasing population of individuals with severe aortic stenosis (AS). Echocardiography is crucial in the assessment of AS patients from pre- to post-procedure. Transthoracic echocardiography (TTE) may be used to assess patient suitability for TAVI, as well as evaluate the severity of AS, the aortic valve complex, aortic valve morphology, mitral regurgitation (MR), and left ventricular function. Transesophageal echocardiography (TEE) is usually used as an intra-procedural monitoring tool to provide feedback during the procedure, to assess prosthetic valve function, and to detect complications rapidly before and after balloon aortic valvuloplasty (BAV) or transcatheter heart valve (THV) deployment. In this review, the role of echocardiography in the pre-, intra-, and post-TAVI procedure periods is described in detail.


Efficient Estimation of the Cox Model With Auxiliary Subgroup Survival Information.
With the rapidly increasing availability of data in the public domain, combining information from different sources to infer about associations or differences of interest has become an emerging challenge to researchers. This paper presents a novel approach to improve efficiency in estimating the survival time distribution by synthesizing information from the individual-level data with t-year survival probabilities from external sources such as disease registries. While disease registries provide accurate and reliable overall survival statistics for the disease population, critical pieces of information that influence both choice of treatment and clinical outcomes usually are not available in the registry database. To combine with the published information, we propose to summarize the external survival information via a system of nonlinear population moments and estimate the survival time model using empirical likelihood methods. The proposed approach is more flexible than the conventional meta-analysis in the sense that it can automatically combine survival information for different subgroups and the information may be derived from different studies. Moreover, an extended estimator that allows for a different baseline risk in the aggregate data is also studied. Empirical likelihood ratio tests are proposed to examine whether the auxiliary survival information is consistent with the individual-level data. Simulation studies show that the proposed estimators yield a substantial gain in efficiency over the conventional partial likelihood approach. Two sets of data analysis are conducted to illustrate the methods and theory.


Sponges as sentinels: Metal accumulation using transplanted sponges across a metal gradient.
To be effective sentinels, organisms must be able to be readily translocated to contamination hotspots. The authors sought to assess metal accumulation in genetically identical explants of a relatively common estuarine sponge, Suberites cf. diversicolor. Explants were transplanted to 7 locations across a metal contamination gradient in a large coastal estuary in southeastern Australia to establish, first, that explants of this species could be successfully translocated; second, that explants accumulated metals (cadmium, copper, lead, selenium, and zinc) sufficiently rapidly to be effective sentinels; third, that rates of metal accumulation in explants were in agreement with metal concentrations within sediments (<63-µm fraction) at each of the transplant locations; and finally, that changes in explant biomass correlated with overall metal load. Suberites were readily transplanted, with no mortality observed for the 2 mo of transplantation. Metal accumulation for lead, cadmium, and zinc was in close agreement with sediment metal concentrations, and explants showed dramatic increases in these metals in the heavily contaminated northern sections of the estuarine lake. No striking patterns were apparent for copper and selenium. Finally, growth was negatively correlated with total metal load and standardized total metal load in our explants. Taken together, these outcomes confirm that explants of this sponge are amenable to translocation and show considerable promise as biomonitors.


Clinical end points for drug treatment trials in BCR-ABL1-negative classic myeloproliferative neoplasms: consensus statements from European LeukemiaNET (ELN) and Internation Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT).
The discovery of somatic mutations, primarily JAK2V617F and CALR, in classic BCR-ABL1-negative myeloproliferative neoplasms (MPNs) has generated interest in the development of molecularly targeted therapies, whose accurate assessment requires a standardized framework. A working group, comprised of members from European LeukemiaNet (ELN) and International Working Group for MPN Research and Treatment (IWG-MRT), prepared consensus-based recommendations regarding trial design, patient selection and definition of relevant end points. Accordingly, a response able to capture the long-term effect of the drug should be selected as the end point of phase II trials aimed at developing new drugs for MPNs. A time-to-event, such as overall survival, or progression-free survival or both, as co-primary end points, should measure efficacy in phase III studies. New drugs should be tested for preventing disease progression in myelofibrosis patients with early disease in randomized studies, and a time to event, such as progression-free or event-free survival should be the primary end point. Phase III trials aimed at preventing vascular events in polycythemia vera and essential thrombocythemia should be based on a selection of the target population based on new prognostic factors, including JAK2 mutation. In conclusion, we recommended a format for clinical trials in MPNs that facilitates communication between academic investigators, regulatory agencies and drug companies.


Collagenase clostridium histolyticum for Dupuytren's contracture.
Dupuytren's disease is a non-malignant, progressive disorder of the hands that can severely limit hand function and diminish overall quality of life. With global life expectancy increasing, the prevalence of this disease appears to be increasing amongst all ethnic groups. Treatment has traditionally remained surgical with few effective, nonsurgical options. However, with the introduction of collagenase clostridium histolyticum to treat Dupuytren's contractures, physicians and surgeons may be provided with a new, office-based, non-surgical option to treat this disease. The literature behind the use of collagenase to treat Dupuytren's disease; including its mechanism of action, safety, efficacy and clinical evidence behind its recent FDA approval. The latest information available on collagenase through a comprehensive review of PubMed and the websites of licensing organizations for medicinal products. Phase III, clinical trials on collagenase for treatment of Dupuytren's contractures have recently been completed. Meeting primary and secondary objectives, collagenase has obtained FDA approval for clinical use. Collagenase now provides a non-operative option for Dupuytren's disease. Although short-term results show that collagenase is safe and efficacious, long-term effects of repeat injections and contracture recurrence rates have yet to be examined.


Antibody targeting of cell-bound MUC1 SEA domain kills tumor cells.
The cell-surface glycoprotein MUC1 is a particularly appealing target for antibody targeting, being selectively overexpressed in many types of cancers and a high proportion of cancer stem-like cells. However the occurrence of MUC1 cleavage, which leads to the release of the extracellular α subunit into the circulation where it can sequester many anti-MUC1 antibodies, renders the target problematic to some degree. To address this issue, we generated a set of unique MUC1 monoclonal antibodies that target a region termed the SEA domain that remains tethered to the cell surface after MUC1 cleavage. In breast cancer cell populations, these antibodies bound the cancer cells with high picomolar affinity. Starting with a partially humanized antibody, DMB5F3, we created a recombinant chimeric antibody that bound a panel of MUC1+ cancer cells with higher affinities relative to cetuximab (anti-EGFR1) or tratuzumab (anti-erbB2) control antibodies. DMB5F3 internalization from the cell surface occurred in an efficient temperature-dependent manner. Linkage to toxin rendered these DMB5F3 antibodies to be cytotoxic against MUC1+ cancer cells at low picomolar concentrations. Our findings show that high-affinity antibodies to cell-bound MUC1 SEA domain exert specific cytotoxicity against cancer cells, and they point to the SEA domain as a potential immunogen to generate MUC1 vaccines.


Irritable bowel syndrome and diet: where are we in 2018?
The aim is to review the most recent advances in the evidence supporting the use of various dietary interventions for the management of irritable bowel syndrome (IBS). There is insufficient evidence of the effect of fibres other than psyllium in IBS, whereas the recent studies on prebiotics suggest a limited effect in IBS. Recent probiotic trials continue to provide varying results, with some probiotic strains exhibiting beneficial effects, whereas others show no effect. Recent trials have also confirmed the clinical effectiveness of a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols (i.e. low FODMAP diet) in IBS. Although gluten sensitivity has also been recently investigated, its presence cannot be confirmed yet because of the presence of other potential contributing compounds in wheat. Studies also suggest a potential beneficial effect of peppermint oil, which warrants further research. It is clear that a low FODMAP diet has a beneficial effect in a majority of patients with IBS. Probiotics also have great potential in the management of IBS; however, it is still unclear which strains and doses are the most beneficial. Further research is needed on the effect of different fibres, or combinations of fibres, in IBS.


Honokiol as a specific collagen receptor glycoprotein VI antagonist on human platelets: Functional ex vivo and in vivo studies.
Honokiol, derived from Magnolia officinalis, has various pharmacological properties. Platelet activation plays a critical role in cardiovascular diseases. Honokiol has been reported to inhibit collagen-stimulated rabbit platelet aggregation. However, detailed further studies on the characteristics and functional activity of honokiol in platelet activation are relatively lacking. In the present study, honokiol specifically inhibited platelet aggregation and Ca+2 ion mobilization stimulated with collagen or convulxin, an agonist of glycoprotein (GP) VI, but not with aggretin, an agonist of integrin α2β1. Honokiol also attenuated the phosphorylation of Lyn, PLCγ2, PKC, MAPKs, and Akt after convulxin stimulation. Honokiol have no cytotoxicity in zebrafish embryos. Honokiol diminished the binding of anti-GP VI (FITC-JAQ1) mAb to human platelets, and it also reduced the coimmunoprecipitation of GP VI-bound Lyn after convulxin stimulation. The surface plasmon resonance results revealed that honokiol binds directly to GP VI, with a KD of 289 μM. Platelet function analysis revealed that honokiol substantially prolonged the closure time in human whole blood and increased the occlusion time of thrombotic platelet plug formation in mice. In conclusion, honokiol acts as a potent antagonist of collagen GP VI in human platelets, and it has therapeutic potential in the prevention of the pathological thrombosis.


Visual verification and analysis of cluster detection for molecular dynamics.
A current research topic in molecular thermodynamics is the condensation of vapor to liquid and the investigation of this process at the molecular level. Condensation is found in many physical phenomena, e.g. the formation of atmospheric clouds or the processes inside steam turbines, where a detailed knowledge of the dynamics of condensation processes will help to optimize energy efficiency and avoid problems with droplets of macroscopic size. The key properties of these processes are the nucleation rate and the critical cluster size. For the calculation of these properties it is essential to make use of a meaningful definition of molecular clusters, which currently is a not completely resolved issue. In this paper a framework capable of interactively visualizing molecular datasets of such nucleation simulations is presented, with an emphasis on the detected molecular clusters. To check the quality of the results of the cluster detection, our framework introduces the concept of flow groups to highlight potential cluster evolution over time which is not detected by the employed algorithm. To confirm the findings of the visual analysis, we coupled the rendering view with a schematic view of the clusters' evolution. This allows to rapidly assess the quality of the molecular cluster detection algorithm and to identify locations in the simulation data in space as well as in time where the cluster detection fails. Thus, thermodynamics researchers can eliminate weaknesses in their cluster detection algorithms. Several examples for the effective and efficient usage of our tool are presented.


Interim recruitment prediction for multi-center clinical trials.
We introduce a general framework for monitoring, modeling, and predicting the recruitment to multi-center clinical trials. The work is motivated by overly optimistic and narrow prediction intervals produced by existing time-homogeneous recruitment models for multi-center recruitment. We first present two tests for detection of decay in recruitment rates, together with a power study. We then introduce a model based on the inhomogeneous Poisson process with monotonically decaying intensity, motivated by recruitment trends observed in oncology trials. The general form of the model permits adaptation to any parametric curve-shape. A general method for constructing sensible parameter priors is provided and Bayesian model averaging is used for making predictions which account for the uncertainty in both the parameters and the model. The validity of the method and its robustness to misspecification are tested using simulated datasets. The new methodology is then applied to oncology trial data, where we make interim accrual predictions, comparing them to those obtained by existing methods, and indicate where unexpected changes in the accrual pattern occur.


Endogenous opiates regulate the nocturnal reduction in luteinizing hormone pulse frequency during the luteal phase of the macaque menstrual cycle.
Twenty-four-hour pulsatile patterns of bioactive luteinizing hormone (LH) and immunoactive estradiol (E2) and progesterone (P4) were measured during the mid-follicular (FP, Days 5, 6, or 7) and mid-luteal (LP, Days 7, 8, 9, or 10) phases of the menstrual cycle in six intact and in four ovariectomized (OVX) rhesus monkeys. Blood samples were collected remotely at 7.5-min (FP) and 15-min (LP, OVX) intervals via catheters in freely moving, vested monkeys. Hormonal patterns were analyzed by the MUNRO computer program. A significant coupling of LH and E2 pulses was observed during the FP and between the LH and P4 pulses during the LP. No diurnal rhythm of LH pulse frequency was observed during the FP or in OVX monkeys. In contrast, day/night differences in frequency were seen during the luteal phases (0.35 +/- 0.03 vs. 0.24 +/- 0.05 pulses/h, day vs. night, p less than 0.05). Naloxone (NAL), an opiate antagonist, was continuously infused (2 mg/h.i.v.) for 12 h at night during the LP. NAL treatment increased nighttime LH pulse frequency to 0.33 +/- 0.07 pulses/h, which was not different from the daytime LH pulse frequency, thereby abolishing the normal diurnal pattern. Interestingly, NAL treatment did not achieve the approximately 1 pulse/h frequency seen in the FP or OVX condition. These results support the hypothesis that P4 modulates the activity of an opioid system that is responsible both for a slowing of LH pulse frequency during the LP and for an additional nightly reduction in hypothalamic LH pulse-generating activity.


Extraparticulate chain interaction between different electron transport particles.
Interaction or cross-linking between the respiratory chains of the electron transport particles of bacterial origin occurs with a mixture of active and inactive particles. Interaction between bacterial particles and liver sub-mitochondrial particles also occurs. Irradiation of the bacterial particles at 360 nanometers resulted in the destruction of quinone and consequent loss of ability of reduced nicotinamide adenine, dinucleotides to reduce cytochromes b, c(1), c, and a plus a(3). A mixture of both irradiated and untreated particles in the presence of the reduced dinucleotide resulted in the reduction of cytochromes c and a plus a(3), in an amount equivalent to the total concentration of these cytochromes in both types of particles. In contrast, the amount of cytochrome b reduced was equivalent to half the particle concentration or to that observed with the active particles alone. The rate of reduction of cytochromes c and a plus a(3) with the mixture of particles was similar to that with the active particles alone. The interaction or cross-linking between the particulate respiratory chains of bacteria or of bacterial and mammalian systems occurs after cytochrome b and before or at cytochrome c.


Receptor-activated cytoplasmic Ca2+ oscillations in pancreatic acinar cells: generation and spreading of Ca2+ signals.
Receptor-activated cytoplasmic Ca2+ oscillations have been investigated using both single cell microfluorometry and voltage-clamp recording of Ca(2+)-dependent Cl- current in single internally perfused acinar cells. In these cells there is direct experimental evidence showing that the ACh-evoked [Ca2+]i fluctuations are due to an inositol trisphosphate-induced small steady Ca2+ release which in turn evokes repetitive Ca2+ spikes via a caffeine-sensitive Ca(2+)-induced Ca2+ release process. There is indirect evidence suggesting that receptor-activation in addition to generating the Ca2+ releasing messenger, inositol trisphosphate, also produces another regulator involved in the control of Ca2+ signal spreading. Intracellular inositol trisphosphate or Ca2+ infusion produce short duration repetitive spikes confined to the cytoplasmic area close to the plasma membrane, but these signals can be made to progress throughout the cell by addition of caffeine or by receptor activation.


Psychometric testing of the Agitation Severity Scale for acute presentation behavioral management patients in the emergency department.
Agitation is a vexing problem frequently observed in emergency department acute psychiatric patients, yet no instruments to measure agitation in this setting and population were found upon review of the literature. Previously developed agitation rating scales are limited by the length of observation they require, their need for participation by the patient, complexity in scoring, and a lack of validity in this setting and population. The purpose of this study was to psychometrically evaluate and refine an observation-based agitation scale for use with emergency department acute psychiatric patients. Using a methodological design, the 21-item Agitation Severity Scale was utilized to assess 270 adult psychiatric patients in the emergency setting in a prospective, observational fashion. Reliability analysis, item analysis, exploratory factor analysis, and validity assessments were completed. The relationship between Agitation Severity Scale scores and scores on the previously established Overt Agitation Severity Scale was evaluated. The instrument was reduced to 17 items representing four factors (Aggressive Behaviors, Interpersonal Behaviors, Involuntary Motor Behaviors, and Physical Stance) that accounted for nearly 70% of observed variance, Cronbach's α = 0.91. Evidence of internal consistency reliability, equivalence reliability, construct validity, and convergent validity was established. Through this study, the 17-item Agitation Severity Scale demonstrated acceptable levels of reliability and validity when used with acute psychiatric patients in the emergency setting. This instrument holds promise as a method of enhancing clinical communication about agitation, evaluating the efficacy of interventions aimed at decreasing agitation, and as a research tool.


A systematic review and economic evaluation of epoetin alpha, epoetin beta and darbepoetin alpha in anaemia associated with cancer, especially that attributable to cancer treatment.
To assess the effectiveness and cost-effectiveness of epoetin alpha, epoetin beta and darbepoetin alpha (referred to collectively in this report as epo) in anaemia associated with cancer, especially that attributable to cancer treatment. Electronic databases were searched from 2000 (1996 in the case of darbepoetin alpha) to September 2004. Using a recently published Cochrane review as the starting point, a systematic review of recent randomised controlled trials (RCTs) comparing epo with best standard was conducted. Inclusion, quality assessment and data abstraction were undertaken in duplicate. Where possible, meta-analysis was employed. The economic assessment consisted of a systematic review of past economic evaluations, an assessment of economic models submitted by the manufacturers of the three epo agents and development of a new individual sampling model (the Birmingham epo model). In total 46 RCTs were included within this systematic review, 27 of which had been included in the Cochrane systematic review. All 46 trials compared epo plus supportive care for anaemia (including transfusions), with supportive care for anaemia (including transfusions), alone. Haematological response (defined as an improvement by 2 g/dl(-1)) had a relative risk of 3.4 [95% confidence interval (CI) 3.0 to 3.8, 22 RCTs] with a response rate for epo of 53%. The trial duration was most commonly 16-20 weeks. There was little statistical heterogeneity in the estimate of haematological response, and there were no important differences between the subgroups examined. Haemoglobin (Hb) change showed a weighted mean difference of 1.63 g/dl(-1) (95% CI 1.46 to 1.80) in favour of epo. Treatment with erythropoietin in patients with cancer-induced anaemia reduces the number of patients who receive a red blood cell transfusion (RBCT) by an estimated 18%. Health-related quality of life (HRQoL) data were analysed using vote counting and qualitative assessment and a positive effect was observed in favour of an improved HRQoL for patients on epo. Published information on side-effects was of poor quality. New trials provided further evidence of side-effects with epo, particularly thrombic events, but it is still unclear whether these could be accounted for by chance alone. The results of the previous Cochrane review had suggested a survival advantage for epo (HR 0.84, 95% CI 0.69 to 1.02), based on 19 RCTs. The update, based on 28 RCTs, suggests no difference (HR 1.03, 95% CI 0.88 to 1.21). Subgroup analysis suggested some explanations for this heterogeneity, but it is difficult to draw firm conclusions without access to the substantial amounts of missing or unpublished data, or more detailed results from some of the trials with heterogeneous patient populations. The conclusions are, however, broadly in line with those of a Food and Drug Administration (FDA) safety briefing, which recommended that patients with a haemoglobin above 12 g/dl(-1) should not be treated; the target rate of rise in Hb should not be too great, and further carefully conducted trials are required to determine which subgroups of patients may be harmed by the use of these products, in particular through the stimulation of tumour activity. Five published economic evaluations identified from the literature had inconsistent results, with estimates ranging from a cost per quality-adjusted life-year (QALY) under pound 10,000 through to epo being less effective and more costly than standard care. The more favourable evaluations assumed a survival advantage for epo. The three company models submitted each relied on assumed survival gains to achieve relatively low cost per QALY, from pound 13,000 to pound 28,000, but generated estimates from pound 84,000 to pound 159,000 per QALY when no survival gain was assumed. Each of these models relied on Hb levels alone driving utility, and each assumed gradual normalisation of Hb in the standard treatment arm after the end of treatment. The Birmingham epo model followed the company models in regard to the relationship between Hb levels and utility, and also assumed normalisation in the base case. With no survival gain, the incremental cost per QALY was pound 150,000, falling to pound 40,000 when the lower, more favourable, confidence interval for survival was used. Epo is effective in improving haematological response and reducing RBCT requirements, and appears to have a positive effect on HRQoL. The incidence of side-effects and effects on survival remains highly uncertain. However, if there is no impact on survival, it seems highly unlikely that epo would be considered a cost-effective use of healthcare resources. The main target for further research should be improving estimates of impact on survival, initially through more detailed secondary research, such as the individual patient data meta-analysis started by the Cochrane group. Further trials may be required, and have been recommended by the FDA, although many trials are in progress, completed but unreported or awaiting mature follow-up. The Birmingham epo model developed as part of this project contains new features that improve its flexibility in exploring different scenarios; further refinement and validation would therefore be of assistance. Finally, further research to resolve uncertainty about other parameters, particularly quality of life, adverse events, and the rate of normalisation, would also be beneficial.


Preliteracy Speech Sound Production Skill and Linguistic Characteristics of Grade 3 Spellings: A Study Using the Templin Archive.
This archival investigation examined the relationship between preliteracy speech sound production skill (SSPS) and spelling in Grade 3 using a dataset in which children's receptive vocabulary was generally within normal limits, speech therapy was not provided until Grade 2, and phonological awareness instruction was discouraged at the time data were collected. Participants (N = 250), selected from the Templin Archive (Templin, 2004), varied on prekindergarten SSPS. Participants' real word spellings in Grade 3 were evaluated using a metric of linguistic knowledge, the Computerized Spelling Sensitivity System (Masterson & Apel, 2013). Relationships between kindergarten speech error types and later spellings also were explored. Prekindergarten children in the lowest SPSS (7th percentile) scored poorest among articulatory subgroups on both individual spelling elements (phonetic elements, junctures, and affixes) and acceptable spelling (using relatively more omissions and illegal spelling patterns). Within the 7th percentile subgroup, there were no statistical spelling differences between those with mostly atypical speech sound errors and those with mostly typical speech sound errors. Findings were consistent with predictions from dual route models of spelling that SSPS is one of many variables associated with spelling skill and that children with impaired SSPS are at risk for spelling difficulty.


Patient activation and visit preparation in African American veterans receiving mental health care.
Patient activation refers to one's ability and willingness to manage their health and health care. Visit preparation, question formulation, and other elements of patient activation are core components of patient-centered care. However, they are inconsistently translated into clinical practice. Multiple factors have been shown to influence patient activation and associated activities, such as patients' race and ethnicity, illness, and clinical settings. Because race and ethnicity are important factors in patient activation, and we know little about ethnic minority patients with respect to patient activation, the goal of this study was to examine the contexts, barriers, and facilitators influencing African American veterans' involvement in visit preparation in mental health outpatient settings. We conducted qualitative interviews with 49 African American veterans with mental illness receiving outpatient psychiatric care at a large, urban U.S. Department of Veterans Affairs (VA) Medical Center, and used a grounded theory approach to analyze the data. Findings from this study identify patients' beliefs about preparing for the clinical encounter, the patient-provider relationship, and lack of information about patient activation as barriers to engaging in visit preparation activities. Findings indicate the need for greater awareness of the challenges of visit preparation as well as the potential consequences of lack of preparation. Results suggest the incorporation of visit preparation as part of routine mental health visits, and as a tool to increase patient activation, especially among minorities. Findings also inform intervention studies by emphasizing the need to explore sociocultural factors that may impact patient activation programs. (PsycINFO Database Record


Lanadelumab: A Review in Hereditary Angioedema.
Lanadelumab (Takhzyro™), a first-in-class fully human monoclonal antibody against plasma kallikrein, has been approved in several countries, including Australia, Canada, those of the EU, Switzerland and the USA, for the prevention of hereditary angioedema (HAE) attacks in patients aged ≥ 12 years. Subcutaneous lanadelumab significantly reduced HAE attack rates relative to placebo in the pivotal HELP trial. The clinical benefits of lanadelumab were seen regardless of prior long-term prophylaxis use, baseline disease activity, sex or body mass index. Lanadelumab therapy was associated with clinically meaningful improvements in HAE-specific quality of life. Lanadelumab was generally well tolerated. The most common adverse events with lanadelumab were injection-site reactions, which were generally mild and transient. Lanadelumab has a low potential for immunogenicity. It offers the convenience of self-administered subcutaneous injections once every 2 weeks (starting dosage). Currently available data indicate that lanadelumab is an effective, well-tolerated, novel prophylactic option for patients with HAE aged ≥ 12 years.


Acid-base curve nomogram for chimpanzee blood and comparison with human blood characteristics.
An acid-base nomogram for chimpanzee blood was constructed. Blood was drawn from eight lightly anesthetized chimpanzees. Each sample of blood was oxygenated and nine aliquots were prepared with three different concentrations of hemoglobin and three different amounts of added acid or base. Each aliquot was equilibrated at two PCO2 levels and the pH was measured and plotted on pH-logPCO2 coordinates. Using the intersection point of these pH-logPCO2 lines as a point of equal hemoglobin-independent "base excess" for each condition, values for true base excess were plotted. Connecting these values provided a Cartesian PCO2-pH base excess nomogram for the chimpanzee comparable to that devised by Siggaard-Andersen for humans. Examination of blood from normal human subjects by the same methods showed no appreciable differences from the original Siggaard-Andersen nomogram. However, the PCO2-pH-base excess nomogram for chimpanzee blood deviated slightly from that for human blood. It is possible that the deviation is related to an arterial bicarbonate concentration in the chimpanzee slightly higher than that in human.


Does Computed Tomography Change our Observation and Management of Fracture Non-Unions?
The purpose of this study was to determine whether Multi-Detector Computed Tomography (MDCT) in addition to plain radiographs influences radiologists' and orthopedic surgeons' diagnosis and treatment plans for delayed unions and non-unions. A retrospective database of 32 non-unions was reviewed by 20 observers. On a scale of 1 to 5, observers rated on X-Ray and a subsequent Multi Detector Helical Computer Tomography (MDCT) scan was performed to determine the following categories: "healed", "bridging callus present", "persistent fracture line" or "surgery advised". Interobserver reliability in each category was calculated using the Interclass Correlation Coefficient (ICC). The influence of the MDCT scan on the raters' observations was determined in each case by subtracting the two scores of both time points. All four categories show fair interobserver reliability when using plain radiographs. MDCT showed no improvement, the reliability was poor for the categories "bridging callus present" and "persistent fracture line", and fair for "healed" and "surgery advised". In none of the cases, MDCT led to a change of management from nonoperative to operative treatment or vice versa. For 18 out of 32 cases, the treatment plans did not alter. In seven cases MDCT led to operative treatment while on X-ray the treatment plan was undecided. In this study, the interobserver reliability of MDCT scan is not greater than conventional radiographs for determining non-union. However, a MDCT scan did lead to a more invasive approach in equivocal cases. Therefore a MDCT is only recommended for making treatment strategies in those cases.


Social Relationships of Dually Diagnosed Homeless Adults Following Enrollment in Housing First or Traditional Treatment Services.
Strong and effective social support is a critical element of mental health recovery, yet social support is often lacking for adults experiencing homelessness. This study examines differences in the social networks of participants newly enrolled in programs that use either a Housing First (HF) approach (i.e., provides immediate access to permanent housing with ongoing consumer-driven support services) or a treatment first (TF) approach (i.e., traditional clinician-driven staircse model that requires temporary or transitional housing and treatment placements before accessing permanent housing). We use a mixed-methods social network analysis approach to assess group differences of 75 individuals based on program type (HF or TF) and program retention. Quantitative results show that compared with TF, HF participants have a greater proportion of staff members in their network. TF participants are more likely than HF participants to maintain mixed-quality relationships (i.e., relationships with elements of support and conflict). As compared with participants who remain in a program, those who disengage from programs have a greater proportion of mixed relationships and relationships that grow distant. Qualitative analyses suggest that HF participants regard housing as providing a stable foundation from which to reconnect or restore broken relationships. However, HF participants are guarded about close relationships for fear of being exploited due to their newly acquired apartments. TF participants report that they are less inclined to develop new relationships with peers or staff members due to the time-limited nature of the TF programs. These findings suggest that HF participants are not more socially isolated than those in traditional care. Implications for practice, policy and future research are discussed.


Confined Water Molecules in Binary Mixtures of Water and 2,6-Lutidine Near Lower Solution Critical Temperature.
We study the concentration and temperature dependence of the reorientation dynamics of water molecules in binary mixtures of water and 2,6-lutidine below the lower solution critical temperature (LSCT) with femtosecond mid-infrared pump-probe spectroscopy. The measurements reveal the presence of water molecules interacting with both the hydrophobic groups of lutidine and forming a hydrogen bond with the nitrogen atom of lutidine. Both types of molecules show a strongly decreased rotational mobility in comparison to bulk water. From the temperature dependence of the slow water fraction, we conclude that the lutidine molecules form clusters that decrease in size when the temperature is decreased further below the LSCT.


A forgotten group during humanitarian crises: a systematic review of sexual and reproductive health interventions for young people including adolescents in humanitarian settings.
Young people including adolescents face barriers to healthcare and increased risk of poor sexual and reproductive health (SRH), which are exacerbated in humanitarian settings. Our systematic review assessed the evidence on SRH interventions for young people including adolescents in humanitarian settings, strategies to increase their utilisation and their effects on health outcomes. We searched peer-reviewed and grey literature published between 1980 and 2018 using search terms for adolescents, young people, humanitarian crises in low- and middle- income countries and SRH in four databases and relevant websites. We analysed literature matching pre-defined inclusion criteria using narrative synthesis methodology, and appraised for study quality. We found nine peer-reviewed and five grey literature articles, the majority published post-2012 and mostly high- or medium-quality, focusing on prevention of unintended pregnancies, HIV/STIs, maternal and newborn health, and prevention of sexual and gender-based violence. We found no studies on prevention of mother-to-child transmission (PMTCT), safe abortion, post-abortion care, urogenital fistulae or female genital mutilation (FGM). Thirteen studies reported positive effects on outcomes (majority were positive changes in knowledge and attitudes), seven studies reported no effects in some SRH outcomes measured, and one study reported a decrease in number of new and repeat FP clients. Strategies to increase intervention utilisation by young people include adolescent-friendly spaces, peer workers, school-based activities, and involving young people. Young people, including adolescents, continue to be a neglected group in humanitarian settings. While we found evidence that some SRH interventions for young people are being implemented, there are insufficient details of specific intervention components and outcome measurements to adequately map these interventions. Efforts to address this key population's SRH needs and evaluate effective implementation modalities require urgent attention. Specifically, greater quantity and quality of evidence on programmatic implementation of these interventions are needed, especially for comprehensive abortion care, PMTCT, urogenital fistulae, FGM, and for LGBTQI populations and persons with disabilities. If embedded within a broader SRH programme, implementers and/or researchers should include young people-specific strategies, targeted at both girls/women and boys/men where appropriate, and collect age- and sex-disaggregated data to help ascertain if this population's diverse needs are being addressed.


Techniques used to define human MHC antigens: polymerase chain reaction and oligonucleotide probes.
The various HLA class II specificities, identifiable by serological or cellular typing reagents, reflect underlying polymorphisms of the constituent alpha and beta chains, encoded at several loci within the HLA-D region. Variation in these genes is concentrated in allelic hypervariable regions but can also be found elsewhere. Sequence-specific oligonucleotides (SSO) can be used to detect individual alleles with a high degree of accuracy by probing dot-blotted DNA, amplified to high copy number by the polymerase chain reaction (PCR). The classic DR specificities (DR1-DRw14) can be identified with certainty by sequential hybridization to a series of 14 SSO probes. In addition, fine resolution of specificities such as the subtypes of DR4 is possible using a combination of SSO probes and group-specific amplification in which PCR primers designed to amplify only DR4 alleles are employed. Similar methods can be applied to the typing of DQ and DP alleles even on whole blood samples which have been stored at -20 degrees C for up to 8 years. A full HLA class II type may be obtained on a large number of samples simultaneously without the need to separate and store viable lymphocytes. Thus, the sensitivity and robustiness of this technique give it major applications in the analysis of histocompatibility and disease associations, particularly in circumstances where facilities for the initial preparation and storage of samples may be limited.


Effect of cell differentiation for neuroblastoma by vitamin k analogs.
Lack of receptor tyrosine kinase (TrkA), a high-affinity nerve growth factor (NGF) receptor, is closely associated with the malignant progression of neuroblastoma (NB) and its prognosis. Vitamin K3 (VK3) analogs inhibit the activity of protein tyrosine phosphatases (PTPases), which causes hydrolysis of the phosphate groups bound to the tyrosine residues on tyrosine kinase, resulting in sustained tyrosine phosphorylation. In order to reverse this abnormal NGF/TrkA signal transduction in NB cells, we synthesized new VK3 analogs and examined their activity against NB cells. VK3 analogs increased or maintained the expression level of c-fos mRNA in the NB cells, which express the downstream genes of NGF/TrkA signal transduction. Moreover, the expression level of GAP-43 mRNA, which is a marker of neurite outgrowth and neuronal differentiation, was increased and morphological differentiation was also observed. VK3 analogs (especially COOH analog) continued to express c-fos and GAP-43 mRNAs and induced differentiation of NB cells after stimulation of NGF by strong inhibition of PTPase without affecting TrkA autophosphorylation. Vitamin K3 analogs may have potential as clinical therapeutic agents for NB.


Optimisation of the dosage of tranexamic acid in trauma patients with population pharmacokinetic analysis.
Tranexamic acid is used both pre-hospital and in-hospital as an antifibrinolytic drug to treat or prevent hyperfibrinolysis in trauma patients; dosing, however, remains empirical. We aimed to measure plasma levels of tranexamic acid in patients receiving pre-hospital anti-hyperfibrinolytic therapy and to build a population pharmacokinetic model to propose an optimised dosing regimen. Seventy-three trauma patients were enrolled and each received tranexamic acid 1 g intravenously pre-hospital. A blood sample was drawn after arrival in the emergency department, and we measured the plasma tranexamic acid concentration using liquid chromatography-mass spectrometry, and modelled the data using non-linear mixed effect modelling. Tranexamic acid was administered at a median (IQR [range]) time of 43 (30-55 [5-135]) min after trauma. Plasma tranexamic acid levels were determined on arrival at hospital, 57 (43-70 [20-148]) min after pre-hospital administration of the drug. The measured concentration was 28.7 (21.5-38.5 [8.7-89.0]) μg.ml-1 . Our subjects had sustained severe trauma; injury severity score 20 (16-29 [5-75]), including penetrating injury in 2.8% and isolated traumatic brain injury in 19.7%. The pharmacokinetics were ascribed a two-compartment open model with body-weight as the main covariate. As tranexamic acid concentrations may fall below therapeutic levels during initial hospital treatment, we propose additional dosing schemes to maintain a specific target blood concentration for as long as required. This is the first study to investigate plasma level and pharmacokinetics of tranexamic acid after pre-hospital administration in trauma patients. Our proposed dosing regimen could be used in subsequent clinical trials to better study efficacy and tolerance profiles with controlled blood concentrations.


What drives academic data sharing?
Despite widespread support from policy makers, funding agencies, and scientific journals, academic researchers rarely make their research data available to others. At the same time, data sharing in research is attributed a vast potential for scientific progress. It allows the reproducibility of study results and the reuse of old data for new research questions. Based on a systematic review of 98 scholarly papers and an empirical survey among 603 secondary data users, we develop a conceptual framework that explains the process of data sharing from the primary researcher's point of view. We show that this process can be divided into six descriptive categories: Data donor, research organization, research community, norms, data infrastructure, and data recipients. Drawing from our findings, we discuss theoretical implications regarding knowledge creation and dissemination as well as research policy measures to foster academic collaboration. We conclude that research data cannot be regarded as knowledge commons, but research policies that better incentivise data sharing are needed to improve the quality of research results and foster scientific progress.


TGF-β1-mediated differentiation of fibroblasts is associated with increased mitochondrial content and cellular respiration.
Cytokine-dependent activation of fibroblasts to myofibroblasts, a key event in fibrosis, is accompanied by phenotypic changes with increased secretory and contractile properties dependent on increased energy utilization, yet changes in the energetic profile of these cells are not fully described. We hypothesize that the TGF-β1-mediated transformation of myofibroblasts is associated with an increase in mitochondrial content and function when compared to naive fibroblasts. Cultured NIH/3T3 mouse fibroblasts treated with TGF-β1, a profibrotic cytokine, or vehicle were assessed for transformation to myofibroblasts (appearance of α-smooth muscle actin [α-SMA] stress fibers) and associated changes in mitochondrial content and functions using laser confocal microscopy, Seahorse respirometry, multi-well plate reader and biochemical protocols. Expression of mitochondrial-specific proteins was determined using western blotting, and the mitochondrial DNA quantified using Mitochondrial DNA isolation kit. Treatment with TGF-β1 (5 ng/mL) induced transformation of naive fibroblasts into myofibroblasts with a threefold increase in the expression of α-SMA (6.85 ± 0.27 RU) compared to cells not treated with TGF-β1 (2.52 ± 0.11 RU). TGF-β1 exposure increased the number of mitochondria in the cells, as monitored by membrane potential sensitive dye tetramethylrhodamine, and expression of mitochondria-specific proteins; voltage-dependent anion channels (0.54 ± 0.05 vs. 0.23 ± 0.05 RU) and adenine nucleotide transporter (0.61 ± 0.11 vs. 0.22 ± 0.05 RU), as well as mitochondrial DNA content (530 ± 12 μg DNA/106 cells vs. 307 ± 9 μg DNA/106 cells in control). TGF-β1 treatment was associated with an increase in mitochondrial function with a twofold increase in baseline oxygen consumption rate (2.25 ± 0.03 vs. 1.13 ± 0.1 nmol O2/min/106 cells) and FCCP-induced mitochondrial respiration (2.87 ± 0.03 vs. 1.46 ± 0.15 nmol O2/min/106 cells). TGF-β1 induced differentiation of fibroblasts is accompanied by energetic remodeling of myofibroblasts with an increase in mitochondrial respiration and mitochondrial content.


Cerebral Oxygenation and Pain of Heel Blood Sampling Using Manual and Automatic Lancets in Premature Infants.
Heel blood sampling is a common but painful procedure for neonates. Automatic lancets have been shown to be more effective, with reduced pain and tissue damage, than manual lancets, but the effects of lancet type on cortical activation have not yet been compared. The study aimed to compare the effects of manual and automatic lancets on cerebral oxygenation and pain of heel blood sampling in 24 premature infants with respiratory distress syndrome. Effectiveness was measured by assessing numbers of pricks and squeezes and duration of heel blood sampling. Pain responses were measured using the premature infant pain profile score, heart rate, and oxygen saturation (SpO2). Regional cerebral oxygen saturation (rScO2) was measured using near-infrared spectroscopy, and cerebral fractional tissue oxygen extraction was calculated from SpO2 and rScO. Measures of effectiveness were significantly better with automatic than with manual lancing, including fewer heel punctures (P = .009) and squeezes (P < .001) and shorter duration of heel blood sampling (P = .002). rScO2 was significantly higher (P = .013) and cerebral fractional tissue oxygen extraction after puncture significantly lower (P = .040) with automatic lancing. Premature infant pain profile scores during (P = .004) and after (P = .048) puncture were significantly lower in the automatic than in the manual lancet group. Automatic lancets for heel blood sampling in neonates with respiratory distress syndrome significantly reduced pain and enhanced cerebral oxygenation, suggesting that heel blood should be sampled routinely using an automatic lancet.


Highly multiplexed imaging of single cells using a high-throughput cyclic immunofluorescence method.
Single-cell analysis reveals aspects of cellular physiology not evident from population-based studies, particularly in the case of highly multiplexed methods such as mass cytometry (CyTOF) able to correlate the levels of multiple signalling, differentiation and cell fate markers. Immunofluorescence (IF) microscopy adds information on cell morphology and the microenvironment that are not obtained using flow-based techniques, but the multiplicity of conventional IF is limited. This has motivated development of imaging methods that require specialized instrumentation, exotic reagents or proprietary protocols that are difficult to reproduce in most laboratories. Here we report a public-domain method for achieving high multiplicity single-cell IF using cyclic immunofluorescence (CycIF), a simple and versatile procedure in which four-colour staining alternates with chemical inactivation of fluorophores to progressively build a multichannel image. Because CycIF uses standard reagents and instrumentation and is no more expensive than conventional IF, it is suitable for high-throughput assays and screening applications.


A Signal Processing Approach for Detection of Hemodynamic Instability before Decompensation.
Advanced hemodynamic monitoring is a critical component of treatment in clinical situations where aggressive yet guided hemodynamic interventions are required in order to stabilize the patient and optimize outcomes. While there are many tools at a physician's disposal to monitor patients in a hospital setting, the reality is that none of these tools allow hi-fidelity assessment or continuous monitoring towards early detection of hemodynamic instability. We present an advanced automated analytical system which would act as a continuous monitoring and early warning mechanism that can indicate pending decompensation before traditional metrics can identify any clinical abnormality. This system computes novel features or bio-markers from both heart rate variability (HRV) as well as the morphology of the electrocardiogram (ECG). To compare their effectiveness, these features are compared with the standard HRV based bio-markers which are commonly used for hemodynamic assessment. This study utilized a unique database containing ECG waveforms from healthy volunteer subjects who underwent simulated hypovolemia under controlled experimental settings. A support vector machine was utilized to develop a model which predicts the stability or instability of the subjects. Results showed that the proposed novel set of features outperforms the traditional HRV features in predicting hemodynamic instability.


Multicultural assessment of child and adolescent psychopathology with ASEBA and SDQ instruments: research findings, applications, and future directions.
Around the world, cultural blending and conflict pose challenges for assessment and understanding of psychopathology. Economical, evidence-based, culturally robust assessment is needed for research, for answering public health questions, and for evaluating immigrant, refugee, and minority children. This article applies multicultural perspectives to behavioral, emotional, and social problems assessed on dimensions describing children's functioning, as rated by parents, teachers, children, and others. The development of Achenbach System of Empirically Based Assessment (ASEBA) and Strengths and Difficulties Questionnaire (SDQ) forms and their applications to multicultural research are presented. A primary aim of both questionnaires is to identify children at high risk of psychiatric disorders and who therefore warrant further assessment. The forms are self-administered or administered by lay interviewers. ASEBA problem items are scored on 6 DSM-oriented scales and 3 broader band scales, plus 8 syndromes derived statistically as taxonomic constructs and supported by uniform confirmatory factor analyses of samples from many populations. Comparisons of ASEBA scale scores, psychometrics, and correlates are available for diverse populations. SDQ forms are scored on one broad-band scale and 5 a priori behavioral dimensions supported by data from various populations. For both instruments, factor analyses, psychometrics, and correlates are available for diverse populations. The willingness and ability of hundreds of thousands of respondents from diverse groups to complete ASEBA and SDQ forms support this approach to multicultural assessment. Although particular items and scales may have differential relevance among groups and additional assessment procedures are needed, comparable results are found in many populations. Scale scores vary more within than between populations, and distributions of scores overlap greatly among different populations. Ratings of children's problems thus indicate more heterogeneity within populations than distinctiveness between populations. Norms from multiple populations can be used to compare children's scores with relevant peer groups. Multicultural dimensional research can advance knowledge by diversifying normative data; by comparing immigrant children with nonimmigrant compatriots and with host country children; by identifying outlier findings for elucidation by emic research; and by fostering efforts to dimensionalize DSM-V diagnostic criteria.


Site-directed mutagenesis of alpha 2A-adrenergic receptors: identification of amino acids involved in ligand binding and receptor activation by agonists.
Molecular cloning of the alpha 2A-adrenergic receptor has shown that this receptor is a member of the gene superfamily of guanine nucleotide-binding protein (G protein)-coupled receptors. The alpha 2A-adrenergic receptor expressed in Chinese hamster ovary (CHO) cells attenuates and potentiates forskolin-stimulated cAMP production through independent signaling pathways. To examine the role of three conserved aspartic acid and two conserved serine residues in alpha 2A-adrenergic receptor function, we substituted asparagine for aspartic acid or alanine for serine and characterized the mutant receptors in stably transfected CHO cells. Asn113 mutant alpha 2-adrenergic receptors display no [3H] yohimbine specific binding, at concentrations up to 1000 nM. In transfected cells expressing the Asn113 mutant receptor, agonists, at concentrations up to 0.1 mM, produce small decreases (approximately 10% of wild-type values) in forskolin-stimulated cAMP and potentiate forskolin-stimulated cAMP concentrations in a dose-dependent manner, with EC50 values approximately 500-fold higher than those for the wild-type receptor. These findings suggest that Asp113 may be involved in high affinity binding of agonists and antagonists, as has been previously reported for beta 2-adrenergic and m1 muscarinic acetylcholine receptors. Asn79 mutant alpha 2-adrenergic receptors display high affinity agonist binding that is insensitive to guanine nucleotides, suggesting an altered receptor-G protein coupling. Furthermore, agonist binding to Asn79 mutant receptors elicits no change in forskolin-stimulated cAMP concentrations, similar to earlier findings that the corresponding residue in beta 2-adrenergic and muscarinic receptors is required for effector stimulation. Asp130 appears to influence receptor-G protein coupling. Mutation of this residue eliminates high affinity, guanine nucleotide-sensitive, agonist binding and produces a rightward shift in the dose-response curves for agonist-mediated inhibition of forskolin-stimulated cAMP production, compared with the wild-type receptor. Moreover, agonist potentiation of forskolin-stimulated cAMP levels is abolished if Asp130 is replaced by Asn, supporting the hypothesis that inhibition and potentiation of forskolin-stimulated cAMP production in CHO cells proceed through distinct signaling pathways. Characterization of Ala204 mutant alpha 2A-adrenergic receptors suggests a possible role for Ser204 in hydrogen bond interactions with the para-hydroxyl group of the phenyl ring of the catecholamines, as has been previously described for the corresponding serine in beta 2-adrenergic receptors.(ABSTRACT TRUNCATED AT 400 WORDS)


The antidiabetic effect of low doses of Moringa oleifera Lam. seeds on streptozotocin induced diabetes and diabetic nephropathy in male rats.
The antidiabetic activity of two low doses of Moringa seed powder (50 and 100 mg/kg body weight, in the diet) on streptozotocin (STZ) induced diabetes male rats was investigated. Forty rats were divided into four groups. The diabetic positive control (STZ treated) group showed increased lipid peroxide, increased IL-6, and decreased antioxidant enzyme in the serum and kidney tissue homogenate compared with that of the negative control group. Immunoglobulins (IgA, IgG), fasting blood sugar, and glycosylated hemoglobin (HbA1c) were also increased as a result of diabetes in G2 rats. Moreover albumin was decreased, and liver enzymes and α-amylase were not affected. In addition, the renal functions and potassium and sodium levels in G2 were increased as a sign of diabetic nephropathy. Urine analysis showed also glucosuria and increased potassium, sodium, creatinine, uric acid, and albumin levels. Kidney and pancreas tissues showed also pathological alteration compared to the negative control group. Treating the diabetic rats with 50 or 100 mg Moringa seeds powder/kg body weight in G3 and G4, respectively, ameliorated the levels of all these parameters approaching the negative control values and restored the normal histology of both kidney and pancreas compared with that of the diabetic positive control group.


Anti-vascular endothelial growth factor for diabetic macular oedema.
Diabetic macular oedema (DMO) is a common complication of diabetic retinopathy. Although grid or focal laser photocoagulation has been shown to reduce the risk of visual loss in DMO, or clinically significant macular oedema (CSMO), vision is rarely improved. Antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF) modalities is used to try to improve vision in people with DMO. To investigate the effects in preserving and improving vision and acceptability, including the safety, compliance with therapy and quality of life, of antiangiogenic therapy with anti-VEGF modalities for the treatment of DMO. We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to April 2014), EMBASE (January 1980 to April 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to April 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 28 April 2014. We included randomised controlled trials (RCTs) comparing any antiangiogenic drugs with an anti-VEGF mechanism of action versus another treatment, sham treatment or no treatment in people with DMO. We used standard methodological procedures expected by The Cochrane Collaboration. The risk ratios (RR) for visual loss and visual gain of three or more lines of logMAR visual acuity were estimated at one year of follow-up (plus or minus six months) after treatment initiation. Eighteen studies provided data on four comparisons of interest in this review. Participants in the trials had central DMO and moderate vision loss.Compared with grid laser photocoagulation, people treated with antiangiogenic therapy were more likely to gain 3 or more lines of vision at one year (RR 3.6, 95% confidence interval (CI) 2.7 to 4.8, 10 studies, 1333 cases, high quality evidence) and less likely to lose 3 or more lines of vision (RR 0.11, 95% CI 0.05 to 0.24, 7 studies, 1086 cases, high quality evidence). In meta-analyses, no significant subgroup difference was demonstrated between bevacizumab, ranibizumab and aflibercept for the two primary outcomes, but there was little power to detect a difference. The quality of the evidence was judged to be high, because the effect was large, precisely measured and did not vary across studies, although some studies were at high or unclear risk of bias for one or more domains. Regarding absolute benefit, we estimated that 8 out of 100 participants with DMO may gain 3 or more lines of visual acuity using photocoagulation whereas 28 would do so with antiangiogenic therapy, meaning that 100 participants need to be treated with antiangiogenic therapy to allow 20 more people (95% CI 13 to 29) to markedly improve their vision after one year. People treated with anti-VEGF on average had 1.6 lines better vision (95% CI 1.4 to 1.8) after one year compared to laser photocoagulation (9 studies, 1292 cases, high quality evidence). To achieve this result, seven to nine injections were delivered in the first year and three or four in the second, in larger studies adopting either as needed regimens with monthly monitoring or fixed regimens.In other analyses antiangiogenic therapy was more effective than sham (3 studies on 497 analysed participants, high quality evidence) and ranibizumab associated with laser was more effective than laser alone (4 studies on 919 participants, high quality evidence).Ocular severe adverse events, such as endophthalmitis, were rare in the included studies. Meta-analyses conducted for all antiangiogenic drugs compared with either sham or photocoagulation did not show a significant difference regarding serious systemic adverse events (15 studies, 441 events in 2985 participants, RR 0.98, 95% CI 0.83 to 1.17), arterial thromboembolic events (14 studies, 129 events in 3034 participants, RR 0.89, 95% CI 0.63 to 1.25) and overall mortality (63 events in 3562 participants, RR 0.88, 95% CI 0.52 to 1.47). We judged the quality of the evidence on adverse effects as moderate due to partial reporting of safety data and the exclusion of participants with previous cardiovascular events in some studies. There is high quality evidence that antiangiogenic drugs provide a benefit compared to current therapeutic options for DMO, that is grid laser photocoagulation, in clinical trial populations at one or two years. Future research should investigate differences between drugs, effectiveness under real-world monitoring and treatment conditions, and safety in high-risk populations, particularly regarding cardiovascular risk.


The TRPM7 channel is inactivated by PIP(2) hydrolysis.
TRPM7 (ChaK1, TRP-PLIK, LTRPC7) is a ubiquitous, calcium-permeant ion channel that is unique in being both an ion channel and a serine/threonine kinase. The kinase domain of TRPM7 directly associates with the C2 domain of phospholipase C (PLC). Here, we show that in native cardiac cells and heterologous expression systems, G alpha q-linked receptors or tyrosine kinase receptors that activate PLC potently inhibit channel activity. Numerous experimental approaches demonstrated that phosphatidylinositol 4,5-bisphosphate (PIP(2)), the substrate of PLC, is a key regulator of TRPM7. We conclude that receptor-mediated activation of PLC results in the hydrolysis of localized PIP(2), leading to inactivation of the TRPM7 channel.


The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation.
SLC12A3 encodes the thiazide-sensitive sodium chloride cotransporter (NCC), which is primarily expressed in the kidney, but also in intestine and bone. In the kidney, NCC is located in the apical plasma membrane of epithelial cells in the distal convoluted tubule. Although NCC reabsorbs only 5 to 10% of filtered sodium, it is important for the fine-tuning of renal sodium excretion in response to various hormonal and non-hormonal stimuli. Several new roles for NCC in the regulation of sodium, potassium, and blood pressure have been unraveled recently. For example, the recent discoveries that NCC is activated by angiotensin II but inhibited by dietary potassium shed light on how the kidney handles sodium during hypovolemia (high angiotensin II) and hyperkalemia. The additive effect of angiotensin II and aldosterone maximizes sodium reabsorption during hypovolemia, whereas the inhibitory effect of potassium on NCC increases delivery of sodium to the potassium-secreting portion of the nephron. In addition, great steps have been made in unraveling the molecular machinery that controls NCC. This complex network consists of kinases and ubiquitinases, including WNKs, SGK1, SPAK, Nedd4-2, Cullin-3, and Kelch-like 3. The pathophysiological significance of this network is illustrated by the fact that modification of each individual protein in the network changes NCC activity and results in salt-dependent hypotension or hypertension. This review aims to summarize these new insights in an integrated manner while identifying unanswered questions.


Pilot study of a moderate dose multivitamin/mineral supplement for children with autistic spectrum disorder.
Determine the effect of a moderate dose multivitamin/mineral supplement on children with autistic spectrum disorder. Randomized, double-blind, placebo-controlled 3-month study. Twenty (20) children with autistic spectrum disorder, ages 3-8 years. A Global Impressions parental questionnaire found that the supplement group reported statistically significant improvements in sleep and gastrointestinal problems compared to the placebo group. An evaluation of vitamin B(6) levels prior to the study found that the autistic children had substantially elevated levels of B6 compared to a control group of typical children (75% higher, p < 0.0000001). Vitamin C levels were measured at the end of the study, and the placebo group had levels that were significantly below average for typical children, whereas the supplement group had near-average levels. The finding of high vitamin B(6) levels is consistent with recent reports of low levels of pyridoxal-5-phosphate and low activity of pyridoxal kinase (i.e., pyridoxal is only poorly converted to pyridoxal-5-phosphate, the enzymatically active form). This may explain the functional need for high-dose vitamin B(6) supplementation in many children and adults with autism.


Discovery and structure determination of the orphan enzyme isoxanthopterin deaminase .
Two previously uncharacterized proteins have been identified that efficiently catalyze the deamination of isoxanthopterin and pterin 6-carboxylate. The genes encoding these two enzymes, NYSGXRC-9339a ( gi|44585104 ) and NYSGXRC-9236b ( gi|44611670 ), were first identified from DNA isolated from the Sargasso Sea as part of the Global Ocean Sampling Project. The genes were synthesized, and the proteins were subsequently expressed and purified. The X-ray structure of Sgx9339a was determined at 2.7 A resolution (Protein Data Bank entry 2PAJ ). This protein folds as a distorted (beta/alpha)(8) barrel and contains a single zinc ion in the active site. These enzymes are members of the amidohydrolase superfamily and belong to cog0402 within the clusters of orthologous groups (COG). Enzymes in cog0402 have previously been shown to catalyze the deamination of guanine, cytosine, S-adenosylhomocysteine, and 8-oxoguanine. A small compound library of pteridines, purines, and pyrimidines was used to probe catalytic activity. The only substrates identified in this search were isoxanthopterin and pterin 6-carboxylate. The kinetic constants for the deamination of isoxanthopterin with Sgx9339a were determined to be 1.0 s(-1), 8.0 muM, and 1.3 x 10(5) M(-1) s(-1) (k(cat), K(m), and k(cat)/K(m), respectively). The active site of Sgx9339a most closely resembles the active site for 8-oxoguanine deaminase (Protein Data Bank entry 2UZ9 ). A model for substrate recognition of isoxanthopterin by Sgx9339a was proposed on the basis of the binding of guanine and xanthine in the active site of guanine deaminase. Residues critical for substrate binding appear to be conserved glutamine and tyrosine residues that form hydrogen bonds with the carbonyl oxygen at C4, a conserved threonine residue that forms hydrogen bonds with N5, and another conserved threonine residue that forms hydrogen bonds with the carbonyl group at C7. These conserved active site residues were used to identify 24 other genes which are predicted to deaminate isoxanthopterin.


Which instrument should we use to assess hand function after digital replantation?
The functional recovery of a replanted body part is as important as its viability. We compared four instruments frequently used for the evaluation of hand function after digital replantation. The functional results of 17 patients at least one year after replantation of a total digital amputation between 2004 and 2007 were evaluated according to the Tamai, Ipsen, Chen and Disabilities of the Arm, Shoulder and Hand questionnaires. Scores of each patient for each test were calculated and intra-individual comparisons were made. Correlation was significant at the 0.05 level (two tailed) for all tests. A high correlation (>0.71) was found between the Ipsen, Tamai and DASH tests. The Chen test had a moderate correlation with the other tests. We determined that Ipsen, Tamai and DASH tests have similar effectiveness in assessing hand function after replantation.


Association between respiratory capacity, quality of life and cognitive function in elderly individuals.
To investigate associations between respiratory capacity, quality of life and cognitive function in elderly individuals. The sample included 386 elderly individuals (232 women). Respiratory capacity assessment was based on maximal expiratory pressure measured at peak expiratory flow. Subjects were classified according to peak expiratory flow values adjusted for sex, age and height of individuals with normal (peak expiratory flow curve <80% and >60%) or reduced (peak expiratory flow curve < 60%) respiratory capacity. The World Health Organization Quality of Life Questionnaire and the Mini-Mental State Examination were used to assess quality of life and cognitive function, respectively. Elderly women with reduced respiratory capacity scored lower on the Mini-Mental State Examination (p=0.048) and quality of life questionnaire (p=0.040) compared to those with normal respiratory capacity. These differences were not observed in men (p>0.05). Reduced respiratory capacity was associated with poorer quality of life and cognitive function in elderly women. These associations were not observed in elderly men.


An investigation of presence of 2- and 3-monochloropropanediol fatty acid esters in Canadian human milk samples.
Occurrence of 2- and 3-monochloropropanediol fatty acid esters (MCPDEs) in 199 human milk samples collected from Canadian women was examined in this study. MCPDEs were determined via indirect analytical approach by using acidic hydrolysis/transesterification and derivatization with cyclohexanone using a fluorinated sulfonic acid resin as a catalyst followed by GC-MS analysis. Analyses were done by a stable isotope dilution assay (SIDA) using 3-monochloropropanediol-d5 dipalmitate and 2-monochloropropanediol-d5 distearate as internal standards. In all samples 2-MCPD esters were not detected, at LOD = 1 ng/g for 2-MCPD equivalent. 3-MCPD esters were not detected, at LOD = 2 ng/g for 3-MCPD equivalent, in 193 samples. Six samples had the apparent concentration of 3-MCPD equivalent in the range of 2.0-5.1 ng/g, which was likely caused by accidental contamination during processing of samples. For selected samples, these findings were confirmed by direct analysis via LC-MS/MS analysis based on SIDA for 3-MCPD dipalmitate and 2-MCPD distearate. To our best knowledge, this is the first study to analyze human milk samples for 2-MCPD esters.


Disaster Averted, For Now: How the American Health Care Act Would Have Affected Californians.
Although the American Health Care Act (AHCA) was recently defeated, the policies in the bill represented a mix of ideas long favored by conservatives. If enacted, this repeal-and-replace bill would have had devastating consequences for most of the 5 million Californians currently receiving direct benefits from the Affordable Care Act (ACA), including more than 1 million who receive subsidies through Covered California and almost 4 million who have enrolled in the Medi-Cal expansion. Although the bill failed to garner enough votes for passage, it is likely that efforts to chip away at the ACA will continue and that some of the ideas contained within the AHCA will be revisited. This policy brief summarizes some of the most significant reversals that would have occurred under the Republican plan in the individual and small group insurance markets.


Rift Valley fever in a zone potentially occupied by Aedes vexans in Senegal: dynamics and risk mapping.
This paper presents an analysis of the interaction between the various variables associated with Rift Valley fever (RVF) such as the mosquito vector, available hosts and rainfall distribution. To that end, the varying zones potentially occupied by mosquitoes (ZPOM), rainfall events and pond dynamics, and the associated exposure of hosts to the RVF virus by Aedes vexans, were analyzed in the Barkedji area of the Ferlo, Senegal, during the 2003 rainy season. Ponds were identified by remote sensing using a high-resolution SPOT-5 satellite image. Additional data on ponds and rainfall events from the Tropical Rainfall Measuring Mission were combined with in-situ entomological and limnimetric measurements, and the localization of vulnerable ruminant hosts (data derived from QuickBird satellite). Since "Ae. vexans productive events" are dependent on the timing of rainfall for their embryogenesis (six days without rain are necessary to trigger hatching), the dynamic spatio-temporal distribution of Ae. vexans density was based on the total rainfall amount and pond dynamics. Detailed ZPOM mapping was obtained on a daily basis and combined with aggressiveness temporal profiles. Risks zones, i.e. zones where hazards and vulnerability are combined, are expressed by the percentages of parks where animals are potentially exposed to mosquito bites. This new approach, simply relying upon rainfall distribution evaluated from space, is meant to contribute to the implementation of a new, operational early warning system for RVF based on environmental risks linked to climatic and environmental conditions.


Balance versus hearing after cochlear implant in an adult.
The effect of vestibular rehabilitation (VR) on anxiety, dizziness and poor balance that developed after cochlear implant (CI) surgery is described. A 54-year-old woman, with profound hearing loss since the age of 2 years, underwent right CI surgery 2 years previously. On implant activation, the patient immediately felt dizziness and imbalance, which affected the ability to perform activities of daily living and increased anxiety to where the patient considered the CI removal. Prior to VR the patient was evaluated with the Dizziness Handicap Inventory and the Visual Vertigo Dizziness Questionnaire and clinically with the Zur Balance Scale and Video Head Impulse Test. The patient underwent 14 VR sessions over 4 months that included compensation, adaptation and habituation exercises. After VR the patient was able to maintain good balance while using the CI. Dizziness and anxiety improved dramatically. This report increases awareness that a CI could compromise balance, which can be overcome with personalised VR.


Insulin secretory actions of extracts of Asparagus racemosus root in perfused pancreas, isolated islets and clonal pancreatic beta-cells.
Asparagus racemosus root has previously been reported to reduce blood glucose in rats and rabbits. In the present study, the effects of the ethanol extract and five partition fractions of the root of A. racemosus were evaluated on insulin secretion together with exploration of their mechanisms of action. The ethanol extract and each of the hexane, chloroform and ethyl acetate partition fractions concentration-dependently stimulated insulin secretion in isolated perfused rat pancreas, isolated rat islet cells and clonal beta-cells. The stimulatory effects of the ethanol extract, hexane, chloroform and ethyl acetate partition fractions were potentiated by glucose, 3-isobutyl-1-methyl xanthine IBMX, tolbutamide and depolarizing concentration of KCl. Inhibition of A. racemosus-induced insulin release was observed with diazoxide and verapamil. Ethanol extract and five fractions increased intracellular Ca(2+), consistent with the observed abolition of insulin secretory effects under Ca(2+) -free conditions. These findings reveal that constituents of A. racemosus root extracts have wide-ranging stimulatory effects on physiological insulinotropic pathways. Future work assessing the use of this plant as a source of active components may provide new opportunities for diabetes therapy.


A qualitative review of issues arising in the use of psycho-stimulant medications in patients with ADHD and co-morbid substance use disorders.
This review addresses the relationship between attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUDs), with an emphasis on factors that determine the potential for psychostimulant abuse. Strategies for identification and treatment of patients with ADHD who are at risk for, or have, co-morbid SUD are also addressed. The article was based on a qualitative review of current literature addressing co-morbid ADHD and SUD. Adolescent and adult patients with ADHD are at increased risk for SUD, as well as a number of other psychiatric disorders. Psychostimulant agents like methylphenidate (MPH) and mixed amphetamine salts (MAS) are effective first-line pharmacotherapies for ADHD; however, they are Schedule II controlled substances with a potential for abuse. Evidence suggests that treatment of ADHD during childhood with stimulant agents may reduce the risk of developing SUD later on. Factors associated with the highest risk of SUD in patients with ADHD include co-morbid antisocial personality disorder, bipolar disorder, an eating disorder, severe ADHD and/or antisocial behavior symptoms, and dropping out of school. Treatment initiation during adolescence or young adulthood also has been linked to increased risk of polydrug use and non-medical stimulant use, a pattern of behavior consistent with a risk of SUD development. Treatment plans for patients with ADHD and co-morbid SUD should include behavioral interventions, careful monitoring, and when appropriate, pharmacotherapy. When oral formulations of psychostimulants are used at recommended doses and frequencies, they are unlikely to yield effects consistent with abuse potential in patients with ADHD. Long-acting stimulant formulations and non-stimulants, like atomoxetine or bupropion, have a lower potential for abuse, and provide several safe and effective treatment options for the development of a comprehensive management plan for patients with co-morbid ADHD and SUD. The present review is neither exhaustive nor systematic. Moreover, the reviewed studies vary widely with regards to methodology and patient populations. In light of these limitations, several conclusions are still warranted. Patients with ADHD are at increased risk for SUD. Under certain conditions, psychostimulants may be a pharmacologic option in the treatment of patients with co-morbid ADHD and SUD. However, clinicians should be mindful of the risks and benefits of this treatment approach in a high-risk population and should also bear in mind the labeling guidelines when working with this co-morbidity.